Timolol maleate gel emplastrum and preparation method thereof

Abstract

The invention discloses timolol maleate gel emplastrum and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The gel paste comprises timolol maleate, a gel skeleton, a cross-linking agent, a cross-linking regulator, a filler, a penetration enhancer, a tackifier, a humectant, a pH regulator, a preservative and purified water. The preparation method comprises the following steps: preparing an oil phase; preparing the medicine and the water-soluble auxiliary materials into a solution; the tackifier adopts methyl acrylate / acrylic acid 2-ethylhexyl copolymer resin emulsion as a single phase; mixing the oil phase with the solution and the tackifier to obtain uniform gel paste with better ductility; and uniformly coating the paste on a backing layer, covering with a protective layer, and packaging to obtain the timolol maleate gel emplastrum. Through optimized prescription composition and process, the preparation has the characteristics of stable drug content and good skin adhesion, can realize continuous transdermal release of drugs, and is especially suitable for long-term safe treatment of infantile hemangioma.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a transdermal drug delivery formulation of a β-receptor blocker, and more specifically, to a gel patch containing timolol maleate as an active ingredient, and its preparation method. Background Technology

[0002] Infantile hemangiomas are benign tumors originating from blood vessels in the skin, most commonly occurring on the head, face, and neck of infants. During their rapid growth phase, they can affect appearance and even affect important functional areas. Clinical treatment has long faced significant challenges. Oral beta-blockers (such as propranolol) carry the risk of systemic side effects, requiring close monitoring. Therefore, topical treatment, especially potent and highly selective beta-blockers like timolol maleate, has become a first-line or important adjuvant treatment for superficial infantile hemangiomas.

[0003] Currently, the main topical formulations of timolol maleate are eye drops or topical solutions, as well as creams. However, these formulations have inherent drawbacks: liquid formulations have a short retention time on the skin surface, are easily volatile or wiped away, resulting in insufficient effective drug action time, requiring multiple daily doses, and leading to poor patient compliance; while traditional creams, although having improved retention, still suffer from limited penetration efficiency and easy staining of clothing. To overcome these shortcomings and achieve long-acting, sustained-release transdermal drug delivery, gel patches are a promising new formulation. Combining the smoothness and skin-friendliness of gels with the long-lasting adhesion of patches, they are expected to form a drug reservoir at the affected area, improving local bioavailability and reducing the frequency of administration.

[0004] Existing technologies have attempted to prepare timolol into a patch. For example, prior art document 1 (CN111067905A) discloses a timolol hydrogel patch containing a stabilizer, which aims to solve the problem of instability of the active ingredient under light by adding benzophenone or salicylate-based UV sunscreens as stabilizers. However, after in-depth research, the applicant found that this technical solution may introduce new limitations in pursuit of photochemical stability: on the one hand, the added small molecule chemical stabilizers may interfere with the three-dimensional network structure of the gel, affecting its cohesive strength and long-term adhesion to the skin, causing the patch to easily loosen or "cold flow" (patch run-off) after prolonged wear (e.g., more than 12 hours). This seriously affects the reliability of drug delivery and the sustainability of efficacy for infants and young children who require continuous application; on the other hand, this solution does not fully consider the delicate and easily irritated characteristics of infant skin, and its formulation system still has room for optimization in ensuring a balance between extremely low skin irritation, excellent moisturizing properties, and adhesion.

[0005] In addition, other technologies have explored different sustained-release pathways. For example, comparative documents 2 (CN115957198A) and 3 (CN115501208A) use acylated casein or modified complex protein as core carrier materials to encapsulate drugs, aiming to reduce irritation and regulate release. While these protein-based systems have certain advantages in sustained release, their preparation processes are usually more complex. Protein materials may have potential sensitizing properties, and their compatibility with synthetic polymer gel matrices and the physical stability (such as sweat resistance and tackiness) of the final patch are challenged, which may not provide ideal skin affinity and user experience.

[0006] In summary, although existing technologies offer various dosage forms for topical timolol maleate, there is currently a lack of a gel patch specifically designed for infantile hemangiomas that simultaneously meets the comprehensive performance requirements of long-lasting strong adhesion, stable sustained release and high stability, excellent skin safety, and superior manufacturing processability. Therefore, developing a patch that perfectly balances these core needs is of significant clinical value in improving the treatment efficacy, safety, and medication adherence for infantile hemangiomas. Summary of the Invention

[0007] This invention addresses the problems of insufficient adhesion and poor overall stability of timolol maleate patches in existing technologies. By creatively employing a specific tackifying system composed of polyvinylpyrrolidone K-90, sodium carboxymethyl cellulose, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and optimizing the proportions and processes of key excipients, this invention provides a gel patch with strong adhesion (especially extremely long holding time), stable properties, and suitable for infant skin, as well as its preparation method.

