wearable automatic injection device for controlled delivery of therapeutic agents

专利摘要:
USABLE AUTOMATIC INJECTION DEVICE FOR CONTROLLED DISTRIBUTION OF THERAPEUTIC AGENTS. Illustrative embodiments provide usable automatic injection devices for subcutaneous injection of a therapeutic agent into a patient's body at controlled rates, for example, in a single bolus. Illustrative modalities provide methods for assembling automatic injection devices usable for subcutaneous injection of a therapeutic person into a patient's body at controlled rates. Illustrative modalities provide methods of using automatic injection devices usable for subcutaneous injection of a therapeutic agent into a patient's body at controlled rates.
公开号:BR112012026886B1
申请号:R112012026886-4
申请日:2011-04-21
公开日:2020-11-24
发明作者:Philip D. Anderson；Joseph F. Julian；Linas P. Laurusonis；Timothy PARMER；Travis YOCH；Samuel M. Jang；Sean Corrigan；Tomas Matusaitis；William Fienup；Chris STRAHM
申请人:Abbvie Biotechnology Ltd.；
IPC主号:

专利说明:

Related Orders
[001] This application is related to and claims priority of provisional patent application No. 61 / 326,637, filed on April 21, 2010, the total content of which is expressly incorporated here by reference in its entirety. Foundations
[002] Automatic injection devices offer an alternative to manually operated se-rings for delivering therapeutic agents to patients' bodies and allowing patients to administer their own injections. Automatic injection devices have been used to deliver medications under emergency conditions, for example, to administer epinephrine to react to the effects of a severe allergic reaction. Automatic injection devices have also been described for use in the administration of antiarrhythmic drugs and selective thrombolytic agents during a heart attack (see, for example, US Patent Nos. 3,910,260; 4,004,577; 4,689,042; 4,755,169 and 4,795,433). Various types of automatic injection devices are also described, for example, in U.S. Patent Nos. 3,941,130; 4,261,358; 5,085,642; 5,092,843; 5,102,393; 5,267,963; 6,149,626; 6,270,479 and 6,371,939; and in international patent publication No. WO / 2008/005315.
[003] Conventionally, an automatic injection device houses a syringe and, when operated, causes the syringe to move forward and a needle protrudes from the housing so that a therapeutic agent contained in the syringe is ejected into the syringe. skin of a patient. An automatic injection device typically includes a stopper disposed within the syringe which, when activated, moves within the syringe to expel the therapeutic agent from the ring and into the patient's skin. Summary
[004] Illustrative modalities provide usable automatic injection devices that can adhere to a patient's skin or clothing and deliver a therapeutic agent into the patient's body by subcutaneous injection at slow, controlled injection rates, for example, in a single bolus slow. Illustrative modalities provide methods of assembling illustrative usable automatic injection devices. The illustrative embodiments also provide methods of using automatic injection devices used by a patient for the controlled and slow delivery of therapeutic agent. Illustrative usable automatic injection devices reduce or eliminate a burning sensation often felt or perceived by patients using a conventional automatic injection device. Illustrative usable automatic injection devices maintain the sterility of the therapeutic agent container (e.g., syringe), are easy to use, capable of pre-filling, easy to manufacture, and / or do not require an aseptic assembly. The usable automatic injection devices provided by the illustrative modes may adhere to the patient's skin or clothing to deliver any therapeutic agent subcutaneously including, but not limited to, a biological drug, such as, for example, an antibody, insulin, etc.
[005] According to an illustrative embodiment, a usable automatic injection device is provided to provide a subcutaneous injection of a therapeutic agent within a patient. The device includes a housing comprising a patient contact part that can be attached to the patient. The device also includes an injection set arranged movably in the housing while maintaining a hypodermic injection needle for insertion into the patient, the injection set being movable between a retracted position in which the injection needle does not protrude out of the housing. and an extended position in which the injection needle protrudes out of the housing. The device also includes a container provided in the housing to retain the therapeutic agent, a plunger movably disposed in the container to eject the therapeutic agent from the container into the injection set, and a plunger drive mechanism to drive the plunger inside the container. The device also includes a retraction trigger in response to a change of state of the automatic injection device usable from an injection state to a post-injection state, and a retraction mechanism to automatically retract the injection assembly from the extended position. in the injection state to the retracted position in the post-injection state by actuation by the retraction trigger.
[006] According to another illustrative embodiment, a method is provided for the subcutaneous injection of a therapeutic agent in a patient. The method includes providing an automatic injection device including a housing comprising a patient contact portion that can be attached to the patient. The device also includes an injection set movable in the housing holding a hypodermic injection needle for insertion into the patient, the injection set being movable between a retracted position in which the injection needle does not protrude out of the housing and a extended position in which the injection needle protrudes out of the housing. The device also includes a container provided in the housing to hold the therapeutic agent, a piston movably arranged in the container to eject the therapeutic agent from the container into the injection assembly and a piston drive mechanism to drive the piston inside of the container. The device also includes a retraction trigger that responds to a change in the state of the automatic injection device usable from an injection state to a post-injection state, and a retraction mechanism for the automatic retraction of the injection set. from the extended position in the injection state to the retracted position in the posinjection state by actuation by the retraction trigger. The method includes attaching the wearable automatic injection device to the patient's skin or a garment on the patient using the patient contact portion of the housing. The method also includes administering a therapeutic agent into the patient's skin using the usable automatic injection device.
[007] According to another illustrative embodiment, a usable automatic injection device is provided for subcutaneous injection of a therapeutic agent into a patient. The device includes a housing and a cartridge assembly movable within the housing. The cartridge includes a barrel part for retaining the therapeutic agent, and a hollow needle in fluid communication with the barrel part to eject the therapeutic agent from the barrel part. The cartridge also includes a stopper to seal the barrel part and selectively apply pressure to the therapeutic agent to force the therapeutic agent through the hollow needle. The cartridge additionally includes a plunger actuator for applying pressure to the cap, and a trigger mechanism that activates the plunger actuator to apply pressure to the cap when the cartridge is pressed from a ready position (in a pre-injection state) ) to a pressed position (in an injection state) within the housing. The trigger mechanism activates the plunger trigger so that the therapeutic agent is ejected from the barrel part and into the patient at a slow, controlled rate with little or no sensation of what image is felt or perceived by the patient. The device also includes a securing layer arranged on a contact surface with the patient or the patient's clothing or an article of the patient's clothing. The fixation layer may include an adhesive for temporary fixation of the automatic injection device usable to the patient at least during the controlled injection of the therapeutic agent.
[008] The usable automatic injection device includes a retraction mechanism that retracts the cartridge from the pressed position to a retracted position (in a post-injection state). The usable automatic injection device also includes a retraction trigger that activates the retraction mechanism, the retraction trigger fires when the delivery of the therapeutic agent is completed, or expires in the past time, or when the usable automatic injection device is removed from the patient, for example, before delivery of the therapeutic agent is completed. The usable automatic injection device operates and works entirely on mechanical principles or in combination with a controlled reaction to transition from any state (i.e., a pre-injection state, an injection state, a post-injection state), and it controls the rate of injection of the therapeutic agent during a period of time that is selected for comfort, convenience or user preference, or exceeds a period of time for injection by a conventional automatic portable device. In an illustrative embodiment, the time period of injection by a usable automatic injection device can vary between about 10 seconds and about 12 hours. In a preferred embodiment, the time period can vary between about 5 minutes and about 30 minutes.
[009] In another illustrative embodiment, a method is provided for subcutaneous injection of a therapeutic agent into a patient. The method includes providing a usable automatic injection device comprising a housing and a movable cartridge assembly disposed within the housing. The cartridge includes a barrel part for holding a therapeutic agent, and a hollow needle in fluid communication with the barrel part to eject the therapeutic agent from the barrel part. The cartridge also includes a stopper to seal the barrel part and selectively apply pressure to the therapeutic agent to force the therapeutic agent through the hollow needle. The cartridge additionally includes a plunger actuator for applying pressure to the cap, and a trigger mechanism that activates the plunger actuator to apply pressure to the cap when the cartridge is pressed from a ready position (in a ready state). -injection) to a pressed position (in an injection state) inside the housing. The release mechanism drives the plunger actuator so that the therapeutic agent is ejected from the barrel part and into the patient at a slow, controlled rate and substantially free of any sensation of burning.
[010] The method also includes pressing the cartridge from a ready position to a pressed position inside the housing. Pressing the tappet automatically causes the injection needle that is used to pierce the patient's skin to protrude from an opening in the housing to penetrate the patient's skin, and activates the plunger actuator to apply pressure to the cap. so that the therapeutic agent is delivered to the patient at a slow, controlled rate and substantially free of any sense of what is imaged.
[011] The method additionally includes the automatic retraction of the cartridge from the pressed position to a retracted position (in a post-injection state) in the housing when the delivery of the therapeutic agent is completed, or time expires due to a period of time last, or when the usable automatic injection device is removed from the patient's skin or clothing, for example, before the delivery of the therapeutic agent is completed.
[012] In an illustrative embodiment, an automatic injection device is usable and supplied. The usable automatic injection device provides a subcutaneous injection of a therapeutic agent into a patient. The usable automatic injection device includes a housing having a patient contact part attached to the patient and an internal part defined by a plurality of walls and defining at least one open end opposite the patient contact part. The usable automatic injection device also includes a cartridge assembly movable within the housing and movable from any of the ready, injection and retraction positions. The usable automatic injection device further includes a trigger mechanism that responds to a change in the state of the usable automatic injection device from a pre-injection state to an injection state to drive a plunger driver arranged in the cartridge assembly to initiate the ejection of a therapeutic agent from the cartridge assembly, and a retraction trigger in response to a change in the state of the usable automatic injection device from the injection state to a post-injection state. The usable automatic injection device also includes a retraction mechanism that responds to the retraction trigger to automatically retract the patient's cartridge assembly when the automatic injection device enters the post-injection state.
[013] In another illustrative embodiment, a method of subcutaneous injection of a therapeutic agent into a patient is provided. The method includes attaching a usable automatic injection device to a patient comprising a housing having a patient contact part that can be attached to the patient and an inner part defined by a plurality of walls and defining at least one open end opposite to contact part with the patient and a cartridge assembly movably disposed within the interior of the housing and movable from any of the ready position, injection position, and retraction position, the cartridge assembly retaining the agent pre-fueled and / or pre-fueled form. The method also includes pressing the cartridge assembly down towards the patient contact part to cause the usable automatic injection device to enter an injection state from a pre-injection state to automatically project a needle from a needle opening in the housing and penetrate the patient's skin and expel the therapeutic agent into the patient at a controlled rate. Brief Description of the Drawings
[014] The objectives, aspects, characteristics and advantages above as well as others of the illustrative modalities will become more apparent and can be better understood by reference to the following description taken together with the attached drawings, in which:
[015] Figure 1a illustrates a first end view and a first side view of an illustrative usable device including a cartridge assembly in a pre-injected packaged state;
[016] Figure 1b illustrates the first end view and the first side view of the illustrative device of figure 1a before an injection in a pre-injection state where a needle cover covering the injection needle is removed to prepare for an injection;
[017] Figure 1c shows a first end view and the first side view of the illustrative device of figure 1a during an injection in an injection state in which the patient's skin is pierced by the injection needle;
[018] Figure 1d illustrates the first end view and the first side view of the illustrative device of figure 1a during an injection in an injection state in which a pipe part of the device containing a dose of the therapeutic agent peutico and developed forwards inside the housing of the device;
[019] Figure 1e illustrates an end view and the first side view of the illustrative device of figure 1a during an injection in an injection state in which a cap of the device is actuated by a plunger driver to expel the dose of the therapeutic agent the pipe part;
[020] Figure 1f shows a first end view and the first side view of the illustrative device of figure 1a after an injection in a post-injection state in which the injection needle is retracted into the housing of the device;
[021] Figure 2a illustrates a first end view and a first side view of an illustrative usable device including a syringe assembly in a pre-injected packaged state;
[022] Figure 2b illustrates the first end view and the first side view of the illustrative device of figure 2a before an injection in a pre-injection state in which a needle cover covering the injection needle is removed to stop if you prepare to stop an injection;
[023] Figure 2c illustrates the first end view and the first view there of figure 2a during an injection in an injection state in which the patient's skin is pierced by the injection needle;
[024] Figure 2d illustrates the first end view and the first view there of figure 2a during an injection in an injection state in which a tube part of the device containing a dose of therapeutic agent is developed forward within the housing of the device;
[025] Figure 2e illustrates the first end view and the first side view of the illustrative device of figure 2a during an injection in an injection state in which a cap of the device is actuated by a plunger driver to expel the dose of the therapeutic agent from the barrel part;
[026] Figure 2f illustrates the first end view and the first view there of figure 2a after an injection in a post-injection state in which the injection needle is retracted into the housing of the device;
[027] Figure 3 is a flow chart of an illustrative method of assembling an illustrative usable automatic injection device;
[028] Figure 4 is a flow chart of an illustrative method of using an illustrative automatic usable injection device;
[029] Figure 5 is a (flowchart of an illustrative method of using an illustrative usable automatic injection device to inject a therapeutic agent into a patient;
[030] Figure 6a illustrates an illustrative usable automatic injection device suitable for linear insertion in a patient in a pre-injection state;
[031] Figure 6b illustrates the illustrative device of figure 6a in an injection state ready to inject or injecting a dose of a therapeutic agent into a patient;
[032] Figure 6c illustrates the illustrative device of figures 6a and 6b in a post-injection state after having completed the injection of the therapeutic agent in the patient or removed from the patient before the completion of the injection of the therapeutic agent;
[033] Figure 7a illustrates an illustrative usable automatic injection device suitable for rotary insertion in a pre-injection state ready for use by a patient;
[034] Figure 7b illustrates the illustrative device of figure 7a in an injection state ready to inject or injecting a dose of a therapeutic agent into a patient;
[035] Figure 7c illustrates the illustrative device of figures 7a and 7b in a post-injection state after having completed the injection of the therapeutic agent into the patient or removed from the patient prior to the completion of the therapeutic agent injection;
[036] Figure 8 is a flowchart of an illustrative method of assembling an illustrative usable automatic injection device;
[037] Figure 9 is a flow chart of an illustrative method of using an illustrative usable automatic injection device;
[038] Figure 10 is a flow chart of an illustrative method of using an illustrative usable automatic injection device to inject a therapeutic agent into a patient;
[039] Figure 11 illustrates an illustrative barrel part in which a distal end of the barrel part supports an injection needle that extends substantially along the longitudinal geometric axis of the barrel part;
[040] Figure 12 illustrates an illustrative barrel part in which an end supports an injection needle that extends about 90 degrees with respect to the longitudinal geometric axis of the barrel part;
[041] Figure 13 illustrates an illustrative needle set in which an illustrative adapter couples a syringe needle to an injection needle;
[042] Figure 14 illustrates an illustrative needle assembly in which a fluid conduit couples a syringe needle to an injection needle;
[043] Figure 15 illustrates an illustrative transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle;
[044] Figure 16 illustrates an illustrative transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle;
[045] Figure 17 illustrates an illustrative transfer mechanism for providing a fluid conduit between a syringe needle and an injection needle;
[046] Figure 18a illustrates a perspective view of an illustrative usable automatic injection device;
[047] Figure 18b illustrates a disassembled view illustrating the components of the illustrative device of figure 18a;
[048] Figure 19a illustrates a side view of an illustrative usable aumato injection device;
[049] Figure 19b illustrates a perspective view illustrating the components of the device of figure 19a;
[050] Figure 20a illustrates a perspective view of an illustrative usable automatic injection device;
[051] Figure 20b shows a top view of the device of figure 20a;
[052] Figure 20c illustrates a side view of the transfer mechanism of the device of figure 20a;
[053] Figure 21a illustrates a perspective view of an illustrative usable automatic injection device including an illustrative cartridge assembly;
[054] Figure 21b illustrates a sectional view of the cartridge assembly illustrative of Figure 21a taken along a longitudinal geometric axis;
[055] Figure 21c shows a transparent top view of the illustrative device of figure 21a;
[056] Figure 22 illustrates an illustrative syringe or cartridge driver that can be used to advance a barrel part and / or cartridge assembly from a retracted position to an extended position within the housing of a usable automatic injection device;
[057] Figure 23 illustrates an illustrative syringe or cartridge driver including a first part, a second part and a hinge part provided between the first and the second part;
[058] Figure 24 illustrates a schematic of a part of an illustrative automatic injection device including a piston drive mechanism employing a fusee and a viscous damping mechanism;
[059] Figure 25 illustrates a usable automatic injection device that can include a platform, a slide cart attached to the platform, and a cart assembly mounted on the slide cart;
[060] Figure 26 illustrates a usable automatic injection device that can include a platform, a slide cart attached to the platform, and a cart assembly mounted on the slide cart;
[061] Figure 27 is a top view through a cover of an illustrative automatic injection device including a piston drive mechanism to automatically activate a stopper on a pipe part;
[062] Figure 28 is a side view of the automatic injection device of Figure 27 illustrating a fusee and a damping mechanism;
[063] Figure 29 is a perspective view through a cover of the automatic injection device illustrative of Figure 27;
[064] Figure 30 illustrates the x and y coordinates (in inches) of the cam profiles for: (i) the combination of spring 1 and a viscous damper, (ii) the combination of spring 1 and an exhaust, (iii) the combination of spring 2 and a viscous damper, and (iv) the combination of spring 2 and an exhaust.
[065] Figure 31 illustrates a graph of therapeutic agent flow rates (in millimeters per minute) X time (in seconds) distributed by: (i) the combination of spring 1 and a viscous buffer, (ii) the combination of spring 1, a viscous damper and a cam spool, (iii) the combination of spring 1 and an exhaust, (iv) the combination of spring 1, an exhaust and a cam spool, (v) the combination of spring 2 and a viscous damper, (vi) the combination of spring 2, a viscous damper and a cam spool, (vii) the combination of spring 2 and an exhaust, (viii) the combination of spring 2, an exhaust and a cam spool and (ix) and an ideal flow rate at which the therapeutic agent is delivered at a substantially constant rate.
[066] Figure 32 illustrates a graph of therapeutic agent volume (in mi-meters) X time (in seconds) distributed by the combinations of the components of figure 31.
[067] Figure 33 illustrates a graph of the therapeutic agent volume (in mi-meters) versus time (in seconds) distributed using: (i) a damping mechanism G having a damping coefficient of about 10.3 lbf * s / in with a gear ratio of 4: 1, (ii) a damping mechanism B having a damping coefficient of about 15.1 lbf * s / in with a gear ratio of 4: 1, (iii) a damping mechanism K having a damping coefficient of about 18.9 lbf * s / in with a gear ratio of 4: 1, (iv) a damping mechanism V having a damping coefficient of about 24 , 9 lbf * s / in with a gear ratio of 4: 1, (v) a damping mechanism G having a damping coefficient of about 24.1 lbf * s / in with a gear ratio of 6.25 : 1, (vi) a damping mechanism B having a damping coefficient of about 37.0 lbf * s / in with a gear ratio of 6.25: 1, (v ii) a damping mechanism K having a damping coefficient of about 46.1 lbf * s / in with a gear ratio of 6.25: 1, (viii) a damping mechanism V having a coefficient damping of about 60.7 lbf * s / in with a gear ratio of 6.25: 1, (ix) a damping mechanism G having a damping coefficient of about 164 lbf * s / in with a gear ratio of 16: 1, (x) a damping mechanism B having a slurry-cement ratio of about 242 lbf * s / in with a gear ratio of 16: 1, (xi) a damping mechanism K having a damping coefficient of about 303 lbf * s / in with a gear ratio of 16: 1, (xii), a damping mechanism V having a damping coefficient of about 398 lbf * s / in with a gear ratio of 16: 1, and (xiii) an ideal flow rate at which the therapeutic agent is delivered at a substantially constant rate.
[068] Figure 34 shows a graph of illustrative shock absorber torques (which can be calculated retroactively from the displacement of the piston driver) against the shock absorber speeds (in rpm) for shock absorbers models G, B, K and V having increased damping coefficients.
[069] Figure 35 shows a graph of therapeutic agent volume (in millimeters) against time (in seconds) distributed by different illustrative syringes using a model V shock absorber with a damping coefficient of around 24.9 lbf * s / in and an illustrative gear ratio of 4: 1.
[070] Figure 36 illustrates a graph of therapeutic agent volume (in millimeters) distributed and the diameter of the fusee or cam spool (in inches) X the time (in seconds).
[071] Figure 37 illustrates a graph of therapeutic agent volume (in millimeters) distributed X time (in seconds) reached by: (i) a first damper at room temperature, (ii) the first damper at about 4.44 C (in the refrigerator), (iii) a second damper, (iv) the second damper at about 17.77 C (in the freezer), (v) a third damper having manufacturing variation with respect to the first and second buffers, and (vi) a fourth shock absorber with manufacturing variation with respect to the first and second dampers.
[072] Figure 38 illustrates a schematic of a part of an automatic injection device including a piston drive mechanism that employs a fusee and an exhaust mechanism.
[073] Figure 39 illustrates an illustrative plunger drive mechanism that employs one or more linear guidance mechanisms to provide a force to express a therapeutic agent from the barrel part of a usable automatic injection device.
[074] Figure 40 illustrates an illustrative piston drive mechanism that employs one or more clock springs to provide a force to expel the therapeutic agent from the barrel part of a usable automatic injection device.
[075] Figure 41 is a schematic of an illustrative automatic injection device including a piston drive mechanism that employs one or more fluid circuits.
[076] Figure 42 is an illustrative automatic injection device that engages one or more fluid circuits in perspective view of a force to a stopper to expel a dose of a therapeutic agent from a pipe part.
[077] Figure 43 illustrates a graph of the cumulative amount of the therapeutic agent (in grams) versus time (in seconds) as delivered by an illustrative delivery system at an illustrative delivery pressure of 113.76 kPa.
[078] Figure 44 illustrates a graph of cumulative volume of therapeutic agent (in millimeters) X time (in seconds) as distributed by an illustrative delivery system including a first flow restriction element.
[079] Figure 45 illustrates a graph of the cumulative volume of therapeutic agent (in millimeters) X time (in seconds) as distributed by an illustrative delivery system including a second flow restriction element.
[080] Figure 46 is a schematic drawing of an illustrative automatic injection device that employs one or more fluid circuits to provide a force to expel a therapeutic agent from a cartridge assembly.
[081] Figure 47 is a top view of the illustrative device in Figure 46.
[082] Figure 48 illustrates a top view of an illustrative automatic injection device illustrating a duct coupling of the main cylinder with a flow restriction element, a duct coupling of the flow reduction element with the cap, and a main cylinder duct coupling with a retraction mechanism through a valve.
[083] Figure 49 illustrates a schematic diagram of the device of figure 48.
[084] Figure 50 shows a graph of the pressure after a check valve and behind a plug (in psi) X time (in seconds) in an illustrative mode.
[085] Figure 51 illustrates a side view of an illustrative automatic injection device in which the housing of the usable automatic injection device includes a skin sensor piece.
[086] Figures 52a and 52b illustrate an illustrative needle protection system that holds an injection needle in a retracted position within the housing of an illustrative automatic injection system.
[087] Figures 53a and 53b illustrate another illustrative needle protection system provided in an illustrative automatic injection system.
[088] Figure 54 illustrates another illustrative needle protection system provided in an illustrative automatic injection system.
[089] Figure 55 illustrates another illustrative needle protection system provided in an illustrative automatic injection system. Detailed Description
[090] Subcutaneous injection is a primary method of delivering the therapeutic agent and involves administering a bolus of a therapeutic agent into a patient. Subcutaneous injections are highly efficient in the administration of various therapeutic agents including insulin, vaccines, and drugs as well as morphine. Automatic injection devices offer an alternative to a syringe for delivery of a therapeutic agent and allow patients to administer subcutaneous injections of therapeutic agents themselves. Conventional automatic injection devices include portable automatic injection devices and patch pumps, which are automatic injectors fitted to the patient by adhesive. In use, a patch pump containing a therapeutic agent is mounted on a patient's skin or clothing and activated to inject the therapeutic agent into the patient. Conventional patch pumps are typically filled by a patient before use. In addition, certain conventional patch pumps have an exposed needle inside the pump, and therefore require secondary sterile packaging to maintain sterility.
[091] Studies show that there is a direct correlation between the rate of injection of certain therapeutic agents and the pain perceived by a patient after the injection of the therapeutic agents or agents. Some therapeutic agents cause pain, for example, a burning or stinging sensation when injected quickly into the patient. The sensation of pain may be the result of the physiological response of the patient's skin to subcutaneous injection of a therapeutic agent. Large volumes of any therapeutic agent, greater than one millimeter, can also cause pain when injected into the skin. Antibodies, and parts of them, are illustrative therapeutic agents that are less painful when delivered at low injection rates. Currently, there are no conventional commercially viable patch pumps that efficiently resolve the discomfort associated with rapid injection rates for portable automatic injection devices.
[092] Illustrative modalities are described below with reference to certain illustrative modalities. While the illustrative modalities are described with respect to the use of an automatic injection device usable to provide an injection of a dose of a liquid drug, those skilled in the art will recognize that illustrative modalities are not limited to illustrative modalities and that automatic injection devices illustrative can be used to inject any suitable substance to a patient. Additionally, the components of the illustrative automatic injection devices and methods of creating and using the illustrative automatic injection devices are not limited to the illustrative modalities described below.
[093] A syringe assembly of the illustrative automatic injection devices can confer a dose of a TNFα inhibitor. In an illustrative embodiment, the TNFα inhibitor can be a human TNFα antibody or an antigen binding part. In an illustrative embodiment, the human TNFα antibody or antigen binding part thereof can be adalimumab or glimumab.
[094] Illustrative modalities provide usable automatic injection devices that can adhere to the patient's skin or clothing and deliver a therapeutic agent to the patient by subcutaneous injection at slow controlled injection rates, for example, in a single slow bolus. The slow controlled injection rates achieved by the illustrative devices minimize the sensation of pain associated with a volume of a therapeutic agent entering the patient's tissue. The illustrative time periods for the slow delivery achieved by the illusive devices may vary from about 5 minutes to about 30 minutes, but are not limited to that illustrative range. The illustrative volumes of therapeutic agent delivered by the illustrative devices can vary from about 0.8 millimeter to about 1 millimeter, but are not limited to that illustrative range. In addition, the illustrative devices can advantageously minimize inflections in the timing profile of the therapeutic agent.
[095] Illustrative modalities minimize the size envelope of the illustrative automatic injection devices and provide scalable solutions with configurable delivery times and delivery profiles that can be used for a range of therapeutic agent viscosities.
[096] The illustrative modalities provide usable automatic injection devices that deliver a therapeutic agent to a patient by subcutaneous injection at controlled and slow injection rates, for example, in a single slow bolus without battery power or other components requiring electrical current or load to operate. The illustrative embodiments also provide methods of using the automatic injection devices usable for the slow and controlled delivery of the therapeutic agent. The usable automatic injection devices provided by the illustrative modalities are pre-filled before delivery to the patient, maintain the sterility of the therapeutic agent and all surfaces are subcutaneous (ie, a hypodermic needle and one or more membranes) for avoid the need to use an aseptic set and solve the discomfort perceived by the patient due to injection by conventional portable automatic injection devices. Illustrative usable automatic injection devices include a primary therapeutic tube part that maintains sterility and therefore does not require any aseptic assembly. Illustrative usable automatic injection devices are disposable, easy to use, capable of being pre-filled, and can substantially or completely eliminate the sensation of the image often suffered by a patient using a usable automatic injection device. Usable automatic injection devices provided by the illustrative modes can be used to deliver a therapeutic agent that can be delivered subcutaneously including, but not limited to, an antibody or insulin, etc. I. Definitions
[097] Certain terms are defined in this section to facilitate understanding of the illustrative modalities.
[098] The usable automatic injection device of the illustrative embodiments may include a "therapeutically efficient amount" or a "prophylactically efficient amount" of an antibody or antibody part of the invention. A "therapeutically efficient amount" refers to an efficient amount, in dosages and for necessary periods of time, to achieve the desired therapeutic result.A therapeutically efficient amount of antibody, part of antibody or other TNFα inhibitor can vary according to factors such as disease status, age, sex, and patient's weight, and the ability of the antibody, antibody part, or other TNFα inhibitor to obtain a desired response in the patient, a therapeutically efficient amount is also one in which any toxic or detrimental effects of the antibody, antibody part, or other inhibitor of TNFa are outweighed by the therapeutically beneficial effects. A “prophylactically efficient amount” refers to re to an efficient amount, in dosages and for necessary periods of time, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in patients before or at an earlier stage of the disease, the prophylactically efficient amount will be less than the therapeutically efficient amount.
[099] The terms "substance" and "therapeutic agent" refer to any type of drug, biologically active agent, biological substance, chemical substance or biochemical substance that can be administered in a therapeutically efficient amount for a patient using the devices Illustrative automatic injection systems. Illustrative substances include, but are not limited to, agents in a liquid state. Such agents can include, but are not limited to, adalimumab (HUMIRA®) and proteins that are in a liquid solution, for example fusing proteins and enzymes. Examples of proteins in solution include, but are not limited to, Pulmozyme (Dronase alfa), Regranex (Becaplermin), Acrivase (Alteplase), Aldurazyme (Laronidase), Amevise (Alefacept), Aranesp (Darbepoetin alfa), Becaplermin concentrate, Betaseron ( Interferon beta-1 b), BOTOX (botulinum toxin type A), Elitek (Rasburicase), Elspar (Asparaginase), Epogen (Epoetin Alpha), Enbrel (Etanercept), Fabrazyme (Agalsidase beta), Infergen (Interferon Alfacon-1), Intron A (Interferon Alpha-2a), Kineret (Anakinra), MYOBLOC (Botulinum toxin type B), Neulasta (Pegfilgrastim), Neumega (Oprelvekin), Neupogen (Filgrastim), ONtak (Denileukin diftitox), PEGASYS (Peginterferon alfa-2a) , Proleukin (Aldesleukin), Pul-mozyme (Dornase alfa), Rebif (Interferon beta-1 a), Regranex (Becaplermin), Retavase (Reteplase), Roferon-A (interferon alfa-2), TNKase (Tenecteplase) and Xigris ( Drotrecogin alfa), Arcalyst (Rilonacept), NPIate (Romiplostim), Mircera (methoxypolyethylene glycol-epoetin beta), Cinryze (inhibit stearase pain C1), Elaprase (idursulfase), Myozyme (alglucosidase alfa), Orencia (abatacept), Naglazyme (galsulfase), Kepivance (palifermin) and Actimmune (interferon gamma-1b).
[0100] A protein in solution may also be an immunoglobulin or antigen-binding fragment, such as an antibody or antigen-binding part thereof. Examples of the antibodies that can be used in an illustrative automatic injection device include, but are not limited to, chimeric antibodies, non-human antibodies, human antibodies, humanized antibodies, and domain antibodies (dAbs). In an illustrative embodiment, the immunoglobulin or antigen-binding fragment thereof is an anti TNFα and / or an anti IL-12 antibody (for example, it may be a 1gTM0 double variable domain (DVD) immunoglobulin. Other examples of immunoglobulin or antigen binding fragments thereof that may be used in the methods and compositions of the illustrative modalities include, but are not limited to 1D4.7 (anti-IL-12 / IL-23 antibody; Abbott Laboratories), 2, 5 (E) mg1 (anti-IL-18; Abbott Laboratories); 13C5.5 (anti-IL-13 antibody; Abbott Laboratories); J695 (anti-IL-12; Abbott Laborato-ries); Afelimomab (Fab 2 anti -TNF; Abbott Laboratories); HUMIRA (adalimumab) Abbott Laboratories); Campath (Alemtuzumab); CEA-Scan Arcitumomab (FAB fragment), Erbitux (Cetuximab); Herceptin (Trastuzumab); Myoscint (Imciromab Pentetate); ProstaScint (Capromab Pendetide); Remicade (Infliximab); ReoPro (Abeiximab); Rituxan (Rituximab); Simulect (Basiliximab); Synagins (Palivizumab); Verluma (Nofetumomab); Xolair (Omalizumab); Zenapax (Daclizumab); Zevalin (Ibritumomab Tiuxetan); OKT3 Orthoclone (Muromonab-CD3); Panorex (Edrecolomab); Mylotarg (Gemtuzumab ozogamicin); golimumab (Centocor); Cimzia (Certolizumab pegol); Soliris (Eculizumab); CNTO 1275 (ustekinumab); Vectibix (panitumumab); Bexxar (tositumomab and 1131 tositumomab); and Avastin (bevacizumab).
