External preparation containing rapamycin and method for producing external preparation

Abstract

The present invention addresses the problem of providing a rapamycin-containing external preparation which has excellent stability and is effective in the treatment of skin diseases. Provided is an external preparation containing (a) rapamycin, (b) at least one substance selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, and (c) propylene glycol and / or polyethylene glycol, also provided are: an external preparation which further contains an antioxidant; and an external preparation which further contains a lipophilic solvent solution of an antioxidant.

Description

[0001] This application is a divisional application with the application date of January 23, 2021, application number 2021800059060, and name “Topical preparation containing rapamycin”. Technical Field

[0002] The present invention relates to an external preparation containing rapamycin. Specifically, the present invention relates to an external preparation containing rapamycin, which has excellent stability and is effective for treating skin diseases. Background Art

[0003] Rapamycin (generic name: sirolimus) is a macrolide produced by microorganisms. Due to its immunosuppressive properties, rapamycin has been used as a therapeutic agent for various diseases. For example, in addition to being used as an oral medication for the treatment of lymphangioleiomyomatosis, it has also recently been used as a topical agent for the treatment of skin lesions associated with tuberous sclerosis complex.

[0004] On the other hand, rapamycin is soluble in some organic solvents, such as ethanol, but is almost insoluble or poorly soluble in most solvents, such as water.

[0005] When rapamycin is used as an external preparation, it must be dissolved in a solvent and dispersed in an ointment base, etc. As mentioned above, rapamycin is almost insoluble in most solvents except for some solvents such as ethanol. However, alcohol is a skin irritant, so careful selection of solvents is necessary.

[0006] Furthermore, rapamycin is easily degraded by oxidation and easily decomposed in the presence of water. Therefore, although pharmaceutical preparations containing rapamycin and antioxidants have been developed, it is difficult to disperse fat-soluble antioxidants in non-alcoholic solutions of rapamycin.

[0007] Patent Document 1 discloses an alcohol-free composition for treating skin diseases containing rapamycin and polyethylene glycol. Patent Document 2 also discloses an anhydrous composition for treating skin diseases containing an mTOR inhibitor such as rapamycin, an antioxidant, and a gelling agent. In this document, propylene glycol, etc., is used as a solvent.

[0008] Prior art literature Patent Literature Patent Document 1: WO2018 / 031789 Patent Document 2: WO2018 / 129364 Summary of the Invention Problems to be solved by the invention The present invention has been made in view of the above circumstances, and an object of the present invention is to provide an external preparation containing an effective amount of rapamycin that does not contain alcohol and has ensured stability.

[0009] Means of solving the problem The inventors have studied combinations of various solvents that are alcohol-free and capable of containing an effective amount of rapamycin while ensuring the stability of rapamycin. They have found that the above-mentioned problems can be solved by combining specific solvents, thereby completing the present invention.

[0010] That is, the present invention is an external preparation comprising: (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, and (c) Propylene glycol and / or polyethylene glycol.

[0011] In addition, the present invention is an external preparation comprising: (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) propylene glycol and / or polyethylene glycol, and (d) Antioxidants.

[0012] Furthermore, the present invention is an external preparation comprising: (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) propylene glycol and / or polyethylene glycol, and (d1) Antioxidant solution in a lipophilic solvent.

[0013] In addition, the present invention is a method for producing an external preparation, comprising: Step (i), (d1) dissolving an antioxidant in a lipophilic solvent; and Step (ii) of mixing the solution obtained in step (i) with a solution containing the following (a), (b) and (c), (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

[0014] The present invention is an external preparation obtained by mixing the following mixture (i) and solution (ii), (i) a mixture obtained by dissolving an antioxidant in a lipophilic solvent, (ii) a solution containing the following (a), (b) and (c), (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

[0015] Effects of the Invention According to the present invention, it is possible to provide a highly stable preparation, particularly an external preparation, in which rapamycin is stably present without precipitation during storage of the preparation and decomposition of rapamycin in the preparation is suppressed. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1A This is a graph showing the stability (residual rate) of sirolimus in an ethanol aqueous solution of sirolimus and various sirolimus-BHT prepared solutions at 40°C.

