High-concentration capsaicin composition

Abstract

The invention relates to a high-concentration capsaicin composition, and more specifically, the composition comprises capsaicin and menthol, further comprises a high polymer material and an emulsifier, further comprises oil, and further comprises one or more of a thickening agent, a humectant, a preservative and an antioxidant. The composition does not need to use an organic solvent, contains high-concentration capsaicin, is free of drug crystal precipitation after being placed for a long time, is controllable in quality, and also has the beneficial effect that the transdermal rate is obviously higher than that of common cream.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and specifically relates to a high-concentration capsaicin composition. Background Technology

[0002] Transient receptor potential vanilloid 1 (TRPV1), often referred to as the capsaicin receptor, is mainly distributed in the terminals of small and medium-sized nociceptive sensory neurons in the central and peripheral nervous systems. Chili peppers contain a compound called capsaicin, which possesses pharmacological and physiological activities such as analgesia, anti-inflammatory and swelling-reducing effects, anti-rheumatism properties, and appetite regulation. Its unique long-lasting analgesic effect is particularly prominent. The mechanism of action of capsaicin is well-defined: it specifically binds to TRPV1 to exert its analgesic effect. Current treatments for chronic pain (neuralgic pain, muscle pain, musculoskeletal pain, etc.) are often unsatisfactory; the TRPV1 channel is an excellent therapeutic target for analgesics / analgesics.

[0003] According to the search results on the website of the National Medical Products Administration, all currently marketed capsaicin-containing products are low-concentration over-the-counter drugs, with a concentration not exceeding 0.075%, and are in the form of creams or gels. Low-concentration capsaicin preparations have low transdermal absorption and insufficient analgesic effect. They are usually administered 3 to 4 times daily for at least 4 to 6 weeks. More than 60% of patients experience burning sting pain (BSP) after using low-concentration capsaicin preparations, resulting in poor compliance (Derry S, Moore RA. Topical capsaicin (low concentration) for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2012 Sep12; 2012(9):CD010111. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004 Apr 24; 328(7446):991.). Many patients discontinue treatment before achieving the expected analgesic effect. Low-concentration capsaicin preparations have the following disadvantages: low transdermal absorption, insufficient efficacy, need for long-term administration, and poor compliance due to BSP.

[0004] It is currently the only commercially available high-concentration capsaicin preparation. It was approved by the FDA and the EU in 2009 for the treatment of postherpetic neuralgia (PHN) and diabetic peripheral neuropathy (DPN). Containing 8% capsaicin, it can deliver a large amount of capsaicin to the skin in a short time compared to low-concentration capsaicin products. A single use can maintain the therapeutic effect for 3 months and has good compliance. Use the organic solvent diethylene glycol monoethyl ether Dissolving high concentrations of capsaicin promotes transdermal absorption, while It has a penetration-enhancing effect. Extensive use of organic solvents It may cause some problems, such as: strong hygroscopicity, which promotes the entry of irritating ingredients into the skin and causes irritation (Javadzadeh Y, Adibkia K, Hamishekar H). (diethylene glycolmonoethyl ether): Apotential penetration enhancer[J]. Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Modification of the Stratum Corneum, 2015: 195-205.).

[0005] Poor patient compliance due to basal body surface area (BSP) is the biggest problem facing the clinical use of capsaicin. Improving patient compliance is an important research topic. Existing studies have shown that increasing the transdermal penetration rate of capsaicin and reducing the duration and frequency of administration can effectively improve patient compliance. Currently marketed low-concentration over-the-counter capsaicin preparations increase intradermal capsaicin accumulation through long-term, repeated administration, but long-term use results in poor patient compliance. Prescription capsaicin available in the United States... By increasing drug loading and penetration-enhancing excipients Increasing the transdermal transdermal rate of capsaicin allows a single application of 30-60 minutes to maintain its efficacy for up to 3 months. Therefore, improving the transdermal transdermal rate of capsaicin preparations has significant clinical value.

[0006] Capsaicin in liquid form has higher thermodynamic activity and faster transdermal penetration, which may mean a lower BSP (body surface area concentration). Capsaicin is almost insoluble in water, and solid capsaicin is difficult to transdermally; current technologies use large amounts of ethanol... While organic solvents can dissolve capsaicin, the extensive use of organic solvents often damages the skin barrier, leading to direct or indirect local irritation. This invention provides a novel high-concentration capsaicin composition that does not use organic solvents. The formulation ensures a high concentration of capsaicin in a liquid state at room temperature, without capsaicin crystals, simplifying quality control. Summary of the Invention

[0007] On one hand, the present invention provides a high-concentration capsaicin composition, characterized in that the composition comprises:

[0008] (a) Capsaicin;

[0009] (b) Menthol;

[0010] Preferably, capsaicin accounts for 0.01% to 20% of the composition by mass, more preferably 0.25% to 16%, more preferably 1% to 12%, more preferably 2% to 10%, and more preferably 2% to 8%.

[0011] More specifically, capsaicin accounts for 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, and 12% of the composition by mass.

