CA2171294C - Viscous surfactant emulsion compositions - Google Patents
Viscous surfactant emulsion compositions Download PDFInfo
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- CA2171294C CA2171294C CA002171294A CA2171294A CA2171294C CA 2171294 C CA2171294 C CA 2171294C CA 002171294 A CA002171294 A CA 002171294A CA 2171294 A CA2171294 A CA 2171294A CA 2171294 C CA2171294 C CA 2171294C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q5/00—Preparations for care of the hair
- A61Q5/02—Preparations for cleaning the hair
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N33/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds
- A01N33/16—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds
- A01N33/24—Biocides, pest repellants or attractants, or plant growth regulators containing organic nitrogen compounds containing nitrogen-to-oxygen bonds only one oxygen atom attached to the nitrogen atom
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/18—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
- A01N37/20—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof containing the group, wherein Cn means a carbon skeleton not containing a ring; Thio analogues thereof
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- 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
- A61K31/13—Amines
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/06—Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
- A61K8/442—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof substituted by amido group(s)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
- A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/731—Cellulose; Quaternized cellulose derivatives
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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
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0088—Liquid substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- 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
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/10—Washing or bathing preparations
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/017—Mixtures of compounds
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/88—Ampholytes; Electroneutral compounds
- C11D1/94—Mixtures with anionic, cationic or non-ionic compounds
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/20—Organic compounds containing oxygen
- C11D3/2003—Alcohols; Phenols
- C11D3/2065—Polyhydric alcohols
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/20—Organic compounds containing oxygen
- C11D3/22—Carbohydrates or derivatives thereof
- C11D3/221—Mono, di- or trisaccharides or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/20—Organic compounds containing oxygen
- C11D3/22—Carbohydrates or derivatives thereof
- C11D3/222—Natural or synthetic polysaccharides, e.g. cellulose, starch, gum, alginic acid or cyclodextrin
- C11D3/225—Natural or synthetic polysaccharides, e.g. cellulose, starch, gum, alginic acid or cyclodextrin etherified, e.g. CMC
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/38—Products with no well-defined composition, e.g. natural products
- C11D3/384—Animal products
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/59—Mixtures
- A61K2800/596—Mixtures of surface active compounds
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D1/00—Detergent compositions based essentially on surface-active compounds; Use of these compounds as a detergent
- C11D1/66—Non-ionic compounds
- C11D1/75—Amino oxides
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- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11D—DETERGENT COMPOSITIONS; USE OF SINGLE SUBSTANCES AS DETERGENTS; SOAP OR SOAP-MAKING; RESIN SOAPS; RECOVERY OF GLYCEROL
- C11D3/00—Other compounding ingredients of detergent compositions covered in group C11D1/00
- C11D3/16—Organic compounds
- C11D3/20—Organic compounds containing oxygen
- C11D3/2003—Alcohols; Phenols
- C11D3/2041—Dihydric alcohols
- C11D3/2044—Dihydric alcohols linear
Abstract
Antiinfective water-in-oil or oil-in-water emulsions comprising amphoteric surfactants of betaines and amine oxides, hydrophobic materials and emulsion aids.
Description
' ~1'~1294 ' WO 95/07692 ~ PCT/US94/10067 Viscous Surfactant Emulsion Compositions The present invention relates to novel hydrophobe-containing viscous surfactant compositions that are stable emulsions and have antiinfective activity. This invention also relates to novel hydrophobe-containing viscous surfactant compositions that are stable emulsions and have spermicidal activity. In particular, the invention relates to compositions that are stable oil-in-water or water-ia-oil emulsions. More particularly, the invention is concerned with compositions comprising betaiaes and amine oxides, substantially nonpolar hydrophobic materials and water soluble, nonionic, cationic or amphoteric materials that act as emulsion aids. The compositions of this invention are of special value for cosmetic, dermatological and pharmaceutical preparations. Compositions of this invention can be used to prepare hair and body shampoos, cleansers, spermicides, dentrifices and compositions for wound healing.
Compositions of betaines and amine oxides having antimicrobial activity are known from U.S. Patents 4,062,976 (Michaels);
4,0.75,350 (Michaels); 4,107,328 (Michaels);
I WO 95/07692 . ~ ~~ PGT/US94/10067 ' 4,145,436 (Michaels); 4,183,952 (Michaels);
4,839,158 (Michaels); 5,244,652 (Michaels), and 5,314,917 (Michaels et al.).
Applicant sought to prepare stable emulsions of betaines and amine oxides having good antiinfective and/or spermicidal properties ~xsing hydrophobic materials.
U.5. Patent 5,244,652 discloses in Example 21 creme formulations comprising C31G
(amphoteric surfactant compositions of alkyl betaines and alkyl amine oxides) (registered trademark), Type A gelatin, glycerine, hydroxyethyl cellulose and water. Example 23 of U.S. Patent 5,244,652 discloses an ointment for xeroderma comprising C3lG, Type A gelatin, glycerine, hydroxypropyl cellulose and petroleum j elly .
It has been found that amphophilic hydrophobic materials such as Tween 80 (HLB 15) (HLB is hydrophilic/lipophilic balance number), a polyoxyethylene derivative of mono fatty esters of sorbitol is not a suitable hydrophobic materials as it neutralizes the antiinfective properties of the betaine and amine oxide compositions of U.S. Patents 4,062,976, 4,075,350, 4,107.328, 4,145,436, 4,183,952 and 4,839,158. It is also kaowu that Tween 80 (HLB
15) is unsuitable as it is used to neutralize quaternary ammonium disinfectants: A 3:1 ratio of Tween 80 to a 0.5% solution of the betaines and amine oxides of this disclosure inactivated the antimicrobial effect of these betaines and amine oxides. Compositions containing combinations of betaines and amine oxides exhibited antimicrobial activity at a 30:1 ratio of the hydrophobic material isopropyl myristate to the betaines and amine oxides. Brij 78 (HLB
WO 95107692 . PCT/US94/10067 15.3) a polyoxyethylene ether of fatty alcohols decreases the aatiinfective properties of the aforementioned betaine and amine oxide compositions.
Applicant has found that hydrophobic materials that are self-emulsifying or that are good emulsifiers deactivate the aatiinfective activity of the surfactant formulations of this disclosure. In general, such deactivating hydrophobic materials will have an HLH value greater than 1 and lower than cleansers which generally have HLB's of 25 or higher such as natural or synthetic soaps.
Applicant has now found that certain substantially nonpolar hydrophobic materials typically having a HLB value of 1 or less or having HLB value of 25 or more when combined with the surfactant formulations of this disclosure and emulsion aids create stable emulsions which have antiinfective activity.
The expression "surfactant formulations of this disclosure" means these amphoteric betaine and amine oxide compositions of U.S. Patents 4,062,976, 4,075,350, 4,107,328, 4,145.436, 4,183,952, 4,839,158, 5,244,652 and 5,314,917 and the amphoteric betaine and amine oxide surfactant compositions disclosed in the specification of the present application. The expression "C31G" (registered trademark) is defined as a surfactant composition of "alkyl betaines and alkyl amine oxides."
Accordingly, a primary object of the present invention is to provide stable emulsions containing hydrophobic materials having antiinfective properties.
A further object of the present invention is to provide stable emulsions PCT/IJS94/100G7 . - .
WO 95/07692 ~ ' containing hydrophobic materials having spermicidal properties.
Another object of the invention is to provide compositions that are easily applied and promote skin integrity. i Still another object of this invention is to provide compositions that are less irritating to mammalian tissues or cells than the usual surfactants used for cleaning or disinfecting.
Yet another object of this invention is to provide compositions of surfactant formulations of this disclosure that can be used for antiinfective or disinfectioa purposes at higher concentrations or for longer periods of time than other previously known compositions containing betaiaes and amine oxides.
A further object of this invention is to provide compositions that aid in wound healing and can be used to treat damaged skin, and prevent desiccation of traumatized tissue.
It has now unexpectedly bees found that compositions comprising the surfactant formulations of this disclosure (as hereinbefore defined) substantially aonpolar hydrophobic materials typically having a HLB value of 1 or less or an HLB value of 25 or more and water soluble, nonionic, cationic or amphoteric, emulsion aids that increase viscosity and do not deactivate the aatiinfective activity of the surfactant formulations of this disclosure. form stable emulsions having antiiafective activity.
Compositions according to this invention may also have spermicidal activity. An emulsion is considered to be stable when the emulsion, either oil-in-water or water-in-oil, does not separate into separate phases under normal WO 95!07692 :~ PCT/US94/10067 conditions of storage and use.
Applicant has discovered that the use of substantially noapolar hydrophobic materials and emulsion aids provides surfactant formulations of this invention having useful emolliency effects and decreased dermal toxicity over knows preparations used in cleansing or disinfection. Compositions according to this invention have improved adherence to the skin.
Ia accordance with this invention stable emulsions having finer particle sizes are prepared in minutes as compared to the prior art where emulsions having fine particle sizes are prepared is hours. and still may not be stable.
Emulsions according to this invention may also have good foaming groperties often essential to assure adequate use of cleansers.
This invention overcomes a problem in the art, gamely to create emulsions such as cleansers. lotions, ointments, cremes, jellies and gels that are stable and exhibit antiinfective activity.
