A pharmaceutical composition comprising honokiol and borneol and use thereof

Abstract

The application discloses a kind of comprising and thick magnolia bark extract and borneol pharmaceutical composition and application thereof.The weight ratio of and thick magnolia bark extract and borneol in the pharmaceutical composition provided by the application is 1:0.1-10, and the pharmaceutical composition is made into oral preparation and injection with pharmaceutically acceptable adjuvant.The pharmaceutical composition of the application has synergistic effect when treating cerebrovascular disease, especially ischemic cerebrovascular disease, can significantly increase the therapeutic effect of and thick magnolia bark extract, reduce the onset dose of and thick magnolia bark extract, reduce its dosage, improve curative effect and reduce the occurrence of adverse reactions.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition comprising magnolol and borneol, and its use in the preparation of a medicament for treating cerebrovascular diseases. Background Technology

[0002] Cerebrovascular disease is a general term for brain diseases caused by impaired blood supply to the brain, including cerebral arteriosclerosis, thrombosis, stenosis, occlusion, cerebral arteritis, cerebral artery injury, cerebral aneurysm, intracranial vascular malformation, and cerebral arteriovenous fistula. Its pathological change involves the sudden rupture or occlusion of cerebral blood vessels, resulting in functional impairment of the brain tissue innervated by that vessel. Cerebrovascular disease is characterized by "five highs": high incidence, high recurrence rate, high disability rate, high mortality rate, and high economic burden, making it one of the major diseases threatening the health of the Chinese population. Statistics show that there are over 12.4 million people aged 40 and above with stroke in my country. On average, one person experiences a first-time or recurrent stroke every 10 seconds, and one person dies from stroke every 28 seconds. Among survivors, approximately 75% suffer from sequelae, and 40% experience severe disability, causing enormous economic losses and physical and mental suffering for patients and their families. Therefore, the future prospects of cerebrovascular disease in my country are extremely grim, and cerebrovascular disease has become a hot topic in medical research.

[0003] Cerebrovascular diseases can be divided into ischemic cerebrovascular diseases and hemorrhagic cerebrovascular diseases. Ischemic cerebrovascular disease (ICVD) mainly includes cerebral infarction (including cerebral thrombosis and cerebral embolism) and transient ischemic attacks (TIAs); hemorrhagic cerebrovascular diseases include cerebral hemorrhage or cerebral hemorrhage, as well as subarachnoid hemorrhage. The incidence of ischemic cerebrovascular disease is higher than that of hemorrhagic cerebrovascular disease, accounting for more than 70% of all cerebrovascular diseases, and it is showing a continuous increasing trend, while the incidence of hemorrhagic cerebrovascular disease is showing a decreasing trend year by year.

[0004] Brain cells have a high demand for energy, nutrients, and oxygen. Once ischemia and hypoxia occur in the brain, metabolic disorders will occur rapidly, leading to cell damage. If the blood supply to the brain is impaired for a certain period, it will result in cerebral infarction. Pathological studies show that an ischemic penumbra typically forms around the lesion of a cerebral infarction, containing a large number of brain cells that are only able to maintain their morphology and are in a dormant or semi-dormant state. The ischemic penumbra generally exists for about 6-24 hours. Within this time, timely restoration of blood flow to the ischemic area can prevent further necrosis of the ischemic tissue and save the damaged tissue. If this time is exceeded or the blood supply condition worsens, and the degree of ischemia further increases, the integrity of the cell membrane will be damaged, and nerve cells will die, causing irreversible damage. In recent years, with the widespread clinical application of interventional techniques and thrombolysis, ischemic tissues and organs have received timely blood supply. However, clinical and animal experiments have also revealed that the damage and functional impairment in ischemic brain regions are not alleviated by the restoration of blood supply; in fact, clinical symptoms may worsen. This phenomenon is known as cerebral ischemia-reperfusion injury (CIRI), and in severe cases, it can even lead to cerebral edema and hemorrhage. The pathogenesis of CIRI is highly complex, involving numerous factors such as free radical damage, hypoxia and energy metabolism failure, inflammatory damage, calcium overload, and excitatory amino acid toxicity, ultimately resulting in neuronal necrosis and loss of functional symptoms.

[0005] Therefore, ischemic cerebrovascular disease is caused by a transient or persistent decrease in blood flow in the main arteries of the brain. Its pathological process involves complex temporal and spatial cascade reactions, and the treatment of this disease cannot be done with a single model, which remains a major challenge in clinical practice.

[0006] Honokiol is an active ingredient isolated from the dried bark, root bark, and branch bark of Magnolia officinalis Rehd. et Wils. or Magnolia offinalis Rehd. et Wils. var. biloba Rehd. et Wils., belonging to the Magnoliaceae family. It can also be synthesized chemically. Its molecular formula is: C 18 H 18 O2, with a molecular weight of 266.3343, has the following structural formula:

[0007]

[0008] Honokiol is a multi-target drug for ischemic cerebrovascular diseases, exhibiting the ability to inhibit oxygen free radicals and enhance the activity of antioxidant enzymes. For example, it significantly and dose-dependently reduces malondialdehyde (MDA) levels in ischemic / reperfused brain tissue and increases the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and peroxidase (POD) in ischemic / reperfused brain tissue. It also significantly increases sodium levels in ischemic / reperfused brain tissue. + -K + -ATPase activity (P<0.05). It exhibits significant antithrombotic activity; for example, honokiol significantly reduces endothelial cell apoptosis by inhibiting caspase-3 activity, maintaining endothelial cell integrity and releasing antithrombotic active substances. It exerts its antithrombotic effect by upregulating endothelial cell PGIS protein expression, increasing PGI2 production and release. It also shows significant neuroprotective effects; for example, honokiol reduces neurotoxic NO and H2S production in ischemia-reperfusion tissue cells, inhibits the opening of mPTP in brain tissue, and reduces PARP-1 activity, thus alleviating neuronal damage. Furthermore, it demonstrates significant anti-inflammatory activity; for example, honokiol inhibits the release of inflammatory factors from activated glial cells in brain tissue during ischemia-reperfusion, suppressing the inflammatory response and reducing cerebral edema. Animal pharmacodynamic studies have shown that magnolol has a strong anti-cerebral ischemia effect: it significantly improves microcirculation and blood flow in the ischemic brain area, increases the number of capillaries in the ischemic area; reduces cerebral edema and shrinks the infarct area of ​​local cerebral ischemia in rats; improves brain energy metabolism and inhibits nerve cell apoptosis; and inhibits thrombus formation, etc.

