CA2115279C - Pharmaceutical products with a content of dexpanthenol for topical applications - Google Patents
Pharmaceutical products with a content of dexpanthenol for topical applicationsInfo
- Publication number
- CA2115279C CA2115279C CA002115279A CA2115279A CA2115279C CA 2115279 C CA2115279 C CA 2115279C CA 002115279 A CA002115279 A CA 002115279A CA 2115279 A CA2115279 A CA 2115279A CA 2115279 C CA2115279 C CA 2115279C
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical products
- sterile
- polyacrylic acid
- dexpanthenol
- acid gel
- 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
Links
Classifications
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The invention relates to sterile pharmaceutical products with a content of dexpanthenol for topical application and is characterized in that as a vehicle they contain polyacrylic acid in partially neutralized form with a molecular weight of between approximately 3 and 5 million, and optionally preservatives in chelating agents, and that the pH value of the polyacrylic acid gel is adjusted to 6.8 ~ 0.2.
Description
CA 0211~279 1998-04-20 PHARMACEUTICAL PRODUCTS WITH A CONTENT OF DEXPANTHENOL
FOR TOPICAL APPLICATION
The invention relates to pharmaceutical products with a content of dexpanthenol for topical application.
Pantothinic acid is (R-3-2,4-dihydroxy-3,3-dimethylbutyramido~propionic acid and occurs in widespread form in nature in both animal and vegetable material. Only the natural R-form of pantothinic acid is biologically effective, but the alcohol corresponding to pantothinic acid, namely dexpanthenol, also exhibits full vitamin effectiveness, since the alcohol can be oxidized to make pantothinic acid in the warm-blooded organism. Since pantothinic acid itself is an unstable, viscous, highly hygroscopic oil, its industrial processing is difficult, so that pharmaceutically either alcohol or salts are used, because they are more easily prepared. Pantothinic acid and panthenol are relatively sensitive compounds, which are decomposed by acids, bases and heat, so that preparing them requires special precautions.
Pantothinic acid is present in the tissue predominately in the form of the coenzyme A, which has a key position in metabolism. The transfer of acetyl radicals, which has fundamental significance in metabolism, is possible only with the aid of the coenzyme A.
Therapeutically, pantothinic acid or panthenol is given in growth disturbances, dermatitises, degenerative changes in the central and peripheral nervous system, in cases of diminished antibody formation, and to promote wound healing.
Administering dexpanthenol in the form of tablets, ampules, solutions or ointments has been usual until now, because the great instability of dexpanthenol makes it difficult to produce certain forms of pharmaceutical preparations.
CA 0211~279 1998-04-20 For topical applications, dexpanthenol is as a rule given in ointment form, including in opthalmology. In this field, but also in the treatment of skin defects, it is often found that with ointments, patient's compliance is relatively poor, since to many people the greasy bases of the ointment feels unpleasant on the skin or on the cornea.
This is particularly true for opthalmological products, because greasy ointments combine with the tears to make a streaky film over the cornea and thus impair vision.
There is accordingly still a need for pharmaceutical preparations with dexpanthenol that can be applied topically yet do not use greasy ointment bases.
According to the invention, sterile pharmaceutical products with a dexpanthenol content for topical application are now proposed that are characterized in that they contain polyacrylic acid in partially neutralized form with a molecular weight between approximately 3 and 5 million as their vehicle.
The preparation of sterile pharmaceutical products with a content of dexpanthenol for topical application on a nonfat basis was unsuccessful until now, because on the one hand dexpanthenol is unstable in heat and in an aqueous solution the decomposition product forms 3-aminopropanol.
On the other hand, sterile filtration of polyacrylate gels is known to be impossible. Surprisingly, it has now been found that these difficulties can be overcome if the preparation off such gels in performed in multiple stages.
To that end, first, a polyacrylic acid suspension is prepared from water for injection purposes and from a polyacrylic acid having a molecular weight between approximately 3 and 5 million and preferably 4 million, and this suspension is autoclaved while stirring at approximately I20~C at an overpressure of 1 bar for a period of 20 minutes. Parallel to this, a solution of dexpanthenol, optionally a preservative, and a gelatizing agent is prepared and filtered in sterile fashion in a manner known per se. This solution is added under aseptic conditions to the polyacrylic acid suspension.
After careful mixing, this composition is then neutralized with sterile caustic soda, and the gel forms. The neutralization is a critical point in the preparation, because dexpanthenol is incompatible with acids and bases, so that adding the neutralizing agent while stirring must be done in highly dilute form and with immediate mixing, to prevent decomposition. The sterile gel is finally rendered free of bubbles by evacuation and then made up and packaged in the usual way. Preferably, the entire preparation process takes place in a sterile inert gas, preferably nitrogen.
