Topical preparation containing rapamycin

Abstract

To provide a topical preparation containing rapamycin that has high stability and is effective in treating skin diseases.SOLUTION: A topical preparation comprising: (a) rapamycin; (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin; and (c) propylene glycol and / or polyethylene glycol, the topical preparation further comprising an antioxidant, and further comprising an oil-soluble solvent solution of the antioxidant.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an external preparation containing rapamycin. The present invention relates to an external preparation that is highly stable and effective in treating skin diseases. [Background technology]

[0002] Rapamycin (generic name: sirolimus) is a macrolide produced by microorganisms. Rapamycin has been used as a therapeutic agent for various diseases due to its immunosuppressive effect. For example, it has been used as an oral drug for the treatment of lymphangioleiomyomatosis. In recent years, it has also been used as an external agent to treat skin lesions associated with tuberous sclerosis complex. are.

[0003] On the other hand, although rapamycin is soluble in some organic solvents such as ethanol, It has the property of being almost insoluble or hardly soluble in many solvents, including water. are.

[0004] When rapamycin is used as an external preparation, it is dissolved in a solvent and dispersed in an ointment base or the like. As mentioned above, rapamycin is easily dissolved in water except for some solvents such as ethanol. It is practically insoluble in many other solvents, but alcohol is a skin irritant. Therefore, the solvent must be selected carefully.

[0005] Rapamycin is also susceptible to oxidative degradation and to decomposition in the presence of water. Therefore, pharmaceutical preparations containing rapamycin and antioxidants have been developed, but the lipid-soluble It was difficult to disperse the antioxidant in an alcohol-free solution of rapamycin.

[0006] Patent Document 1 describes a compound containing rapamycin and polyethylene glycol but not alcohol, A composition for treating skin diseases is disclosed. Patent Document 2 also discloses a compound such as rapamycin. An anhydrous composition for treating skin disorders is disclosed, comprising an mTOR inhibitor, an antioxidant, and a gelling agent. In this document, propylene glycol and the like are used as the solvent. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2018 / 031789 publication [Patent Document 2] WO2018 / 129364 publication Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention has been made in view of the above circumstances, and provides a method for producing a liquid medicine which does not contain alcohol and has high stability. The object of the present invention is to provide an external preparation containing a guaranteed effective amount of rapamycin. [Means for solving the problem]

[0009] The inventors have developed an effective amount of rapamycin that does not contain alcohol and ensures the stability of rapamycin. Various solvent combinations capable of containing rapamycin were investigated, and specific solvents were selected. It was discovered that the above problems could be solved by combining the above two methods, and the present invention was completed. This has led to the

[0010] That is, the present invention provides: (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from the group consisting of (c) propylene glycol and / or polyethylene glycol, .

[0011] The present invention also provides (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from (c) propylene glycol and / or polyethylene glycol, and (d) an antioxidant.

[0012] Furthermore, the present invention provides (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from (c) propylene glycol and / or polyethylene glycol, and (d1) An external preparation comprising a lipophilic solvent solution of an antioxidant.

[0013] Furthermore, the present invention provides (i)(d1) dissolving an antioxidant in a lipophilic solvent; and (ii) Mix the solution obtained in (i) with a solution containing the following (a), (b), and (c): The method for producing an external preparation includes the steps of: (a) rapamycin (b) Composed of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from the group (c) propylene glycol and / or polyethylene glycol.

[0014] The present invention provides (i) a mixture obtained by dissolving an antioxidant in a lipophilic solvent; (ii) A topical preparation obtained by mixing a solution containing the following (a), (b), and (c): be. (a) rapamycin (b) Composed of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from the group (c) propylene glycol and / or polyethylene glycol. [Effects of the Invention]

[0015] According to the present invention, rapamycin is present stably without precipitation during storage of the formulation. In addition, it is also possible to provide a highly stable preparation, particularly an external preparation, in which decomposition during the preparation is suppressed. It becomes possible. [Brief explanation of the drawings]

[0016] [Figure 1A] FIG. 1 is a graph showing the stability (residual rate) of sirolimus in an aqueous ethanol solution of sirolimus and various sirolimus-BHT blend solutions at 40° C. [Figure 1B] FIG. 1 is a graph showing the stability (residual rate) of sirolimus in an aqueous ethanol solution of sirolimus and various sirolimus-BHT blend solutions at 50° C. [Figure 2] FIG. 1 is a graph showing the stability (residual rate) of sirolimus at 40° C. or 50° C. when BHT is added at concentrations of 1% to 10%. DETAILED DESCRIPTION OF THE INVENTION

[0017] Topical preparations containing rapamycin The topical preparation of the present invention comprises: (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from the group consisting of (c) propylene glycol and / or polyethylene glycol.

