JPS60501604A - Improved composition for psoriasis treatment - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Title of the invention: Improved composition for soft scar treatment Technical field The present invention provides a topical composition of anthralin for the treatment of soft scars containing dithranol or anthralin. 1,8.9-) Lihydroxyanthracene, also known as phosphorus, is used to treat psoriasis. It is one of the few effective drugs available for treatment.

However, this compound is highly irritating to unaffected skin, making it undesirable to Shows no dyeing properties and a tendency to be oxidized leading to product instability. Historically , this compound is used in concentrated formulations such as Lassars paste and emulsifying ointments. It has been formulated as a paste and ointment.

The use of oxalic acid to stabilize anthralin compositions is disclosed in U.S. Pat. No. 4,367.2. It is described in the specification of No. 24. However, such compositions are anhydrous and do not aggregate. It takes the form of a sticky yellow ointment.

The topical compositions described in U.S. Pat. No. 4,203,969 were previously This represents a cosmetically more elegant anthralin formulation than the formulations of .

Furthermore, the spreadable compositions described in that patent have been shown to be excessively It seems to satisfy a certain level of stability in that no decomposition is observed. .

However, a more rigorous analysis of this formulation indicates that it may become more desirable over time. This indicates that they are exposed to a transformation that is not possible. In particular, high performance liquid chromatography (HPLO) The overall pharmaceutical formulation appears to retain its stability, but Anthralin dispersed in the oak oil phase undergoes an unacceptable chemical change, reducing its effective concentration. It has been shown that not only does it reduce the degree of deterioration, but it also generates deterioration products whose effects are unknown. Ru. Although the structure of the decomposition products of anthralin has not yet been completely clarified, Recent evidence strongly suggests dimer formation [e.g. Oarow et al. , Brlt-J-Derm-, (1981) 105, 5upp1.2o, 57 reference〕.

Disclosure of invention The present invention is cosmetically acceptable and has a high concentration of active ingredients in contrast to conventional formulations. The present invention relates to improved aqueous anthralin formulations with significantly reduced chemical degradation. The formulation described is the conventional formulation of U.S. Pat. No. 4,203,969. It has some characteristics in common with things. In particular, it deals with two-phase systems of water and hydrocarbon substances. It is something to be used. Additionally, water-soluble acids such as citric acid or sodium bisulfite It has been confirmed that sexual components are desirable.

However, the formulations of the present invention contain a large proportion of hydrocarbons as the anthralin support phase. rather than using an exclusively aqueous medium, the water-to-hydrocarbon ratio is On the order of at least 5:1. Second, hydrocarbons used in prior art Rather than being semi-solid in nature, petrolatum is mostly liquid. Third , the formulation includes at least one anionic emulsifier. Despite high moisture content First, the formulation produces a high internal phase emulsion with an oil continuous phase and a water dispersed phase. do. Fourth, instead of utilizing water-soluble, oil-insoluble, antioxidants, the composition of the present invention uses the exact opposite: an oil-soluble antioxidant. Fifth, the composition of the present invention contains a difunctional sequestering agent.

BEST MODE FOR CARRYING OUT THE INVENTION Particularly, one aspect of the present invention is an anthralin cream set comprising the following ingredients: Regarding the composition: (a) (1) about 0.05% to about 5% anthrax of the composition; phosphorus (Depletion) The weight ratio of water to liquid hydrocarbon is at least about 5=1, but Components included in a water-to-liquid hydrocarbon emulsion having a continuous phase; (b) at least one anionic emulsifier in an emulsifying amount of up to about 3% by weight of the composition; (C) at least one oil-soluble antioxidant in an amount of about 0.02 to about 2N in the composition; , (d) about 0.5% to about 1% by weight of the composition; (at least one difunctional metal ion in an amount of about 0.02 to about 2 by weight of the composition) Sequestrant.

In addition to the above ingredients, the compositions of the invention may contain one or more polyols, such as glycerol. role, propylene glycol, sorbitol, etc.; one or more hydroxy rests Fragrance acid or alkyl (C1-04) hydroxybenzoate preservatives, e.g. Chilic acid, methylparaben, ethylparaben and propylparaben; and fatty alkaline up to about 6 parts of cole and/or non-ionic emulsifiers, preferably both. Emulsifiers may advantageously be included.