[0101] Additional examples of immunoglobin, or antigen-binding fragments thereof, that can be used in the methods and compositions of the illustrative modalities include, but are not limited to, proteins comprising one or more of the following: light chain variable D2E7 (Sequence ID No .: 1), heavy chain variable region D2E7 (sequence ID No. 2), light chain variable region D2E7 CDR3 (sequence ID No. 3), heavy chain variable region D2E7 CDR3 (ID sequence No. 4), light chain variable region D2E7 CDR2 (sequence ID No. 5), heavy chain variable region D2E7 CDR2 (sequence ID No. 6), light chain variable D2E7 CDR1 (sequence ID No. 7), heavy chain variable region D2E7 CDR1 (sequence ID No. 8), light chain variable region 2SD4 (sequence ID No. 9), heavy chain variable region 2SD4 (sequence ID No. 10) , variable region of light current 2SD4 CDR3 (sequence ID No 11), light current variable region EP B12 CDR3 (sequence ID No. 12), light current variable VL10E4 CDR3 (sequence ID No. 13); light current variable VL100A9 CDR3 (sequence ID No. 14), light current variable VLL 100D2 CDR3 (sequence ID No. 15), light current variable VLL0F4 CDR3 (sequence ID No. 16), light current variable LOE5 CDR3 (sequence ID No. 17), light current variable VLLOG7 CDR3 (sequence ID No, 18), light current variable VLLOG9 CDR3 (sequence ID No. 19), light current variable VLLOH1 CDR3 (ID of string No. 20), light current variable VLLOH10 CDR3 (sequence ID No. 21), light current variable VL1B7 CDR3 (sequence ID No. 22), light current variable VL1C1 CDR3 (sequence ID No. 23) , light current variable VL0.1 F4 CDR3 (sequence ID No. 24), light current variable VL0.1H8 CDR3 (sequence ID No. 25), light current variable LOE7.A CDR3 (sequence ID No. 26), heavy chain variable region 2SD4 CDR (sequence ID No. 27), heavy chain variable region VH1B11 CDR (sequence ID No. 28), color variable region heavy chain VH1D8 CDR (sequence ID No. 29), heavy chain variable region VH1A11 CDR (sequence ID No. 30), heavy chain variable region VH1B12 CDR (sequence ID No ,. 31), VH1E4 CDR heavy chain variable region (sequence ID No. 32), VH1F6 CDR heavy chain variable region (sequence ID No. 33), 3C-H2 CDR heavy chain variable region (sequence ID No. 34), and VH1-D2.N CDR heavy chain variable region (sequence ID No. 35).
[0102] The term “human TNFa (abbreviated here as hTNFa, or simply hTNF) refers to a human cytokine that exists as a secreted 17 kD form and an associated 26 kD membrane, the biologically active form of which is made up of a trimer of 17 kD molecules joined non-covalently. The structure of hTNFa is further described, for example, in Pennica, D., et al. (1984) Nature 312: 724-729; Davis, J.M., et al. (1987) Biochem. 26: 1322-1326; and Jones, E.Y., et al., (1989) Nature 338: 225-228. The term human TNFa should include recombinant human TNFa (rhTNFa), which can be prepared by standard recombinant expression methods or commercially purchased (R & D Systems, Catalog No. 210-TA, Minneapolis, MN). TNFa is also referred to as TNF.
[0103] The term "TNFα inhibitor" refers to an agent that interferes with TNFα activity. The term also includes each of the human anti-TNFα antibodies (normally interchanged here with TNFα antibodies) and antibody portions described herein in addition to those described in U.S. Patent Nos. 6,090,382; 6,258,562; 6,509,015; 7,223,394; and 6,509,015. In one embodiment, the TNFα inhibitor used in the invention is an antiTNFα antibody, or a fragment thereof, including infli-ximab (Remicade®, Johnson and Johnson; described in U.S. Patent No. 5,656,272); CDP571 (a humanized anti-TNF-alpha IgG4 monoclonal antibody); CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment); an anti-TNF dAb (Peptech); ONTO 148 (golimumab; Centocor, See WO 02/12502 and U.S. 7,521,206 and U.S. 7,250,165); and adalimumab (HUMIRA® Abbott Laboratories, a human anti-TNF mAb, described in U.S. 6,090,382 as D2E7). Additional TNF antibodies that can be used in the invention are described in U.S. Patent Nos. 6,593,458; 6,498,237; 6,451,983; and 6,448,380. In another embodiment, the TNFα inhibitor is a TNF fusion protein, for example, etanercept (Enbrel®, Amgen; described in WO 91/03553 and WO 09/406476). In another embodiment, the TNFα inhibitor is a recombinant TNF binding protein (r-TBP-1) (Serono).
[0104] In one embodiment, the term "TNFα inhibitor" excludes infliximab. In another embodiment, the term "TNFα inhibitor" excludes adalimumab. In another embodiment, the term "TNFα inhibitor" excludes adalimumab and infliximab.
[0105] In one embodiment, the term "TNFα inhibitor" excludes etanercept, and, optionally, adalimumab, infliximab, and adalimumab and infliximab.
[0106] In one embodiment, the term "TNFα antibody" excludes infliximab. In one embodiment, the term "TNFα antibody" excludes adalimumab. In another modality, the term "TNFα antibody" excludes adalimumab and infliximab.
[0107] The term "antibody" refers to immunoglobulin molecules generally consisting of four polypeptide chains, two heavy chains (H) and two light chains (L) interconnected by disulfide bonds. Each heavy chain is made up of a variable heavy chain region (abbreviated here as HCVR or VH) and a constant heavy chain region. The heavy current constant region consists of three domains, CH1, CH2 and CH3. Each light current is made up of a variable light current region (abbreviated here as LCVR or VL) and a constant light current region. The constant region of light current is made up of a CL domain. The VH and VL regions can be further subdivided into regions of hypervariation, called regions of complementarity determination (CDR) interspersed with regions that are more conserved, called regions. of structure (FR). Each VH and VL is made up of three CDRs and four FRs, arranged from amino terminal to carboxy terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The antibodies of the invention are described in more detail in U.S. Patent Nos. 6,090,382; 6,258,562 and 6,509,015.
[0108] The term “antigen binding part” of an antibody (or simply “antibody part”) refers to one or more fragments of an antibody that retain the ability to specifically agglutinate an antigen (for example, hTNFa) . Fragments of a full-length antibody can perform the antigen-binding function of an antibody. Examples of binding fragments encompassed within the term "antigen binding part" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of VL, VH, CL and CH1 domains; (ii) an F (ab ') 2 fragment, a divalent fragment comprising two Fab fragments connected by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of VL and VH domains of a single antibody antibody, (v) a dAb fragment (Ward et al. (1989) Nature 341: 544-546), which consists of a VH domain or VL; (vi) an isolated complementary determination region (CDR); and (vii) a double variable domain immunoglobulin (DVD-lg). In addition, although two Fv fragment domains, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic crosslinker that allows them to be created as a united protein chain in which the pair of VL and VH regions to form monovalent molecules (known as single Fv current (seFv); see, for example, Bird et al. (1988) Sci-ence 242: 423-426; and Huston et al. ( 1988) Proc. Natl. Acad. Sci. USA 85: 5879-5883). Such single-chain antibodies are also included within the term "antigen-binding part" of an antibody. Other forms of single chain antibodies, such as diabodies, are also included. Diabodies are bispecific and bivalent antibodies in which the VH and VL domains are expressed in a single polypeptide chain, but using a crosslinker that is too short to allow pairing between two domains in the same chain, thereby forgiving the domains to pair with complementary domains of another chain and creating two antigen binding sites (see, for example, Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448; Poljak et al. (1994) Structure 2 : 1121-1123). The antibody parts of the invention are described in more detail in U.S. Patent Nos. 6,090,382; 6,258,562; and 6,509,015.
[0109] The term "recombinant human antibody" refers to all human antibodies that are prepared, expressed, created or isolated by recombinant means, as well as antibodies expressed using a re-combining expression vector transfected in a host cell (further described) below), antibodies isolated from a recombinant human combinatorics antibody library (further described below), antibodies isolated from an animal (for example, a mouse) that is transgenic to human immunoglobulin genes (see, for example, Taylor et al., (1992) Nucl. Acids Res. 20: 6287) or antibodies prepared, expressed, created or isolated by any other means that involve joining human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regibes, derived from human germline immunoglobulin sequences. In certain embodiments, however, such re-combining human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL of recombinant antibodies are sequences that, while derived from and related to human germ line VH and VL sequences, may not naturally exist within the human antibody germ line in vivo repertoire.
Such chimeric, humanized, human and double specific antibodies can be produced by recombinant DNA techniques known in the art, for example, using methods described in international PCT application No. PCT / US86 / 02269; European patent application No. 184,187; European patent application No. 171,496; European patent application No. 173,494; international PCT publication No. WO 86/01533; U.S. Patent No. 4,816,567; European patent application No. 125,023; Better et al. (1988) Science 240: 1041-1043; Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84: 3439-3443; Liu et al. (1987) J. Immunol 139: 3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci. USA 84: 214-218; Nishimura et al. (1987) Cancer Res. 47: 999-1005; Wood et al. (1985) Nature 314: 446-449; Shaw et al. (1988) J. Natl. Cancer Inst. 80: 1553-1559; Morrison (1985) Science 229: 1202-1207; Oi et al. (1986) BioTechniques 4: 214; U.S. Patent No. 5,225,539, Jones et al. (1986) Nature 321: 552-525; Verhoeyan et al. (1988) Science 239: 1534; and Beidler et al. (1988) J. Immunol. 141: 4053-4060, Queen et al. (1989) Proc. Natl. Acad. Sci. USA 86: 1002910033 (1989); U.S. Patent No. 5,530,101; U.S. Patent No. 5,585,089, U.S. 5,693,761; U.S. 5,693,762; WO 90/07861 and U.S. 5,225,539.
[0111] The term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (for example, an isolated antibody that specifically binds hTNFa and is substantially free of antibodies that specifically bind antigens in addition to hTN-Fa ). An isolated antibody that specifically binds hTNFa may cross-react with other antigens, such as TNFα molecules of other species. In addition, an isolated antibody can be substantially free of other cellular material and / or other chemicals.
[0112] The term "neutralizing antibody" (or an "antibody that neutralizes hTNFa activity") refers to an antibody whose binding with hTNFa results in the inhibition of biological hTNFa activity. This inhibition of hTNFa biological activity can be determined by measuring one or more indicators of hTNFa biological activity, such as hTNFa-induced cytotoxicity (in vitro or in vivo), hTNFa-induced cell activation and hTNFa binding to hTNFa receptors. Such indicators of hTNFa biological activity can be determined by one or more various in vitro or in vivo standard tests known in the art (see U.S. Patent No. 6,090,382). Preferably, the ability of an antibody to neutralize hTNFa activity is determined by the inhibition of hTNFa-induced cytotoxicity of L929 cells. As an additional or alternative parameter of hTNFa activity, the ability of an antibody to inhibit hTNFa-induced expression of ELAM-1 in HUVEC, as a measure of hTNFa-induced cell activation can be determined.
[0113] The term "surface plasmon resonance" refers to an optical crack that allows the analysis of biospecific interactions in real time by detecting changes in protein concentrations within a biosensor matrix, for example, using the BIAcore system (Pharmacia Biosensor, AB, Uppsala, Sweden and Piscataway, NJ). For further description, see example 1 from U.S. relative 6,258,562 and Jonsson et al. (1993) Ann. Biol. Clin. 51:19; Jonsson et al. (1991) Biotechniques 11: 620-627; Johnson et al. (1995) J. Mol. Recognit. 8: 125, and Johnson etal. (1991) Anal. Biochem. 198: 268.
[0114] The term "Koff" refers to the out-of-rate constant for dissociation of an antibody from the antibody / antigen complex.
[0115] The term "Kd" refers to the dissociation constant of a particular antibody and antigen interaction.
[0116] The term "IC50" refers to the concentration of inhibitor necessary to inhibit the end point of biological interest, for example, neutralizing cytotoxicity activity.
[0117] The term "dose" or "dosage" refers to an amount of a substance, such as a TNFα inhibitor, which is administered to a patient preferably using a usable automatic injection device of the invention. In one embodiment, the dose comprises an effective amount, for example, including, but not limited to, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, and 160 mg, of the TNFα inhibitor of adalimumab.
[0118] The term "dosage" refers to the administration of a substance (for example, an anti-TNFα antibody) to achieve a therapeutic goal (for example, treatment of rheumatoid arthritis).
[0119] The term "dosage regimen" describes a treatment schedule for a substance, such as a TNFα inhibitor, for example, a treatment schedule for an extended period of time and / or for the entire course of treatment. , for example, administration of a first dose of a TNFα inhibitor at week 0 followed by a second dose of a TNFα inhibitor in a fortnightly dosing regimen.
[0120] The term "biweekly dosing regimen", "biweekly dosing", and "biweekly administration" refers to the time course of administration of a substance (for example, an antiTNFa antibody) to a patient to achieve a therapeutic goal for example, throughout the course of treatment, the biweekly dosing regimen should not include a weekly dosing regimen, preferably the substance is administered every 9 to 19 days, more preferably, every 11 to 17 days, even more preferably at every 13 to 15 days, and more preferably every 14 days In one embodiment, the biweekly dosing regimen is started with a patient in treatment week 0. In another modality, a maintenance dose is administered in a biweekly dosing regimen. In one embodiment, both loading and maintenance doses are administered according to a fortnightly dosing regimen In one embodiment, the fortnightly dosing includes a dosing regimen where the doses of a TNFα inhibitor are the administered to a patient every other week, starting at week 0. In one embodiment, the fortnightly dosage includes a dosing regimen where doses of a TNFα inhibitor are administered to a patient every other week, consecutively. for a specified period of time, for example, 4 weeks, 8 weeks, 16 weeks, 24 weeks, 26 weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks, etc. Biweekly dosing methods are also described in U.S. 2003/0235585. second agent nation "includes the joint administration of a first agent and a second agent, which, for example, can be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration second agent, followed by the first agent.
[0121] The term "combination" as in the phrase "a first agent in combination with a second agent" includes the joint administration of a first agent and a second agent, which, for example, can be dissolved or intermixed in the same pharmaceutically acceptable carrier, or administration of a first agent, followed by the second agent, or administration of the second agent, followed by the first agent.
[0122] The term "concomitant" as in the phrase "concomitant therapeutic treatment" includes the administration of an agent in the presence of a second agent. A method of concomitant therapeutic treatment includes methods in which first, second, third or additional substances are administered together. A method of concomitant therapeutic treatment also includes methods in which the first or additional agents are administered in the presence of a second substance or additional substances, where the second agents or additional agents, for example, may have been previously administered. A method of concomitant therapeutic treatment can be performed in the sense of scheduling by different patients. For example, a subject can administer a patient a first agent and a second subject can administer a second substance to the patient, and the administration steps can be performed at the same time, almost at the same time, or at distant moments, provided that the first substance (and the additional substances) are after administration in the presence of the second substance (and additional substances). The administrator and the patient can be the same entity (for example, a human).
[0123] The term "combinatorial therapy" refers to the administration of two or more therapeutic substances, for example, an antiTNFa antibody and another drug. Other drugs can be administered simultaneously with, before or after the administration of an antiTNFa antibody.
[0124] The term "treatment" refers to therapeutic treatment, in addition to prophylactic or suppressive measures, for the treatment of a disorder, such as the disorder in which TNFa is harmful, for example, rheumatoid arthritis.
[0125] The term "patient" or "user" refers to any type of animal, human or non-human, that can be injected with a substance using illustrative automatic injection devices.
[0126] The terms "usable automatic injection device" and "usable auto injector" refer to a device used by a patient that allows the patient to self administer a therapeutically efficient dose of a therapeutic agent by fixing the usable device directly to your skin or by attaching the wearable device to a garment that allows penetration of a hypodermic needle, where the wearable device differs from a conventional syringe by including a mechanism for the automatic delivery of therapeutic agent to the patient by injection when the mechanism is engaged.
[0127] The terms "syringe" and "cartridge" encompass a part of a sterile tube that is filled with a dose of a therapeutic agent prior to distribution or sale to a patient or other non-medical professional for administration of the therapeutic agent to a patient. In an illustrative embodiment, a distal end of the barrel portion of a syringe can be attached to a sterile hypo-dermal needle. In an illustrative embodiment, a distal end of the barrel part of a cartridge may not be attached to a needle. That is, and in illustrative embodiments, a syringe can be a cartridge with a pre-fixed hollow needle coupled to its barrel part.
[0128] Illustrative modalities described here with reference to a syringe set can also be implemented using a cartridge set. Similarly, illustrative modalities described here with reference to a cartridge set can also be implemented using a syringe set.
[0129] The term "container" refers to a syringe or cartridge that can be used in an illustrative usable automatic injection device to maintain a dose of a therapeutic agent.
[0130] The term "injection needle" refers to a needle in a usable automatic injection device that is inserted into a patient's body to deliver a dose of a therapeutic agent to the patient's body. In an illustrative embodiment, the injection needle can be coupled directly with or in contact with a syringe or cartridge assembly that maintains the dose of the therapeutic agent. In another illustrative embodiment, the injection needle can be coupled indirectly to the syringe or cartridge assembly, for example, via a syringe needle and / or a transfer mechanism that provides fluid communication between the syringe or cartridge and the injection needle. injection.
[0131] The term "syringe needle" refers to a needle in a usable automatic injection device that is coupled to or in contact with a syringe or cartridge assembly to transport a dose of a syringe therapeutic agent or set of cartridge for an injection needle which, in turn, delivers the therapeutic agent into the patient's body. In an illustrative embodiment, the syringe needle is not inserted into the patient's body. In another illustrative way, the syringe needle can be inserted into the patient's body.
[0132] In the illustrative usable automatic injection device including a syringe assembly, the syringe needle can be coupled directly to the barrel part of the syringe and can be in fluid communication with the barrel part. In an illustrative usable automatic injection device including a cartridge assembly, the syringe needle may be provided separately from the barrel portion of the cartridge, for example, within an injection button or a transfer mechanism. During an injection stage, the syringe needle can be inserted at a distal end of the barrel part of the cartridge to establish fluid communication between the syringe needle and the barrel part.
[0133] The term "pre-injection state" refers to a state of a usable automatic injection device prior to the start of delivery of a therapeutic agent contained in the device.
[0134] The term "injection status" refers to one or more states of an automatic injection device usable during the delivery of a therapeutic agent contained in the device.
[0135] The term "post-injection status" refers to completing the delivery of a therapeutically efficient dose of a therapeutic agent contained in the device and removing the device from the patient prior to completing the delivery of a therapeutically efficient dose of the therapeutic agent.
[0136] The term "slow" refers to a rate of distribution of a volume of a therapeutic agent. In an illustrative embodiment, a volume of about 0.1 millimeter to about 1 millimeter or more can be distributed over a distribution time period of about ten seconds to about twelve hours. In a preferred embodiment, the distribution time period can vary from about five minutes to about thirty minutes.
[0137] The term “vestuario” refers to any adequate coverage on the body of a patient when! an illustrative usable automatic injection device can be coupled or attached. The garment can thus form an intermediate layer between the device and the patient's skin and can be used to indirectly couple the device to the patient's skin. In an illustrative modality, the article of clothing can be a tight fit on the patient's body, for example, nylon stockings. In another illustrative embodiment, the garment may be a cover on the patient's skin including, but not limited to, medical tape, bandages, and the like. In another illustrative embodiment, the garment may be a coupling mechanism that adheres the device close to the patient's skin including, but not limited to, a sleeve that can fit around a part of the patient's body, a belt, a strap (for example, a velcro strip), and the like. II. Illustrative modalities
[0138] Certain illustrative usable automatic injection devices are described with reference to figures 1 to 10. Certain illustrative needle systems that can be used in illustrative usable automatic injection devices to carry a therapeutic agent are described with reference to figures 11 to 23. Certain illustrative piston drive systems that can be used in illustrative usable automatic injection devices to expel a therapeutic agent from a syringe or cartridge are described with reference to figures 24 to 51. Certain illustrative needle protection systems that can to be used in illustrative usable automatic injection devices to hold an injection needle in a retracted position after the injection state is described with reference to figures 52 to 55.
[0139] Illustrative usable automatic injection devices may employ a syringe assembly (as illustrated in figures 1a to 1f) or a cartridge assembly (as illustrated in figures 2a to 2f) to maintain a dose of therapeutic agent that can be delivered to a patient's body via an injection needle.
[0140] Figures 1a to 1f illustrate an illustrative embodiment of a usable automatic injection device 100 including a syringe assembly that can be used to inject a dose of a therapeutic agent into a patient's body. Figure 1a shows a first end view and a first side view of the illustrative wearable device 100 in a packaged pre-injection state. Figure 1b illustrates the first end view and the first side view of the illustrative device 100 in a pre-injection state in which a needle protection cover of the injection needle is removed in preparation for an injection. Figure 1c illustrates the first end view and the first side view of the illustrative device 100 during an injection in an injection state in which the patient's skin is pierced by the injection needle. Figure 1d illustrates the first end view and the first side view of the illustrative device 100 during an injection in an injection state in which the barrel part containing the dose of therapeutic agent is developed forward into the housing of the device 100 ,. Figure 1e illustrates the first end view and the first side view of the illustrative device 100 during an injection in an injection state in which the plug is actuated by a plunger driver to expel the dose of therapeutic agent from the barrel. Figure 1f shows the first end view and the first side view of the illustrative device 100 after an injection in a post-injection state where the injection needle is restricted within the housing of the device 100.
[0141] The wearable automatic injection device 100 may include housing 102. In an illustrative embodiment, housing 102 may have an elongated configuration, although those skilled in the art recognize that housing 102 can have any shape, size and configurations suitable for housing a pipe part containing a dose of a therapeutic agent to be injected. In an illustrative embodiment, housing 102 may be formed from any suitable material including, but not limited to, plastic and other known materials.
[0142] Housing 102 of the wearable automatic injection device 100 may include an adhesive layer 124 disposed along the patient contact portion at the bottom of housing 102 which is located close to the patient's skin or a patient's garment. In some illustrative embodiments, the adhesive layer 124 can be configured to be placed on the patient's skin in order to fix the housing 102 to the patient to distribute the therapeutic agent dose. The adhesive layer 124 may include a non-adhesive tab 126 that is not adhesive. The non-adhesive tab 126 can be grasped by the patient and pulled to remove the wearable automatic injection device 100 from the patient's skin or clothing.
[0143] Before the usable automatic injection device 100 is put into use, for example, in the package state illustrated in figure 1a, the adhesive layer 124 can be covered by a protective film 128 that preserves the adhesive nature of the adhesive layer 124 The protective film 128 may include a tongue 130 that can be grasped by the patient and pulled to remove the protective film 128 from adhesive layer 124. This exposes adhesive layer 124 allowing the patient to attach housing 102 to his skin or article of clothing by placing the side with the layer 124 on the skin or article of clothing.
[0144] Housing 102 can accommodate a syringe assembly extending substantially along a longitudinal geometric axis L between a proximal end (farthest from the injection needle) and a distal end (closest to the injection needle). The syringe assembly may include a barrel part 106 to hold a dose 108 of a therapeutic agent to be injected into the patient's skin. The barrel portion 106 can extend substantially along the longitudinal geometric axis between a proximal end (furthest from the injection needle) and a distal end (furthest from the injection needle). In an illustrative embodiment, the pipe part 106 can be a substantially cylindrical element having a circular cross section, although those skilled in the art recognize that the pipe part 106 can be of any desired shape or configuration.
[0145] In an illustrative embodiment, the barrel part 106 can be parked inside housing 102 so that the injection process does not result in movement of barrel part 106 within and with respect to housing 102. In another illustrative embodiment, the barrel part 106 may initially do so and, prior to an injection in a pre-injection state, be in a retracted position towards the proximal end of the device 100 (as shown in figures 1a to 1c) and can be triggered during an injection in an injection state to a position stretched towards the distal end of the device 100.
[0146] A plug 110 can be provided at the proximal end of the barrel part 106 to seal the dose of therapeutic agent within the barrel part 106 and to apply a dose force to expel the dose from the barrel part 106. The plug 110 it can be movable within the barrel part 106 towards the distal end of the barrel part 106 in order to expel the dose of the barrel part 106 during an injection in an injection state. In an illustrative embodiment, the stopper 110 can be configured to perform both dose-sealing and dose-tightening functions outside the barrel part 106. In another illustrative embodiment, a stopper can be provided to seal the dose within the barrel part. pipe 106 and a separate piston or piston rod can be provided to impart a force to the cap in order to squeeze the dose out of the pipe portion 106.
[0147] The syringe assembly may include, at or near its distal end, a syringe stop or a distal portion of syringe 114 which may include a syringe needle 120 and a needle cover 134 to cover syringe needle 120 The needle cover 134 may include a soft needle shield, a rigid needle shield, or both. In an illustrative embodiment, the syringe needle 120 can be aligned in parallel with the longitudinal geometric axis L of the device 100. The syringe needle 120 can be of any size, shape and configuration suitable for piercing a membrane, and is not limited to the modality illustrative.
[0148] The syringe assembly may include, at or near its proximal end, a plunger driver 112 to selectively drive the plug 110 forward within the barrel portion 106 towards the distal end in order to inject the therapeutically efficient dose contained in the barrel portion 106 in the patient's skin. The piston driver 112 can employ an energy store and energy release mechanism controlled to actuate the cap 110. In illustrative embodiments, the piston driver 112 can be located outside the barrel part 106 or partially or completely inside the barrel part. barrel 106. In an illustrative embodiment, the plunger driver 112 can actuate the plug 110 directly or indirectly through the use of a plunger disposed between the plug 110 and the plunger driver 112.
[0149] In an illustrative embodiment, the plunger driver 112 may include a guiding mechanism, for example, a spring, which is retracted before injection and which is released during injection to drive the plug 110 forward inside the barrel part 106. In another illustrative embodiment, the plunger driver 112 may include a chemical gas generator, for example, an expansion foam, which is an unexpanded phase before injection and which expands during injection to activate the cap 110 forward into the barrel portion 106. In other illustrative embodiments, the piston driver 112 may employ hydraulic pressure from working fluids, compressed gas pressure, osmotic pressure, hydrogel expansion and the like.
[0150] In an illustrative embodiment, the piston driver 112 can be moved forward within the barrel portion 106 in a substantially linear manner, i.e., substantially constant speed. This can allow the dose to be delivered to the patient at a substantially constant rate of delivery. Plunger driver 112 may include or may be coupled to a damping mechanism that can be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during the release of energy by the piston driver 112. Controlled release of energy can result in a substantially linear distribution profile, i.e., a substantially constant rate of dose distribution over time, and can prevent sudden changes in the rate of delivery. In an illustrative embodiment, a plunger driver 112 can employ the hydraulic pressure of a working fluid and a damping mechanism can employ a flow restriction element located in a fluid path between the working fluid and the plug 110. In in another illustrative embodiment, a plunger driver 112 may employ a guiding mechanism and a damping mechanism may employ a viscous damper, a dirty lever exhaust, an outlet chute, and the like. In another illustrative embodiment, a piston driver 112 may employ a stepper motor connected to a gear drive system to provide a constant linear distribution profile.
[0151] The housing 102 of the usable automatic injection device 100 can also accommodate an injection button 116 supporting a hollow hypodermic injection needle 118 which is configured to pierce the patient's skin. In an illustrative embodiment, the injection needle 118 can be aligned orthogonally with the longitudinal geometric axis L of the device 100. In an illustrative embodiment, the injection needle 118 can be held in place by an injection needle holder (not shown) provided at the injection button 116 or separately from the injection button 116. The injection needle 118 can be of any size, shape and configuration suitable for piercing the patient's skin to deliver the therapeutic agent, and is not limited to the modality illustrative. Suitable needles can be configured or selected in length to provide an injection depth suitable for the desired therapy. Subcutaneous injections typically penetrate about six to ten millimeters into the skin. In an illustrative embodiment, the injection needle 118 can be about 12 mm long. and can be injected to a depth of about seven mm. in the skin. In other illustrative embodiments, the injection needle 118 can be of suitable length for intradermal therapies, other subcutaneous or intramuscular therapies. Suitable injection needles can have a suitable wall thickness to provide sufficient mechanism resistance, a suitable diameter to allow a desired flow rate of the injected substance while minimizing the sensation of the patient and an appropriate tip geometry for the desired therapy while minimizing the feeling of the patient. Suitable injection needles can be coated as needed to minimize the patient's feeling as allowed by the therapy. The injection needle 118 can be covered and maintained in aseptic conditions, i.e., sterile condition, by a needle cover 122, for example, a rigid needle shield, a soft needle shield, or both.
[0152] Injection button 116 may also include a pierceable membrane disposed in the vicinity of syringe needle 120. In a pre-injected state, syringe needle 120 does not pierce the membrane, thus preventing fluid co-communion between the barrel part 106 and the syringe needle 120. In an injection state, when pierced by a needle, for example, the ring needle 120, the membrane can allow the dose to leave the barrel part 106 and enter on the syringe needle 120. In an illustrative embodiment, one or more covers 115 can enclose the membrane in a sterile shield. Covers 115 can be pierced when syringe needle 120 pierces the membrane.
[0153] In an illustrative embodiment, the injection needle 118 and the syringe needle 120 can be coupled to and can be in fluid communication with each other through the body of the injection button 116. In another illustrative embodiment, the injection needle 118 and syringe needle 120 can be coupled to and can be in fluid communication with one another through one or more fluid conduits (not shown). In another illustrative embodiment, the injection needle 118 and the syringe needle 120 can be coupled directly to and can be in fluid communication with each other.
[0154] In an illustrative embodiment, prior to an injection in a pre-injection state, the injection button 116 can be in a vertically elevated position with respect to housing 102 so that the injection button 116 protrudes from the top of housing 102, as shown in figures 1a and 1b. In that position, the injection needle 118 can be retracted into housing 102 and can be inserted into the patient's skin. In this position, the syringe needle 120 can be aligned vertically below the membrane at the syringe stop 114 and may not pierce the membrane. At the beginning of the injection process, the injection button 116 can be pressed down, for example by a user of the device or automatically. This can push the injection button 116 to a vertically pressed position relative to the housing 102 closest to the patient's skin so that the injection button 116 no longer protrudes from the top of the housing 102, as illustrated in figures 1c to 1e. In this position, the injection needle 118 can project from the bottom of the housing 102 and can be inserted into the patient's skin. In this position, the syringe needle 120 can be aligned with the membrane at the syringe stop 114 and can pierce the membrane.
[0155] In an illustrative embodiment, the membrane can initially be removed from the injection button 116. In this embodiment, the syringe needle 120 can pierce the membrane when the syringe stop 114 supporting the syringe needle 120 and advanced into the housing 102 towards the membrane. That is, prior to an injection in the pre-injection state, the syringe needle 120 can be removed from the membrane so that there is no fluid communication between the barrel part 106 and the injection needle 118 coupled to the injection button 116 In an injection state, the barrel part 106 can advance into the housing 102 towards the distal end of the device 100 so that the syringe needle 120 can pierce the membrane and establish fluid communication between the barrel part 106 and the injection needle 118 coupled to the injection button 116. Such fluid communication may allow the dose of therapeutic agent to flow from the barrel part 106 into the patient's skin through the syringe needle 120 and the injection needle 118 when the pressure is applied to the dose by the plug 110 during an injection in an injection state.
[0156] Referring now to Figure 1f, in an illustrative embodiment, the housing 102 of the usable automatic injection device 100 may include a skin sensor piece 132, which is a structure housed under or in the housing part 102 near the site injection. Prior to the injection of the therapeutic agent and during the injection, the skin sensor piece 132 is retained within or forms a part of the underside of housing 102. When the wearable automatic injection device 100 is attached to the injection site and activated , the skin sensor foot 132 may be free to move, but may be restricted by the injection site. When the wearable automatic injection device 100 is removed from the injection site, regardless of whether the drug delivery has been completed, the skin sensor foot 132 is no longer restricted, and extends and protrudes out of the housing periphery 102 This, in turn, triggers a retraction trigger. When the retraction trigger is activated, a retraction mechanism retracts the injection needle 120 which can also raise the injection button 116 from the vertically lowered position to the vertically raised position, so that the injection button 116 protrudes from the the top of the housing 102 and the injection needle 118 is retracted into the housing 102.
[0157] Figure 1a illustrates the usable automatic injection device 100 in a pre-injection state, for example, as packaged, where the barrel part 106 can be pre-filled with dose 108 of the therapeutic agent and in a retracted position ready to use. The barrel part 106 can contain the dose 108 of the therapeutic agent in the internal space defined between the wall or walls of the barrel part 106 and the plug 110. In one embodiment, the plunger driver 112 can store energy which, when released, can activate the cap 110. The injection button 116 can be partially arranged inside the housing 102 in the vertically elevated position above the injection site, and the injection needle 118 can be retracted inside the housing 102. The protuberance of the injection button 116 stops off the top of housing 102 can provide a visual indication to the patient that the usable automatic injection device 110 is not in operation.
[0158] Figure 1b illustrates the usable automatic injection device 110 in a pre-injection state in which the needle cover 122 and the memory cover are removed. In illustrative embodiments, the protective film 128 may include a connection element which is connected to the needle cover 122, the syringe needle cover and membrane at the syringe stop 114. The connection element may include a tie-down or other connection mechanism . When the protective film 128 is removed, the connecting element of the protective film 128 can remove the needle cover 122 and the syringe needle membrane and covers on the syringe stop 114.
