CA1179599A - Pharmaceutical preparations - Google Patents
Pharmaceutical preparationsInfo
- Publication number
- CA1179599A CA1179599A CA000380219A CA380219A CA1179599A CA 1179599 A CA1179599 A CA 1179599A CA 000380219 A CA000380219 A CA 000380219A CA 380219 A CA380219 A CA 380219A CA 1179599 A CA1179599 A CA 1179599A
- Authority
- CA
- Canada
- Prior art keywords
- weight
- composition
- peroxide
- erythromycin
- benzoyl peroxide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- 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
- A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- 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
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/38—Percompounds, e.g. peracids
-
- 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
- A61K8/60—Sugars; Derivatives thereof
- A61K8/602—Glycosides, e.g. rutin
-
- 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
-
- 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
-
- 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
- A61K2800/41—Particular ingredients further characterized by their size
- A61K2800/412—Microsized, i.e. having sizes between 0.1 and 100 microns
-
- 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
- A61K2800/52—Stabilizers
-
- 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
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/88—Two- or multipart kits
Abstract
A B S T R A C T
Process and composition for the topical treatment of acne which comprises as ingredients a per-oxide of an organic acid and an erythromycin compound selected from the group consisting of erythromycin and its stearate and glucoheptonate derivatives and in which said peroxide is from one-half of thirty times, the weight of said erythromycin compound, and a suitable pharmaceutically acceptable carrier.
Process and composition for the topical treatment of acne which comprises as ingredients a per-oxide of an organic acid and an erythromycin compound selected from the group consisting of erythromycin and its stearate and glucoheptonate derivatives and in which said peroxide is from one-half of thirty times, the weight of said erythromycin compound, and a suitable pharmaceutically acceptable carrier.
Description
?
This invention relates to pharmaceutical prepa-rations and particularly to active ingredients which are useful for the topical treatment of acne. The invention also includes a method of treatment of humans with the pharmaceutical preparations and ingredients to medici-nally treat acne.
Acne is a common inflammatory disease in skin areas where sebaceous glands are largest, most numerous, and most active. In its milder types it is a more or less superficial disorder which is evidenced by slight, spotty irritations and ordinary skin hygiene is a satis-factory treatment. However, in the more inflammatory types of acne, bacterial invasion of or about the pilo-sebaceous follicles occurs and pustules, infected cysts and, in extreme cases, canalizing inflamed and infected sacs appear. These lesions may become extensive and leave permanent, disfiguring scars.
Acne is very common at puberty and at least 80 of teenagers are afflicted. The facial eruptions are known to cause such psychic trauma in many adolescents that they find it difficult to make personal adjustments and consequently, withdrawal and self-pity occur. The sufferer may be constantly aware of the obvious facial blemishes. For these reasons a medicinal preparation and treatment are of definite benefit and may eliminate the need for psychotherapy.
To reduce the severity of acne, various forms ~`
of medication have previously been topically applied to the skin. Antibacterial soaps have been used as well as bactericidal agents such as sulfur and resorcinol.
Other topical compositions have separately contained benzoyl peroxide, hexachlorophene, erythromycin or neomycin sulfate. None of these prior preparations has been completely effective.
U.S. Patent No. 3,535,422 discloses a thera-peutic composition for the treatment of acne comprising a uniform dispersion of benzoyl peroxide in a fluid medium containing water and at least one organic emollient.
U.S. Patent No. 4,056,611 discloses a thera-peutic composition for the treatment of acne comprising a stable dispersion of finely divided particles of benzoyl peroxide in an aqueous alcohol vehicle having a single phase. The single phase of the composition is non-lipid and contains a non-ionic surface active agent that is solub]e in the aqueous alcohol vehicle.
British specification 2,054,375, published February 18, 1981, discloses use of dioctyl sodium sulfosuccinate as a stabilizing agent for benzoyl per-oxide formulations and the increased stability of benzoyl peroxide in micronized form.
Prior art peroxide compositions which contain merely finely divided peroxide particles in an emulsion of water and certain select emollients provides the disadvantage that when the water content of the emulsion evaporates there remains most of the organic emollients and the large benzoyl peroxide particles on the surface of the skin near and in contact with the acne sites which may cause irritation.
Additionally, the use of large amounts of non-ionic surface active agents in such compositions, unless extremely fine particles of peroxide are utilized, would cause a likelihood of irritation from the peroxide.
Also, because of the powerful oxidizing proper-ties of the peroxide component, the inclusion of this substance in a conventional ointment or emulsion or with other active ingredients results in unstable compositions that soon display an unacceptable loss in keratolytic potency.
In accordance with the present invention, it has been discovered that a mixture on the skin of a per-oxide, especially benzoyl, and erythromycin is particu-larly beneficial as they exert a statistically signifi-cant synergistic effect. Benzoyl peroxide inhibits theformation of free fatty acids in the skin, primarily through inactivation of extracellular lipase (via oxidation) necessary to cleave triglycerides into free fatty acids and glycerol. Erythromycin effectively reduces the concentration of Corynebac~erium ~cne~ (i.e., P. acnes), a normal anaerobic bacteria which is the prime source of the lipase. Instead of the benzoyl peroxide, 1~'7~
which is preferred, other peroxides of organic acids may be used such as lauroyl peroxide. Instead of erythro-mycin, which is preferred, erythromycin derivatives may be substituted such as erythromycin stearate or gluco-heptonate.
These two ingredients may be applied to the skin as a mixture or they may separately be applied to the skin. In the latter practice the erythromycin would preferably first be applied to the skin and immediately or shortly thereafter the peroxide would be applied. Or, the order of application would be reversed. If a mixture is to first be made up and then applied to the skin it is best that the mixture be made at the time of application or that the mixture be used within twenty-four hours.
The prompt use of a premix is due to the rela-tive incompatibility of the two active agents and because of this it is advisable that the two agents be put in separate vials, hottles or other containers. However, as a feature of the present invention there is provided a novel vehicle for the active ingredients whereby the mixture of the ingredients has a surprising stability and shelf life at temperatures conventionally employed for the storage of erythromycin solutions; additionally, the novel vehicle provides a more uniform dispersion of active ingredients.
The therapeutic gel composition of the present invention must contain sufficient peroxide to be thera-r --5~
peutically effective, and should not contain more per-oxide than can be uniformly dispersed in the vehicle to form a smoothly spreadable composition. Such consider-ations dictate that the composition contain at least 1%
and not more than 30% by weight of peroxide, and prefer-ably that the composition contain from about 2.5% to 15~, by weight peroxide. The peroxide constituent of the composition should be of the high purity and in the form of finely divided crystalline particles, preferably, micronized par*icles having a mean average particle size of less than 35 microns. Utilizing a peroxide which has been micronized provides greater stability and shelf-life to the composition when used in combination with dioctyl sodium sulfosuccinate as the surfactant. The gel compo-sition of the present invention may advantageously include a further wetting agent such as the esters of polyols and sugars, the products of the condensation of ethylene oxide with fatty aci~s, fatty alcohols, long-chain alkyl phenols, long-chain mercaptans, long-chain amides, polyethers of polyhydroxylated fatty alcohols and alkyl polyglycol ethers in an amount of from about 3% to about 6%, by weight.