[0017] Figure 1B This is a graph showing the stability (residual rate) of sirolimus at 50° C. in an ethanol aqueous solution of sirolimus and various sirolimus-BHT prepared solutions.

[0018] Figure 2 This is a graph showing the stability (residual rate) of sirolimus at 40° C. or 50° C. by formulating BHT at a concentration of 1% to 10%. DETAILED DESCRIPTION

[0019] Topical preparations containing rapamycin The external preparation of the present invention contains: (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, and (c) Propylene glycol and / or polyethylene glycol.

[0020] (a) Rapamycin is widely known as sirolimus, and commercially available products are available. In this specification, rapamycin and sirolimus are used as synonyms.

[0021] Furthermore, instead of rapamycin, everolimus or temsirolimus, which are known as rapamycin derivatives, can also be used in place of rapamycin or in combination with rapamycin.

[0022] The amount of rapamycin used may be 0.05 to 1% by weight, preferably 0.1 to 0.8%, and particularly preferably 0.1 to 0.5%, relative to the weight of the entire preparation.

[0023] As the solvent (b), at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate may be used, and these may be mixed in any ratio and used.

[0024] As the solvent (c), propylene glycol or polyethylene glycol, or a mixture thereof is used, and a mixture of propylene glycol and polyethylene glycol (Macrogol 400) is particularly preferred. These can be mixed in any ratio and used.

[0025] The mixing ratio of the solvent (b) and the solvent (c) is not particularly limited. For example, the weight ratio is (b):(c) = 2:1 to 2:6, and (b):(c) = 2:5 is particularly preferred.

[0026] On the other hand, the mixing ratio of (a) rapamycin and the solvent (c) is not limited as long as rapamycin is dissolved in the mixed solution of the solvent (b) and the solvent (c). For example, the weight ratio is (a):(c) = 1:20 to 1:70, preferably (a):(c) = 1:60. The weight ratio including the solvent (b) is (a):(b):(c) = 1:20 to 80:20 to 70, preferably (a):(b):(c) = 1:25:60.

[0027] The topical preparation of the present invention may further contain an antioxidant (d). Adding an antioxidant to the topical preparation can prevent the degradation of rapamycin and ensure long-term storage stability. Specific examples of antioxidants include butylated hydroxytoluene (BHT), tocopherol, and ascorbic acid, with butylated hydroxytoluene (BHT) being particularly recommended.

[0028] The amount of the antioxidant used is, for example, 1 to 10% by weight, preferably 1 to 5%, and particularly preferably 1 to 2% based on the weight of the entire preparation.

[0029] The antioxidant may be directly added to the preparation containing (a), (b), and (c), but preferably, a solution (d1) obtained by dissolving the antioxidant in a lipophilic solvent is added to the preparation containing (a), (b), and (c).

[0030] Examples of such lipophilic solvents include liquid paraffin and a mixture of liquid paraffin and polyethylene (gelled hydrocarbon), and liquid paraffin is preferably recommended.

[0031] The weight ratio of the lipophilic solvent to the antioxidant is 1:10 to 3:10, preferably 3:10.

[0032] A surfactant may be further added to the solution (d1) obtained by dissolving the antioxidant in the lipophilic solvent. Preferred surfactants include surfactants having an HLB of 4 to 7, and preferably at least one surfactant having an HLB of 5 to 6.

[0033] By adding such a surfactant, the resulting preparation can be further stabilized.

[0034] Examples of the surfactant include at least one selected from the group consisting of polyoxyethylene cetyl ether, glyceryl monostearate, and polyoxyethylene hydrogenated castor oil, and preferably at least two selected from the group.

[0035] Specific examples of surfactants include: -POE cetyl ether: glyceryl monostearate = 1:4 (weight ratio), - Glyceryl monostearate: POE hydrogenated castor oil = 4:1 (weight ratio).

[0036] In the scope that does not hinder the effect of the present invention, the external preparation of the present invention may also contain other excipients or additives that are commonly used in pharmaceutical administration forms. For example, as such excipients or additives, gelling agents, tackifiers, pH adjusting agents, inorganic salts etc. may be used.

