CA2092861A1 - Transdermal compositions - Google Patents
Transdermal compositionsInfo
- Publication number
- CA2092861A1 CA2092861A1 CA002092861A CA2092861A CA2092861A1 CA 2092861 A1 CA2092861 A1 CA 2092861A1 CA 002092861 A CA002092861 A CA 002092861A CA 2092861 A CA2092861 A CA 2092861A CA 2092861 A1 CA2092861 A1 CA 2092861A1
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Classifications
-
- 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
Abstract
Abstract HOE 92/S 015 Transdermal Compositions Novel compositions comprising an antiandrogenic compound of the formula
Description
, 2092861 ~)ECHST-ROUSSEL PHARMACEUTICALS INC. HOE 92/S 015 Description Transdermal Compositions The present invention relates to a pharmaceutical composition comprising an antiandrogenic tricyclic compound of formula 1 OR
CH
o wherein R is CORl wherein Rl is loweraLkyl and a vehicle comprising a metabolismmodulator and a polar organic solvent.
The skin, the largest organ of the mammalian body, having a surface area of about two square meters, provides a fer~ile field for the topical, local, and systemicadministration of medicaments. Applied to the skin, medicaments elicit topical effects on the surface and in the horny layer, the stratum corneum, the barrier to skin penetration.
Medicaments that surmount this barrier elicit local effects in the epidermis, and those which further penetrate the skin into the dermis enter the microcirculation and eventually the general circulation to elicit systemic effects. Control of the penetration of a medicarnent into the epidermis or dermis to achieve therapeutic levels of the agent for desired topical OI systemic effects, respectively, is generally hindered by the poor diffusion characteristics of most medicaments in the skin and by biotransformations, primarily in the epidermis, leading to metabolites having greater or lesser pharmacological activity, toxicity, or retention properties than the precursor. To improve the diffusion characteristics of medicaments in skin, membrane penetration enhancers such as arnides, lactams, and sucrose, and glycerol monofatty acid esters have been employed in adrnixtures with the medicaments. Such enhancers promote percutaneous transport across the stratum corneum thereby facilitating passage into the viable epidermisldermis region 20928fil ` f the skin. See U.S. Patent 4,808,41~ issued February 28, 1989, U.S. Patent 3,969,516 issued July 13, 1976, and U.S. Patent 4,788,062 issued November 29,1988, respectively, for a discussion of the roles played by amides, lactams, and fatty acid esters æ penetration enhancers. Alcohols, such æ ethanol, 2-propanol, and the like, have also been used æ
vehicles for the administration of medicarnents to skin to obtain high sates of transport for systemic treatment of various disorders. See U.S. Patent 4,804,541 issued February 14, 1989.
To modu1ate biotransformations in dhe skin, particular1y enzymatic hydro1ysis inthe epidermis/dermis regions of dhe skin, esteræe inhibitors have been utilized. One such inhibitor, diisopropylfluorophosphate, which hæ been found to efficiendy limit enzymatic hydrolysis of medicaments, e.g., sal*ylate esters in skin, suffers from being highly toxic.
See R. O. Potts, et al., Pharmaceutical Research, 6, 119 (1989).
It has now been found that compositions comprising a polar organic solvent and ametabolism modulator provide a vehicle for controlling the rate and extent of membrane permeation and degree of metabolic conversion of topically administered antiandrogenic tricyclic esters of formula 1 OR
CH
H C
wherein R is CORI wherein Rl is loweralkyl by modulating the metabolic and modifying the transport properties of mammalian skin, mucosa, or other permeable membranes, thereby attaining the objectives of the present invention, namely, to enhance the percutaneous delivery of tricyclic esters 1 (wherein R is CORI wherein Rl is loweraU~yl) through mammalian membranes, to modify the metabolic conversion of tricyclic esters 1 (wherein R is CORl wherein Rl is loweraLltyl) to tricyclic alcohols 1 wherein R is hydrogen (i.e., to control the dermal biotransformation of, e.g., 3~acetoxy-6-ethyl-3ap-methyl-1,2,3,3a,4,5,8,9,9a,9~decahydro-7H-benz(e)inden-7-one, inocoterone acetate ~ -herein R is CORI wherein Rl i~ rn~lhyl) to the more active metabolite, 6-ethyl-3a~ methyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3-ol-7-one, inocoterone (wherein R is CORl wherein Rl is hydrogen), and to regulate the rate of permeation of topically applied tricyclic ester 1 (wherein R is CORl wherein Rl is loweralkyl) so as to reduce or eliminate systemic effects of the medicament.
As used through the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon containing no unsaturation and having 1 to 8 carbon atoms such as methyl, ethyl, 1-, 2-propyl, butyl, l-penql, 3-hexyl, 4-heptyl, 2-octyl, and the like, unless specified otherwise. The term "lower" as applied thereto refers to a group having up to and including 6 carbon atoms.
Control of the rate and extent of membr~ne penetration and degree of metabolic conversion is achieved by selecting a vehicle comprising the appropriate polar organic solvent and metabolism modulator, and varying the proportion of polar organic solvent and metabolism modulator in the vehicle. Thus, for example, control of the rate and extent of membrane penetration and degree of metabolic conversion is achieved byemploying a carbinol of the formula R20H wherein R2 is aL~cyl of 1 to 12 carbon atoms, such as those described above and l-nonyl, 2-decyl, 3-undecyl, dodecyl, and the like, or alkenyl of 3 to 12 carbon atoms, such as propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 3-heptenyl, 4-octenyl, ~nonenyl, S-decenyl, 5-undecenyl, 6-dodecenyl, and the like, or a Il .
