Rapamycin compositions

Abstract

Rapamycin is a known pharmaceutical therapeutic substance. One problem with rapamycin is that it is very unstable and prone to chemical degradation during storage. This can result in the drug becoming "under strength" within the shelf life. It is an object of the present invention to at least to some extent address this problem. Disclosed is a composition for topical treatment comprising as an active ingredient rapamycin; a carrier comprising glyceryl monolaurate, such as glyceryl monolaurate and glyceryl monomyristate, such as glyceryl monomyristate; and water as a solvent.

Description

Technical Field

[0001] This invention relates to a rapamycin composition for human administration. Background Technology

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

[0003]

[0004] One problem with rapamycin is that it is very unstable and prone to chemical degradation during storage. This can cause the drug to become "insufficient in strength" by the end of its shelf life. Summary of the Invention

[0005] Objective of the present invention

[0006] The objective of a preferred embodiment of the present invention is to at least partially address the above-mentioned problems. While this applies to the preferred embodiment, it should be understood that the objectives of the invention are not limited thereto. It is merely intended to provide the public with a useful alternative. Therefore, any objective, advantage, or benefit of any preferred embodiment should not be construed as a limitation on any claim made in the broader sense.

[0007] definition

[0008] When used herein in connection with a combination of features or steps, the term "comprising" or its derivatives, such as "comprises," should not be construed as excluding the option of having additional features or steps not yet mentioned. Therefore, the term is inclusive rather than exclusive. Invention Overview

[0010] In this section, reference to a composition or its characteristics means any of the options given for the composition, unless it is explicitly stated that only one or more specific options of the composition are referred to.

[0011] According to one aspect of the present invention, a composition for local treatment is provided, characterized in that it comprises:

[0012] a) Rapamycin as the active ingredient;

[0013] b) Carrier, including:

[0014] o-Glyceryl monolaurate, such as glyceryl monolaurate; and

[0015] o-Myristate glycerides, such as glyceryl myristate ester; and

[0016] c) Water as a solvent.

[0017] Optionally, the rapamycin is present in an amount of 0.5 wt% to 5 wt%.

[0018] Optionally, the rapamycin is present in an amount of about 0.5 wt%.

[0019] Optionally, the rapamycin is present in an amount of about 1.0 wt%.

[0020] Optionally, the rapamycin is present in an amount of about 5.0 wt%.

[0021] Optionally, it can be used to treat angiofibroma.

[0022] Optionally, it can be used to treat facial angiofibroma.

[0023] Optionally, it can be used to treat skin vascular lesions.

[0024] Optionally, it can be used to treat port-wine stains.

[0025] Optionally, it can be used to treat port-wine stains after laser treatment.

[0026] Glyceryl monolaurate

[0027] Optionally, the monolaurate contains one or more monolaurates (e.g., glyceryl monolaurate).

[0028] Optionally, the monolaurate glyceride is present in an amount of about 7 wt% to 28 wt%, about 5 wt% to 10 wt%, or about 7 wt%.

[0029] Glyceryl monomyristic acid glyceride

[0030] Optionally, the glyceryl monomyristicate comprises one or more monomyristic esters, such as glyceryl monomyristicate.

[0031] Optionally, the glyceryl monomyristicate, such as glyceryl monomyristicate, is present in an amount of about 7 wt% to 28 wt%, about 15 wt% to 25 wt%, or about 21 wt%.

[0032] Optionally, the composition comprises:

[0033] a) 5 wt% to 9 wt% glyceryl monolaurate + 19 wt% to 23 wt% glyceryl monomyristate;

[0034] b) 26wt% to 30wt% glyceryl monolaurate + 0wt% to 2wt% glyceryl monomyristate;

[0035] c) 0 wt% to 2 wt% glyceryl monolaurate + 26 wt% to 30 wt% glyceryl monomyristate;

[0036] d) 12wt% to 16wt% glyceryl monolaurate + 12wt% to 16wt% glyceryl monomyristate.

[0037] Optionally, the composition comprises:

[0038] a) Approximately 7 wt% glyceryl monolaurate + approximately 21 wt% glyceryl monomyristate;

[0039] b) Approximately 28 wt% glyceryl monolaurate + approximately 0 wt% glyceryl monomyristate;

[0040] c) Approximately 0 wt% glyceryl monolaurate + approximately 28 wt% glyceryl monomyristate;

[0041] d) Approximately 14 wt% glyceryl monolaurate + approximately 14 wt% glyceryl monomyristate.

[0042] For each combination mentioned in a) to d) above, rapamycin is optionally present in an amount of about 1% wt.

