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    • 专利摘要:
    Method of gravimetric filling of one or more solid pharmaceutical substances in the form of powders, freeze-dried, granules, pellets, nanoparticles or microparticles, in sterile conditions, in a small pharmaceutical container, as well as the container usable in said procedure. The method consists essentially of confining the empty container inside a container that is sealed in a sealed manner, and then adding to the container the pharmaceutical substance while carrying out the gravimetric weighing of the container together with the added product. This method allows the gravimetric weighing of the added product to be controlled with high precision without interfering either with the weight of the container where the container is inserted or with the environmental conditions, such as the laminar airflow conditions that are common in steric filling rooms of pharmaceutical products, and that usually interfere to a large extent in high precision gravimetric weighings. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2684403A1
    申请号:ES201730587
    申请日:2017-03-31
    公开日:2018-10-02
    发明作者:Elena Cebadera Miranda；Ibon GUTIERRO ADURIZ；María García Amo
    申请人:Laboratorios Farmaceuticos Rovi SA；
    IPC主号:
    专利说明:

    Procedure for gravimetric filling under sterile conditions of solids in a pharmaceutical container and pharmaceutical container usable in it.
    Field of the Invention
    The present invention relates to a gravimetric filling process under sterile conditions of small pharmaceutical containers, including syringes, vials, capsules, ampoules, single dose devices, inhalers, bottles, blister cartridges, envelopes or bags with solid substances selected from the group consisting of powder, lyophilized, granules, pellets, nanoparticles or microparticles. More particularly, it
    10 refers to a procedure for gravimetric filling of pharmaceutical containers with one or more sterile solid pharmaceutical substances or sterile excipients dosed and prepared in an aseptic environment.
    State of the art
    The regulations of the pharmaceutical industry imposes harsh safety conditions in the
    15 filling of pharmaceutical containers with pharmaceutical substances. Currently, the filling of small pharmaceutical containers such as syringes, vials or cartridges among others, with pharmaceutical substances must comply with Good Manufacturing Practices (GMPs). For this, controlled air flow is used in general to work in sterile environments.
    20 The flow of a fluid or gas is controlled when the air is ordered, stratified and smooth. In a laminar flow the fluid moves in parallel sheets without intermingling and each fluid particle follows a path called a streamline. The controlled air flow can be considered as laminar itself or
    25 turbulent. Reynolds predicted the type of flow we find through a dimensionless parameter called the Reynolds number, which represents the relationship between viscosity and inertia in the movement of a fluid and is represented by the following equation:
    Re = Vs x DI Vc 30 where:
    Vc = Kinematic viscosity.Vs = Characteristic velocity of the fluid.
    D = Diameter of the section through which the fluid circulates.
    In such a way that when:
    • Re <2000 is called "Laminar Flow ~, that is, where the viscous forces are
    5 proportionally stronger than the forces of inertia and therefore, the particles tend to move in streamlines.
    • Re> 4000 is called "Turbulent flow ie, where viscous forces are weak compared to inertial forces and therefore particles move in irregular paths.
    10. 2000 <Re <4000 is called "Transitional Flow ~, that is, it cannot be modeled.
    The Reference Standard defines as a controlled air flow the one in which the current lines go in one direction, are approximately parallel and have a uniform velocity through the entire cross section of the clean zone. Thus, GMPs indicate speeds between 0.36m and 0.54m (ie 0.45m ± 20%) and define it as "Unidirectional Flow", according to Annex I relating to the manufacture of sterile drugs of the Standards of Correct Manufacture of Medicinal Products for Human and Veterinary Use published by the European Medicines Evaluation Agency (EMA) According to this guide, the
    20 laminar flow systems must provide a homogeneous air velocity in the aforementioned interval at the level of the work point in an open environment, that is, where the dosing task is performed.
    The main function of a unidirectional / laminar flow is to provide a free work area
    25 of particles and contamination in which the protection of critical processes is guaranteed, ensuring total protection of the products during their handling process and an isolation of the surrounding environment.
    Protection occurs at the "core of the process," that is, at the location where the
    30 process and the interaction of the environment with the process occur. This is achieved thanks to the absence of particles by a type of filtration called HEPA filtration. HEPA is the acronym for Hight Efficiency Pal1ic / e Arresting. It is a type of high capacity filter that can trap a very high amount of microparticles, such as pollen, dust mites or tobacco smoke. Besides going
    35 filtered by a HEPA filter, the driven air must have a controlled speed uniformity according to the regulations to be complied with (according to the GMPs: 0.36-0.54 mIs). This uniformity involves 3 factors: the air diffuser screen used. fan speed regulation and air ducting and return.
    5 Depending on the use and design of the laminar flow, product protection can be guaranteed,operator protection or both protection. In any case, the air flowcontrolled allows the control of the process in a sterile environment, which favors thecan dispense with additional processes, such as terminal sterilization.
    10 When the products with which the containers are filled are liquid, their filling is simpler than that of the solid products, whether it is carried out by a volumetric or gravimetric method. In any case, in volumetric methods, in which what is determined is the volume of product to be filled in the container instead of its weight, the dosage of the product is much simpler because they do not require the presence of a cell of
    15 heavy that determines the accuracy of filling or dosing and which can also be altered by the impact of the air flow.
    In another order of things, when referring to the filling of solid substances such as microparticles, nanoparticles, granules, pellets, dust, etc., in containers
    20 pharmacists of small dimensions, the problem is much higher because in this case it is essential that the powder flows in a consistent and predictable manner, without any blockage or turbulence, thus ensuring that the volume or weight of the solid pharmaceutical substance in The pharmaceutical container is adequate. And if the filling is also carried out in laminar air flow cabinets, the problem is even greater, because the laminar flow can
    25 influence both the accuracy of the measurement by the balance, and the flow of solid particles when deposited in the container, and therefore can alter the result observed in the balance, and consequently the amount of product filled in the container.
    30 In this regard, it should be borne in mind that, for the pharmaceutical industry, an error in filling the active substance can cause patients to perceive an inadequate dose of the product, which can have very harmful and even lethal effects in extreme cases. . For this reason, in the procedures described in the state of the art it is necessary to regularly check, by means of various previously qualified processes, the quantity
    35 effective filling of all pharmaceutical containers and discarding those in which the quantity of pharmaceutical substance, be they medicines, active ingredients or excipients, are out of range.
    These checks may be destructive or non-destructive. When they are from
    5 non-destructive character, 100% control of the containers filled by gravimetric weighing methods is carried out, discarding only those units that are outside the predetermined specification. However, when the checks are of a destructive nature, as is usually the case with volumetric filling processes, these controls are carried out using heavy statistics every so often in order to control the
    10 dosing during the process, which greatly affects the performance of the filling process since all control units are discarded even though they are compliant because the method is destructive.
    Consequently, due to the high cost and value of the pharmaceutical substances that are
    15 manipulate and the fact that the production is carried out by large batches, for pharmaceutical companies it is a very high economic cost to be able to control the accuracy of the dosage of the products, preferably using non-destructive control methods. However, contrary to this precept, state-of-the-art documents that refer to filling procedures in small containers,
    20 refers to volumetric filling procedures that generally carry out destructive control processes that cause a loss of productivity, or that require multiple weighing controls in a multiplicity of stations or stages, which makes the procedure too expensive. In addition, state-of-the-art documents refer to dosage forms in devices or containers of dimensions greater than
    25 used in the present invention.
    Thus we find, the US patent publication US 2016/0200461 A1 requested by VANRX Pharmasystems INC., Which describes a method for volumetric filling and aseptic sealing of containers such as vials, bottles, syringes and ampoules with a liquid or solid pharmaceutical product lyophilisate (which implies that the filling process is carried out in liquid phase) in a controlled environment enclosure. This invention has the advantage of being able to fill a large number of containers at the same time, all of them located in the same sealed enclosure. This sealed enclosure where the containers are located is inserted into a closing box, and at least the sealed enclosure or the closing box must be
    35 decontaminated. The sealing of the containers is carried out under conditions of vacuum or inert atmosphere.
