CA2130867C - An aerosol container and the use of an aerosol container - Google Patents

An aerosol container and the use of an aerosol container Download PDF

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Publication number
CA2130867C
CA2130867C CA002130867A CA2130867A CA2130867C CA 2130867 C CA2130867 C CA 2130867C CA 002130867 A CA002130867 A CA 002130867A CA 2130867 A CA2130867 A CA 2130867A CA 2130867 C CA2130867 C CA 2130867C
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CA
Canada
Prior art keywords
container
suspension
metering chamber
pharmaceutically active
aerosol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA002130867A
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French (fr)
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CA2130867A1 (en
Inventor
Francois Brugger
Angelika Stampf
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Novartis AG
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Publication date
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Application filed by Novartis AG filed Critical Novartis AG
Publication of CA2130867A1 publication Critical patent/CA2130867A1/en
Application granted granted Critical
Publication of CA2130867C publication Critical patent/CA2130867C/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D83/00—Containers or packages with special means for dispensing contents
    • B65D83/14—Containers or packages with special means for dispensing contents for delivery of liquid or semi-liquid contents by internal gaseous pressure, i.e. aerosol containers comprising propellant for a product delivered by a propellant
    • B65D83/44—Valves specially adapted therefor; Regulating devices
    • B65D83/52—Valves specially adapted therefor; Regulating devices for metering
    • B65D83/54—Metering valves ; Metering valve assemblies

Abstract

The invention relates to an aerosol container for pharmaceutically active aerosols that are to be administered in predetermined amounts and that are supplied in the container in the form of a suspension, the suspension also comprising, in addition to a pharmaceutically active substance, at least a propellant gas. The aerosol container has a metering valve that comprises a metering chamber and a valve.stem. In a first position of the valve stem, the metering chamber is in communication with the interior of the container and has been filled with a predetermined amount of the aerosol. In a second position of the valve stem, the amount of aerosol disposed in the metering chamber is released. The propellant gas is an alternative propellant gas that is free of fluorochlorohydrocarbons, preferably a propellant gas that comprises only fluorohydrocarbons, and the inner wall of the container is coated with a plastics coating.

