CA2303443A1 - Compositions adapted for prolonged residence in the nasal pharynx - Google Patents
Compositions adapted for prolonged residence in the nasal pharynx Download PDFInfo
- Publication number
- CA2303443A1 CA2303443A1 CA002303443A CA2303443A CA2303443A1 CA 2303443 A1 CA2303443 A1 CA 2303443A1 CA 002303443 A CA002303443 A CA 002303443A CA 2303443 A CA2303443 A CA 2303443A CA 2303443 A1 CA2303443 A1 CA 2303443A1
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- CA
- Canada
- Prior art keywords
- composition according
- nasal
- fatty acid
- alcohol
- ester
- 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.)
- Abandoned
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-
- 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
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Otolaryngology (AREA)
- Epidemiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Compositions for administering a medicament are described which are adapted for prolonged residence in the nasal passage, in particular the nasal pharynx.
Description
COMPOSITIONS ADAPTED FOR PROLONGED RESIDENCE IN THE NASAL PHARYNX
The present invention relates to a novel composition for nasal administration of medicaments.
The nasal passages may be used as a route of administration, for instance an ointment such as Bactroban Nasal may be applied to the anterior hares of the nose for a local topical effect. Spray formulations may applied to the nostrils. In addition, medicaments may administered to the lungs via the nostrils, using an aerosol or 1o nebuliser. The nasal passages comprise mucosal tissues which might be used as means of systemically delivering a medicament. Such local topical or systemic delivery would be enhanced if the formulation was to have a prolonged residence time in the nasal passages.
~ 5 Accordingly the present invention provides for a composition adapted for prolonged residence in the nasal passage, in particular the nasal pharynx, consisting essentially of:
The present invention relates to a novel composition for nasal administration of medicaments.
The nasal passages may be used as a route of administration, for instance an ointment such as Bactroban Nasal may be applied to the anterior hares of the nose for a local topical effect. Spray formulations may applied to the nostrils. In addition, medicaments may administered to the lungs via the nostrils, using an aerosol or 1o nebuliser. The nasal passages comprise mucosal tissues which might be used as means of systemically delivering a medicament. Such local topical or systemic delivery would be enhanced if the formulation was to have a prolonged residence time in the nasal passages.
~ 5 Accordingly the present invention provides for a composition adapted for prolonged residence in the nasal passage, in particular the nasal pharynx, consisting essentially of:
2 - 8 % by wt. of a medicament, preferably an antibiotic;
50 - 70 % by wt. of a fatty acid triglyceride;
2 - 6 % by wt. of a polyoxyethylene ether or ester surfactant;
20 2 - 4 % by wt. of a fatty alcohol or ester;
30 - 40 % by wt. of water; and up to 2 % by wt. of conventional additive such as preservatives and flavourings.
For nasal administration the issue of patient comfort is important in compliance with the 25 intended treatment regime. The composition of this invention provides a low viscosity cream that is easy to administer and which readily changes in consistency and softens in the temperature conditions of the nose. Accordingly when inserted into the upper regions of the nose it can be transported deeper into the nasal passages by natural processes. The composition is intended to be in the form of an oil-in-water cream 3o emulsion. In view of the large triglyceride content which provides the desired consistency for nasal administration, and the relatively low content of surfactant, the amounts of the components within the above ranges must be selected for individual components by routine trials to ensure that an oil-in-water emulsion is obtained.
35 The fatty acid triglycerides are typically vegetable ( i.e. plant-derived) oils, such as coconut oil, sesame oil or soya bean oil. An especially suitable vegetable oil is one that has to been fractionated so that it is predominantly medium chain length triglycerides.
Suitable medium-chain fatty acid triglycerides for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different medium chain fatty acid triglycerides. The term "medium-chain fatty acid" as used herein refers to a fatty acid having from 6 to 12, preferably 8 to 10 carbon atoms which may be branched or unbranched, preferably unbranched and which may be optionally substituted. Certain neutral plant oils, such as fractionated coconut oils, provide convenient sources of medium-chain fatty acid triglycerides. The triglyceride suitably comprises from 50 to 100% (w/w) of caprylic (Cg) acid and from 0 to 50% (w/w) of cupric (C 10) acid triglycerides. Suitable examples include those available under the 1o trade names MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus OH), for instance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850 and CAPTEX
8000; MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 AND MIGLYOL 818 (which also comprises a linoleic acid triglyceride) and MAZOL
1400 (blazer Chemical, Guernee, II). The fatty acid content of representative products 15 is: CAPTEX 355TM - CAPROIC ACID (2%), CAPRYLIC ACID (55%) and cupric acid (42%); CAPTEX 8000 - at least 98% caprylic acid, MYGOL 810 - caproic acid (2%), caprylic acid (65-75%), cupric acid (25-35%) and MIGLYOL 812 - caproic acid (3%), caprylic acid (50-65%), cupric acid (30-45%) and lauric acid (5%) (manufacturer's data).
