CA2300806C - Dexamethasone gel - Google Patents
Dexamethasone gel Download PDFInfo
- Publication number
- CA2300806C CA2300806C CA002300806A CA2300806A CA2300806C CA 2300806 C CA2300806 C CA 2300806C CA 002300806 A CA002300806 A CA 002300806A CA 2300806 A CA2300806 A CA 2300806A CA 2300806 C CA2300806 C CA 2300806C
- Authority
- CA
- Canada
- Prior art keywords
- preparation
- gel
- dexamethasone
- carbomer
- pharmacologically acceptable
- 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
- A61K31/56—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
-
- 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
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Ophthalmology & Optometry (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Abstract
The invention relates to an ophthalmological preparation containing dexamethasone dihydrogenphosphate disodium as the active ingredient and, optionally, also containing the usual additives and water, which is characterized by a content of at least one gel-forming pharmacologically acceptable substance in a quantity sufficient for adjusting the viscosity of the preparation as a gel.
Description
DEXAMETHASONE GEL
FIELD OF THE INVENTION
The invention relates to an ophthalmological preparation containing S dexamethasone as the active ingredient and, optionally, also containing the usual additives and water.
BACKGROUND TO THE INVENTION
Dexamethasone preparations are known in the form of eye-drops and eye ointments. Eye-drops usually have concentrations between 0.05 and 0.1%, whereas eye ointments usually contain about 0.05% dexamethasone sodium phosphate.
Known eye-drop formulations comprising dexamethasone esters as the active ingredient are adjusted to slightly alkaline pH values. For example, solutions of drops which are currently available commercially typically have a pH value of about 7.3. These slightly alkaline values are selected because dexamethasone esters manifest greatest stability in the slightly alkaline range, as is also the case with prednisolone esters.
In this regard, the pH value is typically selected to be as close as possible to neutral, since higher alkalinities are suspected of causing eye irntations and other tolerance problems.
It is known that the antiphlogistic efficacy of eye-drops is superior to that of eye ointments. In experiments, the bio-availability of eye ointments was substantially poorer than that of eye-drop solutions, even in cases of extended contact times (Cox et al., Arch. Ophthalmol. 88, 549 (1972);
Kupferman et al., Arch. Ophthalmol. 91, 373 (1974)).
FIELD OF THE INVENTION
The invention relates to an ophthalmological preparation containing S dexamethasone as the active ingredient and, optionally, also containing the usual additives and water.
BACKGROUND TO THE INVENTION
Dexamethasone preparations are known in the form of eye-drops and eye ointments. Eye-drops usually have concentrations between 0.05 and 0.1%, whereas eye ointments usually contain about 0.05% dexamethasone sodium phosphate.
Known eye-drop formulations comprising dexamethasone esters as the active ingredient are adjusted to slightly alkaline pH values. For example, solutions of drops which are currently available commercially typically have a pH value of about 7.3. These slightly alkaline values are selected because dexamethasone esters manifest greatest stability in the slightly alkaline range, as is also the case with prednisolone esters.
In this regard, the pH value is typically selected to be as close as possible to neutral, since higher alkalinities are suspected of causing eye irntations and other tolerance problems.
It is known that the antiphlogistic efficacy of eye-drops is superior to that of eye ointments. In experiments, the bio-availability of eye ointments was substantially poorer than that of eye-drop solutions, even in cases of extended contact times (Cox et al., Arch. Ophthalmol. 88, 549 (1972);
Kupferman et al., Arch. Ophthalmol. 91, 373 (1974)).
Although eye-drops manifest a greater bio-availability than ointments, it is often difficult to achieve the desired dwell time, when using solutions of drops. Drop solutions are washed away relatively rapidly, for example by lacrimal fluid, with the result that the concentration of the active ingredient decreases relatively rapidly.
SUMMARY OF THE INVENTION
For many applications, it would be advantageous if it were possible to achieve an extended constant concentration of the active ingredient on the eye, after a once-only application. In this regard, recourse may be had to ointments only at the price of considerable drawbacks, owing to the known bio-availability problems.
It is an object of the invention to provide an ophthalmological preparation which does not involve these difficulties.
This object is met by the features as defined in the attached principal claim.
Advantageous further developments and embodiments are defined in the subordinate claims.