[0012] Preferably, the mass ratio of menthol to capsaicin is 1:5 to 10:1, more preferably 1:5 to 6:1, more preferably 1:1 to 6:1, more preferably 1:1 to 3:1, and even more preferably 1:1 to 2:1;

[0013] More specifically, the mass ratio of menthol to capsaicin is 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 4:1, 5:1, or 6:1.

[0014] Preferably, menthol accounts for 0.01% to 30% of the composition by mass, more preferably 1% to 28%, more preferably 2% to 24%, and more preferably 4% to 16%.

[0015] Preferably, the composition does not contain organic solvents;

[0016] Preferably, the organic solvent is selected from one or more of ethanol, propylene glycol, isopropanol, diethylene glycol monoethyl ether, PEG300, PEG400, dimethyl sulfoxide, dimethylacetamide, and N-methylpyrrolidone;

[0017] Preferably, the organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, diethylene glycol, triethylene glycol, propanol, propylene glycol, glycerol, polypropylene glycol, isopropanol, n-butanol, isobutanol, tert-butanol, butanediol, pentanediol, diethylene glycol monoethyl ether, isosorbide dimethyl ether, acetonitrile, acetone, butanone, diethyl ether, propane, hexane, cyclohexane, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, dimethylformamide, dimethylacetamide, and methylpyrrolidone.

[0018] In a preferred embodiment of the present invention, the composition further comprises:

[0019] (c) Optionally, one or more polymeric materials;

[0020] (d) Optional, one or more emulsifiers;

[0021] Preferably, the polymer material is selected from one or more of polyvinyl alcohol, polyvinylpyrrolidone, carbomer, gelatin, shellac, pectin, guar gum, xanthan gum, polyethylene glycol, polyacrylic acid, sodium polyacrylate, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, polyvinyl butyral, acrylic resin, poloxamer, alginate, sodium alginate, hyaluronic acid, and sodium hyaluronate, and is more preferably one or more of polyvinyl alcohol, polyvinylpyrrolidone, and carbomer;

[0022] Preferably, the polymeric material accounts for 0.01% to 50% of the composition by mass; more preferably, 0.1% to 40%; more preferably, 0.5% to 30%; more preferably, 1% to 20%.

[0023] More specifically, the polymeric material accounts for 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20% of the composition by mass.

[0024] Preferably, the emulsifier is selected from emulsifiers with an HLB value of 3 to 17;

[0025] Preferably, the emulsifier is selected from Span 20, Span 40, Span 60, Span 80, Tween 20, Tween 40, Tween 60, Tween 80, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (35) castor oil, glyceryl monostearate, PEG-1,4-diethyl-3-octanoic acid, lauroyl polyoxyethylene (32) glyceryl monostearate, and a mixture of polyoxyethylene-75 stearate (GELOT). 64. One or more of the following: poloxamer 188, sodium lauryl sulfate, sodium hexadecyl sulfate, sodium stearoyl sulfate, triethanolamine lauryl sulfate, soybean lecithin, egg yolk lecithin, and polyvinyl alcohol; preferably, the emulsifier is selected from one or more of Span 20, Span 40, Span 60, Span 80, Tween 80, polyoxyethylene (40) hydrogenated castor oil, glyceryl monostearate, PEG-32 polyoxyethylene monostearate, glyceryl monostearate, and a mixture of polyoxyethylene-75 stearate GELOT 64;

[0026] Preferably, the emulsifier accounts for 0.01% to 20% of the composition by mass; more preferably 0.5% to 10%, and even more preferably 1% to 5%.

[0027] More specifically, the emulsifier accounts for 1%, 2%, 3%, 4%, or 5% of the composition by mass.

[0028] In a preferred embodiment of the present invention, the composition further comprises:

[0029] (c) Optionally, one or more polymeric materials;

[0030] (d) Optional, one or more emulsifiers;

[0031] (e) Optional, one or more oils;

[0032] (c) and (d) The components and their contents are as described above;

[0033] Preferably, the oil is selected from one or more of liquid paraffin, squalene, isopropyl myristate, medium-chain triglycerides, white petrolatum, stearic acid, ethylene glycol fatty acid esters, dimethyl silicone oil, lanolin, coconut oil, sesame oil, peanut oil, rapeseed oil, castor oil, olive oil, soybean oil, and corn oil, and more preferably from one or more of liquid paraffin, squalene, isopropyl myristate, medium-chain triglycerides, and white petrolatum;

[0034] Preferably, the oil phase accounts for 0.01% to 15% of the composition by mass, more preferably 1% to 12%, and even more preferably 1% to 9%.

[0035] More specifically, the oil phase comprises 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9% of the composition by mass.

[0036] In a preferred embodiment of the present invention, the composition further comprises:

[0037] (f) Optional, one or more thickeners;

[0038] Preferably, the thickener is selected from one or more of anhydrous dicalcium phosphate, talc, calcium carbonate, diatomaceous earth, microcrystalline cellulose, magnesium aluminum silicate, and bentonite; more preferably, it is selected from one or more of anhydrous dicalcium phosphate and diatomaceous earth.