It has been surprisingly found that in an aqueous alcoholic gel vehicle the utilization of a per-oxide and an erythromycin compound in combination with dioctyl sodium sulfosuccinate as the surface act7ve agent results in a composition which displays full stability with respect to the peroxide component even when subject-ed to temperatures higher than those normally expected in the ordinary use of the product. Also, the mixture of the present invention upon evaporation allows a uniform release of the peroxide so as to obviate the burning and erythema experienced with other harsh formulations.
The aqueous gel composition of the present invention contains from about 1% to about 30%, and preferably from about 5% to 15%, by weight, of peroxide, especially, micronized benzoyl peroxide having a particle size of less than about 150 microns with the mean average particle size being less than about 35 microns. Dioctyl sodium sulfosuccinate which serves as a surface active agent as well as providing for the increased stability of the composition is present in the amount of about 0.1~ to
This invention relates to pharmaceutical prepa-rations and particularly to active ingredients which are useful for the topical treatment of acne. The invention also includes a method of treatment of humans with the pharmaceutical preparations and ingredients to medici-nally treat acne.
Acne is a common inflammatory disease in skin areas where sebaceous glands are largest, most numerous, and most active. In its milder types it is a more or less superficial disorder which is evidenced by slight, spotty irritations and ordinary skin hygiene is a satis-factory treatment. However, in the more inflammatory types of acne, bacterial invasion of or about the pilo-sebaceous follicles occurs and pustules, infected cysts and, in extreme cases, canalizing inflamed and infected sacs appear. These lesions may become extensive and leave permanent, disfiguring scars.
Acne is very common at puberty and at least 80 of teenagers are afflicted. The facial eruptions are known to cause such psychic trauma in many adolescents that they find it difficult to make personal adjustments and consequently, withdrawal and self-pity occur. The sufferer may be constantly aware of the obvious facial blemishes. For these reasons a medicinal preparation and treatment are of definite benefit and may eliminate the need for psychotherapy.
To reduce the severity of acne, various forms ~`
of medication have previously been topically applied to the skin. Antibacterial soaps have been used as well as bactericidal agents such as sulfur and resorcinol.
Other topical compositions have separately contained benzoyl peroxide, hexachlorophene, erythromycin or neomycin sulfate. None of these prior preparations has been completely effective.
U.S. Patent No. 3,535,422 discloses a thera-peutic composition for the treatment of acne comprising a uniform dispersion of benzoyl peroxide in a fluid medium containing water and at least one organic emollient.
U.S. Patent No. 4,056,611 discloses a thera-peutic composition for the treatment of acne comprising a stable dispersion of finely divided particles of benzoyl peroxide in an aqueous alcohol vehicle having a single phase. The single phase of the composition is non-lipid and contains a non-ionic surface active agent that is solub]e in the aqueous alcohol vehicle.
British specification 2,054,375, published February 18, 1981, discloses use of dioctyl sodium sulfosuccinate as a stabilizing agent for benzoyl per-oxide formulations and the increased stability of benzoyl peroxide in micronized form.
Prior art peroxide compositions which contain merely finely divided peroxide particles in an emulsion of water and certain select emollients provides the disadvantage that when the water content of the emulsion evaporates there remains most of the organic emollients and the large benzoyl peroxide particles on the surface of the skin near and in contact with the acne sites which may cause irritation.
Additionally, the use of large amounts of non-ionic surface active agents in such compositions, unless extremely fine particles of peroxide are utilized, would cause a likelihood of irritation from the peroxide.
Also, because of the powerful oxidizing proper-ties of the peroxide component, the inclusion of this substance in a conventional ointment or emulsion or with other active ingredients results in unstable compositions that soon display an unacceptable loss in keratolytic potency.
In accordance with the present invention, it has been discovered that a mixture on the skin of a per-oxide, especially benzoyl, and erythromycin is particu-larly beneficial as they exert a statistically signifi-cant synergistic effect. Benzoyl peroxide inhibits theformation of free fatty acids in the skin, primarily through inactivation of extracellular lipase (via oxidation) necessary to cleave triglycerides into free fatty acids and glycerol. Erythromycin effectively reduces the concentration of Corynebac~erium ~cne~ (i.e., P. acnes), a normal anaerobic bacteria which is the prime source of the lipase. Instead of the benzoyl peroxide, 1~'7~
which is preferred, other peroxides of organic acids may be used such as lauroyl peroxide. Instead of erythro-mycin, which is preferred, erythromycin derivatives may be substituted such as erythromycin stearate or gluco-heptonate.
These two ingredients may be applied to the skin as a mixture or they may separately be applied to the skin. In the latter practice the erythromycin would preferably first be applied to the skin and immediately or shortly thereafter the peroxide would be applied. Or, the order of application would be reversed. If a mixture is to first be made up and then applied to the skin it is best that the mixture be made at the time of application or that the mixture be used within twenty-four hours.
The prompt use of a premix is due to the rela-tive incompatibility of the two active agents and because of this it is advisable that the two agents be put in separate vials, hottles or other containers. However, as a feature of the present invention there is provided a novel vehicle for the active ingredients whereby the mixture of the ingredients has a surprising stability and shelf life at temperatures conventionally employed for the storage of erythromycin solutions; additionally, the novel vehicle provides a more uniform dispersion of active ingredients.
The therapeutic gel composition of the present invention must contain sufficient peroxide to be thera-r --5~
peutically effective, and should not contain more per-oxide than can be uniformly dispersed in the vehicle to form a smoothly spreadable composition. Such consider-ations dictate that the composition contain at least 1%
and not more than 30% by weight of peroxide, and prefer-ably that the composition contain from about 2.5% to 15~, by weight peroxide. The peroxide constituent of the composition should be of the high purity and in the form of finely divided crystalline particles, preferably, micronized par*icles having a mean average particle size of less than 35 microns. Utilizing a peroxide which has been micronized provides greater stability and shelf-life to the composition when used in combination with dioctyl sodium sulfosuccinate as the surfactant. The gel compo-sition of the present invention may advantageously include a further wetting agent such as the esters of polyols and sugars, the products of the condensation of ethylene oxide with fatty aci~s, fatty alcohols, long-chain alkyl phenols, long-chain mercaptans, long-chain amides, polyethers of polyhydroxylated fatty alcohols and alkyl polyglycol ethers in an amount of from about 3% to about 6%, by weight.
