WO2001021209A1 - Utilisation de savons d'acide gras ou d'acide amine pour ameliorer l'efficacite anti-microbienne de compositions pharmaceutiques topiques - Google Patents
Utilisation de savons d'acide gras ou d'acide amine pour ameliorer l'efficacite anti-microbienne de compositions pharmaceutiques topiques Download PDFInfo
- Publication number
- WO2001021209A1 WO2001021209A1 PCT/US2000/024765 US0024765W WO0121209A1 WO 2001021209 A1 WO2001021209 A1 WO 2001021209A1 US 0024765 W US0024765 W US 0024765W WO 0121209 A1 WO0121209 A1 WO 0121209A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fatty acid
- amino acid
- agents
- antimicrobial
- group
- Prior art date
Links
Classifications
-
- 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
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/02—Local antiseptics
Definitions
- the present invention relates generally to the preservation of pharmaceutical compositions.
- the present invention relates to the use of fatty acid/amino acid soaps to prevent or to reduce binding of the antimicrobial components of topically administrable pharmaceutical compositions to other components contained therein, thereby improving the antimicrobial efficacy of such compositions.
- ophthalmic compositions that contain a variety of components, such as carboxyvinyl polymers (e.g., Carbopol ® ), ion exchange resins (e.g., Amberlite ® ), or other large polyelectrolytes, which provide sustained release of the ophthalmic agent(s), as well as increased patient comfort.
- carboxyvinyl polymers e.g., Carbopol ®
- ion exchange resins e.g., Amberlite ®
- Such compositions are described, for example, in US 4,911 ,920 (Jani et al.).
- compositions are comfortable and have sustained release characteristics, cationic antimicrobials, such as benzalkonium chloride (BAC), which are often added as preservatives to such compositions, tend to bind to the anionic polyelectrolytes present in the formulations, resulting in loss of antimicrobial effectiveness.
- BAC benzalkonium chloride
- Sarcosinate surfactants are composed of acylated sarcosines.
- Sarcosine (CH 3 -NH-CH 2 -COOH), an amino acid normally found in starfish and sea urchins, is chemically related to glycine (NH 2 -CH 2 -COOH), a basic amino acid in mammals.
- Common fatty acids and their derivatives utilized in the manufacture of sarcosinate surfactants are lauric, oleic, and myristic acids and their esters and halides. Because of their mildness, sarcosinate surfactants have been utilized in shampoos, mouthwashes, skin cleansers, sunscreens, aerosol shaving lathers and other personal care products. To date, the main applications of these types of surfactants have been in the cosmetic industry.
- European Patent Application No. 0 194 097 (Schmidt et al.), assigned to Procter & Gamble, mentions sodium lauroyl sarcosinate as the mild anionic surfactant utilized in an aerosol skin-cleansing and moisturizer mousse.
- U.S. Patent No. 5,520,920 (Castillo, et al.) discloses the use of certain modified sarcosinates and lactylates to enhance antimicrobial effectiveness of ophthalmic compositions, particularly in the case where cationic preservatives otherwise bind to anionic polyelectrolytes.
- the modified sarcosinates have the formula:
- Representative modified sarcosinates include those sold under the Hamposyl ® trade name, such as lauroyl sarcosine (Hamposyl ® L), oleoyl sarcosine (Hamposyl ® O), myristoyl sarcosine (Hamposyl ® M), cocoyl sarcosine (Hamposyl ® C), stearoyl sarcosine (Hamposyl ® S), and pelargodoyl sarcosine (Hamposyl ® P).
- Representative lactylates include sodium capryl lactylate (Pationic ® 122A). Additional solutions to the problem of cationic preservative - anionic polyelectrolyte binding problem in topically administrable pharmaceutical compositions are desirable.
- Fatty acid/amino acid soaps are known and include, for example, those surfactants sold under the Aminosoap ® trade name (Ajinomoto Co., Inc., Tokyo, Japan). According to product brochures, Aminosoap ® surfactants are used in hair and body care (hair shampoo, body wash and bath foam), facial care (facial cleanser, facial washing foam, facial washing creme, and makeup remover), and household and health care.