[0039] Preferably, the thickener accounts for 0.01% to 35% of the composition by mass; more preferably 1% to 30%, and even more preferably 5% to 28%.

[0040] More specifically, the thickener constitutes 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, or 28% of the composition by weight.

[0041] In a preferred embodiment of the present invention, the composition further comprises:

[0042] (g) Optional, one or more humectants;

[0043] Preferably, the moisturizer is selected from one or more of sorbitol, glycerin, propylene glycol, urea, hyaluronic acid, sodium lactate, glyceryl glucoside, and polyethylene glycol, and more preferably from one or more of sorbitol and glycerin.

[0044] Preferably, the moisturizer accounts for 0.01% to 25% of the composition by mass, more preferably 1% to 20%, and even more preferably 5% to 20%.

[0045] More specifically, the humectant accounts for 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, and 20% of the composition by weight.

[0046] In a preferred embodiment of the present invention, the composition further comprises:

[0047] (h) Optional, one or more preservatives;

[0048] Preferably, the preservative is selected from one or more of methylparaben, propylparaben, ethylparaben, benzoic acid, potassium sorbate, sodium benzoate, calcium sorbate, benzalkonium bromide, benzalkonium chloride, o-phenylphenol, and chlorhexidine acetate; more preferably, one or more of methylparaben and propylparaben.

[0049] Preferably, the preservative accounts for 0.01% to 2% of the composition by mass, more preferably 0.01% to 1%, and even more preferably 0.01% to 0.5%.

[0050] More specifically, the preservative accounts for 0.1%, 0.2%, 0.3%, 0.4%, and 0.5% of the composition by mass.

[0051] In a preferred embodiment of the present invention, the composition further comprises:

[0052] (i) Optional, one or more antioxidants;

[0053] Preferably, the antioxidant is selected from one or more of butylated hydroxytoluene, vitamin E acetate, thioglycerol, sodium bisulfite, butylated hydroxyanisole, 2,6-di-tert-butyl-p-cresol, sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, vitamin C, and vitamin E, and more preferably from one or more of butylated hydroxytoluene and vitamin E acetate.

[0054] Preferably, the antioxidant accounts for 0.01% to 2% of the composition by mass, more preferably 0.01% to 1%, and even more preferably 0.01% to 0.5%.

[0055] More specifically, the antioxidant accounts for 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, and 1% of the composition by weight.

[0056] In a preferred embodiment of the present invention, the composition is a cream.

[0057] The composition described in any of the preceding claims, wherein the composition further comprises water.

[0058] In a preferred embodiment of the present invention, the composition is used as a patch matrix, and a backing and release film are added to prepare a patch.

[0059] In a preferred embodiment of the present invention, the composition is preferably a topical skin composition.

[0060] The present invention also provides a method for preparing the capsaicin composition according to any one of the above claims, the method comprising: simultaneously heating and mixing capsaicin, menthol and other excipients until homogeneous;

[0061] Alternatively, capsaicin and menthol can be heated and melted first, and then other excipients can be added and heated to mix evenly.

[0062] Alternatively, capsaicin and menthol can be heated and melted first, while the polymer material can be dissolved in a solvent. If necessary, other excipients can be added. All components can be heated and mixed evenly to obtain the final product.

[0063] The present invention also provides the use of the capsaicin composition described in any one of the above claims in the preparation of pain medications, wherein the pain is neuropathic pain, preferably, the neuropathic pain is peripheral neuropathic pain or central neuropathic pain, preferably, the peripheral neuropathic pain is selected from painful diabetic peripheral neuropathy, postherpetic neuralgia, postoperative or post-traumatic peripheral neuropathic pain, drug-induced peripheral neuropathic pain, cancer pain, trigeminal neuralgia, and glossopharyngeal neuralgia.

[0064] Beneficial effects

[0065] (1) Capsaicin is poorly soluble in water, and most capsaicin preparations exist in crystalline form, thus failing to exert their therapeutic effect. (US marketed products) Extensive use of organic solvents Dissolving capsaicin. This invention provides a novel high-concentration capsaicin composition that allows high-concentration capsaicin to exist in a liquid form at room temperature without the use of organic solvents.

[0066] (2) The capsaicin composition prepared by the present invention contains no drug crystals and is simple to control in terms of quality.

[0067] (3) The capsaicin composition prepared by the present invention has a stronger skin delivery ability.

[0068] (4) The composition of the present invention has a significant analgesic effect, comparable to that of US-marketed formulations. It has a considerable analgesic effect. Attached Figure Description

[0069] Figure 1 The appearance changes of different molar ratios of capsaicin / menthol in Example 1.

[0070] Figure 2 This is a polarized light microscope photograph of the high-concentration capsaicin conventional cream in Example 2 after being stored at 25°C for 7 days.

[0071] Figure 3 This is a polarized light microscope photograph of the capsaicin-menthol cream containing polymeric materials from Example 3, taken after being stored at 25°C for 3 months.

[0072] Figure 4 This is a polarized light microscope photograph of the capsaicin and menthol cream containing liquid paraffin and polymer materials from Example 4, after being stored at 25°C for one month.

