Cartridge for a liquid

(12) PATENT DESCRIPTION (19) PL (11) 196860 (13) B1 (21) Application number: 350247 ⁽¹³⁾ (22) Date of notification: February 16, 2000 ^{(51) Int.Cl.}

A61J 1/14 (2006.01) (86) Date and number of international application: A61M 11/00 (2006.01)

16.02.2000, PCT / EP00 / 01249 B05B 11/00 (2006.01) (87) International application publication number and date:

August 31, 2000, WO00 / 49988 PCT Gazette No. 35/00 (54) Liquid cartridge for connection to a dosing device and its use

<td>(30) Priority:</td><td>(73) The right holder of the patent: BOEHRINGER INGELHEIM INTERNATIONAL GmbH, Ingelheim am Rhein, DE</td>

<td>1999-02-23, MY, PI9900627</td><td>(72) Inventor (s):</td>

<td>1999-08-26, DE, 19940713.4</td><td>Heinrich Kladders, Muelheim, DE Bernd Zierenberg, Bingen am Rhein, DE Dieter Hochrainer, Bingen am Rhein, DE</td>

<td>(43) Application was announced:</td><td>Joachim Eicher, Dortmund, DE</td>

<td>02.12.2002 BUP 25/02</td><td>Matthias Hausmann, Dortmund, DE Gilbert Wuttke, Dortmund, DE Michael Schyra, Wuppertal, DE</td>

<td>(45) The grant of the patent was announced: 29 February 2008 WUP 02/08</td><td>Andreas Fiol, Wuppertal, DE Johannes Geser, Dortmund, DE (74) Representative: Lidia Chlebicka, KULIKOWSKA &amp; KULIKOWSKI</td>

(57) 1. A liquid cartridge for connection to a dispensing device comprising an upper cartridge-receiving part and a lower part to be pressed onto the associated cartridge, wherein the upper part of the device is provided with a cartridge coupling part and a dispensing spout for withdrawing the liquid, characterized in that the cartridge (1 ) is a three-layer container consisting of an outer rigid sleeve (4), with a stable container (5) located inside it, and a flexible bag (6) accommodated therein containing a liquid, wherein the rigid sleeve (4) has a bottom with an opening (22), and the shape-stable container (5) has an opening (14) closed with a stopper (7), the stopper it is equipped with an immersion spout (17), forming a tightly closing, centered guide of the dosing spigot (15), and moreover, the cork is inseparably connected by a sleeve (4) with a stable container (5) and the cartridge (1) is releasably connected to a connecting portion (2) provided in the upper part of the dispensing device.

35. The use of a cartridge according to claim 1 1 or 33 or 34 for dispensing a medical liquid containing a pharmacologically active ingredient.

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PL 196 860 B1

Description of the invention

The subject of the invention is a liquid cartridge intended to be connected to a dispensing device and the use of the cartridge. The dispensing device comprises an upper part that houses the cartridge and a lower part that is designed to be slipped over an attached cartridge. The upper part of the device is equipped with a cartridge coupling part and a liquid discharge port.

The liquids according to the invention may be solutions, suspensions or emulsions. Liquids which contain the active ingredient are preferred. The active substances can be pharmacologically active substances for the treatment of the human or animal body, or active substances for diagnostic or cosmetic purposes.

The object of the invention is to adapt an economically produced cartridge of this type to the specific requirements.

Various thin-walled liquid containers of this type are known which are not diffusion-tight with respect to volatile liquid components. In this case, part of the liquid is lost by diffusion, and the concentration level of the liquid components changes unfavorably or even unacceptably. Such containers are suitable for a relatively short storage time. For other containers of the type mentioned, unacceptable changes in the liquid occur due to diffusion or the action of air before or during use. Particularly in the case of liquid containers that contain medically active substances, stringent requirements are required to avoid unacceptable deleterious effects on the quality of the medicament.