It has been surprisingly found that in an aqueous alcoholic gel vehicle the utilization of a per-oxide and an erythromycin compound in combination with dioctyl sodium sulfosuccinate as the surface act7ve agent results in a composition which displays full stability with respect to the peroxide component even when subject-ed to temperatures higher than those normally expected in the ordinary use of the product. Also, the mixture of the present invention upon evaporation allows a uniform release of the peroxide so as to obviate the burning and erythema experienced with other harsh formulations.
The aqueous gel composition of the present invention contains from about 1% to about 30%, and preferably from about 5% to 15%, by weight, of peroxide, especially, micronized benzoyl peroxide having a particle size of less than about 150 microns with the mean average particle size being less than about 35 microns. Dioctyl sodium sulfosuccinate which serves as a surface active agent as well as providing for the increased stability of the composition is present in the amount of about 0.1~ to
2%, by weight of composition. The composition may also advantageously contain a further wetting agent in an amount of about 1.0~ to about 6.0% by weight and prefer-ably about 3~ to 6~ by weight.
Further advantage and objects of the present invention will become more apparent when viewed with the drawings in which:
Fig. 1 is a perspective view of a package con-taining two containers, one for each active agent;
Fig. 2 is a section on the line 2-2 of Fig. l;
Fig. 3 is a section on the line 3-3 of Fig. 2, and;
Fig. 4 is a perspective view of a package con-taining a singIe jar.
A mixture of the two active ingredients may be lightly dusted on the affected skin area much in the same manner that ordinary face powder would be applied. This could be an application of either the prernix shown in Fig. 4, or of the successively applied separate agents in the two containers of Fig. 1, or of a premix of the two agents of Fig. 1 made at the time of application. How-ever, it is possible to dilute the mixture with a carrierwhich may be a powder, a semi-solid vehicle of creamlike consistency or a liquid such as a water emulsion or with an organic solvent, especially an aqueous mixture con-taining as a surfactant dioctyl sodium sulfosuccinate.
On a weight basis, the selected erythromycin and the selected peroxide should be measured out so that as applied to the skin the latter is from about one to about thirty times the weight of the former, preferably from about one to about five times. In a premix compo-sition including a diluent to be applied to the skin, theselected erythromycin should be present at a level ranging from 0.5% to 5.0% w/w and the selected peroxide should be present at a level ranging from 1.0% to 30%
w/w. A preferred concentration is about 2% to about 3%
of the selected erythromycin and about 5% to about 10% of the selected peroxide.
As erythromycin is ~imited in its solubility, ~ :~'7!~
the preferred dermatologic solvents are alcohol or ace-tone but the composition is not limited to these liquids.
In solution, erythromycin rapidly degrades, even at normal room temperature. Refrigeration somewhat extends the shelf-life of such solution.
A preferred diluent or carrier is a hydro-alcoholic gel system, but liquid suspensions and emul-sions, as well as creams, ointments and powders are acceptable. Conventional pharmaceutical processes may be used in making up these common forms of medicinal, topi-cal compositions. For instance, a premix may be placed in a capped conventional ointment or like container 9 as shown in Fig. 4, as this would minimize the stability problem. The patient should be instructed to refrigerate the preparation. Ordinarily, the jar 9 would be in a cardboard or like package 10.
For commercial preparation it is best to make up a cardboard package 5 with a cover 6, which includes two capped containers as is shown in the accompanying drawing. One container would have only the erythromycin in it and it would be large enough to accommodate all the other ingredients to later be mixed with. The other con-tainer would contain an aqueous gel benzoyl peroxide composition, with or without the solvent for the erythro-mycin, as well as the other ingredients to make up the topical composition. However, it has been surprisingly found that the use of dioctyl sodium sulfosuccinate as a surfactant provides stability to the composition.
The gelling agent used in this invention may be selected both as to type and quantity to give products of various viscosities. In the preferred form of this invention, the gelling agent is selected so as to produce an elegantly formed and stable gel. A variety of gelling agents may be used for the present purposes. However, preferred gelling agents are pure micro-crystalline cel-lulose, colloidal magnesium aluminum silicate, hydroxy-propyl methyl cellulose and the so-called hydroxylated vinylic polymers, particularly, those disclosed in U.S.
Patent No. 2,798,053. Among those hydroxylated vinylic polymers of special interest herein are described gener-ally as interpolymers of a monomeric monoolefinic acrylic acid, and from about 0.1% to about 10% by weight based on the total monomer of a monomeric polyether of an oligo-saccharide in which the hydroxyl groups which are modi-fied are esterified with allyl groups with said polyether containing at least two allyl ether groups per oligo-saccharide molecule. Commercially available inter-polymers of this type are marketed under the trade name Carbopols . These are described as being polymers of acrylic acid cross-lined with about 1~ of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each sucrose molecule. These polymers have molecular weight in the order of magnitude of 1,000,000.
Such polymers are available from the B.F. Goodrich ~.~'7~
..
Chemical Company and are sold under such trademarks as Carbopol~ 934, Carbopol~ 940, and Carbopol 941.
The quantity of gelling agent that may be con-tained in the present compositions may also vary some-what. Ordinarily, this will constitute about 0.1% to about 15% by weight, and preferably about 0.5% to about
Further advantage and objects of the present invention will become more apparent when viewed with the drawings in which:
Fig. 1 is a perspective view of a package con-taining two containers, one for each active agent;
Fig. 2 is a section on the line 2-2 of Fig. l;
Fig. 3 is a section on the line 3-3 of Fig. 2, and;
Fig. 4 is a perspective view of a package con-taining a singIe jar.
A mixture of the two active ingredients may be lightly dusted on the affected skin area much in the same manner that ordinary face powder would be applied. This could be an application of either the prernix shown in Fig. 4, or of the successively applied separate agents in the two containers of Fig. 1, or of a premix of the two agents of Fig. 1 made at the time of application. How-ever, it is possible to dilute the mixture with a carrierwhich may be a powder, a semi-solid vehicle of creamlike consistency or a liquid such as a water emulsion or with an organic solvent, especially an aqueous mixture con-taining as a surfactant dioctyl sodium sulfosuccinate.
On a weight basis, the selected erythromycin and the selected peroxide should be measured out so that as applied to the skin the latter is from about one to about thirty times the weight of the former, preferably from about one to about five times. In a premix compo-sition including a diluent to be applied to the skin, theselected erythromycin should be present at a level ranging from 0.5% to 5.0% w/w and the selected peroxide should be present at a level ranging from 1.0% to 30%
w/w. A preferred concentration is about 2% to about 3%
of the selected erythromycin and about 5% to about 10% of the selected peroxide.
As erythromycin is ~imited in its solubility, ~ :~'7!~
the preferred dermatologic solvents are alcohol or ace-tone but the composition is not limited to these liquids.
In solution, erythromycin rapidly degrades, even at normal room temperature. Refrigeration somewhat extends the shelf-life of such solution.