[0073] Figure 5 Example 6 compares the absorption of different capsaicin preparations in the skin.

[0074] Figure 6Example 7 illustrates the effect of capsaicin preparations on mechanical pain sensitivity in a mouse model of chronic compression injury (CCI). BL represents pre-CCI surgery, Pre represents post-CCI surgery and pre-administration, and solid black dots indicate statistically significant differences compared to the corresponding time points in the blank preparation group (p<0.05).

[0075] Figure 7 Example 7 illustrates the effect of capsaicin preparations on thermal pain sensitivity in a mouse model of chronic compression injury (CCI). BL represents pre-CCI, Pre represents post-CCI administration, and solid black dots indicate statistically significant differences compared to the blank preparation group at the corresponding time points (p<0.05). Detailed Implementation

[0076] Example 1: Capsaicin and menthol cannot form a room-temperature stable eutectic liquid.

[0077] In recent years, eutectic technology has been frequently used to convert solid drugs into liquids, promoting transdermal drug delivery. This invention attempts to prepare eutectic compounds of capsaicin and menthol. Capsaicin and menthol were mixed in different molar ratios and heated until completely melted. The appearance changes after being left at room temperature were observed. Comparative studies were also conducted using capsaicin and menthol alone. The results are shown in Tables 1-1 and 1-2. The appearance changes after mixing capsaicin and menthol in different molar ratios are shown in Tables 1-1 and 1-2. Figure 1 .

[0078] Table 1-1 Studies on capsaicin / menthol mixtures with different molar ratios

[0079]

[0080]

[0081] Table 1-2 Appearance changes of capsaicin and menthol as single components after heating.

[0082] Components Before heating After heating After cooling, let it stand at room temperature for 1 hour. Capsaicin White solid Clear liquid solidification Menthol White solid Clear liquid solidification

[0083] The results showed that the molten mixture of capsaicin and menthol could maintain a liquid state for a short time under certain proportions, but both turned into a solid state after 72 hours. This example demonstrates that capsaicin and menthol cannot form a eutectic liquid at room temperature.

[0084] Example 2: Adding menthol to a conventional high-concentration capsaicin cream still resulted in a large amount of crystal precipitation.

[0085] According to literature reports (Liu Kechun, Liu Changheng, Wang Ximin, et al. Experimental study on the optimal formulation of capsaicin ointment matrix and its formulation [J]. Shandong Science, 2004, 17(2):4.), the release rate of capsaicin in emulsion matrix is ​​significantly higher than that in oil-soluble and water-soluble matrix. The optimal formulation of capsaicin ointment T2-1 was prepared based on the literature. Preparation method: Stearic acid, white petrolatum, liquid paraffin, octadecanol, glycerin and capsaicin were weighed into a beaker, heated in an 80℃ water bath, and mixed evenly using a high-speed shearing machine. Water and triethanolamine were then weighed into a beaker, heated in a water bath to 80℃, and mixed using a high-speed shearing machine to prepare an ointment. An exploratory formulation T2-2 was prepared, the formulation is shown in Table 2, the preparation method is the same as T2-1, menthol and capsaicin were added at the same time. The sample was kept at 25℃, the appearance was observed with the naked eye, and the presence of crystals was observed under a polarizing microscope.

[0086] See polarizing microscope images Figure 2 The results showed that no crystals were found in the blank cream, while crystals precipitated in the conventional capsaicin cream T2-1. Adding menthol (formulas T2-2, T2-3, and T2-4) to the conventional high-concentration capsaicin creams also resulted in a large amount of crystal precipitation.

[0087] Table 2. Commonly Used Creams with High Concentration Capsaicin

[0088]

[0089]

[0090] Example 3: Preparation and Microscopic Observation of High-Concentration Capsaicin-Menthol Polymer Cream

[0091] According to the prescriptions in Tables 3-1, 3-2, and 3-3, capsaicin, menthol, Span 40 (emulsifier), polyvinyl alcohol (polymer), and water were weighed into a beaker, heated in a water bath, and mixed using a high-speed shear mixer to prepare a cream. The sample was retained at 25℃. The appearance was observed visually, and the presence of crystals was examined under a polarizing microscope. The polarizing microscope images are shown below. Figure 3 .

[0092] Table 3-1 High Concentration Capsaicin and Menthol Cream

[0093]

[0094] Table 3-2 High Concentration Capsaicin and Menthol Cream

[0095]

[0096] Table 3-3 High Concentration Capsaicin and Menthol Cream

[0097]

[0098]

[0099] According to the prescription in Table 3-4, each component was weighed and placed in a beaker. The mixture was heated in a water bath and then mixed using a high-speed shear mixer to prepare a cream. Samples were retained at 25°C, and the appearance was observed visually and under a polarizing microscope for crystals. The results showed that emulsifiers with HLB values ​​between 3 and 17 could be used to prepare the cream of this patent, resulting in a uniform and fine appearance. No crystals were observed in any of the groups under a polarizing microscope.