[0159] Figure 1c illustrates a usable automatic injection device 100 during an injection in an injection state in which the injection button 116 is close to the lowered position inside the housing 102. In the vertically lowered position, the injection button 116 can be arranged inside housing 102 in a pressed or vertically lowered location above the injection site and the injection needle 118 can project from the bottom of the housing 102 through the opening in the housing 102 so that it can penetrate on the skin at the injection site. In the vertically lowered state, the injection button 116 may not protrude from the top of housing 102, which may provide a visual indication to the patient that the usable automatic injection device 100 is in operation.
[0160] Figure 1d illustrates the usable automatic injection device 100 during an injection in an injection state in which the barrel portion 106 containing the dose 108 of therapeutic agent is developed forward from a retracted position to a extended position within the housing of the device 100. The advance of the barrel part 106 can place the distal end of the barrel part 106 or the syringe stop 114 in the vicinity of or in contact with the injection button 116. In an illustrative embodiment, the syringe needle 120 can pierce the membrane held in the syringe stop 114 in order to establish fluid communication between the barrel portion 106 and the injection needle 118.
[0161] Figure 1e illustrates the usable automatic injection device 100 during an injection in an injection state in which the piston actuator 112 is actuated to move the cap 110. The actuation of the piston actuator 112 can release energy stored in the piston driver 112 in order to move the plug 110 into the plunger part 106 towards the distal end of the device 100. The movement of the plug 110 can eject the dose of therapeutic agent from the tube part 106 through the end distal from the barrel portion 106. Any suitable mechanism can be used to drive the plunger driver 112, including, but not limited to, a connecting element which is coupled to and activated by pressing the injection button 116 or removing the water cover -122, a trigger button that can be used by the user, and the like.
[0162] Figure 1f illustrates the usable automatic injection device 100 after an injection in a post-injection state, for example, after the injection of a therapeutically efficient dose of the therapeutic agent or removal of the usable automatic injection device 100 from the patient prior to delivery of a therapeutically efficient dose of the therapeutic agent, where the injection button 116 is in the vertically elevated position. In the vertically elevated position, the injection button 116 can be partially arranged inside the housing 102 at an elevated or vertically elevated location above the injection site and the injection needle 118 can be retracted within the housing 102. A part of the injection button 116 can protrude from the top of housing 102 to provide a visual indication to the patient that the usable automatic injection device assembly 100 is not in operation (i.e., in a post-injection state). The barrel portion 106 may be empty of therapeutic agent and the plunger driver 112 may no longer store energy. A skin sensor piece 132 can extend from the bottom of housing 102 by removing device 100 from the injection site.
[0163] Housing 102 may include a retractor mechanism that automatically raises the injection button 116 from the vertically lowered injection state (shown in figures 1c to 1e) to the vertically raised post-injection state (shown in figure 1f). In an illustrative embodiment, the retraction mechanism may include an orientation mechanism, for example, a spring, which guides the syringe assembly away from the injection site when the retraction mechanism is operated.
[0164] A retraction trigger, when activated, can activate the retraction mechanism in order to raise the injection button 116 from the vertically lowered state to the vertically elevated state. In an illustrative embodiment, the plug 110 and / or the plunger driver 112 may include a connection element connected to the retraction trigger. The connecting element may include a tie or other connection mechanism. The connecting element can be of a suitable length so that when the cap 110 has been moved to the end of the barrel part 106 (delivering a full dose), the connecting element activates a lock which, in turn, activates the trigger of retraction. In another illustrative embodiment, extending the skin sensor foot 132 from the housing 102 button can trigger the retraction trigger.
[0165] In an illustrative embodiment, the retraction mechanism may include an end-dose retraction trigger that, when triggered, activates the retraction mechanism. The end-of-dose retraction trigger can be triggered when the therapeutically effective dose of the therapeutic agent in the usable, automatic injection device is dispensed. In an illustrative embodiment, the end-dose retraction trigger may include a lock, for example, a flexible plastic hook, which is released upon complete drug delivery. The retraction mechanism can also include a premature removal retraction trigger that, when activated, activates the retraction mechanism. The premature withdrawal trigger can be triggered when the usable automatic injection device is removed from the injection site before the therapeutically efficient dose of the therapeutic agent is fully delivered. In an illustrative embodiment, the premature removal retraction trigger may include a lock, for example, a flexible plastic hook, which is released by removing the usable automatic injection device 100 from the injection site. The retraction mechanism responds to the end of dose retraction trigger and responds to the premature withdrawal retraction trigger to automatically retract the syringe assembly from the injection site.
[0166] In an illustrative embodiment, raising the injection button 116 to the vertically elevated position can cause the syringe needle 120 to bend upwards, thereby preventing the unwanted reuse of the syringe needle and the automatic injection device usable.
[0167] Figures 2a to 2f illustrate an illustrative embodiment of a usable automatic injection device 200 including a cartridge assembly that can be used to inject a dose of a therapeutic person into a patient's body. Figure 2a shows a first end view and a first side view of the illustrative wearable device 200 in a pre-injection packaged state. Figure 2b illustrates the first end view and the first side view of the illustrative device 200 in a pre-injection state in which a needle shield covering the injection needle is removed in preparation for an injection. Figure 2c shows the first end view and the first side view of the illustrative device 200 during an injection in an injection state in which the patient's skin is pierced by the injection needle. Figure 2d shows the first end view and the first side view of the illustrative device 200 during an injection in an injection state in which the barrel part containing the dose of therapeutic agent is developed forward into the housing of the device 200. A figure 2e illustrates the first end view and the first side view of the illustrative device 200 during an injection in an injection state where the plug is actuated by a plunger actuator to expel the dose of therapeutic agent from the part pipe. Figure 2f shows the first end view and the first side view of the illustrative device 200 after an injection in a post-injection state in which the injection needle is retracted into the housing of the device 200.
[0168] The usable automatic injection device 200 may include housing 202. In an illustrative embodiment, housing 202 may have an elongated configuration, although those skilled in the art recognize that housing 202 may have any shape, size and configurations suitable for housing a pipe part containing a dose of a therapeutic agent to be injected. In an illustrative embodiment, housing 202 may be formed from any suitable material including, but not limited to, plastic and other known materials.
[0169] The housing 202 of the usable automatic injection device 200 may include an adhesive layer 224 disposed along a patient contact portion at the bottom of the housing 202 which is located close to the patient's skin or a patient's garment . In some illustrative embodiments, the adhesive layer 224 can be configured to be placed on the patient's skin in order to fix the housing 202 to the patient to distribute the dose of therapeutic agent. The non-adhesive tab 226 can be grasped by the patient and pulled to remove the wearable automatic injection device 200 from the patient's skin or clothing.
[0170] Before the usable automatic injection device 200 is put to use, for example, in the packaged state illustrated in figure 2a, the adhesive layer 224 can be covered by a protective film 228 that preserves the adhesive nature of the adhesive layer 124. The protective film 228 may include a tongue 230 that can be grasped by the patient and pulled to move the protective film 228 from adhesive layer 224. This exposes adhesive layer 224, allowing the patient to attach housing 202 to his skin or clothing. by placing the side with the adhesive layer 224 on the skin or article of clothing.
[0171] The housing 202 can accommodate a set of therapeutics agent cartridge extending substantially along a longitudinal geometric axis L between a proximal end (farthest from the injection needle) and a distal end (closest to the injection needle). The cartridge assembly can include a barrel part 206 to hold a dose 208 of a therapeutic agent to be injected into the patient's skin. The barrel part 206 may extend substantially along the longitudinal geometric axis between a proximal end (furthest from the injection needle) and a distal end (furthest from the injection needle). In an illustrative embodiment, the pipe part 206 may be a substantially cylindrical element having a circular cross-section, although those skilled in the art recognize that the pipe part 206 may have any suitable shape or configuration.
[0172] In an illustrative embodiment, the pipe part 206 may be stationary within housing 202 so that the injection process does not result in movement of the pipe part 206 within and with respect to housing 202. In another illustrative embodiment, the pipe part 206 may initially do so and, prior to an injection in a pre-injection state, be in a retracted position towards the proximal end of the device 200 (as shown in figures 2a to 2c), and can be triggered during an injection in an injection state to an extended position towards the distal end of the device 200.
[0173] A plug 210 may be provided at the proximal end of the barrel part 206 to seal the dose of a therapeutic agent within the barrel part 206 and to force the dose to expel the dose from the barrel part 206. The plug 210 can be movable within the barrel part 206 towards the distal end of the barrel part 206 in order to expel the dose from the barrel part 206 during an injection in an injection state. In an illustrative embodiment, the cap 210 can be configured to perform both dose-sealing functions and squeeze the dose out of the pipe part 206. In another illustrative embodiment, a cap can be provided to seal the dose within the part of the barrel. pipe 206 and a separate piston can be provided to force the cap in order to squeeze the dose out of the pipe part 206.
[0174] The cartridge assembly may include, at or near its proximal end, a plunger driver 212 to selectively drive the plug 210 forward within the barrel portion 206 towards the distal end in order to inject the therapeutically efficient dose contained in the barrel part 206 within the patient's skin. Plunger actuator 212 can employ an energy store and a controlled energy release mechanism to actuate plug 210. In illustrative embodiments, plunger actuator 212 can be located outside of pipe part 206 or partially or totally inside part barrel 206. In an illustrative embodiment, the plunger driver 212 can actuate the plug 210 directly or indirectly through the use of a plunger arranged between the plug 210 and the plunger driver 212.
[0175] In an illustrative embodiment, the plunger actuator 212 can include a guiding mechanism, for example, a spring, which is retracted before injection and which is released during injection to actuator a plug 210 forward inside the part of pipe 206. In another illustrative embodiment, piston actuator 212 may include a chemical gas generator, for example, an expanding gas foam, which is an unexpanded phase prior to injection and which expands during injection to trigger the plug 210 forward within the barrel part 206. In other illustrative embodiments, the plunger driver 212 may employ hydraulic pressure of working fluids, compressed gas pressure, osmotic pressure, hydrogel expansion, and the like.
[0176] In an illustrative embodiment, the plunger driver 212 can be moved forward within the barrel part 206 in a substantially linear manner, that is, at a substantially constant speed. This can allow the dose to be delivered to a patient at a substantially constant rate of delivery. Plunger driver 212 can include or can be coupled to a damping mechanism that can be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during the release of energy by the plunger driver 212. Controlled release of energy can result in a substantially linear distribution profile, i.e., a substantially constant rate of dose distribution over time, and can prevent sudden changes in the speed of delivery.
[0177] In an illustrative embodiment, a plunger actuator 212 can employ one or more fluid circuits containing a working fluid in which the hydraulic pressure of the working fluid applies a force to the cap to move the cap within the pipe part of the cartridge. A damping mechanism can employ a flow restrictor located in the fluid circuit between a working fluid source and the cap.
[0178] In another illustrative embodiment, a plunger driver 212 may employ a guiding mechanism, for example, a spiral spring or a helical compression spring. A damping mechanism can employ a viscous damper, a dirty lever exhaust, an exhaust exhaust, and the like.
[0179] In another illustrative embodiment, a plunger driver 212 may employ a stepper motor connected to a gear drive system to provide a constant linear distribution profile.
[0180] The cartridge assembly may include, at or near its distal end, a cartridge stop 214 which may include a membrane and a cover 215 for the membrane. The membrane can be a perforable layer of material that is disposed adjacent to the distal end of the pipe part 206 in order to seal the dose in the pipe part 206. When intact, the membrane can seal the dose inside the pipe part 206. When perforated by a needle, for example, a syringe needle, the membrane may allow the dose to leave the barrel part 206 and enter the syringe needle. The membrane can be formed from a material that can be pierced by a syringe needle. A cover can be provided to protectively cover the membrane against accidental puncture by the syringe needle when the device 200 is in the pre-injection packaged state as illustrated in figure 2a. In an illustrative embodiment, the cartridge stop 214 may also include a cover to protectively cover a syringe needle provided in the vicinity of the cartridge stop 214, thereby preventing accidental puncture of the membrane by the syringe needle when device 200 it is in a pre-injection packaged state as illustrated in figure 2a.
[0181] The housing 202 of the usable automatic injection device 200 can also accommodate an injection button 216 supporting a hollow hypodermic injection needle 218 which is configured to pierce the patient's skin. In an illustrative embodiment, the injection needle 218 can be aligned orthogonally with the longitudinal geometric axis L of the device 200. In an illustrative embodiment, the injection needle 218 can be held in place by an injection needle holder (not shown) provided at the injection button 216 or separately from the injection button 216. The injection needle 218 can be of any size, shape and configuration suitable for piercing the patient's skin to deliver the therapeutic agent, and is not limited to the modality illustrative. Suitable needles can be configured or selected in length to provide an injection depth suitable for the desired therapy. Subcutaneous injections typically penetrate about six to ten millimeters into the skin. In an illustrative embodiment, the injection needle 218 can have a length of about twelve mm and can be injected to a depth of about seven mm into the skin. In other illustrative embodiments, the injection needle 218 can be of suitable length for intradermal therapies, other subcutaneous therapies or intramuscular therapies. Suitable injection needles can have a suitable wall thickness to provide sufficient mechanism resistance, a suitable diameter to allow a desired flow rate of the injected substance while minimizing the sensation of the patient, and an appropriate tip geometry for the desired therapy while minimizing the patient's feeling. Appropriate injection needles can be coated as needed to minimize patient sensation as allowed by therapy. The injection needle 218 can be covered and maintained in a septic condition by a needle cover 222, for example, a rigid needle shield, a soft needle shield, or both.
[0182] The injection button 216 can also support a hollow syringe needle 220 configured to pierce the membrane and establish fluid communication with the pipe part 206. In an illustrative embodiment, the syringe needle 220 can be aligned in parallel with the longitudinal geometric axis L of the device 200. The syringe needle 220 can be of any shape, size and configuration suitable for piercing the membrane and is not limited to this illustrative embodiment.
[0183] In an illustrative embodiment, the injection needle 218 and the syringe needle 220 can be coupled to and in fluid communication with each other through the body of the injection button 216. In another illustrative embodiment, the injection needle 218 and the syringe needle 220 can be coupled to and in fluid communication with one another through one or more fluid conduits (not shown). In another illustrative embodiment, the injection needle 218 and the ring needle 220 can be coupled directly to and in fluid communication with each other.
[0184] In an illustrative embodiment, prior to an injection in a pre-injection state, the injection button 216 may be in a vertically elevated position with respect to housing 202 so that the injection button 216 protrudes from the top of housing 202, as shown in figures 2a and 2b. In that position, the injection needle 218 may be retracted into the housing 202 and may not be inserted into the patient's skin. In this position, the syringe needle 220 can be aligned vertically above the membrane at the cartridge stop 214 and may not pierce the membrane. At the beginning of the injection process, the injection button 216 can be pressed down, for example, by a user of the device or automatically. This can push the injection button 216 to a vertically pressed position with respect to the housing 202 closer to the patient's skin so that the injection button 216 no longer protrudes from the top of the housing 202, as shown in figures 2c to 2e. In this position, the injection needle 218 can project from the bottom of the housing 202 and can be inserted into the patient's skin. In that position, the syringe needle 220 can be aligned with the membrane on the cartridge stop 214 and can pierce the membrane.
[0185] In an illustrative embodiment, the membrane can initially be erased from the injection button 216. In that embodiment, the syringe needle 220 can pierce the membrane when the cartridge stop 214 supporting the membrane is advanced into housing 202 towards the injection button 216. that is, before an injection in a pre-injection state, the syringe needle 220 can be blown off the membrane so that there is no fluid communication between the barrel part 206 and the injection needle 218 coupled to the injection button 216. In an injection state, the barrel part 206 can advance into the housing 202 towards the distal end of the device 200 so that the syringe needle 220 can pierce the membrane and establish fluid communication between the barrel part 206 and the injection needle 218 coupled to the injection button 216. Such fluid communication may allow the dose of the therapeutic agent to flow from the barrel part 206 into the patient's skin through syringe needle 220 and injection needle 218 when pressure is applied through cap 210 during an injection in an injection state.
[0186] Referring now to figure 2f, in an illustrative embodiment, housing 202 of the usable automatic injection device 200 may include a skin sensor piece 232, which is a structure housed under or in part of housing 202 proximal to the location injection. Prior to the injection of the therapeutic agent and during the injection, the skin sensor piece 232 is retained within or forms a part of the underside of housing 202. When the usable automatic injection device 200 is attached to the injection site and activated , the skin sensor piece 232 may be free to move, but may be restricted by the injection site. When the wearable automatic injection device 200 is removed from the injection site, regardless of whether the drug delivery has been completed, the skin sensor piece 232 is no longer restricted, and extends and protrudes out of the housing 202 This, in turn, triggers a retraction trigger. When the retraction trigger is activated, a retraction mechanism retracts the injection needle 220 which can also raise the injection button 216 from the vertically lowered position to the vertically raised position, so that the injection button 216 protrudes from the top of the housing 202 and the injection needle 218 is retracted into the housing 202.
[0187] Figure 2a illustrates the usable automatic injection device 200 in a pre-injection state, for example, as packaged, where the barrel part 206 can be pre-filled with dose 208 of the therapeutic agent and in a retracted position ready to use. The pipe part 206 can contain the dose 208 of the therapeutic agent in the internal space defined between the wall or walls of the pipe part 206 and the plug 210. In one embodiment, the plunger driver 212 can store energy which, when released, can activate the cap 210. The injection button 216 can be partially arranged inside the housing 202 in the vertically elevated position above the injection site and the injection needle 218 can be retracted inside the housing 202. The protrusion of the injection button 216 outwards from the top of the housing 202 can provide a visual indication to the patient that the usable automatic injection device 200 is not in operation.
[0188] Figure 2b illustrates the usable automatic injection device 200 in a pre-injection state in which the needle cover 222 and the memory cover are removed. In illustrative embodiments, the protective film 228 may include a connection element which is connected to the needle cover 222 and the membrane and syringe needle covers on the cartridge stop 214. The connection element may include a tie or other connection mechanism . When the protective film 228 is removed, the protective film connecting element 228 can remove the needle cover 222 and the membrane and syringe needle covers on the cartridge stop 214.
[0189] Figure 2c illustrates the usable automatic injection device 200 during an injection in an injection state in which the injection button 216 is in the vertically lowered position within housing 202. In the vertically lowered position, the injection button 216 can be arranged inside housing 202 in a pressed or vertically lowered location above the injection site, and the injection needle 21 can project from the bottom of housing 202 through an opening in housing 202 so that it can penetrate the injection site skin. In the vertically lowered state, the injection button 216 may not protrude from the top of housing 202, which can provide a visual indication to the patient that the usable automatic injection device 200 is in operation.
[0190] Figure 2d illustrates the usable automatic injection device 200 during an injection in an injection state in which the barrel part 206 containing dose 208 of the therapeutic agent is developed forward from a retracted position to an extended position inside the housing of the device 200. The lead of the barrel part 206 can place the distal end of the barrel part 206 or cartridge stop 214 in the vicinity of or in contact with the injection button 216. In an illustrative embodiment, the syringe needle 220 can pierce the membrane held in the cartridge stop 214 in order to establish fluid communication between the barrel part 206 and the injection needle 218.
[0191] Figure 2e illustrates the usable automatic injection device 200 during an injection in an injection state in which the plunger actuator 212 is actuated to move the cap 210. Activating the plunger actuator 212 can release energy stored in the plunger driver 212 in order to move the cap 210 into the barrel part 206 towards the distal end of the device 200. The movement of the cap 210 may eject the dose of therapeutic agent from the barrel part 206 through the end distal from the barrel part 206. Any suitable mechanism can be used to drive the plunger driver 212 including, but not limited to, a connecting element that is coupled and activated by pressing the injection button 216 or removing the needle cover 222 , a trigger button that can be used by the user, and the like.
[0192] Figure 2f illustrates the usable automatic injection device 200 after an injection in a post-injection state, for example, after the injection of a therapeutically efficient dose of the therapeutic agent or removal of the usable automatic injection device 200 of the patient before delivery of a therapeutically efficient dose of the therapeutic agent, where the injection button 216 is in the vertically elevated position. In the vertically elevated position, the injection button 216 can be partly disposed within housing 202 at an elevated or vertically elevated location above the injection site, and the injection needle 218 can be retracted within housing 202. A portion of the injection button 216 can project from the top of housing 202 to provide a visual indication to the patient that the usable automatic injection device assembly 200 is not in operation (that is, in a post-injection state) . The barrel part 206 may not impart therapeutic agent and the plunger driver 212 may not store more energy. A skin sensor piece 232 can extend from the bottom of housing 202 by removing device 200 from the injection site.
[0193] Housing 202 may include a retractor mechanism that automatically raises the injection button 216 from the vertically lowered injection state (shown in figures 2c to 2e) to the vertically raised post-injection state (shown in figure 2f). In an illustrative embodiment, the retractor mechanism may include a guide mechanism, for example, a spring, which guides the cartridge assembly away from the injection site when the retraction mechanism is operated.
[0194] A retraction trigger, when activated, can activate the retraction mechanism in order to raise the injection button 216 from the vertically lowered state to the vertically elevated state. In an illustrative embodiment, the plug 210 and / or the plunger driver 212 may include a connection element connected to the retraction trigger. The connecting element may include a tie or other connection mechanism. The connecting element can be of a suitable length so that when the plug 210 has been moved to the end of the pipe part 206 (delivering a full dose), the connecting element activates a lock which, in turn, triggers the trigger of retraction. In another illustrative embodiment, extending the skin sensor foot 232 from below housing 202 may trigger the retraction trigger.
[0195] In an illustrative embodiment, the retraction mechanism may include an end-dose retraction trigger that, when activated, activates the retraction mechanism. The end of dose retraction trigger can be triggered when the therapeutically efficient dose of the therapeutic agent in the usable automatic injection device is dispensed. In an illustrative embodiment, the end-dose retraction trigger may include a lock, for example, a flexible plastic hook which is released upon complete drug delivery. The retraction mechanism can also include a premature removal retraction trigger that, when activated, activates the retraction mechanism. The premature withdrawal trigger can be activated when the usable automatic injection device is removed from the injection site before the therapeutically efficient dose of the therapeutic agent is dispensed completely. In an illustrative embodiment, the premature reset retraction trigger may include a lock, for example, a flexible plastic hook, which is released by removing the usable automatic injection device 200 from the injection site. The retraction mechanism responds to the end of dose retraction trigger and responds to the premature removal retraction trigger to automatically retract the cartridge assembly from the injection site.
[0196] In the illustrative embodiments, the barrel part of the usable automatic injection device 100 (in figure 1) / 200 (in figure 2) can be pre-filled with any volume of a therapeutic agent, for example, a therapeutic antibody , desired for interdermal, subcutaneous or intramuscular injections. In an illustrative embodiment, the barrel part 106 can be pre-filled with a volume of between 0.1 mm to about 1 mm, although the illusive devices are not limited to this illustrative range of therapeutic agent volumes.
[0197] In the illustrative embodiments, the usable automatic injection device 100 (in figure 1) / 200 (in figure 2) can be used to inject a therapeutically efficient amount of the therapeutic agent over a period of time ranging from about ten seconds about twelve hours. Certain other illustrative embodiments provide drive devices and systems that cause the syringe plunger to activate at a slow rate in order to deliver the therapeutic agent to a patient at a low rate. Illustrative slow modalities can deliver therapeutic agent volumes from about 0.1 mm to about 1 mm or more in about five minutes and about thirty minutes, although illustrative delivery rates are not limited to that illustrative range.
[0198] Illustrative modalities can provide a line-to-air delivery profile for the therapeutic agent so that the delivery rate is substantially constant over time. In some cases, a linear distribution profile can reduce the discomfort suffered by the patient. In an illustrative embodiment, the therapeutic agent can be delivered in a single slow bolus.
[0199] The rate of distribution of the therapeutic agent may depend on the ambient temperature. At room temperature, that is, about 22.22 ° C, the accuracy of the distribution time can vary between about 3% and about 10%.
[0200] The illustrative dimensions of the illustrative devices are described with reference to tables 1 to 6. However, those skilled in the art will recognize that the illustrative dimensions are provided for illustrative purposes, and that the illustrative automatic injection devices are not. limited to illustrative dimensions.
[0201] In an illustrative embodiment, a usable automatic injection device can have an illustrative length of about 11 cm., An illustrative width of about 5.38 cm, and an illustrative height of about 3.17 cm. In an illustrative embodiment, the diameter of the pipe part is about 3.73 cm and the length of the pipe part is about 6.4 cm. Tables 1 to 3 summarize the components of length, width and height, respectively, for two illustrative types of the illustrative device. Table 1: Summary of the components of the length of an illustrative device (cm.). ElementType 1Type 2 wall thickness0,460.30 membrane1,000.69 needle 1,271.27 pipe part6,406.4 avangol spring, 190,81 hydraulic connection 0,280,28 wall thickness 0,460.30 total 11,0910,07 Table 2: Summary of the width components of an illustrative device (cm). ElementType 1Type 2 wall thickness0,460.30 needle lock 1,042,37 width of kennel part, 191,19 syringe lock0,570,57 wall thickness 0,460.30 total 5,384.77 Table 3: Summary of height components of an illustrative device (cm). ElementType 1Type 2 wall thickness0,250.30 needle cover 1,091.09 membrane1,010.88 solid spring height0,500.00 wall thickness 0,460.31 total 3,342.60 In an illustrative embodiment, the diameter of the pipe part in production it can be increased from about 3.73 to about 0.31 cm, and the length of the pipe part can be reduced in production from about 6.40 cm by about 1.85 cm, respectively, to two illustrative types of illustrative device. Table 4: Summary of the length components of an illustrative device (cm) ElementType 1Type 2 wall thickness0,460,30 membrane, 000,69 needle 1,270,63 part of pipe6,404,54 avangol spring, 190,81 hydraulic connection 0,280,28 wall thickness 0,460.30 total 11,097.58 Table 5: Summary of the width components of an illustrative device (cm). ElementType 1Type 2 wall thickness0,460.30 needle lock 1,042,37 width of kennel part, 191,51 syringe lock0,570,57 wall thickness 0,460.30 total 5,385.09 Table 6: Summary of height components of an illustrative device (cm). ElementType 1Type 2 wall thickness0,250,30 needle cover 1,091,25 membrane, 010,88 solid spring height0,500.00 wall thickness 0,460.31 total 3,342.76
[0202] Figure 3 is a flow chart of an illustrative method 300 of assembling an illustrative automatic injection device 100. In step 302, a se-ring or cartridge assembly can be sterilized and assembled. In step 304, an injection button can be sterilized and assembled. In step 306, the barrel part of the syringe or cartridge assembly can be filled with a dose of a therapeutic person that must be administered to a patient. In step 308, a sterile plug can be placed on the barrel part of the syringe or cartridge assembly to seal the therapeutic agent within the barrel part. The restriction of the therapeutic agent within the automatic injection device usable by the sterile tube part and the sterile plug maintains the sterility of the therapeutic agent. As such, in an illustrative embodiment, the remaining components of the usable automatic injection device can be assembled in a non-sterile environment after the pipe part has been pre-filled with the therapeutic agent. For example, in step 310, a non-sterile plunger driver, for example, a guiding mechanism can be inserted behind the cap.
[0203] In step 312, the syringe or cartridge assembly can be inserted into a non-sterile housing. The housing can be pre-assembled with other non-sterile components, for example, an adhesive layer, a protective film, a skin sensor piece, and the like. In step 314, the injection button (with a closed sterile fluid path and one or more needles) can be inserted into the non-sterile housing. In the illustrative embodiments, the barrel part, the closed hypodermic injection needle, the syringe needle, the needle cover and the plug can provide sterility protection for the therapeutic agent and the fluid path. Thus, since the pipe part is filled with the therapeutic agent and the plug is inserted into the pipe part, the assembly of the remaining parts of the device does not require aseptic conditions. No transfer of therapeutic agent needs to be performed by the user. In step 316, the assembled automatic injection device can be placed in an external envelope, if necessary, and can then be commercially packaged for sale. Figure 1a illustrates an illustrative embodiment of the automatic injection device assembled in the pre-injection packaged state
[0204] Figure 4 is a flowchart of an illustrative method 400 of using an illustrative automatic injection device. The usable automatic injection device packaged and pre-filled with a therapeutic agent can generally be stored in a refrigerated storage prior to use. In step 402, the packaged automatic injection device can be removed from the store. In step 404, the usable automatic injection device can be removed from its packaging and any external wrapping, and heated to room temperature, for example, by leaving the usable device out of the package at room temperature or by heating the usable device. In step 406, the patient can confirm that the tube part contains a volume of therapeutic agent through a therapeutic agent inspiration window arranged in the device housing, and can also confirm the clarity of the therapeutic agent if necessary.
[0205] In step 408, the patient's skin injection site can be selected and prepared for delivery of the therapeutic agent. In step 410, the patient uses the usable automatic injection device to inject the therapeutic agent at the injection site. The steps generally involved within step 410 are described below with reference to figure 5. In step 412, after performing the injection, the usable automatic injection device can be removed from the patient and disposed of properly.
[0206] Figure 5 is a flow chart of an illustrative method 500 of using an illustrative automatic injection device to inject a therapeutically efficient amount of a therapeutic agent into a patient. Illustrative method 500 is a detailed representation of step 410 of figure 4. In step 502, the patient removes the protective film that covers and protects the adhesive layer of the usable automatic injection device. In some illustrative embodiments, removing the protective film also removes the needle cover and membrane cover on the syringe or cartridge stop.
[0207] In step 504, the patient applies the patient contact part of the automatic injection device usable with the adhesive layer at the injection site (or a garment around the injection site) so that the device is retained reliably at the injection site during injection of the therapeutically efficient dose of the therapeutic agent.
[0208] In step 506, once the automatic injection device is usable and attached to the injection site, the patient can press the injection button from a vertically raised position in the pre-injection state to a vertically lowered position in the injection status inside the housing. In the vertically elevated position, the end of the injection button supporting the injection needle is retracted into the housing and is not exposed to the outside of the housing. When pressed, the end of the injection button supporting the injection needle is moved downwards in a linear or rotating manner within the housing so that the injection needle emerges from an opening in the housing and is exposed. This allows the injection needle to penetrate the patient's skin at a depth suitable for injecting the therapeutic agent. The downward movement of the injection button in the housing can be linear (i.e., vertical downward movement) or rotary (i.e., in a circular motion around a hinge point).
[0209] In an illustrative embodiment, the injection button is pressed into the housing by the patient by pushing the injection button manually. In another illustrative embodiment, the patient can activate an injection trigger, for example, a trigger button located in a conventionally accessible location such as the top of the housing, which causes the injection trigger to automatically press the injection button. injection into the housing and in turn cause the injection needle to pierce the patient's skin. In an illustrative embodiment, the pressure of the injection trigger button can release a lock on the injection trigger which allows a spring to orient the injection button downwardly in the housing. The same movement of the injection button can cause the injection needle to be inserted into the injection site at an appropriate depth.
