Composition with anti-inflammatory and analgesic effects, soluble microneedle patch and preparation method thereof

Abstract

The present invention relates to a composition with anti-inflammatory and analgesic effects, a soluble microneedle patch and a preparation method thereof. The composition with anti-inflammatory and analgesic effects comprises the following components in parts by weight: 0.5-2 parts of capsaicin, 3-10 parts of methyl salicylate, 5-20 parts of cannabis leaf extract, and 5-20 parts of paeonol. The soluble microneedle patch is composed of needle tips and a base. The needle tips are prepared from the above composition with anti-inflammatory and analgesic effects, a solubilizer and a microneedle skeleton material; the mass ratio of the composition with anti-inflammatory and analgesic effects, the solubilizer and the microneedle skeleton material is 1:0.1-2:8-20. The soluble microneedle patch has good mechanical properties and a fast intradermal dissolution rate, and has a good anti-inflammatory and analgesic effect.

Description

Field of the Invention

[0001] The present invention belongs to the field of microneedles, and particularly relates to a composition with anti-inflammatory and analgesic effects, a soluble microneedle patch and a preparation method thereof. Background Art

[0002] Capsaicin and methyl salicylate are commonly used drugs for anti-inflammatory and analgesic purposes. Currently, the common dosage forms are gels or cataplasms. Capsaicin and methyl salicylate have great irritation to the skin and mucous membranes. When administered in the form of gels or cataplasms, due to the low transfer efficiency of the active substances, relatively large doses are often required.

[0003] Soluble microneedles are a new type of transdermal delivery method. They use micron-sized needles to pierce the skin, and then the needles that pierce the skin dissolve in the body after absorbing body fluids. The drug directly breaks through the skin barrier and enters the body to play a role. Compared with the traditional transdermal drug delivery route, the transfer efficiency of the active substances of microneedles is significantly improved, and accurate quantitative dosing can be achieved.

[0004] When capsaicin and methyl salicylate are prepared into soluble microneedles for administration, the drug directly breaks through the skin barrier and enters the body, with high transfer efficiency of the active substances. The dose of the active substances can be greatly reduced compared with gels or cataplasms, thereby reducing the irritation of capsaicin and methyl salicylate to the skin. On the other hand, soluble microneedles have a faster transfer rate compared with gels or cataplasms, and can play a role in rapid anti-inflammatory and analgesic effects.

[0005] However, the drug delivery efficiency and the drug effect of soluble microneedles depend on their mechanical properties and dissolution rate in the skin; if the mechanical properties of the microneedles are poor, resulting in low needle strength and poor toughness, the microneedles will not be able to pierce the skin and thus cannot effectively deliver the drug active ingredients; if the dissolution rate of the microneedles in the skin is too slow, it also cannot meet the requirement of rapid drug release, thereby affecting the absorption and utilization of the active ingredients. Summary of the Invention

[0006] Based on this, the purpose of the present invention is to provide a soluble microneedle patch containing capsaicin and methyl salicylate. Further, the microneedle patch has good mechanical properties and a relatively fast dissolution rate in the skin.

[0007] In order to achieve the above object, the present invention first provides a composition with anti-inflammatory and analgesic effects. By combining it with a specific type and dosage of microneedle skeleton material and solubilizer, a soluble microneedle patch with good mechanical properties and a fast dissolution rate in the skin can be prepared, and the microneedle patch has a good anti-inflammatory and analgesic effect.

[0008] The specific technical solution is as follows:

[0009] A composition with anti-inflammatory and analgesic effects, comprising the following components in parts by weight:

[0010] 0.5 - 2 parts of capsaicin, 3 - 10 parts of methyl salicylate, 5 - 20 parts of cannabis leaf extract, 5 - 20 parts of paeonol.

[0011] In some of the embodiments, the composition with anti - inflammatory and analgesic effects comprises the following components in parts by weight:

[0012] 0.8 - 1.2 parts of capsaicin, 4 - 6 parts of methyl salicylate, 8 - 12 parts of cannabis leaf extract, 8 - 12 parts of paeonol.

[0013] In some of the embodiments, the composition with anti - inflammatory and analgesic effects comprises the following components in parts by weight:

[0014] 1 part of capsaicin, 5 parts of methyl salicylate, 10 parts of cannabis leaf extract, 10 parts of paeonol.

[0015] In some of the embodiments, the mass fraction of the cannabis leaf extract is 9 - 11%.

[0016] The present invention also provides an application of the above - mentioned composition with anti - inflammatory and analgesic effects.

[0017] The specific technical solution is as follows:

[0018] The application of the above - mentioned composition in the preparation of anti - inflammatory and analgesic drugs.

[0019] The present invention also provides a soluble microneedle patch with anti - inflammatory and analgesic effects.

[0020] The technical solution is as follows:

[0021] A soluble microneedle patch with anti - inflammatory and analgesic effects, wherein the active ingredient in the soluble microneedle patch is the above - mentioned composition with anti - inflammatory and analgesic effects.

[0022] In some of the embodiments, the soluble microneedle patch is composed of needle tips and a base, and the needle tips are prepared from raw materials including an active ingredient, a solubilizer, and a microneedle skeleton material;

[0023] The mass ratio of the active ingredient, the solubilizer, and the microneedle skeleton material is 1:0.1 - 2:8 - 20

[0024] The active ingredient is the above - mentioned composition with anti - inflammatory and analgesic effects;

[0025] The solubilizer is one or more of Tween 60, Tween 80, PEG - 400, PEG - 40 hydrogenated castor oil, and cyclodextrin;

[0026] The micro-needle skeleton material is selected from one or more of polyvinylpyrrolidone, dextran, sodium hyaluronate, carbomer, mannose, glucose, fructose, sodium polyacrylate, chitosan, and chondroitin sulfate.

[0027] In some embodiments, the mass ratio of the active ingredient, solubilizer, and micro-needle skeleton material is 1: 0.3-1.5: 10-15.

[0028] In some embodiments, the mass ratio of the active ingredient, solubilizer, and micro-needle skeleton material is 1: 0.5-1: 11-12.

[0029] In some embodiments, the solubilizer is PEG-400.

[0030] In some embodiments, the micro-needle skeleton material is composed of dextran 40, mannose, polyvinylpyrrolidone, and sodium hyaluronate.

[0031] In some embodiments, the micro-needle skeleton material is composed of the following components in parts by weight:

[0032] Dextran 40 4-6 parts, mannose 2-4 parts, polyvinylpyrrolidone 5-7 parts, sodium hyaluronate 13-17 parts.

[0033] In some embodiments, the micro-needle skeleton material is composed of the following components in parts by weight:

[0034] Dextran 40 5 parts, mannose 3 parts, polyvinylpyrrolidone 6 parts, sodium hyaluronate 15 parts.

[0035] In some embodiments, the molecular weight of the polyvinylpyrrolidone is 25-35 kDa.

[0036] In some embodiments, the molecular weight of the sodium hyaluronate is 7000 Da-9000 Da.

[0037] In some embodiments, the substrate is prepared from glycerol and hydroxypropyl cellulose.

[0038] In some embodiments, the substrate is prepared from 0.3-0.5 parts of glycerol and 18-22 parts of hydroxypropyl cellulose.

[0039] The present invention also provides a preparation method of the above-mentioned soluble micro-needle patch with anti-inflammatory and analgesic effects.

[0040] The specific technical solution is as follows:

[0041] A preparation method of a soluble micro-needle patch with anti-inflammatory and analgesic effects, comprising the following steps:

[0042] (1) Preparation of the needle tip: Mix the active ingredient, solubilizer, microneedle matrix material, ethanol, and water evenly to obtain the needle tip solution; use the method of vacuum pumping or centrifugation to fill the needle holes of the microneedle mold with the needle tip solution.

[0043] (2) Preparation of the substrate: Dissolve the material for preparing the substrate in water to obtain the substrate solution, and use the method of vacuum pumping or centrifugation to evenly coat the substrate solution in the microneedle mold treated in step (1), dry and demold to obtain the soluble microneedle patch with anti-inflammatory and analgesic effects.

[0044] In some embodiments, in step (1), the ratio of the total mass of the active ingredient, solubilizer, and microneedle matrix material to the total mass of ethanol and water is 3:5 - 8; the mass ratio of ethanol to water is 2:7 - 9.

[0045] In some embodiments, the vacuum degree of the vacuum pumping is -0.06~-0.07 Mpa.

[0046] In some embodiments, the conditions of centrifugation include: the rotation speed is 3000 ± 1000 rpm, and the time is 3 - 5 min.

[0047] In some embodiments, the conditions of drying include: the temperature is 25 ± 3 °C, the relative humidity is 10% ± 5%, and the time is 15 ± 3 h.

[0048] The advantages of the soluble microneedle patch with anti-inflammatory and analgesic effects of the present invention are as follows:

[0049] The present invention selects capsaicin, methyl salicylate, cannabis leaf extract, and paeonol to be compounded in a certain proportion as the active ingredient, which has a synergistic effect, so that the obtained compound composition has a good anti-inflammatory and analgesic effect. Among them, the addition of cannabis leaf extract and paeonol can improve the anti-inflammatory and analgesic effects of capsaicin and methyl salicylate, reduce their dosage, and thus can reduce the irritation of capsaicin and methyl salicylate to the skin. Preparing the compound composition into a soluble microneedle patch for transdermal drug delivery can improve the delivery efficiency of the active drug, increase its transdermal absorption rate, further reduce the dosage of capsaicin and methyl salicylate, thus further reducing the irritation of capsaicin and methyl salicylate to the skin, and improving its rapid anti-inflammatory and analgesic effect.

[0050] Furthermore, using this compound composition as the active ingredient, together with a certain amount and specific types of solubilizers and microneedle matrix materials, a soluble microneedle patch with good mechanical properties and puncture performance and relatively fast intradermal dissolution rate was prepared. This microneedle patch can effectively penetrate the skin stratum corneum barrier, form micropores on the skin surface, enabling the anti-inflammatory and analgesic active ingredients (capsaicin, methyl salicylate, cannabis leaf extract, and paeonol) at the tips of the microneedles to quickly dissolve in the skin and be absorbed by the dermis, thereby achieving a rapid anti-inflammatory and analgesic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is a diagram showing the microneedle forming situation of the soluble microneedle patch with anti-inflammatory and analgesic effects prepared in Example 1 of the present invention. Among them, A is the overall forming situation diagram observed under a microscope at 10x magnification, and B is the side view observed under a microscope at 500x magnification. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0052] To facilitate the understanding of the present invention, the present invention will be described more comprehensively below with reference to the embodiments. The following are the preferred embodiments of the present invention. However, the present invention can be implemented in many different forms and is not limited to the embodiments described herein. The purpose of providing these embodiments is to make the understanding of the disclosure content of the present invention more thorough and comprehensive.

[0053] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which the present invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention. The term “and / or” used herein includes any and all combinations of one or more of the related listed items.

[0054] The following further elaborates on the present invention in conjunction with specific embodiments.

[0055] The raw materials used in the embodiments of the present invention are as follows:

[0056] Capsaicin, with a mass fraction of 97%, from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0057] Methyl salicylate, with a mass fraction of 99%, from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0058] Cannabis leaf extract, with a mass fraction of 10%, from Yunnan Hanshu Biotechnology Co., Ltd.

[0059] Paeonol, with a mass fraction of 98%, from Weinan Changtong Pharmaceutical and Chemical Technology Co., Ltd.

[0060] PEG400, from Shanghai Macklin Biochemical Co., Ltd.

[0061] Dextran 40, with a molecular weight of 40,000 Da, Shanghai Macklin Biochemical Co., Ltd.;

[0062] Mannose, with a mass fraction of 97%, Shanghai Aladdin Biochemical Technology Co., Ltd.

[0063] Sodium hyaluronate, with a molecular weight of 8,000 Da and a mass fraction of 99%, Xi'an Meichuan Biotechnology Co., Ltd.;

[0064] Sodium hyaluronate, with a molecular weight of 60,000 Da and a mass fraction of 99%, Shandong Anhua Biopharmaceutical Co., Ltd.;

[0065] Tween 60, with a mass fraction of 98%, Shanghai Macklin Biochemical Co., Ltd.;

[0066] Polyvinylpyrrolidone, with a molecular weight of 30 kDa and a mass fraction of 99%, Ashland Chemical Trading Shanghai Co., Ltd.;

[0067] Glycerol, with a mass fraction of 99.9%, PTNUBIKAJAYA;

[0068] Hydroxypropyl cellulose, with a mass fraction of 99%, Ashland Chemical Trading Shanghai Co., Ltd.

[0069] Example 1

[0070] The soluble microneedle patch with anti-inflammatory and analgesic effects provided in this example is composed of needle tips and a base; the raw material composition of its needle tips is as follows (by weight): 0.1 part of capsaicin, 0.5 part of methyl salicylate, 1 part of cannabis leaf extract, 1 part of paeonol, 2 parts of PEG-400, 13 parts of ethanol, 5 parts of dextran 40, 3 parts of mannose, 6 parts of polyvinylpyrrolidone (with a molecular weight of 30 kDa), 15 parts of sodium hyaluronate (with a molecular weight of 8,000 Da); the raw material composition of the base is as follows: 0.4 part of glycerol, 20 parts of hydroxypropyl cellulose.

[0071] The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects provided in this example is as follows:

[0072] S1: Prepare the needle tips: After mixing the above raw materials for preparing the needle tips evenly, add 53.12 parts of distilled water and stir to dissolve to obtain a needle tip solution; fill the needle holes of the microneedle mold with the needle tip solution using a coater under a vacuum degree of -0.06 to -0.07 Mpa, and remove the excess needle tip solution.

[0073] S2: Fabricate the microneedle base: Dissolve the raw materials for preparing the base in 79.6 parts of distilled water by stirring to obtain a base solution. Coat the base solution evenly in the microneedle mold processed in step S1 under a vacuum of -0.06 to -0.07 Mpa, and dry it at 25 ± 3°C and a relative humidity of 10% ± 5% for 15 ± 3 h, then demold to obtain a soluble microneedle patch with anti-inflammatory and analgesic effects.

[0074] Investigation of microneedle formation: Cut a round piece with an area of about 1 cm 2 in size from the microneedle patch with a cutter die, and observe its overall formation under a microscope at 10x magnification. Then cut the middle column with a small knife and observe its needle length from the side under a microscope at 500x magnification. Use the microscope computer software to count the average length of 20 microneedles as the average length of the microneedle body. Figure 1 For the formation of the microneedles prepared in Example 1, it can be seen from the figure that the microneedles are well formed, and their needle length is 400 ± 10 μm.

[0075] Example 2

[0076] The difference between this example and Example 1 is that the solubilizer is Tween 60. Specifically as follows:

[0077] The soluble microneedle patch with anti-inflammatory and analgesic effects provided in this example is composed of a needle tip and a base; the raw material composition of its needle tip is as follows (by weight): 0.1 part of capsaicin, 0.5 part of methyl salicylate, 1 part of cannabis leaf extract, 1 part of paeonol, 2 parts of Tween 60, 13 parts of ethanol, 5 parts of dextran 40, 3 parts of mannose, 6 parts of polyvinylpyrrolidone (molecular weight 30 kDa), 15 parts of sodium hyaluronate (molecular weight 8000 Da); the raw material composition of the base is as follows: 0.4 part of glycerol, 20 parts of hydroxypropyl cellulose.

[0078] The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects provided in this example is as follows:

[0079] S1: Prepare the needle tip: After mixing the raw materials for preparing the needle tip evenly, add 53.12 parts of distilled water and stir to dissolve to obtain a needle tip solution; fill the needle holes of the microneedle mold with the needle tip solution using a coater under a vacuum of -0.06 to -0.07 Mpa, and remove the excess needle tip solution.

[0080] S2: Fabricate the microneedle base: Dissolve the raw materials for preparing the base in 79.6 parts of distilled water by stirring to obtain a base solution. Coat the base solution evenly in the microneedle mold processed in step S1 under a vacuum of -0.06 to -0.07 Mpa, and dry it at 25 ± 3°C and a relative humidity of 10% ± 5% for 15 ± 3 h, then demold to obtain a soluble microneedle patch with anti-inflammatory and analgesic effects.

[0081] Example 3

[0082] The difference between this embodiment and Embodiment 1 lies in the different molecular weights of sodium hyaluronate in the microneedle skeleton material. Specifically as follows:

[0083] The soluble microneedle patch with anti-inflammatory and analgesic effects provided in this embodiment is composed of a needle tip and a base; the raw material composition of its needle tip is as follows (by weight): 0.1 part of capsaicin, 0.5 part of methyl salicylate, 1 part of cannabis leaf extract, 1 part of paeonol, 2 parts of PEG-400, 13 parts of ethanol, 40 parts of dextran, 3 parts of mannose, 6 parts of polyvinylpyrrolidone (molecular weight 30 kDa), 15 parts of sodium hyaluronate (molecular weight 60000 Da); the raw material composition of the base is as follows: 0.4 part of glycerol, 20 parts of hydroxypropyl cellulose.

[0084] The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects provided in this embodiment is as follows:

[0085] S1: Prepare the needle tip: After mixing the above raw materials for preparing the needle tip evenly, add 53.12 parts of distilled water and stir to dissolve to obtain a needle tip solution; use a coater to fill the needle holes of the microneedle mold with the needle tip solution under a vacuum of -0.06 to -0.07 Mpa, and remove the excess needle tip solution.

[0086] S2: Make the microneedle base: Stir and dissolve the above raw materials for preparing the base with 79.6 parts of distilled water to obtain a base solution, and evenly coat the base solution in the microneedle mold treated in step S1 under a vacuum of -0.06 to -0.07 Mpa, and dry at 25 ± 3°C and 10% ± 5% relative humidity for 15 ± 3 h, then demold to obtain the soluble microneedle patch with anti-inflammatory and analgesic effects.

[0087] Embodiment 4

[0088] The difference between this embodiment and Embodiment 1 lies in that the microneedle skeleton material does not include dextran 40 and mannose. Specifically as follows:

[0089] The soluble microneedle patch with anti-inflammatory and analgesic effects provided in this embodiment is composed of a needle tip and a base; the raw material composition of its needle tip is as follows (by weight): 0.1 part of capsaicin, 0.5 part of methyl salicylate, 1 part of cannabis leaf extract, 1 part of paeonol, 2 parts of PEG-400, 13 parts of ethanol, 8.3 parts of polyvinylpyrrolidone (molecular weight 30 kDa), 20.7 parts of sodium hyaluronate (molecular weight 8000 Da); the raw material composition of the base is as follows: 0.4 part of glycerol, 20 parts of hydroxypropyl cellulose.

[0090] The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects provided in this embodiment is as follows:

[0091] S1: Preparation of the needle tip: After uniformly mixing the raw materials for preparing the needle tip, add 53.12 parts of distilled water and stir to dissolve to obtain a needle tip solution; fill the needle holes of the microneedle mold with the needle tip solution using a coater under a vacuum of -0.06 to -0.07 Mpa, and remove the excess needle tip solution.

[0092] S2: Fabrication of the microneedle base: Dissolve the raw materials for preparing the base with 79.6 parts of distilled water by stirring to obtain a base solution, and uniformly coat the base solution in the microneedle mold treated in step S1 under a vacuum of -0.06 to -0.07 Mpa, and dry at 25 ± 3 °C and a relative humidity of 10% ± 5% for 15 ± 3 h, then demold to obtain a soluble microneedle patch with anti-inflammatory and analgesic effects.

[0093] Comparative Example 1

[0094] The difference between this comparative example and Example 1 is that the active ingredients do not include cannabis leaf extract and paeonol. Specifically as follows:

[0095] The soluble microneedle patch with anti-inflammatory and analgesic effects provided in this comparative example is composed of a needle tip and a base; the raw material composition of its needle tip is as follows (by weight): 0.4 part of capsaicin, 2.2 parts of methyl salicylate, 2 parts of PEG-400, 13 parts of ethanol, 405 parts of dextran, 3 parts of mannose, 6 parts of polyvinylpyrrolidone (molecular weight 30 kDa), 15 parts of sodium hyaluronate (molecular weight 8000 Da); the raw material composition of the base is as follows: 0.4 part of glycerol, 20 parts of hydroxypropyl cellulose.

[0096] The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects provided in this comparative example is as follows:

[0097] S1: Preparation of the needle tip: After uniformly mixing the raw materials for preparing the needle tip, add 53.12 parts of distilled water and stir to dissolve to obtain a needle tip solution; fill the needle holes of the microneedle mold with the needle tip solution using a coater under a vacuum of -0.06 to -0.07 Mpa, and remove the excess needle tip solution.

[0098] S2: Fabrication of the microneedle base: Dissolve the raw materials for preparing the base with 79.6 parts of distilled water by stirring to obtain a base solution, and uniformly coat the base solution in the microneedle mold treated in step S1 under a vacuum of -0.06 to -0.07 Mpa, and dry at 25 ± 3 °C and a relative humidity of 10% ± 5% for 15 ± 3 h, then demold to obtain a soluble microneedle patch with anti-inflammatory and analgesic effects.

[0099] Comparative Example 2

[0100] The difference between this comparative example and Example 1 is that the active ingredients do not include cannabis leaf extract. Specifically as follows:

[0101] The soluble microneedle patch with anti-inflammatory and analgesic effects provided in this comparative example is composed of a needle tip and a base; the raw material composition of the needle tip is as follows (in parts by weight): 0.1 part of capsaicin, 0.5 part of methyl salicylate, 2 parts of paeonol, 2 parts of PEG-400, 13 parts of ethanol, 5 parts of dextran 40, 3 parts of mannose, 6 parts of polyvinyl pyrrolidone (molecular weight 30kDa), and 15 parts of sodium hyaluronate (molecular weight 8000Da); the raw material composition of the base is as follows: 0.4 parts of glycerol and 20 parts of hydroxypropyl cellulose.

[0102] The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects provided in this comparative example is as follows:

[0103] S1: Preparing needle tips: After uniformly mixing the raw materials for preparing needle tips, 53.12 parts of distilled water are added and stirred to dissolve to obtain a needle tip solution; the needle tip solution is filled into the pinholes of the microneedle mold with an applicator under a vacuum degree of -0.06 to -0.07 MPa, and excess needle tip solution is removed.

[0104] S2: Preparation of microneedle substrate: Stir and dissolve the raw materials for preparing the substrate with 79.6 parts of distilled water to obtain a substrate solution, and evenly apply the substrate solution on the microneedle mold treated in step S1 under a vacuum degree of -0.06 to -0.07 MPa, dry at 25±3°C and 10%±5% relative humidity for 15±3h, and demold to obtain a soluble microneedle patch with anti-inflammatory and analgesic effects.

[0105] Example 5 Microneedle puncture performance investigation

[0106] 1. Operating environment temperature and humidity conditions: temperature 10℃~35℃, humidity 30%~45%RH

[0107] 2. Parafilm TM The film was cut into 2.0×2.0 small pieces. According to the theoretical needle length L, the x pieces of cut film were stacked into a whole piece, pressed tightly, and placed on the PMDS board to form a simulated skin.

[0108] x=L / 127 (Note: unit: um, add 1 to the integer part of the result)

[0109] 3. Take the microneedle patch and use a cutter to cut it into small round pieces as the microneedle patch test sample. Observe under a microscope and count and record the total number of needles N of the test sample.

[0110] 4. Place the simulated skin on the loading platform of the hardness tester, place the microneedle patch on the simulated skin, rotate the push rod knob on the hardness tester, press the microneedle down with a force of 1N, stay for 30 seconds, pull out the microneedle, and repeat n times in parallel.

[0111] 5. Uncovering Parafilm TMUnder a microscope, observe the puncture situation of each layer of the thin film, and statistically obtain the insertion depth of the microneedles and the number of puncture holes K in each layer.

[0112] 6. Calculate the puncture rate P and the average puncture rate P’

[0113] (1) P = K2 / N

[0114] K2: The number of holes punctured in the second layer of Parafilm TM membrane

[0115] N: The total number of needles in the microneedle patch test sample

[0116] (2) P’ = P / n

[0117] 7. Penetration evaluation

[0118] Average puncture rate P’ Puncture property determination P’≥90％ Excellent 80％≤P’<90％ Good 70％≤P’<80％ Fair P’<70％ Poor

[0119] 8. Test results

[0120] The average puncture rates of the microneedle patches prepared in Examples 1-4 and Comparative Examples 1-2 are shown in Table 1 below.

[0121] Table 1

[0122]

[0123]

[0124] As can be seen from the results in Table 1: The penetration of the microneedle patches prepared in Example 1, Example 3 and Comparative Examples 1-2 is excellent; the penetration of the microneedle patch prepared in Example 2 is average, and the penetration of the microneedle patch prepared in Example 4 is good, indicating that replacing the solubilizer PEG-400 with Tween 60 will reduce the penetration performance of the microneedles, and removing dextran 40 and mannose from the matrix material will also reduce the penetration performance of the microneedles. Therefore, the solubilizer is preferably PEG-400, and the matrix material is preferably a combination of dextran 40, mannose, polyvinylpyrrolidone (molecular weight 30 kDa) and sodium hyaluronate (molecular weight 8000 Da).

[0125] Microneedle solubility test of Example 6

[0126] Prepare a gelatin gel with a water content of 35%, cover the surface of the gel with a layer of plastic wrap, cut out a microneedle disc with an area of 1 cm 2 and place it on the gel with the needle tip facing down. Place a 100 g weight on the back of the microneedle, press the weight firmly for 30 s, let it stand for 10 min, take out the microneedle, and observe its dissolution under a microscope. After testing, the dissolution percentages of the microneedle patches prepared in Examples 1-4 and Comparative Examples 1-2 in the gel within 10 min are shown in Table 2 below.

[0127] Table 2

[0128] Microneedle patch Microneedle dissolution percentage Example 1 95％ Example 2 80％ Example 3 40％ Example 4 65％ Comparative example 1 90％ Comparative example 2 90％

[0129] As can be seen from the results in Table 2: Replacing the solubilizer PEG-400 with Tween 60, removing dextran 40 and mannose from the matrix material, and replacing sodium hyaluronate with a molecular weight of 8000 Da with sodium hyaluronate with a molecular weight of 60000 Da will all affect the dissolution rate of the resulting microneedle patch, significantly decreasing the dissolution rate of the resulting microneedle patch, which is not conducive to the rapid release of the microneedles in the skin.

[0130] Example 7 Anti-inflammatory and Analgesic Efficacy Test

[0131] The anti-inflammatory and analgesic efficacy of the soluble microneedle patch with anti-inflammatory and analgesic efficacy of the present invention was investigated through the acetic acid-induced writhing test in mice and the ear swelling test in mice.

[0132] Acetic acid-induced writhing test in mice: Sixty mice were randomly divided into 4 groups, with 15 mice in each group, all male, and divided into a blank matrix control group, Example 1 group, Comparative Example 1 group, and Comparative Example 2 group. The blank matrix control group used a blank microneedle patch (the preparation raw materials did not contain capsaicin, methyl salicylate, cannabis leaf extract, and paeonol, and other raw materials and preparation methods were the same as in Example 1). The Example 1 group, Comparative Example 1 group, and Comparative Example 2 group used the soluble microneedle patches with anti-inflammatory and analgesic efficacy prepared in Example 1, Comparative Example 1, and Comparative Example 2, respectively. The administration area of each group of microneedle patches was 1 cm * 1 cm. The abdominal hair of each group of mice was removed 12 hours before administration, and the skin was checked for no damage. On the next morning, the microneedle patch was applied to the depilated area of the mice by skin patch and pasted with medical tape, and pressed for 2 min. Based on the principle that the microneedles did not fall off and did not affect the activities of the mice, the drug was administered once a day, and each microneedle patch was attached to the skin for 2 h each time, and the drug was administered continuously for 5 days. 1 h after the last administration, 0.6% glacial acetic acid was injected intraperitoneally at 0.2 ml / 20 g, and the number of writhing times of the mice within 20 min after inflammation induction was recorded. The experimental results are shown in Table 3 below.

[0133] Table 3

[0134] Group Number of animals Number of writhing times (times / 20 min) Blank microneedle patch 15 30.50±25.45 Microneedle patch of Example 1 15 5.66±7.34 Microneedle patch of Comparative example 1 15 15.22±16.48 Microneedle patch of Comparative example 2 15 8.78±9.67

[0135] It can be seen from the data in Table 3 that there were significant differences between the Example 1 group, Comparative Example 1 group, and Comparative Example 2 group and the blank control group, indicating that the acetic acid-induced writhing model in mice was successfully established. At the same time, the number of writhing times of the mice in the Example 1 group was significantly less than that in the Comparative Example 1 group and the Comparative Example 2 group, indicating that the microneedle patch prepared in Example 1 had better analgesic efficacy than the other two groups, indicating that the addition of cannabis leaf extract and paeonol could improve the analgesic effect of capsaicin and methyl salicylate, and the analgesic effect of the four-component compound was better.

[0136] Mouse auricle swelling experiment: 60 male mice were randomly divided into 4 groups of 15 each, namely a blank matrix control group, an Example 1 group, a Comparative Example 1 group, and a Comparative Example 2 group. The blank matrix control group used a blank microneedle patch (the preparation raw materials did not contain capsaicin, methyl salicylate, cannabis leaf extract, and paeonol, and other raw materials and preparation methods were the same as those in Example 1). The Example 1 group, the Comparative Example 1 group, and the Comparative Example 2 group used the soluble microneedle patches with anti-inflammatory and analgesic effects prepared in Example 1, Comparative Example 1, and Comparative Example 2, respectively. The administration area of each group of microneedle patches was 1 cm * 1 cm. 12 hours before drug administration for each group of mice, the abdomen was depilated, and the skin was checked for no damage. On the next morning, the microneedle patch was externally applied to the depilated area of the mice and pasted with medical tape, and pressed for 2 minutes. Based on the principle that the microneedles did not fall off and did not affect the activities of the mice, the drug was administered once a day, and each microneedle patch was attached to the skin for 2 hours each time. After 5 consecutive days of drug administration, 1 hour after the last drug administration, 0.05 ml of xylene and normal saline were respectively applied to the left ears of each group of mice. 20 minutes after drug application, the mice were sacrificed by cervical dislocation. The ears were cut off, and 7-mm circular ear pieces were taken with a punch and weighed on an analytical balance. The following formula was used for calculation: Swelling rate = [(weight of left ear piece - weight of right ear piece) / weight of right ear piece] * 100%; Swelling inhibition rate = [(swelling rate of blank group - swelling rate of drug administration group) / swelling rate of blank group] * 100%. The experimental results are shown in Table 4 below.

[0137] Table 4

[0138] Group Number of animals / each Difference between left and right ears / mg Swelling rate / % Swelling inhibition rate / % Blank matrix control group 15 9.33±2.67 1.44±0.31 Example 1 group 15 2.60±1.55 0.41±0.25 72 Comparative example 1 group 15 5.03±1.67 0.75±0.27 48 Comparative example 2 group 15 3.98±1.83 0.56±0.33 61

[0139] It can be seen from the data in Table 4 that there were significant differences between the Example 1 group, the Comparative Example 1 group, and the Comparative Example 2 group and the blank control group, indicating that the mouse auricle swelling model was successfully established. At the same time, the swelling inhibition rate of the Example 1 group was significantly higher than that of the Comparative Example 1 group and the Comparative Example 2 group, indicating that the microneedle patch prepared in Example 1 had better anti-inflammatory effects than the other two groups, indicating that the addition of cannabis leaf extract and paeonol could improve the anti-inflammatory effects of capsaicin and methyl salicylate, and the anti-inflammatory effect of the four-component compound use was better.

[0140] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered to be within the scope described in this specification.

[0141] The above-described embodiments merely represent several implementation manners of the present invention. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A soluble microneedle patch with anti-inflammatory and analgesic effects, Characterized in that, The soluble microneedle patch is composed of needle tips and a base. The needle tips are prepared from raw materials including an active ingredient, a solubilizer, and a microneedle skeleton material; The mass ratio of the active ingredient, solubilizer, and microneedle skeleton material is 1: 0.5 - 1.0: 11 - 12; The active ingredient is a composition with anti-inflammatory and analgesic effects; the composition with anti-inflammatory and analgesic effects is composed of the following components in parts by weight: 0.8 - 1.2 parts of capsaicin, 4 - 6 parts of methyl salicylate, 8 - 12 parts of cannabis leaf extract, 8 - 12 parts of paeonol; the mass fraction of the cannabis leaf extract is 9 - 11%; The solubilizer is PEG - 400; The microneedle skeleton material is composed of the following components in parts by weight: 4 - 6 parts of dextran 40, 2 - 4 parts of mannose, 5 - 7 parts of polyvinylpyrrolidone, 13 - 17 parts of sodium hyaluronate; The molecular weight of the sodium hyaluronate is 7000Da - 9000Da; The molecular weight of the polyvinylpyrrolidone is 25 - 35kDa.

2. The soluble microneedle patch with anti-inflammatory and analgesic effects according to claim 1, Characterized in that, The composition with anti-inflammatory and analgesic effects is composed of the following components in parts by weight: 1 part of capsaicin, 5 parts of methyl salicylate, 10 parts of cannabis leaf extract, 10 parts of paeonol.

3. The soluble microneedle patch with anti-inflammatory and analgesic effects according to any one of claims 1 - 2, Characterized in that, The mass fraction of the cannabis leaf extract is 10%.

4. The soluble microneedle patch with anti-inflammatory and analgesic effects according to any one of claims 1 - 2, Characterized in that, The base is prepared from glycerol and hydroxypropyl cellulose.

5. The soluble microneedle patch with anti-inflammatory and analgesic effects according to claim 4, Characterized in that, The base is prepared from 0.3 - 0.5 parts of glycerol and 18 - 22 parts of hydroxypropyl cellulose.

6. The soluble microneedle patch with anti-inflammatory and analgesic effects according to claim 1, Characterized in that, The microneedle skeleton material is composed of the following components in parts by weight: 5 parts of dextran 40, 3 parts of mannose, 6 parts of polyvinylpyrrolidone, 15 parts of sodium hyaluronate.

7. A preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects according to any one of claims 1 - 6, Characterized in that, Comprises the following steps: (1) Prepare the needle tips: Mix the active ingredient, solubilizer, microneedle skeleton material, ethanol, and water evenly to obtain a needle tip solution; use the method of vacuum pumping or centrifugation to fill the needle holes of the microneedle mold with the needle tip solution; (2) Prepare the base: Dissolve the material for preparing the base in water to obtain a base solution, use the method of vacuum pumping or centrifugation to evenly coat the base solution in the microneedle mold treated in step (1), dry and demold to obtain the soluble microneedle patch with anti-inflammatory and analgesic effects.

8. The preparation method of the soluble microneedle patch with anti-inflammatory and analgesic effects according to claim 7, Characterized in that, In step (1), the ratio of the total mass of the active ingredient, solubilizer and microneedle skeleton material to the total mass of the ethanol and water is 3:5 - 8; the mass ratio of ethanol to water is 2:7 - 9; and / or, the degree of vacuum for the vacuum pumping is -0.06~-0.07 Mpa; and / or, the conditions for the centrifugation include: the rotation speed is 3000 ± 1000 rpm and the time is 3 - 5 min; and / or, the conditions for the drying include: the temperature is 25 ± 3 °C, the relative humidity is 10% ± 5%, and the time is 15 ± 3 h.

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