The emulsion compositions of this invention comprise the surfactant formulations of this disclosure (as defined above);
substantially aoapolar hydrophobic materials typically having a HLB value of 1 or less or a HLB value of 25 or more sad water soluble nonionic, cationic or amphoteric emulsion aids that increase viscosity sad do not deactivate the antiinfective activity of the surfactant formulations of this disclosure. The materials used in this invention should be derm,atologically and/or pharmaceutically acceptable depending on the intended use of the final composition.
The surfactant formulations of use in . . CA 02171294 2003-03-19 the present invention include those of the type disclosed in U.S. Patents 4,062,976, 4 ,075,350, 4,107,328, 4,145,436, 4,183,952, 4,839,158, 5,244,652 and 5,314,917, and the surfactant formulations disclosed in the present application.
The betaines used in this invention are selected from the group consisting of alkyl-N-betaines, alkyl amido ethyl betaines, alkyl am3.do propyl betaines, alkyl sultai:nes, alkyl amido propyl hydroxy sultaines, alkyl hydroxy propyl sultaines, alkyl-N-sulfobetaines. acyl-N-betaines and mixtures of two or more thereof.
The amine oxides used in this invention are selected from the group consisting of alkyl-N,N-dimethylamine oxides, alkyl-N,N-.
dihydroxyethylamine oxides, aeylamide t-amine oxides and mixtures of two or more thereof. The alkyl and acyl groups of such betaines and sulfobetaines typically contain from 10 to 18 carbon atoms, preferably from 12 to 16 carbon atoms.
Typically, the betaine and amine oxide components are gresent in a molar ratio of from 1:5 to 5:1, preferably in a molar ratio of from 1:3 or 3:1, and more preferably in a molar ratio of 1:l. Examples of betaines that can be used in this invention are: corn-N-betaine, cetyl-N-betaine, stearyl-N-betaine, isostearyl-N-betaine, oleyl-N-betaine, lauryl-N-betaine;
myristyl-N-betaine coco-N-sulphobetaine, cetyl-N-sulphobetaine, stearyl-N-sulfobetaine, isostearyl-N-sulfobetaine, oleyl-N-sulfobetaine, myristylamido-N-betaine, cocoamido-N-betaine, cetylamido-N-betaine, stearylamido-N-betaine, myristyl-N-sulphobetaine, isostearylamido-N-WO 95107692 ~ ~ PGT/US94/1006T
betaine, and oleyl-amido-N-betaine.
When used here the term "coco" is that used in the CTFA (designations of Cosmetic and Toiletry and Fragrance Association, Was., D.C.) and is used to indicate alkyl groups present in coconut oil, i.e. a mixture of alkyl groups of from 10 to 18 carbon atoms.' The designations of the compounds listed herein are those of the CTFA.
Exemplary of the amine oxides used in this invention are: decyl-N,N-dimethylamiae oxide, lauryl-N,N-dimethylamine oxide, lauxamine oxide, myristamiae oxide, stearyl-N-N-dimethylamine oxide, oleyl-N,N-dimethylamine oxide, coco-N,N dihydroxyethylamine oxide, cetyl-N,N-dihydroxyethylamine oxide, oleyl-N,N-dihydroxyethyl-amine oxide, N,N-dihydroxyethylamine oxide, oleyl-N,N-dihydroxyethyl-amine oxide and mixtures of the same.
The hydrophobic materials used in this invention are substantially nonpolar hydrophobic materials. Typically, the hydrophobic materials have an HLB value of 1 or less or as HLB value of 25 or more. The hydrophobic materials used in this invention can be esters or ethers of long chain alkyl alcohois or polyhydric alcohols wherein there are no free hydroxyl groups in the esters or ethers. Hydrophobic materials that can also be used in this invention are isopropyl myristate, coconut oil. peanut oil, palm oil, mineral oils, paraffin oils and other highly saturated oils, trialkylates of glycerin, waxes, animal, mineral and vegetable waxes, high molecular weight oils, mixtures of waxes and oils, petrolatum, and lanolin. Mixtures of hydrophobic materials can be used. Fatty . ~1 WO 95/07692 ~ ' PGT/US94/10067 -_ g _ alcohols such as cetyl alcohol can also be used as a hydrophobic material, although cetyl alcohol does decrease slightly the aatiinfective properties of the surfactant formulations of this disclosure. In general, the use of anionic fatty acids such as coco fatty acid and stearic acid or soaps of these fatty acids, and sulfates and sulfonates should be avoided as it is expected that they will inactivate the antiinfective actions of the surfactants of this disclosure. However, if the surfactants of this disclosure are present in a high enough concentration it may be possible to use one or more of these anionic components at low concentrations without inactivating the antiinfective activity of the surfactants of this disclosure.
The compositions of this invention include water soluble, nonionic, cationic or amphoteric. natural or synthetic emulsion aids that increase viscosity and do not deactivate the antiinfective activity of the surfactant formulations of this disclosure. Examples of such emulsion aids are polyhydric alcohols, gelatin and cellulose gums. These emulsion aids and other emulsion aids will be described below.
Polyhydric alcohols are used to make viscous creams, lotions and pastes.
Illustrative of the polyhydric alcohols useful in this invention are ethylene glycol, glycerine, propylene glycol, polyethylene glycols such as the carbowaxes (trademarks), xylitol, sorbitol, and mannitol.
Low molecular weight monohydric alcohols that modify viscosity and aid in penetration of the surfactant formulations of this disclosure into the skin are useful in this WO 95107692 ~ PGT/US94/l0067 _ g _ invention. hsopropanol and ethanol are useful..
Cellulose gums useful in this invention are high molecular weight nonionic gums such as methyl. hydroxyethyl, hydroxypropyl, and hydroxypropylmethyl cellulose. Hydroxylated or methylated cellulose gums can be used. Polymers that may be used in place of the cellulose gums are synthetic materials having some properties analogous to said gums such as polyvinyl alcohol. polyvinyl pyrrolidone and some nonionic polyacrylic acid polymers (such polymers are herein referred to as synthetic equivalents of cellulose gums).
Cationic gums such as the polyquateraiums and cationic guar gums can be used in the composition of this invention. Hyaluronic acid and starch derivatives (hydrolyzed starches) are examples of other materials that can be used.
Protein based fat replacements or derivatives of starch that can be used as fat replacements such as a hydrolyzed mixture of amylose and amylopectia or maltopectin may also be used.
Gelatin and/or pectin can be used is these compositions. Gelatin, a high molecular weight preparation of hydrolyzed collagen has inherently low viscosity wader conditions where it is not forming rigid gels. .
Type A and Type B gelatins can be used in this invention. Type A gelatins have isoelectric points between pH 7 and 9. Type B
gelatins have isoelectric points-between p8 4.6 and 5.2. Type B gelatins become cloudy at the isoelectric point and have limited use at low pH. The gelatins most useful in this invention will have Bloom strengths of about 100 to 300, and may have average molecular weights from about 25,000 to 300,000.
_ _' WO 95107692 ~~ ' ) PGT/US94110067 -~~'~~~~4 . .
- ~o -. Pectin can be used in addition to or as an alternative to gelatin in the compositions of this invention. Pectin is a high molecular weight hydrocolloidal substance (polyurinade) related to carbohydrates and fojind in varying proportions in fruits and plants. Wheat proteins such as hydrolyzed whole wheat protein and vegetable proteins are also useful as emulsion aids.
In a preferred embodiment of this invention, gelatsn, cellulose gums, and glycerin are used as co-emulsion aids.
The operating pH of the composition is 4.0 to 7.0, preferably, from about 4.5 to 6.5.
In general, the acid used to the supply the required pH can be any organic or inorganic acid, such as hydrochloric acid, phosphoric acid, sulfuric acid, citric acid, acetic acid, tartaric acid or nicotinic acid. Acids with high buffering capacity are preferred.
Compositions of this invention can be formulated as shampoos. cleansers, lotions, ointments, cremes, jellies, gels, foams, and suppositories. Coanpositions of this invention can be used to prepare hair and body shampoos, cleansers, spermicides, contraceptive devices, deatrifices, cosapositions for wound healing, dressings, surgical scrubs and moisturizers.
Preferred compositions of this invention contain generally the following components in aqueous and nonaqueous phases of water-i.n-oil or oil-in-water emulsions:
0.1-10~ Active ingredient amphoteric surfactant of betaines and amine oxides of this disclosure;
0.5-90~ hydrophobic materials; and 1-25~ emulsion aids.
.. P~'/I1S94/I0067 More preferred compositions of this invention contain generally the following components in aqueous and nonaqueous phases of water-in-oil or oil-in-water emulsions:
0.1-10% Active ingredient amphoteric surfactant of betaines and amine oxides of this disclosure;
0.1-10% nonionic and/or cationic cellulose gums or synthetic analogs thereof;
0-4% gelatin;
0-3.0 pectin;
1-15% polyhydric alcohols and 0.5-90% hydrophobic materials.
Compositions of this invention are readily prepared by one skilled in the art. The amphoteric surfactants are premixed. In general the gums are hydrated and dissolved in part of the water used. The golyhydric alcohols may be used for trituration of the gums if necessary.
The premixed surfactants are added to the hydrated gums. The hydrophobic material is combined with the aqueous phase. If necessary, high shear mixing is used. .
A fuller understanding of the present invention will be gained from the following illustrative examples.