ketone of the formula R3CR4 wherein R3 and R4 are independen~y allcyl of 1 to 4 carbon atoms, or mixtures thereof, as the polar organic solvent, and an ester of an aliphatic monocarboxylic acid of the formula RsCO2R6 wherein Rs and R6 are independently alkyl or aL~cenyl having a total of 3 to 35 carbon atoms, and mixtures thereof, or a diester of an aliphatic dicarboxylic acid of the formula R,(CO2R6)2 wherein R6 is as above and R7 is aLlcyl or alkenyl having a total of S to 46 carbon atoms, or mixtures thereof, or a triester of glycerol of the formula 20~2~61 ..~
CH20CORg CH20CORIo wherein R8, Rg and Rlo are independently alkyl or alkenyl having a total of 3 to 54 carbon atoms, as the metabolism modulator. Esters of aliphatic monocarboxylic acids include ethyl acetate, cetyl acetate, myristyl acetate, ethyl laurate, propyl laurate, butyl laurate, isopropyl myristate, isopropyl palmitate, ethyl oleate, decyl oleate, ethyl linoleate, ethyl linolenate and the like; diesters of aliphatic dicarboxylic acids include dioctyl succinate, dibutyl adipate, dihexyl adipate, dicapryl adipate, diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, dioctyl sebacate, and the like; triesters of glycerol include glyceryl triacetate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tnoleate, glyceryl trilinoleate, and the like, as well as triglycerides of coconut oil fatty acids having 8 to 10 carbon atoms, such as~hliglyol 810 and~liglyol 812 available from Dynamit Nobel of America, Inc., 105 Stonehurst Court, Northvale, New Jersey 07647. Preferred aliphatic monocarboxylic acid esters include isopropyl myristate, ethyl laurate, propyl laurate, butyl laurate, isopropyl palmitate and ethyl oleate, isopropyl myristate being most preferred.
Carbinols include ethanol, 1- and 2-propanol, l-butanol, 2-pentanol, 3-hexanol, l-heptanol, 2-octanol, 3-nonanol, l-decanol, 1-undecanol, l-dodecanol, and the like.
Ketones include acetone, 3-pentanone, 4-heptanone, 5-nonanone, and the like.
Ethanol, including 95% ethanol and 2-propanol, and acetone are the prefelred carbinol and ketone, respectively, ethanol being most preferred.
To achieve the objects of the present invendon, a tricyclic compound of formula 1 wherein R is CORl wherein Rl is lowerallcyl is dissolved in a vehicle comprising a metabolism modulator and a polar organic solvent, and the composition is applied to mammalian skin, mucosa, or other membrane tissue. The metabolism modulator is generally present in the amount of about 0.5 to about 99.5% by weight of the vehicle, the amount of polar solvent, by necessary, being from about 99.5 to 0.5% by weight of the 20928fil ~hicle. While the amounts o~ meta~iism modulator and polar solvent are not narrowly critical within the aforementioned ranges, the presence of both modulator and solvent is necessary to achieve the stated objectives. The amount of antiandrogenic tricyclic ester 1 wherein R is CORI wherein Rl is loweraLkyl admixed with the vehicle is such that the desired pharmacological effect, antiandrogenic activity, is achieved over the desired time period. Generally, the amount of ester I wherein R is CORl wherein Rl is loweralkyl admixed with the vehicle falls within the range of from about 0.1 to about 40% by total weight of the vehicle, most preferably about 0.5 to about 20% by total weight of the vehicle.
The compositions of the present invention maybe applied direcdy to membrane tissue or may be incorpoIated into a solution, suspension, ointment, cream, lotion, gel, or plastic, using conventional inert excipients (carriers). These pharmaceutical compositions should contain at least 0.1% of the acdve composition; the amount may vary, however, between about Q 1% and about 20% of the weight thereof. The amount of active composidon in the pharmaceutical for nulation is such that a suitable dosage is obtained.
For the fonnulation of solutions the compositions of the present invention may be dissolved in glycerin, propylene glycol, polyethylene glycols, or other synthetic solvents, and the solution may be applied directly to the skin, or adsorbed onto a colton pad, sterile gauæ, or porous membrane and applied topicaUy. The suspensions, creams, lotions, and gels may contain emulsifying and/or solubilizing agents such as acacia, glycerylmonostearate, lecithin, Poloxamer brand of polyoxyethylene, polyoxypropylene block polymer available from BASF Wyandotte Corporation, 1609 Biddle Avenue, Wyandotte, MI 48192, polysorbates, Spans brand of sorbitan mono- and tri-fatty acid esters available from ICI America Inc., Wilmington, DE 19899, and the like, and suspending and/orviscosity-increasing agents such as agar, algiluc acid, aluminum monostearate,6~Carbopol 940 o~Carbomer 934P brand of polyacrylic acid available from B.F. Goodrich Chemical Co., 6100 Oak Tree Blvd., Cleveland, OH 04431, sodium carboxymethylcellulose, carrageenan, dextTin, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxethyl cellulose, methylcellulose, pectin, polyethylene oxide, Povidone brand of polyvinylpyrrolidone available from GAF Corporation, 1361 Alps Road, Wayne, `~J 07470, propylene glycol alginate; ~agacanth and the like, and ointmen~ bases such as lanolin, polyethylene glycol, petrolatum, squarene and the l~ce, and humectants such as glycerin, propylene glycol, sorbitol and the like, in an amount of about 1 to about 10% by weight of the formuladon.
The antiandrogenic compounds of the compositions of the present invention as prepared by the processes described in U.S. Patent Nos. 4,466,971, 4,607,054, and 4,849,454, issued August 21, 1984, August 19, 1986, and July 18, 1989, and are reported to be useful for the treatment of acne, hirsutism, seborrhea, among other, affliations due to hyperandrogenicity.
The invention is further illustrated by the foUowing examples which are illustrative of a specific mode of practicing the invention and is not intended as limiting the scope of the appended claims.