[0043] The first mention of some preferences of the present invention

[0044] Preferably, the composition comprises 0.5 wt% to 5 wt% rapamycin, 5 wt% to 9 wt% glyceryl monolaurate and 19 wt% to 23 wt% glyceryl monomyristate.

[0045] Preferably, the composition comprises 0.5 wt% to 5 wt% rapamycin, 7 wt% glyceryl monolaurate and 21 wt% glyceryl monomyristate.

[0046] Preferably, the composition comprises 1 wt% rapamycin, 7 wt% glyceryl monolaurate and 21 wt% glyceryl monomyristate.

[0047] Preferably, the composition comprises 0.5 wt% to 5 wt% rapamycin, 12 wt% to 16 wt% glyceryl monolaurate and 12 wt% to 16 wt% glyceryl monomyristate.

[0048] Preferably, the composition comprises

[0049] Preferably, the composition comprises 0.5 wt% to 5 wt% rapamycin, 14 wt% glyceryl monolaurate and 14 wt% glyceryl monomyristate.

[0050] Preferably, the composition comprises 1 wt% rapamycin, 14 wt% glyceryl monolaurate and 14 wt% glyceryl monomyristate.

[0051] Preferably, the composition comprises 0.5 wt% to 5 wt% rapamycin, 17.5 wt% (±2 wt%) glyceryl monolaurate and 10.5 wt% (±2 wt%) glyceryl monomyristate.

[0052] Preferably, the composition comprises 1 wt% rapamycin, 17.5 wt% glyceryl monolaurate and 10.5 wt% glyceryl monomyristate.

[0053] Preferably, the composition comprises 1 wt% rapamycin, 21 wt% glyceryl monolaurate and 7 wt% glyceryl monomyristate.

[0054] Preferably, the monolaurate is glyceryl monolaurate, and the monomyristic acid glyceride is glyceryl monomyristic acid ester.

[0055] Preferably, the composition is formulated to treat human angiofibroma, cutaneous vascular lesions, or port-wine stains.

[0056] In a preferred embodiment, the composition comprises:

[0057] a) 0.5 wt% to 5 wt% rapamycin;

[0058] b) A carrier comprising: 7 wt% to 28 wt% monolaurin; and 7 wt% to 28 wt% monomyristin; and

[0059] c) Water as a solvent.

[0060] In another preferred embodiment, the composition comprises:

[0061] a) 0.5 wt% to 5 wt% rapamycin;

[0062] b) A carrier comprising: 7 wt% to 28 wt% monolaurin; and 7 wt% to 28 wt% monomyristin; and

[0063] c) Water as a solvent.

[0064] In another preferred embodiment, the composition comprises:

[0065] a) 0.5 wt% to 5 wt% rapamycin;

[0066] b) A carrier comprising: 10 wt% to 18 wt% monolaurin; and 10 wt% to 18 wt% monomyristin; and

[0067] c) Water as a solvent.

[0068] Water-retaining agent

[0069] Optionally, the composition comprises a water-retaining compound, such as polyoxyethylene stearate, which is present in an amount of about 1% wt.

[0070] Other moisturizing agents, such as hyaluronic acid, can be used as appropriate.

[0071] softener

[0072] Optionally, the composition includes a plasticizer, such as propylene glycol. Preferably, the plasticizer, such as propylene glycol, is present in an amount of about 2% wt.

[0073] Other optional softeners include one or more of petrolatum, lanolin, mineral oil, glycerin, lecithin, and sorbitol.

[0074] buffer

[0075] Optionally, the composition comprises 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 3-5, more preferably in the range of 3.5 to 4.5.

[0076] Optional buffers include one or more of sodium bicarbonate and triethanolamine.

[0077] Chelating agents

[0078] Optionally, the composition includes a chelating agent, such as disodium ethylenediaminetetraacetate. Preferably, the chelating agent, such as disodium ethylenediaminetetraacetate, is present in an amount of about 0.05% wt.

[0079] Other optional chelating agents include one or more of citric acid and tetrasodium EDTA.

[0080] pH adjuster

[0081] Optionally, the composition includes a hydroxide for pH adjustment, such as sodium hydroxide. Optionally, sodium hydroxide is present in an amount of about 0.18% wt.

[0082] preservative

[0083] Optionally, the composition includes a preservative, such as potassium sorbate. Preferably, the preservative, such as potassium sorbate, is present in an amount of about 0.2% wt.

[0084] Other preservatives that may be used include one or more of diazourea, phenoxyethanol, and sodium hydroxymethylglycinate.