[0008] The technical solution of the present invention is as follows: In a first aspect, the present invention provides a timolol maleate gel patch, the patch comprising, in sequence, a backing layer, a gel paste, and a protective layer; characterized in that the gel paste comprises the following components: the pharmaceutically active ingredient timolol maleate, a gel matrix, a crosslinking agent, a crosslinking regulator, a filler, a penetration enhancer, a thickener, a humectant, a pH adjuster, a preservative, and purified water; the thickener is composed of polyvinylpyrrolidone K-90, sodium carboxymethyl cellulose, and a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion.

[0009] The gel patch containing timolol maleate, by weight percentage of the gel patch, contains 0.10%~5.0% timolol maleate, 5.0%~10.0% gel matrix, 0.03%~0.13% crosslinking agent, 0.005%~0.10% crosslinking regulator, 0.2%~3.0% filler, 1.0%~5.0% penetration enhancer, 2.0%~10.0% thickener, 20.0%~40.0% humectant, 0.01%~1.0% preservative, an appropriate amount of pH adjuster, and purified water to 100%.

[0010] The gel patch containing timolol maleate, wherein the gel skeleton is selected from hydrophilic polymer materials, such as sodium alginate, sodium cross-linked cellulose, carbomer, sodium polyacrylate, or partially neutralized sodium polyacrylate, preferably partially neutralized sodium polyacrylate NP700, and its amount is 5.0% to 10.0% by weight of the gel patch, more preferably 5.0% to 7.0%.

[0011] The gel patch containing timolol maleate, wherein the crosslinking agent can be selected from aluminum hydroxyl, aluminum hydroxide, magnesium aluminum silicate, aluminum chloride, aluminum citrate, preferably aluminum hydroxyl, and its amount is 0.03%-0.13% by weight of the gel patch, more preferably 0.05%-0.10%.

[0012] The gel patch containing timolol maleate, wherein the crosslinking regulator, preferably disodium edetate, a metal ion chelating agent, is used to adjust the crosslinking reaction rate of the gel patch and prolong the application time, and its amount is 0.005%-0.10% by weight of the gel patch, more preferably 0.01%-0.08%.

[0013] The gel patch containing timolol maleate, wherein the filler can be selected from one or more of titanium dioxide, kaolin, anhydrous dicalcium phosphate, calcium carbonate, bentonite, and talc; more preferably calcium carbonate, kaolin, or a combination of calcium carbonate and kaolin, and its amount is 0.2% to 3% by weight of the gel patch, more preferably 1.0% to 2.0%.

[0014] The described gel patch containing timolol maleate may contain one or more of the following penetration enhancers: menthol, propylene glycol, polyethylene glycol 400, N-methyl-2-pyrrolidone, and isopropyl myristate; for infant skin, a combination of polyethylene glycol 400 and N-methyl-2-pyrrolidone is preferred, and its dosage is 1.0% to 5.0% by weight of the gel patch, more preferably 1.0% to 2.0%.

[0015] The gel patch containing timolol maleate, wherein the tackifier is selected from one or more of polyvinylpyrrolidone K-90, xanthan gum, polyvinyl alcohol, gelatin, polyacrylic acid solution, sodium carboxymethyl cellulose, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion; more preferably, it is polyvinylpyrrolidone K-90, sodium carboxymethyl cellulose, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and its amount is 2.0% to 10.0% by weight of the gel patch, more preferably 5.0% to 10.0%.

[0016] The gel patch containing timolol maleate, wherein the moisturizer is selected from one or more of glycerin, propylene glycol, sodium hyaluronate, sorbitol solution, and acrylic grafted starch 300; more preferably glycerin and acrylic grafted starch 300, the amount of which is 20.0%~40.0% by weight of the gel patch, more preferably 30.0%-40.0%.

[0017] The gel patch containing timolol maleate, wherein the preservative is preferably one or more of phenoxyethanol, parabens, and ethylhexylglycerin; for infant skin, a combination of phenoxyethanol and ethylhexylglycerin is more preferred, and the amount used is 0.01% to 1.0% by weight of the gel patch, more preferably 0.10% to 0.80%.