Examples 1 - 5 - Amphoteric surfactant formulations that can be used is preparing the compositions of this invention:
Lauryl Betaine (30% AI) 1000 pts Lauramine Oxide (30% AI) 809 pts Citric Acid monohydrate 63 pts Purified water 100 pts The above are stirred to a uniform solution. At a dilution of one part to 30, the composition should have a pH of 4.85 at the glass electrode.
Putative concentration equal to 27.5$ active ,.-s WO 95107692 ~~' PGT/US94/10067 .
ingredients (AI).
Example 2 Cetyl betaine 20% AI: 200 lbs Myristamine oxide 30% AI: 95 lbs Citric acid monohydra~te: 6.8 lbs Purified water: 100 lbs Prepare as in Example 1 To make about 402 lbs at 17% AI, at dilution 1% AI; pH 4.9.
Example 3 Coco amido propylbetaine 30% AI: 530 lbs Cocoamido propylamine oxide 30% AI:
470 lbs Citric acid monohydrate, USP 60 lbs Purified water, USP: 100 lbs Prepare as in Example 1 To make about 1160 lbs at 25.9% AI:
at a dilution 1% AI, pH - 4.9.
Example 4 Cocohydroxypropyl sultaine, 30% AI:
347 lbs Cocoamine oxide 30% AI: 240 lbs Citric acid monohydrate 24 lbs Purified Water 100 lbs Prepare as in Example 1 To make about 711 1b at about 24.8%
AI, at a dilution 1% AI, pH - 5Ø
Example 4A
Coco hydroxy propyl sultaine, 30% AI 76.5 g laurylamine oxide, 30% AI 36.5 g citric acid monohydrate 9.1 g Purified water 40.0 g Prepare as in Example 1 WO 95/07692 .~ ~ PCT/US94110067 Example 5 Cocoamido-2-hydroxypropyl sultaine 30% AI--89 g Laurylamine oxide 30% AI------------------36.5 g citric acid monohydrate-------------------13 g NaOH-_-_____________-_________L___________ .3 g Purified Water----------------------------40.0 g Prepare as in Example 1 The emulsions of Example 6 - 14 were prepared using a manual pump homogenizer.
Examt~le 6 - 8 The following grotocal was used to test the aatiinfective groperties of the listed compositions:
Type of Experiment: MIC (Minimum Inhibitory Concentration) Title: C31G Cream Formulations vs. E. coli Bacteria: E. coli Method:
Set up 10 test tubes for each bacteria, to be tested against the agent. First tube contains 4.5 ml of media (TSB or BHI), pH
5.2. In the following 9 tubes put 2.5 ml. Add 0.5 ml of ageat (usiag 5% as working solution) to be tested, so the total volume in the first tube is 5.0 ml. Traasfer 2.5 ml to the second tube and mix well and continue transferring 2.5 ml until last tube. Discard the last 2.5 ml.
Add 0.1 ml of bacteria to each tube (1 ml 'frozen bacteria in 10 ml media). Incubate at 37°C.
over-night.
W O 95/07692 ~ ~ i ~ ~ ~ g ~ W PGT/OS94/I0067 Ex 6 Ex 7 Ex 8 Surfactant % 0.5 0.5 0.5 (C31G of Example 1) Gelatin % 0.75 0.75 0.75 s Hydroxypropylmethyl 0.5 . 0.5 0.5 cellulose %
Propylene Glycol % 10 10 10 Tartaric Acid % 0.06 0.06 0.06 Isopropyl myristate % 5.0 10.0 15.0 H20 to 100%
MIC for E. Coli (ppm) 40 60 80 MIC for C31G of Example 1 = 80 ppm Examples 8A - 15 Type of Experiment: MIC (Minimum Inhibitory Concentration) Title: C31G Cream Formulations vs. S. Aureus Bacteria: S. Aureus Method:
Set up 10 test tubes for each bacteria, to be tested against each agent.
First tube contains 4.5 mI of media (TSB or BHI), pH 5Ø In the following 9 tubes put 2.5 ml. Add .5 ml of agent (using 5% as working solution) to be tested. so the total volume in the first tube is 5.0 ml. Transfer 2.5 ml to the second tube and mix well and continue transferring.2.5 ml until you get to~the last tube. Discard the last 2.5 ml. Add .1 ml of bacteria to each tube (1 ml previously frozen bacteria in l0 ml media). Incubate at 37°C.
over-night.
Conclusion:
Results vs. S. Aureus shown in the table below Type of Experiment: Zone of Inhibition Title: Zone of Inhibition Testing on C31G
Creams Bacteria: E. Coli . ~.. . ~
WO 95!07692 . ~ PGT/US94/1006?
Drug Concentration: 0.5% C31G Formulations and dg2p.
Method:
Set up the plates (TSA or BHI), using 7.0 ml of the media EpH 7..2), with 8.0 ml of the seed layer on top. (1000 ml of media with 10 ml of bacteria). Put 4 sterilized pads on each plate and add .0l ml of the drug (using 5% as our Working solution) to be tested.
Incubate at 37°C. over-night. Measure the zoae next day.
Results vs. E. Coli shown in the Table below Formulation MIC (ppm) Meaa Zone of Inhibition (mm) Ex. 8A C31G 0.5%, Tartaric Acid 0.06%, 80 10.75 Gelatin 0.75%, HPMC
0.5%. Isopropyl Myristate 15%, Propylene Glycol 12%, Purified H20 to 100%
Ex. 9 C31G 0.5%, Tartaric Acid 0.06%, 160 10.25 Gelatin 0.75%, HPMC
0.5%, Isopropyl Myristate 15%, Propylene Glycol 10%, Purified H20 to 100%
Ex. 10 C31G 0.5%, Tartaric Acid 0.06%, 40 12 Gelatin 0.75%, HPMC
2%, Isopropyl I
v ~.-WO 95107692 ~" ~ PCT/US94J10067 Myristate 5%, Propylene Glycol 10%, Purified H20 to 100%
Ex. 11 C31G 0.5%.
Tartaric Acid 0.06%, 80 11 Gelatin 0.75, HPMC
0.5%, Isopropyl Myristate 10%, Propylene Glycol 12.0%, Purified H20 to 100%
Ex. 12 C31G 0.5%, Tartaric Acid 0.06%, 80 11.25 Gelatin 0.75%, HPMC 0.5%, Isopropyl Myristate 5%, Propylene Glycol 12.0%, Purified H20 to 100%
Ex. 13 C31G 0.5%, Tartaric Acid 0.06%, 80 10.5 Gelatin 0.75%, HPMC
2.5%. Isopropyl Myristate 5%, Propylene Glycol 10%, Purified H20 to 100%
Ex. 14 C31G 0.5%, Tartaric Acid 0.06% 80 12 Gelatin 0.75%, HPMC 2%, Isopropyl Myristate 10%, Propylene Glycol 10%, Purified H20 to 100%
. ... .
WO 95/07692 ~ ~ PCF/US94/10067 Ex. 15 0.5% C31G
(control) 60 12.5 Examines 16 - 23 The following are examples of stable water-in-oil emulsions prepared as antiinfective ointments for use as barrier creams, for use on wounds, burns or other sanitizing purpose.
The aqueous phase in all of these examples comprise:
Examx~le 16 - Aqueous Phase C31G of Example 1 diluted to 5%
actives 0.8 Pts. Hydroxypropyl cellulose, high viscosity [HPCI
1.25 Pts. Gelatin type A100 2.0 Pts. Glycerin U.S.P.
The gums were triturated with the glycerin and then hydrated by stirring into about 50 pts.
purified water at 60°C. to disperse and they hydrated while cooling to ambient temperature.
18.2 pts of the C31G diluted with 27.25 parts of water are added to equal 100 pts of the aqueous phase.
Example 17: - Aqueous Phase C31G of Example 1 to be diluted to 5%
actives with purified water. No excipients were added.
The viscous aqueous solution of surfactant with the excipients of Example 16 was used for the following emulsion preparations, using the following method.
A laboratory colloid mill (Silverson Fiomogenizer Model L2R) is mounted over a tall form 350m1 beaker in a water bath with the base of the rotor assembly 5mm above the bottom of the WO 95/07692 ~ , ~ PGT/US94/10067 beaker. 80 grams of the oil phase and 20 grams of the aqueous phase. are placed in the beaker and prewarmed to 40°C. in the water bath and the colloid mill lowered, into the beaker in the water bath. The homogeniziag is started using 50 volts to control the operating speed so as not to overheat the HPC which can precipitate above 43°C. After homogenizing for 10 _ minutes at temperatures between 40 43°C. ice is added to the bath and mixing continued to bring the temperature to below 30°C.
This procedure was used with various lipids to form the following stable water-in-oil emulsions having excellent antiinfective properties. This was shown using a modification of the zone of inhibition studies shown above. The modification comprises smearing 0.05 grams of the ointment on the paper disk and pressing the disk, ointment side down. on the prepared streaked plate.
Lipid Aqueous Zone of Phase Phase Inhibition Example Petrolatum Example 16.5 a~
18 U.S.P. 16 Example 19 Glycerol Tripalmitate Example 16 16 a~
Example 20 Coconut Oil Example 16 17 mm Example 21 Mineral Oil Example 16 16 mm Note: the control using 0.1 ml of a .5~ C31G
solution of Ex. 1 was 17.5 amt in the zone of inhibition protocol.
