US3592930A - Moisture-deterioratable topical medicaments,particularly anti-inflammatory steroids,in a substantially non-aqueous fatty alcohol-propylene glycol vehicle - Google Patents

Moisture-deterioratable topical medicaments,particularly anti-inflammatory steroids,in a substantially non-aqueous fatty alcohol-propylene glycol vehicle Download PDF

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US3592930A
US3592930A US745989A US3592930DA US3592930A US 3592930 A US3592930 A US 3592930A US 745989 A US745989 A US 745989A US 3592930D A US3592930D A US 3592930DA US 3592930 A US3592930 A US 3592930A
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vehicle
dione
parts
fatty alcohol
diene
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Martin Katz
Herbert M Neiman
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Syntex Pharmaceuticals International Ltd
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Roche Palo Alto LLC
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Assigned to SYNTEX PHARMACEUTICALS INTERNATIONAL LIMITED A CORP OF BERMUDA reassignment SYNTEX PHARMACEUTICALS INTERNATIONAL LIMITED A CORP OF BERMUDA RE-RECORD TO EXCLUDE PATENT 3,592,930 INADVERTENTLY RECITED IN DOCUMENT PREVIOUSLY RECORDED AUGUST 11, 1982, REEL 4068 FRAME 0237 ASSIGNORS HEREBY ASSIGN AS OF APRIL 1, 1981 THE ENTIRE INTEREST IN SAID OATENT TO SAID ASSIGNEE. Assignors: SYNTEX (U.S.A.) INC. A DE CORP, SYNTEX CORPORATION A CORP OF PANAMA
Assigned to SYNTEX PHARMACEUTICAL INTERNATIONAL LIMITED reassignment SYNTEX PHARMACEUTICAL INTERNATIONAL LIMITED TO CORRECT THE NAME OF THE ASSIGNEE IN AN ASSIGNMENT RECORDED AUGUST 11, 1982 AT REEL 4068, FRAMES 237-250 Assignors: SYNTEX CORPORATION, A CORP OF PANAMA
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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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions

Definitions

  • a substantially non-aqueous medicant vehicle containing from to 45 parts saturated fatty alcohol having from 16 to 24 carbons, from 55 to 85 parts glycol solvent, from 0 to 10 parts plasticizer, from O to 10 parts coupling agent, 0 to parts penetrant, and if desired, other pharmaceutical adjuvants.
  • This base is a suitable vehicle for all types of therapeutic agents for topical application including antibiotics, steroids, antihistamines, antiseptics, anesthetics, antibacterials, fungicides, and the like.
  • the vehicle has shown particular advantages with anti-inflammatory topical corticoids.
  • This invention relates to vehicles for topical applications of medicants (i.e., active ingredients) and to mixtures of the vehicles and medicants.
  • this invention relates to new, improved medicant vehicles having advantages over previously known vehicles.
  • ointment a preparation containing active medications that can be readily spread on and rubbed into the skin. It serves as a means for distributing the medication uniformly over the skin surface and maintaining it there until beneficial action can occur.
  • the earlier preparations were based on fats, greases and petrolatum. These are, by nature, greasy, are not water-washable and have a limited ability to release medication to the skin.
  • a nonaqueous ointment of more recent origin is Carbowax, a grease-like mixture of polyethylene glycols (molecular weight of 1000 to 20,000). This vehicle, although waterwashable, has a greasy texture and does not provide an occlusive coating on a treated surface.
  • these anhydrous ointment bases were the only vehicles available for medicants which deteriorate in the presence of moisture.
  • Emulsified creams such as cold creams, were developed to reduce greasiness, while still maintaining the unctuousness and spreadability of the older grease-type ointments.
  • the emulsified creams have an aqueous base, however, and are not suitable as vehicles for many drugs because their pH or water content may destroy the medicant.
  • the medicant in turn may destroy the emulsions, that is, break the emulsions and permit separation of the vehicle components.
  • These emulsions also must contain surfactants as emulsifiers and wetting agents.
  • the fatty alcohol ingredient in the vehicle composition of this invention can be any saturated fatty alcohol having from 16 to 24 carbons or mixtures thereof, and is preferably a monohydric primary alcohol.
  • Suitable fatty alcohols include cetyl alcohol, stearyl alcohol, behenyl alcohol, and the like. Vehicles having excellent properties have been made using stearyl alcohol, or mixtures of cetyl, stearyl and behenyl alcohols as the fatty alcohol component.
