Two-chamber cartridge for propellant-free metering aerosols

Information

  • Patent Grant
  • 7213593
  • Patent Number
    7,213,593
  • Date Filed
    Monday, July 11, 2005
    19 years ago
  • Date Issued
    Tuesday, May 8, 2007
    17 years ago
Abstract
A cartridge having two chambers for separate storage of active substance and solvent.
Description
BACKGROUND OF THE INVENTION

1. Field of the Invention


The present invention relates to a two-chamber cartridge for liquids, particularly for drug formulations for use in propellant-free metering aerosols.


2. Description of Related Art


International Patent Application W091/14468 “Atomizing Device and Methods” describes a device for propellant-free administration of a metered quantity of a liquid pharmaceutical composition for use by inhalation. A further developed embodiment is described, for example, in PCT/EP96/04351. For applications of this kind it is required to package the solutions containing the active substance into containers in such a way as to include only tiny residues of air and gas. Gas bubbles would lead to uncertainty in the accurate metering of the active substance. Containers of this kind are disclosed for example in International Patent Application PCT/EP95/03183. The containers described therein are particularly suitable for those pharmaceutical compositions which can be stored for lengthy periods in the form of an aqueous or ethanolic solution. For active substances which decompose in their solutions after only a few months there have not hitherto been any suitable containers which would allow commercial use of such sensitive preparations in propellant-free metering aerosols.


BRIEF SUMMARY OF THE INVENTION

The invention now relates to a cartridge which has two chambers for separate storage of active substance and solvent. The cartridge is constructed so that, when the cartridge is inserted in a device for producing the aerosol, the chamber containing the active substance is pierced by means of a cannula, with the result that the active substance comes into contact with the solvent and is dissolved. The storage time of the pharmaceutical preparation can be extended significantly by the separate storage of active substance and solvent. The active substance may be present in the chamber as a powder, granules or in the form of a tablet. Similarly, pharmacologically acceptable excipients may be present. Generally, those galenic formulations which ensure ease of solution of the active substance in the solvent are preferred. In the case of tablets, excipients which bring about better dissolution of the tablet may be added. Similarly excipients may be added which increase the stability of the active substances. In many cases, the active substance may also be present 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 other chamber, hereinafter also referred to as container.





BRIEF DESCRIPTION OF THE DRAWINGS

The invention is hereinafter explained in more detail with reference to some specific embodiments by way of example.



FIG. 1 shows an axial section along the longitudinal axis of the cartridge (1) in accordance with the invention with the chamber (2) for receiving the active substance, the chamber (2) being an integral part of the closure cap (3)



FIG. 2 shows another embodiment of the closure cap (3) with chamber (2) when the cartridge is in its closed state, the container (4) being merely indicated.



FIGS. 3
a to 3c show further embodiments of the closure cap (3) in accordance with the invention with chamber (2).



FIG. 4 shows a section along the longitudinal axis of an embodiment of the closure cap in accordance with the invention, in which the chamber (2) contains a minitablet (16a) as its supply of active substance.





DETAILED DESCRIPTION OF THE DRAWINGS


FIG. 1 shows the cartridge (1) in accordance with the invention consisting of a container (4) and a closure cap (3). The closure cap has a device (5)—in this case in the form of an immersed connector—through which some of the contents of the container (4) are displaced during the closure process and the container is filled with virtually no air bubbles. An internal encircling bead (6) on the lower edge of the closure cap (3) engages underneath a cylindrical ring (7) running around the outside of the neck of the container in the closed position. In the closed position the gap between the flat part of the closure cap (3) and the upper edge of the neck of the container, which may optionally have an encircling rib (10) to improve the seal, is filled by a sealing ring (11) and in this way the interior of the container (3) is sealed off. The internal diameter of the sealing ring (11) is appropriately such that it fits tightly against the connector (5). The vent opening or opening(s) (8) may also be located at other points on the outside of the cap, e.g. on the side in the cylindrical part of the cap.


In another embodiment (FIG. 2a) the closure cap (3) is closed off by a sleeve (20) made of aluminum which is crimped in position. The sleeve (20) is constructed so as to have a central opening (21) for the insertion of the cannula (22). This opening may be closed off by a septum as a protection against dust and other contaminants. This closure technique is known, for example, in injection ampoules.


