Rapamycin treatment method and composition

Abstract

The present invention is a method for treating vascular abnormalities in the skin of human subjects, a) Rapamycin, b) Monolaurin and monomyristate as vehicles, and c) water A composition containing d) 1cm 2 4-8 mg of rapamycin per unit, and / or e) 1-6 mg of rapamycin This includes local administration of a certain amount, more than once a day.

Description

Technical Field

[0001] The present invention relates to a rapamycin composition for administration to humans, and methods of manufacturing or using the same.

Background Art

[0002] Rapamycin was isolated from a sample of Streptomyces hygroscopicus around 1972. This compound was first developed as an antifungal agent, and its production is described in U.S. Patent No. 3,929,992 to Ayerst McKenna & Harrison. Rapamycin has the following structural formula:

Chemical Formula

[0003] Rapamycin has the problem that it often needs to be used for a long period of time, and accumulates in the bloodstream in an undesirable amount due to overuse, thereby causing harmful side effects such as stomatitis, interstitial pneumonia, hyperlipidemia, anemia, thrombocytopenia, nephrotoxicity, arthralgia, and edema. Furthermore, rapamycin is a drug in U.S. FDA category C, and harmful effects on the developing fetus, which is a potential problem for pregnant women having an undesirable amount of rapamycin in their system, have been seen in animal studies.

Summary of the Invention

Problems to be Solved by the Invention

[0004] It is an object of a preferred embodiment of the present invention to address the above problems in at least some way. While this applies to the preferred embodiments, it should be understood that the object of the present invention itself is not so limited, but simply provides options useful to the public. Thus, any object, advantage, or benefit of any preferred embodiment should not be construed as a limitation to any more broadly expressed claim.

[0005] definition The term “comprising” or its derivatives, such as “comprise,” when used herein in relation to a combination of features or steps, should not be construed as excluding the option of further features or steps not mentioned. Therefore, the term is inclusive and not exclusive. [Means for solving the problem]

[0006] First aspect - Treatment method According to a first aspect, the present invention is a method for treating vascular abnormalities of the skin in a human subject, a) Rapamycin, b) Monolaurin and monomyristate as vehicles, and c) water A composition containing d) 4-8 mg of rapamycin / cm² 2 , and / or e) With a dose of 1-6 mg of rapamycin, This method involves local administration at a rate of more than once a day.

[0007] Second aspect - Use in manufacturing According to the first aspect, the present invention is In the manufacture of compositions a) Rapamycin, b) Monolaurin and monomyristate as vehicles, and c) water The use is, and the composition is d) 1cm 2 4-8 mg of rapamycin per unit, and / or e) This composition is intended to treat vascular abnormalities in the skin of human subjects by topical administration of rapamycin at a dose of 1-6 mg once daily to the vascular abnormality.

[0008] Third aspect - Composition for treatment According to a third aspect, the present invention is a) Rapamycin, b) Monolaurin and monomyristate as vehicles, and c) water The composition includes, d) 1cm 2 4-8 mg of rapamycin per unit, and / or e) 1-6 mg of rapamycin This composition is intended to treat vascular abnormalities in the skin of human subjects by topical administration of the composition to the vascular abnormality once a day in the specified amount.

[0009] Fourth aspect - Further treatment method According to a fourth aspect, the present invention is a method for treating vascular abnormalities of the skin in a human subject, a) As an active ingredient, rapamycin, b) A vehicle containing monolaurin and monomyristate, c) Applying a composition containing water as a solvent abnormally locally once a day for at least one, two, three, four, five, or six months, As a result, at the end of at least one, two, three, four, five, or six months, the concentration of rapamycin in the target bloodstream, if present, does not exceed 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL, or 5 ng / mL (preferably, at the end of one month or multiple months, it does not exceed 0.1 mg / mL, 0.2 mg / mL, 0.3 mg / mL, 0.4 mg / mL, 0.5 mg / mL, 0.6 mg / mL, 0.7 mg / mL, 0.8 mg / mL, or 0.9 mg / mL). To avoid misunderstanding, the ng / mL figures used herein may apply to any such period described herein.