[0018] (a) Rapamycin, known generically as sirolimus, is commercially available. Herein, rapamycin and sirolimus are used synonymously.

[0019] Instead of rapamycin, everolimus or Temsirolimus in place of or in combination with rapamycin It is also possible.

[0020] The amount of rapamycin used can be 0.05 to 1% by weight based on the total weight of the formulation. The content can be preferably set to 0.1 to 0.8%, and particularly preferably to 0.1 to 0.5%.

[0021] The solvent (b) may be ethylene glycol salicylate, diethyl sebacate, or triethyl methacrylate. At least one selected from the group consisting of acetin and methyl acetone is used, and they are mixed in any ratio. It may also be used as such.

[0022] The solvent (c) may be propylene glycol or polyethylene glycol, or Mixtures of propylene glycol and polyethylene glycol (macroglycol) are used. A mixture of these compounds (e.g., ethanol 400) is preferred, and they may be mixed and used in any ratio.

[0023] The mixing ratio of the solvent (b) and the solvent (c) is not particularly limited, but for example, the weight ratio is ( A ratio of (b):(c)=2:1 to 2:6 is exemplified, and a ratio of (b):(c)=2:5 is particularly preferred. Recommended.

[0024] On the other hand, the mixing ratio of (a) rapamycin to solvent (c) is as follows: rapamycin is mixed with solvent (b ) and solvent (c), but is not limited thereto. For example, A ratio of (a):(c)=1:20 to 1:70 is exemplified, and preferably, a ratio of (a):(c)=1:60. The weight ratio including the solvent (b) is (a):(b):(c) = 1:20 to 80:20 70, and preferably (a):(b):(c)=1:25:60.

[0025] The topical preparation of the present invention may further contain an antioxidant (d). Adding an anti-inflammatory agent can prevent the decomposition of rapamycin and ensure long-term storage stability. Specific antioxidants include dibutylhydroxytoluene (BHT), tocopherol, Examples include methyl ether and ascorbic acid, and preferably dibutylhydroxytoluene ( BHT) is recommended.

[0026] The amount of antioxidant used is, for example, 1 to 10% by weight based on the total weight of the preparation, and preferably The recommended range is 1 to 5%, and particularly preferably 1 to 2%.

[0027] The antioxidant can be added directly to the formulation containing (a), (b), and (c). However, a solution (d1) in which an antioxidant is dissolved in a lipophilic solvent is added to the above (a), (b), and ( It is preferably added to a formulation containing c).

[0028] Such lipophilic solvents include liquid paraffin and a mixture of liquid paraffin and polyethylene. Examples of suitable solvents include gelled hydrocarbons, and liquid paraffin is preferred.

[0029] The amount of lipophilic solvent used relative to the antioxidant is antioxidant:lipophilic solvent = 1:10 or more by weight. An example is 3:10, and 3:10 is preferably recommended.

[0030] A surfactant may be further added to the solution (d1) in which an antioxidant is dissolved in a lipophilic solvent. A preferred surfactant is one having an HLB of 4 to 7. , and preferably one or more surfactants of 5 to 6 are exemplified.

[0031] The addition of such surfactants further stabilizes the resulting formulation.

[0032] Examples of surfactants include polyoxyethylene cetyl ether and monostearate. At least one selected from the group consisting of glycerin and polyoxyethylene hydrogenated castor oil species, preferably at least two species.

[0033] Specific examples of surfactants include: - POE cetyl ether: glycerin monostearate = 1:4 (weight ratio), - Glycerin monostearate: POE hydrogenated castor oil = 4:1 (weight ratio) is exemplified.

[0034] The topical preparation of the present invention may be prepared in a form of pharmaceutical administration as long as the effect of the present invention is not impaired. The composition may also contain other excipients or additives that are useful in the formulation. For example, these may include: Gelling agents, thickeners, pH adjusters, inorganic salts, etc. may also be added.