In one particular embodiment the container (4) contains a collapsible internal container (4a) of flexible material. The internal container may, in a preferred embodiment, be fixed to the lower part of the container (4) by a device (12).


The chamber (2) is located in the lower part of the connector (5), the chamber being closed off to the outside by means of a partition, e.g. in the form of a septum (13), and to the interior of the container (4b) by means of a partition, e.g. in the form of a film (14). The septum (13) and film (14) are made from a material which can easily be pierced by a cannula having a pointed or rounded tip. The septum (13) is preferably made of a material which seals the interior (4b) off to the outside even when the cannula has pierced it. Usually, the partitions consist of thin plastics or aluminum foil. In one embodiment the septum (13) may have frangible points where it is connected to the side wall of the connector (5), so that when the partition is pierced it tears open at the frangible points. Preferably, the film (14) is in the form of a welded-on diffusion-tight sealing film which tears when pierced and allows the active substance to enter the interior (4b) of the container. The frangible points may also be provided in the region of the lower side wall of the connector (5) so that the lower part of the side wall of the connector is also torn away.


The position of the partition (13) may vary within wide areas of the interior of the connector (5), but it is preferably arranged in accordance with the quantity of active substance (16) so that the interior formed by the two partitions (13) and (14) contains, in addition to the powder, the least possible amount of gas (air).



FIG. 2 also shows an axial section through the neck of a container with a closure cap (3) fitted thereon, the chamber (2) being of different configuration.



FIG. 3
a shows another embodiment of the closure cap according to the invention, in which the interior of the immersed connector is constructed so as to form a guide (17) for a cannula for drawing off liquid. In the present instance, the vent openings (8) are provided in the upper part of the container (4). As already described, the vent openings may alternatively be provided on the closure cap. The chamber (2) for holding the active substance is arranged separately in the lower part of the connector (5). Instead of a pierceable partition (14), frangible points (18) may be provided so that, as the partition (13) is pierced the chamber is torn away at the frangible points (18) by pressure on the partition (14). In this embodiment, the partition (14) may be constructed as the base of the connector (5).



FIGS. 3
b, 3c show other embodiments regarding the construction of the immersed connector (5) and the guide (17) for the cannula for withdrawing the liquid.



FIG. 3
b shows an embodiment in which the guide (17) merges into a press fit (19). The press fit is designed, in terms of diameter and length, so that on the one hand the resistance for pushing the cannula through is kept to a minimum and, on the other hand, a sufficient seal is achieved between the connector and the cannula.



FIG. 3
c shows an embodiment with an elastic O-ring seal (20) between the connector and the piercing cannula (not shown in the drawing). The device which prevents the O-ring from accidentally becoming detached is not shown.


As shown in FIGS. 3b and 3c, the lower end of the immersed connector with the partition (14) may appropriately be chamfered, preferably by 20° to 60° relative to the axis of the connector. This makes it easier for the partition to be pierced with a “blunt” cannula the end face of which is perpendicular to the axis of the cannula. The advantages of a “blunt” as against a “sharp pointed” cannula are the small risk of injury to the user, the reduced machining work required to produce the end face of the cannula and the reduced risk of particle abrasion on the wall of the connector as the cannula is inserted.


As shown in FIG. 4, which corresponds largely to FIG. 3a, the chamber (2) contains the active substance in the form of a small tablet. Compared with a powdered active substance, the active substance in the form of the minitablet according to the invention is substantially easier to introduce into the chamber (2), and also a tablet has advantages when the septum (13) is pierced by a cannula and subsequently the tablet (16a) is pushed through the foil (14). On the one hand, this ensures that the relatively hard tablet does not block the cannula, and on the other hand it ensures that the full amount of active substance from the chamber enters the container (4). With the highly effective drugs commonly used in metering aerosols nowadays, a precisely metered solution of active substance is absolutely necessary for purposes of drug safety. Moreover, if the chamber (2) is filled with a tablet, the sealing surface is not contaminated with dust, as would be the case if it were filled with powder.