In accordance with a principal aspect of this invention, an ophthalmological preparation contains dexamethasone as the active agent, and optionally, also contains usual additives and water, and is characterized in that the preparation contains at least one gel-forming pharmacologically acceptable substance in a quantity sufficient for adjusting the viscosity of the preparation as a gel, wherein the preparation has a pH value above 7.3.
SUMMARY OF THE INVENTION
For many applications, it would be advantageous if it were possible to achieve an extended constant concentration of the active ingredient on the eye, after a once-only application. In this regard, recourse may be had to ointments only at the price of considerable drawbacks, owing to the known bio-availability problems.
It is an object of the invention to provide an ophthalmological preparation which does not involve these difficulties.
This object is met by the features as defined in the attached principal claim.
Advantageous further developments and embodiments are defined in the subordinate claims.
In accordance with a principal aspect of this invention, an ophthalmological preparation contains dexamethasone as the active agent, and optionally, also contains usual additives and water, and is characterized in that the preparation contains at least one gel-forming pharmacologically acceptable substance in a quantity sufficient for adjusting the viscosity of the preparation as a gel, wherein the preparation has a pH value above 7.3.
In further aspects of the invention:
(a) the preparation has pH value between 7.6 and 8.2;
(b) the preparation has a pH value between 7.8 and 8.0;
(c) the preparation contains at least one carbomer, especially of the 5 Carbopol 980 NF type, as a gel-forming agent;
(d) the preparation contains 0.05 to 1 % by weight, preferably between 0.1 and 0.60% by weight, and most preferably about 0.3% by weight of carbomer;
(e) the preparation contains dexamethasone dihydrogenphoshate;
10 disodium in a concentration of about 0.1 % by weight.
DETAILED DESCRIPTION OF THE INVENTION
The attempt to formulate a gel preparation according to the invention, on the basis of the known drop solutions, such that a suitable gelling agent is added, leads to surprising difficulties.
15 When working on the basis of the known drop solutions in the pH range of 7 to about 7.3, the addition of carbomer surprisingly leads to a considerable decomposition of the active ingredient after only a short interval, such that the required stability is not achieved.
It appears that there is an intensified conversion of dexamethasone 20 dihydrogenphosphate disodium ("dexamethasone sodium phosphate") into the free base.
(a) the preparation has pH value between 7.6 and 8.2;
(b) the preparation has a pH value between 7.8 and 8.0;
(c) the preparation contains at least one carbomer, especially of the 5 Carbopol 980 NF type, as a gel-forming agent;
(d) the preparation contains 0.05 to 1 % by weight, preferably between 0.1 and 0.60% by weight, and most preferably about 0.3% by weight of carbomer;
(e) the preparation contains dexamethasone dihydrogenphoshate;
10 disodium in a concentration of about 0.1 % by weight.
DETAILED DESCRIPTION OF THE INVENTION
The attempt to formulate a gel preparation according to the invention, on the basis of the known drop solutions, such that a suitable gelling agent is added, leads to surprising difficulties.
15 When working on the basis of the known drop solutions in the pH range of 7 to about 7.3, the addition of carbomer surprisingly leads to a considerable decomposition of the active ingredient after only a short interval, such that the required stability is not achieved.
It appears that there is an intensified conversion of dexamethasone 20 dihydrogenphosphate disodium ("dexamethasone sodium phosphate") into the free base.
Surprisingly, it is possible for this decomposition to be prevented by selecting a higher pH value. Gelling agents, such as Carbopol~, appear to have an adverse effect on the durability of aqueous dexamethasone phosphate solutions in the acid to neutral range and also in the weakly 5 alkaline range, while, surprisingly, distinctly improving said durability in the more alkaline range.
Accordingly, when carbomers, in particular of the Carbopol 980 NF type or similar Carbopol products, are used as gelling agents in the gels according to the invention, the required stability is provided in the pH
range above 7.3.
Storable stable gel preparations at pH values above 7.3, preferably above 7.6 and most preferably at about 7.8 and above, are provided at a concentration of 0.05 to about 1% by mass, preferably between 0.1 and 0.6% by mass and, most preferably, at about 0.3% by mass of carbomer, in 15 particular of the Carbopol 980 NF type, and active-ingredient concentrations of the order of about 0.1 % by mass. The upper limit depends on the ophthalmological compatibility of the preparation, since very high alkalinities may lead to irritations. Accordingly, pH values above 8 will not be used in practice, or only under exceptional 20 circumstances, such as where irritation either does not arise or does not play any significant role.