In Vitro Skin Permeation and Metabolism Studies The freshly excised hairless mouse skin was used in the two-compartment diffusion ceU method of Chien et al., Dru~ Develo~ment and Industrial PhannacY, 11, 1333-1173 (1985). The hairless mouse (HRS/J strain) was sacdficed just prior to the expedment by cervical dislocadon. A square section of the abdominal skin was surgically removed and m~unted between two side-by-side half ceUs; the exposed area of the skin being approximately 0.64 cm2. A 1-10% weight/volume (wtv) solution of inocoterone acetate and vehicle was added to the donor compartment and a 40% w/v polyethylene glycol 400/normal saline solution was added to the receptor compartment. Simultaneous sldn permeation and biotransformation studies were conducted in a thermostated diffusion ceU apparatus at 37C. At approprdate intervals samples were withdrawn from the receptor compaltment and analyzed for inocoterone acetate and its metabolite, inocoterone, by high pressure liquid chromatography. No significant hyd~olysis of the inocoterone acetate in the blank receptor solution was noted during the time course of the permeation expedment. Each experiment was carried out in at least triplicate. This 209286i nethod was used in Examples 3 to 6i~
For the evaluation of pharrnaceutical compositions of the present invention, thefreshly excised hairless mouse skin was used in the diffusion cell method of Franz, Current Problems in Dermatolo~, 7, 58-68 (1978), in a vertical position, the exposed area of the skin being approximately 1.8 cm2. The pharmaceutical formulation of knownconcentration in vehicle was added to the upper compartment of the cell, which was exposed to the stratum corneum side of the skin, and a 40% polyethylene glycol 400/normal saline solution was placed in the lower compartment. The penetration and metabolism rates were studied in a therrnostated diffusion ceU at 37C using the analytical method described above. Each experiment was carried out in at least triplicate. This method was used in Examples 7 and 13.
In Vivo Antiandro~en Activitv Test - Rat Male rats (intact or castrated) were treated topically with specified doses of inocoterone acetate solution in various solvent systems on days I, 2, 3, 6 and 7 of each week for 1 to 3 weeks. The castrated rats received daily injections of testosterone propionate (250 ~lg/day) subcutaneously. One day after the last administration, the animals were sacrificed and fragments of the skin and prostates were removed. The skin fragments were prepared for quantitative measurement of volume density of smoothendoplasmic reticulum (SER) by means of electron microscopy and the prostates were weighed. The studies using intact rats and castrated rats stimulated with testosterone propionate demonstrated a dose related reduction in volume density of SER with inocoteione acetate at a dose image from 0.25 to 25 m~kat/day, whereas there was no significant effect on prostate weight at any doæ.
Compositions of 10% w/v of inocoterone acetate in vehicle solutions were prepared by dissolving 1 g of the medicament in 10 ml of a mixture of isopropyl myristate and 95% ethanol in the following volume percent ratios: 100:0, 95:5, 70:30, 60:40, 50:50, 40:60, 30:70, 5:95 and 0:100, respectively. The in vitro skin permeation and metabolism rates were measured using the method described under the in vitro skin permeation test method. The results of these measurements, in terms of the cumulative amount of unchanged medicament and its metabolite permeated in ~moles per square centimeter with time, over S hours are given in Fig. 1.
The procedure of Example 3 was repeated except that the mixtures comprised isopropyl myristate and acetone in the following volume percent ratios: 100:0, 80:20, 50:50 and 20:80, respectiveb. The simultaneous skin permeation and metabolism rates generated from these medicament so!utions using the method described in Example 1 are J given in Fig. 2.
EXA~LE 4 The procedure of E~cample 3 was repeated except that the mixtures comprised isopropyl myristate and isopropyl alcohol in the following volume percent ratios: 100:0, 80:20, 50:50, 20:80 and 0:100, respectively. The simultaneous skinpermeation andmetabolism rates generated from these medicament solutions using the method described _/ under Example 1 are given in Fig. 3.
In this example, isopropyl mynstate is used as a metabolism modulator in combination with a polar organic solvent having various polari~es (dielectric constants) in a 50:50 volume percent ratio for the evaluation of the skin permeation and metabolism rates of inocoterone acetate. The relationship between the -- ~ercent metabolite de~ermined based~on the total medicament permeated i2tQe~
hour time period and the dielectric constant of the polar organic of in the solvent mixtures ,~ is given in Fig. 4.
In this example, the results of the use of ethanol as the polar organic solvent in combination with various fatty acid esters for the simultaneous skin permeation and metabolism of inocoterone acetate solution are shown.
Transdermal Flux Ql (x102 llmoles/cm2/S hrs) Inocoterone Total %
Vehicle Acetate Inocoterone Inocoterone Metabolite Ethanol 0 1.1 1.1 100.0 10% Ethyl laurate - 28.1 58.3 86.467.5 90% Ethanol 10% Propyl laurate - 25.8 60.8 86.670.2 90% Ethanol lO~o Butyl laurate - 39-954-5 94-4 57-7 90~Q Ethanol 10% Isopropyl pa1mitate - 9.4 27.536.9 74.5 90~oEthanol lO~o Ethyl oleate - 18.5 36.6 55.166.4 90% Ethanol A composition, in the form of a gel, suitable for topical application of inocoterone acetate is prepared by mixing the following components in the given concentrations.
209286~
Component Wei~ht %
lnocoterone acetate l-lO
Butyl laurate 5-20 Ethanol 10-50 Polyacrylic acid ~Carbopol 904)0.5-2 Triethanolamine (neutra1izing agent) q.s.
Sorbic acid (presenative) q.s.
Deionized water q.s. to lO0 Ethyl laurate, propyl laurate, isopropyl myristate, isopropyl palmitate, dioctylsebacate, ethyl oleate, isopropyl laurate, diisopropyl sebacate, and the like, may be substituted for butyl laurate in Example 7, to provide a topical composition suitable for the topical delivery of inocoterone acetate.
A polar organic solvent, e.g., n-propanol or isopropanol, is subsdtuted for ethanol in Example 7, to provide a top*al composition suitable for the topical delivery of inocoterone acetP~e.
EXAMPLE lO
- A neutralizing agent, e.g., triethylene amine, sodium hydroxide or~5~thomeen cns brand of polyethylene glycol amine of coconut acid available from Akzo Chemical Co., 8201 West 47th Street, McCook, IL 60525, may be substituted for triethanola nine in Example 7, to provide a topical gel preparation suitable for the percutaneous delivery of inocoterone acetate.
2~92861 A pharmaceutical composition in the form of a cellulose gel is prepared by mixing the following components in the following given concentrations:
Component Wei~ht %
Inocoterone acetate 1-10 Butyl laurate 10-50 Ethanol 5-20 Sorbic acid (preservative) q.s.
