EA044455B1 - METHOD FOR FILLING PHARMACEUTICAL CONTAINERS WITH SOLID SUBSTANCES AND THEIR CLOCKING UNDER STERILE CONDITIONS - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to the field of filling and sealing, under sterile conditions, pharmaceutical containers, including syringes, vials, capsules, ampoules, disposable devices or cartridges, filled with solids selected from the group consisting of powders, granules, pellets, nanoparticles or microparticles, providing sealing of these solids. More particularly, the scope of the invention relates to a method for filling and sealing pharmaceutical containers filled with one or more sterile solid pharmaceutical substances or sterile excipients, dispensed and prepared in an aseptic environment that prevents said substances from adhering to the walls of the pharmaceutical containers, thereby ensuring an airtight closure of the container .

State of the art

In the pharmaceutical industry, the filling process of pharmaceutical containers is often carried out using liquid pharmaceutical substances and/or lyophilized solids, since they are much easier to handle and cause fewer dispensing problems than solid substances such as powders, granules, pellets, nanoparticles, microparticles, etc. The use of the above-mentioned solids in the process of filling a container has a major disadvantage in that these solids tend to adhere to the walls or body of the container, preventing or at least preventing the necessary sealing of the container from being achieved. This adhesion to the walls or to the body, in addition to preventing the desired seal, leads to contamination of containers and loss of dosage accuracy, therefore containers in which such adhesion to the walls is observed should be discarded, since some of the solid material remains in the sealing area of the container walls and cannot be installed the exact amount of solid that will be received by the patient. On the other hand, regarding contamination, since the dispersed solid remains stuck to the walls of the capping area, the stopper used to seal the container is not sealed and will not be able to prevent substances from the environment from entering the container and guarantee the integrity of the product, so that its physical chemical and microbiological properties may change, affecting the quality of the medicinal product. This is the biggest drawback in pharmaceuticals in this area, due to the strict conditions imposed by industry regulations, which must also meet standards known as good manufacturing practices (GMP).

Another challenge in pharmaceuticals is ensuring closure integrity, which also has safety implications as small losses of drug product can impact the safety of healthcare workers handling it. The term integrity here refers to the physical ability of a container closure system to maintain product sterility and the quality of final sterile pharmaceutical, biological and vaccine products throughout the shelf life. A sterile product is also defined as a product free of microorganisms that is composed of one or more elements under aseptic conditions that ultimately constitute a sterile finished pharmaceutical product. These elements include containers, closures, and finished pharmaceutical product components.

When dispensing powder into pharmaceutical containers, several factors must be taken into account that affect the cleanliness of the inside walls of the containers, since lack of cleanliness leads to contamination. These factors are listed below:

static charge of the walls of pharmaceutical containers used for filling, as well as the static charge of the solid substance placed in them: if the walls and solid substances have opposite charges, the placed solid substance will stick to the walls of the container;

kinetic energy gained by both the solid being placed in a container and the elements in contact with it when the solid falls into the container: the greater the height from which the solid freely falls to the bottom of the containers, the greater the kinetic energy gained by the solid and the elements due to friction;

the length of the dispenser needles (also called nozzles) used for dispensing, since the longer the dispenser and the closer it is to the top of the solid being placed in the container, the less its kinetic energy will be. In addition, the dispenser delivers the solid to an area away from the wall surfaces of the container being used. The ideal distance between the solid being dispensed and the tip of the dispenser will depend on the feed rate and the density of the solid being dispensed;

changing the direction of movement of air displaced from the container. This phenomenon is related to the kinetic energy of the dosed solid as it enters the container. During dispensing, solids entering the container displace air upward from the container. This displaced air is filled with suspended particles. Thus, the dispenser can be considered as a chimney that diverts the air flow from the internal walls, protecting them from contamination;

use of significant air flows (unidirectional or turbulent mode) in filling chambers or filling areas in accordance with international headlight requirements

- 1 044455 makopias to ensure the removal of any foreign particles that could contaminate the final product during the aseptic filling and capping process. The use of these air currents makes filling solids much more difficult by creating a disturbance that causes the solid to adhere to the walls of the container being filled.

To prevent the solid from sticking to the walls of the container, one of the measures used is to perform an ionization process on both the container and the solid that is to be filled. In the present invention, the terms process, step and phase, as well as the terms ionization and deionization or ionizer and deionizer, are used interchangeably.

Ionization is a chemical or physical phenomenon that produces ions. Ions are atoms or molecules that are electrically charged due to an excess or deficiency of electrons compared to a neutral atom or molecule. A chemical particle with a higher number of electrons than the neutral atom or molecule is called an anion, and has a net negative charge, and a particle with fewer electrons is called a cation, and has a net positive charge.

The ionization process used in the present invention is used to both neutralize the electrostatic charge of the pharmaceutical container being filled with the pharmaceutical solid and to neutralize the electrostatic charge of the dispensed solid, that is, both the container and its contents. This ionization is also used to neutralize parts of dispensing and capping equipment that come into contact with the container and/or powder. To do this, the ionizer generates ions of both polarities, which are projected onto the surface of the object being neutralized, where ions of opposite signs are combined, and ions of the same sign are repelled. As used herein, ionizer means any element or device capable of ionizing molecules in the surrounding air so that they can then be projected onto a surface having static electrical charges that neutralize those charges, thereby ionizing the surface.

However, with this ionization process alone, it is not possible to avoid the serious problem of sticking to container walls during filling of containers with solids, because when a solid is fed through a nozzle, the kinetic energy transferred by the solid creates turbulence inside the container, which eventually forces some of the solid back stick to the walls or body of the container.

Regarding the background to the invention, the documents cited below describe an ionization method that results in the neutralization of electrical charges applied in various situations:

In this regard, US 2016/0200461 A1 filed by VAKRX Pharmasystems INC. describes a method for volumetric filling and aseptic sealing of containers such as vials, bottles, syringes and ampoules with a liquid pharmaceutical product (which can subsequently be lyophilized) under controlled conditions. . This publication mentions concerns about the materials used to make containers, whether glass or polymer materials. On the one hand, glass containers can be broken, scratched and release particles when they hit each other. On the other hand, containers made from polymer materials are more durable than containers made from glass, although they may have cosmetic defects, such as scratches, which can degrade the quality of the pharmaceutical product upon impact.

A significant difference between the present invention and the above document is that the compounds used are solids, which are much more difficult to dose because they are highly charged and have a large specific surface area. Moreover, in the above document, the capping process includes two stages: a partial and a second full stage due to the need for freeze drying after the first partial capping, whereas in the present invention, the sealing process is carried out in one stage with full capping, without the need to resort to subsequent stages of capping.

In addition, it should be noted that the solid filling process is much more difficult due to the fact that the solids remain stuck to the walls of pharmaceutical containers, impairing dosage accuracy, which is more important for small containers in which small quantities of drugs must be dosed very accurately. This disadvantage is overcome by the method of the present invention, since it must be taken into account that in the pharmaceutical industry, an error in the packaging of an active ingredient can mean that patients receive the wrong dose of the drug.

This is a serious drawback when filling containers with solids, caused by the problem of the solid sticking to the body of the containers. For this reason, in most procedures used in the pharmaceutical industry today, equipment certification is mandatory to ensure that the dosage amount is correct. Additionally, various manufacturing controls are used during packaging to verify the actual fill quantity of all pharmaceutical containers. A common means of control is the weighing of containers, which allows the correction or rejection of containers in which the amount of pharmaceutical substance

- 2 044455 product, whether a drug or an active ingredient, does not meet the required weighing accuracy. Control during the production process can be complete (100%) or statistical; Statistical control is carried out from time to time to check the correct dosage. These control measures are associated with high production and economic costs required to control the accuracy of product dosage.

When it comes to eliminating electrostatic charge, several types of ionizers are available to solve this problem. These ionizers come in a variety of shapes, such as ring, rod, gun, curtain, blade, cylindrical, needle, or filter ionizers, including but not limited to insulators with an ionizer at the top. For the purposes of the present invention, these ionizers can be installed on equipment used for filling, to produce ions of both polarities that neutralize the surface of containers or preparations, or they can be placed in packaging areas, rooms or isolators, in particular on the ceiling of insulators, to providing ionization that neutralizes both the environment and the air flow in the room, thereby eliminating the problem of static charges.

Regarding the removal of the static charge of solids by ionizers, several documents are cited below.

European patent EP 2711096 A2, applied for by TRINC Corporation, relates to a device for removing electrostatic charge and dirt from objects such as film, foil, glass, clothing, paper, etc. The device includes a large container with openings at the top and bottom to suck in and discharge powder, and a small cylindrical or conical container within the larger container. This small container is designed to generate cyclonic and tornado currents and contains at least one corona discharge ion generator. This ion generator consists of electrical discharge needles that are placed either on top of or inside a small container. The small container contains air injection holes through which compressed air is forced, as well as ultrasonic generators inside or outside the small container designed to vibrate the powder so that it can be separated from the object after it is neutralized by the ion generator. This powder can be collected using a vacuum suction inside a large container.

In contrast, the present invention relates to deionization of both the container and the powder prior to packaging in order to prevent the powder from sticking to the walls of the container during the filling process and thus provide an airtight seal. Additionally, as a safety factor, deionization is performed on and/or within the container to remove any remaining powder adhering to the walls of the compaction area.

The present invention also uses an ionizer in the form of a ring, a rod, a gun, a curtain, knives, cylinders, needles or nozzles, or an ionization filter, including insulators with an ionizer at the top, to eliminate static charge, but this occurs as a powdery solid, and with a filled container, which is not in the European patent EP 2711096 A2, since only the powder is ionized there, and the container is not ionized. Another significant difference between the present invention and the said document is that in the said European patent EP 2711096, compressed air is used to facilitate suction, whereas the present invention does not require an air flow, and if it does, it must be a sterile carrier gas. Among sterile carrier gases, ionized nitrogen flow has advantages that will be discussed below.

