Melogabalin besylate patch as well as preparation method and application thereof

Abstract

The invention relates to a melogabalin besylate patch as well as a preparation method and application thereof. The melogabalin besylate patch is prepared from the following raw materials in percentage by mass: 0.5 to 10 percent of melogabalin besylate, 25 to 40 percent of matrix, 0.1 to 1.5 percent of antioxidant, 0.05 to 0.15 percent of functional additive, 0.5 to 10 percent of cosolvent, 0.1 to 10 percent of transdermal enhancer, 36.5 to 48 percent of plasticizer and 13 to 32 percent of tackifier. On the basis of the total mass of the melogabalin besylate patch, the transdermal enhancer is prepared from the following components in percentage by mass: 0 to 2 percent of L-menthol and 0.5 to 1.5 percent of sucrose laurate; the antioxidant is butylated hydroxytoluene; the functional additive is chitosan oligosaccharide. The patch has good physical adhesion, and the release rate gt of the medicine after 24 hours; the cumulative permeation amount gt of the medicine after 24 hours; the medicine is convenient and safe to use, and the medicine effect is stable.

Description

Technical Field

[0001] This application relates to the field of drug-loaded polymeric medical formulation technology, and in particular to a melogabalin benzyl sulfonate patch, its preparation method and application. Background Technology

[0002] Merogabalin besylate is a calcium channel modulator with a high affinity for the α2δ subunit of calcium channels. It primarily acts on the α2δ subunit of voltage-gated calcium channels, reducing calcium ion influx. At nerve endings, calcium ion influx typically triggers neurotransmitter release; reducing calcium ion influx can inhibit excessive neurotransmitter release, thereby reducing neuronal excitability and alleviating neuropathic pain.

[0003] Most existing melogabalin besylate formulations are oral; however, oral melogabalin besylate has many adverse reactions, such as drowsiness and dizziness. Long-term use may lead to elevated transaminase levels, which in turn may cause a decline in liver function. Oral administration requires frequent dosing, which is inconvenient. Summary of the Invention

[0004] This invention provides a melogabalin besylate patch, its preparation method, and its application, in order to solve the problem of numerous adverse reactions associated with oral melogabalin besylate.

[0005] In a first aspect of this application, a melogabalin benzyl sulfonate patch is provided, comprising the following raw materials in weight percentages: 0.5-10% melogabalin benzyl sulfonate, 25-40% matrix, 0.1-1.5% antioxidant, 0.05-0.15% functional additive, 0.5-10% cosolvent, 0.1-10% transdermal penetration enhancer, 36.5-48% plasticizer, and 13-32% tackifier; based on the total weight of the melogabalin benzyl sulfonate patch, the transdermal penetration enhancer is composed of 0-2% L-menthol and 0.5-1.5% sucrose laurate; the antioxidant is butylated hydroxytoluene; and the functional additive is chitosan oligosaccharide.

[0006] By adopting the above technical solution, the present invention provides a merogabalin besylate patch, which has good physical adhesion, a drug release rate of >76% after 24 hours, and a cumulative drug permeation of >350 μg / cm³ after 24 hours. 2This may be because, on the one hand, butylated hydroxytoluene, as a phenolic antioxidant, can scavenge free radicals through hydrogen donation from its phenolic hydroxyl groups, thus inhibiting the oxidative degradation of melogabalin; chitosan oligosaccharides have a certain reducing property, which may indirectly slow down the consumption of butylated hydroxytoluene. The two work synergistically to inhibit the oxidative degradation of melogabalin besylate, thereby increasing the drug release rate. On the other hand, L-menthol disrupts the lipid order in the ester phase, reducing the diffusion barrier, while sucrose laurate solubilizes the drug in the patch matrix. The two work synergistically to promote permeation, thereby increasing the amount of drug that can be absorbed.

[0007] Furthermore, the above-mentioned melogabalin benzyl sulfonate patch, by total mass of the patch, includes the following raw materials in the following mass percentages: melogabalin benzyl sulfonate 1-5%, matrix 30-35%, antioxidant 0.3-0.5%, cosolvent 1-5%, transdermal penetration enhancer 1-3%, plasticizer 36.5-41.5%, and tackifier 13-30%.

