“DROPLET GENERATOR DEVICE FOR USE IN THE SUPPLY OF A VOLUME OF OPHTHALMIC FLUID FOR AN EYE OF A SUBJ

专利摘要:
DROPS GENERATION DEVICE. The present invention relates to a method for providing suitable, repeatable safe dosages for a subject for topical, oral, nasal, or pulmonary use, and a droplet ejection device includes a fluid delivery system capable of delivering a defined volume. of the fluid in the form of droplets that have properties that provide an adequate and repeatable high percentage deposition upon application. The method and device include a housing, a reservoir arranged within the housing to receive a volume of fluid, an ejector mechanism configured to eject a flow of droplets having an average droplet diameter greater than 15 microns, the flow of droplets having a low flow of entrained air so that the flow of droplets deposits over the subject's eye during use.
公开号:BR112013001030B1
申请号:R112013001030-4
申请日:2011-07-15
公开日:2020-09-08
发明作者:Bernard L. Ballou Jr.；Jurgen Klaus Vollrath；Arthur H. Tew；Joshua Richard Brown；James Thornhill Leath；Nathan R. Faulks；Bradley G. Johnson；J. Sid Clements；Phillip E. Russel；John H. Hebrank；Tsontcho Ianchulev；Mark N. Packer；Troy ELLIOTT；Walter M. Fierson；Thomas J. Lindner；Charles Eric Hunter
申请人:Corinthian Ophthalmic, Inc.；
IPC主号:

专利说明:

