Traditional Chinese medicine composition for improving cerebral ischemia and preparation method thereof

Abstract

The invention discloses a traditional Chinese medicine composition for improving cerebral ischemia and a preparation method thereof, and belongs to the technical field of traditional Chinese medicine preparation. The preparation method comprises the following steps: mixing, stirring and dispersing a polyurethane pressure-sensitive adhesive, a copper sulfide-polyacrylate glue solution, mixed traditional Chinese medicine powder, ethyl acetate and a penetration enhancer, and standing to obtain a drug-loaded composite pressure-sensitive adhesive; and coating a polyethylene backing layer with the drug-loaded composite pressure-sensitive adhesive, and then drying, evaporating and curing to obtain the traditional Chinese medicine composition. Ginseng is used as a monarch drug, astragalus membranaceus is used as a ministerial drug, fructus aurantii, caulis spatholobi, poria cocos, gastrodia elata and coptis chinensis are used as adjuvant drugs, and liquorice is used as a conductant drug, so that the whole traditional Chinese medicine composition can enhance qi and blood, improve microcirculation, protect neurons and reduce ischemia consequences, and can regulate the drug properties of all the drugs to play a synergistic effect. And then preparing the traditional Chinese medicine composition patch with photo-thermal penetration promotion to realize the treatment of cerebral ischemia.

Description

Technical Field

[0001] The invention belongs to the technical field of Chinese medicine preparation, and particularly relates to a Chinese medicine composition for improving cerebral ischemia and a preparation method thereof. Background Art

[0002] Ischemic brain disease refers to a disease in which the blood vessels supplying the brain are damaged or the hemodynamics are disturbed, resulting in insufficient blood supply to the brain, which in turn causes ischemia and hypoxia of the brain tissue, leading to necrosis or softening of the brain tissue, and causing short-term or persistent, local or diffuse brain damage. Such diseases not only have a high incidence and mortality rate, but also a worrying disability rate, which seriously affects people's physical health and quality of life. Stroke is one of the important causes of human death, among which ischemic stroke accounts for a high proportion of stroke. Therefore, it is particularly important to deeply study the causes, mechanisms and treatment methods of cerebral ischemia. There are many causes of cerebral ischemic diseases and complex pathological mechanisms, but different causes may involve three basic pathological processes: vascular wall lesions, changes in blood composition and hemodynamic changes. The interaction of these factors may lead to local or widespread brain damage, which in turn leads to a series of neurological deficit syndromes. Vascular wall lesions are an important basis for cerebral ischemia, usually manifested as arteriosclerosis, thrombosis, etc. These lesions lead to stenosis of the vascular lumen and obstruction of blood flow, which in turn affects the blood supply and oxygen supply to the brain tissue. Atherosclerosis is a major cause of ischemic stroke, and its pathological process includes vascular endothelial damage, lipid deposition, and inflammatory response. Changes in blood components, such as increased blood viscosity and platelet aggregation, can also affect the normal circulation of cerebral blood flow. Abnormal blood components can slow blood flow, increase the risk of thrombosis, and lead to insufficient blood supply to the brain. Hemodynamic changes are an important factor in cerebral ischemia. When systemic blood pressure drops or local hemodynamics are affected, brain tissue may be ischemic. In this case, insufficient oxygen and nutrients are supplied to brain tissue, which may lead to cell dysfunction and death. After cerebral ischemia, the occurrence of damage usually goes through two stages: acute damage and delayed damage: (1) Acute damage occurs in the early stage of cerebral ischemia, usually accompanied by a significant decrease in cerebral blood flow. At this stage, arterial blood flow obstruction leads to insufficient glucose and oxygen supply in the ischemic area, thereby promoting a series of pathological reactions such as calcium ion influx, oxidative stress, neurotoxicity, and excitatory amino acid toxicity, ultimately leading to cell death and blood-brain barrier damage; (2) Delayed damage occurs after ischemia-reperfusion. During the process of restoring blood flow, local inflammatory reactions and excessive reactive oxygen species may cause secondary brain damage. This stage involves complex mechanisms such as oxidative stress, nitrative stress and inflammatory response. The restored blood flow activates enzymes and pumps that were inhibited during ischemia, leading to the release of a large amount of reactive oxygen species, further aggravating cell damage and even causing more serious consequences such as cerebral edema and cerebral hemorrhage. Cerebral ischemia-reperfusion injury refers to the fact that after the ischemic state is restored, the brain tissue does not improve, but instead suffers more serious damage. The occurrence of this phenomenon is closely related to a variety of physiological and pathological processes, including: (1) Oxidative stress response. After blood flow is restored, the rate of reactive oxygen generation often exceeds the clearance capacity of intracellular antioxidant defense, leading to the emergence of oxidative stress response.Excessive production of reactive oxygen species not only damages cell membranes, but may also trigger a series of cascade reactions within cells, aggravating neuronal damage; (2) Inflammatory response. During reperfusion, local inflammatory responses can also aggravate brain damage. Immune cells that are suppressed during ischemia are activated after reperfusion, releasing a large amount of inflammatory mediators, further destroying surrounding healthy tissues and causing greater damage.