The tablet in accordance with the invention has a diameter of between 2 and 3 mm, preferably between 2.2 and 2.3 mm, and is between 1.8 and 3.5 mm long. The tablet in accordance with the invention has a compressive strength of between 2 and 10 N/mm2. The compressive strength is measured by clamping the tablet between flat surfaces and increasing the force until the tablet breaks up. The tablets were clamped in such a way as to come into contact with the flat surfaces along two generatrices (not with the top and bottom surfaces). The compressive strength is the force divided by the cross-sectional area (diameter times length of the cylindrical tablet).


The tablets in accordance with the invention consist of the active substance and conventional tableting excipients. Preferred active substances are those which can be used in low doses, e.g. up to 100 micrograms of active substance per single dose. These include, for example, atrovent, anticholinergics, β-sympaticomimetics, e.g. formoterol. The preferred excipients are lactose (200 mesh), glucose (200 mesh) and shape separating agents.


The container in accordance with the invention has a solvent volume of 4 ml, so that 0.5% solutions of active substance can be produced with a minitablet weighing 20 mg. The solvents are preferably water or ethanol or mixtures thereof. Other physiologically acceptable solvents are also suitable.


For removing liquid from the cartridge (1) in accordance with the invention, the partitions (13 and 14) are pierced with a cannula. Preferred embodiments are those wherein the container (4) has a readily deformable inner bag (4a) and the end of the cannula is located half way up the container when the liquid is drawn off. In this case, air bubbles have the least disruptive effect. Preferably, the minitablet (16a) in accordance with the invention is used as the supply of active substance.


The container and closure cap are generally made of plastics. Since the liquid packaged therein is virtually incompressible, the system of container and closure cap must be sufficiently deformable as the liquid expands in the warm. Similarly, when the liquid is drawn off, the walls of the container must yield or collapse sufficiently. The partition generally consists of a thin plastics film. Preferably, the partition (14) consists of a thin coated aluminum which is sealed.


Containers of this kind as well as the closure cap may be produced using the suitable plastics, e.g. polyethylene or preferably polypropylene, available to those skilled in the art.


The cartridge in accordance with the invention which is for drug formulations for an inhaler should have a long shelf life. For this reason it is necessary that the solvent cannot diffuse out of the interior (4b) of the container into the chamber (2) containing the active substance before use. In addition to having a sufficiently thick-walled chamber, an aluminum coating may also be applied to the outer or inner surfaces of the chamber (2). It should be emphasized that the insertion of the cartridge with the chamber (2) in the inhaler does not require any further manual strength on the part of the patient than the insertion of a conventional cartridge.

