CA2214436C - Corticosteroid-containing pharmaceutical composition - Google Patents
Corticosteroid-containing pharmaceutical composition Download PDFInfo
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- CA2214436C CA2214436C CA002214436A CA2214436A CA2214436C CA 2214436 C CA2214436 C CA 2214436C CA 002214436 A CA002214436 A CA 002214436A CA 2214436 A CA2214436 A CA 2214436A CA 2214436 C CA2214436 C CA 2214436C
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- Prior art keywords
- pharmaceutical composition
- foamable pharmaceutical
- active substance
- alcohol
- composition according
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- 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
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/122—Foams; Dry foams
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/08—Antiseborrheics
Abstract
The present invention provides a foamable pharmaceutical composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant and a buffering agent. The quick-break foaming agent typically comprises an aliphatic alcohol, water, a fatty alcohol and surface active agent. The compositions of the invention can be used to treat various skin disease, and in particular scalp psoriasis.
Description
Wu 90/27.3/0 CA 02214436 2005-09-08 PCT/GB96/00490 ~
CORTICOSTEROID-CONTAINING PHARMACEUTICAL COMPOSITION
The present invention relates to an improved composition for the topical application of corticosteroid active substances to the skin of a subject.
Corticosteroids, particularly in the form of the ester compounds, are used, inter alia, in the treatment of skin diseases in humans, such as eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrhoeic dermatitis, neurodermatitis, psoriasis and intertrigo. Formulations containing such active substances have conventionally been applied to the skin site in the form of alcoholic solutions, lotions or creams. However, there is a high degree of ineffectiveness with such formulations. Lotions and creams are generally too viscous to allow efficient penetration of the active to the epidermis, and solutions have a tendency to evaporate before.penetrating the epidermis.
In addition, conventional cream bases are irritating to the skin, particularly over the often long exposure that is required, and the fluidity of lotions often makes the physical application difficult to control.
Moreover, it is necessary to rub such formulations into the target site to improve the penetration of the active substance into the epidermis, an action which itself produces irritation.
There has therefore been a very real need in the treatment of skin disorders requiring treatment with corticosteroids for improved formulations which target the most effective corticosteroid to the skin site with improved delivery of active, with decreased inconvenience and irritation, and increased ease of use for the patient.
CORTICOSTEROID-CONTAINING PHARMACEUTICAL COMPOSITION
The present invention relates to an improved composition for the topical application of corticosteroid active substances to the skin of a subject.
Corticosteroids, particularly in the form of the ester compounds, are used, inter alia, in the treatment of skin diseases in humans, such as eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrhoeic dermatitis, neurodermatitis, psoriasis and intertrigo. Formulations containing such active substances have conventionally been applied to the skin site in the form of alcoholic solutions, lotions or creams. However, there is a high degree of ineffectiveness with such formulations. Lotions and creams are generally too viscous to allow efficient penetration of the active to the epidermis, and solutions have a tendency to evaporate before.penetrating the epidermis.
In addition, conventional cream bases are irritating to the skin, particularly over the often long exposure that is required, and the fluidity of lotions often makes the physical application difficult to control.
Moreover, it is necessary to rub such formulations into the target site to improve the penetration of the active substance into the epidermis, an action which itself produces irritation.
There has therefore been a very real need in the treatment of skin disorders requiring treatment with corticosteroids for improved formulations which target the most effective corticosteroid to the skin site with improved delivery of active, with decreased inconvenience and irritation, and increased ease of use for the patient.
The present invention provides an improved composition which addresses this need.
In one aspect, the present invention provides a foamable phdrmaceutical composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant and a buffering agent.
Such a composition is applied to the skin site (after foaming) as a foam which is a thermophobic (heat sensitive) quick-break foam. On application to the skin, the composition is initially in the form of a mousse-like foam. The quick-break foam slowly breaks down at the skin temperature to a liquid to allow the alcohol and active substance to saturate the treatment site. Such a system provides enhanced penetration of the alcohol and active substance through the epidermis. Because the composition is supplied as a mousse, the semi-rigid behaviour of the composite makes it easier to handle and physically control. The foamed composition, when applied, provides a thick ball of foam which disintegrates easily when spread, allowing proper coverage of the skin site to be treated without premature evaporation of the solvent. It has been found important to include a buffering agent in the composition to stabilize the active isomer of the corticosteroid active substance in the complex foamable composition , otherwise the complex interactions within the foamable composition may result in the instability of the more active isomer.
Use of a quick-break foaming agent is required in the present invention. Such agents are known. Suitable quick-break foaming agents in the present invention are those described in Australian Patent No.
463216 and International Patent Application WO 85/01876. It is generally preferred that the quick-breaking foaming agent comprises an aliphatic alcohol, water, a fatty alcohol and a surface active agent. Particularly preferred is a quick-break foaming agent having the following composition:
WO 96/27376 PCT/GB96/004%
In one aspect, the present invention provides a foamable phdrmaceutical composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant and a buffering agent.
Such a composition is applied to the skin site (after foaming) as a foam which is a thermophobic (heat sensitive) quick-break foam. On application to the skin, the composition is initially in the form of a mousse-like foam. The quick-break foam slowly breaks down at the skin temperature to a liquid to allow the alcohol and active substance to saturate the treatment site. Such a system provides enhanced penetration of the alcohol and active substance through the epidermis. Because the composition is supplied as a mousse, the semi-rigid behaviour of the composite makes it easier to handle and physically control. The foamed composition, when applied, provides a thick ball of foam which disintegrates easily when spread, allowing proper coverage of the skin site to be treated without premature evaporation of the solvent. It has been found important to include a buffering agent in the composition to stabilize the active isomer of the corticosteroid active substance in the complex foamable composition , otherwise the complex interactions within the foamable composition may result in the instability of the more active isomer.
