Compound ligustrazine transdermal patch as well as preparation method and application thereof

Abstract

The invention relates to the technical field of transdermal drug delivery, and provides a compound ligustrazine transdermal patch and a preparation method and application thereof, and the compound ligustrazine transdermal patch is composed of ligustrazine, a polymer auxiliary material, a cosolvent, eugenol, a penetration enhancer, a pH regulator, an antioxidant and a preservative. Pharmacodynamic tests prove that ligustrazine and eugenol in the compound ligustrazine transdermal patch are combined for use, a remarkable synergistic effect is achieved, and the compound ligustrazine transdermal patch has a positive treatment effect on cerebral ischemia. According to the compound ligustrazine transdermal patch, the transdermal penetration amount of the medicine can be increased, the medicine can play a better role, and the utilization rate of the medicine is increased.

Description

Technical Field

[0001] The present invention relates to the technical field of transdermal drug delivery, and in particular to a compound ligustrazine transdermal patch and a preparation method and application thereof. Background Art

[0002] Ligustrazine is also known as tetramethylpyrazine. It is produced by the acetoin produced by the decomposition of reducing sugars and polysaccharides in Ligustrazine by endogenous Bacillus subtilis in Ligustrazine, and the ammonia produced by the decomposition of protein by deamination, which is condensed through a thermodynamic reaction. Related material basis research shows that Ligustrazine is a characteristic alkaloid of Ligustrazine, and its content is closely related to the source of Ligustrazine, the topdressing conditions and the extraction process. As a characteristic alkaloid of Ligustrazine in the traditional Chinese medicine, Ligustrazine has a very wide range of pharmacological effects and functions, such as antibacterial, anti-inflammatory, anti-rheumatic, anti-tumor, anti-allergic, antiviral, anti-parasitic, anti-arrhythmic, detumescent and diuretic, immune and biological response regulation, etc.

[0003] At present, the common preparations of ligustrazine commonly used in clinical practice include tablets, capsules and injections. Among them, oral preparations have a first-pass effect in the liver, low bioavailability, and injections are inconvenient to administer. Due to the significant efficacy of ligustrazine, in recent years, domestic scholars have done a lot of effective research work based on its pharmacodynamic characteristics and clinical applications, which are mainly divided into two categories: one is to develop it into a fast-acting preparation; the other is to develop it into a sustained-release preparation to make it have a lasting effect.

[0004] Ligustrazine and its related preparations have accumulated a lot of experience in the pharmacological effects of treating cerebrovascular diseases. At the same time, with the continuous improvement of medical technology, clinical practice has successively proved that this type of drug can effectively treat cerebrovascular diseases and their complications, which has also led to the continuous expansion of the clinical application scope of this type of drug. Injections with ligustrazine as the main ingredient are mainly used in clinical practice, such as ligustrazine injection, ligustrazine hydrochloride injection and ligustrazine phosphate injection. This type of injection has the effect of promoting blood circulation and removing blood stasis, can effectively inhibit platelet aggregation, improve the patient's blood viscosity and promote blood flow, and has the characteristics of dose dependence and low incidence of adverse reactions.

[0005] Oral medications are prone to gastrointestinal reactions, and drug residues can also be harmful to human health. Injection medications are the least safe, have the greatest risk, and are prone to multiple side effects.

[0006] The transdermal drug delivery system is a drug delivery route in which drugs are absorbed through the skin into the human blood circulation and reach effective blood drug concentrations to achieve disease treatment or prevention. Summary of the invention

[0007] The present invention aims to provide a compound ligustrazine transdermal patch and its preparation method and application. The compound ligustrazine transdermal patch of the present invention can increase the transdermal permeation of the drug, make the drug play a better role, and improve the utilization rate of the drug.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] The first aspect of the present invention provides a compound ligustrazine transdermal patch, which is made of the following components: ligustrazine, polymer excipients, cosolvents, eugenol, penetration enhancers, pH regulators, antioxidants and preservatives.