[0100] Table 3-4 Capsaicin and Menthol Cream

[0101]

[0102] According to the formula in Table 3-5, weigh each component and place it in a beaker. Heat in a water bath and mix using a high-speed shear mixer to prepare a cream. Leave the sample at 25℃, observe its appearance with the naked eye, and examine for crystals under a polarizing microscope. The results show that different polymer materials can all be used to prepare creams with a uniform and delicate appearance, and no crystals were observed in any group under a polarizing microscope.

[0103] Table 3-5 Capsaicin and Menthol Cream

[0104]

[0105]

[0106] Example 4: Preparation and Microscopic Observation of High-Concentration Capsaicin-Menthol Polymer Oil Cream

[0107] According to the prescriptions in Tables 4-1, 4-2, and 4-3, capsaicin, menthol, liquid paraffin (oil), Span 40 (emulsifier), polyvinyl alcohol (polymer), and water were weighed into a beaker, heated in a water bath, and mixed using a high-speed shear mixer to prepare a cream. The sample was retained at 25°C, and its appearance was observed visually and examined under a polarizing microscope for the presence of crystals. Polarizing microscope images are shown below. Figure 4 .

[0108] Table 4-1 Capsaicin, Menthol, Polymer Materials, Liquid Paraffin Cream

[0109]

[0110] Table 4-2 Capsaicin, Menthol, Polymer Materials, Liquid Paraffin Cream

[0111]

[0112] Table 4-3 Capsaicin, Menthol, Polymer Materials, Liquid Paraffin Cream

[0113]

[0114]

[0115] The results of Example 1 showed that the mixture of capsaicin and menthol easily solidified and existed in a solid form. In Examples 3 and 4, obvious rod-shaped crystals were observed in the cream containing only capsaicin, while no crystals were found in the capsaicin-menthol combination cream in a specific ratio. In summary, this invention unexpectedly discovered that preparing a cream from capsaicin and menthol in a specific ratio can eliminate drug crystals, thereby obtaining a high-concentration, stable capsaicin cream free of drug crystals and organic solvents.

[0116] Oil composition investigation

[0117] According to the prescription in Table 4-4, weigh each component and place them in a beaker. Heat in a water bath and mix using a high-speed shear mixer to prepare a cream. Leave the sample at 25°C, observe its appearance with the naked eye, and examine under a polarizing microscope for crystals. Composition T4-22 has poor appearance and shows stratification during sample retention. Polarizing microscope examination revealed no crystals in any component.

[0118] Table 4-4 Investigation of oil composition in capsaicin-menthol cream

[0119]

[0120] Determination of capsaicin solubility in different oils

[0121] Approximately 3g of each oil was weighed out, and an excess of capsaicin was added. The mixture was then placed in a constant-temperature shaker and shaken for 24 hours (25℃, 500rpm). After centrifugation at 10000rpm for 30 minutes, the supernatant was collected, filtered, and the capsaicin content was determined. The solubility of capsaicin in different oils is shown in Tables 4-5. Since white petrolatum is a semi-solid and cannot dissolve capsaicin, its solubility was not determined.

[0122] The results showed that capsaicin has low solubility in the commonly used oil phase of creams, and adding an oil phase to creams cannot dissolve high concentrations of capsaicin.

[0123] Table 4-5 Solubility of capsaicin in different oils

[0124] Different oils Solubility (g / mL) Liquid paraffin 0.00017 Squalene 0.00056 Isopropyl myristate 0.01053 Medium-chain fatty acid glycerides 0.01400

[0125] Oil usage survey

[0126] According to the prescription in Table 4-6, weigh each component and place it in a beaker. Heat in a water bath and mix using a high-speed shear mixer to prepare a cream. Leave the sample at 25℃. Observe the appearance with the naked eye and examine under a polarizing microscope; no crystals were found in any of the components.

[0127] Table 4-6 Investigation on the dosage of capsaicin and menthol in creams and oils

[0128]

[0129] Emulsifier Types Survey

[0130] According to the prescriptions in Tables 4-7 and 4-8, each component was weighed and placed in a beaker. The mixture was heated in a water bath and then mixed using a high-speed shear mixer to prepare a cream. Samples were retained at 25°C. The appearance was observed with the naked eye and under a polarizing microscope. The results showed that emulsifiers with HLB values ​​between 3 and 17 could be used to prepare the cream of this patent. The cream had a uniform and delicate appearance, and no crystals were observed in any of the groups under a polarizing microscope.

[0131] Table 4-7 Investigation of Emulsifier Types in Capsaicin and Menthol Creams

[0132]

[0133]

[0134] Table 4-8 Investigation of Emulsifier Types in Capsaicin and Menthol Creams

[0135]

[0136] Emulsifier dosage study

[0137] According to Table 4-9, weigh each component and place it in a beaker. Heat in a water bath and mix using a high-speed shear mixer to prepare a cream. Leave the sample at 25℃. Observe the appearance with the naked eye and observe under a polarizing microscope; no crystals were found in any group.