Hydroxypropyl cellulose 1-5 Deionized water q.s. to 100 A cellulose-type gelling agent, e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or sodium carboxymethyl cellulose may be substituted for hydroxypropyl cellulose of Example 11 to provide a topical composition suitable for the dermal delivery of inocoterone acetate.
In this example the simultaneous skin peImeation and metabolism rates of inocoterone acetate incorporated in the~Carbopol 940 gels formulated using the compositions described in Example 7 are shown.
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3 --' ~ ~n _1 ~ ~ ~ v~ ~
,~54~ ~5 1 ~y ~5 ~~ XAMPL~ 14 2 0 9 2 8 61 In this examp1e, the comparative effect of the vehicle systems of ethanol and a 40% isopropyl myristate-60% ethanol mixture on the in vivo efficacy of inocoterone acetate on the rat sebaceous gland is shown. The medicament in a dose of 0.5 mg/cm2/day for S days in S cm2 area was applied to the skin of testosterone propionate-treated castrated rats using the solvent systems described above. From the isopropyl myristate-ethanol system, inocoterone acetate completely inhibited the testosterone-induced increase in the volume density of the smooth endoplasmic reticulum vesicles in the interrnediate cells on the rat sebaceous gland. When the same dose of inocoterone acetate was applied using ethanol as the solvent, the effects of testosterone on the sebaceous gland wae inhibited by 60%. Topical administration of the medicament with the isopropyl myristate-ethanol mixture resulted in a systemic antiandrogenic effect as evidenced by changes in the prostate.
The greater efficacy of inocoterone acetate when applied in the isopropyl myristate-ethanol mixture is consistent with the increased transcutaneous penetradon obseNed in Example 3.
.~
'~'
CH
o wherein R is CORl wherein Rl is loweraLkyl and a vehicle comprising a metabolismmodulator and a polar organic solvent.
The skin, the largest organ of the mammalian body, having a surface area of about two square meters, provides a fer~ile field for the topical, local, and systemicadministration of medicaments. Applied to the skin, medicaments elicit topical effects on the surface and in the horny layer, the stratum corneum, the barrier to skin penetration.
Medicaments that surmount this barrier elicit local effects in the epidermis, and those which further penetrate the skin into the dermis enter the microcirculation and eventually the general circulation to elicit systemic effects. Control of the penetration of a medicarnent into the epidermis or dermis to achieve therapeutic levels of the agent for desired topical OI systemic effects, respectively, is generally hindered by the poor diffusion characteristics of most medicaments in the skin and by biotransformations, primarily in the epidermis, leading to metabolites having greater or lesser pharmacological activity, toxicity, or retention properties than the precursor. To improve the diffusion characteristics of medicaments in skin, membrane penetration enhancers such as arnides, lactams, and sucrose, and glycerol monofatty acid esters have been employed in adrnixtures with the medicaments. Such enhancers promote percutaneous transport across the stratum corneum thereby facilitating passage into the viable epidermisldermis region 20928fil ` f the skin. See U.S. Patent 4,808,41~ issued February 28, 1989, U.S. Patent 3,969,516 issued July 13, 1976, and U.S. Patent 4,788,062 issued November 29,1988, respectively, for a discussion of the roles played by amides, lactams, and fatty acid esters æ penetration enhancers. Alcohols, such æ ethanol, 2-propanol, and the like, have also been used æ
vehicles for the administration of medicarnents to skin to obtain high sates of transport for systemic treatment of various disorders. See U.S. Patent 4,804,541 issued February 14, 1989.
To modu1ate biotransformations in dhe skin, particular1y enzymatic hydro1ysis inthe epidermis/dermis regions of dhe skin, esteræe inhibitors have been utilized. One such inhibitor, diisopropylfluorophosphate, which hæ been found to efficiendy limit enzymatic hydrolysis of medicaments, e.g., sal*ylate esters in skin, suffers from being highly toxic.
See R. O. Potts, et al., Pharmaceutical Research, 6, 119 (1989).
It has now been found that compositions comprising a polar organic solvent and ametabolism modulator provide a vehicle for controlling the rate and extent of membrane permeation and degree of metabolic conversion of topically administered antiandrogenic tricyclic esters of formula 1 OR
CH
H C
wherein R is CORI wherein Rl is loweralkyl by modulating the metabolic and modifying the transport properties of mammalian skin, mucosa, or other permeable membranes, thereby attaining the objectives of the present invention, namely, to enhance the percutaneous delivery of tricyclic esters 1 (wherein R is CORI wherein Rl is loweraU~yl) through mammalian membranes, to modify the metabolic conversion of tricyclic esters 1 (wherein R is CORl wherein Rl is loweraLltyl) to tricyclic alcohols 1 wherein R is hydrogen (i.e., to control the dermal biotransformation of, e.g., 3~acetoxy-6-ethyl-3ap-methyl-1,2,3,3a,4,5,8,9,9a,9~decahydro-7H-benz(e)inden-7-one, inocoterone acetate ~ -herein R is CORI wherein Rl i~ rn~lhyl) to the more active metabolite, 6-ethyl-3a~ methyl-1,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz(e)inden-3-ol-7-one, inocoterone (wherein R is CORl wherein Rl is hydrogen), and to regulate the rate of permeation of topically applied tricyclic ester 1 (wherein R is CORl wherein Rl is loweralkyl) so as to reduce or eliminate systemic effects of the medicament.
As used through the specification and appended claims, the term "alkyl" refers to a straight or branched chain hydrocarbon containing no unsaturation and having 1 to 8 carbon atoms such as methyl, ethyl, 1-, 2-propyl, butyl, l-penql, 3-hexyl, 4-heptyl, 2-octyl, and the like, unless specified otherwise. The term "lower" as applied thereto refers to a group having up to and including 6 carbon atoms.