As the vehicle, polyacrylic acids in partially neutralized form are used; the acids should have a molecular weight in the range from approximately 3 to 5 million and preferably 4 million. Such polyacrylic acids are available on the market, for instance under the tradename "Carbopol~".
Neutralization of the polyacrylic acids is done in the final preparation step preferably with highly dilute sterile caustic soda, but instead of caustic soda as the alkali, potassium hydroxide, alkali carbonates or amines, such as B
~lIS~7~
c triethanolamine or diisopropanolamine, may also be used.
Whether the neutralization is done with inorganic or organic bases is not of decisive importance, as long as they are physiologically harmless.
The preparations according to the invention preferably contain a preservative to make it possible for them to be germ-free or nearly so even after being used many times.
The familiar pharmaceutically usable compounds may be employed as preservatives, including in particular quaternaries such as cetrimides. To trap undesired traces of metal, a chelating agent is added to the product, such as the disodium salt of EDTA, sodium salts of phosphoric acids, or sodium salts of nitrilotriacetic -3a-~ ~B
CA 0211~279 1998-04-20 -acid. Entirely surprisingly and as yet unexplained is that effect that a slight addition of EDTA markedly increase the stability of dexpanthenol solutions; as various experiments have shown, this effect is not based on the chelating of the traces of ions of metals with a valence of two or higher that may possibly be present, but rather appears to ensue via some other mechanism. In any case, experiments with the storage stability and also the thermal resistance have shown that a slight addition of EDTA, in contrast to other complexing agents, markedly inhibits decomposition into 3-aminopropanol.
Adjusting the pH value of the final gel is done to a pH of 6.8 + 0.2, so that the final gels match the physiological pH. When used in the eye or on mucous membranes, these gels are precisely as free of reaction as when applied to the skin, for instance if a sterile covering is needed in the care of skin lesions of large surface area, such as burns.
The invention will be described in further detail below in terms of an example:
Example In a Becomix process system with a sterile 0.2~m filter and a gas sterile filter, a homogeneous suspension of 160.0 kg of water for injection purposes and 1.14 kg of polyacrylic acid with a molecular weight of 4 million (available on the market by the tradename "Carbopol 940") is introduced via a fiber trap filter with a pore width of approximately 25 to 40~m. The system is then closed and heated. The suspension is autoclaved while stirring at 121~C and 1 bar of overpressure for 20 minutes, and finally cooled down to room temperature, with venting taking place via the sterilized air filter.
In the meantime, 180.0 kg of water for injection purposes is stored beforehand in a suitable attached container at a temperature of approximately 40~C, and 19.0 kg of dexpanthenol is dissolved in it while stirring. Some CA 0211~279 1998-04-20 .
of this solution, approximately 10.1, is removed 38 g of cetrimide and 38 g of the disodium of ETA ~ 2H20 are dissolved and in it, while stirring. This partial solution is then recombined with the main quantity of dexpanthenol solution.
The salt solution is then added, with the aid of sterile nitrogen as a compressed gas, via the sterile filter to the already autoclaved polyacrylic acid suspension. The mixture is then homogenized by stirring.
Finally, evacuation is performed multiple times, down to 0.1 bar, and venting is again done via the air filter, in order to breakdown the foam produced.
Under sterile conditions, 581 g of sodium hydroxide is dissolved while stirring in 19.203 kg of water for injection purposes, producing an approximately 3~ sodium hydroxide solution. This caustic soda is then filtered via the sterile filter into the suspension of dexpanthenol and polyacrylic acid, with simultaneous stirring, and the developing gel is recirculated. The delivery of caustic soda is done drop by drop.
The pH value of the resultant gel is determined, it should be 6.8 + 0.2. If the pH value is below 6.6, sodium hydroxide solution is carefully added drop by drop until the desired value is attained. It should be taken into account that although as a rule stirring must be done while the alkali is added in order to avoid decomposition of the dexpanthenol, nevertheless overly long stirring at relatively high speed can destroy the gel structure. If a pH over 6.6 is measured for the mixture, then replenishment with sterile water is done up to a total weight of 380.00 kg.
The composition is then stirred once again for approximately 15 minutes at a low agitator speed of approximately 8 rpm and finally evacuated until the gel is practically free of bubbles. The final gel is then made up and packaged under sterile conditions, in a manner known per se.