A preferred diluent or carrier is a hydro-alcoholic gel system, but liquid suspensions and emul-sions, as well as creams, ointments and powders are acceptable. Conventional pharmaceutical processes may be used in making up these common forms of medicinal, topi-cal compositions. For instance, a premix may be placed in a capped conventional ointment or like container 9 as shown in Fig. 4, as this would minimize the stability problem. The patient should be instructed to refrigerate the preparation. Ordinarily, the jar 9 would be in a cardboard or like package 10.
For commercial preparation it is best to make up a cardboard package 5 with a cover 6, which includes two capped containers as is shown in the accompanying drawing. One container would have only the erythromycin in it and it would be large enough to accommodate all the other ingredients to later be mixed with. The other con-tainer would contain an aqueous gel benzoyl peroxide composition, with or without the solvent for the erythro-mycin, as well as the other ingredients to make up the topical composition. However, it has been surprisingly found that the use of dioctyl sodium sulfosuccinate as a surfactant provides stability to the composition.
The gelling agent used in this invention may be selected both as to type and quantity to give products of various viscosities. In the preferred form of this invention, the gelling agent is selected so as to produce an elegantly formed and stable gel. A variety of gelling agents may be used for the present purposes. However, preferred gelling agents are pure micro-crystalline cel-lulose, colloidal magnesium aluminum silicate, hydroxy-propyl methyl cellulose and the so-called hydroxylated vinylic polymers, particularly, those disclosed in U.S.
Patent No. 2,798,053. Among those hydroxylated vinylic polymers of special interest herein are described gener-ally as interpolymers of a monomeric monoolefinic acrylic acid, and from about 0.1% to about 10% by weight based on the total monomer of a monomeric polyether of an oligo-saccharide in which the hydroxyl groups which are modi-fied are esterified with allyl groups with said polyether containing at least two allyl ether groups per oligo-saccharide molecule. Commercially available inter-polymers of this type are marketed under the trade name Carbopols . These are described as being polymers of acrylic acid cross-lined with about 1~ of a polyallyl ether of sucrose having an average of about 5.8 allyl groups for each sucrose molecule. These polymers have molecular weight in the order of magnitude of 1,000,000.
Such polymers are available from the B.F. Goodrich ~.~'7~
..
Chemical Company and are sold under such trademarks as Carbopol~ 934, Carbopol~ 940, and Carbopol 941.
The quantity of gelling agent that may be con-tained in the present compositions may also vary some-what. Ordinarily, this will constitute about 0.1% to about 15% by weight, and preferably about 0.5% to about
3% by weight, based on the total weight of the finished composition.
As mentioned above, the simplest topical prepa-ration is a mixture of powdered benzoyl peroxide anderythromycin with no diluent, but it would have to be sparingly applied to the skin. Instead of applying a premixture of them, one may first be applied to the skin and then the other would be applied with slight rubbing to mix them on the skin. A suitable, simplified prepa-ration is the following:
Benzoyl peroxide 1 - 35 w/w Calcium phosphate 63 - 98.5 w/w Erythromycin .5 - 5 w/w These ingredients are intimately mixed together and dusted on the affected skin area, from one to four times daily. It could be sold in the container 9 of Fig. 4.
If a liquid preparation is desired, the follow~
ing is a simplified compositiGn which may be made and applied to the skin from one to four times daily as -~ ~1'7~
though it were an ordinary face lotion. It could be sold in one of the bottles of Fig. 1 with or without the carton 5.
EXA~lPLE 2 Ethanol Q.S. - 100 w~w Erythromycin 0.5 - 5 w/w Benzoyl peroxide1 - 30 w/w Other examples which are representative of the invention are the following:
Lotion In a first container 7 are placed the following ingredients, by weight:
100 %
Ethoxylated cetyl-stearyl alcohol 7.00%
Cetyl alcohol 0.75%
Isopropyl myristate 5.00%
Butylated hydroxyanisole 0.10%
Polyoxyl 40 stearate0.25%
Water, deionized or distilled 68.80~
Propylene glycol 3.00%
Benzoyl peroxide 5.00~
Acetone 10.00%
Dioctyl sodium sulfosuccinate 0.10%
In a second container 8 is placed the following ingredient by itself, the container being large enough to accommodate a quantity of a solvent, preferably, ethanol or acetone, in the ration of 3 cc./20 grams of the compo-sition in container 7.
Erythromycin 2% w/w of the contents of container 7.
Both containers are put in a single marketable package such as 5 with the instructions that the contents of container 8 is added to container 7 and be thoroughly mixed. Alternately, to container 8 having the erythro-mycin is added 3 cc. ethanol per each 20 grams of material in container 7. The solution of erythromycin in ethanol is then added to container 7 and thoroughly mixed. This would either be done by the pharmacist or by the patient. The patient would apply the lotion to the skin as though it were an ordinary lotion from one to four times daily.
A variation of Example 3 is to further dilute container 8 with the same solvent so that some of the contents of container 7 would first be applied to the skin and then some of the contents of container 8 would be applied to the skin so that the mixture occurs on the skin. This eliminates loss due to the shelf-life or storage of the mixture.
Cream In a first container 7 are placed the following ingredients, by weight:
Ethoxylated cetyl-stearyl alcohol 15.00%
Cetyl alcohol 1.25%
Isopropyl myristate 5.00%
sutylated hydroxyanisole 0.10%
Polyoxyl 40 stearate 0.25%
Water, deionized or distilled 60.60%
Propylene glycol 3.00%
Benzoyl peroxide 5.00%
Acetone 10.00%
Dioctyl sodium sulfosuccinate 0.10%
In a second container 8 is placed the following ingredient by itself, the container being large enough to accommodate a quantity of a solvent, preferably, ethanol or acetone, in the ration of 3 cc./20 grams of the compo-sition in container 7.
Erythromycin 3% w/w of the contents of container 7.
The explanation for sale and use in Example 3 applies to this cream. As the preparation is of creme consistency the containers 7 and 8 should have wide mouths to facilitate mixing and removal of the creme.
Gel Container 7 has in it the following, by weight:
Water, deionized or distilled 54.65%
Colloidal Bentonite 2.50%
Carboxy vinyl polymer (acid 1.00%
form) Dioctyl sodium sulfosuccinate 1.00%
Diisopropanolamine 0.75%
Ethyl alcohol, 200 35.00%
Butylated hydroxyanisole 0.10%
Benzoyl peroxide (micronizea) 5.00%
Container 8 has in it only the following:
Erythromycin 3% w/w of the contents of container 7.
The explanation for packaging in wide mouth containers, and compounding at the time of dispensing in Example 4 applied to this gel.
Suspension Container 7 has în it the following, by weight:
Water, deionized or distilled 56.97%
Colloidal Bentonite 1.50%
Carboxyl vinyl polymer (acid 0.25%
form) Dioctyl sodium sulfosuccinate 1.00%
Diisvpropanolamine 0.18%
Ethyl alcohol, 200 35.00%
Butyla-ted hydroxyanisole 0.10%
Benzoyl peroxide (micronized) 5.00%
Container 8 has in it only the following:
5~
Erythromycin 2% w/w of the contents of container 7.