Control of the rate and extent of membr~ne penetration and degree of metabolic conversion is achieved by selecting a vehicle comprising the appropriate polar organic solvent and metabolism modulator, and varying the proportion of polar organic solvent and metabolism modulator in the vehicle. Thus, for example, control of the rate and extent of membrane penetration and degree of metabolic conversion is achieved byemploying a carbinol of the formula R20H wherein R2 is aL~cyl of 1 to 12 carbon atoms, such as those described above and l-nonyl, 2-decyl, 3-undecyl, dodecyl, and the like, or alkenyl of 3 to 12 carbon atoms, such as propenyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 3-heptenyl, 4-octenyl, ~nonenyl, S-decenyl, 5-undecenyl, 6-dodecenyl, and the like, or a Il .
ketone of the formula R3CR4 wherein R3 and R4 are independen~y allcyl of 1 to 4 carbon atoms, or mixtures thereof, as the polar organic solvent, and an ester of an aliphatic monocarboxylic acid of the formula RsCO2R6 wherein Rs and R6 are independently alkyl or aL~cenyl having a total of 3 to 35 carbon atoms, and mixtures thereof, or a diester of an aliphatic dicarboxylic acid of the formula R,(CO2R6)2 wherein R6 is as above and R7 is aLlcyl or alkenyl having a total of S to 46 carbon atoms, or mixtures thereof, or a triester of glycerol of the formula 20~2~61 ..~
CH20CORg CH20CORIo wherein R8, Rg and Rlo are independently alkyl or alkenyl having a total of 3 to 54 carbon atoms, as the metabolism modulator. Esters of aliphatic monocarboxylic acids include ethyl acetate, cetyl acetate, myristyl acetate, ethyl laurate, propyl laurate, butyl laurate, isopropyl myristate, isopropyl palmitate, ethyl oleate, decyl oleate, ethyl linoleate, ethyl linolenate and the like; diesters of aliphatic dicarboxylic acids include dioctyl succinate, dibutyl adipate, dihexyl adipate, dicapryl adipate, diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, dioctyl sebacate, and the like; triesters of glycerol include glyceryl triacetate, glyceryl trilaurate, glyceryl trimyristate, glyceryl tripalmitate, glyceryl tnoleate, glyceryl trilinoleate, and the like, as well as triglycerides of coconut oil fatty acids having 8 to 10 carbon atoms, such as~hliglyol 810 and~liglyol 812 available from Dynamit Nobel of America, Inc., 105 Stonehurst Court, Northvale, New Jersey 07647. Preferred aliphatic monocarboxylic acid esters include isopropyl myristate, ethyl laurate, propyl laurate, butyl laurate, isopropyl palmitate and ethyl oleate, isopropyl myristate being most preferred.
Carbinols include ethanol, 1- and 2-propanol, l-butanol, 2-pentanol, 3-hexanol, l-heptanol, 2-octanol, 3-nonanol, l-decanol, 1-undecanol, l-dodecanol, and the like.
Ketones include acetone, 3-pentanone, 4-heptanone, 5-nonanone, and the like.
Ethanol, including 95% ethanol and 2-propanol, and acetone are the prefelred carbinol and ketone, respectively, ethanol being most preferred.
To achieve the objects of the present invendon, a tricyclic compound of formula 1 wherein R is CORl wherein Rl is lowerallcyl is dissolved in a vehicle comprising a metabolism modulator and a polar organic solvent, and the composition is applied to mammalian skin, mucosa, or other membrane tissue. The metabolism modulator is generally present in the amount of about 0.5 to about 99.5% by weight of the vehicle, the amount of polar solvent, by necessary, being from about 99.5 to 0.5% by weight of the 20928fil ~hicle. While the amounts o~ meta~iism modulator and polar solvent are not narrowly critical within the aforementioned ranges, the presence of both modulator and solvent is necessary to achieve the stated objectives. The amount of antiandrogenic tricyclic ester 1 wherein R is CORI wherein Rl is loweraLkyl admixed with the vehicle is such that the desired pharmacological effect, antiandrogenic activity, is achieved over the desired time period. Generally, the amount of ester I wherein R is CORl wherein Rl is loweralkyl admixed with the vehicle falls within the range of from about 0.1 to about 40% by total weight of the vehicle, most preferably about 0.5 to about 20% by total weight of the vehicle.
The compositions of the present invention maybe applied direcdy to membrane tissue or may be incorpoIated into a solution, suspension, ointment, cream, lotion, gel, or plastic, using conventional inert excipients (carriers). These pharmaceutical compositions should contain at least 0.1% of the acdve composition; the amount may vary, however, between about Q 1% and about 20% of the weight thereof. The amount of active composidon in the pharmaceutical for nulation is such that a suitable dosage is obtained.
For the fonnulation of solutions the compositions of the present invention may be dissolved in glycerin, propylene glycol, polyethylene glycols, or other synthetic solvents, and the solution may be applied directly to the skin, or adsorbed onto a colton pad, sterile gauæ, or porous membrane and applied topicaUy. The suspensions, creams, lotions, and gels may contain emulsifying and/or solubilizing agents such as acacia, glycerylmonostearate, lecithin, Poloxamer brand of polyoxyethylene, polyoxypropylene block polymer available from BASF Wyandotte Corporation, 1609 Biddle Avenue, Wyandotte, MI 48192, polysorbates, Spans brand of sorbitan mono- and tri-fatty acid esters available from ICI America Inc., Wilmington, DE 19899, and the like, and suspending and/orviscosity-increasing agents such as agar, algiluc acid, aluminum monostearate,6~Carbopol 940 o~Carbomer 934P brand of polyacrylic acid available from B.F. Goodrich Chemical Co., 6100 Oak Tree Blvd., Cleveland, OH 04431, sodium carboxymethylcellulose, carrageenan, dextTin, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxethyl cellulose, methylcellulose, pectin, polyethylene oxide, Povidone brand of polyvinylpyrrolidone available from GAF Corporation, 1361 Alps Road, Wayne, `~J 07470, propylene glycol alginate; ~agacanth and the like, and ointmen~ bases such as lanolin, polyethylene glycol, petrolatum, squarene and the l~ce, and humectants such as glycerin, propylene glycol, sorbitol and the like, in an amount of about 1 to about 10% by weight of the formuladon.
The antiandrogenic compounds of the compositions of the present invention as prepared by the processes described in U.S. Patent Nos. 4,466,971, 4,607,054, and 4,849,454, issued August 21, 1984, August 19, 1986, and July 18, 1989, and are reported to be useful for the treatment of acne, hirsutism, seborrhea, among other, affliations due to hyperandrogenicity.