[0003] The clinical manifestations of cerebral ischemia vary depending on the degree of ischemia, duration and affected brain regions. Common symptoms include: (1) motor dysfunction: patients may experience limb weakness, numbness, unsteady gait, etc.; (2) language disorders: varying degrees of language expression and comprehension disorders, even aphasia; (3) sensory disorders: such as visual field defects, hearing loss, etc.; (4) cognitive dysfunction: including inattention, memory loss, etc. Traditional Chinese medicine has the characteristics of multiple components, multiple targets and multiple pathways, and has unique advantages and potential in the treatment of cerebral ischemia-reperfusion injury. More and more studies are devoted to finding effective ingredients from traditional Chinese medicine to treat ischemic cerebrovascular diseases and reduce cerebral ischemia-reperfusion injury. Modern pharmacological studies have shown that some traditional Chinese medicine ingredients have shown good potential in resisting cerebral ischemia-reperfusion injury, and have played a positive role in reducing inflammatory response, improving brain microcirculation, repairing damaged blood-brain barrier, reducing brain edema and inhibiting oxidative stress damage.

[0004] Therefore, further development of traditional Chinese medicine for the treatment of cerebral ischemia can not only provide patients with better treatment options and quality of life, but also has important significance in improving the medicinal value of traditional Chinese medicine and reducing the side effects of using Western medicine. Summary of the invention

[0005] According to the deficiencies in the prior art, the present invention uses ginseng as the main drug, astragalus as the ministerial drug, fructus aurantii, millet vine, tuckahoe, gastrodia elata and coptis chinensis as adjuvants, and licorice as the guiding drug. The whole can not only enhance qi and blood, improve microcirculation, protect neurons, reduce the consequences of ischemia, but also reconcile the medicinal properties of each drug and exert a synergistic effect. Then it is prepared into a Chinese medicine composition patch with photothermal penetration to achieve the treatment of cerebral ischemia, solving the technical problems raised in the background technology. Specifically, the technical solution of the present invention includes the following contents:

[0006] One of the purposes of the present invention is to provide a method for preparing a Chinese medicine composition for improving cerebral ischemia, the preparation method comprising the following steps:

[0007] The polyurethane pressure-sensitive adhesive, the copper sulfide-polyacrylate adhesive solution, the mixed Chinese medicine powder, the ethyl acetate and the penetration enhancer are mixed in a weight ratio of 10-20:40-50:20-30:30-40:0.3-0.6, heated to 50-60° C., stirred and dispersed, and after standing treatment, a drug-loaded composite pressure-sensitive adhesive is obtained;

[0008] The drug-loaded composite pressure-sensitive adhesive is coated on a polyethylene backing layer, and then dried, evaporated and solidified to obtain the traditional Chinese medicine composition.

[0009] Furthermore, the polyurethane pressure-sensitive adhesive is a medical solvent-free polyurethane pressure-sensitive adhesive 602.

[0010] Furthermore, the preparation method of the copper sulfide-polyacrylate glue comprises the following steps:

[0011] Polyacrylate pressure-sensitive adhesive, acrylic acid, emulsifier, ethyl acetate and deionized water are mixed and dispersed in a mass ratio of 200-300:5-10:0.1-0.2:500-600:100-200 to obtain a mixed solution, and the mixed solution and an initiator are mixed and heated to 70° C.-80° C. and reacted for 1 h-2 h to obtain a carboxyl-terminated polyacrylate adhesive solution;

[0012] The carboxyl-terminated polyacrylate glue and copper sulfate solution are mixed, and then sodium sulfide solution is added and the temperature is raised to 80° C. to 90° C. for reaction for 30 min to 40 min, and then the copper sulfide-polyacrylate glue is obtained by filtering and dialysis.

[0013] Furthermore, the polyacrylate pressure-sensitive adhesive is polyacrylate pressure-sensitive adhesive CF-68 or polyacrylate pressure-sensitive adhesive CF-68A.

[0014] Furthermore, the emulsifier includes polysorbate 80 or Span 80.

[0015] Furthermore, the initiator includes benzoyl peroxide or ammonium persulfate.

[0016] Furthermore, the weight ratio of the mixed solution:initiator is 1:0.001-0.002.

[0017] Furthermore, the mass concentration of the copper sulfate solution is 10%, and the mass concentration of the sodium sulfate solution is 10%.

[0018] Furthermore, the weight ratio of the carboxyl-terminated polyacrylate glue solution: the copper sulfate solution: the sodium sulfide solution is 1: 0.01-0.02: 0.02-0.03.

[0019] Furthermore, the preparation method of the mixed Chinese medicine powder comprises the following steps:

[0020] 90-100 parts by weight of ginseng, 30-40 parts by weight of astragalus, 5-7 parts by weight of fructus aurantii, 5-10 parts by weight of millet spatholobi, 3-5 parts by weight of poria cocos, 3-5 parts by weight of gastrodia elata, 5-8 parts by weight of coptis chinensis and 3-5 parts by weight of liquorice are mixed and crushed through a 50-mesh sieve to obtain mixed particles, 10 times the weight of deionized water is added to the mixed particles, the mixed particles are heated to 100° C., boiled for 80-90 minutes, and then filtered to separate to obtain a first filtrate and a first filter residue;

[0021] Deionized water 8 times its weight is added to the first filter residue, heated to 100° C. and boiled for 50 to 60 minutes, and then filtered and separated to obtain a second filtrate and a second filter residue;

[0022] The first filter residue and the second filter residue are combined, and then added with 10 times the amount of 75% ethanol solution, and soaked for 2 hours, and then heated to 60° C. and refluxed for 3 hours to obtain a third filtrate;

[0023] The first filtrate, the second filtrate and the third filtrate are combined, evaporated under reduced pressure and dried with hot air in sequence to obtain the mixed Chinese medicine powder.

[0024] Furthermore, the ginseng is the main drug, the astragalus is the ministerial drug, the fructus aurantii, millettia reticulata, poria cocos, gastrodia elata and coptis chinensis are adjuvant drugs, and the licorice is the guiding drug.