- Aminosoap ® surfactants are used in hair and body care (hair shampoo, body wash and bath foam), facial care (facial cleanser, facial washing foam, facial washing creme, and makeup remover), and household and health care.
- the present invention provides a method of enhancing the preservative efficacy of topically administrable pharmaceutical compositions containing an anionic polyelectrolyte and a cationic preservative. According to the method of the present invention, a fatty acid/amino acid soap is added to the topically administrable pharmaceutical composition.
- fatty acid/amino acid soaps to the compositions results in the release of the bound cationic preservative from the anionic polyelctrolyte by the formation of a loose and reversible surfactant-preservative complex.
- the surfactant-preservative complex has antimicrobial effectiveness.
- the soaps may themselves possess antimicrobial activity.
- the fatty acid/amino acid soaps of the present invention improve the preservative efficacy of topically administrable pharmaceutical compositions. Accordingly, the present invention also relates to topically administrable pharmaceutical compositions containing one or more pharmaceutically active agents, an anionic polyelectrolyte, a cationic preservative, and a fatty acid/amino acid soap.
- composition ingredients expressed in percentage terms are expressed as weight/weight.
- Fatty acid/amino acid soaps useful in the preservative systems of the present invention are those wherein the fatty acid component is derived from a C 8 - C 24 fatty acid and the amino acid component is selected from the group consisting of lysine and arginine.
- the fatty acid component is selected from the group consisting of cocoyl, linoleoyl, lauroyl, myristoyl, stearoyl, oleoyl, and pelargodoyl fatty acid residues.
- Such fatty acid/amino acid soaps are commercially available or can be made by known methods.
- the soap where the fatty acid component is cocoyl and the amino acid component is derived from arginine is commercially available as
- AMINOSOAP AR-12 from Ajinomoto Co., Inc. (Tokyo, Japan).
- the soap where the fatty acid component is cocoyl and the amino acid component is derived from lysine is available as AMINOSOAP LYC-12.
- the amount of fatty acid/amino acid soap present in the compositions of the present invention is from about 0.001 to about 1 %, preferably from about 0.01 to about 0.2%, and most preferably from about 0.03 to about 0.12%.
- concentration of the fatty acid/amino acid soap should not be so high that it causes severe discomfort.
- compositions of the present invention contain cationic antimicrobials and anionic polyelectrolytes.
- Cationic antimicrobials are known in the art and include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride and polyquaternium-1.
- Anionic polyelectrolytes include high molecular weight, anionic mucomimetic polymers (e.g., carboxyvinyl polymers such as Carbopol ® ), polystyrene sulfonic acid polymers, cationic exchange resins (e.g., Amberlite ® or Dowex ® ), and the like.
- High molecular weight, anionic mucomimetic polymers have a molecular weight between about 50,000 and 6 million.
- the polymers are characterized as having carboxylic acid functional groups and preferably contain between 2 and 7 carbon atoms per functional group.
- Suitable high molecular weight, anionic polymers are carboxyvinyl polymers, preferably those called Carbomers, e.g., Carbopol ® (B.F. Goodrich Co., Cleveland, Ohio). Specifically preferred are Carbopol ® 934P, Carbopol ® 974P and Carbopol ® 940.
- Suitable high molecular weight, anionic polymers include: alginates, carrageenans, natural gums (xanthan, karaya and tragacanth) and carboxy methyl cellulose. Such polymers will typically be employed in an amount between about 0.05 and about 6%, depending on the desired viscosity of the composition.
- Pourable liquid compositions generally comprise an amount of the polymer between about 0.05 and about 2%.
- Cation exchange resins are characterized as either strongly acidic, such as those having sulfonic acid or sulfuric acid functionality, or weakly acidic, such as those having carboxylic acid functionality. Such resins are readily available, for example, from Rohm & Haas (Philadelphia,
- the average particle size of the commercially available forms of the resins is about 40 to 150 microns.
- the particle size of the resin is critical for topically administrable ophthalmic compositions. Accordingly, for topically administrable ophthalmic compositions, commercially available resin particles are reduced by known techniques, including ball milling, to a particle size of about 20 ⁇ m or less such that the average particle size is ⁇ 10 ⁇ m, and are preferably reduced to a particle size of about 10 ⁇ m or less. Ion exchange resins are typically used in an amount from about 0.05 to about 10%. Anionic mucomimetic polymers and cation exchange resins are discussed in greater detail in U.S. 4,911 ,920 issued March 27, 1990, the entire contents of which are hereby incorporated by reference herein.
