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.
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.
In accordance with one or more embodiments of the present invention, a cartridge for propellant-free administration of a liquid pharmaceutical composition by inhalation, includes: an elongate displacing device including an upper end and a lower end, the lower end for at least partial insertion into a container; a cartridge chamber disposed at the lower end of the displacing device and operable store a pharmaceutical formulation, the cartridge chamber including at least one pierceably sealed opening; and a cannula guide extending from the upper end of the displacing device to the cartridge chamber, wherein insertion of a cannula through the guide pierces the sealed opening and releases the pharmaceutical formulation through the opening into a liquid solvent in the container to form the liquid pharmaceutical composition.
The invention is hereinafter explained in more detail with reference to some specific embodiments by way of example.
a to 3c show further embodiments of the closure cap (3) in accordance with the invention with chamber (2).
In another embodiment (
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).
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).
b, 3c show other embodiments regarding the construction of the immersed connector (5) and the guide (17) for the cannula for withdrawing the liquid.
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.
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
As shown in
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.
Number | Date | Country | Kind |
---|---|---|---|
196 15 422 | Apr 1996 | DE | national |
PCT/EP97/01958 | Apr 1997 | WO | international |
This application claims priority to and is a continuation of: U.S. patent application Ser. No. 11/178,689, filed Jul. 11, 2005 now U.S. Pat. No. 7,793,655, which 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.
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 | Jul 1947 | A |
2568029 | George | 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 | Modderno | Mar 1965 | A |
3193993 | Barton | Jul 1965 | A |
3198194 | Wilburn | Aug 1965 | A |
3255972 | Hultgren | Jun 1966 | A |
3354883 | Southerland | Nov 1967 | A |
3355238 | Schwartzman | Nov 1967 | A |
3425598 | Kobernick | Feb 1969 | A |
3441177 | Treharne | Apr 1969 | A |
3625403 | Rousselot | Dec 1971 | A |
3644096 | Lewis et al. | Feb 1972 | A |
3648899 | Lukesch | Mar 1972 | A |
3655096 | Easter | Apr 1972 | A |
3674028 | Ogle | Jul 1972 | A |
3715189 | Nighohossian et al. | Feb 1973 | A |
3842836 | Ogle | 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 | Katchur | Dec 1975 | A |
3946732 | Hurscham | Mar 1976 | A |
3949751 | Birch | 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 | May 1978 | A |
4116336 | Sorensen | Sep 1978 | A |
4162030 | Capra | 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 | 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 | May 1985 | A |
4516967 | Kopfer | May 1985 | A |
4526823 | Farrell | Jul 1985 | A |
4559052 | Babson | Dec 1985 | A |
4619651 | Kopfer | Oct 1986 | A |
4637934 | White | Jan 1987 | A |
4638927 | Morane | Jan 1987 | A |
4676775 | Zolnierczyk | Jun 1987 | A |
4727985 | McNeirney | Mar 1988 | A |
4732299 | Hoyt | Mar 1988 | A |
4781679 | Larkin | Nov 1988 | A |
4799599 | Hermann | Jan 1989 | A |
4817830 | Yavorsky | Apr 1989 | A |
4821923 | Skorka | Apr 1989 | A |
4883641 | Wicks | Nov 1989 | A |
4886177 | Foster | Dec 1989 | A |
4979941 | Ogle | Dec 1990 | A |
4982875 | Pozzi | Jan 1991 | A |
5004123 | Stoody | Apr 1991 | A |
5024087 | Nagasaki | Jun 1991 | A |
5031384 | Rebeyrolle | Jul 1991 | A |
5038958 | Dreier | Aug 1991 | A |
5084042 | McPhee | Jan 1992 | A |
5102010 | Osgar | Apr 1992 | A |
5105995 | Martin | Apr 1992 | A |
5129894 | Sommermeyer | Jul 1992 | A |
5137175 | Kowalski | Aug 1992 | A |
5158810 | Oishi | Oct 1992 | A |
5176178 | Schurter | Jan 1993 | A |
5188628 | Rani | Feb 1993 | A |
5213227 | Koyama | May 1993 | A |
5242085 | Richter | Sep 1993 | A |