[0037] Examples of gelling agents include water-soluble cellulose-derived polymers, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, hydroxyethylmethylcellulose, methylcellulose, and carrageenan. Examples of thickening agents include hydroxypropylcellulose. Examples of pH adjusters include acidic additives such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, malic acid, methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid, and buffers containing alkali metal salts, alkaline earth metal salts, and ammonium salts. Inorganic salts include calcium chloride, sodium chloride, calcium oxide, and magnesium sulfate.

[0038] Furthermore, other pharmaceutical ingredients may be added to the external preparation of the present invention as long as they do not interfere with the effect of rapamycin as the main active ingredient. Examples of such other pharmaceutical ingredients include tacrolimus and steroids.

[0039] Method for producing external preparation The external preparation of the present invention can be produced as follows.

[0040] For example, mix the following (a) to (c): (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

[0041] In addition, when an antioxidant is used, the product can be produced by the following steps (i) and (ii): Step (i), (d1) dissolving an antioxidant in a lipophilic solvent; and Step (ii) of mixing the solution obtained in step (i) with a solution containing the following (a), (b) and (c), (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

[0042] Furthermore, in order to obtain an external preparation with higher stability, for example, it can be produced through the following steps (i) and (ii): Step (i), (d2) dissolving an antioxidant in a lipophilic solvent to prepare a mixed solution, and then adding one or more surfactants having an HLB of 5 to 7 to the mixed solution; and Step (ii) of mixing the solution obtained in step (i) with a solution containing the following (a), (b), and (c) (hereinafter sometimes referred to as "rapamycin hydrophilic solvent solution"), (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

[0043] In particular, by adding one or more surfactants having an HLB of 5 to 7 to the mixed solution obtained by dissolving the antioxidant in the lipophilic solvent in step (d2) of the above step (i), the compatibility between the mixed solution of the antioxidant and the lipophilic solvent and the hydrophilic solvent solution of rapamycin in the above step (ii) can be further improved.

[0044] In order to prepare the external preparation of the present invention into an external preparation in an optimal administration form, such as an ointment, liniment, lotion, etc. in the form of a cream, paste, jelly, gel, emulsion, liquid, etc., in addition to the other excipients or additives mentioned above, sodium alginate; gelatin, corn starch, tragacanth gum, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, xanthan gum, dextrin, carboxymethyl starch, polyvinyl alcohol, sodium polyacrylate, methyl vinyl ether-maleic anhydride copolymer may be appropriately added. , polyvinyl ether, polyvinyl pyrrolidone and other polymers; beeswax, olive oil, cocoa butter, sesame oil, soybean oil, tea oil, peanut oil, tallow, lard, lanolin; white petrolatum, yellow petrolatum and other petrolatums; a mixture of paraffin, liquid paraffin and polyethylene (gelled hydrocarbon); stearic acid; lauric acid ester, myristate ester, n-octanoate; cetyl alcohol, stearyl alcohol; polyethylene glycol; dimethyl sulfoxide, lauryl pyrrolidone; urea; azone; olive oil; one or more of kaolin, bentonite, zinc oxide, titanium oxide, etc.

[0045] How to use topical agents The rapamycin-containing external preparation of the present invention has an immunosuppressive effect and can therefore be used, for example, to treat skin diseases.

[0046] Specific examples of skin diseases include dermatitis, contact dermatitis, psoriasis, atopic dermatitis, seborrheic dermatitis, nummular eczema, vitiligo, rosacea, keloids, autosensitive dermatitis, stasis dermatitis, sebaceous hypoderma, skin tumors of tuberous sclerosis, seborrheic keratosis, and skin tumors of neurofibromatosis (Recklinghausen disease).

[0047] The dosage of the pharmaceutical product using the external preparation of the present invention can of course be changed according to the patient's sex, age, physiological state, condition, etc., but in the case of external preparation, for example, 0.01 to 100 mg / m2 of rapamycin can be applied daily to adults. 2 (body surface area) for drug administration.

