Rapamycin composition

Abstract

The present invention provides a composition that suppresses the chemical decomposition of rapamycin during storage. [Solution] A local therapeutic composition, a) Rapamycin as the active ingredient; b) Vehicles including the following: ○Monolaurin, for example, as glyceryl monolaurate; and ○Monomyristate, for example, as glyceryl monomyristate; and c) Water as a solvent A composition containing the following:

Description

Technical Field

[0001] The present invention relates to a rapamycin composition for administration to humans.

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 US Patent No. 3,929,992 to Ayerst McKenna & Harrison. Rapamycin has the following structural formula:

Chemical Formula

[0003] [[ID=z1]] A problem with rapamycin is that it is very unstable and prone to chemical decomposition during storage. As a result, the pharmaceutical product may become "underpowered" during its shelf life.

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. It should be understood that while this applies to the preferred embodiment, the object of the present invention itself is not so limited. The object of the present invention is simply to provide useful choices for the general public. Therefore, any object, advantage, or benefit of any preferred embodiment should not be "read-in" as a limitation to any claim expressed more broadly.

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

[0006] In this section, references to compositions or their characteristics mean any of the options available for a composition, unless it becomes clear that only one or more specific options for a composition are being referred to.

[0007] According to one aspect of the present invention, a local therapeutic composition, • Rapamycin as an active ingredient; Vehicles including the following: ○Monolaurin, for example, as glyceryl monolaurate; and ○Monomyristate, for example, as glyceryl monomyristate; and • Water as a solvent A composition containing the following is provided.

[0008] Optionally, rapamycin may be present in an amount of 0.5 to 5% by weight.

[0009] Optionally, rapamycin is present in an amount of approximately 0.5% by weight.

[0010] Optionally, rapamycin is present in an amount of approximately 1.0% by weight.

[0011] Optionally, rapamycin is present in an amount of approximately 5.0% by weight.

[0012] Optionally, the composition is intended for the treatment of angiofibromas.

[0013] Optionally, the composition is intended for the treatment of facial angiofibromas.

[0014] Optionally, the composition is for treating skin vascular lesions.

[0015] Optionally, the composition is for treating port-wine stains.

[0016] Optionally, the composition is for treating port-wine stains after laser treatment of port-wine stains.

[0017] Monolaurin Optionally, monolaurin contains one or more monolaurates (e.g., glycerol monolaurate).

[0018] Optionally, monolaurin is present in an amount of about 7 - 28 wt% or about 5 wt% - 10 wt%, preferably about 7 wt%.

[0019] Monomyristin Optionally, monomyristin contains one or more monomyristates, e.g., glyceryl monomyristate.

[0020] Optionally, monomyristin, e.g., glyceryl monomyristate, is present in an amount of about 7 wt% - 28 wt% or about 15 wt% - 25 wt%, preferably about 21 wt%.

[0021] Combined amount of monolaurin and monomyristin Optionally, the composition a) 5 wt% - 9 wt% monolaurin + 19 wt% - 23 wt% monomyristin; b) 26 wt% - 30 wt% monolaurin + 0 wt% - 2 wt% monomyristin; c) 0 wt% - 2 wt% monolaurin + 26 - 30 wt% monomyristin; d) 12 wt% - 16 wt% monolaurin + 12 - 16 wt% monomyristin and optionally, the composition a) about 7 wt% monolaurin + about 21 wt% monomyristin; b) Approximately 28% by weight of monolaurin + approximately 0% by weight of monomyristin; c) Approximately 0% by weight + approximately 28% by weight of monomyristin; d) Approximately 14% by weight of monolaurin + approximately 14% by weight of monomyristin which contains.

[0022] For each of the combination amounts shown in each of the above sets a) - d), rapamycin is optionally present in an amount of approximately 1% by weight.

[0023] Some priorities for the first mentioned aspect of the present invention Preferably, the composition contains 0.5 - 5% by weight of rapamycin, 5% - 9% by weight of monolaurin and 19% - 23% by weight of monomyristin.

[0024] Preferably, the composition contains 0.5 - 5% by weight of rapamycin, 7% by weight of monolaurin and 21% by weight of monomyristin.

[0025] The composition preferably contains 1% by weight of rapamycin, 7% by weight of monolaurin and 21% by weight of monomyristin.