[0008] Furthermore, the transdermal penetration enhancer consists of 0.5-1.5% by mass of L-menthol and 0.5-1.5% by mass of sucrose laurate.

[0009] Optionally, the mass ratio of L-menthol to sucrose laurate is (0.33-3):1.

[0010] By adopting the above technical solution and adjusting the dosage of L-menthol and sucrose laurate according to the above mass ratio, the drug permeation effect is better when the mass ratio of L-menthol to sucrose laurate is (0.33-3):1.

[0011] Optionally, the mass ratio of the butylated hydroxytoluene to the chitosan oligosaccharide is (2.33-9):1.

[0012] By adopting the above technical solution and adjusting the dosage of butylated hydroxytoluene and chitosan oligosaccharide according to the above mass ratio, the drug release effect is better when the mass ratio of butylated hydroxytoluene and chitosan oligosaccharide is (2.33-9):1.

[0013] Optionally, the preparation method of the chitosan oligosaccharide includes the following steps: a1: Dissolve chitosan in an acid solution to obtain colloidal chitosan; a2: Add compound enzyme A to the colloidal chitosan obtained in step a1, heat and stir, then add compound enzyme B, keep the temperature constant and stir, heat again and add chitosanase, continue stirring to obtain chitosan hydrolysate. a3: Centrifuge, concentrate, and dry the chitosan hydrolysate obtained in step a2 to obtain chitosan oligosaccharide; Further, the acid solution in step a1 is acetic acid or hydrochloric acid.

[0014] Optionally, in step a2, the complex enzyme A includes chitosanase and bromelain, and the complex enzyme B includes chitosanase and lipase PS-Im.

[0015] Optionally, the matrix is ​​selected from one or more of natural rubber, polyisoprene, styrene-isoprene-styrene block copolymer, styrene-butadiene-styrene block copolymer, styrene-butadiene rubber, and polyisobutylene.

[0016] Preferably, the matrix comprises styrene-isoprene-styrene block copolymer and polyisobutylene; Based on the total mass of the melogabalin benzyl sulfonate patch, the matrix consists of 20-25% by mass of styrene-isoprene-styrene block copolymer and 5-15% by mass of polyisobutylene.

[0017] Optionally, the co-solvent is selected from at least one of ethanol, acetone, propylene glycol, 1,3-butanediol, isopropanol, polyethylene glycol, sodium hydroxide, potassium hydroxide, and diethylamine.

[0018] Preferably, the co-solvent is polyvinyl alcohol and / or sodium hydroxide; Based on the total mass of the melogabalin benzyl sulfonate patch, the co-solvent is 0-4% polyvinyl alcohol and / or 0-2% sodium hydroxide by mass.

[0019] Optionally, the average molecular weight of polyethylene glycol is 6000 g / mol.

[0020] Optionally, the plasticizer is selected from at least one of squalane, squalene, liquid paraffin, silicone oil, diethylene glycol, propylene glycol, and clomiphene.

[0021] Preferably, the plasticizer is liquid paraffin.

[0022] Optionally, the tackifier is an alicyclic saturated hydrocarbon resin or hydrogenated rosin glycerol ester; The total mass of the melogabalin benzenesulfonate patch is used as the calculation basis, and the tackifier is 28-32% by mass of alicyclic saturated hydrocarbon resin or 13-30% by mass of hydrogenated rosin glycerol ester.

[0023] In a second aspect, this application provides a method for preparing a melogabalin benzyl sulfonate patch as described in the first aspect of this application, comprising the following steps: S1: At 120-160℃, the matrix, thickener, plasticizer, antioxidant and functional additives are melt-blended to obtain a matrix mixture; S2: Melogabalin besylate, transdermal penetration enhancer, and solubilizer are dissolved by heating at 100-120℃ to obtain a solution of the active pharmaceutical ingredient; S3: Add the raw material solution prepared in step S2 to the matrix mixture prepared in step S1, stir evenly, coat it onto the anti-adhesive layer, attach it to the backing layer, cut it to obtain the melogabalin benzyl sulfonate patch.