[0010] Any feature Any of the following features, unless otherwise excluded, apply individually or in any combination with one or more of the following features or sets of features to all of the first, second, third, and fourth aspects of the present invention.

[0011] Dosage composition, a) 1 cm 2 rapamycin at 5 - 7 mg per, or b) is administered once daily in an amount of 2 - 5 mg of rapamycin, or is for administration.

[0012] The composition is c) 1 cm 2 about 6 mg of rapamycin per, or d) is administered once daily in an amount of 3 - 4 mg of rapamycin, or is for administration.

[0013] The composition is administered for at least 1 month, 2 months, 3 months, 4 months, 5 months or 6 months.

[0014] At the end of administration for at least 1 month, 2 months, 3 months, 4 months, 5 months or 6 months, a composition is administered, or is for administration, such that the concentration of rapamycin in the subject's bloodstream, if present, does not exceed 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL or 5 ng / mL.

[0015] At the end of administration for at least 1 month, 2 months, 3 months, 4 months, 5 months or 6 months, a composition is administered, or is for administration, such that the concentration of rapamycin in the subject's bloodstream, if present, does not exceed 0.1 ng / mL, 0.2 ng / mL, 0.3 ng / mL, 0.4 ng / mL, 0.5 ng / mL, 0.6 ng / mL, 0.7 ng / mL, 0.8 ng / mL or 0.9 ng / mL.

[0016] Component amounts The composition contains 0.5 - 5% by weight of rapamycin.

[0017] The composition contains 0.5 - 1% by weight of rapamycin.

[0018] The composition contains about 0.5% of rapamycin.

[0019] The composition contains about 1% of rapamycin.

[0020] Medical conditions to be treated Vascular abnormalities include angiofibromas.

[0021] Vascular abnormalities include facial angiofibromas.

[0022] Vascular abnormalities include cutaneous vascular lesions.

[0023] Vascular abnormalities include port-wine stains.

[0024] Port-wine stains are treated after the laser treatment.

[0025] Further features The composition contains approximately 7-28% by weight, or approximately 5-10% by weight, or approximately 7% by weight of monolaurin.

[0026] The composition contains approximately 7-28% by weight, or approximately 15-25% by weight, or approximately 21% by weight of monomyristate.

[0027] composition, a) 5% to 9% by weight of monolaurin + 19% to 23% by weight of monomyristate, or b) Contains 12% to 16% by weight of monolaurin + 12% to 16% by weight of monomyristate.

[0028] composition, a) Approximately 7% by weight of monolaurin + approximately 21% by weight of monomyristate, or b) Contains approximately 14% by weight of monolaurin + approximately 14% by weight of monomyristate.

[0029] Water-retaining agent Contains a water-retaining agent for tatami mats.

[0030] The water-retaining agent contains polyoxyethylene stearate.

[0031] Softener The composition contains a softening agent.

[0032] The softening agent contains one or more of the following: propylene glycol, petrolatum (petrolatum), lanolin, mineral oil, glycerin, lecithin, and sorbitol.

[0033] cushioning agent The composition includes a buffering agent.

[0034] The buffering agent contains one or more of the following: anhydrous citric acid, sodium bicarbonate, and triethanolamine.

[0035] Metal ion chelating agent The composition contains a metal ion chelating agent.

[0036] The metal ion chelating agent contains one or more of the following: disodium edetate, citrate, and tetrasodium EDTA.

[0037] pH adjuster The composition contains hydroxides for pH adjustment.

[0038] Preservatives The composition contains preservatives.

[0039] The preservatives include one or more of the following: potassium sorbate, diazolidinyl urea, phenoxyethanol, and sodium hydroxymethylglycinate.

[0040] water The composition contains 58% to 72% by weight of water.