FOR TOPICAL APPLICATION
The invention relates to pharmaceutical products with a content of dexpanthenol for topical application.
Pantothinic acid is (R-3-2,4-dihydroxy-3,3-dimethylbutyramido~propionic acid and occurs in widespread form in nature in both animal and vegetable material. Only the natural R-form of pantothinic acid is biologically effective, but the alcohol corresponding to pantothinic acid, namely dexpanthenol, also exhibits full vitamin effectiveness, since the alcohol can be oxidized to make pantothinic acid in the warm-blooded organism. Since pantothinic acid itself is an unstable, viscous, highly hygroscopic oil, its industrial processing is difficult, so that pharmaceutically either alcohol or salts are used, because they are more easily prepared. Pantothinic acid and panthenol are relatively sensitive compounds, which are decomposed by acids, bases and heat, so that preparing them requires special precautions.
Pantothinic acid is present in the tissue predominately in the form of the coenzyme A, which has a key position in metabolism. The transfer of acetyl radicals, which has fundamental significance in metabolism, is possible only with the aid of the coenzyme A.
Therapeutically, pantothinic acid or panthenol is given in growth disturbances, dermatitises, degenerative changes in the central and peripheral nervous system, in cases of diminished antibody formation, and to promote wound healing.
Administering dexpanthenol in the form of tablets, ampules, solutions or ointments has been usual until now, because the great instability of dexpanthenol makes it difficult to produce certain forms of pharmaceutical preparations.
CA 0211~279 1998-04-20 For topical applications, dexpanthenol is as a rule given in ointment form, including in opthalmology. In this field, but also in the treatment of skin defects, it is often found that with ointments, patient's compliance is relatively poor, since to many people the greasy bases of the ointment feels unpleasant on the skin or on the cornea.
This is particularly true for opthalmological products, because greasy ointments combine with the tears to make a streaky film over the cornea and thus impair vision.
There is accordingly still a need for pharmaceutical preparations with dexpanthenol that can be applied topically yet do not use greasy ointment bases.
According to the invention, sterile pharmaceutical products with a dexpanthenol content for topical application are now proposed that are characterized in that they contain polyacrylic acid in partially neutralized form with a molecular weight between approximately 3 and 5 million as their vehicle.
The preparation of sterile pharmaceutical products with a content of dexpanthenol for topical application on a nonfat basis was unsuccessful until now, because on the one hand dexpanthenol is unstable in heat and in an aqueous solution the decomposition product forms 3-aminopropanol.
On the other hand, sterile filtration of polyacrylate gels is known to be impossible. Surprisingly, it has now been found that these difficulties can be overcome if the preparation off such gels in performed in multiple stages.
To that end, first, a polyacrylic acid suspension is prepared from water for injection purposes and from a polyacrylic acid having a molecular weight between approximately 3 and 5 million and preferably 4 million, and this suspension is autoclaved while stirring at approximately I20~C at an overpressure of 1 bar for a period of 20 minutes. Parallel to this, a solution of dexpanthenol, optionally a preservative, and a gelatizing agent is prepared and filtered in sterile fashion in a manner known per se. This solution is added under aseptic conditions to the polyacrylic acid suspension.
After careful mixing, this composition is then neutralized with sterile caustic soda, and the gel forms. The neutralization is a critical point in the preparation, because dexpanthenol is incompatible with acids and bases, so that adding the neutralizing agent while stirring must be done in highly dilute form and with immediate mixing, to prevent decomposition. The sterile gel is finally rendered free of bubbles by evacuation and then made up and packaged in the usual way. Preferably, the entire preparation process takes place in a sterile inert gas, preferably nitrogen.
As the vehicle, polyacrylic acids in partially neutralized form are used; the acids should have a molecular weight in the range from approximately 3 to 5 million and preferably 4 million. Such polyacrylic acids are available on the market, for instance under the tradename "Carbopol~".
Neutralization of the polyacrylic acids is done in the final preparation step preferably with highly dilute sterile caustic soda, but instead of caustic soda as the alkali, potassium hydroxide, alkali carbonates or amines, such as B
~lIS~7~
c triethanolamine or diisopropanolamine, may also be used.
Whether the neutralization is done with inorganic or organic bases is not of decisive importance, as long as they are physiologically harmless.
The preparations according to the invention preferably contain a preservative to make it possible for them to be germ-free or nearly so even after being used many times.