  • the fatty alcohol component must be substantially free from any significant amount of unsaturated alcohols or fatty alcohols having fewer than 16 carbons. The terms substantially free from, as used herein, is defined as indicating the compositions of this invention contain less than irritating or otherwise medically undesirable amounts of the indicated substances.
  • the glycol solvent component can be a propylene glycol such as 1,2-propylenediol, 1,3-propylenediol, polyethylene glycol having a molecular weight of from 100 to 800, dipropylene glycol, etc., and mixtures thereof.
  • the fatty alcohol and glycol solvent ingredients are the principle components and are satisfactory as the sole vehicle components in the composition of this invention.
  • the glycol solvent can function either as a solvent for a glycol-soluble medicant or a carrier for a glycol-insoluble medicant.
  • the fluidity of the composition increases with increased concentrations of the glycol solvent.
  • the fatty alcohol a solid component which naturally thickens the composition
  • forms a unique protective, lubricant and occlusive film which is highly desirable in several types of dermatological preparations.
  • the composition can also contain a compatible plasticizer such as polyethylene glycol having a molecular weight of from above 800 to 20,000, 1,2,6-hexanetriol, sorbitol, glycerol, and the like.
  • a compatible plasticizer such as polyethylene glycol having a molecular weight of from above 800 to 20,000, 1,2,6-hexanetriol, sorbitol, glycerol, and the like.
  • the plasticizer maintains homogeneity in the fatty alcohol-glycol solvent mixture at ambient temperatures that is, temperatures at which the fatty alcohol is naturally a solid.
  • This component also improves the plasticity and uniformity of medicant mixtures with the vehicle and provides to the vehicle smoothness and a more pleasing feel; hence the vehicle containing the plasticizer is more pharmacologically acceptable.
  • compatible is defined herein to indicate a component which will not cause separation (loss of homogeneity) of the other components, that is, the fatty alcohol and glycol solvent at temperature up to 45 C.
  • the plasticizer concentration can be within the range of from to percent. Concentrations above 15 percent may provide a composition which has a consistency unsuitable for normal applications or cause instability of the vehicle mixture and some separation of the components. In general, the particular plasticizer concentration necessary to provide a desired consistency, degree of smoothness and plasticity will vary with the choice of the fatty alcohol component, the choice of glycol solvent, and the ratio of these components in the vehicle.
  • plasticizer concentration should be balanced so the vehicle has freeze-thaw stability, i.e., does not separate after repeated cycles of solidification (by cooling) and liquefaction (by heating).
  • the vehicle of this invention can also contain a compatible, pharmaceutically acceptable coupling agent, the term compatible having the above-defined meaning.
  • Suitable coupling agents include saturated fatty acids having from 16 to 24 carbons such as stearic acid, almitic acid, behenic acid; fatty amides such as oleamide, palmitamide, stearamide, behenamide; and esters of fatty acids having from 16 to 24 carbons such as sorbitan monostearate, polyethylene glycol monostearate, propylene glycol monostearate and the corresponding mono-esters of other fatty acids such as oleic acid and palmitic acid.
  • the fatty group of the coupling agent and fatty alcohol is the same or has approximately the same number of carbons. It is essential that the fatty acids be saturated and the fatty acids and amides be essentially free from irritating amounts of acids or amides having fewer than 16 carbons.
  • the coupling agent concentration can be within the range of from O to 10 percent.
  • the coupling agents maintain homogeneity of the vehicle and prevent exudation or bleeding of the more liquid components of the vehicle (glycol solvent) upon prolonged storage at elevated temperatures.
  • the medicant vehicle preferably contains a quantity of the coupling agent sufficient to prevent visible exudation of the glycol solvent from the vehicle after storage at for 48 hours. No more of the coupling agent is required than is needed to prevent this exudation. Excess quantities are undesirable because other ingredients and their functions are needlessly diluted. If the coupling agent concentration is not carefuly balanced with the other components, stability of the medicant vehicle after one or more repeated cycles of solidification (by cooling) and liquefaction (by heating), that is, the freeze-thaw stability is impaired.
  • the penetrants increase the penetration and therapeutic activity of the medicants and are usually solvents or cosolvents for the medicants.
  • the penetrants can be used in concentrations which are pharmaceutically acceptable for the intended use not to exceed 20 percent of the weight of the vehicle.