Although it is recognized in the prior art that it is desirable to incorporate antioxidants, However, its role was directed towards reducing the oxidation of the oleophobic components of the emulsifier. It seems that The requirement that antioxidants be water-soluble and oil-insoluble is Its component in the discontinuous hydrocarbon (oil) phase where anthralin is mainly distributed. was excluded from exhibiting its characteristics. Not to be bound by any particular theory. Although it is not desired that large proportions of hydrocarbon materials in prior art compositions Degradation was reduced by providing a high dilution factor for anthralin (but However, it seems that it was not removed. This is due to the semi-solid nature of the hydrocarbon and the valve pressure Simple principles of chemical kinetics dictate whether the reaction is mediated by oxygen or otherwise. It is thought that the reaction involved in the decomposition of the active compound is reduced. .

However, this results in a relatively high content of carbohydrates remaining on the skin upon evaporation of the aqueous phase. This naturally limits the effective concentration of active ingredients and also creates oily, difficult-to-spread compositions. I got it.

The present invention discloses, in part, that the presence of antioxidants in such anthralin emulsions While important for the stability of the formulation, it prevents the degradation of anthralin itself. Based on the discovery that it must be soluble in the hydrocarbon phase if it is to be It is something. Unexpectedly, this finding also shows that the proportion of hydrocarbon materials (relative to the aqueous phase) This allows for a considerable reduction and the use of liquid hydrocarbon materials.

Despite this considerable reduction in hydrocarbon content, the hydrocarbon component remains in the emulsion. constitutes the continuous phase of This hydrocarbon continuous phase contains one or more anionic emulsifiers, preferably Preferably fatty acid metal soap emulsifiers such as aluminum stearate, calcium or or phosphonic acid ester of magnesium and/or mono- or di-glyceride This can be achieved by using salt, etc. The amount of emulsifier present is at least This is the amount necessary to give a certain emulsifying effect, and the amount is generally about 3% at most. , often less.

The use of such emulsifiers in high internal phase water-in-oil emulsions of cosmetic formulations It is described in US Pat. No. 4,104,403. However, anime On-type emulsifiers have a trace amount of metal that catalyzes the decomposition of anthralin or It does not appear to be useful for anthralin formulations as it initiates degradation. do not have. However, incorporating oil-soluble antioxidants into the formulation and even less (both By providing a kind of bifunctional sequestering agent, the overall composition and active ingredients Both exhibit improved stability as well as a sensually pleasing creaminess. Having cosmetic consistency, easily spreading and absorbing it. It is possible to formulate a high internal phase oil emulsion formulation of anthralin that can be.

Suitable oil-soluble antioxidants include ascorbyl palmitate, alpha tocov erol, butylated hydroxyctoluene, hydroxyquinone, and butylated hydride Examples include substances such as roxyanisole. Its content is the antioxidant of the substance used. It varies depending on the fastening strength, but generally a range of about 0.02 to about 2 weight coefficient is satisfactory. It is something. Using several antioxidants can reduce the content of each. It is not only possible, but often desirable. For example, Habo et al. amounts of tocopherol, BHT and ascorbyl palmitate, e.g. tocopherol, 0.05% BHT and 0.05% ascorbyl palmite Satisfactory stabilization can be achieved by utilizing a ternary oil-soluble antioxidant mixture. can be achieved.

Preferably, the formulations of the invention contain higher alkanols, such as octyldecanol. Especially 2-octyldecanol and nonionic surfactants such as polyglycerol. oleate, glycerol oleate, propylene glycol cocoaate, polymer lyoxyethylene and polyoxypropylene ethers and esters, e.g. Good to include other emulsifiers such as polyoxypropylene stearyl ether . The amount of such additional emulsifier that may be present depends on the particular reagent or combination. Depends on the effectiveness of the adjustment. However, the reduction in hydrocarbon substances achieved and By using metal soaps, the total amount of nonionic emulsifier can be reduced considerably, approximately There is almost no need to exceed the 5 weight limit. In fact, in a preferred embodiment, the The amount is less than 5%, such as from about 1 to about 4.5%.

