HK1018420A - Cartridge for propellant-free metered aerosols and closure cap for the container of the cartridge - Google Patents

Description

Cartridge for propellant-free metered aerosols and closure for a cartridge container

The invention relates to a dual chamber cartridge for liquids, in particular for dispensing medicaments for the use of propellant-free metered aerosols.

In international patent application WO 91/14468, "aerosolization apparatus and method" a device is described for delivering a metered dose of a liquid medicament for inhalation in the absence of a propellant. A modified embodiment of the dispensing device is described in International patent application PCT/EP 96/04351. In practice, it must be achieved that the solution containing the active substance is injected into the container with only a small amount of residual air and gas, since bubbles can cause uncertainties in the exact metering of the active substance. These containers are disclosed in International patent application No. PCT/EP 95/03183. They are suitable above all for drugs which can be reliably stored for a long period of time in the form of aqueous or ethanolic solutions.

However, for active substances which decompose in solution after a few months, suitable containers of commercial interest have not been available to date for sensitive dispensing in propellant-free metered aerosols.

The invention therefore relates to a cartridge having two chambers for storing the active substance and the solvent separately. The cartridge is constructed so that when it is inserted into a device for dispensing an aerosol, a needle cannula is used to pierce a chamber containing the active substance, allowing the active substance to contact and dissolve in the solvent. Since the active substance is stored separately from the solvent, the shelf life of the pharmaceutical formulation is significantly prolonged.

The active substance may be present in the chamber in powder, granular or tablet form. And pharmacologically acceptable auxiliary substances can also be stored. Substances formulated according to pharmacopoeia which promote dissolution of the active substance in the solvent are generally preferred. In the case of tablets, auxiliary substances which enable better dissolution of the tablets may be added. Substances which increase the stability of the active substance can likewise be added. In some cases, the active substance may also be present in the dissolved state in a chamber, as long as the active substance is stable in the solvent and the solvent can be mixed with the solvent in another chamber, hereinafter also referred to as container.

The invention will be described in detail below with the aid of an embodiment shown in the drawing, in which:

fig. 1 shows an axial section in the direction of the longitudinal axis of a cartridge 1 according to the invention, which has a chamber 2 for receiving an active substance, while the chamber 2 is an integral part of a closure 3;

fig. 2 shows a further embodiment of the closure 3 with the chamber 2 in the closed state of the cartridge, only the container 4 being indicated;

fig. 3a to 3c show a further embodiment of a closure 3 according to the invention with a chamber 2;

fig. 4 shows a section in the longitudinal direction of a closure according to one embodiment of the invention, in which the chamber 2 contains a microtablet 16a as the active substance to be stored.

Fig. 1 shows that a cartridge 1 according to the invention consists of a container 4 and a closure 3. The closure has a device (here a flush-on nipple 5) by means of which a part of the contents of the container 4 can be discharged during the closing process, so that the container can be filled without the formation of air bubbles. An internal annular flange 6 at the lower edge of the closure 3 latches into a closed position at the lower part of a cylindrical ring 7 around the outside of the neck of the container. In this closed position, the space between the flat portion of the closure 3 and the top rim of the container neck may be filled with a sealing ring 11 to completely close the interior of the container 3, while the top rim of the container neck is provided with an annular rib 10 to enhance the seal. The inner diameter of the sealing ring 11 is selected so that it fits tightly over the adapter 5. The vent hole 8 may be provided elsewhere outside the closure, for example on the side of the cylindrical portion of the closure.

In another embodiment (fig. 2a), the cover 3 is closed by an aluminium sleeve 20 made in the form of an accordion. Sleeve 20 is designed to leave a central opening 21 to facilitate insertion of needle cannula 22. The aperture may be closed with a membrane to prevent the ingress of dust and other dirt. This closure technique is well known and has been used, for example, on injection vials.

In a particular embodiment, the container 4 comprises a collapsible inner container 4a made of an elastic material. In a preferred embodiment, the inner container is secured to the bottom of the container 4 by a means.

The chamber 2 is located at the bottom of the connecting piece 5 and is isolated from the outside by a barrier, for example a membrane 13, and from the container interior 4b by a barrier, for example a membrane 14. The septum 13 and membrane 14 are made of a material that is easily pierced by a sharp or round-ended needle cannula. Septum 13 is preferably made of a material that will seal interior 4b from the outside even if it is pierced by a needle cannula. The spacers are usually made of plastic or aluminum film. In one embodiment, the septum 13 may have a frangible point at its junction with the side wall of the nipple 5, enabling it to break at the frangible point when the septum is pierced. The membrane 14 is preferably a fusion-welded impermeable closure membrane that tears open when pierced to allow the active substance to enter the container interior 4 b. The easy-to-tear point can also be arranged on the side wall of the bottom of the connecting pipe 5, so that the bottom of the side wall of the connecting pipe 5 is torn off together.