[0138] Table 4-9 Investigation on the dosage of capsaicin-menthol emulsifier in creams

[0139]

[0140] Investigation of polymer materials

[0141] According to the prescriptions in Tables 4-10 and 4-11, each component was weighed and placed in a beaker. The mixture was heated in a water bath and mixed using a high-speed shear mixer to prepare a cream. Samples were retained at 25℃. The appearance was observed visually, and under a polarizing microscope, different polymer materials were observed to produce creams with a uniform and fine appearance. No crystals were observed in any of the groups under the polarizing microscope. The results in Table 4-11 show that no crystals were found in creams of different viscosities prepared using different types and proportions of polyvinyl alcohol.

[0142] Table 4-10 Investigation of Polymer Materials in Capsaicin and Menthol Cream

[0143]

[0144] Table 4-11 Investigation of Polymer Materials in Capsaicin and Menthol Cream

[0145]

[0146] Thickener Investigation

[0147] According to the prescription in Table 4-12, weigh each component and place it in a beaker. Heat in a water bath and mix using a high-speed shear mixer to prepare a cream. The sample was retained at 25℃. Visual inspection and observation under a polarizing microscope revealed that adding the thickeners anhydrous calcium phosphate and diatomaceous earth could also produce a cream with a uniform and smooth appearance. No crystals were observed in any of the groups under a polarizing microscope.

[0148] Table 4-12 Formula for Capsaicin-Menthol Cream Containing Thickener

[0149]

[0150] Formula containing preservatives and antioxidants

[0151] According to the formula in Table 4-13, each component was weighed and placed in a beaker. The mixture was heated in a water bath and then mixed using a high-speed shear mixer to prepare a cream. Samples were retained at 25°C, and their appearance was observed visually and under a polarizing microscope for crystals. The results showed that adding preservatives and / or antioxidants to the formula could also produce a cream with a uniform and smooth appearance. No crystals were observed in any of the groups under a polarizing microscope.

[0152] Table 4-13 Formula for Capsaicin and Menthol Cream Containing Preservatives and Antioxidants

[0153]

[0154] Formula containing moisturizer

[0155] According to the formula in Table 4-14, each component was weighed and placed in a beaker. The mixture was heated in a water bath and then mixed using a high-speed shear mixer to prepare a cream. Samples were retained at 25℃, and their appearance was observed with the naked eye and under a polarizing microscope. The results showed that adding a moisturizer to the formula could also prepare a cream with a uniform and smooth appearance. No crystals were observed in any of the groups under a polarizing microscope.

[0156] Table 4-14 Formulas for Capsaicin and Menthol Creams Containing Moisturizers

[0157]

[0158] Formula without polymers / emulsifiers

[0159] According to the prescription in Table 4-15, each component was weighed and placed in a beaker. The mixture was heated in a water bath and then mixed using a high-speed shear mixer to prepare a cream. Samples were retained at 25°C, and their appearance was observed visually and under a polarizing microscope. The results showed that crystals precipitated during the sample preparation process in all creams without polymer materials, and crystals also precipitated during the sample preparation process in prescriptions without emulsifiers.

[0160] Table 4-15 Capsaicin and Menthol Cream Formula (Free of Polymers / Emulsifiers)

[0161]

[0162] Example 5: Preparation and Observation of Capsaicin Patch

[0163] The patch matrix was prepared according to the formulation in Table 5-1. Capsaicin, menthol, isopropyl myristate (oil), Tween 80 (emulsifier), Span 80 (emulsifier), sodium polyacrylate (polymer material), and water were weighed and placed in a container. The mixture was heated in a water bath and mixed using a high-speed shearing machine to prepare a cream as the patch matrix. The matrix was evenly coated onto a non-woven fabric, allowed to stand and solidify, and then laminated with a PET release film before being cut to the appropriate size to obtain the capsaicin patch. The appearance was observed visually and under a polarizing microscope. The results showed that capsaicin patches T5-1 and T5-3 contained crystals, while capsaicin-menthol patches T5-2 and T5-4 did not contain crystals.

[0164] Table 5-1 Capsaicin and Menthol Patch Prescription

[0165]

[0166] Example 6: In vitro transdermal study of a composition containing capsaicin and menthol

[0167] Different capsaicin creams and US-marketed formulations The transdermal properties of capsaicin were studied, and the formulation composition and results of polarized light microscopy observations are shown in Table 6-1. Since the site of action of capsaicin is in the skin, this experiment only measured the capsaicin content in the skin.

[0168] Pig skin was used as the ex vivo skin sample for in vitro transdermal studies using a Franz diffusion cell. The receiving medium was 10% ethanol, the rotation speed was 200 rpm, the experimental temperature was 32℃, and the dosage was 300 mg. After 6 hours, the pig skin was removed, residual drug was wiped off, rinsed with water for 2 minutes, and then scrubbed with PEG400 until no surface residue remained. The capsaicin content in the pig skin was then measured. Each experiment was performed in quadruplicate, and the results are shown below. Figure 5 .