[0025] Furthermore, the penetration enhancer includes azone.

[0026] The second object of the present invention is to provide a Chinese medicine composition prepared by a method for preparing a Chinese medicine composition for improving cerebral ischemia.

[0027] Furthermore, the dosage form of the Chinese medicine composition is a patch.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention firstly starts from the perspective of invigorating qi, promoting blood circulation and removing blood stasis in traditional Chinese medicine for treating cerebral ischemia, and then combines the characteristics of oxidative damage of cerebral ischemia, takes ginseng as the main medicine, and astragalus as the ministerial medicine, and ginseng and astragalus have the effects of invigorating qi, enhancing immunity, anti-oxidation and promoting blood circulation; takes fructus aurantii, caulis spatholobi, poria cocos, rhizoma gastrodiae and rhizoma coptidis as adjuvants, and liquorice as the guiding medicine, and the adjuvants play the effects of enhancing blood circulation, promoting blood circulation and removing blood stasis, relaxing muscles and tendons, and promoting diuresis and anti-inflammation, and liquorice as the guiding medicine plays the effects of detoxifying and moistening the lungs, reconciling various medicines and enhancing drug efficacy, thereby increasing the curative effect on cerebral ischemia. After these Chinese medicines are prepared into mixed Chinese medicine powders, they are mixed with copper sulfide-polyacrylate glue liquid modified by copper sulfide on the surface and polyurethane pressure-sensitive adhesive, and heated, stirred and dispersed, and a drug-loaded composite pressure-sensitive adhesive containing active Chinese medicine components for treating cerebral ischemia is prepared. Copper sulfide is combined in the carboxyl-terminated polyacrylate glue by coordination, and then deposited by reaction with sodium sulfide to form copper sulfide-polyacrylate glue. Copper sulfide has a photoresponsive heating function, and can promote the permeability of the stratum corneum of the skin, microvascular dilation and increase blood flow by heating under infrared irradiation, so that the Chinese medicine ingredients can effectively penetrate the skin barrier into the body to exert therapeutic effects, and the use of penetration enhancers can also be reduced. However, it is found in the present invention that the deposition of copper sulfide weakens the adhesion properties of polyacrylate, so polyurethane pressure-sensitive adhesive is additionally introduced as a second phase adhesive to the drug-loaded composite pressure-sensitive adhesive to improve the adhesion properties of the prepared drug-loaded composite pressure-sensitive adhesive. The drug-loaded composite pressure-sensitive adhesive is finally coated on a polyethylene backing layer to form a Chinese medicine composition patch, which can not only avoid the first-pass effect of the liver, but also avoid drug absorption being affected by factors such as pH, food and transit time in the digestive tract, and can be flexibly administered, and patient compliance is good. DETAILED DESCRIPTION

[0030] The technical solution of the present invention will be clearly and completely described below through the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative work are within the scope of protection of the present invention.

[0031] Unless otherwise specified, the raw materials and reagents used in the present invention are commercially available or can be prepared by known methods.

[0032] Polyacrylate pressure-sensitive adhesive was purchased from Shandong Carformole Polymer Materials Co., Ltd. Jinan Branch;

[0033] Medical solvent-free polyurethane pressure-sensitive adhesive 602 and medical solvent-free polyurethane pressure-sensitive adhesive 501 were purchased from Guangzhou Haoyi New Materials Technology Co., Ltd.

[0034] Preparation Example 1:

[0035] The preparation of copper sulfide-polyacrylate glue specifically includes the following processes:

[0036] 200 g of polyacrylate pressure-sensitive adhesive CF-68, 5 g of acrylic acid, 0.1 g of polysorbate 80, 500 g of ethyl acetate and 100 g of deionized water were mixed and placed in a reactor and stirred until uniformly dispersed to obtain a mixed solution. 0.001 times the total weight of the mixed solution was added to the mixed solution, and nitrogen was introduced to remove oxygen in the reactor. The mixture was then heated to 70° C. and reacted for 1 h to obtain a carboxyl-terminated polyacrylate adhesive solution.

[0037] 1 part by weight of carboxyl-terminated polyacrylate glue and 0.01 part by weight of copper sulfate solution with a mass concentration of 10% are mixed and stirred at a stirring speed of 200-300 r / min, and then 0.02 part by weight of sodium sulfide solution with a mass concentration of 10% is added and the temperature is raised to 80°C for reaction for 30 minutes. After the reaction is completed, a large amount of deionized water is added, mixed and stirred, and the mixture is allowed to stand for stratification, and then the organic phase is collected by filtration. The organic phase is dialyzed with a dialysis bag with a molecular weight cutoff of 1000Da to obtain copper sulfide-polyacrylate glue.

[0038] Preparation Example 2:

[0039] The preparation of copper sulfide-polyacrylate glue specifically includes the following processes:

[0040] 250 g of polyacrylate pressure-sensitive adhesive CF-68, 7 g of acrylic acid, 0.15 g of polysorbate 80, 550 g of ethyl acetate and 150 g of deionized water were mixed and placed in a reactor and stirred until uniformly dispersed to obtain a mixed solution. 0.001 times the total weight of the mixed solution was added to the mixed solution, and nitrogen was introduced to remove oxygen in the reactor. The mixture was then heated to 75°C and reacted for 1.5 hours to obtain a carboxyl-terminated polyacrylate adhesive solution.