[0210] In step 508, pressing the injection button can trigger a syringe or cartridge trigger that moves the syringe or cartridge assembly, more specifically, the barrel part, forward into and with respect to the housing from a retracted position (in which the distal end of the syringe or cartridge assembly is spread out from the injection button) to an extended position (in which the distal end of the syringe or cartridge assembly is adjacent to and / or is in contact with the injection). In another illustrative embodiment, the syringe or cartridge trigger is activated not by pressing the injection button, but by the user activating a trigger, for example, in the form of a trigger button. In an illustrative embodiment, the movement of the syringe or cartridge assembly towards the injection button can cause the syringe needle to pierce the membrane.
[0211] In step 510, when the distal end of the barrel part makes contact with the injection button, the plunger driver can break the static friction (i.e., stiction) between the cap and the inner wall or walls of the part of the barrel and cause the cap to move forward towards the syringe needle at the injection button to deliver the therapeutic agent through the injection needle. The plunger driver can overcome the cap stiction in one step and activate the cap in a subsequent step, or the plunger driver can overcome the cap stiction and actuate the cap simultaneously. The movement of the stopper can cause the dose to be delivered through the syringe needle into the injection needle and thus into the patient's skin.
[0212] In an illustrative embodiment, the advance of the syringe or cartridge assembly inside the housing and the advance of the cap inside the barrel part can occur in separate steps. In another illustrative embodiment, the advance of the syringe or cartridge assembly within the housing and the advance of the cap within the barrel part can occur in the same step, for example, simultaneously.
[0213] The rate of delivery of therapeutic agent may depend on the characteristics of the plunger trigger. The plunger driver can take the form of several illustrative modalities. In some illustrative embodiments, the plunger driver may employ means for storing and releasing energy, for example, guiding mechanisms (including, but not limited to, one or more springs, for example, spiral springs or helical compression springs) , compressed gases, chemical gas generators (such as expanding foams), osmotic pressure, hydrogel expansion, etc. A damping or control mechanism (including, but not limited to, the viscous damper or an exhaust) can be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during the release of energy by the plunger driver. A flow restriction element located in a fluid path between the needle and the stopper can be used to further regulate the therapeutic agent delivery rate, for example, where the plunger driver delivers an unrestricted spring force across of a working fluid. In this way, the appropriate plunger driver and a suitable control mechanism can be selected to deliver the dose at a controlled rate, for example, in a single slow bolus that is free of or substantially free of any sensation of burning to the patient.
[0214] In an illustrative embodiment, the pressure of the injection button can arm the retraction mechanism which, when activated, retracts the injection button into the housing 102 after an injection in a post-injection state.
[0215] In step 512, after dispensing the therapeutically efficient dose, the plug and / or plunger trigger can trigger the retraction end-dose trigger of the retraction mechanism. The plug and / or plunger actuator may include a connecting element connected to the end-dose retraction trigger. The connecting element can include a mooring or other connection mechanism. The connecting element can be of suitable length so that when the cap has been moved to the end of the syringe or cartridge assembly (delivering a full dose), the connecting element activates a lock which, in turn, triggers the trigger of retraction.
[0216] In step 514, once the end of dose retraction trigger is activated, the retraction mechanism can retract the injection button up and into the housing and away from the patient contact part so the syringe or cartridge assembly to enter a post-injection state. In an illustrative embodiment, the movement of the injection button from the injection state to the post-injection state creates an audible sound, for example, a “click” that provides aural indication of the end of the delivery of the therapeutic agent. Once retracted, the injection button projects out of the housing, which provides a visual indication of the status of the usable automatic injection device, for example, the completion of the delivery of therapeutic agent, or a visual indication of the device in the post-injection state.
[0217] However, if the wearable device is removed from the patient's skin prior to the completion of the therapeutically efficient dose of the therapeutic agent, the skin sensor foot may extend out of the housing and trigger the premature removal retraction trigger of the retraction mechanism. Once the premature removal retraction trigger is activated, the retraction mechanism develops the injection button upward in the housing away from the patient contact part so that the syringe or cartridge assembly enters a welled state. -injection. In an illustrative embodiment, the plunger driver can continue to move forward in the barrel toward the syringe needle when the device is removed from the patient prior to completion of the delivery of a therapeutically efficient dose of the therapeutic agent.
[0218] In step 516, upon retraction, a needle lock engages the injection needle to prevent further development of the injection needle to provide needle stick protection. The needle lock can be an element that prevents the injection needle from leaving the housing once it is engaged, and can be located in the housing near the injection needle. Illustrative needle locks may include, but are not limited to, a plastic plate, a metal plate, a fastener, etc.
[0219] Figures 6a to 6c illustrate an illustrative embodiment of a usable automatic injection device 600 suitable for linear insertion of a needle into a patient's skin. By linear insertion, the end of a cartridge assembly supporting a needle descends linearly into a housing of the usable automatic injection device so that the needle is inserted into the patient. More specifically, figure 6a illustrates the illustrative wearable device in a pre-injection state, for example, as packaged; figure 6b illustrates the illustrative usable device in an injection state shortly before, during or after injecting a therapeutic agent into a patient; and Figure 6c illustrates the illustrative wearable device at a post-injection station after it has completely delivered the therapeutic agent to the patient or removed from the patient prior to completion of the delivery of the therapeutic agent.
[0220] The wearable automatic injection device 600 includes a housing 635 for housing a therapeutic agent cartridge assembly 610, containing a dose of a therapeutic agent to be injected subcutaneously into a patient. In an illustrative embodiment, the exterior of the therapeutic agent cartridge assembly 610 may be provided with one or more projections, and the interior of housing 635 may be provided with one or more grooves or channels that provide a smooth path to the projections of the assembly of cartridge 610 as the cartridge assembly moves within housing 635. The one or more projections on the outside of cartridge assembly 610 may take the form of raised lines on cartridge assembly 610. One or more grooves or channels within of the housing 635 may take the form of a pressed U or through the lines. The top of the grooves or channels can open so that the projections can slide in and out of the top of the grooves or channels. In the linear insertion mode illustrated in figures 6a to 6c, the projections and grooves / channels can be straight lines. In the rotating insertion mode illustrated in figures 7a to 7c, the projections and grooves / channels can be lines that are curved around the center of rotation, i.e., the pivot point of the cartridge assembly 610.
[0221] In another illustrative embodiment, the exterior of the cartridge assembly 610 may not have any protrusions, and the interior of housing 635 may not have any grooves or channels.
[0222] The housing 635 preferably has an elongated configuration, although those skilled in the art recognize that housing 635 can be of any size, shape and configuration suitable for housing a hypodermic needle coupled to a barrel part of a therapeutic agent to be injected . The housing 635 can be formed of any suitable material including, but not limited to, plastic and other known materials. In another embodiment, the therapeutic agent cartridge 610 can be formed from any compatible material suitable for sterilization including, but not limited to, glass and other known materials.
[0223] Housing 635 includes an adhesive layer 640 disposed along a patient contact portion of housing 635 which is located close to the patient's skin or a patient's garment. In some embodiments, adhesive layer 640 is configured to be placed on the patient's skin to secure housing 635 to the patient to deliver a therapeutic agent. The adhesive layer 640 includes a non-adhesive tab 645 that is not adhesive. The non-adhesive tab 645 can be grasped by the patient and pulled to remove the adhesive layer 640 and thus the usable automatic injection device 600 from the patient's skin or clothing.
[0224] Before the usable automatic injection device 600 is put to use, for example, in the pre-injection state, the adhesive layer 640 is covered with a protective film 650 that preserves the adhesive nature of the adhesive layer 640. The film protector 650 may include a tab 655 which can be grasped by the patient and pulled to remove protective film 650 from adhesive layer 640. This exposes adhesive layer 640, allowing the patient to attach housing 635 to his skin or clothing by placing on the side with the adhesive layer 640 on the skin or article of clothing.
[0225] In the illustrative modalities, the protective film 650 (in figure 6a) / 750 (in figure 7a) can include a connection element that is connected to the plunger driver 630 (in figure 6a) / 730 (in figure 7a). The connecting element may include a tie or other connection mechanism. When protective film 650 (in figure 6a) / 750 (in figure 7a) relieves the static friction between cap 615 (in figure 6a) / 715 (in figure 7a) and the inner wall of pipe 605 (in figure 6a) / 705 (in figure 7a), and drives the plunger driver 630 (in figure 6a) / 730 (in figure 7a).
[0226] Therapeutic agent cartridge assembly 610 may include a hollow barrel part 604 to maintain a therapeutically efficient dose of the therapeutic agent to be injected. The illustrative pipe part 605 is substantially cylindrical in shape, although those skilled in the art recognize that the pipe part 604 can have any suitable shape or configuration. A stopper 615 seals the dose of the therapeutic agent within the plunger part 605.
[0227] Therapeutic agent cartridge assembly 610 may also include a hollow hypodermic needle 625 connectable to or connected to and in fluid communication with the barrel part 605, through which the dose can be ejected by applying pressure to the cap 615 The needle 625 can be of any shape, size and configuration suitable for piercing the patient's skin to deliver the therapeutic agent subcutaneously and is not limited to the illustrative modality. Suitable needles can be configured or selected in length to provide an injection depth suitable for the desired therapy. Subcutaneous injections typically penetrate about six to ten millimeters into the skin. In an illustrative embodiment, the needle 625 can be about twelve mm long and can be injected to a depth of about seven mm into the skin. In other illustrative embodiments, needle 625 may be of suitable length for intradermal therapies, other subcutaneous therapies, or intramuscular. Suitable needles can have an adequate wall thickness to provide sufficient resistance to the mechanism, a suitable diameter to allow a desired flow rate of the injected substance while minimizing the sensation of the patient and a suitable tip geometry for the desired therapy while minimizing the feeling of a patient. Suitable needles can be coated as needed to minimize the patient's feeling as allowed by the therapy. Needle 625 can be covered and maintained in a septic condition by a soft, rigid needle shield assembly 620.
[0228] In the illustrative embodiment illustrated in Figures 6a to 6c, the needle 625 projects substantially at a right angle to the longitudinal geometric axis of the usable device 600. In this illustrative embodiment, the barrel part 605 includes an elbow 607 that extends substantial at a right angle to the longitudinal geometric axis of the device 600. In this embodiment, the needle 625 is connected to the elbow 607.
[0229] The wearable automatic injection device 600 may include a plunger actuator 630 to selectively drive the cap 615 forward towards the distal end of the therapeutic agent cartridge assembly 610 to inject the therapeutically efficient dose contained in the portion of pipe 605 on the patient. The plunger driver 630 may employ an energy store and controlled energy release mechanism to actuate the cap 615. In an illustrative embodiment, the plunger driver 630 may include a guiding mechanism, for example, a grinder, which is retracted prior to injection and which is released during injection to drive the cap 615 forward on the barrel part 605. In another illustrative embodiment, the plunger driver 630 may include a chemical gas generator, for example, an expansion foam, which it is an unexpanded phase prior to injection and which expands during injection to drive the cap 615 forward on the barrel part 605 towards the distal end of the therapeutic agent cartridge assembly 610. In other illustrative embodiments, the plunger driver 630 it can employ compressed gases, osmotic pressure, hydrogel expansion, etc. A damping mechanism can be used to absorb energy, for example, an initial release of energy, and to provide a controlled release of energy during the release of energy by plunger driver 630 (in figure 6a) / 730 (in figure 7a ). A flow restriction element located in a fluid path between the needle and the cap 615 (in figure 6a) / 715 (in figure 7a) can be used to further regulate the delivery rate of therapeutic agent, for example, where the plunger actuator 630 (in figure 6a) / 730 (in figure 7 a) distributes an unrestricted spring force.
[0230] In an illustrative embodiment, the plunger driver 630 can be advanced into the barrel part 605 in a constant linear motion. Any number of mechanisms, internal or external to the usable automatic injection device 600, can be used to provide constant linear motion including, but not limited to, a stepper motor connected to a gear drive system. Other illustrative mechanisms for providing a substantially constant linear motion in a controlled manner are described with reference to figures 24 to 45.
[0231] The cap 615 (in figure 6A) / 715 (in figure 7a) and / or the plunger driver 630 (in figure 6a) / 730 (in figure 7a) can include a connection element connected to the retraction trigger. The connecting element may include a harness or other connecting mechanism. The connecting element may be of suitable length so that when the cap 615 (in figure 6a) / 715 (in figure 7a) has been moved to the end of the cartridge assembly 610 (in figure 6a) / 710 (in figure 7a) (distributing a complete dose), the connecting element activates a lock which, in turn, activates the retraction trigger.
[0232] Referring now to figure 6c, in an illustrative embodiment, housing 635 includes a skin sensor part 660, which is a structure housed under or in part of housing 635 proximal to the injection site. prior to injection of the therapeutic agent and during injection, the skin sensor foot 660 is retained within or forms a part of the underside of housing 635. When the usable automatic injection device 600 is attached to the injection site and activated , the skin sensor foot 660 may be free to move, but may be restricted by the injection site. When the wearable automatic injection device 600 is removed from the injection site, regardless of whether the drug delivery has been completed, the skin sensor foot 660 is no longer restricted, and extends and protrudes out of the periphery of the housing 635. This, in turn, triggers the retraction retraction trigger.
[0233] Figure 6a illustrates the usable automatic injection device 600 in a pre-injection state, for example, as packaged and ready to use or as ready to pack. Device 600 may include a pre-filled syringe or cartridge assembly. In an illustrative embodiment, in a pre-injected state, the syringe or cartridge assembly may be in a retracted position ready for use. In the pre-injection state, the therapeutic agent cartridge assembly 610 is partially disposed within housing 635 at an elevated location distal from the injection site and needle 625 is retracted within housing 635. Visual indications for the patient that the usable automatic injection device 600 projecting out of housing 635 in the pre-injection state. The barrel part 605 contains a dose of a therapeutic agent that is contained by the internal space defined between the wall or walls of the barrel part 605 and the plug 615. In one embodiment, the plunger driver 630 stores energy.
[0234] Figure 6b illustrates a usable automatic injection device 600 in an injection state ready to inject, injecting or just after injecting a therapeutically efficient dose of a therapeutic agent, where the therapeutic agent cartridge set 610 is in a pressed position. In the pressed position, the therapeutic agent cartridge assembly 610 is disposed within housing 635 in a pressed location near the injection site and needle 625 projects out of housing 635 through an opening in housing 635 so that it can penetrate the skin at the injection site. In the injection state, the therapeutic agent cartridge assembly 610 does not protrude out of housing 635 to provide a visual indication to the patient that the usable automatic injection device 600 is in operation. The plunger driver 630 releases its stored energy to activate the plug 615. This cooperative movement of the plunger driver 630 and the cap 615 ejects the therapeutic agent into the barrel part 605 through the needle 625.
[0235] Figure 6c illustrates the usable automatic injection device 600 in a post-injection state, for example, after the injection of a therapeutically efficient dose of the therapeutic agent or removal of the patient's usable automatic injection device 600 prior to delivery of a therapeutically effective dose of the therapeutic agent, where the therapeutic agent cartridge assembly 610 is in a retracted position. In the retracted position, the therapeutic agent cartridge assembly 610 is disposed within housing 635 at an elevated distal location with respect to the injection site, and needle 625 is retracted within housing 635. A part of the therapeutic agent cartridge assembly 610 projects out of housing 635 to provide a visual indication to the patient that the wearable automatic injection device assembly 600 is not in operation (i.e., in a post-injection state). The barrel part 605 may not confer any therapeutics agent, and the plunger driver 630 may have no more stored energy.
[0236] Housing 635 includes a retraction mechanism that automatically raises the therapeutic agent cartridge assembly 610 from the injection state (pressed position shown in figure 6b) to the post-injection state (retracted position shown in figure 6c ). In an illustrative embodiment, the retractor mechanism may include a guide mechanism, for example, a spring, which guides the cartridge assembly away from the injection site when the retractor mechanism is operated.
[0237] The retraction mechanism includes an end of dose retraction trigger that, when activated, activates the retraction mechanism. The end-dose retraction trigger is triggered when the therapeutically efficient dose of the therapeutic agent in the usable automatic injection device is dispensed. In an illustrative embodiment, the end-dose retraction trigger may include a lock, for example, a flexible plastic hook, which is released upon completion of drug delivery. The retraction mechanism also includes a premature removal retraction trigger which, when activated, activates the retraction mechanism. The premature withdrawal trigger is triggered when the usable automatic injection device is removed from the injection site before the therapeutically efficient dose of the therapeutic agent is fully delivered. In an illustrative embodiment, the premature removal retraction trigger may include a lock, for example, a flexible plastic hook which is sealed by removing the usable automatic injection device 600 from the injection site. The retraction mechanism responds to the end of dose retraction trigger and responds to the premature removal retraction trigger to automatically retract the cartridge assembly from the injection site.
[0238] Figures 7a to 7c illustrate an illustrative embodiment of a usable automatic injection device 700 suitable for rotating needle insertion into the patient's skin. In rotating insertion, the end of a therapeutic agent cartridge assembly 710 supporting the needle 725 rotates downwardly around a pivot point to insert the needle 725 into the patient's skin. More specifically, figure 7a illustrates the illustrative wearable device in a pre-injection state, for example, as packaged with a pre-filled and curved sterile hypodermic needle and barrel part holding a therapeutic agent; figure 7b illustrates the illustrative wearable device while in an injection state shortly before, during or after another injection of a therapeutic entity into a patient; and figure 7c illustrates the illustrative wearable device in a post-injection state after delivery of the therapeutic agent to the patient or removal of the wearable device from the patient prior to complete delivery of the therapeutic agent to the patient.
[0239] The therapeutic agent cartridge assembly 710 is rotatably movable within housing 735 around a hinge point 765 in the housing. In an illustrative embodiment, the exterior of the therapeutic agent cartridge assembly 710 may be provided with one or more projections, and the interior of accommodation 735 may be provided with one or more grooves or channels that provide a path to the projections of the cartridge 710 as the cartridge moves within housing 735 between the various states. In another illustrative embodiment, the exterior of the cartridge assembly 710 is free from protrusions, and the interior of the housing 735 is free from grooves or channels.
[0240] When the therapeutic agent cartridge assembly 710 is pressed into housing 735, the therapeutic agent cartridge assembly 710 rotates downwardly around hinge point 765 so that needle 725 becomes exposed and penetrates on the patient's skin. In this illustrative embodiment, the needle 725 penetrates the patient's skin at a 90 ° offset angle. Similarly, when the therapeutic agent cartridge assembly 710 and backrest, the therapeutic agent cartridge assembly 710 rotates upwardly around hinge point 765 so that needle 725 retracts into housing 735. 0 The mechanism for implementing this rotary movement of the therapeutic agent cartridge assembly 710 may be simpler and more robust than the mechanism necessary for the linear insertion of figures 6a to 6c.
[0241] Needle 725 is curved, with a radius defined by hinge point 765 and the distance from needle 715 to hinge point 765 along the longitudinal geometric axis of housing 735. The curvature of needle 725 increases patient comfort during needle insertion. The needle 725 can preferably be oriented with the sharp tip of the needle closer to the pivot point 765.
[0242] The characteristics of figures 7a to 7c similar to those illustrated in figures 6a to 6c are described above with reference to figures 6a to 6c.
[0243] In the illustrative embodiments, the therapeutical agent cartridge set 610 and 720 of figures 6a to 6c and 7a to 7c, respectively, can be pre-filled with any volume of a therapeutic agent, for example, a therapeutic antibody , desired for intradermal, subcutaneous or intramuscular injections. In an illustrative embodiment, the cartridge assembly 610 and 720 can be pre-filled with a volume of about 0.8 to 0.85 millimeter, although the illustrative cartridge assemblies are not limited to these illustrative volumes. In another illustrative embodiment, the cartridge assembly 610 and 720 can be pre-filled with a volume of about 1 millimeter or more.
[0244] In the illustrative embodiments, the usable automatic injection device 600 (in figure 6a) / 700 (in figure 7a) can be used to inject the therapeutically efficient amount of the therapeutic agent over a period of time ranging from about ten seconds to about twelve hours. In an illustrative embodiment, the therapeutic agent can be delivered at a fixed rate for a delivery time of between about five minutes and about thirty minutes. The usable automatic injection dis-positive 600 (in figure 6a) / 700 (in figure 7a) can be used to inject a volume of therapeutic agent into a single slow bolus.
[0245] The rate of distribution of the therapeutic agent may depend on the ambient temperature. At room temperature, that is, about 22.22 ° C, the accuracy of the dispensing time can vary between about 3% and about 10%.
[0246] Figure 8 is a flow chart of an illustrative method 800 for assembling an illustrative usable automatic injection device 600 or 700. In step 805, the barrel part 605/705, the needle 625/725 and the needle guard 620/720 are sterilized. In step 810, the barrel part 605/705 is filled with a dose of therapeutic agent that must be administered to the patient. In step 815, a sterile plug 615/715 is placed on the barrel part 605/705 to seal the therapeutic agent within the barrel part 605/705. The restriction of the therapeutic agent within the usable automatic injection device 600 or 700 by the part of sterile pipe 605/705, the sterile plug 615/715 and the needle protection 620/720 maintain the sterility of the therapeutic people and the needle 625/725 . As such, the remaining components of the usable automatic injection device can be mounted in a non-sterile environment after the 605/705 pipe part is pre-filled with a therapeutic staff. For example, in step 820, a non-sterile plunger driver 630/730 is inserted behind the cap 616/715 in the therapeutics cartridge assembly 610/710.
[0247] In step 825, the therapeutic agent cartridge set 610/710 is inserted into a non-sterile housing 635/735. The housing 635/735 can be pre-filled with other non-sterile components, for example, the adhesive layer 640/740, the protective film 650/750, the foot of the skin sensor 660/760. In the illustrative modalities, the barrel part 605/705, the needle 625/725, the needle guard 620/720 and the cap 615/715 of the therapeutic agent cartridge set 610/710 provide sterility protection for the therapeutic agent and subcutaneous contact surfaces. Thus, once the barrel part 605/705 is filled with a therapeutic agent, the plunger 615/715 is inserted into the barrel part 605/705 and the needle shield 620/720 is in place: the assembly of the parts remainders of the 610/710 therapeutic agent cartridge assembly and mounting of the 635/735 housing do not require aseptic conditions. No transfer of therapeutic agent needs to be performed by the user. Figures 6a and 7a illustrate illustrative modalities of the mounted automatic injection device usable 600/700 in a pre-injection state.
[0248] In step 830, the 600/700 mounted usable automatic injection device can be located in an external wrap, if necessary, and is then commercially packaged for sale.
[0249] Figure 9 is a flow chart of an illustrative method 900 of using an illustrative usable automatic injection device 600 or 700. The usable automatic injection device 600/700 packaged and pre-filled with a therapeutic agent and generally stored in the refrigerated storage before use. In step 905, the usable automatic injection device is packaged 600/700 and removed from the store. In step 910, the usable automatic injection device 600/700 is removed from its package and any external wrapping and heated to room temperature, for example, by leaving the usable device out of the package at room temperature or by heating the usable device. In step 915, the patient confirms that the therapeutic agent cartridge set 610/710 includes a volume of therapeutic agent in the usable device 600/700 through a therapeutic agent inspiration window arranged in the usable device housing and can also confirm the clarity of the therapeutic agent, if necessary. In step 720, the injection site into the patient's skin is selected and prepared for delivery of the therapeutic agent. In step 925, the patient uses the 600/700 usable automatic injection device to inject the therapeutic agent into the injection site. The steps generally involved in step 920 are described below with reference to figure 10, In step 930, after the 600/700 usable automatic injection device is removed from the patient, the usable automatic injection device 600/700 is removed and disposed of proper.
[0250] Figure 10 is a flow chart of an illustrative method 1000 of using an illustrative 600 or 700 usable automatic injection device to inject a therapeutically efficient amount of a therapeutic person into a patient. Illustrative method 1000 is a detailed representation of step 920 in figure 9. In step 1005, the patient removes protective film 650/750 that covers and protects adhesive layer 640/740 from the usable automatic injection device 600/700. In some illustrative embodiments, removing protective film 650/750 also removes needle protection 620/720 and exposes needle 625/725 for injection. In some illustrative embodiments, removing protective film 650/750 also breaks the static friction (i.e., stiction) between the cap 615/715 and the inner wall of the barrel 605/705 and drives the plunger driver 630/730. In the illustrative embodiments, the protective film 650/750 may include a connecting element which is connected to the plunger driver 630/730. The connecting element may include a tie or other connection mechanism. When the protective film 650/750 is removed, the connecting element of the protective film 650/750 relieves the static friction between the cap 615/715 and the inner wall of the barrel 605/705 and drives the plunger driver 630/730.
[0251] In step 1010, the patient applies the patient contact part of the usable automatic injection device 600/700 with the adhesive layer 640/740 to the injection site (or a garment around the injection site) of so that the usable device is reliably retained at the injection site during the injection of the therapeutically efficient dose of the therapeutic agent.
[0252] In step 1015, once the usable automatic injection device 600/700 is attached to the injection site, the 610/710 therapeutic agent cartridge assembly is pressed from a ready position in the pre-injection state to a pressed position in the injection state within housing 635/735. In the ready position, the end of the therapeutic agent cartridge assembly 610/710 supporting the needle 625/725 is retracted into the housing 635/735 and is not exposed to the outside of the housing. When pressed, the end of the therapeutic agent cartridge assembly 610/710 supporting the needle 625/725 and moved down in a linear or rotating manner within the housing 635/735 so that the needle 625/725 emerges from an opening in the housing 635/735 and be exposed. This allows the 625/725 needle to penetrate the patient's skin at a depth suitable for injecting the therapeutic agent. The downward movement of the therapeutic agent cartridge assembly 610/710 in the housing 635/735 can be linear (i.e., vertical downward movement) or rotary (i.e., in a circular motion around a hinge point). Figures 6b and 7b illustrate illustrative modalities of the usable automatic injection device 600 and 700 in an injection state with the therapeutic agent cartridge 610/710 pressed into housing 635/735 after step 1015 is performed.
[0253] In an illustrative embodiment, the 610/710 therapeutic agent cartridge assembly is pressed into the 635/735 housing by the patient manually pushing down the 610/710 therapeutic agent cartridge assembly. In another illustrative embodiment, the patient can activate an insertion trigger, for example, an insertion trigger button located in a conveniently accessible location such as the top of housing 635/735, which causes an insertion trigger to automatically press the therapeutic agent cartridge assembly 610/710 into housing 635/735 and, in turn, cause the 625/725 needle to pierce the patient's skin. In an illustrative embodiment, the pressure of the trigger trigger button may release a lock on the trigger trigger that allows a spring to orient the cartridge assembly 610/710 downwardly in housing 635/735. The same movement of the 610/710 cartridge assembly can cause the 625/725 needle to be inserted into the injection site at an appropriate depth.
[0254] In an illustrative embodiment, pressing the therapeutic agent cartridge assembly 610/710 activates the plunger driver 630/730 to initiate the movement of the cap 615/715 to cooperatively inject the therapeutically efficient dose on the patient. Pressing the therapeutic agent cartridge assembly 610/710 causes the plunger driver 630/730 to break the static friction (i.e., stiction) between the cap 615/715 to move forward towards the needle 625/725 in the therapeutic agent cartridge assembly 610/710 to deliver the therapeutic agent through needle 625/725. The 630/730 piston driver can overcome the cap stiction in one step and activate the cap in a subsequent step, or the 630/730 piston driver can overcome the cap stiction and activate the cap simultaneously. In another illustrative embodiment, the 630/730 piston actuator is activated not by pressing the therapeutic agent cartridge, but by the user activating an injection trigger, for example, in the form of an injection trigger button.
[0255] The rate of delivery of therapeutic agent may depend on the characteristics of the 630/730 plunger driver. The plunger driver 630/730 can take the form of several illustrative modalities. In some illustrative embodiments, the plunger driver 630/730 may employ means for storing and releasing energy, for example, guiding mechanisms (such as springs), compressed gases, chemical gas generators (such as foams in expansion), osmotic pressure, hydrogel expansion, etc. A damping mechanism can be used to absorb energy, for example, an initial release of energy, and to provide a more controlled release of energy during the release of energy by the plunger driver 630/730. A flow restriction element located in a fluid path between the needle and the cap 615/715 can be used to further regulate the rate of delivery of therapeutic agent, for example, where the plunger driver 630/730 distributes a force unrestricted spring. In this way, a suitable 630/730 plunger driver and a suitable flow restriction element can be selected to distribute the dose at a controlled rate, for example, in a single slow bolus free of or substantially free of any sensation of what image for the patient.
[0256] In an illustrative embodiment, pressing the 610/710 therapeutic agent cartridge assembly also arms the retraction mechanism which, when triggered, retracts the 610/710 therapeutic agent cartridge assembly into housing 635 / 735.
[0257] In step 1020, the 610/710 therapeutic agent cartridge assembly is retracted from the pressed position to a retracted position in a posinjection state so that it protrudes out of housing 635/735 and the needle 625/725 is retracted into housing 635/735 or protected by the skin sensor foot 660/760 or both. Figures 6c and 7c illustrate the illustrative modalities of the automatic injection device 600 and 700, respectively, in a retracted position after step 1020. Step 1020 is performed when the therapeutically efficient dose of the therapeutic agent is delivered or when the device usable 600/700 injection is removed from the injection site before the therapeutically efficient dose is fully dispensed.
[0258] After the therapeutically efficient dose delivery, the stopper 615/715 and / or the plunger driver 630/730 activates the end-dose retraction trigger of the retraction mechanism. The cap 615/715 and / or the plunger driver 630/730 may include a connection element connected to the retraction trigger. The connecting element may include a tie or other connection mechanism. The connecting element can be of suitable length so that when the cap 615/715 has been moved to the end of the cartridge assembly 610/710 (dispensing a full dose), the connecting element triggers a lock which in turn activates the retraction trigger.
[0259] Once the end of dose retraction trigger is triggered, the retraction mechanism develops the therapeutic agent cartridge set 610/710 upward into housing 635/735 and away from the contact part the patient so that the 610/710 therapeutic agent cartridge assembly enters a post-injection state. In an illustrative embodiment, the movement of the therapeutic agent cartridge set 610/710 from the injection state to the post-injection state creates an audible sound, for example, a “click” that provides an auditory indication of the completion of the injection. delivery of the therapeutic agent. Once retracted, the 610/710 therapeutic agent cartridge assembly protrudes out of housing 635/735 (as shown in figures 6c and 7c), which provides a visual indication of the status of the usable automatic injection device 600/700, for example, completion of the delivery of therapeutic agent or a visual indication of the device in the post-injection state.
[0260] However, if the 600/700 wearable device is removed from the patient's skin prior to completion of the therapeutically efficient dose of the therapeutic agent, the skin sensor foot 660/760 extends out of housing 635/735 and activates the premature removal retraction trigger of the retraction mechanism. Once the premature removal retraction trigger is activated, the retraction mechanism develops the therapeutic agent cartridge assembly 610/710 upward in the housing 635/735 away from the patient contact part so that the therapeutic agent cartridge 610/710 is returned to a retracted position. In an illustrative embodiment, the plunger driver 630/730 can continue to move forward on the therapeutic agent cartridge 610/710 towards needle 625/725 when the usable device 600/700 is removed from the patient before the delivery of the a therapeutically efficient dose of the therapeutic agent.
[0261] In step 1025, upon retraction, an automatic needle lock engages the injection needle 625/725 to prevent further development of the 625/725 needle to provide needle prick protection. The needle lock can be an element that prevents needle 625/725 from leaving housing 635/735 once engaged, and can be located in housing 635/735 near needle 625/725. Illustrative needle locks may include, but are not limited to, a plastic plate, a metal plate, a fastener, etc. III. Illustrative Needle Systems
[0262] Illustrative modalities provide different sets of illusive needles for injecting a dose of a therapeutic person into a patient's skin. In some illustrative embodiments, an injection needle, coupled to a barrel part of an illustrative automatic injection device containing the dose, can be inserted into the patient's skin to inject the dose into the patient's skin. In other illustrative embodiments, a syringe needle can be attached to a barrel part containing the dose to drive the dose out of the barrel part, and an injection needle attached to the syringe needle can be inserted into the patient's skin to inject the dose on the patient's skin. ~
[0263] In some illustrative embodiments, as illustrated in figures 11 and 12, a syringe can include a barrel part and an injection needle coupled to a distal end of the barrel part. The injection needle can be inserted into the patient's skin to deliver a therapeutic agent contained in the barrel part of the syringe. The injection needle can be aligned at any suitable angle with respect to the longitudinal geometric axis of the barrel part ranging from 0 degrees to about 180 degrees.