Use of a quick-break foaming agent is required in the present invention. Such agents are known. Suitable quick-break foaming agents in the present invention are those described in Australian Patent No.
463216 and International Patent Application WO 85/01876. It is generally preferred that the quick-breaking foaming agent comprises an aliphatic alcohol, water, a fatty alcohol and a surface active agent. Particularly preferred is a quick-break foaming agent having the following composition:
WO 96/27376 PCT/GB96/004%
(a) an aliphatic alcohol, preferably in amounts of 40-90% w/w composition, more preferably 55-70% w/w, especially 57-59%
w/w;
(b) water, preferably in amounts of 10-40% w/w;
(c) at least one fatty alcohol, preferably in amounts of 0.5-10%
w/w; and (d) a surface active agent, preferably an ethoxylated sorbitan ester (as emulsifier), typically in amounts of 0.1-15% w/w.
In the quick-break foaming agent, the fatty alcohol may be chosen from, for example, cetyl, stearyl, lauryl, myristyl and palmityl alcohols and mixtures of two or more thereof. Mixtures of cetyl alcohol and a stearyl alcohol such as octadecan-l-ol have been found to be particularly preferred; the ratio between these two components may be adjusted to maintain foam viscosity throughout the broadest possible temperature range. In this situation, the stearyl alcohol maintains the viscosity at temperatures above 20 C whilst cetyl alcohol maintains the viscosity below 20 C.
The aliphatic alcohol may preferably be chosen from methyl, ethyl, isopropyl and butyl alcohols, and mixtures of two or more thereof. Ethanol has been found to be particularly preferred.
Surface active agents utilised in the quick-break foaming agent may preferably be chosen from ethoxylated sorbitan stearate, paimitate, oleate, nonyl phenol ethoxylates and fatty alcohol ethoxylates, and mixtures of two TM
or more thereof. Thus, for example, Polysorbate 60 (a mixture of partial stearic esters of sorbitol and its anhydrides copolymerised with approximately 20 moles of ethylene oxide for each mole of sorbitol and its anhydrides) has been found to be particularly preferred. The surface active agent enhances the fatty alcohol solubility in the system and enhances foam formation.
w/w;
(b) water, preferably in amounts of 10-40% w/w;
(c) at least one fatty alcohol, preferably in amounts of 0.5-10%
w/w; and (d) a surface active agent, preferably an ethoxylated sorbitan ester (as emulsifier), typically in amounts of 0.1-15% w/w.
In the quick-break foaming agent, the fatty alcohol may be chosen from, for example, cetyl, stearyl, lauryl, myristyl and palmityl alcohols and mixtures of two or more thereof. Mixtures of cetyl alcohol and a stearyl alcohol such as octadecan-l-ol have been found to be particularly preferred; the ratio between these two components may be adjusted to maintain foam viscosity throughout the broadest possible temperature range. In this situation, the stearyl alcohol maintains the viscosity at temperatures above 20 C whilst cetyl alcohol maintains the viscosity below 20 C.
The aliphatic alcohol may preferably be chosen from methyl, ethyl, isopropyl and butyl alcohols, and mixtures of two or more thereof. Ethanol has been found to be particularly preferred.
Surface active agents utilised in the quick-break foaming agent may preferably be chosen from ethoxylated sorbitan stearate, paimitate, oleate, nonyl phenol ethoxylates and fatty alcohol ethoxylates, and mixtures of two TM
or more thereof. Thus, for example, Polysorbate 60 (a mixture of partial stearic esters of sorbitol and its anhydrides copolymerised with approximately 20 moles of ethylene oxide for each mole of sorbitol and its anhydrides) has been found to be particularly preferred. The surface active agent enhances the fatty alcohol solubility in the system and enhances foam formation.
The propellant used may be chosen from conventional aerosol propellants. Thus, one may select the propellant from propane, butane, dichloro difluoro methane, dichloro tetrafluoro ethane, octafluoro cyclobutane, and mixtures of two or more thereof. It is necessary to select a propellant most compatible with the entire system. It is particularly preferred that the propellant be present in amounts preferably of 3-30%
w/w, more preferably 3-10%w/w, especially 3-5% w/w. The maximum level of propellant will be determined as the amount miscible with the utilized water/aliphatic alcohol ratio. In addition to acting as a propellant, the propellant will also act as a solvent for the fatty acids and active substances in the aqueous/alcoholic system.
It is possible that other additives may be used. Thus, it is preferred to add a humectant to reduce the drying effects of the aqueous aliphatic alcohol. Such a humectant may preferably be present in an amount of 0.1-10.0% w/w, more preferably 0.5-3.0% w/w. Itis particularly preferred that the humectant be propylene glycol, but other humectants such as glycerine, panthenol and sorbitol may be used.
The composition of the present invention may be used to deliver corticosteroid compounds which have utility in the topical treatment of skin disorders. Thus, for example, the composition of the present invention may be used to deliver the following topically-effective corticosteroids:
alclometasone dipropionate fluclorolone acetonide amcinonide fluocinolone acetonide beclamethasone dipropionate fluocinonide betamethasone benzoate fluocortin butyl betamethasone dipropionate fluocortolone preparations betamethasone valerate fluprednidene acetate budesonide flurandrenolone clobetasol propionate halcinonide WO 96/27376 CA 02214436 2005-09-08 pCr/GB96/00490 clobetasone butyrate hydrocortisone desonide hydrocortisone acetate desoxymethasone hydrocortisone butyrate diflorasone diacetate methylprednisolone acetate diflucortolone valerate mometasone furoate flumethasone pivalate triamcinolone acetonide and pharmacologically effective mixtures thereof.