[0009] Borneol, including natural borneol (dextral borneol) and synthetic borneol, is a commonly used traditional Chinese medicine. The 2020 edition of the Pharmacopoeia of the People's Republic of China includes both natural borneol (dextral borneol) and synthetic borneol. Natural borneol (dextral borneol) is extracted and processed from the fresh branches and leaves of the camphor tree (Cinnamomum camphora (h.) Presl), a plant of the Lauraceae family. Its main component is dextrorotatory borneol [(+)-boreol, (+)-2-camphor, CAS: 464-43-7], with a content of not less than 96%. Synthetic borneol is a refined product chemically synthesized from turpentine oil or camphor. It is a racemic mixture of dextrorotatory borneol [(+)-boreol] and levorotatory borneol [(-)-boreol], with a borneol content of not less than 55%. The structures of dextrorotatory borneol [(+)-boreol, (+)-2-camphor] and levorotatory borneol ((-)-boreol, (-)-2-camphor, CAS: 464-45-9) are as follows:

[0010]

[0011] Borneol has a pungent and bitter taste, is slightly cold in nature, and enters the heart, spleen, and lung meridians. It has the functions of opening the orifices and waking the mind, clearing heat and relieving pain. It is used for febrile delirium, convulsions, stroke with phlegm syncope, sudden syncope due to qi stagnation, coma due to sudden illness, chest pain, red eyes, mouth sores, sore throat, and ear discharge. Modern pharmacological studies have shown that borneol (natural borneol) promotes the opening of the blood-brain barrier, helping other drugs to cross the blood-brain barrier and exert their effects. It is often combined with other drugs to significantly prolong the retention time of effective drugs. Borneol (natural borneol) can effectively reduce the number of errors in the step-down response after cerebral ischemia-reperfusion injury in mice, enhance the memory ability of mice, significantly reduce the neurological behavioral scores of mice with middle cerebral artery embolism, and reduce the area of ​​cerebral infarction. Dextrorotatory borneol can significantly improve neurological deficits in rats with permanent middle cerebral artery embolism, improve pathological damage from cerebral ischemia, promote angiogenesis and neurogenesis coupling through the Ang1-VEGF-BDNF pathway, exert neuroprotective effects, reduce inflammatory responses in cardiovascular and cerebrovascular system injuries, improve ischemia-reperfusion injury, prevent cardiovascular diseases, reduce cerebral infarction, significantly reduce cerebral edema rate in model rats, and protect damaged nerves.

[0012] The 2020 edition of the Chinese Pharmacopoeia includes natural borneol (dextral borneol) and borneol (synthetic borneol), with natural borneol (dextral borneol) being the most effective and synthetic borneol being less effective. Summary of the Invention

[0013] The purpose of this invention is to provide a pharmaceutical composition comprising magnolol and borneol, which, when used in combination, has a synergistic effect and can improve the efficacy of treating cerebrovascular diseases, especially ischemic cerebrovascular diseases.

[0014] The magnolol mentioned includes an active ingredient isolated from the dried bark, root bark, and branch bark of Magnolia officinalis Rehd. et Wils. or Magnolia offinalis Rehd. et Wils. var. biloba Rehd. et Wils., belonging to the Magnoliaceae family, or obtained by chemical synthesis. Preferably, it is a natural magnolol with a purity of ≥90%, more preferably a natural magnolol with a purity of ≥99.0%.

[0015] The borneol is natural borneol (dextral borneol) or borneol (synthetic borneol), preferably natural borneol and dextral borneol ((+)-2-borneol) with a purity ≥96%, more preferably natural borneol and (+)-2-borneol with a purity ≥98%.

[0016] In the pharmaceutical composition, magnolol and borneol can be present in any suitable ratio. Considering factors such as therapeutic efficacy, safety, and cost, the weight ratio of magnolol to borneol is 100.0–1.0:1.0–100.0, preferably 20.0–1.0:1.0–20.0, more preferably 10.0–1.0:1.0–10.0, and most preferably 5.0–1.0:1.0–5.0.

[0017] The pharmaceutical compositions described above may also contain pharmaceutically acceptable excipients. The applicable excipients depend on the dosage form being formulated.

[0018] Since both magnolol and borneol are fat-soluble substances, studies have shown that magnolol is poorly absorbed orally, with an absorption rate of less than 10%. Therefore, to improve the oral absorption rate of magnolol, the above-mentioned drug composition can be prepared into solid dispersions, cyclodextrin inclusion complexes, self-emulsifying microemulsions, liposomes, etc., with cyclodextrin inclusion complexes, self-emulsifying microemulsions, and liposomes being preferred. Dosage forms include oral preparations and injections.

[0019] The carrier materials of the solid dispersion include, but are not limited to, polyvinylpyrrolidone, poloxamer 188 copolyvinylpyrrolidone, polyethylene glycol, cellulose derivatives (methylcellulose, ethylcellulose, hydroxypropylcellulose), hydroxypropyl methylcellulose, β-cyclodextrin (β-CD) derivatives, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polypropylene resin, modified starch, microcrystalline cellulose, starch, micronized silica gel, surfactants, cholesterol, sitosterol, glyceryl palmitate, cholesterol stearate, organic acids, sugars, urea, and alcohols.