    On the other hand, the international publication WO 2006/074904 granted to MA lIFE S.R.l., refers to the packaging of injectable liquid products in containers such as vials, syringes or more preferably bottles, in a sterile environment by sterilization and depyrogenation. More specifically, it refers to a complete and compact system for sterile packaging comprising a station for washing the containers intended for cleaning and decontamination of said containers, a sterilization station for sterilizing the containers leaving the station. washing, this sterilization station has two sterilization modules, each module has in its upper part suitable ducts and separate baffles with which an air flow is achieved that
    10 affects the bottles, said flow flows over the conveyor into a hood, below which filter means defined by a HEPA filter are provided, both sterilization modules can function as hot or cold sterilizers, and finally, a filling and sealing station to fill such containers with said liquids that are subsequently sealed.
    15 Also, European Patent Publication EP 2 832 648 A1 in the name of Grifols Worldwide Operations, discloses a machine and a method of filling pharmaceutical containers with liquid pharmaceutical compounds that eliminate the problem of having to reject pharmaceutical containers, preferably vials. whose amount of
    The pharmaceutical substance is outside the range specified in the regulations of the pharmaceutical industry, avoiding for that industry a significant additional cost in terms of the investment in the machine proposed by said patent and increasing the productivity of the process. The procedure of this publication consists of the weighing phases of the empty container, filling the container with the pharmaceutical substance and subsequent weighing.
    25 of the full container at a full container weighing station to confirm the amount of pharmaceutical substance.
    On the other hand, the international publication WO 2012/023118 A1 on behalf of IMA Industria Macchine Automatiche S.P.A., refers to a filling machine comprising a total weight checking system and a method for weighing units individually. More specifically, this publication describes a filling machine suitable for filling capsules comprising a total weight checking system for filled capsules with a pharmaceutical product, which contains a weighing apparatus for weighing all the capsules and transfer means for transferring the capsules. capsules of said filling machine 35 to the weighing apparatus. This machine has, in the case of microdose weighing, an additional electronic balance that has one or more load cells, to weigh the caps.
    empty, by means of transfer the capsules are transferred to the filling machines and the filled capsules are transported to another weighing apparatus comprising electronic scales equipped with one or more load cells capable of measuring the weight of each filled capsule. This patent in no case uses laminar flow during the process or
    5 contemplates the use of aseptic filling conditions.
    US patent US 4640322 applied by Cozzoli Machine Co., discloses a machine for filling containers with particulate material with some fluidity, such as dust and the like. Mainly, the machine applies subatmospheric pressure through a filter to suction the particulate material and then, after filling the measuring chamber or filling station, a super-thermospheric pressure is applied through a filter to force the material down particulate inside the pharmaceutical container. This patent discloses a volumetric filling procedure that does not take into account the specific properties of the product to be filled without mentioning the impact of the process of
    15 filling subjected to laminar flow.
    However, the present invention presents an alternative to filling pharmaceutical containers with solid pharmaceutical substances, specifically by means of a gravimetric filling process with laminar flow in an aseptic environment.
    20 Within the documents of the state of the art, we also find the international publication WO 021092430 requested by IMA Industria Macchine Automatiche SPA, which refers to the automated filling of bottles with solid powders or granules, and in particular refers to a machine for filling bottles with powdered pharmaceutical substances
    25 dosed and to a propeller of filling mechanism that is part of the machine. This procedure consists of several stages, the first one is the weighing of the empty bottles in a first station, later, the bottles are filled in a filling station comprising powder dosing discs and a feeding device for the Pharmaceutical powder, these bottles pass to a second station of
    30 heavy bottles to weigh full bottles, and finally, to a bottle capping station. All this is done through a volumetric filling system. This system has the advantages of quick and easy access to the dosing discs without having to remove the adjustment mechanisms, the ease of maintenance and cleaning of the machine, being a process to follow, faster and less laborious. Logically, this procedure being
    Volumetric 35 only works for pharmaceutical powder with homogeneous granulometry and with a constant apparent density since it does not in any way ensure a specific particle size distribution as well as does not allow the filling of different batches of different chemical nature. In addition, although it mentions that it works under sterile conditions, it does not specify the method used to achieve such sterility, so it is assumed that it uses terminal sterilization methods after plugging.
    European Patent Publication EP 2902327 81, requested by Harro Hofliger Verpackungsmaschinen GmbH, refers to a dosing device for volumetric dosing of a pharmaceutical powder and simultaneous filling of containers such as capsules and blister packs, among others, with the dosed powder . The device comprises a dosing station with a container for storing the powder, a filling station and a mobile measuring element in which this measuring element moves from the dosing station to the filling station and vice versa. It also has a sealing material that is elastically flexible, airtight, porous and air permeable. The measuring element moves from the dosing station to the filling station 15 with a maintained negative pressure difference, in which the dosing cavities are superimposed with the pharmaceutical containers. The negative pressure difference is eliminated and the powder passes from the dosage cavities to the pharmaceutical containers. The measuring element moves back to the dosing station. In this case, the filling is volumetric so the dosage is much easier for those
    20 components that do not have concrete granulometry to control.
    On the other hand, the international publication WO 2010/128455 A1 on behalf of IMA Industria Macchine Automatiche SPA, refers to an apparatus and a dosing unit that can be associated with an automatic filling machine to dispense pre-established 25 and precise quantities of product in pharmaceutical containers , said machine has means for the dosing of both liquid and solid substances, for this, said dosing means comprises: a volumetric piston pump, a peristaltic pump, a diaphragm or membrane pump, a time-pressure dosing system, a flow control dosing system, a flow meter dosing system or a system
    30 volumetric dosing for powders and granules. In this case, the filling is volumetric, so the dosage is much simpler for those components that do not have specific granulometry to control.
    On the other hand, in the international publication WO 2012/004606 A2 in the name of 3P Innovation 35 you describe a powder dispenser for pharmaceutical substances comprising a dispensing system where there is an agitator formed by flexible material and a
    hopper from which dust can flow. This hopper is divided into two parts, a first part
    formed by a flexible material and a second formed by a rigid material, a device
    of piezoelectric vibration to vibrate the hopper, and a device to weigh the
    pharmaceutical containers while these are filled with dust. 3P Innovation
    5 also has the international patent application WO 2016/185230 A2. which describes a
    apparatus and method for filling pharmaceutical containers such as syringes, vials,
    capsules, cartridges and blisters with pharmaceutical powder material by vibration. This
    device has a support for the pharmaceutical container, a container to hold
    Powdered pharmaceutical substance that is in contact with a filling needle responsible for filling the pharmaceutical container with the powdered pharmaceutical substance, and a piezoelectric vibration device.
    In any case, none of the documents published by 3P Innovation you mention the physicochemical and rheological properties of the components of the formulation 15 and always focus on a vibration filling system in such a way that the solution posed to the technical problem is it exclusively limits vibration filling machines as well as eliminating the impact of the harmful effects of said vibration on the dose of the medicine. In no case does it mention another type of filling that is not vibratory since it describes as an essential element a piece of vibration damping
    20 to be able to control the powder filling procedure.
    On the other hand, the mentioned patent applications do not have examples of realization
    that allow validating the suitability of the claimed filling system; What's more, the degree of
    vibration to which the system is subjected together with the speed and force of the air flow to which the filling procedure is subjected makes the process of
    precise filling of dust in the container as well as its weighing; since they don't have any
    element that prevents the loss of verticality of the container in such a way that it
    remain properly so that the dispenser needle (nozzle) enters the
    container enabling dosing or that the container is kept suspended vertically (without touching the walls of the vibration damping piece) so that the
    Weighing device can guarantee the preset dose.
