CN1095661C - Novel therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and process for manufature thereof - Google Patents
Novel therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and process for manufature thereof Download PDFInfo
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- CN1095661C CN1095661C CN96108873A CN96108873A CN1095661C CN 1095661 C CN1095661 C CN 1095661C CN 96108873 A CN96108873 A CN 96108873A CN 96108873 A CN96108873 A CN 96108873A CN 1095661 C CN1095661 C CN 1095661C
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Abstract
The present invention relates to an anti-inflammatory and analgesic medicinal composition of transdermal administration, which contains nimesulide. The composition contains the nimesulide and excipient base materials for increasing transdermic absorption. The excipient base materials for increasing the transdermic absorption act as microcarrier preconcentration substances or microcarriers and contain surface active agents for strengthening the transdermic absorption, gelling agents or thickening agents and one kind of or many kinds of excipient containing water.
Description
The present invention relates to the novel antiinflammatory that contains nimesulide (for N-(4-nitro-2-Phenoxyphenyl) Methanesulfomide) and therapeutic combination of analgesic transdermal use and preparation method thereof.
For the medicine of Transdermal absorption, it needed through each layer of skin before arriving site of action.
The character of each layer of skin is different, and some is hydrophilic, and some is lipophilic (Montagna W.Parrakhal PF:The structure and function of the skin, the 3rd edition, AcademicPress, New York, 1974).Therefore, any medicine of transdermal use must while possess hydrophilic property and lipotropy.Nimesulide is N-(4-nitro-2-Phenoxyphenyl) Methanesulfomide chemical compound, and it is extremely hydrophobic medicine, therefore is considered to the bad medicine of Transdermal absorption.When it is coated on skin, can only absorb minute quantity or absorption.
The transdermal administration approach of anti-inflammatory drug has various advantages such as dosage is lower, low toxicity/side effect, no GI irritation, medicament can not piled up and higher (the ChienYW:Novel Drug Delivery System of position selectivity in vivo than oral administration, Marcel Dekker, New York, 1982).
Document and market survey show still do not have the nimesulide percutaneous drug administration preparation of the suitable effect of tool at present.
(United States Patent (USP) 3,840,597) have disclosed the application of nimesulide as anti-inflammatory agent in the patent of nimesulide drug molecule, and the dosage range of its cream, gel, plaster and so on dosage form is 1-500 milligram/kg body weight.According to our research, medicine or be precipitated out in the preparation of routine perhaps is deposited on the human body skin with the conventional gel of above-mentioned dosage or cream coating the time, does not in fact have percutaneous to absorb.Key difficulty is inherent insoluble in aqueous medium of nimesulide, and the preparation that therefore contains nimesulide must have sufficiently high concentration to use for routine, and satisfies the desired standard of bioavailability, as be effective from skin absorbs.
United States Patent (USP) 5,446,070 (Mantell etc.) have disclosed the bioadhesive composition tool flexibility, that area is limited.But the present invention is not the compositions of limited compositions of area or bioadhesion.The present invention includes a kind of non-limited compositions, in other words, said composition can be coated on big body surface area, for example is used for the occasion of knuckle synovia.
Secondly, the patent of Mantell is limited to 5-70% (weight) with the solvent scope, and solvent strength of the present invention can reach 99.99%, because compositions of the present invention is the compositions that can apply without restriction.
In addition, the patent of Mantell etc. requires plasticizer, and the present invention does not require plasticizer with different afterwards, because it is useless.
As for the existence of polysaccharide, the present invention uses polysaccharide also can not use polysaccharide, and the use amount of polysaccharide is more much lower than the said 20-50% of Mantell (weight).
In addition, it is that bioadhesion is needed that Mantell uses a large amount of polysaccharide, and the present invention does not then need.
It is non-existent that Mantell also discloses water, and water then is that compositions is necessary among the present invention.
By intramuscular injection with nimesulide as analgesic administration do not succeed because nimesulide is in fact water insoluble, it makes conventional oil preparation or suspending agent, forms the storage storehouse in muscular tissue, this does not reach the purpose of rapid release.