Description

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An aerosol container and the use of an aerosol container The invention relates to an aerosol container and to the use of an aerosol container in accordance with the respective independent patent claim.
Aerosols are today a common dosage form for pharmaceutically active substances. Many of those aerosols are to be administered in predetermined (metered) amounts.
For various reasons (for example stability), certain pharmaceutically active substances are supplied in the form of a suspension, that is to say the pharmaceutically active substance is present in the aerosol container, usually under pressure, in the form of small solids particles in a liquid, the liquid also comprising at least a propellant gas. That kind of formulation of pharmaceutically active substances has proved suitable for many substances, and especially also for corticosteroids.
In order to administer a predetermined amount of the pharmaceutically active substance, customary aerosol containers are provided with a metering valve having a metering chamber. In a first position of the valve, the metering chamber is in communication with the interior of the container and, in that position, has been filled with the predetermined amount of suspension. In a second position of the metering valve, the amount disposed in the metering chamber is then released in the form of an aerosol, since the liquid/solid mixture can expand. In that manner the aerosol can be administered, fox example orally or nasally, to the user.
Hitherto, the propellant gases used have been the widely known fluorochlorohydro-carbons. Those chlorinated propellant gases are now known to be harmful, since they destroy the ozone layer, and they therefore should, and must, be abolished and replaced by other propellant gases that do not damage the ozone layer. In some countries, very recently those propellant gases which comprise chlorinated hydrocarbons have even been banned by law.
So-called "alternative propellant gases" are therefore presented as an alternative, since they do not damage the ozone layer (ozone-depleting potential = 0). However, many pharmaceutical substances, when stored in the form of a suspension, are deposited on the inner wall of the container when those propellant gases are used, whereas that did not occur, or occurred only to a very small extent, when chlorinated hydrocarbons were used. Such deposits on the inner wall of the container may result in the desired amount of pharmaceutical active substance that is to be administered to the user not being present in the metering chamber. A further consequence is that the total amount of pharmaceutically active substance stored in the container cannot be administered, since a very considerable proportion of the total amount of pharmaceutically active substance introduced into the container remains deposited on (adheres to) the inner wall of the container.
The aim of the invention is therefore to provide a container in which the pharmaceutically active substance can be supplied in the formulation that has already proved suitable and in which, at the same time, it is possible for alternative propellant gases that do not damage the ozone layer to be used, without significant amounts of the pharmaceutically active substance being deposited on the inner wall of the container. In particular, that is to be possible for anti-asthmatically active pharmaceutical substances (for example cortico-steroids), but of course the intention is for it also to be possible for other classes of pharmaceutical substances to be stored in such containers without any significant deposits of active substance being deposited on the inner wall of the container.
The aim is achieved in accordance with the invention by a container in which the inner wall is coated with a plastic coating and in which the propellant gas is a propellant gas that is free of fluorochlorohydrocarbons, preferably a propellant gas that comprises only fluorohydrocarbons and, - 2a -where appropriate, also cosolvents and/or surfactants. With such an arrangement, on the one hand no or no significant ~ amounts of active substance are deposited on the inner wall of the container, and on the other hand the ozone layer is not damaged or destroyed. Especially advantageous materials that may be used for the plastics coating are, for example, polytetrafluoroethylene, widely known as Teflon, and also perfluoroethylenepropylene.
In accordance with this invention, there is provided an aerosol container system for metering and administering pharmaceutically active aerosols supplied in the form of a suspension, the suspension including a pharmaceutically active agent and a propellant gas free of fluorochlorohydrocarbons, said aerosol container system comprising: a container for storing the suspension comprising a container wall, the inner portion of said container wall which defines the interior of the container being coated with a plastics coating which inhibits the pharmaceutically active agent in the suspension from depositing thereon, and a metering valve system for dosing and releasing the suspension comprising a metering chamber and a valve stem, said valve stem capable of being displaced from a first position to a second position, wherein in the first position the valve stem affords communication between the interior of the container and the metering chamber while simultaneously blocking communication between the metering chamber and the outside of the aerosol container system such that the metering chamber can be filled with a dose of the suspension from the container, and wherein in the second position the valve stem blocks communication between the interior of the container and the metering chamber while simultaneously affording communication between the metering chamber and the outside of the aerosol container system such - 2b -that the dose of suspension in the metering chamber can be released from the aerosol container system.
In specific example embodiments of such containers, the thickness of the container wall may be in the range from approximately 0.1 mm to approximately 2 mm, and may be especially approximately 0.4 mm (depending on the material used), and the thickness of the plastics coating may be in the range from approximately 1 nm to approximately 1 mm, and may be especially some 10 nm. The wall thicknesses mentioned are customary for aerosol containers, so that the aerosol containers according to the invention, purely ~1~U~S0 externally and especially in respect of external dimensions, do not differ from customary containers and therefore, even if they have to be used to deliver the aerosol, for example, into an applicator for customary aerosol containers, their use poses no problem.
The volume of the interior of the container of such aerosols is in the 'range from approxim- , , ately 1 ml to approximately 100 ml and the volume of the metering chamber is~in the range from approximately 5 w1 to approximately 400 w1. Those volumes are customary, for example, when corticosteroids are used as the pharmaceutically active substance, for example for the corticosteroid with the chemical name "9«-chloro-6«-fluoro- 11 x,17«-dihydroxy-16«-methyl-3-oxo-androsta-1,4-diene-17~-methoxycarbonyl-17-propionate", but also for other pharmaceutically active and, especially, anti-asthmatically active substances, such as, for example; Formoterol, which may be in the form of its salt, Formoternl fumarate, the name of which according to IUPAC nomenclature is "(t)2'-hydroxy-5'-[(RS)-1-hydroxy-2-[[(RS)-p-methoxy-«-methylphenethyl]amino]ethyl]form-anilide ~ funaarate ~ dihydrate", or also for mixtures of Formoterol and the mentioned corticosteroid.
An especially suitable pharmaceutically active substance is the substance called "(1R,2S)-(3E,5~-7-[1-(3-trifluoromethylphenyl~l-hydroxy-10-(4-acetyl-3-hydroxy-pmpylphenoxy)-3,5-decadien-2-ylthio]-4-oxo-4H-1-benzopyrane-2-carboxylic acid"
or a sodium salt of that substance, since with those substances especially small deposits, or no deposits at all, occur on the inner wall of the container. The complete aerosol may there-fore in that case comprise 0.1 °Ro.to 296 of that active substance and HFA propellant gases (where appropriate, cosolvents and/or surfactants may also be included).
In the following, the invention is explained in detail with reference to the drawing. The single drawing is a diagrammatic representation in section of an example embodiment of an aerosol container according to the invention. The aerosol container is shown in the drawing in its "in use" position.
The aerosol container is indicated generally by the reference numeral 1. The inner wall of the container 1 is coated with a plastics coating 3, the importance of which will be dealt with in more detail further below. Mounted on the aerosol container 1 is a metering valve 2. The metering valve 2 comprises a valve stem 21, which is guided in a valve housing 25 and is displaceable against the force of a spring F in the valve housing 25.
Provided in the wall of the valve housing 25 are individual slots 26 which place the interior 10 of the ~~vVav~
container 1 in communication with the interior 27 of the valve housing 25. The metering valve 2 also comprises a metering chamber 20, which is filled in a manner explained hereinafter through the slots 26 in the wall of the valve housing 25 with the aid of the valve stem 21. The interior 27 of the valve housing 25 is sealed from the metering chamber 20 by means of a seal 250; the metering chamber 20 is in turn sealed from the outside by a seal 251. Finally, the entire interior 10 of the container is in addition sealed from the outside by means of a seal 28 provided in the metering valve 2.
The stem 21 of the metering valve 2 has two channels 29 and 22. The channel 29 has at its "inner" end a transverse bore 24 which, in the illustrated first position of the stem 21, opens into the interior 27 of the valve housing 25 and thus places the interior 27 of the valve housing, and therefore the interior 10 of the container, in communication with the metering chamber 20. The volume of the metering chamber 20 determines the desired amount of aerosol that is to be administered. How that chamber is filled will be explained later. In any event, in that first position of the stem 21 no aerosol can escape from the metering chamber 20 to the outside, since the metering chamber 20 is sealed from the outside by the seal 251.
In the second position of the valve stem 21, the spring F is compressed and the stem 21 is pushed so far into the interior 27 of the valve housing 25 that there is no communication from the interior 27 of the valve housing 25 and from the interior 10 of the container 1 via the channel 29. In that second position of the stem 21, however, there is communication from the metering chamber 20 out to the user by means of a transverse bore 23 at the "inner" end of the channel 22. The amount of aerosol disposed in the metering chamber 20 can expand through that transverse bore 23 and the channel 22 and thus be administered to the user either directly or by means of a special applicator.
When the valve stem 21 is released again after the administration, the transverse bore 23 passes into the region of the seal 251, and the metering chamber 20 is sealed from the outside again. The stem 21 is at that point not yet back in its first end position, but the transverse bore 24 is already in communication with the interior 10 of the container 1, so that, as a result of the pressure difference (excess pressure in the container interior, dis-charged metering chamber), suspension immediately flows from the interior 10 of the container into the metering chamber 20 and fills that chamber. The metering chamber 20 is thus immediately refilled when the stem 21 is released or returned and the next admin-istration can therefore follow straightaway.