A characteristic disadvantage of the present invention is the need to carry out deionization under sterile conditions, which necessitates the use of sterile carrier gases. It should be noted that this sterile state of the carrier gas does not affect the deionization process.

On the other hand, the European patent EP 2711096 A2 differs from the present invention in that, although in both cases it is important to eliminate the electrostatic charge of the solid, the said document does not discuss in detail the method by which this is accomplished, specifying only the use of an ion generator such as discharge needles for deionization, without mentioning the problems caused by electric discharge needles when approaching any solid body, namely the appearance of combustion of the product, the formation of impurities and changes in the physico-chemical composition of the product.

Japanese patent JP 2005001818 A, which has been applied for by YMS KK, relates to a powder feeding device and an air supply device capable of supplying lightly charged powder and charged powder. This device contains a hopper equipped with aeration means, which in turn are equipped with a microporous diaphragm for aerating the powder in the hopper. The air for aeration is pre-ionized using an ionizing device, for example a corona discharge device. For aeration, compressed air supplied by an air compressor is used. This compressed air is ionized using an ionizing device containing a corona discharge device or equivalent. When aerated with ionized air, the ionized air neutralizes or removes the surface charge of the powder, and the surface charge of the charged powder disappears. In addition, aeration causes the powder in the hopper to fill with air and a layer of air is formed between the powder and the inner wall of the hopper, preventing the powder from being recharged. Moreover, in the present

- 3 044455 This document refers to a suction nozzle or needle made of conductive material, which forms part of the air supply device. This nozzle is not a metering nozzle.

In the present invention, on the one hand, a solid substance is ionized, and on the other hand, a pharmaceutical container is used using a stream of sterile carrier gas as the ionized gas (usually a stream of sterile nitrogen). Another difference between the present invention and this Japanese patent is the nozzle or needle; in the case of this Japanese patent, the suction nozzle is made of a conductive material, whereas in the present invention, the nozzle is a metering needle and is not made of a conductive material. Unlike this Japanese patent, the present invention also uses an ionizer in the form of a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or ionization filter, including insulators with an ionizer on top of the insulator or any other type that can neutralize electrostatic charge both the container to be filled and the solid to be dispensed, whereas the Japanese patent only mentions the use of a corona discharge ionizing device, etc.

Chinese utility model CN 203265193U from Meech Static Eliminators Shanghai Co LTD is in the technical field of eliminating static electricity and removing powder from the inner wall of bottles before filling to clean containers, using an ion needle with compressed air for this purpose to eliminate static electricity and remove powder , stuck to the walls of the bottle. The device described in this utility model consists of a needle, a first tube connecting the needle to a second tube for connecting an electrical cable, the two ends of which have internal or external threads, respectively. The needle tip and the second tube are screwed and secured together, and the needle tip, the first tube and the second tube have an interconnected internal passage for the passage of air, the second tube also having at least two threads so that the through thread is also connected to the internal hole of the first tube . The tube has wire holes evenly spaced between the inner and outer walls, each of which forms an ion-generating end at one end of the second tube entering the first tube element. Ions can be delivered to the surface of an object through an ion needle and using compressed air.

Instead, in the present invention, the ionizer can be of any type, such as a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or even an ionizing filter, which may also include insulators with an ionizer at the top, but not necessarily , so that it is a needle as specifically stated in the Chinese utility model. Moreover, in this utility model, compressed air is required to displace the ions, whereas in the present invention, a stream of sterile carrier gas, which may consist of sterile compressed nitrogen or air, may or may not be used, not only to facilitate the ionization process by dispensing solid substances, as well as to maintain the necessary sterile conditions required for these procedures in the pharmaceutical industry by creating an inert atmosphere inside the containers. On the other hand, the utility model relates to cleaning bottles with powder before filling, while the present invention relates to deionization and wall cleaning after filling and applies to containers smaller than bottles, such as syringes, vials, capsules, ampoules, single dispensing devices or cartridges that are more difficult to fill with a solid such as powder.

International application WO 2016/185230 A2 filed by 3P Innovation Limited describes a device and method for filling pharmaceutical containers such as syringes, vials, capsules, cartridges and blister packs with powdered pharmaceutical material by vibration. This device has a support for a pharmaceutical container, a reservoir containing pharmaceutical powder, this reservoir being in contact with a nozzle or a filling needle responsible for filling the pharmaceutical container with pharmaceutical powder, and a piezoelectric vibration device. This document addresses the advantage of using a cylinder containing an electrically conductive material that can be grounded through a load cell, thereby helping to dissipate the static charge of plastic pharmaceutical containers to improve the powder filling process without compromising cleanliness. However, the invention described herein does not require the material to be electrically conductive since it is a filling process through the neck of the container, so the closure problem encountered when filling from the back of the container does not arise.

On the other hand, the present invention relates to a method for closing pharmaceutical containers containing solid pharmaceutical substances, in which the filling is carried out under aseptic conditions without the need for terminal sterilization, whereas the aforementioned international application WO 2016/185230 A2 describes filling through the neck of the container, as shown in FIG. . 2. On the other hand, this international publication only mentions the filling of plastic pharmaceutical containers, whereas the present invention includes all types of container materials such as polymeric materials or glass. In addition, the international publication mentions a cylinder or washer with an electrically conductive material for dissipating the static charge of pharmaceutical containers used, whereas in the present invention the presence of a cylinder acting as a support for the container is an optional element, not having

- 4 044455 relevant to the problem being solved, and intended for various other functions, such as: using such an element to work with a container without contact with it;

the cylinder protects the process from air flows, being part of the exhaust hood;

This is an element of vertical support of the container on the mass sensor for accurate weighing.

In addition, any ionizer of any shape may be used in the present invention, such as a ring, rod, gun, curtain, blade, cylindrical, needle or nozzle, or ionization filter, including isolators with an ionizer at the top, which can be installed on packaging equipment before, during and after filling, with or without the use of a sterile carrier gas, whereas the invention described in the said international publication concerns only a cylinder (washer) with an electrically conductive material capable of dissipating the static charge of the plastic container used during filling.

The essence of the invention

Accordingly, the problem to be solved by the present invention is to provide a method for filling pharmaceutical containers in the form of vials, capsules, ampoules, single dose devices, inhalers, bottles, blister cartridges, sachets, pouches, Eppendorf® tubes and syringes. The syringes of the present invention may have a needle, a catheter-type cone, or a luer-lock type cone, that is, a non-threaded tip or a female or external threaded tip, respectively. For the purposes of the present invention, a Luer taper refers to the tapered tip invented by Wulfing Luer, with a typical 6% taper that can be either internal or external, depending on the connection. Similarly, a luer-lock cone refers to a cone-shaped tip, invented by Hermann Wulfing Luer, with an airtight threaded mount.

The container compounds of the present invention are materials such as plastics of various compositions, such as polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, polyvinyl chloride, polyacrylonitrile, polyamides, etc., polyesters (containing an ester functional group in the main chain: poly (ethylene terephthalate), polycarbonate), acrylic polymers (poly(methyl methacrylate), polyacrylonitrile), thermoplastic resins (polyacetals and polyhaloethylenes), polyurethanes, formaldehyde resins (phenol resin, urea resin), phenolic resins, aminoplasts, duroplastic resins (unsaturated polyesters, polyurethanes) , polyvinylidene silicones, cellulose derivatives, polycarbonates and mixtures thereof, etc. Alternatively, the container can also be made of metal, such as steel or titanium, suitable for drug delivery, glass, etc., with solid particles under sterile conditions, which eliminates the problems existing in recent advances, and in particular which prevent the solid from adhering to the walls of the container while ensuring that the container is sealed tightly.

In turn, the cylinder or washer, hopper and nozzle or needle will preferably consist of various non-conductive materials, such as various plastics, for example polyetheretherketone (PEEK), glass, stone, resin, glass, but may also consist of grounded conductive materials such like steel, titanium, etc.

Both the materials used for the container and the cylinder materials must be waterproof, inert, not very permeable or impervious, not absorbent and/or adsorbent to the product contained therein, not coarse and free of particles.

The solution to the problem described in the present invention is based on the fact that the inventors have discovered that such a problem can be satisfactorily solved by the following methods, which can be used independently or in any combination:

on the one hand, ionization of both the solid and the pharmaceutical container in which it is to be placed, as well as the ionization of elements of dispensing and capping equipment that come into contact with the container and/or powder, at one or more stages of the filling procedure, to prevent sticking solid matter to the walls of the container, and also to prevent the solid particles from being attracted to the walls of the container, so that the solid material settles only on the bottom of the container and not on its walls. This deionization method can be applied to the container and solid separately, or to the container with the product inside. This deionization can be applied as many times as there are filling and capping steps;

on the other hand, by controlling the potential applied to the ionizers, which should be such that the resulting electrostatic charge on the walls of the container and/or the solid being dosed is preferably less than 2000 V, more preferably less than 500 V, and most preferably less than 200 V.

In addition, the filling of a pharmaceutical container with a solid is preferably carried out using a dispensing needle, the tip or dispensing end of which is located throughout the filling stage at a height of 1 to 3 mm above the surface of the solid at the bottom of the container in order to avoid turbulence that could lift the deposited solid to walls. Even if this turbulence phenomenon occurs to some extent, the ionization of both solids and internal

- 5 044455 them the walls of the container will cause these raised particles to settle back to the bottom of the container without significant loss of product on the walls of the container.

