Timolol maleate gel transdermal patch and preparation method thereof

Abstract

The present invention discloses a timolol maleate gel transdermal patch and a preparation method thereof, which belongs to a timolol maleate patch, comprising a drug layer and a backing layer bonded together, wherein a protective layer is affixed to the surface of the drug layer. The drug layer is composed of timolol maleate, modified composite protein, polyvinyl alcohol, glycerol, a penetration enhancer, a pH regulator and deionized water; the modified composite protein is prepared by adding acylated casein, ovalbumin and dopamine to a Tris buffer in proportion, heating and stirring; then filtering, washing, dialyzing and freeze-drying the solution. When in use, tear off the protective layer of the timolol maleate patch, and apply the drug layer to the surface of an infantile hemangioma. The present invention selects the modified composite protein as a sustained-release coating material, and exerts a synergistic effect with polyvinyl alcohol as a gel matrix to improve the stability of the drug layer.

Description

Technical Field

[0001] The invention belongs to the technical field of timolol maleate preparations, in particular to a timolol maleate gel transdermal patch and a preparation method thereof. Background Art

[0002] Infantile hemangiomas are benign tumors that originate from the blood vessels of the skin. Their clinical incidence is approximately between 4% and 10%, and there is a trend of increasing each year. Hemangiomas have their own growth and regression patterns, but during the entire growth cycle of hemangiomas, symptoms such as bleeding, erosion, affecting appearance, and even affecting the functions of important parts may occur. For infantile hemangiomas, the current common treatments include surgical resection, radiotherapy, cryotherapy, laser therapy, sclerotherapy injection, etc., and a combination of therapies is generally used. Timolol maleate is a potent beta-receptor blocker that has a blocking effect on both β1 and β2 receptors, with an action strength 8 times that of propranolol. It can be made into topical emulsions, gels, and patches for use in the treatment of infantile hemangiomas.

[0003] In the existing technology, Chinese patent application CN111067905A provides a hydrogel patch of timolol or its salt, wherein the raw materials of the hydrogel layer contain stabilizers, penetration enhancers, moisturizers, crosslinking agents, crosslinking regulators, pH value regulators, viscosity regulators, etc. in addition to timolol. Chinese authorized patent CN104274390B also provides a long-acting transdermal preparation of timolol, wherein timolol is made into a suspension, porous nanoparticles are added to adsorb timolol, and then penetration enhancers, thermosensitive gels, preservatives and moisturizers are added to make a long-acting transdermal preparation. The document "Preparation of timolol maleate transdermal patch and study on drug release mechanism" discloses a simple preparation method of timolol maleate transdermal patch and its transdermal diffusion effect. However, the above-mentioned several public topical timolol patch technologies or related technologies have average stability of the timolol maleate drug layer, unsatisfactory drug sustained release rate, and relatively low transdermal diffusion efficiency, which is not conducive to the long-term and rapid efficacy of the patch. Summary of the invention

[0004] In view of the above deficiencies in the prior art, the present invention provides a timolol maleate gel transdermal patch and a preparation method thereof, which are specifically achieved through the following technologies.

[0005] A timolol maleate gel transdermal patch comprises a drug layer and a backing layer which are bonded together, wherein a protective layer is bonded to the surface of the drug layer, wherein raw materials of the drug layer comprise 5-10wt% of timolol maleate, 16-22wt% of modified composite protein, 3-8wt% of polyvinyl alcohol, 6-12wt% of glycerol, 0.5-2wt% of a penetration enhancer, and the remainder is a pH regulator and deionized water, wherein the amount of the pH regulator is based on adjusting the pH value of the drug layer to 8-8.5;

[0006] The preparation method of the modified composite protein is as follows: acylated casein, ovalbumin and dopamine are added into 200 ml, 10 mM, pH=8.5 Tris buffer at a weight ratio of 1.5-3:2.5-5:2, and heated and stirred; then the solution is filtered, washed, dialyzed, and freeze-dried to obtain the modified composite protein.