[0048] Example The present invention is described below with reference to a specific embodiment, but the present invention is not limited to this embodiment, and those skilled in the art will understand that various changes and modifications can be made in this embodiment without departing from the scope or spirit of the present invention as defined in the appended claims.

[0049] Reference Example 1 Sirolimus was mixed with each of the solvents listed in Table 1 at a sirolimus:solvent ratio of 1:50 (weight ratio). The mixture was heated in a water bath at approximately 50°C and irradiated with ultrasonic waves. Solubility was then visually observed. As shown in Table 1, no dissolution of sirolimus was observed in the solvent alone.

[0050] [Table 1] Solubility of sirolimus in various solvents

[0051] (Quantitative test of sirolimus) An HPLC (High Performance Liquid Chromatography) test was performed under the following conditions, and sirolimus was quantified by comparing the area of ​​the sirolimus peak in the test substance with the area of ​​the sirolimus peak in the sirolimus standard substance.

[0052] Detector: UV spectrophotometer (measurement wavelength: 278nm) Chromatographic column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 250 mm is filled with octadecylsilane bonded silica gel used for chromatography. Column temperature: Constant temperature around 40°C Mobile phase: acetonitrile / 0.02 mol / L ammonium acetate buffer (pH 6.0) = 13 / 7 Flow rate: 0.8mL / min Example 1, Comparative Example 1 Various preparations were prepared using a mixed solvent consisting of each solvent listed in Table 1 and propylene glycol at a weight ratio of sirolimus:solvent:propylene glycol of 1:50:25. The mixture was heated in a water bath at approximately 50°C and irradiated with ultrasound. The solubility of the resulting preparations was confirmed by visual inspection.

[0053] The solubility results are shown in Table 2. The dissolution of sirolimus was confirmed using ethylene glycol salicylate, diethyl sebacate, and a mixed solution of triacetin and propylene glycol.

[0054] [Table 2] Solubility of sirolimus in mixtures of various solvents and propylene glycol (PG)

[0055] Furthermore, the same effects can be obtained even when polyethylene glycol is used instead of propylene glycol to prepare the external preparation.

[0056] Reference Examples 2-3 (Study on the Preparation of Antioxidants) A solution containing 0.2% sirolimus dissolved in a 50% ethanol aqueous solution (hereinafter referred to as the sirolimus ethanol aqueous solution) was prepared. A solution containing 0.1% BHT in the sirolimus ethanol aqueous solution (hereinafter referred to as the sirolimus BHT prepared solution) was also prepared. Furthermore, solutions were prepared by adding sodium EDTA (ethylenediaminetetraacetic acid) or sodium tocopheryl acetate to the sirolimus BHT prepared solution. The sirolimus ethanol solution and various sirolimus BHT prepared solutions were stored at 40°C and 50°C, respectively. Samples were quantified after 7 and 30 hours using the method described in the "Quantitative Test" section above, and the residual sirolimus ratio was calculated.

[0057] The composition of the sample solution is shown in Table 3, and the results are shown in Table 4 and Figure 1A 、 Figure 1B Regardless of the temperature, the residual rate of sirolimus in an ethanol aqueous solution decreased with the passage of time (Reference Example 2).

[0058] On the other hand, in various sirolimus-BHT prepared solutions, the decrease in the residual rate was well suppressed at any temperature (Reference Example 3).

[0059] [Table 3] Research prescription of antioxidants

[0060] [Table 4] The blending effect of BHT

[0061] Reference Example 4 (Study on the blending amount of BHT) Liquids were prepared by mixing various concentrations of BHT in an ethanol solution of sirolimus and stored at 40°C and 50°C for 2 weeks. For each sample after storage, sirolimus was quantified by the same method as in Reference Example 2, and the residual rate was calculated. The results are shown in Tables 5 and 6. Figure 2 It was confirmed that the stability of sirolimus was maintained by formulating BHT at a concentration of 1% or more.

[0062] [Table 5] Effect of BHT dosage on the stability of sirolimus

[0063] Example 2 (Mixing of Thickened Sirolimus Solution and BHT Solution) A solution was prepared by dissolving 1.6% sirolimus in a mixture of triacetin and propylene glycol (5:7). Hydroxypropylcellulose was added to the solution to increase its viscosity (hereinafter referred to as the thickened sirolimus solution) at 1.6% by weight.