The invention is further illustrated by the foUowing examples which are illustrative of a specific mode of practicing the invention and is not intended as limiting the scope of the appended claims.
In Vitro Skin Permeation and Metabolism Studies The freshly excised hairless mouse skin was used in the two-compartment diffusion ceU method of Chien et al., Dru~ Develo~ment and Industrial PhannacY, 11, 1333-1173 (1985). The hairless mouse (HRS/J strain) was sacdficed just prior to the expedment by cervical dislocadon. A square section of the abdominal skin was surgically removed and m~unted between two side-by-side half ceUs; the exposed area of the skin being approximately 0.64 cm2. A 1-10% weight/volume (wtv) solution of inocoterone acetate and vehicle was added to the donor compartment and a 40% w/v polyethylene glycol 400/normal saline solution was added to the receptor compartment. Simultaneous sldn permeation and biotransformation studies were conducted in a thermostated diffusion ceU apparatus at 37C. At approprdate intervals samples were withdrawn from the receptor compaltment and analyzed for inocoterone acetate and its metabolite, inocoterone, by high pressure liquid chromatography. No significant hyd~olysis of the inocoterone acetate in the blank receptor solution was noted during the time course of the permeation expedment. Each experiment was carried out in at least triplicate. This 209286i nethod was used in Examples 3 to 6i~
For the evaluation of pharrnaceutical compositions of the present invention, thefreshly excised hairless mouse skin was used in the diffusion cell method of Franz, Current Problems in Dermatolo~, 7, 58-68 (1978), in a vertical position, the exposed area of the skin being approximately 1.8 cm2. The pharmaceutical formulation of knownconcentration in vehicle was added to the upper compartment of the cell, which was exposed to the stratum corneum side of the skin, and a 40% polyethylene glycol 400/normal saline solution was placed in the lower compartment. The penetration and metabolism rates were studied in a therrnostated diffusion ceU at 37C using the analytical method described above. Each experiment was carried out in at least triplicate. This method was used in Examples 7 and 13.
In Vivo Antiandro~en Activitv Test - Rat Male rats (intact or castrated) were treated topically with specified doses of inocoterone acetate solution in various solvent systems on days I, 2, 3, 6 and 7 of each week for 1 to 3 weeks. The castrated rats received daily injections of testosterone propionate (250 ~lg/day) subcutaneously. One day after the last administration, the animals were sacrificed and fragments of the skin and prostates were removed. The skin fragments were prepared for quantitative measurement of volume density of smoothendoplasmic reticulum (SER) by means of electron microscopy and the prostates were weighed. The studies using intact rats and castrated rats stimulated with testosterone propionate demonstrated a dose related reduction in volume density of SER with inocoteione acetate at a dose image from 0.25 to 25 m~kat/day, whereas there was no significant effect on prostate weight at any doæ.
Compositions of 10% w/v of inocoterone acetate in vehicle solutions were prepared by dissolving 1 g of the medicament in 10 ml of a mixture of isopropyl myristate and 95% ethanol in the following volume percent ratios: 100:0, 95:5, 70:30, 60:40, 50:50, 40:60, 30:70, 5:95 and 0:100, respectively. The in vitro skin permeation and metabolism rates were measured using the method described under the in vitro skin permeation test method. The results of these measurements, in terms of the cumulative amount of unchanged medicament and its metabolite permeated in ~moles per square centimeter with time, over S hours are given in Fig. 1.
The procedure of Example 3 was repeated except that the mixtures comprised isopropyl myristate and acetone in the following volume percent ratios: 100:0, 80:20, 50:50 and 20:80, respectiveb. The simultaneous skin permeation and metabolism rates generated from these medicament so!utions using the method described in Example 1 are J given in Fig. 2.
EXA~LE 4 The procedure of E~cample 3 was repeated except that the mixtures comprised isopropyl myristate and isopropyl alcohol in the following volume percent ratios: 100:0, 80:20, 50:50, 20:80 and 0:100, respectively. The simultaneous skinpermeation andmetabolism rates generated from these medicament solutions using the method described _/ under Example 1 are given in Fig. 3.
In this example, isopropyl mynstate is used as a metabolism modulator in combination with a polar organic solvent having various polari~es (dielectric constants) in a 50:50 volume percent ratio for the evaluation of the skin permeation and metabolism rates of inocoterone acetate. The relationship between the -- ~ercent metabolite de~ermined based~on the total medicament permeated i2tQe~
hour time period and the dielectric constant of the polar organic of in the solvent mixtures ,~ is given in Fig. 4.
In this example, the results of the use of ethanol as the polar organic solvent in combination with various fatty acid esters for the simultaneous skin permeation and metabolism of inocoterone acetate solution are shown.
Transdermal Flux Ql (x102 llmoles/cm2/S hrs) Inocoterone Total %
Vehicle Acetate Inocoterone Inocoterone Metabolite Ethanol 0 1.1 1.1 100.0 10% Ethyl laurate - 28.1 58.3 86.467.5 90% Ethanol 10% Propyl laurate - 25.8 60.8 86.670.2 90% Ethanol lO~o Butyl laurate - 39-954-5 94-4 57-7 90~Q Ethanol 10% Isopropyl pa1mitate - 9.4 27.536.9 74.5 90~oEthanol lO~o Ethyl oleate - 18.5 36.6 55.166.4 90% Ethanol A composition, in the form of a gel, suitable for topical application of inocoterone acetate is prepared by mixing the following components in the given concentrations.
209286~
Component Wei~ht %
lnocoterone acetate l-lO
Butyl laurate 5-20 Ethanol 10-50 Polyacrylic acid ~Carbopol 904)0.5-2 Triethanolamine (neutra1izing agent) q.s.
Sorbic acid (presenative) q.s.
Deionized water q.s. to lO0 Ethyl laurate, propyl laurate, isopropyl myristate, isopropyl palmitate, dioctylsebacate, ethyl oleate, isopropyl laurate, diisopropyl sebacate, and the like, may be substituted for butyl laurate in Example 7, to provide a topical composition suitable for the topical delivery of inocoterone acetate.