Therefore, in a first aspect, the invention relates to a method for filling pharmaceutical containers with solids under sterile conditions, comprising the steps of:

a) provision of a pharmaceutical container (1) with walls and bottom;

b) dispensing the solid into the pharmaceutical container (1) using a dosing needle (4), gravimetrically checking the mass of the solid distributed into the container (1); and

c) closing the pharmaceutical container with a stopper (6), characterized in that at least one of stages a), b) and c) or several of them in any combination, static electric charges on the inner walls of the container (1) on a solid substance dispensed into the container, and/or on any parts in contact with the walls of the container or with the solid substance dispensed into the container, are neutralized by means of an ionizer (2), to which an ionization potential is applied so that the electrostatic charge inside the container (1) after each ionization was less than 2000 V. This ionization prevents the solid dispensed into the container from sticking to the inner walls of the container (1), which could distort the amount of solid dispensed into the container, make it difficult to visually assess the level of the dispensed product, or even cause incomplete administration of the drug to the patient .

In a second aspect, the invention relates to a container (1) containing a solid product, wherein the solid product is dosed into the container using the described method.

In the case of ionization in the rod/ring casing, re-ionization is preferably performed using a needle with or without gas flow.

In general, throughout the present description, filling is preferably carried out using a dispensing needle, the tip or dispensing end of which is located throughout the filling stage at a height of 1 to 3 mm above the surface of the solid deposited at the bottom of the container to prevent turbulence that could raise the solid body to the walls of the container.

This method has two advantages: on the one hand, it achieves precise filling of the container with substances even when using two or more filling stations by preventing solid substances from sticking to the walls of the container. On the other hand, ensuring the integrity of the closure of a pharmaceutical container, which is especially important in the case of pharmaceuticals, since it prevents both foreign substances that could contaminate the product from entering the container and leakage of the product outside, which affects the effective dose of the drug.

In addition, the present invention also addresses the problem of static charges resulting from collisions between containers used for filling, whether made of glass or polymeric material, in a sterile environment that is typically subject to laminar or turbulent flows increasing movement and dispersion electrostatic charges.

Although the invention is generally applicable to powdered solids of any nature, this procedure is particularly applicable to solids having the following particle size distribution:

Dio > 20 µm < D50 <110 µm

150 µm < D90 <215 µm where D ₁₀ is the average particle size dividing the population into two equal halves, with 50% of the composition above this value, and 50% below. In general, in this specification, the value referred to as d0.X or Dx represents the mass fraction of drug with a particle size below the specified value, having a range from 0.0 to 1.0. By this definition, a d0.1 or D ₁₀ value means that 10% of the total mass of drug particles are 10 μm or less in size.

Ideally this applies to solids having the following particle size distribution:

Dio > 25 µm

100 µm < D50 <155 µm

245 µm < D90 < 325 µm

Examples of such compounds are risperidone, paliperidone, fentanyl, activon olan-dependent compound, letrozole, aripiprazole, anastrozole, activon azeno compound, brexiprazole, cariprazine, activon closo compound, iloperidone, lurasidone, activon closo compound, ziprasidone, including derivatives, metabolites and salts (as pamoate or palmitate ) alone or in combination.

Other examples of such compounds are also biocompatible polymers such as polylactic acid (PLA), polyglycolic acid (PGA) and their copolymers, polylactic acid-glycolic acid (PLGA) copolymers, including any derivatives or copolymers, alone or in combination.

- 6 044455

Brief description of the figures

The figures of the drawings appended to the present invention serve to illustrate the essence of the invention. These figures are for illustration purposes only and do not limit the claimed invention. Regarding the ionization phenomenon, the present invention provides various methods, some of which are shown in FIG. 1-7 below. For a correct understanding of the figures, the phenomenon of ionization is represented by alternating plus (+) and minus (-) signs. It is understood that this flow of ions of different signs may or may not be accompanied by a flow of sterile carrier gas, although the latter in FIG. not shown as such.

Fig. 1: Shows a specific embodiment of the aseptic filling and capping of the present invention, in which the pharmaceutical container depicted is, in this case, an externally attached syringe (1) that remains with the nozzle cap (8) closed throughout the entire process. The syringe (1) is subjected to the first stage of ionization (a) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including insulators with an ionizer in the upper part, although in this case a needle ionizer is shown. The syringe with external attachment (1) is then supplied to a filling station (b), where the method of the present invention may include several filling stations, in particular if several solids are to be dispensed into the syringe. At this station, the syringe, which can be inserted into the barrel (7), is weighed by a mass sensor (5) during filling, which occurs with the help of a hopper (3) and a nozzle or dosing needle (4). After filling, the externally attached syringe (1) is subjected to another ionization step (c) using an ionizer (2) provided in this step with a ring, rod, gun, shutter, knife, cylinder, needle or nozzle, or an ionization filter including insulators with an ionizer at the top, although in this case a ring ionizer is shown. Finally, the syringe with external fastening (1) is transferred to the capping station (d), where it is hermetically sealed at the top with a stopper (6).

Fig. 2: shows another particular variant of the method according to the present invention, where the syringe with external attachment in FIG. 1 is replaced by a syringe with internal fastening as a pharmaceutical container (1).

Fig. 3: shows a specific variant of the process according to the present invention, where the syringe as a pharmaceutical container (1) is replaced by an Eppendorf® tube that has undergone an ionization stage (a) due to the presence at this stage of an ionizer (2) with a ring, a rod, a gun, a shutter, a knife , cylinder, needle or nozzle, or ionizing filter, including isolators with an ionizing element at the top, although a needle ionizing element is shown here. It is then transferred to a filling station (b) (there may be several filling stations), where there is an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter, including insulators with an ionizer at the top parts, in this case an ionizing filter is shown. In addition to the ionizer, this stage contains a mass sensor (5), a hopper (3) and a nozzle or dosing needle (4). Finally, once filled, the Eppendorf® tube is subjected to an ionization process using an ionizer with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including isolators with an ionizer on top, in this case a rod ionizer (2) is shown.

Fig. 4: shows a specific embodiment of the procedure of the present invention, in which the presented container in this case is a syringe with a needle (1) previously closed by a nozzle cap (8) throughout the capping process, which undergoes first an ionization process (a) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including insulators with an ionizer at the top, although in this case a needle ionizer is indicated. The syringe with the needle (1) then passes to a filling station (b), where in the method described in the present invention there may be several filling stations, in particular if several solids need to be dosed into the syringe. At this station, a syringe with a needle, which can be inserted into a barrel (7), is weighed by a mass sensor (5) during filling, which occurs with the help of a hopper (3) and a nozzle or dosing needle (4). After filling, the syringe with a needle (1) undergoes an additional stage of ionization (c) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter, including insulators with an ionizer in the upper part, although in this case a ring ionizer is shown. Finally, the syringe with a needle (1) is transferred to the capping station (d), where it is hermetically sealed at the top with a stopper (6), and is subjected to an additional stage of ionization using the ionizer (2) provided at this stage with a ring, rod, gun, curtain , knife, cylinder, needle or nozzle, or ionizing filter, including insulators with an ionizing device at the top, although a rod ionizing device is shown here.

Fig. 5: another particular embodiment of the method of the present invention is shown, in which the depicted container is, in this case, a syringe with an internal fastening (1), closed throughout the entire process by a nozzle cap (8), undergoing the first process.

- 7 044455 ionization (a) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter. The syringe with internal attachment (1) then passes to a filling station (b), where in the method described in the present invention there may be several filling stations, in particular if several solids are to be dosed into the syringe. At this station, the syringe, which can be inserted into the barrel (7), is weighed by a mass sensor (5) during filling, which occurs using the hopper (3) and the nozzle or dosing needle (4). After filling, the syringe goes through an ionization stage (c) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including insulators with an ionizer at the top, although in this case a needle is shown ionizer Finally, the syringe with internal fastening (1) is transferred to the capping station (d), where it is sealed at the top with a stopper (6), while it undergoes an additional deionization phase using the ionizer (2) provided at this stage with a ring, rod , gun, curtain, knife, cylinder, needle or nozzle, or ionizing filter, including insulators with an ionizer at the top, although a rod ionizer is shown in this case.

Fig. 6: shows another particular embodiment of the method of the present invention, in which the presented container in this case is a cartridge (1) subjected to a first ionization process (a) using an ionizer (2) with a ring, a rod, a gun, a curtain, a knife, cylinder, needle or nozzle, or ionizing filter, including isolators with an ionizing element at the top, although a needle ionizing element is indicated in this case. The cartridge (1) then passes to a filling station (b), where in the method described in the present invention there may be several filling stations, especially if several solids need to be dosed into the cartridge. At this station, the cartridge is weighed by a mass sensor (5) during filling, which occurs using a hopper (3) and a nozzle or dosing needle (4). Finally, the cartridge (1), which can be inserted into the cylinder (7), is transferred to the ionization station, where the ionizer (2) with ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or ionization filter, including insulators with an ionizer at the top, although in this case a rod ionizer is shown.

Fig. 7: shows a specific embodiment of the method of the present invention, in which the presented container in this case is a pre-filled syringe with an internal attachment (1), which is first subjected to an ionization process (a) using an ionizer (2) with a ring, rod, gun , curtain, knife, cylinder, needle or nozzle, or ionizing filter, including insulators with an ionizer at the top, although in this case a ring ionizer is indicated. The syringe, which is filled from the threaded end, is then placed at a filling station (b), where in the method described in the present invention there may be several filling stations, in particular if several solids are to be dosed into the syringe. At this station, the syringe, which can be inserted into the barrel (7), is weighed by a mass sensor (5) during filling, which occurs with the help of a hopper (3) and a nozzle or dosing needle (4). After filling, the internal syringe (1) undergoes a further ionization phase (c) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or ionization filter, including isolators with an ionizer at the top (in this case, a rod ionizer).