[0041] 1 part by weight of carboxyl-terminated polyacrylate glue and 0.015 parts by weight of copper sulfate solution with a mass concentration of 10% were mixed and stirred at a stirring speed of 250 r / min, and then 0.025 parts by weight of sodium sulfide solution with a mass concentration of 10% was added and the temperature was raised to 85°C for reaction for 35 minutes. After the reaction was completed, a large amount of deionized water was added, mixed and stirred, and the mixture was allowed to stand for stratification, and then the organic phase was collected by filtration. The organic phase was dialyzed with a dialysis bag with a molecular weight cutoff of 1000 Da to obtain copper sulfide-polyacrylate glue.

[0042] Preparation Example 3:

[0043] The preparation of copper sulfide-polyacrylate glue specifically includes the following processes:

[0044] 300 g of polyacrylate pressure-sensitive adhesive CF-68A, 10 g of acrylic acid, 0.2 g of Span 80, 600 g of ethyl acetate and 200 g of deionized water were mixed and placed in a reactor and stirred until uniformly dispersed to obtain a mixed solution. To the mixed solution, 0.002 times the weight of acrylic acid was added benzoyl peroxide, and nitrogen was introduced to remove oxygen in the reactor. The mixture was heated to 80°C and reacted for 2 hours to obtain a carboxyl-terminated polyacrylate adhesive solution.

[0045] 1 part by weight of carboxyl-terminated polyacrylate glue and 0.02 parts by weight of copper sulfate solution with a mass concentration of 10% were mixed and stirred at a stirring speed of 300 r / min, and then 0.03 parts by weight of sodium sulfide solution with a mass concentration of 10% was added and the temperature was raised to 90°C for reaction for 40 minutes. After the reaction was completed, a large amount of deionized water was added, mixed and stirred, and the mixture was allowed to stand for stratification, and then the organic phase was collected by filtration. The organic phase was dialyzed with a dialysis bag with a molecular weight cutoff of 1000Da to obtain copper sulfide-polyacrylate glue.

[0046] Preparation Example 4:

[0047] The preparation of copper sulfide-polyacrylate glue specifically includes the following processes:

[0048] The polyacrylate pressure-sensitive adhesive CF-68 in Preparation Example 2 was replaced with polyacrylate pressure-sensitive adhesive CF-62K, and the other conditions remained the same as in Preparation Example 2.

[0049] Preparation Example 5:

[0050] The preparation of copper sulfide-doped polyacrylate adhesive specifically includes the following steps:

[0051] 250 g of polyacrylate pressure-sensitive adhesive CF-68 and 0.25 g of commercially available copper sulfide powder particles were directly mixed, heated to 50° C. and stirred for 30 min to obtain a copper sulfide-doped polyacrylate adhesive solution.

[0052] Preparation Example 6:

[0053] The preparation of mixed Chinese medicine powder specifically includes the following processes:

[0054] Wash ginseng, astragalus, fructus aurantii, millet spatholobi, tuckahoe, gastrodia elata, coptis chinensis and licorice and dry them to constant weight. Weigh 90 parts by weight of ginseng, 30 parts by weight of astragalus, 5 parts by weight of fructus aurantii, 5 parts by weight of millet spatholobi, 3 parts by weight of tuckahoe, 3 parts by weight of gastrodia elata, 5 parts by weight of coptis chinensis and 3 parts by weight of licorice, cut them into small pieces with a slicer, mix them and put them into a grinder for grinding, and then sieve them with a 50-mesh sieve to obtain mixed particles. Mix the mixed particles with 10 times their own weight of deionized water, then heat to 100°C and boil for 80 minutes, then filter and separate to obtain a first filtrate and a first filter residue; mix the first filter residue with 8 times their own weight of deionized water, stir and heat to 100°C and boil for 50 minutes, then filter and separate to obtain a second filtrate and a second filter residue;

[0055] The first filter residue and the second filter residue are combined, and then added with an ethanol solution with a mass concentration of 75% and a volume of 10 times the total amount of the two, and the mixture is soaked for 2 hours, and then heated to 60° C. and refluxed for 3 hours to obtain a third filtrate;

[0056] The first filtrate, the second filtrate and the third filtrate obtained above are combined, concentrated by evaporation under reduced pressure to remove part of the solvent, and then dried by hot air at 70° C. to obtain a mixed Chinese medicine powder.

[0057] Preparation Example 7:

[0058] The preparation of mixed Chinese medicine powder specifically includes the following processes:

[0059] Wash ginseng, astragalus, fructus aurantii, millet spatholobi, tuckahoe, gastrodia, coptis and licorice and dry them to constant weight. Weigh 95 parts by weight of ginseng, 35 parts by weight of astragalus, 6 parts by weight of fructus aurantii, 8 parts by weight of millet spatholobi, 4 parts by weight of tuckahoe, 4 parts by weight of gastrodia, 7 parts by weight of coptis and 4 parts by weight of licorice, cut them into small pieces with a slicer, mix them and put them into a grinder for grinding, and then sieve them with a 50-mesh sieve to obtain mixed particles. Mix the mixed particles with 10 times their own weight of deionized water, then heat to 100°C and boil for 85 minutes, then filter and separate to obtain a first filtrate and a first filter residue; mix the first filter residue with 8 times their own weight of deionized water, stir and heat to 100°C and boil for 55 minutes, then filter and separate to obtain a second filtrate and a second filter residue;

[0060] The first filter residue and the second filter residue are combined, and then added with an ethanol solution with a mass concentration of 75% and a volume of 10 times the total amount of the two, and the mixture is soaked for 2 hours, and then heated to 60° C. and refluxed for 3 hours to obtain a third filtrate;

[0061] The first filtrate, the second filtrate and the third filtrate obtained above are combined, concentrated by evaporation under reduced pressure to remove part of the solvent, and then dried by hot air at 70° C. to obtain a mixed Chinese medicine powder.