The preparation according to the invention is usually adjusted to the required pH value by means of pharmacologically acceptable alkalis, for example sodium hydroxide.
25 In addition to the active ingredient, the gelling agent and the alkali for adjusting the alkalinity, it also contains a preservative, such as, in particular, benzododecinium chloride (BAC-C 12), from the group including the benzalkonium chlorides. In addition, the preparation -S-preferably contains an isotonic agent, such as sorbitol, and a chelating agent, such as sodium EDTA. Water is used as the solvent for the preparation.
A typical formulation according to the invention for a batch of 100 kg 5 substantially contains the following documents:
Designation Quantity Dexamethasone dihydrogen phosphate 0.0985 kg disodium Benzododecinium chloride (BAC-C12) 0.0100 kg Carbopol 980 NF 0.3000 kg Sorbitol 4.9000 kg Sodium hydroxide, solid 0.1460-0.1540 kg Sodium EDTA 0.0100 kg Water for injection purposes 94.5275-94.5355 kg 100.000 kg Surprisingly, a preparation of this kind is as stable as a comparable solution of drops, i.e. two or three years. The preparation is very well tolerated when applied, does not cause eye irritations (with the choice of 10 the preservative contributing in this regard), and permits the desired extended dwell time, in the course of which the bio-availability of the active ingredient is not adversely affected, in contrast to drop solutions.
Accordingly, when carbomers, in particular of the Carbopol 980 NF type or similar Carbopol products, are used as gelling agents in the gels according to the invention, the required stability is provided in the pH
range above 7.3.
Storable stable gel preparations at pH values above 7.3, preferably above 7.6 and most preferably at about 7.8 and above, are provided at a concentration of 0.05 to about 1% by mass, preferably between 0.1 and 0.6% by mass and, most preferably, at about 0.3% by mass of carbomer, in 15 particular of the Carbopol 980 NF type, and active-ingredient concentrations of the order of about 0.1 % by mass. The upper limit depends on the ophthalmological compatibility of the preparation, since very high alkalinities may lead to irritations. Accordingly, pH values above 8 will not be used in practice, or only under exceptional 20 circumstances, such as where irritation either does not arise or does not play any significant role.
The preparation according to the invention is usually adjusted to the required pH value by means of pharmacologically acceptable alkalis, for example sodium hydroxide.
25 In addition to the active ingredient, the gelling agent and the alkali for adjusting the alkalinity, it also contains a preservative, such as, in particular, benzododecinium chloride (BAC-C 12), from the group including the benzalkonium chlorides. In addition, the preparation -S-preferably contains an isotonic agent, such as sorbitol, and a chelating agent, such as sodium EDTA. Water is used as the solvent for the preparation.
A typical formulation according to the invention for a batch of 100 kg 5 substantially contains the following documents:
Designation Quantity Dexamethasone dihydrogen phosphate 0.0985 kg disodium Benzododecinium chloride (BAC-C12) 0.0100 kg Carbopol 980 NF 0.3000 kg Sorbitol 4.9000 kg Sodium hydroxide, solid 0.1460-0.1540 kg Sodium EDTA 0.0100 kg Water for injection purposes 94.5275-94.5355 kg 100.000 kg Surprisingly, a preparation of this kind is as stable as a comparable solution of drops, i.e. two or three years. The preparation is very well tolerated when applied, does not cause eye irritations (with the choice of 10 the preservative contributing in this regard), and permits the desired extended dwell time, in the course of which the bio-availability of the active ingredient is not adversely affected, in contrast to drop solutions.
Claims (10)
1. An ophthalmological preparation having a content of dexamethasone dihydrogenphosphate disodium as the active agent, and optionally comprising amounts of commonly used additives and water, characterized in that the preparation includes at least one gel-forming pharmacologically acceptable substance in an amount sufficient for adjusting the vicosity of the preparation to become a gel, wherein the preparation has a pH-value above 7.3.
2. The preparation according to claim 1, characterized in that the preparation has a pH-value between 7.6 and 8.2.
3. The preparation according to claim 2, characterized in that the preparation has a pH-value between 7.8 and 8Ø
4. The preparation according to any one of claims 1 to 3, characterized in that the preparation includes at least one carbomer, as the gel-forming pharmacologically acceptable substance.