    Continuing with the state of the art, we find the European patent publication EP
    2138447 A1, on behalf of I.M.A Industria Macchine Automatiche S.P.A, which refers to a machine for the production of vials and bottles, particularly for filling vials
    and bottles with dosage of pharmaceutical product in liquid or powder form, this machine is
    It consists of a station for feeding the open vials or bottles at an upper end OR mouth, a filling station for the vials or bottles with predetermined doses of product, a station for feeding a succession of closures to seal the mouth of the vial or the bottle, a station to apply the closures to the vials or bottles and feed them in a collection area, and optionally, there may be an additional station for weighing the vials or bottles. All devices are located in a sterile environment, closing units are used to create a sterile environment in the machine for the production of vials or bottles. Again, this invention refers to a powder filling system in containers, generally bottles and vials, by a filling process by
    10 vibration that does not take into account the necessary granulometry of the components of the formulation.
    Finally. International publication WO 2006/075227 A2, on behalf of IMA Industria Macchine Automatiche SPA, refers to a sterilization unit and 15 depyrogenation of empty containers, mainly bottles. Said sterilization and depyrogenation is carried out by selecting as desired the four possible alternative modes of combined sterilization, hot-cold, hot-hot, cold-hot and cold-cold, such process is carried out with empty bottles, which after said process they will be transported to a filling phase with the material in liquid or powder, which is not
    20 mentions in said document. Such publication therefore only refers to a sterilization and depyrogenation station of empty containers suitable for filling in a subsequent procedure, which it does not mention.
    In general, the previous publications describe the filling of the containers
    25 pharmacists but without taking into account neither the physicochemical and rheological properties of the products (in such a way that they do not contemplate the filling of several products of different nature in the same process or dosing equipment), nor the necessary and standardized process conditions for aseptic filling of pharmaceutical products, particularly without taking into account those cases in which the environment in which it is carried
    The process is an aseptic environment, with gravimetric filling subjected to laminar flow. In the case of previous publications that use volumetric filling in most cases, this procedure presents a series of drawbacks that are exacerbated when the dosed product is a solid, such as inaccuracy of the process, poor dosing reliability. of substances when there are different substances
    35 granulometry or nature, the need to constantly calibrate the dispenser according to the material before each use and the inability to automatically compensate for changes 10
    in the properties of the material preventing filling several different products in the same equipment or process, such as oscillations in the bulk density of the packaged products. Therefore, volumetric methods are not adequate even when there are variations in bulk density in a single product, or when there is heterogeneity in grain size in a single product because they cannot ensure that the content in the entire production lot is homogeneous. In addition, volumetric methods can alter the integrity of the dosed substance depending on the nature of the product because they can form agglomerates, and more taking into account that these processes are very dependent on the filling temperature and the viscosity of the product,
    10 generated insurmountable fluctuations in dose accuracy.
    However, the control of weighing and dosing is essential for certain medications, since they require a gravimetric filling process in the containers that respects the nature of the solid, as well as the particle size distribution of the active agents and / or the solid excipients that are part of the formulation.
    15 These aspects condition that for some types of medications, such as sustained-release medications or inhalers, volumetric methods are discarded and gravimetric filling procedures are required, so that once the appropriate amount of each dose is dosed one of the compounds occurs a
    20 dispersion of the active ingredient in the composition as well as an active diffusion phenomenon of the agent within the release system causing a controlled release phenomenon of the active principle in the formulation. If we also take into account the systems of sustained release and inhalers - which need to ensure the correct release and / or activity of the formulation over time -, it becomes more necessary to control whether the dosage fits
    25 with the granulometric properties that it has to ensure the activity of the formulation during the entire period of prescription, in such a way that small variations in the dose give rise to less lasting or more lasting activities of the prescribed ones, which obliges to reject these formulations of the production chain.
    The invention described herein is applicable to powdery solid compounds of any
    30 nature, although optimally it is applicable to solids that have the following particle size distribution: no more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 230 or less than 140, a dO value, 5 in the range of 60-160 microns,
    where dO, 5 indicates the average value of the particle size that divides the population into exactly two halves, with 50% of the distribution above this value, and 50% below. In general, throughout the present specification, a value called "dO, X" represents the mass fraction of the drug with sizes of
    5 particle below the specified value, having a range of 0.0 to 1.0.According to this definition, a value of dO, 1 of 10 microns means that 10% of the total mass ofThe drug particles have a particle size equal to or less than 10 microns.
    Therefore, an object of the present invention is a method for filling or dosing
    10 gravimetric solid substances selected from the group consisting of powder, lyophilized granules, pellets, nanoparticles or microparticles in small pharmaceutical containers, including devices such as syringes, vials, capsules, ampoules, single dose devices, inhalers, bottles, blister cartridges , envelopes and bags, and more particularly refers to a procedure for gravimetric filling in
    15 pharmaceutical containers of one or more sterile solid pharmaceutical substances dosed and prepared in an aseptic environment of controlled air flow so that the weight measurement is accurate and not influenced by the existence of a laminar flow.
    An additional advantage of the process of the present invention is that it does not need to weigh the
    Pharmaceutical container before and after being filled with the solid pharmaceutical substance at stations other than the dosing station, since the present invention defines a gravimetric filling method in which the weighing cell is located in the filling station itself. container, which allows to confirm that, after the tare of the container, the amount of solid pharmaceutical substance with which it is filled is
    25 accurate.
    The present procedure is capable of being used in an aseptic environment in all its stages, filling the containers by a gravimetric process subjected to a controlled laminar or turbulent flow, ensuring that the air flow used does not alter the weighing of the product, thus avoiding the inconveniences produced by said flow such as the disturbance
    or the impediment of filling solids in pharmaceutical containers in a precise way.
    The process object of the present invention has the additional advantage of achieving
    Precision in filling several substances of different nature in a single container from at least one filling station, thus filling more than two solid compounds of different nature without interacting with each other, because they are in shape solid and that the degree of humidity is less than 10%. This advantage is very important since the humidity can alter the weighing and cause the formation of agglomerates in the products, a fact that would alter the heavy dose in the container and that would alter the rheology
    5 of the compounds dispensed in the containers.
    and another additional advantage is that, throughout the entire procedure, it is possible to maintain an aseptic environment that ensures the sterility of the final pharmaceutical product. At present, in order to achieve sterility of pharmaceutical products in general, the pharmaceutical containers are subjected to a terminal sterilization process generally carried out with moist heat in an autoclave, whereby the pharmaceutical containers are sterilized with steam. However, this process is not suitable for sterilizing solid pharmaceutical products since, when water vapor occurs in this type of sterilization, damage to the integrity of the solid product occurs
    15 that absorbs moisture. In addition, this type of sterilization fails to penetrate the powder, so sterilization of the pharmaceutical product within the pharmaceutical container would not occur.
    Therefore, in order to sterilize solid products included in a pharmaceutical container,
    20 requires terminal sterilization by dry heat. However, this other sterilization process also has several drawbacks such as the deterioration of the material used in the procedure, the difficult control monitoring during the process, in addition to the long period of time used in sterilization, which can alter the physicochemical properties of the product.
    All these disadvantages that both types of terminal sterilization have, are also solved with the present invention since this type of sterilization is not necessary, since in the present invention, while filling the pharmaceutical containers with sterile solid pharmaceutical substances, maintains an environment
    30 aseptic that ensures the sterility of the final pharmaceutical product during and after the process.
    Brief description of the figures
    Figure 1 shows a general view of the container (1) used in the present invention, consisting of a body (2) and a flange (3). 13
    Figure 2 shows a general view of the hollow cylinder (4) also used in the present invention, showing its inner hollow (5) and the recess (6) located in the upper area of said inner hollow (5).
    Figure 3 shows a view of the container (1) inserted in the cylinder (4), so that the5 flange (3) of the container (1) rests on the recess (6) of the cylinder (4), so thatIt is the only contact area between container (1) and cylinder (4).
    Figure 4 shows a view of the cylinder assembly (4) and the container (1) that is inserted therein, when both pieces are about to be placed on top of the weighing cell (9) that is provided, in its weighing surface (10), of a projection (11). When the cylinder assembly (4) and container (1) descend on said projection, the container (1) rises slightly from its position supported by the recess (6) of the cylinder (4) so that it is completely suspended above of the projection (11), supporting all its weight thereon, so that the weighing cell (9) can accurately measure the weight of the container (1). Also shown is the cover (12) intended to cover the assembly so that
    15 is tightly insulated from the outside.