The hydrocarbon material typically includes one or more light mineral oils. Semi-solid hydrocarbon However, these liquid The proportion of hydrocarbons is so large that the total hydrocarbon component loses its liquid character. It shouldn't be. The hydrocarbon component acts as a solubilizer for anthralin and its The liquid nature allows this active ingredient to be easily spread and penetrate the affected area. Ru. Typically, a hydrocarbon that is solid at standard conditions is dissolved in a hydrocarbon that is liquid at standard conditions. The total content of liquid hydrocarbons in the composition is on the order of 10-15% by weight. while the water content is at least about 75% by weight, preferably about 80%.

Therefore, a typical formulation is 10.6 part 2.3:2.3:6.0 petrol. Contains a mixture of latam, paraffin and light mineral oil and 81% water, with a ratio of water to hydrocarbons. The ratio is approximately 7.6:1.

In addition to the above ingredients, at least one acid in an amount of about 5 to about 1 part by weight of the composition. About (1+02 to about 2 % by weight of at least one difunctional sequestering agent; Both layers are satisfied.

Acidic substances typically include topically acceptable weak organic and inorganic acids and acid salts, e.g. These include malic acid, citric acid, salicylic acid and sodium metabisulfite.

Two or more such substances may be used in an amount of +1.5% to 1% of the composition. can.

The difunctional sequestering agent component is disodium ethylenediaminetetraacetate. and related chelating agents, thiourea, thioacetic acid, cysteine, tyroqunes, Substances such as cotinic acid and sarcosine may be mentioned.

Again, more than one such sequestering agent may be used, and the total amount ranges from about (1+02% to about 2% by weight).

Both functional ranges must be satisfied, but only by the same compound. can be satisfied.

In other words, a certain kind of substance falls into both categories of these components and fulfills two functions. vinegar. For example, malic acid, salicylic acid, and citric acid are acidic substances and also metal It can also serve as a sequestering agent (salicylic acid is also a hydroxylated benzoic acid derivative). (can also function as a conductor).

On the other hand, IJium, which is an acidic substance, is not a sequestering agent. Therefore, there must be an additional ingredient that satisfies this second range of sensuality. . There can be several substances in each range.

The composition of the present invention forms a hydrocarbon phase and an aqueous phase, and various components are added to these phases. It is prepared by The selection of the phase to which a certain component is added depends on the Preferential solubility, i.e. whether it is primarily hydrophobic or hydrophilic This will be carried out accordingly. Generation of uniform individual phases and uniformization of two combined phases Heat can easily be used to generate emulsions. excessive Substances that are sensitive to heat, such as tocopherol or tocopherol acetate can be added subsequently.

A typical formulation utilizing the principles of the present invention is as follows: 46 g of light mineral oil in 120 g of light mineral oil. Add petrolatum and 46 g paraffin. 14g in this hydrocarbon mixture of aluminum stearate as an emulsifier, 30 g of polyglyceryl oleate and 60 g of 2-octyldodecanol. Then 4.8g of As anthralin and one oil-soluble antioxidant (L, 4g ascorbyl pal Add mitate. Finally, 8g of salicylic acid is added and the whole is heated to 90℃. Mix with This hydrocarbon phase weighs about 330g and is about 16.5g of the final composition. It constitutes 5chi.

Separately, heat 1,646 g of deionized water to about 90°C, and add 18 g of citric acid to it. dissolve in it. To this was added 1.2 g of disodium ethylenediaminetetraacetate and 5 g of a 1.5:1 mixture of methylparaben and ethylparaben. Approximately 1. This aqueous mixture weighs 670 g and constitutes approximately 83.5% of the final composition. Once it becomes homogeneous, it is combined with the above hydrocarbon components in a homogenizer. - to do. After this emulsion is well mixed, it is cooled to 50 °C and 0 ．． Add 6 g of tocopherol acetate. This mixture is further mixed, It appears that the formulation maintains its stability and that anthralin does not undergo undue degradation. For example, the degree of deterioration is less than 10 inches by HPLC. 0.2% homogeneous Obtain 2,000 g of anthralin cream.