[0010] In one embodiment of the present invention, in the compound ligustrazine transdermal patch of the present invention, the mass percentage of ligustrazine is 20%-35%, the mass percentage of polymer excipients is 6%-15%, the mass percentage of cosolvent is 5%-10%, the mass percentage of eugenol is 10%-15%, the mass percentage of penetration enhancer is 0.05%-0.2%, the mass percentage of pH adjuster is 0.8%-1.5%, the mass percentage of antioxidant is 0.8%-2.5% and the mass percentage of preservative is 1.0%-5.0%.

[0011] In one embodiment of the present invention, the polymer auxiliary materials are carbomer, hydroxyethyl cellulose and chitosan, and the mass ratio of carbomer, hydroxyethyl cellulose and chitosan is 1:1-3:2-5.

[0012] In one embodiment of the present invention, the co-solvent is PPG-25 sorbitol and 1,2-pentanediol, and the mass ratio of PPG-25 sorbitol to 1,2-pentanediol is 1:2-4.

[0013] In one embodiment of the present invention, the penetration enhancer is polyglycerol fatty acid ester.

[0014] In one embodiment of the present invention, the pH adjuster is lactic acid-sodium lactate.

[0015] In one embodiment of the present invention, the antioxidant is butylated hydroxytoluene.

[0016] In one embodiment of the present invention, the preservative is potassium sorbate.

[0017] A preferred prescription of the present invention is: 25 g of ligustrazine, 10 g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8 g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12 g of eugenol, 0.1 g of polyglycerol fatty acid ester, 0.93 mg of lactic acid, 1.0 g of sodium lactate, 1.5 g of butylated hydroxytoluene and 3.0 g of potassium sorbate.

[0018] Another preferred prescription of the present invention is: 25 g of ligustrazine, 10 g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8 g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12 g of eugenol, 0.1 g of polyglycerol fatty acid ester, 0.93 mg of lactic acid, 1.0 g of sodium lactate, 1.5 g of butylated hydroxytoluene and 3.0 g of potassium sorbate.

[0019] The second aspect of the present invention provides a method for preparing the above-mentioned compound ligustrazine transdermal patch, comprising the following steps: S1. dissolving ligustrazine and eugenol in a cosolvent, then adding a penetration enhancer, and stirring thoroughly to completely dissolve it; S2. adding a pH adjuster, an antioxidant, a preservative and a polymer excipient, stirring evenly to obtain a drug-loaded matrix; S3. coating the drug-loaded matrix on a protective layer to obtain a drug-containing layer; S4. drying at 45°C-55°C for a period of time, and naturally cooling to room temperature; S5. covering the drug-containing layer with a backing layer, and cutting into the required size to obtain a transdermal patch.

[0020] In one embodiment of the present invention, the temperature in S4 is 50°C.

[0021] The third aspect of the present invention provides the use of the above-mentioned compound ligustrazine transdermal patch in the preparation of a drug for preventing or treating cerebral ischemia.

[0022] The efficacy examples of the present invention respectively adopt mouse decapitation, mouse bilateral common carotid artery ligation, and mouse stroke models to study the protective effect of the compound ligustrazine transdermal patch of the present invention on experimental cerebral ischemia in mice from the effects on acute cerebral ischemia and stroke neurobehavior. The results show that the compound ligustrazine transdermal patch of the present invention can prolong the decapitation panting time of mice and the survival time of bilateral common carotid artery ligation of mice, and reduce the stroke index of mice. The compound ligustrazine transdermal patch of the present invention has a protective effect on experimental cerebral ischemia in mice.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The efficacy test proves that the combination of ligustrazine and eugenol in the compound ligustrazine transdermal patch of the present invention exhibits a significant synergistic effect and has a positive therapeutic effect on cerebral ischemia. The compound ligustrazine transdermal patch of the present invention can increase the transdermal permeation of the drug, make the drug play a better role, and improve the utilization rate of the drug.

[0025] The compound ligustrazine transdermal patch of the present invention directly penetrates into the diseased part through the skin, effectively improves the therapeutic efficiency of the drug, avoids the first-pass effect of the liver and the elimination and degradation of the gastrointestinal tract, and reduces the dosage of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1Comparison of stroke index among groups. Different lowercase letters above the bar graph indicate significant differences among different groups (P<0.05).