[0020] The cyclodextrin inclusion complex system is selected from water-soluble cyclodextrins; the cyclodextrin is at least one selected from α-cyclodextrin and its derivatives, β-cyclodextrin and its derivatives, and γ-cyclodextrin and its derivatives; preferably β-cyclodextrin and its derivatives, including but not limited to hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin, more preferably hydroxypropyl-β-cyclodextrin. The formulation includes, but is not limited to, oral delivery systems, oral, nasal, pulmonary, and rectal delivery systems, ocular delivery systems, injections, and transdermal formulations. Injections and oral delivery systems are preferred.

[0021] The self-emulsifying microemulsion drug delivery system comprises an oil phase, surfactants, cosolvents, antioxidants, etc. The oil phase includes, but is not limited to, peanut oil, sesame oil, corn oil, soybean oil, almond oil, peach kernel oil, cottonseed oil, sunflower seed oil, olive oil, ethyl oleate, medium-chain triglycerides, oleic acid, isopropyl myristate, and coconut oil triglycerides, preferably soybean oil and medium-chain triglycerides. The emulsifiers include lecithin, soybean lecithin, polysorbates, sorbitan derivatives, poloxamer, glyceryl monostearate, and tristearate. The formulation includes, but is not limited to, glyceryl esters, sucrose stearate, benzyl esters, and methyl esters, with lecithin and soybean lecithin being preferred; cosolvents include, but are not limited to, ethanol, propylene glycol, glycerol, and polyethylene glycol compounds, with propylene glycol and polyethylene glycol 400 being preferred; antioxidants include, but are not limited to, sulfites, sodium metabisulfite, thiourea, thioglycerol, ascorbic acid, cysteine, α-tocopherol, butylated hydroxyanisole, dibutylcresol, tartaric acid, citric acid, preferably dibutylhydroxytoluene, and vitamin C, with vitamin C being the most preferred. The formulation includes, but is not limited to, oral delivery systems and injections. Injections and oral delivery systems are preferred.

[0022] The liposome delivery system comprises phospholipids, cholesterol, and additives. The phospholipids are natural or synthetic. The natural phospholipids are one or a mixture of soybean phospholipids and egg yolk lecithin. The synthetic phospholipids are any one or a combination of at least two of hydrogenated soybean phospholipids, hydrogenated lecithin, dipalmitoylphosphatidylcholine, phosphatidylethanolamine, lipid phosphatidic acid, phosphatidylinositol, hydrogenated phosphatidylcholine, dimyristoylphosphatidylcholine, distearyl phosphatidylcholine, dioleoylphosphatidylcholine, dioleoylphosphatidylethanolamine, or lecithin. The additives comprise emulsifiers, co-emulsifiers, and stabilizers. The emulsifiers are one or more of polyglycerol 10 stearate, PEG-8 caprylic / capric glyceride, sucrose stearate, polyoxyethylene hydrogenated castor oil, PEG 40 hydrogenated castor oil, Tween-80, and Tween-20. The co-emulsifiers are one or more of glycerol, 1,3-propylene glycol, butylene glycol lauryl ether-23, PPG-26-butanol polyether-26, tridecyl alcohol polyether-12, and hexyldecyl alcohol. The stabilizers are one or more of vitamin E and vitamin C.

[0023] Another object of the present invention is to provide the use of the above-described pharmaceutical composition in the preparation of a medicament for treating cerebrovascular diseases. Certain specific embodiments relate to the use of the above-described pharmaceutical composition in the preparation of a medicament for treating ischemic cerebrovascular diseases or cerebral infarction.

[0024] Another object of the present invention is to provide the use of a combination of magnolol and borneol in the preparation of a medicament for treating cerebrovascular diseases. Certain specific embodiments relate to the use of a combination of magnolol and borneol in the preparation of a medicament for treating ischemic cerebrovascular diseases or for treating cerebral infarction.

[0025] The pharmaceutical composition provided by this invention includes magnolol and borneol, which has a synergistic effect in the treatment of cerebrovascular diseases, especially ischemic cerebrovascular diseases. It can significantly increase the therapeutic effect of magnolol, reduce the effective dose of magnolol, reduce the dosage of the drug, and reduce the occurrence of adverse reactions with long-term use.

[0026] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Detailed Implementation

[0027] The present invention will be further described below with reference to embodiments, but these embodiments do not constitute any limitation on the present invention. In the embodiments, natural borneol refers to the natural borneol listed in Part I of the 2020 edition of the Pharmacopoeia of the People's Republic of China, namely dextrorotatory borneol.

[0028] Example 1: Preparation of Injectable Form

[0029] (1) Preparation of injection-grade magnolol sulfonyl-β-cyclodextrin inclusion solution

[0030] Accurately weigh 100 mg of magnolol, 10.0 g of sulfobutyl-β-cyclodextrin, and 100 mg of vitamin C, add them to 800 mL of water for injection, stir to dissolve, and finally bring the volume to 1000 mL with water for injection. This is the inclusion solution containing 100 μg of magnolol and sulfobutyl-β-cyclodextrin per ml.

[0031] (2) Preparation of borneol solution for injection

[0032] Accurately take 1.0g of natural borneol and place it in a 250ml beaker. Add 20ml of 95% ethanol and stir to dissolve. Then quickly add 80ml of water for injection. A large amount of white precipitate will precipitate out. Filter the precipitate and add it to 100ml of 10% sulfobutyl-β-cyclodextrin solution. Stir until the solution is clear, then add water for injection to 1000ml. Stir and mix well to obtain an inclusion solution containing 1.0mg of sulfobutyl-β-cyclodextrin per ml of borneol.

[0033] (3) Preparation of injection and magnolol + borneol solution

[0034] Take a given ratio of magnolol solution and borneol solution, mix them well, and the mixture ratio is as follows:

[0035]

[0036] The above solution is aseptically processed, filled and prepared into an injection.