  • Representative examples of penetrants include dimethylsulfoxide, dimethylacetanide, dimethylformamide, and the like.
  • the medicant vehicles of this invention can also contain non-essentiall ingredients.
  • the vehicle can contain up to 10 Weight percent of conventional pharmaceutical adjuvants. These adjuvants or additives are conventionally used to improve consistency, homogeneity, spreadability, texture and appearance of the vehicle or its residual film. They can be used to give to a residual film, varying degrees of continuity, flexibility, ad-
  • Typical adjuvants include surfactants (cationic, anionic, or nonionic) such as Pluronics, polyoxyethylene-polyoxypropylene copolymers; gums such as natural gums including agar, acacia gum, guar gum, tragacanth, and the like; cellulose derivatives including cellulose ethers such as methyl cellulose, ethyl cellulose, carboxymethyl cellulose, and the like; starch and starch derivatives; and water-soluble vinyl polymers such as polyvinylpyrrolidone, polyvinyl acohol, vinylpyrrolidone-vinyl alcohol copolymers, and the like.
  • surfactants cationic, anionic, or nonionic
  • Pluronics polyoxyethylene-polyoxypropylene copolymers
  • gums such as natural gums including agar, acacia gum, guar gum, tragacanth, and the like
  • cellulose derivatives including cellulose ethers such as methyl
  • the vehice base of this invention does not contain any significant quantity of petrolatum or mineral oil. It is therefore not a classical ointment and is not Waterinsoluble.
  • the medicant vehicle of this invention is essentially a non-aqueous base, that is, it is not an emulsion and consequently is not a cream in the technical sense. It is preferably anhydrous, but can contain minor amounts of water such as up to 3 percent water. The water concentration should not be sufiicient to cause separation of the other vehicle components or precipitant medicants dissolved in the vehicle.
  • the vehicle of this invention can be made from the above ingredients by thoroughly mixing them at ambient or elevated temperatures. Preferably the components are thoroughly mixed while each is in a liquid state, and the mixture is cooled with good agitation to room temperature.
  • cetyl alocohl, stearyl alcohol, bethenyl alcohol, stearic acid, polyethylene glycol and 1,2,6-hexanetriol can be mixed with stirring to about -85" C.
  • propylene glycol can be heated to 95 C. with stirring (a medicant stable at this temperature could be added to either phase during this step); and the two liquids can be mixed with stirring. Good agitation is provided until the mixture cools to room temperature.
  • additional mechanical agitation and/or shock cooling steps can be used as intermediate or final steps in the manufacturing process to impart more homogeneity or improve texture.
  • Processing equipment suitable for these steps is known and includes heat exchangers, propeller mixers, colloid mills, homogenizers, roller mills, and the like.
  • the base of this invention can be used successfully as a vehicle for most types of therapeutic agents for topical application including antibiotics such as oxytetracycline, chlortetracycline, streptomycin, bacitracin, chloramphenical, tyrothricin and the like; steroids having anti-inflammatory or other beneficial activity; antihistamines such as prophenpyridamine maleate and diphenhydramine hydrochloride; anesthetics such as benzocaine and lidocaine; antibacterials including iodine, nitrofurazone, sulfanilamide and derivatives, and benzalkonium chloride; fungicides such as undecylenic acid; and older therapeutic agents including coal tar, balsam Peru, ammoniated mercury, chrysarobin, ichthammol, sulfur, and the like.
  • antibiotics such as oxytetracycline, chlortetracycline, streptomycin, bacitracin, chloramphenical, tyrothricin and
  • Medicants which are insoluble in propylene glycol can be dissolved or suspended in the melted fatty alcohol composition.
  • Heat sensitive medicants in particular some antibiotics
  • the amount of medicant to be incorporated into the base will, of course, depend upon the type of medicant and its intended use; the determination of suitable medicant concentrations is a routine matter fully within the conventional skills of the art. In general, therapeutically effective amounts of the medicant are incorporated into the vehicle.
  • the vehicle of this invention is particularly suitable for use with anti-inflammatory topical steroids represented by Formulas I, II and III.