    Figure 5 shows an illustrative scheme of the different steps that may be present in the filling process according to the invention and which may comprise, according to the illustrative example shown in the figure, the following components: (1): Neutralization electrostatic charges of the container by means of an ionizer bar 20; (2): Neutralization of electrostatic charges of the container by means of an ionizing needle; (3) Neutralization of electrostatic charges of product A to be dosed, and dosage thereof; (4): Neutralization of electrostatic charges of the container after dosing of product A; (5) Neutralization of electrostatic charges of product B to be dosed, and dosage thereof; (6): Neutralization of electrostatic charges of
    25 container after dosing of product B; (7): Container capping.
    Detailed description of the invention
    The process of filling a solid pharmaceutical formulation in a pharmaceutical device or pharmaceutical container must overcome several difficulties. In the first place, the dosing of very small quantities of product with great precision is necessary in many cases. To this first point is added the need to comply with the regulations indicated in the different international Pharmacopoeias for aseptic fillings where the presence of large air flow currents (unidirectional or turbulent regime) is necessary that
    ensure the elimination of any particles outside the process that can contaminate the final product.
    These two conditions are essential for the achievement of the proposed purpose (aseptic filling of solid in pharmaceutical devices) but the achievement of them in many occasions is unfeasible, since the presence of large air currents harm and alter the dosage precisely.
    This fact is more complicated if possible, when we refer to a gravimetry filling process, where the only unit of measurement and dose control is weight. And it is that the incidence of an air current inside the device, during or after dosing, can cause the displacement of the solid, impregnating the walls of the device and even escaping to the outside (preventing the accuracy of the dose). This damage is aggravated if the filling is carried out by gravimetric control (by weight) since the air will affect the sensor element and also distort the measurement.
    This fact is important, since the basic function of industrial filling systems is to dose predetermined amounts of solids in a specific period of time and precisely. Therefore, the important thing is not the volume but the mass of the product to be dosed. On the contrary, the dosing result does depend on other variables such as the physicochemical characteristics of the bulk product, the granulometry of the solid, the environmental conditions and the dosing process in relation to the selected dosing organ. With regard to the procedure, the principle of volumetric and gravimetric dosing can be distinguished.
    In volumetric dosing, the expulsion of the material occurs exclusively based on the volume, and with it, the quantities. That is, the volume is defined before the powder dosing begins. In this way, since the dosers that work in a volumetric way do not measure the mass, their dosing organs will have to be calibrated according to the material before each use: it is necessary to determine how much mass the organ has to dose in a period of defined time. The same also applies when changing the material and the batch. In addition, volumetric dosing systems cannot automatically compensate for changes in material properties, such as oscillations in bulk density, viscosity, particle size distribution, and even the nature of different solid products. Thus, in order to compensate for possible oscillations in the pouring weight, the volumetric systems often operate with an overdose, since their operation is a function of the volume so that the dosing organ is always filled uniformly. It is for this reason, that although the volumetric dosing system is the most compatible with the laminar flow system, it becomes absolutely unfeasible in the case of sophisticated medicines that have certain granulometric and physicochemical properties.
    For all the above, the volumetric filling presents a series of drawbacks that are exacerbated when the dosed product is a solid, such as the inaccuracy of the process, the poor reliability of the dosing of the substances when there are substances of different granulometry or nature, the The need to constantly calibrate the dispenser according to the material before each use and the inability to automatically compensate for changes in the properties of the material preventing filling several different products in the same equipment or process, such as oscillations in the apparent density of the packaged products. Therefore, volumetric methods are not suitable even when there is variation in bulk density in a single product, or when there is heterogeneity in grain size in a single product because they cannot ensure that the content in the entire production batch is homogeneous . In addition, volumetric methods can alter the integrity of the dosed substance depending on the nature of the product because they can form agglomerates, and more taking into account that these processes are very dependent on the filling temperature and the viscosity of the product, generated insurmountable fluctuations in dose accuracy.
    However, in the gravimetric dosing principle or as a function of weight, one or more weighing cells integrated in the process measure (weigh) the material to be dosed. Therefore the only unit of measure is weight. In such a way that the real weight regulates the dosage, so gravimetric systems can automatically compensate for possible deviations of the apparent density as well as other characteristics intrinsic to the product such as the particle size distribution of the solid. Logically, the gravimetric dosing system is practically incompatible with the laminar flow system, since the incidence of an air current inside the device, and in particular in, on or around the weighing cell during or after the dosing can cause several inconveniences in the process: the displacement of the solid impregnating the walls of the same and even escaping to the outside (preventing the accuracy of the dose), the impact of the air flow on the sensor element or weighing cell, distorting the measurement, affectation to the cleaning of the interior of the device, alteration of the integrity of the filled dose and consequent contamination, alteration of the particle size distribution since the flow disperses the particles of smaller size varying the homogeneity of lots, etc. .
    Therefore, one of the challenges to face when performing aseptic filling is the protection of the filling process from the incidence of air currents that aseptic conditions require in the case of medications, preferably parenteral ones. For this, it is necessary to create an exclusion area where the dosing process is protected from these currents. Thus, both the sterility of the process and the dosage by weight are accurately preserved, since on one hand the weighing cell is isolated (allowing the correct gravimetric dosing) and on the other hand, around this small area of exclusion (limited environment to the pharmaceutical device during filling) the effect of air currents (turbulent regime or unidirectional regime) continues to prevent access to any viable particle (with the ability to generate microbiological colonies or not) or non-viable (any impurity or particle outside the product) inside the device or container.
    This area of exclusion of air around the filling process should exist only during said filling process, so that the incidence of the currents on all surfaces of the system is possible the rest of the time. Thus the aseptic character is preserved whenever possible, minimizing the risk of contamination and eliminating microbial contamination of the pharmaceutical formulation.
    Consequently, the problem to be solved by the present invention is to provide a method for filling or gravimetric dosing of solid substances selected from the group consisting of powder, lyophilized, granules, pellets, nanoparticles or microparticles in a small pharmaceutical container between the that devices such as syringes, vials, capsules, ampoules, single-dose devices, inhalers, bottles, blister cartridges, envelopes and bags are found, and more particularly refers to a procedure for gravimetric filling in pharmaceutical containers of one or more solid pharmaceutical substances Sterile dosed and prepared in an aseptic environment of controlled air flow so that the weight measurement is accurate and not influenced by the existence of a laminar flow.
    The solution is based on a method of gravimetric filling of a solid product in a container comprising the following steps, which are illustrated in the attached Figures 1 to 4:
    a) providing a container (1) comprising a generally cylindrical body (2) and which is provided in its upper part with a flange (3) of diameter slightly larger than the diameter of the body (2) of the container (1),
    b) insert the container (1) into a hollow cylinder (4), whose inner hollow (5) has a diameter slightly larger than the diameter of the body (2) of the container (1), and which is provided with a recess (6) in the upper area of the inner hollow (5), so that the flange
    (3) of the container (1) rest on the recess (6) of the upper area of the inner hole5 (5) of the cylinder, and the contact area being between the flange (3) of the container (1) and the recess
    (6) from the upper area of the inner hollow (5) of the cylinder the only contact area between container (1) and cylinder (4), such that the container (1) is suspended inside the inner hollow (5) of the cylinder (4) and with its upper surface (7) located slightly below the upper surface (8) of the cylinder;
    c) arrange the cylinder assembly (4) and container (1) on top of a weighing cell
    (9) which is provided, on its weighing surface (10), with a projection (11) having a diameter smaller than the diameter of the inner hollow (5) of the cylinder (4) and a suitable height for raising the container (1 ) in height (h) sufficient for the flange (3) of the container to leave
    15 of being in contact with the recess (6) of the upper area of the inner hollow (5) of the cylinder (4) but without the upper surface (7) of the container (1) exceeding the height of the upper surface (8) of the cylinder (4), so that the container (1) is completely suspended above the projection (11) provided on the surface (10) of the weighing cell (9) and therefore supporting all its weight thereon;
    d) cover the upper surface (8) of the cylinder (4) tightly by means of a cover
    (12) provided with a hole (13) through which it is possible to add the solid product by means of a dosing element (14) or dosing needle;
    E) weigh the container (1) with the desired precision while it is suspended above the projection (11) provided on the surface (10) of the weighing cell (9) and supporting all its weight thereon, and
    f) fill the container (1) with the solid product through the hole (13) of the lid (12),
    30 by gravimetrically controlling the amount of product added thereto by the weighing cell (9).
