Two-chamber cartridge for aerosol dispensers without any propellant gas

The present invention relates to a propellant dispenser cartridge free of propellant gas, used in particular for liquid drug preparations.

In international patent application WO 9114468 a device for applying without propellant gas dosing amounts of liquid drug for inhalation is presented.

A device for generating high pressure in a fluid to be sprayed is also known from the international patent application WO 9712687. For the proper operation of such a device, it is necessary to fill the container with solutions containing the active substance so that it contains a small amount of air or gas. The content of air bubbles in the container has a negative effect on the dosing accuracy of the active substance.

Also known from international patent application WO 9606011 is a container with a closing lid, which when closing ejects part of its contents. Such a container is particularly suitable for drugs that exhibit high stability during storage in the form of an aqueous or ethanolic solution.

The cartridge for the aerosol dispenser devoid of propellant gas is composed of a container for filling with liquid, with a closing lid, which at its lower edge has an internal peripheral bead mounted in a closed position under a cylindrical ring extending circumferentially on the outside of the neck of the container. In addition, the closing lid is equipped with a displacement connector. The solution is characterized in that the displacement nozzle comprises at least one chamber closed relative to the external environment and relative to the interior of the container with two piercing partitions.

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It is preferred that the chamber contains the drug and the solvent is placed in the container. The active substance for inhalation administration can also be placed in the chamber, the active substance being in the form of a tablet. From the outside, the chamber has an integral partition, and from the inside of the container it has a partition in the form of a welded foil. At its places of connection with the stub pipe, the chamber has weaknesses. A mini-tablet with a hardness of 2-10 N / mm is placed in the chamber² containing the active substance for inhalation administration and preferably pharmacologically acceptable excipients. The mini-tablet has a diameter of 2-3 mm and a length of 1.0-4.0 mm.

The solution according to the invention makes it possible to use in aerosol dispensers such substances whose solutions have low stability over time. By separately storing the active substance and the solvent, the shelf life of the drug preparation can be significantly extended. The active substance may be present in the chamber as a powder, granules or in the form of a tablet. Pharmacologically compatible excipients may also be used. Usually, such galenical preparations which require simple dissolution of the active substance in a solvent are preferred. In the case of tablets, excipients can be added that make the tablets dissolve better. Excipients that increase the stability of the active substances can also be added. In some cases, the active substance may exist in the chamber in dissolved form if the active substance is stable in the solvent and the solvent is miscible with the solvent in the second chamber also called the container.

The subject of the invention is illustrated in the examples of the drawing, in which Fig. 1 shows an axial section of a cartridge with a chamber for receiving an active substance, the chamber being an integral component of the closing lid, Fig. 2 - embodiment of a closing lid with a closed chamber, Fig. 2a - another embodiment of the closing lid with an additional sleeve, Fig. 3a - embodiment of the closing lid with a guide, Fig. 3b - embodiment of the closing lid with a different guide, Fig. 3c - embodiment of the closing lid with a circular sealing ring, and Fig. 4 - axial section of the closing lid according to the invention, with the chamber containing the active substance in the form of a mini-tablet.

In Fig. 1 a cartridge 1 is shown, with a chamber 2 for receiving an active substance, having a closing lid 3 screwed on to the container 4. The closing lid 3 has an element in the form of a displacement stub 5 entering the interior, which during the closing operation displaces part of the contents from the container. 4 so that the container is filled with virtually no air bubbles. A peripheral bead 6 located at the lower edge of the closing lid 13 jumps in closed position under the cylindrical ring 7 extending circumferentially on the outside of the container neck. In the closed position, the space 9 between the flat part of the closing lid 3 and the upper edge of the container neck is filled by a sealing ring 11. For better sealing, the upper edge of the container neck is provided with a circumferential rib 10. The inner diameter of the sealing ring 11 is deliberately chosen so that it adheres to the displacement stub 5. The vent hole (s) 8 may also be located at other places on the outside of the lid, for example from the side in the cylindrical portion of the lid.

In another embodiment, in Fig. 2a the closing lid 3 is closed by an aluminum sleeve 20 that is crimped. This aluminum sleeve 20 has a central hole 21 for guiding the cannula 22. This hole can be closed by a wall to protect against dust and other contaminants. Such a sealing technique is, for example, known in the case of injectable drug ampoules.

In a particular embodiment, the container 4 comprises a weakened inner container 4a of flexible material. This inner container can in a preferred embodiment be fixed at the bottom of the container _4 by means of a fastening element 12.

A chamber 2 is located in the lower part of the displacement stub 5, which is closed from the outside with a separation, for example in the form of a partition 13, and from the inside 4b of the container is closed by a separation, with a partition 14, e.g. in the form of a film. Partitions 13 and 14

184 445 are made of a material that can be easily pierced by a cannula with a sharp or rounded end. The partition 13 is preferably made of a material that even after piercing the cannula seals the interior 4b. Usually the separations are made of thin plastic or aluminum foils. In one embodiment, the septum 13 may have weak spots at its connection with the side wall of the displacement stub 5, so that when the septum is pierced, these weak spots break. Preferably, the septum 14 is made as a welded diffusion-tight sealing film, which is broken during piercing and the active substance enters the container 4b. The weakening points can also be located in the area of ​​the lower side wall of the displacement stub 5, so that the bottom side wall of the stub is also torn off.