[0024] Optionally, the anti-stick layer is a siliconized PEI film, and the backing layer is a polyester fabric.

[0025] In summary, the present invention has at least one of the following beneficial technical effects: 1. This invention provides a method for preparing a merogabalin besylate patch. The patch has good physical adhesion, a drug release rate >76% after 24 hours, and a cumulative drug permeation >350 μg / cm³ after 24 hours. 2 On the one hand, butylated hydroxytoluene (BHT), as a phenolic antioxidant, can scavenge free radicals through hydrogen donation from its phenolic hydroxyl groups, thus inhibiting the oxidative degradation of melogabalin. Chitosan oligosaccharides have certain reducing properties and may indirectly slow down the consumption of BHT. The two work synergistically to inhibit the oxidative degradation of melogabalin besylate, thereby increasing the drug release rate. On the other hand, L-menthol disrupts the lipid order in the ester phase, reducing the diffusion barrier, while sucrose laurate solubilizes the drug in the patch matrix. The two work synergistically to promote permeation, thereby increasing the amount of drug that can be absorbed.

[0026] 2. This invention provides a melogabalin besylate patch that can be easily applied or removed, making medication convenient and safe, greatly improving patient compliance, and providing stable efficacy to meet clinical needs. Detailed Implementation

[0027] The embodiments of the present invention will be described in detail below with reference to the examples. However, those skilled in the art will understand that the following examples are only for illustrating the present invention and should not be regarded as limiting the scope of the present invention. Specific conditions not specified in the examples shall be carried out according to conventional conditions or conditions recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0028] Merogalin benzyl sulfonate was purchased from Suzhou Zhengji Pharmaceutical Co., Ltd.; styrene-isoprene-styrene block copolymer was purchased from ENEOS Materials Co., Ltd. (5229); polyisobutylene was purchased from BASF Europe; alicyclic saturated hydrocarbon resin was purchased from Arakawa Chemical Industry Co., Ltd.; hydrogenated rosin ester was purchased from Arakawa Chemical Industry Co., Ltd. (KE-311); L-menthol was purchased from Takasago Flavor Industry Co., Ltd.; sucrose laurate was purchased from Shaoyuan Technology (Shanghai) Co., Ltd. (SY278842); and isopropyl myristate was purchased from... The following products were purchased from Zhejiang Wumart Biotechnology Co., Ltd.: butylated hydroxytoluene (BHT), chitosan (Chitosan), polyethylene glycol (PEG), chitosanase (HBWS-T106), bromelain (S10009), and lipase PS-Im (L299015).

[0029] Preparation Example 1 Preparation method of chitosan oligosaccharide a1: Dissolve 5g of chitosan in 2% acetic acid solution and bring the volume to 100mL. Heat in a water bath with stirring at 40℃ for 30min to obtain colloidal chitosan. a2: Add compound enzyme A to the colloidal chitosan obtained in step a1, heat to 50℃ and stir for 3 min, then add compound enzyme B, stir at a constant temperature for 30 min, heat again to 53℃ and add chitosanase, continue stirring for 20 min to obtain chitosan hydrolysate; wherein, the mass of compound enzyme A is 0.1% of the mass of colloidal chitosan, and the mass of compound enzyme B is 0.3% of the mass of colloidal chitosan; the mass of chitosanase added after heating to 53℃ again in step a2 is 0.1% of the mass of colloidal chitosan; compound enzyme A is chitosanase and bromelain in a weight ratio of 2:1, and compound enzyme B is chitosanase and lipase PS-Im in a weight ratio of 5:2; a3: The chitosan hydrolysate obtained in step a2 is centrifuged, concentrated by membrane, and freeze-dried to obtain chitosan oligosaccharide; The chitosan oligosaccharides used in the following examples are all derived from Preparation Example 1.

[0030] Example 1

[0031] Example 1 provides a merogalaline benzyl sulfonate patch. The formulation and dosage of the merogalaline benzyl sulfonate patch are shown in Table 1.

[0032] Table 1. Prescription composition and dosage of Example 1

[0033] Preparation process: S1: At a temperature of 120°C, the matrix, thickener, plasticizer, and antioxidant are fully melted and mixed to obtain a matrix mixture; S2: Melogabalin besylate, transdermal penetration enhancer, and solubilizer are heated and dissolved at 100℃ to obtain a drug substance solution; S3: Add the active pharmaceutical ingredient solution obtained in step S2 to the matrix mixture obtained in step S1, stir well, and coat it onto a silicone-treated PET film. The coating amount is 125 g·m³. -2 (Wet weight), laminate with polyester fabric, cut into 80mm×90mm sizes to obtain melogabalin benzenesulfonic acid patch.

[0034] Example 2

[0035] Example 2 provides a merogalaline benzyl sulfonate patch. The formulation and dosage of the merogalaline benzyl sulfonate patch are shown in Table 2.

[0036] Table 2. Prescription composition and dosage of Example 2

[0037] Preparation process: S1: At a temperature of 130°C, the matrix, thickener, plasticizer, and antioxidant are fully melted and mixed to obtain a matrix mixture; S2: Melogabalin besylate, transdermal penetration enhancer, and solubilizer are heated and dissolved at 110°C to obtain a drug substance solution; S3: Add the active pharmaceutical ingredient solution obtained in step S2 to the matrix mixture obtained in step S1, stir well, and coat it onto a silicone-treated PET film. The coating amount is 125 g·m³. -2 (Wet weight), laminate with polyester fabric, cut into 80mm×90mm sizes to obtain melogabalin benzenesulfonic acid patch.

[0038] Example 3

[0039] Example 3 provides a merogalaline benzyl sulfonate patch. The formulation and dosage of the merogalaline benzyl sulfonate patch are shown in Table 3.

[0040] Table 3. Prescription composition and dosage of Example 3

[0041] Preparation process: S1: At a temperature of 140℃, the matrix, thickener, plasticizer, and antioxidant are fully melted and mixed to obtain a matrix mixture; S2: Merogabalin besylate, transdermal penetration enhancer, and solubilizer are heated and dissolved at 120°C to obtain a drug substance solution; S3: Add the active pharmaceutical ingredient solution obtained in step S2 to the matrix mixture obtained in step S1, stir well, and coat it onto a silicone-treated PET film. The coating amount is 125 g·m³. -2 (Wet weight), laminate with polyester fabric, cut into 80mm×90mm sizes to obtain melogabalin benzenesulfonic acid patch.

[0042] Example 4

[0043] Example 4 provides a merogalaline benzyl sulfonate patch. The formulation and dosage of the merogalaline benzyl sulfonate patch are shown in Table 4.

[0044] Table 4. Prescription composition and dosage of Example 4

[0045] Preparation process: S1: At a temperature of 150°C, the matrix, tackifier, plasticizer, and antioxidant are fully melted and mixed to obtain a matrix mixture; S2: Melogabalin besylate and a solubilizer are heated and dissolved at 100°C to obtain a solution of the active pharmaceutical ingredient; S3: Add the active pharmaceutical ingredient solution obtained in step S2 to the matrix mixture obtained in step S1, stir well, and coat it onto a silicone-treated PET film. The coating amount is 125 g·m³. -2 (Wet weight), laminate with polyester fabric, cut into 80mm×90mm sizes to obtain melogabalin benzenesulfonic acid patch.

[0046] Example 5

[0047] Example 5 provides a merogabalin besylate patch. The formulation and dosage of the merogabalin besylate patch are shown in Table 5.

[0048] Table 5. Prescription composition and dosage of Example 5

[0049] Preparation process: S1: At a temperature of 160℃, the matrix, thickener, plasticizer, and antioxidant are fully melted and mixed to obtain a matrix mixture; S2: Melogabalin besylate and transdermal penetration enhancer are heated and dissolved at 120°C to obtain a drug substance solution; S3: Add the active pharmaceutical ingredient solution obtained in step S2 to the matrix mixture obtained in step S1, stir well, and coat it onto a silicone-treated PET film. The coating amount is 125 g·m³.-2 (Wet weight), laminate with polyester fabric, cut into 80mm×90mm sizes to obtain melogabalin benzenesulfonic acid patch.

