Cartridge for a liquid

CARTRIDGE FOR LIQUID

The present invention relates to a cartridge for a fluid to be connected to a fluid extraction device. The fluid extraction device comprises a top portion of the device engaging the cartridge and a bottom portion of the device pushed onto the attached cartridge. The upper part of the device is provided with a cartridge mounting element and a cannula for removing fluid.

Liquids within the scope of the present invention may be solutions, suspensions, or emulsions. Liquids containing the active ingredient are preferred. The active ingredients may be pharmacologically active substances for human or animal therapy, diagnostic agents or cosmetic agents.

The object of the present invention is to match such industrially manufactured cartridges to specific requirements.

Various general purpose thin-walled fluid containers are known which are not diffusion-resistant to the volatile components of the liquid. When these containers are used, some of the liquid is lost by diffusion and the concentration of the liquid components is accidentally changed in an unacceptable manner. Such containers are suitable for a relatively short shelf life. The use of other commonly used containers will result in undesirable changes in the fluids prior to and during use, either by diffusion or by exposure to air. In order to avoid undesirable effects on the quality of the medicinal product, particularly high requirements must be placed on containers in which liquids containing medicinal active substances are stored.

Thus, it is an object of the invention to provide a cartridge that is manufactured in large quantities for a liquid which, even when filled, is capable of long-term storage, even under adverse conditions. The liquid must be easily withdrawn and must not come into contact with the surrounding environment. In addition, the cartridge must be secured to the fluid removal device as easily and interchangeably as possible; the cartridge must also be accessible to inexperienced persons.

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The cartridge must also be suitable for liquids containing medical active ingredients and must meet the increased requirements.

According to the invention, this object is solved by a cartridge attached to the fluid withdrawal device. The fluid extraction device comprises a top portion of the device engaging the cartridge and a bottom portion of the device pushed onto the attached cartridge. The upper part of the device is provided with an element for securing the cartridge and a cannula for removing fluid. The cartridge may consist of a three-layer container comprising an outer rigid sleeve, a molded container within the sleeve, and a fluid, deformable (compressible) inner bag, contained within the molded container. The rigid sleeve may have a bottom which may have an opening. The mold-proof container may also be provided with an opening which is closed by a closure with a cannula. The closure cap may form a sealed centered guide path for the cannula. The closure cap may be secured to the mold-proof container in a non-detachable manner through a rigid sleeve. The cartridge may be detachably connected to the fastener of the upper part of the fluid withdrawal device.

The connection between the cartridge and the closure may be a plug, a twist or a bayonet. Preferably, the connection is detachable. If necessary, the connection may also be difficult to disassemble or not.

The closure cap is preferably made of thermoplastic and can be force and shape-tightly connected to a rigid container by means of a gripping connection. The closure lid may also be welded to a thermoplastic molded container. The cap of the closure cap may be provided with a funnel-shaped centered guide for the cannula. The guide track may be provided with guide rails. The closure cap may seal tightly around the cannula and form a tight seat area on the cannula. It may be expedient to close the deformable (collapsible) end of the inner nozzle of the nozzle with a separating film, which is inclined in the direction of the nozzle axis and pierced when the cannula is inserted into the cartridge. The separating film prevents liquid from penetrating into the nozzle while the cartridge is being stored.

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There may be a sealing ring between the upper edge of the mold-proof container and the inside of the closure cap, which may be provided with a sealing ring. The inner side of the closure cap may be provided with a sealing rib or ribs, which may be pressed into the sealing ring at the upper edge of the molded container.

The rigid sleeve, excluding the opening in it, is diffusion-resistant to gases and liquids. The sleeve may be a one-piece deep-drawn metal sleeve, preferably made of aluminum. The rigid sleeve can also be made in two parts; in this case, the parts of the sleeve are sealed together by either sealing elements, welding or gluing. The rigid sleeve may also be made of plastic, preferably thermoplastic.

There may be a protruding bead at the bottom edge of the rigid sleeve. The bottom may have a recess which may be a centrally pressed region in the bottom.