The separation position, associated with the position of the partition 13, can be different within a wide range of the interior of the displacement stub 5, however, it is preferred, depending on the amount of active substance 16, that the interior formed by both partitions 13 and 14 contains as little gas as possible, e.g. air. Figure 2 also shows an axial section of the neck of the container with the closing lid 3 attached, the chamber 2 having a different shape.

Figure 3a shows a further embodiment of the closing lid 3, in which the interior of the displacement stub 5 has a guide 17 for the liquid filling cannula. In the case shown, the vent holes 8 are located in the upper part of the container 4. As described, the vent holes can alternatively also be located at the closing lid 3. The chamber 2 containing the active substance is located separately in the lower part of the displacement stub 5. Instead of piercing septum 14, weakening points 18 may be provided such that the chamber when piercing the separation is torn apart by pressure at septum 14 to the weakening position 18. In this embodiment, the septum 14 can be made as the bottom of the displacement stub 5.

Figures 3b, 3c show other embodiments of the displacement stub 5 and guide 17 for the liquid filling cannula.

Figure 3b shows an embodiment in which the guide 17 passes the interference fit 19. This interference fit is made in terms of diameter and length so that, on the one hand, the resistance to sliding the cannula is small, and on the other hand, a sufficient seal between the connector and the cannula is obtained.

Figure 3c shows an embodiment with a flexible circular sealing ring 15 with a circular cross section between the stub and the inserted cannula, without showing the cannula. Also not shown is the solution that prevents unintentional loosening of the O-ring seal.

As shown in Figs. 3b and 3c, the lower end of the immersion stub with the partition 14 can be preferably bevelled, especially at an angle of 20-60 degrees with respect to the stub axis. This is facilitated by piercing the separation with a blunt cannula whose front surface is perpendicular to the axis of the cannula. The advantages of a blunt cannula compared to a sharply ground cannula are that there is less risk of injury to the user, less processing cost in producing the cannula end face, and less risk of tearing particles at the wall of the connector when inserting the cannula.

As shown in Figure 4, which essentially corresponds to Figure 3a, the chamber 2 contains the active substance in the form of a small tablet. In comparison with the active substance in the form of a powder, the active substance in the form of a mini-tablet according to the invention can be placed much more easily in the chamber 2, and in addition the tablet is advantageous when the septum 13 is pierced with a cannula, where then the mini-tablet 16a is pushed through the septum 14 in the form of foil. Firstly, it is ensured that the relatively hard tablet does not clog the cannula, and secondly, it is ensured that all the active substance passes from the chamber into the container 4. With currently highly effective drugs used in aerosol dispensers , an exactly set active substance solution is absolutely necessary in the sense of drug safety. In addition, when filling chamber 2 with a tablet, the welded surface is not contaminated with dust, as was the case with powder filling.

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The tablet according to the invention has a diameter of 2-3 mm, preferably 2.2-2.3 mm and a length of 1.8-3.5 mm and a compressive strength of 2-10 N / mm². Compressive strength is measured in such a way that the tablets are attached between flat surfaces and the strength is increased until the tablets are crushed. The tablets are attached so that they contact flat surfaces along two mantle lines (not the bottom surface or the top surface). The compressive strength is the force divided by the cross-sectional area (diameter multiplied by the length of the cylindrical tablet).

The tablets of the invention are composed of the active substance and normal excipients used in tablets. Preferred active ingredients are those which can be used at lower dosages, for example up to 100 micrograms of active substance per use. Examples include Atroven, anticholinergics, B-sympathomimetics, e.g. Formoterol. Preferred excipients are lactose (No. 200 sieve), glucose (No. 200 sieve) and shaping release agents.

The container according to the invention has a solvent capacity of 4 ml, so that when using a mini tablet weighing 20 mg, 0.5% active substance solutions can be produced. Preferably water or ethanol or mixtures thereof are used as the solvent. In addition, other physiologically compatible solvents are suitable.

To withdraw liquid from the cartridge 1 according to the invention, the partitions 13 and 14 are pierced by a cannula. Embodiments in which the container 4 has an easily deformable inner container 4a are preferred, and the end of the cannula is located at half the height of the container when liquid is drawn. In this case, air bubbles have the least disturbing effect. Preferably, a mini tablet 16a is used as the storage of active substance.

The container and closing lid are generally made of plastic. Since the filling liquid is practically not compressible, the system consisting of the container and the closing lid must be sufficiently deformable when the liquid expands under the influence of heat. Similarly, when collecting liquid, the walls of the container must be sufficiently flexible or collapse. The partition 14 is usually made of a thin plastic film. Preferably, the baffle 14 is made of thin and coated aluminum, which is welded.

The skilled person has at his disposal suitable plastics, e.g. polyethylene or preferably polypropylene, for the production of such containers as well as the closing lid.

Cartridges of the invention for drug formulations for an inhaler should have a long shelf life. To this end, it is necessary that the solvent cannot diffuse from the inner container 4a before use into the chamber 2, which contains the active substance. Despite the sufficient thickness of the chamber wall 2, an aluminum coating can be additionally applied to its external or internal surfaces. It should be emphasized that the use of the cartridge with the chamber 2 in the inhaler does not require patients to perform more operations than when inserting a regular cartridge.

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FIG. 3c

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FIG. 3b

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FIG. 2a

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FIG.1

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