[0035] Gelling agents include water-soluble cellulose-derived polymers, such as hydroxymethylcellulose. cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxypropyl propyl methyl cellulose, carboxymethyl cellulose, methyl hydroxyethyl cellulose Examples of thickeners include hydroxypropyl cellulose, methylcellulose, and carrageenan. Examples of pH adjusters include hydrochloric acid, sulfuric acid, phosphoric acid, and the like. Acidic additives such as carboxylic acid, citric acid, tartaric acid, malic acid, mesylic acid, tosylic acid, and besylic acid, Examples of the buffer include buffers containing alkali metal salts, alkaline earth metal salts, and ammonium salts. Inorganic salts include calcium chloride, sodium chloride, calcium oxide, magnesium sulfate, Examples include Mu.

[0036] Furthermore, the topical preparation of the present invention may contain any of the following compounds as long as they do not interfere with the effect of rapamycin, the main active ingredient: Other medicinal ingredients may be added, such as tacrolimus. , steroids, etc.

[0037] Manufacturing method of topical preparation The topical preparation of the present invention can be produced as follows.

[0038] for example, (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from (c) Propylene glycol and / or polyethylene glycol are mixed.

[0039] When antioxidants are used, (i)(d1) dissolving an antioxidant in a lipophilic solvent; and (ii) The solution obtained in (i) and the following (a), (b), and (c) (a) rapamycin, (b) Composed of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from the group (c) Mixing a solution containing propylene glycol and / or polyethylene glycol do.

[0040] In order to obtain a more stable topical preparation, for example, (i) (d2) An antioxidant is dissolved in a lipophilic solvent to prepare a mixed solution, and then a solution having an HLB value of 5 to 100% is prepared. adding one or more surfactants according to claim 7 to the mixture; and (ii) The solution obtained in (i) and the following (a) rapamycin, (b) Composed of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from the group (c) a solution containing propylene glycol and / or polyethylene glycol (hereinafter (sometimes referred to as "rapamycin solution in a hydrophilic solvent"). You may do so.

[0041] In particular, in the step (d2) of the above (i), a mixture of an antioxidant dissolved in a lipophilic solvent is By adding one or more surfactants having an HLB of 5 to 7, the above-mentioned step (ii) The mixture of antioxidant and lipophilic solvent is more compatible with the hydrophilic solvent solution of rapamycin. It is possible to do this.

[0042] The topical preparation of the present invention can be administered in an optimal form, for example, in the form of a cream, paste, jelly, gel, or the like. For making into emulsion, emulsion, liquid, etc., such as ointments, liniments, lotions, etc. In addition to the other excipients or additives mentioned above, sodium alginate; gelatin, corn Starch, tragacanth gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose Dimethyl cellulose, xanthan gum, dextrin, carboxymethyl starch, poly Vinyl alcohol, sodium polyacrylate, methoxyethylene-maleic anhydride copolymer Polymers such as copolymers, polyvinyl ether, polyvinylpyrrolidone; beeswax, olive Oil, cocoa oil, sesame oil, soybean oil, camellia oil, peanut oil, beef fat, pork fat, lanolin; white Vaseline types such as colored petrolatum and yellow petrolatum; paraffin, liquid paraffin and polyethylene A mixture of hydroxypropyl esters (gelling hydrocarbons); stearic acid; lauric acid esters, myristate esters ester, octanoic acid ester; cetyl alcohol, stearyl alcohol; polyethylene Recall; dimethyl sulfoxide, dodecylpyrrolidone; urea; Azone; olive oil; Add one or more selected from kaolin, bentonite, zinc oxide, titanium oxide, etc. as needed. It is possible.

[0043] How to use topical medications The topical preparation containing rapamycin of the present invention has an immunosuppressive effect, and therefore can be used for, for example, skin It can be used to treat skin diseases.

[0044] Examples of specific skin diseases include dermatitis, contact dermatitis, psoriasis, atopic dermatitis, and oily skin. Dermatitis, nummular eczema, vitiligo, rosacea, keloid, autosensitization dermatitis, stasis dermatitis, Asteatotic eczema, tuberous sclerosis skin tumors, seborrheic keratosis, Recklinghausen's disease skin Skin tumors and the like.