  • R is hydrogen, methyl, fiuoro, or chloro and when Z is a single bond, R can be either a or B oriented;
  • R is hydrogen, chloro, or fluoro
  • R is keto or wherein R is hydrogen, hydroxy, chloro, or fluoro
  • R is hydrogen, methyl, hydroxy, or conventional hydrolyzable esters thereof
  • R is hydrogen, hydroxy, conventional hydrolyzable esters thereof, or when taken together with R ...0 /Re )a .0 R7
  • R is hydrogen or alkyl of up to eight carbons
  • R is hydrogen, or alkyl or an aryl group of up to eight carbons
  • R is hydroxy, conventional hydrolyzable esters thereof, tetrahydropyranyloxy, tetrahydrofuranyloxy, 4'-(lower)- alkoxytetrahydropyran- 4' -yloxy, lower alkoxy, lower cycloalkoxy, lower cycloalkenyloxy, chloro, or fluoro;
  • R and R are hydrogen, methyl, phenyl, chlorophenyl, fluorophenyl, methylphenyl, or methoxyphenyl (the substituted phenyls preferably being substituted in the para position);
  • R and R each is hydrogen, chloro, or fluoro
  • Z and Z each is a single bond, double bond, or
  • alkyl groups having from one to six carbon atoms, inclusive, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, amyl, hexyl, and the like.
  • hydrolyzable ester denotes those hydrolyzable ester groups conventionally employed in the steroid art, preferably those derived from hydrocarbon carboxylic acids or phosphoric acids and their salts.
  • hydrocarbon carboxylic acid defines both substituted and unsubstituted hydrocarbon carboxylic acids. These acids can be completely saturated or possess varying degrees of unsaturation (including aromatic), can be of straight chain, branched chain, or cyclic structure, and preferably contain from one to 12 carbon atoms.
  • Typical conventional hydrolyzable esters thus included within the scope of the term and the instant invention are acetate, propionate, butyrate, valerate, caproate, enanthrate, caprylate, pelargonate, acrylate, undecenoate, phenoxyacetate, benzoate phenylacetate, diphenylacetate, diethylacetate, trimethylacetate, t-butylacetate, trimethylhexanoate, methylneopentylacetate, cyclohexylaceate, cyclopentylpropionate, adamantoate, glycolate, methoxyacetate, hemisuccinate, hemiadipate, hemi-(Lfi-dimethylglutarate, acetoxyacetate 2-chloro-4-nitrobenzoate, aminoacetate, diethylaminoacetate, piperidinoacetate, ,B-chloropropionate, trichloroacetate, ,B-chlorobuty
  • aryl are included aryl, aralkyl, and alkaryl groups, such as phenyl, p-chlorophenyl, p-methoxyphenyl, benzyl, phenethyl, tolyl, ethylphenyl, and the like.
  • the wavy line (E) designates and includes both the alpha and beta configurations.
  • the 4-(lower)alkoxytetrahydropyran-4'-yl are prepared from the corresponding hydroxy compounds by reacting the latter compounds under substantially anhydrous conditions with an excess of 4'-(lower)alkoxy-5',6'- dihydro-ZH-pyran.
  • the reaction is conducted in the presence of a small amount of an acidic catalyst, such as hydrochloric acid, p-toluenesulfonic acid, boron trifluoride etherate, and the like, either alone or together with an inert, organic solvent such as benzene, diethyl ether, or the like, at a temperature ranging from about 0 C. to about C.
  • hydroxyl groups other than the C-21 hydroxyl groups eg 16a-hydroxy group.
  • Such a group should be selectively acylated such as by reaction with acetic anhydride in pyridine, the quantity of acetic anhydride being sufficient to acylate both the C-16 and C-2l hydroxyl groups.
  • Hydrolysis of the diacetate in methanol with less than one molar equivalent of sodium carbonate in water yields the l6-acetoxy-2l-hydroxy product which can be separated by conventional chromatography on neutral alumina, for example.
  • the acetoxy protecting groups can be removed by treatment of the ester in a methanol solution of potassium hydroxide.
  • the above anti-inflammatory topical medicants are thoroughly mixed with the base in therapeutically effective amounts.
  • concentration of the medi cant in the base will vary depending upon the particular activity of the steroid used considered in conjunction with thet condition and subject to be treated.
  • therapeutically effective amounts of these compounds can be as low as 0.00001 weight percent or lower, for example.
  • as high as 5 weight percent steroid or higher may be desired.
  • the medicant base of this invention has been found to be unexpectedly superior to previously known vehicles for use with known topical corticoids, for example fluocinolone acetonide (6a,9a-ditluoro-l1B,21-dihydroxy-l6a, 17u-isopropylidenedioxypregna-l,4-diene-3,20-dione) and the corresponding 21 acetate (6a,9a-difiuoro-1lB-hydroxy- 16a,l7a-isopropylidenedioxy 21 acetoxypregna-l,4-diene-3,20-dione).