[0001] [0001] This application claims the benefit of the filing date of US Provisional Application Number 61 / 400,864, filed on July 15, 2010, US Provisional Application Number 61 / 401.850, filed on August 20, 2010, US Provisional Application Number 61 / 401,920 filed on August 20, 2010, US Provisional Application Number 61 / 401,918 filed on August 20, 2010, US Interim Application 61 / 401,848 filed on August 20, 2010, US Provisional Application Number 61 / 401,849 filed on August 20, 2010, US Provisional Application Number 61 / 462,576 filed on February 4, 2011, US Provisional Application Number 61 / 462,791 filed on February 5, 2011, US Provisional Application Number 61 / 463,280 filed on February 15, 2011 , US Provisional Application Number 61 / 516,462, filed on April 4, 2011, US Provisional Application Number 61 / 516,496 filed on April 4, 2011, US Provisional Application Number. 61 / 516,495, filed on April 4, 2011, and U.S. Provisional Application Number 61 / 516,694, filed on April 6, 2011, the entire content of each of which is hereby specifically incorporated by reference for all purposes. This application is also related to U.S. Provisional Application Number 61 / 396,531 filed on May 28, 2010, which entire content of which is hereby specifically incorporated by reference for all purposes. Background of the Invention
[0002] [0002] The use of spray applicators to administer products in the form of mists or sprays is an area with great potential for safe, easy-to-use products. The biggest challenge in providing such an applicator is to provide a consistent and accurate supply of adequate doses.
[0003] [0003] An important area where spray applicators are needed is in the supply of eye medications. The application of fluids, as in the case of eye drops, has always presented a problem, especially for children and animals which tend to blink or shake at the critical moment, causing the droplet to land on the eyelid, nose or other part of the face. The impact of a large drop of fluid on the eyeball, especially when the fluid is at a different temperature, also tends to produce a blink reaction. The elderly also often lose the manual coordination needed to place eye drops inside their oils. Stroke victims also have similar difficulties. The supply of drippers often requires a specific physical position, such as tilting the head to a horizontal position. None can be practical.
[0004] [0004] It is often critical that the patient administer the correct dose the requested number of times per day. However, in practice, patients who are prescribed eye medications for home use tend to forget to dose, or over-dose or cross-dose with other medications. One of the biggest problems with obedience is that, even if the patient is attentive to following the treatment regimen, he or she often forgets to dose.
[0005] [0005] Currently, many of these medications are administered by eye drippers. Current eye drop devices often either require the head to be tilted back, the patient to lie down or provide a traction downward on the lower eyelid or a combination of traction and tilt, as the delivery mechanism is typically based on gravity to apply the medication. This is not only uncomfortable, but involves a good amount of coordination, flexibility and cooperation on the part of the patient to ensure that the medication enters the eye while avoiding hitting the eye with the tip of the drip. Eye drip bottles are at risk of hitting the user's eye, potentially causing physical damage to the eye, and also exposing the tip to bacterial contamination due to contact with the eye. As such, the patient is at risk of contaminating the medication inside the eye drop bottle and subsequently infecting the eye. In addition, a large volume of the medication flows out of the eye or is washed away by the tearing reflex. As a result, this method of administration is also inaccurate and wasteful. Furthermore, technology does not provide a satisfactory way to control the amount of medication that is applied, nor does it provide a way to ensure that the medication that is applied does indeed land on the eye and remain on the eye.
[0006] [0006] Eye drippers also do not provide a way of checking compliance with a patient. Even if after one week of use the eyedropper bottle could be checked for the total volume of medication applied, for example, weighing the bottle, this does not provide a day-to-day obedience record. A patient may have missed one or more doses and overdosed on other occasions. Also, the poor precision with which eye drippers deliver eye drops leaves a question whether the medication actually enters the eye, although it may have been applied.
[0007] [0007] Consequently, there is a need for a delivery device that provides safe, suitable, and repeatable dosages for a patient for ophthalmic, topical, oral, nasal, or pulmonary use. Summary of the Invention
[0008] [0008] The present invention relates to a device and method providing safe, suitable, and repeatable dosages for a patient for ophthalmic, topical, oral, nasal, or pulmonary use. The present invention also includes a fluid delivery system capable of delivering a defined volume of the fluid in the form of droplets that have properties that generate an adequate and repeatable high percentage deposition upon application.
[0009] [0009] The present invention includes and provides a device for delivering fluid to a patient's eye, the device comprising a housing; a reservoir arranged inside the housing to receive a volume of fluid, an ejector mechanism configured to eject a stream of droplets having an average droplet diameter greater than 15 microns, the droplet stream having a low flow of entrained air the flow of droplets to deposit over the patient's eye during use.
[0010] [00010] The invention further includes and provides a device in which the ejector mechanism comprises a plate an ejector plate that has a first surface that engages a fluid supply area of the reservoir, the ejector plate including a plurality of openings formed through its thickness, an actuator coupled to a second surface of the ejector plate, the actuator being operable to oscillate the ejector plate at a frequency and generate a directed flow of droplets.
[0011] [00011] Yet another implementation of the invention includes and provides a device for delivering a volume of ophthalmic fluid to an eye, which comprises a housing, a reservoir arranged within the housing to receive a volume of ophthalmic fluid, an ejector plate being in communication. fluid with the reservoir, the ejector plate including a plurality of openings formed through its thickness, an actuator formed on a surface of the ejector plate, opposite the reservoir, the actuator being operable to oscillate the ejector plate in a frequency and generate a directed flow of droplets, where the droplets in the directed stream have an average ejection diameter in the range of 5-2500 microns, including, but not limited to 20-100 microns, and an average initial velocity in the range of 1-100 m / s, including but not limited to, 2-20 m / s.
[0012] [00012] Yet another implementation of the invention includes and provides a method for delivering a volume of ophthalmic fluid to a patient's eye, the method comprising ejecting a directed flow of droplets of an ophthalmic fluid contained in an aperture reservoir of an ejector plate , the droplets in the directed stream having an average ejection diameter in the range of 5-2500 microns, including but not limited to 20-100 microns, and an average initial velocity in the range of 1-100 m / s, including but not limited to , 2-20 m / s. Brief Description of Drawings
[0013] [00013] Figure 1 shows a three-dimensional view of a presentation of a substrate structure of an ejector device.
[0014] [00014] Figure 2 is a cross section through an implementation of a substrate.
[0015] [00015] Figure 3A is a cross section through an implementation of an ejector device that includes a reservoir.
[0016] [00016] Figure 3B is an alternative implementation of an ejector device with an alternative reservoir arrangement.
[0017] [00017] Figure 4 shows a circuit diagram of an implementation of an electrical circuit that forms part of the fluid ejector device of the invention.
[0018] [00018] Figure 5 shows a three-dimensional view of a device housing.
[0019] [00019] Figure 6 shows a circuit diagram of an electrical circuit used in an implementation of the device.
[0020] [00020] Figure 7 shows a three-dimensional view of another implementation of the device housing.
[0021] [00021] Figure 8 shows a side view of an implementation of the invention providing a medication for a human eye.
[0022] [00022] Figure 9 shows a front view of an implementation of Figure 8.
[0023] [00023] Figure 10 shows a side view of another implementation of the device.
[0024] [00024] Figure 11 shows a front view of yet another implementation of the device.
[0025] [00025] Figure 12 shows a front view of yet another implementation of the device.
[0026] [00026] Figures 13A-B show another implementation of the device that includes a spacer.
[0027] [00027] Figures 14A-B show another implementation of the device that includes a spacer.
[0028] [00028] Figures 15A shows another implementation of the device that includes a spacer.
[0029] [00029] Figures 15B-H show several examples of coverage.
[0030] [00030] Figure 16A shows a schematic cross-sectional view of another implementation of the device that uses a piezoelectric ejector mechanism.
[0031] [00031] Figure 16B shows an enlarged top view of the assembly.
[0032] [00032] Figure 16C shows an enlarged cross-sectional view of a portion of the assembly.
[0033] [00033] Figure 16D shows a schematic rear view of the assembly.
[0034] [00034] Figure 16E shows a schematic cross-sectional view of a portion of the assembly.
[0035] [00035] Figure 16F shows a schematic top view of an ejection region of the assembly.
[0036] [00036] Figure 16G shows a partial cross-sectional view of the ejector plate of the assembly.
[0037] [00037] Figure 16H shows a perspective view of a portion of the assembly, which includes an alternative implementation of the reservoir.
[0038] [00038] Figure 16I shows a sectional view of a portion of the assembly shown in Figure 16H.
[0039] [00039] Figures 16L-R show partial cross-sectional views showing examples of shapes for the openings in the ejector plate.
[0040] [00040] Figures 17A and 17B show cross-sectional views of activated ejector plates.
[0041] [00041] Figures 18A-C show graphs of droplet stopping distance versus average droplet diameter.
[0042] [00042] Figure 18D shows a graph of droplet evaporation time versus average droplet diameter.
[0043] [00043] Figures 19A-F show directed flows of droplets of different average size.
[0044] [00044] Figure 20 shows a perspective view of a portion of the assembly, which includes an alternative implementation of the reservoir.
[0045] [00045] Figure 21A shows an alternative implementation of the device with a sliding cover in the closed position.
[0046] [00046] Figure 21B shows an alternative implementation of the device with the sliding cover open.
[0047] [00047] Figure 21C shows a perspective view of Figure 21A.
[0048] [00048] Figure 21D shows a perspective view of the rear of the device shown in Figure 21A.
[0049] [00049] Figure 21E shows an exploded perspective view of the housing parts of the device of Figure 21A in an implementation.
[0050] [00050] Figure 21F shows a diagram showing the device aligned with a user's eye.
[0051] [00051] Figure 22A shows a communications system that includes the device.
[0052] [00052] Figure 22B shows a block diagram showing a device and a docking station in communication.
[0053] [00053] Figure 22C shows a block diagram of a processor and driver circuit.
[0054] [00054] Figure 23A shows a top view of an exemplary configuration that includes the electronics module.
[0055] [00055] Figure 23B shows a bottom view of the exemplary configuration that includes the electronics module.
[0056] [00056] Figure 24 shows an exemplary process for operating the device.
[0057] [00057] Figure 25 shows another exemplary process for operating the device.
[0058] [00058] Figure 26 shows methods for illuminating the surface of the ejector.
[0059] [00059] Figure 27 shows a graph of the ratio of nozzle speed to terminal speed as a function of droplet diameter.
[0060] [00060] Figure 28 shows a graph of evaporation time as a function of droplet diameter for water at NTP
[0061] [00061] Figure 29 shows a graph of the percentage of mass deposition as a function of droplet diameter and distance from the ejection plate.
[0062] [00062] Figure 30 shows a graph of the percentage of mass deposition as a function of distance from the ejection plate and droplet diameter. Detailed Description
[0063] [00063] The present invention relates generally to ejection devices useful, for example, in the delivery of a fluid such as an ophthalmic fluid to the eye. In certain respects, ejection devices include an ejection assembly which generates a controllable flow of fluid droplets. The fluid includes, without limitation, suspensions or emulsions which have viscosities in a range capable of droplet formation using an ejection mechanism.
[0064] [00064] As explained in further detail, in accordance with certain aspects of the present description, the ejector mechanism presently described can form a directed flow of droplets which can be directed towards a target. The droplets will be formed in size distribution, each distribution having an average droplet size. The average droplet size can be in the range of approximately 15 microns to more than 100 microns, greater than 20 microns to approximately 100 microns, approximately 20 microns to approximately 80 microns, approximately 25 microns to approximately 75 microns, approximately 30 microns to approximately 60 microns, approximately 35 microns to approximately 55 microns, etc. However, the average droplet size can be as large as 2500 microns, depending on the intended application. In addition, the droplets can have an average initial velocity of approximately 0.5 m / s approximately 100 m / s, for example approximately 0.5 m / s approximately 20, for example, 0.5 to 10 m / s, approximately 1 m / s approximately 5 m / s, approximately 1 m / s approximately 4 m / s, approximately 2 m / s, etc. As used herein, the ejection size and initial velocity are the initial size and velocity when the droplets leave the ejection plate. The flow of droplets directed at a target will result in the deposition of a percentage of the droplet mass including its composition over the desired location.
[0065] [00065] Fluids suitable for use by the ejection device may have very low viscosities, for example, as water at 1 cP, or less, for example, 0.3 cP. The fluid can additionally have viscosities in ranges up to 600 cP. More specifically, the fluid can have a viscosity range of approximately 0.3 to 100 cP, 0.3 to 50 cP, 0, 3 and 30 cP, 1 cP to 53 cP, etc. In some implementations, solutions or medications that have adequate viscosities and surface tensions can be used directly inside the reservoir without modification. In other implementations, additional materials can be added to adjust the fluid parameter.
[0066] [00066] The technology presented includes droplets ejected without substantial evaporation, air entrainment, or deflection of the eye surface, which facilitates consistent dosing. The average ejection droplet size and average initial velocity are dependent on factors including fluid viscosity, surface tension, ejector plate properties, geometry and dimensions, as well as operating parameters of the injector mechanism including its frequency of activation. In some implementations, approximately 60% to approximately 100%, approximately 65% to approximately 100%, approximately 75% to approximately 100%, approximately 80% to approximately 100%, approximately 85 to approximately 100%, approximately 90% to approximately 100% , approximately 95% to approximately 100%, etc., of the mass ejected from droplets are deposited on the surface of the eye, such deposition being repeatable. The flow direction of the droplet flow can be horizontal, or any direction a user chooses to point the actuation mechanism during use.
[0067] [00067] Without wishing to be limited by this theory, it is believed that as the droplet diameter decreases, the ratio of the total surface area to the total volume increases. That is, more surface area is exposed for a given total fluid volume. Therefore, smaller droplets can create a larger surface area which creates more drag. In the low Reynolds number regime (Re <1), the drag force is given by Stoke's law, a solution to the Navier-Stokes equations. Thus, the drag force is believed to be proportional to the square root of the surface area of a droplet. Assuming the droplet is spherical, the drag force is believed to be the ratio to the droplet diameter.
[0068] [00068] Each particle carries air along with it (entrained air), creating an air flow. This effect of this flow of entrained air is believed to be approximately proportional to the diameter. When the airflow hits a target, it can deflect or suddenly turn, say 90 degrees adjacent to the target's surface to maintain the flow. If the flow of the air flow is very large, it can load some of the droplets with it, causing them to deflect and not deposit on the target's surface. Particles with a sufficiently large moment will overcome this effect and deposit successfully on the surface. The stopping distance is an approximation of the distance the particle will travel before the initial moment is reduced to zero by air friction. The entrained air created by surrounding particles will increase the stopping distance, giving each droplet the widest possible range and more opportunity for deflection. The droplets also fall vertically during their flight path due to gravity. After a short time of acceleration, the droplets reach their terminal speed where the drag force is equal and opposite to the gravitational force. Larger particles fall faster because the terminal velocity is proportional to its surface area. The droplet life span also depends on the local and ambient partial pressures, the local and ambient temperatures, the particle diameter, all of which affect this evaporation rate. Generally, larger particles will evaporate more slowly.
[0069] [00069] Again not limited by any specific theory, the droplets are formed by an actuation mechanism that forms the flow of fluid droplets contained in a reservoir coupled to the ejector mechanism. The ejector mechanism and the reservoir can be disposable or reusable. These can be packed inside an accommodation. The housing can be disposable or reusable. The housing can be portable, miniaturized, formed to attach to a base, and can be adapted for communication with other devices. The housings can be color coded or configured for easy identification. Droplet ejection devices, in some implementations, may include a lighting medium, an alignment medium, a temperature control medium, a diagnostic medium, or other characteristics. Other implementations may be part of a larger network of interconnected and interacting devices used for patient care and treatment. The ejector in an implementation can be a thermal injector. In another, it may be an ultrasonic ejector. In yet another implementation, the ejector can be a piezoelectric ejector.
[0070] [00070] Figures 18A-C show the stopping distances in the still air of the droplet that have different droplet diameters and at an ejection speed of 0.5 m / s, 1 m / s, and 2 m / s, respectively. Specifically, referring to Figure 18A, in this implementation, the longest stopping distance of a droplet that has an ejection diameter of 100 microns or less and an initial speed of 0.5 m / s is approximately 1.25 cm. Consequently, in this implementation, without the aid of an air flow, these droplets cannot be effectively deposited within an eye located more than 1.25 cm away from the ejection plate 102. Referring to Figure 18B, the longest stopping distance of a droplet that has an ejection diameter of 100 microns or less and an ejection speed of 1 m / s is approximately 2.2 cm. Consequently, in this respect, without the aid of an air flow, these droplets cannot be effectively deposited within an eye located more than 2.2 cm away from the ejector plate 1902 (Figure 19A). Referring to Figure 18C, the longest stopping distance of a droplet that has an ejection diameter of 100 microns or less and an ejection speed of 2 m / s is approximately 4 cm. Consequently, without the aid of an air flow, these droplets cannot be effectively deposited within an eye located more than 4 cm away from the ejector mechanism. Stopping distances for fluids containing ingredients other than water may differ from those shown in Figures 18A-C.
[0071] [00071] Before reaching the target, the ejected droplets can evaporate in the air. The delivery of droplets that have an ejection speed of approximately 1 m / s to approximately 5 m / s to a target located approximately 3 cm from the ejector mechanism can take approximately 0.03 s or less to reach the surface of the target. Without wishing to be limited by this theory, it is believed that the rate of evaporation is related to the diameter of the droplets and the environmental parameters that include temperature and humidity. It is also believed that a long evaporation time, for example, longer than the supply time of approximately 0.03 s, is desired to effectively deposit the droplets. Assuming the temperature is 20 ° C and the fluid is water, Figure 18D shows that a droplet that has a diameter of approximately 40 microns evaporates completely in approximately 1 s, and a droplet that has a diameter of approximately 100 microns evaporates completely. in approximately 10 s. In some implementations, a saline solution or other additives can be added to the fluid to reduce the rate of evaporation.
[0072] [00072] Figures 19A-F show the deflection of the droplets and the entrained air flow against a target. Droplets without sufficient moment to counteract the forces of this flow are carried by it and are similarly deflected. After all, those droplets that have enough momentum, either due to high speed or high mass or both, continue on their own trajectory and are not carried by the air flow. These droplets can be effectively delivered to the target. Sufficient momentum can be achieved from a high initial ejection speed and a moment to drag ratio. Speed, however, should not create discomfort when the droplets impact the target, whether the target is for human or animal use, and should not be such as to adversely affect other parameters such as drag. Alternatively, a sufficient moment can be achieved by an increase in the mass of the droplet.
[0073] [00073] Referring to Figures 19A-F, in this implementation, water droplets 1912 that have different average ejection diameters are ejected at an ejection speed of 4 m / s from an ejector plate 1902 horizontally towards a localized 1916 surface 3 away from the ejector plate 1902. The surface 1916 may be a glass surface that has characteristics, for example, smoothness, similar to an eye surface. Other than the diameter of the openings (for example, as the openings 1626 of Figure 16A) in the ejector plate 1902, all other parameters are kept the same in all Figures 19A-F.
[0074] [00074] Referring to Figure 19A, in this implementation, the droplets ejected 1912 have an average ejection diameter of approximately 11 microns. The flow 1914a of the droplets 1912 has a variable cross-sectional area, indicating that some of the droplets 1912 may have stopped before reaching the surface 1916. Furthermore, a substantial amount 1918a of droplets 1912 reaching the surface 1916 is carried by air to the air. along the 1916 surface without being deposited on the surface.
[0075] [00075] Referring to Figure 19B, in this implementation, the ejected droplets have an average ejection diameter of approximately 17 microns. The 1914b flow of the 1912 droplets also has a variable cross-sectional area (like the 1914a flow), indicating that some of the droplets may have stopped before reaching the 1916 surface. However, the cross-sectional area variation of the 1914b flow is less than the 1914a flow variation. As a result, more droplets 1912 in flow 1914b reach the surface 1916 than in flow 1914a. However, a substantial quantity 19 of droplets 1912 reaching the surface 1916 is carried by air along the surface 1916 without being deposited on the surface 1916. The quantity 1918b is greater than the quantity 1918a so that despite a greater number of droplets 1912 reach surface 1916, the amount deposited on surface 1916 does not increase substantially compared to Figure 19A.
[0076] [00076] Referring to Figure 19C, the ejected droplets have an average ejection diameter of approximately 32 microns. The 1914c flow of the 1912 droplets has a cross-sectional area that varies substantially less than those of the 1914a, 1914b flows, indicating that very few droplets may have stopped before reaching the 1916 surface. Furthermore, a 1918c amount of 1912 droplets reaching the surface 1916 and airborne along the surface 1916 without being deposited on the surface 1916 is less than the quantities 1918a, 1918b.
[0077] [00077] Referring to Figures 19D-19E, in this implementation, the ejected droplets have average diameters of approximately 56 microns, 100 microns, respectively. Figure 19F shows the ejection of large droplets. The streams 1914d, 1914e, 1914f of the droplets 1912 have a substantially constant cross-sectional area, indicating that substantially no droplets stopped before reaching the 1916 surface. Furthermore, substantially no 1912 droplets reaching the surface 1916 are carried along the surface. 1916 without being deposited on the surface.
[0078] [00078] In summary, the calculations in Figures 18A-D and the photographs in Figures 19A-F suggest that the airflow may have an undesirable effect of loading the droplets across the target surface by the movement of the entrained airflow and through this prevents them from depositing on the target. Furthermore, this undesirable effect is more pronounced for smaller droplets. Without wishing to be limited by this theory, it is believed that this problem occurs with small droplets for a number of reasons more fully described below.
[0079] [00079] In addition, loading the droplets can improve your ability to reach the target. The human body, and especially the moist eye surface, is a conductor, so it can attract charged droplets to help it contact the target. While not wishing to be limited by this theory, the charged droplets form a charge cloud of space while in transit to the target. This charge of space creates an electric field E which repels droplets similarly charged to the target by Coulomb's force. When a drop approaches the target, the charged droplet's electric field creates an equal and opposite image charge on the conductive target which attracts the droplet.
[0080] [00080] Several methods for loading the droplets are known. A charge by tribocharging (by friction), apply a voltage to the ejector plate and charge the droplets by induction, and charge by high voltage corona discharge to generate gas ions and charge the droplets by Pauthenier field charging and / or charging diffusion are three such examples. In the tribocharging, the fluid is passed through small holes, for example, through an ejection plate or grid, which results in loading. The effect can be improved by coating the ejection plate or grid.
[0081] [00081] The droplet ejection device includes an ejection mechanism. In some implementations, the mechanism includes an ejection plate or substrate. In some implementations, this is coupled to a fluid reservoir, examples of which are discussed here. An implementation of the ejector mechanism can be a thermal ejector (or "bubble jet"). The implementation of Figure 1 shows a substrate structure 100 with multiple openings 102 formed within the substrate structure. This can be achieved by any of a number of known techniques. This substrate can be formed in a microelectromechanical system (MEMS). Mass micromachining is one of the known techniques for forming silicon-based MEMS. MEMS can be formed on a substrate structure, for example, a silicon substrate. MEMS can be formed in a similar way in a semiconductor package. Alternatively, the mechanical and electronic components can be formed separately and subsequently adhered to each other.
[0082] [00082] In the implementation shown in Figure 1, only 12 openings are shown for illustrative purposes. However, several hundred or even many thousands of openings can be formed on a substrate that has, for example, 0.5 cm x 0.5 cm of surface area. In this implementation the substrate structure is shown inverted with its most distant surface 104 and its closest surface 106. As shown in the implementation of Figure 1, each of the openings 102 is provided with a heating element 108 that surrounds the opening over the most distant surface 104. Thus the MEMS device defines a substrate structure as a disk with multiple channels defined by the openings 102 extending in this implementation from the most distant surface to the closest as shown in Figure 2. The heating elements 108, in this implementation , are shown at the bottom of the channels on the most distant surface. An intervening substrate material, referred to herein as streets 110, is formed between channels 102.
[0083] [00083] In one implementation the openings can be formed in the substrate having a radius of 37 microns and a substrate thickness of 74 microns with intervening streets of 12 microns for a distance from center to center 86 microns. Assuming spherical drops are emitted from each of the openings, the volume of material inside each opening will be ∏ r2x t = ∏ (372 x 74) x 10-18 = 3.18x10-13 m3 = 318 picoliters. The amount of area (opening area and surrounding streets) for each unit or opening is like this (37 + 12 + 37) 2 μm2 = 7.396x10-9 m2. Thus on a substrate of 0.5 cm x 0.5 cm = 0.25x10-4 m2 this provides a total of 3380 openings for a total fluid volume within the openings of approximately 1 μl.
[0084] [00084] In the above implementation an opening size of 74 microns was selected, which provides quite large drops of fluid. It will be appreciated that the opening size chosen will depend on the viscosity of the chemical. The active cycle or firing rate of the openings also depends on the volume flow that is desired and will depend on the application. In an implementation droplet sizes of the order of 300 pL can be ejected from the ejector manufactured from a substrate with an aperture diameter to substrate thickness ratio of 10: 1 to 1:10.
[0085] [00085] In some implementations the use of materials that have a higher operating temperature and a lower coefficient of thermal expansion and also provide a higher thermal conductivity and a lower heat capacity for quick cooling and improved control of active cycle can be used. The preferred material also has a high parameter of thermal shock, as it is provided, for example, by silicon carbide (SiC) or any of its polytypes (different atomic dispositions). In the present implementation the substrate can be made of silicon carbide which has a 6H crystal lattice configuration.
[0086] [00086] As mentioned above, although SiC always involves a combination of silicon and carbon, the crystal lattice structure can vary and includes structures such as 3C atomic (cubic) arrangements with the atoms located in the corners of the cubes that form a lattice structure, or a hexagonal arrangement (4H or 6H) that repeats every four or six layers or rhombohedral arrangement. A comparison of the dispositions and properties of 3C, 4H and 6H is provided in the table below. Such properties can provide guidance for the selection of the appropriate substrate material.
[0087] [00087] As discussed above in this implementation, the substrate is coupled to a reservoir. In Figure 3A, the substrate material 300 with its openings 302 is attached to a substrate that has a central cavity 306 engraved in it to define a housing 304 which, in this implementation, is also made of silicon carbide and defines a chamber 306 between substrate material 300 and housing 304. Chamber 306, in its operating state, is filled with the fluid to be applied. It will be appreciated that more than one housing may be trapped in the substrate material 300, thereby allowing some openings in the substrate material 300 to be in flow communication with the fluid within a chamber while other openings are in flow communication. another fluid. This allows fluids to be mixed by firing a selected number of openings from each group. As shown in Figure 3A an inlet channel 310 is formed in a wall of housing 304 to provide fluid communication with a fluid source for refilling the chamber within housing 304.
[0088] [00088] Figure 3B shows an alternative implementation of the invention. In this implementation, more than one medication can be ejected from the thermal ejector, for example, providing the ejector with multiple holes and providing some of the holes with a first medication and other holes with a second medication, or providing multiple reservoirs, each feeding a different set of holes, as shown in Figure 3B, which shows a disposable reservoir unit 700 which, in this implementation, comprises 4 reservoirs 702, which are attached to a substrate structure 710 (shown here before attachment to the reservoirs) . The controller can be configured to control which holes to fire and the number of times each hole must be fired in succession, thereby allowing different dosages of the various medications to be provided, either simultaneously, or at different times.
[0089] [00089] In order to eject the fluid droplets from the substrate openings, the heating elements such as the elements 108 shown in Figures 1 and 2 are rapidly heated to vaporize the intervening fluid within the heating element loop to compress out the fluid into the channel and effectively shoot the fluid droplets out of the opening through the force generated by the fluid vapor. It will be appreciated that the droplet size and speed will vary depending on many factors including fluid viscosity, surface tension, ejector plate properties, geometry, and dimensions, as well as the operating parameters of the ejector including its cycle active or trigger frequency. As an example, for aperture diameters and lengths of 5 microns, 15 microns, and 38 μm, the droplet volumes are 0.1 picoliters (one millionth of a microliter), 2.7 picoliters and 44 picoliters, respectively.
[0090] [00090] As mentioned above, the present invention makes use of a substrate material such as SiC, which has a high operating temperature to withstand the high heating of the fluid being ejected, a low thermal expansion coefficient (meaning that as the temperature changes, the material remains fairly constant in size), provides high thermal conductivity (thereby allowing rapid heat dissipation between heating cycles to allow precise control of the active cycle), low heat capacity, and high parameter of thermal shock. The material parameters allow you to quickly heat the fluid, causing the fluid disc inside the openings that is surrounded by the heating element to heat very quickly to its boiling point, thereby explosively propelling the fluid droplet above the steam disc from the end closest to the opening. Another suitable substrate material such as silicon can be used.
[0091] [00091] In an implementation, an electrical circuit heats the fluid and affects the droplet ejection process. An implementation of this circuit is shown in Figure 4. An electrical power source in the form of a 400 battery or voltage generator is connected in parallel with the heating elements 404. Controllable switches 406 in this implementation take the form of relays that include a solenoid 408 controlled by a processor 410. Although Figure 4 shows only two resistive elements 404 and two switches 406 controlled by processor 410, it will be appreciated that processor 410 preferably controls each of the heating elements formed around the substrate openings. Thus the processor can control which openings and how many openings to fire and how many times per second to do so in order to obtain a desired volume of fluid. Although this implementation makes use of heating elements formed around the openings, other implementations make use of other configurations of heating elements, for example, plates mounted inside, above, or below opening inlet tubes (through which the fluid inside the hole is refilled).
[0092] [00092] One benefit of the implementation is that it provides the ability to precisely control the droplet ejections by controlling the openings to fire and the selection of the number of openings to fire. It also allows two or more medications to be mixed at the time of ejection, providing different opening sets with different reservoirs filled with different medications. The ratios of two or more medications can be precisely controlled by determining the number of openings to fire for each set or by adjusting the active cycles for each set. The small droplet size of the drugs emitted from the substrate material also ensures a complete mixing of the drugs as they are emitted.
[0093] [00093] An implementation of the droplet ejection device is shown in Figure 5. This shows a substrate structure 500 of a thermal ejector implemented as a MEMS device and housed within a housing 502. Housing 502 includes a trigger 504 actuated by hand, a 506 eye sensor in the form of a CCD network or a near infrared (NIR) sensor to detect an eyeball or the eye's retina, a 508 light source (in this case a focused LED that provides a substantially low intensity along the ejection path of the thermally ejected fluid droplets), and a reservoir 514 which in this case is releasable trapped in housing 502 and is in flow communication with the holes in the substrate structure 500. The reservoirs can be refilled, allowing the rest of the applicator to be refilled.
[0094] [00094] Figure 6 shows a processor 600 that is mounted on a circuit board inside the housing 502 and controls the current flow through an electrical circuit of the power source 602 (implemented in this implementation by a battery) for the elements of heating 604 of the thermal ejector. In this implementation the electrical circuit includes three switches connected in series as shown by the circuit in Figure 6. The first switch 610 is controlled by trigger 604 actuated by hand. The second switch 612 is controlled by processor 600 in response to signals provided by eye sensor 506. The circuit also includes a second heating element 620, a Peltier 622 cooler that are selectively activated based on signals provided to processor 600 by a 624 temperature sensor. In response, processor 600 closes switch 630 or 632 to either heat or cool the fluid within the holes in the substrate structure. Other suitable circuits can be replaced by the one shown in Figure 6.
[0095] [00095] Another implementation of the invention is shown in Figure 7, which shows a three-dimensional view of a contact lens solution applicator of the invention. In this implementation the fluid is applied using a thermal ejector 700. A cover 702 is shown in its recessed position but is movable to a closed position by sliding cover 702 upwards to cover the thermal ejector 700. A button 704, which can be activated by the thumb, controls the application of the fluid. This implementation can also be implemented as a disposable device, just as portions of it can be disposable. For example, a replaceable reservoir or cartridge can be used. In practice, a user can attach reservoir 512 to the housing, for example, if the reservoir is disposable and requires replacement.
[0096] [00096] The device can be aimed at the target, for example, a human or animal eye, using an LED, for example, LED 708, to help align the applicator correctly. Since the eye sensor, for example, sensor 506, detects an eye, it sends a signal to processor 600, which closes second switch 612, which is implemented as a relay in this implementation, to allow the current from the power source to the heating elements of the thermal ejector. An implementation of the device which could be incorporated into any of the implementations may include an ejector assembly and an LED that turns on when the device is turned on, for example, by a power switch or by lifting the device from a docking station. The LED light is illuminated over the target, for example, the patient's eye to correctly aim the eye before applying the fluid. The device may include a support, support, or spacer to assist in alignment as discussed below.
[0097] [00097] Other implementations to ensure the correct alignment of the device with the eye are also contemplated. These implementations, examples of which are shown in Figures 8-13B, can be formed as hand-held or palm-held units and can be miniaturized to an additional degree for additional applications. In one implementation, shown in Figures 8 and 9, a mirror 800 is provided over the housing to reflect an image of the user's eye back into the user's eye when the device is correctly aligned with the eye. In this implementation a reticle is provided over the mirror, as shown in the front view of Figure 9, to help the user center the device for ejecting fluid into the eye. The implementation of Figures 1 and 2 also includes an LED 810 to alert the user when a dose is due and a second LED 812 to illuminate when a total dose has been delivered.
[0098] [00098] Figure 9 shows another implementation. An infrared transmitter 800 (for example, an IR LED) and an infrared (IR) photodetector 801 are mounted on the front surface of the device to transmit an infrared beam or pulse, which is received by an infrared photodetector 802 when the device is correctly aligned with the eye and the IR beam or pulse is reflected from the eye.
[0099] [00099] Yet another implementation of the invention is shown in Figure 10, which makes use of a conical glove 1000 to position the eye in relation to the thermal ejector. The glove 1000 can, for example, be implemented as a rubber or silicone cover, and can serve the additional function of providing a shaded or darkened image formation zone to form the image of the eye with a scanner or a camera. A button 1002 is mounted on the device to trigger the fluid ejection, and a second button 1004 is used to trigger an image capture device (not shown) mounted on the device under the sleeve 1000.
[0100] [000100] Figure 11 shows another implementation of a low intensity light beam, for example, a light emitting diode (LED) 1100 emits a beam when a button 1102 is pressed. The light beam is configured to shine inside the user's eye when the thermal ejector 1106 or other fluid applicator of the device is correctly aligned with the eye, as shown by the implementation of Figure 11. This implementation does not have a camera to capture an image of the eye, but it simply serves to apply a fluid, for example, a washing fluid or medication into the eye by pressing a button or a switch 1104. The button 1104, in the case of a thermal ejector closes a switch to heat the heating elements of the thermal ejector or send a signal to a controller to control one or more heating elements of the ejector as described in more detail below.
[0101] [000101] In Figure 12, an image capture device, which includes cameras, scanners, or other sensors without limitation, for example, load-coupled device (CCD), 1200, can be provided to detect the presence of an eye and ensure that the eye is open. The eye sensor provides control information, which in an implementation provides a control signal to a controller or processor in the device to control fluid ejection. Thus, a processor is included in such implementations to control activation of the ejector mechanism to eject fluids only when the camera image indicates that the eye or a predefined area of the eye is correctly aligned with the fluid applicator. Thus, for example, with a thermal ejector, only the holes that are correctly aligned with the eye can eject the fluid. The device can readily take into account the delay between the camera signal and the device's droplet ejection and can provide a time to overcome the blinking cycle.
[0102] [000102] Implementations of the device provide numerous benefits over other devices for many reasons. For example, not only does this ensure that the fluid that is applied is applied inside the eye allowing the device to be correctly aligned, the device is able to apply at speeds that ensure it overcomes the blink of an eye. Using a thermal ejector-based system according to the invention and integrating it with an optical camera or other eye detector or eye sensor to provide feedback to the device ensures that the eyelid is open and that the eye is correctly closed aligned with the thermal ejector. Only when it is determined that the eye is open will the applicator of the invention apply a carefully measured dose of medicine or vaccine in the form of a fine mist directly into the eye. The sub-second response time is specifically useful for people or animals that are sensitive to anything that comes close to their eyes ensuring that the delivery speed is able to "overcome the blink". Other benefits of the device include providing selectively quantified and repeatable results by applying a precisely controllable volume of a fluid such as a medication or vaccine.
[0103] [000103] Different implementations as understood and described allow a user to turn on the device. A user can simply lift the device from a base which then activates or turns on the device. The user can also turn on the device by pressing a trigger, such as the 504 trigger. In some implementations, where the ejector mechanism is thermal or ultrasonic, attaching the trigger or turning on the device begins to heat or cool the device or its portions to a temperature predetermined. For example, the device can be heated or cooled down to the body temperature of a human or animal.