[0045] The dosage of the pharmaceutical using the topical preparation of the present invention may vary depending on the patient's sex, age, physiological condition, pathological condition, etc. The dosage may vary depending on the individual, but for example, when used as an external preparation, it is recommended to use 100mg of Rapama per day for an adult. 0.01 to 100 mg / m as isin 2 (body surface area) can be administered by application do. [Example]

[0046] The present invention will be described below with reference to specific embodiments, but the present invention is not limited to these embodiments. It is understood that various changes and modifications therein will occur to those skilled in the art without departing from the spirit and scope of the appended claims. may be practiced without departing from the scope or spirit of the invention as defined in the appended claims. It is understood.

[0047] Reference example 1 Sirolimus was added to each of the solvents shown in Table 1 at a ratio of sirolimus to solvent of 1:50 (weight ratio). The mixture was heated in a water bath at approximately 50°C and subjected to ultrasonic irradiation. As a result, as shown in Table 1, there were no solvents that could dissolve sirolimus. It was not confirmed. JPEG2025182103000001.jpg89159

[0048] (Quantitative test of sirolimus) HPLC testing was performed under the following conditions, and the area of ​​the sirolimus peak in the test substance and the Sirolimus was quantified by comparison with the area of ​​the sirolimus peak in a limus standard. .

[0049] Detector: ultraviolet absorption photometer (measurement wavelength: 278 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm, containing octadecyl ether for chromatography. Filled with tadecylsilylated silica gel Column temperature: constant temperature around 40°C Mobile phase: acetonitrile / 0.02 mol / L ammonium acetate buffer (pH 6.0) 13 / 7 Flow rate: 0.8 mL / min

[0050] Example 1, Comparative Example 1 Sirolimus: Mix the solvent and propylene glycol in a ratio of 1:50:25 (by weight) and heat to about 50°C. The resulting preparations were heated in a water bath and irradiated with ultrasound to prepare various preparations. The solubility was confirmed by this method.

[0051] The solubility results are shown in Table 2. Ethylene glycol salicylate, diethyl sebacate, and The mixture of triacetin and propylene glycol was used to dissolve sirolimus. The solution was confirmed. JPEG2025182103000002.jpg100160

[0052] In addition, the topical preparation was prepared using polyethylene glycol instead of propylene glycol. However, the same effect can be obtained.

[0053] Reference Examples 2 and 3 (Study of antioxidant formulation) A solution of sirolimus dissolved in 50% ethanol at a ratio of 0.2% (hereinafter referred to as , referred to as an aqueous ethanol solution of sirolimus), and an aqueous ethanol solution of sirolimus with BH A solution containing sirolimus and BHT at a concentration of 0.1% (hereinafter referred to as sirolimus-BHT solution) was prepared. Furthermore, the sirolimus-BHT compound solution was prepared by adding sodium EDTA or tocopherol. A solution containing sodium sirolimus acetate was prepared. Each of the Limus BHT compound solutions was stored at 40°C and 50°C, and the results were analyzed after 7 hours and 3 hours. The sample after 0 hours was quantified using the method described in the "Quantitative Test" section above. The survival rate of muss was calculated.

[0054] The composition of the sample solution is shown in Table 3, and the results are shown in Table 4 and Figures 1A and 1B. However, the residual rate of sirolimus in ethanol solution decreased over time. (Reference Example 2). On the other hand, for various sirolimus BHT compound solutions, the residual rate was low at all temperatures. The bottom was dominant (Reference Example 3).

[0055] JPEG2025182103000003.jpg66148 JPEG2025182103000004.jpg50141

[0056] Reference Example 4 (Study of the amount of BHT blended) A solution of sirolimus in ethanol was mixed with BHT at various concentrations and incubated at 40°C and The samples were stored at 50°C for 2 weeks. After storage, sirolimus was added to the samples in the same manner as in Reference Example 2. The residual rate was calculated. The results are shown in Table 5 and Figure 2. BHT at a concentration of 1% or more It was confirmed that the stability of sirolimus was maintained by incorporating

[0057] JPEG2025182103000005.jpg49133

[0058] Example 2 (Mixing of thickened sirolimus solution with BHT solution) Sirolimus was added to a mixture of triacetin and propylene glycol (5:7) at a concentration of 1.6%. A solution was prepared by dissolving hydroxypropyl cellulose in the following manner. The solution was thickened by adding sirolimus to a concentration of 6% by weight (hereinafter referred to as thickened sirolimus solution). Separately, a solution of BHT dissolved in liquid paraffin at a concentration of 23% (hereinafter referred to as BHT A solution (hereinafter referred to as a solution) was prepared.