[0041] Other features composition, a) 0.5-5% by weight of rapamycin b) Below: • 7-28% by weight of monolaurin, and • A vehicle containing 7-28% by weight of monomyristate, and c) Contains water as a solvent.

[0042] The composition contains 0.5 to 5% by weight of rapamycin, 5% to 9% by weight of monolaurin, and 19% to 23% by weight of monomyristate.

[0043] The composition contains 0.5 to 5% by weight of rapamycin, 7% by weight of monolaurin, and 21% by weight of monomyristate.

[0044] The composition comprises 0.5% or 1% by weight of rapamycin, 7% by weight of monolaurin, and 21% by weight of monomyristate.

[0045] The composition contains 0.5 to 5% by weight of rapamycin, 12% to 16% by weight of monolaurin, and 12% to 16% by weight of monomyristate.

[0046] The composition contains 0.5 to 5% by weight of rapamycin, 14% by weight of monolaurin, and 14% by weight of monomyristate.

[0047] The composition comprises 0.5% or 1% by weight of rapamycin, 14% by weight of monolaurin, and 14% by weight of monomyristate.

[0048] The composition contains 0.5 to 5% by weight of rapamycin, 17.5% by weight (±2% by weight) of monolaurin, and 10.5% by weight (±2% by weight) of monomyristate.

[0049] The composition contains 0.5 to 5% by weight of rapamycin, 17.5% by weight of monolaurin, and 10.5% by weight of monomyristate.

[0050] The composition comprises 0.5% or 1% by weight of rapamycin, 17.5% by weight of monolaurin, and 10.5% by weight of monomyristate.

[0051] The composition comprises 0.5% or 1% by weight of rapamycin, 21% by weight of monolaurin, and 7% by weight of monomyristate.

[0052] Monolaurin is glyceryl monolaurate, and monomyristate is glyceryl monomyristate.

[0053] composition, a) 0.5-5% by weight of rapamycin b) Below: · 10-18% by weight of monolaurin, and • A vehicle containing 10-18% by weight of monomyristate, and c) Contains water as a solvent.

[0054] All descriptions The compositional components listed for any of the above embodiments or options may be in amounts of ±5% or ±10% of the stated values. For example, 0.5% rapamycin may be ±5%, or 1% rapamycin may be ±5%.

[0055] Some preferred embodiments of the present invention are illustrated by reference to the following images. [Brief explanation of the drawing]

[0056] [Figure 1] The results obtained from particle size analysis of a 1% rapamycin composition for topical application are shown. [Figure 2] The image shows rapamycin particles in the same 1% composition. [Figure 3] This invention provides "before and after" images of the skin of a person who has been treated for angiofibroma according to one embodiment of the present invention. [Modes for carrying out the invention]

[0057] Formulation Examples 1 & 2 Two preferred embodiments of the present invention, namely Formulation 1 and Formulation 2, are for the topical treatment of vascular abnormalities of the skin. These conditions may include, but are not limited to, human angiofibromas, e.g., facial angiofibromas or cutaneous vascular lesions. The formulations may also be used, for example, to treat port-wine stains after laser treatment to limit the potential regrowth of the nevus. These are substantially configured as shown in Table 1 below. [Table 1]

[0058] The composition according to the present invention, comprising formulations 1 and 2, may be manufactured according to the following method.

[0059] Manufacturing of aqueous phase pre-blends Prepare the aqueous phase preblend as follows: Combine rapamycin and propylene glycol and vortex mix. Add water while continuously vortexing. Next, heat the blend to 70°C (±5°C). Add citric acid, disodium EDTA, and potassium sorbate while vortexing until dissolved. Next, adjust the temperature of the mixture to 50°C, and • Add polyoxyethylene stearate (100).

[0060] Manufacturing of oil phase preblends Prepare the oil phase preblend as follows: Combine glyceryl monolaurate and glyceryl monomyristate using a slow vortex mixer while heating to 70°C (±5°C).