~1~U~6~1 .'.1:. ~.\:
As has already been mentioned in the introduction, for various reasons (for example stability), many pharmaceutically active substances are supplied in the container under pressure in the form of a suspension, that is to say in the form of a liquid comprising the active substance in the fonm of solids particles. The liquid also comprises at least a pro-pellant gas so that, in the second position of the stem 21, the metered amount disposed in the metering chamber 20 can expand and can thus be administered to the user directly or by means of a special applicator, as has already been explained above.
Since the propellant gas comprises fluorohydrocarbons (preferably, for example, tetra-fluoroethane or heptafluoropropane) and is therefore not harmful to the ozone layer, the inner wall of the container 1 is coated with a plastics coating 3. That plastics coating 3 is preferably of polytetrafluoroethylene, also widely known by the name Teflon, or of per-fluoroethylenepropylene, or the layer is produced based on the particular plastics and applied. The use of those materials prevents significant deposits of the active substance on the inner wall of the container 1. The effects of corrosion and electrolysis between the container wall and the liquid or suspension are also avoided.
A wide variety of processes may be used to coat the inner wall of the container 1 with the plastics coating 3. For example, the coating process used may be plasma coating, an impregnating/spraying process, hard anodization with PTFE inclusion, chemical vapour deposition (CVD), physical vapour deposition (PVD) and other processes that are customary for that purpose. The use of plasma coating is especially preferred.
The container wall may be made, for example, from aluminium. The thickness of the wall is, for example, in the range from approximately 0.1 mm to approximaiely 2 mm and is preferably approximately 0.4 mm. The thickness of the plastics coating is in the range from approximately 1 nm to approximately 1 mm and is preferably approximately some nm to some 10 tun. Those wall thicknesses are typical of containers that have a total volume in the range from approximately 1 ml to approximately 100 ml and preferably from approximately 5 ml to approximately 20 ml. The metering volume, that is to say the volume of the metering chamber 20, is then, for example, in the range from approximately 5 w1 to approximately 400 t~l and is preferably from approximately 25 p.1 to approximately 200 w1.
The active substance to be administered may be, for example, an anti-asthmatically active substance or substance mixture, especially a substance or substance mixture from the corticosteroid or antiinflammatory steroid classes. Specifically, the corticosteroid may be .
the corticosteroid with the chemical name "9«-chloro-6a-fluoro-11~,17a-dihydroxy-16«-methyl-3-oxo-androsta-1,4-diene-17~-methoxycarbonyl-17-propionate".
Equally possible, however, is the administration of other pharmaceutically active and, especially, f anti-asthmatically active substances, such as ~-sympathomimetics, LTD4 antagonists, parasympatholytics, cromoglycinic acid, or of other active substances that are admin-istered via the lungs, nose or throat, as is the case with some proteins. It is furthermore also possible, for example, to store and administer in that manner Formoterol, for example in the form of its salt, Formoterol fumarate, the name of which according to IUPAC
nomenclature is "(t)2'-hydroxy-S'-[(RS)-1-hydroxy-2-[[(RS)-p-methoxy-«-methyl-phenethyl]amino]ethyl]formanilide ~ fumarate ~ dehydrate", or a mixture of Formoterol and the mentioned corticosteroid.
An especially suitable pharmaceutically active substance is also the substance called "(1R,2S)-(3E,5~-7-[1-(3-trifluoromethylphenyl)-1-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-3,5-decadien-2-ylthio]-4-oxo-4H-1-benzopyrane-2-carboxylic acid", or a sodium salt of that substance, since with those substances especially small deposits, oa no deposits at all, occur on the inner wall of the container. The complete aerosol may therefore in that case comprise 0.1 % to 2 % of that active substance and HFA
propellant gases (where appropriate, cosolvents and/or surfactants may also be included).