[0018] The gel patch containing timolol maleate described herein has a pH range of 5.5-7.0, more preferably 5.8-6.5, to match the slightly acidic environment of healthy skin and reduce irritation; wherein the pH adjuster may be selected from tartaric acid, citric acid, phosphoric acid, triethanolamine, malic acid or its salt, preferably sodium salt, and more preferably tartaric acid.

[0019] The gel patch containing timolol maleate is described herein, wherein the backing layer is a non-woven fabric; and the protective layer is an anti-stick material selected from embossed films made of polypropylene.

[0020] Secondly, the present invention provides a method for preparing the above-mentioned timolol maleate gel patch, characterized by comprising the following steps: (1) Preparation of oil phase: The gel skeleton, crosslinking agent, crosslinking regulator, filler, thickener (sodium carboxymethyl cellulose) and humectant (acrylic acid grafted starch 300) are uniformly dispersed in humectant (glycerol) to obtain oil phase A; the penetration promoter and preservative are added to oil phase A and mixed evenly to obtain oil phase B; (2) Preparation of drug solution: Dissolve timolol maleate in the prescribed amount of purified water and stir until completely dissolved to obtain solution C; (3) Dissolve the pH adjuster in the prescribed amount of purified water and stir until completely dissolved to obtain solution D; (4) Dissolve the thickener (polyvinylpyrrolidone K-90) in the prescribed amount of purified water and stir until completely dissolved to obtain solution E; (5) First step of mixing: Add solution D to oil phase B and mix evenly; then add solution C while stirring to form a paste; (6) Second step mixing: Add solution E to the gel-containing paste, mix well, and make a paste; (7) Third step of mixing: Add methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion to the gel paste, mix evenly to obtain a uniform gel paste with good extensibility, and adjust the pH value of the gel paste to 5.8-6.5; (8) Coating and molding: The gel paste obtained in step (7) is evenly coated on the protective layer, and the coating thickness is controlled to be 0.75mm-1.0mm. Then, the backing is covered, and finally, it is cut and packaged according to the required size to obtain the timolol maleate gel patch.

[0021] Compared with the prior art, the present invention has the following significant advantages: 1. Long-lasting sustained release and improved efficacy: The gel patch can form a drug reservoir at the affected area, continuously releasing the drug, maintaining a stable local effective concentration, and improving the inhibitory effect on hemangioma endothelial cells.

[0022] 2. Excellent safety profile: Local targeted drug delivery greatly reduces systemic absorption, thereby significantly reducing the risk of systemic β-blocker side effects (such as bradycardia and hypoglycemia) that may be caused by oral or even topical solutions, making it particularly suitable for infant patients.

[0023] 3. Stable process and controllable quality: The preparation method provided by this invention has clear steps, is easy to scale up, and the resulting gel paste is uniform, stable in properties, and has good viscosity. Attached Figure Description

[0024] Figure 1 Schematic diagram of the structure of the gel patch; Figure 2 Process flow diagram; Figure 3 Electron micrograph of the gel paste.

[0025] Specific implementation methods The present invention will be further described below with reference to specific embodiments to better understand the invention.

[0026] Example 1: This embodiment provides a timolol maleate gel patch, such as Figure 1As shown, the plaster comprises a backing layer, a gel paste, and a protective layer in sequence, wherein the gel paste comprises:

[0027] Its preparation method is as follows Figure 2 The process, as shown, includes the following steps: Partially neutralized sodium polyacrylate, aluminum hydroxyl, disodium edetate, calcium carbonate, kaolin, acrylic acid grafted starch 300, and sodium carboxymethyl cellulose were uniformly dispersed in a humectant (glycerin) to obtain oil phase A; Polyethylene glycol 400, N-methyl-2-pyrrolidone, phenoxyethanol, and ethylhexylglycerin were added to oil phase A and mixed evenly to obtain oil phase B. Add timolol maleate to purified water and stir until completely dissolved to obtain solution C; Tartaric acid was added to purified water and stirred until completely dissolved to obtain solution D; Polyvinylpyrrolidone K-90 was added to purified water and stirred until completely dissolved to obtain solution E; Step 1: Mixing: Add solution D to oil phase B and mix thoroughly; then add solution C while stirring to form a paste. Step 2: Mixing: Add solution E to the gel-containing paste, mix well, and form a paste. The third step is mixing; add methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion to the gel-containing paste, mix evenly to obtain a uniform gel paste with good extensibility and a pH of 5.86; Coating and molding: The gel paste is evenly coated onto the protective layer, controlling the coating thickness to be 0.75mm-1.0mm. Then, a backing is applied, and the paste is cut into 7.0cm × 10.0cm pieces. Packaging yields the timolol maleate gel patch. Electron microscopy observation shows that... Figure 3 As shown, the gel exhibits a uniform porous network structure, with pore sizes mainly concentrated between 10 and 50 μm. This structure facilitates moisture retention and sustained drug release, and provides the patch with good cohesion and spreadability.