[0264] Figure 11 illustrates an illustrative syringe 1100 suitable for use in an illustrative automatic injection device. Syringe 1100 includes a barrel part 1102 configured to hold a dose of a therapeutic agent and extending between a proximal end and a distal end along a longitudinal geometric axis L. A distal end of the barrel part 1102 is coupled to a needle injection nozzle 1104 that extends along the longitudinal geometric axis L.
[0265] Figure 12 illustrates an illustrative syringe 1200 suitable for use in an illustrative automatic injection device. Syringe 1200 includes a barrel part 1202 configured to hold a dose of a therapeutic person and extending between a proximal end and a distal end along a geometric axis L. A distal end of the barrel part 1202 can include a portion of elbow 1204 extending substantially 90 degrees from the longitudinal geometric axis L. A distal end of the elbow part 1204 is coupled to an injection needle 1206 extending substantially 90 degrees from the longitudinal geometric axis L. One of Those skilled in the art will recognize that the illustrative automatic injection devices may include an injection needle that extends along the longitudinal geometric axis L of the syringe or that extends at any suitable angle with respect to the longitudinal geometric axis L of the syringe. Illustrative angles may include, but are not limited to, about 70 degrees to about 110 degrees.
[0266] In some illustrative embodiments, as illustrated in figures 13 and 14, a syringe can include a barrel part and an injection needle coupled to a distal end of the barrel part. The injection needle can be inserted into a patient's skin to deliver a therapeutic agent contained in the barrel part of the syringe. The injection needle can be aligned at any suitable angle with respect to the longitudinal geometric axis of the barrel part ranging from about 0 degree to about 180 degrees.
[0267] In some illustrative embodiments, as illustrated in figures 13 and 14, a syringe can include a barrel part and an injection needle coupled directly or indirectly to a distal end of the barrel part. The se-ring needle can carry a therapeutic agent contained in the barrel part of the syringe for the injection needle, and the injection needle can deliver the therapeutic agent into the patient's skin. A coupling between the syringe needle and the injection needle can be provided by one or more intermediate components. An illustrative coupling component may include, for example, an adapter, provided between the distal end, the barrel part and the injection needle.
[0268] Figure 13 illustrates an illustrative syringe 1300 suitable for use in an illustrative automatic injection device. Syringe 1300 includes a barrel part 1302 configured to extend from a proximal end to a distal end along a longitudinal geometric axis L and configured to maintain a dose of a therapeutic agent. A distal end of the barrel part 1302 is coupled to a hollow syringe needle 1304. Syringe needle 1304 is, in turn, coupled to a hypodermic injection needle 1306 via an illustrative intermediate adapter 1308. More specifically, a part proximal to adapter 1308 and syringe needle 1304 is attached and a distal part of adapter 1308 is attached to injection needle 1306. Adapter 1308 can establish a substantially 90 degree alignment between the longitudinal geometric axis L of the barrel part 1302 and the hypodermic injection needle 1306.
[0269] The illustrative adapter 1308 is a component including a first part 1310 extending from the barrel part 1302 substantially in parallel with the longitudinal geometric axis L, and a second part 1312 extending from the first part 1310 substantially perpendicular to the longitudinal geometric axis L. More specifically, a proximal end of the first part 1310 and coupled to a distal end of the barrel part 1302. In an illustrative embodiment, the proximal end of the first part 1310 can en-voiver the end distal of the barrel part 1302. A distal end of the first part 1310 is coupled to a proximal end of the second part 1312. A distal end of the second part 1312 is coupled to a proximal end of the injection needle 1306. In an illustrative embodiment, the the first part 1310 and the second part 1312 of the adapter 1308 can be integrally formed.
[0270] Illustrative adapters may be formed from a rigid material including, but not limited to, plastic materials, augers and the like. Illustrative adapters may alternatively be formed of a flexible material including, but not limited to, rubber and the like.
[0271] The configuration of the adapter 1308 coupled to the injection needle 1306 allows the injection needle 1306 to extend around 90 degrees with respect to the longitudinal geometric axis L of the syringe. This configuration simplifies the manufacture of the usable automatic injection device as it eliminates the need to have a bent injection needle. The illustrative injection needle 1306 maintains a low profile against the patient while allowing adequate insertion into the patient's skin during an injection in an injection state. Those skilled in the art will recognize that the illustrative injection needles can be bent from the longitudinal geometric axis of the syringe at any suitable angle not limited to about 90 degrees, for example, about 70 degrees to about 110 degrees.
[0272] In some illustrative embodiments, one or more fluid conduits can be arranged between the syringe needle and the injection needle to allow a flow of therapeutic agent from the barrel part to the injection needle through the syringe needle. Any suitable fluid conduit or fluid transfer mechanism can be used to establish one or more fluid conduits between the syringe needle and the injection needle. In an illustrative embodiment, a pierceable membrane in an intact state can separate the syringe needle from fluid communication with the injection needle. When the syringe needle pierces the membrane during an injection in an injection state, fluid communication can be established between the syringe needle and the injection needle through the fluid conduit.
[0273] Figure 14 illustrates a part of an illustrative automatic injection device in which a fluid conduit couples a syringe needle and an injection needle. The device includes a syringe or cartridge assembly having a barrel part 1400 holding a dose of a therapeutic agent. A distal end of the barrel part 1400 is coupled to a syringe needle 1402. A transfer mechanism 1404 is provided in contact with or in the vicinity of syringe needle 1402, and also in contact with or in the vicinity of a syringe needle. injection (not shown). The transfer mechanism 1404 includes a fluid conduit or passageway 1406 that establishes fluid communication between the syringe needle 1402 and the injection needle.
[0274] In an illustrative embodiment, transfer mechanism 1404 includes a pierceable membrane 1408 that separates syringe needle 1402 from fluid conduit 1406 in transfer mechanism 1404 prior to an injection in a pre-injection state. In an illustrative embodiment, during an injection in an injection state, the syringe or cartridge can be moved towards the transfer mechanism 1404 so that the syringe needle 1402 punctures the membrane 1408 to create a communication path through fluid between the pipe part 1400, the fluid conduit 1406 of the transfer mechanism 1404, and the injection needle. The therapeutic agent can thus flow out of the barrel part 1400 through syringe needle 1402 into fluid conduit 1406. The therapeutic agent can then be transmitted through fluid conduit 1406 into the injection needle to delivery of the therapeutic agent to a patient.
[0275] Figure 15 illustrates an illustrative transfer mechanism 1500 for supplying a fluid conduit 1502 between a syringe needle (not shown) and an injection needle (not shown). Fluid conduit 1502 may include a central extension channel 1504 through which therapeutic personnel flow from the syringe needle to the injection needle, and raised wall parts 1506 extending along the edges of channel 1504 through restrict the fluid to channel 1504. The fluid conduit 1502 can assume any suitable shape and dimension. In the illustrative embodiment, the fluid conduit 1502 has a first substantially straight portion 1508 aligned about 90 degrees from a second substantially straight portion 1510.
[0276] Fluid conduit 1502 may include a fluid inlet 1512 for the therapeutic agent inlet from the syringe needle and a fluid outlet 1514 for the therapeutic agent outlet into the injection needle. Fluid inlet 1512 can be coupled directly or indirectly to the proximal end of a syringe needle. In an illustrative embodiment, a pierceable membrane (not shown) can be provided at fluid inlet 1512 to prevent fluid flow from the syringe needle when the membrane is intact, and to allow fluid flow from the syringe needle when the membrane and punctured by the syringe needle. Fluid outlet 1514 can be coupled directly or indirectly to the distal end of the injection needle in order to establish a fluid flow path between the fluid conduit 1502 and the injection needle.
[0277] Alternatively, 1512 can be used as the fluid outlet and 1514 can be used as the fluid inlet. In this illustrative embodiment, fluid inlet 1514 can be coupled directly or indirectly to a syringe needle, and fluid outlet 1512 can be coupled directly or indirectly to an injection needle.
[0278] The transfer mechanism 1500 can be formed of two housing parts 1516 and 1518 stacked together. In an illustrative embodiment, fluid conduit 1502 can be formed on the surface of part 1516, and part 1518 can be stacked on fluid conduit 1502 in order to seal the edges of fluid assembly 1502 in order to prevent leakage of fluid from the fluid conduit. The compression between the two housing parts 1516 and 1518 can be provided by one or more mechanical interlocking mechanisms, for example, one or more fasteners, pressure fittings, chemical connection, ultrasonic welding, and the like.
[0279] The fluid conduit 1502 can be formed on the surface of the housing part 1516 using any suitable technology. In an illustrative embodiment, the raised wall portions 1506 of the fluid conduit 1502 can be formed of a low durometer material shaped like a gasket to seal the flow path of the therapeutic agent. In another illustrative embodiment, laser welding can be used to down a path around the perimeter of channel 1504 in order to simultaneously create a fence around channel 1504 and join the two housing parts 1516 and 1518.
[0280] Figure 16 illustrates an illustrative transfer mechanism 1600 for providing a fluid conduit 1602 between a syringe with a syringe needle 1604 coupled to a barrel part 1606 and an injection needle (not shown). The transfer mechanism 1600 may include a first part 1608 having a membrane 1610 provided in the vicinity of syringe needle 1604.
[0281] The first part 1608 of the transfer mechanism 1600 can include an internal hollow space to accommodate the therapeutic agent and an inlet port 1612 coupled to one end of a hollow tube 1614. The other end of hollow tube 1614 is coupled directly or indirectly (for example, through a second part similar to the first part 1608) the injection needle. Hollow tube 1614 provides a fluid path from syringe needle 1604 to the injection needle. The hollow tube 1614 can assume any suitable shape, alignment and dimension. In the illustrative embodiment, the hollow tube 1614 extends substantially at right angles to the longitudinal geometric axis of the pipe part 1606.
[0282] In an illustrative embodiment, the transfer mechanism 1600 can be movable up and / or down along the vertical geometric axis. In this embodiment, before an injection in a pre-injection state (for example, when a syringe needle is covered by a needle cover), the transfer mechanism 1600 can be in a vertically elevated position with the 1610 membrane in the transfer mechanism 1600, thus preventing the communication of fluid between the syringe needle 1604 and the transfer mechanism 1600. At the beginning of an injection (for example, by removing the syringe cover from the syringe needle 1604 ), the transfer mechanism 1600 can be lowered automatically to a vertically lowered position so that the syringe needle 1604 becomes aligned with the membrane 1610 in the transfer mechanism 1600, thus allowing the syringe needle 1604 to pierce the membrane 1610. The illustrative modalities can provide any drive mechanism suitable for lowering the transfer mechanism 1600 from the vertically elevated position to the vertical position down at the start of an injection.
[0283] In an illustrative embodiment, the syringe needle 1604 can be initially coupled to or supplied immediately adjacent to the first part 1608. In another embodiment, the syringe can be in a retracted position within the usable automatic injection device and the needle syringe 1604 can be initially separated from the first part 1608 of the transfer mechanism 1600. In this embodiment, before an injection in a pre-injection state, the syringe needle 1604 can be separated from the membrane 1610 in the first part 1608 and may not be in fluid communication with the transfer mechanism 1600. At the beginning of an injection, the syringe can be moved forward by a cartridge driver or syringe to an extended position within the device, and the syringe needle 1604 can puncture the membrane 1610, allowing the therapeutic agent to flow from the barrel part 1606 to the transfer mechanism 1600. The illustrative modalities can provide any mechanism cartridge or syringe drive suitable for advancing the barrel part and / or the cartridge assembly within the housing between the retracted position and the extended position in order to pierce the membrane and transport the therapeutic agent to the patient's skin through the injection needle.
[0284] An advantage of the illustrative transfer mechanism 1600 is that the movements of the syringe needle 1604 and the injection needle are decoupled and independent of each other. For example, the mechanism coupling the syringe needle 1604 to the inlet port 1612 need not take into account how this coupling affects the output of the transfer mechanism 1600 coupled to the injection needle.
[0285] Figure 17 illustrates an illustrative transfer mechanism 1700 for supplying a fluid conduit between a syringe having a syringe needle 1704 coupled to a barrel part 1706 and an injection needle (not shown) . The transfer mechanism 1700 may include an input part (not shown) coupled to the syringe needle 1704 and an output part (not pre-seated) attachable to the injection needle. A hollow tube 1708, for example, a jumper tube, can be used to couple the input part of the transfer mechanism to the output part of the transfer mechanism. Hollow tube 1708 provides a fluid path from syringe needle 1704 to the injection needle. The hollow tube 1708 can take any shape, alignment and dimension. In the illustrative embodiment, the hollow tube 1708 extends substantially at right angles with respect to the longitudinal geometric axis of the pipe part 1706.
[0286] In an illustrative embodiment, the inlet part of the transfer mechanism 1700 may include a membrane (not shown) provided in the vicinity of syringe needle 1704. Perforation of the membrane by syringe needle 1704 can establish fluid communication between the barrel part 1706 and the transfer mechanism 1700. In an illustrative embodiment, the outlet part of the transfer mechanism may include a membrane (not shown) provided in the vicinity of the injection needle. Perforation of the membrane by the injection needle can establish fluid communication between the 1700 transfer mechanism and the patient's skin.
[0287] In an illustrative embodiment, the 1700 transfer mechanism can be moved up and / or down along the vertical geometric axis. In this embodiment, prior to an injection in a pre-injection state (for example, when the syringe needle is covered by a needle cover), the transfer mechanism 1700 may be in a vertically elevated position above the syringe needle 1704 so that the syringe needle 1704 is not aligned with the membrane in the transfer mechanism 1700, thereby preventing fluid communication between the syringe needle 1704 and the transfer mechanism 700. At the beginning of an injection (for example, example, by removing the syringe cover from syringe needle 1704), the transfer mechanism 1700 can be automatically lowered to a vertically lowered position so that syringe needle 1704 becomes aligned with the membrane in the transfer mechanism 1700, thus allowing syringe needle 1704 to pierce the membrane. The illustrative embodiments can provide any drive mechanism suitable for lowering the transfer mechanism 1700 from the vertically raised position to the vertically lowered position at the beginning of an injection.
[0288] In an illustrative embodiment, the syringe needle 1704 can be initially attached to or supplied immediately adjacent to the first part 1708. In another embodiment, the syringe can be in a retractable position within the usable automatic injection device and the needle syringe 1704 can be initially separated from the 1700 transfer mechanism. In this embodiment, before an injection in a pre-injection state, syringe needle 1704 can be separated from the membrane and may not be in fluid communication with the transfer mechanism 1700. At the beginning of an injection, the syringe can be moved forward by a cartridge or syringe driver to an extended position within the device, and syringe needle 1704 can pierce the membrane, allowing the agent therapeutics flow from the barrel part 1706 to the 1700 transfer mechanism. The illustrative modalities can provide any suitable cartridge or syringe drive mechanism It is suitable for advancing the barrel part and / or cartridge assembly within the housing between the retracted position and the extended position in order to pierce the membrane and transport the therapeutic agent to the patient's skin through the injection needle.
[0289] In the illustrative modalities illustrated in 15 to 17, an impermeable and reliable fluid path transports to the therapeutic people the barrel part of a syringe or cartridge through a perforated membrane and a tube or channel in a transfer mechanism and, eventually , into an injection needle. This configuration allows the syringe needle assembly and the injection needle assembly to move independently of each other, which facilitates the retraction of the injection needle into the housing in a post-injection state after an injection has been performed. , while leaving the injection needle in a position in which it punctures the membrane.
[0290] Figures 18a and 18b illustrate an illustrative usable automatic injection device including a syringe and an illustrative transfer mechanism. Figure 18a illustrates a perspective view of the device. Figure 18b shows a disassembled view illustrating the components of the device. The automatic injection device 1800 includes a housing part 1802 that includes an adhesive layer 1804 in a patient contact region that can be removed to secure the device to the patient's body or clothing.
[0291] The housing part 1802 holds a syringe 1806 stationary or mobile in device 1800. Syringe 1806 maintains a dose of a therapeutic agent and is coupled to a syringe needle 1808 at its distal end. The syringe needle 1808 can extend substantially along the longitudinal geometry axis of syringe 1806. In a pre-injected state, syringe needle 1808 can be covered by a syringe needle cover 1805, which can be removed by a patient before an injection. In an injection state, the 1808 syringe needle can be discovered. In an illustrative modality, removing the adhesive layer 1804 can also remove the syringe needle cover 1805.
[0292] An 1810 injection button is provided in the vicinity of the 1808 syringe needle. The 1810 injection button includes maintaining an 1812 injection needle at substantially 90 ° with respect to the 1808 syringe needle, and includes a transfer mechanism. which provides a fluid conduit between the 1808 syringe needle and the 1812 injection needle. In a pre-injection packaged state, the 1812 injection needle can be covered by an 1813 injection needle cover, which can be removed by a patient before an injection. In an injection state, the 1812 injection needle can be discovered. In one embodiment, renaming adhesive layer 1804 can also remove the cover from injection needle 1813.
[0293] The injection button 1810 also includes a membrane 1811 that prevents the syringe needle 1808 from establishing a fluid communication with the fluid conduit at the injection button 1810. An 1813 cover can be provided to cover the 1811 membrane in a pre-injection state, which can be removed by a patient before an injection. In an illustrative embodiment, the membrane cover 1813 and the syringe needle cover 1805 can be coupled so that the removal of one also removes the other.
[0294] In an illustrative embodiment, in a pre- and post-injection state, the syringe needle cover 1805 can cover the syringe needle 1808, and the injection button 1810 can be in a vertically elevated position as offset by the cover. syringe needle 1805 so that injection needle 1812 is retracted into housing 1802. In this state, the membrane 1811 of injection button 1810 can be vertically above syringe needle 1808. Additionally, syringe 1806 can be in a retracted position along the longitudinal geometrical axis of the 1806 assembly, spaced ad membrane 1811 from the injection button 1810.
[0295] When syringe needle cover 1805 is removed from syringe needle 1808, injection button 1810 is lowered to a vertically lowered position so that injection needle 1812 protrudes out of housing 1802 into the region contact with the patient. In an illustrative embodiment, the injection button 1810 can be automatically lowered by removing the syringe needle cover 1805. In another illustrative embodiment, the injection button 1810 is lowered by the patient by pushing the injection button 1810 down.
[0296] In an illustrative embodiment, lowering the injection button 1810 aligns the syringe needle 1808 with the membrane 1811 of the injection button 1810. Lowering the injection button 1810 also drives a syringe driver that advances the syringe 1806 to the along its longitudinal geometric axis towards the 1811 membrane of the injection button 1810. This causes the 1808 injection needle to pierce the 1811 membrane and establishes fluid communication with the 1812 injection needle.
[0297] Figures 19a and 19b illustrate an illustrative usable automatic injection device including a syringe and an illustrative transfer mechanism. Figure 19a shows a side view of the device. Figure 19b illustrates a perspective view illustrating the components of the device. The automatic injection device 1900 includes a housing 1902 holding a syringe 1904 stationary or movable with respect to housing 1902. An injection button 1906 is provided in housing 1902 in the vicinity of syringe 1904 and maintains an injection needle (no represented). Housing 1902 includes an adhesive layer 1908 for attachment to a region of contact with the patient.
[0298] Other components in device 1900 similar to components in device 1800 are described with reference to figures 18a and 18b.
[0299] Figures 20a to 20c illustrate an illustrative usable automatic injection device including an illustrative cartridge assembly and transfer mechanism. Figure 20a illustrates a perspective view of the device. Figure 20b shows a top view of the device. Figure 20c illustrates a side view of the transfer mechanism of the device. The automatic injection device 2000 includes a housing 2002 having an adhesive layer 2003 for attachment to a region of contact with the patient. The 2002 housing maintains a 2004 cartridge stationary or movable with respect to the 2002 housing. The 2004 housing is configured to maintain a dose of a therapeutic agent.
[0300] An injection button 2006 is provided in the housing 2002 in the vicinity of the cartridge 2004. The injection button 2006 can maintain or can be coupled to an injection needle 2008 extending substantially at 90 ° with respect to the longitudinal geometric axis of the 2004 cartridge and a syringe needle 2010 extending substantially parallel to the longitudinal geometric axis of the 2004 cartridge. The injection button 2006 may form or include a transfer mechanism that establishes fluid communication between the 2004 cartridge and the injection needle 2008 through the syringe needle 2010.
[0301] The 2006 injection button may include a 2012 housing hitch part that engages with a 2014 housing part when the 2006 injection button is pressed down during an injection in an injection state. In an illustrative embodiment illustrated in figure 20c, the engagement between the housing en-gate part 2012 and the housing part 2014 causes the housing part 2014 to move in parallel to the longitudinal geometric axis of the cartridge 2004 towards the distal end of the cartridge 2004, thus allowing the syringe needle 2010 to establish fluid communication with the barrel part of the cartridge 2004. In another illustrative embodiment, the engagement between the housing hitch part 2012 and the housing part 2014 causes the 2004 cartridge to move in parallel with the longitudinal geometric axis of the 2004 cartridge towards the 2010 syringe needle, thus allowing the 2010 syringe needle to establish fluid co-munition with the barrel part of the cartridge 2004.
[0302] Other components in device 2000 similar to components in device 1800 are described with reference to figures 18a and 18b.
[0303] Figures 21a to 21c illustrate an illustrative usable automatic injection device including an illustrative cartridge assembly. Figure 21a illustrates a perspective view of the illustrative usable automatic injection device. Figure 21b shows a sectional view of the cartridge assembly taken along a longitudinal geometric axis. Figure 21c illustrates a transparent top view of the transfer mechanism of the device. The automatic injection device 2100 includes a housing 2102 having an adhesive layer 2103 for attachment to a region of contact with the patient. The housing 2102 holds a cartridge 2104 stationary or movable with respect to housing 2102. The cartridge 2104 is configured to maintain a dose of a therapeutic person. A proximal end of the cartridge 2104 includes a cap 2106 and a distal end of the cartridge 2104 includes a membrane 2108 that cooperatively seals the dose within the cartridge 2104.
[0304] An injection button 2110 is provided in housing 2102 in the vicinity of cartridge 2104. The injection button 2110 holds an injection needle at a proximal end that extends substantially 90 degrees with respect to the longitudinal geometric axis of cartridge 2104. The injection button 2110 is coupled to a transfer mechanism 2111 that holds a syringe needle 2112 in the vicinity of cartridge 2104. Syringe needle 2112 extends substantially parallel to the longitudinal geometric axis of cartridge 2104. Transfer mechanism 2111 includes a fluid conduit for establishing fluid communication between cartridge 2104 and injection needle 2108 through syringe needle 2110. In a pre-injection state, the ring needle 2112 may partially extend into a distal end of cartridge 2104, but can be blown off of membrane 2108. In an injection state, cap 2106 can be moved into cartridge 2104 What the pressure of fluid in cartridge 2104 moves membrane 2108 towards syringe needle 2112. This causes syringe needle 2112 to pierce membrane 2108 and establish fluid communication between cartridge 2104 and injection needle through of the 2112 syringe needle.
[0305] Other components in device 2100 similar to components in device 1800 are described with reference to figures 18a and 18b.
[0306] Figure 22 illustrates an illustrative cartridge or syringe driver 2200 that can be used to advance a syringe 2202 or cartridge assembly from a retracted position to an extended position within the housing of a usable automatic injection device. A proximal end of the barrel part and / or the cartridge assembly can be coupled to a guide element 2204, for example, an actuation spring, which applies force to the barrel part of the syringe and / or cartridge assembly to move the barrel part and / or the cartridge assembly towards a membrane in a transfer mechanism (not shown). The 2200 cartridge or syringe driver can react to the orientation force of the guiding element, and can maintain and lock the barrel part and / or the cartridge assembly in a stably and reliably retracted position.
[0307] When triggered, the 2200 cartridge or syringe driver can allow the barrel part and / or the cartridge assembly to move towards the membrane under the force of the guiding element. In an illustrative embodiment, the syringe or cartridge trigger 2200 can be configured and / or determined as a specified distance to control the level of drive force required to advance the barrel part and / or the cartridge assembly from from the retracted position to the extended position.
[0308] Any suitable trigger mechanism can be used to drive the cartridge or syringe drive systems. In an illustrative embodiment, the drive mechanism can automatically drive the syringe or cartridge drive system when the usable automatic injection device moves from the pre-injection state to an injection state. In an illustrative embodiment, the downward vertical movement of an injection button within the housing to provide a fluid path between the cartridge or se-ring assembly and the injection needle can provide a driving force to drive the injection system. piston drive. In another illustrative embodiment, the advance movement of the cartridge or syringe assembly within the housing to establish the fluid path between the cartridge or syringe assembly and the injection needle can provide a driving force for the cartridge or syringe system. In another illustrative embodiment, the cartridge or syringe system can be manually activated by a user.
[0309] Prior to an injection in a pre-injection state, a needle cover, for example, a soft or rigid needle protection set (not shown), provided at the distal end of the syringe can protectively cover the needle syringe At this stage, since the syringe needle is covered with the needle cover, the distal end of the syringe has a larger first diameter. As such, the transfer mechanism including the membrane is held in a vertically elevated position above the needle cover, and the membrane is not aligned with the syringe needle. When the needle cover is removed from the syringe in preparation for an injection (for example, manually by a user or by an automatic mechanism), the transfer mechanism may lower to a vertically lowered position as it is no longer kept displaced by rigid needle shield, and the membrane in the transfer mechanism is aligned with the syringe needle. Removing the needle cover thereby lowers the transfer mechanism from its raised position to its lowered position. Lowering the transfer mechanism, in turn, applies a driving force to the 2200 cartridge or syringe driver and operates as the drive mechanism for the 2200 cartridge or syringe driver.
[0310] Figure 23 shows an illustrative cartridge or syringe driver 2300 including a first part 2302, a second part 2304 and a hinge part 2306 provided between the first and second parts. The hinge part 2306 allows the first and second parts to rotate around the hinge with respect to each other. In different rotation configurations, the first and second parts can have illustrative angles of between about 0 degrees and about 180 degrees to each other. The driver 2300 can be coupled to the syringe and the membrane and / or the transfer mechanism. When the membrane and / or the transfer mechanism is in its first elevated position, the driver 2300 can hold the ring in place in its retracted position. When the membrane and / or transfer mechanism is in its second lowered position, the driver 2300 can release the syringe so that the guiding element can push the syringe towards its extended position towards the point of piercing the membrane.
[0311] IV. Piston Drive Systems and Illustrative Needle Retraction Systems
[0312] The illustrative modalities provide piston drive systems for actuating a stopper on a barrel part of a usable automatic injection device so that the stopper moves forward inside the barrel part and expels a dose of an agent therapeutics contained in the pipe part. Any drive mechanism can be used to drive the plunger drive systems. In an illustrative embodiment, the drive mechanism can automatically activate the plunger drive system when the usable automatic injection device moves from a pre-injection state to an injection state. In an illustrative embodiment, the downward vertical movement of an injection button within the housing to provide a fluid path between the cartridge or syringe assembly and the injection needle can provide a driving force to drive the injection system. piston drive. In another illustrative embodiment, the advance movement of the cartridge or syringe assembly within the housing to establish a fluid path between the cartridge or syringe assembly and the injection needle may provide a driving force to drive the plunger drive system . In another illustrative embodiment, the plunger drive system can be manually operated by a user.
[0313] Certain other illustrative embodiments provide plunger actuating devices and systems that cause the syringe plunger to activate at a slow rate in order to deliver the therapeutic agent to a patient at a slow rate. The illustrative slow modalities can deliver volumes of therapeutic agent from about 0.1 millimeter to about 1 millimeter or more in about five minutes to about thirty minutes, although illustrative delivery rates are not limited to that illustrative range.
[0314] The illustrative embodiments can provide a linear distribution profile for the therapeutic agent so that the rate of distribution is substantially constant over time. In some cases, a linear distribution profile can reduce the discomfort suffered by the patient.
[0315] Figure 24 illustrates a schematic of a part of an illustrative automatic injection device 2400 including an in-bolt drive mechanism employing a fusee and a viscous damping mechanism. The usable automatic injection device 2400 includes a housing 2402 having a platform 2410 which is a mechanical structure for holding a cartridge or syringe assembly 2404 in place within the usable automatic injection device 2400. The cartridge or syringe 2404 includes a part barrel to hold a dose of a therapeutic agent and a stopper 2408 to seal the dose within the barrel part. A piston drive mechanism 2406 is provided to move the cap 2408 into the barrel part to expel the dose from the barrel part. A damping mechanism 2422, for example, a viscous damper, is provided to regulate the movement of the plug 2408 so that the therapeutic agent is distributed in a linear manner, i.e., at a substantially constant flow rate. A gear sequence 2420 including one or more gears can be provided to couple plunger drive mechanism 2406 to damping mechanism 2422. Gear sequence 2420 can include any number of gears suitable to provide any suitable gear ratio.
[0316] The 2410 platform of the usable automatic injection device 2400 can be stationary or mobile. In an illustrative embodiment, the platform 2410 can be a cylindrical or substantially box-like structure with an internal space to accommodate the syringe or cartridge 2404. The peripheral walls surrounding the internal space can be configured to maintain a cartridge assembly or syringe 2404 in place. The platform 2410 may include one or more clamping mechanisms 2412 to hold the cartridge or syringe 2404 in place. Platform 2410 may also include a flange support 2414 provided at the proximal end of the cartridge or syringe 2404. A flange provided at the proximal end of the cartridge or syringe 2404 can slide back against the flange support 2414.
[0317] In an illustrative embodiment, the 2410 platform can keep the cartridge or syringe 2404 stationary inside and with respect to the 2410 platform. In another illustrative embodiment, the 2410 platform can allow the 2404 cartridge or ring to move with relative to platform 2410, for example, towards or away from a fluid transfer mechanism (not shown). In this illustrative model, the internal space of platform 2410 may include one or more grooves, rails or channels to facilitate movement of the cartridge or syringe 2404 within platform 2410. In an illustrative embodiment, platform 2410 may include a window 2416, for example, a cutout or transparent part, in order to allow the patient to view the syringe or cartridge 2404.
[0318] One or more plunger drivers 2406 can be provided in the vicinity of the syringe or cartridge 2404 to store energy and provide a force to drive a stopper 2407 into the syringe or cartridge 2404 towards the distal end of the syringe or cartridge 2404. In an illustrative embodiment, a piston driver 2406, for example, a helical compression spring, can be used to actuate the cap 2408. The piston driver 2406 can be supplied at least partially inside the syringe or cartridge 2404. Before an injection in a pre-injection state, plunger driver 2406 can be maintained in a compressed state. At the beginning of an injection or during an injection in an injection state, the plunger driver 2406 can expand from the compressed state to a relaxed state. The expansion of the plunger driver 2406 can push the cap 2408 towards the distal end of the syringe or cartridge 2404, thus expressing the therapeutic agent of the syringe or cartridge 2404. Advantageously, the configuration of the plunger driver 2406 inside the syringe or cartridge 2404 does not add to the length of the housing required to hold the syringe or cartridge 2404. However, in some illustrative embodiments, the plunger driver 2406 may not provide a constant force to drive the stopper 2408.
[0319] In another illustrative embodiment, a spiral spring can be used to activate the cap 2408. The spiral spring can be supplied outside, but along, the cartridge or syringe 2404 inside platform 2410, which may add to the requirement space of housing 2402. Prior to an injection in a pre-injection state, the spring can be maintained in a compressed state. At the beginning of an injection or during an injection in an injection state, the spring can expand from the compressed state to a relaxed state. The expansion of the spring can push the cap 2408 towards the distal end of the cartridge or syringe 2404, thus expressing the therapeutic agent of the cartridge or syringe 2404. Vanishingly, the spiral spring can provide a substantially constant force to drive the cover 2408
[0320] One or more damping mechanisms can be provided to regulate the release of energy in the plunger driver 2406 in order to control the delivery rate and / or the delivery time to deliver the therapeutic agent. In an illustrative embodiment, in order to achieve a slow and / or controlled distribution, the plunger driver 2406 is prevented from accelerating without resistance from its compressed state to a relaxed state. The movement of plunger driver 2406 can be maintained at a constant speed, for example, by providing linear damping values. Any suitable mechanism can be used to provide resistance against the acceleration of the piston driver 2406. In an illustrative embodiment, a rotary viscous damper 2422 can be used to resist the acceleration of the piston driver 2406. The viscous damper 2422 can use one or more viscous fluids, for example, silicon grease, to provide resistance. The viscous damper 2422 may include a stationary housing that maintains a solid rotating element called a "rotor". The outer circumference of the rotor can include a plurality of teeth configured to be engaged by the teeth of a gear in gear sequence 2420. The rotor can be surrounded by a thin film of a viscous fluid which is sealed within the housing. Rotation of the rotor can provide resistance against the acceleration of plunger driver 2406 by shearing viscous fluid. In an illustrative modality, the viscous damper 2422 can be replaced by a different viscous love-weaver providing a different level of damping.
[0321] The force required to rotate the rotary viscous damper 2422 is described with reference to an x coordinate system where x = 0 in the free length of a spring. If m is the inertia of the system, c and damping coefficient, ekea spring constant, then:


[0322] where the natural frequency:

[0323] and where the damping ratio:

[0324] If the damping is triggered by a rotating damper, the torque T required to turn the damper can be considered linearly proportional to the angular velocity by some constant C:

[0325] If the rotary damper is coupled to the plunger driver by a sequence of reduction gears N and a spool of diameter D, then:

[0326] In another illustrative embodiment, an exhaust can be used to resist the acceleration of the piston driver 2406. The exhaust can use a known period of oscillation of a balance wheel and a spiral hairspring to incrementally release the energy of a mainspring. An exhaust can provide a dependent design and linearity in the release of energy. In another illustrative embodiment, an outlet exhaust can be used to withstand the acceleration of the piston driver 2406. In another illustrative embodiment, a dirty lever exhaust can be used to resist the acceleration of the piston driver 2406.
[0327] A gear sequence 2420 can be provided to couple the piston driver 2406 to the regulating device 2422, that is, the viscous damper or exhaust. The gear sequence 2420 may include a shaft 2424 that can be coupled to housing 2402 of the usable automatic injection device 2400 with a close slip fit. In an illustrative embodiment, the shaft 2424 can support a cylindrical structure 2426, for example, a spool or shaft, and a gear 2428 which is provided below the spool 2426. In an illustrative embodiment, the spool 2426 can be a cam spool. or a fusee. One or more snap-fit rings 2430 can be used to hold spool 2426 and gear 2428 on shaft 2424. Spool 2426 and gear 2428 can be provided around axis 2424 so that the rotation centers of spool 2426 and gear 2428 are aligned with each other and with shaft 2424. Spool 2426 and gear 2428 can be cooperatively coupled to each other and shaft 2424 so that gear 2428 on spool 2426 can rotate together on the shaft 2424. In an illustrative embodiment, spool 2426 and gear 2428 can be removed from shaft 2424 and replaced with a different set of reels and gears. Plunger driver 2406 can be coupled to a gear sequence, for example, spool 2426, using one or more lashings or cables 2442.
[0328] In an illustrative embodiment, the spool 2426 can be any suitable rotation mechanism including, but not limited to, a constant diameter spool, a cam spool or a fusee. If a cam or fusee is used, the outside diameter of the cam or fusee may vary with the linear displacement D. Taking into account the equation for the linear damping coefficient and maintenance of gear reduction N and the coefficient constant rotating love-weave, you get:

[0329] where a is constant. Substituting the above in the equation of motion and considering that the first derivation of x is constant, we obtain:

[0330] where C1, C2 and b are constants that can vary in order to make the veizidity approximately constant. The connection of this variable in the equation of motion and the solution of x as a function of time, x can be substituted in equation (8) to determine D as a function of time, Dt. The instantaneous speed can be represented as:

[0331] where 0 is the angular position of the cam or fusee. Dt and 0t are the polar coordinates of the cam profile.
[0332] The illustrative modalities can couple the plunger driver 2406 to a stopper on the barrel part of a cartridge or syringe using any suitable mechanism. If a compression spring is used as a piston driver 2406, one or more lashings or cables can be used to couple the piston driver 2406 to the cap. If a spiral spring is used as the piston driver 2406, a spur gear can be used to couple the piston driver 2406 to the cap. The torque generated by the spiral spring can be coupled to the cap using a pinion to push a flexible rack around the corner of the syringe or cartridge.
[0333] In an illustrative embodiment, the spool 2426 can be in contact with and / or can be coupled to a sprocket 2434 and claw 2436. A torsion spring (not shown) can be provided below claw 2436 to preload the claw 2436 against sprocket 2434. When the spool 2426 is being rolled up while assembling the usable automatic injection device 2400, the torsion spring can be held in place. After the spool 2426 is wound up and before an injection in a pre-injection state, the sprocket 2434 and the claw 2436 can hold the spool 2426 in place and prevent the spool 2426 from rotating. This maintains the lashing 2442 in place, which in turn keeps the piston driver 2406 in its compressed state, preventing the movement of the piston. At the start of an injection or during an injection in an injection state, the gripper 2436 can be rotated to disengage the sprocket 2434, for example, by a user or automatically by pressing an injection button. This allows the spool 2426 to rotate under the retraction force of the lashing 2442 caused by the spring force of the plunger driver 2406. The spring force of the plunger driver 2406 pulls the lashing 2442 towards the distal end of the syringe or cartridge 2404.
[0334] One or more additional gears can be supplied in contact with and / or coupled to the gear coupled to the spool 2426, thus forming a sequence of gear 2438. Each gear in the sequence of gears 2438 can be supplied in a corresponding axis coupled to the housing 2402 of the usable automatic injection device 2400. In an illustrative embodiment, the gears in the gear sequence 2438 can be removed from their corresponding axes and replaced by a different set of gears. Those skilled in the art will recognize that other illustrative devices may include fewer or more gears.
[0335] Gear sequence 2438 can be coupled to viscous damper 2422 or an exhaust that resists acceleration of cap 2408. That is, the gear sequence can couple viscous damper 2422 or a tailpipe exhaust 2422 while holding cap 2408 of so that when the cap 2408 is moved under the force of the plunger driver 2406, the acceleration of the plunger driver 2406 is resisted by the viscous damper 2422 or exhaust.
[0336] In an illustrative embodiment, the gear sequence 2438 can be coupled to a coding device 2440, for example, a rotary encoder, which detects and files the angular displacement or position of the gear sequence and the corresponding time. A computing device can be associated with the usable automatic injection device to determine the position of the syringe plunger based on data obtained by the 2440 coding device. The computing device can also determine the flow rate of the syringe's therapeutic agent or cartridge 2404 and the corresponding time based on the data obtained by the coding device 2440. The computing device can be supplied entirely with the coding device 2440 or separately from the coding device 2440. During the assembly and testing of the usable automatic injection device , the coding device 2440 can be used to evaluate different gear sequences, viscous dampers and guidance elements, validate mathematical models and compensate for variables not solved by mathematical models. When using the automatic injection device usable for performing an injection, the 2440 coding device can be used to indicate one or more conditions for the user, for example, the flow rate of the therapeutic agent, the malfunction of the device (for example, if the flow rate is too high or too low) and the like.
[0337] In an illustrative embodiment illustrated in figures 25 and 26, a usable automatic injection device may include a mobile syringe assembly relative to a platform in the device. The usable automatic injection device includes a 2500 platform, a sliding cart 2502 attached to the 2500 platform, and a syringe 2504 mounted on the sliding cart 2502. A distal end of syringe 2504 can be attached to a 2512 syringe needle. include a barrel part 2506 containing a dose of a therapeutic agent sealed by a cap 2508. A plunger driver 2510 can be provided near or in contact with cap 2508 to move cap 2508 forward within the barrel part 2506. In an illustrative embodiment, the plunger driver 2510 can include a guiding mechanism coupled by a lashing to a gear sequence and, thus, to a damping mechanism.
[0338] The device can also include an injection button supporting an injection needle (not shown) and including a pierceable membrane that can be punctured by the 2512 syringe needle. The membrane can be attached directly or via a conduit to the injection needle. injection so that, when pierced by the 2512 syringe needle, the membrane establishes fluid communication between the barrel part 2506 and the injection needle.
[0339] In an illustrative embodiment, in a pre-injection state, the 2512 syringe needle can already pierce the membrane and can be in fluid communication with the injection needle. During an injection in an injection state, the dose of therapeutic agent can be expelled from the barrel part 2506 when the plunger driver 2510 is activated to move the cap 2508 forward into the barrel part 2506. In this embodiment, the trolley 2502 can be stationary on platform 2500.
[0340] In another illustrative embodiment, in a pre-injection state, the 2512 syringe needle may be removed from the membrane and may not be in fluid communication with the injection needle. During an injection in an injection state, syringe 2504 can be moved forward within and with respect to platform 2500 towards the membrane in order to pierce the membrane with the 2512 syringe needle. In this illustrative embodiment, the cart 2502 can it will be mobile and can move the 2500 platform with respect to the membrane.
[0341] In an illustrative embodiment, a mooring 2516 can be used to couple the plunger driver 2510 to a gear sequence 2518. The gear sequence 2518 can, in turn, be coupled to a damping mechanism 2520 for providing a linear distribution profile of the therapeutic agent. In a pre-injection state, a locking mechanism 2522 can hold gear sequence 2518 in place and prevent rotation of the gears. This causes the lashing 2516 to hold a piston driver 2510 in place and prevents the release of the plunger driver 2510, thereby preventing the movement of the cap 2508. During an injection in an injection state, the locking mechanism 2522 can be released, for example, manually by a user or automatically, thus allowing gears 2518 to rotate under the guiding force of the plunger driver 2510. This can allow the mobile cart 2502 to move automatically towards the membrane, which results in the 2512 syringe needle piercing the membrane. The cap 2508 can also move within the barrel part 2506 towards the membrane under the guiding force of the plunger driver 2510 to expel the dose through the syringe needle 2512.
[0342] Figures 27 to 29 illustrate a schematic of a part of an illustrative automatic injection device that may include a syringe assembly that is stationary with respect to the device housing. The usable automatic injection device 2800 includes a plunger drive mechanism to automatically activate a plug 2802 on a pipe part 2804. Figure 27 is a top view through a cover of the device 2800. Figure 28 is a side view of the device 2800. Figure 29 is a perspective view through a cover of device 2800.
[0343] The plunger drive mechanism may include a 2806 guidance mechanism that operates as a plunger driver. In an illustrative embodiment, one or more moorings or cables 2812 can be used to couple the steering mechanism 2806 in a stage 3 to gear 2810, for example, a fusee, which unfolds to allow the steering mechanism 2806 to expand. A stage 1 buffer 2808, for example, a viscous buffer or an exhaust, regulates the movement of the cap 2802 during an injection in an injection state in order to achieve a linear flow rate of the therapeutic agent. One or more stage 2 gears or pinions 2814 can be used to couple stage 3 gear 2810 and stage 1 shock absorber 2808.
[0344] Table 7 summarizes the illustrative features of an illustrative stage 1 damper, an illustrative stage 2 gear, an illustrative stage 2 pinion and an illustrative stage 3 gear that can be used in illustrative automatic injection devices. Table 7: Illustrative Features of Illustrative Piston Drive Components. Gear Stage 3Pinhao Stage 2Gear Gear 2Stamp Damper 1 Diametral inclination72 teeth per 2.54 cm.72 teeth per 2.54 cm.31.75 teeth per 2.54 cm.31.75 teeth per 2.54 cm number of teeth50 teeth18 teeth16 teethl 1 teeth faced width, 25 cm0.25 cm. 0.127 cm.0.299 cm. tooth profile14.5 degrees14.5 degrees14.5 degrees14.5 degrees materialnailonnailonnailonacetal inclination diameter1.76 cm. 0.63 cm. 1.28 cm. 0.87 cm. circular inclination0.11 cm./ tooth0.11 cm./ tooth0.25 cm./ tooth0.25 cm./ tooth resulting resistance 1.8 ksi 11.8 ksi 11.8 ksi 10.2 ksi Lewis form factor0.3460 , 2700,2550,192 torque0,59 kg cm0,21 kg cm0,21 kg cm0,14 kg cm tangential force0,90 kgf0,90 kgf0,342 kgf0,342 kgf radial forceO, 17 kgfO, 17 kgf0,09 kgf0,09 kgf safety factor3,712,906,259.62 total gear4.04
[0345] The failure analysis was performed on the illustrative piston drive mechanism. In an illustrative embodiment, the gear sequence (including stage 2 gear) is designed assuming the Lewis bending failure mode which considers that the gear tooth is a simple cantilever with the tooth contact occurring at the tip . The results of the failure analysis summarized in Table 7 indicate that the minimum safety factor for the gear sequence is 3 and that the total gear ratio is 4.04.
[0346] Different combinations of different types of piston actuators (spring 1 and spring 2), reels (constant diameter spool and cam spool), and damping mechanisms (viscous damping or exhaust) were tested to determine their effect on the rate of delivery of the therapeutic agent. Figure 30 illustrates the x and y coordinates (in inches) of the cam profiles for: (1) the combination of spring 1 and a viscous damper, (ii) the combination of spring 1 and an exhaust, (iii) the combination of spring 2 and a viscous damper, and (iv) the combination of spring 2 and an exhaust.
[0347] Figure 31 illustrates a graph of therapeutic agent flow rates (in millimeters per minute) X time (in seconds) distributed by: (i) the combination of spring 1 and a viscous damper, (ii) the combination of spring 1, a viscous damper and a cam reel, (iii) the combination of spring 1 and an exhaust, (iv) the combination of spring 1, an exhaust and a cam reel, (v) the combination of spring 2 and a viscous damper, (vi) the combination of spring 2, a viscous damper and a cam reel, (vii) the combination of spring 2 and an exhaust, (viii) the combination of spring 2, an exhaust and cam reel , and (ix) an ideal flow rate at which the therapeutic agent is delivered at a substantially constant rate. Figure 32 illustrates a graph of the volume of therapeutic agent (in millimeters) X time (in seconds) distributed by the combinations of the components of figure 31.
[0348] Figures 31 and 32 illustrate that a substantially linear flow rate of the therapeutic agent can be achieved by using a cam spool or fusee. The use of an exhaust, sometimes a viscous damper, can be used to improve the linearity of the flow rate. The total delivery time of the therapeutic agent can be controlled by setting the gear ratio.
[0349] Different combinations of illustrative dampers and illustrative gear ratios in illustrative piston drive mechanisms have been tested. Illustrative dampers included: (i) damping mechanism G, (ii) damping mechanism B, (iii) damping mechanism K, and (iv) damping mechanism V. Illustrative gear ratios include: (i) 4: 1, (ii) 6.25: 1 and (iii) 16: 1. Figure 33 illustrates a graph of therapeutical agent volume (in millimeters) against the time (in seconds) distributed using: (i) a damping mechanism G having a damping coefficient of about 10.3 lbf * s / in with a gear ratio of 4: 1, (ii) a damping mechanism B having a damping coefficient of about 15.1 lbf * s / in with a gear ratio of 4: 1, (iii) a mechanism damping K having a damping coefficient of about 18.9 lbf * s / in with a gear ratio of 4: 1, (iv) a damping mechanism V having a damping coefficient of about 24.9 lbf * s / in with a gear ratio of 4: 1, (v) a damping mechanism G having a damping coefficient of about 25.1 lbf * s / in with a gear ratio of 6.25: 1 (vi) a damping mechanism B having a damping coefficient of about 37.0 lbf * s / in with a gear ratio of 6.25: 1, (vii) one mechanism damping mode K having a damping coefficient of about 46.2 lbf * s / in with a gear ratio of 6.25: 1, (viii) a damping mechanism V having a damping coefficient of about 60, 7 lbf * s / in with a gear ratio of 6.25: 1, (ix) a damping mechanism G having a damping coefficient of about 164 lb * s / in with a gear ratio of 16: 1, (x) a damping mechanism B having a damping coefficient of about 242 lbf * s / in with a gear ratio of 16; 1, (xi) a damping mechanism K having a damping coefficient of about 303 lbf * s / in with a gear ratio of 16: 1, (xii) a damping mechanism V having a damping coefficient cement of about 398 lbf * s / in with a gear ratio of 16: 1, and (xiii) an ideal flow rate! in which the therapeutic agent is delivered at a substantially constant rate.
[0350] Figure 33 illustrates that increasing the damping coefficient for the same gear ratio increases the delivery time of the same volume of therapeutic agent. In some cases, increasing the mortar-cement ratio will make the distribution rate more linear. For example, for the gear ratio of 6.25: 1, the higher damping coefficient of about 60.7 lbf * s / in results in a linear distribution rate than the lower damping and coefficients.
[0351] Figure 34 illustrates a graph of illustrative shock absorber torques (which can be calculated retroactively from the displacement of the piston driver) against the shock absorber speeds (in rpm) for shock absorbers model G, B, Ke V having increasing damping coefficients. The dots indicate the actual torque values and the dotted lines indicate the manufacturer's damping torque values considered, which indicates that the manufacturer's values have been underestimated. The data indicate that the torque values were substantially linear in the range between 0 and about 20 rpm. This is evidenced by the high correlation coefficient for the linear fit equations illustrated in the graph. Using the new linear fit equations for the soft-torque torque provided by the linear fit, it adjusts the damping coefficient and includes a static torque value. The substitution of these new values in a computer model allows a closer approximation of the system's response.
[0352] Since the static torque is multiplied by the gear ratio and subtracts directly from the spring force, it may be desirable to choose the highest rate damper and the lowest gear ratio in an illustrative mode, for example, the damper model V and a 4: 1 gear ratio. Figure 35 illustrates a graph of the volume of the therapeutic agent (in millimeters) against the time (in seconds) distributed by different illustrative syringes using a model V damper having a damping coefficient of about 24.9 lbf * s / in and a illustrative gear ratio of 4: 1.
[0353] After adjusting the computer models to reflect the measured damper touch, a fusee was designed to linearize the rate of distribution of the therapeutic agent. Figure 36 illustrates a graph of the volume of therapeutic agent (in millimeters) distributed and the diameter of the fusee or cam spool (in inches) X the time (in seconds). Since the diameter of the fusee changes with distribution, angular position data is numerically integrated along the fusee curve to result in plunger driver linear position data at each data point.
[0354] Figure 36 illustrates that the actual measured distribution rate is about 10% slower than that predicted by the model, but it is almost constant as evidenced by the high correlation coefficient (0.9999). The discrepancy between the measured and predicted data can be explained by the inefficiencies in the gear, for example, areas where the gear joints can be observed as changes in the slope of the graph. The discrepancy can also be explained by the lashing coupling the fusee to the plunger driver not being perfectly in line with the plunger driver, or the spring rate of the plunger driver being actually lower than calculated. Regardless of the source of error, reducing the spring rate of the plunger driver by about 5% can produce an almost perfect correlation (1.0).
[0355] Different illustrative damping mechanisms have been tested at different temperatures to determine the effect of temperature on the damping effect, i.e., linearity of the distribution of the therapeutic agent. The viscous rotary damping torque depends on the viscosity of the silicon grease inside the rotary damper. The viscosity of silicon grease depends in part on the temperature of the surrounding environment. Different illustrative damping mechanisms have also been tested to determine the effect of manufacturing variation on the damping mechanisms on the damping effect, i.e., the linearity of the therapeutic agent distribution. Variations in damper manufacture can affect the resistance torque provided by the damper.
[0356] Figure 37 illustrates a graph of the therapeutic agent volume (in millimeters) distributed X time (in seconds) reached by. (i) a first damper at room temperature, (ii) the first damper at about 4.44 ° C (in a refrigerator), (iii) a second damper, (iv) the second damper at about 17 ° C (in (freezer), (v) a third shock absorber having manufacturing variation with respect to the first and second shock absorbers, and (vi) a fourth shock absorber having manufacturing variation with respect to the first and second shock absorbers.
[0357] Figure 37 illustrates that changes in temperature do not substantially affect the damping effect, that is, the linearity of the distribution of the therapeutic agent. However, the distribution rate has been affected in some cases by the reduction in temperature, for example, for the first damper. Similarly, the manufacturing variation in the damping mechanisms does not substantially affect the damping effect, that is, the linearity of the distribution of the therapeutic agent. However, the distribution rate was affected in some cases by the variation in manufacturing. The damper torque values varied by about 5% in the group of samples tested.
[0358] In this way, one or more factors can be configured to control the linearity and / or rate of distribution of the therapeutic agent including, but not limited to, gear ratio, damping coefficient, manufacturing deviations in the damper, manufacturing deviations in the plunger driver, and the like. In addition, other features of the plunger driver can vary in order to control the linearity and / or flow rate of the therapeutic agent.
[0359] Figure 38 illustrates a schematic of a part of an illustrative automatic injection device 2600 that employs a fusee and an escape mechanism. The 2600 device includes a plunger drive mechanism to automatically activate a stopper 2408 contained in a syringe or cartridge 2404. In the illustrative plunger drive mechanism, an exhaust 2602 can be used to resist the acceleration of plunger driver 2406 by providing linear damping. In illustrative exhaust 2602, an exhaust wheel is provided having a plurality of teeth on its circumferential periphery and a pallet is provided in the vicinity of the exhaust wheel. In an illustrative embodiment, the exhaust wheel may have 30 teeth, although the illustrative exhaust wheels are not limited to 30 teeth. The exhaust wheel can be coupled to the reel 2426 by means of one or more gears forming a gear sequence. In an illustrative embodiment, a gear ratio of 50: 1 can couple the spool 2426 to the exhaust wheel, but other illustrative gear ratios can be used. The pallet may have an inertial mass pulse adjustable through holes that can be aligned with one or more pins, for example, dowel pins.
[0360] In operation, when torque is applied to the exhaust wheel, the exhaust wheel rotates and a tooth of the exhaust wheel prints an impulse torque on the pallet so that the kinetic energy of the pallet is inverted. The tooth pulls a flap from the palette aside. This causes the palette to oscillate which releases the tooth of the exhaust wheel, simultaneously bringing the alternative blast of the palette into the interference with a second tooth of the exhaust wheel. Like Tai, as the exhaust wheel rotates, its movement is prevented by periodic impacts with the pallet, thus allowing the exhaust wheel to rotate only when the pallet is free to swing. As the torque applied to the exhaust wheel increases, the exhaust wheel gives a stronger thrust to the pallet, thereby increasing the pallet's oscillation speed and therefore allowing the exhaust wheel to move more quickly.
[0361] Considering that the collisions between the teeth of the exhaust wheel and the pallet are perfectly elastic, the pallet absorbs, for each impact:

[0362] The energy dissipation of the pellet is directly proportional to the oscillation frequency of the pallet w since two collisions occur between the exhaust wheel and the pallet for each oscillation of the pallet. Thus:

[0363] Considering a pulse time equal to zero, since the collisions are perfectly elastic, the magnitude of the angular velocity 'can be considered constant and related to <t> max, the angular distance between the collisions (in radians) can be represented by

[0364] In this way,

[0365] The rotation speed of the exhaust wheel is related to the number of teeth in the oscillation frequency w and can be represented by:

[0366] So,

[0367] Since 'for a viscous rotary damper:

[0368] that creates a non-linear differential equation.
[0369] In another illustrative piston drive mechanism, a dirty lever exhaust can be used to resist acceleration of the piston driver. Considering that a coordinate system where 0 = 0 is in balance with a spiral spring attached to a balance wheel. If the damping is negligible in that system, then:

[0370] Where k is the torsion spring constant of the spiral spring and J is the inertial mass impulse:

[0371] Where the distance from the center of rotation is mass, the natural frequency of the system is:

[0372] If the exhaust wheel has n teeth and a straight gear reduction sequence N coupling the exhaust to a spool of diameter D, then the spool rotates at an angular speed:

[0373] Considering the derivation of the equation referring to 0 as x:

[0374] which results in:

[0375] Thus,

[0376] The components illustrated in figure 38 that are common to figure 24 are described with reference to figure 24.
[0377] Figure 39 illustrates an illustrative plunger drive mechanism 3900 employing one or more linear guiding mechanisms to provide a force to express a therapeutic agent from the barrel part 3902 of a usable automatic injection device. The barrel part 3902 extends longitudinally between a proximal end and a distal end, and is configured to maintain a dose for a therapeutic person. A distal end of the barrel part 3902 is coupled to a syringe needle 3904. A stopper 3906 is movably provided within the barrel part 3902 to seal the dose of the therapeutic agent.
[0378] One or more linear springs 3908 are provided to provide a guiding force on the cap 3906 in order to move the cap 3906 into the barrel part 3902 towards the syringe needle 3904 during an injecting state. A distal end of the linear spring 3908 is in the vicinity of and / or in contact with a piston 3916 having a plurality of teeth configured to engage a damping mechanism. The plunger 3916 can be provided in the vicinity of and / or in contact with a distal end of a force transmission mechanism, for example, one or more spherical supports 3910.
[0379] A distal end of the 3910 ball supports may also be close to and / or in contact with the 3906 cap so that the spring 3908 orientation force is transmitted to the 3906 cap via the 3910 ball bearings. ball supports 3910 can be enclosed in a closed rail 3912 which restricts the lateral movement of ball supports 3910. That is, the spring guiding force 3908 causes piston 3916 and, in turn, ball supports 3910 to move substantially to back and forth, that is, towards and away from the 3906 cap. The use of 3910 ball supports allows the redirection of the guiding force to the 3906 cap and allows for minimizing the size of the device. When activated, spring 3908 exerts a guiding force towards the cap 3906. The guiding force is transmitted by the plunger 3916 and the ball bearings 3910 to the cap 3906 and causes the cap 3906 to move towards the syringe needle 3904 inside from the barrel part 3902. This causes the therapeutic agent to be expelled through the syringe needle 3904 to the outside of the barrel part 3902.
[0380] A 3914 damping mechanism, for example, a rotary viscous damper, can be provided and associated with spring 3908 and / or plunger 3916 to regulate the rate of delivery of the therapeutic agent. The damper 3914 may include a hub and a plurality of teeth that extend radially around the hub. The teeth of the shock absorber 3914 can be configured to engage with the teeth of the piston 3916. The shock absorber 3914 can provide a force proportional to the speed of movement of the piston 3916 in order to regulate the rate of distribution. As such, the illustrative system 3900 can be used to provide a slow controlled delivery of the therapeutic agent by configuring the force provided by spring 3908 and / or the properties of damper 3914.
[0381] Figure 40 illustrates an illustrative plunger drive mechanism 4000 that employs one or more clock springs to provide a force for a stopper on a pipe part in order to expel a therapeutic agent from the pipe part. An orientation means 4002 is provided by a helical coiled compression spring characterized by progressively increasing diameter spring coils, so that when the spring is compressed, the coils nest within each other in the form of a clock spring. thus, a minimum space. Part of the spring 4002 is in the vicinity of and / or in contact with a mechanical exhaust mechanism 4004 so that the rotating guiding force of the spring 4002 is converted into a linear displacement of the mechanical exhaust mechanism 4004. The mechanical exhaust mechanism 4004 can be close to and / or in contact with the cap so that the guiding force of the spring 4002 is transmitted as a linear displacement to the cap through the movement of the mechanical exhaust mechanism 4004. That is, the guiding force of the spring 4002 causes the mechanical exhaust mechanism 4004 to move substantially back and forth, that is, towards or away from the cap. The use of the mechanical exhaust mechanism 4004 allows the redirection of the guiding force to the cap and allows the minimization of the size of the device.
[0382] When activated, the spring 4002 exerts a guiding force which is converted into a force back and forth by the mechanical exhaust mechanism 4004 towards the cap. The guiding force is transmitted directly or indirectly to the cap and causes the cap to move towards the needle within the barrel part. This causes the therapeutic agent to be expelled through the needle to the outside of the pipe part. As such, the illustrative system 4000 can be used to provide slow controlled delivery of the therapeutic agent by configuring the force provided by the spring 4002 and / or linear displacement provided by the mechanical exhaust mechanism 4004. The mechanical exhaust mechanism 4004 can be configured to control, for example, the amount of advance per cycle. The spring 4002 can be dimensioned to predominate over the sliding forces.
[0383] Figures 41 and 42 illustrate an automatic illusive injection device 4100 that employs a fluid-based plunger drive mechanism in which fluid pressure and / or movement of a working fluid is used to move a stopper inside the barrel part of a syringe or cartridge. The plunger drive mechanism includes one or more fluid circuits to provide a force to a plug to expel a dose of a therapeutic agent from a barrel part 4104 of a syringe or cartridge. Fig. 41 is a schematic of the illustrative automatic injection device 4100 and Fig. 40 is a perspective view of the illustrative automatic injection device 4100. The usable automatic injection device 4100 may include a pressure element 4106 that stores a working fluid non-compressible which provides a fluid pressure. Illustrative working fluids may include, but are not limited to, water, air, oil and the like. Illustrative pressure elements 4106 may include, but are not limited to, an elastic pouch, a master cylinder, a spring loaded syringe and the like.
[0384] The pressure element 4106 can be coupled to a flow restriction element 4108 through a pipe 4110. The flow restriction element 4108 can restrict the flow of the working fluid so that the fluid pressure upstream of the flow restriction element is greater than the fluid pressure downstream of the flow restriction element. The flow restrictor 4108 may include an orifice in diameter ranging from about 0.002 cm. at about 0.02 cm, but the diameters of the illustrative flow restriction ports are not limited to that illustrative range. The orifice of the flow restriction element 4108 can have lengths ranging from about 10 mm to about 50 mm, but the lengths of the orifices of the flow restrictor element are not limited to that illustrative range.
[0385] The illustrative modalities can configure a number of characteristics of the delivery system to control the total delivery time of the therapeutic agent. Illustrative modalities can also configure a number of characteristics of the delivery system based on the viscosity of the working fluid and / or therapeutic agent. Illustrative features may include, but are not limited to, orifice diameter, orifice length, working fluid viscosity and the like. For example, the diameter of the orifice of the flow restriction element can be reduced to increase the total distribution time.
[0386] The flow restriction element 4108 can also be coupled to the cap via a 4112 pipe. When the working fluid is released from the pressure element 4106 through the flow restriction element 4108, the fluid pressure of the flow fluid The work activates the cap forward into the barrel part 4104 in order to expel the dose of therapeutic agent from the barrel part 4104.
[0387] In an illustrative embodiment, before an injection in a pre-injection state, the working fluid may not be released from the pressure element 4106. In this illustrative embodiment, a dispensing trigger (not shown) can be coupled to the pressure element 4106 so that, by activating a distribution trigger, the working fluid is released from the pressure element 4106 into the tubes 4110 and 4112. The fluid pressure of the working fluid advances the plug inside the barrel part 4104, thus injecting the dose into the patient's skin. In this way, the fluid circuit established by the flow of working fluid and the flow restriction element can provide a regulated force for the cap.
[0388] In an illustrative embodiment, the dose is distributed in a linear distribution profile, that is, at a substantially constant distribution rate. The linearity of the distribution profile can be achieved by the high pressure of the working fluid provided by the pressure element 4106 upstream of the flow restriction element 4108 and the damping effect provided by the flow reduction element 4108. The pressure a upstream of the flow restriction element 4108 can be maintained at a high level with respect to the designed sliding forces so that a highly damped system is reached. For the cap to be moved towards the barrel part 4104, the cap needs to draw a vacuum in the working fluid between the flow restriction element 4108 and the barrel part 4104, which is difficult to reach to an appreciable degree since the working fluid is essentially not compressive.
[0389] Illustrative damped hydraulic distribution circuits allow the movement of the cover through volumetric dosing, instead of by a direct application of force, thus minimizing the sliding gap in the distribution profile of the therapeutic agent.
[0390] In an illustrative embodiment, an illustrative volume of 0.8 millimeters of therapeutic agent can be delivered at an illustrative delivery pressure of about 16.5 psi within an illustrative duration of about 12 minutes. In another illustrative embodiment, an illustrative volume of 0.8 millimeters of therapeutic agent can be delivered at an illustrative delivery pressure of about 5 psi within an illustrative duration of about 17 minutes.
[0391] Figure 43 illustrates a graph of cumulative amount of therapeutic agent (in grams) versus time (in seconds) as delivered by an illustrative delivery system at an illustrative delivery pressure of about 16.5 psi. Figure 44 illustrates a graph of cumulative therapeutic agent volume (in millimeters) versus time (in seconds) as delivered by an illustrative delivery system including an illustrative first flow restrictor having an illustrative diameter of about 0.02 cm . and an illustrative length of about 34.3 mm. The total delivery time for delivering about 1 millimeter of a therapeutic agent was about twenty seconds. Figure 45 illustrates a graph of cumulative therapeutic agent volume (in millimeters) versus time (in seconds) as delivered by an illustrative delivery system including a second illustrative flow restrictor having an illustrative diameter of about 0.005 cm. and an illustrative length of about 34.3 mm. The total delivery time for delivering about 1 millimeter of a therapeutic agent was about 15 minutes. In the illustrated graphs, the distribution profile is substantially linear, this is, substantially constant over time, and does not exhibit an initial bolus or sudden changes or inflections representing inconsistent distribution rates.
[0392] Figure 46 is a schematic drawing of an illustrative automatic injection device 4600 that employs one or more fluid circuits to provide a way to expel a therapeutic agent from a cartridge assembly. Fig. 47 is a top view of illustrative device 4600. Illustrative au-tomatic injection device 4600 includes a barrel part 4602 containing a dose of a therapeutic agent. A distal end of the barrel part 4602 is provided in the vicinity of or coupled to a syringe needle (hidden by a needle cover 4604) which is covered protectively by a needle cover 4604. The 4600 device includes an injection button which includes a membrane and supports an injection needle (not shown). In an illustrative embodiment, device 4600 may include an injection needle holder 4606 for holding the injection needle. In an illustrative embodiment, the injection needle can extend substantially orthogonal to the piano of the device as illustrated, and can be held in place by needle holder 4606. A needle lock 4608 can be provided to prevent the injection needle leave the housing once it is engaged and can be located in the housing near the injection needle.
[0393] In an illustrative embodiment, a 4610 cartridge or syringe driver can be provided to advance the barrel part 4602 into the housing towards the membrane. A trigger can be provided to trigger the 4610 cartridge or syringe driver, for example, when the injection button is pressed down or when the needle cover 4604 is removed.
[0394] In this illustrative embodiment, a main cylinder 4612 containing a working fluid is provided to provide a fluid pressure to drive a plug 4614 within the barrel part 4602. The main cylinder 4612 can be coupled to a distribution trigger. 4616 which, when activated, releases the working fluid into the fluid communication with the cap 4614 and allows fluid pressure to advance the cap 4614 into the barrel part 4602.
[0395] The illustrative modalities also provide needle retraction systems for retracting an injection needle from a vertically lowered position (or an extended or developed position) outside the device housing in the region of contact with the patient to a vertically elevated position ( or a stowed position) within the housing of the device. The wearable 4600 auto-matic injection device includes a retracting mechanism that automatically raises the injection button from a vertically pressed position within the housing during an injection in an injection state to a vertically elevated position within the housing in a state post-injection after an injection. In an illustrative embodiment, the retraction mechanism can be a telescopic element. The main cylinder 4612 can be coupled to a retraction trigger which, when activated, releases the working fluid into the fluid communication with the retraction trigger and allows the fluid pressure to activate the retraction mechanism.
[0396] Figure 48 shows a top view of the device 4600 showing a conductor 4802 coupling the main cylinder 4612 to a flow restriction element 4804, a conduit 4806 coupling the flow restriction element 4804 to the plug on the pipe part of the device and a conduit 4808 coupling the main cylinder 4612 to a restriction mechanism 4810 through a valve 4812, for example, a check valve. Fig. 49 illustrates a schematic diagram of the 4600 device.
[0397] Check valve 4812 may have an adequate crack pressure at or above which check valve 4812 allows fluid to enter conduit 4808 coupled to retraction mechanism 4810. In an illustrative manner, the pressure of The crack is greater than the maximum fluid pressure in the 4806 conduit needed to activate the plug during an injection in an injection state. Otherwise, desirably, the needle retraction process can begin during or even before the injection. In an illustrative embodiment, the pressure in the conductor 4806 at the end of the movement of the plug during an injection in an injection state is greater than the crack pressure. Otherwise, at the end of the cap movement, the pressure in the duct 4808 may be sufficient to activate the 4810 retraction mechanism. The volume of the working fluid in the main cylinder 4612 is sufficient to distribute the entire dose of the therapeutic agent and activate the mechanism. of retraction 4810.
[0398] In an illustrative embodiment, the 4810 retractor mechanism and the 4812 check valve can be supplied separately. In another illustrative embodiment, the 4810 retraction mechanism and the 4812 check valve can be provided as a single element, for example, as an inverted diaphragm.
[0399] Figure 50 illustrates a pressure graph after the check valve and behind the plug (in psi) X the time (in seconds) in an illustrative mode. In an illustrative embodiment, the crack pressure of the check valve can be about 7.5 psi and the diameter of the orifice of the flow restriction element can be about 0.02 cm.
[0400] During an injection in an injection state, the flow restriction element 4804 can cause the pressure in conduit 4802 to be about 10 to about 15 psi, while the pressure in conduit 4806 can be about 5 to about 6 psi. The check valve 4812 thus prevents any flow of working fluid from entering the conduit 4808 while the cap is moving during the injection. Once the stopper stops moving at the end of the injection, that is, when the dose has been completely expelled from the pipe part, the pressure in the 4806 conduit increases beyond 7.5 psi. This causes the check valve 4812 to open, allowing the working fluid to flow into the conduit 4808 that activates the 4810 retractor mechanism. The 4810 retractor mechanism in turn unlocks the needle lock and retracts the button. injection / carrier 4606 supporting the injection needle. Since it is based on pressure equalization in the hydraulic circuit, the needle retraction process ensures that the entire dose is delivered before the injection needle is retracted, maximizes the use of the therapeutic agent, and minimizes the overfilling required in the barrel 4602.
[0401] Any suitable drive mechanism can be used to drive the needle retraction systems. In an illustrative embodiment, the trigger mechanism can automatically activate the needle retraction system when a usable automatic injection device moves from an injection state to a post-injection state. In an illustrative embodiment, completion of delivery of a therapeutic effect dose of the therapeutic agent can trigger the needle retraction system. In another illustrative embodiment, the removal of the patient's dis-positive prior to the completion of the delivery of a therapeutic dose of the therapeutic agent can trigger the needle retraction system. In another illustrative embodiment, the needle retraction system can be manually activated by the user.
[0402] Figure 51 illustrates a side view of an illustrative au-tomatic injection device 5100 in which housing 5102 of the usable auto-injection device 5100 includes a skin sensor piece 5104, which is a frame in one embodiment illustrative housed under or in part of housing 5102 near the injection site. In an illustrative embodiment, prior to the injection of the therapeutic agent and during the injection, the skin sensor piece 5104 is retained within or forms a part of the underside of housing 5102. When the wearable automatic injection device 5100 is attached to the injection site is activated, the skin sensor foot 5104 may be free to move, but may be restricted by the injection site. In an illustrative embodiment, when the usable automatic injection device 5100 is removed from the injection site, regardless of whether the drug delivery has been completed, the skin sensor 5104 is no longer restricted, and extends and protrudes outward from the periphery of housing 5102. This, in turn, triggers a retraction trigger. When the retraction trigger is activated, a retraction mechanism retracts the injection needle which can also raise the injection button from a vertically lowered position to a vertically raised position, so that the injection button protrudes from the top of the housing 5102 and the injection needle is retracted into housing 5102. V. Illustrative Needle Protection Systems
[0403] The illustrative embodiments provide illustrative needle protection systems for maintaining the injection needle within a usable automatic injection device in a post-injection state after an injection. Protecting the needle prevents accidental needle sticks to the patient and others in the vicinity of the usable automatic injection device.
[0404] Figures 52a and 52b illustrate an illustrative needle shielding system 5200 that holds an injection needle 5202 in a retracted position within a housing 5204 of an automatic injection system. Injection needle 5202 is movable relative to housing 5204 away from or towards the patient's skin. When needle 5202 is in a position within housing 5204 furthest from the patient's skin, needle 5202 is in a retracted position and does not protrude out of housing 5204. When needle 5020 is in a position within housing 5204 more close to the patient's skin, the needle 5202 is in an inserted or developed position and protrudes totally or partially from the housing 5204. The housing 5204 can be provided with an opening 5206 through which the needle 5202 can protrude out of the housing 5204.
[0405] The needle protection system 5200 employs a protection mechanism 5208 that prevents needle 5202 from projecting from housing 5204 in a pre-injection state before an injection and in a post-injection state after an injection when needle 5202 is in the retracted position. Fig. 52a illustrates the system 5200 in which the needle 5202 is in an inserted or developed position and projects totally or partially through the opening 5206 outside the housing 5204, for example, during an injection in an injection state. In that case, the protective mechanism 5208 is moved away from opening 5206 so that opening 5206 is open out of housing 5204, and needle 5202 is free to project through opening 5206 out of housing 5204. The figure 52b illustrates system 5200 in which needle 5202 is in a retracted position and does not protrude from housing 5204, for example, in a pre-injection state, and a post-injection state. In this case, the protective mechanisms 5208 is aligned with and covers aperture 5206 so that aperture 5206 is no longer open out of housing 5204, and needle 5202 is not free to protrude through aperture 5206 out of housing 5204. In an illustrative embodiment, the protection mechanism 5208 can be rotatably moved above a rotating point between a first position in which it exposes the opening 5206 (in figure 52a) to a second position in which it covers the opening 5206 ( in figure 52b).
[0406] Figures 53a and 53b illustrate another illustrative needle protection system 5300 provided in housing 5302 of an automatic injection system. The automatic injection system includes an injection needle 5304 which is movable with respect to housing 5302 away from or towards the patient's skin. When needle 5304 is in a position within housing 5302 furthest from the patient's skin, needle 5304 is in a retracted position and does not protrude out of housing 5302. When needle 5304 is in a position within housing 5302 more close to the patient's skin, the needle 5304 is in an inserted or developed position and protrudes totally or partially from the housing 5302.
[0407] The needle guard system 5300 includes a needle locking sleeve 5306 provided in the vicinity of injection needle 5304 for locking the injection needle in the retracted position in a pre-injection state and a post-injection state. The needle locking sleeve 5306 can be coupled to a pin 5308 arranged in a partition 5310. The pin 5308 can be in a first position (illustrated in figure 53a) with respect to partition 5310 where the needle locking sleeve 5306 lock the injection needle 5304 in the retracted position inside the housing 5302. The pin 5308 can be in a second position (illustrated in figure 53b) with respect to partition 5310 in which the needle locking sleeve 5306 allows the injection needle 5304 protrudes out of housing 5302.
[0408] In an illustrative embodiment, a premature removal retraction trigger 5312 which, when activated, triggers a retraction mechanism that retracts the injection needle 5304 into the housing 5302.0 premature removal retraction trigger 5312 can be activated when the wearable automatic injection device 5300 is removed from the injection site before the therapeutically efficient dose of the therapeutic agent is fully delivered. In an illustrative embodiment, the premature removal retraction trigger 5312 may include a lock 5314, for example, a flexible plastic hook, which is released by removing the usable automatic injection device 5300 from the injection site. Fig. 53a illustrates the premature removal retract trigger 5312 in which lock 5314 is engaged with part of the locking sleeve 5306 when the injection device is usable and coupled to the injection site. Fig. 53b illustrates the premature removal retraction trigger 5312 in which lock 5314 is released from the part of the locking sleeve 5306 when the injection device is usable and removed from the injection device. Releasing lock 5314 from the part of the locking sleeve 5306 activates the retraction mechanism. An illustrative retraction mechanism can respond to an end of dose retraction trigger, and respond to the premature withdrawal retraction trigger 5310 to automatically retract injection needle 5304 from the injection site.
[0409] Figure 54 illustrates an illustrative needle guard system 5400 that holds an injection needle held by an injection carrier 5402 in a retracted position within a housing 5404 of an automatic injection system. The injection needle is movable with respect to housing 5404 away from or towards the patient's skin. When the injection needle is in a position within the 5404 housing furthest from the patient's skin, the needle is in a retracted position and does not protrude out of the 5404 housing. When the needle is in a position within the nearest 5404 housing from the patient's skin, the needle is in an inserted or developed position and protrudes partially or totally from the housing 5404. The housing 5404 can be provided with an opening through which the needle can protrude out of the housing 5404.
[0410] The needle guard system 5400 includes a needle lock 5408 provided near or in contact with the needle carrier 5402. In an illustrative embodiment, the needle lock 5408 can be an articulated or rotatable element that can articulate or rotate around a pivot point or interface. A needle lock release mechanism 5410 can be provided in the vicinity of or in contact with needle lock 5408. The needle lock release mechanism 5410 may be in a first position when the injection needle is in a vertical position. lowered and protrudes out of housing 5404 (in an injection state) and into a second position when the injection needle is in a vertically raised or retracted position within housing 5404 (in a pre-injection state or a posinjection).
[0411] When the needle lock release mechanism 5410 is in the first position (i.e., when the injection needle is in a vertically lowered injection position), needle lock 5408 may be in an unlocked position where it does not lock the injection needle in the vertically raised position in housing 5404. Alternatively, needle lock 5408 can be in a locked position in which it locks injection needle 5408 in the vertically lowered position in housing 5404. In an embodiment illustrative (that is, when the injection needle is in a vertically lowered injection position), retraction of the injection needle and / or needle carrier 5402 to the vertically raised position within housing 5404 can trigger the release mechanism. needle lock 5410, that is, move the release mechanism from the first position to the second position. When the needle lock release mechanism 5410 is moved to the second position, needle lock 5408 can pivot or rotate, thereby locking the injection needle and / or needle carrier 5402 in the vertically elevated position in the housing 5404.
[0412] Figure 55 illustrates an illustrative needle guard system 5500 that holds an injection needle held by an injection carrier 5502 in a retracted position within housing 5504 of an au-tomatic injection system. The injection needle is movable with respect to housing 5504 away from or towards the patient's skin. When the injection needle is in a position within the 5504 housing furthest from the patient's skin, the needle is in a retracted position and does not protrude out of the 5504 housing. When the needle is in a position within the nearest 5504 housing from the patient's skin, the needle is in an inserted or developed position and protrudes totally or partially from the housing 5504. The housing 5504 can be provided with an opening through which the needle can protrude out of the housing 5504.
[0413] The needle guard system 5500 includes a needle lock 5508 provided in or near the needle carrier 5502. In an illustrative embodiment, the needle lock 5508 can be an articulated or rotatable element that can articulate or rotate around a pivot point or interface. Needle lock 5508 may include a guiding mechanism 5506 that applies a flexible rotating force to the needle carrier 5502 about a longitudinal geometric axis of the guiding mechanism. In an illustrative embodiment, the needle lock 5508 can be provided symmetrically around the needle carrier 5502 so that the rotation force is applied by the guiding mechanism 5506 substantially symmetrically around the needle carrier 5502.
[0414] A 5510 needle lock release mechanism can be provided in or near the 5508 needle lock. The 5510 needle lock release mechanism can be in a first position when the injection needle is in a vertically lowered position and protrudes out of housing 5504 (in an injection state) and into a second position when the injection needle is in a vertically raised or retracted position within housing 5504 (in a pre-injection state or a posinjection state).
[0415] When the needle lock release mechanism 5510 is in the first position (i.e., when the injection needle is in a vertically lowered injection position), the 5506 guidance mechanism can apply a flexible force to the carrier needle 5502 in the clockwise direction towards the patient's body so that the needle holder 5502 is kept in the vertically lowered position. When the needle lock release mechanism 5510 is in the second position (that is, when the injection needle is in a vertically elevated pre-injection or post-injection state), the 5506 guiding mechanism can apply a flexible force to the needle carrier 5502 in the counterclockwise direction away from the patient's body so that the needle carrier 5502 is raised to and held in a vertically elevated position.
[0416] In an illustrative embodiment, the retraction of the injection needle and / or the needle carrier 5502 to the vertically elevated position inside the housing 5504 can activate the 5510 needle lock release mechanism, that is, move the release mechanism from the first position to the second position. When the needle lock release mechanism 5510 is moved to the second position, the needle lock 5508 can pivot or rotate under the force of the guide element 5506 counterclockwise away from the patient's body, thereby locking the injection needle and / or the needle carrier 5502 in the vertically elevated position in the housing 5504. SAW. Therapeutic Agents for Use in Illustrative Automatic Injection Devices.
[0417] Illustrative automatic injection devices can be used to deliver essentially any therapeutic substance or agent that is suitable for administration by injection. Typically, the substance or therapeutic agent will be in a fluid form, for example, a liquid form, although drugs in other forms such as gels or semi-solids, pastes, particulate solutions, etc., may also be suitable for use if the a usable automatic injection device is designed to allow the administration of such forms of medication.
[0418] The preferred drugs are biological agents, such as antibodies, cytokines, vaccines, fusion proteins and growth factors. Methods of making antibodies are described above.
[0419] Non-limiting examples of other biological agents that can be used as a medicine in the automatic injection device include, but are not limited to, antibodies or antagonists of human cytokines or growth factors, for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL15, IL-16, IL-18, IL-21, IL-23, interferons, EMAP- II, GM-CSF, FGF and PDGF; antibodies to such cell surface molecules as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90. CTLA or its linkages including CD154 (gp39 or CD40L); TNFa converting enzyme (TACE) inhibitors; IL-1 inhibitors (interleukin-1 converting enzyme inhibitors, ILIRA, etc.); Interleukin 11; IL-18 antagonists including soluble IL-18 antibodies or IL-18 receptors, or IL-18 binding proteins; anti-CD4 inhibitors not exhausted; co-stimulating pathway (B7.1) or DC86 (B7.2) antagonists including antibodies, soluble receptors or antagonistic linkages; agents that interfere with signaling by pro-inflammatory cytokines such as TNFa or IL-1 (for example, IRAK, NIK, IKK; p38 or MAP kinase inhibitors); conversion enzyme inhibitors IL-1 (ICE); T cell tai inhibitors as kinase inhibitors; metalloproteinase inhibitors; angiotensin converting enzyme inhibitors; soluble cytokine receptors and derivatives thereof (for example, soluble TNF p75 or p55 receptors and derivatives P75TNFRIgG (EnbrelD and p55TNFRIgG (Lenercept), sIL1RI, slL-1 RIL, slL-6R); anti-inflammatory cytokines (for example, IL-4 , IL-10, IL-11, IL13 and TGF-beta); Rituximab; IL-1 TRAP; MRA; CTLA4-lg; IL-18 BP; anti-IL-18; and IL15; IDEC-CE9.1 / SB 210396 (primatized anti-CD-4 antibody not exhausted; IDEC / SmithKline; see, for example, Arthritis & Rheumatism (1995), Vol. 38; S185); DAB 486-IL-2 and / or DAB 389-IL-2 (IL-2 fusion proteins; Seragen; see, for example, Arthritis & Rheumatism (1993), Vol 36, 1223); Anti-Tac (humanized anti-IL-2Ra; Protein Design Labs / Roche); IL-4 ( anti-inflammatory cytokine; DNAX / Schering); IL-10 (SCH 52000; recombinant IL-10, anti-inflammatory cytokine; DNAX / Schering); IL-10 and / or IL-4 agonists (for example, agonist antibodies); IL-1RA ( IL-1 receptor antagonist; Synergen / Amgen); anakinra (Kineret® / Amgen); TNF-bp / s-TNF (soluble TNF binding protein; ve r, for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S284; Amer. J. Physiol. Heart and Circulatory Physiology (1995) 268: 3742); R973401 (phosphodiesterase Type IV Inhibitor, see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S282); MK-966 (COX2Inhibitr; see, for example, Arthritis & Rheumatism (1996) 39 (9-supplement); S81); lloprost (see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement); S82); zap-70 and / or lek inhibitor (zap-70 tyrosine kinase or lek inhibitor); VEGF inhibitor and / or VEGFR inhibitor (vascular endothelial cell growth factor inhibitors or vascular endothelial cell growth factor receptor; angiogenesis inhibitors); TNF-convertase inhibitors, anti-IL-12 antibodies; anti-IL-18 antibodies; interleukin-11 (see, for example, Arthritis & Rheumatism (1996) 39 (9, supplement), S296); interleukin-13 (see, for example, Arthritis & Rheumatism (1996), 39 (9, supplement), S308); interleukin-17 inhibitors (see, for example, Arthritis & Rheumatism (1996), 39 (9, supplement), S120); anti-thymocyte globulin .; anti-CD4 antibodies; CD5 toxins; ICAM-1 antisense phosphorothiate oligo-deoxynuycleotides (ISIS 2302; Isis Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell Sciences, Inc.); and anti-IL2R antibodies. VII. TNFa inhibitors for use in illustrative automatic injection devices
[0420] In accordance with an embodiment of the invention, the illustrative automatic injection device can be used to deliver a dose of a TNF inhibitor used to treat arthritis and other diseases. In one embodiment, the solution contained in the syringe contains 40 or 80 millimeters of drug product (TNFα blocker or inhibitor) / 1 ml, for example, 40 to 80 mg of adalimumab, 4.93 mg of sodium chloride, 0.69 mg of sodium phosphate dehydrate monobasic, 1.22 mg of sodium phosphate dehydrate dibasic, 0.24 mg of sodium citrate, 1.04 mg of citric acid monohydrate, 9.6 mg of mannitol, 0.8 polysorbate 50 mg and water for injection, with sodium hydroxide USP added as necessary to adjust the pH to be about 5.2.
[0421] The present invention can be used to administer a dose of a substantial, such as a liquid drug, for example, a TNFα inhibitor, to a patient. In one embodiment, the dose delivered by the automated injection device of the invention comprises a human TNFα antibody, or an antigen binder part, therefrom.
[0422] In one embodiment, the TNF inhibitor used in the methods and compositions of the invention includes isolated human antibodies or antigen binding parts thereof, which bind to human TNFα with a high affinity and a low rate of deviation, and has a high capacity neutralization. Preferably, the human antibodies of the invention are neutralizing and recombinant human anti-hTNFa antibodies, such as, for example, the recombinant neutralizing antibody referred to as D2E7, also referred to as HUMIRA or adalimumab (Abbott Laboratories; the VL D2EL region amino acid sequence and illustrated in SEQ ID No: 1 of US Patent No. 6,090,382). Properties and D2E7 have been described in Salfeld et al., U.S. Patent Nos. 6,090,382; 6,258,562 and 6,509,015. Other examples of TNFα inhibitors include anti-chimeric and humanized murine anti-hTNFa antibodies that have undergone clinical testing for the treatment of rheumatoid arthritis (see, for example, Elliott et al. (1994) ILancet 344; 1125-1127; Elliot et al., (1994 ) Lancet 344: 1105-1110; and Rankin et al. (1995) Br. J. Rheumatol. 34: 334-342).
[0423] An anti-TNFa antibody (also referred to herein as a TNFa antibody), or an antigen binder fragment thereof, includes chimeric, humanized and human antibodies. Examples of TNFα antibodies that can be used in the invention include, but are not limited to, infliximab (Remicade®, Johnson and Johnson; described in US patent No. 5,656,272, incorporated by reference here), CDP571 (an anti lgG4 antibody - humanized monoclonal TNF-alpha) CDP 870 (a humanized anti-TNF-alpha monoclonal antibody fragment), an anti-TNF dAB (Peptech) and CNTO 148 (golumumab; Medarex and Centocor, see WO 02/12502). Additional TNF antibodies that can be used in the invention are described in U.S. Patent Nos. 6,593,458; 6,498,237; 6,451,983 and 6,448,380).
[0424] Other examples of TNF-alpha inhibitors that can be used in the methods and compositions of the invention include etanercept (Enbrel, described in WO 91/03553 and WO 09/406476), TNF soluble TNF receptor Type I, a pegylated TNF soluble receptor I (TNF-R1 PEGs), p55TNFRIgG (Lenercept), and recombinant TNF binding protein (r-TBP-1) (Serono).
[0425] In one embodiment, the illustrative modalities provide improved uses and compositions for the treatment of a disorder in which TNF-alpha is harmful, for example, rheumatoid arthritis, with a TNF-alpha inhibitor, for example, a TNF antibody -human alpha, or an antigen binding part thereof, via a usable automatic injection device.
[0426] A TNF-alpha inhibitor includes any agent (or substance) that interferes with TNF-alpha activity. In a preferred embodiment, the TNF-alpha inhibitor can neutralize TNF-alpha activity particularly detrimental to TNF-alpha activity which is associated with disorders in which TNFalpha activity is harmful, including, but not limited to rheumatoid arthritis , juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, and psoriatic arthritis. VIII. Pharmaceutical Composition for Use in Illustrative Auto-matic Injection Devices
[0427] The pharmaceutical compositions can be loaded into the automatic injection device of the invention for delivery to a patient. In one embodiment, the antibodies, the antibody parts, in addition to other TNFalpha inhibitors, can be incorporated into the pharmaceutical compositions suitable for administration to a patient using the device of the invention. Typically, the pharmaceutical composition comprises an antibody, an antibody part, or another TNFα inhibitor, and a pharmaceutically acceptable carrier. The "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, absorption retarding and isotonic agents, and the like that are physiologically compatible. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate-enhanced saline, dextrose, glycerol, ethanol and the like, in addition to combinations thereof. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol or sodium chloride in the composition. Pharmaceutically acceptable carriers may additionally comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or storage agents, which improve the useful life or efficiency of the antibody, antibody part or other TNF-alpha inhibitor.
[0428] The compositions for use in the methods and compositions of the invention can be in a variety of forms according to administration through the device of the invention including, for example, liquid solutions (for example, injectable and infusible solutions), dispersions or suspensions . In a preferred embodiment, the antibody or other TNF-alpha inhibitor is administered by subcutaneous injection using the device of the invention. In one embodiment, the patient administers the TNFα inhibitor, including, but not limited to the TNFα antibody, or part of the antigen binder thereof, to themselves using the device of the invention. under the conditions of manufacture and storage. The composition can be formulated as a solution, micro emulsion, dispersion, liposome, or other ordered structure suitable for high drug concentration. Sterile injectable solupbes can be prepared by incorporating the active compound (i.e., antibody, antibody part, or other TNF-alpha inhibitor) in the required amount in a suitable solvent with one or a combination of ingredients listed above, as needed, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and other necessary ingredients from those listed above. In the case of sterile pbs for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze drying which result in a bp of active ingredient plus any desired additional ingredient of a previously filtered and sterilized solution. The proper fluidity of a solution can be maintained, for example, by the use of such a coating as lecithin, by maintaining the required particle size in the case of dispersion and by using surfactants. Prolonged absorption of injectable composites can be accomplished by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
[0429] Therapeutic compositions should typically be sterile and stable
[0430] In one embodiment, the illustrative embodiments provide a usable automatic injection device, for example, an automatic injection pen, comprising an efficient TNF-alpha inhibitor and a pharmaceutically acceptable carrier. Accordingly, the invention provides a pre-filled automatic injection device comprising a TNF-alpha inhibitor.
[0431] In one embodiment, the antibody or antibody part for use in the methods of the invention is incorporated into a pharmaceutical formulation as described in PCT / IB03 / 04502 and U.S. Patent Publication No. 2004/0033228. This formulation includes a concentration of 50 mg / ml of D2E7 antibody (adalimumab), where a usable automatic injection device contains 40 mg of antibody for subcutaneous injection. In one embodiment, the automatic injection device of the invention (or more specifically the syringe of the device) comprises a formulation of adalimumab having the following formula: adalimumab. sodium chloride, monobasic sodium phosphate dihydrate, dibasic sodium phosphate dihydrate, sodium citrate, citric acid monohydrate, mannitol, polysorbate 80 and water, for example, water for injection. In another embodiment, the automatic injection device comprises a volume of adalimumab including 40 mg of adalimumab, 4.93 mg of sodium chloride, 0.69 mg of monobasic sodium phosphate dihydrate; 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg sodium citrate, 1.04 mg. of citric acid monohydrate, 9.6 mg of mannitol, 0.8 mg of polysorbate 80 and water, for example, water for injection. In one embodiment, sodium hydroxide is added as needed to adjust the pH.
[0432] The amount of TNFα inhibitor dose in the automatic injection device may vary according to the disorder for which the TNFα inhibitor is being used to treat. In one embodiment, the invention includes a usable automatic injection device comprising an adalimumab dose of about 20 mg adalimumab; 40 mg adalimumab; 80 mg adalimumab; and 160 mg of ada-limumab. It should be noted that for all ranges described here, including dose ranges, all numbers intermediate to the mentioned values are included in the invention, for example, 36 mg adalimumab; 48 mg adalimumab; etc. In addition, the bands mentioned using said numbers are also included, for example 40 to 80 mg of adalimumab. The numbers recited here should not limit the scope of the invention.
[0433] The TNFα antibodies and inhibitors used in the invention can also be administered in the form of protein crystal formulations that include a combination of protein crystals encapsulated within a polymeric carrier to form coated particles. Particles coated with protein crystal formulation may have a spherical morphology and may be microspheres up to 500 micro meters in diameter or may have some other morphology and be micro particles. The improved concentration of protein crystals allows the antibody of the invention to be delivered subcutaneously. In one embodiment, the TNF-alpha antibodies of the invention are delivered through a protein delivery system, in which one or more of a protein crystal composition or composition, is administered to a patient with a TNF-related disorder. -alpha. The compositions and methods of preparing stabilized formulations of whole antibody crystals or antibody fragment crystals are also described in WO 02/072636, which is incorporated by reference here.
[0434] In one embodiment, a formulation comprising the crystallized antibody fragments described in international patent application No. PCT / IB03 / 04502 and U.S. patent publication No. 2004/0033228 and used to treat rheumatoid arthritis using the methods of the invention.
[0435] Supplementary active compounds can also be incorporated into compositions. In certain embodiments, an antibody or antibody part for use in the methods of the invention is formulated simultaneously with and / or administered simultaneously with one or more additional therapeutic agents, including a rheumatoid arthritis inhibitor or antagonist. For example, an antihTNF-alpha antibody or antibody part can be formulated simultaneously with and / or administered simultaneously with one or more additional antibodies that bind other targets associated with TNFalpha-related disorders (for example, antibodies that bind other cytokines or that bind cell surface molecules), one or more cytokines, soluble TNF-alpha receptor (see, for example, PCT publication No. WO 94/06476) and / or one or more chemical agents that inhibit the production of hTNF -alpha or activity (such as cyclohexane-ylidene derivatives as described in PCT Publication No. WO 93/19751) or any combination thereof. In addition, one or more antibodies of the invention can be used in communication with two or more of the above therapeutic agents. Such combination therapies can advantageously use lower dosages of therapeutic agents administered, thus avoiding possible side effects, complications or low level of response by the patient associated with the various monotherapies. Additional agents that can be used in combination with a TNF-alpha antibody or part of the antibody are described in U.S. Patent Application No. 11 / 800,531, which is expressly incorporated herein by reference in its entirety. IX. Incorporation by Reference
[0436] The contents of all references, including patents and patent applications, cited throughout this application are hereby incorporated by reference in their entirety. The appropriate components and methods of these references can be selected for the invention and its modalities. In addition, the components and methods identified in the Fundamentals section are integral to that description and can be used in conjunction with or replaced by components and methods described elsewhere in the description within the scope of the invention. X. Equivalences
[0437] In describing illustrative modalities, specific terminology is used for clarity purposes. For purposes of description, each specific term must include at least all technical and functional equivalences that operate in a similar way to accomplish a similar purpose. In addition, in some cases where a particular illustrative embodiment includes a plurality of system elements or method steps, these elements or steps can be replaced by a single element or step. Likewise, a single element or step can be replaced by a plurality of elements or steps that serve the same purpose. Additionally, where parameters for various properties are specified here for illustrative modalities, these parameters can be adjusted up or down by 1/20, 1/10, 1/5, 1/3, 1/2, etc., or by rounded approximations, unless otherwise specified. Furthermore, while illustrative modalities have been illustrated and described with reference to the particular modalities, those skilled in the art will understand that various substitutions and alterations in shape and details can be made here without departing from the scope of the invention. In addition, other aspects, functions and advantages are also within the scope of the invention.
[0438] Illustrative flowcharts are provided here for purposes of illustration and not to limit methods. One of those skilled in the art will recognize that the illustrative methods may include more or less steps than those illustrated in the illustrative flowcharts and that the steps in the illustrative flowcharts can be performed in a different order than that illustrated.