[0007] The timolol maleate patch provided by the present invention can be made of a non-woven fabric or other commonly used patch backing materials, and the protective layer can be made of a water-impermeable protective film such as a PE film. The modified composite protein selected can be used as a sustained-release coating material for the timolol maleate drug, and can also be used with polyvinyl alcohol as a gel matrix to exert a synergistic effect and improve the stability of the drug layer. When in use, the protective layer of the timolol maleate patch is torn off, and the drug layer is applied to the surface of the infantile hemangioma.

[0008] Preferably, the raw materials of the drug layer include 7wt% timolol maleate, 18wt% modified composite protein, 5wt% polyvinyl alcohol, 8wt% glycerol, 1wt% penetration enhancer, and the rest are pH regulator and deionized water. The amount of the pH regulator is based on adjusting the pH value of the drug layer to 8-8.5.

[0009] Preferably, the weight ratio of acylated casein, ovalbumin and dopamine is 2:3:2.

[0010] Preferably, in the method for preparing the modified protein, the heating and stirring are carried out at 45-50° C. and 2000-4000 rpm for 10-15 hours.

[0011] More preferably, in the method for preparing the modified protein, the heating and stirring are carried out at 45-50° C. and 3500 rpm for 10 hours.

[0012] Preferably, the penetration enhancer is at least one of lauryl alcohol, menthol, geraniol, anethole, decyl methyl sulfoxide and sodium tetradecyl sulfate.

[0013] The preparation method of the above-mentioned timolol maleate gel transdermal patch comprises the following steps:

[0014] P1, taking timolol maleate and a penetration enhancer and stirring and dissolving them in ethanol to obtain a first solution, taking the modified composite protein, taking polyvinyl alcohol, glycerol, and deionized water and stirring them evenly to obtain a second solution;

[0015] P2, adding the first solution of step P1 to the second solution, keeping warm at 50-55°C to remove ethanol, and shearing at 10000-14000 rpm for 35-50 min to obtain a third solution;

[0016] P3, adding a pH adjuster to the third solution of step S2 to adjust the pH value, and stirring and dispersing at 300-500 rpm for 20-25 min to prepare a drug layer;

[0017] P4, coating the drug layer on the backing layer and letting it stand to solidify, and then pasting a protective layer on the surface of the drug layer to obtain a timolol maleate external patch.

[0018] Preferably, in step P2 of the preparation method of the timolol maleate gel transdermal patch, the shearing method is shearing at 13000 rpm for 35 min.

[0019] Compared with the prior art, the present invention is beneficial in that: the timolol maleate gel transdermal patch prepared by the raw materials and preparation method of the present invention, the modified composite protein and polyvinyl alcohol work synergistically together to play the role of a good gel substrate, and can be coated on the surface of the timolol maleate drug particles, while ensuring the wettability of the gel-like drug layer, the drug stability and sustained-release effect are better. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The transdermal test results of the timolol maleate gel transdermal patch of Examples 1-5;

[0021] Figure 2 The transdermal test results of the timolol maleate gel transdermal patches of Comparative Examples 1-6 are as follows; DETAILED DESCRIPTION

[0022] The technical solution of the present invention will be described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] The timolol maleate gel transdermal patches prepared in the following examples and comparative examples all include a drug layer and a backing layer bonded together, and a protective layer is bonded to the surface of the drug layer; the backing layer is made of non-woven fabric, and the protective layer is made of PE film.

[0024] Example 1

[0025] The raw materials of the drug layer of the timolol maleate gel transdermal patch provided in this embodiment include 7wt% of timolol maleate, 18wt% of modified composite protein, 5wt% of polyvinyl alcohol, 8wt% of glycerol, 1wt% of lauryl alcohol (penetration enhancer), and the rest are pH regulator and deionized water, and the amount of the pH regulator is based on adjusting the pH value of the drug layer to about 8.5.

[0026] The preparation method of the modified composite protein is as follows: acylated casein, ovalbumin and dopamine are added into 200 ml, 10 mM, pH=8.5 Tris buffer in a weight ratio of 2:3:2, heated and stirred at 50°C and 3500 rpm for 10 hours; then the solution is filtered, washed, dialyzed, and freeze-dried to obtain the modified composite protein.