5246142 | DiPalma | Sep 1993 | A |
5273189 | Jouillat | Dec 1993 | A |
5289818 | Citterio | Mar 1994 | A |
5292033 | Gueret | Mar 1994 | A |
5316135 | Kneer | May 1994 | A |
5316221 | Glover | May 1994 | A |
5325977 | Haynes | Jul 1994 | A |
5331121 | Tsuji | Jul 1994 | A |
5332113 | Kusler, III | Jul 1994 | A |
5332121 | Schmidt | Jul 1994 | A |
5347999 | Poss | Sep 1994 | A |
5352196 | Haber | Oct 1994 | A |
5355872 | Riggs | Oct 1994 | A |
5370272 | Gueret | Dec 1994 | A |
5385251 | Dunn | Jan 1995 | A |
5395365 | Weiler | Mar 1995 | A |
5421485 | Furuta | Jun 1995 | A |
5455124 | Schollenberger | Oct 1995 | A |
5480067 | Sedlimeirer | Jan 1996 | A |
5487739 | Aebischer | Jan 1996 | A |
5497909 | Wirsig | Mar 1996 | A |
5497944 | Weston | Mar 1996 | A |
5507409 | Paradine | Apr 1996 | A |
5509564 | Knoop | Apr 1996 | A |
5509578 | Livingstone | Apr 1996 | A |
5511558 | Shepard | Apr 1996 | A |
5514123 | Adolf | May 1996 | A |
5520972 | Ezaki | May 1996 | A |
5520975 | Inoue | 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 | Mar 1998 | A |
5738670 | Grippi | Apr 1998 | A |
5752629 | Hardy | May 1998 | A |
5772080 | De Pous | Jun 1998 | A |
5782345 | Guasch | Jul 1998 | A |
5813570 | Fuchs | Sep 1998 | A |
5827262 | Neftel | Oct 1998 | A |
5833088 | Kladders | Nov 1998 | A |
5873491 | Garcia | Feb 1999 | A |
5875936 | Turbett | Mar 1999 | A |
5878915 | Gordon | Mar 1999 | A |
5893484 | Fuchs | Apr 1999 | A |
5894841 | Voges | Apr 1999 | A |
5910138 | Sperko | Jun 1999 | A |
5934510 | Anderson | Aug 1999 | A |
5935101 | Kato | Aug 1999 | A |
5968619 | Carmen | Oct 1999 | A |
5994217 | Ng | Nov 1999 | A |
6013363 | Takahishi et al. | Jan 2000 | A |
6041696 | Su | Mar 2000 | A |
6062213 | Fuisz | May 2000 | A |
6062430 | Fuchs | May 2000 | A |
6073807 | Wilford et al. | Jun 2000 | A |
6109315 | Stern | Aug 2000 | A |
6129236 | Osokin | 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 | 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 |
6481535 | Fargo et al. | Nov 2002 | B1 |
6598762 | McKune | Jul 2003 | B2 |
6742677 | Petit | 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 |
Number | Date | Country |
---|---|---|
230 997 | Jun 2002 | AU |
2 251 828 | Oct 1997 | CA |
442671 | Apr 1927 | DE |
2847929 | May 1980 | DE |
3446697 | Jun 1986 | DE |
0 114 964 | Aug 1984 | EP |
0 169 501 | Jan 1986 | EP |
0 182 094 | May 1986 | EP |
0 217 425 | Apr 1987 | EP |
0 315 440 | Apr 1989 | EP |
0 322 980 | Jul 1989 | EP |
0 368 112 | May 1990 | EP |
0 495 330 | Jul 1992 | EP |
0 532 873 | Mar 1993 | EP |
0 585 908 | Mar 1994 | EP |
0 621 027 | Oct 1994 | EP |
0 622 311 | Nov 1994 | EP |
0 577 200 | Jan 1995 | EP |
0 635254 | Jan 1995 | EP |
0 653359 | May 1995 | EP |
0 654419 | May 1995 | EP |
0 661 218 | Jul 1995 | EP |
0 763 482 | Mar 1997 | EP |
0 812 625 | Dec 1997 | EP |
0 629165 | Jul 1998 | EP |
0 972 723 | Jan 2000 | EP |
780 143 | Apr 1935 | FR |
1.112 540 | Mar 1956 | FR |
1 159 909 | Jul 1958 | FR |
854163 | Nov 1960 | GB |
449648 | Dec 1949 | IT |
64 034367 | Feb 1989 | JP |
01-195858 | Aug 1989 | JP |
09-225356 | Sep 1997 | JP |
9006267 | Jun 1990 | WO |
WO 9007319 | Jul 1990 | WO |
WO 9114468 | Oct 1991 | WO |
WO 9216439 | Oct 1992 | WO |
9316917 | Sep 1993 | WO |
WO 9323165 | Nov 1993 | WO |
WO 9403373 | Feb 1994 | WO |
WO 9515895 | Jun 1995 | WO |
PCTUS9509384 | Feb 1996 | WO |
WO 9603218 | Feb 1996 | WO |
WO 9603344 | Feb 1996 | WO |
WO 9701329 | Jan 1997 | WO |
WO 9706842 | Feb 1997 | WO |
WO 9712687 | Apr 1997 | WO |
WO 9718143 | May 1997 | WO |
WO 9726998 | Jul 1997 | WO |
WO 9739831 | Oct 1997 | WO |
WO 9827959 | Jul 1998 | WO |
WO 9848943 | Nov 1998 | WO |
WO 9943571 | Sep 1999 | WO |
WO 0027543 | May 2000 | WO |
WO 0049988 | Aug 2000 | WO |
Number | Date | Country | |
---|---|---|---|
20080033391 A1 | Feb 2008 | US |
Number | Date | Country | |
---|---|---|---|
Parent | 11178689 | Jul 2005 | US |
Child | 11759507 | US | |
Parent | 10638458 | Aug 2003 | US |
Child | 11178689 | US | |
Parent | 09805818 | Mar 2001 | US |
Child | 10638458 | US | |
Parent | 09171471 | Nov 1998 | US |
Child | 09805818 | US |