[0050] Example 6

[0051] Example 6 provides a merogalaline benzyl sulfonate patch. The formulation and dosage of the merogalaline benzyl sulfonate patch are shown in Table 6.

[0052] Table 6. Prescription composition and dosage of Example 6

[0053] Preparation process: S1: At a temperature of 140℃, the matrix, thickener, plasticizer, antioxidant, and functional additives are fully melted and mixed to obtain a matrix mixture; S2: Melogabalin besylate, transdermal penetration enhancer, and solubilizer are heated and dissolved at 110°C to obtain a drug substance solution; S3: Add the active pharmaceutical ingredient solution obtained in step S2 to the matrix mixture obtained in step S1, stir well, and coat it onto a silicone-treated PET film. The coating amount is 125 g·m³. -2 (Wet weight), laminate with polyester fabric, cut into 80mm×90mm sizes to obtain melogabalin benzenesulfonic acid patch.

[0054] Example 7

[0055] Example 7 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the total mass of L-menthol and sucrose laurate remains unchanged, and the mass ratio of L-menthol to sucrose laurate is 3:1.

[0056] Specifically, based on the total mass of the melogabalin besylate patch, the mass percentage of L-menthol is 1.5%, and the mass percentage of sucrose laurate is 0.5%.

[0057] The preparation process is the same as in Example 6.

[0058] Example 8

[0059] Example 8 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the total mass of L-menthol and sucrose laurate remains unchanged, and the mass ratio of L-menthol to sucrose laurate is 1:3.

[0060] Specifically, based on the total mass of the melogabalin besylate patch, the mass percentage of L-menthol is 0.5%, and the mass percentage of sucrose laurate is 1.5%.

[0061] The preparation process is the same as in Example 6.

[0062] Example 9

[0063] Example 9 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the total mass of butylated hydroxytoluene and chitosan oligosaccharide remains unchanged, and the mass ratio of butylated hydroxytoluene to chitosan oligosaccharide is 9:1.

[0064] Specifically, based on the total mass of the melogabalin benzyl sulfonate patch, the mass percentage of butylated hydroxytoluene is 0.45%, and the mass percentage of sucrose laurate is 0.05%.

[0065] The preparation process is the same as in Example 6.

[0066] Example 10

[0067] Example 10 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the total mass of butylated hydroxytoluene and chitosan oligosaccharide remains unchanged, and the mass ratio of butylated hydroxytoluene to chitosan oligosaccharide is 7:3.

[0068] Specifically, based on the total mass of the melogabalin benzyl sulfonate patch, the mass percentage of butylated hydroxytoluene is 0.35%, and the mass percentage of sucrose laurate is 0.15%.

[0069] The preparation process is the same as in Example 6.

[0070] Comparative Example 1 Comparative Example 1 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that L-menthol is replaced by sucrose laurate.

[0071] The preparation process is the same as in Example 6.

[0072] Comparative Example 2 Comparative Example 2 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the mass of sucrose laurate is replaced with L-menthol.

[0073] The preparation process is the same as in Example 6.

[0074] Comparative Example 3 Comparative Example 3 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the butylated hydroxytoluene is replaced by chitosan oligosaccharide.

[0075] The preparation process is the same as in Example 6.

[0076] Comparative Example 4 Comparative Example 4 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that chitosan oligosaccharide is replaced by dibutylhydroxytoluene.

[0077] The preparation process is the same as in Example 6.

[0078] Comparative Example 5 Comparative Example 5 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that the mass of sucrose laurate is replaced with isopropyl myristate.

[0079] The preparation process is the same as in Example 6.

[0080] Comparative Example 6 Comparative Example 6 provides a melogabalin benzyl sulfonate patch, which differs from Example 6 in that chitosan oligosaccharide is replaced by chitosan.