[0104] [000104] After the device is turned on, the ejection mechanism can be triggered. In the implementation of Figures 8 and 9, the activation trigger 802 serves as the triggering mechanism for firing the holes in the actuation mechanism, subject to control by a controller in the device that monitors the amount of fluid that needs to be applied and the amount of fluid that has already been applied. Of course, the button can be any suitable means of connecting a device including electrical and mechanical activation triggers, push buttons, levers, slide switches, tactile switches including momentary switches, pressure blocks, motion sensors, magnetic and effect switches. Hall, electrostatic switches, resistive or capacitive touch switches, Reeves switches, infrared operated switches, radio frequency, light, or sound detectors, or timers or internal activation signals. Activation can be locally or remotely controlled.
[0105] [000105] Some implementations may include a watchdog timer which monitors the device to ensure proper operation. In another implementation, the device can detect the presence of droplet flow for purposes of self-diagnosis and to confirm proper operation. As an example, one or more light emitters, for example, an LED, a laser diode, can be used to illuminate the light against the flow of droplets. In an implementation, the light can be shown perpendicular to the flow. A device may include, in an implementation, light detectors, for example, a photodetector, which can be used in conjunction with an illuminated light to detect reflection and refraction, such as the reflection of illuminated light from the stream, and use this detection to determine the proper operation of the device. A system may also react in response to the detection and determination of an appropriate operation, for example, by alerting an agent or compliance system that the device may not be functioning properly.
[0106] [000106] In the implementation of Figure 12, the device also includes a hand-operated trigger 1202, however, in this implementation the ejection is subject to correct the positioning of the ejector mechanism 1210 in relation to the eye as defined by the image information obtained from the camera 1200.
[0107] [000107] The lighting mechanism, like the LED explained above, can be in wavelength ranges above 280 nm, including, for example, 290-1600 nm, to illuminate the target. The lighting mechanism can be operable to pulse the light for different periods of time, for example, 120 ns to limit the pupil reaction and allow the analysis of the eye with different optical frequency detectors, scanners, or cameras as explained above. Furthermore, the device may include an adaptive optical chip to perform a wavefront correction for clearer images. The device may also include a fixation source, for example, an LED or an LED pattern to define a moving eye focusing image and assist with pediatric use. This also serves to move or rotate the eyeball while applying medication to assist in dispersing the medication across the corneal surface.
[0108] [000108] Characteristics of the devices can be formed in alternative implementations. The following are some examples. Figures 13A and 13B show another implementation of the invention. In the device shown in Figure 13B, the ejector includes a removable reservoir 1300, which allows both the reservoir and the ejector to be discarded once the fluid inside the reservoir is exhausted. This helps to maintain a sterile application area and prevents excessive accumulation of dust and impurities on the thermal ejector. Also, Figures 13A and 13B present a cover which is articulated in these implementations. The cover 1301 moves down to provide a cover for the ejector. This protects the ejector mechanism when not in use or in transport. Also, coupling with a peripheral seal 1302, the cover 1301 reduces fluid evaporation. The cover 1301 can also be used as a spacer or support to support against, for example, the eyebrow, to align the device against the target, for example, the eye.
[0109] [000109] The cover can also articulate upwards as shown in Figures 14A and 14B. A spacer can also be formed as a separate or integral part on the exterior of the device as shown by 1500 in Figure 15A. The spacer supports against a portion of the anatomy to assist in aligning the device with the target. In addition to the noticed coverages, the coverage can be omitted. In addition, the cover can be of any suitable mechanism, including an iris-type closure, covers that slide from left to right, covers that are coupled with a friction fit, in a threaded, louvered or clipped manner. The cover can be coupled with any suitable mechanical, magnetic, or electromechanical means. For disposable packaging, the cover can be a wrap or protective outer cover. In addition, the cover can be sealed against the ejection area by a leaf spring or other polymeric seal. This seal can be made of a suitable polymer, for example, polypropylene, polyethylene, high density polyethylene or teflon. Furthermore, other seals such as ceramic seals, metal seals, or gaskets can be used to cover against the housing. Figures 15B-H show alternative implementations of coverage.
[0110] [000110] In some cases, it may be desirable to control the temperature of the fluid inside the device outside the ejection cycle. In these implementations, the device can include a cooler, for example, a Peltier device, to keep the fluid cool where needed. The device may also include a heater to heat the fluid to a predefined temperature, for example, the eye surface temperature of the person to whom the fluid is to be administered. The temperature range can be controlled by the controller.
[0111] [000111] In addition to the thermal and ultrasonic ejector mechanism, the ejector mechanism can be piezoelectric. Referring to Figure 16A, an assembly 1600 may include an ejector mechanism 1601 and a reservoir 1620. Ejector mechanism 1601 may include an ejector plate 1602 that can be activated to vibrate and deliver a fluid 1610, contained in a reservoir 1620, in the form of droplets ejected 1612 along a direction 1614. In the example in Figure 16A, the fluid can again be an ophthalmic fluid that is ejected into the eye 1616 of a human adult, child, or animal. In addition, the fluid may contain an active pharmaceutical product to treat a human or animal's discomfort, condition, or disease.
[0112] [000112] Referring to Figures 16A-16C, the ejector plate 1602 as shown has a circular shape with two opposite surfaces 1622, 1625. Although not shown, the ejector plate can also have other shapes, for example, an oval, square shape , or generally polygonal. In addition, the ejector plate does not have to be flat. The plate may include a surface curvature making it concave or convex. The ejection plate may be a perforated plate that contains at least one opening 1626. The opening or openings 1626 form the droplets as the fluid 1610 is passed through. The ejector plate 1602 can include any suitable configuration of openings, a configuration being shown in Figures 16A, 16B, and 16F. The openings can be formed in an ejection plate, a grid, a spiral, rectangular, rectilinear, or other pattern. The pattern can be regular or irregular. The pattern can maintain uniform gap spacing, or the spacing can be varied. For example, the density of openings may increase or decrease towards the center of the plate. The pattern can also cover all or part of the plate. These standards are not limited to piezoelectric ejection devices and can be used in conjunction with other types of ejection mechanisms, including thermal and ultrasonic. A more detailed discussion of the pattern and the 1632 region that contains the 1626 openings appears below.
[0113] [000113] In addition, openings 1626 can be formed in any suitable shape or volume with an appropriate aspect ratio. An example is shown in Figure 16A. Figure 16A shows openings having a cylindrical shape, that is, the diameter of the opening extending from the surface 1622 to 1625 remains generally constant. After all, the openings need not be limited to this cylindrical shape and can be tapered or tapered. The thinning may extend over the entire thickness of the surface 1622 to 1625, or it may extend partially. The opening can also be chamfered on one or both sides. The chamfer can have a sloping edge or a curved edge. The cross section of the opening can be round as shown in Figure 16F or it can have any other suitable shape. A few examples can be round, oval, rectangular or polygonal. The openings can be regularly formed or irregularly formed. The shape can be symmetrical or asymmetric. The size and shape of the openings 1626 affect the size and shape of the droplets and the flow of droplets created by the ejection mechanism 1601. These can also affect the density of distribution throughout the entire flow of droplets. Thus, the size and shape of the openings as well as their pattern are selected to produce the desired properties of the droplet flow according to the principles and teachings of the present description. The droplet flow properties affect the fluid supply and the dosage of any therapeutic or active ingredient. The flow properties also affect patient comfort. For example, a flow which provides a lot of strength would induce pain or discomfort. Such a flow can also induce tearing or blinking, which in turn can reduce the amount of fluid actually delivered to the patient. In contrast, an appropriately formulated flow will have little or no discomfort and will not induce blinking or tearing. Some examples of different shapes for the openings are shown in Figures 16L-16R. These shapes are not limited to piezoelectric ejection devices and can be used in conjunction with other types of ejection mechanisms, including thermal and ultrasonic.
[0114] [000114] The ejector plate 1602 is coupled to an ejector which activates the plate to form the droplets upon activation. The manner and location of attachment of the ejector 1604 to the plate 1602 affects the operation of the ejection assembly and the creation of droplet flow. In the implementation of Figure 16B, the ejector 1604 is coupled to a peripheral region of the surface 1622 of the plate 1602. The central region 1630 is not covered by the piezoelectric ejector 1604. The region 1632 of the ejector plate 1602 contains a central region 1630 which contains a or more openings 1626. Fluid 1610 is passed through openings 1626 to form droplets 1612. Piezoelectric ejector 1604 can be of any suitable form or material. For example, the ejector can be oval, square, or generally polygonal in shape. Ejector 1604 can conform to the shape of ejector plate 1602, or to regions 1630/1632. Alternatively, the ejector 1604 may have a different shape. Furthermore, ejector 1604 may be coupled to plate 1602 or surface 1622 in one or more sections. In the example shown in Figure 16B, the piezoelectric ejector 1604 is illustrated in the form of a ring, which is concentric to the regions 1630 and 1632. The openings 1626 may be located in the ejection region 1632. The region 1632 may occupy a portion of the region 1630 , as shown in Figure 16B, or it can occupy the entire area of the 1630 region (not shown). The portion of region 1630 occupied by region 1632 may be in the center of region 1632 or it may be offset from the center (not shown). In some implementations, for example, as shown in Figures 16A and 16E, the size of region 1638 of reservoir housing 1608 substantially corresponds to the size of ejection region 1632. In some implementations, open region 1638 may be substantially larger than ejection region 1632.
[0115] [000115] As with the size and shape of the openings 1626, the size and shape of the ejection region 1632 can be selected based on the desired droplet flow properties. As shown in Figure 16F, as an example, openings 1626 are arranged in a circular pattern in the ejection region 1632 of ejector plate 1602, but other patterns can also be used as explained above. The distance l between adjacent openings 1626 can be any suitable value, including, 1 micron to a few microns for example 150 microns to 300 microns. In a specific implementation, l is chosen to be 200 microns. In addition, also as explained above, the separation of the openings 1626 need not be uniform.
[0116] [000116] Figure 16D shows ejector plate 1602 arranged over reservoir housing 1608 which contains fluid 1610. Surface 1625 of plate 1602 is adjacent to fluid 1610. Reservoir 1608 has an open region 1638 as shown in Figure 16E which is adjacent to surface 1625 and region 1632 of plate 1602. In this implementation, surface 1625 contains fluid 1610 within reservoir 1608. Reservoir housing 1608 can be coupled to ejector plate 1602 in a peripheral region 1646 of surface 1625 using a suitable seal or coupling. As an example, Figure 16E shows an O-ring 1648a. Although not shown, more than one O-ring can be used. As is known in the art, O-rings can have any suitable cross-sectional shape. Furthermore, other couplers such as polymeric, ceramic or metallic seals can be used to couple housing 1608 to ejector plate 1602. Alternatively, the coupling can be eliminated altogether and housing 1608 can be integrally connected to plate 1602, for example , by welding or overmoulding. In such an implementation, an opening through which fluid is supplied to the reservoir housing 1608 can be provided. Furthermore, the couplings can be made removable, such as a joint, or they can be made of a flexible or non-rigid connector, for example, a polymeric connector. When housing 1608 is coupled to the ejector plate, fluid 1610 is contained within the reservoir, fluid 1610 does not leak between cycles of use - even if openings 1626 are exposed to the outside. This is due to the surface tension of the fluid 1610 given the size scale of the openings. Peripheral region 1646 may at least partially overlap with peripheral region 1624 and may extend beyond peripheral region 1624, although such overlap is not required. The contact in which the reservoir housing 1608 and the ejector plate 1602 are coupled together is relatively small so that the attachment of the reservoir housing 1608 to the plate 1602 does not substantially affect the vibration of the ejector plate 1602 when the ejector plate is activated .
[0117] [000117] In addition to the open region 1638, portions of the ejector plate 1602 can be covered by an additional reservoir wall 1650. In the implementation of Figure 16E, the wall 1650 does not directly contact the ejector plate 1602, on the contrary it is coupled to O- 1648a rings. Alternatively, wall 1650 can be directly attached to plate 1602. Furthermore, housing 1608 can be directly attached to plate 1602 and wall 1650 can be omitted altogether.
[0118] [000118] As the ejection set 1600 is used to deliver therapeutic agents or other fluids to the oils, the ejection set 1600 is designed to prevent fluid 1610 contained in reservoir 1620 and ejected droplets 1612 from being contaminated. In some implementations, for example, as shown in Figure 16C, a coating 160 can be formed on the exposed surface of the piezoelectric ejector 1604 and at least part of the surface 1622 of the ejector plate 1602. The coating can be used to prevent direct contact of piezoelectric ejector 1604 and electrodes 1606a and 1606b with fluid 1610. The liner can be used to prevent the interaction of the plate or ejector with the fluid or it can be used to protect the piezoelectric ejector 1604 and electrodes 1606a and 1606b from the environment. For example, the coating may be a conformal coating that includes a non-reactive material, for example, polymers that include polypropylene, nylon, or high density polyethylene (HDPE), gold, platinum, or palladium, or coatings such as Teflon® .
[0119] [000119] Referring to Figure 16G, in some implementations, the ejector plate 1602 can be coated with a protective coating 1662 that is anti-contamination and / or antimicrobial. The protective coating 1662 can be conformal on all surfaces of the ejector plate 1602, including the surfaces 1664 that define the openings 1626 (only one opening shown). In other implementations, protective coating 1662 can be applied on selected surfaces, for example, surfaces 1622, 1625, or surface regions, for example, parts of surfaces 1622, 1625, 1664. The protective coating can be formed as a biocompatible metal, for example, gold, iridium, rhodium, platinum, palladium or their alloys, or a biocompatible polymer, for example, polypropylene, HDPE, or Teflon®. Antimicrobial materials include metals such as silver or polymers such as polyketones. The protective coating may be in direct contact with fluid 1610 or droplets 1612. The coating may provide an inert barrier around the fluid or may inhibit microbial growth and sanitize fluid 1610 and / or droplets 1612.
[0120] [000120] In addition, the surface 1622 of the plate 1602, for example, Figures 16A and 16E, can also be coated. The coating can be a hydrophilic or hydrophobic coating. In addition, the coating can be coated with a protective layer. The surface can also be coated with a reflective layer. A coating layer can be both protective and reflective. Alternatively, the surface may have been formed to be reflective. For example, the surface can be made of stainless steel, nickel-cobalt, or other reflective material. A surface may have been formed or polished to be reflective. In addition to making the surface 1622 reflective, the surface can also be lit from behind on its surface or around its perimeter and shown in Figure 26. In ophthalmic applications, a reflective surface assists the user in aligning the ejector assembly with the eye .
[0121] [000121] In some implementations, ejector plate 1602 may itself be formed of a metal, for example, stainless steel, nickel, cobalt, titanium, iridium, platinum, or palladium or its alloys. Alternatively, the plate can be formed from a suitable material, including other metals or polymers, and can be coated as noted above. The board can be a composite of one or more materials or layers. The plate can be manufactured, for example, by cutting from a metal plate, preforming, rolling, casting or otherwise forming. The openings in the plate can be formed using suitable methods that include, but are not limited to, perforation by mechanical or optical means such as laser perforation or ablation, or chemical processing such as engraving with or without stencil or lithographic patterning. The openings can also be preformed when forming the plate. Coatings can be preformed by immersion, deposition, including electrodeposition, or otherwise by encapsulation such as molding or casting. Coatings can also be deposited by suitable deposition techniques such as crackling, vapor deposition including physical vapor deposition (PAD), chemical vapor deposition (COD), or electrostatic powder deposition. The protective coating may have a thickness of approximately less than 0.1 μm to approximately 500 μm. It is desirable that the coating adhere to plate 102 sufficiently to prevent delamination when vibrating at high frequency.
[0122] [000122] The configuration of reservoir 1620, including shape and dimension, can be selected based on the amount of fluid 1610 to be stored and the geometry of the ejector plate 1602. Alternative forms of reservoirs include gravity-fed, wick or collapsible bags which operate under pressure differentials. These reservoirs can be pre-filled, filled using a micro pump or by replacing a cartridge. The micro-pump can fill the reservoir by pumping the fluid into or out of a collapsible or non-collapsible container. The cartridge can include a container which is loaded into the reservoir. Alternatively, the cartridge itself can be coupled to a disposable ejector assembly which is then replaced inside the housing after a specified number of discharges.
[0123] [000123] Figure 16H shows a reservoir 1620 connected to a micro pump set 1670. The set includes a micro pump 1672 and a larger reservoir 1671. Figure 16I shows a sectional view of the set 1600. An alternative reservoir for use with the device shown in 20. The reservoir housing 1608 'is coupled to the ejector mechanism. The housing 1608 'includes a wick material. This material maintains the fluid supply against the ejector mechanism even when the fluid level falls below the ejector plate 1602. Not wanting to be limited by this theory, this type of reservoir operates by action capillary, an implementation of these types of reservoir is more fully described in US Patent No. 7,192,129 to Droege.
[0124] [000124] In the example shown in Figure 16D, the reservoir housing 1608 has a rectangular cross section. Other forms can also be used. In some implementations, reservoir housing 1608 includes curved edges. An example showing curved corners 140 is shown in Figure 16D. Thus, little or no fluid 1610 is trapped within the edges of the reservoir 120 and the fluid within the reservoir can be effectively used. The 1620 tank can be refilled or disposable. The reservoir can be pre-filled for disposable reservoirs or can be refilled using a filling hole.
[0125] [000125] In some implementations, reservoir housing 1608 includes hollow holes 1642 (only one shown in Figure 16A) to allow air to escape or enter reservoir 1620 and keep fluid 1610 within the reservoir at the appropriate ambient pressure. Hollow holes 1642 have a small diameter so that fluid 1610 does not leak from the holes. Alternatively, no opening is formed in the reservoir housing 1608, and at least a portion, for example, the portion 1644 or the entire reservoir housing 1608 can be collapsible, for example, in the form of a pouch. The entire reservoir can also be made in the form of a flexible or collapsible bag. Consequently, as fluid 1610 is ejected through ejector plate 1602, reservoir 1620 changes its shape and volume to keep up with changes in the amount of fluid 1610 within reservoir 1620.
[0126] [000126] In the implementation of Figures 16A to 17B, the ejector plate 1602 is activated by being vibrated by the piezoelectric ejector 1604. As shown in Figures 16A and 16C, two electrodes 1606a and 1606b are formed on two opposite surfaces 1634 and 1636 of the piezoelectric ejector 1604 which are parallel to the surface 1622 of the ejector plate 1602 and activate the piezoelectric ejector 1604 to vibrate the ejector plate 1602. The electrodes can be attached to the plate by any known means including adhesive fastening or otherwise bonding. These can also be overmolded in place on plate 1602. Wires or other conductive connectors can be used to make the necessary electrical contact between plate 1602 and the electrodes. Alternatively, electrodes can be formed on plate 1602 by electrodeposition or otherwise depositing in place. As an example, the electrodes are attached by adhesive 1628 which is applied between electrode 1606a and ejector plate 1602. Electrode 1606a is in electrical contact with plate 1602. When a voltage is applied through electrodes 1606a and 1606b, the actuator piezoelectric 1604 deflects ejector plate 1602 to change shape to more concave or convex as shown in Figures 17A and 17B. For example, Figure 17A shows electrodes 1606a and 1606b coupled to plate 1602 and causing the plate to deflect to shape 1700. An extensive voltage range that corresponds to different piezoelectric materials is known in the art, but as an example, a voltage differential 40 or 60 V can be applied to the electrodes in Figure 17A. When the direction of the voltage differential is reversed, for example, to -40 or -60 the plate will deflect in the opposite direction to shape 1601 as shown in Figure 17B. In this way, actuator 1604 causes plate 1602 to oscillate which constitutes vibration and results in the formation of droplets 1612 of fluid 1610. In the implementation shown in Figure 17a the volume of reservoir 1620 is reduced and fluid 1610 within reservoir 1620 is compressed by ejector plate 1602 and forced into openings 1626. In the implementation shown in Figure 17B, the volume of reservoir 1620 is increased. As alternating voltage is applied to electrodes 1606a and 1606b, ejector plate 1602 oscillates between form 2600 and form 2602, causing droplets of fluid 1612 to accumulate inside openings 1626 and eventually eject from openings 1626 along the direction 1614 moving away from reservoir 1620. The frequency and wavelength of oscillation can depend on many factors such as the volume of the openings 1626, the number of openings 1626, the viscosity of the fluid, the rigidity of the plate 1602, the temperature and other factors. These parameters can be adjusted or selected to create the desired droplet flow. The droplet ejection frequency of plate 1602 also depends on many factors. In some implementations, droplets 1612 are ejected at a lower frequency than the pulse frequency for the piezoelectric actuator 1604. For example, droplets 1612 are ejected every 1-1000 cycles, and more specifically 8-12 cycles, from vibration of the ejector plate. A droplet ejection frequency is discussed in more detail below.
[0127] [000127] Many piezoelectric materials can be used to create the 1604 actuator. As an example, in some implementations the piezoelectric actuator can be formed from PZT. But PZT includes lead and must be sealed from 1610 fluid. Other lead-free materials include barium titanate or polymer-based piezoelectric materials, such as polyvinylidene fluoride. Electrodes 1606a and 1606b can be formed of suitable conductors including gold, platinum, or silver. Materials suitable for use as the 1628 adhesive may include, but are not limited to, adhesives such as silicone adhesives, epoxies, silver paste. An example of a conductive adhesive includes a Thixotropic adhesive such as Dow Corning DA6524 and DA6533. Reservoir housing 1608 can be formed of a polymer material, some examples of which include Teflon®, rubber, polypropylene, polyethylene, or silicone. As previously mentioned, all or part of the reservoir can be flexible or collapsible. The size and speed of the droplets ejected by the ejection set 1600 can be affected by various parameters used in the manufacture of the ejection set 1600 The parameters can include the dimensions of the piezoelectric actuator 1604, the properties (for example, dimensions, elasticity and others) of the ejector plate 1602, the size and pattern of the openings 1626 in the ejector plate 1602, the frequency, shape, and magnitude of the pulses applied to the electrodes 1606a, 1606b by the drive electronics, the fluid properties (for example, the viscosity and surface tension), and others.
[0128] [000128] The magnitude and frequency of the ejection plate vibration can also be controlled by controlling the voltage pulses applied to the electrodes 1606a, 1606b. As discussed above, the pulses are created by voltage differentials that deflect plate 1602, as shown in Figures 17A and 17B. In some implementations, one of the electrodes 1606a or 1606b is grounded and voltage pulses, for example, bipolar pulses are applied to the other of electrodes 1606a or 1606b, for example, to vibrate the ejector plate 1602. Details of voltage pulses and others features are discussed here in additional detail. As an example, in an implementation, the 1604 piezoelectric actuator can have a resonant frequency of approximately 60 KHz to approximately 120 KHz, for example, 118 KHz. The applied voltage pulses can have a lower, higher frequency, or the same as the resonant frequency of the 1604 piezoelectric actuator.
[0129] [000129] In the implementation of Figure 16A, the droplet delivery time is approximately 0.1 ms to approximately several seconds. Without wishing to be limited by theory, it is believed that human eyes take approximately 300 ms to approximately 400 ms between blinks. Therefore, for implementations where the delivery is desired to be between flashes, the delivery time can be from approximately 50 ms to approximately 300 ms and more specifically from 25 ms to 200 ms. In an implementation, the delivery time is 50 ms to 100 ms. In this way, the ejected droplets can be effectively applied and deposited inside the eye during a blink cycle. In some implementations, for example, shelf saline applicators, the application time can be as long as several seconds, for example 3-4 seconds, spanning several blink cycles. Alternatively, a single application can be administered by several jets or droplet ejection pulses.
[0130] [000130] Furthermore, and I do not intend to be limited to this theory, the pulse can reduce the peak amplitude of the air flow by extending the impulse over time, similar to the effect of a car's denting zone during an accident. Therefore, the pressure of the ejection on the target can be mitigated. That is, for example, for an eye application, the patient might not feel as much air and experience higher levels of discomfort. Furthermore, pulsation can also reduce droplet agglomeration and result in less generation of entrained air. Using a single example, 25 ms pulses can be administered with 25 ms stop times by separating the pulses. As an example, in an implementation, the pulses can be repeated for a total of 150 ms of total time.
[0131] [000131] Figures 21A-D show another implementation of the device housing. Housing 502 formed of molded components of plastic or other suitable material is generally defined by a front portion 2104 and a rear portion 2106. The front portion 2104 includes a fluid supply area 2108 and an activation mechanism 2110. The supply area fluid 2108 further defines a supply opening 2112 formed through a cover chamfer 2114 and through the housing. Fluid supply area 2108 also includes a multi-function LED 2116 that has a function as previously described with respect to other implementations. The trigger trigger 2110 includes an opening cover plate 2118 and a thumb pad 2120. One or more raised edges 2122 can be formed around the perimeter of the thumb pad 2120 to assist with positioning a user's thumb on the activation trigger 2110. In the implementation shown, cover plate 2118 and thumb support 2120 can be formed integrally in one piece or in multiple pieces. The cover plate 2118 mounts within a slot formed by the front portion 2104 and the cover chamfer 2114 (Figure 5E) and is operable to slide up and down into the slot thereby allowing the cover plate 2118 to seal the supply opening 2112 and protect the ejector assembly behind the opening and the internal components from external debris and contamination. Optionally, a rear surface of the cover plate 2118 can be coated with a material containing silver particles to prevent bacteria from forming in and around the interior of the supply area. Figure 21F is a schematic diagram showing a user aligning the device towards their eye before applying a dose of ophthalmic fluid droplets. The ergonomic design of the device allows the user to place his thumb on the thumb rest located on the device and promotes the thumb to assume a slightly bent position. The phalanx closest to the thumb can then be placed against the user's face bone to stabilize the device while the user aligns the delivery opening with their eye. A multi-function LED, which optionally includes a polished ejector plate illuminated from behind, can also assist in alignment. When the user's thumb is placed against his cheekbone, the delivery opening can be easily aligned at an optimum distance of 2-3 cm from the surface of the eye. The user can then locate his index finger on the application button, and when ready he can press the application button to apply the ophthalmic fluid to the surface of his eye.
[0132] [000132] Thus, the combination of the position of the thumb rest and the placement of the back of the thumb on the cheekbone provides a natural and repeatable feature and alignment process. Depending on the user's anatomy, a different portion of the thumb or hand can be aligned with an alternate location on the face to perform the proper alignment. Alternatively, the device can be secured at a suitable distance during use, for example, as noted with respect to the distance d shown in Figure 16A. The proper distance may vary with the type of patient and application. For example, for veterinary patients, the device can be held at a longer distance than for a human patient. In addition, the device can be held in the palm of the hand and aligned without using the hand or your fingers and instead with a spacer or aided by an alignment device as described above. Alternatively, any portion of the hand or fingers can be used for the device and any portion of the hand or fingers can be used to activate the application button. As an example, the device can be held in the hand with the little finger spacing the device from the face and thumb by pressing the application button located on the device housing side.
[0133] [000133] During use, the device is secure, connected, aligned, and the application button is pressed. The device can be powered on manually by activating a physical activation trigger, or it can occur automatically or in response to a condition, for example, removing the device from a docking station. The device can cycle through a cleaning cycle once activated. The properly aligned housing applies the fluid in the form of droplet flow to the target.
[0134] [000134] Figure 22A shows a communication system that includes the fluid ejection device. The device can be used in combination with a docking station. Details of this system and a docking station are more fully described in US Order Proxy Protocol Number 24591.003-US02, entitled "Method and System for Performing Remote Treatment and Monitoring", filed concurrently with this and incorporated herein by reference.
[0135] [000135] Figure 22B shows a block diagram showing a device 2202 and a docking station 2250 in communication. The device 2202 can include a housing 2206, an electronics 2208, an actuator of the ejection mechanism, for example, a piezo 2210, a reservoir 2212, a sighting device 2214, an electronic storage 2216, and an input / output interface ( I / O) 2218. Device 2702 may also include an image forming device 2220, a look-up table 2222, a speaker 2224, and an LED 2226.
[0136] [000136] Housing 2206 may be made of, for example, injection molded plastic or any other suitable, durable, or lightweight material. Housing 2206 may include an opening 2228, a positionable slide 2230, an interface 2232 that sends communications to and receives communications from the docking station 2250, a flow activator 2234, and a communications interface 2236. The communications interface 2236 sends data stops and receives data from a source external to accommodation 2206 (see US Order Proxy Protocol Number 24591.003-US02, entitled "Method and System for Performing Remote Treatment and Monitoring", which is concurrently deposited with this and incorporated by reference in its entirety ) for device 2202, and docking station 2250. For example, communications interface 2236 may be communicating with the database or with an input / output device, such as a keyboard.
[0137] [000137] Opening 2228 may be in the form of an opening formed through an external surface of housing 2206, and opening 2228 allows fluid stored in reservoir 2212 to exit housing 2206. Opening 2228 may be similar to those previously explained.
[0138] [000138] The positionable slide 2230, which may be similar to the thumb slide previously described. Housing 2206 also includes an interface 2232 configured to receive connection 2204. Connection 2204 can be, for example, a single-wire, two-wire, or 12C interface. The 2232 interface allows device 2202 to send data to and receive data from the 2250 docking station over connection 2204.
[0139] [000139] Housing 2206 also includes a trigger trigger 2234. The trigger can be, for example, a button that projects from the outer surface of housing 2206, a switch, or any other touch interface that is accessible to a user of the device, such as the switches described above. Trigger 2234 can be on one side of housing 2206 which is opposite the side of housing 2206 which includes aperture 2228 and slide 2230.
[0140] [000140] Housing 2206 may also include a communications 2236 that is in communication with electronic storage 2216 and allows retrieval of data stored in electronic storage 2216 and writing of data in electronic storage 2216. The interface 2236 can be, for example, example, a universal serial bus (USB) connection, a serial connection, an Ethernet connection, or any other connection that allows data to be read and written. A further discussion of these aspects appears in US Order Proxy Protocol Number 24591.003-US02, entitled "Method and System for Performing Remote Treatment and Monitoring", filed concurrently with it.
[0141] [000141] Device 2202 includes electronics 2208, which provides one or more output driver signals for the 2210 ejector or piezo actuator. The 2210 piezo vibrates, moves, or distorts the ejector plate 2202 in response to application of exit signs. The ejector plate 2202 is in contact with the fluid stored inside the reservoir 2212, and, when the piezo 2210 distorts, the fluid in the reservoir 2212 is pulled through one or more openings formed in the ejector plate. In the piezoelectric implementation, the movement of the ejection plate, and in general, the operation of the ejection mechanism, causes a directed flow of droplets to exit housing 2206 through opening 2228.
[0142] [000142] As discussed in more detail with respect to the Figures that describe the electronics, the 2208 electronics determines the frequency, voltage, active cycle, and duration of the 2342 output driver signal that is applied to the 2210 piezo. , electronics 2208 is programmable so that the characteristics or properties of the output driver signals applied to the piezo 2210 can be adjusted to accommodate changes in the fluid and / or a dosing plan.
[0143] [000143] Figure 22C includes a 2304 processor and a 2806 driver circuit. The 2804 processor provides a 2340 excitation signal for the 2306 driver circuit, and the 2306 driver circuit generates a 2342 output driver signal that is applied in piezo 2210. The properties of the output driver signal 2342 are determined from the properties of the excitation signal 2340. As discussed below, the output driver signal 8232 can include, for example, two or four separate output driver signals.
[0144] [000144] Reservoir 2212 can be pre-filled with fluid when device 2202 is manufactured. Device 2202 can be programmed at the time of manufacture of device 2202. Alternative reservoirs as discussed can be used without limitation.
[0145] [000145] The device 2202 also includes a targeting device 2214. The targeting device 2214 can assist the user to align the device 2202 with a patient's eye. The targeting device 2214 can be, for example, an LED that glows inside the patient's eye, a reflective or shiny surface that reflects the patient's eye, and / or a CCD camera that forms an image of the patient's eye and provides a signal to electronics 2208. The targeting device 2204 may include a reflector to provide the user with an image of his eye when the device 2202 is correctly positioned, or it may include a light source, such as a low intensity LED for shine within the user's eye when the 2202 device is correctly positioned. The targeting device 2214 may include an element that shows a reflection of the patient's eye when the device 2202 is properly aligned with the eye. For example, the ejector plate and / or piezo 2210 can be made of a reflective material that shows a reflection of the patient's eye when opening 2228 and piezo 2210 are aligned with the patient's eye. This type of aiming device is useful in cases where the patient is using the 2202 device to deliver a direct flow of droplets into his own eye.
[0146] [000146] In alternative implementations all or part of the surface of the ejector mechanism or the housing adjacent to it may be coated with a reflective layer. A coating layer can be both protective and reflective. Alternatively, the surface may have been formed to be reflective. For example, the surface can be made of stainless steel, nickel - cobalt, or other reflective material. A surface may have been formed or polished to be reflective. In addition to making the surface reflective, the surface can also be lit from behind on its surface or around its perimeter. In ophthalmic applications, a reflective surface assists the user in aligning the ejector assembly with the eye.
[0147] [000147] Device 2202 also includes electronic storage 2216 and I / O interface 2218. In addition to storing data such as images of the patient's eye, electronic storage 2216 stores instructions, perhaps as a computer program, which , when executed, cause a processor included in electronics 2208 to communicate with other components in device 2202. The processor can be, for example, a state machine such as an FPGA or ASIC. The excitation signal 2340 can be generated by a signal generator. Information about 2216 electronic storage can be accessed via interface 2218 or interface 2236 (which communicates with a database), and access to the content of electronic storage is controlled, for example, by a restricted password to allow certain activities are conducted by certain medical personnel, for example, doctors or pharmacists who wish to adjust dosages. As the computer is enabled on the Internet, information can be uploaded over the Internet, for example, to a server for access by medical personnel to allow progress and appropriate patient usage to be monitored and allow dosages to be monitored. adjusted via the Internet, for example, uploading revised dosing information to a server by medical personnel and then pushed to the device via the Internet or downloaded by the user. The device itself can be enabled on the Internet to allow usage information and image information to be loaded in real time and new information to be downloaded to the device in real time. As the device is enabled on the Internet it can be provided with a user interface, for example, a screen and keyboard or a touch screen.
[0148] [000148] The input / output interface 2218 provides an interface that allows data and / or commands to be entered into device 2202 and / or read from device 2202. The input / output interface 2218 can receive data from a device such as a keyboard, a mouse, a communications port, an electronic processor that runs on a device separate from the 2202 device, or a display. Input / output interface 2218 may also include software that allows communication between device 2202, components of device 2202, and / or an external device. The 2218 interface can provide the user with access to the 2202 device when the 2202 device is plugged into a computer, such as a laptop or palmtop or cell phone with a screen and user input capability, through the 2218 interface.
[0149] [000149] Device 2202 may also include an imaging device 2220. Imaging device 2220 may be a charged coupled device (CCD) that is aligned with aperture 2228 so that the imaging device captures an image of the patient's eye through the same opening that provides the targeted flow of fluid droplets. In some implementations, the imaging device 2220 is mounted on an outer surface of housing 706 at a location other than the location of aperture 2228. Images collected by imaging device 2220 can be transferred from device 2202 via the interface I / O 2218, communications interface 2236 or 2256, and / or images can be stored in electronic storage 2216. Images can be uploaded to the database and stored in association with the patient's medical records, as more fully explained in the US Order Proxy Protocol Number 24591.003-US02, entitled "Method and System for Performing Remote Treatment and Monitoring", deposited concurrently with this and incorporated herein by reference in its entirety.
[0150] [000150] The imaging device 2220 and electronics 2208 can be operable to control image capture during or at selectable times before or after fluid ejection from device 2202. In some implementations, image capture can be triggered by the user, for example, by pressing a button or the 2234 flow activator. For example, droplets of saline can be directed from the device 2202 towards the eye to exert pressure on the cornea and images can be taken to determine the effect. The images can be saved as discussed above.
[0151] [000151] Device 2202 can also include a lookup table 2222. Lookup table 2222 can be stored on device 2202, for example, in electronic storage 2216, or the lookup table can be stored separately from device 2202, for example , in the database. Lookup table 2222 includes specific information about fluids that can be used in device 2202. For example, as fluid drug viscosities vary, depending on the fluid inside the reservoir, the 2210 piezo may require the application of outgoing driver signals that have a modeled frequency for the fluid inside the reservoir. This specific medication variation can be considered by varying the properties, such as frequency, voltage, and / or the duration of the output driver signals produced by the 2208 electronics and applied to the 2210 piezo. The 2222 lookup table can include specific information for medication that are retrieved and used by the 2208 electronics to adjust the output driver signals.
[0152] [000152] Lookup table 2222 can also include specific medication information that relates to the patient's treatment plan. For example, the look-up table may include information that specifies that a first medication should be applied three times a day, while a second medication should be applied once a day. This treatment plan information is used by electronics 2208 to determine, for example, when to trigger a reminder alert for the patient based on the type of medication that is placed inside the reservoir.
[0153] [000153] In some implementations, lookup table 2222 on a specific device 2202 can be edited by a professional, for example, a medical professional to take into account changes in the patient's condition. The 2236 interface can be operable to download information, for example, via an external I / O device or directly from the database, perhaps via the Internet. The downloaded information may include one or more of the quantities of doses reviewed, times of doses reviewed, and type of medication to be applied. Device 2202 can be configured so that electronics 2208 controls medication delivery in response to pre-defined information or downloaded information.
[0154] [000154] The device 2202 can also include a speaker 2224 and an illuminator 2226, both of which can be used, in conjunction with electronics 2208, to provide a noticeable alert for the user of device 2202. Device 702 can provide other noticeable alerts. For example, the 2202 device may vibrate to attract the user's attention. The device 2202 can produce an audible alarm or an announcer, or a visual indicator controllable by electronics 2208 to provide feedback to the user, for example, a visual or audible feedback to indicate when a total dose has been reached. The 2226 illuminator can be an LED or other device that emits visible radiation in response to an electrical input.