The explanation for use in Example 3 applies to this suspension.
In any of the Examples 3 to 6, the amount of benzoyl peroxide is reduced or increased within the range of 1% to 30% w/w of the container 7 contents, the amount of water being proportionately increased or reduced. The amount of erythromycin in container 2 should be measured to amount of one-fifth to two times w/w of the measured benzoyl peroxide.
In any of the above examples another organic acid peroxide is substituted for the benzoyl peroxide.
In any Examples 3 to 6, water is substituted for acetone and or lower alkanol such clS methanol, ethanol, etc.
In any of the above examples an erythromycin derivative ls substituted for the erythromycin.
These examples are shown as illustrations of this invention and are not to be construed as limitations thereof. Thus, for example, certain of the above in-gredients may be substituted for other ingredients which would be well known to the skilled artisan in dermato-~ ~ 7~ 3 logical preparations. Varying amounts of other ingredi-ents or alternate excipients may be added or interchanged as the artisan sees pits and falls within the meaning for this invention. The use of acetone or alcohol may also be changed depending on the wishes of the artisan.
(A) 495.0 mg of purified water was mixed and 15.0 mg of Carbopol~ 940 (a carboxyl vinyl polymer, acid form, of B.F. Goodrich Co.) were added to the water while stirring. Stirring of the mixture was contained for 45 minutes. Then 4.095 mg of sodium hydroxide in 4.91 ml of purified water was added thereto. Stirring of the mixture was continued for 10 minutes, whereupon 150.0 mg of ethyl alcohol, 0.50 mg of perfume and 0.50 mg of methyl salicylate was added. The stirred mixture was then added a mixture comprising 210.0 mg of wet pack micronized benzoyl peroxide (50% benzoyl peroxide - 50%
water), 2.0 mg of dioctyl sodium sulfosuccinate, 41.0 mg of alkyl polyglycol ether and 41.0 mg of purified water.
The mixture was stirred for 30 more minutes until a smooth and elegant gel mixture was obtained.
(B) Three samples of gel formulation from Part A weighing approximately 20.0 gm of gel were mixed with 0.3 gm erythromycin in 3.0 ml abs. EtOH to yield a total weight of 23.25 gm. Each gram of sample contained 34.40 mg of erythromycin.
On the initial day of the experiment ~ tim ~'7~S~3 three 20.0 gm gel samples of active gel were mixed with the erythromycin-EtOH soln. for three minutes with a plastic spatula and allowed to rest for approximately 15 minutes.
A 1.0 gm sample in duplicate was removed from each of the three samples and placed with first addition MeOH and second 0.lM pH 8.0 PO4 buffer for a total of 200 ml volume. This mixture was blended on a blender at low speed for three minutes at room temperature. The so-lution was allowed to lose its foam layer by waiting fiveminutes and then a 1.0 ml sample was removed and Q.S.'d to 109 ml with 0.lM PO4 pH 8.0 buffer.
This was placed in the stainless steel cylin-ders that had been previously dropped onto seeded Agar plates. The 4 ml top seed layer contained 1.5 ml stocks of S. Zutea (at 25% light transmission in a 1:40 dilution of standardizing solution) per 100 ml of the Agar.
The plates also had appropriate reference standards of ~g/ml erythromycin solution in alternate 2Q cylinders.
The standard curve plates as well as test plates were incubated at 35C for 18 hours. The cylin-ders were removed and zone sizes read and compared with standard zone sizes.
(A) 536.0 mg of purified water was mixed and 15.0 mg of Carbopol 940 (a carboxyl vinyl polymer, acid ~7~
form, of B.F. Goodrich Co.) were added to the water while stirring. Stirring of the mixture was contained for 45 minutes. Then 4.095 mg of sodium hydroxide in 4.91 ml of purified water was added thereto. Stirring of the mixture was continued for 10 minutes, whereupon 150.0 mg of ethyl alcohol, 0.50 mg of perfume and 0.50 mg of methyl salicylate was added. To the stirred mixture was then added a mixture comprising 210.0 mg of wet pack micronized benzoyl peroxide (50% benzoyl peroxide - 50%
10 water), 2.0 mg of dioctyl sodium sulfosuccinate and 41.0 mg of purified water. The mixture was stirred for 30 more minutes until a smooth and elegant gel mixture was obtained.
(B) Samples of gel formulation from Part A
weighing approximately 20.0 gm of gel were mixed with 0.5 gm erythromycin in 3.0 ml ethanol to yield a total weight of 22.87 gm and placed in containers. Each gram of sample contained about 21.85 mg of erythromycin. The resultant product was suitable for use in the treatment of acne.
Following the procedure of Example 12, the following g~l formulation was prepared:
5~a~
Benzoyl peroxide (micronized) 5.46% by weight Erythromycin 2.00% by weight Ethyl alcohol 44.10% by weight - Polyoxyethylene lauryl ether 6.00% by weight Colloidal magnesium aluminum 2.50% by weight silicate Hydroxypropylmethylcellulose 1.00% by weight Citric acid 0.05% by weight Dioctyl sodium sulfosuccinate 0.02% by weight Water Q.S.
The resultant product had good stability and was effective for use in the treatment of acne.
As mentioned above, the simplest topical prepa-ration is a mixture of powdered benzoyl peroxide anderythromycin with no diluent, but it would have to be sparingly applied to the skin. Instead of applying a premixture of them, one may first be applied to the skin and then the other would be applied with slight rubbing to mix them on the skin. A suitable, simplified prepa-ration is the following:
Benzoyl peroxide 1 - 35 w/w Calcium phosphate 63 - 98.5 w/w Erythromycin .5 - 5 w/w These ingredients are intimately mixed together and dusted on the affected skin area, from one to four times daily. It could be sold in the container 9 of Fig. 4.
If a liquid preparation is desired, the follow~
ing is a simplified compositiGn which may be made and applied to the skin from one to four times daily as -~ ~1'7~
though it were an ordinary face lotion. It could be sold in one of the bottles of Fig. 1 with or without the carton 5.
EXA~lPLE 2 Ethanol Q.S. - 100 w~w Erythromycin 0.5 - 5 w/w Benzoyl peroxide1 - 30 w/w Other examples which are representative of the invention are the following:
Lotion In a first container 7 are placed the following ingredients, by weight:
100 %
Ethoxylated cetyl-stearyl alcohol 7.00%
Cetyl alcohol 0.75%
Isopropyl myristate 5.00%
Butylated hydroxyanisole 0.10%
Polyoxyl 40 stearate0.25%
Water, deionized or distilled 68.80~
Propylene glycol 3.00%
Benzoyl peroxide 5.00~
Acetone 10.00%
Dioctyl sodium sulfosuccinate 0.10%
In a second container 8 is placed the following ingredient by itself, the container being large enough to accommodate a quantity of a solvent, preferably, ethanol or acetone, in the ration of 3 cc./20 grams of the compo-sition in container 7.