[0026] Preferably, the composition contains 0.5 - 5% by weight of rapamycin, 12% - 16% by weight of monolaurin and 12% - 16% by weight of monomyristin.

[0027] Preferably, the composition contains 0.5 - 5% by weight of rapamycin, 14% by weight of monolaurin and 14% by weight of monomyristin.

[0028] Preferably, the composition contains 1% by weight of rapamycin, 14% by weight of monolaurin and 14% by weight of monomyristin.

[0029] Preferably, the composition contains 0.5 - 5% by weight of rapamycin, 17.5% by weight (±2% by weight) of monolaurin and 10.5% by weight (±2% by weight) of monomyristin.

[0030] Preferably, the composition comprises 1% by weight of rapamycin, 17.5% by weight of monolaurin, and 10.5% by weight of monomyristate.

[0031] Preferably, the composition comprises 1% by weight of rapamycin, 21% by weight of monolaurin, and 7% by weight of monomyristate.

[0032] Preferably, monolaurin is glyceryl monolaurate, and monomyristate is glyceryl monomyristate.

[0033] Preferably, the composition is formulated to be suitable for treating angiofibromas, cutaneous vascular lesions, or port-wine stains in humans.

[0034] One preferred option is the composition, a) 0.5-5% by weight of rapamycin; b) Vehicles including the following: • 7-28% by weight of monolaurin; and • 7-28% by weight of monomyristate; and c) Water as a solvent Includes.

[0035] Another preferred option is the composition, a) 0.5-5% by weight of rapamycin; b) Vehicles including the following: • 7-28% by weight of monolaurin; and • 7-28% by weight of monomyristate; and c) Water as a solvent Includes.

[0036] Another preferred option is the composition, a) 0.5-5% by weight of rapamycin; b) Vehicles including the following: • 10-18% by weight of monolaurin; and • 10-18% by weight of monomyristate; and c) Water as a solvent Includes.

[0037] Water-retaining agent Optionally, the composition may contain a water-retaining compound, such as polyoxyethylene stearate, in an amount of about 1% by weight.

[0038] Any other moisturizing agent, such as hyaluronic acid, may be used.

[0039] Softener Optionally, the composition may contain a softening agent, such as propylene glycol. Preferably, the softening agent, such as propylene glycol, is present in an amount of about 2% by weight.

[0040] Any other emollients may include one or more of petrolatum, lanolin, mineral oil, glycerin, lecithin, and sorbitol.

[0041] cushioning agent Optionally, the composition includes a buffer, such as anhydrous citric acid. Preferably, the buffer, such as anhydrous citric acid, is present in an amount of about 2% by weight. Preferably, the buffer maintains the pH of the composition in the range of 3 to 5, more preferably in the range of 3.5 to 4.5.

[0042] Any other buffering agent may include one or more of sodium bicarbonate and triethanolamine.

[0043] Metal ion chelating agent Optionally, the composition may contain a metal ion chelating agent, such as disodium edetate. Preferably, the metal ion chelating agent, such as disodium edetate, is present in an amount of about 0.05% by weight.

[0044] Any other metal ion chelating agent may include one or more of citrate and tetrasodium EDTA.

[0045] pH adjuster Optionally, the composition may contain a hydroxide, such as sodium hydroxide, for pH adjustment. Optionally, sodium hydroxide may be present in an amount of approximately 0.18% by weight.

[0046] Preservatives Optionally, the composition may contain a preservative, such as potassium sorbate. Preferably, the preservative, such as potassium sorbate, is present in an amount of about 0.2% by weight.

[0047] Any other preservatives available for use include one or more of diazolidinyl urea, phenoxyethanol, and sodium hydroxymethylglycinate.

[0048] water Optionally, water is present in an amount of approximately 58% to 72% by weight.

[0049] Optionally, the composition is in the form of any of the above combinations, wherein rapamycin is in the form of multiple layers of insoluble or suspended particles, each layer being formed to be substantially located between layers of vehicle. Preferably, the particles have a size in the range of 1 to 100 μm.

[0050] In another aspect, the present invention includes the use of one or more of the above-described components in the manufacture of a composition for the topical treatment of angiofibroma.

[0051] In a further embodiment, the present invention includes a method for treating human angiofibroma with a composition comprising one or more of the above-described elements.