5. The preparation according to claim 4, characterized in that the carbomer is Carbopol 980 NF.TM..
6. The preparation according to claims 4 or 5, characterized in that the preparation includes 0.05 to 1 weight % of carbomer as the gel-forming pharmacologically acceptable substance.
7. The preparation according to claims 4 or 5, characterized in that the preparation includes between 0.1 and 0.6 weight % of carbomer as the gel-forming pharmacologically acceptable substance.
8. The preparation according to claims 4 or 5, characterized in that the preparation includes about 0.3 weight % of carbomer as the gel-forming pharmacologically acceptable substance.
9. The preparation according to any one of claims 1 to 5, characterized in that the preparation includes dexamethasone dihydrogenphosphate disodium in a concentration of about 0.1% by weight.
10. The preparation according to any one of claims 1 to 6, characterized in that the preparation further includes benzododecinium chloride as a preservative.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19744113A DE19744113A1 (en) | 1997-10-06 | 1997-10-06 | Ophthalmological dexamethasone preparation |
| DE19744113.0 | 1997-10-06 | ||
| PCT/EP1998/006339 WO1999017780A1 (en) | 1997-10-06 | 1998-10-05 | Dexamethasone gel |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2300806A1 CA2300806A1 (en) | 1999-04-15 |
| CA2300806C true CA2300806C (en) | 2004-02-03 |
Family
ID=7844743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002300806A Expired - Lifetime CA2300806C (en) | 1997-10-06 | 1998-10-05 | Dexamethasone gel |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1021192B1 (en) |
| JP (1) | JP4156793B2 (en) |
| KR (1) | KR100392481B1 (en) |
| CN (1) | CN1142782C (en) |
| AR (1) | AR017170A1 (en) |
| AT (1) | ATE230601T1 (en) |
| BR (1) | BR9812849A (en) |
| CA (1) | CA2300806C (en) |
| DE (2) | DE19744113A1 (en) |
| DK (1) | DK1021192T3 (en) |
| ES (1) | ES2191352T3 (en) |
| HK (1) | HK1030748A1 (en) |
| HU (1) | HU224986B1 (en) |
| IL (1) | IL135001A0 (en) |
| MX (1) | MXPA00003363A (en) |
| PL (1) | PL189727B1 (en) |
| WO (1) | WO1999017780A1 (en) |
| ZA (1) | ZA989066B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW200808375A (en) | 2006-05-12 | 2008-02-16 | Otsuka Pharma Co Ltd | Hydrogel suspension and manufacturing process thereof |
| CN101190177B (en) * | 2006-11-24 | 2010-09-01 | 上海医药工业研究院 | Dectancyl partial film forming gel composition and uses thereof |
| US20150190407A1 (en) * | 2014-01-07 | 2015-07-09 | Insite Vision Incorporated | Methods for treatment of postoperative inflammation with reduced intraocular pressure |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2212392C3 (en) * | 1972-03-15 | 1981-03-19 | Avicon Inc., Fort Worth, Tex. | Use of microcrystalline collagen for the manufacture of an aqueous pharmaceutical composition for topical application to the eye |
| JPS6056684B2 (en) * | 1977-11-07 | 1985-12-11 | 東興薬品工業株式会社 | eye drops |
| US4271143A (en) * | 1978-01-25 | 1981-06-02 | Alcon Laboratories, Inc. | Sustained release ophthalmic drug dosage |
| DE3066859D1 (en) * | 1979-10-26 | 1984-04-12 | Smith & Nephew Ass | Autoclavable emulsions |
| JPS63174924A (en) * | 1987-01-14 | 1988-07-19 | Toko Yakuhin Kogyo Kk | Ointment base and ointment |
| US5252318A (en) * | 1990-06-15 | 1993-10-12 | Allergan, Inc. | Reversible gelation compositions and methods of use |