    The cover of step d) should be generally understood as any element that can tightly cover the cylinder (4), so that, for example, said cover can be implemented in practice in the form of the bottom or even side walls of a 35 flexible hopper that incorporates a dosing element or dosing needle, always
    that this hopper adapts to the cylinder in such a way that it does not allow access to air flow in it.
    Steps e) and f) are preferably carried out in the same dosing station with a view tothat the weighing accuracy is optimal, although nothing would prevent it from being performed5 in different dosing stations.
    Through the steps of the described method the verticality or suspension of the container (1) is achieved such that the container (1) is kept suspended vertically without touching the walls of the cylinder (4), so that the device Heavy can accurately guarantee the preset weight of solid product added. In addition, such verticality facilitates
    10 that the dosing needle (14) or nozzle (nozzle) can enter the container (1) enabling dosing. All this can occur even in the presence of vibration provided by an external vibrating element, which in embodiments of the invention can help in correct dosing of the product in the container (1).
    In a preferred embodiment, the process is carried out in an insulator. In another preferred embodiment, the procedure is carried out in a sterile open room in both cases complying with Grade A according to the classification of rooms and clean air devices commonly accepted by EN ISO 14644-1.
    In the case of insulators, and according to a preferred embodiment, before the operation of
    In the dosage set forth in the present invention, a sterilization with nebulized or vaporized hydrogen peroxide or mixture of hydrogen peroxide with peracetic acid is required.
    Through the indicated procedure, the following advantages are achieved:
    1) Thanks to the provision of the cylinder with the described characteristics, which contains the container in suspension and that is sealed tightly before weighing, it is achieved
    25 that the container is hermetically isolated from the laminar air flow existing in the measuring booth, and therefore its weighing, both of the full and empty container, can no longer be affected by the existence of the laminar flow;
    2) Also, the product to be filled in the container, as well as its access path to the
    30, they are also hermetically insulated from the outside, so that the laminar flow existing in the measuring booth cannot affect the fall of the solid product in the container;
    3) The empty container is weighed in exactly the same conditions and normally only a few seconds apart before it begins to be filled with the solid product, which avoids the errors that exist when weighing is done at different times and / or circumstances of the process.
    4) Thanks to the provision of the cylinder, solids can be precisely dosed that have certain characteristics such as apparent density, intrinsic viscosity, concrete particle size distribution of the solid, etc. aseptically in laminar flow conditions.
    It will be clear to the person skilled in the art that the indicated procedure can be implemented in different embodiments of the invention, all of which are included within the scope of the invention according to the content of the appended claims. For example, and without limitation, the following particular embodiments are included within the present invention, all of them independent of each other but which at the same time can be combined with each other without limitation:
    In one embodiment, between container and cylinder it is possible to provide one or more intermediate pieces in the manner of "shirts" of the container as long as the presence of such shirts does not alter the described procedure, which can provide additional advantages such as an improved balance of the container inside the cylinder hollow. Illustratively, such a ~ jacket ~ between container and cylinder can have a height between
    0.5 mm and 10 mm high, and preferably between 0.5 and 5 mm high. This "jacket" achieves adequate verticality or suspension of the container so that it remains properly so that the needle of the dispenser (nozzle) enters the container empowering the dosing as well as that the container is kept suspended vertically (without touch the walls of the vibration damping part) so that the weighing device can guarantee the preset dose.
    In another embodiment, the cylinder may be provided, for practical reasons, with additional outer surfaces, such as an outer flange of a certain thickness, so that the cylinder can be easily supported by pliers or pliers on which the surface rests. bottom of said flange without the risk that the cylinder can slide and fall, or also so that the cylinder provided with said flange can be moved from one place to another within the different points of the filling stations by means of a series of elevated rails .
    In yet another embodiment, the projection provided on the weighing surface may have a generally cylindrical shape but may also take other forms such as square, hexagonal or others. Also, its upper surface may be flat or it may end in other geometric shapes, such as in a conical or conical-trunk shape. All these variations may be possible as long as the projection continues to fulfill its function of raising the container, optionally covered with one or more sleeves, enough so that the flange thereof separates from the recess of the upper surface of the cylinder so that The entire weight of the container, with or without product, is supported on the projection of the balance and therefore on the balance itself, thereby ensuring correct weighing. It is also important that the height of the projection is not so high that the upper surface of the container is above the upper surface of the cylinder, which would prevent the sealing of the container by means of the indicated cover. Therefore, it is important to precisely control the height of the projection of the balance surface.
    In yet another embodiment, steps c) to f) of the above-described method can be repeated as many times as necessary, for example in case the filling of more than one distinct solid product is carried out in the container, in which case the Different products would be filled in the container at different stages of filling. Alternatively, if there were no reasons to keep the different solid products in differentiated stages, it would also be possible to mix the different products beforehand and to fill the mixture in a single filling and weighing stage in a single weight measurement.
    In another additional embodiment, steps a) to f) of the method described above may be accompanied, previously, subsequently and / or simultaneously, by ionization stages of the container and / or the cylinder to neutralize its electrostatic charges, for example through ionizers in bar, needle, curtain, filter, ring, etc. With this process it is achieved that, when the solid product in powder form falls to the container, particularly when it is made of plastic material, the dust particles are not adhered to the inner or outer wall of the container but fall to the bottom thereof.
    In yet another embodiment, the filling of the product (s) can be simultaneously accompanied by a stream of air that is preferably N2 or compressed air both sterile to aid in dosing and provide the necessary sterility conditions required by the process. In addition, when the air flow is N2, it displaces the oxygen present inside the container preventing oxidation of the product and consequently its subsequent degradation.
    In yet another embodiment, the container can be filled by a screw screw dosing process, with a weight loss gravimetric dispenser provided with a hopper and a high precision dosing needle, with single thread dosing, with double dosing thread, with dispenser with vibrating channel or with vibrating hopper, with dispenser with conveyor belt, with dispenser with a compaction system, etc. For products that do not slide easily it is necessary to add an agitator in the upper hopper of the dispenser that guarantees a constant feeding of the solid.
    In yet another additional embodiment, the dispenser may be provided with a mixer.
    In another embodiment, the weighing cell can be multiple in such a way that a multiplicity of containers can be filled, whereby the cylinder of the present invention can be provided with a multiplicity of interior gaps each and every one of them with a diameter slightly larger than the diameter of the container body, and which are in turn provided with a recess in the upper area so that the flanges of the containers are supported by the recess of the upper area of the cylinder holes, and the area being of contact between the flange of each container and each recess of the upper area of the cylinder hollow the only contact area between container and cylinder, so that each container is suspended within each cylinder hollow and with its upper surface located slightly below the upper surface of the cylinder;
    In another embodiment, the weighing cell must be of high precision, preferably waterproof, environmental dust, vapors, disinfectants, etc.
    The pharmaceutical container is preferably filled with the container in an upright position preferably by its widest part, although it can also be filled by its narrowest part, provided its diameter allows access to the filling or dosing needle into the container.
    A possible overall scheme of the process, shown for illustrative purposes only, may be the one shown in the attached Figure 5.