[0169] Comparing compositions T6-1, T6-2, T6-3, and T6-4, the results showed that the higher the capsaicin content, the more capsaicin entered the skin, and high-concentration capsaicin formulations exhibited stronger skin drug delivery capabilities. Comparing compositions T6-4 and T6-5, at the same capsaicin content, composition T6-4 (containing both capsaicin and menthol) showed stronger skin drug delivery capabilities than composition T6-5 (containing only capsaicin). This may be because capsaicin exists in a liquid form, has higher thermodynamic activity, and thus stronger transdermal absorption.

[0170] Table 6-1 Capsaicin Cream Formula and Polarizing Microscope Observation Results

[0171]

[0172] Example 7: Pharmacodynamic study of a composition containing capsaicin and menthol

[0173] A mouse model of chronic constriction injury (CCI) was established, and the paw withdrawal threshold under mechanical and thermal stimulation was used as an indicator of neuropathic pain. The analgesic efficacy and duration of topical application of capsaicin-menthol cream were investigated, using US-marketed drugs... As a positive control, the drug-free formulation served as a blank control.

[0174] The compositions were prepared according to the prescription in Table 7-1, and their analgesic effects were evaluated. The compositions in Table 7-1 were applied to the soles of the feet on the modeling side, respectively. The drug was removed 3 hours later. The plantar pain threshold was measured using the hot plate method and the von Frey method before administration and at 4 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days, 9 days, 11 days, 13 days, 15 days, 17 days, and 19 days after administration. Results are shown below. Figure 6 and Figure 7 .

[0175] Figure 6 The results showed that compared with the blank formulation, T7-2 significantly increased the mechanical pain threshold in mice from day 3 to day 19 after administration (p<0.05); T7-2 significantly increased the mechanical pain threshold in mice from day 2 to day 19 after administration (p<0.05). Compared with the positive control... Comparison between T7-2 and There were no significant differences at any time point (p>0.05).

[0176] Figure 7 The results showed that, compared with the blank formulation, T7-2 and The drug significantly increased the latency period for thermal pain withdrawal in mice from day 1 to day 19 after administration (p<0.05); compared with the positive control. In comparison, T7-2 showed better efficacy on days 2–19 after administration compared to... There were no significant differences (p>0.05).

[0177] Evaluations showed that T7-2 exhibited significant and long-lasting analgesic effects on both mechanical and thermal pain sensitivities. The duration and intensity of analgesia were comparable to those of the US-marketed formulation. quite.

[0178] Table 7-1 Composition of the Composition

[0179] Composition T7-1 T7-2 Capsaicin 0 4 Menthol 0 6 Vaseline 10 6 Span 40 1 1 Polyvinyl alcohol 05-88 15 12 Methylparaben 0.1 0.1 Propylparaben 0.05 0.05 Purified water 48.85 43.85 Anhydrous calcium hydrogen phosphate 25 27 total 100 100 Phenomenon amorphous amorphous

[0180] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A high-concentration capsaicin composition, characterized in that, The composition comprises: (a) Capsaicin; (b) Menthol; Preferably, capsaicin accounts for 0.01% to 20% of the composition by mass, more preferably 0.25% to 16%, more preferably 1% to 12%, more preferably 2% to 10%, and more preferably 2% to 8%. Preferably, the mass ratio of menthol to capsaicin is 1:5 to 10:1, more preferably 1:5 to 6:1, more preferably 1:1 to 6:1, more preferably 1:1 to 3:1, and even more preferably 1:1 to 2:1; Preferably, the composition does not contain organic solvents; Preferably, the organic solvent is selected from one or more of ethanol, propylene glycol, isopropanol, diethylene glycol monoethyl ether, PEG300, PEG400, dimethyl sulfoxide, dimethylacetamide, and N-methylpyrrolidone.

2. The capsaicin composition according to claim 1, characterized in that, The composition further comprises: (c) Optionally, one or more polymeric materials; (d) Optional, one or more emulsifiers; Preferably, the polymer material is selected from one or more of polyvinyl alcohol, polyvinylpyrrolidone, carbomer, gelatin, shellac, pectin, guar gum, xanthan gum, polyethylene glycol, polyacrylic acid, sodium polyacrylate, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, polyvinyl butyral, acrylic resin, poloxamer, alginate, sodium alginate, hyaluronic acid, and sodium hyaluronate, and is more preferably one or more of polyvinyl alcohol, polyvinylpyrrolidone, and carbomer; Preferably, the polymeric material accounts for 0.01% to 50% of the composition by mass; more preferably, 0.1% to 40%; more preferably, 0.5% to 30%; more preferably, 1% to 20%. Preferably, the emulsifier is selected from emulsifiers with an HLB value of 3 to 17; Preferably, the emulsifier is selected from Span 20, Span 40, Span 60, Span 80, Tween 20, Tween 40, Tween 60, Tween 80, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (35) castor oil, glyceryl monostearate, PEG-1,4-diethyl-3-octanoic acid, lauroyl polyoxyethylene (32) glyceryl monostearate, and a mixture of polyoxyethylene-75 stearate (GELOT).