The position of the partition (diaphragm 13) can vary over a wide range inside the mouthpiece 5, but is preferably set in accordance with the amount of active substance 16 so that the internal space defined by the two partitions 13 and 14 contains as little gas (air) as possible in addition to the powder.

Fig. 2 also shows an axial section through the neck of a container, which is covered by a closure 3, but the chamber 2 is of a different design.

Fig. 3a shows a further embodiment of the closure according to the invention, in which the interior of the flush-type connection is provided with a guide 17 for the needle cannula to withdraw fluid. In this embodiment, the vent 8 is provided at the top of the container 4. As previously mentioned, a vent hole may also be provided in the closure. And the chamber 2 for containing the active material is separately provided at the bottom of the adapter tube 5. The pierceable separator 14 may be replaced by a frangible point 18 so that the chamber is torn at the frangible point 18 by the pressure acting on the separator 14 when the separator 13 is pierced. In this embodiment, the spacer 14 may constitute the bottom of the nipple 5.

Fig. 3b and 3c show the construction of the flush adapter 5 and the guide 17 for the needle cannula for withdrawing fluid in other embodiments.

In one exemplary embodiment, shown in fig. 3b, the guide 17 merges into a crimp 19. The diameter and length of the crimp are designed so that on the one hand the resistance encountered by the needle cannula as it is pushed through is kept to a minimum and on the other hand there is an adequate seal between the adapter and the needle cannula.

The embodiment shown in fig. 3c has an elastic O-ring seal 20 between the adapter and the pierced needle cannula (not shown). Means for preventing accidental removal of the O-ring seal are also not shown.

Fig. 3b and 3c show that the end of the flush fitting with the spacer 14 can be moderately beveled, preferably at an angle of 20 to 60 degrees to the fitting axis. This will facilitate penetration of the spacer by a "blunt" needle cannula, meaning that the end face of the needle cannula is perpendicular to the axis of the needle cannula. "blunt" needles have the advantage over "pointed" needles of reduced risk of injury to the user, reduced cost of manufacturing the end face of the needle cannula, and reduced possibility of even minimal abrasion with the wall of the adapter tube during insertion of the connecting needle cannula.

Figure 4 shows, in much the same way as figure 3a, a chamber 2 containing a micro tablet of active substance. The active substance according to the invention in the form of microtablets is obviously easier to place in the chamber 2 than a powdered active substance, and the advantage of the tablet is that when the septum 13 is pierced by the needle and the tablet 16a subsequently breaks the membrane 14, it is ensured on the one hand that the harder tablet does not block the needle and on the other hand that all the active substance in the chamber is introduced into the container 4. For the highly effective pharmaceutical agents which are used today in metered aerosols, the precise metering of the active substance solution is of crucial importance for safe administration. In addition, the tablet contained in the chamber 2 does not contaminate the cover with dust as does the powder.

The tablets according to the invention have a diameter of between 2 and 3 mm, preferably between 2.2 and 2.3 mm, a length of between 1.8 and 3.5 mm and a compression strength of between 2 and 10N/mm². To measure the compressive strength, the tablet is held between flat surfaces and the pressure is increased until the tablet breaks, and the tablet contacts the flat surfaces along two outer contour lines (rather than top and bottom). Compressive strength is given by the pressure divided by the cross-sectional area (i.e. the diameter times the length of the cylindrical tablet).

Tablets according to the invention consist of an active substance and a tablet-forming auxiliary substance in general. The active substance can advantageously be applied in small doses, for example in amounts of up to 100 mg of active substance per dose. Including atrophin (Atrovent), anticholinergic (anticholinergic), beta-sympathomimetic (beta-sympathomimetic-methika), such as Formoterol. Preferred auxiliary substances are lactose (200 mesh), glucose (200 mesh) and a forming separator.

The container according to the invention has a volume of 4 ml, in which a 0.5% solution of the active substance can be prepared with 20 mg of microtablets. The solvent is preferably water or ethanol or a mixture of the two. Other physiologically acceptable solvents are also suitable.