[0064] Separately, a solution in which BHT was dissolved in liquid paraffin to a concentration of 23% (hereinafter referred to as a BHT solution) was prepared.

[0065] The thickening sirolimus solution and the BHT solution were mixed at a ratio of 70:30 and heated for 11000 min. -1 The mixture was stirred at high speed under the conditions of . The resulting liquid was allowed to stand for 3 hours and was visually observed. As a result, the solution, which appeared to be uniformly mixed immediately after stirring, gradually separated into two phases.

[0066] Example 3 (Mixing of Viscosity-Increasing Sirolimus Solution with BHT / Surfactant Solution) Various substances known as surfactants were mixed in the ratios shown in Table 6 to prepare surfactants having various HLB values.

[0067] The prepared surfactants were added to the BHT solution at 13% under heating (50-60°C), and the obtained liquid was mixed with the thickening sirolimus solution at a ratio of 62:38. -1 The mixture was stirred at high speed under the conditions of , to obtain a preparation. The obtained preparation was then left for 22 hours, and the state of the liquid was visually observed.

[0068] Visual observation revealed that formulations using surfactants a and b did not undergo phase separation, maintaining a stable, turbid mixed state. On the other hand, formulations using surfactants with an HLB value of 7.25 or higher did experience phase separation. These results suggest that to suppress phase separation, it is preferable to use surfactants with an HLB value of 5 to 7.

[0069] [Table 6] Prepared surfactant

[0070] Example 4 and Comparative Example 2 An ointment was prepared according to the following procedure and stored at 50°C. The residual rate of sirolimus was measured after 2 weeks and 4 weeks.

[0071] (Example 4) A solution of rapamycin dissolved in a triacetin / propylene glycol / polyethylene glycol mixture (a mixture of triacetin, propylene glycol, and polyethylene glycol in approximately equal proportions) was added to a gelled hydrocarbon so that the rapamycin content reached 0.2% of the final dose. A solution of BHT in liquid paraffin was then added to the mixture in the presence of a surfactant (a mixture of glyceryl monostearate and polyoxyethylene hydrogenated castor oil, with an HLB of approximately 6) so that the BHT content reached 1.5% of the final dose. When the gelled hydrocarbon content was adjusted to approximately 75% of the final dose, a gel-like ointment was formed.

[0072] (Comparative Example 2) A solution of rapamycin dissolved in a triacetin / propylene glycol mixture was added to the gelled hydrocarbon so that the rapamycin content was 0.2% relative to the final dose. When the content of the gelled hydrocarbon was adjusted to approximately 80% of the final dose, a gel-like ointment was obtained.

[0073] The results are shown in Table 7. As can be seen from the table, in the ointment not formulated with BHT (Comparative Example 2), the amount of sirolimus remaining decreased rapidly with the passage of the storage period, whereas in the ointment formulated with BHT (Example 4), the decrease in the amount of sirolimus remaining was suppressed and remained stable.

[0074] [Table 7] Stability of sirolimus ointment

[0075] Example 5 Ointment penetration test The sirolimus ointment prepared in Example 4 was used as a test substance, and a permeation test of the ointment on a skin model was conducted using an EFT-400 kit manufactured by MetTec Corporation as a skin model.

[0076] The cells used as the skin model were transferred to a 6-well plate filled with EFT-400 assay medium and cultured overnight (16-18 hours) in a carbon dioxide incubator (37°C, 5% CO2, humidified conditions).

[0077] Approximately 50 mg of the test substance was applied to the center of cultured skin cells and evenly spread over the cells. The cells were incubated for 24 hours in a carbon dioxide incubator (37°C, 5% CO2, humidified). After incubation, the test substance was wiped off the cells three times with cotton wool moistened with phosphate-buffered saline, and the surface moisture was removed. The dermis was then exfoliated, the surface washed with phosphate-buffered saline, the surface moisture removed, and the mass measured.