    The container can take the form of syringes, vials, caps, ampoules, single-dose devices, inhalers, bottles, blister cartridges, envelopes and bags intended to contain solid substances, although preferably a syringe or a cartridge is treated as they are already provided with the upper flange previously described. In such a case, the flange described above is the flange that the syringes or cartridges ("carpules" in English) usually have at their upper end, that is, at the end through which the plunger or plug of the cartridge, respectively. Although, as also specified, the invention
    it also contemplates the possibility that the container can be filled at the endopposite, that is, by the smaller diameter end by which normallywould attach the needle. In any of the cases indicated above, the material of the containerIt may consist of plastics of different composition, such as polyolefins and5 cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, polyvinylchloride,polyacrylonitrile, polyamides etc., polyesters (containing the ester functional group in theirMain chain: pOli (ethylene terephthalate), polycarbonate), acrylic polymers(poly (methyl methacrylate), polyacrylonitrile), thermoplastic resins (polyacetals andpolyhaloethylenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenoplasts,
    10 aminoplasts, thioplasts, duroplast resins (unsaturated polyester, polyurethanes), silicones, polyvinylidenes, cellulose derivatives, polycarbonates, and mixtures thereof, etc. Alternatively, the container can also be metallic, for example, of steel or titanium suitable for the administration of drugs, glass, glass, etc.
    In turn, the cylinder will preferably be composed of a metallic material such as steel 15 or titanium, although the possibility that it may be made of various materials, such as different plastics, glass, stone, resin, glass, etc. is contemplated.
    Both the materials used for the container and the cylinder materials must be watertight, inert, poorly permeable or impervious, and that do not absorb and / or adsorb the contained product.
    20 Preferably, the containers of the present invention are both syringes and cartridges with the nozzle terminated in a threaded cone (male or female) or in a single cone.
    The invention described herein is applicable to powdery solid compounds of any nature, although optimally it is applicable to solids having the following particle size distribution:
    25 not more than 10% of the total volume of particles is less than 20 microns,
    no more than 10% of the total volume of particles is greater than 230 or less than 140,
    a value dO, S in the range of 60-160 microns,
    where dO, 5 indicates the average value of the particle size that divides the population into exactly two equal halves, with 50% of the distribution above this
    30 value, and 50% below. In general, throughout the present specification, a value called "dO, X" represents the mass fraction of the drug with particle sizes below the specified value, having a range of 0.0 to 1, O.
    In a preferred embodiment of the invention, the particle size distribution is:
    no more than 10% of the total volume of particles is less than 20 microns,
    no more than 10% of the total volume of particles is greater than 230 or less than 140,
    a dO value, 5 in the range of 60-130 microns.
    5 According to another preferred embodiment:
    no more than 10% of the total volume of particles is less than 20 microns,
    no more than 10% of the total volume of particles is greater than 325 or less than 245,
    a dO value, 5 in the range of 100-155 microns.
    Examples of such compounds can be risperidone, paliperidone, fentanyl,
    10 olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole, caripracin, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, among others including any derivative, metabolite or salt (such as pamoate or palmitate) alone or in combination.
    The invention described herein is applicable to pulverulent solid compounds of any nature, although optimally it is applicable to solids of polymeric nature, generally 15 copolymers of lactic or glycolic acid (PLGA) with a ratio of glycolic lactic monomer in the range of 40:60 at 70:30, preferably in the range of 45:55 to 75:25. Polylactic acid (PLA) polymer is also preferably used, as well as other materials, such as polydioxanone, polytrimethylene carbonate in the form of copolymers and homopolymers, pOli copolymers (e-caprolactone), polyanhydrides and plioleters.
    20 which have been accepted as biomedical materials.
    The preferred polymers in this invention are selected from copolymers with an intrinsic viscosity inherently preferably in the range of 0.16-0.60 dll g, and more preferably between 0.25-0.55 dl lg, measured in chloroform at 25 ° C and a concentration of 0.1%. The concentration of the polymer component in the compositions of the invention is
    25 preferably in the range of 25-50%, (expressed as the percentage of polymer weight based on the total polymer solution component) and more preferably between 30-40%.
    For the purpose of the present invention, throughout the present specification, the term intrinsic or inherent viscosity ('linh) of the polymer is defined as the ratio of the
    30 natural logarithm of the relative viscosity, ('lr), relative to the mass concentration of the polymer, e, that is:
    taking into account that the relative viscosity (r'lr) is the ratio of the viscosity of the solution r'l to the viscosity of the solvent r'l s, that is:
    In addition, it will be understood that intrinsic viscosity values throughout the present specification are measured at 25 ° C in a chloroform solution with a concentration of 0.1%. The term intrinsic viscosity is commonly considered as an indirect indicator of the molecular weight of the polymer. Thus, a reduction in the intrinsic viscosity of a polymer, measured at a given concentration in a certain solvent, with the same
    The composition of monomer and terminal groups is an indicator of the reduction in the molecular weight of the polymer (IUPAC. Basic definitions of terms relating to polymers 1974. Pure Appl. Chem. 40, 477-491 (1974).
    The polymers can be of synthetic, semi-synthetic and natural origin. These also include cellulose derivatives (for example, cellulose acetate, ethyl cellulose, cellulose acetaphthalate 15, cellulose ethers such as hydroxypropylmethyl cellulose), acrylate derivatives (eg Eudragit, poly (methyl methacrylate), cyanoacrylates) and Biocompatible and biodegradable polymers such as polyanhydrides, polyesters, polyorthoesters, polyurethanes, polycarbonates, polyphosphazenes, polyacetals, polyoxyethylene polyoxypropylenes. In this, polyesters such as polylactic, polyglycolide, polycaprolactone are important,
    20 polyhydroxybutyrate or polyhydroxyvalerate. In addition, polysaccharides such as sodium alginate, chitosan or chitin or proteins can also be used. A large number of support materials have been described in the literature and all of them are potentially considered for the preparations according to the invention.
    25 EXAMPLES
    Below are several examples of container filling by the process of the present invention, which should be taken into account for illustrative purposes only and not limiting the scope of the invention. To explain these examples, it should be mentioned that syringes are used as pharmaceutical containers
    30 with a female or male connection system interchangeably, as excipients PLGA and PLA, and as active compounds Riperidone and Letrozole respectively.
    Example 1: Fill letrozole in syringe at a dose of 50 mg.
    In the first example the compound to be filled is the active compound Letrozole, for a filling dose in a 50mg pre-filled syringe. It should be noted that the filling process takes place within an aseptic rigid wall insulator Tesltar Azbil®. Before starting the filling process, all the equipment must be clean and sterile, for this, first, a sterilization is carried out with nebulized or vaporized hydrogen peroxide or mixture of hydrogen peroxide with peracetic acid.
    To start filling, you start by taking the syringes and sterile caps, delivering these caps to an operator that is in the capping station.
    First, each syringe is ordered under a stream of ionized nitrogen preferably, although a stream of compressed air can also be used to achieve its ionization and elimination of electrostatic charge. Next, the syringe is transferred to the filling station to be introduced into the cylinder (4). The syringe will be placed on top of the weighing cell, which tares the weight of the empty syringe, leaving the data recorded in the weight follower of the control system. After this, the syringe is filled with an amount of 50 mg ± 30% of letrozole using a dispensing needle (nozzle in English). The syringe as it is being loaded during filling is heavy, so that the system can be controlled to stop filling when reaching the desired weight, in this case 50 mg ± 30% letrozole.
    Subsequently, if we wanted to fill a second substance, such as an excipient, the cylinder
    (4) And the syringe filled with letrozole would be transported to a second filling station, performing the same steps described above.
    Once the letrozole has been filled, the cylinder (4) together with the syringe passes to the capping or sealing station, but not before proceeding to an ionization stage of the filled syringe. Once the syringe filling procedure is finished, and having sealed it, it can be placed in a tray with the rest of the syringes filled and sealed.
    This example has been carried out for doses of 50, 75, 100, 200, 300, 400 and 500 mg of letrozole, functioning properly by dosing accurately.
    Example 2: Risperidone filling in syringe at a dose of 100 mg.