[0037] Example 2: Preparation of Oral Self-Emulsifying Microemulsion Soft Capsules

[0038] Precisely weigh 20 g of honokiol and 40 g of natural borneol, place them in a beaker, add 200 g of polyethylene glycol 400, stir until completely dissolved, then add 300 g of medium-chain triglyceride, 300 g of polyethylene glycol stearate 15, and 200 g of lecithin respectively, stir well to obtain a self-emulsifying microemulsion, and press it into soft capsules.

[0039] Example 3: Preparation of Solid Dispersible Tablets

[0040] Precisely weigh 10 g of honokiol, 20 g of natural borneol and 110 g of PEG4000, mix them, heat them in a water bath at 80 - 90 °C, wait until completely melted, quickly cool and solidify, freeze in a refrigerator for 24 h, grind finely, and pass through an 80-mesh sieve to obtain a solid dispersion. Take 218 g of lactose - microcrystalline cellulose (1∶1), 38 g of cross-linked polyvinylpyrrolidone (PVPP), mix them evenly with the above solid dispersion, add 4.0 g of colloidal silica, and directly compress into tablets. Each tablet is 400 mg, containing 10 mg of honokiol and 20 mg of borneol.

[0041] Example 4: Mouse Acute Whole-Brain Ischemia Test (Investigation of Borneol Dosage)

[0042] 1. Animal Experiment Materials

[0043] 1.1 Drugs: The test drugs are the honokiol injection solution prepared in Example 1, the natural borneol injection solution, the honokiol + natural borneol injection solution, the model control is 1% HP-β-CD solution, and the positive control solution is Nimodipine injection.

[0044] 1.2 Animals: SPF-grade KM mice, male, 18 - 22 g, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., with the experimental animal production license number SCXK (Beijing) 2016 - 0006. The experimental animal use license number: SCXK (Beijing) 2011 - 0039.

[0045] 1.3 Data Processing: The data is analyzed by variance analysis and between-group tests using SPSS11.5 statistical software.

[0046] 2. Mouse Acute Whole-Brain Ischemia Test

[0047] 2.1 Animal Grouping and Drug Administration: 90 Kunming mice are randomly divided into 10 groups, namely the model control group (1% HP-β-CD), the honokiol group (50 μg·kg -1 ), the dextrorotatory borneol group (125, 250, 500 μg·kg -1), and magnolol + dextrorotatory borneol groups (50+125, 50+250, 50+500 μg·kg) -1 ), 10 per group.

[0048] 2.2 Experimental procedure and index observation: 30 minutes after intravenous administration, the mice were decapitated from behind the ears and neck. The time (s) of panting after decapitation and the number of panting breaths were observed.

[0049] 3. Results

[0050] The experimental results are shown in Table 1.

[0051] Table 1. Effects on acute global cerebral ischemia in mice (x±s, n=10)

[0052]

[0053] *p<0.05, **p<0.01, compared with the model group.

[0054] As shown in Table 1, magnolol was administered intravenously at a single dose of 50 μg / kg. -1 It significantly prolonged the number and duration of panting in mice after decapitation, showing a significant difference compared to the model group (p<0.05). Dextrorotatory borneol 0.125, 0.250, and 0.500 mg / kg -1 A single intravenous administration showed no significant difference compared to the model group. (and honokiol (50 μg·kg)) -1 ) and 125, 250, 500 μg·kg -1 The combined administration of dextrorotatory borneol and cauterin showed a trend of prolonging the number and duration of panting in mice after decapitation, with the latter showing the highest efficacy. -1 ) and natural borneol (500 μg·kg -1 The combined treatment group showed a highly significant difference compared to the model group (p<0.01), while other combined groups showed significant differences compared to the model group (p<0.05). This suggests that combined administration of magnolol and natural borneol can enhance the protective effect of magnolol against ischemia-hypoxia in mice, with magnolol (50 μg·kg⁻¹) being the most effective. -1 ) and natural borneol (500 μg·kg -1 Combination therapy yields the best results.

[0055] Therefore, the following examples use a borneol dosage of 500 μg·kg. -1 The synergistic effect of combined use with honokiol was investigated.

[0056] Example 5: Acute Cerebral Ischemia Experiment in Mice

[0057] 1. Animals and experimental materials

[0058] 1.1 Drugs: The honokiol injection solution prepared in Example 1, the injection solution of honokiol + natural borneol, the model control was 1.0% HP-β-CD solution, and the positive control solution was Nimodipine injection. Lactic acid assay kit, product of Nanjing Jiancheng Bioengineering Research Institute (20231025); ATP luminescence detection kit, product of Vigorous Biotechnology (Beijing) Co., Ltd. (20231127); Chloral hydrate, product of Beijing Tongguang Reagent Co., Ltd. (20221216).

[0059] 1.2 Animals: SPF-grade KM mice, male, 18 - 22 g, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., with the experimental animal production license number SCXK(Beijing)2016 - 0006. The experimental animal use license number: SCXK(Beijing)2011 - 0039.

[0060] 1.3 Data processing: The data was analyzed by variance analysis and inter-group test using SPSS11.5 statistical software.

[0061] 2. Acute cerebral ischemia test in mice

[0062] 2.1 Animal grouping and administration: 80 Kunming mice were randomly divided into 8 groups, namely the model control group (30% HP-β-CD), the honokiol group (50, 10, and 2.0 μg·kg -1 ), the honokiol + natural borneol group (50 + 500 μg·kg -1 , 10 + 500 μg·kg -1 , and 2.0 + 500 μg·kg -1 ), the positive control drug: nimodipine group (100.0 μg·kg -1 ), with 10 mice in each group.

[0063] 2.2 Test operation and index observation: 30 minutes after intravenous administration to mice, decapitate the animals from the back of the ears and neck, observe the decapitation gasping time and gasping frequency of the mice. And take the ischemic brain tissue, make it into a 10% homogenate with the lysis solution in the ATP kit, and measure the lactic acid (LA) and ATP content in the brain tissue according to the operation steps of the kit.