[0061] Final Blend Combine the aqueous and oil phase pre-blends at 70°C (±5°C) and mix thoroughly until homogeneous. Then, slowly cool the mixture at a rate of 1°C per minute, vortex-mixing until a smooth white and iridescent cream is formed. Once the cream has cooled to below 32°C, fill it into 30 mL aluminum tubes fitted with polypropylene screw caps.

[0062] Formulation Examples 3 & 4 Formulations 3 and 4 were manufactured for the same purposes and in the same manner as described for Formulations 1 and 2. These are listed in Table 2 below. [Table 2]

[0063] Particle size characteristics Figures 1 and 2 show the characteristics of the rapamycin active ingredient in the 1% cream identified above as Formulation 2. The information was obtained by analyzing the formulation using a Malvern Morphologi GS3 image analyzer, which is essentially an automated microscope scanning the formulation to detect the 3D morphological features of rapamycin particles.

[0064] Referring to Figure 1, the CE diameter ("circular equivalent diameter") value represents the particle size on a number-weighted basis. In other words, this represents the particle as a two-dimensional shape converted to the nearest applicable circle, and then its diameter is calculated. Referring to the specific notation shown, D[n,0.10](μm):3.17 means that 10% of the particles are of the number of particles. This means that the base is 3.17 μm or less, and D[n,0.16](μm) means that 16% are smaller than 3.83 μm, and D[n,0.50](μm): This means that 50% of the particles are smaller than 8.33 μm on a particle number basis.

[0065] Referring to Figure 2, the image shows the shape and relative size of rapamycin particles in formulation 2.

[0066] Figures 1 and 2 show that rapamycin does not dissolve in the rest of the composition, but rather is suspended in the carrier or vehicle component.

[0067] Clinical trial - Rapamycin blood concentration method Multicenter, double-blind, randomized, placebo-controlled, dose-response study. Parallel studies were conducted in accordance with the guidelines of the International Conference on Harmonisation of Standards for the Conduct of Clinical Trials of Medicinal Products and the Declaration of Helsinki. The purpose was to evaluate the efficacy in topically treating vascular abnormalities of the skin, including whether rapamycin enters the bloodstream when applied topically via Formulation 1 or Formulation 2, and, if so, to what extent.

[0068] This study consisted of 107 human participants aged 6–65 years diagnosed with facial angiofibroma associated with tuberous sclerosis. The facial angiofibroma was mild to moderate in severity. In other words, each participant had a score of 2 or 3 on the Investigator Global Assessment (IGA) scale.

[0069] Participants were randomized to one of three treatment groups: rapamycin 0.5% cream (Formulation 1, n=36), rapamycin 1% cream (Formulation 2, n=33), or placebo cream (i.e., the same excipients but without the active ingredient, n=38).

[0070] The formulation and placebo were applied to a 1 cm area of ​​skin. 2 Rapamycin was applied topically to the angiofibroma once daily at a dose of 6 mg per 100 mcg for 26 weeks. Considering that various participants had angiofibroma areas of varying sizes, they did not all receive the same dose. However, the group-average daily dose of rapamycin is shown in Table 3 below. [Table 3]

[0071] Safety and efficacy were assessed on days 14, 56, 98, 140, and 182 (visit days 1-5, respectively). The primary endpoint was based on the IGA score after 26 weeks of administration.

[0072] Secondary evaluation criteria included the Facial Angiofibromas Severity Index (FASI) and percentage-based improvements reported by the subjects and clinicians.

[0073] All participants who underwent treatment were included in the final analysis.

[0074] result The degree of improvement at the end of the treatment period is shown in Table 4 below. [Table 4]

[0075] Participants who did not have at least one improved IGA score are not included in the above results.

[0076] Figure 3 shows an example of a reduction in facial angiofibroma achieved in one patient during the clinical trial who was treated with formulation 2 as described above. This subject had an IGA score of 3 at the start of the trial and an IGA score of 2 on visit day 5.