The procedure of Example 20 was modified using the aqueous phases of Examples 16 WO 95/07692 PCFlUS94I10067 ~1'~1~294 and 1? but diluted to 2.5% actives to determine the comparative effect of the excipients on the emulsion stability of the coconut oil at reduced surfactant concentration.
i Liuid Phase AaiYeous Phase Example 22 Coconut Oil As Example 16 with the C31G diluted to 2.5%
Example 23 Coconut Oil As Example 17 with the C31G diluted to 2 .5%
Results: The water in oil emulsions formed after the homogenization and cooling were observed. The product of Example 22 was stable at ambient temperatures of 85 - 90° far 14 days and to date.
The emulsion of Example 23 appeared uniform during packaging but when observed after f our hours showed about 2 0 % by volume o f as aqueous phase had separated. This indicates the value of the co~atbined excipients is modifying the emulsification character of the agent with this lipid.
In the following examples the procedures of homogenization used above in making water-ia-oil emulsions were used as a preliminary stage in preparing fine grained oil-in-water emulsions by inverting the water-in-oil emulsion to an oil-ia-water emulsion.
Ia Examples 23A and 238 which follow the aqueous phases of Examples 16 and 17 are used. A medium viscosity, 70 weight Saybolt, NF,.mineral oil was used for the oil phase.
The preliminary preparation of the water-in-oil emulsion produced exactly as for the homogenization is Examples 18 to 21 above.
However, instead of cooling, the aqueous phase WO 95/07692 >~ ~ PGT/US94/10067 -~~7129~
as gradually increased to 120 grams by adding 100 grams is three equal portions over a 15 minute period and then cooling the emulsion while continuing mixing until the temperature decreased to below 30°C. The following are the compositions of the phases of the formulation with ratios of.20/120 in the oil/water phases.
Lipid Phase Aaueous Phase Example 23A mineral oil 70 wght. Example 16 Example 23B mineral oil 70 wght. Example 17 For age testing of stability judgements were made by observation over the noted time periods at ambient temperatures of 30°C., and at 43°C.
An additional observation was performed on dilutions of the above o/w emulsions. The dilutions were made in pure water using 5% of the above examples and storing the preparations at ambient temperature as above.
Results: Age Test separation (visual) as % of total volume Temperature/
Time Ex 23A Ex 23B
(with excipieats) (no excipients) Ambient no separation 25% (bottom) 48 hours Ambient no separation 25% (bottom) 10 days 43°C. -14 hours 5% bottom (cloudy) 35% (bottom) Note: Bottom separation is a clear aqueous phase and top separation is cream unless otherwise noted.
WO 95107692 . PCT/US94110067 Temperature/
Time Ex 23A diluted Ex 23B diluted Ambient no separation 28% Ebottom), 8% ( top) 20 hours Ambient no separation 35% (bottom), 5% (top) days Example 24 10 Type of Experiment: Zone Of Inhibition Title: C31G Formulations - mixed 1:1 with different chemicals; in order to identify inactivators.
Bacteria: S. sanguis M5.
Drug Concentration: 0.5% C31G Formulations, and purified water.
Method:
Set up the plates (TSA or BFiI) , using 7.0 ml of the media (pH 7.2), with 8.0 ml of the seed layer on top. (1000 ml of media with 10 ml of bacteria) . Put 4 sterilized pads on each plate and add .O1 ml of the drug (using 5% as working solution) to be tested. Incubate at 37°C. over-sight. Measure the zone next day.
WO 95/07692 ~ ~ PCT/US94/10067 -~~'~129~ _ _ Incrredient Conc. C31G Conc. Mean Zone POE (5) Oleyl ether 0% 0 5%
POE(5) Oleyl ether 0.5% 0 5%
Sorbitol ?0% 5% 0% 0 i Sorbitol ?0% 5% p.5% 12 Glycerin 5% 0% 0 Glycerin 5% 0.5% 12 Brij ?8 5% 0% 0 Brij ?8 5% 0.5% 9.5 PEG 400 5% 0% 0 PEG 400 5% 0.5% 11.25 TEA Stearate 5% 0% 0 TEA Stearate 5% 0.5% 0 Pluronic Acid F- 68 5% 0% 0 Pluronic Acid F- 68 5% 0.5% 10 Gelatin (B) 0.2% 0% pH ? .4 0 Gelatin (B) 0.2% 0.5% pH ?.4 12 HPMC 0.2% 0% 0 HPMC 0.2% 0.5% 11 C3IG - 0.5% 12.2 5 dH20 I00% 0 % 0 Discussion: POE(5) ther has oleyl e a HLB of 8.2 and completely inactivated C31G.
Compounds showing inhibitioa are Brij partial ?8 having a HLB of 1S and F68 has a Pluronic Acid HLB of 24. The anionic~aoap triethanolamine stearate~ also showed complete inhibition of C3IG activity. The hydrophilic gelatin gums, and polyhydroxy alcohols showed no inhibition of C31G activity.
Example 25 - 30 Example -0.5% C31G of Example 0.06% tartaric acid 1.250 gelatin - r '- wo 9s~o7s . % ~ ~ 1 ~ 12 9 ~ -92 _ PGT/US94/10067 Example 26 Composition of Example 25 With 15% isopropyl myristate, and H20 to 100%
Example 27 Composition of Example 25 with 15% isopropyl myristate, 4% cetyl alcohol and H20 to 100%
Example 28 Composition of Example 25 with 15% isopropyl myristate, 4% stearic acid and H20 to 100%
Example 29 Composition of Example 25 with 20% isopropyl myristate, 4% Brij 78, 4% cetyl alcohol and H20 to 100%
Example 30 Composition of Example 25, with 20% isopropyl myristate, 4% stearic acid and H20 to 100%
WO 95/07692 ' m m ~ .~ .4 ~ m m ~ m m ~ m a o ~ o cn m m O m O ' m O
y o a~ o vv 00 O
t~ ~ o N o~
-c ri rt r~ co~-I
O
m O
o ~
N
,Q m H O O O O O O
~ tp ~Cto toC~
ri e-1rf ra A A
m O
U O
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-.i of ~ ~ m -t~
a a a ~
~ ~
U o O O o o N
U in o inin tnr-1 H e-1 lt1N N N
,'F,'' W A A A
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r1 tD t~ 0041 O
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Example 31 - Sut~t~ositori.es 4-8% - gelatin type A I00 - 300 Bloom 5-20% - glycerin U.S.P.
5.9-17% - C31G of Example 2 0.5-2% - hydroxypropyl metriyl cellulose;
3-8% - triacyl glycerols; and water, pure to 100%
The gums are hydrated in water, the C31G dissolved and the triacyl glycerols homogenized at 50°C. and cooled to about 40°C.
and poured into mold to~cool and form a firm gel.
Compositions of betaines and amine oxides having antimicrobial activity are known from U.S. Patents 4,062,976 (Michaels);
4,0.75,350 (Michaels); 4,107,328 (Michaels);
I WO 95/07692 . ~ ~~ PGT/US94/10067 ' 4,145,436 (Michaels); 4,183,952 (Michaels);
4,839,158 (Michaels); 5,244,652 (Michaels), and 5,314,917 (Michaels et al.).
Applicant sought to prepare stable emulsions of betaines and amine oxides having good antiinfective and/or spermicidal properties ~xsing hydrophobic materials.
U.5. Patent 5,244,652 discloses in Example 21 creme formulations comprising C31G
(amphoteric surfactant compositions of alkyl betaines and alkyl amine oxides) (registered trademark), Type A gelatin, glycerine, hydroxyethyl cellulose and water. Example 23 of U.S. Patent 5,244,652 discloses an ointment for xeroderma comprising C3lG, Type A gelatin, glycerine, hydroxypropyl cellulose and petroleum j elly .
It has been found that amphophilic hydrophobic materials such as Tween 80 (HLB 15) (HLB is hydrophilic/lipophilic balance number), a polyoxyethylene derivative of mono fatty esters of sorbitol is not a suitable hydrophobic materials as it neutralizes the antiinfective properties of the betaine and amine oxide compositions of U.S. Patents 4,062,976, 4,075,350, 4,107.328, 4,145,436, 4,183,952 and 4,839,158. It is also kaowu that Tween 80 (HLB
15) is unsuitable as it is used to neutralize quaternary ammonium disinfectants: A 3:1 ratio of Tween 80 to a 0.5% solution of the betaines and amine oxides of this disclosure inactivated the antimicrobial effect of these betaines and amine oxides. Compositions containing combinations of betaines and amine oxides exhibited antimicrobial activity at a 30:1 ratio of the hydrophobic material isopropyl myristate to the betaines and amine oxides. Brij 78 (HLB
WO 95107692 . PCT/US94/10067 15.3) a polyoxyethylene ether of fatty alcohols decreases the aatiinfective properties of the aforementioned betaine and amine oxide compositions.
Applicant has found that hydrophobic materials that are self-emulsifying or that are good emulsifiers deactivate the aatiinfective activity of the surfactant formulations of this disclosure. In general, such deactivating hydrophobic materials will have an HLH value greater than 1 and lower than cleansers which generally have HLB's of 25 or higher such as natural or synthetic soaps.
Applicant has now found that certain substantially nonpolar hydrophobic materials typically having a HLB value of 1 or less or having HLB value of 25 or more when combined with the surfactant formulations of this disclosure and emulsion aids create stable emulsions which have antiinfective activity.
