Polysulfonic acid mucopolysaccharide transdermal patch as well as preparation method and application thereof

Abstract

The invention provides a polysulfonic acid mucopolysaccharide transdermal patch and a preparation method thereof. The preparation method comprises the following steps: dissolving polysulfonic acid mucopolysaccharide and a transdermal enhancer in a water phase to form a homogeneous solution, mixing a hydrophilic matrix, an adhesive and a humectant under the protection of inert gas to form a gel matrix, finally mixing the homogeneous solution and the gel matrix, homogenizing, coating an anti-sticking layer, drying, and covering a backing layer and the anti-sticking layer. The patch disclosed by the invention has the characteristics of stable, convenient and comfortable drug release, and can keep stable on the skin surface for a long time, so that continuous release of the drug is realized, and a better treatment effect is achieved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and particularly relates to a transdermal patch with mucopolysaccharide polysulfate as the core active ingredient and a preparation method thereof, which is applicable to phlebitis, scar repair, anti-inflammation and promotion of skin barrier function improvement. Background Art

[0002] Mucopolysaccharide Polysulfate (MPS) is a naturally occurring glycosaminoglycan, a mixture of highly sulfated chondroitin sulfate-like polysaccharide molecules with a molecular weight between 5000 and 15000 daltons. The structural formula of mucopolysaccharide polysulfate is as follows:

[0003]

[0004] Mucopolysaccharide polysulfate widely exists in animal tissues, can promote the synthesis of mesenchymal cells and restore the ability of intercellular substances to retain moisture, and has various biological activities such as anti-inflammation, anti-oxidation, moisturizing, anti-thrombosis formation, and promotion of connective tissue regeneration. Research shows that MPS can promote fibroblast proliferation and collagen synthesis, and inhibit the activity of matrix metalloproteinases, thereby playing an anti-aging and scar repair-promoting role.

[0005] Currently, only the cream formulation of mucopolysaccharide polysulfate has been developed, applied and marketed, and it has achieved certain effects in the clinical treatment of phlebitis. However, its dosage form limitations are significant: 1) The semi-solid matrix results in a short residence time of the drug on the skin surface, and multiple daily administrations are required; 2) The penetration rate of the cream dosage form into the dermis is insufficient, and in vitro experiments show that only 12-15% of the drug can penetrate the stratum corneum; 3) The emulsifier in the matrix may cause skin irritation reactions, and a considerable number of patients have contact dermatitis in clinical trials; 4) The cream drug is easily wiped off by clothing, has a short action time, large fluctuations in local drug concentration, and is difficult to release continuously, resulting in low patient compliance (requiring frequent application). These defects limit the application of MPS in indications that require long-term administration such as chronic wound healing and scar repair. At the same time, when using the cream, it is easily rubbed by close-fitting clothes, resulting in the cream being rubbed off, thus affecting the drug effect. In addition, the cream is also easily contaminated and oxidized and deteriorated when exposed to the environment, and there are great inconveniences in clinical use.

[0006] Transdermal drug delivery systems (TDDS) refer to the systems in which drugs enter the systemic circulation through the skin and capillaries at a certain rate, so as to achieve the effect of systemic or local treatment. Broadly defined, TDDS includes all topical dosage forms, such as ointments, patches, cataplasms, aerosols, and paints, etc. Narrowly defined, TDDS specifically refers to transdermal patches. Compared with other drug delivery routes, transdermal patches bring many advantages in the way of drug administration. For example, the operation is simple, the first-pass metabolism in the liver is avoided, and the interference of gastrointestinal factors on drug absorption is avoided, etc. The design feature of transdermal patches is a multi-layer structure, mainly including a backing layer, an optional drug reservoir or matrix system, an adhesive layer (adhesive layer), and a release liner / anti-adhesive layer. The backing layer is a waterproof protective layer that can protect the skin from being invaded by external substances and prevent drug loss or skin moisture evaporation. The drug reservoir or matrix system is used to store and release drugs. The adhesive layer keeps the patch in contact with the skin. The release liner is used to protect the patch during storage and must be removed before use.