[0078] The collected dermis was finely dissected, 1 mL of methanol was added, and the mixture was vigorously stirred. The mixture was centrifuged (20,400 × g, 5 minutes, 4°C), and the supernatant was used as the sample solution. Alternatively, the same procedure was repeated without applying the test substance, and the resulting solution was used as a blank matrix. Separately, a methanol solution of natagamicin (20 ng / mL) was prepared as an internal standard solution.

[0079] The sample solution was diluted 10-fold with a blank matrix, and 20 μL of this was collected into a PP tube. To this solution, 20 μL of acetonitrile, 20 μL of an internal standard solution, and 50 μL of methanol were added and mixed. The sample was then submitted to an LC / MS / MS under the following conditions to quantify the sirolimus concentration in the measurement sample. The mass of sirolimus transferred to the dermis was calculated based on the obtained sirolimus concentration and the mass of the dermis used to prepare the sample solution. The transfer rate to the dermis (% relative to the applied dose) was calculated based on the mass of sirolimus transferred to the dermis and the mass of sirolimus in the applied test substance. The results confirmed that the transfer rate of sirolimus to the dermis was 1.402 (% relative to the applied dose), indicating that skin permeability was adequately maintained.

[0080] (LC conditions) Chromatographic column: A stainless steel tube with an inner diameter of 2.0 mm and a length of 50 mm is filled with octadecylsilane bonded silica gel for chromatography. Column temperature: a certain temperature around 50℃ Flow rate: 0.6mL / min Mobile phase: Mix 5 mmol / L ammonium formate (solution A) and methanol (solution B) according to the following gradient conditions [Table 8] Gradient conditions

[0081] (MS / MS conditions) Ionization method: ESI Polarity: Positive Scan type: MRM (multiple reaction monitoring) Confirming ion species (m / z, Q1>Q3): Sirolimus (931>864) :Changchuanmycin (809>756) Industrial applicability According to the present invention, a stable external preparation of rapamycin with excellent solubility and a high transfer rate to the dermis can be provided. Therefore, the present invention enables the treatment of skin diseases with rapamycin to be carried out more widely and effectively.

Claims

1. An external preparation, wherein contain: (a) Rapamycin; (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate; (c) propylene glycol and / or polyethylene glycol; and (d) butylated hydroxytoluene (BHT), one or more surfactants having an HLB value of 5 to 7 after formulation, and a lipophilic solvent.

2. The external preparation according to claim 1, wherein The weight ratio of (a) to (c) is 1:20~1:

70.

3. The external preparation according to claim 1, wherein The weight ratio of (b) to (c) is 2:1~2:

6.

4. The external preparation according to claim 1, wherein The weight ratio of (a), (b) and (c) is 1:20~80:20~70.

5. The external preparation according to any one of claims 1 to 4, wherein The one or more surfactants having an HLB of 5 to 7 after formulation are at least two selected from the group consisting of polyoxyethylene cetyl ether, glyceryl monostearate, and polyoxyethylene hydrogenated castor oil.

6. A method for producing an external preparation, for producing the external preparation according to any one of claims 1 to 5, wherein: The manufacturing method comprises: Step (i) (d1) dissolving butylated hydroxytoluene (BHT) in a lipophilic solvent, and mixing one or more surfactants having an HLB of 5 to 7 with the obtained solution, Step (ii) is to mix the solution obtained in step (i) with a solution containing the following (a), (b) and (c), (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

7. The method for producing an external preparation according to claim 6, wherein The one or more surfactants having an HLB of 5 to 7 after formulation are at least two selected from the group consisting of polyoxyethylene cetyl ether, glyceryl monostearate, and polyoxyethylene hydrogenated castor oil.

8. An external preparation, wherein The mixture of (i) and the solution of (ii) are mixed to obtain: (i) a mixed solution containing one or more surfactants having an HLB of 5 to 7 after preparation, obtained by dissolving butylated hydroxytoluene (BHT) in a lipophilic solvent; (ii) a solution containing the following (a), (b) and (c), (a) Rapamycin, (b) at least one selected from the group consisting of ethylene glycol salicylate, diethyl sebacate, and glyceryl triacetate, (c) Propylene glycol and / or polyethylene glycol.

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