[0064] 3. Test results

[0065] The experimental results are shown in Table 2 and Table 3.

[0066] Table 2. Effects on acute global cerebral ischemia in mice (x±s, n = 10)

[0067]

[0068] *p < 0.05, **p < 0.01, compared with the model group.

[0069] The results are shown in Table 2, and the results were obtained from a single intravenous administration of magnolol at a dose of 50 μg / kg. -1 It can prolong the number of panting breaths in mice after decapitation, at concentrations of 50 and 10 μg / kg. -1 It can prolong the panting time in mice after decapitation, with a significant difference compared to the model group (p<0.05), suggesting that magnolol can enhance the tolerance of the whole brain to acute hypoxia in mice, thereby strengthening their ability to resist stroke. Combined administration of magnolol and natural borneol at doses of 50 and 10 μg / kg... -1 Both treatments significantly prolonged the number and duration of panting in mice after decapitation, showing a highly significant difference compared to the model group (p<0.01). The dosage was 2.0 μg·kg. -1 There was also a significant difference between the group and the model group (p<0.05), suggesting that the combined administration of natural borneol and magnolol can enhance the neuroprotective effect of magnolol on ischemic hypoxic mice, improve the ability to resist stroke, and enable magnolol to improve the ischemic hypoxia effect in mice at a lower dose, thereby reducing the dosage of magnolol and reducing its adverse reactions.

[0070] Table 3. Effects on lactate content and ATP levels in brain tissue of mice with acute global cerebral ischemia (Table 3) n=10)

[0071]

[0072] Compared with the model group: *P<0.05, **P<0.01.

[0073] The results are shown in Table 3, and the results were obtained from a single intravenous administration of magnolol at a dose of 50 μg / kg. -1 It can effectively reduce lactate content in brain tissue of mice with acute global cerebral ischemia, showing a significant difference compared with the model group. Combined administration of magnolol and natural borneol at doses of 50 and 10 μg / kg... -1 Both drugs significantly reduced lactate levels in brain tissue from mice with acute global cerebral ischemia, showing a highly significant difference compared to the model group (p<0.01). The dosage was 2.0 μg·kg. -1 There were also significant differences between the group and the model group (p<0.05); and the intravenous single administration of magnolol at 50 and 10 μg / kg. -1 The combined treatment group effectively increased the ATP level in the brain tissue of mice with acute global cerebral ischemia, showing a significant difference compared with the model group (p<0.05). The combined administration of magnolol and natural borneol at doses of 50 and 10 μg / kg was also effective. -1 Both drugs significantly increased ATP levels in brain tissue of mice with acute global cerebral ischemia, showing a highly significant difference compared to the model group (p<0.01). The dosage was 2.0 μg·kg. -1There was also a significant difference between the group and the model group (p < 0.05); it was suggested that the combined administration of borneol and honokiol could enhance the brain protection effect of honokiol on ischemic and hypoxic mice.

[0074] Example 6: Effects on cerebral vascular Evans blue exudation and brain water content in mice with cerebral ischemia-reperfusion

[0075] 1. Experimental materials

[0076] Kunming mice, half male and half female, weighing 30 ± 3 g, provided by Beijing Vital River Laboratory Animal Technology Co., Ltd., with the experimental animal production license number SCXK (Beijing) 2016-0006.

[0077] The honokiol injection solution prepared in Example 1, the injection solution of honokiol + borneol, the positive control was the Ginkgo biloba extract injection (Ginaton) produced by Dr. Willmar Schwabe Pharmaceuticals Germany, and the model control was 1.0% HP-β-CD solution. Sodium pentobarbital, a product of Beijing Dongfang Longshun Chemical Synthesis Technology Development Center; the rest of the reagents were commercially available analytical grade. ELISA reader, a product of Biorad; constant temperature operating table, a product of Huaibei ZhengHua; electronic analytical balance, a product of Ohaus; forced air drying oven, a product of Shanghai Boxun Medical Instrument Co., Ltd.

[0078] 2. Experimental methods

[0079] 2.1 Grouping of mice, preparation of cerebral ischemia-reperfusion model and drug treatment

[0080] Ninety healthy Kunming mice were randomly divided into 9 groups (10 mice in each group) according to body weight: sham operation group, model group (cerebral ischemia-reperfusion group), honokiol dose groups (50, 10 and 2.0 μg·kg -1 ), honokiol + borneol groups (50 + 500, 10 + 500 and 2.0 + 500 μg·kg -1 ); positive drug group (Ginkgo biloba extract injection, 60 mg·kg -1 ).

[0081] After weighing, the mice were anesthetized by intraperitoneal injection of sodium pentobarbital (50 mg·kg -1 ), fixed in the supine position on a constant temperature operating table, the skin in the middle of the neck was incised, the bilateral common carotid arteries were separated, and a cotton thread moistened with normal saline was passed through. After waiting for 5 min, when the animal's blood pressure was stable, the cotton thread was fixed and tightened to block the blood flow of the bilateral common carotid arteries for 30 min. The thread was loosened to restore blood flow, the neck skin was sutured aseptically, and 24 h of reperfusion was carried out. In the sham operation group, only the bilateral common carotid arteries were separated without blocking blood flow.

[0082] Mice in the magnolol group and the positive control group were administered the drug via intraperitoneal injection twice, 15 minutes after blood flow was blocked and 15 minutes after blood flow was restored. The sham-operated group and the model group were injected with an equal volume of physiological saline at the same time.