[0062] Preparation Example 8:

[0063] The preparation of mixed Chinese medicine powder specifically includes the following processes:

[0064] Wash ginseng, astragalus, fructus aurantii, millet blood vine, tuckahoe, gastrodia elata, coptis chinensis and licorice and dry them to constant weight. Weigh 100 parts by weight of ginseng, 40 parts by weight of astragalus, 7 parts by weight of fructus aurantii, 10 parts by weight of millet blood vine, 5 parts by weight of tuckahoe, 5 parts by weight of gastrodia elata, 8 parts by weight of coptis chinensis and 5 parts by weight of licorice, cut them into small pieces with a slicer, mix them and put them into a grinder for grinding, and then sieve them with a 50-mesh sieve to obtain mixed particles. Mix and stir the mixed particles with 10 times their own weight of deionized water, then heat to 100°C and boil for 90 minutes, then filter and separate to obtain a first filtrate and a first filter residue; mix and stir the first filter residue with 8 times their own weight of deionized water, heat to 100°C and boil for 60 minutes, then filter and separate to obtain a second filtrate and a second filter residue;

[0065] The first filter residue and the second filter residue are combined, and then added with an ethanol solution with a mass concentration of 75% and a volume of 10 times the total amount of the two, and the mixture is soaked for 2 hours, and then heated to 60° C. and refluxed for 3 hours to obtain a third filtrate;

[0066] The first filtrate, the second filtrate and the third filtrate obtained above are combined, concentrated by evaporation under reduced pressure to remove part of the solvent, and then dried by hot air at 70° C. to obtain a mixed Chinese medicine powder.

[0067] Preparation Example 9:

[0068] The preparation of mixed Chinese medicine powder specifically includes the following processes:

[0069] The 95 parts by weight of ginseng and 35 parts by weight of astragalus in Preparation Example 7 were further increased to 100 parts by weight of ginseng and 40 parts by weight of astragalus, and the other conditions remained the same as in Preparation Example 7.

[0070] Preparation Example 10:

[0071] The preparation of mixed Chinese medicine solution specifically includes the following processes:

[0072] Ginseng, astragalus, fructus aurantii, millet blood vine, Yun Fuling, gastrodia elata, coptis chinensis and licorice were cleaned and dried to constant weight. 100 parts by weight of ginseng, 40 parts by weight of astragalus, 7 parts by weight of fructus aurantii, 10 parts by weight of millet blood vine, 5 parts by weight of Yun Fuling, 5 parts by weight of gastrodia elata, 8 parts by weight of coptis chinensis and 5 parts by weight of licorice were weighed and cut into small pieces with a slicer, mixed and put into a grinder for crushing, and then screened with a 50-mesh screen to obtain mixed particles. The mixed particles were mixed and stirred with deionized water 10 times their own weight, and then heated to 100°C and boiled for 90 minutes, and then filtered and separated to obtain a first filtrate and a first filter residue; the first filter residue was mixed and stirred with deionized water 8 times its own weight, heated to 100°C and boiled for 60 minutes, and then filtered and separated to obtain a second filtrate and a second filter residue; the first filtrate and the second filtrate obtained above were combined to obtain a mixed Chinese medicine liquid.

[0073] Embodiment 1:

[0074] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0075] 10 parts by weight of medical solvent-free polyurethane pressure-sensitive adhesive 602, 40 parts by weight of copper sulfide-polyacrylate glue obtained in Preparation Example 1, 20 parts by weight of mixed Chinese medicine powder obtained in Preparation Example 6, 30 parts by weight of ethyl acetate and 0.3 parts by weight of azone are mixed and heated to 50°C, and stirred at a speed of 400 r / min until uniformly dispersed, and then allowed to stand for 1 hour to remove bubbles to obtain a drug-loaded composite pressure-sensitive adhesive. The drug-loaded composite pressure-sensitive adhesive is evenly coated on the surface of the polyethylene backing layer, and then placed in an oven at 80°C for evaporation and curing to remove ethyl acetate to obtain a Chinese medicine composition in the form of a patch.

[0076] Embodiment 2:

[0077] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0078] 15 parts by weight of medical solvent-free polyurethane pressure-sensitive adhesive 602, 45 parts by weight of copper sulfide-polyacrylate glue obtained in Preparation Example 2, 25 parts by weight of mixed Chinese medicine powder obtained in Preparation Example 7, 35 parts by weight of ethyl acetate and 0.5 parts by weight of azone were mixed and heated to 55°C, and stirred at a speed of 450 r / min until uniformly dispersed, and then allowed to stand for 1.5 hours to remove bubbles to obtain a drug-loaded composite pressure-sensitive adhesive. The drug-loaded composite pressure-sensitive adhesive was evenly coated on the surface of the polyethylene backing layer, and then placed in an oven at 80°C for evaporation and curing to remove ethyl acetate to obtain a Chinese medicine composition in the form of a patch.

[0079] Embodiment 3:

[0080] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0081] 20 parts by weight of medical solvent-free polyurethane pressure-sensitive adhesive 602, 50 parts by weight of copper sulfide-polyacrylate glue obtained in Preparation Example 3, 30 parts by weight of mixed Chinese medicine powder obtained in Preparation Example 8, 40 parts by weight of ethyl acetate and 0.6 parts by weight of azone are mixed and heated to 60°C, and stirred at a speed of 500 r / min until uniformly dispersed, and then allowed to stand for 2 hours to remove bubbles to obtain a drug-loaded composite pressure-sensitive adhesive. The drug-loaded composite pressure-sensitive adhesive is evenly coated on the surface of the polyethylene backing layer, and then placed in an oven at 80°C for evaporation and curing to remove ethyl acetate to obtain a Chinese medicine composition in the form of a patch.

[0082] Comparative Example 1:

[0083] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0084] 60 parts by weight of medical solvent-free polyurethane pressure-sensitive adhesive 602, 25 parts by weight of mixed Chinese medicine powder obtained in Preparation Example 7, 35 parts by weight of ethyl acetate and 0.5 parts by weight of azone were mixed and heated to 55°C, and stirred at a speed of 450 r / min until uniformly dispersed, and then allowed to stand for 1.5 hours to remove bubbles to obtain a drug-loaded composite pressure-sensitive adhesive. The drug-loaded composite pressure-sensitive adhesive was evenly coated on the surface of the polyethylene backing layer, and then placed in an oven at 80°C for evaporation and curing to remove ethyl acetate to obtain a Chinese medicine composition in the form of a patch.

[0085] Comparative Example 2:

[0086] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0087] 60 parts by weight of medical solvent-free polyurethane pressure-sensitive adhesive 602, 25 parts by weight of mixed Chinese medicine powder obtained in Preparation Example 7, 35 parts by weight of ethyl acetate and 3 parts by weight of azone were mixed and heated to 55°C, and stirred at a speed of 500 r / min until uniformly dispersed, and then allowed to stand for 2 hours to remove bubbles to obtain a drug-loaded composite pressure-sensitive adhesive. The drug-loaded composite pressure-sensitive adhesive was evenly coated on the surface of the polyethylene backing layer, and then placed in an oven at 80°C for evaporation and curing to remove ethyl acetate to obtain a Chinese medicine composition in the form of a patch.

[0088] Comparative Example 3:

[0089] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0090] The medical solvent-free polyurethane pressure-sensitive adhesive 602 in Example 2 was replaced with the medical solvent-free polyurethane pressure-sensitive adhesive 501. It was found that during the preparation process, the medical solvent-free polyurethane pressure-sensitive adhesive 501 had a high viscosity and could not be mixed and stirred in this system, resulting in a failed preparation.

[0091] Comparative Example 4:

[0092] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0093] The copper sulfide-polyacrylate adhesive in Example 2 was replaced by the copper sulfide-polyacrylate adhesive prepared in Preparation Example 4, and the other conditions remained the same as in Example 2.

[0094] Comparative Example 5:

[0095] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0096] The copper sulfide-polyacrylate adhesive in Example 2 was replaced by the copper sulfide-doped polyacrylate adhesive prepared in Preparation Example 5, and the other conditions remained the same as in Example 2.

[0097] Comparative Example 6:

[0098] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0099] The medical solvent-free polyurethane pressure-sensitive adhesive 602 in Example 2 was removed and not added, and the other conditions remained the same as in Example 2.

[0100] Comparative Example 7:

[0101] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0102] The mixed Chinese medicine powder in Example 2 was replaced by the mixed Chinese medicine powder prepared in Preparation Example 9, and the other conditions remained the same as in Example 2.

[0103] Comparative Example 8:

[0104] A method for preparing a Chinese medicine composition for improving cerebral ischemia, specifically comprising the following steps:

[0105] The mixed Chinese medicinal liquid prepared in Preparation Example 10 was directly used as a Chinese medicinal composition for improving cerebral ischemia.

[0106] 1. Testing the adhesion properties of the Chinese medicine compositions in the form of patches prepared in Examples 1 to 3 and Comparative Examples 1 to 7 (except Comparative Example 3):

[0107] Adhesion test:

[0108] One end of the Chinese medicine composition was pasted on a stainless steel plate to obtain a sample, and then the sample was hung on an adhesion tester. A weight of 1 kg was hung at the lower end of the sample. When the sample tape was completely peeled off, it was removed and the time from hanging to removal was recorded. The results are shown in Table 1 below.

[0109] Table 1 Adhesion performance test results

[0110]

[0111]

[0112] The following conclusions can be drawn from the test results in Table 1:

[0113] (1) It can be found from Examples 1 to 3 that the present invention combines with the terminal carboxyl polyacrylate glue through the coordination effect of sulfide ions and then deposits to form copper sulfide-polyacrylate glue, which is then coordinated with the medical solvent-free polyurethane pressure-sensitive adhesive 602 to achieve good adhesion performance, which is beneficial to the continuous treatment of the patch.

[0114] (2) It can be found from Comparative Example 4 that compared with the polyacrylate pressure-sensitive adhesives CF-68 and CF-68A, the polyacrylate pressure-sensitive adhesive CF-62K is too viscous and has extremely poor fluidity. The copper sulfate solution cannot effectively infiltrate into the interior of the polyacrylate pressure-sensitive adhesive CF-62K. The amount of deposited copper sulfide is small and unevenly distributed. As a result, even if the polyurethane pressure-sensitive adhesive is added to the system, it is difficult to mix due to poor fluidity. The Chinese medicine composition patch finally prepared has poor adhesion performance and is easy to fall off, which is not conducive to treatment.

[0115] (3) It can be found from Comparative Example 5 that although directly doping copper sulfide powder particles can achieve physical mixing with polyacrylate pressure-sensitive adhesive to achieve photothermal performance, due to the agglomeration of copper sulfide powder particles, physical mixing alone can easily cause agglomeration of copper sulfide powder particles, resulting in uneven distribution. The adhesion performance of the Chinese medicine composition patch finally prepared is poor, easy to fall off, and is not conducive to treatment.