The polyoxyethylene ether or ester used in this invention is one which will function as a non-ionic surfactant. Especially suitable materials include polyoxyethylene glycol monocetyl ethers, such as Cetomacrogol 1000. Other suitable non-ionic surfactants include:
(a) polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type available under the trade name MYRJ (ICI Americas, Inc.), for instance the product MYRJ 52 (a polyoxyethylene 40 stearate);
(b) polyoxyetheylene-sorbitan fatty acid esters (polysorbates), for example the mono-and tri-lauryl, palmityl, stearyl and oleyl esters, for instance the polyoxyethylene 3o sorbitan monooleates available under the trade name of TWEEN (ICI Americas Inc.), such as TWEEN 20, 21, 40, 60, 61, 65, 80, 81 and 85, of which class TWEEN 80 is especially preferred;
(c) polyoxyethylene glycol long-chain alkyl ethers, such as polyoxyethylated glycol lauryl ether; and (d) polyoxyethylene glycol long-chain alkyl esters, such as PEG-monostearate.
For use herein, the surfactant preferably has an HLB value in the range of 13 to 20.
z As fatty alcohol or ester there may be used any of such materials conventionally used in pharmaceutical or veterinary compositions such as stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, myristyl alcohol and glycerin monostearate. Preferably, cetostearyl alcohol is used, or a mixture of stearyl alcohol and cetyl alcohol.
A particularly preferred vehicle composition comprises fractionated coconut oil (typically about 55 to 60, especially about 57, parts by weight);
polyoxyethylene glycol monocetyl ether (typically about 2 to 4, especially about 3, parts by weight);
cetostearyl alcohol (typically about 2 to 4, especially about 3, parts by weight); with water for 1o emulsification, and also preservatives, and flavourings if desired.
Typical preservatives include benzyl alcohol and phenoxyethanol.
The composition of the present invention is particularly suitable for nasal 15 administration. The prolonged residence time of formulations of the present invention in the nasal passages, especially the nasal pharynx, makes them particularly suitable for topical treatment with local action or, since it provides prolonged contact of the formulation with an absorptive region, systemic delivery of a medicament.
2o Suitable medicaments include antibiotics, for instance mupirocin or a pharmaceutically acceptable salt or ester thereof.
Compositions of the present invention may be used to treat a range of conditions, for instance a topically effective antibiotic such as mupirocin or a pharmaceutically 25 acceptable salt or ester thereof, may be used to treat recurrent sinusitis or recurrent otitis media.
Suitable pharmaceutically acceptable salts of mupirocin are well known in the art and include alkali metal salts such as sodium and lithium and alkaline earth metal salts such 3o as calcium, of which the calcium salt is preferred, in particular the crystalline dihydrate from thereof described in EP 0 167 856-A (Beecham Group). Other suitable salts include silver and aluminium salts and ammonium and substituted- ammonium salts.
The salts may be anhydrous or may be in the form of pharmaceutically acceptable solvates, for instance alcoholates and, especially, hydrates. Preferred salts include the 35 calcium, silver and lithium salts, in particular the calcium salt. In the case of the calcium salt of Mupirocin, the crystalline salt is preferably used, especially the crystalline hydrated calcium salt, more preferably the crystalline dihydrate salt.
50 - 70 % by wt. of a fatty acid triglyceride;
2 - 6 % by wt. of a polyoxyethylene ether or ester surfactant;
20 2 - 4 % by wt. of a fatty alcohol or ester;
30 - 40 % by wt. of water; and up to 2 % by wt. of conventional additive such as preservatives and flavourings.
For nasal administration the issue of patient comfort is important in compliance with the 25 intended treatment regime. The composition of this invention provides a low viscosity cream that is easy to administer and which readily changes in consistency and softens in the temperature conditions of the nose. Accordingly when inserted into the upper regions of the nose it can be transported deeper into the nasal passages by natural processes. The composition is intended to be in the form of an oil-in-water cream 3o emulsion. In view of the large triglyceride content which provides the desired consistency for nasal administration, and the relatively low content of surfactant, the amounts of the components within the above ranges must be selected for individual components by routine trials to ensure that an oil-in-water emulsion is obtained.