Market and literature survey show, do not report the parenteral administration dosage form of nimesulide.(Drugs?48(3)431-454，1994)
One object of the present invention provides and contains the therapeutic combination that can change the chemical compound of nimesulide hydrophobic property when nimesulide and other share, and preparation method thereof, make described compositions can be applied directly to skin, by Transdermal absorption treatment inflammation.
Another object of the present invention, provide and contain the new therapeutic combination that can change the chemical compound of nimesulide physicochemical properties when nimesulide and other share, make described compositions can be applied directly to skin, by Transdermal absorption treatment inflammation, and its dosage is significantly less than the dosage level of known technology.
The invention provides the pharmaceutical composition that novel antiinflammatory and analgesic topical therapeutic are used, it comprises: 1. nimesulide: 0.1-10% (weight) 2. increases the excipient substrate that percutaneous absorbs: 90-99.9% (weight)
The excipient substrate that described increase percutaneous absorbs can be used as microcarrier preconcentrate or microcarrier, it comprises: 1. the 2. described surfactant of described percutaneous absorption enhancer: 0.5-60% (weight): the 3. described gellant/thickening agent of 0.0-12% (weight): 4. described one or more the excipient/substrate of 0.2-19% (weight) comprise water 5-97% (weight)
The substrate that increases the percutaneous absorption preferably comprises: 1. the 2. described surfactant of described percutaneous absorption enhancer: 6-15% (weight): the 3. described gellant/thickening agent of 0.5-12% (weight): 4. described one or more excipient/substrate of 0.5-19% (weight): 5-60% (weight)
The scope of required water is 1-15% (weight) in the compositions, is preferably 9-11% (weight), is more preferably 9.5-10.5% (weight).
Except above-mentioned component, the local compositions of using also comprises described nertralizer/pH regulator agent, and its amount ranges is 0.0-2.0%.
According to the present invention, have now found that the high hydrophobicity medicament solubilization that can make, and reach site of action through transdermal route resemble the nimesulide.The present invention relates to nimesulide is mixed the method for preparation, it can make medicament solubilization and intactly carry institute's site of action by skin barrier.
The substrate that increases the percutaneous absorption preferably comprises: 1. the 2. described surfactant of described percutaneous absorption enhancer: 6-15% (weight): the 3. described gellant/thickening agent of 0.5-12% (weight): 4. described one or more the excipient/substrate of 0.5-19% (weight) comprise water: 5-60% (weight)
The amount ranges of nimesulide is preferably 1-5% (weight).
Be more preferably, the local compositions of using also comprises described nertralizer/pH regulator agent, and its amount ranges is 0.0-2.0% (weight).
The antiinflammatory of novel local topical of the present invention and analgesic composition make by the method that comprises the following steps:
(a) with described one or more excipient of the percutaneous absorption enhancer of described 0.5-30% (weight) and 2.5-30% (weight) or substrate in container by mixing, the nimesulide that adds 0.1-10% (weight) in the mixture of gained is stirred to dissolving fully.
(b) the described surfactant of 0.5-12% (weight), the described gellant/thickening agent of 0.2-50% (weight) and described one or more the excipient/substrate of 2.5-30% (weight) are mixed in homogenizer and obtain uniform mixture.
(c) stir but do not produce whirlpool with the situation of avoiding inflating under, the mixture of step (a) gained is added in the homogeneous mixture of step (b) gained.Make required antiinflammatory and analgesic composition in stirring at a slow speed to add 0.0-2.0% nertralizer or pH regulator agent neutralise mixt down or its pH is transferred to described acidity.
Can use any known percutaneous absorption enhancer, be preferably C
12-24List or polyunsaturated fatty acid, as vaccenic acid, suitable-vaccenic acid, linoleic acid, linolenic acid, elaidic acid, oleic acid, petroselic acid, erucic acid or nervonic acid or their corresponding alcohols, particularly oleic acid or oleyl alcohol, or 1-dodecyl-aza-cycloheptane alkane-2-ketone (being also referred to as azone); Sulfoxide class such as dimethyl sulfoxine, positive decyl methyl sulfoxide; Such as dimethyl acetylamide, dimethyl formamide and N, the amide-type of N-n,N-diethyl meta-toluamide; Pyrrolidinone compounds such as 2-Pyrrolidone and N-N-methyl-2-2-pyrrolidone N-.