权利要求:
Claims (19)
[0001]
1. Usable automatic injection device (100, 600, 1800, 2400, 2800, 4100, 5100) free of a battery to provide a subcutaneous injection of a therapeutic agent to a patient, the usable automatic injection device (100, 600 , 1800, 2400, 2800, 4100, 5100) FEATURED by the fact that it comprises: an accommodation (102, 202, 635, 735, 1802, 2002, 2102, 2402, 5102, 5204, 5302, 5404, 5504) comprising a part contact with the patient liable to be attached to the patient; an injection set arranged movably in the housing holding a hypodermic injection needle (118, 218, 625, 725, 1206, 1306, 1812, 2008, 5202, 5304) for patient insertion, the injection set being movable between a retracted position in which the injection needle does not protrude out of the housing and an extended position in which the injection needle protrudes out of the housing; a container (106, 206, 605, 705, 1102, 1202, 1302, 1400, 1606, 1706, 2004, 2506, 2804, 2902, 4104, 4602) provided in the housing to hold the therapeutic agent; a plunger (110, 210, 615, 715, 2408, 2508, 2802, 3916) movably disposed in the container to eject the therapeutic agent from the container into the injection set; a piston drive mechanism for driving the piston using a mechanical or hydraulic mechanism within the container; a retraction trigger (5312, 5314) that responds to a change of state of the usable automatic injection device from an injection state to a post-injection state, where the usable automatic injection device enters the post-injection state after the completion of the delivery of a therapeutically effective dose of the therapeutic agent and enters the post-injection state after the renaming of the patient's usable automatic injection device prior to the completion of the delivery of the therapeutically effective dose of the therapeutic agent; and a retraction mechanism (4810) for automatically retracting the injection set from the extended position in the injection state to the retracted position in the post-injection state upon activation by the retraction trigger.
[0002]
2. Usable automatic injection device according to claim 1, CHARACTERIZED by the fact that the container comprises a syringe, the ring comprising: a barrel part (106, 1102, 1202, 1302, 1400, 1606, 1706 , 2506, 2804, 3902, 4104) to maintain the therapeutic agent; and a syringe needle (120, 1304, 1402, 1604, 1704, 3904) coupled to a distal end of the barrel part to establish fluid communication between the barrel part of the syringe and the injection needle (118, 1306).
[0003]
3. Usable automatic injection device, according to claim 2, CHARACTERIZED by the fact that the injection set comprises: a membrane (114, 1408, 1610, 1811) which is pierceable by the se-ring needle (120, 1304 , 1402, 1604, 1704, 1808, 2512, 3904) of the syringe; and a fluid conduit extending (1406, 1602, 1700) between the injection needle and the membrane, where the perforation of the membrane by the syringe needle (120, 1402, 1604, 1808) of the syringe couples the barrel part (106 , 1102, 1202, 1302, 1400, 1606,1706, 2506, 2804, 3902, 4104) of the syringe and the injection needle; wherein the syringe needle (120, 1402, 1604, 1808) of the syringe is blown off the membrane (114, 1408, 1610, 1811) when the device is in a pre-injection state, and where the syringe needle ( 120, 1402, 1604, 1808) perforates the membrane (114,1408,1610,1811) when the device is in the injection state.
[0004]
4. Usable automatic injection device according to claim 1, CHARACTERIZED by the fact that the container comprises a cartridge (610, 710, 2004, 2104), the cartridge comprising: a barrel part (206, 605, 705, 1400,1606, 2004, 4104, 4602) to maintain the therapeutic agent; and a membrane (1610, 2108) that is pierceable by a piercing needle (220, 1304, 1402, 1604, 2010, 2112).
[0005]
5. Usable automatic injection device, according to claim 4, CHARACTERIZED by the fact that the injection set comprises: the puncture needle (220, 1304, 1402, 1604, 2010, 2112) to establish fluid communication between the barrel part (206, 605, 705, 1400, 1606, 2004, 4104, 4602) of the cartridge and the injection needle (218, 1306); and a fluid conduit (1502) provided between the injection needle and the piercing needle to establish fluid communication between the injection needle and the barrel portion of the cartridge; wherein the membrane (1610, 2108) of the cartridge (610, 710, 2004, 2104) is bleed from the injection needle of the injection set when the device is in a pre-injection state, and where the needle of the needle pierces the membrane when the device is in an injection state; and wherein the piercing of the membrane by the injection needle of the injection set establishes fluid communication between the barrel portion of the cartridge and the injection needle.
[0006]
6. Usable automatic injection device, according to claim 1, CHARACTERIZED by the fact that the container (106, 206, 605, 705, 1102, 1202, 1302, 1400, 1606, 1706, 2004, 2506, 2804, 2902 , 4104, 4602) and mobile inside the housing (102, 202, 635, 735, 1802, 2002, 2102, 2402, 5102, 5204, 5302, 5404, 5504) between a first position in a pre-injection state and a second well-followed in the injection state, in which the usable automatic injection device further comprises a container driver to automatically drive the container from the first position to the second position, in which a fluid path is established between the injection needle injection and the container when the injection set is in the extended position and the container is in the second position in the injection state.
[0007]
7. Usable automatic injection device according to claim 1, CHARACTERIZED by the fact that the plunger drive mechanism ejects the therapeutic agent into the patient at a controlled rate, in which a volume of the therapeutic agent ranging from 0, 8 millimeters to 1 millimeter and distributed over the device over a period of time ranging from 5 minutes to 30 minutes.
[0008]
8. Usable automatic injection device, according to claim 1, CHARACTERIZED by the fact that the piston drive mechanism comprises: a fusee (2810, 2426); and a lashing (2812 2442, 2516) coupling the guiding mechanism to the fusee and plunger.
[0009]
9. Usable automatic injection device, according to claim 8, CHARACTERIZED by the fact that the piston drive mechanism additionally comprises: a damping mechanism (2808, 2422, 2520, 3914) coupled to the fu-see to regulate the fusee movement; and a gear sequence (2420, 2438, 2518, 2814) including one or more gears for coupling the fusee to the damping mechanism.
[0010]
10. Usable automatic injection device, according to claim 1, CHARACTERIZED by the fact that the piston drive mechanism (3900) comprises: an orientation mechanism (3908); one or more spherical supports (3910) for coupling the guiding mechanism to the piston; and a damping mechanism (3914) coupled to the steering mechanism and the spherical supports to regulate the movement of the spherical supports.
[0011]
11. Usable automatic injection device according to claim 1, CHARACTERIZED by the fact that the plunger drive mechanism further comprises: a source (4106) of a working fluid to provide a hydraulic pressure to eject the agent therapeutics of the container; and a fluid conduit (4110, 4112) provided between the working fluid source and the plunger.
[0012]
12. Usable automatic injection device according to claim 11, CHARACTERIZED by the fact that the piston drive mechanism further comprises: a damping mechanism (4108) coupled to the container and the source of the working fluid to regulate ejection of the therapeutic agent in the container.
[0013]
13. Usable automatic injection device according to claim 12, CHARACTERIZED by the fact that the damping mechanism comprises a flow restriction element (4108) to maintain the hydraulic pressure downstream of the flow restriction element towards the container at a pressure less than the hydraulic pressure upstream of the flow restriction element towards the source of the working fluid, and in which the flow restriction element is coupled to the retraction trigger and where the delivery of the therapeutic agent to the container causes the flow restriction element to activate the retraction trigger.
[0014]
14. Usable automatic injection device according to claim 1, CHARACTERIZED by the fact that it further comprises: a needle locking mechanism (4608, 5408, 5508) to automatically lock the injection needle in the retracted position within the accommodation in the state of post-injection.
[0015]
15. Usable automatic injection device according to claim 14, CHARACTERIZED by the fact that the needle locking mechanism (4608, 5408, 5508) comprises: a protection mechanism (5208) movably arranged over an opening injection needle (5206) in the housing: wherein the injection needle opening is opened and allows the injection needle (5202) to protrude out of the housing when the protection mechanism is in a first position; and wherein the injection needle opening is closed and prevents the injection needle (5202) from protruding out of the housing when the guard mechanism is in a second position.
[0016]
16. Usable automatic injection device according to claim 14, CHARACTERIZED by the fact that the needle locking mechanism comprises: a needle lock release mechanism (5410, 5510) that responds to the retraction of the injection set to from the extended position in the injection state to the retracted position in the post injection state; and a hinge element (5508) coupled to the injection needle and the needle lock release mechanism; wherein activation of the needle lock release mechanism causes the hinge element to pivot the injection needle away from an injection needle opening in the housing.
[0017]
17. Usable automatic injection device, according to claim 1, CHARACTERIZED by the fact that the retraction trigger (5312, 5314) is activated by completing the delivery of a therapeutically effective dose of the therapeutic agent or by removing the delivery device usable automatic injection of the patient prior to completion of delivery of a therapeutically effective dose of the therapeutic agent.
[0018]
18. Usable automatic injection device, according to claim 1, CHARACTERIZED by the fact that, by actuation by the retraction trigger, the retraction mechanism automatically raises an injection button vertically (116, 216, 2006) holding the injection needle in the injection set.
[0019]
19. Usable automatic injection device, according to claim 1, CHARACTERIZED by the fact that the retraction trigger is coupled to the piston actuation mechanism or to a sensor piece (132, 232) provided at the bottom of the housing .

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法律状态:
2017-11-28| B25D| Requested change of name of applicant approved|Owner name: ABBVIE BIOTECHNOLOGY LTD. (BM) |

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2018-12-26| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-08-13| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-05-19| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2020-10-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-24| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 21/04/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US32663710P| true| 2010-04-21|2010-04-21|

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US61/326,637|2010-04-21|

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PCT/US2011/033504|WO2011133823A1|2010-04-21|2011-04-21|Wearable automatic injection device for controlled delivery of therapeutic agents|

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