[0085] water

[0086] Optionally, water is present in an amount of approximately 58% to 72% wt.

[0087] Optionally, the composition is formed according to any of the above combinations such that rapamycin is in the form of multiple layers of undissolved or suspended particles, wherein each layer is substantially located between the carrier layers. Preferably, the particle size is in the range of 1 μm to 100 μm.

[0088] According to another objective, the present invention includes the use of one or more of the components stated above for the manufacture of a composition for the topical treatment of angiofibroma.

[0089] According to another objective, the present invention includes a method for treating human angiofibroma with one or more of the compositions described above.

[0090] According to another object of the present invention, a method is provided for treating one or more of the following conditions by topical application of a composition according to any one of the foregoing claims, said conditions including:

[0091] • Angiofibroma (e.g., facial angiofibroma);

[0092] • Skin vascular lesions; and

[0093] • Port-wine stains (e.g., after laser treatment).

[0094] Optionally, the composition may be applied topically to a person.

[0095] Optionally, the composition is applied to a person so that it comes into contact with their dermis.

[0096] Optionally, the composition may be applied by the person himself or by another person to that person.

[0097] Optionally, the composition is contained in and administered from a squeeze tube.

[0098] According to some specific examples of the present invention, the components or methods are as described above, except that they consist of, or are substantially composed of, the features or steps described in various cases.

[0099] According to another purpose, the present invention includes (or consists of, or substantially consists of) the following uses:

[0100] Rapamycin is the active ingredient;

[0101] • Carrier, including:

[0102] o-Glyceryl monolaurate, such as glyceryl monolaurate; and

[0103] o-Myristate glycerides, such as glyceryl myristate ester; and

[0104] Water is used as a solvent.

[0105] In the process of preparing the above-described composition for treating any of the conditions mentioned in the above methods, the composition may optionally conform to any of the above options or preferences. Attached Figure Description

[0106] Some preferred embodiments of the present invention are described with reference to the following figures, wherein:

[0107] Figure 1 This presents the results of particle size analysis of a 1% rapamycin composition obtained for topical application; and

[0108] Figure 2 Images showing rapamycin particles in the same 1% composition. Detailed Implementation

[0109] Example formulations 1 and 2

[0110] Two preferred embodiments of the present invention, namely formulation 1 and formulation 2, are used for the topical treatment of human angiofibromas, such as facial angiofibromas or skin vascular lesions. The formulations can be used to treat port-wine stains, for example, after laser treatment. Their composition is approximately as follows:

[0111]

[0112] The compositions according to the invention, including formulation 1 and formulation 2, can be produced according to the following methods.

[0113] Production of aqueous premixes

[0114] The aqueous premix was prepared as follows:

[0115] Combine rapamycin and propylene glycol and vortex mix;

[0116] Add water and continue vortexing;

[0117] The mixture is then heated to 70°C (±5°C).

[0118] • Add citric acid, disodium EDTA, and potassium sorbate, and vortex until dissolved;

[0119] Then adjust the temperature of the mixture to 50°C; and

[0120] • Polyoxyethylene (100) stearate has been added.

[0121] Production of oil phase premixes

[0122] The oil-phase premix was prepared as follows:

[0123] • Glyceryl monolaurate and glyceryl monomyristate are combined and vortexed at low speed and heated to 70°C (±5°C).

[0124] Final mixture

[0125] The aqueous and oil premixes, both premixed at 70°C (±5°C), were combined and thoroughly mixed until homogeneous. The mixture was then slowly cooled and vortexed at a rate of 1°C / min until a smooth, white, iridescent cream was formed. When the cream had cooled to no more than 32°C, it was packaged into 30 mL aluminum tubes with polypropylene screw caps.

[0126] Example formulations 3 and 4

[0127] The preparation purposes and methods of formulations 3 and 4 are the same as those described for formulations 1 and 2. They are as follows:

[0128]

[0129]

[0130] Stability studies of formulations 1-4

[0131] Studies were conducted to determine whether formulations 1-4 were stable at room temperature (i.e., 25°C (±2°C) and 60% (±5°C) 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 each case, the reference to the test value "specification" is related to the patentee's preferred threshold.

[0132]

[0133]

[0134]

[0135]

[0136]

[0137]

[0138]

[0139]

[0140] The tests showed that formulations 1, 2, and 4 remained stable at room temperature. These results are significant, especially considering that current market products lose stability much earlier. For example, Nobelpharma supplies the Japanese market with a 0.2% by weight rapamycin gel formulation under the brand name Rapalimus. TM It has a stability of only 12 months, and that stability is only present when refrigerated.