As surfactant, available any pharmaceutically acceptable hydrophilic or lipophilic surfactant or their mixture, specially suitable surfactant is the product of natural or hydrogenant vegetable oil and ethylene glycol, it is the acidifying natural or hydrogenant vegetable oil of polyoxyethylene ethanol, as, the acidifying natural or castor oil hydrogenated of polyoxyethylene ethanol; Particularly commodity are called the various surfactants of CREMORPHOR, especially CREMOPHOR RH40 and CREMOPHOR EL.The various surfactants that also are fit to commodity in use NIKKOL by name are as NIKKOL HCO-60;
Polyoxyethylene-fatty acid esters of sorbitan, as list and three lauroyl, palmityl, stearoyl and oleoyl ester, the various materials as commodity tween by name are preferably polysorbate40 and Tween 80;
Polyox-yethylene-polyoxypropylene block copolymer as commodity POLOXAMER by name, is preferably the material of POLOXAMER 188;
Polyoxyethylene fatty acid ester, as Myrj 45, the polyoxyethylene fatty acid ester of commodity MYRJ by name and commodity CEIIOL HE by name;
Propylene glycol list and di fatty acid ester are such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxy stearic acid ester, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate ester, propylene glycol stearate;
Suitable lipophilic surfactant's example comprises the transesterification products of crude vegetal triglyceride and polyalkylene polyhydric alcohol.Be preferably the product of the transesterification gained that makes 2 moles of crude vegetal triglyceride and 1 mole of Polyethylene Glycol (is 200-800 as mean molecule quantity).The various forms of commodity of this class transesterification product are called LABRAFIL, are preferably LABRAFIL M 1944 CS;
The fatty acid esters of sorbitan of commodity span by name comprises anhydro sorbitol list lauroyl ester, single palmityl ester, single stearoyl ester, three stearoyl esters, single oleoyl ester and three oleoyl esters;
Monoglyceride, as glycerin mono-fatty acid ester, glycerol monopalmitate and glyceryl monostearate, trade name is followed successively by MYVATEX, MYVAPIEX and MYVEROL.
As gellant/thickening agent, available any known pharmaceutically acceptable this class material, comprise synthetic or semisynthetic polymeric material, polyacrylate and acrylate copolymer resin, as polyacrylic acid and polyacrylic acid/methacrylic resin, commodity are called CARBOPOL, particularly CARBOPOL 934,940 and 941 and EUDRAGIT, particularly EUDRAGIT E, L, S, RL and RS;
Cellulose and cellulose derivative comprise alkylcellulose, as methyl-, ethyl-and propyl group-cellulose; Hydroxy alkyl cellulose, as hydroxypropyl cellulose, such as the hydroxypropylalkylce,lulose of hydroxypropyl emthylcellulose, acylated cellulose is as cellulose ethanoate, cellulosic phthalic acetate and their salt, as sodium carboxymethyl cellulose;
Comprise the polyvinyl resin of polyvinyl acetate and polyvinyl alcohol, and comprise alginate such as alginic acid and their salt such as sodium alginate and other polymeric material of propanediol alginate.
This class material of any routine be can use as nertralizer/pH regulator agent, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tetraborate, sodium hydrogen phosphate and sodium dihydrogen phosphate comprised.Also can use the polarity organic amine preferably, as diethylamine, diisopropanolamine (DIPA), triethylamine and triethanolamine.
As excipient/substrate, can use following material:
Pharmaceutically acceptable rudimentaryly (have C
1-5) alkanol, particularly ethanol; Water miscible macromole alcohols is the Polyethylene Glycol of 200-600 as mean molecule quantity; 1,2-propylene glycol carbonic ester, the third-1,2-glycol or 1,2-propylene glycol; Glycerol triacetate or (1,2,3)-glyceryl triacetate; Lower ketones, particularly acetone and 1,2, the 3-glycerol.