The object of the invention is to provide a liquid cartridge which can be manufactured cheaply in a large number of pieces and which, when filled, can be stored for a long time even under difficult conditions. The discharge of the liquid should be easy and should not come into contact with the surroundings. Furthermore, the cartridge should be as easily and replaceably attached to the dispensing device as possible. It can also be reliably manipulated by non-professionals. Such a cartridge should also be suitable for liquids containing medicinal substances under stringent conditions.

According to the invention, this task is solved by a cartridge attached to a dosing device. The dispensing device comprises an upper part receiving the cartridge and a lower part sliding over the attached cartridge. The upper part is equipped with a part for attaching the cartridge and with a nozzle for discharging the liquid. The cartridge may be designed as a three-layer container that is composed of an outer rigid sleeve, a shape-stable outer sleeve situated inside this container-sleeve and of a flexible, fluid-containing bag placed in this stable-shape container. The rigid bushing may have a bottom which may be provided with an opening. The shape-stable container may also have an opening and be closed with a stopper which has a dip tube. The plug can form a tightly closing, centered guide of the dispensing spout. The stopper may be permanently connected to the shape-stable container by a rigid sleeve. Such a cartridge may be detachably connectable to a coupling portion on the top of the dispensing device.

The connection between the cartridge and the coupling part can be made as a plug connection, as a threaded connection or as a bayonet connection. Such a connection may advantageously be a releasable connection. It can advantageously be made as a hard-to-detach or non-detachable connection.

The stopper can advantageously be made of a thermoplastic material and can be connected to a dimensionally stable container in a firm and tight manner by means of a snap-fit ​​connection. Moreover, the stopper can also be inseparably welded to a shape stable container made of thermoplastic material by joining these materials together. The plug may be equipped with a dip tube with a funnel-shaped, centered guide which preferably has guide ribs. The stopper can tightly surround the dosing nozzle and be made with an interference fit on the dosing nozzle. It is preferable that the end of the immersion pipe facing the interior of the flexible bag is closed by a membrane that is inclined to the axis of the immersion pipe and pierced when the dosing nozzle is inserted into the cartridge. This diaphragm prevents any liquid from escaping into the immersion nozzle while the cartridge is being stored.

Between the top edge of the shape-stable container and the inside of the stopper, a sealing disc can be provided, which can be provided with sealing beads. The inner side of the stopper may be provided with a sealing lip or several sealing lips which are pressed into the sealing disc on the upper edge of the shape-stable container.

PL 196 860 B1

Outside of its bore, the rigid sleeve is diffusion-tight for gases and liquids. The sleeve may be a one piece deep drawn metal sleeve, preferably aluminum. Moreover, this rigid bushing can be made in two parts. The two parts of the sleeve are then joined to each other and sealed to one another by sealing elements, by welding or gluing. Moreover, the rigid sleeve can be made of plastic, preferably thermoplastic.

The rigid bushing may have a protruding bead at the edge of its bottom. The bottom may be provided with a recess which may be centrally located as an arch into the bottom area.

The rigid sleeve preferably has a hole in the center of its bottom, which can be designed as a circular hole. Additionally, an insert, preferably made of plastic, can be placed in the recess in the bottom of the sleeve, containing a hole in the form of a micro-hole which is connected to the hole in the bottom of the rigid sleeve. A filter can be placed inside this insert in front of the micro-opening.

The hole in the bottom of the rigid sleeve may have a diameter of 0.1-5 mm with a circular cross section.

With a circular cross-section, the micro-hole in the insert has a diameter of 10-500 ..m and a length of 100-5000 ..m. This micro-hole allows the time needed to equilibrate the pressure between the inside of the cartridge and the surroundings to be adjusted.

The rigid metal sleeve may be provided with at least one circumferential fold in the vicinity of its open end to fit tightly and snugly against the plug. A rigid thermoplastic sleeve can be connected to the plug by welding both materials. Moreover, the rigid sleeve may in its upper part be provided with a circumferential, outwardly open groove which surrounds the lower edge of the plug. The rigid sleeve at its outer end may have a flange ridge surrounding the top edge of the plug.