[0155] [000155] In some implementations, the illuminator 2226 may include multiple light sources of different frequencies to illuminate the eye, or it may include a light source of varying frequency, such as light of different colors and frequencies (for example, red, blue, green, white, infrared (IR), ultraviolet (UV)). The device may include a cobalt blue light (generated, for example, using a filter) for use with fluorescence to illuminate the cornea to identify corneal ulcers and scratches. Illuminator 726 can be a source of radiation that emits frequencies above wavelengths of 280 nm to illuminate the eye. The 2226 illuminator can be operable to pulse light for different periods of time, for example, 20 nanoseconds (ns) to limit the pupil reaction and allow analysis of the eye with optical detectors, scanners or cameras of different frequencies. The 2226 illuminator may include an adaptive optical chip to perform wavefront correction for clearer images. For example, an adaptive optical chip based on MEMS.
[0156] [000156] The device can also include a fixation source, for example, an LED or an LED pattern to define a moving eye focusing image and assist with pediatric use. This also serves to move or rotate the eyeball while applying medication to assist in dispersing the medication across the surface of the cornea.
[0157] [000157] Docking station 2250 includes a housing port 2252 (which includes, without limitation, a docking station) which is configured to receive device 2202. Housing port 2252 can be lowered so that when device 2202 is received by the docking station 2250, the device 2202 sits securely and is stably secured by the docking station 2250. The docking station 2250 can also include a communications interface 2256 that reads and writes data from the docking station 2250 and / or device 2202. The 2256 communications interface can be, for example, a USB connection, an Ethernet connection, or a serial connection. The docking station 2250 can also include a memory or electronic storage 2254.
[0158] [000158] The electronic storage components 2216 and 2254 can be a volatile memory, such as a RAM. In some implementations, electronic storage components 2216 and 2254 may include both non-volatile and volatile portions or components.
[0159] [000159] Figure 23A shows a top view of an exemplary 2300 configuration for the electronics used in the device, and Figure 23B shows a bottom view of the 800 configuration. Although the following description is discussed with respect to device 2202, the configuration 2300, or a similar configuration can be employed on the device. The configuration can be implemented on a printed circuit board (PCB) sized to mount inside a housing that is small enough to be held in a single human hand. The configuration can be implemented on a single PCB board, or on multiple PCB boards. In the example shown in Figures 8A and 8B, the configuration is implemented on a single 2301 PCB board.
[0160] [000160] Referring now to Figure 23A, a top view of the 2300 configuration is shown. The top view includes a reservoir 2302, and a processor 2304, the driver circuit 2306, a pressure switch 2308, a programming interface 2310, and a slide switch 2312. Processor 2304 can be a logic circuit with an oscillator that runs free designed to control and sequence the signals used to control pulses to the ejector and droplet formations. Alternatively, a field programmable gate network (FPGA), an application specific integrated circuit (ASIC), a complex programmable logic device (CPLD), or Erasable Programmable Logic Device (EPLD) can be used as the processor. Alternatively, a microprocessor or other programmable processor such as a PIC18F14K50-I / SS microcontroller, available from Microchip Technology, Inc. of Chandler, Arizona, FPGAs and ASICs are generally less expensive than microprocessors. Free-running logic circuits and oscillators, like the LM555 used in both stable and monostable modes, are also less expensive and generate high control signal accuracy. In some implementations, any low power processor that has a voltage range of approximately 2.4 to 6 volts that generates a clock signal and has a sleep or low power mode can be used as the 2304 processor. driver 806 can be, for example, an LT3572EUF # PBF engine driver, available from Linear Technologies of Milpitas, California. In addition, the device may include a microcontroller with a watchdog timer which monitors the device to ensure proper operation.
[0161] [000161] The 2306 driver circuit is controlled by, and receives the 2340 excitation signal at a specific frequency from the 2304 processor. Controlling the 2306 driver circuit with the processor can provide a system that has increased flexibility and applicability compared to a system that relies on a driver circuit alone. For example, controlling the driver circuit with the processor allows the frequency of the 2342 output driver signals produced by the driver circuit to be determined and changed quickly by modifying the properties of the 2340 driver signal produced by the processor. This can allow the 2202 device to adapt to changing patient needs and operate with the various fluids that can be replaced in the 2302 reservoir. In addition, controlling the 2306 driver circuit with the 2304 processor can eliminate the need for a separate potentiometer for controlling the frequency of the 2340 excitation signal. Using the 2304 processor to control the 2306 driver circuit may allow the electronics to be reduced in size so that the device 2202 can be held and operated by a single human hand.
[0162] [000162] The 2304 processor receives data and control signals from a 2308 pressure switch, a 2310 programming interface, and a 2312 slide switch. The processor can be connected to the driver circuit via an electrically conductive path 2314, such as a copper trail. Pressure switch 2308, programming interface 2310, and slide switch 2312 can be electrically connected to the processor via tracks 2314, 2316, and 2318, respectively.
[0163] [000163] The pressure switch 2308 is coupled to the activation trigger 2234, the mechanism by which a user of the device 2202 causes the release of the directed droplet flow. Pressure switch 2308 and a portion of flow activator 2234 can physically contact each other when the user of device 2202 presses or otherwise selects flow activator 2234. In implementations where flow activator 2234 is electronic (for example, example, a software key), flow activator 2234 may not necessarily be in physical contact with pressure switch 2308, unlike flow activator 2234 may provide an electronic selection indication for pressure switch 808. In response to Upon receiving an activation indication from the trigger trigger 2234, the pressure switch 2308 generates a spray signal to the 2304 processor.
[0164] [000164] The programming interface 810 allows the processor 804 to be programmed, for example, to produce an excitation signal 840 that has a specific frequency, duration, or time between the active states. For example, processor 804 can be programmed to generate an excitation signal 840 having a frequency between approximately 108 kiloHertz (kHz) and 183 kHz. The programming interface 810 can be, for example, a 5-pin interface. In some implementations, the 810 programming interface may be accessible through a graphical user interface (not shown).
[0165] [000165] Processor 2304 provides excitation signal 2340 to driver circuit 2306, and the driver circuit uses excitation signal 2340 to produce two output driver signals that are applied to piezo 2320. Each driver signal from output 2342 can be a square wave, or approximately a square wave, and each output driver signal 2342 can have approximately the same maximum and minimum voltage. The maximum voltage of the output driver signals can be approximately 20 to 40 volts, and the minimum voltage can be approximately zero (0) volts. The second 2342 outgoing driver signal may be out of phase with the first outgoing driver signal, and the first and second outgoing driver signals may be out of phase by approximately 180 degrees.
[0166] [000166] Slide switch 2312 is attached to slide 2330. For example, in implementations where slide 2230 is a physical slide, slide switch 2312 can be physically connected to slide 2230 so that slide switch 2312 generates a signal when slide 2230 is positioned in one or more predefined positions on housing 2206. In some implementations, slide 2230 can be electronic and can communicate with slide switch 2312 electronically instead of mechanically. Slide 2330 may also be provided with an operable metallized surface, when slide 2330 is moved to the open position, traversing the gap between two metal contacts, thereby defining a slide switch. Slide switch 2312 can generate a signal when slide 2330 is moved to a position that reveals (or discovers) aperture 2228. This signal can be referred to as a start signal. Slide switch 2312 can generate another signal when slide 2230 is moved from that position. The signals generated by the slide switch 812 are provided for the 2304 processor.
[0167] [000167] Referring to Figure 23B, a bottom view of the 2300 configuration is shown. The bottom view is shown as the mirror image of the top view of Figure 23A. The bottom view shows a 2320 piezo, a 2322 LED, the 2306 driver circuit, the 2304 processor, a 2324 speaker, an 826 power module, and a 2328 remote control module.
[0168] [000168] The piezo 2320 retains and / or is in contact with the ejector plate 1602 (Figure 16A) which contacts a fluid contained inside the reservoir 2302, and the piezo 2320 receives the driver signals from the 2306 driver circuit through a conductive path 2330. The piezo 2320 moves, vibrates, distorts and / or changes shape in response to the application of driver output signals 842 from driver circuit 2306.
[0169] [000169] In one implementation, the piezo 2320 is mounted on the printed circuit board (PCB) 2301 and contacts a conductive surface (not shown) on the PCB board 2301. The conductive surface can be stainless steel. In some implementations, the 830 conductive path is a discrete wiring, not integrated with the 2301 board, which connects the piezo 2320 to an output of the 2306 driver circuit. In some implementations, the 2330 conductive path is a track made directly on the plate of PCB 2301. In these implementations, a conductive material is placed between the piezo 820 and the O-ring and the reservoir 2302. The conductive material can be, for example, an elastomer or "zebra list". In these implementations, the discrete wire is eliminated and the driver output signal 2342 of the driver circuit 2306 is provided for the piezo 2320 by a conductive track formed directly on the PCB board 2301. The piezo 2320 can be aligned with the opening 2228 for allow the directed droplet flow to exit device 2202.
[0170] [000170] In some implementations, the 800 configuration includes a second piezo that is coupled to the reservoir that is mounted on the top of the PCB board. In this implementation, driver circuit 2306 is configured to generate four driver signals from output 2342 to drive the two separate piezo. The second piezo can be mounted directly on the surface of the reservoir 2302 so that the reservoir 2302 vibrates with the second piezo. This vibration can help to ensure that the fluid within the 2302 reservoir remains in a fluid state to help prevent the formation of crystals and other solid particles within the 2302 reservoir. In the case of medications provided as a suspension, the vibration may be operable for revolve the medication.
[0171] [000171] LED 2322 receives power from power module 2326 and a signal to turn ON or OFF from processor 2304. Processor 2304 also provides a signal to speaker 2324 to turn ON or OFF. The 2300 configuration includes a 2328 remote control module that allows remote configuration and / or control of the 2304 processor. The 2326 power module can have one or more batteries. For example, the 2326 power module can include three batteries.
[0172] [000172] Figure 24 shows an exemplary 2400 process for operating a device that provides a flow of droplets directed to a patient's eye. The 2400 process can be performed using, for example, the device. Process 2400 can be performed by electronics 2208 or processor 2304. Process 2400 can be performed by processor 2304 in conjunction with driver circuit 2306. An indication of activation of a touch device is received 2402. The touch device can be, for example, the flow activator 2234, and the activation indication can be the spray signal that is generated by the pressure switch 2308 when the flow activator contacts the pressure switch 2308 physically or interacts with the switch 2308 electronically. The activation indication results from a user of the 2202 device specifying that a directed flow of fluid droplets is to be released from the 2202 device.
[0173] [000173] Whether an opening in the housing is substantially free of obstruction is determined 2404. The directed droplet flow is released from device 2202 when slide 2230 is in a position that reveals, rather than covers, opening 2228. When slide 2230 is positioned in a position on the housing that reveals opening 2228, slide switch 2312 generates a signal that is provided to processor 2304. If this signal is not generated, opening 2228 is not substantially free of obstructions. If the signal was generated, aperture 2228 is substantially free of obstruction so that a directed flow of droplets can be released from device 2202.
[0174] [000174] An excitation signal is generated in response to receiving the activation indication and determining that the opening in the housing is substantially free of obstruction 2406. Excitation signal 2340 is applied to driver circuit 2306, which in turn generates two voltage signals (output driver signals) that are applied to the piezo 2320 (or piezo 2210) to cause the piezo and the ejector plate 1602 attached to the piezo to vibrate, move, or otherwise distort. The movement of ejector plate 1602 draws fluid from reservoir 2302 and through one or more holes in the ejector plate, creates a directed flow of fluid droplets for application to the patient's eye. The 2340 excitation signal can be a square wave that has a frequency of approximately 95 kHz to 183 kHz. The excitation signal 2340 is applied to the driver circuit 2306, and the driver circuit 2306 produces two square wave output driver signals that are 180 ° out of phase with each other and that are applied to the 2320 piezo. The signal voltages 2342 square wave output driver can be, for example, 20 to 40 volts, and the frequency of each 2342 output driver signal can be between approximately 95 kHz to 183 kHz.
[0175] [000175] Figure 25 shows another exemplary 2500 process for operating a device that directs a flow of fluid droplets into a patient's eye. The 2500 process can be performed using, for example, the device. Process 2500 can be performed by electronics 2208 or processor 2304. Process 2500 can be performed by processor 2304 in conjunction with driver circuit 2306.
[0176] [000176] An indication that the thumb slide has moved to a second position is received (2502). The thumb slide can be a slide similar to slide 2230, and the second position can be a location on the surface of housing 2206 that reveals aperture 2228 so that the directed flow of droplets can exit device 2202. The indication that slide 2230 moved can be a signal generated by slide switch 2312 in response to the slide making an electrical or mechanical contact with slide switch 2312. An excitation signal 2340 is generated in response to receiving the indication (2504). Excitation signal 2340 can be generated by processor 2304, and excitation signal 2340 can be a signal that controls driver circuit 2306 to produce the output driver signals that drive the piezo to perform a setup sequence. The preparation sequence can be referred to as an initiation sequence, a purge cycle, or a cleaning cycle.
[0177] [000177] The preparation sequence causes device 2202 to produce one or more directed flows of droplets that are not intended for placement in the patient's eye. In contrast, the one or more flows produced in the preparation sequence wash the barrier, the hole in the barrier, the reservoir, and other internal components of the 2202 device. The preparation cycle can reduce or eliminate the contaminants and residues that can accumulate in the device 2202 between uses. In some implementations, approximately 8 to 10 targeted droplet streams are produced during the preparation sequence. Although the directed flow of droplets released during the preparation sequence is not intended for placement in the patient's eye, medication within the reservoir is used as the fluid during the preparation cycle to clean and / or prepare the device for use.
[0178] [000178] In some implementations, driver signal 2340 applied to driver circuit 2306 causes the driver circuit to produce two output driver signals with a waveform that has a cycle that lasts for a total of approximately 50 milliseconds , and for approximately 30 milliseconds of the cycle while the 2342 output driver signal is ON, and for approximately 20 milliseconds while the 2342 output driver signal is OFF (that is, essentially no 2342 output driver signal is applied to the piezo ). The preparation cycle may include applying these output waveforms to the piezo for approximately 8 to 10 cycles of the waveform. When the output waveform is ON, the piezo vibrates and draws fluid from the reservoir through the barrier to clean the 2202 device components.
[0179] [000179] An indication that the preparation sequence is complete is received 2506, and a noticeable alert is displayed upon completion of the preparation sequence 2508. The noticeable alert may be, for example, LED 2322 ON. The alert takes the user of the 2202 device to the knowledge that the 2202 device is ready for use. If an indication of an activation of the touch interface is not received within a predetermined amount of time after the completion of the preparation sequence, a sleep mode is initiated 2512. If an indication of an activation is received within the predetermined amount of time, it is determined whether the opening in the housing is substantially free of obstruction so that the directed flow of droplets can leave the housing (2516).
[0180] [000180] If an indication that the thumb slide has moved to a first position is received, then the sleep mode is initiated 2512. The first position can be a position in which the thumb slide covers the opening in the housing. If an indication that the thumb slide has moved to the first position has not been received, the device 2202 remains ready to receive input from the user until a predetermined amount of time has elapsed. After the predetermined amount of time has elapsed, the sleep mode is initiated.
[0181] [000181] Processor 2304 can be programmed to apply only a predetermined number of dosages, such as 30 dosages, 60 dosages, or 180 dosages, and further activation of the touch interface does not produce a directed flow of droplets.
[0182] [000182] Other alternative implementations are also contemplated. As an example, in an implementation, ejection plates are created by precise microfabrication techniques. A size of microspheres ejected from such a plate will vary in volume according to the magnitude of plate movement. The frequency of the plate movement is influenced by the frequency of an electrical voltage (typically a square wave) that drives the piezoelectric actuator attached to the ejector plate. Typically the actuation frequency will be in the range of 50 kHz to 200 kHz and will have a duration greater than approximately 0.1 milliseconds.
[0183] [000183] The volume of drug per dose is calculated from the diameter of the ejected spheres, the number of holes in the plate, the frequency of vibration, the number of voltage cycles per ejection per hole, and the length of time the plate is vibrated . For example, an ejection plate that has 1000 holes that is 20 microns in diameter can eject spheres approximately 40 microns in diameter. If a sphere ejects from each hole approximately once for ten cycles, then a vibration of 100 kHz from the piezoelectric element will eject approximately 100,000 / 10 balls per hole per second or approximately 10,000,000 balls per second when all 1000 holes are ejecting fluid . If each sphere is 40 microns in diameter then the ejector plate will apply approximately 10,000,000 * 4/3 * pi * ((40e-6) / 2) ˄3 cubic meters per second or approximately 10,000,000 * 4/3 * pi * ((40e-3) / 2) ˄3 = 335 microliters per second. If the plate is actuated for 20 milliseconds then approximately 6.5 microliters of drug will be ejected.
[0184] [000184] Without being limited by theory, the sphere size and speed are related to the amplitude and frequency of the waveform voltage that drives the piezoelectric element. This is partly because the magnitude of the ejection plate movement and the piezoelectric movement is related to the frequency of the trigger signal. The magnitude of the piezoelectric movement is related to the voltage of the applied voltage. The ejection speed is also dependent on the frequency and magnitude of the applied voltage. In some implementations, spheres are not effectively ejected except near resonant frequencies or their harmonics. In an implementation, the spheres ejected at these frequencies will be optimized for maximum speed and volume. Unfortunately, the variation in the manufacture of piezoelectric elements can cause the resonant frequencies to vary approximately 10% from the average. This variation results in each application unit needing a slightly different voltage or frequency to achieve the same application speed and volume. Each unit can be tuned during manufacture to a specific frequency. The oscillation of the piezoelectric element is highly dependent on the frequency. Therefore, frequency optimization is often necessary and frequency control of a square wave can be performed by changing the frequency of the internal square wave generator (typically a microprocessor or FPGA).
[0185] [000185] In certain implementations of a portable device, the voltage and power applied to the piezoelectric element can be limited by breakdown voltages of electrical components and total battery power. The voltage can be minimized to reduce energy consumption while still achieving optimal ball ejection. The tuning of the frequency slightly outside the resonant frequency allows the control of the ejection speed and plume shape for a given applied voltage. Similarly, the total mass ejected per dose is controlled by the duration of ejection. Thus, a final tuning of the trigger frequency and pulse time is necessary to adjust the ejection speed and dose volume.
[0186] [000186] An implementation described here is a device and method for tuning the ejection speed and dose size for a portable ophthalmic applicator. In an implementation of this a small target plate with an associated weighing mechanism and a vision system that looks at the region between the applicator and the target plate. A test template controller applies the dose for a fixed time and receives the weight and speed of the applied dose. A controller calculates the appropriate modifications to the ophthalmic application device. An ophthalmic applicator has a programmable internal controller with a static memory (such as an EEPROM) to store the optimized parameters.
[0187] [000187] A vision system will measure the speed of the application. Typical application speeds are in the range of 0.5 to 10 meters per second with a typical flight time of 4 to 80 milliseconds covering a distance of 4 cm. So a camera with a frame rate faster than 100 frames per second and ideally 10,000 frames per second would measure the leading edge of an application as it moves from the applicator to the weighing station. The measurement accuracy of the droplet front edge depends on an effective light source, an effective optics, and the camera resolution.
[0188] [000188] In an implementation operation, an applicator will be placed in the tuning station in a rigid template (or brought to the test area in a template) with electrical connections to the applicator. A dose will be applied towards the target approximately 4 cm away as the vision system measures the speed of the front edge of the ejected droplets. Then the target will be weighed. A controller then calculates the application volume and speed. Typically applications will be made at multiple frequencies to determine the optimal application frequency for the correct droplet speed. The dosage per application will be measured by the weighing system at this frequency and then the application time will be adjusted to a value that provides the correct dosage.
[0189] [000189] At appropriate times the application fluid is cleaned from the target with a jet of air followed by another weighing to tare the system. For accurate dose measurement, multiple applications can be made to increase the total measured mass. Then, an average can be calculated to determine the mass of a single dose.
[0190] [000190] In addition, a vision system can be used to check the width of the application plume and even infer the droplet size according to the degree to which the droplets are carried around the target by the air flow. This data can be collected in one or two directions (for example, from above or from the side) to check the scope of the applicator plate if necessary. Similarly, a vision system that observes the droplet flight from the side can infer the application speed and droplet size from the amount that the application falls under the target. With higher application speeds, the vertical position of the droplets will change less.
[0191] [000191] In order for this system to work, each portable device can have an externally programmable memory to contain the calibration constants or the formula for piezoelectric frequency and pulse duration. For consumer and specifically prescription applications, each unit can, if desired for that implementation, store the number of doses it is allowed to apply. Knowing the volume of the fluid allows an excess filling, which you can optionally use for calibration sprays and cleaning sprays which can occur each time the unit is opened. In an implementation an entire wet ejector plate for a full dose application. A requirement for total wetting can result in an excess of drug that can be stored in the applicator so that at the end of user dosing there will be drug left in the applicator.
[0192] [000192] In an implementation, the number of ejected doses can be restricted both to the consumer to prevent partial doses from being used and to the supplier of the device so that the quantity per dose is precisely performed. For example, if a unit was over 20% full then the consumer could buy 20% fewer units on an annual basis in the event of long term use of the device.
[0193] [000193] In an implementation, together with the calibration constants and dose limits, the memory can be programmable to allow the same unit to apply doses of different sizes in the case where a smaller person or child should receive lower doses of the drug . Similarly, in cases where the unit must alert the user if a dose is overdue, as in the case of a glaucoma medication where regular application of the drug is the key to minimizing disease damage, medication intervals or even an internal clock could be adjusted. For example, during the day doses could be required every four hours, but no dose is required from 9 pm until 6 am when the person is sleeping. In an implementation, a calibration point of the application system or later during packaging or prescription sales the user's constants could be downloaded to the device.
[0194] [000194] Many implementations of the invention have been described. This description contemplates combining any of the characteristics and an implementation with the characteristics of one or more of the other implementations. For example, any of the ejector mechanisms, or reservoirs can be used in combination with any of the described housings or housing characteristics, for example, covers, supports, supports, lights, seals and gaskets, filling mechanisms, or alignment mechanisms . Additional variations of any of the elements of any of the inventions within the scope of persons skilled in the art are covered by this description. Such variations include the selection of materials, coatings, or manufacturing methods. Any of the electrical and electronic technology can be used with any of the implementations without limitation. Furthermore, any network, remote access, patient monitoring, e-health, data storage, data mining, or Internet functionality is applicable to any and all implementations and can be applied with these. Furthermore, additional diagnostic functions, such as the performance of tests or measurements of physiological parameters can be incorporated into the functionality of any of the implementations. The performance of a glaucoma or other eye tests can be performed by the devices as a part of their diagnostic functionality. Other manufacturing methods known in the art and not explicitly listed here can be used to manufacture, test, repair or maintain the device. Furthermore, the device may include more sophisticated imaging or alignment mechanisms. For example, the device or the base can be equipped with the coupled to an iris or retina scanner to create a unique id to match a device to the user, and to outline between the eyes. Alternatively, the device or base may be coupled with or include sophisticated imaging devices for any suitable type of photography or radiology.
[0195] [000195] To assist in understanding the present invention, the following Example is included. The experiments described herein should not, of course, be considered as specifically limiting the invention and such variations of the invention, now known or later developed, which would be within the reach of someone skilled in the art are considered to fall within the scope of the invention as here described and hereinafter claimed. Example
[0196] [000196] An implementation of the description can be performed using this example. Although many arrangements are possible, an implementation uses an annular PZT piezo attached directly to a circular 80-micron thick Ni-Co ejector plate, which has a diameter of 0.5 cm. The ejector plate contains eighty-nine 30 micron cylindrical holes drilled through the center with a 380 micron center-to-center distance between adjacent holes. A 60 Vpp amplitude square wave is applied to the piezo at the resonant frequency (108.0 kHz) causing the ejector plate to oscillate at approximately the same frequency.
[0197] [000197] When operating with these parameters, the device produces droplets with a size distribution in which the mediating diameter is 55 microns. In this example, the ideal range for the device is assumed to be 3.0 cm orthogonal to the target plane. If the target has a diameter of bottom to top target of 8.0 mm, then the average distance that a droplet would fall due to gravity before leaving the target is 4.0 mm. The terminal velocity for a 55 micron water droplet is 0.09 m / s. So it takes at least 0.044 s to drop 4 mm. Assuming that the average horizontal velocity of a droplet is 1/2 the initial velocity, the minimum initial velocity required to propel the droplet to a target 3.0 cm away at 0.44 s is 1.4 m / s.
[0198] [000198] Droplets with a diameter of 55 microns have an evaporation time of approximately 3 seconds. Therefore, a particle that moves at the minimum speed necessary to reach the eye would still contain more than 99% of its initial volume when impacted with the eye.
[0199] [000199] Without taking into account the effects of entrained air, the moment ratio for drag force (relaxation time) of this medium-sized particle would be 0.0093 s, leading to a theoretical stopping distance of 9.3 mm . However, the entrained air reduces the drag force on the droplets, increasing the effective range by up to an order of magnitude.
[0200] [000200] Particle diameter measurement and analysis were performed with a Malvern Spraytec instrument. These systems use a 632.8 nm collimated laser for a 10 mm diameter beam. When the laser interacts with the particles in this path, the light is scattered at various angles depending on the droplet size. A lens focuses light scattered over elements of a photodiode detector. The control software subtracts the electrical and optical background noise, applies a multiple dispersion correction filter, and then calculates the droplet size distribution as a function of time.
[0201] [000201] Mass deposition experiments were performed with a 20 MHz BK Precision 4040A function generator, a NF Electronic Instruments 4025 high speed bipolar power / power amplifier, and an Ohaus Pioneer PA214 digital scale (210 g capacity x 0.1 mg resolution). Glass slides (7.5 cm x 7.5 cm) were used to collect the droplets ejected from the Corinthian Ophthalmic drug delivery invention. These large slides are important for observing the effect of entrained air on the deposition of mass. A 36 inch Edmund Optics dovetail rail was used to vary the distance of mass deposition while maintaining straight line accuracy.
[0202] [000202] Droplet size distributions were measured with the Malvern Spraytec instrument and software. A drop generation device was maintained at a constant distance of 3.0 cm from the center of the collimated laser beam and sprayed horizontally into the beam. The function generator was used to drive the high speed power amplifier using a pulse width modulation. The high-speed power amplifier produced a square wave with 108.0 kHz frequency, pulse width of 0.150 s, 50% active cycle, and 60 Vpp amplitude, thereby activating the piezo at its resonant frequency. Malvern Spraytec fired to start measurements when the laser transmission dropped below 98%.
[0203] [000203] Dosing efficiency measurements were carried out observing the deposition of mass on the glass slide at distances of 0.0 - 6.0 cm from the ejector plate. This experiment was performed on 5 different ejector plate hole sizes.
[0204] [000204] The graphs were normalized to 100% mass deposition, and plotted as a function of distance and median particle diameter as measured by the Malvern Spraytec device (Figures 3 and 4). Figure 3 shows how the 10 and 17 micron particles only deliver a partial dose (68-85%) at distances of 3 cm. However, the 32, 56, and 70 micron particles provide 92-99% of the dose at 3 cm. At a greater distance of 6 cm, the 10 and 17 micron particles only seem to provide 21-51%, while the 32, 56, and 70 micron particles appear to provide 70-84% of the original dose. This graph suggests that droplet size is a relevant variable to consider when trying to supply ophthalmic fluids with an ejector-type delivery device.
[0205] [000205] Droplets with insufficient mass will have a low momentum to drag force as shown in equation 3. These droplets will create more entrained air in relation to their diameter during flight time, because they have a higher surface ratio for volume. When these smaller droplets approach the eye, they have an insufficient moment to overcome the entrained air effect described above, and consequently are often deflected. Small droplets also have a shorter stopping distance. This factor contributes to its rapid deceleration before they reach the target. An evaporation rate is also higher for droplets in the range of 17 microns in diameter. A higher evaporation rate helps to increase the stopping distance, air entrainment, and moment to force drag problems.
[0206] [000206] Droplet diameters and mass deposition rates are measured at various distances. Droplets with a diameter greater than or equal to 32 microns have a noticeably higher percentage of mass deposited. Particles with diameters less than or equal to 17 microns do not appear to deposit significant mass over a wide range of distances. Droplets with diameters greater than or equal to 32 microns perform mass deposited at higher levels seen for diameters equal to or less than 17 microns.
[0207] [000207] In an implementation, a portable, hand-held ophthalmic applicator is typically safe 3 cm from the eye as it creates microspheres or microdroplets that move into the user's eye. The microspheres of the drug are formed and released as a piezo material vibrates an ejection plate in the applicator in a precise pattern of frequency and duration. A material piezo changes shape as a voltage is applied across it. A change of shape is mechanically connected to vibrate the ejection plate. The size and speed of the microspheres are critical so that the spheres are not too small and slow to move or they cannot reach the eye. Similarly, the quantities and mass of the beads are important for maintaining a correct dosage of drugs for the eye. The ejection plates are created by precise microfabrication techniques. The diameter of the microsphere is related to the diameter of holes in the ejection plate. Ejection plates will typically have hundreds of holes in the plate, all manufactured to have the same diameter with a nominal diameter typically between 15 microns and 60 microns.
[0208] [000208] In an implementation, the size of the microspheres ejected from such a plate will vary in volume according to the magnitude of plate movement. The frequency of the plate movement is determined by the frequency of an electrical voltage (typically a square wave) that acts on the piezo actuator attached to the ejector plate. Typically, the actuation voltage will be in the range of 100 kHz to 150 kHz and will last from 10 milliseconds to 100 milliseconds per dose.
[0209] [000209] In one implementation, the volume of drug per dose is calculated from the diameter of the ejected spheres, the number of holes in the plate, the frequency of vibration, the number of voltage cycles per ejection per hole, and the length of time that the plate is vibrated. For example, an ejection plate that has 1000 holes that is 20 microns in diameter can eject spheres approximately 40 microns in diameter. If a sphere ejects from each hole approximately once for ten cycles, then a vibration of 100 kHz from the piezoelectric element will eject approximately 100,000 / 10 balls per hole per second or approximately 10,000,000 balls per second from all 1000 holes. If each sphere is 40 microns in diameter then the ejector plate will apply approximately 10,000,000 * 4/3 * pi * ((40e-6) / 2) Λ3 cubic meters per second or approximately 10,000,000 * 4/3 * pi * ((40e-6) / 2 ^ 3 cubic meters per second or approximately 10,000,000 * 4/3 * pi * (((40e-3) / 2 ^ 3 = 334 microliters per second. If the plate is operated for 20 milliseconds then approximately 13 microliters of drug will be ejected.
[0210] [000210] Despite not being limited by these, the sphere size and speed are related to the magnitude and frequency of the voltage applied to the piezo. This is partly because the magnitude of the ejection plate movement and piezo movement is related to the frequency of the trigger signal. The magnitude of the piezo movement is directly related to the voltage of the applied voltage. The ejection speed is also dependent on the frequency and magnitude of the applied voltage. It has been found that the spheres are not ejected except in a very narrow frequency band with an optimum for maximum speed and volume. Unfortunately, the variation in piezo making makes this optimum vary approximately 10% between the piezo batch. This variation results in each application unit needing a slightly different voltage frequency to achieve the same speed and volume of application. Thus, the unit must be tuned during manufacture to a specific frequency. Typically, the frequency instead of the voltage is tuned due to the increase in circuit complexity and the associated cost of having voltage control. On the other hand, controlling the frequency of a square wave is performed by changing the frequency of the internal square wave generator (typically a microprocessor or FPGA).
[0211] [000211] In an implementation, in a portable device, the voltage and power applied to the piezo is limited by breakdown voltages of electrical components and total battery power. Thus, tuning for optimal ball ejection is required to achieve good ejection with minimum and maximum voltages. The tuning frequency slightly outside the optimum allows the control of the ejection speed for a given applied voltage. Similarly, the total mass ejected per dose is controlled by the duration of ejection. Thus, a final tuning of the activation frequency and activation time is necessary to adjust the ejection speed and dose volume.
[0212] [000212] In one implementation, described here is a device and method for tuning the ejection speed and dose size for a portable ophthalmic applicator.
[0213] [000213] In an implementation, a small target plate with an associated weighing mechanism and a vision system that observes the region between the applicator and the target plate and a test template controller that starts the applicator applications, receives the weight and the speed of the applied dose and calculates the appropriate modifications to apply constants in the ophthalmic application device. An ophthalmic applicator has an internal, externally programmable controller with a static memory (such as an EEPROM) to receive and store these constants.
[0214] [000214] In an implementation, the vision system will measure the speed of the application. Typical application speeds are in the range of 0.5 to 5 meters per second or times to transit 5 cm from 10 to 100 milliseconds. So a camera with a frame rate faster than 100 frames per second and ideally approximately 1000 frames per second would measure the leading edge of an application as it moves from the applicator to the weighing station. Obviously the accuracy of measuring the leading edge of the droplets depends on an effective light source that is part of the vision system.
[0215] [000215] In an implementation, an applicator will be placed in the tuning station in a rigid template (or brought to the test area in a template) with electrical connections to the applicator. A dose will be applied towards the target approximately 3 cm away as the vision system measures the speed of the front edge of the ejected droplets. Then the target will be weighed. The controller then calculates the application volume and speed. Typically, applications will be made at multiple frequencies to determine the optimal application frequency for the correct droplet speed. The dosage per application will be measured by the weighing system at this frequency and then the application time will be adjusted to a value that provides the correct dosage.
[0216] [000216] In an implementation, the application target approaches the area of an eye. At appropriate times, the application fluid is cleaned from the target with a jet of air followed by another weighing to tare the system. For accurate dose measurement, multiple applications can be made to increase the total measured mass.
[0217] [000217] In an implementation a vision system can be used to check the width of the application plume and even infer the droplet size according to the degree to which the droplets are carried around the target by the air flow. This data can be collected in one or two directions (for example, from above or from the side) to check the scope of the applicator plate if necessary. Similarly, a vision system that observes the droplet flight from the side can infer the application speed and droplet size from the amount that the application falls under the target. With higher application speeds, the vertical position of the droplets will change less.
[0218] [000218] In an implementation so that this system works, each portable device can have an externally programmable memory to contain the calibration constants for piezo frequency and duration. In addition, for consumer and prescription applications, each unit must be able to store the number of doses it is allowed to apply. This is necessary because each unit will need to be slightly overfilled to allow both calibration sprays and cleaning sprays which can occur each time the unit is opened. Furthermore, due to the nature of a multi-hole ejector, it is necessary to have the entire ejector plate wet for a full dose application. The total wetting requirement will require that excess drug will need to be stored in the applicator so that at the end of user dosing, drug will remain in the applicator.
[0219] [000219] In an implementation, the number of ejected doses can be restricted both to the consumer to prevent partial doses from being used and to the supplier of the device so that the quantity per dose is precisely performed. For example, if a unit was over 20% full then the consumer could buy 20% fewer units on an annual basis in the event of long term use of the device.
[0220] [000220] In an implementation, together with the calibration constants and dose limits, the memory can be programmable to allow the same unit to apply doses of different sizes in the case where a smaller person or child should receive lower doses of the drug . Similarly, in cases where the unit must alert the user if a dose is overdue, as in the case of a glaucoma medication where regular application of the drug is the key to minimizing disease damage, medication intervals or even an internal clock could be adjusted. For example, during the day doses could be required every four hours, but no dose is required from 9 pm until 6 am when the person is sleeping.
[0221] [000221] In an implementation, at the point of calibration of the application system or later during packaging or prescription sales the user constants could be downloaded to the device.
[0222] [000222] Although the above describes various modalities as an illustration and example, the person skilled in the art will appreciate that various changes and applications can be practiced within the spirit and scope of this application.
[0223] [000223] US Application Number 13 / 184,446 (Proxy Protocol Number 24591.003-US01), filed concurrently with this one entitled "Ophthalmic Drug Application" and US Application Number 13 / 184,468 (Proxy Protocol Number 24591.003-US02), filed concurrently with this entitled "Method and System for Performing Remote Treatment and Monitoring" are also incorporated by reference in their entirety.