Can add the water of various concentration so that provide required hydrophilic nmature to compositions.
Also available pharmaceutically acceptable C
1-5The material of the diether of alkyl or tetrahydrofuran methyl and low-molecular-weight list or polyoxyalkylene glycols or monoether, particularly commodity TRANSCUTOL by name and COLYCOFUROL.
As the substrate of the lipophilic phase for preparing Emulsion, can use fatty acid triglycercide, be preferably the fatty acid triglycercide of medium chain; As Oleum Cocois, olive oil, Oleum Ricini and their vegetable oil such as derivant; Ethyl oleate.
For described therapeutic combination is made ointment, the fatty acid of available animal origin, fat, oil and wax are as substrate, and as Cera Flava, spermaceti, lanoline, the wax in plant origin or mineral source is as hard paraffin, soft paraffin and liquid paraffin.
Topical dosage forms is made into is easy to apply and do not cause the product of pollution.The therapeutic combination of the aerosol form of using for local coating, available as Propellant 11, Propellant 12, the Chlorofluorocarbons (CFCs) of Propellant 114; Propellant as the hydro carbons of normal butane, iso-butane and propane; As compressed gas propellant of nitrogen oxide, carbon dioxide and nitrogen etc. as pharmaceutically acceptable propellant.
Novel therapeutic combination of the present invention can adopt following dosage forms: 1. part aqueous gel.2. oil-in-water or water-in-oil emulsion or microemulsion or cream.3. the solution of local coating external.4. ointment.5. the aerosol preparations used of local coating.
Therapeutic combination of the present invention can utilize as physical form such as electric energy or ultrasonic wave energy can be coated on skin so that medicine better percutaneous absorb.
The present invention is described with reference to the following example:
Embodiment 1
The preparation of topical gels agent
Sl.No. component consumption
1. nimesulide 2.0g
2. dimethyl acetylamide 22.0g
3. ethanol 40.0g
4. acetone 10.0g
5. Cremophor?RH?40 4.0g
6. the third ethanol 38.0g
7. PEG400 48.8g
8. Carbopol?934 4.0g
9. water 30.0g
10. diethylamine 1.2g
Amount to 200.0g
Step (a): dimethyl acetylamide is mixed in container for stirring under 30 ℃ with ethanol and acetone.In the mixture of gained, add nimesulide, and be stirred to till the dissolving fully.Step (b): propylene glycol, PEG400 and water are mixed in homogenizer.At room temperature each a small amount of adds 1.5% (weight) carbopol 934 in the homogeneous mixture of gained, and the speed of homogenizer is maintained at about 1500-2000r/min.Step (c): stir but do not produce whirlpool with the condition of avoiding inflating under, be preferably under vacuum (25mmHg), the mixture of step (a) gained is added in the mixture of step (b) gained.The mixture of gained neutralizes to form gel preparation by slowly add diethylamine under slow stirring of 25-30 ℃ of temperature and vacuum (25mmHg).
Embodiment 2
The preparation of topical creams
Sl.No. component consumption
1. nimesulide 1.0g
2. Transcutol 35.0g
3. water 10.0g
4. sodium hydrogen phosphate 0.1g
5. Cremophor?RH?40 5.0g
6. Labrafil?M?1944?CS 10.0g
7. mono stearate glyceryl ester 8.0g
8. stearic acid 13.0g
9. ethyl oleate 2.9g
10. dimethyl sulfoxine 15.0g
Amount to 100.0g
Under warm nimesulide is dissolved in the mixture of (6), (7), (8), (9) and (10).Mix (2), (3), (4) and (5) separately, and under agitation slowly add the nimesulide mixture to one mixture of back.