Claims (9)

1. An aerosol container system for metering and administering pharmaceutically active aerosols supplied in the form of a suspension, the suspension including a pharmaceutically active agent and a propellant gas free of fluorochlorohydrocarbons, said aerosol container system comprising:

a container for storing the suspension comprising a container wall, the inner portion of said container wall which defines the interior of the container being coated with a plastics coating which inhibits the pharmaceutically active agent in the suspension from depositing thereon, and a metering valve system for dosing and releasing the suspension comprising a metering chamber and a valve stem, said valve stem capable of being displaced from a first position to a second position, wherein in the first position the valve stem affords communication between the interior of the container and the metering chamber while simultaneously blocking communication between the metering chamber and the outside of the aerosol container system such that the metering chamber can be filled with a dose of the suspension from the container, and wherein in the second position the valve stem blocks communication between the interior of the container and the metering chamber while simultaneously affording communication between the metering chamber and the outside of the aerosol container system such that the dose of suspension in the metering chamber can be released from the aerosol container system.
2. An aerosol container according to claim 1, wherein the plastics coating disposed on the inner wall of the container is of polytetrafluoroethylene or perfluoroethylenepropylene.
3. An aerosol container according to either claim 1 or claim 2, wherein the thickness of the container wall is in the range from 0.1 mm to 2 mm, and the thickness of the plastics coating is in the range from 1 nm to 1 mm.
4. An aerosol container according to any one of claims 1 to 3, wherein the volume of the interior of the container is in the range from 1 ml to 100 ml and the volume of the metering chamber is from 5 µl to 400 µl.
5. The use of an aerosol container according to any one of claims 1 to 4 for the storage and administration of a predetermined amount of a pharmaceutically active aerosol in the form of a suspension.
6. The use according to claim 5, wherein the pharmaceutically active substance in the suspension is an anti-asthmatically active substance or substance mixture.
7. The use according to claim 6, wherein the pharmaceutically active substance in the suspension is Formoterol or a corticosteroid.
8. The use according to claim 7 wherein the pharmaceutically active substance in the suspension is 9.alpha.-chloro-6.alpha.-fluoro-11.beta.,17.alpha.-dihydroxy-16.alpha.-methyl-3-oxo-androsta-1,4-diene-17.beta.-methoxycarbonyl-17-propionate, or a mixture thereof.
9. ~The use according to claim 6, wherein the pharmaceutically active substance is (1R,2S)-(3E,5Z)-7-[1-(3-trifluoromethylphenyl)-1-hydroxy-10-(4-acetyl-3-hydroxy-2-propylphenoxy)-3,5-decadien-2-ylthio]-4-oxo-4H-1-benzopyrane-2-carboxylic acid.
CA002130867A 1993-08-27 1994-08-25 An aerosol container and the use of an aerosol container Expired - Lifetime CA2130867C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP93810614.3 1993-08-27
EP93810614 1993-08-27

Publications (2)

Publication Number Publication Date
CA2130867A1 CA2130867A1 (en) 1995-02-28
CA2130867C true CA2130867C (en) 2006-07-11

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Family Applications (1)

Application Number Title Priority Date Filing Date
CA002130867A Expired - Lifetime CA2130867C (en) 1993-08-27 1994-08-25 An aerosol container and the use of an aerosol container

Country Status (11)

Country Link
US (2) US6596260B1 (en)
EP (1) EP0642992B1 (en)
JP (1) JP3610438B2 (en)
AT (1) ATE163623T1 (en)
AU (1) AU690913B2 (en)
CA (1) CA2130867C (en)
DE (1) DE59405357D1 (en)
DK (1) DK0642992T3 (en)
ES (1) ES2113074T3 (en)
GR (1) GR3026507T3 (en)
HK (1) HK1010716A1 (en)

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CA2130867A1 (en) 1995-02-28
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DK0642992T3 (en) 1998-12-07
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