权利要求:
Claims (15)
[0001]
Piezoelectric driven droplet generating device to deliver a fluid to a target as an ejected droplet stream, the device comprising: a housing (502); a reservoir (1620) disposed within the housing (502) for receiving a volume of fluid (1610); the device characterized by: an ejector mechanism (1601) comprising an ejector plate (1602) having a first surface (1625) coupled to a fluid distribution area of the reservoir (1620), the ejector plate (1602) including a plurality of openings (1626) formed through its thickness; and a piezoelectric actuator (1604) coupled to a second surface (1622) of the ejector plate (1602), the actuator being operable to oscillate the ejector plate (1602) at a frequency to generate, thus, an ejected flow of droplets; where the manner and location of attachment of the piezoelectric actuator (1604) to the ejector plate (1602) and the size, shape and pattern of the openings through the ejector plate (1602) of the ejector mechanism (1601) are configured to generate a droplet ejection flow having an average droplet ejected diameter greater than 20 microns and an average initial droplet ejection speed between 0.5 m / s and 10 m / s, the droplet flow having a low entrained air flow of so that at least 75% of the mass of the droplet ejected stream deposits on a target during use.
[0002]
Device according to claim 1, characterized by the fact that the target is a subject's eye.
[0003]
Device according to claim 1, characterized by the fact that at least 80% of the mass of the ejected droplets is deposited on the target.
[0004]
Device according to claim 1, characterized by the fact that the ejector mechanism (1601) is configured to eject a stream of droplets that have an average droplet diameter in the range of 20 to 100 microns.
[0005]
Device according to claim 1, characterized by the fact that the actuator extends around a peripheral region of the ejector plate (1602).
[0006]
Device according to claim 1, characterized by the fact that the openings are arranged in a central region of the ejector plate (1602) that is not covered by the actuator.
[0007]
Device according to claim 1, characterized by the fact that the reservoir (1620) comprises a characteristic selected from the group consisting of a collapsible wall that collapses as the fluid volume decreases and a reservoir (1620) of wick.
[0008]
Device according to claim 1, characterized in that the ejector plate (1602) comprises a protective coating.
[0009]
Device according to claim 1, characterized in that the ejector plate (1602) comprises a reflective coating.
[0010]
Device according to claim 1, characterized in that it still comprises a cover that can be sealed against the ejector plate (1602) when the device is not in use.
[0011]
Device according to claim 10, characterized in that the cover made comprising polypropylene, polyethylene, high density polyethylene or teflon can be sealed against the ejector plate (1602).
[0012]
Device according to claim 1, characterized in that the housing (502) comprises an opening to expose the openings of the ejector plate (1602), and also includes a cover configured to cover or discover the openings of the ejector plate (1602) .
[0013]
Device according to claim 12, characterized by the fact that the cover is coupled to an activation trigger which activates the ejector plate (1602).
[0014]
Device according to claim 1, characterized by the fact that the droplet ejected flow has an average ejection diameter in the range of 20-100 microns and an average ejection speed in the range of 2-5 m / s.
[0015]
Device according to claim 1, characterized in that it still comprises at least one diagnostic characteristic, in which the diagnostic characteristic comprises a light emitter and a wave detector, and in which the light emitter directs the waves in the direction droplets and the detector detects the reflected or refracted portions of the said droplets.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US11011270B2|2021-05-18|Drop generating device