Embodiment 3
The local coating preparation of solution dosage
Sl.No. component consumption
1. nimesulide 1.0g
2. dimethyl acetylamide 10.0g
3. Poloxamer?188 2.0g
4. ethanol 20.0g
5. propylene glycol 25.0g
6. PEG400 42.0g
7. hydroxypropyl emthylcellulose 1.0g
8. triethanolamine 0.2g
9. water 1.0g
Amount to 100.0g
Under agitation nimesulide is dissolved in (2), under agitation adds (3), (4), (5), (6), (7) and (8) to obtain clear solutions.
Embodiment 4
The local coating preparation of ointment
Sl.No. component consumption
1. nimesulide 2.0g
2. dimethyl sulfoxine 21.0g
3. glyceryl monostearate 16.0g
4. mineral oil 62.0g
5. white vaseline 97.0g
6. water 2.0g
Amount to 200.0g
Warm (3), (4) and (5), and under agitation add the dimethyl sulfoxide solution of nimesulide.
Embodiment 5
Local preparation with aerosol dosage forms
Sl.No. component consumption
1. nimesulide 1.0g
2. dimethyl acetylamide 10.0g
3. ethanol 10.0g
4. Cremophor?RH?40 10.0g
5. propellant 114 29.0g
6. propellant 12 39.0g
7. water 1.0g
Amount to 100.0g
It is found that the analgesic activity of the therapeutic combination that makes according to the present invention has dose dependent, and passed through the test of subacute toxicity and excessive toxicity.
To compare the dosage level of the antiinflammatory of novelty of the present invention and analgesic composition much lower with producing the conventional nimesulide preparation equate curative effect.
The therapeutic combination of the various dosage forms that make according to the present invention, with have strengthen the pond (Pharm Tech.Jan.1995 52-58) carries out the vitro drug release test through improved USP digestion instrument.Used dissolution medium is the pH7.4 phosphate buffer.The result shows that release amount of medicine totally and infiltration capacity and drug load are proportional.
Described compositions has also been carried out the pharmacological testing of standard to measure its anti-inflammatory activity, as rat paw edema and Cavia porcellus erythema.Comparing these tests with placebo shows significantly active.
Described therapeutic combination is also tested zest or other over-drastic side effect 60 healthy volunteers.It was reported does not stimulate/side effect.
Because the present invention can draw technical schemes different on many surfaces also without departing from the spirit and scope of the present invention, here explanation of the present invention is only also provided constraints never in any form as illustration.
Claims (23)
1. one kind contains the antiinflammatory of the big water gaging that makes medicine dissolution and more absorb and the pharmaceutical composition that the local usefulness/transdermal of analgesic uses, and it comprises:
0.1-10% weight nimesulide: and
The excipient substrate that the increase percutaneous of 90-99.9% weight absorbs,
The excipient substrate that wherein said increase percutaneous absorbs comprises:
The percutaneous absorption enhancer of 0.5% to 60% weight and the excipient/substrate of 5.0-97% weight,
Wherein said excipient/substrate comprises the water of 1-15% weight.
2. compositions according to claim 1, it also comprises the gellant/thickening agent of 0.2-19% weight.
3. compositions according to claim 1, it also comprises the most nearly surfactant of 12% weight.
4. compositions according to claim 1, it further comprises the most nearly nertralizer/pH regulator agent of 2.0% weight.
5. compositions according to claim 1, wherein said percutaneous absorption enhancer is selected from C
12-24List or polyunsaturated fatty acid or their corresponding alcohols.、
6. compositions according to claim 1, wherein said percutaneous absorption enhancer is selected from sulfoxide class, amide-type or pyrrolidinone compounds.
7. compositions according to claim 6, wherein the percutaneous absorption enhancer is a dimethyl acetylamide.
8. compositions according to claim 3, wherein surfactant is pharmaceutically acceptable hydrophilic or lipophilic surfactant or its mixture.
9. compositions according to claim 8, wherein surfactant is selected from polyoxyethylene-fatty acid esters of sorbitan, polyox-yethylene-polyoxypropylene block copolymer, polyoxyethylene fatty acid ester, propylene glycol list and di fatty acid ester, the lipophilic surfactant, fatty acid esters of sorbitan or monoglyceride.