[0027] Figure 2 Comparison of decapitation breathing time among groups. Different lowercase letters above the bar graph indicate significant differences among different groups (P<0.05).

[0028] Figure 3 Comparison of survival time after bilateral common carotid artery ligation in each group. Different lowercase letters above the bar graph indicate significant differences among different groups (P<0.05). Specific embodiments

[0029] The content of the present invention is further described in detail below through specific implementation methods, but this should not be understood as the scope of the above subject matter of the present invention is limited to the following examples. The following examples are used to illustrate the technical solution of the present invention rather than to limit the scope of protection of the present invention. If a person of ordinary skill in the art modifies or replaces the technical solution of the present invention with an equivalent without departing from the essence and scope of the technical solution of the present invention, it still belongs to the scope of protection of the present invention.

[0030] Example 1

[0031] A compound ligustrazine transdermal patch is prepared by the following method:

[0032] 30g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12g of eugenol, 0.1g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 1.5g of butylated hydroxytoluene and 3.0g of potassium sorbate.

[0033] S1. Dissolve ligustrazine and eugenol in PPG-25 sorbitol and 1,2-pentanediol, then add polyglycerol fatty acid ester and stir well to dissolve it completely; S2. Add lactic acid-sodium lactate, butylated hydroxytoluene, potassium sorbate and carbomer, hydroxyethyl cellulose and chitosan, stir evenly to obtain a drug-loaded matrix; S3. Apply the drug-loaded matrix on the protective layer to obtain a drug-containing layer; S4. Dry at 50℃ for a period of time and cool naturally to room temperature; S5. Cover the drug-containing layer with a backing layer and cut it into the required size to obtain a transdermal patch.

[0034] Example 2

[0035] A compound ligustrazine transdermal patch is prepared by the following method:

[0036] 30g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12g of eugenol, 0.1g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 1.5g of butylated hydroxytoluene and 3.0g of potassium sorbate.

[0037] S1. Dissolve ligustrazine and eugenol in PPG-25 sorbitol and 1,2-pentanediol, then add polyglycerol fatty acid ester and stir well to dissolve it completely; S2. Add lactic acid-sodium lactate, butylated hydroxytoluene, potassium sorbate and carbomer, hydroxyethyl cellulose and chitosan, stir evenly to obtain a drug-loaded matrix; S3. Apply the drug-loaded matrix on the protective layer to obtain a drug-containing layer; S4. Dry at 45℃ for a period of time and cool naturally to room temperature; S5. Cover the drug-containing layer with a backing layer and cut it into the required size to obtain a transdermal patch.

[0038] Example 3

[0039] A compound ligustrazine transdermal patch is prepared by the following method:

[0040] 25g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:3:5, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:2, 15g of eugenol, 0.05g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 2.5g of butylated hydroxytoluene and 2.0g of potassium sorbate.

[0041] S1. Dissolve ligustrazine and eugenol in PPG-25 sorbitol and 1,2-pentanediol, then add polyglycerol fatty acid ester and stir thoroughly to make it completely dissolved; S2. Add lactic acid-sodium lactate, butylated hydroxytoluene, potassium sorbate and carbomer, hydroxyethyl cellulose and chitosan, stir evenly to obtain a drug-loaded matrix; S3. Apply the drug-loaded matrix on the protective layer to obtain a drug-containing layer; S4. Dry at 55℃ for a period of time and cool naturally to room temperature; S5. Cover the drug-containing layer with a backing layer and cut it into the required size to obtain a transdermal patch.

[0042] Example 4

[0043] A compound ligustrazine transdermal patch is prepared by the following method:

[0044] 20g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:1:2, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:4, 10g of eugenol, 0.05g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 0.8g of butylated hydroxytoluene and 3.0g of potassium sorbate.