Compositions according to theinvention areespecially advantageous for the topical administration to the skin of human subjects of betamethasone and its derivatives such as betamethasone benzoate, betamethasone dipropionate, and betamethasone valerate. It is particularly preferred to use the valerate ester, especially in the treatment of psoriasis.
The corticosteroid active substance is preferably present in an amount of 0.01-1.0% w/w more preferably 0.05-0.2% w/w.
In view of the complexity of the composition, it has been found that unexpectedly in order to ensure stability of the active isomer of the corticosteroid in the composition and thus to ensure delivery of the most active isomer to the epidermis, it is necessary to buffer the composition by including a suitable buffering agent. Suitable buffering agents are acetic acid/sodium acetate, citric acid/sodium citrate and phosphoric acid/sodium phosphate, and it is desirable generally to buffer the composition to pH
3 - 6 , preferably 4 - 5 , and to this end the buffering agent may preferably be present in an amount of 0.01-1.0% w/w, more preferably 0.05-0.2% w/w. It is particularly preferred to use a citrate buffer system, more preferably anhydrous citric acid/potassium citrate, to buffer the composition to pH 4.5, when betamethasone valerate is used as the active substance; in this case citrate buffering stabilises the more active 17-valerate ester over the less active 21-valerate ester in the complex composition and ensures that the most effective form of the active substance is efficiently delivered to the epidermis.
Preparation of thecomposition may be effected by conventional means so as to produce a homogeneous solution of fatty alcohol(s) (wax[es]) in an alcohol/water base. The relative proportions of the fatty alcohol(s), water/aliphatic alcohol and propellant are conveniently controlled according to conventional means so as to provide a homogeneous clear solution and so as to provide a homogeneous clear solution and so as to allow the formation of a suitable quick-break foam. Generally speaking the fatty alcohol(s), surface active agent, aliphatic alcohol and humectant (if present) are preferably mixed together with the corticosteroid active substance to produce an "Alcohol Phase". An "Aqueous Phase" is preferably produced by mixing the buffering agent and water. These phases are then mixed, preferably in the final container, in the required amounts. The propellant is then added under pressure to produce the composition according to the invention.
In the case of betamethasone valerate, for example, it is particuiarly preferred to use a composition comprising cetyl alcohol and octadecan-l-ol as fatty alcohols, together with Polysorbate 60 surface active agent, with purified water and ethanol as the aliphatic alcohol. The system is preferably buffered with anhydrous citric acid/potassium citrate and the propellant is preferably butane/propane. It is generally preferred to choose the proportion of the components to achieve a fixed pressure in the container of around 50-70 psi.
The composition of the present invention may be contained in and dispensed from a container capable of withstanding the pressure of the propellant gas and having an appropriate valve/nozzle for dispensing the composition as a foam under pressure. If the container is made of a metal material likely to suffer corrosion under the action of the composition, the composition may include a corrosion inhibitor as an additive. Thus, the presence of a corrosion inhibitor may be necessary if the container is made of tin plate. Suitable corrosion inhibitors include organic acid salts, pre-erably chosen from sorbic acid, benzoic acid, sodium benzoate and potassium sorbate. If used, the corrosion inhibitor may be present in amounts of 0.1-15% w/w, more preferably 0.1-3% w/w. In the present invention, aluminium cans are preferred as containers, particularly when utilising theabove-mentioned composition for betamethasonevalerate as the corticosteroid active substance; in this case there is no corrosion problem and there is no need for the inclusion of a corrosion inhibiting agent.
In use, the composition is sprayed, producing a semi-solid form (a foam or mousse) which is suitable for the topical application to the site of interest, eg the scalp when treating dermatological conditions of the scalp.
On application, heat from the skin causes the mousse to break down into liquid form, thus releasing the aliphatic alcohol and corticosteroid active substance which penetrate the skin site, leaving a low amount of residue, many times lower than those obtained when delivering active from a cream base. This route of administration facilitates the ease of specific local application, and the composition according to the invention provides a convenient, controllable and efficient vehicle for delivering topically active corticosteroids to the skin. This gives greater physical control compared to conventional topical corticosteroid formulations, minimises rubbing of the target site and allows the alcoholic vehicle to penetrate the skin to deliver the active to where it will have the greatest effect.
The composition of the present invention may be used in treating skin diseases which are conventionally treated with corticosteroid active substances. Thus, the composition may be used in the treatment of, inter alia, eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrhoeic dermatitis, neurodermatitis, psoriasis and WO 96/27376 PCf/GB96/00490 intertrigo. The composition is especially useful in the treatment of scalp psoriasis in human subjects.
The present invention will now be illustrated by means of the fo-flowing non-limiting Example:
EXAMPLE
Betamethasone valerate composition A betamethasone valerate formulation having the following composition was prepared:
6 w /w Betamethasone Valerate 0.12 Cetyl Alcohol BP 1.10 Octadecan-l-ol BP 0.50 Polysorbate 60 BP 0.40 Ethanol 57.79 Purified Water 33.69 Propylene Glycol BP 2.00 Citric Acid Anhydrous BP 0.073 Potassium Citrate 0.027 Butane/Propane 4.30 100.00 TM
Cetyl alcohol (HYFATOL 1698, Efkay Chemicals Limited, London), TM
octadecan-l-ol (HYFATOL 1898, Efkay Chemicals Limited, London), TM
Polysorbate 60 (CRILLET 3, Croda Chemicals, North Humberside) and ethanol in the correct proportions were mixed and heated to about 45 C, with continuous stirring until the mix became clear. Betamethasone valerate BP (Roussel Uclaf, Virtolaye, France) was slowly transferred into the mix, again with continuous stirring until the mix became clear.