[0027] The preparation method of timolol maleate gel transdermal patch is as follows:

[0028] P1, taking timolol maleate and a penetration enhancer and stirring and dissolving them in ethanol to obtain a first solution, taking the modified composite protein, taking polyvinyl alcohol, glycerol, and deionized water and stirring them evenly to obtain a second solution;

[0029] P2, adding the first solution of step P1 to the second solution, keeping warm at 55°C to remove ethanol, and shearing at 13000 rpm for 35 min to obtain a third solution;

[0030] P3, adding a pH adjuster to the third solution of step S2 to adjust the pH value, and stirring and dispersing at 500 rpm for 20 minutes to prepare a drug layer;

[0031] P4, coating the drug layer on the backing layer and letting it stand to solidify, and then pasting a protective layer on the surface of the drug layer to obtain a timolol maleate external patch.

[0032] Example 2

[0033] The timolol maleate gel transdermal patch provided in this embodiment comprises 10wt% timolol maleate, 16wt% modified composite protein, 8wt% polyvinyl alcohol, 8wt% glycerol, 1wt% menthol (penetration enhancer), and the remainder is a pH regulator and deionized water, wherein the amount of the pH regulator is based on adjusting the pH value of the drug layer to about 8.5. The preparation method of the modified composite protein and the timolol maleate gel transdermal patch is the same as that of Example 1.

[0034] Example 3

[0035] The timolol maleate gel transdermal patch provided in this embodiment comprises 5wt% timolol maleate, 22wt% modified composite protein, 3wt% polyvinyl alcohol, 8wt% glycerol, 1wt% menthol (penetration enhancer), and the remainder is a pH regulator and deionized water, wherein the amount of the pH regulator is based on adjusting the pH value of the drug layer to about 8.5. The preparation method of the modified composite protein and the timolol maleate gel transdermal patch is the same as that of Example 1.

[0036] Example 4

[0037] The timolol maleate gel transdermal patch, the raw material formula of the drug layer, and the preparation method of the timolol maleate gel transdermal patch provided in this embodiment are the same as those in Example 1.

[0038] In the preparation method of the modified composite protein, the weight ratio of acylated casein, ovalbumin and dopamine is 1.5:5:2.

[0039] Example 5

[0040] The timolol maleate gel transdermal patch, the raw material formula of the drug layer, and the preparation method of the timolol maleate gel transdermal patch provided in this embodiment are the same as those in Example 1.

[0041] In the preparation method of the modified composite protein, the weight ratio of acylated casein, ovalbumin and dopamine is 3:2.5:2.

[0042] Comparative Example 1

[0043] The timolol maleate gel transdermal patch, the raw material formula of the drug layer, and the preparation method of the timolol maleate gel transdermal patch provided in this comparative example are the same as those in Example 1. In the preparation method of the modified composite protein, the weight ratio of acylated casein, ovalbumin, and dopamine is 1:6:2.

[0044] Comparative Example 2

[0045] The timolol maleate gel transdermal patch, the raw material formula of the drug layer, and the preparation method of the timolol maleate gel transdermal patch provided in this comparative example are the same as those in Example 1. In the preparation method of the modified composite protein, the weight ratio of acylated casein, ovalbumin, and dopamine is 2:1:1, i.e., 4:2:2.

[0046] Comparative Example 3

[0047] The timolol maleate gel transdermal patch, the raw material formula of the drug layer, and the preparation method of the timolol maleate gel transdermal patch provided in this comparative example are the same as those in Example 1. The preparation method of the modified composite protein is as follows: acylated casein and dopamine are added to 200 ml, 10 mM, pH=8.5 Tris buffer in a weight ratio of 5:2, heated and stirred; then the solution is filtered, washed, dialyzed, and freeze-dried to obtain the modified composite protein.

[0048] Comparative Example 4

[0049] The timolol maleate gel transdermal patch, the raw material formula of the drug layer, and the preparation method of the timolol maleate gel transdermal patch provided in this comparative example are the same as those in Example 1. The preparation method of the modified composite protein is as follows: taking ovalbumin and dopamine in a weight ratio of 5:2, adding them to 200 ml, 10 mM, pH=8.5 Tris buffer, heating and stirring; then filtering, washing, dialyzing, and freeze-drying the solution to obtain the modified composite protein.