[0007] In recent years, the research on novel transdermal drug delivery systems has provided new ideas for breaking through the above limitations. Although technologies such as nanostructured lipid carriers and microneedle arrays can improve the transdermal efficiency, they have problems such as complex preparation processes and high costs. The existing research on transdermal drug delivery systems mostly focuses on chemically synthesized drugs, and the research on drug loading technologies for polysaccharide macromolecular drugs lags significantly. Some pressure-sensitive adhesives commonly used in traditional patches have poor compatibility with certain active ingredients; although hydrogel patches can improve the loading of hydrophilic drugs, they are volatile, have low skin adhesion, have a burst release phenomenon in drug release, and the release rate fluctuates greatly. In addition, most drugs cannot directly penetrate the skin and enter the body, and it is difficult for transdermal patches to have the same bioavailability as other preparations, which to a certain extent limits the development of transdermal patches. Therefore, developing a novel patch that can achieve controlled release of MPS, improve transdermal efficiency, and maintain its structural and functional integrity has become the key to breaking through the existing technical bottlenecks. If this dosage form can be successfully developed, it can not only solve the defect of inconvenient use of traditional creams, but also expand the application of MPS in the fields of medical beauty (such as anti-wrinkle and scar repair) and chronic wound management, and more importantly, it can provide a technical paradigm for the transdermal administration of other polysaccharide macromolecular drugs.

[0008] The purpose of the present invention is to develop a novel patch based on MPS, and conduct drug transmission through a transdermal drug delivery system to ensure that the drug penetrates the skin to reach the lesion tissue at a stable and continuous rate, can maintain a stable blood drug concentration for a long time, so as to maintain an effective therapeutic concentration, increase the bioavailability of the drug, and improve patient compliance. Summary of the Invention

[0009] The present invention provides a patch of mucopolysaccharide polysulfate which can directly adhere to the skin, avoid the drug being wiped off by clothes, and improve the compliance of patients. Under the action of the penetration enhancer, the drug in the patch penetrates through the stratum corneum of the skin and maintains a stable blood drug concentration for a long time, increasing the bioavailability of the drug. In addition, an inert gas is used in the preparation process to control the oxygen content in the preparation environment to meet the requirements (oxygen content < 0.5%). At the same time, an antioxidant is added to the formulation to further protect the stability of mucopolysaccharide polysulfate and avoid the reduction of drug efficacy and the enhancement of skin irritation caused by the oxidation of the sulfate group (-OSO3 - ) and hydroxyl group (-OH) on the molecular chain.

[0010] The patch of the present invention comprises a backing layer, an adhesive layer and a release liner, and is characterized in that the adhesive layer contains mucopolysaccharide polysulfate, sodium carboxymethylcellulose, menthol, polyacrylate, glycerol, vitamin E and water.

[0011] The material of the backing layer in the patch can be selected from two types: breathable and non-breathable. The non-breathable backing materials are mainly some plastic films, such as composite aluminum foil, polyester film, polyethylene film, polyvinylidene chloride copolymer (PVDC), and polyurea; the breathable backing materials mainly include three categories: textiles, non-woven fabrics and microporous membranes. Textiles such as cotton cloth, polyester cloth, polyester-cotton cloth, acetate fiber cloth and various plush cloths, elastic cloths, etc.; non-woven fabrics include hydrospun non-woven fabrics, thermally bonded non-woven fabrics and meltblown non-woven fabrics of various specifications; microporous membranes include porous, microporous or macroporous microporous membranes. The shape of the backing layer is a fabric such as a film, sheet, sheet-like porous body, sheet-like foam, woven fabric, knitted fabric, non-woven fabric, etc., and its laminate, etc. There is no particular limitation on the thickness of the backing layer, and it is generally preferably about 2 to 3000 μm.

[0012] The thickness of the release liner material in the patch is generally 50 to 125 nm, and it can be an inert, impermeable or light-shielding metallized polyester film or aluminum. The adhesive layer needs to be covered with a good release material, and polyethylene release film, polyethylene terephthalate film containing a fluoride coating, etc. can be selected. The release liner covers the adhesive layer as a protective layer to facilitate the packaging and storage of the patch and can be easily separated from the adhesive layer during use.

[0013] The main inventive point of the patch of the present invention lies in the adhesive layer of the patch. The backing layer and the release liner can be selected from suitable materials and shapes as needed, on the premise of not reacting with and / or not causing reactions to the components in the adhesive layer.