[0081] The preparation process is the same as in Example 6.

[0082] Comparative Example 7 Comparative Example 7 provides a melogabalin benzenesulfonic acid patch, which differs from Example 6 in that it does not contain the cosolvent polyethylene glycol.

[0083] The preparation process is the same as in Example 6.

[0084] Test Example 1: Physical Adhesion Test of Merogabalin Benzyl Sulfate Patch The melogabalin besylate patches prepared in Examples 1-6 were subjected to physical adsorption tests. The initial tack of the melogabalin besylate patches was tested according to Method 1 (Initial Tack Test Method) of Chinese Pharmacopoeia 0952, and the adhesion of the melogabalin besylate patches was tested according to Method 4 (Adhesive Strength Test Method) of Chinese Pharmacopoeia 0952.

[0085] Table 7 Physical Adhesion of Merogabalin Benzyl Sulfate Patch

[0086] As can be seen from Examples 1-6 and Table 7, the amounts of tackifier and matrix have a significant impact on the physical adhesion of the melogabalin benzyl sulfonate patch. In Example 6, the melogabalin benzyl sulfonate patch exhibited the best physical adhesion when the proportions of styrene-isoprene-styrene block copolymer (22.5%), polyisobutylene (10%), and hydrogenated rosin glycerol ester (20%) were present.

[0087] Experimental Example 2: In vitro release test of merogabarine besylate patch In vitro release tests were conducted using melogabalin benzyl sulfonate patches prepared in Examples 6, 9-10, Comparative Examples 3-4, and Comparative Examples 6-7.

[0088] In vitro release process: A 0.45μm nylon filter membrane (used only as a support membrane) was placed at 32℃ in 12mL of receiving solution, which was a phosphate buffer solution with pH=7.4 (1.36g of potassium dihydrogen phosphate, 79ml of 0.1mol / L sodium hydroxide solution, diluted with water to 200ml). After sonication for 10 minutes to degas the membrane, it was soaked for another 30 minutes. The nylon filter membrane was then removed, and the surface moisture was absorbed with filter paper. Merogabalin besylate patch was cut into circular patches with a diameter of 15mm. The release film was removed, and the patch was adhered to the nylon filter membrane with the paste side. The patch was placed in a 50mL vial, and 12mL of receiving solution at 32℃ was added as the release medium. The patch was then placed in a water bath shaker (100 rpm) for 24 hours. After 24 hours, all receiving liquid was collected, and the concentration of melogabalin besylate in the receiving liquid was determined by high-performance liquid chromatography (HPLC, Shimadzu, Japan). Three parallel experiments were set up for each group, and the average value was taken. The results are shown in Table 8. The formula for the release rate is: Release rate (%) = VC t / m×100%; In the formula, C t V represents the concentration of melogabalin in the receiving liquid at time t, where V represents the volume of the receiving liquid and m represents the initial mass of melogabalin.

[0089] Table 8. Cumulative release rate of merogabalin besylate patch after 24 hours

[0090] Based on Examples 6, 9-10 and Table 8, it can be seen that adjusting the ratio of butylated hydroxytoluene to chitosan oligosaccharide can affect the release rate of melogabalin besylate patch. In Example 6, when the mass ratio of butylated hydroxytoluene to chitosan oligosaccharide is 4:1, the release rate of melogabalin besylate patch after 24 hours is the best, which is better than that in Examples 9 and 10.

[0091] Based on Example 6, Comparative Examples 3-4, and Table 8, it can be seen that in Comparative Examples 3 and 4, after replacing butylated hydroxytoluene and chitosan oligosaccharides with each other by equal mass, the release rate of melogabalin besylate patch after 24 hours decreased significantly. This may be because the synergistic effect of butylated hydroxytoluene and chitosan oligosaccharides was disrupted, leading to accelerated oxidation of melogabalin besylate, and thus a significant decrease in the release rate of melogabalin besylate patch after 24 hours.