[0052] According to another aspect of the present invention, a method is provided for treating one or more of the following conditions, comprising the step of administering a composition according to any of the above-described methods to a human: Facial angiofibroma; • Skin vascular lesions; and • Port-wine stain (for example, after laser treatment of a port-wine stain).

[0053] Optionally, the composition may be administered topically to humans.

[0054] Optionally, the composition may be administered to humans so as to reach the human dermis.

[0055] Optionally, the composition may be administered to the person by themselves or to the person by another person.

[0056] Optionally, the composition may be contained in a squeeze tube and administered through the squeeze tube.

[0057] According to some embodiments of the present invention, compositions or methods are described as above, except that they consist of or essentially consist of the features or steps described in each case.

[0058] In a further embodiment, the present invention relates to the preparation of the above compositions for use in treating any of the conditions mentioned above in the above methods, • Rapamycin as an active ingredient; Vehicles including the following: ○Monolaurin, for example, as glyceryl monolaurate; and ○Monomyristate, for example, as glyceryl monomyristate; and • Water as a solvent This includes (or consists of, or essentially consists of) the use of. Optionally, the composition may conform to any of the above options or priorities.

[0059] Some preferred embodiments of the present invention are illustrated by reference to the following images. [Brief explanation of the drawing]

[0060] [Figure 1] Figure 1 shows the results obtained from particle size analysis of a 1% rapamycin composition for topical application. [Figure 2] Figure 2 shows an image of rapamycin particles in the same 1% composition. [Modes for carrying out the invention]

[0061] Formulation Examples 1 and 2 Two preferred embodiments of the present invention, namely Formulation 1 and Formulation 2, are for the topical treatment of human angiofibromas, such as facial angiofibromas or cutaneous vascular lesions. The formulations may be used, for example, to treat port-wine stains after laser treatment. They are substantially configured as follows: [Table 1]

[0062] The compositions according to the present invention, comprising formulations 1 and 2, can be manufactured according to the following method.

[0063] 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).

[0064] Preparation of the oil phase preblend The oil phase preblend is prepared as follows: Combine glyceryl monolaurate and glyceryl monostearate using a slow vortex mixing method and heating to 70°C (±5°C).

[0065] 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 / min and vortex mix 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.

[0066] Formulation Examples 3 and 4 Formulations 3 and 4 were manufactured for the same purposes and in the same manner as described for Formulations 1 and 2. They are as follows: [Table 2]

[0067] Stability testing of formulations 1-4 Tests were conducted to determine whether formulations 1-4 were stable when stored at room temperature, i.e., 25°C (±2°C) and 60% (±5%) relative humidity. The test results are shown in the table below. In each case, T0 refers to the test result at 0 months, T1 to the test result at 1 month, T3 to the test result at 3 months, and so on. In all cases, the reference to the "specification" of the test value refers to the patent holder's preferred threshold. [Table 3-1] [Table 3-2] [Table 4] [Table 5]

[0068] The tests showed that formulations 1, 2, and 4 remained stable at room temperature. These results were noteworthy, especially considering that current commercially available products are thought to lose stability significantly faster. For example, Nobelpharma supplies a 0.2 wt% rapamycin gel formulation to the Japanese market under the trademark Rapalimus®, which is stable for only 12 months when refrigerated.

[0069] In a further example, a formulation in the form of 0.1% by weight rapamycin cream was sourced from the US market and tested, and was found to be unstable at room temperature, as follows: [Table 6]

[0070] Surprisingly, formulation 3 (0.1% rapamycin) was found to be unstable. After storage for 12 and 18 months, the rapamycin had degraded to only 79.3% and 67.9% of the labeled amount, respectively. In comparison, higher potencies of 0.5% to 5% yielded unexpectedly superior results. The better results for higher potencies are difficult to explain and appear to be due to a surprising synergistic effect.

[0071] Formulation Examples 5-11 The following further formulations were prepared for the same therapeutic purposes using the same methods as described above for formulations 1-4. [Table 7]

[0072] These were subjected to storage stability tests for 6 months at room temperature of 25°C (±2°C) and relative humidity of 60% (±5%).