Preferably, the bottom of the rigid sleeve has a hole at the center which may be formed by drilling. Further, a recess, preferably made of plastic, may be provided in the recess at the bottom of the sleeve, which contains a micro-hole connected to the opening in the bottom of the rigid sleeve. The insert may have a filter in front of the micro-opening.

The diameter of the opening at the bottom of the rigid sleeve may be circular in cross-section

0.1 mm to 5 mm. The insert has a diameter of 10 µm to 500 µm for circular cross-section and 100 µm to 5000 µm in length. The micro-opening allows you to select the time needed to balance the pressure difference between the cartridge and its surrounding environment.

The open end of the rigid sleeve made of metal may have a furrow which surrounds the closure cover in a force and shape-resistant manner. The rigid sleeve made of thermoplastic may be impermeably welded to the closure. Further, the rigid sleeve in its upper part may be surrounded by an outwardly opening groove which

EE 04518 B1 surrounds the lower edge of the closure cover. There may be a bead at the top of the open end of the rigid sleeve that covers the upper edge of the closure cap.

The rigid sleeve may be provided with a plurality of cams extending into the sleeve, which frictionally secures a mold-proof container inside the rigid sleeve. Preferably, there are three cams in the middle to lower portion of the rigid sleeve which are in one plane perpendicular to the axis of the sleeve. If the rigid sleeve is made of metal, these cams can be made by machining the open end of the rigid sleeve.

The cartridge may be sealed with a sealing film in the region of the closure cap which, if necessary, is diffusion resistant and closes the open end of the cap in the cap.

The outer face of the sleeve bottom may also be covered with a sealing film which, if necessary, is diffusion resistant and closes the sleeve bottom opening or insert at the bottom of the sleeve. Both sealing films protect the coated apertures from contamination and prevent diffusion of fluid constituents in the cartridge during storage of the cartridge. Both sealing films are removed or pierced just before the cartridge is first used for its intended purpose.

The detachable connection between the cartridge and the fluid extraction device attachment element may be a plug connection, in which case the fluid extraction device attachment element 20 is provided with a plurality of grippers which engage with the rigid sleeve in the groove surrounding the upper edge of the fluid extraction device. The use of a plug-in connection is also preferable for other containers of the same type if the mold-proof container or closure is provided with a gripping groove.

Plastic clamps may be provided with resilient elements made of metal, which ensure long-term resilience of the clamps, even at elevated temperatures.

In the middle of the sealing film covering the bottom of the sleeve, a free space may be formed in the film. The lower part of the bottom of the lower part of the fluid extraction device may have a stationary or resilient puncture device which upon first partial fluid extraction

EE 04518 B1 The cartridge strikes through the sleeve to seal the bottom. This opens the opening at the bottom of the cartridge or the micro-opening in the insert and allows air to enter the cartridge.

If necessary, a means for removing the used cartridge from the fluid withdrawal device may be used, which is pressed under the rim of the rigid sleeve, thereby facilitating the extraction of the cartridge.

The sealing films are removed from the closure cap and the bottom of the cartridge prior to attaching the cartridge to the fluid removal device or pierced through the cartridge attachment to the fluid removal device. The difference between the pressure inside the cartridge and the outside pressure is balanced, if necessary, by an opening in the bottom of the rigid sleeve.

When a certain amount of liquid is removed from a cartridge attached to the fluid retrieval device, the deformable inner bag of the cartridge shrinks and its volume decreases by the volume of liquid removed. This creates a negative pressure in the gas-containing part of the cartridge (i.e., the free space between the outside of the deformable inner bag and the inside of the rigid sleeve) relative to the ambient pressure of the cartridge.

Within a relatively short period of time, this pressure difference is balanced when the rigid sleeve is thin-walled and has an opening of 0.1 mm to 5 mm.

When the insert is provided with a micro-aperture at the bottom of the rigid sleeve of the cartridge, the time required to balance the pressure difference between the cartridge and the surrounding environment can be adjusted. For example, for a 3-liter gas cartridge and for a pressure difference between the cartridge and its surroundings of 20 hPa (20 mbar) and a circular micropore of 200 µm, 80 µm to 50 µm in diameter, the pressure half-life can range from 2 hours to 13 hours.