The rigid sleeve may be provided with a plurality of projections extending into the sleeve which support a shape stable container within the rigid sleeve. Preferably, the three projections extend from the center to the bottom of the rigid sleeve in a plane perpendicular to the sleeve axis. In the case of a rigid sleeve made of metal, these protrusions may be produced by turning the flange of the upper end of the rigid sleeve.

The cartridge may be sealed in the region of the stopper, preferably by a liquid-gas diffusion-proof sealing foil, to close the open end of the dip tube. The outside of the sleeve body can also be sealed with a sealing material, preferably by a liquid and gas diffusion resistant sealing foil that covers the bottom opening or the liner in the sleeve bottom.

Both sealing foils prevent dirt from penetrating into the holes below and diffusion of liquid components during long storage of the cartridge. The two sealing films are only detached or punctured immediately before the first intended use of the cartridge.

The detachable connection between the cartridge and the coupling part of the dispensing device may be a plug connection, in which the coupling part is provided with a plurality of latch hooks which engage in a circumferentially extending groove in the upper part of the rigid sleeve after the cartridge has been inserted into the dispensing device. The plug-in connection is also advantageously applicable to other containers of this type, the shape-stable container or the stopper having a groove into which the latching hooks engage.

Plastic snap hooks can be equipped with a metal spring element that maintains the springiness of the snap hooks over a long period of time and at elevated temperatures.

A free space covered by the sealing foil can be provided in the central region of the sealing foil on the outer side of the sleeve bottom. A rigid or resilient piercing device can be provided on the inside of the bottom of the bottom of the device, which pierces the sealing foil on the bottom side of the bottom of the sleeve before the first dispensing of a portion of the liquid from the cartridge. This opens a hole in the bottom of the sleeve or a micro hole in the insert and allows air to enter the interior of the cartridge.

Extraction aids may be used to withdraw the used cartridge from the dispensing device, which are inserted under a bead at the bottom of the rigid sleeve, thereby facilitating extraction of the cartridge.

Before the cartridge is attached to the dispensing device, the sealing foil is detached on the stopper or on the bottom of the cartridge, or the sealing foils are punctured when the cartridge is attached to the dispensing device. The existing pressure difference between the interior of the cartridge and the exterior of the cartridge is then equalized by an opening in the bottom of the rigid sleeve.

PL 196 860 B1

When a certain amount of liquid is discharged from the cartridge connected to the dispensing device, the flexible bag collapses and its volume is reduced by the volume of the discharged amount of liquid. As a result, a negative pressure is created in the gas space of the cartridge (i.e. in the free space between the outside of the flexible bag and the inside of the rigid sleeve) compared to the pressure in the vicinity of the cartridge. This pressure difference equalizes in a relatively short time when the rigid sleeve is thin-walled and has an opening of 0.1-5 mm.

If the cartridge at the bottom of the rigid sleeve has an insert that contains a micro-orifice, the time of pressure equalization between the gas space in the cartridge and the environment is adjustable. For example, with a volume of 3 ml of gas space in the cartridge and a pressure difference of 20 hPa (20 mbar) between the vicinity of the cartridge and the gas space inside a cartridge with a circular micro-hole 200 μm long and 80-50 μm in diameter, a half pressure equalization time of 2-13 h can be obtained .

If the pressure equalization time is adjusted to a fixed temporal interval between two dispensing treatments from the cartridge, diffusion of the liquid components from the flexible bag is hindered.

The cartridge according to the invention may, for example, have a length of 55 mm and a diameter of 17 mm. The plug may have an immersion nozzle, the inside diameter of which ensures a good interference fit on a dispensing nozzle with an outside diameter of 2 mm.

The cartridge of the invention can be used in the sprayer shown in Figures 6a and 6b of WO-97/12687. The cartridge 1 of the present invention corresponds to the container 71 of Figs. 6a and 6b, the spring element provided as a connection part 2 of the clamping locking mechanism corresponds to the spring part 56, and the lower part 3 of the device corresponds to the lower part 70 of the housing.