[0050] Comparative Example 5

[0051] The timolol maleate gel transdermal patch provided in this comparative example comprises 7wt% timolol maleate, 18wt% composite protein, 5wt% polyvinyl alcohol, 8wt% glycerol, 1wt% penetration enhancer, and the rest is pH regulator and deionized water, and the amount of the pH regulator is based on adjusting the pH value of the drug layer to 8-8.5. The preparation method of the timolol maleate gel transdermal patch is the same as that of Example 1. The composite protein is prepared by adding ovalbumin and dopamine to 200ml, 10mM, pH=8.5 Tris buffer in a weight ratio of 5:2, heating and stirring; then filtering, washing, dialyzing, and freeze-drying the solution to obtain.

[0052] Comparative Example 6

[0053] The timolol maleate gel transdermal patch provided in this comparative example comprises 7wt% of timolol maleate, 18wt% of poloxamer 188 (instead of modified composite protein), 5wt% of polyvinyl alcohol, 8wt% of glycerol, 1wt% of penetration enhancer, and the remainder is a pH regulator and deionized water, wherein the amount of the pH regulator is based on adjusting the pH value of the drug layer to 8-8.5. The preparation method of the timolol maleate gel transdermal patch is the same as that of Example 1.

[0054] Test example: Transdermal penetration test of timolol maleate gel transdermal patch

[0055] The percutaneous permeation test of the transdermal patches of the above-mentioned embodiments and comparative examples was carried out by referring to the methods of percutaneous absorption test of timolol maleate disclosed in the references "Effect of enhancers on the percutaneous permeation of timolol maleate" (Ji Xuefang, Journal of China Pharmaceutical University, 1996, 2(1), pp. 6-9), "Preparation and drug release mechanism of timolol maleate transdermal patch" (Ji Xuefang, Chinese Pharmaceutical Journal, April 1996, Vol. 31, No. 4, pp. 217-219), and "Effect of permeation enhancers on corneal permeability of timolol maleate, Wei Gang, Chinese Pharmaceutical Journal, June 2002, Vol. 3, No. 6, pp. 430-433).

[0056] The specific method is:

[0057] 1. Preparation of ex vivo skin: Take rats weighing 220±10g, treat the abdomen of the rats with sulfide depilatory to remove hair, rinse, feed them normally for 24 hours and then kill them, cut the abdominal skin, peel off the subcutaneous fat and mucous tissue, wash them with physiological saline, and obtain the ex vivo skin for later use.

[0058] 2. Take the above ex vivo skin and assemble a double-chamber osmotic diffusion device, including a super constant temperature water bath, a diffusion cell, and a receiving cell. The receiving solution is physiological saline. The volume of the receiving cell is 5 ml. The temperature is maintained at 37±0.5℃. The diffusion area is about 3.14cm 2 ;

[0059] 3. After trimming the timolol maleate gel transdermal patches of the embodiment and the comparative example, apply them to the ex vivo skin and start timing; at 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 7h, and 8h, take 2ml of normal saline from the receiving pool as a sample for standby use, and then replenish it with normal saline;

[0060] 4. The physiological saline samples obtained at each time were subjected to HPLC determination. After conversion, the cumulative drug penetration of the timolol maleate gel transdermal patch of each embodiment and comparative example was obtained as follows: Figure 1 , 2 shown.

[0061] From the attached Figure 1 , 2 It can be seen that the cumulative drug release of the timolol maleate gel transdermal patch prepared by Examples 1-5 is in a state of continuous increase, the initial drug release rate is slightly slow, and then gradually increases, so the drug cumulative release curve is "J" shaped, and when the test is carried out from 6h to 8h, the cumulative release gradually reaches a peak value, that is, the drug in the patch is nearly completely released. The peak value of the cumulative release of Example 2 is the highest due to the high drug dosage, and the peak value of Example 3 is slightly lower; the peak time of Example 4 is slightly earlier than that of Example 1, and the peak time of Example 5 is slightly later than that of Example 1, which may be related to the ratio of acylated casein and ovalbumin in the modified composite protein.

[0062] The peak of Comparative Example 1 appears earlier than that of Example 4, while that of Comparative Example 2 appears later than that of Example 5. The peak of Comparative Example 3 does not appear until the 8th hour. The peaks of Comparative Examples 4 and 5 appear earlier than that of Comparative Example 1. The cumulative release curve of Comparative Example 6 is not much different from that of Comparative Example 5.