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When the pressure equilibration time is matched with a predetermined time interval between two successive fluid withdrawals from the cartridge, the diffusion of the fluid constituents from the deformable inner bag is inhibited.

The cartridge of the invention may be, for example, 55 mm long and 17 mm in diameter. The closure cap may have a nozzle having an inner diameter so selected that it forms a tight fit for a cannula with an outer diameter of 2 mm.

The cartridge of the invention may be inserted into the nozzle shown in Figures 6a and 6b of WO 97/1268710. The cartridge 1 according to the invention corresponds to the figures

6a and 6b, the fastening element 2 corresponds to the device 56 and the lower part 3 of the device corresponds to the lower part 70 of the device.

The cartridge may contain water or alcohol-containing liquids.

When using aqueous liquids, the molded container and closure cap may be made of polypropylene. The deformable inner bag may be made of polyethylene. The rigid sleeve may be made of plastic, preferably polypropylene. The opening at the bottom of the rigid sleeve may be drilled. The sealing lid of the mold-proof container may be provided with a nozzle having an inner end that may be closed by a membrane inclined relative to the axis of the nozzle. The nozzle may have a tight seat area for the cannula. The closure cap may be connected to the molded container by means of a gripping connection. The plug connection between the cartridge and the fluid extractor attachment may be a jaw connection whereby the fluid extractor attachment grips engage the groove surrounding the upper portion of the cartridge. A resilient puncturing device may be provided on the inside of the bottom of the lower portion of the retractable device for piercing the sealing film covering the bottom of the sleeve.

For alcoholic liquids, the mold-proof container and closure cap may be made of polypropylene. The deformable inner bag may be made of polyethylene.

The rigid sleeve may be made of metal, preferably aluminum. The recess in the bottom of the rigid sleeve may be fitted with a micro-opening insert which is

EE 04518 ΒΙ connected to a drilled hole in the bottom of the sleeve. The sealing lid of the mold-proof container may be provided with a nozzle having an inner end that may be closed by a membrane inclined relative to the axis of the nozzle. The nozzle may have a centered guide path for the cannula that is tightly closed with the seat region of the seat. The closure cap may be secured to the mold-proof container in a non-detachable manner by means of a rigid sleeve. The detachable plug-in attachment between the cartridge and the fluid extractor fastener may be a jaw connection whereby the fluid extractor fastener jaws engage the groove surrounding the top of the cartridge. The lower portion io of the lower portion i of the retractable fluid withdrawal device may have a resilient piercing device for puncture sealing the bottom of the sleeve.

The cartridge of the invention may be filled with a medical liquid containing, for example, a pharmacologically active agent, as well as, for example, water, ethanol or mixtures thereof.

WO 98/27959 describes stabilized, aqueous-based pharmaceutical compositions for the manufacture of compressed gas-free aerosols for inhalation. The compositions described in this document and exemplified herein are provided herein.

Suitable pharmaceutical compositions prepared in ethanol solution are disclosed, for example, in WO 97/01329, with particular reference to the active ingredients mentioned therein (see pages 2 and 3 therein) as well as the stabilized compositions described therein.

Berotec (phenoterol hydrobromide; 1- (3,5-dihydroxyphenyl) -2 - [[1- (4-hydroxybenzyl) ethyl] amino] ethanol hydrobromide), Atrovent (ipratropium bromide), Berodual (a combination of fenoterol 30 hydrobromide, Salbutamol, Salbutamolsulfat, Combivent, Oxivent, (Oxytropium Bromide), Ba 679 (tiotropium Bromide), BEA

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2108 (di (2-thienyl) glycolic acid tetropenol ester), Flunisolides, Budesonid, Beclomethason and others.

The cartridge of the invention has the following advantages.

· The concentration of medical fluid stored in a sealed cartridge will only change within acceptable limits for years of storage and elevated storage temperatures.

• The contents of the cartridge are very well protected from contamination.

• The cartridge installed in the fluid extraction unit may be used for several months.