| EP0551626A1 (en) * | 1991-12-19 | 1993-07-21 | LEK, tovarna farmacevtskih in kemicnih izdelkov, d.d. | Thermoreversible gel as a liquid pharmaceutical carrier for a galenic formulation |
| WO1993017664A1 (en) * | 1992-03-02 | 1993-09-16 | Alcon Laboratories, Inc. | Combinations of cellulosic polymers and carboxy vinyl polymers and their use in pharmaceutical compositions |
| DE4209722C3 (en) * | 1992-03-25 | 1997-06-19 | Medproject Pharma Entwicklungs | Dripable gel for ophthalmology |
| WO1995005803A1 (en) * | 1993-08-20 | 1995-03-02 | Alcon Laboratories, Inc. | Topical ophthalmic pharmaceutical vehicles |
| DE4404990C1 (en) * | 1994-02-17 | 1995-05-04 | Mann Gerhard Chem Pharm Fab | Process for producing a sterile prednisolone gel |
| US5683993A (en) * | 1995-06-22 | 1997-11-04 | Ciba Vision Corporation | Compositions and methods for stabilizing polymers |
| DE19614823A1 (en) * | 1996-04-15 | 1997-10-16 | Mann Gerhard Chem Pharm Fab | Ophthalmic composition with prolonged retention time on the eye |
-
1997
- 1997-10-06 DE DE19744113A patent/DE19744113A1/en not_active Withdrawn
-
1998
- 1998-10-05 DK DK98954349T patent/DK1021192T3/en active
- 1998-10-05 AR ARP980104965A patent/AR017170A1/en active IP Right Grant
- 1998-10-05 MX MXPA00003363A patent/MXPA00003363A/en active IP Right Grant
- 1998-10-05 PL PL98341026A patent/PL189727B1/en unknown
- 1998-10-05 WO PCT/EP1998/006339 patent/WO1999017780A1/en active IP Right Grant
- 1998-10-05 KR KR10-2000-7003665A patent/KR100392481B1/en active IP Right Grant
- 1998-10-05 ES ES98954349T patent/ES2191352T3/en not_active Expired - Lifetime
- 1998-10-05 BR BR9812849-3A patent/BR9812849A/en active Search and Examination
- 1998-10-05 ZA ZA989066A patent/ZA989066B/en unknown
- 1998-10-05 DE DE59806884T patent/DE59806884D1/en not_active Expired - Lifetime
- 1998-10-05 CA CA002300806A patent/CA2300806C/en not_active Expired - Lifetime
- 1998-10-05 JP JP2000514651A patent/JP4156793B2/en not_active Expired - Lifetime
- 1998-10-05 EP EP98954349A patent/EP1021192B1/en not_active Expired - Lifetime
- 1998-10-05 IL IL13500198A patent/IL135001A0/en not_active IP Right Cessation
- 1998-10-05 AT AT98954349T patent/ATE230601T1/en active
- 1998-10-05 HU HU0003796A patent/HU224986B1/en unknown
- 1998-10-05 CN CNB988081091A patent/CN1142782C/en not_active Expired - Lifetime
-
2001
- 2001-03-08 HK HK01101674A patent/HK1030748A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP1021192B1 (en) | 2003-01-08 |
| KR100392481B1 (en) | 2003-07-23 |
| IL135001A0 (en) | 2001-05-20 |
| DE59806884D1 (en) | 2003-02-13 |
| DK1021192T3 (en) | 2003-05-05 |
| WO1999017780A1 (en) | 1999-04-15 |
| PL189727B1 (en) | 2005-09-30 |
| ATE230601T1 (en) | 2003-01-15 |
| HU224986B1 (en) | 2006-05-29 |
| ES2191352T3 (en) | 2003-09-01 |
| JP2001518510A (en) | 2001-10-16 |
| CA2300806A1 (en) | 1999-04-15 |
| HK1030748A1 (en) | 2001-05-18 |
| AR017170A1 (en) | 2001-08-22 |
| DE19744113A1 (en) | 1999-04-15 |
| MXPA00003363A (en) | 2007-12-07 |
| HUP0003796A2 (en) | 2001-04-28 |
| BR9812849A (en) | 2000-08-08 |
| KR20010030939A (en) | 2001-04-16 |
| HUP0003796A3 (en) | 2001-05-28 |
| PL341026A1 (en) | 2001-03-26 |
| ZA989066B (en) | 1999-06-15 |
| JP4156793B2 (en) | 2008-09-24 |
| CN1142782C (en) | 2004-03-24 |
| CN1266369A (en) | 2000-09-13 |
| WO1999017780A8 (en) | 2000-01-27 |
| EP1021192A1 (en) | 2000-07-26 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20181005 |