35 The fatty acid triglycerides are typically vegetable ( i.e. plant-derived) oils, such as coconut oil, sesame oil or soya bean oil. An especially suitable vegetable oil is one that has to been fractionated so that it is predominantly medium chain length triglycerides.
Suitable medium-chain fatty acid triglycerides for use in the present invention may be of natural, semi-synthetic or synthetic origin and may include blends of different medium chain fatty acid triglycerides. The term "medium-chain fatty acid" as used herein refers to a fatty acid having from 6 to 12, preferably 8 to 10 carbon atoms which may be branched or unbranched, preferably unbranched and which may be optionally substituted. Certain neutral plant oils, such as fractionated coconut oils, provide convenient sources of medium-chain fatty acid triglycerides. The triglyceride suitably comprises from 50 to 100% (w/w) of caprylic (Cg) acid and from 0 to 50% (w/w) of cupric (C 10) acid triglycerides. Suitable examples include those available under the 1o trade names MYRITOL; CAPTEX (Karlshams Lipid Specialties, Columbus OH), for instance CAPTEX 355, CAPTEX 300, CAPTEX 350, CAPTEX 850 and CAPTEX
8000; MIGLYOL (BASF), for instance the grades MIGLYOL 810, MIGLYOL 812 AND MIGLYOL 818 (which also comprises a linoleic acid triglyceride) and MAZOL
1400 (blazer Chemical, Guernee, II). The fatty acid content of representative products 15 is: CAPTEX 355TM - CAPROIC ACID (2%), CAPRYLIC ACID (55%) and cupric acid (42%); CAPTEX 8000 - at least 98% caprylic acid, MYGOL 810 - caproic acid (2%), caprylic acid (65-75%), cupric acid (25-35%) and MIGLYOL 812 - caproic acid (3%), caprylic acid (50-65%), cupric acid (30-45%) and lauric acid (5%) (manufacturer's data).
The polyoxyethylene ether or ester used in this invention is one which will function as a non-ionic surfactant. Especially suitable materials include polyoxyethylene glycol monocetyl ethers, such as Cetomacrogol 1000. Other suitable non-ionic surfactants include:
(a) polyoxyethylene fatty acid esters, for example polyoxyethylene stearic acid esters of the type available under the trade name MYRJ (ICI Americas, Inc.), for instance the product MYRJ 52 (a polyoxyethylene 40 stearate);
(b) polyoxyetheylene-sorbitan fatty acid esters (polysorbates), for example the mono-and tri-lauryl, palmityl, stearyl and oleyl esters, for instance the polyoxyethylene 3o sorbitan monooleates available under the trade name of TWEEN (ICI Americas Inc.), such as TWEEN 20, 21, 40, 60, 61, 65, 80, 81 and 85, of which class TWEEN 80 is especially preferred;
(c) polyoxyethylene glycol long-chain alkyl ethers, such as polyoxyethylated glycol lauryl ether; and (d) polyoxyethylene glycol long-chain alkyl esters, such as PEG-monostearate.
For use herein, the surfactant preferably has an HLB value in the range of 13 to 20.
z As fatty alcohol or ester there may be used any of such materials conventionally used in pharmaceutical or veterinary compositions such as stearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, myristyl alcohol and glycerin monostearate. Preferably, cetostearyl alcohol is used, or a mixture of stearyl alcohol and cetyl alcohol.
A particularly preferred vehicle composition comprises fractionated coconut oil (typically about 55 to 60, especially about 57, parts by weight);
polyoxyethylene glycol monocetyl ether (typically about 2 to 4, especially about 3, parts by weight);
cetostearyl alcohol (typically about 2 to 4, especially about 3, parts by weight); with water for 1o emulsification, and also preservatives, and flavourings if desired.
Typical preservatives include benzyl alcohol and phenoxyethanol.
The composition of the present invention is particularly suitable for nasal 15 administration. The prolonged residence time of formulations of the present invention in the nasal passages, especially the nasal pharynx, makes them particularly suitable for topical treatment with local action or, since it provides prolonged contact of the formulation with an absorptive region, systemic delivery of a medicament.
2o Suitable medicaments include antibiotics, for instance mupirocin or a pharmaceutically acceptable salt or ester thereof.
Compositions of the present invention may be used to treat a range of conditions, for instance a topically effective antibiotic such as mupirocin or a pharmaceutically 25 acceptable salt or ester thereof, may be used to treat recurrent sinusitis or recurrent otitis media.