The expression "surfactant formulations of this disclosure" means these amphoteric betaine and amine oxide compositions of U.S. Patents 4,062,976, 4,075,350, 4,107,328, 4,145.436, 4,183,952, 4,839,158, 5,244,652 and 5,314,917 and the amphoteric betaine and amine oxide surfactant compositions disclosed in the specification of the present application. The expression "C31G" (registered trademark) is defined as a surfactant composition of "alkyl betaines and alkyl amine oxides."
Accordingly, a primary object of the present invention is to provide stable emulsions containing hydrophobic materials having antiinfective properties.
A further object of the present invention is to provide stable emulsions PCT/IJS94/100G7 . - .
WO 95/07692 ~ ' containing hydrophobic materials having spermicidal properties.
Another object of the invention is to provide compositions that are easily applied and promote skin integrity. i Still another object of this invention is to provide compositions that are less irritating to mammalian tissues or cells than the usual surfactants used for cleaning or disinfecting.
Yet another object of this invention is to provide compositions of surfactant formulations of this disclosure that can be used for antiinfective or disinfectioa purposes at higher concentrations or for longer periods of time than other previously known compositions containing betaiaes and amine oxides.
A further object of this invention is to provide compositions that aid in wound healing and can be used to treat damaged skin, and prevent desiccation of traumatized tissue.
It has now unexpectedly bees found that compositions comprising the surfactant formulations of this disclosure (as hereinbefore defined) substantially aonpolar hydrophobic materials typically having a HLB value of 1 or less or an HLB value of 25 or more and water soluble, nonionic, cationic or amphoteric, emulsion aids that increase viscosity and do not deactivate the aatiinfective activity of the surfactant formulations of this disclosure. form stable emulsions having antiiafective activity.
Compositions according to this invention may also have spermicidal activity. An emulsion is considered to be stable when the emulsion, either oil-in-water or water-in-oil, does not separate into separate phases under normal WO 95!07692 :~ PCT/US94/10067 conditions of storage and use.
Applicant has discovered that the use of substantially noapolar hydrophobic materials and emulsion aids provides surfactant formulations of this invention having useful emolliency effects and decreased dermal toxicity over knows preparations used in cleansing or disinfection. Compositions according to this invention have improved adherence to the skin.
Ia accordance with this invention stable emulsions having finer particle sizes are prepared in minutes as compared to the prior art where emulsions having fine particle sizes are prepared is hours. and still may not be stable.
Emulsions according to this invention may also have good foaming groperties often essential to assure adequate use of cleansers.
This invention overcomes a problem in the art, gamely to create emulsions such as cleansers. lotions, ointments, cremes, jellies and gels that are stable and exhibit antiinfective activity.
The emulsion compositions of this invention comprise the surfactant formulations of this disclosure (as defined above);
substantially aoapolar hydrophobic materials typically having a HLB value of 1 or less or a HLB value of 25 or more sad water soluble nonionic, cationic or amphoteric emulsion aids that increase viscosity sad do not deactivate the antiinfective activity of the surfactant formulations of this disclosure. The materials used in this invention should be derm,atologically and/or pharmaceutically acceptable depending on the intended use of the final composition.
The surfactant formulations of use in . . CA 02171294 2003-03-19 the present invention include those of the type disclosed in U.S. Patents 4,062,976, 4 ,075,350, 4,107,328, 4,145,436, 4,183,952, 4,839,158, 5,244,652 and 5,314,917, and the surfactant formulations disclosed in the present application.
The betaines used in this invention are selected from the group consisting of alkyl-N-betaines, alkyl amido ethyl betaines, alkyl am3.do propyl betaines, alkyl sultai:nes, alkyl amido propyl hydroxy sultaines, alkyl hydroxy propyl sultaines, alkyl-N-sulfobetaines. acyl-N-betaines and mixtures of two or more thereof.
The amine oxides used in this invention are selected from the group consisting of alkyl-N,N-dimethylamine oxides, alkyl-N,N-.
dihydroxyethylamine oxides, aeylamide t-amine oxides and mixtures of two or more thereof. The alkyl and acyl groups of such betaines and sulfobetaines typically contain from 10 to 18 carbon atoms, preferably from 12 to 16 carbon atoms.
Typically, the betaine and amine oxide components are gresent in a molar ratio of from 1:5 to 5:1, preferably in a molar ratio of from 1:3 or 3:1, and more preferably in a molar ratio of 1:l. Examples of betaines that can be used in this invention are: corn-N-betaine, cetyl-N-betaine, stearyl-N-betaine, isostearyl-N-betaine, oleyl-N-betaine, lauryl-N-betaine;
myristyl-N-betaine coco-N-sulphobetaine, cetyl-N-sulphobetaine, stearyl-N-sulfobetaine, isostearyl-N-sulfobetaine, oleyl-N-sulfobetaine, myristylamido-N-betaine, cocoamido-N-betaine, cetylamido-N-betaine, stearylamido-N-betaine, myristyl-N-sulphobetaine, isostearylamido-N-WO 95107692 ~ ~ PGT/US94/1006T
betaine, and oleyl-amido-N-betaine.
When used here the term "coco" is that used in the CTFA (designations of Cosmetic and Toiletry and Fragrance Association, Was., D.C.) and is used to indicate alkyl groups present in coconut oil, i.e. a mixture of alkyl groups of from 10 to 18 carbon atoms.' The designations of the compounds listed herein are those of the CTFA.
Exemplary of the amine oxides used in this invention are: decyl-N,N-dimethylamiae oxide, lauryl-N,N-dimethylamine oxide, lauxamine oxide, myristamiae oxide, stearyl-N-N-dimethylamine oxide, oleyl-N,N-dimethylamine oxide, coco-N,N dihydroxyethylamine oxide, cetyl-N,N-dihydroxyethylamine oxide, oleyl-N,N-dihydroxyethyl-amine oxide, N,N-dihydroxyethylamine oxide, oleyl-N,N-dihydroxyethyl-amine oxide and mixtures of the same.
The hydrophobic materials used in this invention are substantially nonpolar hydrophobic materials. Typically, the hydrophobic materials have an HLB value of 1 or less or as HLB value of 25 or more. The hydrophobic materials used in this invention can be esters or ethers of long chain alkyl alcohois or polyhydric alcohols wherein there are no free hydroxyl groups in the esters or ethers. Hydrophobic materials that can also be used in this invention are isopropyl myristate, coconut oil. peanut oil, palm oil, mineral oils, paraffin oils and other highly saturated oils, trialkylates of glycerin, waxes, animal, mineral and vegetable waxes, high molecular weight oils, mixtures of waxes and oils, petrolatum, and lanolin. Mixtures of hydrophobic materials can be used. Fatty . ~1 WO 95/07692 ~ ' PGT/US94/10067 -_ g _ alcohols such as cetyl alcohol can also be used as a hydrophobic material, although cetyl alcohol does decrease slightly the aatiinfective properties of the surfactant formulations of this disclosure. In general, the use of anionic fatty acids such as coco fatty acid and stearic acid or soaps of these fatty acids, and sulfates and sulfonates should be avoided as it is expected that they will inactivate the antiinfective actions of the surfactants of this disclosure. However, if the surfactants of this disclosure are present in a high enough concentration it may be possible to use one or more of these anionic components at low concentrations without inactivating the antiinfective activity of the surfactants of this disclosure.
The compositions of this invention include water soluble, nonionic, cationic or amphoteric. natural or synthetic emulsion aids that increase viscosity and do not deactivate the antiinfective activity of the surfactant formulations of this disclosure. Examples of such emulsion aids are polyhydric alcohols, gelatin and cellulose gums. These emulsion aids and other emulsion aids will be described below.
Polyhydric alcohols are used to make viscous creams, lotions and pastes.
Illustrative of the polyhydric alcohols useful in this invention are ethylene glycol, glycerine, propylene glycol, polyethylene glycols such as the carbowaxes (trademarks), xylitol, sorbitol, and mannitol.
Low molecular weight monohydric alcohols that modify viscosity and aid in penetration of the surfactant formulations of this disclosure into the skin are useful in this WO 95107692 ~ PGT/US94/l0067 _ g _ invention. hsopropanol and ethanol are useful..
Cellulose gums useful in this invention are high molecular weight nonionic gums such as methyl. hydroxyethyl, hydroxypropyl, and hydroxypropylmethyl cellulose. Hydroxylated or methylated cellulose gums can be used. Polymers that may be used in place of the cellulose gums are synthetic materials having some properties analogous to said gums such as polyvinyl alcohol. polyvinyl pyrrolidone and some nonionic polyacrylic acid polymers (such polymers are herein referred to as synthetic equivalents of cellulose gums).
Cationic gums such as the polyquateraiums and cationic guar gums can be used in the composition of this invention. Hyaluronic acid and starch derivatives (hydrolyzed starches) are examples of other materials that can be used.
Protein based fat replacements or derivatives of starch that can be used as fat replacements such as a hydrolyzed mixture of amylose and amylopectia or maltopectin may also be used.
Gelatin and/or pectin can be used is these compositions. Gelatin, a high molecular weight preparation of hydrolyzed collagen has inherently low viscosity wader conditions where it is not forming rigid gels. .