A polar organic solvent, e.g., n-propanol or isopropanol, is subsdtuted for ethanol in Example 7, to provide a top*al composition suitable for the topical delivery of inocoterone acetP~e.
EXAMPLE lO
- A neutralizing agent, e.g., triethylene amine, sodium hydroxide or~5~thomeen cns brand of polyethylene glycol amine of coconut acid available from Akzo Chemical Co., 8201 West 47th Street, McCook, IL 60525, may be substituted for triethanola nine in Example 7, to provide a topical gel preparation suitable for the percutaneous delivery of inocoterone acetate.
2~92861 A pharmaceutical composition in the form of a cellulose gel is prepared by mixing the following components in the following given concentrations:
Component Wei~ht %
Inocoterone acetate 1-10 Butyl laurate 10-50 Ethanol 5-20 Sorbic acid (preservative) q.s.
Hydroxypropyl cellulose 1-5 Deionized water q.s. to 100 A cellulose-type gelling agent, e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or sodium carboxymethyl cellulose may be substituted for hydroxypropyl cellulose of Example 11 to provide a topical composition suitable for the dermal delivery of inocoterone acetate.
In this example the simultaneous skin peImeation and metabolism rates of inocoterone acetate incorporated in the~Carbopol 940 gels formulated using the compositions described in Example 7 are shown.
C
c E~ ~ -- ~_ X ~
~'C X , C~
~ ~ C ~ o E-~ o ~ ~ ~ <`1 ~t~ ~
c~ ooo~o ooo~o ooo~o o~oooo~ o~oooo~ o~oooo~
3 --' ~ ~n _1 ~ ~ ~ v~ ~
,~54~ ~5 1 ~y ~5 ~~ XAMPL~ 14 2 0 9 2 8 61 In this examp1e, the comparative effect of the vehicle systems of ethanol and a 40% isopropyl myristate-60% ethanol mixture on the in vivo efficacy of inocoterone acetate on the rat sebaceous gland is shown. The medicament in a dose of 0.5 mg/cm2/day for S days in S cm2 area was applied to the skin of testosterone propionate-treated castrated rats using the solvent systems described above. From the isopropyl myristate-ethanol system, inocoterone acetate completely inhibited the testosterone-induced increase in the volume density of the smooth endoplasmic reticulum vesicles in the interrnediate cells on the rat sebaceous gland. When the same dose of inocoterone acetate was applied using ethanol as the solvent, the effects of testosterone on the sebaceous gland wae inhibited by 60%. Topical administration of the medicament with the isopropyl myristate-ethanol mixture resulted in a systemic antiandrogenic effect as evidenced by changes in the prostate.
The greater efficacy of inocoterone acetate when applied in the isopropyl myristate-ethanol mixture is consistent with the increased transcutaneous penetradon obseNed in Example 3.
.~
'~'
Claims (10)
1. A pharmaceutical composition comprising an antiandrogenic tricyclic compound of the formula I
I
wherein R is COR1 wherein R1 is loweralkyl,a vehicle comprising a metabolism modulator and a polar organic solvent, and a suitable carrier therefor.
I
wherein R is COR1 wherein R1 is loweralkyl,a vehicle comprising a metabolism modulator and a polar organic solvent, and a suitable carrier therefor.
2. A pharmaceutical composition according to claim 1 wherein the metabolism modulator is a compound of the formula R5CO2R6 wherein R5 and R6 are independently alkyl or alkenyl having a total of 3 to 35 carbon atoms; a compound of the formula R7(CO2R6)2 wherein R6 is as defined above and R7 is alkyl or alkenyl having a total of 5 to 46 carbon atoms; or a compound of the formula wherein R8, R9, and R10 are independently alkyl or alkenyl having a total of 3 to 54 carbon atoms or mixtures thereof, and wherein the polar organic solvent is a compound of the formula R2OH where R2 is alkyl of 1 to 12 carbon atoms or alkenyl of 3 to 12 carbon atoms, or a compound of the formula wherein R3 and R4 are independently alkyl of 1 to 6 carbon atoms, or mixtures thereof.
3. A pharmaceutical composition according to claim 2, wherein the metabolism modulator of the formula R5CO2R6 is selected from the group consisting of ethyl acetate, cetyl acetate, ethyl laurate, myristyl acetate, ethyl laurate, propyl laurate, butyl laurate, isopropyl myristate, isopropyl palmitate, ethyl oleate, decyl oleate, ethyl linoleate, and ethyl linolenate.
4. A pharmaceutical composition according to claim 2 wherein, the metabolism modulator of the formula R7(CO2R6)2 is selected from the group consisting of dioctyl succinate, dibutyl adipate, dihexyl adipate, dicapryl adipate, diethyl sebacate, diisopropyl sebacate, dibutyl sebacate, and dioctyl sebacate.
5. A pharmaceutical composition according to claim 2, wherein the metabolism modulator of the formula is selected from the group consisting of Miglyol 810 and Miglyol 812.
6. A pharmaceutical composition according to claim 2, wherein the polar organic solvent is ethanol, 2-propanol or acetone.
7. A pharmaceutical composition according to claim 1, wherein R1 is methyl, the metabolism modulator is isopropyl myristate and the polar organic solvent is ethanol.
8. A pharmaceutical composition according to claim 1, wherein the carrier is a gelling agent.
9. A pharmaceutical composition according to claim 1, wherein the weight percent of the metabolism modulator is from about 0.5 to about 99.5 % of the vehicle.
10. A pharmaceutical composition according to claim 1, wherein the weight percent of the compound of the formula 1 is about 0.1 to about 40 % of the vehicle.