[0141] In a further embodiment, a formulation of 0.1% by weight rapamycin cream was sourced from the US market and tested, and was found to be unstable even at room temperature, as shown below-

[0142]

[0143] Surprisingly, formulation 3 (0.1% rapamycin) was found to be unstable. After 12 and 18 months of storage, rapamycin degraded to 79.3% and 67.9% of the labeled amount, respectively. In contrast, the higher strengths (0.5%–5%) yielded unexpectedly superior results. The better results from the higher strengths are difficult to explain and appear to be due to a surprising synergistic effect.

[0144] Example formulation 5-11

[0145] The following further formulations are prepared in the same manner as described above, for use in formulations 1-4, and for the same therapeutic purpose.

[0146]

[0147]

[0148] These formulations underwent storage stability testing at room temperature, i.e., 25°C (±2°C) and 60% (±5%) relative humidity, for a period of 6 months.

[0149] The test results are shown in the table below. In each case, the T value represents the time since the sample was tested; for example, T0 indicates testing at 0 months, T1 indicates testing at 1 month, and so on. The percentage (%) shows the proportion of 1% by weight of the rapamycin label retained at each test point. Lower rapamycin levels indicate that the compound has undergone degradation.

[0150]

[0151] Formulations 5-11 were also retested at each time interval to check for excessive water content. Samples were considered acceptable if they met the limit of 62–72% by weight. Results are as follows—

[0152]

[0153] *Note: In addition, Formulation 6 failed to meet appearance specifications.

[0154]

[0155] For useful formulations, the rapamycin content should not be less than 90% of the original amount, as this represents a 10% loss of the potency of the active ingredient and is consistent with formulations that are unstable due to the hydrolysis / oxidation of the active ingredient.

[0156] Regarding water content, each composition is an oil-in-water product, therefore the amount of water present is related to maintaining a stable and homogeneous formulation. Water content exceeding acceptable limits indicates a lack or loss of formulation stability. Skin absorption was measured using a Franz cell diffusion apparatus. Studies of preferred formulations 1 and 2 showed higher absorption and permeability in a human skin model than formulation 3, with validated restoration of mass balance. More specifically, absorption of 5% bovine serum albumin in a 0.9% NaCl aqueous solution was measured through healthy human skin using a Franz cell diffusion apparatus. Only the higher-strength formulations, namely formulations 1 and 2, met the acceptance criteria for human skin absorption and permeation. Formulation 3 failed this test. This failure of formulation 3 was not related to stability, as the test was conducted with freshly prepared material. The difference in skin absorption and permeation was unexpected.

[0157] Figure 1 and Figure 2 This describes the characteristics of the rapamycin active ingredient in the 1% cream of formulation 2 described above. This information was obtained by analyzing the formulation using a Malvern Morphologi GS3 image analyzer. This is essentially an automated microscope that scans the formulation to detect the 3D shape characteristics of the rapamycin particles.

[0158] See Figure 1 The CE diameter (circle equivalent diameter) value represents a number-weighted granularity. In other words, it represents the particles as a two-dimensional shape that is closest to the applicable circle, and then calculates the diameter of said circle. Referring to the specific notation shown, D[n,0.10](μm): 3.17 means that, based on the number of particles, 10% of the particles are 3.17 μm or smaller; D[n,0.16](μm): means that 16% are less than 3.83 μm; and D[n,0.50](μm): means that, based on the number of particles, 50% are less than 8.33 μm, and so on.

[0159] refer to Figure 2 The image represents the shape and relative size of rapamycin particles in formulation 2.

[0160] Figure 1 and Figure 2 This indicates that rapamycin does not dissolve in the rest of the composition, but is suspended in the carrier or excipient component.

[0161] For the purposes of disclosure, this document hereby discloses combinations of each item, feature, or step mentioned herein with one or more of any other item, feature, or step disclosed herein, in each case whether such combination is claimed.

[0162] While some preferred embodiments of the invention have been described by way of example, it should be understood that modifications and improvements can be made without departing from the scope of the appended claims.

Claims

1. A composition for topical treatment, characterized by: Comprising: a) 0.5 wt% to 5 wt% of rapamycin as an active ingredient; b) a vehicle comprising: 5 wt% to 9 wt% of glyceryl monolaurate; and 19 wt% to 23 wt% of glyceryl monomyristate; and c) water as a solvent.