(Alcoholic Phase) Purified water was separately heated to 45 C and anhydrous citric acid BP and potassium citrate BP transferred to the water, with continuous stirring until dissolved. (Aqueous Phase) The Alcoholic and Aqueous phases were each filtered through 75 micron screens and the required weights filled into a can (aluminium, epoxy lined) at room temperature. After attaching a valve, the TM
butane/propane propellant (Propellant P70) was added to the mix in the can to the required weight, and an actuator added to the valve.
The composition, on being sprayed from the can onto the skin, produces a thermophobic foam which breaks down under heating from the skin to release the active to the epidermis. The presence of the citrate buffer stabilizes the 17-valerate configuration of the betamethasone valerate over the less active 21-valerate configuration, thus producing a composition which efficaciously delivers active to the epidermis and which is particulariy suitable for the treatment of psoriasis, especially scalp psoriasis.
w/w, more preferably 3-10%w/w, especially 3-5% w/w. The maximum level of propellant will be determined as the amount miscible with the utilized water/aliphatic alcohol ratio. In addition to acting as a propellant, the propellant will also act as a solvent for the fatty acids and active substances in the aqueous/alcoholic system.
It is possible that other additives may be used. Thus, it is preferred to add a humectant to reduce the drying effects of the aqueous aliphatic alcohol. Such a humectant may preferably be present in an amount of 0.1-10.0% w/w, more preferably 0.5-3.0% w/w. Itis particularly preferred that the humectant be propylene glycol, but other humectants such as glycerine, panthenol and sorbitol may be used.
The composition of the present invention may be used to deliver corticosteroid compounds which have utility in the topical treatment of skin disorders. Thus, for example, the composition of the present invention may be used to deliver the following topically-effective corticosteroids:
alclometasone dipropionate fluclorolone acetonide amcinonide fluocinolone acetonide beclamethasone dipropionate fluocinonide betamethasone benzoate fluocortin butyl betamethasone dipropionate fluocortolone preparations betamethasone valerate fluprednidene acetate budesonide flurandrenolone clobetasol propionate halcinonide WO 96/27376 CA 02214436 2005-09-08 pCr/GB96/00490 clobetasone butyrate hydrocortisone desonide hydrocortisone acetate desoxymethasone hydrocortisone butyrate diflorasone diacetate methylprednisolone acetate diflucortolone valerate mometasone furoate flumethasone pivalate triamcinolone acetonide and pharmacologically effective mixtures thereof.
Compositions according to theinvention areespecially advantageous for the topical administration to the skin of human subjects of betamethasone and its derivatives such as betamethasone benzoate, betamethasone dipropionate, and betamethasone valerate. It is particularly preferred to use the valerate ester, especially in the treatment of psoriasis.
The corticosteroid active substance is preferably present in an amount of 0.01-1.0% w/w more preferably 0.05-0.2% w/w.
In view of the complexity of the composition, it has been found that unexpectedly in order to ensure stability of the active isomer of the corticosteroid in the composition and thus to ensure delivery of the most active isomer to the epidermis, it is necessary to buffer the composition by including a suitable buffering agent. Suitable buffering agents are acetic acid/sodium acetate, citric acid/sodium citrate and phosphoric acid/sodium phosphate, and it is desirable generally to buffer the composition to pH
3 - 6 , preferably 4 - 5 , and to this end the buffering agent may preferably be present in an amount of 0.01-1.0% w/w, more preferably 0.05-0.2% w/w. It is particularly preferred to use a citrate buffer system, more preferably anhydrous citric acid/potassium citrate, to buffer the composition to pH 4.5, when betamethasone valerate is used as the active substance; in this case citrate buffering stabilises the more active 17-valerate ester over the less active 21-valerate ester in the complex composition and ensures that the most effective form of the active substance is efficiently delivered to the epidermis.
Preparation of thecomposition may be effected by conventional means so as to produce a homogeneous solution of fatty alcohol(s) (wax[es]) in an alcohol/water base. The relative proportions of the fatty alcohol(s), water/aliphatic alcohol and propellant are conveniently controlled according to conventional means so as to provide a homogeneous clear solution and so as to provide a homogeneous clear solution and so as to allow the formation of a suitable quick-break foam. Generally speaking the fatty alcohol(s), surface active agent, aliphatic alcohol and humectant (if present) are preferably mixed together with the corticosteroid active substance to produce an "Alcohol Phase". An "Aqueous Phase" is preferably produced by mixing the buffering agent and water. These phases are then mixed, preferably in the final container, in the required amounts. The propellant is then added under pressure to produce the composition according to the invention.
In the case of betamethasone valerate, for example, it is particuiarly preferred to use a composition comprising cetyl alcohol and octadecan-l-ol as fatty alcohols, together with Polysorbate 60 surface active agent, with purified water and ethanol as the aliphatic alcohol. The system is preferably buffered with anhydrous citric acid/potassium citrate and the propellant is preferably butane/propane. It is generally preferred to choose the proportion of the components to achieve a fixed pressure in the container of around 50-70 psi.
The composition of the present invention may be contained in and dispensed from a container capable of withstanding the pressure of the propellant gas and having an appropriate valve/nozzle for dispensing the composition as a foam under pressure. If the container is made of a metal material likely to suffer corrosion under the action of the composition, the composition may include a corrosion inhibitor as an additive. Thus, the presence of a corrosion inhibitor may be necessary if the container is made of tin plate. Suitable corrosion inhibitors include organic acid salts, pre-erably chosen from sorbic acid, benzoic acid, sodium benzoate and potassium sorbate. If used, the corrosion inhibitor may be present in amounts of 0.1-15% w/w, more preferably 0.1-3% w/w. In the present invention, aluminium cans are preferred as containers, particularly when utilising theabove-mentioned composition for betamethasonevalerate as the corticosteroid active substance; in this case there is no corrosion problem and there is no need for the inclusion of a corrosion inhibiting agent.