The familiar pharmaceutically usable compounds may be employed as preservatives, including in particular quaternaries such as cetrimides. To trap undesired traces of metal, a chelating agent is added to the product, such as the disodium salt of EDTA, sodium salts of phosphoric acids, or sodium salts of nitrilotriacetic -3a-~ ~B
CA 0211~279 1998-04-20 -acid. Entirely surprisingly and as yet unexplained is that effect that a slight addition of EDTA markedly increase the stability of dexpanthenol solutions; as various experiments have shown, this effect is not based on the chelating of the traces of ions of metals with a valence of two or higher that may possibly be present, but rather appears to ensue via some other mechanism. In any case, experiments with the storage stability and also the thermal resistance have shown that a slight addition of EDTA, in contrast to other complexing agents, markedly inhibits decomposition into 3-aminopropanol.
Adjusting the pH value of the final gel is done to a pH of 6.8 + 0.2, so that the final gels match the physiological pH. When used in the eye or on mucous membranes, these gels are precisely as free of reaction as when applied to the skin, for instance if a sterile covering is needed in the care of skin lesions of large surface area, such as burns.
The invention will be described in further detail below in terms of an example:
Example In a Becomix process system with a sterile 0.2~m filter and a gas sterile filter, a homogeneous suspension of 160.0 kg of water for injection purposes and 1.14 kg of polyacrylic acid with a molecular weight of 4 million (available on the market by the tradename "Carbopol 940") is introduced via a fiber trap filter with a pore width of approximately 25 to 40~m. The system is then closed and heated. The suspension is autoclaved while stirring at 121~C and 1 bar of overpressure for 20 minutes, and finally cooled down to room temperature, with venting taking place via the sterilized air filter.
In the meantime, 180.0 kg of water for injection purposes is stored beforehand in a suitable attached container at a temperature of approximately 40~C, and 19.0 kg of dexpanthenol is dissolved in it while stirring. Some CA 0211~279 1998-04-20 .
of this solution, approximately 10.1, is removed 38 g of cetrimide and 38 g of the disodium of ETA ~ 2H20 are dissolved and in it, while stirring. This partial solution is then recombined with the main quantity of dexpanthenol solution.
The salt solution is then added, with the aid of sterile nitrogen as a compressed gas, via the sterile filter to the already autoclaved polyacrylic acid suspension. The mixture is then homogenized by stirring.
Finally, evacuation is performed multiple times, down to 0.1 bar, and venting is again done via the air filter, in order to breakdown the foam produced.
Under sterile conditions, 581 g of sodium hydroxide is dissolved while stirring in 19.203 kg of water for injection purposes, producing an approximately 3~ sodium hydroxide solution. This caustic soda is then filtered via the sterile filter into the suspension of dexpanthenol and polyacrylic acid, with simultaneous stirring, and the developing gel is recirculated. The delivery of caustic soda is done drop by drop.
The pH value of the resultant gel is determined, it should be 6.8 + 0.2. If the pH value is below 6.6, sodium hydroxide solution is carefully added drop by drop until the desired value is attained. It should be taken into account that although as a rule stirring must be done while the alkali is added in order to avoid decomposition of the dexpanthenol, nevertheless overly long stirring at relatively high speed can destroy the gel structure. If a pH over 6.6 is measured for the mixture, then replenishment with sterile water is done up to a total weight of 380.00 kg.
The composition is then stirred once again for approximately 15 minutes at a low agitator speed of approximately 8 rpm and finally evacuated until the gel is practically free of bubbles. The final gel is then made up and packaged under sterile conditions, in a manner known per se.
Claims (12)
1. Sterile pharmaceutical products with a content of dexpanthenol for topical application, characterized in that as a vehicle, they contain polyacrylic acid gel in partially neutralized form, with a molecular weight between approximately 3 and 5 million.
2. The sterile pharmaceutical products of claim 1, characterized in that they contain polyacrylic acid gel with a molecular weight of about 4 million.
3. The sterile pharmaceutical products of claim 1 or 2, characterized in that polyacrylic acid gel is present in the form of an alkali.
4. The sterile pharmaceutical products of claim 1 or 2, characterized in that polyacrylic acid gel is present in the form of a sodium or amine salt.
5. The pharmaceutical products of any one of claims 1 to 4, characterized in that the pH value of the polyacrylic acid gel is 6.8 ~ 0.2.
6. The pharmaceutical products of any one of claims 1 to 5, characterized in that the polyacrylic acid gel contains a preservative.