[0116] (4) Comparative Example 6 shows that since copper sulfide particles are introduced into polyacrylate by chemical deposition, the adhesion performance of polyacrylate may be reduced. Therefore, if no second phase adhesive is added in this system, the prepared Chinese medicine composition patch is difficult to effectively adhere to the skin surface and is easy to fall off, which is not conducive to treatment.

[0117] 2. Verify the therapeutic effects of the Chinese medicine compositions prepared in Examples 1 to 3 and Comparative Examples 1 to 8 (except Comparative Example 3):

[0118] (1) Establishment of animal model:

[0119] Healthy male SD rats were taken and adapted to be raised in an environment with a temperature of 23±1℃ and a humidity of 65±1% for two weeks, and then the weight of all rats was weighed and recorded. One rat was randomly selected as a blank control group for conventional feeding, and the remaining rats were treated with the "four-vessel occlusion method" for cerebral ischemia modeling. After treatment, according to the cerebral ischemia evaluation criteria of animal loss of consciousness, darkening of eyeballs, disappearance of righting reflex, erection of hair, and accelerated spontaneous breathing within 1 minute after bilateral carotid artery clamping, 10 rats with successful cerebral ischemia modeling were retained for the next step of treatment.

[0120] (2) Efficacy verification:

[0121] The neck hair of 10 rats with successful cerebral ischemia model was removed and numbered from 1 to 10. The Chinese medicine composition patches of Examples 1 to 3 and Comparative Examples 1 to 7 (except Comparative Example 3) were applied to the necks of the rats with the removed hair, and then the patches were heated with a power of 0.5 W / cm 2, infrared light with a wavelength of 1064nm was used to irradiate the patch area, and the patch area was 1cm×1cm, and one patch was applied every day for 5 consecutive days; the Chinese medicine composition prepared by comparative example 8 was administered by gavage (2.5ml was administered each time, once in the morning and evening, for 5 days). After the 5th day, the neurological deficit of rats was observed by Zea Longa scoring (0 points: no neurological deficit symptoms; 1 point: the contralateral front paw could not be fully extended; 2 points: the body circled to the opposite side of the lesion when crawling; 3 points: the body fell to the opposite side of the lesion when crawling; 4 points: could not walk spontaneously or lost consciousness), and the redness, swelling and peeling of the skin in the patch area were recorded, and the results are shown in Table 2 below.

[0122] Table 2 Neurological deficit scores

[0123]

[0124]

[0125] After the neurological deficit scoring was completed, all rats were anesthetized and killed, the brains were cut and placed in -20℃ for 15min, and then slices with a thickness of 2.5mm were prepared. The slices were placed in a 2% TTC (2,3,5-triphenyltetrazolium chloride) dye solution, stained in a 37℃ water bath in the dark for 15min, and then moved to 4% paraformaldehyde and soaked for 30min. The surface liquid of the brain slices was gently blotted with filter paper and photographed. The cerebral infarction area of ​​the rats was measured by Image-pro plus image analysis software, and the percentage of infarction area was calculated. The results are shown in Table 3 below.

[0126] Table 3 Percentage of cerebral infarction area

[0127]

[0128]

[0129] The following conclusions can be drawn from the test results in Tables 2 and 3:

[0130] (1) Through Examples 1 to 3, it can be found that the present invention uses ginseng as the main drug, astragalus as the ministerial drug, fructus aurantii, millet spatholobi, poria cocos, gastrodia elata and coptis chinensis as adjuvants, and licorice as the guiding drug, which can not only enhance qi and blood, improve microcirculation, protect neurons, reduce the consequences of ischemia, but also reconcile the medicinal properties of each drug and exert a synergistic effect. Then it is prepared into a Chinese medicine composition patch with photothermal penetration, which achieves the treatment of cerebral ischemia.

[0131] (2) Comparative Example 1 shows that the photothermal penetration-promoting effect of the copper sulfide-polyacrylate glue is lacking, and the amount of penetration-promoting agent azone used in this system may be difficult to effectively allow the drug to penetrate the skin and enter the body to exert its effect.

[0132] (3) It can be found from Comparative Example 2 that further increasing the dosage of azone can increase the drug penetration into the skin to exert its therapeutic effect, but the high dose of azone produces a greater irritation to the skin, and the skin at the pasting site has the adverse effects of redness, swelling and peeling, and the use effect is poor.

[0133] (4) Comparative Example 4 shows that the use of overly viscous polyacrylate pressure-sensitive adhesive CF-62K has extremely poor fluidity, which not only affects the deposition of copper sulfide, but is also not conducive to mixing with the polyurethane pressure-sensitive adhesive, resulting in a short adhesion time and poor efficacy.

[0134] (5) It can be found from Comparative Example 5 that although physically doped copper sulfide powder particles can achieve photothermal performance, the copper sulfide powder particles are easy to agglomerate, which leads to a short adhesion time and poor therapeutic effect.

[0135] (6) Comparative Example 6 shows that without the additional introduction of polyurethane pressure-sensitive adhesive for mixing and viscosity enhancement, the prepared traditional Chinese medicine composition has a short adhesion time and poor therapeutic effect.

[0136] (7) It can be found from Comparative Example 7 that although ginseng and astragalus have the effects of replenishing qi, enhancing immunity, anti-oxidation and promoting blood circulation, in this system, if the dosage of the two is simply increased, the synergistic therapeutic effect of the overall Chinese medicine formula will be weakened.