[0014] The above-mentioned patch is characterized in that the adhesive layer is prepared from 2-5% mucopolysaccharide polysulfate, 10-20% sodium carboxymethylcellulose, 3-10% menthol, 10-20% polyacrylate, 20-30% glycerol, 0.1-1% vitamin E and 20-40% water by mass percentage.

[0015] The above-mentioned patch is characterized in that the adhesive layer is prepared from the following prescription by mass percentage:

[0016] Material Feeding Quantity (%) Mucopolysaccharide Polysulfate 2～5 Sodium Carboxymethylcellulose 10～20 Menthol 3～10 Polyacrylate 10～20 Glycerol 20～30 Vitamin E 0.1～1 Purified Water Up to 100%

[0017] The above-mentioned patch is characterized in that the adhesive layer is prepared from the following prescription:

[0018] Material Feeding Quantity (%) Mucopolysaccharide Polysulfate 2～5 Sodium Carboxymethylcellulose 10～20 Menthol 3～10 Polyacrylate 10～20 Glycerol 20～30 Vitamin E 0.3～1 Purified Water Up to 100%

[0019] The above-mentioned patch

[0020] The above-mentioned patch is characterized in that it is prepared by the following method:

[0021] 1) Take 50% of the prescription amount of purified water, dissolve menthol in water at 50-60 °C, and then add mucopolysaccharide polysulfate to dissolve it completely;

[0022] 2) Heat the remaining purified water to 50-70 °C, add sodium carboxymethylcellulose, polyacrylate, vitamin E and glycerol under the protection of inert gas, stir at a speed of 500-800 rpm for 20-30 min to form a gel matrix;

[0023] 3) Add the gel matrix to a stirring homogenizer, and slowly drop the solution in step 1) into the gel matrix under the protection of inert gas, with the homogenizer rotating at 2000-4000 rpm and the dropping time being 10-15 min;

[0024] 4) After homogenization, coat it on a polyethylene anti-adhesive film, with a thickness of about 100 μm, dry it with hot air circulation at 40 °C, with a humidity of 30%-40% for 20-30 min;

[0025] 5) After drying, cover the backing layer and the anti-adhesive layer;

[0026] 6) Cut it into 5×7 cm 2 , and package it in an aluminum-plastic composite bag.

[0027] In the above preparation method, the inert gas mentioned in steps 2) and 3) is nitrogen, helium or argon, preferably nitrogen.

[0028] The above-mentioned patch is characterized in that the moisture content of the patch is ≤2%.

[0029] During the development process, the technical personnel of the present invention found that it is difficult to obtain a homogeneous component by mixing the raw and auxiliary materials in the prescription at one time. When mixing all the used raw and auxiliary materials at one time, aggregation or caking is likely to occur, and it is impossible to uniformly disperse all the materials within a short time. When the mixing time is extended, degradation of the components will inevitably occur. Through a large number of experiments, the technical personnel of the present invention adopted a combined scheme of step-by-step mixing and inert gas protection, shortening the production cycle by more than 50% and maintaining the stability of the components.

[0030] Sodium carboxymethylcellulose and polyacrylate are prone to form lumps during the dissolution process. Through a large number of experiments, it was found that they can be completely dissolved without particle residue when the temperature is 50 - 70°C and the appropriate stirring speed and time are matched. The matching of the stirring speed and time is the key. When heated to 50 - 70°C, the stirring speed is 500 - 800 rpm, and it lasts for 20 - 30 min, a good uniform matrix can be ensured.

[0031] In step 3) of the above-mentioned preparation method, the rotation speed and working time of the homogenizer are also important. When the rotation speed is too fast and the working time is too long, a large amount of heat will be introduced, which will cause degradation of the active ingredient. In the experiments without nitrogen protection, the technical personnel of the present invention recorded cases of degradation of the active ingredient to varying degrees. When the homogenizer works under nitrogen protection, as the rotation speed and working time increase, the active ingredient also begins to show degradation. In the preparation method of the patch of the present invention, the optimal rotation speed of the homogenizer is 2000 - 4000 rpm, and the working time is 10 - 15 min. Under this condition, the stability of the homogenization process can be ensured.