Erythromycin 2% w/w of the contents of container 7.
Both containers are put in a single marketable package such as 5 with the instructions that the contents of container 8 is added to container 7 and be thoroughly mixed. Alternately, to container 8 having the erythro-mycin is added 3 cc. ethanol per each 20 grams of material in container 7. The solution of erythromycin in ethanol is then added to container 7 and thoroughly mixed. This would either be done by the pharmacist or by the patient. The patient would apply the lotion to the skin as though it were an ordinary lotion from one to four times daily.
A variation of Example 3 is to further dilute container 8 with the same solvent so that some of the contents of container 7 would first be applied to the skin and then some of the contents of container 8 would be applied to the skin so that the mixture occurs on the skin. This eliminates loss due to the shelf-life or storage of the mixture.
Cream In a first container 7 are placed the following ingredients, by weight:
Ethoxylated cetyl-stearyl alcohol 15.00%
Cetyl alcohol 1.25%
Isopropyl myristate 5.00%
sutylated hydroxyanisole 0.10%
Polyoxyl 40 stearate 0.25%
Water, deionized or distilled 60.60%
Propylene glycol 3.00%
Benzoyl peroxide 5.00%
Acetone 10.00%
Dioctyl sodium sulfosuccinate 0.10%
In a second container 8 is placed the following ingredient by itself, the container being large enough to accommodate a quantity of a solvent, preferably, ethanol or acetone, in the ration of 3 cc./20 grams of the compo-sition in container 7.
Erythromycin 3% w/w of the contents of container 7.
The explanation for sale and use in Example 3 applies to this cream. As the preparation is of creme consistency the containers 7 and 8 should have wide mouths to facilitate mixing and removal of the creme.
Gel Container 7 has in it the following, by weight:
Water, deionized or distilled 54.65%
Colloidal Bentonite 2.50%
Carboxy vinyl polymer (acid 1.00%
form) Dioctyl sodium sulfosuccinate 1.00%
Diisopropanolamine 0.75%
Ethyl alcohol, 200 35.00%
Butylated hydroxyanisole 0.10%
Benzoyl peroxide (micronizea) 5.00%
Container 8 has in it only the following:
Erythromycin 3% w/w of the contents of container 7.
The explanation for packaging in wide mouth containers, and compounding at the time of dispensing in Example 4 applied to this gel.
Suspension Container 7 has în it the following, by weight:
Water, deionized or distilled 56.97%
Colloidal Bentonite 1.50%
Carboxyl vinyl polymer (acid 0.25%
form) Dioctyl sodium sulfosuccinate 1.00%
Diisvpropanolamine 0.18%
Ethyl alcohol, 200 35.00%
Butyla-ted hydroxyanisole 0.10%
Benzoyl peroxide (micronized) 5.00%
Container 8 has in it only the following:
5~
Erythromycin 2% w/w of the contents of container 7.
The explanation for use in Example 3 applies to this suspension.
In any of the Examples 3 to 6, the amount of benzoyl peroxide is reduced or increased within the range of 1% to 30% w/w of the container 7 contents, the amount of water being proportionately increased or reduced. The amount of erythromycin in container 2 should be measured to amount of one-fifth to two times w/w of the measured benzoyl peroxide.
In any of the above examples another organic acid peroxide is substituted for the benzoyl peroxide.
In any Examples 3 to 6, water is substituted for acetone and or lower alkanol such clS methanol, ethanol, etc.
In any of the above examples an erythromycin derivative ls substituted for the erythromycin.
These examples are shown as illustrations of this invention and are not to be construed as limitations thereof. Thus, for example, certain of the above in-gredients may be substituted for other ingredients which would be well known to the skilled artisan in dermato-~ ~ 7~ 3 logical preparations. Varying amounts of other ingredi-ents or alternate excipients may be added or interchanged as the artisan sees pits and falls within the meaning for this invention. The use of acetone or alcohol may also be changed depending on the wishes of the artisan.
(A) 495.0 mg of purified water was mixed and 15.0 mg of Carbopol~ 940 (a carboxyl vinyl polymer, acid form, of B.F. Goodrich Co.) were added to the water while stirring. Stirring of the mixture was contained for 45 minutes. Then 4.095 mg of sodium hydroxide in 4.91 ml of purified water was added thereto. Stirring of the mixture was continued for 10 minutes, whereupon 150.0 mg of ethyl alcohol, 0.50 mg of perfume and 0.50 mg of methyl salicylate was added. The stirred mixture was then added a mixture comprising 210.0 mg of wet pack micronized benzoyl peroxide (50% benzoyl peroxide - 50%
water), 2.0 mg of dioctyl sodium sulfosuccinate, 41.0 mg of alkyl polyglycol ether and 41.0 mg of purified water.
The mixture was stirred for 30 more minutes until a smooth and elegant gel mixture was obtained.
(B) Three samples of gel formulation from Part A weighing approximately 20.0 gm of gel were mixed with 0.3 gm erythromycin in 3.0 ml abs. EtOH to yield a total weight of 23.25 gm. Each gram of sample contained 34.40 mg of erythromycin.
On the initial day of the experiment ~ tim ~'7~S~3 three 20.0 gm gel samples of active gel were mixed with the erythromycin-EtOH soln. for three minutes with a plastic spatula and allowed to rest for approximately 15 minutes.
A 1.0 gm sample in duplicate was removed from each of the three samples and placed with first addition MeOH and second 0.lM pH 8.0 PO4 buffer for a total of 200 ml volume. This mixture was blended on a blender at low speed for three minutes at room temperature. The so-lution was allowed to lose its foam layer by waiting fiveminutes and then a 1.0 ml sample was removed and Q.S.'d to 109 ml with 0.lM PO4 pH 8.0 buffer.
This was placed in the stainless steel cylin-ders that had been previously dropped onto seeded Agar plates. The 4 ml top seed layer contained 1.5 ml stocks of S. Zutea (at 25% light transmission in a 1:40 dilution of standardizing solution) per 100 ml of the Agar.
The plates also had appropriate reference standards of ~g/ml erythromycin solution in alternate 2Q cylinders.
The standard curve plates as well as test plates were incubated at 35C for 18 hours. The cylin-ders were removed and zone sizes read and compared with standard zone sizes.