Suitable pharmaceutically acceptable salts of mupirocin are well known in the art and include alkali metal salts such as sodium and lithium and alkaline earth metal salts such 3o as calcium, of which the calcium salt is preferred, in particular the crystalline dihydrate from thereof described in EP 0 167 856-A (Beecham Group). Other suitable salts include silver and aluminium salts and ammonium and substituted- ammonium salts.
The salts may be anhydrous or may be in the form of pharmaceutically acceptable solvates, for instance alcoholates and, especially, hydrates. Preferred salts include the 35 calcium, silver and lithium salts, in particular the calcium salt. In the case of the calcium salt of Mupirocin, the crystalline salt is preferably used, especially the crystalline hydrated calcium salt, more preferably the crystalline dihydrate salt.
Suitable pharmaceutically acceptable esters of mupirocin are well known in the art and include lower alkyl esters, especially the methyl and ethyl esters.
The mupirocin is preferably present as a finely divided powder. This may be achieved by milling, and most suitably by micronising (fluid energy milling) so that the medicament has a particle size less than 100 pm, preferably less than 10 Vim.
In the composition of this invention a medicament, for instance an antibiotic, is used at between 2 and 8%, typically about 4 to 6%, by weight of the formulation. For an to antibiotic, it is preferred to use a relatively high dosage level, to reduce the risk of the development of bacterial resistance. Also, to avoid excessive delivery volumes which will be uncomfortable in nasal administration, the antibiotic is preferably present at a relatively high loading compared to other topical administration formulations.
15 The composition of the invention may typically be administered into the nasal passages by a pump, such as an air lift pump. This may be adapted for nasal administration by addition of a modified nozzle.
The composition of this invention may be produced by conventional pharmaceutical 2o techniques. Thus, for example, the components of the carrier may be blended by mixing together at an elevated temperature until an emulsion has formed. The mixture may then be cooled to room temperature, and, after the addition of any further optional ingredients, stirred to ensure adequate dispersion. The antibiotic may be added during hot preparation of the base, or may be added with additional ingredients after cooling of 25 the base. If necessary the composition may be provided in sterile condition.
Optional ingredients that may be added if desired include colourings and flavourings.
The invention is illustrated by the following Example.
Example An oil-in-water emulsion cream was prepared from the following:
Calcium Mupirocin 4%
Fractionated Coconut Oil* 57.3%
Polyoxyethylene glycol monocetyl ether 3%
Cetostearyl alcohol 3%
Benzyl Alcohol 1 %
The mupirocin is preferably present as a finely divided powder. This may be achieved by milling, and most suitably by micronising (fluid energy milling) so that the medicament has a particle size less than 100 pm, preferably less than 10 Vim.
In the composition of this invention a medicament, for instance an antibiotic, is used at between 2 and 8%, typically about 4 to 6%, by weight of the formulation. For an to antibiotic, it is preferred to use a relatively high dosage level, to reduce the risk of the development of bacterial resistance. Also, to avoid excessive delivery volumes which will be uncomfortable in nasal administration, the antibiotic is preferably present at a relatively high loading compared to other topical administration formulations.
15 The composition of the invention may typically be administered into the nasal passages by a pump, such as an air lift pump. This may be adapted for nasal administration by addition of a modified nozzle.
The composition of this invention may be produced by conventional pharmaceutical 2o techniques. Thus, for example, the components of the carrier may be blended by mixing together at an elevated temperature until an emulsion has formed. The mixture may then be cooled to room temperature, and, after the addition of any further optional ingredients, stirred to ensure adequate dispersion. The antibiotic may be added during hot preparation of the base, or may be added with additional ingredients after cooling of 25 the base. If necessary the composition may be provided in sterile condition.
Optional ingredients that may be added if desired include colourings and flavourings.
The invention is illustrated by the following Example.
Example An oil-in-water emulsion cream was prepared from the following:
Calcium Mupirocin 4%
Fractionated Coconut Oil* 57.3%
Polyoxyethylene glycol monocetyl ether 3%
Cetostearyl alcohol 3%
Benzyl Alcohol 1 %
Phenoxy ethanol 0.5%
Water 35%
Lemon juice flavour (powdered) 0.2%
*Commercial product Miglyol, obtainable from BASF
Water 35%
Lemon juice flavour (powdered) 0.2%
*Commercial product Miglyol, obtainable from BASF
Claims (8)
1. A composition adapted for prolonged residence in the nasal passage, in particular the nasal pharynx, consisting essentially of:
2 - 8% by wt. of a medicament;
50 - 70 % by wt. of a fatty acid triglyceride;
2 - 6 % by wt. of a polyoxyethylene ether or ester surfactant;
2 - 4 % by wt. of a fatty alcohol or ester;
30 - 40 % by wt. of water; and up to 2 % by wt. of conventional additives.