[0045] S1. Dissolve ligustrazine and eugenol in PPG-25 sorbitol and 1,2-pentanediol, then add polyglycerol fatty acid ester and stir well to dissolve it completely; S2. Add lactic acid-sodium lactate, butylated hydroxytoluene, potassium sorbate and carbomer, hydroxyethyl cellulose and chitosan, stir evenly to obtain a drug-loaded matrix; S3. Apply the drug-loaded matrix on the protective layer to obtain a drug-containing layer; S4. Dry at 50℃ for a period of time and cool naturally to room temperature; S5. Cover the drug-containing layer with a backing layer and cut it into the required size to obtain a transdermal patch.

[0046] Example 5

[0047] A compound ligustrazine transdermal patch is prepared by the following method:

[0048] 30g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:4, 12g of eugenol, 0.2g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 2.0g of butylated hydroxytoluene and 5.0g of potassium sorbate.

[0049] S1. Dissolve ligustrazine and eugenol in PPG-25 sorbitol and 1,2-pentanediol, then add polyglycerol fatty acid ester and stir well to dissolve it completely; S2. Add lactic acid-sodium lactate, butylated hydroxytoluene, potassium sorbate and carbomer, hydroxyethyl cellulose and chitosan, stir evenly to obtain a drug-loaded matrix; S3. Apply the drug-loaded matrix on the protective layer to obtain a drug-containing layer; S4. Dry at 50℃ for a period of time and cool naturally to room temperature; S5. Cover the drug-containing layer with a backing layer and cut it into the required size to obtain a transdermal patch.

[0050] Example 6

[0051] A compound ligustrazine transdermal patch is prepared by the following method:

[0052] 35g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:3:4, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:2, 15g of eugenol, 0.2g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 1.5g of butylated hydroxytoluene and 1.0g of potassium sorbate.

[0053] S1. Dissolve ligustrazine and eugenol in PPG-25 sorbitol and 1,2-pentanediol, then add polyglycerol fatty acid ester and stir well to dissolve it completely; S2. Add lactic acid-sodium lactate, butylated hydroxytoluene, potassium sorbate and carbomer, hydroxyethyl cellulose and chitosan, stir evenly to obtain a drug-loaded matrix; S3. Apply the drug-loaded matrix on the protective layer to obtain a drug-containing layer; S4. Dry at 45℃ for a period of time and cool naturally to room temperature; S5. Cover the drug-containing layer with a backing layer and cut it into the required size to obtain a transdermal patch.

[0054] Comparative Example 1

[0055] Prepared by the following method:

[0056] 42g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8g of ethanol and 1,2-pentanediol in a mass ratio of 1:3, 0.1g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 1.5g of butylated hydroxytoluene and 3.0g of potassium sorbate.

[0057] The preparation method is similar to that of Example 1.

[0058] Compared with Example 1, the difference of this comparative example is that eugenol is not contained and the dosage of ligustrazine is increased.

[0059] Comparative Example 2

[0060] Prepared by the following method:

[0061] Eugenol 42g, carbomer, hydroxyethyl cellulose and chitosan 10g in a mass ratio of 1:2:4, PPG-25 sorbitol and 1,2-pentanediol 8g in a mass ratio of 1:3, polyglycerol fatty acid ester 0.1g, lactic acid 0.93mg, sodium lactate 1.0g, butylated hydroxytoluene 1.5g and potassium sorbate 3.0g.

[0062] The preparation method is similar to that of Example 1.

[0063] Compared with Example 1, the difference of this comparative example is that ligustrazine is not contained and the dosage of eugenol is increased.

[0064] Comparative Example 3

[0065] Prepared by the following method:

[0066] 30g of ligustrazine, 10g of carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:4:6, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12g of eugenol, 0.1g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 1.5g of butylated hydroxytoluene and 3.0g of potassium sorbate.

[0067] The preparation method is similar to that of Example 1.

[0068] Compared with Example 1, the difference of this comparative example is that the dosage of each component of the polymer auxiliary material is different.

[0069] Comparative Example 4

[0070] Prepared by the following method:

[0071] 30g of ligustrazine, 10g of carbomer and chitosan in a mass ratio of 1:4, 8g of PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12g of eugenol, 0.1g of polyglycerol fatty acid ester, 0.93mg of lactic acid, 1.0g of sodium lactate, 1.5g of butylated hydroxytoluene and 3.0g of potassium sorbate.