In use, the composition is sprayed, producing a semi-solid form (a foam or mousse) which is suitable for the topical application to the site of interest, eg the scalp when treating dermatological conditions of the scalp.
On application, heat from the skin causes the mousse to break down into liquid form, thus releasing the aliphatic alcohol and corticosteroid active substance which penetrate the skin site, leaving a low amount of residue, many times lower than those obtained when delivering active from a cream base. This route of administration facilitates the ease of specific local application, and the composition according to the invention provides a convenient, controllable and efficient vehicle for delivering topically active corticosteroids to the skin. This gives greater physical control compared to conventional topical corticosteroid formulations, minimises rubbing of the target site and allows the alcoholic vehicle to penetrate the skin to deliver the active to where it will have the greatest effect.
The composition of the present invention may be used in treating skin diseases which are conventionally treated with corticosteroid active substances. Thus, the composition may be used in the treatment of, inter alia, eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrhoeic dermatitis, neurodermatitis, psoriasis and WO 96/27376 PCf/GB96/00490 intertrigo. The composition is especially useful in the treatment of scalp psoriasis in human subjects.
The present invention will now be illustrated by means of the fo-flowing non-limiting Example:
EXAMPLE
Betamethasone valerate composition A betamethasone valerate formulation having the following composition was prepared:
6 w /w Betamethasone Valerate 0.12 Cetyl Alcohol BP 1.10 Octadecan-l-ol BP 0.50 Polysorbate 60 BP 0.40 Ethanol 57.79 Purified Water 33.69 Propylene Glycol BP 2.00 Citric Acid Anhydrous BP 0.073 Potassium Citrate 0.027 Butane/Propane 4.30 100.00 TM
Cetyl alcohol (HYFATOL 1698, Efkay Chemicals Limited, London), TM
octadecan-l-ol (HYFATOL 1898, Efkay Chemicals Limited, London), TM
Polysorbate 60 (CRILLET 3, Croda Chemicals, North Humberside) and ethanol in the correct proportions were mixed and heated to about 45 C, with continuous stirring until the mix became clear. Betamethasone valerate BP (Roussel Uclaf, Virtolaye, France) was slowly transferred into the mix, again with continuous stirring until the mix became clear.
(Alcoholic Phase) Purified water was separately heated to 45 C and anhydrous citric acid BP and potassium citrate BP transferred to the water, with continuous stirring until dissolved. (Aqueous Phase) The Alcoholic and Aqueous phases were each filtered through 75 micron screens and the required weights filled into a can (aluminium, epoxy lined) at room temperature. After attaching a valve, the TM
butane/propane propellant (Propellant P70) was added to the mix in the can to the required weight, and an actuator added to the valve.
The composition, on being sprayed from the can onto the skin, produces a thermophobic foam which breaks down under heating from the skin to release the active to the epidermis. The presence of the citrate buffer stabilizes the 17-valerate configuration of the betamethasone valerate over the less active 21-valerate configuration, thus producing a composition which efficaciously delivers active to the epidermis and which is particulariy suitable for the treatment of psoriasis, especially scalp psoriasis.
Claims (63)
1. ~A foamable pharmaceutical composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant and a buffering agent for buffering the pH of the composition in the range 3 to 6, with the proviso that the corticosteroid active substance is not budesonide.
2. ~A foamable pharmaceutical composition adapted for topical administration, the composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant and a buffering agent to maintain the pH
of the composition within the range of 3 to 6.
of the composition within the range of 3 to 6.
3. ~A foamable pharmaceutical composition comprising a corticosteroid active substance, a quick-break foaming agent, a propellant, and a buffering agent present in an amount from 0.05 to 0.2% w/w for buffering the pH of the composition in the range of 3 to 6.
4. ~A foamable pharmaceutical composition according to claim 1 or 2, wherein the buffering agent is present in an amount from 0.01 to 1.0% w/w.
5. ~A foamable pharmaceutical composition according to claim 4, wherein the buffering agent is present in an amount in the range 0.05 to 0.2% w/w.
6. ~A foamable pharmaceutical composition according to any one of claims 1 to 5, wherein the buffering agent is a citrate buffer, an acetic acid/sodium acetate buffer, or a phosphoric acid/sodium phosphate buffer.
7. ~A foamable pharmaceutical composition according to claim 6, wherein the buffering agent is a citric acid/sodium citrate buffer.
8. A foamable pharmaceutical composition according to claim 6, wherein the buffering agent is an anhydrous citric acid/potassium citrate buffer.
9. A foamable pharmaceutical composition according to any one of claims 1 to 8, which is buffered to a pH in the range 4 to 5.
10. A foamable pharmaceutical composition according to any one of claims 1 to 9, wherein the corticosteroid active substance is of a type which exhibits isomerism and has a more active isomer and a less active isomer, the corticosteroid active substance being predominantly present as the more active isomer, and the buffering agent is present in an amount effective to buffer the pH
of the composition and stabilise the more active isomer against isomerisation to the less active isomer.
of the composition and stabilise the more active isomer against isomerisation to the less active isomer.
11. A foamable pharmaceutical composition according to any one of claims 1 to 10, wherein the corticosteroid active substance is topically-effective and comprises:
alclometasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, flumethasone pivalate, fluclorolone acetonide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate, triamcinolone acetonide, or a pharmacologically-effective mixture thereof.
alclometasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, flumethasone pivalate, fluclorolone acetonide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate, triamcinolone acetonide, or a pharmacologically-effective mixture thereof.
12. A foamable pharmaceutical composition according to any one of claims 1 to 10, wherein the corticosteroid active substance is betamethasone or a pharmacologically-effective ester or salt thereof.