Carrying out the invention

Dosing of solids by volumetric or gravimetric means, such as powders, granules, pellets, nanoparticles or microparticles, into small pharmaceutical containers such as vials, capsules, ampoules, disposable devices, inhalers, vials, blister cartridges, sachets, pouches, test tubes, test tubes Eppendorf® type and syringes (with internal or external, threaded or non-threaded nozzles) and from various materials, such as plastics of various compositions, e.g. polyolefins and cyclopolyolefins, polypropylene, polybutadiene, polyethylene, polystyrene, polyvinyl chloride, polyacrylonitrile, polyamides, etc. ., polyesters (containing an ester functional group in the main chain), poly(ethylene terephthalate), polycarbonate), acrylic polymers (polymethyl methacrylate, polyacrylonitrile), thermoplastic resins (polyacetals and polyhaloethylenes), polyurethanes, formaldehyde resins (phenolic resin, urea resin) , phenoplasts, aminoplasts, thioplastics, duroplasts (unsaturated polyesters, polyurethanes), polyvinylidene silicones, cellulose derivatives, polycarbonates and mixtures thereof, etc., where also alternatively the container can be made of metal, for example steel or titanium, suitable for the administration of drugs , or glass, among others, currently poses a serious problem for the pharmaceutical industry due to the great disadvantage that these substances adhere to the walls of the closure area of the containers used. This sticking causes significant inconvenience to the said industry as it has to comply with the regulations specified in various international pharmacopoeias in addition to adhering to Good Manufacturing Practices (GMP). The present invention addresses the disadvantages associated with the adhesion of said solids to the walls of containers used for filling, since this adhesion interferes with both the filling and aseptic sealing processes. For aseptic filling and capping process,

- 8 044455 mentioned in the present invention, only the solids mentioned above are used.

International Pharmacopoeias require significant air flows (unidirectional or turbulent) for aseptic filling and sealing to ensure the removal of any foreign particles that could contaminate the final product. The use of these air currents makes filling solids much more difficult by creating a disturbance that causes the solid to adhere to the walls of the container being filled.

Because the dispensed solids adhere to the walls in the container closure area, they cannot adhere to the container neck area, preventing the desired closure from being achieved. This lack of closure results in two serious problems: loss of dosed solids and contamination of the container being filled.

Waste of doses leads to inaccurate administration of the pharmaceutical drug because solids adhering to the walls in the container closure area will be measured by the mass sensor indicating the exact amount of product to be administered to the patient, however, when administered to the patient, he will receive a lower dose than indicated , since solids stuck to the walls of the container will not be introduced and will remain stuck to the walls of the container.

With regard to contamination of the container used for filling, this is perhaps the most serious of the disadvantages that can arise from the lack of airtightness caused by the substance adhering to the walls in the closure area, since this affects the integrity of the drug and affects the health of the patient receiving pharmaceutical drug. When sealing a container with a stopper, if there are solid substances on the walls of the container stuck to the area of the closure, these substances will remain in this area after the container is sealed, which means that the stopper cannot guarantee the integrity of the sealed product, since substances from the environment may enter the preparation after capping. Microbial contamination is a very serious problem for pharmaceutical companies because their products provide an ideal environment for the growth of microorganisms such as bacteria, fungi or yeast. Theoretically, a sterile but contaminated drug can lead to drug deterioration, loss of drug potency, pyrogenic reactions after administration to the patient, especially if administered parenterally, infection and colonization of microorganisms in the patient with a risk of secondary infection. Any microorganism, pathogenic or non-pathogenic, found in a supposedly sterile pharmaceutical product poses a hazard.

In view of the significant problems caused by lack of sealing, the present invention provides a solution to the problem of solids adhering to the walls in the closure area of a pharmaceutical container by sealing said substance. Two methods are used to ensure sealing of solids, namely control of the height of the dispensing needle and ionization of both the pharmaceutical container being filled and the solid being dispensed, as well as ionization of the dispensing and capping equipment elements in contact with the syringe and/or powder.

As mentioned in the background section, there are a number of factors that affect the adhesion of solids to the interior walls of a container, including the length of the nozzle. The longer the nozzle and the closer it is to the top level of the powder in the container, the less its kinetic energy will be. In addition, the nozzle removes powder from the surface of the walls in the capping area. The present inventors have found that the ideal distance between the powder and the nozzle tip depends on the dosage, dosing speed and density of the powder, although it is typically 1-3 mm, more preferably about 2 mm. The present invention offers several nozzle height options:

the first of these is based on the presence of a nozzle with a precise height (h) measured from the bottom of the container. In this case, the filling process is carried out at the rear of the container, i.e. when the container is a syringe, at the neck or end with the largest diameter. A minimum height h between the dispensed solid and the nozzle must always be observed, in particular 2 mm;

second option - the nozzle is always kept at a minimum distance of h=2 mm from the solid substance dosed into the container. This method means that the nozzle is not stationary, but can rise and fall during filling, maintaining a distance of 2 mm from the solid at all times;

As an alternative to the above, the nozzle may be provided with a retaining element to prevent the powder from being dispersed over the area to be filled during filling.

Regarding ionization, the approach is based on a solution to prevent the generation of electrostatic charges contained both in the pharmaceutical container being filled and in the solid substance dispensed into it. The walls of the container and the solid matter have static charges. If these charges have opposite signs, the solid will stick to the inner walls of the container. For this reason, both the container and the solid become ionized.

There are two types of electrostatic charges: negative charges, which are the electrons of the atoms of chemical elements, and positive charges, which are atomically equivalent to the action of protons

- 9 044455th nucleus, deprived of electrons in the last shell. Electrons on the surface of an insulating material cannot be easily scattered unless they have a conductive path to ground, so the cylinder is a conductive element as mentioned above. Because they cannot circulate easily, they cause what is called static electricity. Electrons in conductors can move freely from molecule to molecule, but protons are inseparable from the atom and cannot move unless the atom itself is moving. The magnitude of the electrostatic charge depends on the position or distance between the materials connected in series, and its sign is determined by the tendency of the material to give up or gain electrons, which is what the series connection actually indicates.

The present invention uses any type of ionizer, such as a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or ionization filter, including insulators with an ionizer at the top. For example, the rod can be used to ionize and neutralize both the environment and air flow, thereby eliminating static charges. The ionizer may in practice be implemented using a stream of sterile carrier gas such as compressed air or nitrogen N2, preferably using a nitrogen stream, which has the following functions and/or advantages:

this nitrogen flow serves as a means of transporting ions generated at the electrodes of the ionization elements, which ionize the surrounding air, producing ions carried away by the N ₂ flow. These positive and negative ions are generated by applying alternating current, which through a transformer reaches values of up to 8000 V at almost negligible current (4 mA). Surfaces treated in this way end up with a neutral charge due to the recombination of charges of different signs and the repulsion of charges of the same sign;

creating an inert atmosphere inside containers by displacing oxygen inside the containers, which protects the product from its oxidative effect. The introduction of an inert gas into a vessel, known as inerting, is based on reducing the percentage of oxygen below the limiting oxygen concentration (LOC);

carriers with a sweeping effect inside containers. The generation of alternating ions eliminates the static forces that cause powder to stick to the walls of the container. This causes the solid particles to stay in place without sticking to the container or to each other. Then a small air flow (0.1-0.8 l/min) produces the effect of sweeping away the already broken into particles solid matter.

Regarding the ionization phenomenon, the present invention provides various methods for its implementation, shown in the accompanying FIGS. 1-7, in which the pharmaceutical container is represented, inter alia, as an internal or external syringe, a syringe with a needle, a cartridge or capsule, or an Eppendorf® tube. Ionizers can be used with any type of ionizer (whether accompanied by a stream of sterile carrier gas or not), such as a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or ionizing filter, including isolators with an ionizer in the upper part, for example, a rod, to ionize and neutralize both the environment and the air flow, thereby eliminating static charges. In the case of isolators and according to a preferred embodiment, sterilization with nebulized or vaporized hydrogen peroxide or a mixture of hydrogen peroxide and peracetic acid is required before dosing as described in the present invention.

When the pharmaceutical container is removed from the tray, it has a very high electrostatic charge (over 30,000 V). This is caused by constant friction between the container and the tray. Therefore, as shown in the various figures, both before and after the containers are inserted into the cylinder, they are preferably exposed to any type of ionizer and a stream of sterile carrier gas. This gas can be nitrogen, carrying molecules of ionized air, or compressed air entering the container, as well as the sealing area, eliminating the existing electrostatic charge.

In fig. Figure 1 shows a general method for aseptically sealing a container, consisting of several steps:

The container (1), optionally inserted into the support cylinder (7) and closed with the nozzle cover (8), is subjected to ionization (a) using an ionizer (2) of any type, for example with a ring, rod, gun, curtain, knife, cylinder, needle or a nozzle or an ionizing filter, including isolators with an ionizer at the top or any other type of ionizer. The ionizer (2) is used to remove electrostatic charge from the container both on the internal walls and in the closure area. This ionizer may or may not be used in conjunction with a stream of sterile carrier gas, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although it is more preferable to use a stream of nitrogen carrying ionized air molecules. The nitrogen flow used, carrying ionized air molecules, reaches both the inside of the container and the closure area. These two ionization processes (ionizer ionization and additional application of a sterile gas stream) remove electrostatic charges in the container so that the container can be filled.

After the ionization process (a), the syringe (1) enters the aseptic filling station (b). On

- 10 044455 At this stage, the container (1) is aseptically filled with a solid substance. This process requires the use of a hopper (3) containing the solid to be dosed and a dosing needle or nozzle (4) through which the solid is dosed. To accurately measure the amount of solids being dosed, a mass sensor (5) is also required. This station may or may not have a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably using nitrogen carrying ionized air molecules to provide ion transport. There are as many filling stations as the number of drugs or combinations thereof will be dosed.

After filling the container (1) with a solid, it is subjected to a deionization step (c) using a deionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter, including isolators with an ionizer at the top. The ionizer may or may not be accompanied by a stream of sterile carrier gas, such as compressed air or nitrogen, carrying ionized air molecules; it is preferable to use nitrogen carrying molecules of ionized air, which is used to prevent the solid from sticking to the walls in the area of the container closure (1).