10. compositions according to claim 2, wherein said gellant/thickening agent are selected from synthetic or semisynthetic polymeric material, polyacrylate and acrylate copolymer resin, cellulose and cellulose derivative or polyvinyl resin.
11. compositions according to claim 1, wherein the amount of water is a 9-11% weight.
12. pharmaceutical composition according to claim 11, wherein the amount of water is a 9.5-10.5% weight.
13. pharmaceutical composition according to claim 4, wherein said nertralizer/pH regulator agent is selected from sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium tetraborate, sodium hydrogen phosphate or sodium dihydrogen phosphate.
14. compositions according to claim 4, wherein said nertralizer/pH regulator agent is the polarity organic amine.
15. compositions according to claim 1, wherein said excipient/substrate is selected from: pharmaceutically acceptable C
1-5Alkanol; The water-soluble polyethylene glycol class; 1,2-propylene glycol carbonic ester; The third-1, the 2-glycol; 1, the 2-propylene glycol; Glycerol triacetate; (1,2,3)-glyceryl triacetate or lower ketones.
16. the pharmaceutical composition that antiinflammatory and analgesic topical transdermal are used, it comprises:
Nimesulide: 0.1%-10% weight,
The percutaneous absorption enhancer: 0.5-60% weight,
Gellant/thickening agent: 0.2-19% weight,
Excipient/the substrate that comprises water: 5-97% weight,
Reach most the surfactant of 12% weight.
17. the pharmaceutical composition that antiinflammatory and analgesic topical transdermal are used, it comprises:
Nimesulide: 0.1%-10% weight,
The percutaneous absorption enhancer: 0.5-60% weight,
Gellant/thickening agent: 0.2-19% weight.
Excipient/substrate: 5-97% weight,
The most nearly surfactant of 12% weight and the most nearly nertralizer/pH regulator agent of 2% weight.
18. one kind prepares the antiinflammatory that part/transdermal uses and the method for analgesic pharmaceutical composition, it comprises the following steps:
(a) the percutaneous absorption enhancer with 0.5-30% weight mixes with one or more excipient or the substrate of 2.5-30% weight;
(b) in the mixture of step (a) gained, add the nimesulide of 0.1-10% (weight), be stirred to dissolving fully then;
(c) surfactant of 0.5-12% weight, the gellant/thickening agent of 0.2-50% weight and one or more excipient/substrate of 2.5-30% weight are mixed separately, and the whole mixture of mixture;
(d) under agitation, the mixture of step (b) gained is added in the homogeneous mixture of step (c) gained, obtain required compositions.
19. method according to claim 18 wherein adds to the pH of the compositions of step d) gained with neutralization or adjusting mixture with nertralizer or pH regulator agent.
20. method according to claim 19, the addition that wherein adds described nertralizer/pH regulator agent in the step d) in compositions reaches 2.0% weight most.
21. compositions according to claim 1, it is non-staining.
22. compositions according to claim 16, it is non-staining.
23. compositions according to claim 17, it is non-staining.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96108873A CN1095661C (en) | 1996-07-23 | 1996-07-23 | Novel therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and process for manufature thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN96108873A CN1095661C (en) | 1996-07-23 | 1996-07-23 | Novel therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and process for manufature thereof |
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| CN1189337A CN1189337A (en) | 1998-08-05 |
| CN1095661C true CN1095661C (en) | 2002-12-11 |
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| CN96108873A Expired - Fee Related CN1095661C (en) | 1996-07-23 | 1996-07-23 | Novel therapeutic anti-inflammatory and analgesic composition containing nimesulide for use transdermally and process for manufature thereof |
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| CN102631324A (en) * | 2011-02-15 | 2012-08-15 | 南京正科制药有限公司 | Nimesulide self-emulsification particle and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996011002A1 (en) * | 1994-10-05 | 1996-04-18 | Hisamitsu Pharmaceutical Co., Inc. | Antiinflammatory agent for external use |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996011002A1 (en) * | 1994-10-05 | 1996-04-18 | Hisamitsu Pharmaceutical Co., Inc. | Antiinflammatory agent for external use |
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