[0072] The preparation method is similar to that of Example 1.

[0073] Compared with Example 1, the difference of this comparative example is that the types of polymer auxiliary materials are different.

[0074] Efficacy Example 1 Protective effect of the compound ligustrazine transdermal patch of the present invention on cerebral ischemia mice

[0075] 1. Establishment of Stroke Mouse Model

[0076] SPF grade Kunming mice were lightly anesthetized with ether, placed supine, fixed on the operating table, the neck was straightened, the skin was cut longitudinally, and the left and right common carotid arteries and vagus nerves were separated. A "0" silk thread was passed under the common carotid artery and vagus nerve on one side, and a 0.2mm diameter fine steel wire was inserted, tied together with the silk thread, and then the fine steel wire was pulled out. The other common carotid artery and vagus nerve were ligated with "O" silk thread, and the skin was sutured after surgery and returned to the cage to make a mouse stroke model.

[0077] The mice with successful modeling were randomly divided into model control group, embodiment 1 group, comparative example 1 group, comparative example 2 group, comparative example 3 group and comparative example 4 group, with 10 mice in each group.

[0078] After the animals were revived from modeling, treatment was started. The "Dazhui", "Qihai" and "Mingmen" acupoints were taken, and the mouse skin was locally depilated with 8% sodium sulfide (1 cm × 1 cm area). The corresponding transdermal patches were applied to the acupoints of Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4. The transdermal patches were applied to the above acupoints, gently massaged for 5 minutes, applied with adhesive tape, and removed after 3 hours. The skin was washed with clean water, 3 times a day, and the treatment was continued for 7 days. The model control group did not receive any treatment after modeling.

[0079] 2.Indicator observation

[0080] After the treatment, the behavioral performance of each animal was observed and the stroke index score was performed, as shown in Table 1.

[0081] Table 1 Stroke Index Score Table

[0082]

[0083]

[0084] 3. Statistical methods

[0085] SPSS 22.0 software was used for data processing and the data were expressed as mean ± standard deviation. The data of each group were subjected to normal distribution test and variance homogeneity test, and the inter-group comparison was performed with one-way analysis of variance, with P < 0.05 as the difference being statistically significant.

[0086] 4. Experimental Results

[0087] Effect of the compound ligustrazine transdermal patch of the present invention on the stroke index of each group of mice

[0088] Compared with the model control group, the stroke index of mice in Example 1 group was significantly reduced. The effect of improving the stroke index in Example 1 group was better than that in each control group. Figure 1 .

[0089] The transdermal patch of comparative example 1 does not contain eugenol, the transdermal patch of comparative example 2 does not contain ligustrazine, the type of polymer material in the transdermal patch of comparative example 3 is changed, and the amount of polymer material in the transdermal patch of comparative example 4 is changed, which will affect the anti-cerebral ischemia effect of the transdermal patch. The combination of ligustrazine and eugenol in the compound ligustrazine transdermal patch of the present invention presents a significant synergistic effect.

[0090] This experiment uses a mouse stroke model to study the protective effect of the compound ligustrazine transdermal patch of the present invention on experimental cerebral ischemia in mice. The results show that the compound ligustrazine transdermal patch of the present invention can reduce the stroke index of mice. The compound ligustrazine transdermal patch of the present invention has a protective effect on experimental cerebral ischemia in mice.

[0091] Efficacy Example 2 Study on the effect of the compound ligustrazine transdermal patch of the present invention on the decapitation panting model mice

[0092] 1. Establishment of the Decapitation Panting Model in Mice

[0093] SPF grade Kunming mice were decapitated from the neck behind both ears to prepare the mouse decapitation gasping model.

[0094] The mice with successful modeling were randomly divided into model control group, embodiment 1 group, comparative example 1 group, comparative example 2 group, comparative example 3 group and comparative example 4 group, with 10 mice in each group.