    In this example the compound to be filled is the active compound risperidone, for a filling dose in a pre-filled syringe of 100 mg. It should be noted that the filling process takes place within an aseptic rigid wall insulator Tesltar Azbil®. Before starting the filling process, all equipment must be clean and sterile, for this, first,
    a sterilization with nebulized or vaporized hydrogen peroxide or mixture of hydrogen peroxide with peracetic acid is performed.
    To start filling, you start by taking the syringes and sterile caps, delivering these caps to an operator that is in the capping station.
    5 First, each syringe is ordered under a stream of ionized nitrogenpreferably, although a compressed air stream can also be used, forget its ionization and elimination of electrostatic charge. Then thesyringe to the filling station to introduce it into the cylinder (4). The syringe will be placedon top of the weighing cell, which tares the weight of the empty syringe, leaving the data
    10 registered in the weight tracker of the control system. After this, the syringe is filled with an amount of 100 mg ± 30% risperidone using a dispensing needle (nozzle in English). The syringe as it is being loaded during filling is heavy, so that the system can be controlled to stop filling when reaching the desired weight, in this case 100 mg ± 30% risperidone.
    15 Subsequently, if we wanted to fill a second substance, such as an excipient, the cylinder
    (4) and the syringe filled with risperidone would be transported to a second filling station, performing the same steps described above.
    Once the risperidone has been filled, the cylinder (4) together with the syringe passes to the capping or sealing station, but not before proceeding to an ionization stage of the syringe
    20 full. Once the syringe filling procedure is finished, and having sealed it, it can be placed in a tray with the rest of the syringes filled and sealed.
    This example has been carried out for doses of 50, 75, 100, 200, 300, 400 and 500 mg of risperidone, functioning properly by dosing accurately.
    Example 3: Filling of polylactic acid (pLAl in syringe at a dose of 90 mq.
    In the first example the compound to be filled is the PLA excipient for a medicated formulation, in a pre-filled syringe filling dose of 90 mg. It should be noted that the filling process takes place within an aseptic rigid wall insulator Tesltar Azbil®. Before starting the filling process, all equipment must be clean and sterile, for this, first, a sterilization with hydrogen peroxide is performed
    Nebulized or vaporized or mixture of hydrogen peroxide with peracetic acid.
    To start filling, you start by taking the syringes and sterile caps, delivering these caps to an operator that is in the capping station.
    First, each syringe is ordered under a stream of ionized nitrogen preferably, although a stream of compressed air can also be used to achieve its ionization and elimination of electrostatic charge. Next, the syringe is transferred to the filling station to be introduced into the cylinder (4). The syringe will be placed on top of the weighing cell, which tares the weight of the empty syringe, leaving the data recorded in the weight follower of the control system. After this, the syringe is filled with a quantity of 90 mg ± 30% of PLA using a dispensing needle (nozzle in English). The syringe as it is being loaded during filling is heavy, so that the system can be controlled to stop filling when reaching the desired weight, in this case 90 mg ± 30% of PLA.
    Once the PLA has been filled, the cylinder (4) together with the syringe passes to the capping or sealing station, but not before proceeding to an ionization stage of the filled syringe. Once the syringe filling procedure is finished, and having sealed it, it can be placed in a tray with the rest of the syringes filled and sealed.
    This example has been carried out for doses between 90 and 1000 mg of PLA, functioning properly by dosing accurately.
    Example 4: Filling of PLGA in syringe at a dose of 100 mg after example 2 (filling of risperidone).
    After carrying out the steps of example 2, the syringe passes to a second filling station inside the cylinder (4). The syringe will be placed on top of the weighing cell, which tares the weight of the empty syringe, leaving the data recorded in the weight follower of the control system. After this, the syringe is filled with an amount of 100 mg ± 30% PLGA (Resomer 503®) using a dispensing needle (nozzle in English). The syringe as it is loaded during filling is heavy, so that the system can be controlled to stop filling when reaching the desired weight, in this case 100 mg ± 30% of Resomer 503®.
    Subsequently, if we wanted to fill a third substance, such as another excipient or other active compound, the cylinder (4) and the previously filled syringe would be transported to a next filling station, performing the same steps described above as many times as necessary.
    Once the PLGA has been filled, the cylinder (4) together with the syringe passes to the capping or sealing station, but not before proceeding to an ionization stage of the filled syringe. Once the syringe filling procedure is finished, and having sealed it, it can be placed in a tray with the rest of the syringes filled and sealed.
    This example has been carried out for doses of 100 to 500 mg of PLGA, functioning properly by dosing accurately.
    权利要求:
    Claims (22)
    [1]
    1. Gravimetric filling method of a solid product in a container (1) that
    It comprises the following stages:
    5 a) providing a container (1) comprising a generally cylindrical body (2) andwhich is provided in its upper part with a flange (3) of diameter slightly greater thanbody diameter (2) of the container (1),
    b) insert the container (1) into a hollow cylinder (4), whose inner hollow (5) has a diameter slightly larger than the diameter of the body (2) of the container (1), and which is provided with a recess (6 ) in the upper area of the inner hollow (5), so that the flange
    (3) of the container (1) rest on the recess (6) of the upper area of the inner hollow
    (5) of the cylinder, and the contact area being between the flange (3) of the container (1) and the recess
    (6) from the upper area of the inner hollow (5) of the cylinder (4) the only contact area between
    15 container (1) and cylinder (4), so that the container (1) is suspended inside the inner hollow (5) of the cylinder (4) and with its upper surface (7) located slightly below the surface upper (8) of the cylinder;
    c) arrange the cylinder (4) and container assembly (1) on top of a cell (9) of
    20 which is provided, on its weighing surface (10), with a projection (11) having a diameter smaller than the diameter of the inner hollow (5) of the cylinder (4) and a height suitable for raising the container (1) at sufficient height (h) so that the flange (3) of the container ceases to be in contact with the recess (6) of the upper area of the inner hollow (5) of the cylinder (4) but without the upper surface (7 ) of the container (1) exceeds the surface height
    25 (8) of the cylinder (4), so that the container (1) is completely suspended above the projection (11) provided on the surface (10) of the weighing cell (9) and therefore supporting all its weight in the same;
    d) cover the upper surface (8) of the cylinder (4) tightly by means of a cover
    30 (12) provided with a hole (13) through which it is possible to add the solid product by means of a dosing element (14) or dosing needle;
    e) weigh the container (1) with the desired precision while it is suspended above the projection (1 1) provided on the surface (10) of the weighing cell (9) and supporting
    35 all its weight in it, and

    f) fill the container (1) with the solid product through the hole (13) of the lid (12), gravimetrically controlling the amount of product added thereto by the cell
    (9) weighing.
    [2]
    2. Method according to claim 1, wherein between container (1) and cylinder (4) at least one wrapping jacket of the container (1) is provided to ensure the verticality and suspension of the container (1) within the inner hollow ( 5) of the cylinder (4) so that neither the container (1) nor its surrounding jacket touch the inner walls of the cylinder (4).
    [3]
    3. Method according to claims 1 or 2, wherein steps c) to f) are repeated as many times as necessary in case there is more than one solid product to be dosed in the container (1).
    [4]
    Four. Method according to any one of claims 1 to 3, wherein
    previously, subsequently or simultaneously to any of the stages a) to f) an ionization stage of the container (1) and / or of the cylinder (4) is introduced to neutralize its electrostatic charges.
    [5]
    5. Method according to claim 4, wherein the ionization step is carried out by introducing into the container (1) and / or in the cylinder (4) an ionizer bar, needle or ring.
    [6]
    6. Method according to claims 4 or 5, wherein simultaneously with the ionization, a sterile compressed air stream or N2 is introduced into the container (1) and / or the cylinder (4) to aid in dosing and providing the sterility conditions required.
    [7]
    7. Method according to any one of the preceding claims, wherein the filling of solid product in the container (1) of step f) is carried out by means of an auger, a weight loss gravimetric dispenser provided with a hopper and a High-precision dosing needle, a single-threaded dispenser, a double-threaded dispenser, a vibrating channel or vibrating hopper dispenser, a dosing device provided with a conveyor belt, or a dosing device provided with a compaction system.