[0092] As can be seen from Example 6, Comparative Example 6 and Table 8, when chitosan was replaced with an equal amount of chitosan oligosaccharide, the release rate of melogabalin besylate patch decreased after 24 hours. This may be because chitosan oligosaccharide has stronger reducing and free radical scavenging abilities than chitosan, and can better inhibit the oxidation of melogabalin besylate.

[0093] As can be seen from Example 6, Comparative Example 7 and Table 8, the absence of a solubilizer in Comparative Example 7 reduced the solubility of melogabalin besylate, which further led to a significant reduction in drug release.

[0094] Experimental Example 3: In vitro transdermal test of merogabarine benzylbenzene patch on isolated porcine skin The effect of melogabalin benzyl sulfonate patches prepared in Examples 6-8, Comparative Examples 1-2, Comparative Examples 5 and 7 on transdermal efficacy was evaluated using transdermal tests.

[0095] In vitro transdermal process: Skin from the back of a 1-month-old Bama miniature pig was taken, rinsed with 10 mL of physiological saline beforehand, and the integrity of the skin was checked to ensure that there was no damage. It was trimmed to a diameter of 25 mm and a thickness of 500 μm, which is the detached pig skin. Merogabalin besylate patches prepared in Examples 6-8, Comparative Examples 1-2, Comparative Examples 5 and Comparative Example 7 were cut into circular patches with a diameter of 15 mm. The release film was removed, and the paste side was adhered to the keratin layer of the detached pig skin. The patch was placed in the supply tank of a vertical diffusion cell and fixed with a metering ring. 12 mL of pH 7.4 phosphate buffer solution (1.36 g of potassium dihydrogen phosphate, 79 mL of 0.1 mol / L sodium hydroxide solution, diluted with water to 200 mL) was added to the receiving tank at 32°C. The receiving tank was rotated at a speed of 100 rpm. After 24 hours, all the receiving liquid was collected and filtered through a 0.22 μm filter membrane. The concentration of melogabalin benzyl sulfonate in the receiving solution was determined by high performance liquid chromatography (HPLC, Shimadzu, Japan), and the permeation per unit area was calculated based on this. Three parallel experiments were set up for each group, and the average value was taken for calculation. The results are shown in Table 9.

[0096] The formula for calculating the permeability per unit area on detached pigskin is as follows: Q n =VC n / A Among them, Q n The unit area permeability (μg / cm²) of melogabalin benzyl sulfonate at time t. 2 ), A is the permeation area, C n t represents the concentration of melogabalin benzyl sulfonate in the receiving solution at time t, and V represents the total volume of the receiving solution.

[0097] Table 9. Cumulative permeation of merogabalin besylate patch after 24 hours

[0098] As shown in Examples 6-8 and Table 9, adjusting the amounts of L-menthol and sucrose laurate can affect the cumulative permeation of the melogabalin besylate patch after 24 hours. In Example 6, the cumulative permeation of the melogabalin besylate patch after 24 hours was the highest when the mass ratio of L-menthol to sucrose laurate was 1:1, which was superior to that in Examples 7 and 8.

[0099] Based on Example 6, Comparative Examples 1-2 and Table 9, it can be seen that in Comparative Examples 1 and 2, replacing L-menthol and sucrose laurate with each other by equal mass significantly reduced the cumulative permeation of the melogabalin besylate patch after 24 hours. This may be because the synergistic effect of L-menthol and sucrose laurate was disrupted, thereby reducing the permeation of the melogabalin besylate patch.

[0100] Based on Example 6, Comparative Example 5, and Table 9, it can be seen that in Comparative Example 5, when sucrose laurate was replaced with isopropyl myristate, the cumulative permeation of melogabalin besylate patch decreased after 24 hours. This may be because sucrose laurate can reduce interfacial tension and has amphiphilic properties, which can form a synergistic permeation-enhancing mechanism with L-menthol. In contrast, isopropyl myristate only has a lipid-phase solubilizing effect and has a weaker disturbance to the skin barrier. Its synergistic mechanism is singular, thus the overall permeation-enhancing efficiency decreases.