---

JP6408504B2|2018-10-17|Drop generation device

---

BR112013001030B1|2020-09-08|“DROPLET GENERATOR DEVICE FOR USE IN THE SUPPLY OF A VOLUME OF OPHTHALMIC FLUID FOR AN EYE OF A SUBJECT”

---

US10646373B2|2020-05-12|Ejector mechanism, ejector device, and methods of use

---

US7883031B2|2011-02-08|Ophthalmic drug delivery system

---

US20100222752A1|2010-09-02|Ophthalmic fluid delivery system

---

US8545463B2|2013-10-01|Ophthalmic fluid reservoir assembly for use with an ophthalmic fluid delivery device

---

CN104582647B|2016-11-30|Injection equipment, injection apparatus and using method

同族专利:

---

公开号 | 公开日

---

CN103118642A|2013-05-22|

---

CA2805426C|2020-03-24|

---

JP5964826B2|2016-08-03|

---

KR101545413B1|2015-08-18|

---

EP2593056B1|2020-10-21|

---

MX339173B|2016-05-12|

---

AU2011278934B2|2015-02-26|

---

AU2011278934A1|2013-02-21|

---

EA201390122A1|2014-05-30|

---

JP2013535250A|2013-09-12|

---

US20120143152A1|2012-06-07|

---

WO2012009706A1|2012-01-19|

---

CA2805426A1|2012-01-19|

---

EP2593056A1|2013-05-22|

---

US8684980B2|2014-04-01|

---

KR20130054352A|2013-05-24|

---

BR112013001030A2|2016-05-24|

---

MX2013000605A|2013-06-28|

---

ES2835886T3|2021-06-23|

---

BR112013001030B8|2021-05-11|

---

CN103118642B|2015-09-09|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US1482747A|1921-11-26|1924-02-05|Howe Frank Morgan|Spraying outfit|

---

US1988637A|1933-02-01|1935-01-22|Mccord Radiator & Mfg Co|Fire extinguisher|

---

US2189643A|1936-04-25|1940-02-06|Lawrence T Ward|Dispensing apparatus|

---

US2200008A|1938-03-04|1940-05-07|John J Nowak|Therapeutic apparatus for vapor treatment of the ear|

---

US2249608A|1939-07-03|1941-07-15|Fred E Greene|Fluid gas gun|

---

US2322808A|1940-05-21|1943-06-29|American Can Co|Lubricating dispenser|

---

GB558866A|1942-04-01|1944-01-25|Walter Albin Robinson|Improvements in and relating to nozzles for the discharge of fluids|

---

US2595317A|1946-05-06|1952-05-06|Jr Roby Byron White|Spray gun|

---

US2552857A|1946-09-18|1951-05-15|Knapp Monarch Co|Aerosol bomb|

---

US2987439A|1958-01-07|1961-06-06|William Cooper & Nephews Inc|Method of applying an aerosol to the eye|

---

FR1271341A|1959-12-14|1961-09-08|Hitachi Ltd|Method of applying coating materials and devices for its implementation|

---

US3170462A|1962-01-05|1965-02-23|Merck & Co Inc|Aerosol ophthalmic device|

---

US3187757A|1962-12-17|1965-06-08|J & J Casting Inc|Plural dispensing units and toilet kit with central compartmented storage member|

---

FR1355588A|1963-01-07|1964-06-19|Oreal|New fixing device for vials and in particular for vials containing an aerosol solution|

---

US3314426A|1964-05-20|1967-04-18|Lever Brothers Ltd|Eyecup and spray dispenser|

---

US3310830A|1965-01-18|1967-03-28|Daniel H Gattone|Self-contained applicator for use with pressurized containers|

---

US3439674A|1966-02-18|1969-04-22|Jhon Lelicoff|Liquid eyewash dispensing device including eyelid engaging means|

---

BE756003A|1969-09-11|1971-02-15|Nordson Corp|SPRAY NOZZLE|

---

US3602399A|1969-09-16|1971-08-31|Gen Ordnance Equip|Non-lethal weapon dispenser|

---

US3934585A|1970-08-13|1976-01-27|Maurice David M|Method and apparatus for application of eye drops|

---

US3795351A|1971-01-05|1974-03-05|Polaroid Corp|Apparatus for dispensing a metered amount of fluid|

---

US3709235A|1971-03-17|1973-01-09|Washburn W & Sons Inc|Travel cases|

---

US3780950A|1972-02-07|1973-12-25|W Brennan|Paint accomodating modules adapted for use with spray guns|

---

US3826258A|1972-02-07|1974-07-30|S Abraham|Gradual release medicine carrier|

---

US3906949A|1972-05-03|1975-09-23|Research Corp|Corneal bath|

---

US3845764A|1972-06-13|1974-11-05|R Windsor|Device for applying material to the area of the eye|

---

US3779245A|1972-06-13|1973-12-18|R Windsor|Device for applying materials to the area of the eye|

---

US3812854A|1972-10-20|1974-05-28|A Michaels|Ultrasonic nebulizer|

---

US3901443A|1973-02-06|1975-08-26|Tdk Electronics Co Ltd|Ultrasonic wave nebulizer|

---

US3913575A|1973-11-08|1975-10-21|Robert K Windsor|Eye dropper device with a mirror|

---

US4002168A|1975-04-24|1977-01-11|Tor Petterson|Method of, and dispenser for introducing an opthalmic product into the occular cavity|

---

DE2537765B2|1975-08-25|1981-04-09|Siemens AG, 1000 Berlin und 8000 München|Medical inhalation device for the treatment of diseases of the respiratory tract|

---

US4012798A|1975-09-29|1977-03-22|Liautaud John R|Portable emergency eye wash fountain|

---

US4175704A|1976-02-17|1979-11-27|Cohen Milton J|Non-aerosol continuous spray dispenser|

---

US4067499A|1976-02-17|1978-01-10|Cohen Milton J|Non-aerosol continuous spray dispenser|

---

US4052985A|1976-06-28|1977-10-11|Coleman D Jackson|Apparatus for medicinally spraying an eyeball|

---

GB1569707A|1976-07-15|1980-06-18|Ici Ltd|Atomisation of liquids|

---

IE45426B1|1976-07-15|1982-08-25|Ici Ltd|Atomisation of liquids|

---

US4173226A|1977-11-10|1979-11-06|Alza Corporation|Device for administering solid drug particles to an eye|

---

US4131115A|1976-09-20|1978-12-26|Peng Sung S|Eyelids-turning and eye-washing fixture|

---

USD249709S|1976-11-22|1978-09-26|Trovinger Douglas J|Eye drop bottle guide|

---

US4098431A|1977-01-13|1978-07-04|Cine Magnetics Inc.|Chemical replenishing system|

---

US4122556A|1977-03-23|1978-10-31|Stanley Poler|Intra-ocular lens|

---

ES485764A1|1978-11-15|1980-10-01|Thomae Gmbh Dr K|Method and apparatus for dotting moulding devices by means of discrete droplets of a liquid or suspended lubricant during the manufacture of moulded objects in the pharmaceutical, food or catalytic field.|

---

CH628572A5|1977-04-20|1982-03-15|Thomae Gmbh Dr K|METHOD FOR SPRAYING THE COMPRESSION TOOLS OF MACHINES FOR PRODUCING MOLDINGS.|

---

US4175706A|1977-07-18|1979-11-27|Scientific Energy Systems Corporation|Spray nozzle|

---

FR2421513B1|1978-03-31|1983-02-11|Gaboriaud Paul|

---

DE2851532C2|1978-11-29|1981-02-19|Boehringer Mannheim Gmbh, 6800 Mannheim|Pipette with elastic bellows|

---

JPS5848225B2|1979-01-09|1983-10-27|Omron Tateisi Electronics Co|

---

US4465234A|1980-10-06|1984-08-14|Matsushita Electric Industrial Co., Ltd.|Liquid atomizer including vibrator|

---

US4338936A|1980-10-27|1982-07-13|Byron Nelson|Device and method for delivering solid medication to an eye|

---

US4390542A|1980-12-02|1983-06-28|Schachar Ronald A|Method for inhibiting contraction of opthalmic wounds or incisions|

---

US4580721A|1981-02-12|1986-04-08|Imperial Chemical Industries Plc|Fluid container|

---

JPS5861857A|1981-10-09|1983-04-13|Matsushita Electric Works Ltd|Liquid atomizer|

---

US4398909A|1981-12-31|1983-08-16|Portnoff Joel B|Unit dose applicator|

---

AT28792T|1982-01-09|1987-08-15|Baumann M Fa|DEVICE FOR TREATING THE EYES WITH A BATHING LIQUID.|

---

US4605167A|1982-01-18|1986-08-12|Matsushita Electric Industrial Company, Limited|Ultrasonic liquid ejecting apparatus|

---

US4471890A|1982-04-29|1984-09-18|St. Luke's Hospital|Eye drop dispenser|

---

US4564016A|1982-05-24|1986-01-14|The Board Of Trustees Of The Leland Stanford Junior University|Apparatus for introducing ionized drugs into the posterior segment of the eye and method|

---

US4658290A|1983-12-08|1987-04-14|Ctba Associates|Television and market research data collection system and method|

---

US4543096A|1983-08-05|1985-09-24|Thomas Keene|Eyedrop dispenser with eyelid opening means|

---

AU574716B2|1983-08-18|1988-07-14|Imperial Chemical Industries Plc|Electrostatic spraying apparatus and process|

---

US4917274A|1983-09-27|1990-04-17|Maurice Asa|Miniscule droplet dispenser tip|

---

US4798599A|1984-01-03|1989-01-17|George Thomas|Eye washing method and apparatus|

---

US4544570A|1984-01-26|1985-10-01|Nordson Corporation|Electrostatic high voltage isolation system with internal charge generation|

---

EP0156409A3|1984-02-23|1986-06-25|Jean Michel Anthony|Device for moistening parts of the human body|

---

US4605398A|1984-04-20|1986-08-12|Herrick Robert S|Dispensing device for container having fluid to be controllably dispensed into an eye|

---

US4742713A|1984-06-01|1988-05-10|Omron Tateisi Electronics Co.|Ultrasonic flaw detecting system|

---

US4750650A|1984-06-12|1988-06-14|Ling Carl P C|Extended surface apparatus for use in dispensing liquids|

---

FR2569663B1|1984-08-28|1986-10-17|Oreal|FLEXIBLE BOTTLE FOR PERFORMING EITHER SPRAYING, EITHER DRIPPING, OF A LIQUID IT CONTAINS|

---

DE3574344D1|1984-08-29|1989-12-28|Omron Tateisi Electronics Co|Ultrasonic atomizer|

---

DE3582287D1|1984-09-07|1991-05-02|Omron Tateisi Electronics Co|VIBRATION GENERATOR FOR AN INHALATION DEVICE WITH ULTRASONIC SPRAYING.|

---

US5048727A|1984-11-02|1991-09-17|Alcon Laboratories, Inc.|Preassembled unit dose dispenser having a compressible container and a tube prefilled with a unit dose of opthalmic gel.|

---

US4627845A|1984-12-04|1986-12-09|Demotte Frank E|Eyes-bathing faucet-mateable structure|

---

US4759755A|1985-03-05|1988-07-26|Lincoln Diagnostics, Inc.|Device for transferring liquid from a vial to a multi-pointed applicator|

---

SE447337B|1985-03-27|1986-11-10|Tobin Ab|POCKET PACKAGING FOR OGONS SCHOOL LIQUID|

---

SE451295B|1985-03-27|1987-09-28|Fagersta El & Diesel Ab|OGONDUSCH|

---

EP0200258A3|1985-04-29|1988-02-03|Jean Michel Anthony|Ultrasonic spraying device|

---

US4642581A|1985-06-21|1987-02-10|Sono-Tek Corporation|Ultrasonic transducer drive circuit|

---

US4750902A|1985-08-28|1988-06-14|Sonomed Technology, Inc.|Endoscopic ultrasonic aspirators|

---

US4659014A|1985-09-05|1987-04-21|Delavan Corporation|Ultrasonic spray nozzle and method|

---

US4702418A|1985-09-09|1987-10-27|Piezo Electric Products, Inc.|Aerosol dispenser|

---

US4701167A|1985-09-16|1987-10-20|The Kendall Company|Multi-dimensional applicator|

---

US5053000A|1985-11-13|1991-10-01|Imperial Chemical Industries Plc|Ocular treatment|

---

GB8528032D0|1985-11-13|1985-12-18|Ici Plc|Ocular treatment|

---

US4758727A|1986-02-12|1988-07-19|Ohio State University Research Foundation|Method and apparatus for the measurement of low-level laser-induced fluorescence|

---

US4641384A|1986-02-14|1987-02-10|Maddak, Inc.|Battery operated eyewash system|

---

US4685906A|1986-03-31|1987-08-11|Murphy William F|Eye-drops application device|

---

DE3616713A1|1986-05-20|1987-11-26|Siemens Ag|ULTRASONIC MHZ SWINGERS, IN PARTICULAR FOR LIQUID SPRAYING|

---

DE3627222A1|1986-08-11|1988-02-18|Siemens Ag|ULTRASONIC POCKET SPRAYER|

---

EP0261649B2|1986-09-22|1995-04-26|Omron Tateisi Electronics Co.|Nebulizer|

---

US4706848A|1986-10-06|1987-11-17|Andrade Bruce M D|High efficiency battery operated water gun|

---

GB8624670D0|1986-10-15|1986-11-19|Glaxo Group Ltd|Valve for aerosol container|

---

US4826025A|1986-11-21|1989-05-02|Toppan Printing Co., Ltd. & Mect Corp.|Ampoule package|

---

US4863457A|1986-11-24|1989-09-05|Lee David A|Drug delivery device|

---

US4758237A|1987-01-20|1988-07-19|Herman Sacks|Device for applying liquid to the corneal surface of the eye|

---

AT46836T|1987-03-17|1989-10-15|Lechler Gmbh & Co Kg|ULTRASONIC LIQUID SPRAYER.|

---

US4850534A|1987-05-30|1989-07-25|Tdk Corporation|Ultrasonic wave nebulizer|

---

US4969869A|1987-07-09|1990-11-13|Burgin Kermit H|Pillow construction and medication dispenser|

---

US4779768A|1987-07-24|1988-10-25|St. Amand Manufacturing Co., Inc.|Volumetric dispensing pipette|

---

US4896832A|1987-09-07|1990-01-30|Bespak Plc|Dispensing apparatus for metered quantities of pressurised fluid|

---

US5047009A|1987-09-22|1991-09-10|Vitreoretinal Development, Inc.|Method and apparatus for ocular perfusion|

---

US5032111A|1987-09-22|1991-07-16|Vitreoretinal Development, Inc.|Method and apparatus for ocular perfusion|

---

US4981479A|1987-11-06|1991-01-01|Py Daniel C|Ocular treatment apparatus|

---

US5133702A|1987-11-06|1992-07-28|O.P.T.I.C.|Ocular treatment apparatus|

---

US4792334A|1987-11-06|1988-12-20|Py Daniel C|Occular treatment apparatus|

---

US4946452A|1987-11-06|1990-08-07|Py Daniel C|Ocular treatment apparatus|

---

US4863443A|1988-01-15|1989-09-05|Sterwin Laboratories Inc.|Automatic spray apparatus|

---

US4886189A|1988-02-29|1989-12-12|Vanderjagt John A|System for selectively containing metering and dispensing liquids|

---

US4908024A|1988-05-04|1990-03-13|Py Daniel C|Ocular self-treatment apparatus and method|

---

US4880146A|1988-06-08|1989-11-14|Hudgins J S|Drop dispenser which automatically stirs the contents of the dispenser when the cap is removed|

---

US5614545A|1988-06-09|1997-03-25|Leonard Bloom|Topical composition for treatment of blepharitis|

---

US5066276A|1988-06-21|1991-11-19|Alcon Laboratories, Inc.|Method and apparatus for injecting viscous fluid into the eye to lift pre-retinal and post-retinal membrane with linear pressure control|

---

CA1325568C|1988-06-24|1993-12-28|Pineway Ltd.|Eye-bathing devices|

---

US4881283A|1988-09-09|1989-11-21|Liautaud John R|Self contained eye wash fountain|

---

US4927062A|1988-09-22|1990-05-22|Walsh James W|Precision micro-liter drop dispenser|

---

US4871091A|1988-09-29|1989-10-03|Mason-Keller Corporation|Disposable package for liquids|

---

JPH0520456Y2|1988-10-01|1993-05-27|

---

EP0373237A1|1988-12-13|1990-06-20|Siemens Aktiengesellschaft|Pocket inhaler device|

---

US5029579A|1989-01-13|1991-07-09|Ballard Medical Products|Hyperbaric oxygenation apparatus and methods|

---

US5178856A|1989-02-02|1993-01-12|Board Of Regents Of The University Of Oklahoma|Enhancing growth of megakaryocytes in mammals using interleukin 6|

---

WO1990010469A1|1989-03-07|1990-09-20|Karl Holm|An atomizing nozzle device for atomizing a fluid and an inhaler|

---

US5085651A|1989-03-13|1992-02-04|Py Daniel C|Ocular vial|

---

US5163929A|1989-03-13|1992-11-17|O.P.T.I.C., Inc.|Ocular vial|

---

US5040706A|1989-03-17|1991-08-20|Insite Vision, Inc.|Liquid droplet dispensing apparatus|