[0095] After modeling, the "Dazhui", "Qihai" and "Mingmen" acupoints were taken, and the mouse skin was locally depilated with 8% sodium sulfide (1 cm × 1 cm area). The corresponding transdermal patches were applied to the above acupoints in Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4. The transdermal patches were applied to the above acupoints, gently massaged for 5 minutes, applied with adhesive tape, and removed after 3 hours. The skin was washed with clean water, 3 times a day, and the treatment was continued for 7 days. The model control group did not receive any treatment after modeling.

[0096] 2.Indicator observation

[0097] Observe the panting time of mice after decapitation.

[0098] 3. Statistical methods

[0099] SPSS 22.0 software was used for data processing and the data were expressed as mean ± standard deviation. The data of each group were subjected to normal distribution test and variance homogeneity test, and the inter-group comparison was performed with one-way analysis of variance, with P < 0.05 as the difference being statistically significant.

[0100] 4. Experimental Results

[0101] Effect of the compound ligustrazine transdermal patch of the present invention on the decapitation and panting time of mice in each group

[0102] Compared with the model control group, the panting time of mice in Example 1 group was significantly prolonged. The effect of extending the panting time of mice in Example 1 group was better than that of the control groups. Figure 2 .

[0103] After the mouse is decapitated, due to the termination of blood supply to the brain, the original blood and nutrients in the brain can still maintain brain function for a short period of time, and the mouse shows regular panting. Taking the panting time as an indicator, the protective effect of the drug on cerebral ischemia can be observed. All drugs that can reduce brain oxygen consumption can prolong the panting time of mice. The compound ligustrazine transdermal patch of the present invention can prolong the panting time of mice after decapitation.

[0104] Efficacy Example 3 Protective effect of the compound ligustrazine transdermal patch of the present invention on the mouse model of bilateral common carotid artery ligation

[0105] 1. Establishment of bilateral common carotid artery ligation model in mice

[0106] SPF grade Kunming mice were anesthetized with 10% chloral hydrate (3 mL / kg), and bilateral common carotid arteries were isolated and ligated simultaneously with surgical thread to establish a mouse bilateral common carotid artery ligation model.

[0107] The mice with successful modeling were randomly divided into model control group, embodiment 1 group, comparative example 1 group, comparative example 2 group, comparative example 3 group and comparative example 4 group, with 10 mice in each group.

[0108] After the animals were revived from modeling, treatment was started. The "Dazhui", "Qihai" and "Mingmen" acupoints were taken, and the mouse skin was locally depilated with 8% sodium sulfide (1 cm × 1 cm area). The corresponding transdermal patches were applied to the acupoints of Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4. The transdermal patches were applied to the above acupoints, gently massaged for 5 minutes, applied with adhesive tape, and removed after 3 hours. The skin was washed with clean water, 3 times a day, and the treatment was continued for 7 days. The model control group did not receive any treatment after modeling.

[0109] 2.Indicator observation

[0110] The survival time of mice after bilateral common carotid artery ligation was observed.

[0111] 3. Statistical methods

[0112] SPSS 22.0 software was used for data processing and the data were expressed as mean ± standard deviation. The data of each group were subjected to normal distribution test and variance homogeneity test, and the inter-group comparison was performed with one-way analysis of variance, with P < 0.05 as the difference being statistically significant.

[0113] 4. Experimental Results

[0114] Effect of the compound ligustrazine transdermal patch of the present invention on the survival time of each group of mice with bilateral common carotid artery ligation

[0115] Compared with the model control group, the survival time of the mice in Example 1 group after ligation of bilateral common carotid arteries was significantly prolonged. The effect of extending the survival time of the mice in Example 1 group after ligation of bilateral common carotid arteries was better than that of the control groups. Figure 3 .

[0116] This experiment adopts the mouse bilateral common carotid artery ligation model, and the study shows that the compound ligustrazine transdermal patch of the present invention can prolong the survival time of the mouse bilateral common carotid artery ligation.