• The half-life of the pressure differential equilibrium is determined by the shape of the micro-opening.

• The cartridge can be manufactured in a medically perfect form.

• Conformity of the cartridge and its interior to its original condition can be determined unmistakably on the basis of the integrity of the sealing films.

• The cartridge has high reliability. Abuse is prevented.

• The cartridge is securely held in the fluid extraction unit.

• Firmly sealed cartridge is child resistant and difficult to manipulate with its contents • Empty cartridge is easily removable from the fluid extraction unit due to the edge on the rigid sleeve bottom.

The cartridge of the invention containing the medical fluid is usable by means of a nebulizer for preparing an inhaled aerosol. The aerosol is useful for treating diseases.

The cartridge of the present invention will now be explained with reference to the drawings (Figs. 1 to 4b).

Figure 1 shows a cartridge 1, a fluid retention device attachment element and a lower portion 3 of the device which is pushed onto the attached cartridge.

Inside the rigid sleeve 4 is a mold-proof container 5 with a deformable (collapsible)

EE 04518 B1 with inner bag 6. The mold-proof container is closed by a closure cap 7 and a gripping connection 8. Between the upper edge of the mold-resistant container and the lower part of the closure cap is a sealing ring 9 which is sealed with a sealing rib 10. has a pressed closure cover. The closure cap is held in place by a rim 13 on the upper edge of a rigid sleeve extending to its upper side. An opening 14 is provided in the mold-proof container 5.

The fluid retention device attachment is provided with a cannula 15 which has already broken at the upper side of the sealing film 16 and penetrated into the nozzle 17. Further pushed into the cannula, the cartridge penetrates through the seat region 17a and punctures the inclined diaphragm 18.

The grips 19 of the fluid withdrawal device attachment member 2 engage the groove 11 surrounding the rigid sleeve.

The bottom of the rigid sleeve is surrounded by a protruding bead 20. In the center of the recess 21, which is an embossed area, there is an opening 22 in the rigid sleeve. The bottom of the rigid sleeve is covered with sealing foil 23. There is free space between the sealing foil and spring loaded puncture device 25.

Figure 2 shows a cartridge 1 with a fully retracted cannula 15 and attached to the fluid retention device attachment 2, the membrane at the tip of the nozzle being pierced and the grips 19 engaging in a groove surrounding the rigid sleeve. The closure cover 7 is provided with guide ribs 7a. In the region 17a, there is a tight seat between the cannula and the closure cap. A spacer 26 is mounted in the recessed area of ​​the sleeve bottom.

The rigid sleeve 4 is provided in its central part with cam 4a which is in a plane perpendicular to the sleeve axis. These cams prove the shape-proof container.

Fig. 3a is an enlarged view of the lower part of the rigid sleeve 4, the lower part 3 of the device and the insert 26. The device is provided with a micro opening 27 which is

EE 04518 B1 is connected to a hole 28 in the bottom of the rigid sleeve 28. A filter 29 is provided in front of the micro-opening. The bottom of the rigid sleeve is covered with a sealing film 23.

Figure 3b shows a situation where the puncturing device 25 has pierced the sealing film 23.

Fig. 4a is a cross-sectional view of the auxiliary device 30 mounted on the cartridge 1 which presses against the ridge 20 on a rigid sleeve. The cartridge is pressed between auxiliary device and can be rotated through its axis by auxiliary device and pulled out of io fluid extraction device

Figure 4b shows a top view of the attached support means 30 in cross-section of the rigid sleeve 4. The auxiliary device has a cut-out having a diameter of the central part to be mounted approximately equal to the outer diameter of the rigid sleeve 4 and smaller than the rim

20th diameter. The central portion of the cutout passes to the expanded portion 31, which allows for easy attachment of the aid to the cartridge. In the central portion of the cut-out, the diameters 32 and 33 are reduced at two diametrically opposed locations and the arcuate portion of the cut-out is straightened. At these locations, the rigid sleeve of the cartridge is compressed when the accessory is applied and a rigid connection between the accessory and the cartridge is achieved.