13. A foamable pharmaceutical composition according to claim 12, wherein the corticosteroid active substance is betamethasone benzoate, betamethasone dipropionate or betamethasone valerate.
14. A foamable pharmaceutical composition according to claim 13, wherein the corticosteroid active substance is betamethasone valerate.
15. A foamable pharmaceutical composition according to any one of claims 1 to 14, wherein the corticosteroid active substance is present in an amount from 0.01 to 1.0% w/w.
16. A foamable pharmaceutical composition according to claim 15, wherein the corticosteroid active substance is present in an amount from 0.05 to 0.2%
w/w.
w/w.
17. A foamable pharmaceutical composition according to any one of claims 1 to 16, wherein the quick-break foaming agent comprises an aliphatic alcohol, water, a fatty alcohol and a surface-active agent.
18. A foamable pharmaceutical composition according to claim 17, wherein the aliphatic alcohol is present in an amount corresponding to 40 to 90% by weight of the total weight of the composition.
19. A foamable pharmaceutical composition according to claim 18, wherein the aliphatic alcohol is present in an amount corresponding to 55 to 70% by weight of the composition.
20. A foamable pharmaceutical composition according to claim 19, wherein the aliphatic alcohol is present in an amount corresponding to 57 to 59% by weight of the composition.
21. A foamable pharmaceutical composition according to any one of claims 17 to 20, wherein the aliphatic alcohol is methanol, ethanol, isopropyl alcohol, butyl alcohol, or a mixture of two or more thereof.
22. A foamable pharmaceutical composition according to claim 21, wherein the aliphatic alcohol is ethanol.
23. A foamable pharmaceutical composition according to any one of claims 17 to 22, wherein the water is present in an amount in the range 10 to 40% by weight of the composition.
24. A foamable pharmaceutical composition according to any one of claims 17 to 23, wherein the fatty alcohol is present in an amount corresponding to 0.5 to 10% by weight of the composition.
25. A foamable pharmaceutical composition according to any one of claims 17 to 24, wherein the fatty alcohol is a cetyl, stearyl, lauryl, myristyl or palmityl alcohol, or a mixture of two or more thereof.
26. A foamable pharmaceutical composition according to claim 25, wherein the fatty alcohol is a mixture of cetyl alcohol and stearyl alcohol.
27. A foamable pharmaceutical composition according to any one of claims 17 to 26, wherein the surface-active agent is present in an amount from 0.1 to 15%
w/w of the composition.
w/w of the composition.
28. A foamable pharmaceutical composition according to any one of claims 17 to 27, wherein the surface-active agent is ethoxylated sorbitan stearate, ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonyl phenol ethoxylate, a fatty alcohol ethoxylate, or a mixture thereof.
29. A foamable pharmaceutical composition according to claim 28, wherein the surface-active agent is a mixture of partial stearic esters of sorbitol and its anhydrides, copolymerised with about 20 moles of ethylene oxide for each mole of sorbitol and its anhydrides.
30. A foamable pharmaceutical composition according to claim 1, 2 or 3, having the following composition:
% w/w Betamethasone Valerate ~~0.12 Cetyl Alcohol BP ~~~1.10 Octadecan-1-ol BP ~~~0.50 Polysorbate 60 BP ~~~0.40 Ethanol ~~~~57.79 Purified Water ~~~33.69 Propylene Glycol BP ~~~2.00 Citric Acid Anhydrous BP ~~0.073 Potassium Citrate ~~~0.027 Butane/Propane ~~~4.30 100.00 wherein the percentages given are weight-per-weight percentages.
% w/w Betamethasone Valerate ~~0.12 Cetyl Alcohol BP ~~~1.10 Octadecan-1-ol BP ~~~0.50 Polysorbate 60 BP ~~~0.40 Ethanol ~~~~57.79 Purified Water ~~~33.69 Propylene Glycol BP ~~~2.00 Citric Acid Anhydrous BP ~~0.073 Potassium Citrate ~~~0.027 Butane/Propane ~~~4.30 100.00 wherein the percentages given are weight-per-weight percentages.
31. A pharmaceutical product comprising a foamable pharmaceutical composition according to any one of claims 1 to 30 contained within a container capable of withstanding the pressure of a propellant gas, and having a valve or nozzle for dispensing the foamable composition as a foam under pressure.
32. Use of a foamable pharmaceutical composition according to any one of claims 1 to 30 or a pharmaceutical product according to claim 31 in the treatment of eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrhoeic dermatitis, neurodermatitis, psoriasis or intertrigo.
33. Use of a foamable pharmaceutical composition or pharmaceutical product according to claim 32 in the treatment of scalp psoriasis.
34. A foamable pharmaceutical composition comprising a corticosteroid active substance; a quick-break foaming agent that comprises an aliphatic alcohol, water, a fatty alcohol and a surface-active agent; a propellant; and a buffering agent present in an amount sufficient to provide a pH within the range of 3 to 6, for the treatment of a skin disease susceptible to treatment with a corticosteroid active substance.
35. A foamable pharmaceutical composition as defined in claim 34, wherein the skin disease is eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrheic dermatitis, neurodermatitis, psoriasis or intertrigo.
36. A foamable pharmaceutical composition as defined in claim 34, for the treatment of scalp psoriasis in human subjects.
37. A foamable pharmaceutical composition comprised of a quick-break foaming agent that comprises an aliphatic alcohol, water, a fatty alcohol and a surface-active agent; a propellant; an active isomer of an isomeric corticosteroid active substance; and an amount of a buffering agent effective to stabilize the active isomer against isomerization to a less active isomer, for the treatment of a skin disease susceptible to treatment with a corticosteroid active substance.