  • these medicants have been observed to have several times greater activity in comparison to their activity in previously known vehicls at the same concentration.
  • EXAMPLE 1 The following ingredients were mixed at 90 C. and cooled to room temperature with good agitation.
  • compositions were found to have the spreadability, penetrability and solvent powder required for use with medicants such as steroids, anesthetics, antiseptics, antibiotics and the like.
  • Example 2 The compositions of Example 1 were found to have greater plasticity and uniformity when mixed with polyethylene glycol and/or hexanetriol to provide the following formulas.
  • Formula D Ingredients: Concentration, wt. percent Cetyl alcohol 1.75 Stearyl alcohol 7.00
  • Cetyl alcohol 1. 75 1. 75 Stearyl alcohol 3. 50 7. 00 Behenyl alcohol 12. 25 I 75 Stearic acid 3. 50
  • Stearyl alcohol 25 Stearic acid Polyethylene glycol 1 Hexanetriol 2 Sorbitan monostearate. Propylene glycol It Polyethylene glycol 4 1 Molecular weight, 6,000. 2 1,2,6-hexanetriol.
  • EXAMPLE 6 In this example, 0.25 gm. of 6a,9a-difiuoro-ll/3-hydroxy-16a,17a-isopropylidenedioxy 21 acetoxypregna- 1,4-diene-3,20-dione, was mixed with 100 gm. of Formula A, Example 1 to form a highly effective anti-inflammatory mixture.
  • the steroid was dissolved in 680 gm. of propylene glycol at 9095 C. The latter then was mixed with a mixture of the other ingredients at 85 C. The mixture was cooled to room temperature with good agitation, mixed with the remainder of the propylene glycol heated to 45 C., allowed to settle and deaerate overnight, gently mixed and filled into containers.
  • the mixture was tested and found to be mold and bacteria resistant as follows.
  • the test organisms used in the study were Bacteria: ATCC# Pseudomonas aeruginosa 10145 Proteus vulgaris 881 Staphylococcus aureus 6538 Bacillus cereus 11778 Molds:
  • test samples were prepared in Tryptose Phosphate Broth. The molds were grown in Sabouraud Liquid Medium. Just prior to the performance of the assay, all the test organisms were diluted 1:100 with the specific media as diluent. 0.01 ml. of each diluted organism was intimately mixed with a 15 ml. portion of the test material. Test samples inoculated with the mixture of bacteria were incubated at 37 C., and portions inoculated with the mixture of molds were incubated at room temperature. At the end of 48 hours contact and two weeks contact, samples were removed and plated out on appropriate media using the standard serial dilution technique.
  • test compounds were found to be highly effective against both bacteria and mold pooled cultures after two days and two weeks exposure.
  • EXAMPLE 7 The steroids used in Example 6 (0.25 gm.) are mixed with 1000 gm. of each of Formulas B, C, D, E, F, G, H, I, J, K and L by the general procedure described in Example 6, the steroid being dissolved in glycol solvent before being mixed with the other components.
  • the product compositions are mold and bacteria resistant when tested by the procedure described in Example 6.
  • a substantially anhydrous composition consisting essentially of an effective amount of a topical medicament and a vehicle consisting essentially of (a) from 15 to 45 parts by weight saturated fatty alcohol having from 16 to 24 carbons,
  • composition being substantially free from petrolatum, mineral oil, monohydric fatty alcohols and fatty acids which are unsaturated and monohydric alcohols, fatty acids and fatty amides which have less than 16 carbons.
  • composition of claim 1 wherein the vehicle consists essentially of (a) from 20 to 35 parts by weight saturated fatty alcohol having from 16 to 24 carbons,
  • composition of claim 1 wherein the glycol solvent is propylene glycol, polyethylene glycol having a molecular weight of from to 800, dipropylene glycol or mixtures thereof.
  • composition of claim 1 wherein the compatible plasticizer is polyethylene glycol having a molecular weight of from above 800 up to 20,000, hexanetriol, sorbitol, glycerol or mixtures thereof.
  • composition of claim 1 wherein the compatible coupling agent is fatty acid having from 16 to 24 carbons, fatty amide having from 16 to 24 carbons, fatty acid monoester with aliphatic alcohols or mixtures thereof.