Type A and Type B gelatins can be used in this invention. Type A gelatins have isoelectric points between pH 7 and 9. Type B
gelatins have isoelectric points-between p8 4.6 and 5.2. Type B gelatins become cloudy at the isoelectric point and have limited use at low pH. The gelatins most useful in this invention will have Bloom strengths of about 100 to 300, and may have average molecular weights from about 25,000 to 300,000.
_ _' WO 95107692 ~~ ' ) PGT/US94110067 -~~'~~~~4 . .
- ~o -. Pectin can be used in addition to or as an alternative to gelatin in the compositions of this invention. Pectin is a high molecular weight hydrocolloidal substance (polyurinade) related to carbohydrates and fojind in varying proportions in fruits and plants. Wheat proteins such as hydrolyzed whole wheat protein and vegetable proteins are also useful as emulsion aids.
In a preferred embodiment of this invention, gelatsn, cellulose gums, and glycerin are used as co-emulsion aids.
The operating pH of the composition is 4.0 to 7.0, preferably, from about 4.5 to 6.5.
In general, the acid used to the supply the required pH can be any organic or inorganic acid, such as hydrochloric acid, phosphoric acid, sulfuric acid, citric acid, acetic acid, tartaric acid or nicotinic acid. Acids with high buffering capacity are preferred.
Compositions of this invention can be formulated as shampoos. cleansers, lotions, ointments, cremes, jellies, gels, foams, and suppositories. Coanpositions of this invention can be used to prepare hair and body shampoos, cleansers, spermicides, contraceptive devices, deatrifices, cosapositions for wound healing, dressings, surgical scrubs and moisturizers.
Preferred compositions of this invention contain generally the following components in aqueous and nonaqueous phases of water-i.n-oil or oil-in-water emulsions:
0.1-10~ Active ingredient amphoteric surfactant of betaines and amine oxides of this disclosure;
0.5-90~ hydrophobic materials; and 1-25~ emulsion aids.
.. P~'/I1S94/I0067 More preferred compositions of this invention contain generally the following components in aqueous and nonaqueous phases of water-in-oil or oil-in-water emulsions:
0.1-10% Active ingredient amphoteric surfactant of betaines and amine oxides of this disclosure;
0.1-10% nonionic and/or cationic cellulose gums or synthetic analogs thereof;
0-4% gelatin;
0-3.0 pectin;
1-15% polyhydric alcohols and 0.5-90% hydrophobic materials.
Compositions of this invention are readily prepared by one skilled in the art. The amphoteric surfactants are premixed. In general the gums are hydrated and dissolved in part of the water used. The golyhydric alcohols may be used for trituration of the gums if necessary.
The premixed surfactants are added to the hydrated gums. The hydrophobic material is combined with the aqueous phase. If necessary, high shear mixing is used. .
A fuller understanding of the present invention will be gained from the following illustrative examples.
Examples 1 - 5 - Amphoteric surfactant formulations that can be used is preparing the compositions of this invention:
Lauryl Betaine (30% AI) 1000 pts Lauramine Oxide (30% AI) 809 pts Citric Acid monohydrate 63 pts Purified water 100 pts The above are stirred to a uniform solution. At a dilution of one part to 30, the composition should have a pH of 4.85 at the glass electrode.
Putative concentration equal to 27.5$ active ,.-s WO 95107692 ~~' PGT/US94/10067 .
ingredients (AI).
Example 2 Cetyl betaine 20% AI: 200 lbs Myristamine oxide 30% AI: 95 lbs Citric acid monohydra~te: 6.8 lbs Purified water: 100 lbs Prepare as in Example 1 To make about 402 lbs at 17% AI, at dilution 1% AI; pH 4.9.
Example 3 Coco amido propylbetaine 30% AI: 530 lbs Cocoamido propylamine oxide 30% AI:
470 lbs Citric acid monohydrate, USP 60 lbs Purified water, USP: 100 lbs Prepare as in Example 1 To make about 1160 lbs at 25.9% AI:
at a dilution 1% AI, pH - 4.9.
Example 4 Cocohydroxypropyl sultaine, 30% AI:
347 lbs Cocoamine oxide 30% AI: 240 lbs Citric acid monohydrate 24 lbs Purified Water 100 lbs Prepare as in Example 1 To make about 711 1b at about 24.8%
AI, at a dilution 1% AI, pH - 5Ø
Example 4A
Coco hydroxy propyl sultaine, 30% AI 76.5 g laurylamine oxide, 30% AI 36.5 g citric acid monohydrate 9.1 g Purified water 40.0 g Prepare as in Example 1 WO 95/07692 .~ ~ PCT/US94110067 Example 5 Cocoamido-2-hydroxypropyl sultaine 30% AI--89 g Laurylamine oxide 30% AI------------------36.5 g citric acid monohydrate-------------------13 g NaOH-_-_____________-_________L___________ .3 g Purified Water----------------------------40.0 g Prepare as in Example 1 The emulsions of Example 6 - 14 were prepared using a manual pump homogenizer.
Examt~le 6 - 8 The following grotocal was used to test the aatiinfective groperties of the listed compositions:
Type of Experiment: MIC (Minimum Inhibitory Concentration) Title: C31G Cream Formulations vs. E. coli Bacteria: E. coli Method:
Set up 10 test tubes for each bacteria, to be tested against the agent. First tube contains 4.5 ml of media (TSB or BHI), pH
5.2. In the following 9 tubes put 2.5 ml. Add 0.5 ml of ageat (usiag 5% as working solution) to be tested, so the total volume in the first tube is 5.0 ml. Traasfer 2.5 ml to the second tube and mix well and continue transferring 2.5 ml until last tube. Discard the last 2.5 ml.
Add 0.1 ml of bacteria to each tube (1 ml 'frozen bacteria in 10 ml media). Incubate at 37°C.
over-night.
W O 95/07692 ~ ~ i ~ ~ ~ g ~ W PGT/OS94/I0067 Ex 6 Ex 7 Ex 8 Surfactant % 0.5 0.5 0.5 (C31G of Example 1) Gelatin % 0.75 0.75 0.75 s Hydroxypropylmethyl 0.5 . 0.5 0.5 cellulose %
Propylene Glycol % 10 10 10 Tartaric Acid % 0.06 0.06 0.06 Isopropyl myristate % 5.0 10.0 15.0 H20 to 100%
MIC for E. Coli (ppm) 40 60 80 MIC for C31G of Example 1 = 80 ppm Examples 8A - 15 Type of Experiment: MIC (Minimum Inhibitory Concentration) Title: C31G Cream Formulations vs. S. Aureus Bacteria: S. Aureus Method:
Set up 10 test tubes for each bacteria, to be tested against each agent.
First tube contains 4.5 mI of media (TSB or BHI), pH 5Ø In the following 9 tubes put 2.5 ml. Add .5 ml of agent (using 5% as working solution) to be tested. so the total volume in the first tube is 5.0 ml. Transfer 2.5 ml to the second tube and mix well and continue transferring.2.5 ml until you get to~the last tube. Discard the last 2.5 ml. Add .1 ml of bacteria to each tube (1 ml previously frozen bacteria in l0 ml media). Incubate at 37°C.
over-night.
Conclusion:
Results vs. S. Aureus shown in the table below Type of Experiment: Zone of Inhibition Title: Zone of Inhibition Testing on C31G
Creams Bacteria: E. Coli . ~.. . ~
WO 95!07692 . ~ PGT/US94/1006?
Drug Concentration: 0.5% C31G Formulations and dg2p.
Method:
Set up the plates (TSA or BHI), using 7.0 ml of the media EpH 7..2), with 8.0 ml of the seed layer on top. (1000 ml of media with 10 ml of bacteria). Put 4 sterilized pads on each plate and add .0l ml of the drug (using 5% as our Working solution) to be tested.
Incubate at 37°C. over-night. Measure the zoae next day.
Results vs. E. Coli shown in the Table below Formulation MIC (ppm) Meaa Zone of Inhibition (mm) Ex. 8A C31G 0.5%, Tartaric Acid 0.06%, 80 10.75 Gelatin 0.75%, HPMC
0.5%. Isopropyl Myristate 15%, Propylene Glycol 12%, Purified H20 to 100%
Ex. 9 C31G 0.5%, Tartaric Acid 0.06%, 160 10.25 Gelatin 0.75%, HPMC
0.5%, Isopropyl Myristate 15%, Propylene Glycol 10%, Purified H20 to 100%
Ex. 10 C31G 0.5%, Tartaric Acid 0.06%, 40 12 Gelatin 0.75%, HPMC
2%, Isopropyl I
v ~.-WO 95107692 ~" ~ PCT/US94J10067 Myristate 5%, Propylene Glycol 10%, Purified H20 to 100%
Ex. 11 C31G 0.5%.
Tartaric Acid 0.06%, 80 11 Gelatin 0.75, HPMC
0.5%, Isopropyl Myristate 10%, Propylene Glycol 12.0%, Purified H20 to 100%
Ex. 12 C31G 0.5%, Tartaric Acid 0.06%, 80 11.25 Gelatin 0.75%, HPMC 0.5%, Isopropyl Myristate 5%, Propylene Glycol 12.0%, Purified H20 to 100%
Ex. 13 C31G 0.5%, Tartaric Acid 0.06%, 80 10.5 Gelatin 0.75%, HPMC
2.5%. Isopropyl Myristate 5%, Propylene Glycol 10%, Purified H20 to 100%
Ex. 14 C31G 0.5%, Tartaric Acid 0.06% 80 12 Gelatin 0.75%, HPMC 2%, Isopropyl Myristate 10%, Propylene Glycol 10%, Purified H20 to 100%
. ... .