38. A foamable pharmaceutical composition as defined in claim 37, wherein the amount of the corticosteroid active substance is from 0.01 to 1.0% w/w of the composition.
39. A foamable pharmaceutical composition as defined in any one of claims 34 to 38, wherein the corticosteroid active substance is a topically-effective corticosteroid active substance which is alclometasone dipropionate, amcinonide, beclamethasone dipropionate, betamethiasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, flumethasone pivalate, fluclorolone acetonide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone preparations, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate or triamcinolone acetonide, or a pharmacologically-effective mixture thereof.
40. A foamable pharmaceutical composition as defined in claim 39, wherein the corticosteroid active substance is betamethasone valerate.
41. A foamable pharmaceutical composition as defined in any one of claims 34 to 40, wherein the aliphatic alcohol component is methanol, ethanol, isopropyl alcohol, butyl alcohol, or a mixture thereof.
42. A foamable pharmaceutical composition as defined in claim 41, wherein the aliphatic alcohol component is ethanol.
43. A foamable pharmaceutical composition as defined in any one of claims 34 to 42, wherein the fatty alcohol component is a cetyl, stearyl, lauryl, myristyl or palmityl alcohol, or a mixture thereof.
44. A foamable pharmaceutical composition as defined in claim 43, wherein the fatty alcohol component is a mixture of cetyl alcohol and stearyl alcohol.
45. A foamable pharmaceutical composition as defined in any one of claims 34 to 44, wherein the surface active agent is ethoxylated sorbitan stearate, ethoxylated sorbitan paimitate, ethoxylated sorbitan oleate, a nonyl phenol ethoxylate, a fatty alcohol ethoxylate, or a mixture thereof.
46. A foamable pharmaceutical composition as defined in any one of claims 34 to 45, wherein the buffering agent is a citrate buffer, an acetic acid/sodium acetate buffer or a phosphoric acid/sodium phosphate buffer.
47.A foamable pharmaceutical composition as defined in claim 46, wherein the buffering agent is a citrate buffer.
48. A foamable pharmaceutical composition as defined in claim 34, wherein the foamable pharmaceutical composition comprises:
%w/w Betamethasone Valerate ~~0.12 Cetyl Alcohol BP ~~~1.10 Octadecan-1-ol BP ~~~0.50 Polysorbate 60 BP ~~~0.40 Ethanol ~~~~57.79 Purified Water ~~~33.69 Propylene Glycol BP ~~~2.00 Citric Acid Anhydrous BP ~~0.073 Potassium Citrate ~~~0.027 Butane/Propane ~~~4.30 100.00 wherein the percentages given are weight-per-weight percentages.
%w/w Betamethasone Valerate ~~0.12 Cetyl Alcohol BP ~~~1.10 Octadecan-1-ol BP ~~~0.50 Polysorbate 60 BP ~~~0.40 Ethanol ~~~~57.79 Purified Water ~~~33.69 Propylene Glycol BP ~~~2.00 Citric Acid Anhydrous BP ~~0.073 Potassium Citrate ~~~0.027 Butane/Propane ~~~4.30 100.00 wherein the percentages given are weight-per-weight percentages.
49. Use of a corticosteroid active substance; a quick-break foaming agent that comprises an aliphatic alcohol, water, a fatty alcohol and a surface active agent;
a propellant; and a buffering agent present in an amount sufficient to provide a pH within the range of 3 to 6, in the preparation of a pharmaceutical composition for treatment of a skin disease susceptible to treatment with a corticosteroid active substance.
a propellant; and a buffering agent present in an amount sufficient to provide a pH within the range of 3 to 6, in the preparation of a pharmaceutical composition for treatment of a skin disease susceptible to treatment with a corticosteroid active substance.
50. Use according to claim 49, wherein the skin disease is eczema, infantile eczema, atopic dermatitis, dermatitis herpetiformis, contact dermatitis, seborrheic dermatitis, neurodermatitis, psoriasis or intertrigo.
51. Use according to claim 50, wherein the skin disease is scalp psoriasis in a human subject.
52. Use of a quick-break foaming agent that comprises an aliphatic alcohol, water, a fatty alcohol and a surface-active agent; a propellant; an active isomer of an isomeric corticosteroid active substance; and an amount of a buffering agent effective to stabilize the active isomer against isomerization to a less active isomer, in the preparation of a pharmaceutical composition for treatment of a skin disease susceptible to treatment with a corticosteroid active substance.
53. Use according to any one of claims 49 to 52, wherein the amount of the corticosteroid active substance is from 0.01 to 1.0% w/w of the composition.
54. Use according to any one of claims 49 to 53, wherein the corticosteroid active substance is a topically-effective corticosteroid active substance which is alclometasone dipropionate, amcinonide, beclamethasone dipropionate, betamethiasone benzoate, betamethasone dipropionate, betamethasone valerate, budesonide, clobetasol propionate, clobetasone butyrate, desonide, desoxymethasone, diflorasone diacetate, diflucortolone valerate, flumethasone pivalate, fluclorolone acetonide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone preparations, fluprednidene acetate, flurandrenolone, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone acetate, mometasone furoate or triamcinolone acetonide, or a pharmacologically-effective mixture thereof.
55. Use according to claim 54, wherein the corticosteroid active substance is betamethasone valerate.
56. Use according to any one of claims 49 to 55, wherein the aliphatic alcohol component is methanol, ethanol, isopropyl alcohol, butyl alcohol, or a mixture thereof.
57. Use according to claim 56, wherein the aliphatic alcohol component is ethanol.
58. Use according to any one of claims 49 to 57, wherein the fatty alcohol component is a cetyl, stearyl, lauryl, myristyl or palmityl alcohol, or a mixture thereof.