[0059] The thickened sirolimus solution and the BHT solution were mixed in a ratio of 70:30 and incubated for 11,000 min. - 1 The resulting solution was left to stand for 3 hours and then visually observed. As a result, the liquid, which appeared homogeneously mixed immediately after stirring, gradually separated into two phases.

[0060] Example 3 (Mixing Thickened Sirolimus Solution with BHT / Surfactant Solution) Various substances known as surfactants were mixed in the proportions shown in Table 6, and various HLB values ​​were obtained. A value of surfactant was prepared. Add the prepared surfactants to the BHT solution at a concentration of 13% and heat (50-60°C). The liquid added in step 1 was mixed with the thickened sirolimus solution in a ratio of 62:38, and the mixture was stirred for 11,000 min. The resulting formulation was then left to stand for 22 hours. The state of the liquid was observed visually.

[0061] As a result of visual observation, the formulations using surfactants a and b were found to be free from phase separation. On the other hand, surfactants with an HLB value of 7.25 or higher maintained a stable cloudy mixture. From these results, it was found that in order to prevent phase separation, It was suggested that it is preferable to use a surfactant with an LB value of 5 to 7.

[0062] JPEG2025182103000006.jpg76161

[0063] Example 4 and Comparative Example 2 Sirolim ointment was prepared as follows and stored at 50°C. After 2 and 4 weeks, The residual rate of the substance was measured.

[0064] Example 4 For the gelling hydrocarbon, rapamycin was added at 0.2% of the final formulation. Isin was dissolved in a mixture of triacetin, propylene glycol, and polyethylene glycol (triacetin A liquid mixture of approximately equal amounts of tin, propylene glycol, and polyethylene glycol ) was added to the liquid paraffin solution. The surfactants (glycerin monostearate and polyoxyethylene) were added to the mixture to make a total of 1.5% of the total. The mixture was mixed in the presence of ethylene hydrogenated castor oil (mixed to an HLB of approximately 6). When the content of hydroxylated hydrocarbons was adjusted to be about 75% of the final formulation, a gel-like ointment was obtained. It became.

[0065] (Comparative Example 2) For the gelling hydrocarbon, rapamycin was added at 0.2% of the final formulation. A solution of isin dissolved in a triacetin / propylene glycol mixture was added. When the hydrogen content was adjusted to about 80% of the final formulation, a gel-like ointment was obtained.

[0066] The results are shown in Table 7. From this table, it can be seen that the ointment containing no BHT (Comparative Example 2) had a long shelf life. The remaining amount of sirolimus rapidly decreased over time, whereas the amount of sirolimus in the BHT-containing In the ointment (Example 4), the decrease in the residual amount of sirolimus was suppressed and it was kept stable. I understand.

[0067] JPEG2025182103000007.jpg37163

[0068] Example 5 Ointment penetration test The test substance was sirolimus ointment prepared in Example 4, and Met Using the EFT-400 kit manufactured by Tec Corporation, the ointment skin model A penetration test was conducted. The skin model cells were placed in a 6-well plate containing EFT-400 assay medium. Transfer and incubate overnight (16-18 hours) in a carbon dioxide incubator (37°C, 5% CO2, humidified conditions). Incubated.

[0069] Approximately 50 mg of the test substance was applied to the center of the cultured skin cells and spread evenly over the cells. The mixture was incubated in a carbon dioxide incubator (37°C, 5% CO2, humidified conditions) for 24 hours. After the incubation, the coated cells were removed using cotton wool moistened with phosphate-buffered saline. After wiping off the test substance three times, the surface moisture was removed. The dermis layer was peeled off and the area was soaked in phosphate buffered saline. After washing the surface with salt water, the moisture on the surface was removed and the mass was measured.

[0070] The collected dermal layer was cut into small pieces, and 1 mL of methanol was added and vigorously stirred. The supernatant was used as the sample solution. A solution prepared in the same manner as above without using the same solution was used as a blank matrix. A methanol solution of ascomycin (20 ng / mL) was prepared and used as an internal standard solution. .