  • composition of claim 1 wherein the medicament is an anti-inflammatory steroid.
  • composition of claim 6 wherein the steroid is (a) a pregn-4-ene-3,20-dione having at each of positions C-1, 2 and C-6, 7, a single bond, double bond or group having the formula wherein R and R each is hydrogen, chloro or fiuoro; at position C-6, hydrogen, methyl, fluoro or chloro; at position C-9, hydrogen, chloro, or fluoro; at position C-11, keto or wherein R is hydrogen, hydroxy, chloro or fluoro; at position C-16, hydrogen, methyl, hydroxy or conventional hydrolyzable esters thereof, at position C-17rx, hydrogen, hydroxy, conventional hydrolyz- 12 able esters thereof, or when taken together with able esters thereof, or when taken together with C-16a, a group having the formula C16 1, a gr up havi g t e f rmula R ---O ⁇ /Ru C o --0 R1 7 wherein R is hydrogen or alkyl of up to 8 carbons
  • composition of claim 7 wherein the steroid is carbons; and at position C21, hydroxy, conventional hydrolyzable esters thereof, tetrahydropyranyloxy, tetrahydrofuranyloxy, 4'- (lower)alkoxytetrahydropyran-4'-yloxy, lower alkoxy, lower cycloy cycloalkenyloxy chloro or fiuoro; 6a,9a-difluoro-11,8-hydroxy-16a,17a-isoproylidene dioxy- (b) a 2 -substrtuted-pregn-4-en-20-one-[3,2-c]-pyrazole 2l acetoxypregna l,4 diene 3,zo dionc Ora -p -BJ- J- y 9.
  • composition of claim 7 wherein the steroid is having at the respective 0r positions, 6a,9ot-difluoro-11fl,2l-dihydroxy-16a,l7a isopropylidenedrogen, methyl, p y chlorophenyl, fluorophenyl, dioxypregna-l,4-diene3,20-dione.
  • composition of claim 7 wherein the steroid is 7, a single bond, double bond or group having the 6oc-fluoro-9a,11fi-dichloro-16u,17a isopropylidenedioityformula 2l-hydroxypregna-1,4-diene-3,20-dione.

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  • Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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US745989A 1968-07-19 1968-07-19 Moisture-deterioratable topical medicaments,particularly anti-inflammatory steroids,in a substantially non-aqueous fatty alcohol-propylene glycol vehicle Expired - Lifetime US3592930A (en)

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CA (1) CA989304A (d)
CH (1) CH516312A (d)
DE (1) DE1934334C3 (d)
DK (1) DK124857B (d)
FR (1) FR2013281A1 (d)
GB (1) GB1259858A (d)
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US3888995A (en) * 1968-07-19 1975-06-10 Syntex Corp Fatty alcohol-propylene glycol vehicle
DE2515599A1 (de) * 1974-04-10 1975-10-30 Squibb & Sons Inc Arzneimittel zur lokalen anwendung und verfahren zu ihrer herstellung
US3924004A (en) * 1971-11-24 1975-12-02 Syntex Corp Fatty alcohol-propylene carbonate-glycol solvent cream vehicle
US3987198A (en) * 1973-10-16 1976-10-19 Syntex (U.S.A.) Inc. Method for lowering the free fatty acid content in sebum using certain fatty acid amides
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US4775529A (en) * 1987-05-21 1988-10-04 Schering Corporation Steroid lotion
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US5952392A (en) * 1996-09-17 1999-09-14 Avanir Pharmaceuticals Long-chain alcohols, alkanes, fatty acids and amides in the treatment of burns and viral inhibition
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US20040033982A1 (en) * 2001-10-16 2004-02-19 Katz David H Viral inhibition by n-docosanol
US6723750B2 (en) 2002-03-15 2004-04-20 Allergan, Inc. Photodynamic therapy for pre-melanomas
US20040198709A1 (en) * 2001-12-21 2004-10-07 Gans Eugene H. Compositions and methods for enhancing corticosteroid delivery
US20040247604A1 (en) * 2001-04-11 2004-12-09 Cohen Irun R. Anti-inflamatory fatty alcohols and fatty acid esters useful as antigen carriers