7. The pharmaceutical products of any one of claims 1 to 6, characterized in that the gel contains a chelating agent.
8. The pharmaceutical products of any one of claims 1 to 7, characterized in that the gel contains EDTA.
9. A process for preparing sterile pharmaceutical products as defined in claim 1, characterized in that a polyacrylic acid solution is autoclaved, a solution with dexpanthenol is filtered in a sterile manner, the two solutions are combined, and the mixture is adjusted to a pH
of 6.8 ~ 0.2 with the intended sterile bases.
of 6.8 ~ 0.2 with the intended sterile bases.
10. A process for preparing sterile pharmaceutical products as defined in claim 9, wherein the solution of dexpanthenol includes a preservative and a chelating agent.
11. The process of claim 9 or 10, characterized in that the neutralized mixture is rendered free of bubbles by evacuation.
12. The process of claim 9, 10 or 11, characterized in that the entire course of the process is carried out in a sterile inert gas.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4303818A DE4303818C1 (en) | 1993-02-10 | 1993-02-10 | Sterile medicament for topical admin. of dexpanthenol - contg. a polyacrylate carrier to improve stability of active agent |
| DEP4303818.2 | 1993-02-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2115279A1 CA2115279A1 (en) | 1994-08-11 |
| CA2115279C true CA2115279C (en) | 1998-09-22 |
Family
ID=6480036
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002115279A Expired - Lifetime CA2115279C (en) | 1993-02-10 | 1994-02-09 | Pharmaceutical products with a content of dexpanthenol for topical applications |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0610655B1 (en) |
| JP (1) | JP2604541B2 (en) |
| AT (1) | ATE139116T1 (en) |
| CA (1) | CA2115279C (en) |
| DE (1) | DE4303818C1 (en) |
| DK (1) | DK0610655T3 (en) |
| ES (1) | ES2087774T3 (en) |
| GR (1) | GR3020544T3 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9407302D0 (en) * | 1994-04-13 | 1994-06-08 | Rank Brimar Ltd | Display device driving circuitry and method |
| DE19938668B4 (en) * | 1999-08-14 | 2006-01-26 | Bausch & Lomb Inc. | Artificial tears |
| TW586945B (en) | 2001-01-12 | 2004-05-11 | Novartis Ag | Lens care product containing dexpanthenol |
| JP5832289B2 (en) * | 2009-07-30 | 2015-12-16 | 住友精化株式会社 | Water-soluble polymer composition, composition for forming plaster layer of skin patch, and skin patch |
| WO2016133471A1 (en) | 2015-02-20 | 2016-08-25 | Pharmacti̇ve İlaç Sanayi̇ Ve Ti̇caret A. Ş. | A topical composition comprising mupirocin and dexpanthenol |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6056684B2 (en) * | 1977-11-07 | 1985-12-11 | 東興薬品工業株式会社 | eye drops |
| DE3416209A1 (en) * | 1984-05-02 | 1985-11-21 | Mohamed Roshdy Dr Ismail | EYE TREATMENT PREPARATIONS |
| GB9109757D0 (en) * | 1991-05-04 | 1991-06-26 | Procter & Gamble | Cosmetic compositions |
| GB9109796D0 (en) * | 1991-05-04 | 1991-06-26 | Procter & Gamble | Cosmetic compositions |
| GB9109775D0 (en) * | 1991-05-04 | 1991-06-26 | Procter & Gamble | Cosmetic compositions |
-
1993
- 1993-02-10 DE DE4303818A patent/DE4303818C1/en not_active Expired - Lifetime
-
1994
- 1994-01-07 AT AT94100146T patent/ATE139116T1/en active
- 1994-01-07 ES ES94100146T patent/ES2087774T3/en not_active Expired - Lifetime
- 1994-01-07 EP EP94100146A patent/EP0610655B1/en not_active Expired - Lifetime
- 1994-01-07 DK DK94100146.3T patent/DK0610655T3/en active
- 1994-02-09 CA CA002115279A patent/CA2115279C/en not_active Expired - Lifetime
- 1994-02-09 JP JP6015439A patent/JP2604541B2/en not_active Expired - Lifetime
-
1996
- 1996-07-16 GR GR960401912T patent/GR3020544T3/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK0610655T3 (en) | 1996-07-08 |
| JP2604541B2 (en) | 1997-04-30 |
| EP0610655A1 (en) | 1994-08-17 |
| EP0610655B1 (en) | 1996-06-12 |
| GR3020544T3 (en) | 1996-10-31 |
| ES2087774T3 (en) | 1996-07-16 |
| ATE139116T1 (en) | 1996-06-15 |
| CA2115279A1 (en) | 1994-08-11 |
| JPH0748281A (en) | 1995-02-21 |
| DE4303818C1 (en) | 1994-03-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20140210 |