[0071] Then, the sample solution was diluted 10 times with blank matrix, and 20 μL of the diluted solution was added to a PP tube. The sample was collected in a tube. 20 μL of acetonitrile, 20 μL of internal standard solution, 5 μL of methanol were added. Add 0 μL, mix, and subject to LC / MS / MS under the following conditions to determine the sirolimus concentration in the measurement sample. The sirolimus concentration was quantified. The obtained sirolimus concentration value and the quality of the dermis layer used to prepare the sample solution were compared. The mass of sirolimus that had migrated into the dermis layer was calculated from the amount of sirolimus. The penetration rate into the dermis layer (based on the applied dose) was calculated from the mass of the applied test substance and the mass of sirolimus in the test substance. As a result, the penetration rate of sirolimus into the dermis layer was 1.402 (indicated % of the total amount, confirming that sufficient skin permeability was maintained.

[0072] (LC conditions) Column: A stainless steel tube with an inner diameter of 2.0 mm and a length of 50 mm, containing an octachloroisothiazolinone (OCT) for chromatography. Decylsilylated silica gel packed Column temperature: constant temperature around 50°C Flow rate: 0.6mL / min Mobile phase: 5mmol / L ammonium formate (liquid A) and methanol (liquid B) were mixed according to the following graph. Mixing under agent conditions JPEG2025182103000008.jpg69142 (MS / MS conditions) Ionization method: ESI Polarity: Positive Scan type: MRM (multiple reaction monitoring) ) Confirming ion species (m / z, Q1>Q3): Sirolimus (931>864) :Ascomycin (809>756) [Industrial Applicability]

[0073] The present invention provides a topical preparation of rapamycin that is stable and has a high penetration rate into the dermis layer, with excellent solubility. Therefore, the present invention provides a method for treating skin diseases with rapamycin. This will enable treatment to be carried out more widely and effectively.

Claims

1. (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from (c) Propylene glycol and / or polyethylene glycol hand, (a) An external preparation in which the amount of rapamycin used is 0.05 to 1% by weight based on the total amount of the preparation. 。

2. (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from (c) propylene glycol and / or polyethylene glycol, and (d) an antioxidant, (a) An external preparation in which the amount of rapamycin used is 0.05 to 1% by weight based on the total amount of the preparation. 。

3. (a) rapamycin, (b) The group consisting of ethylene glycol salicylate, diethyl sebacate, and triacetin At least one selected from (c) propylene glycol and / or polyethylene glycol, and (d1) A topical preparation comprising a lipophilic solvent solution of an antioxidant, (a) An external preparation in which the amount of rapamycin used is 0.05 to 1% by weight based on the total amount of the preparation. 。

4. Any one of claims 1 to 3, wherein the weight ratio of (a) to (c) is 1:20 to 1:

70. The topical preparation described in 1.

5. A composition according to any one of claims 1 to 3, wherein the weight ratio of (b) to (c) is 2:1 to 2:

6. A topical agent.

6. Claims 1 to 5, wherein the weight ratio of (a), (b), and (c) is 1:20-80:20-70.

3. An external preparation according to any one of claims 1 to 3.

7. The method according to claim 2 or 3, wherein the antioxidant is dibutylhydroxytoluene (BHT). Topical agent.

8. The lipophilic solvent solution of the antioxidant (d1) further contains one or more surfactants having an HLB of 5 to 7. The topical preparation according to claim 3, comprising: (i) (d1) dissolving an antioxidant in a lipophilic solvent; and (ii) Mixing the solution obtained in (i) with a solution containing the following (a), (b), and (c): The method for producing the external preparation according to claim 3, comprising the steps of: (a) rapamycin (b) Composed of ethylene glycol salicylate, diethyl sebacate and triacetin At least one selected from the group (c) propylene glycol and / or polyethylene glycol

10. In step (i), the method further comprises mixing one or more surfactants having an HLB of 5 to 7. The method for producing the external preparation according to claim 9,

11. One or more surfactants having an HLB of 5 to 7 are selected from the group consisting of polyoxyethylene cetyl ether, monostearate, and PEG-100. A small amount selected from the group consisting of glycerin tearic acid and polyoxyethylene hydrogenated castor oil The method for producing an external preparation according to claim 10, wherein the number of types of the external preparation is at least two.

12. (i) a mixture obtained by dissolving an antioxidant in a lipophilic solvent; (ii) An external preparation obtained by mixing a solution containing the following (a), (b), and (c): (a) 0.05 to 1% by weight of rapamycin based on the total weight of the formulation (b) Composed of ethylene glycol salicylate, diethyl sebacate and triacetin At least one selected from the group (c) propylene glycol and / or polyethylene glycol

13. The mixture of claim 12, wherein (i) further comprises one or more surfactants having an HLB of 5 to 7. The topical agent described.

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