Finally, there is an aseptic capping station (d) where the stopper (6) is inserted, sealing the container. The last station may or may not use a stream of sterile carrier gas such as compressed air or nitrogen, preferably carrying ionized air molecules.

In fig. Figure 2 shows another version of the ionization process, consisting of four stages.

The first stage consists of an ionization process (a) similar to that shown in FIG. 1, wherein a stream of sterile carrier gas, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, may or may not be introduced into the container (1), the syringe being previously closed by a nozzle cap (8) and, possibly inserted into the support cylinder (7). This stream of sterile carrier gas is used in conjunction with an ionizer (2) with ring, rod, gun, shutter, knife, cylinder, needle or nozzle, or ionizer filter, including isolators with an ionizer at the top. The flow and ionizer (2) reach the bottom of the container (1) and the capping area; in this figure, the sterile carrier gas stream used is preferably a nitrogen stream carrying ionized air molecules. After this jet is applied, the electrostatic charge is removed from the container to begin filling.

In the second stage of the described process, the container (1) passes to the aseptic filling station (b), where aseptic filling with solids is carried out. This station has several elements, such as a hopper (3) that contains the solid to be dosed, a dosing needle or nozzle (4) responsible for dosing the solid, and a weight sensor (5) to control the exact amount of solid to be dosed. There are as many filling stations as the number of drugs or combinations thereof will be dosed. To ensure the cleanliness of the capping area, a third stage is used, consisting of an ionization stage (i), where an ionizer (2) is used with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including isolators with an ionizer in the top, where a stream of sterile carrier gas such as nitrogen carrying ionized air molecules or compressed air may or may not be used to prevent the solid from adhering to the walls of the container in the closure area. It is preferable for the nitrogen stream carrying ionized air molecules to serve as a means of displacing the ions and as a transport means in a displacement effect, thus achieving the desired closure at this station. The number of ionization stations will vary depending on the needs of each drug.

Finally, the last stage consists of a capping stage (d), in which the container is closed with a stopper (6). At this stage, a sterile stream of carrier gas such as nitrogen, preferably carrying ionized air molecules, may or may not be used because, although there are no solid particles in the capping area, it must be ensured that the container is completely clean and that none of the dispensed solid particles do not adhere to the stopper used for closure and to the walls of the container due to electrostatic charges created by friction when the container is placed in the closure device.

In fig. Figure 3 shows another specific implementation of the ionization process, consisting of the following steps:

The container (1) is subjected to an ionization process (a) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including insulators with an ionizer at the top. This ionizer may or may not be used in conjunction with a stream of sterile carrier gas, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although it is more preferable to use a stream of nitrogen carrying ionized air molecules. The ionizer (2) is used to remove electrostatic charge from the container both on the internal walls and in the closure area. In addition, the nitrogen flow, carrying the ionized air molecules used, reaches both the internal

- 11 044455 both the container part and the capping area; through these two ionization processes, the electrostatic charge is removed from the container so that it can be filled.

Then, after this ionization phase (a), the container (1) passes to an aseptic filling station (b), where it is aseptically filled with solids. This station has several elements, such as: a hopper (3) in which the solid substance to be dosed is located, a dosing needle or nozzle (4) responsible for dosing the solid substance, and a mass sensor (5) to control the exact amount of solid substance dosed and ionizer (2) with ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or ionization filter, including isolators with an ionizer at the top. This station may or may not have a flow of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, it is preferable to use nitrogen carrying ionized air molecules, ensuring the transfer of ions. This ensures that the dosed solid does not remain in the capping area. There are as many filling stations as the number of drugs or their combinations to be dosed, as well as as many ionization stages as necessary.

After the container (1) is filled with a solid substance at the filling station (b), to ensure the cleanliness of the container sealing area, the last stage is the ionization process (c) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter, including isolators with an ionizer at the top, which may or may not employ a stream of sterile carrier gas such as nitrogen carrying ionized air molecules or compressed air to prevent solid adhesion to the walls of the container in the capping area. It is preferable for the nitrogen stream carrying ionized air molecules to serve as a means of displacing the ions and as a transport means in a displacement effect, thus achieving the desired closure at this station. The number of ionization stations will vary depending on the needs of each drug.

In fig. 4 shows another particular embodiment of the method described in the present invention.

The container (1), optionally inserted into the support cylinder (7) and closed with a nozzle cover (8), is subjected to ionization (a) using an ionizer (2) of any type, for example with a ring, rod, gun, curtain, knife, cylinder, needle or a nozzle or an ionizing filter, including isolators with an ionizer at the top or any other type of ionizer. This ionizer may or may not be used in conjunction with a stream of sterile carrier gas, such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although it is more preferable to use a stream of nitrogen carrying ionized air molecules. The ionizer (2) is used to remove electrostatic charge from the container both on the internal walls and in the closure area. In addition, the nitrogen flow, carrying the ionized air molecules used, reaches both the inside of the container and the closure area; through these two ionization processes, the electrostatic charge is removed from the container so that it can be filled.

After this ionization phase (a), the container (1) passes to the aseptic filling station (b), where it is aseptically filled with solids. This process requires the use of a hopper (3) containing the solid to be dosed and a dosing needle or nozzle (4) through which the solid is dosed. To accurately measure the amount of solids being dosed, a mass sensor (5) is also required. This station may or may not have a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably using nitrogen carrying ionized air molecules to provide ion transport. There are as many filling stations as the number of drugs or combinations thereof will be dosed.

After the container (1) is filled with solid substance at the filling station (b), to ensure the cleanliness of the capping area, the third stage is carried out, which is the ionization process (c), which uses an ionizer (2), with a ring, a rod, gun, curtain, knife, cylinder, needle or nozzle, or ionizing filter, including insulators with an ionizer in the upper part. This ionizer may or may not act in conjunction with a stream of sterile carrier gas, such as nitrogen carrying ionized air molecules, or compressed air, to prevent the solid from adhering to the walls of the container in the closure area. It is preferable for the nitrogen stream carrying ionized air molecules to serve as a means of displacing the ions and as a transport means in a displacement effect, thus achieving the desired closure at this station. The number of ionization stations will vary depending on the needs of each drug.

Finally, the container (1) passes to the capping station (d), where it is closed with a stopper (6). This step uses an ionizer (2) with ring, rod, gun, shutter, knife, cylinder, needle or nozzle, or an ionization filter, including isolators with an ionizer on top, which may or may not operate in conjunction with a stream of sterile carrier gas , such as nitrogen, preferably carrying molecules of ionized air, since although there is no solid matter in the sealing zone, it is necessary to ensure that the container is completely clean and that none of the dosage

- 12 044455 solids do not adhere to the stopper used for closure and to the walls of the container due to electrostatic charges created by friction when the container is placed in the closure device.

In fig. 5 shows another particular embodiment of the method described in the present invention.

The container (1), closed by the nozzle cover (8) and optionally inserted into the support cylinder (7), is subjected to an ionization process (a) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter, including isolators with an ionizer at the top, which may or may not employ a stream of sterile carrier gas such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, but more preferably nitrogen carrying ionized air molecules air. The ionizer (2) is used to remove electrostatic charge from the container both on the internal walls and in the closure area. In addition, the nitrogen flow, carrying the ionized air molecules used, reaches both the inside of the container and the closure area; through these two ionization processes, the electrostatic charge is removed from the container so that it can be filled.

After this ionization process (a), the container (1) passes to an aseptic filling station (b), where it is aseptically filled with solids. This station requires the use of several elements, such as: a hopper (3) in which the solid to be dosed is located, a dosing needle or nozzle (4) responsible for dosing the solid, and a mass sensor (5) to control the exact amount of solid being dosed . This station may or may not have a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably using nitrogen carrying ionized air molecules to provide ion transport. This ensures that the dosed solid does not remain in the capping area. There are as many filling stations as the number of drugs or combinations thereof will be dosed.

After this filling stage (b), the container is subjected to an ionization stage (c), in which an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including insulators with an ionizer at the top, may or may not be used with a sterile carrier gas stream such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although it is preferable to use a nitrogen stream carrying ionized air molecules.

Finally, the container (1) passes to the capping station (d), where it is closed with a stopper (6). This stage also uses an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including isolators with an ionizer at the top, which may or may not act in conjunction with the sterile gas flow - carrier such as nitrogen, preferably carrying molecules of ionized air, since although there is no solid matter in the capping area, it is necessary to ensure that the container is completely clean and that none of the dispensed solids is stuck to the stopper used for capping and to the walls of the container due to electrostatic charges created by friction when a container is placed into a closure.

In fig. Figure 6 shows three stages.

After the filling stage, the container (1) undergoes an ionization stage (a), in which the ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionization filter, including insulators with an ionizer in the upper part, can may or may not be used with a sterile carrier gas stream such as nitrogen carrying ionized air molecules or compressed air carrying ionized air molecules, although it is preferable to use a nitrogen stream carrying ionized air molecules. The ionizer (2) is used to remove electrostatic charge from the container both on the internal walls and in the closure area. In addition, the nitrogen flow, carrying the ionized air molecules used, reaches both the inside of the container and the closure area; through these two ionization processes, the electrostatic charge is removed from the container so that it can be filled.

After this ionization process (a), the container (1) passes to an aseptic filling station (b), where it is aseptically filled with solids. This process requires the use of a hopper (3) containing the solid to be dosed and a dosing needle or nozzle (4) through which the solid is dosed. To accurately measure the amount of solids being dosed, a mass sensor (5) is also required. This station may or may not have a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably using nitrogen carrying ionized air molecules to provide ion transport. There are as many filling stations as the number of drugs or combinations thereof will be dosed.