59. Use according to claim 58, wherein the fatty alcohol component is a mixture of cetyl alcohol and stearyl alcohol.
60. Use according to any one of claims 49 to 57, wherein the surface-active agent is ethoxylated sorbitan stearate, ethoxylated sorbitan palmitate, ethoxylated sorbitan oleate, a nonyl phenol ethoxylate, a fatty alcohol ethoxylate, or a mixture thereof.
61. Use according to any one of claims 49 to 60, wherein the buffering agent is a citrate buffer, an acetic acid/sodium acetate buffer or a phosphoric acid/sodium phosphate buffer.
62. Use according to claim 61, wherein the buffering agent is a citrate buffer.
63. Use according to claim 49, wherein the foamable pharmaceutical composition comprises:
% w/w Betamethasone Valerate ~~~0.12 Cetyl Alcohol BP ~~~~1.10 Octadecan-1-ol BP ~~~~0.50 Polysorbate 60 BP ~~~~0.40 Ethanol ~~~~~~57.79 Purified Water ~~~~33.69 Propylene Glycol BP ~~~2.00 Citric Acid Anhydrous BP ~~0.073 Potassium Citrate ~~~~0.027 Butane/Propane ~~~~4.30 100.00 wherein the percentages given are weight-per-weight percentages.
% w/w Betamethasone Valerate ~~~0.12 Cetyl Alcohol BP ~~~~1.10 Octadecan-1-ol BP ~~~~0.50 Polysorbate 60 BP ~~~~0.40 Ethanol ~~~~~~57.79 Purified Water ~~~~33.69 Propylene Glycol BP ~~~2.00 Citric Acid Anhydrous BP ~~0.073 Potassium Citrate ~~~~0.027 Butane/Propane ~~~~4.30 100.00 wherein the percentages given are weight-per-weight percentages.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9504265.1A GB9504265D0 (en) | 1995-03-03 | 1995-03-03 | Corticosteroid-containing pharmaceutical composition |
| GB9504265.1 | 1995-03-03 | ||
| PCT/GB1996/000490 WO1996027376A1 (en) | 1995-03-03 | 1996-03-01 | Corticosteroid-containing pharmaceutical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2214436A1 CA2214436A1 (en) | 1996-09-12 |
| CA2214436C true CA2214436C (en) | 2007-11-20 |
Family
ID=10770568
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002214436A Expired - Lifetime CA2214436C (en) | 1995-03-03 | 1996-03-01 | Corticosteroid-containing pharmaceutical composition |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US6126920A (en) |
| EP (1) | EP0813413B1 (en) |
| JP (1) | JP4557310B2 (en) |
| KR (1) | KR100427492B1 (en) |
| CN (1) | CN1082817C (en) |
| AT (1) | ATE253367T1 (en) |
| AU (1) | AU709320B2 (en) |
| BR (1) | BR9607687A (en) |
| CA (1) | CA2214436C (en) |
| CZ (1) | CZ285913B6 (en) |
| DE (1) | DE69630593T2 (en) |
| DK (1) | DK0813413T3 (en) |
| ES (1) | ES2210349T3 (en) |
| GB (1) | GB9504265D0 (en) |
| HU (1) | HU228890B1 (en) |
| MX (1) | MX9706698A (en) |
| NZ (1) | NZ302727A (en) |
| PL (1) | PL183730B1 (en) |
| PT (1) | PT813413E (en) |
| SK (1) | SK283049B6 (en) |
| WO (1) | WO1996027376A1 (en) |
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-
1995
- 1995-03-03 GB GBGB9504265.1A patent/GB9504265D0/en active Pending
-
1996
- 1996-03-01 US US08/913,144 patent/US6126920A/en not_active Expired - Lifetime
- 1996-03-01 DE DE69630593T patent/DE69630593T2/en not_active Expired - Lifetime
- 1996-03-01 HU HU9900801A patent/HU228890B1/en unknown
- 1996-03-01 NZ NZ302727A patent/NZ302727A/en not_active IP Right Cessation
- 1996-03-01 JP JP52669796A patent/JP4557310B2/en not_active Expired - Lifetime
- 1996-03-01 WO PCT/GB1996/000490 patent/WO1996027376A1/en active IP Right Grant
- 1996-03-01 AT AT96904935T patent/ATE253367T1/en active
- 1996-03-01 KR KR1019970706110A patent/KR100427492B1/en not_active IP Right Cessation
- 1996-03-01 DK DK96904935T patent/DK0813413T3/en active
- 1996-03-01 BR BR9607687-9A patent/BR9607687A/en not_active Application Discontinuation
- 1996-03-01 PT PT96904935T patent/PT813413E/en unknown
- 1996-03-01 ES ES96904935T patent/ES2210349T3/en not_active Expired - Lifetime
- 1996-03-01 CA CA002214436A patent/CA2214436C/en not_active Expired - Lifetime
- 1996-03-01 CN CN96192817A patent/CN1082817C/en not_active Expired - Lifetime
- 1996-03-01 SK SK1190-97A patent/SK283049B6/en not_active IP Right Cessation
- 1996-03-01 AU AU48851/96A patent/AU709320B2/en not_active Expired
- 1996-03-01 PL PL96322088A patent/PL183730B1/en unknown
- 1996-03-01 EP EP96904935A patent/EP0813413B1/en not_active Expired - Lifetime
- 1996-03-01 CZ CZ972758A patent/CZ285913B6/en not_active IP Right Cessation
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1997
- 1997-09-03 MX MX9706698A patent/MX9706698A/en unknown
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2002
- 2002-09-27 US US10/256,754 patent/US7078058B2/en not_active Expired - Fee Related
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2006
- 2006-03-30 US US11/394,848 patent/US20060171898A1/en not_active Abandoned
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