[0077] Table 5 below reports the amounts of rapamycin found in the blood of various participants. The value "N" for the number of participants tested on each visit day is less than the number enrolled in each group because some participants did not provide test samples. In some cases, this was because pediatric participants (children) were unwilling to provide blood at some test points. For example, for 1% rapamycin on visit day 1, the number of subjects tested was N=26, compared to the total number enrolled in the clinical trial for that group, N=33. However, rapamycin was not detected in any participant who returned a test sample at any stage of the trial, with the exception of one participant in Trial 1 (14 days) in the 0.5% formulation group who had 1.1 ng / mL of rapamycin in their blood. [Table 5]

[0078] In this trial, both formulations 1 and 2 were well tolerated and effective in reducing facial angiofibromas in the majority of participants. Notably, this was achieved without rapamycin reaching the bloodstream, and this was not repeated in subsequent trial phases / visit days, except for one case shown above for day 14 of the trial. At 6 months, no participants in the trial were found to have rapamycin in their blood. These results were remarkable considering that rapamycin transfer into the bloodstream was expected, especially given the length of time the drug was administered and the dosage.

[0079] For comparison, the commercially available HYFTOR® gel was tested. This is a topical gel containing 0.2% by weight of rapamycin for the treatment of tuberous sclerosis and similar diseases. This product was applied topically to angiofibroma sites twice daily to 30 human participants. The average total dose per participant per day is shown in Table 6 below. [Table 6]

[0080] A test was conducted to determine the amount of rapamycin in the bloodstream over the period of ingesting HYFTOR® gel, and the results are shown in Table 7 below. [Table 7]

[0081] comparison Formulations 1 & 2 for HYFTOR® Gel As can be seen from Tables 3 and 6, formulations 1 and 2 administered higher doses of rapamycin to trial participants compared to HYFTOR® gel. In particular, for formulation 2, participants aged 12 years and older received an average of 5.67 mg / day of rapamycin, compared to 1.6 mg / day for participants of the same age group with HYFTOR® gel.

[0082] Despite the higher amount of rapamycin in Formulation 2, rapamycin was not found to accumulate in the system / bloodstream, although it did aggregate in the HYFTOR® gel. This suggests that formulations based on monolaurin and monomyristaten vehicles can be used to deliver larger amounts of rapamycin to patients requiring higher doses.

[0083] Furthermore, the results indicate that even in individuals requiring lower doses of rapamycin, monolaurin and monomyristate-based formulations reduced the likelihood of rapamycin accumulating in the system / bloodstream.

[0084] Disclosure details With regard to disclosure, this Specification hereby discloses each item, feature, or process referred to herein in combination with any one or more other items, features, or processes disclosed herein, in any case whether such combination is claimed or not.

[0085] Variation While several preferred embodiments of the present invention have been described as examples, it should be understood that modifications and improvements can be made without departing from the scope of the following claims.

Claims

1. A method for treating vascular abnormalities in the skin of human subjects, a) Rapamycin, b) Monolaurin and monomyristate as vehicles, c) water A composition containing d) 1 cm ２ 4 to 8 mg of rapamycin per unit, and / or e) With a dose of 1-6 mg of rapamycin, A method comprising administering the aforementioned abnormality locally once a day.

2. The composition is a) 1 cm ２ 5-7 mg of rapamycin and / or b) The method according to claim 1, wherein the dose is 2 to 5 mg of rapamycin administered once daily.

3. The composition is a) 1 cm ２ Approximately 6 mg of rapamycin per unit, and / or b) The method according to claim 1, wherein the dose is 3-4 mg of rapamycin administered once daily.

4. The method according to claim 1, 2, or 3, wherein the composition is administered over a period of at least one, two, three, four, five, or six months.