Finally, the container (1) goes to the ionization station. At this stage, an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle is used, or an ionization filter, including insulators with an ionizer at the top, which may or may not be effective

- 13 044455 flow together with a stream of sterile carrier gas such as nitrogen, preferably carrying molecules of ionized air, since although there is no solid matter in the capping area, it is necessary to ensure that the container is completely clean and that none of the dispensed solids is stuck to the stopper and to the walls of the container due to electrostatic charges created by friction when the container is placed in the closure device.

In fig. 7 shows a particular embodiment of the method described in the present invention.

The container (1), already closed with a stopper (6) and optionally inserted into the cylinder (7), is ionized in the ionization stage (a) using an ionizer (2) with a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or an ionizing filter, including isolators with an ionizer in the upper part. This station may or may not have a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably using nitrogen carrying ionized air molecules to provide ion transport.

The container is then placed into an aseptic filling station (b) where it is aseptically filled with the desired solid using a nozzle. This station requires the use of several elements, such as: a hopper (3) in which the solid to be dosed is located, a dosing needle or nozzles (4) responsible for dosing the solid, and a mass sensor (5) to control the exact amount of solid being dosed . This station may or may not have a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules, preferably using nitrogen carrying ionized air molecules to provide ion transport. This ensures that the dosed solid does not remain in the capping area. There are as many filling stations as the number of drugs or combinations thereof will be dosed.

After the container (1) is filled with solid substance at the filling station (b), to ensure the cleanliness of the capping area, the last stage is carried out, which is the ionization process (c), which uses an ionizer (2), with a ring, a rod, gun, curtain, knife, cylinder, needle or nozzle, or ionizing filter, including insulators with an ionizer in the upper part. This ionizer may or may not operate adjacent to a stream of sterile carrier gas such as nitrogen carrying ionized air molecules or compressed air to prevent the solid from adhering to the walls of the container in the closure area. It is preferable for the nitrogen stream carrying ionized air molecules to serve as a means of displacing the ions and as a transport means in a displacement effect, thus achieving the desired closure at this station. The number of ionization stations will vary depending on the needs of each drug.

In the preferred embodiments shown in the figure, the additional step of ionizing the container may be performed after filling with the solid and immediately prior to closure with the stopper. Preferably, ionization should also be performed when the container is empty, before it is filled with solid, and more preferably, each filling and capping station should include ionizers to ionize both the container and the solid, thereby preventing the latter from sticking to the internal walls and ensuring the cleanliness of the container. These ionizers can be of any type, in the form of a ring, rod, gun, curtain, knife, cylinder, needle or nozzle, or even an ionizing filter, which may also include insulators with an ionizer at the top. To facilitate dosing, a stream of sterile carrier gas such as compressed air or nitrogen carrying ionized air molecules may be used as it provides transport to displace ions, create an inert atmosphere, and displace the carrier. This nitrogen stream, carrying ionized air molecules, is used in ionization stations together with an ionizer. It is preferably used at all stations during the aseptic filling and capping process.

Examples

The following specific examples serve to illustrate the nature of the present invention. These examples are provided for illustration purposes only and do not limit the claimed invention.

In these examples, the containers used are cartridges or carpules, syringes with a needle or with a catheter cone, a Luer cone or a Luer lock cone; with internal or external tip and Eppendorf® tubes, biocompatible polymers such as PLGA (lactic or glycolic acid) and PLA (poly(lactic acid)) as fillers, as well as risperidone and letrozole respectively as active ingredients.

Example 1: Filling a 50 mg dose of risperidone into an external or internal tip syringe

In this example, it is necessary to fill a pharmaceutical container with two products, in particular a glass syringe with a male threaded tip, which is previously closed with a cap (8). The products being filled are the excipient polylactic acid (PLA) and the active ingredient letrozole, dose 50 mg. It should be noted that the filling process takes place inside an aseptic isolator with rigid walls. All equipment must be clean and sterile before starting the filling process. To do this, the equipment is first sterilized with sprayed or evaporated hydrogen peroxide or a mixture of hydrogen peroxide and peracetic acid.

- 14 044455

The isolator consists of two main parts: (i) the transfer chamber (TC), which is a chamber that facilitates the loading of sterile materials into and unloading from the working chamber of the isolator, since all materials and instruments loaded into the sterile isolator must be previously sterilized; and (ii) a working chamber (MC), which contains equipment for filling the excipient and active ingredient, as well as a syringe capping unit.

To begin filling, take sterile external syringes (1) and caps (6), and deliver said caps to the operator at the capping or capping station (d) to be inserted into the capping machine. There are as many filling stations as the number of drugs or combinations thereof will be dosed.

Both polylactic acid, used as an excipient, and letrozole, used as an active ingredient, are delivered to filling station operators (b), who load them into their respective bins (3). Externally mounted syringes (1) that will be used for filling are subjected to an ionization process from the back or from the cuff using a needle ionizer (2). Thus, syringes with external fastening (1) are ionized (a) to eliminate the electrostatic charge inside them and in the sealing area of the syringe body. The externally attached syringe (1) is then placed upside down inside the barrel (7).

The cylinder (7), containing the ionized syringe (1), is sent to the filling station (b) to be filled with polylactic acid. A syringe with an external mount (1) is placed on the mass sensor (5), resetting its mass to zero. After this, 90 mg ± 30% polylactic acid is poured into a syringe with an external attachment (1) from the end with a rim. Filling is carried out using a dosing needle or nozzle (4) made of non-conductive material. The externally attached syringe (1) is constantly weighed during filling, so that the system can be controlled to stop filling once the desired weight has been precisely reached, in this case 90 mg±30%.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 1075 V.

After filling the excipient (PLA) at station (b), the externally attached syringe (1) is subjected to an ionization process (c) using a ring ionizer located on the outside of the syringe to facilitate closure by preventing the PLA from sticking to the walls of the syringe (1 ). During this process, the presence of a stream of nitrogen or a sterile carrier gas with ionized air molecules is necessary to displace the ions and act as a carrier for removal.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 775 V.

After excipient filling and ionization, the cylinder (7) with an externally attached syringe (1) filled with PLA is placed in the filling station (b) and filled with 50 mg ± 30% letrozole. The barrel with the externally mounted syringe (1) is placed on the mass sensor (5), where its mass is reset to zero before being filled with the active product. The externally mounted syringe (1) is constantly weighed during filling and filling can be stopped once the required weight has been precisely reached.

After this process of filling the external syringe (1), it is subjected to another ionization process (c) using a ring ionizer (2) to prevent the penetration of both the excipient and the active ingredient with which the external syringe (1) was filled from - for sticking to the walls of the syringe (1). During this process, the presence of a stream of nitrogen or a sterile carrier gas with ionized air molecules is necessary to displace the ions and act as a carrier for powder removal.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 645 V.

After filling with the active ingredient and subsequent ionization, the cylinder (7) with an externally attached syringe (1) passes to the capping station (d), where the stopper (6) is inserted. During this process, the presence of a stream of nitrogen or a sterile carrier gas with ionized air molecules is necessary to displace the ions and act as a carrier.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 375 V.

This achieves the desired closure and keeps the closure area inside the syringe body at the far end from the syringe nozzle clean. It also prevents both PLA and letrozole from sticking to the stopper (6) used for capping and to the walls of the container due to electrostatic charges created by friction generated when the container is placed in the capping machine.

Once the external locking syringe is filled and sealed, it can be placed on the tray with the remaining filled and sealed syringes. Syringe with internal fastening made of plastic.

In this second example, PLA is also used as an excipient and letrozole as the active ingredient for a dose of 400 mg, and the filling process also takes place inside the asep

- 15 044455 tic insulator with rigid walls in the same way as in example 1.

Both PLA, used as an excipient, and letrozole, used as an active ingredient, are delivered to operators at the filling station (b), who load them into their respective hoppers (3), in which case the hoppers are not made of insulating material. Internally mounted syringes (1), previously capped (8), to be used for filling, are positioned under a stream of nitrogen or sterile carrier gas carrying ionized air molecules; a needle ionizer (2) is added to this process so that the internal syringes are ionized (a) to eliminate electrostatic charge inside them and in the closure area.

The cylinder (7), containing an ionized syringe with an internal attachment (1), is sent to the filling station (b) to be filled with polylactic acid. The syringe with internal fastening (1) is placed on the mass sensor (5), resetting its weight to zero. After this, the syringe (1) is filled from the back of the syringe or from the rim side with 500 mg ± 30% PLA, this filling is carried out using a nozzle (4) or a dosing needle made of non-insulating material. The syringe (1) is constantly weighed during filling, so that the system can be controlled to stop filling once the desired weight has been precisely reached, in this case 500 mg ± 30%. During this process, the presence of a stream of nitrogen or a sterile carrier gas with ionized air molecules is necessary to displace the ions and act as a carrier for removal.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 1770 V.

The cylinder (7) with the internal syringe (1) filled with PLA is then subjected to an ionization process (c) before being filled at a second station (b) with the active ingredient letrozole. For ionization, a ring ionizer (2) is used to ionize the PLA adhering to the walls in the syringe closure area (1). A stream of nitrogen or sterile carrier gas carrying ionized air molecules is also used as an ion displacement carrier and as a displacement carrier, thus achieving the desired closure in this ionization process.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 975 V.

After ionization, the cylinder (7) with an externally attached syringe (1) filled with PLA is placed in the filling station (b) and filled with 400 mg ± 30% of the active component letrozole. The barrel (7) with the internally mounted syringe (1) is placed on the mass sensor (5), where its mass is reset to zero before filling with the active product, after which filling with letrozole begins. The syringe (1) is constantly weighed during filling and filling can be stopped once the desired weight has been precisely reached.

It is then transferred to an ionization station (c), which uses a ring ionizer (2) to prevent both the excipient and the active substance from sticking to the walls.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 895 V, since both the dosing needle and the hopper are not insulating materials.