---

EP0389665A1|1989-03-31|1990-10-03|Siemens Aktiengesellschaft|Ultrasonic sprayer for liquids|

---

US4927115A|1989-05-26|1990-05-22|Masco Corporation Of Indiana|Valve for a hand held spray nozzle|

---

IL90763A|1989-06-27|1994-04-12|Menchel Jehoshua|Applicator for liquid eye preparations|

---

US5019037A|1989-07-06|1991-05-28|Alcon Laboratories, Inc.|Pneumatic retinopexy injector|

---

DE3922746C1|1989-07-11|1990-08-23|Richard Wolf Gmbh, 7134 Knittlingen, De|

---

GB8917285D0|1989-07-28|1989-09-13|Harris Pharma Ltd|A valve for an aerosol dispenser|

---

GB8919131D0|1989-08-23|1989-10-04|Riker Laboratories Inc|Inhaler|

---

US4961885A|1989-11-24|1990-10-09|Elecsys Ltd.|Ultrasonic nebulizer|

---

US5152456A|1989-12-12|1992-10-06|Bespak, Plc|Dispensing apparatus having a perforate outlet member and a vibrating device|

---

US5276867A|1989-12-19|1994-01-04|Epoch Systems, Inc.|Digital data storage system with improved data migration|

---

US5065024A|1990-02-07|1991-11-12|Inframetrics, Inc.|Infrared imaging system with simultaneously variable field of view and resolution and fixed optical magnification|

---

US5007905A|1990-02-20|1991-04-16|Bauer George C|Eye drop applicator|

---

SG45171A1|1990-03-21|1998-01-16|Boehringer Ingelheim Int|Atomising devices and methods|

---

US5252318A|1990-06-15|1993-10-12|Allergan, Inc.|Reversible gelation compositions and methods of use|

---

US5030214A|1990-11-01|1991-07-09|Larry Spector|Ocular delivery system|

---

US5064420A|1990-11-16|1991-11-12|Kc Medical Industries Corporation|Eyelid opener|

---

US5269291A|1990-12-10|1993-12-14|Coraje, Inc.|Miniature ultrasonic transducer for plaque ablation|

---

US5139496A|1990-12-20|1992-08-18|Hed Aharon Z|Ultrasonic freeze ablation catheters and probes|

---

WO1994002369A1|1991-03-01|1994-02-03|Plastic Processing Corporation|Dual bottle container|

---

US5171306A|1991-03-13|1992-12-15|Vo Van T|Eyedrop delivery system|

---

US5364405A|1991-04-23|1994-11-15|Allergan, Inc.|Ophthalmic instrument with curved suction conduit and internal ultrasound needle|

---

US6427682B1|1995-04-05|2002-08-06|Aerogen, Inc.|Methods and apparatus for aerosolizing a substance|

---

US6540154B1|1991-04-24|2003-04-01|Aerogen, Inc.|Systems and methods for controlling fluid feed to an aerosol generator|

---

US5164740A|1991-04-24|1992-11-17|Yehuda Ivri|High frequency printing mechanism|

---

US6629646B1|1991-04-24|2003-10-07|Aerogen, Inc.|Droplet ejector with oscillating tapered aperture|

---

US5938117A|1991-04-24|1999-08-17|Aerogen, Inc.|Methods and apparatus for dispensing liquids as an atomized spray|

---

EP0516565B1|1991-05-27|1996-04-24|TDK Corporation|An ultrasonic wave nebulizer|

---

US5152435A|1991-06-13|1992-10-06|Ben Zane Cohen|Ophthalmic dispensing pump|

---

WO1992022385A1|1991-06-14|1992-12-23|Halcro Nominees Pty. Ltd.|Ultrasonic vibration generation and use|

---

US5265288A|1991-07-07|1993-11-30|Gary Allison|Automatic emergency spray means|

---

US5145113A|1991-08-30|1992-09-08|United Technologies Corporation|Ultrasonic generation of a submicron aerosol mist|

---

US5170782A|1991-09-12|1992-12-15|Devilbiss Health Care, Inc.|Medicament nebulizer with improved aerosol chamber|

---

GB9122739D0|1991-10-25|1991-12-11|The Technology Partnership Ltd|System for controlling fluid flow|

---

JP3272722B2|1991-12-02|2002-04-08|パイ，ダニエル|Apparatus for dispensing fluid droplets|

---

WO1993010910A1|1991-12-04|1993-06-10|The Technology Partnership Limited|Fluid droplet production apparatus and method|

---

US5203506A|1991-12-16|1993-04-20|Product Development Ltd.|Liquid pump and nebulizer constructed therewith|

---

US5259385A|1991-12-23|1993-11-09|Advanced Cardiovascular Systems, Inc.|Apparatus for the cannulation of blood vessels|

---

WO1993013737A1|1992-01-21|1993-07-22|Gabriel Meyer|Device for storing a liquid medicinal substance and dispensing eye drops|

---

US5267986A|1992-04-06|1993-12-07|Self-Instill & Co., Inc.|Cartridge for applying medicament to an eye from a dispenser|

---

US5401259A|1992-04-06|1995-03-28|Py Daniel C|Cartridge for applying medicament to an eye|

---

US5405614A|1992-04-08|1995-04-11|International Medical Associates, Inc.|Electronic transdermal drug delivery system|

---

EP0933138B1|1992-04-09|2004-03-03|Omron Healthcare Co., Ltd.|Ultrasonic atomizer|

---

DE69329110T2|1992-04-09|2001-03-22|Omron Tateisi Electronics Co|ULTRASONIC SPRAYER|

---

US5435465A|1992-04-28|1995-07-25|El-Amin; Hassan A.|Hygiene device|

---

FR2690634B1|1992-04-29|1994-10-14|Chronotec|Micro-spray device generated by ultrasonic waves.|

---

US5226538A|1992-07-29|1993-07-13|The Procter & Gamble Company|Filled package exhibiting a substantially colorless transparent appearance|

---

US5366739A|1992-08-06|1994-11-22|Deo Corporation|Method of ophthalmic drug delivery|

---

US5368582A|1992-08-10|1994-11-29|The Schepens Eye Research Institute|Method and apparatus for introducing fluid material into an eye|

---

US5318014A|1992-09-14|1994-06-07|Coraje, Inc.|Ultrasonic ablation/dissolution transducer|

---

AT149102T|1992-09-22|1997-03-15|Schablonentechnik Kufstein Ag|ELECTROSTATIC NOZZLE, IN PARTICULAR TO INJECT HIGH VISCUS LIQUIDS|

---

GB2272389B|1992-11-04|1996-07-24|Bespak Plc|Dispensing apparatus|

---

US5346132A|1992-11-12|1994-09-13|Gary S. Hahn|Mist generator|

---

US5320845A|1993-01-06|1994-06-14|Py Daniel C|Apparatus for delivering multiple medicaments to an eye without premixing in the apparatus|

---

US5607410A|1993-02-16|1997-03-04|Branch; John D.|Vision directed eye wash|

---

US5665079A|1993-02-18|1997-09-09|Stahl; Norman O.|Eye drop dispenser including slide|

---

GB9306680D0|1993-03-31|1993-05-26|The Technology Partnership Ltd|Fluid droplet apparatus|

---

WO1994023788A1|1993-04-20|1994-10-27|Medchem Products, Inc.|Apparatus and method for applying a particulate hemostatic agent to living tissue|

---

JP3211525B2|1993-04-22|2001-09-25|オムロン株式会社|Thin material mesh, its manufacturing method and its manufacturing apparatus|

---

FR2705911B1|1993-06-02|1995-08-11|Oreal|Piezoelectric nebulization device.|

---

AT214575T|1993-06-29|2002-04-15|Ponwell Entpr Ltd|DONOR|

---

JP2854223B2|1993-09-08|1999-02-03|ジャパンゴアテックス株式会社|Oil repellent waterproof ventilation filter|

---

GB9324250D0|1993-11-25|1994-01-12|Minnesota Mining & Mfg|Inhaler|

---

US5564016A|1993-12-17|1996-10-08|International Business Machines Corporation|Method for controlling access to a computer resource based on a timing policy|

---

GB9405952D0|1994-03-25|1994-05-11|Zeneca Ltd|Aqueous ophthalmic sprays|

---

US5435282A|1994-05-19|1995-07-25|Habley Medical Technology Corporation|Nebulizer|

---

ZA954936B|1994-06-17|1996-02-27|Trudell Medical Ltd|Nebulizing catheter system and methods of use and manufacture|

---

GB9412669D0|1994-06-23|1994-08-10|The Technology Partnership Plc|Liquid spray apparatus|

---

IT1274879B|1994-08-03|1997-07-25|Saitec Srl|APPARATUS AND METHOD FOR PREPARING SOLID PHARMACEUTICAL FORMS WITH CONTROLLED RELEASE OF THE ACTIVE INGREDIENT.|

---

GB9417399D0|1994-08-30|1994-10-19|Scherer Corp R P|Ocular treatment device|

---

FR2725247B1|1994-10-03|1996-12-20|Py Daniel C|FLUID PUMP WITHOUT DEAD VOLUME|

---

USD368774S|1994-10-19|1996-04-09|Daniel Py|Eye medication applicator|

---

US6027450A|1994-12-30|2000-02-22|Devices For Vascular Intervention|Treating a totally or near totally occluded lumen|

---

JP3443804B2|1995-02-14|2003-09-08|花王株式会社|Article holding device|

---

US5970974A|1995-03-14|1999-10-26|Siemens Aktiengesellschaft|Dosating unit for an ultrasonic atomizer device|

---

US5657926A|1995-04-13|1997-08-19|Toda; Kohji|Ultrasonic atomizing device|

---

US6357442B1|1995-06-08|2002-03-19|Innovative Devices, Llc|Inhalation actuated device for use with metered dose inhalers |

---

USD374719S|1995-06-22|1996-10-15|Daniel Py|Eye medication applicator|

---

US5584823A|1995-07-20|1996-12-17|Ontario Incorporated|Illuminated eye dropper device|

---

EP0844027B1|1995-08-07|2005-09-21|Omron Healthcare Co., Ltd.|Atomization apparatus and method utilizing surface acoustic waves|

---

US5588564A|1995-08-21|1996-12-31|Hutson; Clifford L.|Eye spray mist dispenser|

---

US5586550A|1995-08-31|1996-12-24|Fluid Propulsion Technologies, Inc.|Apparatus and methods for the delivery of therapeutic liquids to the respiratory system|

---

US6085740A|1996-02-21|2000-07-11|Aerogen, Inc.|Liquid dispensing apparatus and methods|

---

US5758637A|1995-08-31|1998-06-02|Aerogen, Inc.|Liquid dispensing apparatus and methods|

---

DE19536902A1|1995-10-04|1997-04-10|Boehringer Ingelheim Int|Miniature fluid pressure generating device|

---

US5730723A|1995-10-10|1998-03-24|Visionary Medical Products Corporation, Inc.|Gas pressured needle-less injection device and method|

---

US5735811A|1995-11-30|1998-04-07|Pharmasonics, Inc.|Apparatus and methods for ultrasonically enhanced fluid delivery|

---

US6221038B1|1996-11-27|2001-04-24|Pharmasonics, Inc.|Apparatus and methods for vibratory intraluminal therapy employing magnetostrictive transducers|

---

US5803106A|1995-12-21|1998-09-08|Kimberly-Clark Worldwide, Inc.|Ultrasonic apparatus and method for increasing the flow rate of a liquid through an orifice|

---

US5984889A|1996-02-23|1999-11-16|Allergan Sales, Inc.|Apparatus and method for delivering viscoelastic material to an eye|

---

US6083922A|1996-04-02|2000-07-04|Pathogenesis, Corp.|Method and a tobramycin aerosol formulation for treatment prevention and containment of tuberculosis|

---

DE19616300A1|1996-04-25|1997-10-30|Gesim Ges Fuer Silizium Mikros|Eye drop application|

---

US5740947A|1996-05-13|1998-04-21|Chesebrough-Pond's Usa Co., Division Of Conopco, Inc.|Dual compartment pump dispenser|

---

US5843109A|1996-05-29|1998-12-01|Allergan|Ultrasonic handpiece with multiple piezoelectric elements and heat dissipator|

---

US6203759B1|1996-05-31|2001-03-20|Packard Instrument Company|Microvolume liquid handling system|

---

US5724021A|1996-07-09|1998-03-03|Stephen C. Perrone|Self-contained, programmable, time interval alarm reminder device for eyedrop medication administration and a means for affixing such to eyedrop/medication container|

---

US5881956A|1996-08-08|1999-03-16|Ben Z. Cohen|Microdispensing ophthalmic pump|

---

WO1998019383A1|1996-10-30|1998-05-07|Omron Corporation|Vibration generator|

---

GB9622623D0|1996-10-30|1997-01-08|Ici Plc|Dispensing devices|

---

US6039565A|1997-01-14|2000-03-21|Chou; Marilyn M.|Combined ultrasonic and laser device and method of use|

---

US5957943A|1997-03-05|1999-09-28|Ethicon Endo-Surgery, Inc.|Method and devices for increasing ultrasonic effects|

---

US6228046B1|1997-06-02|2001-05-08|Pharmasonics, Inc.|Catheters comprising a plurality of oscillators and methods for their use|

---

USD413668S|1997-06-02|1999-09-07|Pharmacia & Upjohn Ab|Aid device for applying eye drops|

---

US6423040B1|1997-06-02|2002-07-23|Pharmacia Ab|Eye fluid applicator|

---

US5807357A|1997-08-19|1998-09-15|Kang; Meng-Che|Compact nebulizer for treating the eyes|

---

US5855322A|1997-09-10|1999-01-05|Py; Daniel|System and method for one-way spray aerosol tip|

---

US6946117B1|1997-09-29|2005-09-20|Nektar Therapeutics|Stabilized preparations for use in nebulizers|

---

JP3386050B2|1997-10-06|2003-03-10|オムロン株式会社|Spraying equipment|

---

US6159188A|1998-01-14|2000-12-12|Robert L. Rogers|Apparatus and method for delivery of micro and submicro quantities of materials|

---

US5997518A|1998-01-14|1999-12-07|Laibovitz; Robert A.|Apparatus and method for delivery of small volumes of liquid|

---

US6336917B1|1998-02-04|2002-01-08|Nulli Secundus, Inc.|Ocular inspection and eye mist apparatus|

---

IL123290A|1998-02-13|2001-12-23|Hadasit Med Res Service|Iontophoretic device|

---

GB9808182D0|1998-04-17|1998-06-17|The Technology Partnership Plc|Liquid projection apparatus|

---

JP4618964B2|1999-12-30|2011-01-26|パールテクノロジーホールディングスリミテッドライアビリティカンパニー|Facial wrinkle removal device|

---

US6260549B1|1998-06-18|2001-07-17|Clavius Devices, Inc.|Breath-activated metered-dose inhaler|

---

US6131570A|1998-06-30|2000-10-17|Aradigm Corporation|Temperature controlling device for aerosol drug delivery|

---

JP2000043243A|1998-07-31|2000-02-15|Mitsubishi Electric Corp|Ink-jet recording apparatus|

---

GB9820900D0|1998-09-26|1998-11-18|Glaxo Group Ltd|Inhalation device|

---

US6283935B1|1998-09-30|2001-09-04|Hearten Medical|Ultrasonic device for providing reversible tissue damage to heart muscle|

---

GB9822150D0|1998-10-09|1998-12-02|Dignes Roy|Ultrasound driven devices for accelerated transfer of substances across porous boundaries|

---

US6296626B1|1998-11-13|2001-10-02|Bradley Fixtures Corporation|Eye wash station|

---

GB2345010B|1998-12-17|2002-12-31|Electrosols Ltd|A delivery device|

---

JP3312216B2|1998-12-18|2002-08-05|オムロン株式会社|Spraying equipment|

---

US6135427A|1999-01-08|2000-10-24|Kaz, Incorporated|Humidifier|

---

US6231515B1|1999-01-13|2001-05-15|Scimed Life Systems, Inc.|Safety mechanism and method to prevent rotating imaging guide device from exiting a catheter|

---

US20030185892A1|2001-08-17|2003-10-02|Bell Steve J. D.|Intraocular delivery compositions and methods|

---

SE9900369D0|1999-02-04|1999-02-04|Siemens Elema Ab|Ultrasonic nebuliser|

---

GB9903433D0|1999-02-15|1999-04-07|The Technology Partnership Plc|Droplet generation method and device|

---

US6196218B1|1999-02-24|2001-03-06|Ponwell Enterprises Ltd|Piezo inhaler|

---

US6244498B1|1999-04-16|2001-06-12|Micron Semiconductor, Inc.|Ultrasonic vibration mode for wire bonding|

---

JP3709790B2|1999-04-28|2005-10-26|オムロンヘルスケア株式会社|Liquid spray device|

---

US6235024B1|1999-06-21|2001-05-22|Hosheng Tu|Catheters system having dual ablation capability|

---

AT339982T|1999-07-12|2006-10-15|Capnia Inc|ARRANGEMENT FOR THE TREATMENT OF HEADACHE, RHINITIS AND OTHER SUFFERING|

---

DE19934582C2|1999-07-23|2003-09-18|Otto Schill Gmbh & Co Kg|aerosol generator|

---

US6193683B1|1999-07-28|2001-02-27|Allergan|Closed loop temperature controlled phacoemulsification system to prevent corneal burns|

---

US6569387B1|1999-08-10|2003-05-27|S.C. Johnson & Son, Inc.|Dual function dispenser|

---

US6235177B1|1999-09-09|2001-05-22|Aerogen, Inc.|Method for the construction of an aperture plate for dispensing liquid droplets|

---

US6530370B1|1999-09-16|2003-03-11|Instrumentation Corp.|Nebulizer apparatus|

---

US6325811B1|1999-10-05|2001-12-04|Ethicon Endo-Surgery, Inc.|Blades with functional balance asymmetries for use with ultrasonic surgical instruments|

---

US6254579B1|1999-11-08|2001-07-03|Allergan Sales, Inc.|Multiple precision dose, preservative-free medication delivery system|

---

US6152383A|1999-11-22|2000-11-28|King Ultrasonic Co., Ltd.|Ultrasonic nebulizer|

---

JP4198850B2|1999-11-29|2008-12-17|オムロンヘルスケア株式会社|Liquid spray device|

---

US6398766B1|1999-12-27|2002-06-04|Vista Innovations, Inc.|Eye wash system|

---

US6877642B1|2000-01-04|2005-04-12|Joseph S. Kanfer|Wall-mounted dispenser for liquids|

---

US20010049608A1|2000-01-25|2001-12-06|Hochman Mark N.|Injection tracking and management system|

---

GB0003197D0|2000-02-11|2000-04-05|Aid Medic Ltd|Improvements in and relating to controlling drug delivery|

---

TW436285B|2000-03-07|2001-05-28|Lee Wen Tsao|Eye drop aiming device|

---

EP1265659A4|2000-03-22|2006-12-13|Docusys Inc|A drug delivery and monitoring system|

---

US6748944B1|2000-05-03|2004-06-15|Dellavecchia Michael Anthony|Ultrasonic dosage device and method|

---

MXPA02010884A|2000-05-05|2003-03-27|Aerogen Ireland Ltd|Apparatus and methods for the delivery of medicaments to the respiratory system.|

---

US6328035B1|2000-05-09|2001-12-11|Iep Pharmaceutical Devices Inc.|Pneumatic breath actuated inhaler|

---

JP2001353221A|2000-06-16|2001-12-25|Omron Corp|Ultrasonic atomizer|

---

US6341732B1|2000-06-19|2002-01-29|S. C. Johnson & Son, Inc.|Method and apparatus for maintaining control of liquid flow in a vibratory atomizing device|

---

US6543443B1|2000-07-12|2003-04-08|Aerogen, Inc.|Methods and devices for nebulizing fluids|

---

AT449596T|2000-08-15|2009-12-15|Univ Illinois|PROCESS FOR PRODUCING MICROPARTICLES|

---

US20020043262A1|2000-08-22|2002-04-18|Alan Langford|Spray device|

---

AUPQ975100A0|2000-08-29|2000-09-21|Siemensindustrial Services Ltd|Re-locatable partial discharge transducer head|

---

JP3958511B2|2000-09-28|2007-08-15|株式会社リコー|Toner supply device and image forming apparatus|

---

US6863224B2|2000-10-05|2005-03-08|Omron Corporation|Liquid spray device|

---

US6964647B1|2000-10-06|2005-11-15|Ellaz Babaev|Nozzle for ultrasound wound treatment|

---

US6524287B1|2000-10-10|2003-02-25|Advanced Medical Optics|Housing apparatus with rear activated return button for instilling a medication into an eye|

---

US6610033B1|2000-10-13|2003-08-26|Incept, Llc|Dual component medicinal polymer delivery system and methods of use|

---

CN1328149C|2000-10-23|2007-07-25|因斯蒂尔医学技术有限公司|Ophthalmic dispenser and associated method|

---

US7331944B2|2000-10-23|2008-02-19|Medical Instill Technologies, Inc.|Ophthalmic dispenser and associated method|

---

US6554801B1|2000-10-26|2003-04-29|Advanced Cardiovascular Systems, Inc.|Directional needle injection drug delivery device and method of use|

---

US6601581B1|2000-11-01|2003-08-05|Advanced Medical Applications, Inc.|Method and device for ultrasound drug delivery|

---

EP1205199A1|2000-11-13|2002-05-15|The Technology Partnership Public Limited Company|Aerosol drug-dispensing device with membrane for controlling vacuum during dispensing|

---

AUPR184500A0|2000-12-01|2001-01-04|Drug Delivery Solutions Pty Ltd|Dispensing device|

---

US7121275B2|2000-12-18|2006-10-17|Xerox Corporation|Method of using focused acoustic waves to deliver a pharmaceutical product|

---

US6622720B2|2000-12-18|2003-09-23|Xerox Corporation|Using capillary wave driven droplets to deliver a pharmaceutical product|

---

US7914470B2|2001-01-12|2011-03-29|Celleration, Inc.|Ultrasonic method and device for wound treatment|

---

US20020124843A1|2001-02-01|2002-09-12|Skiba Jeffry B.|Eye medication delivery system|