2 - 8% by wt. of a medicament;
50 - 70 % by wt. of a fatty acid triglyceride;
2 - 6 % by wt. of a polyoxyethylene ether or ester surfactant;
2 - 4 % by wt. of a fatty alcohol or ester;
30 - 40 % by wt. of water; and up to 2 % by wt. of conventional additives.
2. A composition according to claim 1 in which the fatty acid triglyceride is a vegetable oil fractionated to medium chain lengths.
3. A composition according to claim 2 in which the fatty acid triglyceride is fractionated coconut oil.
4. A composition according to any one of claims 1 to 3 in which the polyoxyethylene ether is Cetomacrogol 1000.
5. A composition according to any one of claims 1 to 4 in which the fatty alcohol is cetostearyl alcohol or a mixture of cetyl and stearyl alcohols.
6. A composition according to any one of claims 1 to 5 which is an oil in water emulsion containing about 57 % by weight of fractionated coconut oil, about 3 % by weight of Cetomacrogol 1000 and about 3 % by weight of cetostearyl alcohol.
7. A composition according to any one of claims 1 to 6 in which the medicament is an antibiotic.
8. A composition according to claim 7 in which the antibiotic is Mupirocin, or a pharmaceutically acceptable salt or ester there of.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9719203.3 | 1997-09-11 | ||
| GBGB9719203.3A GB9719203D0 (en) | 1997-09-11 | 1997-09-11 | Novel composition and use |
| GBGB9806685.5A GB9806685D0 (en) | 1998-03-26 | 1998-03-26 | Novel composition |
| GB9806685.5 | 1998-03-27 | ||
| PCT/EP1998/005716 WO1999012520A1 (en) | 1997-09-11 | 1998-09-03 | Compositions adapted for prolonged residence in the nasal pharynx |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2303443A1 true CA2303443A1 (en) | 1999-03-18 |
Family
ID=26312214
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002303443A Abandoned CA2303443A1 (en) | 1997-09-11 | 1998-09-03 | Compositions adapted for prolonged residence in the nasal pharynx |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1033969A1 (en) |
| JP (1) | JP2001515850A (en) |
| CA (1) | CA2303443A1 (en) |
| WO (1) | WO1999012520A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050123575A1 (en) * | 2003-12-03 | 2005-06-09 | Eilon Asculai | Spreadable compositions for topical use, an improved process of making same and methods of using same |
| CA2641605A1 (en) * | 2006-02-09 | 2007-08-23 | Schering Corporation | Pharmaceutical formulations |
| EP2444067A1 (en) * | 2010-10-20 | 2012-04-25 | Laboratorios Ojer Pharma S.L. | Anhydrous gel comprising mupirocin |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ200918A (en) * | 1981-07-02 | 1985-07-31 | Gist Brocades Nv | Stable fatty oil-in-water emulsion cream for topical application |
| LU85849A1 (en) * | 1985-04-11 | 1986-11-05 | Cird | BENZONAPHTHALENIC DERIVATIVES, THEIR PREPARATION PROCESS AND THEIR APPLICATION IN THE PHARMACEUTICAL AND COSMETIC FIELDS |
| FR2580277B1 (en) * | 1985-04-15 | 1988-06-10 | Oreal | NOVEL NAPHTHALENIC DERIVATIVES WITH RETINOIC ACTION, THEIR PREPARATION METHOD AND MEDICINAL AND COSMETIC COMPOSITIONS CONTAINING THEM |
| IE59628B1 (en) * | 1986-06-26 | 1994-03-09 | Beecham Group Plc | Treatment of fungal infections |
| DK0727979T3 (en) * | 1993-10-22 | 2001-10-01 | Smithkline Beecham Corp | New preparation |
-
1998
- 1998-09-03 CA CA002303443A patent/CA2303443A1/en not_active Abandoned
- 1998-09-03 JP JP2000510419A patent/JP2001515850A/en active Pending
- 1998-09-03 EP EP98948935A patent/EP1033969A1/en not_active Withdrawn
- 1998-09-03 WO PCT/EP1998/005716 patent/WO1999012520A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999012520A1 (en) | 1999-03-18 |
| JP2001515850A (en) | 2001-09-25 |
| EP1033969A1 (en) | 2000-09-13 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |