Gel composition for cleaning capsaicin on skin surface and application thereof

Abstract

The invention discloses a gel composition for cleaning capsaicin on a skin surface and application of the gel composition. The gel composition comprises an organic solvent, a surfactant, ethyl oleate, menthol, a gel matrix and water, the gel composition is used again after the capsaicin is applied to the skin surface for a proper time, so that the side effects generated by the capsaicin are reduced.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a gel composition for cleaning capsaicin from the skin surface and its application. Background Technology

[0002] Osteoarthritis (OA) is a common degenerative joint disease, affecting more than 10% of the total population. Over 50% of people over 65 years of age with knee pain have OA, and the prevalence exceeds 80% in those over 75 years of age. Osteoarthritis pain impairs joint function and significantly reduces quality of life. According to the "Chinese Clinical Practice Guideline for Pain Management in Osteoarthritis (2020 Edition)," topical analgesics are the first-line treatment for osteoarthritis pain, especially suitable for patients with concurrent gastrointestinal or cardiovascular diseases.

[0003] (Capsaicin) Capsaicin is a recognized topical analgesic. In concentrations between 0.025% and 0.25%, it is classified as an over-the-counter (OTC) topical analgesic. When the concentration exceeds 0.25%, topical capsaicin is generally poorly tolerated due to the burning and stinging sensation at the application site.

[0004] A high-concentration (5% w / w) capsaicin topical formulation is being studied in a clinical trial for the treatment of osteoarthritis pain. After application of the high-concentration (5% w / w) capsaicin topical formulation, researchers are required to thoroughly clean the application site with soapy water foam several times after a certain period of time (exemplarily 60 minutes). During the clinical trial, burning, stinging, and itching were observed at the application site after administration of the high-concentration (5% w / w) capsaicin topical formulation, with the burning and stinging score changing by approximately +2 points from the baseline maximum mean; mild skin reactions (erythema) at the application site were also observed. Based on clinical needs, there is a need to develop a dedicated cleaning product with superior cleaning effectiveness compared to soapy water foam, which can improve cleaning efficacy and ease of use. Summary of the Invention

[0005] This invention discloses a gel composition for cleaning capsaicin from the skin surface and its application; the gel composition includes an organic solvent, a surfactant, ethyl oleate, menthol, a gel matrix, and water; the gel composition is applied to the skin surface at an appropriate time after capsaicin application to reduce the side effects of capsaicin (such as burning, stinging, itching, and skin erythema).

[0006] In a first aspect, the present invention provides a gel composition comprising an organic solvent A, a surfactant, ethyl oleate, menthol, a gel matrix, and water; The gel composition also includes a pH adjuster; Optionally, the gel composition further includes an antioxidant.

[0007] In some embodiments, the organic solvent A is selected from: (i) ethanol, (ii) a combination of ethanol and diethylene glycol monoethyl ether; the organic solvent A is 50-70% by mass in the gel composition (e.g., 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%).

[0008] In some embodiments, the organic solvent A has a mass percentage of 55-65%, 55-57%, 57-59%, 59-61%, 61-63%, or 63-65% in the gel composition.

[0009] In some embodiments, the organic solvent A includes diethylene glycol monoethyl ether, which is present in the gel composition at a mass percentage of 5-20% (e.g., 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%).

[0010] In some embodiments, the organic solvent A is a combination of ethanol and diethylene glycol monoethyl ether, wherein the mass percentage of diethylene glycol monoethyl ether in the gel composition is 5-15% (e.g., 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%).

[0011] In some embodiments, the organic solvent A is a combination of ethanol and diethylene glycol monoethyl ether, wherein the mass percentage of diethylene glycol monoethyl ether in the gel composition is 7-10% or 10-13%.

[0012] In some embodiments, the surfactant is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol glycerol laurate, and polyethylene glycol stearate.

[0013] In some embodiments, the surfactant is present in the gel composition at a mass percentage of 2 to 8% (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%).

[0014] In some embodiments, the ethyl oleate is present in a mass percentage of 0.1-4% in the gel composition (e.g., 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.9%, 4.0%).

[0015] In some embodiments, the menthol comprises 2-10% by mass in the gel composition (e.g., 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%). In some embodiments, the menthol comprises 2.5-5%, 5-7.5%, or 7.5-10% by mass in the gel composition.

[0016] In some embodiments, the gel matrix is ​​selected from one or more of carbomer interpolymers, carbomer copolymers, and carbomer homopolymers.

[0017] In some embodiments, the gel matrix comprises 0.1% to 1% by mass in the gel composition (e.g., 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%). 52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.60%, 0.61%, 0.62%, 0.63%, 0.64%, 0.65%, 0.66%, 0.67%, 0.68%, 0.69%, 0.70%, 0.71%, 0.72%, 0.73%, 0.74%, 0.75%, 0.76%, 0.77%, 0.78%, 0.79%, 0.80%, 0.81%, 0.82%, 0.83%, 0.84%, 0.85%, 0.86%, 0.87%, 0.88%, 0.89%, 0.90%, 0.91%, 0.92%, 0.93%, 0.94%, 0.95%, 0.96%, 0.97%, 0.98%, 0.99%, 1.00%). In some embodiments, the gel matrix comprises 0.1 to 0.35% by mass in the gel composition.

[0018] In some embodiments, the pH adjuster is selected from one or more of triethanolamine, sodium hydroxide, and potassium hydroxide. In some embodiments, the pH adjuster is triethanolamine. In some embodiments, the pH of the gel composition is 5.5 to 8.5 (e.g., pH 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5). In some embodiments, the pH adjuster is triethanolamine, and the pH of the gel composition is 5.5 to 8.5. Unless otherwise specified, adjusting the pH to "neutral or near neutral" in this invention means adjusting the pH to 5.5 to 8.5.

[0019] In some embodiments, the gel composition includes an antioxidant selected from one or more of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, L-ascorbic acid, sodium L-ascorbate, calcium L-ascorbate, ascorbate palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA). In some embodiments, the antioxidant is present in the gel composition at a mass percentage of 0.005-0.05% (e.g., 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.013%, 0.014%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.020%, 0.025%, 0.0030%, 0.035%, 0.040%, 0.045%, 0.05%). In some embodiments, the antioxidant is present in the gel composition at a mass percentage of 0.005-0.02%.

[0020] In some embodiments, the gel composition comprises the organic solvent A, a surfactant, ethyl oleate, menthol, a gel matrix, a pH adjuster, and water.

[0021] In some embodiments, the gel composition comprises the organic solvent A, surfactant, ethyl oleate, menthol, gel matrix, pH adjuster, antioxidant, and water; In some embodiments, the gel composition includes ethanol, diethylene glycol monoethyl ether, polysorbate 80, ethyl oleate, menthol, a gel matrix, butylated hydroxytoluene (BHT), water, and a pH adjuster. In some embodiments, the pH adjuster is triethanolamine.

[0022] In some embodiments, the gel composition includes ethanol, diethylene glycol monoethyl ether, polysorbate 80, ethyl oleate, menthol, a gel matrix, butylated hydroxytoluene (BHT), water, and triethanolamine (pH adjuster); the combined mass percentage of ethanol and diethylene glycol monoethyl ether in the gel composition is 55-65%, the mass percentage of diethylene glycol monoethyl ether in the gel composition is 5-15%, the mass percentage of polysorbate 80 in the gel composition is 2-8%, the mass percentage of ethyl oleate in the gel composition is 0.1-4%, the mass percentage of menthol in the gel composition is 2.5-5%, 5%-7.5%, or 7.5-10%, the mass percentage of the gel matrix in the gel composition is 0.1-0.35%, and the mass percentage of butylated hydroxytoluene (BHT) is... The mass percentage of the gel composition is 0.005~0.05%, the pH is adjusted to 5.5~8.5 using triethanolamine (pH adjuster), and the balance is water.

[0023] In some embodiments, the gel composition comprises, by weight percentage: 2.5% menthol, 52% ethanol, 8% diethylene glycol monoethyl ether, 2% polysorbate 80, 0.5% ethyl oleate, 0.25% carbomer interpolymer or carbomer copolymer or carbomer homopolymer, 0.01% butylated hydroxytoluene (BHT), a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and the balance being water.

[0024] In some embodiments, the gel composition comprises, by weight percentage: 50% ethanol, 10% diethylene glycol monoethyl ether, 7.5% menthol, 2% polysorbate 80, 0.5% ethyl oleate, 0.12% carbomer interpolymer, a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and the balance being water.

[0025] In some embodiments, the gel composition comprises, by weight percentage: 50% ethanol, 10% diethylene glycol monoethyl ether, 3% menthol, 2% polysorbate 80, 0.5% ethyl oleate, 0.2% carbomer interpolymer, a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and the balance being water.

[0026] In some embodiments, the gel composition comprises, by weight percentage: 50% ethanol, 10% diethylene glycol monoethyl ether, 5% menthol, 2% polysorbate 80, 0.5% ethyl oleate, 0.3% carbomer interpolymer, a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and the balance being water.

[0027] In some embodiments, the gel composition comprises, by weight percentage: 50% ethanol, 10% diethylene glycol monoethyl ether, 2.5% menthol, 2% polysorbate 80, 0.1% ethyl oleate, 0.2% carbomer interpolymer, a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and the balance being water.

[0028] In some embodiments, the gel composition comprises, by weight percentage: 50% ethanol, 10% diethylene glycol monoethyl ether, 2.5% menthol, 2% polysorbate 80, 0.2% ethyl oleate, 0.2% carbomer interpolymer, a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and the balance being water.

[0029] A second aspect of the present invention provides a method for preparing the gel composition of the first aspect, specifically comprising the following steps: Organic solvent A, surfactant, ethyl oleate, antioxidant (optional), and menthol are mixed evenly to obtain the first phase; the gel matrix is ​​dispersed in water, and a pH adjuster is added to obtain the second phase; the second phase is added to the first phase and mixed evenly.

[0030] A third aspect of the present invention also provides another method for preparing the gel composition of the first aspect, specifically comprising the following steps: Mix organic solvent A, surfactant, ethyl oleate, antioxidant (optional), and menthol evenly, then add to the gel matrix and disperse evenly, then add water and stir evenly, and finally add pH adjuster.

[0031] A fourth aspect of the present invention provides a composition C having the effect of reducing the side effects of a capsaicin-containing pharmaceutical composition, comprising an organic solvent, a surfactant, ethyl oleate, and water; wherein the organic solvent is selected from: (i) ethanol, (ii) a combination of ethanol and diethylene glycol monoethyl ether; the surfactant is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol glycerol laurate, and polyethylene glycol stearate; the organic solvent accounts for 55-65% by mass of the composition C, the surfactant accounts for 2-8% by mass of the composition C, ethyl oleate accounts for 0.1-4% by mass of the composition C, and the balance is water; when the organic solvent includes diethylene glycol monoethyl ether, the diethylene glycol monoethyl ether accounts for 5-20% by mass of the composition C.

[0032] A fifth aspect of the present invention provides a composition D having the effect of reducing the side effects of a capsaicin-containing pharmaceutical composition, comprising an organic solvent, a surfactant, ethyl oleate, a gel matrix, triethanolamine, and water; wherein the organic solvent is selected from: (i) ethanol, (ii) a combination of ethanol and diethylene glycol monoethyl ether; the surfactant is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol glycerol laurate, and polyethylene glycol stearate; and the organic solvent comprises 5% by mass in composition D. The composition contains 5-65% surfactant, 2-8% oleate, 0.1-4% gel matrix, and triethanolamine to adjust the pH of composition D to 5.5-8.5, with the remainder being water. When the organic solvent includes diethylene glycol monoethyl ether, the mass percentage of diethylene glycol monoethyl ether in composition D is 5-20%. The gel matrix is ​​selected from one or more of carbomer interpolymers, carbomer copolymers, and carbomer homopolymers.

[0033] In a sixth aspect, the present invention provides a composition E having the effect of reducing the side effects of a capsaicin-containing pharmaceutical composition, comprising an organic solvent, a surfactant, ethyl oleate, menthol, and water; wherein the organic solvent is selected from: (i) ethanol, (ii) a combination of ethanol and diethylene glycol monoethyl ether; the surfactant is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol glycerol laurate, and polyethylene glycol stearate; the organic solvent accounts for 55-65% by mass of the composition E, the surfactant accounts for 2-8% by mass of the composition E, ethyl oleate accounts for 0.1-4% by mass of the composition E, menthol accounts for 2.5-5% or 5-7.5% or 7.5-10% by mass of the composition E, and the balance is water; when the organic solvent includes diethylene glycol monoethyl ether, the diethylene glycol monoethyl ether accounts for 5-20% by mass of the composition E.

[0034] A seventh aspect of the present invention provides a composition F having the following composition, which reduces the side effects of a capsaicin-containing pharmaceutical composition, and has the following specific composition: (1) 60% ethanol, 8% polysorbate 80, 4% ethyl oleate, wherein the contents are mass percentages and the balance is water; or, (2) 60% ethanol, 4% polysorbate 80, 1.5% ethyl oleate, wherein the contents are mass percentages and the balance is water; or, (3) 60% ethanol, 2% polysorbate 80, 0.5% ethyl oleate, wherein the contents are mass percentages and the remainder is water; or, (4) 60% ethanol, 8% polysorbate 80, 0.5% ethyl oleate, wherein the contents are mass percentages and the remainder is water; or, (5) 60% ethanol, 2% polysorbate 80, and 3% ethyl oleate, wherein the contents are mass percentages and the balance is water; or, (6) 40% ethanol, 20% diethylene glycol monoethyl ether, 4% polysorbate 80, and 1.5% ethyl oleate, wherein the contents are by mass percentage and the balance is water; or, (7) 60% ethanol, 4% polysorbate 80, 1.5% ethyl oleate, and 0.3% carbomer copolymer, with the pH adjusted to 5.5-8.5 using triethanolamine, wherein the contents are by mass percentage, and the remainder is water; or, (8) 50% ethanol, 10% diethylene glycol monoethyl ether, 2% polysorbate 80, 0.5% ethyl oleate, and 0.16% carbomer, adjusted to pH 5.5-8.5 with triethanolamine, wherein the contents are mass percentages and the remainder is water; or, (9) 7.5% menthol, 65% ethanol, wherein the contents are by mass percentage and the remainder is water; or, (10) 7.5% menthol, 60% ethanol, 4% Tween, 1.5% ethyl oleate, wherein the contents are by mass percentage and the remainder is water; or, (11) 7.5% menthol, 65-75% ethanol, wherein the menthol content is by mass-volume percentage, the ethanol content is by volume percentage, and the remainder is water; or, (12) 10% menthol, 75% ethanol, wherein the menthol content is by mass-volume percentage, the ethanol content is by volume percentage, and the remainder is water; or, (13) 7.5% menthol, 65% ethanol, 0.6% sodium hyaluronate, the contents are mass percentages, and the remainder is water.

[0035] An eighth aspect of the present invention provides a combination package product comprising a first part and a second part; The first part is a capsaicin-containing pharmaceutical composition comprising capsaicin, ethanol, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5% (e.g., 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%). Preferably, the first part is filled into a ball-bearing bottle, which consists of a ball-bearing nozzle, a glass bottle body, and a polypropylene cap.

[0036] Part II is the gel composition described in the first aspect of the present invention; Optionally, the combined packaged product further includes a third part, which is an instruction on using the combined packaged product.

[0037] In some embodiments, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%. In some embodiments, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%.

[0038] In some embodiments, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water. In some embodiments, the capsaicin-containing pharmaceutical composition contains 4.5-10.5% by mass, preferably 5-10%. In some embodiments, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the capsaicin-containing pharmaceutical composition contains 4.5-5.5% or 5.5-6.5% or 6.5-7.5% or 7.5-8.5% or 8.5-9.5% or 9.5-10.5% by mass.

[0039] In some embodiments, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the capsaicin-containing pharmaceutical composition comprises 5-10% by mass of capsaicin, 18-22% by mass of ethanol (e.g., 18%, 19%, 20%, 21%, 22%), and 8-15% by mass of polysorbate 80 (e.g., 8%, 9%, 10%, 11%, 12%, 13%). The composition consists of 14%, 15%, and 8-12% (e.g., 8%, 9%, 10%, 11%, 12%) of diethylene glycol monoethyl ether, 8-12% (e.g., 8%, 9%, 10%, 11%, 12%) of propylene glycol, and 0.3-0.5% (e.g., 0.3%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.4%, 0.45%, 0.5%) of sodium hyaluronate, with the balance being water.

[0040] In some embodiments, the capsaicin-containing pharmaceutical composition comprises the following: 5% capsaicin, 20% ethanol, 10% polysorbate 80, 10% diethylene glycol monoethyl ether, 10% propylene glycol, 0.45% sodium hyaluronate, and 44.55% water; the contents are percentages by mass.

[0041] In some embodiments, the capsaicin-containing pharmaceutical composition comprises the following: 10% capsaicin, 20% ethanol, 13% polysorbate 80, 10% diethylene glycol monoethyl ether, 10% propylene glycol, 0.37% sodium hyaluronate, and 36.63% water; the contents are percentages by mass.

[0042] Exemplarily, the method of using the combined packaged product is as follows: (1) Locate a suitable administration area (e.g., a square area with a side length of about 10 cm) on the target knee joint, and apply the capsaicin-containing drug composition (e.g., about 0.2 g of the drug composition) to the administration area; (2) After waiting for a certain period of time (e.g., about 1 hour), apply the gel composition (e.g., about 2-3 g of the gel composition) to the administration area so that the gel composition covers the administration area, and then wipe off the gel. The application and wiping of the gel composition can be repeated as needed.

[0043] A ninth aspect of the present invention provides a method for preparing a capsaicin-containing pharmaceutical composition as described in the eighth aspect (or other aspects), comprising the following steps: Water and sodium hyaluronate are added to solution preparation tank A and stirred to dissolve, yielding an aqueous solution. Ethanol, polysorbate 80, diethylene glycol monoethyl ether, and propylene glycol are added to solution preparation tank B, followed by capsaicin, and stirred to dissolve, yielding an organic solution. The aqueous solution is then added to the organic solution, and the mixture is stirred to obtain the capsaicin-containing pharmaceutical composition.

[0044] A tenth aspect of the invention provides the use of the gel composition described in the first aspect of the invention in the preparation of a medicament, wherein the gel composition is applied to the application site of the capsaicin-containing medicament after the capsaicin-containing medicament has been applied to the skin surface for 0.5 to 2 hours (e.g., 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, preferably 0.5-1.5 hours, 0.9-1.1 hours, or 1 hour), thereby reducing the side effects of the capsaicin-containing medicament; the capsaicin-containing medicament comprises capsaicin, ethanol, and water, and the mass percentage of capsaicin in the capsaicin-containing medicament is 4.5 to 10.5%.

[0045] In some embodiments, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the capsaicin-containing pharmaceutical composition comprises 5-10% by mass of capsaicin, 18-22% by mass of ethanol, 8-15% by mass of polysorbate 80, 8-12% by mass of diethylene glycol monoethyl ether, 8-12% by mass of propylene glycol, and 0.3-0.5% by mass of sodium hyaluronate.

[0046] In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is burning and stinging of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is itching of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is erythema of the skin. In some embodiments, the side effects of the capsaicin-containing pharmaceutical composition are burning and stinging of the skin and / or itching and / or erythema of the skin.

[0047] The eleventh aspect of the present invention provides a method for removing capsaicin from the skin surface, wherein after applying the capsaicin-containing pharmaceutical composition of the combined package product described in the eighth aspect of the present invention to the skin surface for 0.5 to 2 hours (e.g., 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, preferably 0.5-1.5 hours, 0.9-1.1 hours, or 1 hour), the gel composition described in the first aspect of the present invention is applied to the application site of the capsaicin-containing pharmaceutical composition, and then the gel composition is removed from the skin surface to remove capsaicin from the skin surface.

[0048] Preferably, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, and water, and the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%, preferably, the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 5-10%.

[0049] In some embodiments, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%; preferably, the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 5-10%; more preferably, the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%.

[0050] In some embodiments, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the capsaicin-containing pharmaceutical composition comprises 5-10% by mass of capsaicin, 18-22% by mass of ethanol, 8-15% by mass of polysorbate 80, 8-12% by mass of diethylene glycol monoethyl ether, 8-12% by mass of propylene glycol, and 0.3-0.5% by mass of sodium hyaluronate.

[0051] In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is burning and stinging of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is itching of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is erythema of the skin. In some embodiments, the side effects of the capsaicin-containing pharmaceutical composition are burning and stinging of the skin and / or itching and / or erythema of the skin.

[0052] A twelfth aspect of the present invention also provides the use of the gel composition described in the first aspect of the present invention in reducing the side effects of a capsaicin-containing pharmaceutical composition, wherein the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, and the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5% to 10.5%. Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%; Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition comprises 5-10% capsaicin, 18-22% ethanol, 8-15% polysorbate 80, 8-12% diethylene glycol monoethyl ether, 8-12% propylene glycol, and 0.3-0.5% sodium hyaluronate.

[0053] In some embodiments, after applying a capsaicin-containing pharmaceutical composition to the skin surface for 0.5 to 2 hours (e.g., 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, preferably 0.5-1.5 hours, 0.9-1.1 hours, or 1 hour), the gel composition of the first aspect of the invention is applied to the application site of the capsaicin-containing pharmaceutical composition.

[0054] In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is burning and stinging of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is itching of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is erythema of the skin. In some embodiments, the side effects of the capsaicin-containing pharmaceutical composition are burning and stinging of the skin and / or itching and / or erythema of the skin.

[0055] The thirteenth aspect of the invention provides the use of the gel composition described in the first aspect of the invention in the preparation of a product for removing capsaicin from the skin surface, wherein a pharmaceutical composition containing capsaicin is applied to the skin at the site of pain in a patient, and after 0.5-2 hours (e.g., 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, preferably 0.5-1.5 hours, 0.9-1.1 hours, or 1 hour), the gel composition is applied to the skin surface, and then the gel composition is removed from the skin surface; The capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%; Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition comprises 5-10% capsaicin by mass, 18-22% ethanol by mass, 8-15% polysorbate 80 by mass, 8-12% diethylene glycol monoethyl ether by mass, 8-12% propylene glycol by mass, and 0.3-0.5% sodium hyaluronate by mass. The patient is a patient suffering from neuropathic pain, arthritis-related pain, soft tissue injury, or other pain; preferably, the patient is a patient suffering from osteoarthritis pain.

[0056] A fourteenth aspect of the present invention also provides a method for removing capsaicin from the skin surface, comprising applying the gel composition of the first aspect of the present invention to the skin surface and then removing the gel composition from the skin surface.

[0057] The fifteenth aspect of the invention also provides the use of the gel composition of the first aspect of the invention in removing capsaicin from the skin surface, comprising applying the gel composition of the first aspect of the invention to the skin surface and then removing the gel composition from the skin surface.

[0058] The sixteenth aspect of the present invention provides the use of composition C of the fourth aspect, composition D of the fifth aspect, composition E of the sixth aspect, or composition F of the seventh aspect in reducing the side effects of a capsaicin-containing pharmaceutical composition, wherein the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, and the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5% to 10.5%. Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%; Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition comprises 5-10% capsaicin, 18-22% ethanol, 8-15% polysorbate 80, 8-12% diethylene glycol monoethyl ether, 8-12% propylene glycol, and 0.3-0.5% sodium hyaluronate.

[0059] In some embodiments, after applying a capsaicin-containing pharmaceutical composition to the skin surface for 0.5 to 2 hours (e.g., 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, preferably 0.5-1.5 hours, 0.9-1.1 hours, or 1 hour), the composition C of the fourth aspect of the present invention, or the composition D of the fifth aspect, or the composition E of the sixth aspect, or the composition F of the seventh aspect, is applied to the application site of the capsaicin-containing pharmaceutical composition.

[0060] In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is burning and stinging of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is itching of the skin. In some embodiments, the side effect of the capsaicin-containing pharmaceutical composition is erythema of the skin. In some embodiments, the side effects of the capsaicin-containing pharmaceutical composition are burning and stinging of the skin and / or itching and / or erythema of the skin.

[0061] The seventeenth aspect of the present invention provides a method for cleaning capsaicin from the skin surface, wherein after applying a capsaicin-containing pharmaceutical composition from the combined package product of the eighth aspect of the present invention to the skin surface for 0.5 to 2 hours (e.g., 0.5 hours, 0.6 hours, 0.7 hours, 0.8 hours, 0.9 hours, 1 hour, 1.1 hours, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, preferably 0.5-1.5 hours, 0.9-1.1 hours, or 1 hour), a gel composition of the first aspect of the present invention is applied to the application site of the capsaicin-containing pharmaceutical composition, and then the gel composition is removed from the skin surface to clean the capsaicin from the skin surface and reduce the side effects caused by the capsaicin-containing pharmaceutical composition. Preferably, the side effects caused by the capsaicin-containing pharmaceutical composition are burning and stinging of the skin and / or itching and / or erythema of the skin.

[0062] Polysorbate 20, Polysorbate 60, and Polysorbate 80 are pharmaceutical excipients listed in the Chinese Pharmacopoeia.

[0063] Ethyl oleate is a pharmaceutical excipient listed in the Chinese Pharmacopoeia.

[0064] "Menthol" is a pharmaceutical excipient listed in the Chinese Pharmacopoeia. According to the Chinese Pharmacopoeia (2020 edition) (Volume IV), menthol is commonly used as a flavoring agent and a fragrance agent.

[0065] Carbomer is a high molecular weight polymer. Carbomer copolymers, carbomer homopolymers, and carbomer interpolymers are all pharmaceutical excipients listed in the Chinese Pharmacopoeia; they all contain carboxylic acid groups, and their pH after swelling and uniform dispersion in water is acidic (according to the method described in the Chinese Pharmacopoeia (2020 Edition) (Part IV), the pH should be 2.5~3.5). When using carbomer (a collective term for carbomer copolymers, carbomer homopolymers, and carbomer interpolymers), it is generally necessary to add an alkaline substance (such as sodium hydroxide, potassium hydroxide, or triethanolamine) to obtain a neutral carbomer matrix.

[0066] "Antioxidants" can prevent oxidative degradation. For example, antioxidants are selected from α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, L-ascorbic acid, sodium L-ascorbate, calcium L-ascorbate, ascorbate palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA).

[0067] In this invention, "optional" or "optionally" means that the event or condition described below may but is not required to occur, and the description includes both cases where the event or condition occurs and cases where the event or condition does not occur.

[0068] In this invention, the terms "containing" or "including (comprising)" can be open-ended, semi-closed, or closed-ended. In other words, the terms also include "consisting substantially of" or "consisting of".

[0069] In this invention, "percentage by mass volume" or "% (w / v)" or "% w / v" is a way of expressing mass volume concentration, which indicates the number of grams of solute contained in 100 ml of solution. For example, 20% (w / v) means that 100 ml of solution contains 20 g of solute.

[0070] The beneficial effects of this invention are: (1) The gel composition of the present invention improves the cleansing effect of capsaicin on the skin surface; (2) The application of the gel composition of the present invention is convenient, which improves the convenience of cleaning operation and reduces the difficulty of cleaning operation; while when using soap foam for cleaning, the cleaning operator should be properly trained to avoid capsaicin spreading to the skin surface outside the administration area; (3) The gel composition of the present invention can reduce the burning, stinging, itching and erythema of the skin caused by capsaicin residue when the patient (preferably a patient with osteoarthritis pain) is treated with a capsaicin-containing drug composition for neuropathic pain, arthritis-related pain, soft tissue injury or other pain by skin application. Detailed Implementation

[0071] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer.

[0072] Unless otherwise specified, in the following examples and comparative examples, the carbomer interpolymer is Carbomer 20G (a commercially available type B carbomer interpolymer), the carbomer copolymer is Carbomer TR-1P (a commercially available type B carbomer copolymer), and the carbomer homopolymer is Carbomer 974P (a commercially available type B carbomer homopolymer).

[0073] Preparation Example 1: Preparation of an exemplary pharmaceutical composition containing capsaicin A pharmaceutical composition containing capsaicin: 5% capsaicin, 20% ethanol, 10% polysorbate 80, 10% diethylene glycol monoethyl ether, 10% propylene glycol, 0.45% sodium hyaluronate, and 44.55% water; the contents are percentages by mass.

[0074] Purified water and sodium hyaluronate are added to solution preparation tank A and stirred to dissolve, resulting in an aqueous solution. Ethanol, polysorbate 80, diethylene glycol monoethyl ether, and propylene glycol are added to solution preparation tank B, along with capsaicin, and stirred to dissolve, resulting in an organic solution. The aqueous solution is added to the organic solution and mixed. Approximately 2g of the mixed solution is then filled into a ball-bearing bottle. Exemplarily, the ball-bearing bottle, as disclosed in CN221252350U, comprises a ball-bearing nozzle, a glass bottle body, and a polypropylene cap.

[0075] Preparation Example 2: Preparation of an exemplary pharmaceutical composition containing capsaicin A pharmaceutical composition containing capsaicin: 10% capsaicin, 20% ethanol, 13% polysorbate 80, 10% diethylene glycol monoethyl ether, 10% propylene glycol, 0.37% sodium hyaluronate, and 36.63% water; the contents are percentages by mass.

[0076] The preparation method is the same as in Preparation Example 1.

[0077] Example 1 Control group: Take one piece of pigskin and apply capsaicin liniment (5% specification, prepared according to Preparation Example 1; approximately 0.2g of liniment was applied) to a 10cm×10cm area. One hour later, clean the pigskin three times with soap foam; each time, thoroughly rub the pigskin with soap foam (0.5~1 minute), and then wipe off the soap foam on the surface of the pigskin with a soft cotton towel (soaked in water and then squeezed dry).

[0078] Sample groups (1A-1F) of the present invention: Take one piece of pigskin and apply capsaicin liniment (5% specification, prepared according to Preparation Example 1; approximately 0.2g of liniment was applied) to a 10cm × 10cm area. After 1 hour, clean the pigskin three times with a cleaning sample (as shown in Table 1); wipe the pigskin with the sample once each time (0.5~1 minute), and then wipe off the sample from the surface of the pigskin with a soft cotton towel (soaked in water and then squeezed dry). In Table 1, "Composition", each component is a mass percentage, and the balance is water.

[0079] Sampling and detection of residual capsaicin: Moisten cotton swab #1 with anhydrous ethanol and wipe the cleaned treatment area (the entire 10cm × 10cm area); then moisten cotton swab #2 with anhydrous ethanol and wipe the cleaned treatment area (the entire 10cm × 10cm area). Place the wiped cotton swabs #1 and #2 in a centrifuge tube or beaker, add 10mL or 20mL of 50% methanol (accurately measured), sonicate for 5 minutes, and accurately measure an appropriate amount of solution for HPLC detection of capsaicin (optionally, the sonicated solution can be filtered, and the filtrate can be injected). The HPLC column was a Shim-pack VP-ODS, and the mobile phase was 0.1% phosphoric acid aqueous solution-acetonitrile (40:60).

[0080] Table 1

[0081] Example 2 Take one piece of pigskin and apply capsaicin liniment (5% specification, prepared according to Preparation Example 1; approximately 0.2g of liniment was applied) to a 10cm×10cm area. After 1 hour, clean the pigskin three times with a cleaning sample (as shown in Table 2) (control: soapy water, sample groups of this invention: 2A-2D); wipe the pigskin with the sample once each time (0.5~1 minute), and then wipe off the sample from the surface of the pigskin with a soft cotton towel (soaked in water and then squeezed dry). In Table 2, each component is a mass percentage, and the remainder is water; when using carbomer, it is generally necessary to add alkaline substances (such as sodium hydroxide, potassium hydroxide, triethanolamine) to obtain a neutral carbomer matrix. Therefore, groups (2A), (2B), and (2D) also contain an appropriate amount of triethanolamine (to adjust the sample pH to neutral or near neutral).

[0082] The amount of capsaicin residue on the surface of cleaned pigskin was determined according to the method in Example 1.

[0083] Compared to ethanol, diethylene glycol monoethyl ether has a higher boiling point and is less volatile. In a mixed system of ethanol / polysorbate / ethyl oleate / water, replacing ethanol with a small amount of diethylene glycol monoethyl ether can improve the safety of the mixed system and reduce the requirements for production and storage facilities.

[0084] Adding a gel matrix to a mixed system can not only change the properties of the mixed system (to a gel state), further improving the safety of the mixed system and reducing the requirements for production and storage sites, but also prevent capsaicin from spreading to other parts of the skin along with the cleanser when cleaning the skin.

[0085] Compared with group (2C) and group (2D), the ability of group (2D) to clean capsaicin from the skin surface was significantly reduced after the addition of the gel matrix to make it into a gel. To the inventors’ surprise, based on the ethanol / polysorbate / ethyl oleate / water mixture system of Example 1, compared with group (1C) and groups (2A) and (2B), the ability of groups (2A) and (2B) to clean capsaicin from the skin surface was not reduced after the addition of the gel matrix to make it into a gel.

[0086] Table 2

[0087] Example 3 Subjects (healthy volunteers) applied a 5% capsaicin lotion (prepared according to Preparation Example 1) to the back of their hands. One hour later, they cleaned the skin on the back of their hands with the corresponding cleaning sample (as shown in Table 3) and scored according to their subjective feelings. The baseline score was based on cleaning the skin on the back of the hands with soap and water (50 points), with 100 points indicating that the subject had no pain or no obvious pain.

[0088] In Table 3, scores of 50-59 are represented by "+++", scores of 60-79 by "++++", and scores of 80-100 by "+++++". In Table 3, menthol is expressed as a mass-volume percentage, and ethanol as a volume percentage; for example, "7.5% menthol + 65% ethanol" means that 100 mL of solution contains 7.5 g of menthol, 65 mL of ethanol, and the remainder is water; however, group (3E) in the table represents mass percentages.

[0089] According to Table 3, the presence of menthol in the cleaned samples can alleviate the discomfort caused by capsaicin.

[0090] Table 3

[0091] Example 4 Subjects (healthy volunteers) applied a 5% capsaicin lotion (prepared according to Preparation Example 1) to the back of their hands. One hour later, they cleaned the skin on the back of their hands with the corresponding cleaning sample (as shown in Table 4) and scored according to their subjective feelings. The baseline score was based on cleaning the skin on the back of the hands with soap and water (50 points), with 100 points indicating that the subject had no pain or no obvious pain.

[0092] In Table 4, scores of 50-59 are represented by "+++", scores of 60-79 by "++++", and scores of 80-100 by "+++++". In Table 4, "Composition", each component is listed as a mass percentage, with the remainder being water.

[0093] Existing technologies show (e.g., Chinese Journal of Experimental Traditional Medical Formulae, Vol. 17, No. 18, pp. 40-42) that capsaicin has a solubility of approximately 7.61 g / L in 50% ethanol-PBS solution and approximately 11.3 g / L in 50% PEG400. Therefore, the solubility of capsaicin in solvents used for cleaning samples has no linear relationship with reducing the discomfort caused by capsaicin.

[0094] Table 4

[0095] Example 5 Take one piece of pigskin and apply capsaicin liniment (5% specification, prepared according to Preparation Example 1; approximately 0.2g of liniment was applied) to a 10cm × 10cm area. After 1 hour, clean the pigskin three times with a cleaning sample (as shown in Table 5) (control: soapy water, sample groups of the present invention: 2B, 5A-5E); wipe the pigskin with the sample once each time (0.5~1 minute), and then wipe off the sample from the surface of the pigskin with a soft cotton towel (soaked in water and then squeezed dry). In Table 5, each component is a mass percentage, with the remainder being water; each group also contains an appropriate amount of triethanolamine (to adjust the sample pH to neutral or near neutral).

[0096] The amount of capsaicin residue on the surface of cleaned pigskin was determined according to the method in Example 1.

[0097] Table 5

[0098] Example 6 The cleaning gel of this invention, 40g / tube, has the following formulation: 1.0g menthol, 20.8g ethanol, 3.2g diethylene glycol monoethyl ether, 0.8g polysorbate 80, 0.2g ethyl oleate, 0.1g carbomer interpolymer, 0.004g butylated hydroxytoluene (BHT), a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and approximately 13.8g purified water. Expressed as a percentage by mass, it comprises: 2.5% menthol, 52% ethanol, 8% diethylene glycol monoethyl ether, 2% polysorbate 80, 0.5% ethyl oleate, 0.25% carbomer interpolymer, 0.01% butylated hydroxytoluene (BHT), a suitable amount of triethanolamine (to adjust the pH to neutral or near neutral), and approximately 34.5% purified water.

[0099] Weigh the ingredients according to the prescription, first add ethanol, diethylene glycol monoethyl ether, polysorbate 80, ethyl oleate, butylated hydroxytoluene, and menthol and stir evenly. Then add carbomer interpolymer and disperse evenly. Finally, add purified water and stir evenly. Add an appropriate amount of triethanolamine to form a gel and fill into pharmaceutical aluminum tubes.

[0100] Different subjects (healthy volunteers) applied a 5% capsaicin lotion (prepared according to Preparation Example 1) to the back of their hands. One hour later, they cleaned their hands with the aforementioned cleansing gel (cleansing 3 times, using 2-3g of cleansing gel each time), and scored based on their subjective feelings. The baseline score was based on cleaning the back of the hands with soap and water (50 points), with 100 points indicating no pain or no significant pain. All subjects scored between 95 and 100 points.

[0101] Following the method in Example 1, the amount of capsaicin residue on the surface of cleaned pigskin was measured; the control group (soap) and the gel group of the present invention were measured in parallel 9 times, and the average value was calculated; the results showed that the amount of capsaicin residue in the gel group of the present invention after cleaning was 33.74% of the residue in the control group.

[0102] The cleaning gel was placed in a high-temperature environment (60°C) for 5 and 10 days, and the pH change was examined. The changes in the contents of menthol, diethylene glycol monoethyl ether, and the antioxidant butylated hydroxytoluene were also measured. The results are shown in Table 6, indicating that the cleaning gel of the present invention has good stability. Note: The cleaning gel contains ethanol. A water bath was used instead of a closed device such as a stability test chamber or oven to provide the high-temperature environment.

[0103] Table 6

[0104] Example 6b According to the formulation and method of Example 6, a cleaning gel was prepared; its pH was 7.2, its viscosity was 1790 mPa·s, and its appearance was a colorless and transparent thick liquid; the content (w / w) was determined by HPLC as follows: menthol 2.555%, diethylene glycol monoethyl ether 8.250%, and butylated hydroxytoluene 0.010%. The viscosity was determined according to the General Chapter 0633, Method 3 (3) of the Chinese Pharmacopoeia (2025 Edition) (Part IV); an appropriate amount of the sample to be tested was taken, and an NDJ-1 type rotary viscometer was used with a No. 4 rotor at a speed of 60 revolutions per minute.

[0105] Example 6c Referring to the formulation and method of Example 6, but replacing the carbomer interpolymer with a carbomer homopolymer and without adding butylated hydroxytoluene (BHT), a clean gel was prepared; the viscosity was measured to be 1902 mPa·s.

[0106] Example 7 Subjects (healthy volunteers) applied the medication (10% capsaicin lotion, prepared according to Preparation Example 2) to the back of their hands. One hour later, they cleaned the skin on the back of their hands with the aforementioned cleansing gel (cleansing 3 times, using 2-3g of cleansing gel each time). Subjects reported experiencing mild pain after using the cleansing gel.

[0107] It should be noted that when cleaning the skin on the back of the hand with soap and water, the pain caused by 10% capsaicin lotion is significantly higher than that caused by 5% capsaicin lotion.

[0108] Example 8 Combination packaged products, including Part I, Part II, and Part III.

[0109] Part I: 5% (w / w) capsaicin liniment, prepared according to Preparation Example 1; Quantity: 1 bottle.

[0110] Part II: Cleaning gel, see Example 6; quantity 2 tubes.

[0111] Part III: Instructions for using the packaged product.

[0112] Example 9 Combination packaged products, including Part I, Part II, and Part III.

[0113] Part I: 10% (w / w) capsaicin liniment, prepared according to Preparation Example 2; Quantity: 1 bottle.

[0114] Part II: Cleaning gel, see Example 6; quantity 2 tubes.

[0115] Part III: Instructions for using the packaged product.

[0116] Comparative Example 1 Take one piece of pigskin and apply capsaicin liniment (5% specification, prepared according to Preparation Example 1; approximately 0.2g of liniment was applied) to a 10cm × 10cm area. After 1 hour, clean the pigskin three times with a cleaning sample (as shown in Table 7); wipe the pigskin with the sample once each time (0.5~1 minute), and then wipe off the sample from the pigskin surface with a soft cotton towel (soaked in water and then squeezed dry). In Table 7, each component is a mass percentage, with the remainder being water; each group also contains an appropriate amount of triethanolamine (to adjust the pH to neutral or near neutral).

[0117] The amount of capsaicin residue on the surface of cleaned pigskin was determined according to the method in Example 1.

[0118] Table 7

[0119] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing description of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A gel composition, characterized in that, The gel composition comprises organic solvent A, surfactant, ethyl oleate, menthol, gel matrix, and water; The gel composition also includes a pH adjuster; Optionally, the gel composition further includes an antioxidant; The organic solvent A is selected from: (i) ethanol, (ii) a combination of ethanol and diethylene glycol monoethyl ether; the organic solvent A accounts for 50-70% by mass in the gel composition; when the organic solvent A includes diethylene glycol monoethyl ether, the diethylene glycol monoethyl ether accounts for 5-20% by mass in the gel composition. The surfactant is selected from one or more of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyethylene glycol glycerol laurate, and polyethylene glycol stearate; the surfactant accounts for 2-8% by mass in the gel composition. The ethyl oleate in the gel composition is 0.1-4% by mass; The menthol constitutes 2-10% of the gel composition by mass, preferably 2.5-5%, 5-7.5%, or 7.5-10% by mass. The gel matrix is ​​selected from one or more of carbomer interpolymers, carbomer copolymers, and carbomer homopolymers; the mass percentage of the gel matrix in the gel composition is 0.1% to 1%. Preferably, the pH adjuster is selected from one or more of triethanolamine, sodium hydroxide, and potassium hydroxide; Preferably, the pH adjuster is triethanolamine; Preferably, the pH of the gel composition is 5.5 to 8.

5.

2. The gel composition according to claim 1, characterized in that, The organic solvent A comprises 55-65% by mass in the gel composition; the diethylene glycol monoethyl ether comprises 5-15% by mass in the gel composition; the gel matrix comprises 0.1-0.35% by mass in the gel composition; the gel composition includes an antioxidant selected from one or more of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, L-ascorbic acid, sodium L-ascorbate, calcium L-ascorbate, ascorbate palmitate, propyl gallate, octyl gallate, dodecyl gallate, butylated hydroxytoluene (BHT), and butylated hydroxyanisole (BHA); the antioxidant comprises 0.005-0.05% by mass in the gel composition.

3. The gel composition according to claim 2, characterized in that, The gel composition comprises ethanol, diethylene glycol monoethyl ether, polysorbate 80, ethyl oleate, menthol, a gel matrix, butylated hydroxytoluene (BHT), water, and triethanolamine (pH adjuster); the combined mass percentage of ethanol and diethylene glycol monoethyl ether in the gel composition is 55-65%, the mass percentage of diethylene glycol monoethyl ether in the gel composition is 5-15%, the mass percentage of polysorbate 80 in the gel composition is 2-8%, the mass percentage of ethyl oleate in the gel composition is 0.1-4%, the mass percentage of menthol in the gel composition is 2.5-5%, 5%-7.5%, or 7.5-10%, the mass percentage of the gel matrix in the gel composition is 0.1-0.35%, the mass percentage of butylated hydroxytoluene (BHT) in the gel composition is 0.005-0.05%, the pH is adjusted to 5.5-8.5 using triethanolamine (pH adjuster), and the remainder is water.

4. A method for preparing the gel composition according to claim 1, characterized in that, The preparation method includes one of the following two methods: (1) Mix organic solvent A, surfactant, ethyl oleate, antioxidant (optional), and menthol evenly to obtain the first phase; disperse the gel matrix in water and add a pH adjuster to obtain the second phase; add the second phase to the first phase and mix evenly to obtain the gel composition; or; (2) Mix organic solvent A, surfactant, ethyl oleate, antioxidant (optional) and menthol evenly, then add gel matrix and disperse evenly, then add water and stir evenly, and finally add pH adjuster to obtain the gel composition.

5. A combination packaged product, characterized in that, The combined packaged product comprises Part I and Part II; Part I is a capsaicin-containing pharmaceutical composition comprising capsaicin, ethanol, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%, preferably 5-10% by mass. Part II is the gel composition according to claim 3; Optionally, the combined packaged product further includes a third part, which is an instruction on using the combined packaged product.

6. The combined packaging product according to claim 5, characterized in that, The capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%; preferably, the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 5-10%. Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%, ethanol at a mass percentage of 18-22%, polysorbate 80 at a mass percentage of 8-15%, diethylene glycol monoethyl ether at a mass percentage of 8-12%, propylene glycol at a mass percentage of 8-12%, and sodium hyaluronate at a mass percentage of 0.3-0.5%.

7. A method for preparing the capsaicin-containing pharmaceutical composition in the combined packaged product of claim 6, characterized in that, The preparation method includes the following steps: Water and sodium hyaluronate are added to solution preparation tank A and stirred to dissolve, yielding an aqueous phase solution. Ethanol, polysorbate 80, diethylene glycol monoethyl ether, and propylene glycol are added to solution preparation tank B, along with capsaicin, and stirred to dissolve, yielding an organic phase solution. The aqueous phase solution is then added to the organic phase solution, and the mixture is stirred to obtain the capsaicin-containing pharmaceutical composition.

8. A method for removing capsaicin from the skin surface, characterized in that, After applying the capsaicin-containing pharmaceutical composition of the combined package product of claim 6 to the skin surface for 0.5 to 2 hours, the gel composition of claim 3 is applied to the application site of the capsaicin-containing pharmaceutical composition, and then the gel composition is removed from the skin surface to remove capsaicin from the skin surface; Preferably, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, and water, and the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%, preferably, the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 5-10%. Alternatively, the capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%; preferably, the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 5-10%.

9. The use of the gel composition of claim 1 in reducing the side effects of capsaicin-containing pharmaceutical compositions, characterized in that, The capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%; Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition comprises 5-10% capsaicin by mass, 18-22% ethanol by mass, 8-15% polysorbate 80 by mass, 8-12% diethylene glycol monoethyl ether by mass, 8-12% propylene glycol by mass, and 0.3-0.5% sodium hyaluronate by mass. Preferably, the gel composition is applied to the application site of the capsaicin-containing drug composition 0.5 to 2 hours after applying the capsaicin-containing drug composition to the skin surface; Preferably, the side effects are burning and stinging of the skin and / or itching and / or erythema of the skin.

10. The use of the gel composition of claim 1 in the preparation of a product for removing capsaicin from the skin surface, characterized in that, The pharmaceutical composition containing capsaicin is applied to the patient's skin at the site of pain. After 0.5-2 hours, the gel composition is applied to the skin surface, and then the gel composition is removed from the skin surface. The capsaicin-containing pharmaceutical composition comprises capsaicin, ethanol, polysorbate 80, diethylene glycol monoethyl ether, propylene glycol, sodium hyaluronate, and water, wherein the mass percentage of capsaicin in the capsaicin-containing pharmaceutical composition is 4.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 5-10%; Preferably, the capsaicin-containing pharmaceutical composition contains capsaicin at a mass percentage of 4.5-5.5%, 5.5-6.5%, 6.5-7.5%, 7.5-8.5%, 8.5-9.5%, or 9.5-10.5%. Preferably, the capsaicin-containing pharmaceutical composition comprises 5-10% capsaicin by mass, 18-22% ethanol by mass, 8-15% polysorbate 80 by mass, 8-12% diethylene glycol monoethyl ether by mass, 8-12% propylene glycol by mass, and 0.3-0.5% sodium hyaluronate by mass. The patient is a patient suffering from neuropathic pain, arthritis-related pain, soft tissue injury, or other pain; preferably, the patient is a patient suffering from osteoarthritis pain.

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