[0028] Example 2: This embodiment provides a timolol maleate gel patch, which sequentially comprises a backing layer, a gel paste, and a protective layer. The gel paste comprises:

[0029] Partially neutralized sodium polyacrylate, aluminum hydroxyl, disodium edetate, calcium carbonate, kaolin, acrylic acid grafted starch 300, and sodium carboxymethyl cellulose were uniformly dispersed in a humectant (glycerin) to obtain oil phase A; Polyethylene glycol 400, N-methyl-2-pyrrolidone, phenoxyethanol, and ethylhexylglycerin were added to oil phase A and mixed evenly to obtain oil phase B. Add timolol maleate to purified water and stir until completely dissolved to obtain solution C; Tartaric acid was added to purified water and stirred until completely dissolved to obtain solution D; Polyvinylpyrrolidone K-90 was added to purified water and stirred until completely dissolved to obtain solution E; Step 1: Mixing: Add solution D to oil phase B and mix thoroughly; then add solution C while stirring to form a paste. Step 2: Mixing: Add solution E to the gel-containing paste, mix well, and form a paste. The third step is mixing; add methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion to the gel-containing paste, mix evenly to obtain a uniform gel paste with good extensibility and a pH of 5.87; Coating and molding: The gel paste is evenly coated on the protective layer, and the coating thickness is controlled to be 0.75mm-1.0mm. Then, a backing is covered, and it is cut into 7.0cm×10.0cm pieces and packaged to obtain the timolol maleate gel patch.

[0030] Example 3: This embodiment provides a timolol maleate gel patch, which sequentially comprises a backing layer, a gel paste, and a protective layer. The gel paste comprises:

[0031] Partially neutralized sodium polyacrylate, aluminum hydroxyl, disodium edetate, calcium carbonate, kaolin, acrylic acid grafted starch 300, and sodium carboxymethyl cellulose were uniformly dispersed in a humectant (glycerin) to obtain oil phase A; Polyethylene glycol 400, N-methyl-2-pyrrolidone, phenoxyethanol, and ethylhexylglycerin were added to oil phase A and mixed evenly to obtain oil phase B. Add timolol maleate to purified water and stir until completely dissolved to obtain solution C; Tartaric acid was added to purified water and stirred until completely dissolved to obtain solution D; Polyvinylpyrrolidone K-90 was added to purified water and stirred until completely dissolved to obtain solution E; Step 1: Mixing: Add solution D to oil phase B and mix thoroughly; then add solution C while stirring to form a paste. Step 2: Mixing: Add solution E to the gel-containing paste, mix well, and form a paste. The third step is mixing; add methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion to the gel-containing paste, mix evenly to obtain a uniform gel paste with good extensibility and a pH of 5.93; Coating and molding: The gel paste is evenly coated on the protective layer, and the coating thickness is controlled to be 0.75mm-1.0mm. Then, a backing is covered, and it is cut into 7.0cm×10.0cm pieces and packaged to obtain the timolol maleate gel patch.