[0083] 2.2 Brain water content measurement

[0084] Brain water content was determined using the wet-dry specific gravity method. Mice underwent brain ischemia surgery followed by reperfusion for 24 hours. The brain was then decapitated, and the cerebellum, olfactory bulb, and lower brainstem were removed. The brain was placed in a glass dish, and the wet brain weight was measured using an analytical balance. The dish was then placed in a drying oven at 110℃ for 12 hours, and the dry brain weight was measured after cooling. Brain water content (%) was calculated using the following formula:

[0085] Brain water content = (Wet brain weight - Dry brain weight) / Wet brain weight × 100%

[0086] 2.3 Determination of Evans Blue Content in Brain Tissue

[0087] Twenty-four hours after cerebral ischemia-reperfusion in mice, brain tissue was harvested by decapitation. One hour prior to brain harvesting, Evans blue (50 mg / kg) was injected via the tail vein. The brain tissue was weighed and placed in test tubes, each containing 3 ml of formamide. The tubes were incubated at 45°C for 48 hours. The supernatant was then measured for OD values ​​using a multi-mode microplate reader (λ = 632 nm). Simultaneously, an Evans blue standard solution was prepared, and OD values ​​were measured to plot a standard curve. The amount of Evans blue exudate per unit weight was then calculated.

[0088] 2.4 Statistical Processing

[0089] Experimental results are expressed as mean ± standard deviation (mean ± SD). Statistical analysis was performed using SPSS 17.0 software. Student's t-test was used for comparisons between data groups, and P < 0.05 was considered statistically significant.

[0090] 3. Experimental Results

[0091] Table 4. Effects of Evans blue exudation and brain water content in mice with cerebral ischemia-reperfusion injury ( n=10)

[0092]

[0093] Note: Compared with the pseudo-model group: ## P<0.01; compared with the blank control group * P<0.05, ** P<0.01.

[0094] The results are shown in Table 4. The brain water content of the model group mice increased after ischemia / reperfusion injury, showing a statistically significant difference compared to the sham-operated group (p<0.01). High and medium dose groups of magnolol (10, 50 μg·kg⁻¹) were also observed.-1 ) can reduce the brain water content after cerebral ischemia / reperfusion injury in mice, showing significant differences compared with the model group (p < 0.05); honokiol (50.0 μg·kg -1 ) + borneol (500 μg·kg -1 ) group, honokiol (10.0 μg·kg -1 ) + borneol (500 μg·kg -1 ) group showed highly significant differences compared with the model group (p < 0.01), and honokiol (2.0 μg·kg -1 ) + borneol (500 μg·kg -1 ) group showed significant differences compared with the model group (p < 0.05), suggesting that the combined administration of borneol and honokiol can significantly reduce the degree of ischemic reperfusion brain edema, enabling honokiol to improve the brain edema state in mice at a lower dose.

[0095] Honokiol at a concentration of 50 μg·kg -1 can significantly reduce the Evans blue exudation amount per unit brain tissue in cerebral ischemia / reperfusion mice, suggesting that it inhibits the increase in cerebral capillary permeability caused by ischemia / reperfusion injury, thereby reducing edema (p < 0.05); honokiol (50.0 μg·kg -1 ) + borneol (500 μg·kg -1 ) group, honokiol (10.0 μg·kg -1 ) + borneol (500 μg·kg -1 ) group showed highly significant differences compared with the model group (p < 0.01), and honokiol (2.0 μg·kg -1 ) + borneol (500 μg·kg -1 ) group showed significant differences compared with the model group (p < 0.05), suggesting that the combined administration of borneol and honokiol can significantly reduce the Evans blue exudation amount in the brain tissue of mice after cerebral ischemia / reperfusion injury, enabling honokiol to improve the brain edema state in mice at a lower dose, and has a stronger inhibitory effect than the honokiol group and the positive drug Ginaton (Ginkgo biloba extract injection, 60 mg·kg -1 ).

[0096] Example 7: Study on the effects of antioxidant enzymes and MDA in the brain tissue of cerebral ischemia reperfusion mice <​​​​​​​Example 1 prepared injectable magnolol solution, injectable magnolol + natural borneol solution, positive control group was vitamin E (Beijing Shuanghe Pharmaceutical Factory product); model control and sham-operated group were given 1.0% HP-β-CD solution. Chloral hydrate, 2-thiobarbituric acid (TBA) (Sigma-Aldrich, USA product), pyrogallol (Beijing Chemical Plant product), H2O2 solution (Beijing Chemical Plant product). Super T21 centrifuge (Sorvall, USA product); AIC UV-900 ultraviolet spectrophotometer (Shanghai Dapu Instrument Co., Ltd. product); electronic balance (OHAUS, USA product).

[0100] 2. Experimental Methods

[0101] 2.1 Mouse model of cerebral ischemia-reperfusion

[0102] Male ICR mice, weighing 30±5g, were randomly divided into 9 groups: sham-operated group, model control group (NS), and honokiol (2.0, 10.0, 50.0 μg·kg⁻¹). -1 The dosage group, and the group receiving magnolol + dextrorotatory borneol (50 + 500 μg·kg) -1 10+500μg·kg -1 2.0 + 500 μg·kg -1 Dosage group and vitamin E (VE) 0.5 g / kg -1 Positive control group. Mice were weighed, and chloral hydrate (350 mg / kg) was added. -1 After anesthesia (IP), the mice were fixed in a supine position, and the bilateral common carotid arteries were separated and threaded with silk sutures. The bilateral common carotid arteries were clamped for 30 minutes, followed by 30 minutes of restored blood flow. The model control group and the honokiol dosage group received intravenous injections of the drug before clamping and before restoration of blood flow, respectively. Thirty minutes after restoration of blood flow, the mice were sacrificed, and their brains were immediately removed by decapitation under ice. The vitamin E group received oral administration for 5 days, with surgery performed 1 hour after the last administration. The sham surgery group only had the bilateral common carotid arteries separated, without clamping or administration of the drug, and was decapitated and had its brains removed 1 hour later.

[0103] Preparation of brain tissue homogenate: Under ice bath conditions, brain tissue was mixed with 0.9% physiological saline to prepare a 10% homogenate. The homogenate was centrifuged at 3000 rpm for 10 minutes at 0–4°C. The supernatant was then collected as the sample to be tested.