2. The composition of claim 1, wherein: The rapamycin is present in an amount of 0.5 wt%.

3. The composition of claim 1, wherein: The rapamycin is present in an amount of 1.0 wt%.

4. The composition of claim 1, wherein: The rapamycin is present in an amount of 5.0 wt%.

5. The composition of claim 1, wherein: The composition consists of, by weight: 0.5% rapamycin, 7% glyceryl monolaurate, 21% glyceryl monomyristate, 1% polyoxyl stearate, 2% propylene glycol, 0.9% anhydrous citric acid, 0.05% edetate disodium, 0.18% sodium hydroxide, 0.2% potassium sorbate, and 67.17% water.

6. The composition of claim 1, wherein: The composition consists of, by weight: 1% rapamycin, 7% glyceryl monolaurate, 21% glyceryl monomyristate, 1% polyoxyl stearate, 2% propylene glycol, 0.9% anhydrous citric acid, 0.05% edetate disodium, 0.18% sodium hydroxide, 0.2% potassium sorbate, and 66.67% water.

7. The composition of claim 1, wherein: The composition is: a) 7 wt% of glyceryl monolaurate + 21 wt% of glyceryl monomyristate + 1 wt% to 5 wt% of rapamycin.

8. The composition of claim 1, wherein: The composition includes a water-retaining agent.

9. The composition of claim 8, wherein: The water-retaining agent includes polyoxyl stearate.

10. The composition of claim 1, wherein: The composition includes a softening agent.

11. The composition of claim 10, wherein: The softening agent includes one or more of propylene glycol, paraffin wax, lanolin, mineral oil, glycerin, lecithin, and sorbitol.

12. The composition of claim 1, wherein: The composition includes a buffering agent.

13. The composition of claim 12, wherein: The buffering agent includes one or more of anhydrous citric acid, sodium bicarbonate, and triethanolamine.

14. The composition of claim 1, wherein: The composition includes a chelating agent.

15. The composition of claim 14, wherein: The chelating agent includes one or more of edetate disodium, citric acid, and tetrasodium EDTA.

16. The composition of claim 1, wherein: The composition includes a hydroxide for pH adjustment.

17. The composition of claim 1, wherein: The composition includes a preservative.

18. The composition of claim 17, wherein: The preservative includes one or more of potassium sorbate, diazolidinyl urea, phenoxyethanol, and sodium hydroxymethylglycinate.

19. The composition of claim 1, wherein: Comprising: 1 wt% of rapamycin, 7 wt% of glyceryl monolaurate, and 21 wt% of glyceryl monomyristate.

20. Use of 0.5 wt% to 5 wt% of rapamycin as an active ingredient, 5 wt% to 9 wt% of glycerol monolaurate and 19 wt% to 23 wt% of glycerol monomyristate as a carrier, and water as a solvent in the manufacture of a medicament, characterized in that: The medicament is for topical treatment of one or more of: • angiofibroma; • cutaneous vascular lesions; and • port wine stains. The composition consists of, by weight: 0.5% rapamycin, 7% glyceryl monolaurate, 21% glyceryl monomyristate, 1% polyoxyl stearate, 2% propylene glycol, 0.9% anhydrous citric acid, 0.05% edetate disodium, 0.18% sodium hydroxide, 0.2% potassium sorbate, and 67.17% water. The composition consists of, by weight: 1% rapamycin, 7% glyceryl monolaurate, 21% glyceryl monomyristate, 1% polyoxyl stearate, 2% propylene glycol, 0.9% anhydrous citric acid, 0.05% edetate disodium, 0.18% sodium hydroxide, 0.2% potassium sorbate, and 66.67% water. The composition is: a) 7 wt% of glyceryl monolaurate + 21 wt% of glyceryl monomyristate + 1 wt% to 5 wt% of rapamycin. The composition includes a water-retaining agent. The water-retaining agent includes polyoxyl stearate. The composition includes a softening agent. The softening agent includes one or more of propylene glycol, paraffin wax, lanolin, mineral oil, glycerin, lecithin, and sorbitol. The composition includes a buffering agent. The buffering agent includes one or more of anhydrous citric acid, sodium bicarbonate, and triethanolamine. The composition includes a chelating agent. The chelating agent includes one or more of edetate disodium, citric acid, and tetrasodium EDTA. The composition includes a hydroxide for pH adjustment. The composition includes a preservative. The preservative includes one or more of potassium sorbate, diazolidinyl urea, phenoxyethanol, and sodium hydroxymethylglycinate. Comprising: 1 wt% of rapamycin, 7 wt% of glyceryl monolaurate, and 21 wt% of glyceryl monomyristate. The medicament is for topical treatment of one or more of: • angiofibroma; • cutaneous vascular lesions; and • port wine stains.

Images