[0032] Example 4: This embodiment provides a timolol maleate gel patch, which sequentially comprises a backing layer, a gel paste, and a protective layer. The gel paste comprises:

[0033] Partially neutralized sodium polyacrylate, aluminum hydroxyl, disodium edetate, calcium carbonate, kaolin, acrylic acid grafted starch 300, and sodium carboxymethyl cellulose were uniformly dispersed in a humectant (glycerin) to obtain oil phase A; Polyethylene glycol 400, N-methyl-2-pyrrolidone, phenoxyethanol, and ethylhexylglycerin were added to oil phase A and mixed evenly to obtain oil phase B. Add timolol maleate to purified water and stir until completely dissolved to obtain solution C; Tartaric acid was added to purified water and stirred until completely dissolved to obtain solution D; Polyvinylpyrrolidone K-90 was added to purified water and stirred until completely dissolved to obtain solution E; Step 1: Mixing: Add solution D to oil phase B and mix thoroughly; then add solution C while stirring to form a paste. Step 2: Mixing: Add solution E to the gel-containing paste, mix well, and form a paste. The third step is mixing; add methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion to the gel-containing paste, mix evenly to obtain a uniform gel paste with good extensibility and a pH of 5.93; Coating and molding: The gel paste is evenly coated on the protective layer, and the coating thickness is controlled to be 0.75mm-1.0mm. Then, a backing is covered, and it is cut into 7.0cm×10.0cm pieces and packaged to obtain the timolol maleate gel patch.

[0034] Comparative Example 1 Compared to the previous embodiment, the composition of the gel paste includes:

[0035] Comparative Example 2 Compared to the previous embodiment, the composition of the gel paste includes:

[0036] Test case 1. Excipient test According to the test method for excipients of plasters in Part IV of the 2025 edition of the Chinese Pharmacopoeia, one gel plaster sample was placed in a constant temperature and humidity chamber at 37°C and 64% relative humidity for 30 minutes. After removal, the sample was fixed to a flat steel plate with clamps, the angle of inclination of the steel plate to the horizontal plane being 60°. o After 24 hours, the paste should not run.

[0037] Table 1. Results of excipient testing for timolol maleate gel patch

[0038] 2. Adhesion test According to the Chinese Pharmacopoeia 2020 edition, Part IV, 0952, method for determination of adhesion.

[0039] Method 1: Before the test, the plaster and patch (along with packaging material) should be placed at 18-25℃ and relative humidity 40%-70% for at least 2 hours. Choose an angle of 30 degrees. o Adjust the inclined plate, take 3 test samples, and fix the backing of each test sample to the inclined plate with double-sided tape. The top of the test sample should be 10 mm below the horizontal line of the inclined plate, with the adhesive side facing upwards. The experimental length along the inclined plane should not exceed 5 cm, and the test sample should be flatly attached to the plate. Record the largest steel ball size that the test sample adheres to.

[0040] Method Two: Before the test, the plaster or patch (including packaging material) should be placed at 18-25℃ and 40%-70% relative humidity for at least 2 hours. Take 3 test samples and adhere them parallel to the longitudinal direction of the plate to the middle of the adjacent test plate and loading plate respectively. Roll the test samples back and forth three times with a pressure roller. After the test samples are adhered to the plates, place them at room temperature for 20 minutes, fix them to the test frame, and record the start time of the test. The test results are expressed as the arithmetic mean of the detachment time of a set of test samples.

[0041] Method Four: Before the test, the plaster or patch (including packaging material) should be placed at 18-25℃ and relative humidity 40%-70% for at least 2 hours. Take 3 test pieces, generally cut to 50mm x 70mm (length should not be less than 60mm, and width should not be less than 35mm). The instrument has built-in settings for different measurement modes of the roller's forward and backward speeds, used for roller repositioning and testing respectively. Except in special cases, the roller's forward speed is generally set to 600mm per minute and the backward speed to 21mm per minute. If you need to set the test speed yourself, you must provide the necessary justification. Generally, it is recommended that the adhesive strength of rubber plasters should be 3000-6000mN, and the adhesive strength of gel plasters should be 1000-2000mN.

[0042] Table 2. Adhesion test results of timolol maleate gel patch

[0043] The results showed that the adhesion of the examples was better than that of the comparative examples when using a combination of sodium carboxymethyl cellulose, polyvinyl pyrrolidone K-90, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion. When the amounts of sodium carboxymethyl cellulose, polyvinyl pyrrolidone K-90, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion were 1% / 3% / 7% or 1% / 2% / 7%, the holding power of Examples 3 and 4 was better than that of Examples 1 and 2. 3. Stability test The stability of the timolol maleate gel patches prepared in Examples 3 and 4 above was studied. The patches were placed under long-term conditions (temperature 25℃±2℃, relative humidity 60%±5%) and accelerated conditions (temperature 40℃±2℃, relative humidity 75%±5%), and samples were taken at 1 month, 3 months, and 6 months for evaluation. Evaluation items included: shape properties, initial tack, adhesion, holding power, and content.