[0104] 2.2 Determination of malondialdehyde (MDA) content

[0105] Mix 0.3 ml of brain homogenate, 2 ml of 0.67% TBA, and 1.7 ml of distilled water. For the blank tube, mix 2 ml of 0.67% TBA with 2 ml of distilled water. Heat in a boiling water bath for 60 min, then remove and cool to room temperature under running water. Add 4 ml of n-butanol and mix thoroughly. Centrifuge at 3000 rpm for 10 min and measure the n-butanol phase. Zero the blank tube and measure the absorbance at 535 nm using a spectrophotometer. The absorbance is determined according to the following formula:

[0106] C = OD / ε·D (where C is the concentration, OD is the absorbance, and ε is the extinction coefficient, 1.56 × 10⁻⁶) 5 The MDA concentration can be calculated from the path length (where D is the optical path).

[0107] 2.3 Superoxide dismutase (SOD) activity assay

[0108] Determination of the auto-oxidation rate of pyrogallol: 50 mmol·L -1 Add 4.5 ml of pH 8.3 K2HPO4-KH2PO4 buffer to 50 mmol·L⁻¹ pre-warmed (25°C) water. -1 10 μl of pyrogallol was rapidly mixed and poured into a cuvette with a 1 cm optical path. The OD value was measured every 30 seconds at a wavelength of 325 nm, with the auto-oxidation rate controlled at 0.070 OD·min. -1 about.

[0109] Determination of SOD enzyme activity: The determination method is the same as that for determining the auto-oxidation rate of pyrogallol. Before adding pyrogallol, add the SOD homogenate to be tested, and calculate the enzyme activity according to the following formula based on the measured data.

[0110]

[0111] 2.4 Catalase (CAT) Activity Assay

[0112] Add 0.1 ml of sample to a mixture of 0.4 ml H₂O₂ solution and 0.5 ml phosphate buffer, mix well, and time accurately. Immediately after 60 seconds, add 2 ml potassium dichromate acetate solution to terminate the reaction. Then boil in boiling water for 10 minutes and cool at room temperature. Perform the same procedure for the reagent blank and sample blank tubes, but replace the sample with 0.1 ml phosphate buffer in the reagent blank tube, and add 0.9 ml phosphate buffer to the 0.1 ml sample in the sample blank tube. Zero the wavelength at 570 nm using the sample blank tube and measure the A value of both the sample tube and the reagent blank tube. Calculate the tissue CAT activity using the following formula:

[0113] CAT activity (K / mg.pr.)=Ka(1000 / b)

[0114] a represents the dilution factor of the brain homogenate sample, and b represents the grams of protein per liter of tissue fluid. K = 2.3 / 60 × loga(reagent blank tube A value) / (sample tube A value)

[0115] 2.5 Statistical Analysis

[0116] Experimental results are expressed as mean ± standard deviation (mean ± SD). Statistical analysis was performed using SPSS 17.0 software. Student's t-test was used to compare data between groups, and p < 0.05 was considered statistically significant.

[0117] 3. Experimental Results

[0118] The combination of magnolol and magnolol plus dextrorotatory borneol, administered intravenously to mice before cerebral ischemia and reperfusion, respectively, showed significant effects in increasing the activity of antioxidant enzymes in brain tissue and reducing the level of malondialdehyde (MDA), a lipid peroxidation product. The effects on catalase (CAT) and peroxidase (POD) were more pronounced, and the effects were superior to those of vitamin E (ig once daily for 5 times). The data are shown in Table 5.

[0119] Table 5. Effects on the activity of antioxidant enzymes in brain tissue of mice with cerebral ischemia-reperfusion injury ( n=10)

[0120]

[0121] *p<0.05, **p<0.01, compared with the model group. ^^p<0.01, compared with the pseudo-model group.

[0122] As shown in Table 5, the MDA level in the brain tissue of the model group was significantly higher than that of the sham-operated group (p<0.01), indicating the success of the cerebral ischemia / reperfusion model. Compared with the model group, the levels of magnolol at 10 and 50 μg / kg were significantly higher. -1 It can significantly and dose-dependently reduce MDA levels in ischemic / reperfused brain tissue (p<0.01 or p<0.05), and honokiol 2.0 μg·kg -1 and Vitamin E 0.5g·kg -1 It also significantly reduced MDA levels (P<0.05); and magnolol (50.0 μg·kg⁻¹) -1 ) + Natural borneol (500μg·kg) -1 ), and magnolol (10.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 ), and magnolol (2.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 All groups showed a significant and dose-dependent reduction in MDA levels in ischemic / reperfused brain tissue (p<0.01).

[0123] Table 5 data show that the SOD activity in the brain tissue of the model group was significantly lower than that of the sham-operated group (p<0.01), indicating that the cerebral ischemia / reperfusion model was successfully established. Compared with the model group, honokiol 10 and 50 μg·kg... -1 It can significantly increase SOD activity in ischemic / reperfused brain tissue (p<0.05, p<0.01); and magnolol (50.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 ), and magnolol (10.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 ), and magnolol (2.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 The group that showed significant improvement in SOD activity in ischemic / reperfused brain tissue (p<0.01, p<0.05) and vitamin E 0.5 g / kg also significantly improved SOD activity (p<0.01). However, 2.0 μg / kg -1 Honokiol had no significant effect on increasing SOD activity in ischemic / reperfused brain tissue of mice.

[0124] Table 5 shows that CAT activity in the brain tissue of the model group was significantly lower than that of the sham-operated group (p<0.01), indicating that the cerebral ischemia / reperfusion model was successful. Compared with the model group, the levels of magnolol (2.0, 10, 50 μg·kg⁻¹) were significantly lower. -1 It can significantly increase CAT activity in ischemic / reperfused brain tissue (p<0.01); and magnolol (50.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 ), and magnolol (10.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 ), and magnolol (2.0 μg·kg) -1 ) + Natural borneol (500μg·kg) -1 The group showed a significant increase in CAT activity in ischemic / reperfused brain tissue (p<0.01); Vitamin E 0.5 g·kg -1 It can also significantly increase CAT activity (P<0.01).