64. One or more of the following: poloxamer 188, sodium lauryl sulfate, sodium hexadecyl sulfate, sodium stearoyl sulfate, triethanolamine lauryl sulfate, soybean lecithin, egg yolk lecithin, and polyvinyl alcohol; preferably, the emulsifier is selected from one or more of Span 20, Span 40, Span 60, Span 80, Tween 80, polyoxyethylene (40) hydrogenated castor oil, glyceryl monostearate, PEG-32 polyoxyethylene monostearate, glyceryl monostearate, and a mixture of polyoxyethylene-75 stearate GELOT 64; Preferably, the emulsifier accounts for 0.01% to 20% of the composition by mass; more preferably 0.5% to 10%, and even more preferably 1% to 5%.

3. The capsaicin composition according to claim 1, characterized in that, The composition further comprises: (c) Optionally, one or more polymeric materials; (d) Optional, one or more emulsifiers; (e) Optional, one or more oils; (c) and (d) the components and their contents as described in claim 2; Preferably, the oil is selected from one or more of liquid paraffin, squalene, isopropyl myristate, medium-chain triglycerides, white petrolatum, stearic acid, ethylene glycol fatty acid esters, dimethyl silicone oil, lanolin, coconut oil, sesame oil, peanut oil, rapeseed oil, castor oil, olive oil, soybean oil, and corn oil, and more preferably from one or more of liquid paraffin, squalene, isopropyl myristate, medium-chain triglycerides, and white petrolatum; Preferably, the oil phase accounts for 0.01% to 15% of the composition by mass, more preferably 1% to 12%, and even more preferably 1% to 9%.

4. The capsaicin composition according to claim 1, characterized in that, The composition further comprises: (f) Optional, one or more thickeners; Preferably, the thickener is selected from one or more of anhydrous dicalcium phosphate, talc, calcium carbonate, diatomaceous earth, microcrystalline cellulose, magnesium aluminum silicate, and bentonite; more preferably, it is selected from one or more of anhydrous dicalcium phosphate and diatomaceous earth. Preferably, the thickener accounts for 0.01% to 35% of the composition by mass; more preferably 1% to 30%, and even more preferably 5% to 28%. Preferably, the composition further comprises: (g) Optional, one or more humectants; Preferably, the moisturizer is selected from one or more of sorbitol, glycerin, propylene glycol, urea, hyaluronic acid, sodium lactate, glyceryl glucoside, and polyethylene glycol, and more preferably from one or more of sorbitol and glycerin. Preferably, the moisturizer accounts for 0.01% to 25% of the composition by mass, more preferably 1% to 20%, and even more preferably 5% to 20%. Preferably, the composition further comprises: (h) Optional, one or more preservatives; Preferably, the preservative is selected from one or more of methylparaben, propylparaben, ethylparaben, benzoic acid, potassium sorbate, sodium benzoate, calcium sorbate, benzalkonium bromide, benzalkonium chloride, o-phenylphenol, and chlorhexidine acetate; more preferably, one or more of methylparaben and propylparaben. Preferably, the preservative accounts for 0.01% to 2% of the composition by mass, more preferably 0.01% to 1%, and even more preferably 0.01% to 0.5%. Preferably, the composition further comprises: (i) Optional, one or more antioxidants; Preferably, the antioxidant is selected from one or more of butylated hydroxytoluene, vitamin E acetate, thioglycerol, sodium bisulfite, butylated hydroxyanisole, 2,6-di-tert-butyl-p-cresol, sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate, vitamin C, and vitamin E, and more preferably from one or more of butylated hydroxytoluene and vitamin E acetate. Preferably, the antioxidant accounts for 0.01% to 2% of the composition by mass, more preferably 0.01% to 1%, and even more preferably 0.01% to 0.5%.

5. The capsaicin composition according to claim 1, characterized in that, The composition is a cream.

6. The capsaicin composition according to claim 1, characterized in that, The composition further comprises water.

7. The capsaicin composition according to claim 1, characterized in that, The composition is used as a patch matrix, and a backing and release film are added to prepare a patch.

8. The capsaicin composition according to claim 1, characterized in that, The composition is preferably a topical skin composition.

9. A method for preparing the capsaicin composition according to any one of claims 1-6, the method comprising: The product is obtained by heating and mixing capsaicin, menthol and other excipients simultaneously until homogeneous. Alternatively, capsaicin and menthol can be heated and melted first, and then other excipients can be added and heated to mix evenly. Alternatively, capsaicin and menthol can be heated and melted first, while the polymer material can be dissolved in a solvent. If necessary, other excipients can be added. All components can be heated and mixed evenly to obtain the final product.

10. Use of the capsaicin composition according to any one of claims 1-6 in the preparation of analgesics, wherein, The pain is neuropathic pain, preferably peripheral neuropathic pain or central neuropathic pain. Preferably, peripheral neuropathic pain is selected from painful diabetic peripheral neuropathy, postherpetic neuralgia, postoperative or post-traumatic peripheral neuropathic pain, drug-induced peripheral neuropathic pain, cancer pain, trigeminal neuralgia, and glossopharyngeal neuralgia.

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