Example 2 Concoct part 2 anthralin formulations according to the method of Example 1 using the following ingredients: 1 Oil phase: Mineral oil 6.0% Paraffin 2.3% Petrolatum 2.3% Aluminum stearate 0.7% Glyceryl oleate 1.5 t Anthralin, Section 22 Ascorbyl palmitate, 02% Octyldodecanol 3.0% Salicylic acid 0.4% Water phase: Deionized water 68.82% Citric acid 0.9 N az l D T A O-06% sorbitol (70chi) 13.5 Methylparaben U, 15% Propylparaben 0.10 Alpha tocophero-#0, 034180g light mineral oil, 1,556g deionized On water, and lug 1mulsynt 1055 (polyglycerol-4- oleate and polyethylene glycol-8 propylene glycol cocoate) A formulation is prepared according to the method of Example 1 except that .

Example 4 A total of 1 g of ascorbyl palmitate and 1.4 g of tocopherol was added to the Ig. According to Example 10 proportions and method except added with butylated hydroxytoluene A 0.4% anthralin formulation is prepared. The amount of anthralin to be added is 8 ．． 8g and water to 1,629g. Finally, prior to emulsification, the aqueous phase 2-09 g of sodium bisulfite and 12 g of disodium ethylenediaminetetraacetate. Add lium.

I15 A formulation of the following composition is prepared according to the method of Example 1: Mineral oil 6.0 6. （】　 6.0 6.0 Paraffin 2.3 2.3 2.3 2.3 Petrolatum 2 ．． 3 2.3 2.3 2.3 Aluminum stearate f), 7 0.7 L7 11.7 glyceryl oleate) 1.5 1.5 1.5 1.5 ant Larin 0.12 0.22 0.44 1.1 Ascorbyl palmitate ( Lo5 0.05 (Lo5 0.05 octyldodecanol 3.0 3.0 :Lo 3.0 salicylic acid 0.4 (L4 0.4 0.4 butylated hydro Xytoluene 0-05 0.05 0.05 0.05 Water phase: Deionized water 8L66 81.56 8L34 80.68 Citric acid L9 0 ．． 9 0.9 0.9N az E D T A 0-60 0-60 0- 60 0-60 Sodium Bisulfite 0.10 0.10 0.10 0-N.

Preservative: Probylparaben (Li2 0-15 0.15 0.15 Methylparaben 0.1 OLIOO, 100, 10 international search report

Claims (1)