5. The method according to any one of claims 1 to 4, comprising administering the composition, if present, at the end of the administration period of at least one, two, three, four, five, or six months, the concentration of rapamycin in the bloodstream of the subject not exceeding 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL, or 5 ng / mL.

6. The method according to any one of claims 1 to 4, comprising administering the composition, if present, at the end of the administration of at least one, two, three, four, five, or six months, the concentration of rapamycin in the bloodstream of the subject not exceeding 0.1 ng / mL, 0.2 ng / mL, 0.3 ng / mL, 0.4 ng / mL, 0.5 ng / mL, 0.6 ng / mL, 0.7 ng / mL, 0.8 ng / mL, or 0.9 ng / mL.

7. The method according to any one of claims 1 to 6, wherein the composition comprises 0.5 to 5% by weight of rapamycin.

8. The method according to claim 7, wherein the composition comprises 0.5 to 1% by weight of rapamycin.

9. The method according to claim 7, wherein the composition comprises about 0.5% rapamycin.

10. The method according to claim 7, wherein the composition comprises about 1% rapamycin.

11. The method according to any one of claims 1 to 10, wherein the vascular abnormality includes an angiofibroma.

12. The method according to any one of claims 1 to 11, wherein the vascular abnormality includes a facial angiofibroma.

13. The method according to any one of claims 1 to 11, wherein the vascular abnormality includes cutaneous vascular lesions.

14. The method according to any one of claims 1 to 11, wherein the vascular abnormality includes a port-wine stain.

15. The method according to claim 14, wherein the port-wine stain is treated after the laser treatment.

16. The method according to any one of claims 1 to 15, wherein the composition comprises about 7 to 28% by weight, or about 5% to 10% by weight, or about 7% by weight of monolaurin.

17. The method according to any one of claims 1 to 16, wherein the composition comprises about 7% to 28% by weight, or about 15% to 25% by weight, or about 21% by weight of monomyristaten.

18. The composition is a) 5% to 9% by weight of monolaurin + 19% to 23% by weight of monomyristate, or b) The method according to any one of claims 1 to 17, comprising 12% to 16% by weight of monolaurin and 12% to 16% by weight of monomyristate.

19. The composition is a) Approximately 7% by weight of monolaurin + approximately 21% by weight of monomyristate, or b) The method according to any one of claims 1 to 18, comprising about 14% by weight of monolaurin and about 14% by weight of monomyristate.

20. The method according to claim 18 or 19, wherein the composition comprises about 1% by weight of rapamycin.

21. The method according to any one of claims 1 to 20, wherein the composition comprises a water-retaining agent.

22. The method according to claim 21, wherein the water-retaining agent comprises polyoxyethylene stearate.

23. The method according to any one of claims 1 to 22, wherein the composition comprises a softening agent.

24. The method according to claim 23, wherein the softening agent comprises one or more of propylene glycol, petrolatum, lanolin, mineral oil, glycerin, lecithin, and sorbitol.

25. The method according to any one of claims 1 to 24, wherein the composition comprises a buffering agent.

26. The method according to claim 25, wherein the buffering agent comprises one or more of anhydrous citric acid, sodium bicarbonate, and triethanolamine.

27. The method according to any one of claims 1 to 26, wherein the composition comprises a metal ion chelating agent.

28. The method according to claim 26, wherein the metal ion chelating agent comprises one or more of disodium edetate, citric acid, and tetrasodium EDTA.

29. The method according to any one of claims 1 to 28, wherein the composition comprises a hydroxide for pH adjustment.

30. The method according to any one of claims 1 to 29, wherein the composition comprises a preservative.

31. The method according to claim 30, wherein the preservative comprises one or more of potassium sorbate, diazolidinyl urea, phenoxyethanol, and sodium hydroxymethylglycinate.

32. The method according to any one of claims 1 to 31, wherein the composition comprises 58% to 72% by weight of water.

33. The composition is a) 0.5 to 5% by weight of rapamycin b) Below: 7-28% by weight of monolaurin, 7-28% by weight of monomyristate Vehicles including, and c) The method according to any one of claims 1 to 7, comprising water as a solvent.