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| US85974592A | 1992-03-30 | 1992-03-30 | |
| US859,745 | 1992-03-30 |
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| CA2092861A1 true CA2092861A1 (en) | 1993-10-01 |
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| CA002092861A Abandoned CA2092861A1 (en) | 1992-03-30 | 1993-03-29 | Transdermal compositions |
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| EP (1) | EP0563813B1 (en) |
| JP (1) | JPH069389A (en) |
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| AU (1) | AU658487B2 (en) |
| CA (1) | CA2092861A1 (en) |
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| NZ (1) | NZ247257A (en) |
| PT (1) | PT563813E (en) |
| TW (1) | TW224048B (en) |
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| US5601839A (en) * | 1995-04-26 | 1997-02-11 | Theratech, Inc. | Triacetin as a penetration enhancer for transdermal delivery of a basic drug |
| GR1002807B (en) | 1996-06-20 | 1997-11-13 | Lavipharm A.E. | Device for topical treatment of acne and method of manufacture. |
| US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
| US20040092494A9 (en) * | 2000-08-30 | 2004-05-13 | Dudley Robert E. | Method of increasing testosterone and related steroid concentrations in women |
| US20040002482A1 (en) * | 2000-08-30 | 2004-01-01 | Dudley Robert E. | Androgen pharmaceutical composition and method for treating depression |
| SI1315502T1 (en) * | 2000-08-30 | 2010-07-30 | Unimed Pharmaceuticals Llc | Method for treating erectile dysfunction and increasing libido in men |
| US6495158B1 (en) | 2001-01-19 | 2002-12-17 | Lec Tec Corporation | Acne patch |
| US20070088012A1 (en) * | 2005-04-08 | 2007-04-19 | Woun Seo | Method of treating or preventing type-2 diabetes |
| AU2006299833B2 (en) | 2005-10-12 | 2012-04-12 | Besins Healthcare Luxembourg Sarl | Improved testosterone gel and method of use |
| FR2953832B1 (en) | 2009-12-10 | 2012-01-13 | Galderma Res & Dev | DERIVATIVES OF NEW PEROXIDES, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS FOR THE TREATMENT OR PREVENTION OF ACNE |
| FR2953833B1 (en) * | 2009-12-10 | 2012-01-13 | Galderma Res & Dev | DERIVATIVES OF NEW PEROXIDES, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN MEDICINE AND COSMETICS FOR THE TREATMENT OR PREVENTION OF ACNE |
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| US3551554A (en) * | 1968-08-16 | 1970-12-29 | Crown Zellerbach Corp | Enhancing tissue penetration of physiologically active agents with dmso |
| US3472931A (en) * | 1969-01-17 | 1969-10-14 | Foster Milburn Co | Percutaneous absorption with lower alkyl amides |
| US3969516A (en) * | 1974-12-19 | 1976-07-13 | Nelson Research & Development Company | Composition and method for treatment of acne |
| US4017641A (en) * | 1975-01-31 | 1977-04-12 | The Procter & Gamble Company | Skin moisturizing compositions containing 2-pyrrolidinone |
| US3989816A (en) * | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
| US4202888A (en) * | 1976-07-12 | 1980-05-13 | Kali-Chemie Pharma Gmbh. | Readily enterally absorbable pharmaceutical compositions of cardiac glycosides and preparation thereof |
| FR2500441A1 (en) * | 1981-02-23 | 1982-08-27 | Roussel Uclaf | NOVEL DERIVATIVES OF 3-HYDROXY DODECAHYDRO BENZ (E) INDEN-7-ONE, PRODUCTS DERIVED FROM 3-HYDROXY DODECAHYDRO BENZ (E) INDEN-7-ONE AND PROCESS FOR THEIR PREPARATION |
| US4879119A (en) * | 1984-02-21 | 1989-11-07 | Yamanouchi Pharmaceutical Co., Ltd. | Patch |
| US4684635A (en) * | 1984-05-11 | 1987-08-04 | Norman Orentreich | Compositions and methods for inhibiting the action of androgens |
| IL72684A (en) * | 1984-08-14 | 1989-02-28 | Israel State | Pharmaceutical compositions for controlled transdermal delivery of cholinergic or anticholinergic basic drugs |
| US4897269A (en) * | 1984-09-24 | 1990-01-30 | Mezei Associates Limited | Administration of drugs with multiphase liposomal delivery system |
| US4810499A (en) * | 1984-10-01 | 1989-03-07 | Biotek, Inc. | Transdermal drug delivery system and method |
| US4808414A (en) * | 1986-09-29 | 1989-02-28 | Nelson Research & Development Co. | Amide penetration enhancers for transdermal delivery of systemic agents |
| US4788062A (en) * | 1987-02-26 | 1988-11-29 | Alza Corporation | Transdermal administration of progesterone, estradiol esters, and mixtures thereof |
| US4900555A (en) * | 1987-02-26 | 1990-02-13 | Alza Corporation | Skin permeation enhancer compositions using sucrose esters |
| US4783450A (en) * | 1987-04-13 | 1988-11-08 | Warner-Lambert Company | Use of commercial lecithin as skin penetration enhancer |
| US4804541A (en) * | 1987-08-11 | 1989-02-14 | Moleculon, Inc. | Transdermal administration using benzyl alcohol |
| US4885154A (en) * | 1988-03-01 | 1989-12-05 | Alza Corporation | Method for reducing sensitization or irritation in transdermal drug delivery and means therefor |
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- 1993-03-15 TW TW082101880A patent/TW224048B/zh active
- 1993-03-26 DK DK93105010T patent/DK0563813T3/en active
- 1993-03-26 NZ NZ247257A patent/NZ247257A/en unknown
- 1993-03-26 DE DE69327127T patent/DE69327127T2/en not_active Expired - Fee Related
- 1993-03-26 PT PT93105010T patent/PT563813E/en unknown
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- 1993-03-26 EP EP93105010A patent/EP0563813B1/en not_active Expired - Lifetime
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| DK0563813T3 (en) | 2000-05-22 |
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| GR3032518T3 (en) | 2000-05-31 |
| MX9301752A (en) | 1993-09-01 |
| ES2140422T3 (en) | 2000-03-01 |
| NZ247257A (en) | 1995-07-26 |
| KR930019218A (en) | 1993-10-18 |
| AU3559993A (en) | 1993-10-07 |
| PT563813E (en) | 2000-04-28 |
| DE69327127D1 (en) | 2000-01-05 |
| EP0563813B1 (en) | 1999-12-01 |
| JPH069389A (en) | 1994-01-18 |
| US5482970A (en) | 1996-01-09 |
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