After filling with the active ingredient and subsequent ionization, the cylinder (7) with a syringe with internal fastening (1) (d) is filled with the active component and the plug (6) is inserted into it. During this process, the presence of a stream of nitrogen or a sterile carrier gas with ionized air molecules is necessary to displace the ions and act as a carrier for the powder. This achieves the desired closure and ensures that the closure area inside the syringe body is cleaned, leaving a clean area into which the stopper is inserted. It also prevents both PLA and letrozole from sticking to the stopper (6) used for capping and to the walls of the container due to electrostatic charges created by the friction generated when the container is placed in the capping machine.

At this point, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 495 V.

Once the syringe filling and capping process is complete, the syringe can be placed on the tray with the other filled and capped syringes.

Example 3: Filling 50 mg letrozole into Eppendorf® tubes

In this example, PLA is also used as an excipient and letrozole is used as an active ingredient for a 50 mg dose. It should be noted that the filling process takes place inside an aseptic isolator with rigid walls in the same way as in the previous examples.

Both polylactic acid, used as an excipient, and letrozole, used as an active ingredient, are delivered to filling station operators (b), who load them into their respective bins (3). The Eppendorf® tubes (1) to be used for filling are placed under a stream of nitrogen or sterile carrier gas carrying ionized air molecules; a needle ionizer (2) is added to this process, so that the Ep

- 16 044455 pendorf® (1) are ionized to eliminate electrostatic charge inside them and in the closure area.

At this point, the electrostatic charge inside the inner walls of the container (1) is measured, and the resulting value is 695 V, since the tubes are made of insulating material and the dimensions of the tubes are significantly different from the dimensions of the syringes, they are wider and shorter than the syringes in examples 1 and 2.

An ionized Eppendorf® tube (1) is sent to a filling station containing 50 mg ± 30% letrozole. The Eppendorf® tube (1) is placed on the weight sensor (5) and its weight is reset to zero. The Eppendorf® tube (1) is then filled with the active ingredient using a nozzle (4) made of insulating material. The Eppendorf® tube (1) is continuously weighed during filling, so that the system can be controlled to stop filling once the desired weight has been precisely reached. When filling with letrozole, an ionization filter (2) must be used to prevent it from sticking to the walls in the capping area.

After the filling step (b), the Eppendorf® tube (1) is again subjected to an ionization process (c) using an ionizer rod (2), which ensures that no active component is present on the walls of the container (1).

The electrostatic charge inside the inner walls of the container (1) is again measured and the resulting value is 700 V.

Once filled with the active ingredient, the Eppendorf® tube (1) filled with letrozole is placed in a second filling station (b), this time 90 mg ± 30% PLA excipient. The Eppendorf® tube (1) is placed on the mass sensor (5), where its mass is reset to zero before being filled with excipient, after which the filling of PLA begins. The Eppendorf® tube (1) is continuously weighed during filling and filling can be stopped once the desired weight has been precisely reached. During this process, an ionization filter (2) must be used to prevent letrozole and PLA from sticking to the sealing area.

After this filling process of the Eppendorf® tube (1), it undergoes a further ionization process (c) using a rod ionizer (2), which prevents both the excipient and the active component with which the Eppendorf® tube (1) is filled from sticking to the walls test tubes (1). During this process, the presence of a stream of nitrogen or a sterile carrier gas with ionized air molecules is necessary to displace the ions and act as a carrier. These two means ensure that the electrostatic charge on the inside of the container walls (1) is approximately 595 V, thus achieving the desired closure and keeping the closure area clean, while also preventing both PLA and Letrozole from sticking to the stopper (6), used for capping, and to the walls of the container due to electrostatic charges created by friction when the container is placed in the capping machine.

Example 4 Filling a 75 mg dose of risperidone into a syringe with a needle or a syringe with a plastic needle

In this example, PLGA is used as the excipient and risperidone is used as the active ingredient for a 75 mg dose. The filling process also occurs within an aseptic rigid-walled isolator using the same material sterilization operation as in the previous examples.

The syringes with the needle (1) that will be used for filling are closed with the nozzle cap (8) and subjected to ionization using the needle ionizer (2), thereby ionizing the syringes (1) to eliminate electrostatic charge inside them and in the area capping. The cylinder (7) containing the syringe with the ionized needle (1) is in this case made of insulating material. The syringe (1) is placed on the weight sensor (5), taring its mass to zero. After this, the externally attached syringe (1) is filled with 75 mg ± 30% PLGA using a nozzle (4) made of insulating material. The syringe (1) is constantly weighed during filling, so that the system can be controlled and the filling stopped once the desired weight has been precisely reached, in this case 75 mg ± 30%.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 775 V.

After filling the syringe with the needle (1) with the excipient, it is subjected to an ionization process (c) using a ring ionizer (2), which prevents the PLGA from sticking to the walls in the closure area (1).

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 550 V.

After filling with the excipient and subsequent ionization, the cylinder (7) with the syringe (1) filled with PLGA is placed at the next filling station (b) with the active component risperidone. The cylinder (7) with the syringe (1) is placed on the mass sensor (5), where its mass is reset to zero before filling with the active product, after which filling with risperidone begins. The syringe (1) is constantly weighed during filling and filling can be stopped once the desired weight has been precisely reached.

After filling with the active ingredient, the cylinder (7) with a syringe with a needle (1) is again subjected to

- 17 044455 ionization process, in which, using a ring ionizer (2), sticking of both the active component and the excipient to the walls in the closure area of the syringe (1) is prevented. After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 470 V.

After this ionization process, the syringe with external fastening (1) passes to the capping station (d), where the stopper (6) is installed and subjected to further ionization. This process requires an ionizer rod (2) to ionize the PLGA and risperidone, which adhere to the walls in the closure area.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting measurement is 199 V.

The ionization process ensures optimal closure and complete cleanliness of the closure area, and also prevents PLGA and risperidone from sticking to the stopper (6) used for closure and to the walls of the container due to electrostatic charges created by friction generated when the container is placed in the capping machine.

Example 5 Filling a 100 mg dose of risperidone into a syringe with an internal nozzle or into a syringe with an internal plastic attachment

In this example, PLGA is used as the excipient and risperidone is used as the active ingredient for a 100 mg dose. The filling process also occurs within an aseptic rigid-walled isolator using the same material sterilization operation as in the previous examples.

Internally mounted syringes (1) that will be used for filling are closed with a nozzle cap (8) and subjected to ionization using a needle ionizer (2), thereby ionizing (a) the syringes (1) to eliminate electrostatic charge inside them and in capping area. The cylinder (7) containing the ionized syringe (1) is in this case made of insulating material. The syringe (1) is placed on the weight sensor (5), taring its mass to zero. After this, the syringe (1) is filled with 100 mg±30% PLGA using a nozzle (4) made of insulating material. The syringe (1) is constantly weighed during filling, so that the system can be controlled to stop filling once the desired weight has been precisely reached, in this case 100 mg±30%.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 785 V.

After filling the internal syringe (1) with the excipient, it is subjected to an ionization process (c) using a needle ionizer (2), which prevents the PLGA from sticking to the walls in the closure area (1).

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 580 V.

After filling with the excipient and subsequent ionization, the cylinder (7) with the syringe (1) filled with PLGA is placed at the next filling station (b) with the active component risperidone. The cylinder (7) with the syringe (1) is placed on the mass sensor (5), where its mass is reset to zero before filling with the active product, after which filling with risperidone begins. The syringe (1) is constantly weighed during filling and filling can be stopped once the desired weight has been precisely reached.

After filling with the active ingredient, the cylinder (7) with the syringe (1) is again subjected to an ionization process, in which, using a needle ionizer (2), sticking of both the active component and the excipient to the walls in the closure area of the syringe (1) is prevented. After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 440 V.

After this ionization process, the syringe (1) passes to the capping station (d), where the stopper (6) is installed and subjected to further ionization. This process requires an ionizer rod (2) to ionize the PLGA and risperidone, which adhere to the walls in the closure area. After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 197 V.

The ionization process ensures optimal closure and complete cleanliness of the closure area, and also prevents PLGA and risperidone from sticking to the stopper (6) used for closure and to the walls of the container due to electrostatic charges created by friction generated when the container is placed in the capping machine.

Example 6: Filling 75 mg risperidone into cartridges or carpules

In another example, PLGA is used as an excipient and risperidone is used as an active ingredient for a 75 mg dose. The filling process also occurs within an aseptic rigid-walled isolator using the same material sterilization operation as in the previous examples.

Both PLGA, used as an excipient, and risperidone, used as

- 18 044455 containing the active ingredient, as well as cartridges are delivered to operators at the filling station (b), and loaded into the appropriate bins (3). The cartridges or carpules (1) used for filling are placed under a stream of nitrogen or sterile carrier gas carrying ionized air molecules, a needle ionizer (2) is added to this process, and the cartridges or carpules (1) are ionized to eliminate the electrostatic charge within them .

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 1285 V.

The ionized cartridge or carpule (1) is sent to the filling station (b) to fill with 75 mg ± 30% risperidone. The cartridge (1) is placed face up on the mass sensor (5), resetting its mass to zero. The cartridge (1) is then filled with risperidone through a nozzle using a tip (4) or a dosing needle made of insulating material. The cartridge (1) is constantly weighed during filling, so that the system can be controlled and filling stopped when the required weight has been precisely reached.

After filling the cartridge (1) with the active ingredient, it is placed in a second filling station (b), this time to fill 100 mg ± 30% of the PLGA excipient. The cartridge (1) is placed on the mass sensor (5), where its mass is reset to zero before being filled with this active ingredient, after which the filling of the PLGA also starts from the nozzle. The cartridge (1) is constantly weighed during filling and filling can be stopped once the required weight has been precisely reached.

Once filled with excipient, the PLGA cartridge (1) is further ionized using an ionizer rod (2) and a stream of nitrogen or sterile carrier gas carrying ionized air molecules to displace the ions and used as a carrier to introduce the cartridge nozzle cap. These two processes prevent both the excipient and the active ingredient from sticking to the walls, thus achieving a sealing effect.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 1085 V.