The cartridge may contain an aqueous or alcoholic liquid.

In the case of an aqueous liquid cartridge, the shape-stable container and stopper may be made of polypropylene. The flexible bag can be made of polyethylene. The rigid bushing can be made of plastic, preferably polypropylene. The hole in the bottom of the rigid sleeve may be a circular hole. The shape-stable container stopper may be provided with a dip tube which, at its end facing the inner space, can be closed by a membrane inclined with respect to the axis of this dip tube. The immersion nozzle may have an interference fit for the dosing nozzle. The stopper may be connected to a shape-stable container by a snap-fit ​​connection. The detachable plug connection between the cartridge and the coupling part of the dispensing device may be a snap-fit ​​connection in which the latching hooks in the coupling part of the dispensing device engage in a circumferential groove in the upper region of the cartridge. The inner side of the bottom of the slide-on lower part of the device may be provided with a spring-loaded sealing foil piercing device on the underside of the sleeve bottom.

In the case of an alcoholic liquid cartridge, the shape-stable container and stopper may be made of polypropylene. The flexible bag can be made of polyethylene. The rigid bushing may be made of metal, preferably aluminum. An insert with a micro-hole which is connected to the hole in the bottom of the sleeve can be placed in the recess in the bottom of the rigid sleeve. Equipped with a dip tube, the shape-stable plug for a container at its end facing inwards may be closed with a membrane obliquely situated in relation to the axis of the dip tube. The immersion nozzle can be equipped with an interference fit, tightly closing centered guide of the dispensing spout. The stopper may be permanently connected to the shape-stable container by means of a rigid sleeve. The detachable plug connection between the cartridge and the coupling part of the dispensing device may be a snap-fit ​​connection in which the latching hooks in the coupling part of the dispensing device engage in a circumferential groove in the upper part of the cartridge. The inner side of the bottom of the slide-on lower part of the device may be provided with a spring-loaded device for piercing the sealing foil on the bottom side of the sleeve bottom.

The cartridge according to the invention can be filled with a medical liquid which, for example, contains a pharmacologically active substance and, for example, water, ethanol or mixtures thereof.

WO-98/27959 describes stabilized aqueous drug formulations for producing aerosols without propellant for inhalation.

Suitable medicinal preparations in ethanol solution are shown, for example, in WO-97/01329, and particular attention is paid to the active substances mentioned therein (pages 2 and 3) and to the stabilized preparations claimed therein.

Berotec (fenoterol hydrobromide) can be used as medically active substances; 1- (3,5-dihydroxyphenyl) -2 - [[1- (4-hydroxybenzyl) ethyl] amino] ethanol hydrobromide, Atrovent

PL 196 860 B1 (ipratropium bromide), Berodual (combination of fenoterol hydrobromide and ipratropium bromide), Salbutamol, salbutamol sulphate, Combivent, Oxivent (oxitropium bromide), Ba 679 (tiotropium bromide), BEA-di-tropenol ester (2108) 2-thienyl) glycolic), Flunisolide, Budesonide, Beclomethason.

The cartridge according to the invention has a number of advantages. One of the most important is that the concentration of the medical liquid contained in the sealed cartridge changes only to an acceptable degree even during storage for several years and at elevated storage temperatures. In addition, the cartridge content is effectively protected against contamination. The cartridge inserted into the dispensing device can be used for several months. The pressure equalization half time is governed by the shape of the microhole. The cartridge may be manufactured in a medically acceptable form. The unchanged initial state of the cartridge and its contents can be easily recognized on the intact sealing foil at the stated service life. The cartridge has a high degree of operational reliability and prevents its possible erroneous handling. The cartridge sits securely in the dispensing device. A well-closed cartridge is safe for children and makes it difficult to manipulate the contents. The empty cartridge can be easily removed from the dispensing device due to a bead at the bottom of the rigid sleeve.

The cartridge of the invention, which contains a medical liquid, can be used to generate an inhalable aerosol with the aid of a nebulizer. The aerosol can be used to treat diseases.