[0032] The HPLC test method for the MPS content involved in the present invention can refer to the detection methods disclosed in the pharmacopoeia and / or the prior art. The MPS content of the present invention can be detected by the following HPLC method: using an anion exchange column as the chromatographic column and an anion guard column as the guard column, using mobile phase A (phosphate solution) and mobile phase B (sodium dihydrogen phosphate: sodium perchlorate: water = 1 g: 350 g: 2500 ml) as the mobile phase, separating the mucopolysaccharide polysulfate by gradient elution; and then entering the detector for detection (detection wavelength is 210 nm) to obtain a chromatogram.

[0033] Gradient elution program:

[0034] Time (min) Mobile Phase A: Mobile Phase B (v / v) 0-10 60:40 10-35 20:80 35-45 35:65 45-55 65:35

[0035] By preparing the mucopolysaccharide polysulfate as a patch, the present invention solves the problems that the drug needs to be repeatedly applied and is easily wiped off by clothes. In addition, during the preparation process of the present invention, inert gas and antioxidants are added to the formulation to prevent its oxidative degradation and protect the quality stability of the mucopolysaccharide polysulfate. In addition, by using sodium carboxymethylcellulose and polyacrylate in combination, the adhesion of the patch is enhanced, the adhesion problem is solved, and there is less residue after peeling off after use.

[0036] In the present invention, the terms "comprising" or "including" can be open-ended, semi-closed and closed. In other words, the said terms also include "consisting essentially of" or "consisting of". BRIEF DESCRIPTION OF THE DRAWINGS

[0037] None. DETAILED DESCRIPTION OF THE INVENTION

[0038] The technical solution of the present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually carried out under conventional conditions or according to the conditions recommended by the manufacturer.

[0039] Example 1

[0040] Material Actual Feeding Quantity (%) Mucopolysaccharide Polysulfate 2 Sodium Carboxymethylcellulose 20 Menthol 3 Polyacrylate 10 Glycerol 25 Vitamin E 0.3 Purified Water Up to 100%

[0041] 1) Take 50% of the prescription amount of purified water, heat it to 50 - 60 °C, add menthol, and ultrasonically dissolve it completely. Then add the mucopolysaccharide polysulfate to the solution and dissolve it completely;

[0042] 2) Heat the remaining purified water to 50 - 60 °C, add sodium carboxymethylcellulose, polyacrylate, vitamin E and glycerol under nitrogen protection, stir at a speed of 600 rpm for 20 min to form a gel matrix;

[0043] 3) Add the gel matrix to a stirred homogenizer, and slowly drop the drug solution in step 1) into the gel matrix under nitrogen protection, with the homogenizer rotating at 3000 rpm and the dropping time being 10 min;

[0044] 4) Coat the uniformly mixed drug on a polyethylene release film with a thickness of about 100 μm;

[0045] 5) Dry in a hot air circulation at 40 °C with a humidity of 30% - 40% for about 25 min to ensure that the residual moisture ≤ 2%;

[0046] 6) Cover the backing layer and the release layer after drying;

[0047] 7) Cut into 5 × 7 cm 2 and package it in an aluminum-plastic composite bag.

[0048] Example 2

[0049] Material Actual Feeding Quantity (%) Mucopolysaccharide Polysulfate 3 Sodium Carboxymethylcellulose 15 Menthol 5 Polyacrylate 15 Glycerol 20 Vitamin E 0.5 Purified Water Up to 100%

[0050] 1) Take 50% of the purified water in the prescription amount, heat it up to 50 - 60 °C, add menthol, and ultrasonically dissolve it completely. Then add mucopolysaccharide polysulfate to the solution and dissolve it completely;

[0051] 2) Heat the remaining purified water to 50 - 60 °C, and under nitrogen protection, add sodium carboxymethylcellulose, polyacrylate, vitamin E, and glycerin, stir at a speed of 500 rpm for 20 min to form a gel matrix;

[0052] 3) Add the gel matrix to a stirring homogenizer, and under nitrogen protection, slowly drop the drug solution in step 1) into the gel matrix, with the homogenizer rotating at 3000 rpm and the dropping time being 10 min;

[0053] 4) Coat the uniformly mixed drug on a polyethylene anti-adhesive film with a thickness of about 100 μm;

[0054] 5) Dry it with hot air circulation at 40 °C, with a humidity of 30% - 40% and a time of about 20 min to ensure that the residual moisture ≤ 2%;

[0055] 6) Cover the back lining layer and the anti-adhesive layer after drying;

[0056] 7) Cut it into 5 × 7 cm 2 , and package it with an aluminum-plastic composite bag.