[0117] This experiment uses mouse decapitation, mouse bilateral common carotid artery ligation, and mouse stroke models to study the protective effect of the compound ligustrazine transdermal patch of the present invention on experimental cerebral ischemia in mice from the effects on acute cerebral ischemia and stroke neurobehavioral scores. The results show that the compound ligustrazine transdermal patch of the present invention can prolong the decapitation panting time of mice and the survival time of bilateral common carotid artery ligation of mice, and reduce the mouse stroke index. The compound ligustrazine transdermal patch of the present invention has a protective effect on experimental cerebral ischemia in mice.

[0118] The above embodiments are not any form of limitation to the present invention. For those skilled in the art, any modification, replacement, etc. made within the scope of the technical solution of the present invention based on the technical essence of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A compound ligustrazine transdermal patch, characterized in that: The compound ligustrazine transdermal patch is made of the following components: ligustrazine, polymer excipients, cosolvent, eugenol, penetration enhancer, pH regulator, antioxidant and preservative; The mass percentage of ligustrazine is 20%-35%, the mass percentage of polymer auxiliary material is 6%-15%, the mass percentage of cosolvent is 5%-10%, the mass percentage of eugenol is 10%-15%, the mass percentage of penetration enhancer is 0.05%-0.2%, the mass percentage of pH regulator is 0.8%-1.5%, the mass percentage of antioxidant is 0.8%-2.5% and the mass percentage of preservative is 1.0%-5.0%.

2. The compound ligustrazine transdermal patch according to claim 1, characterized in that: The polymer auxiliary materials are carbomer, hydroxyethyl cellulose and chitosan, and the mass ratio of carbomer, hydroxyethyl cellulose and chitosan is 1:1-3:2-5.

3. The compound ligustrazine transdermal patch according to claim 1, characterized in that: The co-solvent is PPG-25 sorbitol and 1,2-pentanediol, and the mass ratio of PPG-25 sorbitol to 1,2-pentanediol is 1:2-4.

4. The compound ligustrazine transdermal patch according to claim 1, characterized in that: The penetration enhancer is polyglycerol fatty acid ester; the pH adjuster is lactic acid-sodium lactate; the antioxidant is butylated hydroxytoluene; and the preservative is potassium sorbate.

5. The compound ligustrazine transdermal patch according to claim 1, characterized in that: The compound ligustrazine transdermal patch is made of the following components: 25 g ligustrazine, 10 g carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8 g PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12 g eugenol, 0.1 g polyglycerol fatty acid ester, 0.93 mg lactic acid, 1.0 g sodium lactate, 1.5 g butylated hydroxytoluene and 3.0 g potassium sorbate.

6. The compound ligustrazine transdermal patch according to claim 1, characterized in that: The compound ligustrazine transdermal patch is made of the following components: 25 g ligustrazine, 10 g carbomer, hydroxyethyl cellulose and chitosan in a mass ratio of 1:2:4, 8 g PPG-25 sorbitol and 1,2-pentanediol in a mass ratio of 1:3, 12 g eugenol, 0.1 g polyglycerol fatty acid ester, 0.93 mg lactic acid, 1.0 g sodium lactate, 1.5 g butylated hydroxytoluene and 3.0 g potassium sorbate.

7. The compound ligustrazine transdermal patch according to claim 1, characterized in that: The preparation method comprises the following steps: S1. dissolving ligustrazine and eugenol in a cosolvent, then adding a penetration enhancer, and stirring thoroughly to completely dissolve the mixture; S2. adding a pH adjuster, an antioxidant, a preservative and a polymer auxiliary material, and stirring uniformly to obtain a drug-loaded matrix; S3. coating the drug-loaded matrix on a protective layer to obtain a drug-containing layer; S4. drying at 45°C-55°C for a period of time, and naturally cooling to room temperature; S5. covering the drug-containing layer with a backing layer, and cutting the layer into a required size to obtain a transdermal patch.

8. The compound ligustrazine transdermal patch according to claim 7, characterized in that: The temperature in S4 is 50°C.

9. Use of the compound ligustrazine transdermal patch according to any one of claims 1 to 6 in the preparation of a drug for preventing or treating cerebral ischemia.

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