To extract a medical fluid from a cartridge 1 according to the present invention requires a needle cannula to pierce the spacers 13 and 14. In the preferred embodiment, the container 4 has an easily deformable inner bag 4a, and the tip of the needle cannula is located in the middle of the container when the medical fluid is withdrawn. At this point, the disturbing effect of the bubbles is minimal. Preferably, the microtablets 16a according to the invention are used for storing the active substance.

The container and closure are typically made of plastic. Since the liquid contained is virtually incompressible, the system of container and closure must be able to deform sufficiently when the liquid expands when heated. Also, the container wall must be capable of deforming and collapsing sufficiently therewith when withdrawing the medical fluid. The spacer 14 is typically formed of a plastic film, preferably a closed coated aluminum foil.

The container and closure may be made from a plastic suitable for professional use, such as polyethylene or preferably polypropylene.

Cartridges according to the invention for use in an inhaler for dispensing medicament should be capable of long term storage. For this reason, the solvent in the inner container 4a cannot penetrate into the compartment 2 containing the active substance before use. The chamber may have a sufficiently thick wall and may have an aluminium film applied to its inner and outer surfaces. It should be emphasized that there is no need for more operations than a normal cartridge when loading a cartridge with a chamber 2 into a patient's inhaler.

Claims (15)

1. A cartridge for propellant-free metered aerosols comprising a container (4) with a closure (3) for containing a liquid, an internally disposed annular flange (6) formed at the lower edge of the closure (3) and which latches in a closed position under a ring on the outside of the container (4), and a nipple (5) associated with the closure (3) and which, when the closure (3) is pushed onto the neck of the container (4), is capable of discharging a portion of the contents of the container,

characterized in that the adapter (5) comprises at least one chamber (2), the chamber (2) being closed off from the outside and from the inside of the container (4) by two pierceable barriers (13) and (14).

2. A cartridge according to claim 1, wherein the cartridge is adapted to be inserted into a patient,

characterized in that the chamber (2) contains a medicament.

3. A cartridge according to claim 2, wherein the cartridge is adapted to be inserted into a patient,

it is characterized in that the container (4) is filled with solvent.

4. A cartridge according to any of the preceding claims,

characterized in that said chamber (2) contains an active substance suitable for inhalation.

5. The cartridge according to any one of claims 1 to 3,

characterized in that the active substance is present in the form of a tablet.

6. The cartridge according to any one of claims 1 to 3,

characterized in that the separation of the chamber (2) from the outside is constituted by a diaphragm (13) and the separation from the inner container is constituted by a closing film (14).

7. The cartridge according to any one of claims 1 to 3,

characterized in that the chamber (2) has a frangible point at its connection to the nipple (5), at which the chamber will tear by the pressure acting in the chamber (2) when the septum (13) is pierced.

8. A cartridge according to claim 1, characterised in that said chamber (2) contains an active substance for inhalation and possibly a pharmacologically acceptable auxiliary substance of no concern, said active substance and auxiliary substance being present in the form of microtablets having a hardness of between 2 and 10N/mm²In the meantime.

9. The cartridge of claim 8 wherein said pellets have a diameter of 2 to 3 mm and a length of 1.0 to 4.0 mm.

10. A closure (3) for a container (4) for propellant-free metered aerosols, comprising an internally disposed annular flange (6) formed at the lower edge of the closure (3) and which is latched in a closed position under a ring on the outside of the container (4), and a nipple (5) associated with the closure (3) and which, when the closure (3) is pushed onto the neck of the container (4), is capable of discharging a portion of the contents of the container,

characterized in that the adapter (5) comprises at least one chamber (2) which is closed off from the outside and from the inside of the container (4) by means of two spacers (13) and (14).

11. The closure of claim 10, wherein the first and second closure portions are integrally formed,

characterized in that said chamber (2) contains an active substance suitable for inhalation.

12. The closure of claim 10 or 11,

characterized in that the active substance is present in the form of a tablet.

13. The closure of claim 10 or 11,

characterized in that the separation of the chamber (2) from the outside is constituted by a diaphragm (13) and the separation from the inner container is constituted by a closing film (14).

14. The closure of claim 10 or 11,

characterized in that the chamber (2) has a frangible point at its connection to the adapter (5) at which the chamber tears due to the pressure acting on the chamber (2) when the septum (13) is pierced.

15. The closure of claim 10 or 11,

characterized in that the septum is made of an elastic material so that the interior of the container remains sealed against the outside even in the event of penetration by the needle cannula.