Claims
  • 1. In an atomizing device for propellant-free administration of a metered quantity of a liquid pharmaceutical composition for use by inhalation, the improvement which comprises a two-chambered cartridge for separate storage of an active, pharmaceutical substance, which can be either in dry form or in liquid form, and of a liquid solvent for the active, pharmaceutical substance, both of which, when mixed, will form the liquid pharmaceutical composition to be administered by the atomizing device, which cartridge comprises: (a) a container forming a first chamber for holding a liquid solvent within its interior, which container has a neck and around such neck is a cylindrical ring;(b) a closure cap for the container holding the liquid solvent which closure cap has a lower edge whereby the lower edge of the closure cap engages the neck of the container by means of an internal, encircling bead on the lower edge of the closure cap and whereby the encircling bead on the lower edge of the closure cap engages underneath the cylindrical ring around the neck of the container; and(c) a non-sealing, displacing device which is provided or situated on the closure cap so as to be an integral part thereof, and so that the device will displace a portion of any liquid solvent in the container as the closure cap is pushed onto the neck of the container so that the encircling bead on the lower edge of the closure cap engages underneath the cylindrical ring around the neck of the container, and further whereby the non-sealing, displacing device has at least one second chamber within that portion of the device which would displace a portion of any liquid solvent in the container, which second chamber is suitable for storage of a pharmaceutical formulation that can be dissolved in or diluted by the liquid solvent, and whereby the device also has a cannula guide comprising an elongated tube having a vertical axis which extends from the second chamber to that area of the device situated adjacent the lower edge of the closure cap and wherein the second chamber has two openings, where one opening is from the second chamber to the guide and which is sealed by a pierceable septum, and the other opening is between the second chamber and the interior of the container which is sealed by a sealing film and the lower end of the displacing device is chamfered.
  • 2. The atomizing device as recited in claim 1, wherein the cartridge further comprises a liquid solvent in the container and a pharmaceutical formulation within the second chamber in the non-sealing, displacing device that can be diluted or dissolved by the liquid solvent.
  • 3. The atomizing device as recited in claim 2, wherein the chamfering of the displacing device is between about 20° to its vertical axis.
  • 4. In an atomizing device for propellant-free administration of a metered quantity of a liquid pharmaceutical composition for use by inhalation, the improvement which comprises a two-chambered cartridge for separate storage of an active, pharmaceutical substance, which can be either in dry form or in liquid form, and of a liquid solvent for the active, pharmaceutical substance, both of which, when mixed, will form the liquid pharmaceutical composition to be administered by the atomizing device, which cartridge comprises: (a) a container forming a first chamber for holding a liquid solvent within its interior;(b) a closure cap; anda displacing device integral with said closure cap, the device adapted to displace a portion of at least a portion of solvent in the container as the closure cap is pushed onto the container, the displacing device further comprising at least one, second chamber therein, said chamber suitable for storage of a pharmaceutical formulation that can be dissolved in or diluted by said solvent, and further comprising a cannula guide comprising an elongated tube having a vertical axis which extends from the second chamber to that area of the displacing device situated adjacent a lower edge of the closure cap and wherein the second chamber has two pierceably sealed openings, where a first opening is disposed between the second chamber and the guide and is sealed by a pierceable septum, and the second opening is disposed between the first chamber and the second chamber.
  • 5. The invention according to claim 4, wherein said second opening is sealed by a sealing film.
  • 6. The invention according to claim 4, wherein a lower end of the displacing device is chamfered.
  • 7. The invention according to claim 4, wherein said closure cap is non-removable.
Priority Claims (2)
Number Date Country Kind
196 15 422 Apr 1996 DE national
PCT/EP97/01958 Apr 1997 WO international
CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and is a continuation of U.S. patent application Ser. No. 10/638,458, filed Aug. 11, 2003, now abandoned, which is a continuation of U.S. patent application Ser. No. 09/805,818, filed Mar. 14, 2001, now abandoned, which is a continuation of U.S. patent application Ser. No. 09/171,471, filed Nov. 16, 1998, now abandoned.