EP1385500A4 (en) * 2001-04-11 2004-12-29 Yeda Res & Dev FATTY ALCOHOLS AND FATTY ACID ESTERS FOR TREATING INFLAMMATION
US20060173053A1 (en) * 2002-10-10 2006-08-03 Meir Shinitzky Basic esters of fatty alcohols and their use as anti-inflammatory or immunomodulatory agents
WO2007025244A2 (en) 2005-08-25 2007-03-01 Houle Philip R Treatment systems for delivery of sensitizer solutions
US20080221209A1 (en) * 2007-02-26 2008-09-11 Yaacov Herzig Enantiomers of amino-phenyl-acetic acid octadec-9-(z) enyl ester, their salts and their uses
US20080221115A1 (en) * 2007-02-26 2008-09-11 Liat Hayardeny-Nisimov Use of long-chain alcohol derivatives for the treatment of alopecia areata

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DE2614841A1 (de) * 1976-04-06 1977-10-20 Bayer Ag Neue pour-on-formulierungen von anthelmintika
GB2116423B (en) * 1982-01-13 1986-08-28 Quinoderm Ltd Dermatological compositions
DE3233638A1 (de) * 1982-09-10 1984-03-15 Thilo & Co Gmbh Dr Dermatologische zubereitung
US4868168A (en) * 1987-11-13 1989-09-19 E. R. Squibb & Sons, Inc. Steroid ointment formulation

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US3888995A (en) * 1968-07-19 1975-06-10 Syntex Corp Fatty alcohol-propylene glycol vehicle
US4017615A (en) * 1970-10-29 1977-04-12 Syntex Corporation Propylene carbonate ointment vehicle
US3863633A (en) * 1971-06-04 1975-02-04 Pharmacia Ab Composition containing a substance showing a topical effect on the eye, and a method of preparing the same
US3883661A (en) * 1971-11-09 1975-05-13 Syntex Inc Acne treatment
US3924004A (en) * 1971-11-24 1975-12-02 Syntex Corp Fatty alcohol-propylene carbonate-glycol solvent cream vehicle
US3867528A (en) * 1973-10-11 1975-02-18 American Cyanamid Co Steroidal topical cream base
US3987198A (en) * 1973-10-16 1976-10-19 Syntex (U.S.A.) Inc. Method for lowering the free fatty acid content in sebum using certain fatty acid amides
DE2515599A1 (de) * 1974-04-10 1975-10-30 Squibb & Sons Inc Arzneimittel zur lokalen anwendung und verfahren zu ihrer herstellung
DE2624924A1 (de) 1975-05-27 1977-12-15 Syntex Inc Flunisolid und deren pharmazeutische verwendung
DE2661037C2 (d) * 1975-05-27 1989-04-06 Syntex (U.S.A.) Inc., Palo Alto, Calif., Us
US4082881A (en) * 1976-12-23 1978-04-04 E. R. Squibb & Sons, Inc. Topical and other type pharmaceutical formulations containing isosorbide carrier
US4954487A (en) * 1979-01-08 1990-09-04 The Procter & Gamble Company Penetrating topical pharmaceutical compositions
US4496554A (en) * 1979-01-17 1985-01-29 E. R. Squibb & Sons, Inc. Oleaginous emollient vehicle for steroid formulations
US4963555A (en) * 1980-07-18 1990-10-16 Burroughs Wellcome Co. Formulations of heterocyclic compounds
US4626539A (en) * 1984-08-10 1986-12-02 E. I. Dupont De Nemours And Company Trandermal delivery of opioids
EP0215622A2 (en) 1985-09-09 1987-03-25 Syntex (U.S.A.) Inc. Naphthalene anti-psoriatic agents and process for making them
US4775529A (en) * 1987-05-21 1988-10-04 Schering Corporation Steroid lotion
US5132101A (en) * 1990-05-04 1992-07-21 Cytopharm, Inc. Acetylene-cumulene porphycene compounds for photodynamic therapy
US5173302A (en) * 1990-09-28 1992-12-22 Medtronic, Inc. Hydrophilic pressure sensitive adhesive for topical administration of hydrophobic drugs
US5244671A (en) * 1991-01-29 1993-09-14 Cytopharm, Inc. Derivatives of porphycene for photodynamic therapy of cancer
US5179120A (en) * 1991-06-28 1993-01-12 Cytopharm, Inc. Porphycene compounds for photodynamic therapy
US5610175A (en) * 1995-04-06 1997-03-11 Cytopharm, Inc. 9-Substituted porphycenes
US7091190B2 (en) 1996-09-17 2006-08-15 Avanir Pharmaceuticals Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs
US5952392A (en) * 1996-09-17 1999-09-14 Avanir Pharmaceuticals Long-chain alcohols, alkanes, fatty acids and amides in the treatment of burns and viral inhibition
US20030073651A1 (en) * 1996-09-17 2003-04-17 Marcelletti John F. Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs
US6440980B1 (en) 1996-09-17 2002-08-27 Avanir Pharmaceuticals Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs
US6313179B1 (en) 1996-12-17 2001-11-06 Avanir Pharmaceuticals Treatment of hyperproliferative skin disorders with C18 to C20 aliphatic alcohols
US5948822A (en) * 1996-12-17 1999-09-07 Lidak Pharmaceuticals Treatment of hyperproliferative skin disorders with C18 to C26 alphatic alcohols
US20060183797A1 (en) * 2001-04-11 2006-08-17 Cohen Irun R Fatty alcohols and fatty acid esters useful for treatment of inflammation
US20040247604A1 (en) * 2001-04-11 2004-12-09 Cohen Irun R. Anti-inflamatory fatty alcohols and fatty acid esters useful as antigen carriers
EP1385500A4 (en) * 2001-04-11 2004-12-29 Yeda Res & Dev FATTY ALCOHOLS AND FATTY ACID ESTERS FOR TREATING INFLAMMATION
US20040033982A1 (en) * 2001-10-16 2004-02-19 Katz David H Viral inhibition by n-docosanol
US20100210609A2 (en) * 2001-12-21 2010-08-19 Eugene Gans Compositions and methods for enhancing corticosteroid delivery
US7771733B2 (en) 2001-12-21 2010-08-10 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20040198709A1 (en) * 2001-12-21 2004-10-07 Gans Eugene H. Compositions and methods for enhancing corticosteroid delivery
US8232264B2 (en) 2001-12-21 2012-07-31 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20070142344A1 (en) * 2001-12-21 2007-06-21 Gans Eugene H Compositions and methods for enhancing corticosteroid delivery
US20070142343A1 (en) * 2001-12-21 2007-06-21 Gans Eugene H Compositions and methods for enhancing corticosteroid delivery
US7794738B2 (en) 2001-12-21 2010-09-14 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
US20100210615A2 (en) * 2001-12-21 2010-08-19 Eugene Gans Compositions and methods for enhancing corticosteroid delivery
US20090176750A1 (en) * 2001-12-21 2009-07-09 Gans Eugene H Compositions and methods for enhancing corticosteroid delivery
US20100210614A2 (en) * 2001-12-21 2010-08-19 Eugene Gans Compositions and methods for enhancing corticosteroid delivery
US6723750B2 (en) 2002-03-15 2004-04-20 Allergan, Inc. Photodynamic therapy for pre-melanomas
US20060173053A1 (en) * 2002-10-10 2006-08-03 Meir Shinitzky Basic esters of fatty alcohols and their use as anti-inflammatory or immunomodulatory agents
US8987263B2 (en) 2002-10-10 2015-03-24 Meir Shinitzky Basic esters of fatty alcohols and their use as anti-inflammatory or immunomodulatory agents
WO2007025244A2 (en) 2005-08-25 2007-03-01 Houle Philip R Treatment systems for delivery of sensitizer solutions
US20080221115A1 (en) * 2007-02-26 2008-09-11 Liat Hayardeny-Nisimov Use of long-chain alcohol derivatives for the treatment of alopecia areata
US20080221209A1 (en) * 2007-02-26 2008-09-11 Yaacov Herzig Enantiomers of amino-phenyl-acetic acid octadec-9-(z) enyl ester, their salts and their uses
US7964751B2 (en) 2007-02-26 2011-06-21 Yeda Research And Development Co. Ltd. Enantiomers of amino-phenyl-acetic acid octadec-9-(Z) enyl ester, their salts and their uses

Also Published As

Publication number Publication date
DE1934334B2 (de) 1974-07-18
FR2013281A1 (d) 1970-03-27
HK26976A (en) 1976-05-21
SE363975B (d) 1974-02-11
NO129078B (d) 1974-02-25
CA989304A (en) 1976-05-18
DE1934334C3 (de) 1975-03-06
DE1934334A1 (de) 1970-02-12
NL154665B (nl) 1977-10-17
GB1259858A (en) 1972-01-12
CH516312A (de) 1971-12-15
NL6911091A (d) 1970-01-21
DK124857B (da) 1972-12-04
BE737875A (d) 1970-02-02

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