- polystyrene sulfonic acid polymers (and their salts) useful in the compositions of the present invention comprise the following repeating unit:
- the active ingredient or ingredients that can be included in the compositions of the present invention include all ophthalmic, dermatological, otic or nasal agents that can be topically applied.
- ophthalmic agents include (but are not limited to): anti-glaucoma agents, such as beta-blockers (e.g., betaxolol and timolol), muscarinics (e.g., pilocarpine), prostaglandins, carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), dopaminergic agonists and antagonists, and alpha adrenergic receptor agonists, such as para-amino clonidine (also known as apraclonidine) and brimonidine; anti-infectives, such as ciprofloxacin; non-steroidal and steroidal anti-inflammatories, such as suprofen, ketorolac, dexamethasone,
- compositions of the present invention can also include other components, for example, pharmaceutically acceptable buffers; tonicity agents; comfort-enhancing agents; solubilizing aids; pH adjusting agents; antioxidants; and stabilizing agents.
- the compositions may also contain additional preservatives (in conjunction with the cationic preservatives addressed above).
- the compositions may be formulated in various dosage forms suitable for topical delivery, including solutions, suspensions, emulsions, and gels.
- Betaxolol HCI 0.28 Amberlite IRP-69 0.25 Carbopol 974P 0.45 Cocoyl N-Lysine * 0.03 Boric Acid 0.4 Mannitol 4.5
- 0.42g betaxolol hydrochloride, 0.375g amberlite IRP 69 resin, 0.60g boric acid, 6.75g mannitol, 0.015g disodium EDTA were combined in 40ml_ water and stirred for 30 minutes.
- the pH of the formulation was adjusted to 6.5 by the addition of 2.2ml_ of 5N NaOH and the final batch amount was brought to 150ml_ with water.
- the formulation was sterilized for 60 minutes in an autoclave oven at 121°C.
- Betaxolol HCI 0.28 Amberlite IRP-69 0.25 Carbopol 974P 0.45 Cocoyl N-Lysine* 0.03 Boric Acid 0.4 Mannitol 4.5
- Example 2 To the formulation was added 0.3g of 30% cocoyl lysine solution (Aminosoap LYC-12 from Ajinomoto). The formulation was adjusted to pH 6.5 by the dropwise addition of 10% tromethamine solution, and the final batch amount was then adjusted to 300g by the addition of water. The formulation was steam sterilized for 60 minutes at 121°C in an autoclave oven. The formulation of Example 2 was found to have the following characteristics.
- Betaxolol HCI 0.28 Amberlite IRP-69 0.25 Carbopol 974P 0.45 Cocoyl N-Arginine* 0.03 Boric Acid 0.4 Mannitol 4.15
- Antimicrobial preservative effectiveness was determined using an organism challenge test according to the methods described in the United States Pharmacopeia (USP) and European Pharmacopoeia (Ph.Eur.). Samples were inoculated with known levels of one or more of the following: gram-positive (Staphylococcus aureus ATCC 6538) and gram-negative (Pseudomonas aeruginosa ATCC 9027 and Escherichia coli ATCC 8739) vegetative bacteria, yeast (Candida albicans ATCC 10231 ) and mold (Aspergillus niger ATCC 16404).
- the samples were then pulled at specified intervals to determine if the antimicrobial preservative system was capable of killing or inhibiting the propagation of organisms purposely introduced into the formulation.
- the rate or level of antimicrobial activity determined compliance with the USP and/or Ph.Eur. preservative efficacy standards for ophthalmic preparations.