[0044] Table 3. Results of long-term condition study of timolol maleate gel patch

[0045] Table 4 Results of accelerated condition study of timolol maleate gel patch

[0046] According to the research results in Tables 3 and 4, the drug content of the present invention remains stable under long-term or accelerated conditions, and there are no significant changes in excipient properties and adhesion.

[0047] In summary, this invention has successfully prepared a stable and well-adhesive timolol maleate gel patch that enables continuous transdermal drug release, making it particularly suitable for the long-term treatment of infantile hemangiomas.

[0048] The above are merely a few preferred embodiments of the present invention, described in a relatively specific and detailed manner, but they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A timolol maleate gel patch, comprising a backing layer, a gel paste layer on the backing layer, and a protective layer covering the gel paste layer, characterized in that, The gel paste layer is prepared from raw materials containing the following components: Timolol maleate, gel matrix, crosslinking agent, crosslinking regulator, filler, penetration enhancer, thickener, humectant, pH adjuster, preservative, and purified water; The tackifier is composed of polyvinylpyrrolidone K-90, sodium carboxymethyl cellulose, and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion.

2. The timolol maleate gel patch according to claim 1, characterized in that, The gel matrix is ​​partially neutralized sodium polyacrylate NP700, and the dosage is 5.0% to 7.0% based on the total weight of the gel paste layer.

3. The timolol maleate gel patch according to claim 1, characterized in that, The crosslinking agent is aluminum hydroxyacetate, and the amount used is 0.05% to 0.10% based on the total weight of the gel paste layer.

4. The timolol maleate gel patch according to claim 1, characterized in that, The crosslinking regulator is disodium edetate, and the dosage is 0.01%-0.08% based on the total weight of the gel paste layer.

5. The timolol maleate gel patch according to claim 1, characterized in that, The filler is composed of calcium carbonate and kaolin, and its dosage is 1.0% to 2.0% based on the total weight of the gel paste layer.

6. The timolol maleate gel patch according to claim 1, characterized in that, The penetration enhancer is composed of polyethylene glycol 400 and N-methyl-2-pyrrolidone, and is used in an amount of 1.0% to 2.0% based on the total weight of the gel paste layer.

7. The timolol maleate gel patch according to claim 1, characterized in that, The moisturizer is composed of glycerin and acrylic acid grafted starch 300, and is used in an amount of 30.0% to 40.0% based on the total weight of the gel paste layer.

8. The timolol maleate gel patch according to claim 1, characterized in that, The preservative is composed of phenoxyethanol and ethylhexylglycerin, and is used in an amount of 0.10% to 0.80% of the total weight of the gel paste layer.

9. The timolol maleate gel patch according to claim 1, characterized in that, The thickener is composed of polyvinylpyrrolidone K-90, sodium carboxymethyl cellulose and methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and is used in an amount of 5.0% to 10.0% based on the total weight of the gel paste layer.

10. The method for preparing the timolol maleate gel patch according to any one of claims 1-9, characterized in that, Includes the following steps: (1) Preparation of oil phase: The gel skeleton, crosslinking agent, crosslinking regulator, filler, thickener: sodium carboxymethyl cellulose are uniformly dispersed in the humectant to obtain oil phase A; A penetration enhancer and a preservative are added to oil phase A and mixed evenly to obtain oil phase B; (2) Preparation of drug solution: Dissolve timolol maleate in the prescribed amount of purified water and stir until completely dissolved to obtain solution C; (3) Dissolve the pH adjuster in the prescribed amount of purified water and stir until completely dissolved to obtain solution D; (4) Dissolve the thickener, polyvinylpyrrolidone K-90, in the prescribed amount of purified water and stir until completely dissolved to obtain solution E; (5) First step of mixing: Add solution D to oil phase B and mix evenly; then add solution C while stirring to form a paste; (6) Second step mixing: Add solution E to the gel-containing paste, mix well, and make a paste; (7) Third step of mixing: Add thickener: methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion to the gel paste, mix evenly to obtain a uniform gel paste with good extensibility, and adjust the pH value of the gel paste to 5.8-6.5; (8) Coating and molding: The gel paste obtained in step (7) is evenly coated on the protective layer, and the coating thickness is controlled to be 0.75mm-1.0mm. Then, the backing is covered, and finally, it is cut and packaged according to the required size to obtain the timolol maleate gel patch.

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