(A) 536.0 mg of purified water was mixed and 15.0 mg of Carbopol 940 (a carboxyl vinyl polymer, acid ~7~
form, of B.F. Goodrich Co.) were added to the water while stirring. Stirring of the mixture was contained for 45 minutes. Then 4.095 mg of sodium hydroxide in 4.91 ml of purified water was added thereto. Stirring of the mixture was continued for 10 minutes, whereupon 150.0 mg of ethyl alcohol, 0.50 mg of perfume and 0.50 mg of methyl salicylate was added. To the stirred mixture was then added a mixture comprising 210.0 mg of wet pack micronized benzoyl peroxide (50% benzoyl peroxide - 50%
10 water), 2.0 mg of dioctyl sodium sulfosuccinate and 41.0 mg of purified water. The mixture was stirred for 30 more minutes until a smooth and elegant gel mixture was obtained.
(B) Samples of gel formulation from Part A
weighing approximately 20.0 gm of gel were mixed with 0.5 gm erythromycin in 3.0 ml ethanol to yield a total weight of 22.87 gm and placed in containers. Each gram of sample contained about 21.85 mg of erythromycin. The resultant product was suitable for use in the treatment of acne.
Following the procedure of Example 12, the following g~l formulation was prepared:
5~a~
Benzoyl peroxide (micronized) 5.46% by weight Erythromycin 2.00% by weight Ethyl alcohol 44.10% by weight - Polyoxyethylene lauryl ether 6.00% by weight Colloidal magnesium aluminum 2.50% by weight silicate Hydroxypropylmethylcellulose 1.00% by weight Citric acid 0.05% by weight Dioctyl sodium sulfosuccinate 0.02% by weight Water Q.S.
The resultant product had good stability and was effective for use in the treatment of acne.
Claims (10)
1. A composition for the topical treatment of acne which comprises as active ingredients a micronized peroxide of an organic acid and an erythromycin compound selected from the group consisting of erythromycin and its stearate and glucoheptonate derivatives in an amount of from about 0.5% to about 5% by weight and in which said peroxide is from about one-half to about thirty times, the weight of said erythromycin compound.
2. The composition of Claim 1, wherein said peroxide is selected from a group of benzoyl peroxide and lauroyl peroxide.
3. The composition according to Claim 2 including a pharmaceutically acceptable carrier.
4. The composition of Claim 3 which is a gel composition including dioctyl sodium sulfosuccinate as a stabilizing agent and surfactant.
5. The composition of Claims 1 or 3 in which said peroxide is from about 1.0% to about 30% of the weight of the composition and said erythromycin compound is from about 0.5% to about 5% of the weight of the composition.
6. The composition of Claims 1 or 3 in which said peroxide is micronized benzoyl peroxide.
7. The composition of Claims 1 or 3 in which said erythromycin compound is erythromycin.
8. A therapeutic aqueous alcoholic gel compo-sition suitable for the treatment of acne comprising:
(a) from about 1% to about 30% by weight of micronized benzoyl peroxide having a particle size of less than 150 microns with a mean average particle size in said composition of less than 35 microns;
(b) from about 2.0% to about 5.0% by weight of an erythromycin compound;
(c) from about 0.1% to about 6.0% by weight of a dioctyl sodium sulfosuccinate;
(d) from about 1.0% to about 6.0% by weight of a further wetting agent;
(e) from about 0.5% to about 15% by weight of a gelling agent;
(f) from about 10% to about 80% of a lower alkyl alcohol; and (g) water.
(a) from about 1% to about 30% by weight of micronized benzoyl peroxide having a particle size of less than 150 microns with a mean average particle size in said composition of less than 35 microns;
(b) from about 2.0% to about 5.0% by weight of an erythromycin compound;
(c) from about 0.1% to about 6.0% by weight of a dioctyl sodium sulfosuccinate;
(d) from about 1.0% to about 6.0% by weight of a further wetting agent;
(e) from about 0.5% to about 15% by weight of a gelling agent;
(f) from about 10% to about 80% of a lower alkyl alcohol; and (g) water.
9. A therapeutic aqueous alcoholic gel compo-sition suitable for the treatment of acne comprising:
(a) from about 1% to about 30% by weight of micronized benzoyl peroxide having a particle size of less than about 150 microns with a mean average particle size in said composition of less than about 35 microns;
(b) from about 2.0% to about 5.0% by weight of an erythromycin compound;
(c) from about 0.1% to about 6.0% by weight of a dioctyl sodium sulfosuccinate; and (d) a gelling agent.
(a) from about 1% to about 30% by weight of micronized benzoyl peroxide having a particle size of less than about 150 microns with a mean average particle size in said composition of less than about 35 microns;
(b) from about 2.0% to about 5.0% by weight of an erythromycin compound;
(c) from about 0.1% to about 6.0% by weight of a dioctyl sodium sulfosuccinate; and (d) a gelling agent.
10. The composition of Claims 8 or 9, wherein said gelling agent is selected from the group consisting of colloidal magnesium aluminum silicate, hydroxypropyl-methylcellulose, microcrystalline cellulose and hydroxyl-ated vinylic polymers.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US21412480A | 1980-12-08 | 1980-12-08 | |
US214,124 | 1980-12-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1179599A true CA1179599A (en) | 1984-12-18 |
Family
ID=22797872
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000380219A Expired CA1179599A (en) | 1980-12-08 | 1981-06-19 | Pharmaceutical preparations |
Country Status (18)
Country | Link |
---|---|
JP (1) | JPS5799525A (en) |
AR (1) | AR229405A1 (en) |
AT (1) | AT381452B (en) |
AU (1) | AU557147B2 (en) |
BE (1) | BE889327A (en) |
CA (1) | CA1179599A (en) |
CH (2) | CH656307A5 (en) |
DE (1) | DE3124698A1 (en) |
DK (1) | DK273981A (en) |
ES (1) | ES8303087A1 (en) |
FR (1) | FR2495471A1 (en) |
GB (2) | GB2090135A (en) |
IT (1) | IT1210608B (en) |
NL (1) | NL8102997A (en) |
NZ (1) | NZ197491A (en) |
PH (1) | PH19245A (en) |
SE (1) | SE8103925L (en) |