[Claims] 1. Anthralin has improved stability characterized by comprising the following components: Topical anthralin cream composition shown: (a) (+) anthralin in an amount of about 0.05 to about 5% by weight of the composition; (it) having an oil continuous phase in which the weight ratio of water to liquid hydrocarbon is at least about 5:1; components contained in a water-to-liquid hydrocarbon emulsion; (b) at least one anionic emulsifier in an emulsifying amount of up to about 3 weight percent of the composition; , (Q) at least one oil-soluble antioxidant in an amount of about 0.02 to about 2% by weight of the composition; ,as well as (d) one or more water-soluble ingredients that satisfy at least one of the following sensual demands; Ingredients that satisfy both of the sensory ranges. (1) an acidic material in an amount of about 0.5 to about 1 part by weight of the composition; (If) at least one difunctional metal in an amount of about 0.02 to about 2% by weight of the composition; Ion sequestrant. 2. Oil-soluble antioxidant ingredients include alpha-tocopherol and alpha-tocopherol acetate, ascorbyl palmitate, hydroquinone, butylated hydroxy One or more selected from the group consisting of citoluene and butylated hydroxyanisole A topical composition according to claim 1, which is a composition according to claim 1. 3.Water-soluble components are ethylenediaminetetraacetic acid, IJium, thiourea, thio Metals that are one or more of acetic acid, cysteine, tyrosine, nicotinic acid, and sarcosine A topical composition according to claim 1, comprising an ion sequestering agent. 4. Water-soluble ingredients include citric acid, malic acid, salicylic acid, and sodium metabisulfite 2. The topical composition of claim 1, comprising an acidic substance that is one or more of the following. 5. The water-soluble component is disodium ethylenediaminetetraacetate as a metal ion sealant. Contains citric acid, salicylic acid and sodium metabioxide as acidic substances. A topical composition according to claim 1, comprising: 6. The topical composition of claim 1, wherein the anionic emulsifier is a metal soap. . 7. Topical use according to claim 6, wherein the metal salt is aluminum stearate. Composition. 8. Fatty alcohols, glycerol esters, polyoxyalkylene esters and polyoxyalkylene ethers. 7. The topical composition of claim 6, wherein is present as a nonionic emulsifier. 9. The hydrocarbon is a mixture of light mineral oil, paraffin, and petrolatum, and is a non-ionic The agent according to claim 8, wherein the emulsifier is a polyoxyalkylene ester. topical composition, 10. (1) the water to hydrocarbon ratio is at least 7:1, and the hydrocarbon is a light mineral; A mixture of oil, paraffin and petrolatum, containing (It) an oil-soluble antioxidant component. Minutes are alpha tocopherol, alpha tocopherol acetate, ascorbyl Lupalmitate, Hydroquinone, Butylated Hydroxytoluene and Butylated Hydroxytoluene one or more selected from the group consisting of droxyyanine, (Iff) Water-soluble components include disodium ethylenediaminetetraacetate, thiourea, thioacetic acid, Full fat ion sequestration that is one or more of Stine, Tyrosine, Nicotinic acid and Hisarcosine an acidic agent, and one or more of citric acid, salicylic acid, and sodium metabisulfite. and (1v) the anionic thread emulsifier is a metal soap, and the composition also contains a fat. Alcohols, glycerol fatty acid esters, polyoxyalkylene fatty acid esters selected from the group consisting of esters and polyoxyalkylene fatty alcohol ethers; Claim 1 comprising at least one nonionic emulsifier as disclosed in Claim 1. topical compositions. 11. (1) About 6 to about 10% light mineral oil, about 2% to about 3% petrolatum, about 2 % to about 3% paraffin, and about 75% to about 85% water. from about 0.1 to about 1 part of anthralin in the emulsion, and further comprising about 0.1% to about 1% anthralin. Fatty acid metal soap with an emulsifying amount of up to 0.1 to about 0.2% in total (lit) 1 or more oil-soluble antioxidant, (1v) about 0.5 to about 1 t dibasic ethylenediaminetetraacetic acid Thorium, (■) total amount of about 0.5 to about 1.5 t citric acid, salicylic acid and meth One, two or three selected from sodium bisulfite (vl) about 1 to about 5% of higher alkanols, and about 1% to about 3% (vtl) of glyc-74-ol or polyglycyl. A composition according to claim 1, comprising a fatty acid monoester of lycerol. . 12. (1) Approximately 6% light mineral oil, approximately 2.2% to approximately 2.4% petrolatum, approximately 2 ．． Water-to-hydrocarbon emulsion consisting of 2% to about 2.4% paraffin and about 80% water About 0.1 to about 1 part of anthralin in John, (11) about 0.7 part of distearin. Aluminum phosphate, (lit) about 0.07% tocof as an oil-soluble antioxidant erol, approx. (). () 5% butylated hydroxytoluene and about 0.05% ascorbyl palmi tate, (iv) about 0.6% disodium noethylenediaminetetraacetate, (V) about 0.9 citric acid, (vl) approx. 0.4% salicylic acid, (vit) approx. 0.1% of sodium metabisulfite, (v::Q about 3 liters of octyldodecanol, and ( IX) Claim No. 1 comprising about 1.5% polyglyceryl-4 oleate. Composition according to item 1. 13. The composition of claim 12, characterized in that about 0.1% anthralin. 14. The composition of claim 12, characterized in that the composition contains about 0.2 liters of anthralin. 15. The composition of claim 12, characterized in that about 0.4% anthralin. 16. The composition of claim 12, characterized in that about 1% anthralin.