[0057] Example 3

[0058] Material Actual Feeding Quantity (%) Mucopolysaccharide Polysulfate 5 Sodium Carboxymethylcellulose 10 Menthol 10 Polyacrylate 20 Glycerol 30 Vitamin E 1 Purified Water Up to 100%

[0059] 1) Take 50% of the purified water in the prescription amount, heat it up to 50 - 60 °C, add menthol, and ultrasonically dissolve it completely. Then add mucopolysaccharide polysulfate to the solution and dissolve it completely;

[0060] 2) Heat the remaining purified water to 60 - 70 °C, and under nitrogen protection, add sodium carboxymethylcellulose, polyacrylate, vitamin E, and glycerin, stir at a speed of 800 rpm for 20 min to form a gel matrix;

[0061] 3) Add the gel matrix to a stirring homogenizer, and under nitrogen protection, slowly drop the drug solution in step 1) into the gel matrix, with the homogenizer rotating at 3000 rpm and the dropping time being 12 min;

[0062] 4) Coat the uniformly mixed drug on a polyethylene anti-adhesive film with a thickness of about 100 μm.

[0063] 5) Dry with hot air circulation at 40°C, humidity 30%-40%, for about 20 min to ensure that the residual moisture ≤ 2%.

[0064] 6) Cover with a backing layer and a non-stick layer after drying.

[0065] 7) Cut into 5×7 cm 2 , and package with an aluminum-plastic composite bag.

[0066] Control Example 1

[0067] Material Actual Feeding Quantity (%) Mucopolysaccharide Polysulfate 3 Sodium Carboxymethylcellulose 15 Menthol 4 Polyacrylate 5 Glycerol 20 Vitamin E 1 Purified Water Up to 100%

[0068] 1) Take 50% of the prescription amount of purified water, heat it to 50-60°C, add menthol, and ultrasonically dissolve it completely. Then add mucopolysaccharide polysulfate to the solution and dissolve it completely;

[0069] 2) Heat the remaining purified water to 50-60°C, add sodium carboxymethylcellulose, polyacrylate, vitamin E and glycerol under nitrogen protection, stir at a speed of 600 rpm for 20 min to form a gel matrix;

[0070] 3) Add the gel matrix to a stirring homogenizer, and slowly drop the drug solution into the gel matrix under nitrogen protection. The rotation speed of the homogenizer is 3000 rpm, and the dropping time is 12 min;

[0071] 4) Coat the uniformly mixed drug on a polyethylene non-stick film with a thickness of about 100 μm.

[0072] 5) Dry with hot air circulation at 40°C, humidity 30%-40%, for about 20 min to ensure that the residual moisture ≤ 2%.

[0073] 6) Cover with a backing layer and a non-stick layer after drying.

[0074] 7) Cut into 5×7 cm 2 , and package with an aluminum-plastic composite bag.

[0075] Control Example 2

[0076] Material Actual Feeding Quantity (%) Mucopolysaccharide Polysulfate 3 Sodium Carboxymethylcellulose 20 Menthol 4 Polyacrylate 20 Glycerol 30 Vitamin E 1 Purified Water Up to 100%

[0077] 1) Take 50% of the prescription amount of purified water, heat it to 50-60°C, add menthol, and ultrasonically dissolve it completely. Then add mucopolysaccharide polysulfate to the solution and dissolve it completely;

[0078] 2) Heat the remaining purified water to 60°C, add sodium carboxymethylcellulose, polyacrylate, vitamin E and glycerol, stir at a speed of 600 rpm for 20 min to form a gel matrix;

[0079] 3) Add the gel matrix into a stirring homogenizer, slowly drop the drug solution from step 1) into the gel matrix, with the rotational speed of the homogenizer being 3000 rpm and the dropping time being 12 min;

[0080] 4) Coat the uniformly mixed drug on a polyethylene anti-adhesive film with a thickness of about 100 μm;

[0081] 5) Dry with hot air circulation at 40 °C, with the humidity being 30% - 40% and the time being about 20 min to ensure that the residual moisture ≤ 2%;

[0082] 6) Cover the backing layer and the anti-adhesive layer after drying;

[0083] 7) Cut into pieces of 5×7 cm 2 , and package with an aluminum-plastic composite bag.