---

US20030032930A1|2001-02-06|2003-02-13|Vista Innovations, Inc.|Eye drop dispensing system|

---

US6610036B2|2001-02-06|2003-08-26|Vista Innovations, Inc.|Eye drop dispensing system|

---

SE0100418D0|2001-02-08|2001-02-08|Pharmacia Ab|Liquid delivery device and use method|

---

US6758837B2|2001-02-08|2004-07-06|Pharmacia Ab|Liquid delivery device and method of use thereof|

---

US6736904B2|2001-03-02|2004-05-18|Paper Quality Management Associates|Method and apparatus for the generation of ultrasonic energy fields within circular structures containing a liquid|

---

AU2002247280A1|2001-03-09|2002-09-24|Antares Pharma, Inc.|Ocular drug delivery nebulizer|

---

US6546927B2|2001-03-13|2003-04-15|Aerogen, Inc.|Methods and apparatus for controlling piezoelectric vibration|

---

US6550472B2|2001-03-16|2003-04-22|Aerogen, Inc.|Devices and methods for nebulizing fluids using flow directors|

---

US7100600B2|2001-03-20|2006-09-05|Aerogen, Inc.|Fluid filled ampoules and methods for their use in aerosolizers|

---

US7387612B2|2001-03-28|2008-06-17|Cybersonics, Inc.|Floating probe for ultrasonic transducers|

---

US6732944B2|2001-05-02|2004-05-11|Aerogen, Inc.|Base isolated nebulizing device and methods|

---

US6554201B2|2001-05-02|2003-04-29|Aerogen, Inc.|Insert molded aerosol generator and methods|

---

DE10131178A1|2001-06-29|2003-01-16|Boehringer Ingelheim Pharma|Nebulizer for applying liquids to the eyes|

---

DE10131174A1|2001-06-29|2003-01-16|Boehringer Ingelheim Pharma|Nebulizer for applying liquids to the surface of the eye or the blindfold tissue|

---

US6885818B2|2001-07-30|2005-04-26|Hewlett-Packard Development Company, L.P.|System and method for controlling electronic devices|

---

CA2466214A1|2001-09-12|2003-04-03|Ivax U.K., Ltd.|Breath-enhanced ultrasonic nebulizer and dedicated unit dose ampoule|

---

EP1295647A1|2001-09-24|2003-03-26|The Technology Partnership Public Limited Company|Nozzles in perforate membranes and their manufacture|

---

US6913205B2|2001-10-30|2005-07-05|Valois S.A.S.|Fluid product distributor|

---

EP1474196B1|2002-01-15|2016-08-17|Novartis AG|Methods and systems for operating an aerosol generator|

---

US6740107B2|2001-12-19|2004-05-25|Trimedyne, Inc.|Device for treatment of atrioventricular valve regurgitation|

---

US7677467B2|2002-01-07|2010-03-16|Novartis Pharma Ag|Methods and devices for aerosolizing medicament|

---

US6851626B2|2002-01-07|2005-02-08|Aerogen, Inc.|Methods and devices for nebulizing fluids|

---

US8277411B2|2002-01-31|2012-10-02|Boston Scientific Scimed, Inc.|Needle device|

---

KR20040084931A|2002-02-22|2004-10-06|산텐 세이야꾸 가부시키가이샤|Drug delivery system for the subconjunctival administration of fine grains|

---

US6789741B2|2002-03-27|2004-09-14|S. C. Johnson & Son, Inc.|Method and apparatus for atomizing liquids having minimal droplet size|

---

US7427115B2|2002-03-28|2008-09-23|Xerox Corporation|Fluid ejector including a drop size symbol, a method of disposing a drop size symbol in a fluid ejector, and an image forming device including a marking fluid ejector with a drop size symbol|

---

US20030192532A1|2002-04-12|2003-10-16|Hopkins Andrew David|Nebulizer|

---

US20050195598A1|2003-02-07|2005-09-08|Dancs Imre J.|Projecting light and images from a device|

---

PT1509266E|2002-05-16|2009-08-17|Boehringer Ingelheim Int|System comprising a nozzle and a fixing system|

---

US7153315B2|2002-06-11|2006-12-26|Boston Scientific Scimed, Inc.|Catheter balloon with ultrasonic microscalpel blades|

---

FR2841403B1|2002-06-21|2004-10-15|Renault Sa|METHOD OF ELECTRONIC DRIVING OF A CONTROL DEVICE OF AN ULTRASONIC PIEZOELECTRIC ACTUATOR|

---

TW532236U|2002-06-25|2003-05-11|Wen-Bin Chen|Modular water mist generating device|

---

US20040039355A1|2002-08-26|2004-02-26|Gonzalez Jose M.|Fluid dispensing devices and methods|

---

US6684681B1|2002-09-06|2004-02-03|Siemens Westinghouse Power Corporation|Mechanical ultrasonic and high frequency sonic device|

---

TW538823U|2002-09-18|2003-06-21|Kae Jyh Corp|Improved structure for percussion board of water mist|

---

US7070071B2|2002-09-23|2006-07-04|Agouron Pharmaceuticals, Inc.|Dispensing apparatus and method for liquid products, particularly medicinal products|

---

US20070211212A1|2002-09-26|2007-09-13|Percy Bennwik|Eye state sensor|

---

US20050261641A1|2002-09-26|2005-11-24|Warchol Mark P|Method for ophthalmic administration of medicament|

---

ITMI20022323A1|2002-10-31|2004-05-01|Maria Rosa Gasco|PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF OPHTHALMIC DISEASES.|

---

CN1764419A|2003-02-20|2006-04-26|普罗里森姆股份有限公司|Cardiac ablation devices|

---

US7712466B2|2004-02-20|2010-05-11|Pneumoflex Systems, Llc|Intra-oral nebulizer|

---

US6969165B2|2003-02-24|2005-11-29|Hewlett-Packard Development Company, L.P.|Ink reservoirs|

---

US7089635B2|2003-02-25|2006-08-15|Palo Alto Research Center, Incorporated|Methods to make piezoelectric ceramic thick film arrays and elements|

---

US20040199192A1|2003-04-04|2004-10-07|Takayuki Akahoshi|Phacoemulsification needle|

---

US7201732B2|2003-04-10|2007-04-10|Hewlett-Packard Development Company, L.P.|Dispensing method and device for delivering material to an eye|

---

CN100381083C|2003-04-29|2008-04-16|韩力|Electronic nonflammable spraying cigarette|

---

US20100222752A1|2003-05-20|2010-09-02|Collins Jr James F|Ophthalmic fluid delivery system|

---

US8545463B2|2003-05-20|2013-10-01|Optimyst Systems Inc.|Ophthalmic fluid reservoir assembly for use with an ophthalmic fluid delivery device|

---

US7883031B2|2003-05-20|2011-02-08|James F. Collins, Jr.|Ophthalmic drug delivery system|

---

FR2855761B1|2003-06-03|2006-02-24|Optis France Sa|OCULAR DEVICE FOR VARIABLE DELIVERY OF ACTIVE PRINCIPLES BY IONTOPHORESIS|

---

JP3987011B2|2003-06-03|2007-10-03|ソニー株式会社|Vibration generator and electronic device|

---

US8128606B2|2003-07-03|2012-03-06|Hewlett-Packard Development Company, L.P.|Ophthalmic apparatus and method for administering agents to the eye|

---

GB0315791D0|2003-07-07|2003-08-13|3M Innovative Properties Co|Two component molded valve stems|

---

US6976279B1|2003-08-08|2005-12-20|Berke-Tec, Inc.|Eye injury treatment station|

---

DE10347994A1|2003-10-15|2005-06-16|Pari GmbH Spezialisten für effektive Inhalation|Aqueous aerosol preparation|

---

JP2007511295A|2003-11-14|2007-05-10|メディカル・インスティル・テクノロジーズ・インコーポレイテッド|Injection device and injection method|

---

US7819115B2|2004-01-30|2010-10-26|Hewlett-Packard Development Company, L.P.|Inhalers and methods of controlling airflow in inhalers|

---

MXPA06009515A|2004-02-24|2007-03-26|Microdose Technologies Inc|Synthetic jet based medicament delivery method and apparatus.|

---

IN2014DN01746A|2004-04-02|2015-07-10|Government Of The Us Secretary Of The Dept Of Health And Human Services Ct S For Disease Control And|

---

DE102004016985B4|2004-04-07|2010-07-22|Pari Pharma Gmbh|Aerosol generating device and inhalation device|

---

US20050240162A1|2004-04-21|2005-10-27|Wen-Pin Chen|Eye treatment device|

---

USD533658S1|2004-05-20|2006-12-12|James F. Collins, Jr.|Misting device|

---

US20060057216A1|2004-09-15|2006-03-16|Salamone Joseph C|Low-obscuration image transmitting particulate ocular therapeutic formulations|

---

US7192129B2|2004-12-20|2007-03-20|Lexmark International, Inc.|Bridging wick and method for an inkjet printhead|

---

FR2879482B1|2004-12-20|2007-03-30|Oreal|DEVICE FOR SPRAYING A PRODUCT, IN PARTICULAR A FRAGRANCE|

---

EP1848541A4|2005-02-07|2013-01-16|Pharmalight Inc|Method and device for ophthalmic administration of active pharmaceutical ingredients|

---

DE102005005540B4|2005-02-07|2007-10-04|Pari GmbH Spezialisten für effektive Inhalation|In various modes controllable inhalation therapy device|

---

DE102005006374B3|2005-02-11|2006-07-20|Pari GmbH Spezialisten für effektive Inhalation|Aerosol production device, comprises a circular membrane for atomizing liquid, piezoelectric actuator coupled to the membrane, flexible platinum substrate, electrical lines, and reinforcement area|

---

US7631643B2|2005-03-09|2009-12-15|Ric Investments, Llc|Nebulizing drug delivery device with interlock detection and temperature protection|

---

JP4543284B2|2005-03-18|2010-09-15|富士フイルム株式会社|Mist injection apparatus and method, and image forming apparatus|

---

TWI268179B|2005-04-12|2006-12-11|Ind Tech Res Inst|Improved structure of atomizing nozzle the plate can be vibrated by the vibrator element to compress the fluid, so that the fluid is jet from the perforations in form of tiny particle|

---

US7219664B2|2005-04-28|2007-05-22|Kos Life Sciences, Inc.|Breath actuated inhaler|

---

USD537160S1|2005-05-05|2007-02-20|Lowell James R|Combined eye mist applicator and reservoir|

---

TWI293898B|2005-07-29|2008-03-01|Sunnytec Electronics Co Ltd|

---

US20070044792A1|2005-08-30|2007-03-01|Aerogen, Inc.|Aerosol generators with enhanced corrosion resistance|

---

DE102005056488A1|2005-11-21|2007-05-24|Ing. Erich Pfeiffer Gmbh|Dispenser and dosing unit for medium dosing|

---

CN101389313A|2006-02-10|2009-03-18|帕锐制药两和公司|Nebulised antibiotics for inhalation therapy|

---

GB0615303D0|2006-08-02|2006-09-13|Reckitt Benckiser Uk Ltd|An atomiser for the dispersal of a liquid|

---

US8376525B2|2006-09-08|2013-02-19|Canon Kabushiki Kaisha|Liquid discharge head and method of manufacturing the same|

---

FR2908329B1|2006-11-14|2011-01-07|Telemaq|DEVICE AND METHOD FOR ULTRASOUND FLUID DELIVERY|

---

EP1927373B1|2006-11-30|2012-08-22|PARI Pharma GmbH|Inhalation nebulizer|

---

US7673820B2|2006-12-18|2010-03-09|Yehuda Ivri|Subminiature thermoelectric fragrance dispenser|

---

US20090212133A1|2008-01-25|2009-08-27|Collins Jr James F|Ophthalmic fluid delivery device and method of operation|

---

USD597206S1|2007-02-16|2009-07-28|Optimyst Systems, Inc.|Ophthalmic misting device|

---

US7891580B2|2008-04-30|2011-02-22|S.C. Johnson & Son, Inc.|High volume atomizer for common consumer spray products|

---

PT104086B|2008-06-05|2011-07-22|Blueworks Medical Expert Diagnostics Lda|PROCESS FOR MONITORING THE SUCCESS OF THE APPLICATION OF A FLUID TO A NON-STATIC BIOLOGICAL TARGET AND SYSTEM FOR ITS IMPLEMENTATION|

---

US20090192443A1|2008-10-06|2009-07-30|Collins Jr James F|Ophthalmic fluid delivery device and method of operation|

---

US20100211408A1|2009-02-17|2010-08-19|Carl Hyunsuk Park|Systems and methods for generating medical diagnoses|

---

US8884752B2|2009-05-11|2014-11-11|Tai And Tseng Investments Llc|Medication usage monitoring and reminding device and method|

---

KR20130051476A|2010-07-15|2013-05-20|코린시언 아프샐믹 인코포레이티드|Ophthalmic drug delivery|

---

EP2593055A1|2010-07-15|2013-05-22|Corinthian Ophthalmic, Inc.|Method and system for performing remote treatment and monitoring|ES2594867T3|2007-03-09|2016-12-23|Alexza Pharmaceuticals, Inc.|Heating unit for use in a drug delivery device|

---

WO2010150629A1|2009-06-22|2010-12-29|パナソニック電工株式会社|Method for generating mist and microbubbles using surface acoustic waves and device for generating mist and microbubbles|

---

US20180296777A1|2010-05-15|2018-10-18|Rai Strategic Holdings, Inc.|Vaporizer related systems, methods, and apparatus|

---

EP2593055A1|2010-07-15|2013-05-22|Corinthian Ophthalmic, Inc.|Method and system for performing remote treatment and monitoring|

---

KR20130051476A|2010-07-15|2013-05-20|코린시언 아프샐믹 인코포레이티드|Ophthalmic drug delivery|

---

US10154923B2|2010-07-15|2018-12-18|Eyenovia, Inc.|Drop generating device|

---

DE102010044674B9|2010-09-08|2014-05-15|Meddrop Technology Ag|Percutaneous application system|

---

WO2013090468A1|2011-12-12|2013-06-20|Corinthian Ophthalmic, Inc.|High modulus polymeric ejector mechanism, ejector device, and methods of use|

---

US10667943B2|2012-03-13|2020-06-02|Ben Z. Cohen|Nozzle|

---

AU2013245946A1|2012-04-10|2014-11-27|Eyenovia, Inc.|Spray ejector mechanisms and devices providing charge isolation and controllable droplet charge, and low dosage volume opthalmic administration|

---

EA201491906A1|2012-04-20|2015-03-31|Айновиа, Инк.|SPRAYING EJECTOR DEVICE AND METHODS OF ITS USE|

---

EA201492096A1|2012-05-14|2015-08-31|Айновиа, Инк.|DEVICE AND METHODS OF APPLICATION OF A DROP GENERATOR WITH LAMINAR COURSE|

---

SG10201602609XA|2012-05-15|2016-05-30|Eyenovia Inc|Ejector devices, methods, drivers, and circuits therefor|

---

US10152867B2|2012-10-23|2018-12-11|Kali Care, Inc.|Portable management and monitoring system for eye drop medication regiment|

---

WO2014081570A1|2012-11-07|2014-05-30|Eye Drop Imaging Technology, Llc|Performing and monitoring drug delivery|

---

US20150018781A1|2013-04-10|2015-01-15|California Institute Of Technology|Systems, devices, and methods for topical drug delivery to the eye|

---

EP2848306B1|2013-09-13|2016-04-06|Bruker Daltonik GmbH|Dispenser system for mass spectrometric sample preparations|

---

EP3099362B1|2014-01-31|2018-09-12|Eye-go A/S|A device for applying an ophthalmic fluid|

---

JP6363388B2|2014-05-01|2018-07-25|ロレアル|Mist spray equipment|

---

WO2016172712A2|2015-04-23|2016-10-27|Sydnexis, Inc.|Ophthalmic composition|

---

JP2018510668A|2015-01-12|2018-04-19|ケダリオン セラピューティックス，インコーポレイテッド|Apparatus and method for delivering fine droplets|

---

US10441214B2|2015-01-29|2019-10-15|Kali Care, Inc.|Monitoring adherence to a medication regimen using a sensor|

---

US10366207B2|2015-02-12|2019-07-30|Kali Care, Inc.|Monitoring adherence to a medication regimen using a sensor|

---

CA2981070A1|2015-04-10|2016-10-13|Kedalion Therapeutics, Inc.|Piezoelectric dispenser with replaceable ampoule|

---

CN104784789B|2015-04-28|2018-07-24|深圳市杰仕博科技有限公司|Mouthspray device|

---

AU2016260313A1|2015-05-12|2018-01-04|AJAELO, Ikem C|Electronic drop dispensing device and method of operation thereof|

---

EP3302426A4|2015-05-29|2018-12-05|Sydnexis, Inc.|D2o stabilized pharmaceutical formulations|

---

US20160361506A1|2015-06-11|2016-12-15|Delta Electronics, Inc.|Nebulization system, nebulizer and driving method thereof|

---

FR3037535B1|2015-06-19|2017-06-16|Valeo Systemes Thermiques|AIR-REFRIGERATING DEVICE FOR MOTOR VEHICLE AND ASSOCIATED NEBULIZATION HEAD|

---

GB201518337D0|2015-10-16|2015-12-02|The Technology Partnership Plc|Linear device|

---

US10118696B1|2016-03-31|2018-11-06|Steven M. Hoffberg|Steerable rotating projectile|

---

CN107262309B|2016-04-08|2019-09-10|大宇（东莞）电器有限公司|Portable sprayer with dust guard|

---

WO2017192771A1|2016-05-03|2017-11-09|Pneuma Respiratory, Inc.|Methods for generating and delivering droplets to the pulmonary system using a droplet delivery device|

---

WO2018007245A1|2016-07-04|2018-01-11|Stamford Devices Limited|An aerosol generator|

---

US10159157B2|2016-08-08|2018-12-18|Continental Automotive Systems, Inc.|Compliant PCB-to-housing fastener|

---

US10609957B2|2016-11-22|2020-04-07|Funai Electric Co., Ltd.|Vapor delivery device|

---

WO2018136618A2|2017-01-20|2018-07-26|Kedalion Therapeutics, Inc.|Piezoelectric fluid dispenser|

---

CN111093742A|2017-06-10|2020-05-01|艾诺维亚股份有限公司|Method and apparatus for treating and delivering fluid to the eye|

---

CN107185084A|2017-06-23|2017-09-22|苏州卡睿知光电科技有限公司|A kind of Portable trauma therapeutic system|

---

US10342109B2|2017-11-14|2019-07-02|Taiwan Semiconductor Manufacturing Co., Ltd.|Apparatus and method for generating extreme ultraviolet radiation|

---

CN111712219A|2017-12-08|2020-09-25|科达莱昂治疗公司|Fluid delivery alignment system|

---

CA3087969A1|2018-01-17|2019-07-25|Eyenovia, Inc.|Methods and devices for delivering atropine to the eye as a micro-dose stream of droplets|

---

EP3539779B1|2018-03-16|2020-08-12|Ricoh Company, Ltd.|Liquid droplet forming device and liquid droplet forming method|

---

US20190314197A1|2018-04-12|2019-10-17|Kedalion Therapeutics, Inc.|Topical Ocular Delivery Methods and Devices for Use in the Same|

---

US11173258B2|2018-08-30|2021-11-16|Analog Devices, Inc.|Using piezoelectric electrodes as active surfaces for electroplating process|

---

WO2020072028A1|2018-10-01|2020-04-09|Hewlett-Packard Development Company, L.P.|Particle sorting using microfluidic ejectors|

---

CN112752964A|2018-10-01|2021-05-04|惠普发展公司，有限责任合伙企业|Bulk particle sorting|

---

WO2020072030A1|2018-10-01|2020-04-09|Hewlett-Packard Development Company, L.P.|Microscopy systems|

---

CN113543752A|2019-03-06|2021-10-22|科达莱昂治疗公司|Multi-dose ophthalmic fluid delivery system|

---

CN109907880B|2019-04-15|2021-07-20|江苏师范大学|Eye drop dropping system for eye treatment|

---

KR102238881B1|2020-03-31|2021-04-14|메드파크|Bone graft composition and manufacturing method thereof|

---

US20210386759A1|2020-06-10|2021-12-16|Ocular Science, Inc.|Compositions and methods for post-operative ocular care|

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

---

2019-09-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

---

2020-03-10| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|

---

2020-06-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2020-09-08| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/07/2011, OBSERVADAS AS CONDICOES LEGAIS. |

---

2021-05-11| B16C| Correction of notification of the grant|Free format text: REF. RPI 2592 DE 08/09/2020 QUANTO AO INVENTOR. |

优先权:

---

申请号 | 申请日 | 专利标题

---

US40086410P| true| 2010-07-15|2010-07-15|

---

US61/400,864|2010-07-15|

---

US40184810P| true| 2010-08-20|2010-08-20|

---

US40192010P| true| 2010-08-20|2010-08-20|

---

US40184910P| true| 2010-08-20|2010-08-20|

---

US40185010P| true| 2010-08-20|2010-08-20|

---

US40191810P| true| 2010-08-20|2010-08-20|

---

US61/401,850|2010-08-20|

---

US61/401,848|2010-08-20|

---

US61/401,849|2010-08-20|

---

US61/401,920|2010-08-20|

---

US61/401,918|2010-08-20|

---

US201161462576P| true| 2011-02-04|2011-02-04|

---

US61/462,576|2011-02-04|

---

US201161462791P| true| 2011-02-05|2011-02-05|

---

US61/462,791|2011-02-05|

---

US201161463280P| true| 2011-02-15|2011-02-15|

---

US61/463,280|2011-02-15|

---

US201161516462P| true| 2011-04-04|2011-04-04|

---

US201161516496P| true| 2011-04-04|2011-04-04|

---

US201161516495P| true| 2011-04-04|2011-04-04|

---

US61/516,495|2011-04-04|

---

US61/516,462|2011-04-04|

---

US61/516,496|2011-04-04|

---

US201161516694P| true| 2011-04-06|2011-04-06|

---

US61/516,694|2011-04-06|

---

PCT/US2011/044291|WO2012009706A1|2010-07-15|2011-07-15|Drop generating device|

---