[0101] As can be seen from Example 6, Comparative Example 7 and Table 8, in Comparative Example 7, the absence of a solubilizer reduced the solubility of melogabalin besylate, which further led to a significant reduction in the amount of drug permeated.

[0102] The above are all preferred embodiments of this application and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made to the products, methods and principles of this application should be covered within the scope of protection of this application.

Claims

1. A melogabalin benzyl sulfonate patch, characterized in that, The raw materials include the following percentages by weight: melogabalin benzenesulfonic acid 0.5-10%, matrix 25-40%, antioxidant 0.1-1.5%, functional additives 0.05-0.15%, cosolvent 0.5-10%, transdermal penetration enhancer 0.1-10%, plasticizer 36.5-48%, and thickener 13-32%; Based on the total mass of the melogabalin besylate patch, the transdermal penetration enhancer consists of 0-2% L-menthol and 0.5-1.5% sucrose laurate by mass. The antioxidant is butylated hydroxytoluene; The functional additive is chitosan oligosaccharide.

2. The merogabarine benzyl sulfonate patch according to claim 1, characterized in that, The mass ratio of L-menthol to sucrose laurate is (0.33-3):

1.

3. The melogabalin benzyl sulfonate patch according to claim 1, characterized in that, The mass ratio of butylated hydroxytoluene to chitosan oligosaccharide is (2.33-9):

1.

4. The merogabarine benzyl sulfonate patch according to claim 1, characterized in that, The preparation method of chitosan oligosaccharide includes the following steps: a1: Dissolve chitosan in an acid solution to obtain colloidal chitosan; a2: Add compound enzyme A to the colloidal chitosan obtained in step a1, heat and stir, then add compound enzyme B, keep the temperature constant and stir, heat again and add chitosanase, continue stirring to obtain chitosan hydrolysate. a3: Centrifuge, concentrate, and dry the chitosan hydrolysate obtained in step a2 to obtain chitosan oligosaccharide.

5. The melogabalin benzyl sulfonate patch according to claim 4, characterized in that, In step a2, the complex enzyme A includes chitosanase and bromelain, and the complex enzyme B includes chitosanase and lipase PS-Im.

6. The merogabarine benzyl sulfonate patch according to claim 1, characterized in that, The matrix comprises styrene-isoprene-styrene block copolymer and polyisobutylene; Based on the total mass of the melogabalin benzyl sulfonate patch, the matrix consists of 20-25% by mass of styrene-isoprene-styrene block copolymer and 5-15% by mass of polyisobutylene.

7. The merogabarine benzyl sulfonate patch according to claim 1, characterized in that, The co-solvent is polyvinyl alcohol and / or sodium hydroxide; Based on the total mass of the melogabalin benzyl sulfonate patch, the co-solvent is 0-4% polyvinyl alcohol and / or 0-2% sodium hydroxide by mass.

8. The melogabalin benzyl sulfonate patch according to claim 1, characterized in that, The plasticizer is liquid paraffin.

9. The merogabarine benzyl sulfonate patch according to claim 1, characterized in that, The tackifier is an alicyclic saturated hydrocarbon resin or hydrogenated rosin glycerol ester; The total mass of the melogabalin benzenesulfonate patch is used as the calculation basis, and the tackifier is 28-32% by mass of alicyclic saturated hydrocarbon resin or 13-30% by mass of hydrogenated rosin glycerol ester.

10. A method for preparing a melogabalin benzylsulfonic acid patch according to any one of claims 1-9, characterized in that, Includes the following steps: S1: At 120-160℃, the matrix, thickener, plasticizer, antioxidant and functional additives are melt-blended to obtain a matrix mixture; S2: Melogabalin besylate, transdermal penetration enhancer, and solubilizer are dissolved by heating at 100-120℃ to obtain a solution of the active pharmaceutical ingredient; S3: Add the raw material solution prepared in step S2 to the matrix mixture prepared in step S1, stir evenly, coat it onto the anti-adhesive layer, attach it to the backing layer, cut it to obtain the melogabalin benzyl sulfonate patch.

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