[0084] Comparative Example 3

[0085]

[0086]

[0087] 1) Take 50% of the prescription amount of purified water, heat it up to 50 - 60 °C, add menthol, and ultrasonically dissolve it completely. Then add mucopolysaccharide polysulfate into the solution and dissolve it completely;

[0088] 2) Heat the remaining purified water to 50 - 60 °C, add sodium carboxymethylcellulose, polyacrylate, vitamin E and glycerol under nitrogen protection, with the stirring speed being 600 rpm and lasting for 20 min to form a gel matrix;

[0089] 3) Add the gel matrix into a stirring homogenizer, and slowly drop the drug solution into the gel matrix under nitrogen protection, with the rotational speed of the homogenizer being 3000 rpm and the dropping time being 12 min;

[0090] 4) Coat the uniformly mixed drug on a polyethylene anti-adhesive film with a thickness of about 100 μm.

[0091] 5) Dry with hot air circulation at 40 °C, with the humidity being 30% - 40% and the time being about 20 min to ensure that the residual moisture ≤ 2%.

[0092] 6) Cover the backing layer and the anti-adhesive layer after drying.

[0093] 7) Cut into pieces of 5×7 cm 2 , and package with an aluminum-plastic composite bag.

[0094] Test Example 1 Adhesion Force Test

[0095] According to the Adhesion Determination Method 0952 in the Chinese Pharmacopoeia 2020 Edition, the initial adhesion and holding adhesion of the patch were detected. Before the test, the patch (together with the packaging material) should be placed at 18 - 25°C and relative humidity of 40% - 70% for more than 2 hours.

[0096] Initial adhesion determination: The initial adhesion was determined by the rolling ball ramp stop method. The rolling ball device was horizontally fixed on the test bench, and then the test sample was fixed on the inclined plane of the device. Ensure that the release film side of the test sample faces upward. After fixing, tear off the release film to expose the adhesive layer of the test sample upward. The running - start paper (100 mm in length) was fixed at the upper end of the test sample. The rolling ball rolled down from the inclined track, and the largest ball number staying on the test sample was the test result. During the test, the temperature was maintained at 18 - 25°C and the relative humidity was 30% - 60%.

[0097] Holding adhesion determination: The patch was pasted on the surface of the test plate and placed vertically, with a 200 - g weight suspended below, and the detachment time was recorded. During the test, the temperature was maintained at 18 - 25°C and the relative humidity was 30% - 60%.

[0098] Table 1 Adhesion determination results of the patches prepared in Example 1 and Comparative Example 1 (n = 3)

[0099] Category Example 1 Example 2 Example 3 Comparative Example 1 Initial Adhesion 19 19 18 11 Holding Adhesion (min) 38 38 35 15

[0100] The results showed that when the amount of the adhesive in the prescription of Comparative Example 1 was small, the adhesion effect was poor, which would be disadvantageous for the stable adhesion of the patch on the skin. The adhesion of the patch in the examples was good and met the pharmacopoeia standards. There was no significant difference in the adhesion of the patches in Example 2 and Example 3 through the test.

[0101] Test Example 2 Skin irritation test

[0102] Six rabbits were selected, with an equal number of males and females. Before the test, most of the rabbit hair on both sides of the spine was cut off with scissors, and the hair on the skin surface was removed with depilatory cream. The depilated area for each measurement was about 40 cm 2 . The MPS patch was applied to the left side, and the blank patch (without MPS) was applied to the right side, and they were fixed with a non - irritating bandage. After removing the patch, the skin irritation was investigated with the erythema and edema on the skin surface as indexes, and the erythema and edema on the skin surface after drug administration were observed.

[0103] The Draize scoring system was used to evaluate the skin irritation (0 - 4 points, 0 indicating no irritation and 4 indicating severe irritation). The test results are shown in the following table.

[0104] Table 2 Skin irritation results of the patch (n = 3)

[0105]

[0106] The test results showed that the MPS patch prepared by the present invention was observed to have no obvious irritation to the skin.

[0107] Test Example 3 In vitro Release Test

[0108] The in vitro release test of the patch referred to the paddle-disk method in General Chapter 0931, Volume IV of the Chinese Pharmacopoeia 2020 Edition. The dissolution medium was sodium dodecyl sulfate PBS (900 mL), the temperature was set at (32.0 ± 0.5) °C, the release surface of the patch was upward, placed between the mesh disks, the mesh disks were parallel to the stirring paddle, and the placement position was (25 ± 2) mm from the bottom of the paddle. Samples of 5 mL were taken at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 h (and the same temperature and equal amount of PBS were added in time), filtered through a 0.22 μm needle filter, the supernatant was taken, and HPLC was used for detection.