US Referenced Citations (161)
Number Name Date Kind
440316 Long Nov 1890 A
1694851 Glass Dec 1928 A
2342215 Perelson Feb 1944 A
2362103 Smith Nov 1944 A
2424801 Crabbe et al. Jul 1947 A
2568029 Seemar Sep 1951 A
2629421 Ayres Feb 1953 A
2669370 Royall, Jr. Feb 1954 A
2793776 Lipari May 1957 A
2990079 Garvey Jun 1961 A
3172568 Moddema Mar 1965 A
3193993 Barton et al. Jul 1965 A
3198194 Wilburn Aug 1965 A
3255972 Hultgren et al. Jun 1966 A
3354883 Southerland Nov 1967 A
3355238 Schwartzman Nov 1967 A
3425598 Kobermick Feb 1969 A
3441177 Treharne, Jr. Apr 1969 A
3625403 Rousselot Dec 1971 A
3648899 Lukesch et al. Mar 1972 A
3655096 Easter Apr 1972 A
3674028 Ogle Jul 1972 A
3842836 Olge Oct 1974 A
3857392 Ogle Dec 1974 A
3858580 Ogle Jan 1975 A
3870147 Orth Mar 1975 A
3874380 Baum Apr 1975 A
3874381 Baum Apr 1975 A
3878977 Carlisle Apr 1975 A
3924741 Kachur et al. Dec 1975 A
3946732 Hurscham Mar 1976 A
3949751 Birch et al. Apr 1976 A
4008820 Ruetz Feb 1977 A
4019512 Tenczar Apr 1977 A
4045860 Winckler Sep 1977 A
4088246 Klingaman May 1978 A
4089432 Crankshaw et al. May 1978 A
4116336 Sorensen et al. Sep 1978 A
4162030 Capra et al. Jul 1979 A
4177938 Brina Dec 1979 A
4187893 Bujan Feb 1980 A
4195730 Hunt Apr 1980 A
4201316 Klingaman May 1980 A
4202334 Elson May 1980 A
4204606 Micheli May 1980 A
4264018 Warren Apr 1981 A
4315570 Silver et al. Feb 1982 A
4322020 Stone Mar 1982 A
4440316 Christine Apr 1984 A
4457454 Meshberg Jul 1984 A
4457455 Meshberg Jul 1984 A
4469250 Evezich Sep 1984 A
4479989 Mahal Oct 1984 A
4515586 Mendenhall et al. May 1985 A
4516967 Kopfer May 1985 A
4526823 Farrell et al. Jul 1985 A
4559052 Babson Dec 1985 A
4619651 Kopfer et al. Oct 1986 A
4637934 White Jan 1987 A
4638927 Morane Jan 1987 A
4676775 Zolnierczyk et al. Jun 1987 A
4727985 McNeirney et al. Mar 1988 A
4732299 Hoyt Mar 1988 A
4781679 Larkin Nov 1988 A
4799599 Herrmann Jan 1989 A
4817830 Yavorsky Apr 1989 A
4821923 Skorka Apr 1989 A
4883641 Wicks et al. Nov 1989 A
4886177 Foster Dec 1989 A
4979941 Ogle, II Dec 1990 A
4982875 Pozzi et al. Jan 1991 A
5004123 Stoody Apr 1991 A
5024087 Nagasaki et al. Jun 1991 A
5031384 Rebeyroll et al. Jul 1991 A
5038958 Dreier Aug 1991 A
5084042 McPhee Jan 1992 A
5102010 Osgar et al. Apr 1992 A
5105995 Martin Apr 1992 A
5129894 Sommermeyer et al. Jul 1992 A
5137175 Kowalski et al. Aug 1992 A
5158810 Oishi et al. Oct 1992 A
5176178 Schurter et al. Jan 1993 A
5188628 Rani et al. Feb 1993 A
5213227 Koyama et al. May 1993 A
5242085 Richter et al. Sep 1993 A
5246142 DiPalma et al. Sep 1993 A
5273189 Jouillat et al. Dec 1993 A
5289818 Citterio et al. Mar 1994 A
5292033 Gueret Mar 1994 A
5316135 Kneer et al. May 1994 A
5316221 Glover et al. May 1994 A
5325977 Haynes et al. Jul 1994 A
5331121 Tsuji Jul 1994 A
5332113 Kusler, III et al. Jul 1994 A
5332121 Schmidt et al. Jul 1994 A
5347999 Poss et al. Sep 1994 A
5352196 Haber et al. Oct 1994 A
5355872 Riggs et al. Oct 1994 A
5370272 Gueret Dec 1994 A
5385251 Dunn Jan 1995 A
5395365 Weiler et al. Mar 1995 A
5421485 Furuta et al. Jun 1995 A
5455124 Schollenberger Oct 1995 A
5480067 Sedlmeier Jan 1996 A
5487739 Aebischer et al. Jan 1996 A
5497909 Wirsig et al. Mar 1996 A
5497944 Weston et al. Mar 1996 A
5507409 Paradine Apr 1996 A