The liquid cartridge according to the invention is shown in the embodiment in the attached drawing, in which Fig. 1 shows a view of the cartridge with a dosing device in longitudinal section, Fig. 2 - a view of the cartridge with the dispensing spout pressed in, in longitudinal section, Fig. 3a shows the lower part enlarged in longitudinal section of a cartridge with a dosing device, Fig. 3b - the same element in a state after piercing the foil, Fig. 4a is a cross-sectional view of the cartridge extraction aid, and 4b is a cross-sectional view of the same element in a top view.

1 shows a cartridge 1 connecting part 2 of the dispensing device and the lower part 3 of the device which is pushed onto the cartridge to be attached. The rigid sleeve 4 comprises a shape-stable container 5 with a flexible bag 6. The shape-stable container is closed by means of a stopper 7 and a snap-fit ​​connection 8. Between the top edge of the shape-stable container and the bottom side of the stopper, a sealing disc 9 is pressed into it. sealing lip 10. The rigid sleeve has a circumferentially extending groove 11 against which the bottom edge of the plug abuts. A circumferentially extending groove 12 in the rigid sleeve is pressed into the plug. The plug is held on its upper side by a flanged portion 13 of the upper end of the rigid sleeve. An opening 14 is made in the shape-stable container 5.

The connecting part 2 of the dispensing device comprises a dispensing port 15 which pierces the sealing foil 16 on the upper side of the plug and enters the dip port 17. When the cartridge is further pressed onto the dispensing port 15, it passes through the interference-fit area 17a and pierces the sloped diaphragm 18 at the end. immersion pipe 17. Latching hooks 19 on the connection part 2 of the dispensing device engage from the outside into a circumferentially extending groove 11 in the rigid sleeve.

The rigid sleeve 4 has projections 4a in its central area, which are situated in a plane perpendicular to the sleeve axis. The protrusions support the container with a stable shape. The rigid sleeve has a protruding ridge 20 at its lower edge. In the center of the recess in the form of an inwardly directed region 21 is an opening 22 in the rigid sleeve. The bottom of the rigid sleeve is covered with a sealing foil 23. A free space 24 should be formed between the sealing foil and the inwardly bent area. A spring-loaded piercing device 25 is arranged on the inside of the lower part 3 of the dispensing device.

When the cartridge 1 is fully pressed onto the dispensing port and attached to the connection portion 2, the diaphragm at the end of the immersion port is pierced and the latching hooks 19 engage a circumferentially extending groove at the upper end of the rigid sleeve. The plug 7 is provided with guide ribs 7a. Area 17a provides an interference fit between the dispensing spout and the stopper. The insert 26 is positioned in a recess in the form of an inward facing area in the bottom of the sleeve.

The insert 26 shown in Fig. 3a includes a micro-opening 27 which is connected to an opening 28 in the bottom of the rigid sleeve. A filter 29 is positioned in front of this micro-hole. The bottom of the rigid sleeve is covered with a sealing foil 23. The element 30 shown in Fig. 4a for assisting the extraction of the cartridge is applied to the cartridge 1 and compresses the rigid sleeve inwards behind the spine 20. The cartridge is clamped onto the cartridge.

It can be rotated about its axis and pulled out of the dispensing device by means of the pull-out aid. The element 30, in the mounted state on the cartridge and the rigid sleeve 4, shown in Fig. 4b, to aid in the extraction of the cartridge, comprises an opening with a centrally located area, the diameter of which is substantially the same as the outer diameter of the rigid sleeve 4 and which is smaller than the diameter of the ridge. twenty. The central region of the opening fits into the enlarged opening 31 such that a removal aid can be easily applied to the end of the cartridge. The diameter of the central region of the bore is reduced at two diametrically opposed locations 32 and 33 and the arc of the bore circle is flattened. At these locations, the rigid cartridge sleeve is compressed as the pull-back aid is pressed in, thereby providing a tight connection between the pull-out aid and the cartridge.