[0109] Table 3 Cumulative Release Degree of the Patch

[0110]

[0111] Conclusion: The patch of the present invention released about 80% after 6 h of use and reached more than 90% after 24 h. The patch can release stably and play a continuous role.

[0112] Test Example 4 Accelerated Stability Test

[0113] The patch was stored under accelerated conditions (40 °C ± 2 °C, 75% RH ± 5% RH), and the trend of the change in the drug content was tested.

[0114] Table 4 Change in Drug Content under Accelerated Conditions

[0115]

[0116] It can be seen from the results that during the preparation process, MPS degraded during the preparation process without nitrogen protection, resulting in a decrease in the initial drug content; in addition, oxidation degradation products of vitamin E were also detected in Comparative Example 2. Under accelerated conditions, just adding antioxidants, the content of the patch prepared under non-inert gas conditions also decreased significantly, and the stability was poor. It shows the necessity of using inert gas protection in the preparation of the patch of the present invention. The process reduces the oxygen content in the adhesive layer, which can effectively prevent the degradation of MPS and extend the shelf life of the patch.

[0117] Test Example 5 Main Drug Release Amount Test

[0118] The mucopolysaccharide polysulfate patches prepared according to Examples 1-3 and Comparative Example 3 of the present invention were compared:

[0119] The Franz diffusion cell method was used to simulate the skin penetration process. The treated rat skin was fixed between the supply cell and the receptor cell, and the patches were applied to the skin respectively. The cumulative drug release amount (%) of the patches within 8 hours was measured.

[0120] Time (h) Example 1 Example 2 Example 3 Comparative Example 3 1 5.12 5.83 6.27 2.38 2 11.31 12.05 12.85 4.69 4 18.62 19.84 20.37 8.77 8 35.41 36.83 38.21 15.20

[0121] Compared with Comparative Example 3, the patch of the present invention has a stable and high release rate, which can enable the drug to reach the subcutaneous tissue faster and achieve the drug concentration and therapeutic effect.

Claims

1. A polysulfonic acid mucopolysaccharide transdermal patch, comprising a backing layer, an adhesive layer and a release liner, characterized in that, The adhesive layer contains polysulfated glycosaminoglycan, sodium carboxymethylcellulose, menthol, polyacrylate, glycerol, vitamin E, and water.

2. The patch according to claim 1, characterized in that, The adhesive layer is prepared from the following prescription by mass percentage: 。 3. The patch according to claim 2, wherein The prescription is as follows: 。 4. The patch according to any one of claims 1 to 3, characterized in that, The patch is characterized by being prepared by the following method: 1) Take 50% of the prescription amount of purified water, dissolve menthol in water at 50 - 60 °C, and then add polysulfated glycosaminoglycan to dissolve completely; 2) Heat the remaining purified water to 50 - 70 °C, add sodium carboxymethylcellulose, polyacrylate, vitamin E, and glycerol under the protection of inert gas, stir at a speed of 500 - 800 rpm for 20 - 30 min to form a gel matrix; 3) Add the gel matrix to a stirred homogenizer, and slowly drop the solution in step 1) into the gel matrix under the protection of inert gas, with the homogenizer rotating at 2000 - 4000 rpm and the dropping time being 10 - 15 min; 4) After homogenization, coat it on a polyethylene release film with a thickness of about 100 μm, and dry it with hot air circulation at 40 °C and a humidity of 30% - 40% for 20 - 30 min; 5) After drying, cover with a backing layer and a release layer; 6) Cut into 5×7 cm 2 , and packed in an aluminum-plastic composite bag.

5. The patch according to claim 4, characterized in that, The inert gas is nitrogen, helium, or argon, preferably nitrogen.

6. The patch according to any one of claims 1-4, characterized in that The moisture content of the patch is ≤ 2%.

7. The patch according to claim 3, wherein The prescription is as follows: 。 8. The patch according to claim 3, wherein, The prescription is as follows: 。 9. The patch according to claim 3, wherein The prescription is as follows:

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