5509564 Knoop Apr 1996 A
5509578 Livingstone Apr 1996 A
5511558 Shepard et al. Apr 1996 A
5514123 Adolf et al. May 1996 A
5520972 Ezaki et al. May 1996 A
5520975 Inoue et al. May 1996 A
5533994 Meyer Jul 1996 A
5569191 Meyer Oct 1996 A
5579760 Kohler Dec 1996 A
5620434 Brony Apr 1997 A
5642838 Stoody Jul 1997 A
5657910 Keyser Aug 1997 A
5672321 Daykin Sep 1997 A
5730328 Maeder et al. Mar 1998 A
5738670 Grippi Apr 1998 A
5752629 Hardy May 1998 A
5772080 de Pous et al. Jun 1998 A
5782345 Guasch et al. Jul 1998 A
5813570 Fuchs et al. Sep 1998 A
5827262 Nefftel et al. Oct 1998 A
5833088 Kladders et al. Nov 1998 A
5873491 Garcia et al. Feb 1999 A
5875936 Turbett et al. Mar 1999 A
5878915 Gordon et al. Mar 1999 A
5893484 Fuchs et al. Apr 1999 A
5894841 Voges Apr 1999 A
5910138 Sperko et al. Jun 1999 A
5934510 Anderson Aug 1999 A
5935101 Kato et al. Aug 1999 A
5944217 Baena Aug 1999 A
5968619 Carmen et al. Oct 1999 A
6013363 Takahashi et al. Jan 2000 A
6041969 Parise Mar 2000 A
6062213 Fuisz et al. May 2000 A
6062430 Fuchs May 2000 A
6073807 Wilford et al. Jun 2000 A
6109315 Stern Aug 2000 A
6129236 Osokin et al. Oct 2000 A
6152296 Shih Nov 2000 A
6223746 Jewett et al. May 2001 B1
6223933 Hochrainer et al. May 2001 B1
6244472 Hennemann Jun 2001 B1
6280431 Domkowski et al. Aug 2001 B1
6286700 Davidson Sep 2001 B1
6364163 Mueller Apr 2002 B1
6390332 Wakayama May 2002 B2
6481435 Hochrainer et al. Nov 2002 B2
6598762 McKune Jul 2003 B2
6742677 Petit et al. Jun 2004 B2
6986346 Hochrainer et al. Jan 2006 B2
7040311 Hochrainer et al. May 2006 B2
20010009151 Hochrainer Jul 2001 A1
20020007155 Freund et al. Jan 2002 A1
Foreign Referenced Citations (60)
Number Date Country
230997 May 1959 AU
4552085 Jan 1986 AU
2251828 Oct 1997 CA
442671 Apr 1927 DE
28 47 929 May 1980 DE
3446697 Jun 1986 DE
0 114 964 Aug 1984 EP
0169501 Jan 1986 EP
0 182 094 May 1986 EP
0 217 425 Apr 1987 EP
0 315 440 Apr 1989 EP
0322980 Jul 1989 EP
0 368 112 May 1990 EP
0 495 330 Jul 1992 EP
0532873 Mar 1993 EP
0577200 Jan 1994 EP
0 622 311 Feb 1994 EP
0 585 908 Mar 1994 EP
0 621 027 Oct 1994 EP
0635254 Jan 1995 EP
0653359 May 1995 EP
0654419 May 1995 EP
0 661 218 Jul 1995 EP
0763482 Mar 1997 EP
0 812 625 Dec 1997 EP
0629165 Jul 1998 EP
0972723 Jan 2000 EP
780143 Apr 1935 FR
1.112.540 Mar 1956 FR
1112540 Mar 1956 FR
1159909 Jul 1958 FR
854163 Nov 1960 GB
449648 Jun 1949 IT
449648 Dec 1949 IT
01-195858 Aug 1989 JP
1195858 Aug 1989 JP
09225356 Sep 1997 JP
64-034367 Feb 1998 JP
WOX 9006267 Jun 1990 WO
9007319 Jul 1990 WO
WO 9114468 Oct 1991 WO
WO9216439 Oct 1992 WO
WO 9323165 Nov 1993 WO
WO943373 Feb 1994 WO
WO 9515895 Jun 1995 WO
PCT US9509384 Feb 1996 WO
WO 9603218 Feb 1996 WO
WO 9603344 Feb 1996 WO
WO9701329 Jan 1997 WO
WO 9706842 Feb 1997 WO
WO 9712687 Apr 1997 WO
WO9718143 May 1997 WO
WO 9726998 Jul 1997 WO
WO9739831 Oct 1997 WO
W09827959 Jul 1998 WO
WO 9848943 Nov 1998 WO
WO9943571 Sep 1999 WO
WO 0049988 Mar 2000 WO
WO 0027543 May 2000 WO
WO 0049988 Aug 2000 WO
Related Publications (1)
Number Date Country
20050241634 A1 Nov 2005 US
Continuations (3)
Number Date Country
Parent 10638458 Aug 2003 US
Child 11178690 US
Parent 09805818 Mar 2001 US
Child 10638458 US
Parent 09171471 Nov 1998 US
Child 09805818 US