Example 7: Filling a pre-capped internal syringe with 400 mg of risperidone

In this example, PLGA is used as the excipient and risperidone is used as the active ingredient for a 400 mg dose. The filling process also occurs within an aseptic rigid-walled isolator using the same material sterilization operation as in the previous examples.

The internal syringes (1) used for filling are subjected to an ionization process using a ring ionizer (2), so that the syringes (1) are ionized (a) to eliminate electrostatic charge inside them and in the closure area. The cylinder (7) containing the ionized syringe (1) is in this case made of insulating material. The syringe (1) is placed upside down on the mass sensor (5) as it is pre-closed by the plug (6), resetting its mass to zero. After this, the syringe (1) is filled through the nozzle with 100 mg ± 30% PLGA using a nozzle (4) made of insulating material. The syringe (1) is constantly weighed during filling, so that the system can be controlled to stop filling once the desired weight has been precisely reached, in this case 100 mg±30%.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 735 volts.

After filling the internal syringe (1) with the excipient, it undergoes an ionization process (c) using an ionizer rod (2), which prevents the PLGA from sticking to the walls of the container (1) near the nozzle.

After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 530 V.

After filling with the excipient and subsequent ionization, the cylinder (7) with the syringe (1) filled with PLGA is placed at the next filling station (b) with the active component risperidone. The cylinder (7) with the syringe (1) is placed on the mass sensor (5), where its mass is reset to zero before filling with the active product, after which filling with risperidone begins. The syringe (1) is constantly weighed during filling and filling can be stopped once the desired weight has been precisely reached.

After filling the syringe barrel (1) with the active ingredient, it is again subjected to an ionization process, in which the ionizer rod (2) prevents both the active ingredient and the excipient from sticking to the walls of the syringe (1). After this process, the electrostatic charge inside the inner walls of the container (1) is measured and the resulting value is 215 V.

The ionization process ensures optimal sealing and the required precise dosage.

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Claims (36)

CLAIM 1. A method of filling pharmaceutical containers (1) with at least one solid substance and sealing them under sterile conditions, comprising the following steps: a) ensure the presence of a pharmaceutical container (1) with walls and a bottom; b) dispensing the solid into the pharmaceutical container (1) using a dosing needle (4), gravimetrically checking the mass of the solid distributed into the container (1); and c) the pharmaceutical container is sealed with a stopper (6), characterized in that at least one of stages a), b) and c) or several of them in any combination, there are static electric charges on the inner walls of the container (1), on solid dispensed into the container and/or any parts in contact with the walls of the container or with the solid dispensed into the container are neutralized using an ionizer (2) to which an ionization potential is applied so that the electrostatic charge inside the container (1 ) after each ionization was less than 2000 V. 2. The method according to claim 1, in which between step b) and step c) additional ionization with a static electric charge is carried out inside the pharmaceutical container (1). 3. Method according to claim 1 or 2, in which in step a) the ionization is carried out with the pharmaceutical container (1) empty. 4. Method according to any one of claims 1-3, in which the ionizer(s) (2) is located outside or inside the pharmaceutical container (1) in any combination. 5. Method according to any one of claims 1-4, characterized in that in step c) ionization is carried out before and/or during capping. 6. Method according to any one of claims 1-5, characterized in that static electric charges are less than 1000 V. 7. Method according to any one of claims 1-6, characterized in that static electric charges are less than 500 V. 8. Method according to any one of claims 1-7, characterized in that static electric charges are less than 200 V. 9. Method according to any one of claims 1 to 8, in which step b) is carried out with vibration of the dosing needle (4), which promotes uniform dosing of the solid substance. 10. Method according to any one of claims 1-9, in which step b) is repeated several times. 11. Method according to any one of claims 1 to 10, in which in step b) the tip of the dosing needle (4) is located at a height h of 1 to 3 mm above the surface of the solid substance at the bottom of the container (1). 12. Method according to any one of claims 1 to 11, characterized in that in step b) the container (1) is in a fixed position throughout the entire filling phase, while the dosing needle (4) is a movable element that moves upward during the filling phase, maintaining a distance h between the end of the dosing needle and the surface of the solid deposited at the bottom of the container (1). 13. Method according to any one of claims 1 to 11, characterized in that in step b) the dosing needle (4) is in a fixed position throughout the entire filling phase, while the container (1) is a movable element that moves downward as filling occurs, the step being carried out to maintain a distance h between the end of the dispensing needle and the surface of the solid deposited at the bottom of the container (1). 14. Method according to any one of claims 1 to 11, characterized in that in step b) both the dosing needle (4) and the container (1) are movable elements that move synchronously relative to each other during the filling stage in order to maintain the distance h between the end of the dosing needle (4) and the surface of the solid deposited at the bottom of the container (1). 15. Method according to any one of claims 1 to 14, characterized in that in step b) the container (1) is filled from the side of the container farthest in relation to the rim, if the container is a syringe or a cartridge. 16. Method according to any one of claims 1 to 14, characterized in that in step b) the container (1) is filled from the side of the container farthest in relation to the nozzle, if the container is a syringe or cartridge. 17. Method according to any one of claims 1 to 15, in which step c) is carried out in a vacuum. 18. Method according to any one of claims 1 to 16, characterized in that at least one of steps a), b) and c) or any combination thereof, either a stream of sterile carrier gas is supplied inside the pharmaceutical container (1), such as N2, or sterile compressed air. 19. The method according to any one of claims 1 to 18, in which the ionizer (2) can be with a ring, a rod, a gun, a curtain, a knife, a cylinder, a needle or a nozzle, or an ionizing filter, including insulators with an ionizer in the upper part. 20. Method according to any one of claims 1 to 19, in which the dosing needle (4) dispenses a solid substance, with - 20 044455 held in the hopper (c), and both the hopper (c) and the dosing needle (4) are made of non-conductive material. 21. The method according to any one of claims 1 to 20, wherein the pharmaceutical container (1) is inserted into a cylinder of electrically conductive material which is grounded to help dissipate the static charge of the pharmaceutical container. 22. The method according to any one of claims 1 to 20, wherein the pharmaceutical container (1) is inserted into a cylinder of electrically non-conductive material to help dissipate the static charge of the pharmaceutical container. 23. Method according to any one of claims 1 to 22, wherein the pharmaceutical container (1) is made of an electrically non-conductive material. 24. The method according to any one of claims 1 to 23, in which the pharmaceutical container (1) is an internal syringe, an external syringe, a syringe with a needle, a bottle, a capsule, an ampoule, a dispenser, a cartridge, an inhaler, container, blister, sachet, pouch, tube or Eppendorf® tube. 25. Method according to any one of claims 1 to 24, wherein the pharmaceutical container (1) is made of glass, metal such as steel or titanium suitable for drug delivery, or plastics. 26. The method according to claim 25, characterized in that the plastic materials can be made of polyolefin, cyclopolyolefin, polypropylene, polybutadiene, polyethylene, polyetheretherketone, polystyrene, polyvinyl chloride, polyacrylonitrile, polyamides, polyesters such as polymers (ethylene terephthalate, polycarbonate), such as poly(methyl methacrylate), polyacrylonitrile, thermoplastic resins such as polyacetals and polyhaloethylenes, polyurethanes, formaldehyde resins such as phenolic resin and urea resin, phenolic resins, aminoplasts, thioplastics, duroplastic resins such as unsaturated polyether cellulose derivatives, polyurethane polyesters polycarbonates and them combinations. 27. Method according to any one of claims 1 to 26, in which the pharmaceutical container (1) has a diameter of from 9 to 80 mm. 28. Method according to any one of claims 1 to 27, wherein the dispensing needle (4) is provided with a locking member to prevent powder from being dispensed above the level of the dispensing tip or the end of the dispensing needle during filling. 29. Method according to any one of claims 1 to 28, in which the solid product to be dosed into the container (1) has the following particle size distribution: no more than 10% of the total volume of particles less than or equal to 20 µm, no more than 10% of the total volume of solid particles greater than or equal to 230 µm or less than or equal to 140 µm, d0.5 value in the range of 60-180 µm, where d0.5 denotes the average particle size value at which the population is divided into exactly two equal halves, with 50% above this value and 50% below it. 30. Method according to any one of claims 1 to 28, in which the solid product to be dosed into the container (1) has the following particle size distribution: no more than 10% of the total volume of particles less than or equal to 20 µm, no more than 10% of the total volume of solid particles greater than or equal to 325 µm or less than or equal to 245 µm, d0.5 value in the range of 100-155 µm. 31. Method according to any one of claims 1 to 30, characterized in that the solid product intended for dosing into container (1) is selected from the group consisting of risperidone, paliperidone, fentanyl, olanzapine, letrozole, aripiprazole, anastrozole, asenapine, brexprazole, cariprazine, clozapine, iloperidone, lurasidone, quetiapine, ziprasidone, including any derivatives, metabolites or salts thereof, alone or in combination. 32. Method according to any one of claims 1 to 31, characterized in that the solid product which is dosed into the container (1) is selected from the group consisting of biocompatible polymers such as polylactic acid (PLA), polyglycolic acid (PGA) and a copolymer thereof polylactic and glycolic acids (PLGA), including any derivatives or copolymers, alone or in combinations. 33. The method according to any one of claims 1 to 32, characterized in that it is carried out in an aseptic environment in an area with unidirectional air flow. 34. The method according to any one of claims 1 to 33, characterized in that it is carried out in an isolator. 35. The method according to any one of claims 1-34, characterized in that before step b) the insulator is sterilized with sprayed or evaporated hydrogen peroxide or a mixture of hydrogen peroxide and peracetic acid. 36. The method according to any one of claims 1 to 35, which is implemented in software executable on a computer. -