    [8]
    8. Method according to claim 7, wherein the hopper is provided with an agitator to guarantee a constant and fluid feeding of the solid product in the container (1).
    Method according to any one of the preceding claims, in which the cylinder (4) is provided with a multiplicity of interior voids (5), each of which is capable of receiving a container (1).
    [10]
    10. Method according to claim 9, wherein the weighing cell (9) is
    10 in order to be able to weigh the multiplicity of containers (1) provided in the multiplicity of inner holes (5) of the cylinder (4).
    [11]
    11. Method according to any one of the preceding claims, wherein the
    container (1) is a syringe, vial, capsule, vial, single dose device, inhaler, bottle, blister cartridge, envelope or bag intended to contain solid substances.
    [12]
    12. Method according to claim 11, wherein the container (1) is a syringe
    or cartridge
    A method according to any one of the preceding claims, wherein the cylinder (4) is a titanium or steel metallic cylinder.
    [14]
    14. The method according to claim 13, wherein the cylinder (4) is provided with an outer flange so that the cylinder (4) can be supported by pliers or
    25 clamps, or also so that the cylinder (4) can be moved by means of rails elevated from one point to another of the filling stations.
    [15]
    15. Method according to any one of the preceding claims, wherein the
    projection (1 1) provided on the surface (10) of the weighing cell (9) generally has a cylindrical shape and its upper surface has a substantially flat, conical or trunk-conical shape.
    [16]
    16. A method according to any one of the preceding claims, wherein the solid product to be filled in the container (1) has the following particle size distribution:
    35 not more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 230 or less than 140,

    a dO value, 5 in the range of 60-160 microns,
    where dO, 5 indicates the average value of the particle size that divides the population into exactly two equal halves, with 50% of the distribution above this value, and 50% below.
    [17]
    17. Method according to any one of the preceding claims 1 to 15, wherein the solid product to be filled in the container (1) has the following particle size distribution:
    no more than 10% of the total volume of particles is less than 20 microns, 10 no more than 10% of the total volume of particles is greater than 325 or less than 245, a dO value, 5 in the range of 100-155 microns,
    [18]
    18. Method according to claims 16 or 17, wherein the solid product to be filled in the container (1) is selected from the group consisting of risperidone,
    15 paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole, caripracin, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, alone or in combination.
    [19]
    19. Method according to any one of the preceding claims, which is performed in an aseptic environment in a laminar air flow cabinet.
    [20]
    20. Container (1) containing a solid product, wherein the solid product has been filled in the container (1) using the method described in any one of claims 1 to 19 above.
    [21]
    21. Container (1) containing a solid product according to claim 20,
    in which the solid product has the following particle size distribution: no more than 10% of the total volume of particles is less than 20 microns, no more than 10% of the total volume of particles is greater than 230 or less than 140,
    30 a dO value, 5 in the range of 60-160 microns,
    where dO, 5 indicates the average value of the particle size that divides the population into exactly two halves, with 50% of the distribution above this value, and 50% below.

    [22]
    22. Container (1) containing a solid product according to claim 20, wherein the solid product has the following particle size distribution:
    no more than 10% of the total volume of particles is less than 20 microns, 5 no more than 10% of the total volume of particles is greater than 325 or less than 245,
    a value dO, 5 in the range of 100-155 microns, where dO, 5 indicates the average value of the particle size that divides the population into exactly two equal halves, with 50% of the distribution above this value, and 50% below.
    [23]
    23. Container (1) containing a solid product according to any one of claims 20 to 22, wherein the solid product is a medicament.
    [24]
    24. Container (1) containing a solid product according to any one of 15 claims 20 to 23, wherein the medicament is selected from the group consisting of
    risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexiprazole, caripracin, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivative, metabolite or salt thereof, 5010s.
    25. Container (1) containing a solid product according to any one of claims 20 to 24, wherein the container is a syringe or cartridge.
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    同族专利:
    公开号 | 公开日
    HUE053083T2|2021-06-28|
    ZA201905401B|2021-07-28|
    IL268924D0|2019-10-31|
    PT3601060T|2021-02-17|
    SG11201907919SA|2019-10-30|
    GEP20217287B|2021-08-25|
    EP3601060A1|2020-02-05|
    EA037881B1|2021-05-31|
    CA3054473A1|2018-10-04|
    KR20190134601A|2019-12-04|
    SI3601060T1|2021-04-30|
    CN110325447A|2019-10-11|
    CO2019009613A2|2019-09-18|
    DK3601060T3|2021-03-01|
    HRP20210268T1|2021-04-02|
    CN110325447B|2021-11-02|
    LT3601060T|2021-03-10|
    ES2856256T3|2021-09-27|
    ES2684403B1|2019-07-09|
    PL3601060T3|2021-05-31|
    EA201992297A1|2020-02-12|
    US20200024013A1|2020-01-23|
    AU2018246951A1|2019-08-22|
    MX2019011509A|2019-11-01|
    CL2019002278A1|2019-11-08|
    BR112019020258A2|2020-04-22|
    JP2020515478A|2020-05-28|
    WO2018177800A1|2018-10-04|
    EP3601060B1|2020-11-25|
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    CN106082083A|2016-07-14|2016-11-09|江苏爱福特科技开发有限公司|A kind of Novel medicine produces uses Sterile vacuum filling apparatus|
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    法律状态:
    2018-10-02| BA2A| Patent application published|Ref document number: 2684403 Country of ref document: ES Kind code of ref document: A1 Effective date: 20181002 |
    2019-07-09| FG2A| Definitive protection|Ref document number: 2684403 Country of ref document: ES Kind code of ref document: B1 Effective date: 20190709 |
    优先权:
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    ES201730587A|ES2684403B1|2017-03-31|2017-03-31|PROCEDURE FOR GRAVIMETRIC FILLING IN STERILE SOLID CONDITIONS IN A PHARMACEUTICAL CONTAINER AND PHARMACEUTICAL CONTAINER USED IN THE SAME|ES201730587A| ES2684403B1|2017-03-31|2017-03-31|PROCEDURE FOR GRAVIMETRIC FILLING IN STERILE SOLID CONDITIONS IN A PHARMACEUTICAL CONTAINER AND PHARMACEUTICAL CONTAINER USED IN THE SAME|
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    JP2019553986A| JP2020515478A|2017-03-31|2018-03-20|The gravimetric filling process of solids into pharmaceutical containers under sterile conditions.|
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    HUE18713593A| HUE053083T2|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    PCT/EP2018/056968| WO2018177800A1|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    SI201830221T| SI3601060T1|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    PT187135934T| PT3601060T|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    EA201992297A| EA037881B1|2017-03-31|2018-03-20|Process for the gravimetric filing of pharmaceutical containers with solids in sterile conditions|
    CA3054473A| CA3054473A1|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    CN201880011087.9A| CN110325447B|2017-03-31|2018-03-20|Process for the aseptic filling of solids in pharmaceutical containers|
    GEAP201815174A| GEP20217287B|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    MX2019011509A| MX2019011509A|2017-03-31|2018-03-20|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container.|
    ES18713593T| ES2856256T3|2017-03-31|2018-03-20|Procedure for gravimetric filling under sterile conditions of solids in a pharmaceutical container|
    CL2019002278A| CL2019002278A1|2017-03-31|2019-08-12|Process for gravimetric filling in sterile conditions of solids in a pharmaceutical container.|
    ZA2019/05401A| ZA201905401B|2017-03-31|2019-08-15|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    IL26892419A| IL268924D0|2017-03-31|2019-08-26|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
    CONC2019/0009613A| CO2019009613A2|2017-03-31|2019-09-04|Procedure for gravimetric filling under sterile conditions of solids in a pharmaceutical container|
    US16/585,248| US20200024013A1|2017-03-31|2019-09-27|Process and Equipment Assembly for Aseptic Gravimetric Filling of Solids into a Container|
    HRP20210268TT| HRP20210268T1|2017-03-31|2021-02-16|Process for the gravimetric filing in sterile conditions of solids in a pharmaceutical container|
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