- the compendial preservative standards for ophthalmic preparations are presented below:
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Ophthalmology & Optometry (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2001524633A JP2003509474A (ja) | 1999-09-21 | 2000-09-11 | 局所的薬学的組成物の抗菌効果を増強させるための脂肪酸/アミノ酸石鹸の使用 |
EP00961722A EP1214094A1 (fr) | 1999-09-21 | 2000-09-11 | Utilisation de savons d'acide gras ou d'acide amine pour ameliorer l'efficacite anti-microbienne de compositions pharmaceutiques topiques |
BR0014117-8A BR0014117A (pt) | 1999-09-21 | 2000-09-11 | Uso de sabÈes de acido graxo/aminoácido para aumentar a eficácia antimicrobiana de composições farmacêutica tópicas |
CA002391976A CA2391976A1 (fr) | 1999-09-21 | 2000-09-11 | Utilisation de savons d'acide gras ou d'acide amine pour ameliorer l'efficacite anti-microbienne de compositions pharmaceutiques topiques |
AU73637/00A AU7363700A (en) | 1999-09-21 | 2000-09-11 | Use of fatty acid/amino acid soaps to enhance antimicrobial effectiveness of topical pharmaceutical compositions |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US39901399A | 1999-09-21 | 1999-09-21 | |
US09/399,013 | 1999-09-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001021209A1 true WO2001021209A1 (fr) | 2001-03-29 |
Family
ID=23577764
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2000/024765 WO2001021209A1 (fr) | 1999-09-21 | 2000-09-11 | Utilisation de savons d'acide gras ou d'acide amine pour ameliorer l'efficacite anti-microbienne de compositions pharmaceutiques topiques |
Country Status (10)
Country | Link |
---|---|
EP (1) | EP1214094A1 (fr) |
JP (1) | JP2003509474A (fr) |
CN (1) | CN1374874A (fr) |
AR (1) | AR025713A1 (fr) |
AU (1) | AU7363700A (fr) |
BR (1) | BR0014117A (fr) |
CA (1) | CA2391976A1 (fr) |
PL (1) | PL354365A1 (fr) |
TR (1) | TR200200724T2 (fr) |
WO (1) | WO2001021209A1 (fr) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6444710B1 (en) | 1998-10-27 | 2002-09-03 | Alcon Manufacturing, Ltd. | Use of certain fatty acid/amino acid soaps to enhance antimicrobial effectiveness of topically administrable pharmaceutical compositions |
WO2003080025A1 (fr) * | 2002-03-26 | 2003-10-02 | Ellipse Pharmaceuticals | Composition topique a base de resines echangeuses d'ions, notamment pour le traitement des erythemes |
US7402609B2 (en) | 2001-06-27 | 2008-07-22 | Alcon, Inc. | Olopatadine formulations for topical administration |
US7977376B2 (en) | 2001-06-27 | 2011-07-12 | Novartis Ag | Olopatadine formulations for topical nasal administration |
EP2609933A1 (fr) * | 2010-08-27 | 2013-07-03 | Wakamoto Pharmaceutical Co., Ltd. | Composition aqueuse pour administration ophtalmique |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5642929B2 (ja) * | 2005-03-10 | 2014-12-17 | スリーエム イノベイティブ プロパティズ カンパニー | 微小生体汚染の低減方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5397567A (en) * | 1992-03-25 | 1995-03-14 | Medproject Pharma Entwicklungs Und Vertriebs Gesellschaft | Gel, especially for ophthalmology |
US5504113A (en) * | 1994-03-02 | 1996-04-02 | Allergan, Inc. | Enhancement of benzalkonium chloride preservative activity in formulations containing an incompatible drug |
US5520920A (en) * | 1992-08-28 | 1996-05-28 | Alcon Laboratories, Inc. | Use of certain anionic surfactants to enhance antimicrobial effectiveness of ophthalmic compositions |
JPH0977725A (ja) * | 1995-09-13 | 1997-03-25 | Ajinomoto Co Inc | 脂肪酸リジン塩の製造方法 |
WO2000024375A1 (fr) * | 1998-10-27 | 2000-05-04 | Alcon Laboratories, Inc. | Systeme conservateur contenant un savon a base d'acides gras/acides amines pour compositions pharmaceutiques a administration locale |