WO 95/07692 ~ ~ PCF/US94/10067 Ex. 15 0.5% C31G
(control) 60 12.5 Examines 16 - 23 The following are examples of stable water-in-oil emulsions prepared as antiinfective ointments for use as barrier creams, for use on wounds, burns or other sanitizing purpose.
The aqueous phase in all of these examples comprise:
Examx~le 16 - Aqueous Phase C31G of Example 1 diluted to 5%
actives 0.8 Pts. Hydroxypropyl cellulose, high viscosity [HPCI
1.25 Pts. Gelatin type A100 2.0 Pts. Glycerin U.S.P.
The gums were triturated with the glycerin and then hydrated by stirring into about 50 pts.
purified water at 60°C. to disperse and they hydrated while cooling to ambient temperature.
18.2 pts of the C31G diluted with 27.25 parts of water are added to equal 100 pts of the aqueous phase.
Example 17: - Aqueous Phase C31G of Example 1 to be diluted to 5%
actives with purified water. No excipients were added.
The viscous aqueous solution of surfactant with the excipients of Example 16 was used for the following emulsion preparations, using the following method.
A laboratory colloid mill (Silverson Fiomogenizer Model L2R) is mounted over a tall form 350m1 beaker in a water bath with the base of the rotor assembly 5mm above the bottom of the WO 95/07692 ~ , ~ PGT/US94/10067 beaker. 80 grams of the oil phase and 20 grams of the aqueous phase. are placed in the beaker and prewarmed to 40°C. in the water bath and the colloid mill lowered, into the beaker in the water bath. The homogeniziag is started using 50 volts to control the operating speed so as not to overheat the HPC which can precipitate above 43°C. After homogenizing for 10 _ minutes at temperatures between 40 43°C. ice is added to the bath and mixing continued to bring the temperature to below 30°C.
This procedure was used with various lipids to form the following stable water-in-oil emulsions having excellent antiinfective properties. This was shown using a modification of the zone of inhibition studies shown above. The modification comprises smearing 0.05 grams of the ointment on the paper disk and pressing the disk, ointment side down. on the prepared streaked plate.
Lipid Aqueous Zone of Phase Phase Inhibition Example Petrolatum Example 16.5 a~
18 U.S.P. 16 Example 19 Glycerol Tripalmitate Example 16 16 a~
Example 20 Coconut Oil Example 16 17 mm Example 21 Mineral Oil Example 16 16 mm Note: the control using 0.1 ml of a .5~ C31G
solution of Ex. 1 was 17.5 amt in the zone of inhibition protocol.
The procedure of Example 20 was modified using the aqueous phases of Examples 16 WO 95/07692 PCFlUS94I10067 ~1'~1~294 and 1? but diluted to 2.5% actives to determine the comparative effect of the excipients on the emulsion stability of the coconut oil at reduced surfactant concentration.
i Liuid Phase AaiYeous Phase Example 22 Coconut Oil As Example 16 with the C31G diluted to 2.5%
Example 23 Coconut Oil As Example 17 with the C31G diluted to 2 .5%
Results: The water in oil emulsions formed after the homogenization and cooling were observed. The product of Example 22 was stable at ambient temperatures of 85 - 90° far 14 days and to date.
The emulsion of Example 23 appeared uniform during packaging but when observed after f our hours showed about 2 0 % by volume o f as aqueous phase had separated. This indicates the value of the co~atbined excipients is modifying the emulsification character of the agent with this lipid.
In the following examples the procedures of homogenization used above in making water-ia-oil emulsions were used as a preliminary stage in preparing fine grained oil-in-water emulsions by inverting the water-in-oil emulsion to an oil-ia-water emulsion.
Ia Examples 23A and 238 which follow the aqueous phases of Examples 16 and 17 are used. A medium viscosity, 70 weight Saybolt, NF,.mineral oil was used for the oil phase.
The preliminary preparation of the water-in-oil emulsion produced exactly as for the homogenization is Examples 18 to 21 above.
However, instead of cooling, the aqueous phase WO 95/07692 >~ ~ PGT/US94/10067 -~~7129~
as gradually increased to 120 grams by adding 100 grams is three equal portions over a 15 minute period and then cooling the emulsion while continuing mixing until the temperature decreased to below 30°C. The following are the compositions of the phases of the formulation with ratios of.20/120 in the oil/water phases.
Lipid Phase Aaueous Phase Example 23A mineral oil 70 wght. Example 16 Example 23B mineral oil 70 wght. Example 17 For age testing of stability judgements were made by observation over the noted time periods at ambient temperatures of 30°C., and at 43°C.
An additional observation was performed on dilutions of the above o/w emulsions. The dilutions were made in pure water using 5% of the above examples and storing the preparations at ambient temperature as above.
Results: Age Test separation (visual) as % of total volume Temperature/
Time Ex 23A Ex 23B
(with excipieats) (no excipients) Ambient no separation 25% (bottom) 48 hours Ambient no separation 25% (bottom) 10 days 43°C. -14 hours 5% bottom (cloudy) 35% (bottom) Note: Bottom separation is a clear aqueous phase and top separation is cream unless otherwise noted.
WO 95107692 . PCT/US94110067 Temperature/
Time Ex 23A diluted Ex 23B diluted Ambient no separation 28% Ebottom), 8% ( top) 20 hours Ambient no separation 35% (bottom), 5% (top) days Example 24 10 Type of Experiment: Zone Of Inhibition Title: C31G Formulations - mixed 1:1 with different chemicals; in order to identify inactivators.
Bacteria: S. sanguis M5.
Drug Concentration: 0.5% C31G Formulations, and purified water.
Method:
Set up the plates (TSA or BFiI) , using 7.0 ml of the media (pH 7.2), with 8.0 ml of the seed layer on top. (1000 ml of media with 10 ml of bacteria) . Put 4 sterilized pads on each plate and add .O1 ml of the drug (using 5% as working solution) to be tested. Incubate at 37°C. over-sight. Measure the zone next day.
WO 95/07692 ~ ~ PCT/US94/10067 -~~'~129~ _ _ Incrredient Conc. C31G Conc. Mean Zone POE (5) Oleyl ether 0% 0 5%
POE(5) Oleyl ether 0.5% 0 5%
Sorbitol ?0% 5% 0% 0 i Sorbitol ?0% 5% p.5% 12 Glycerin 5% 0% 0 Glycerin 5% 0.5% 12 Brij ?8 5% 0% 0 Brij ?8 5% 0.5% 9.5 PEG 400 5% 0% 0 PEG 400 5% 0.5% 11.25 TEA Stearate 5% 0% 0 TEA Stearate 5% 0.5% 0 Pluronic Acid F- 68 5% 0% 0 Pluronic Acid F- 68 5% 0.5% 10 Gelatin (B) 0.2% 0% pH ? .4 0 Gelatin (B) 0.2% 0.5% pH ?.4 12 HPMC 0.2% 0% 0 HPMC 0.2% 0.5% 11 C3IG - 0.5% 12.2 5 dH20 I00% 0 % 0 Discussion: POE(5) ther has oleyl e a HLB of 8.2 and completely inactivated C31G.
Compounds showing inhibitioa are Brij partial ?8 having a HLB of 1S and F68 has a Pluronic Acid HLB of 24. The anionic~aoap triethanolamine stearate~ also showed complete inhibition of C3IG activity. The hydrophilic gelatin gums, and polyhydroxy alcohols showed no inhibition of C31G activity.
Example 25 - 30 Example -0.5% C31G of Example 0.06% tartaric acid 1.250 gelatin - r '- wo 9s~o7s . % ~ ~ 1 ~ 12 9 ~ -92 _ PGT/US94/10067 Example 26 Composition of Example 25 With 15% isopropyl myristate, and H20 to 100%
Example 27 Composition of Example 25 with 15% isopropyl myristate, 4% cetyl alcohol and H20 to 100%
Example 28 Composition of Example 25 with 15% isopropyl myristate, 4% stearic acid and H20 to 100%
Example 29 Composition of Example 25 with 20% isopropyl myristate, 4% Brij 78, 4% cetyl alcohol and H20 to 100%
Example 30 Composition of Example 25, with 20% isopropyl myristate, 4% stearic acid and H20 to 100%
WO 95/07692 ' m m ~ .~ .4 ~ m m ~ m m ~ m a o ~ o cn m m O m O ' m O
y o a~ o vv 00 O
t~ ~ o N o~
-c ri rt r~ co~-I
O
m O
o ~
N
,Q m H O O O O O O
~ tp ~Cto toC~
ri e-1rf ra A A
m O
U O
O N
-.i of ~ ~ m -t~
a a a ~
~ ~
U o O O o o N
U in o inin tnr-1 H e-1 lt1N N N
,'F,'' W A A A
m O .~.
O
~ ' O
r1 tD t~ 0041 O
Ch O !C ?C ?~k DCC~1 Gra W W W W W U
Example 31 - Sut~t~ositori.es 4-8% - gelatin type A I00 - 300 Bloom 5-20% - glycerin U.S.P.