[0073] The test results are shown in the table below. In each case, the T value indicates when the sample was tested; for example, T0 indicates a test at 0 months, T1 indicates a test at 1 month, and so on. The % value indicates the percentage of rapamycin remaining at each test point, representing 1% by weight of the labeled amount. A lower rapamycin value indicates that the compound was subject to a degradation reaction. [Table 8]

[0074] Formulations 5-11 were also retested at each stage to check for excessive water content. Samples were considered acceptable if they met the range of 62-72% by weight. The results were as follows: [Table 9] [Table 10]

[0075] For a formulation to be useful, the rapamycin content should not fall below 90% of the original amount, as this represents a 10% loss of the active ingredient's potency, which is consistent with the formulation becoming unstable due to hydrolysis / oxidation of the active ingredient.

[0076] Regarding water content, since each composition is an oil-in-water product, the amount of water present is relevant to maintaining a stable and homogeneous formulation. Water content outside the acceptable limits indicates a lack or loss of formulation stability. Skin absorption was measured using a Franz cell diffusion apparatus. Tests of preferred formulations 1 and 2 showed absorption in a human skin model and higher permeability profiles than formulation 3, with effective mass balance restoration. More specifically, absorption of 5% bovine serum albumin into 0.9% NaCl water via healthy human skin was measured using Franz cells. Only formulations 1 and 2, which are higher potency formulations, met the acceptable criteria for absorption and permeability across human skin. Formulation 3 failed this test. This failure of formulation 3 was unrelated to stability, as the test was performed using newly prepared materials. The difference in skin absorption and permeability was surprising.

[0077] 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.

[0078] 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 3.17 μm or less on a particle basis; D[n,0.16](μm): means that 16% are smaller than 3.83 μm; D[n,0.50](μm): means that 50% are smaller than 8.33 μm on a particle number basis, and so on.

[0079] Referring to Figure 2, the image shows the shape and relative size of rapamycin particles in formulation 2.

[0080] 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.

[0081] 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.

[0082] 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 topical therapeutic composition, a) 0.5% to 5% by weight of rapamycin as the active ingredient; b) Vehicles including the following: 12% to 16% by weight of glyceryl monolaurate and 12% to 16% by weight of glyceryl monomyristate, or 15.5% to 19.5% by weight of glyceryl monolaurate and 8.5% to 12.5% ​​by weight of glyceryl monomyristate; and c) Water as a solvent A composition containing the following:

2. The composition according to claim 1, wherein the rapamycin is present in an amount of 0.5% by weight.

3. The composition according to claim 1, wherein the rapamycin is present in an amount of 1% by weight.

4. The composition according to claim 1, wherein the rapamycin is present in an amount of 5% by weight.

5. A composition according to claim 2, 3, or 4 for treating angiofibroma.

6. A composition according to claim 2, 3, or 4 for treating cutaneous vascular lesions.

7. A composition according to claim 2, 3, or 4 for treating port-wine stain.

8. The composition according to claim 2, 3, or 4, comprising 14% by weight of glyceryl monolaurate and 14% by weight of glyceryl monomyristate.

9. The composition according to claim 1, comprising a water-retaining agent.

10. The composition according to claim 1, comprising a softening agent.

11. The composition according to claim 1, comprising a buffering agent.

12. The composition according to claim 1, comprising a metal ion chelating agent.

13. The composition according to claim 1, comprising a hydroxide for pH adjustment.

14. The composition according to claim 1, comprising a preservative.

15. The composition according to claim 1, wherein the water is present in an amount of 58% to 72% by weight.

16. The composition according to claim 1, comprising a water-retaining agent, a softening agent, a buffering agent, a metal ion chelating agent, a hydroxide for pH adjustment, and a preservative.

17. The composition according to claim 3, wherein the glyceryl monolaurate is 14% by weight and the glyceryl monomyristate is 14% by weight.

18. The composition according to claim 3, wherein the amount of glyceryl monolaurate is 17.5% by weight and the amount of glyceryl monomyristate is 10.5% by weight.

19. Angiofibroma, Skin vascular lesions, and Port-wine stain For the manufacture of the composition according to claim 1, 2, 3, or 4 for treating one or more of the following: a) Rapamycin as the active ingredient; b) Vehicles including the following: Glyceryl monolaurate; and Glyceryl monomyristate; and c) Water as a solvent Use.

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