-
2000
- 2000-09-11 EP EP00961722A patent/EP1214094A1/fr not_active Withdrawn
- 2000-09-11 TR TR2002/00724T patent/TR200200724T2/xx unknown
- 2000-09-11 JP JP2001524633A patent/JP2003509474A/ja not_active Withdrawn
- 2000-09-11 AU AU73637/00A patent/AU7363700A/en not_active Abandoned
- 2000-09-11 PL PL00354365A patent/PL354365A1/xx unknown
- 2000-09-11 CA CA002391976A patent/CA2391976A1/fr not_active Abandoned
- 2000-09-11 WO PCT/US2000/024765 patent/WO2001021209A1/fr not_active Application Discontinuation
- 2000-09-11 CN CN00813117A patent/CN1374874A/zh active Pending
- 2000-09-11 BR BR0014117-8A patent/BR0014117A/pt not_active Application Discontinuation
- 2000-09-19 AR ARP000104901A patent/AR025713A1/es unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5397567A (en) * | 1992-03-25 | 1995-03-14 | Medproject Pharma Entwicklungs Und Vertriebs Gesellschaft | Gel, especially for ophthalmology |
US5520920A (en) * | 1992-08-28 | 1996-05-28 | Alcon Laboratories, Inc. | Use of certain anionic surfactants to enhance antimicrobial effectiveness of ophthalmic compositions |
US5504113A (en) * | 1994-03-02 | 1996-04-02 | Allergan, Inc. | Enhancement of benzalkonium chloride preservative activity in formulations containing an incompatible drug |
JPH0977725A (ja) * | 1995-09-13 | 1997-03-25 | Ajinomoto Co Inc | 脂肪酸リジン塩の製造方法 |
WO2000024375A1 (fr) * | 1998-10-27 | 2000-05-04 | Alcon Laboratories, Inc. | Systeme conservateur contenant un savon a base d'acides gras/acides amines pour compositions pharmaceutiques a administration locale |
Non-Patent Citations (2)
Title |
---|
DATABASE WPI Section Ch Week 199722, Derwent World Patents Index; Class D21, AN 1997-241699, XP002159232 * |
VIVES M A ET AL: "IRRITANCY POTENTIAL INDUCED BY SURFACTANTS DERIVED FROM LYSINE", TOXICOLOGY IN VITRO,GB,ELSEVIER SCIENCE, vol. 11, no. 6, 1997, pages 779 - 783, XP000881278, ISSN: 0887-2333 * |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6444710B1 (en) | 1998-10-27 | 2002-09-03 | Alcon Manufacturing, Ltd. | Use of certain fatty acid/amino acid soaps to enhance antimicrobial effectiveness of topically administrable pharmaceutical compositions |
US7402609B2 (en) | 2001-06-27 | 2008-07-22 | Alcon, Inc. | Olopatadine formulations for topical administration |
US7977376B2 (en) | 2001-06-27 | 2011-07-12 | Novartis Ag | Olopatadine formulations for topical nasal administration |
US8399508B2 (en) | 2001-06-27 | 2013-03-19 | Alcon Pharmaceuticals Ltd. | Olopatadine formulations for topical nasal administration |
WO2003080025A1 (fr) * | 2002-03-26 | 2003-10-02 | Ellipse Pharmaceuticals | Composition topique a base de resines echangeuses d'ions, notamment pour le traitement des erythemes |
FR2837710A1 (fr) * | 2002-03-26 | 2003-10-03 | Innovations Pharma Ag | Composition topique a base de resines echangeuses d'ions, notamment pour le traitement des erythemes |
EP2609933A1 (fr) * | 2010-08-27 | 2013-07-03 | Wakamoto Pharmaceutical Co., Ltd. | Composition aqueuse pour administration ophtalmique |
EP2609933A4 (fr) * | 2010-08-27 | 2014-04-09 | Wakamoto Pharma Co Ltd | Composition aqueuse pour administration ophtalmique |
Also Published As
Publication number | Publication date |
---|---|
TR200200724T2 (tr) | 2002-06-21 |
EP1214094A1 (fr) | 2002-06-19 |
AU7363700A (en) | 2001-04-24 |
BR0014117A (pt) | 2002-05-14 |
CN1374874A (zh) | 2002-10-16 |
JP2003509474A (ja) | 2003-03-11 |
PL354365A1 (en) | 2004-01-12 |
AR025713A1 (es) | 2002-12-11 |
CA2391976A1 (fr) | 2001-03-29 |
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