5.9-17% - C31G of Example 2 0.5-2% - hydroxypropyl metriyl cellulose;
3-8% - triacyl glycerols; and water, pure to 100%
The gums are hydrated in water, the C31G dissolved and the triacyl glycerols homogenized at 50°C. and cooled to about 40°C.
and poured into mold to~cool and form a firm gel.
Claims (9)
1. A water-in-oil or oil-in-water emulsion comprising:
(a) an amphoteric surfactant solution comprising:
(i) a mixture of a betaine selected from alkyl-N-betaine, alkyl amido ethyl. betaine, alkyl amido propyl betaine, alkyl sultaine, alkyl amido propyl hydroxy sultaine, alkyl hydroxy propyl sultaine, alkyl-N-sulfobetaine, acyl-N-betaine, and mixtures of two or more thereof; and (ii) an amine oxide selected from alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, and mixtures of two or more thereof;
(b) a pharmaceutically or dermatologically acceptable substantially nonpolar hydrophobic material having an HLB
value of 1 or less; and (c) at least one water soluble, pharmaceutically or dermatologically acceptable nonionic, cationic or amphoteric emulsion aid.
(a) an amphoteric surfactant solution comprising:
(i) a mixture of a betaine selected from alkyl-N-betaine, alkyl amido ethyl. betaine, alkyl amido propyl betaine, alkyl sultaine, alkyl amido propyl hydroxy sultaine, alkyl hydroxy propyl sultaine, alkyl-N-sulfobetaine, acyl-N-betaine, and mixtures of two or more thereof; and (ii) an amine oxide selected from alkyl-N,N-dimethylamine oxide, alkyl-N,N-dihydroxyethylamine oxide, acylamide t-amine oxide, and mixtures of two or more thereof;
(b) a pharmaceutically or dermatologically acceptable substantially nonpolar hydrophobic material having an HLB
value of 1 or less; and (c) at least one water soluble, pharmaceutically or dermatologically acceptable nonionic, cationic or amphoteric emulsion aid.
2. An emulsion according to claim 1, wherein the hydrophobic material is an ester or ether of a long chain alkyl alcohol or alkyl polyhydric alcohol, and wherein there are no free hydroxyl groups in the ester or ether.
3. An emulsion according to claim 1, wherein the hydrophobic material being selected from the group consisting of isopropyl myristate, coconut oil, peanut oil, palm oil, trialkylate of glycerin, animal wax, mineral wax, vegetable wax, lanolin and mixtures thereof.
4. An emulsion according to claim 1, 2 or 3, wherein the emulsion aid is selected from the group consisting of gelatin, pectin, alkyl polyhydric alcohol, alkyl monohydric alcohol, cellulose gum or a synthetic analog thereof, cationic gum, hyaluronic acid, starch derivative and mixtures thereof.
5. An emulsion according to any one of claims 1 to 4, wherein the emulsion aid comprises at least one of gelatin and a cellulose gum and at least one polyhydric or monohydric alcohol.
6. An emulsion according to any one of claims 1 to 5, wherein the emulsion aid is a combination of gelatin, cellulose gum and polyhydric alcohol.
7. A composition according to any one of claims 1 to 4, wherein the emulsion aid is a modified starch.
8. An emulsion according to any one of claims 1 to 7, comprising:
0.1 - 10% amphoteric surfactant of betaine and amine oxide;
1 - 25% emulsion aid; and 0.5 - 90% hydrophobic material.
0.1 - 10% amphoteric surfactant of betaine and amine oxide;
1 - 25% emulsion aid; and 0.5 - 90% hydrophobic material.
9. A composition according to any one of claims 1 to 8, comprising:
0.1 - 10% amphoteric surfactant of betaine and amine oxide;
0.1 - 10% nonionic and/or cationic cellulose gum or a synthetic analog thereof:
0 - 4% gelatin;
0 - 3% pectin;
1 - 15% polyhydric alcohol; and 0.5 - 90% hydrophobic material.
0.1 - 10% amphoteric surfactant of betaine and amine oxide;
0.1 - 10% nonionic and/or cationic cellulose gum or a synthetic analog thereof:
0 - 4% gelatin;
0 - 3% pectin;
1 - 15% polyhydric alcohol; and 0.5 - 90% hydrophobic material.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US08/121,277 US5389676A (en) | 1991-03-22 | 1993-09-13 | Viscous surfactant emulsion compositions |
US08/121,277 | 1993-09-13 | ||
PCT/US1994/010067 WO1995007692A1 (en) | 1993-09-13 | 1994-09-09 | Viscous surfactant emulsion compositions |
Publications (2)
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CA2171294A1 CA2171294A1 (en) | 1995-03-23 |
CA2171294C true CA2171294C (en) | 2004-04-06 |
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CA002171294A Expired - Fee Related CA2171294C (en) | 1993-09-13 | 1994-09-09 | Viscous surfactant emulsion compositions |
Country Status (11)
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US (1) | US5389676A (en) |
EP (1) | EP0719137B1 (en) |
JP (1) | JP3759604B2 (en) |
KR (1) | KR0178857B1 (en) |
AU (1) | AU685507B2 (en) |
CA (1) | CA2171294C (en) |
DE (1) | DE69429922T2 (en) |
ES (1) | ES2173123T3 (en) |
MY (1) | MY112403A (en) |
WO (1) | WO1995007692A1 (en) |
ZA (1) | ZA946991B (en) |
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US5587156A (en) * | 1996-04-18 | 1996-12-24 | Critical Dimension, Incorporated | Shaving compositions containing particulate additives |
EP0942737A1 (en) * | 1996-10-11 | 1999-09-22 | Integrated Research Technology, LLC | Long chain carboxybetaines in antimicrobial formulations |
US5849281A (en) * | 1996-11-12 | 1998-12-15 | S. C. Johnson & Son, Inc. | Method of soap-free shaving |
DK0842606T3 (en) * | 1996-11-13 | 2000-06-05 | Procter & Gamble | Disinfecting microemulsions |
US6210695B1 (en) | 1997-06-04 | 2001-04-03 | The Procter & Gamble Company | Leave-on antimicrobial compositions |
US6287577B1 (en) | 1997-11-12 | 2001-09-11 | The Procter & Gamble Company | Leave-on antimicrobial compositions which provide improved residual benefit versus gram positive bacteria |
US6214363B1 (en) | 1997-11-12 | 2001-04-10 | The Procter & Gamble Company | Liquid antimicrobial cleansing compositions which provide residual benefit versus gram negative bacteria |
US6183763B1 (en) | 1997-06-04 | 2001-02-06 | Procter & Gamble Company | Antimicrobial wipes which provide improved immediate germ reduction |
US6197315B1 (en) | 1997-06-04 | 2001-03-06 | Procter & Gamble Company | Antimicrobial wipes which provide improved residual benefit versus gram negative bacteria |
US6183757B1 (en) | 1997-06-04 | 2001-02-06 | Procter & Gamble Company | Mild, rinse-off antimicrobial cleansing compositions which provide improved immediate germ reduction during washing |
US6284259B1 (en) | 1997-11-12 | 2001-09-04 | The Procter & Gamble Company | Antimicrobial wipes which provide improved residual benefit versus Gram positive bacteria |
US6190674B1 (en) | 1997-06-04 | 2001-02-20 | Procter & Gamble Company | Liquid antimicrobial cleansing compositions |
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-
1993
- 1993-09-13 US US08/121,277 patent/US5389676A/en not_active Expired - Fee Related
-
1994
- 1994-09-09 JP JP50924095A patent/JP3759604B2/en not_active Expired - Fee Related
- 1994-09-09 KR KR1019960701254A patent/KR0178857B1/en not_active IP Right Cessation
- 1994-09-09 DE DE69429922T patent/DE69429922T2/en not_active Expired - Fee Related
- 1994-09-09 WO PCT/US1994/010067 patent/WO1995007692A1/en active IP Right Grant
- 1994-09-09 AU AU76835/94A patent/AU685507B2/en not_active Ceased
- 1994-09-09 ES ES94927365T patent/ES2173123T3/en not_active Expired - Lifetime
- 1994-09-09 EP EP94927365A patent/EP0719137B1/en not_active Expired - Lifetime
- 1994-09-09 CA CA002171294A patent/CA2171294C/en not_active Expired - Fee Related
- 1994-09-12 ZA ZA946991A patent/ZA946991B/en unknown
- 1994-09-12 MY MYPI94002403A patent/MY112403A/en unknown
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MY112403A (en) | 2001-06-30 |
DE69429922T2 (en) | 2002-10-10 |
EP0719137A1 (en) | 1996-07-03 |
JP3759604B2 (en) | 2006-03-29 |
JPH09502968A (en) | 1997-03-25 |
ES2173123T3 (en) | 2002-10-16 |
EP0719137B1 (en) | 2002-02-20 |
WO1995007692A1 (en) | 1995-03-23 |
AU7683594A (en) | 1995-04-03 |
DE69429922D1 (en) | 2002-03-28 |
AU685507B2 (en) | 1998-01-22 |
KR0178857B1 (en) | 1999-03-20 |
KR960704542A (en) | 1996-10-09 |
EP0719137A4 (en) | 1997-06-04 |
US5389676A (en) | 1995-02-14 |
CA2171294A1 (en) | 1995-03-23 |
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