ZA (1) | ZA814215B (en) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3375376D1 (en) * | 1982-10-15 | 1988-02-25 | Procter & Gamble | Storage stable topical pharmaceutical composition including nitrogen-containing stabilizers |
ZA837627B (en) * | 1982-10-15 | 1984-06-27 | Procter & Gamble | Storage stable topical pharmaceutical composition containing low dielectric solvents |
FR2558372B1 (en) * | 1984-01-25 | 1987-08-07 | Oreal | DRUG COMPOSITION FOR THE TREATMENT OF ACNE |
HU193777B (en) * | 1985-06-18 | 1987-11-30 | Biogal Gyogyszergyar | Preparation against acne and process for preparing the same |
FR2604357B1 (en) * | 1986-09-30 | 1988-12-02 | Oreal | PHARMACEUTICAL AND ANTI-ACNE COSMETIC COMPOSITION |
JPS6452724A (en) * | 1987-05-19 | 1989-02-28 | Yakurigaku Chuo Kenkyusho Kk | Novel synthetic aluminum silicate preparation |
US5260292A (en) * | 1991-03-05 | 1993-11-09 | Marvin S. Towsend | Topical treatment of acne with aminopenicillins |
TW203552B (en) * | 1992-02-18 | 1993-04-11 | J Baroody Lloyd | Compositions of clindamycin and benzoyl peroxide for acne treatment |
IL105217A0 (en) * | 1992-04-09 | 1993-07-08 | Allergan Inc | Method and composition for treating acne |
US5470884A (en) * | 1994-05-19 | 1995-11-28 | Procter & Gamble | Anti-acne compositions |
WO1999002133A2 (en) * | 1997-07-08 | 1999-01-21 | Dsm N.V. | Topical application of a combination of benzoyl peroxide and a second active ingredient |
DE19917548A1 (en) * | 1999-04-19 | 2000-10-26 | August Wolff Gmbh & Co Arzneim | Stable topical pharmaceutical composition for treating skin diseases, especially acne, contains erythromycin higher fatty acid salt in liquid or viscous carrier |
AR028666A1 (en) * | 2000-06-02 | 2003-05-21 | Dermik Internat Holding Inc De | COMPOSITION FOR THE TREATMENT OF ACNE |
US7060732B2 (en) * | 2000-12-12 | 2006-06-13 | Imaginative Research Associates, Inc. | Antibiotic/benzoyl peroxide dispenser |
US6495158B1 (en) | 2001-01-19 | 2002-12-17 | Lec Tec Corporation | Acne patch |
US7820186B2 (en) | 2001-12-21 | 2010-10-26 | Galderma Research & Development | Gel composition for once-daily treatment of common acne comprising a combination of benzoyl peroxide and adapalene and/or adapalene salt |
GB0301577D0 (en) * | 2003-01-23 | 2003-02-26 | Edko Pazarlama Tanitim Ltd Sti | Topical pharmaceutical and/or cosmetic dispense systems |
SI1856237T1 (en) * | 2005-03-10 | 2020-12-31 | Obagi Cosmeceuticals Llc | Stable organic peroxide compositions |
WO2007092312A2 (en) | 2006-02-03 | 2007-08-16 | Stiefel Laboratories, Inc. | Topical skin treating compositions |
JP5317968B2 (en) * | 2006-07-13 | 2013-10-16 | ガルデルマ・リサーチ・アンド・デヴェロップメント | A composition comprising a retinoid and benzoyl peroxide |
FR2903604B1 (en) * | 2006-07-13 | 2008-09-05 | Galderma Res & Dev S N C Snc | COMPOSITION COMPRISING A RETINOID AND BENZOYL PEROXIDE |
FR2910321B1 (en) | 2006-12-21 | 2009-07-10 | Galderma Res & Dev S N C Snc | CREAM GEL COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
FR2910320B1 (en) | 2006-12-21 | 2009-02-13 | Galderma Res & Dev S N C Snc | EMULSION COMPRISING AT LEAST ONE RETINOID AND BENZOLE PEROXIDE |
PT2299810T (en) * | 2008-06-05 | 2020-03-04 | Bausch Health Ireland Ltd | Topical pharmaceutical formulations containing a low concentration of benzoyl peroxide in suspension in water and a water-miscible organic solvent |
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 |
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 |
JP6525074B2 (en) | 2017-07-31 | 2019-06-05 | 大日本印刷株式会社 | Thermal transfer sheet, combination of printing sheet and thermal transfer sheet, and thermal transfer printing apparatus |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2368949A1 (en) * | 1976-11-01 | 1978-05-26 | Procter & Gamble | ERYTHROMYCIN ANTIMICROBIAL PRODUCT FOR THE TOPICAL TREATMENT OF ACNE DISORDERS |
FR2378523A1 (en) * | 1977-01-26 | 1978-08-25 | Grupper Charles | ACNE TREATMENT MEDICINE |
-
1981
- 1981-06-18 IT IT8167845A patent/IT1210608B/en active
- 1981-06-19 CA CA000380219A patent/CA1179599A/en not_active Expired
- 1981-06-22 DK DK273981A patent/DK273981A/en not_active Application Discontinuation
- 1981-06-22 ZA ZA814215A patent/ZA814215B/en unknown
- 1981-06-22 NZ NZ197491A patent/NZ197491A/en unknown
- 1981-06-22 BE BE0/205167A patent/BE889327A/en not_active IP Right Cessation
- 1981-06-22 AU AU72029/81A patent/AU557147B2/en not_active Expired
- 1981-06-22 NL NL8102997A patent/NL8102997A/en not_active Application Discontinuation
- 1981-06-22 FR FR8112233A patent/FR2495471A1/en not_active Withdrawn
- 1981-06-22 ES ES503797A patent/ES8303087A1/en not_active Expired
- 1981-06-23 SE SE8103925A patent/SE8103925L/en unknown
- 1981-06-23 GB GB8119333A patent/GB2090135A/en not_active Withdrawn
- 1981-06-24 DE DE19813124698 patent/DE3124698A1/en active Granted
- 1981-06-24 PH PH25809A patent/PH19245A/en unknown
- 1981-06-25 CH CH186/85A patent/CH656307A5/en not_active IP Right Cessation
- 1981-06-25 CH CH4215/81A patent/CH647147A5/en not_active IP Right Cessation
- 1981-06-26 AT AT0285581A patent/AT381452B/en not_active IP Right Cessation
- 1981-07-27 AR AR286227A patent/AR229405A1/en active
- 1981-10-27 JP JP56170865A patent/JPS5799525A/en active Pending
- 1981-12-07 GB GB8136777A patent/GB2088717B/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
NZ197491A (en) | 1985-02-28 |
ES503797A0 (en) | 1983-03-01 |
IT8167845A0 (en) | 1981-06-18 |
CH647147A5 (en) | 1985-01-15 |
AT381452B (en) | 1986-10-27 |
GB2090135A (en) | 1982-07-07 |
FR2495471A1 (en) | 1982-06-11 |
ATA285581A (en) | 1986-03-15 |
ES8303087A1 (en) | 1983-03-01 |
IT1210608B (en) | 1989-09-14 |
BE889327A (en) | 1981-10-16 |
AU7202981A (en) | 1982-06-17 |
AR229405A1 (en) | 1983-08-15 |
DE3124698A1 (en) | 1982-07-08 |
GB2088717A (en) | 1982-06-16 |
NL8102997A (en) | 1982-07-01 |
DE3124698C2 (en) | 1992-06-25 |
DK273981A (en) | 1982-09-09 |
SE8103925L (en) | 1982-06-09 |
ZA814215B (en) | 1983-02-23 |
GB2088717B (en) | 1984-12-12 |
CH656307A5 (en) | 1986-06-30 |
JPS5799525A (en) | 1982-06-21 |
PH19245A (en) | 1986-02-14 |
AU557147B2 (en) | 1986-12-11 |
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