34. The method according to any one of claims 1 to 7, wherein the composition comprises 0.5 to 5% by weight of rapamycin, 5% to 9% by weight of monolaurin, and 19% to 23% by weight of monomyristaten.

35. The method according to claim 34, wherein the composition comprises 0.5 to 5% by weight of rapamycin, 7% by weight of monolaurin, and 21% by weight of monomyristaten.

36. The method according to claim 34, wherein the composition comprises 1% by weight of rapamycin, 7% by weight of monolaurin, and 21% by weight of monomyristaten.

37. The method according to any one of claims 1 to 7, wherein the composition comprises 0.5 to 5% by weight of rapamycin, 12% to 16% by weight of monolaurin, and 12% to 16% by weight of monomyristaten.

38. The method according to claim 38, wherein the composition comprises 0.5 to 5% by weight of rapamycin, 14% by weight of monolaurin, and 14% by weight of monomyristaten.

39. The method according to claim 38, wherein the composition comprises 0.5% or 1% by weight of rapamycin, 14% by weight of monolaurin, and 14% by weight of monomyristaten.

40. The method according to any one of claims 1 to 7, wherein the composition comprises 0.5 to 5% by weight of rapamycin, 17.5% by weight (±2%) of monolaurin, and 10.5% by weight (±2%) of monomyristaten.

41. The method according to any one of claims 1 to 7, wherein the composition comprises 0.5 to 5% by weight of rapamycin, 17.5% by weight of monolaurin, and 10.5% by weight of monomyristaten.

42. The method according to any one of claims 1 to 7, wherein the composition comprises 0.5% by weight or 1% by weight of rapamycin, 17.5% by weight of monolaurin, and 10.5% by weight of monomyristaten.

43. The method according to any one of claims 1 to 7, wherein the composition comprises 0.5% by weight or 1% by weight of rapamycin, 21% by weight of monolaurin, and 7% by weight of monomyristaten.

44. The method according to any one of claims 1 to 43, wherein the monolaurin is glyceryl monolaurate and the monomyristate is glyceryl monomyristate.

45. The method according to any one of claims 1 to 44, wherein the vascular abnormality includes angiofibroma, cutaneous vascular lesion, or port-wine stain.

46. The composition is a) 0.5 to 5% by weight of rapamycin b) Below: 10-18% by weight of monolaurin and 10-18% by weight of monomyristate Vehicles including, and c) The method according to any one of claims 1 to 7, comprising water as a solvent.

47. In the manufacture of compositions a) Rapamycin, b) Monolaurin and monomyristate as vehicles, c) water The use of the composition is d) 1 cm ２ 4 to 8 mg of rapamycin per unit, and / or e) For treating the aforementioned abnormalities on the skin of a human subject by topically administering the composition to vascular abnormalities at a dose of 1 to 6 mg of rapamycin once daily. use.

48. a) Rapamycin, b) Monolaurin and monomyristate as vehicles, c) water A composition comprising, d) 1 cm ２ 4 to 8 mg of rapamycin per unit, and / or e) 1-6 mg of rapamycin This method is for treating the aforementioned abnormalities on the skin of a human subject by topically administering the composition to the vascular abnormalities once a day in the amount specified above. composition.

49. A method for treating vascular abnormalities in the skin of human subjects, a) As the active ingredient, rapamycin, b) A vehicle containing monolaurin and monomyristate, and c) Water as a solvent The method involves applying a composition containing the above to the abnormally localized area once a day for at least one, two, three, four, five, or six months. As a result, the method ensures that, at the end of at least one, two, three, four, five, or six months, the concentration of rapamycin in the target bloodstream, if present, does not exceed 1 ng / mL, 2 ng / mL, 3 ng / mL, 4 ng / mL, or 5 ng / mL.

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