[0063] Test example: Evaluation of the stability of the drug layer of timolol maleate gel transdermal patch

[0064] With reference to the contents of the stability investigation of timolol maleate gel disclosed in the paper "Development of Timolol Maleate Gel for Infantile Hemangioma" (Jie Lili, Master's Thesis of China Medical University, February 2020), the stability of the drug layer of the timolol maleate gel transdermal patch of the embodiment and the comparative example was evaluated.

[0065] The specific evaluation method is: take an appropriate amount of the drug layer of the transdermal patch of the above embodiment and comparative example, place it in a constant temperature box at 40°C and 60°C for 10 days, and observe the appearance of the sample on the 3rd, 6th and 9th day; the results are shown in Table 1 below.

[0066] Table 1 Evaluation of sample appearance of drug layer of timolol maleate gel transdermal patch (high temperature test)

[0067]

[0068] It can be seen from Table 1 above that when the ratio of acylated casein and ovalbumin in the modified composite protein is changed, or acylated casein / ovalbumin is not selected in the modified composite protein, or only acylated casein and ovalbumin are used, the stability of the transdermal patch drug layer will be affected to a certain extent.

Claims

1. A timolol maleate gel transdermal patch, comprising a drug layer and a backing layer bonded together, wherein a protective layer is attached to the surface of the drug layer, characterized in that: The raw materials of the drug layer include 5-10wt% timolol maleate, 16-22wt% modified composite protein, 3-8wt% polyvinyl alcohol, 6-12wt% glycerol and 0.5-2wt% penetration enhancer, and the rest is pH regulator and deionized water, and the amount of the pH regulator is based on adjusting the pH value of the drug layer to 8-8.5; The preparation method of the modified composite protein is as follows: acylated casein, ovalbumin and dopamine are added into 200 ml of 10 mM Tris buffer solution with a pH of 8.5 according to a weight ratio of 1.5-3:2.5-5:2, and heated and stirred; then the solution is filtered, washed, dialyzed, and freeze-dried to obtain the modified composite protein; In the preparation method of the modified composite protein, the heating and stirring method is: 45-50°C, 2000-4000 rpm stirring for 10-15h; The preparation method of the timolol maleate gel transdermal patch comprises the following steps: P1, taking timolol maleate and a penetration enhancer and stirring and dissolving them in ethanol to obtain a first solution, taking the modified composite protein, polyvinyl alcohol, glycerol and deionized water and stirring them evenly to obtain a second solution; P2, adding the first solution of step P1 to the second solution, keeping warm at 50-55°C to remove ethanol, and shearing at 10000-14000 rpm for 35-50 min to obtain a third solution; P3, adding a pH adjuster to the third solution of step P2 to adjust the pH value, and stirring and dispersing at 300-500 rpm for 20-25 min to prepare a drug layer; P4, coating the drug layer on the backing layer and letting it stand to solidify, and then pasting a protective layer on the surface of the drug layer to obtain a timolol maleate external patch.

2. The timolol maleate gel transdermal patch according to claim 1, characterized in that: The raw materials of the drug layer include 7wt% timolol maleate, 18wt% modified composite protein, 5wt% polyvinyl alcohol, 8wt% glycerol and 1wt% penetration enhancer, and the rest are pH regulator and deionized water. The amount of the pH regulator is based on adjusting the pH value of the drug layer to 8-8.

5.

3. The timolol maleate gel transdermal patch according to claim 1 or 2, characterized in that: The weight ratio of acylated casein, ovalbumin and dopamine is 2:3:

2.

4. The timolol maleate gel transdermal patch according to claim 1, characterized in that: In the preparation method of the modified composite protein, the heating and stirring method is: 45-50° C., 3500 rpm stirring for 10 hours.

5. The timolol maleate gel transdermal patch according to claim 1 or 2, characterized in that: The penetration enhancer is at least one of lauryl alcohol, menthol, geraniol, anethole, decyl methyl sulfoxide and sodium tetradecyl sulfate.

6. The timolol maleate gel transdermal patch according to claim 1, characterized in that: In step P2, the shearing method is 13000 rpm for 35 min.

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