[0137] (8) Comparative Example 8 shows that, due to the strong effects of ginseng and astragalus on invigorating qi, enhancing immunity, anti-oxidation and promoting blood circulation, the therapeutic effect was weakened after oral administration of the solution dosage form in the present system, and the neurological deficits of the rats were more serious, indicating that the mixed Chinese medicine liquid obtained by the present system as an oral solution dosage form has a poor therapeutic effect on cerebral ischemia, and has special requirements for the drug dosage form.

[0138] 3. Warming effect of different infrared irradiation:

[0139] In an environment with a temperature of 24±1°C, the Chinese medicine composition in the form of a patch prepared in Example 2 was irradiated with infrared light with a wavelength of 1064 nm for 20 min, and the infrared light at different powers (0 W / cm 2 , 0.5W / cm 2 , 1W / cm 2 and 2W / cm 2 ) heating temperature, the results are shown in Table 4 below.

[0140] Table 4 Heating temperature under different infrared light powers

[0141] <![CDATA[Infrared light power (W / cm 2 )]]> 0 0.5 1 2 Heating temperature(℃) 24.2 43.5 57.8 69.3

[0142] It can be found from Table 4 that the power of infrared light irradiation has a significant effect on the photothermal heating phenomenon under the dosage of the present invention. When the power of infrared light irradiation is increased, although the temperature can be further increased, for the Chinese medicine composition patch prepared by the present invention, since it is used on the skin surface, high temperature can easily cause burns to the skin, so it is necessary to strictly control the power of infrared light irradiation.

[0143] The above-described embodiments provide a detailed description of the technical solutions and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the present invention. Without departing from the spirit and scope of the present invention, the present invention may have various changes and improvements, which fall within the scope of the present invention to be protected.

Claims

1. A method for preparing a Chinese medicine composition for improving cerebral ischemia, characterized in that: The preparation method comprises the following steps: The polyurethane pressure-sensitive adhesive, the copper sulfide-polyacrylate adhesive solution, the mixed Chinese medicine powder, the ethyl acetate and the penetration enhancer are mixed in a weight ratio of 10-20:40-50:20-30:30-40:0.3-0.6, heated to 50-60° C., stirred and dispersed, and after standing treatment, a drug-loaded composite pressure-sensitive adhesive is obtained; The drug-loaded composite pressure-sensitive adhesive is coated on a polyethylene backing layer, and then dried, evaporated and solidified to obtain the traditional Chinese medicine composition.

2. A method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 1, characterized in that: The polyurethane pressure-sensitive adhesive is medical solvent-free polyurethane pressure-sensitive adhesive 602.

3. A method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 1, characterized in that: The preparation method of the copper sulfide-polyacrylate glue comprises the following steps: Polyacrylate pressure-sensitive adhesive, acrylic acid, emulsifier, ethyl acetate and deionized water are mixed and dispersed in a mass ratio of 200-300:5-10:0.1-0.2:500-600:100-200 to obtain a mixed solution, and the mixed solution and an initiator are mixed and heated to 70° C.-80° C. and reacted for 1 h-2 h to obtain a carboxyl-terminated polyacrylate adhesive solution; The carboxyl-terminated polyacrylate glue and copper sulfate solution are mixed, and then sodium sulfide solution is added and the temperature is raised to 80° C. to 90° C. for reaction for 30 min to 40 min, and then the copper sulfide-polyacrylate glue is obtained by filtering and dialysis.

4. A method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 3, characterized in that: The polyacrylate pressure-sensitive adhesive is polyacrylate pressure-sensitive adhesive CF-68 or polyacrylate pressure-sensitive adhesive CF-68A.

5. The method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 3, characterized in that: The weight ratio of the mixed solution to the initiator is 1:0.001-0.

002.

6. The method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 3, characterized in that: The mass concentration of the copper sulfate solution is 10%, and the mass concentration of the sodium sulfate solution is 10%.

7. The method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 3, characterized in that: The weight ratio of the carboxyl-terminated polyacrylate glue solution: the copper sulfate solution: the sodium sulfide solution is 1: 0.01-0.02: 0.02-0.

03.

8. The method for preparing a Chinese medicine composition for improving cerebral ischemia according to claim 1, characterized in that: The preparation method of the mixed Chinese medicine powder comprises the following steps: 90-100 parts by weight of ginseng, 30-40 parts by weight of astragalus, 5-7 parts by weight of fructus aurantii, 5-10 parts by weight of millet spatholobi, 3-5 parts by weight of poria cocos, 3-5 parts by weight of gastrodia elata, 5-8 parts by weight of coptis chinensis and 3-5 parts by weight of liquorice are mixed and crushed through a 50-mesh sieve to obtain mixed particles, 10 times the weight of deionized water is added to the mixed particles, the mixed particles are heated to 100° C., boiled for 80-90 minutes, and then filtered to separate to obtain a first filtrate and a first filter residue; Deionized water 8 times its weight is added to the first filter residue, heated to 100° C. and boiled for 50 to 60 minutes, and then filtered and separated to obtain a second filtrate and a second filter residue; The first filter residue and the second filter residue are combined, and then added with 10 times the amount of 75% ethanol solution, and soaked for 2 hours, and then heated to 60° C. and refluxed for 3 hours to obtain a third filtrate; The first filtrate, the second filtrate and the third filtrate are combined, evaporated under reduced pressure and dried with hot air in sequence to obtain the mixed Chinese medicine powder.

9. A Chinese medicine composition prepared by the method for preparing a Chinese medicine composition for improving cerebral ischemia according to any one of claims 1 to 8.

10. The Chinese medicine composition according to claim 9, characterized in that: The dosage form of the Chinese medicine composition is a patch.

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