[0125] At the same dosage, the combined administration of magnolol and dextrorotatory borneol resulted in better improvement of MDA content and SOD activity in brain tissue, thereby reducing the effective dose of magnolol, decreasing its clinical dosage, and reducing its adverse reactions.

[0126] Example 8: Effects on ischemia-reperfusion injury of the middle cerebral artery in rats

[0127] 1. Animal experiments and materials

[0128] 1.1 Animals Sprague-Dawley (SD) rats, male, weighing 280 ± 20 g, were provided by Beijing Vital River Laboratory Animal Technology Co., Ltd. The production license number of experimental animals was SCXK (Beijing) 2016-0006. The license number for using experimental animals was SCXK (Beijing) 2011-0039.

[0129] 1.2 Drugs Tested drugs: honokiol injection solution prepared in Example 1, honokiol + natural borneol injection solution. The positive control group was nimodipine injection, and the model control and sham operation groups were given 1.0% HP-β-CD solution.

[0130] 1.3 Data processing The data were analyzed by one-way ANOVA and inter-group tests using SPSS 11.5 statistical software.

[0131] 2. Effects on neurological behavior scores and infarction area after cerebral ischemia-reperfusion in rats

[0132] 2.1 Establishment of cerebral ischemia-reperfusion injury model: After the rats were anesthetized with 10% chloral hydrate (350 mg·kg -1 , ip), they were fixed in the supine position. The common carotid artery (CCA) and vagus nerve, internal carotid artery (ICA) and external carotid artery (ECA) were exposed. The ICA and CCA were clamped respectively. A small incision was made on the external carotid artery, and the embolization wire was slowly inserted through the incision towards the proximal end of the external carotid artery. The arterial clamp on the internal carotid artery was released, and the external carotid artery was pulled to be in a straight line with the internal carotid artery. The embolization wire was inserted into the internal carotid artery through the bifurcation of the common carotid artery, with an average insertion length of 20 ± 2 mm. When a slight resistance was felt, it reached the anterior cerebral artery, blocking the blood flow of the middle cerebral artery (MCA), and the embolization wire was fixed. After 2 h, the embolization wire was removed to complete the ischemia-reperfusion injury operation. The body temperature of the animals during the operation was maintained at 37 °C using a thermostatic mouse board. In the sham operation group, only the blood vessels were dissected without inserting the embolization wire.

[0133] 2.2 Grouping and drug administration: Ninety adult male SD rats (weighing 280 ± 20 g) were randomly divided into 9 groups (10 rats in each group): ① sham model group; ② model group; ③ high-dose honokiol group (50 μg·kg -1 ); ④ medium-dose honokiol group (10 μg·kg -1 ); ⑤ low-dose honokiol group (2.0 μg·kg -1 ); ⑥ high-dose honokiol (50 μg·kg -1 ) + natural borneol (500 μg·kg -1 ) group; ⑦ medium-dose honokiol (10 μg·kg -1 ) + natural borneol (500 μg·kg -1 ) group; ⑧ honokiol (2 μg·kg -1) + Natural borneol (500μg·kg) -1 ) Low-dose group; ⑨ Positive control group: Nimodipine group (Nimodipine 1 mg / kg) -1 Different drugs were administered intravenously to each treatment group 15 minutes after ischemia and 15 minutes after reperfusion; the model group was given the same volume of normal saline, and the nimodipine group was given once 15 minutes after ischemia.

[0134] 2.3. Neurological Behavioral Scoring and Infarction Extent Determination: Twenty-four hours after ischemia-reperfusion in rats, their neurological function was scored according to the Bederson scoring system. Subsequently, rats were anesthetized with 10% chloral hydrate, and the brain tissue was flushed with cold saline through the heart to remove blood. The entire brain was quickly removed via craniotomy, frozen at -20°C for 15-20 minutes, and sectioned coronally on an ice pack. Each section was 2 mm thick and incubated in 2% TTC solution at 37°C in the dark for 20 minutes, turning once every 10 minutes to ensure uniform staining. The brain slices were then fixed in 10% formalin for 24 hours. Normal brain tissue appeared bright red, while infarcted brain tissue appeared white. Digital photography was used to photograph the brain slices, and the infarct area was measured using Project 1.2 software to determine the percentage of the total brain area covered by the infarction.

[0135] 3. Experimental Results

[0136] The results are shown in Table 6.

[0137] Table 6. Effects on ischemia-reperfusion injury in rats ( n=10)

[0138]

[0139] *p<0.05, **p<0.01, compared with the model group. ^^p<0.01, compared with the pseudo-model group.

[0140] 3.1 Neurological Function Scoring: The results showed that the brain tissue of rats in the sham-operated group was normal, with no infarction. The model group rats showed significant brain ischemia and severe infarction, with a highly significant difference compared to the sham-operated group (p<0.01), indicating successful model establishment. The high-dose magnolol group showed a highly significant difference compared to the model group (p<0.01), and the medium-dose group showed a significant difference (p<0.05), suggesting that magnolol has a significant effect in reducing cerebral ischemia-reperfusion injury. The high-dose and medium-dose magnolol + natural borneol groups showed highly significant differences compared to the model group (p<0.01), and the low-dose group showed a significant difference (p<0.05). Furthermore, compared to magnolol alone, at the same dosage, the combined administration of magnolol and natural borneol enhanced the improvement of neurological defects after ischemia-reperfusion in rats, allowing magnolol to achieve a therapeutic effect at a lower dose, thereby reducing its clinical dosage and improving efficacy. The combined administration of dextrorotatory borneol and magnolol can reduce the area of ​​ischemic cerebral infarction in rats, enabling magnolol to effectively reduce the infarct area in rats at a lower dose, thereby reducing the dosage of magnolol, improving efficacy, and reducing its adverse reactions.

[0141] 3.2 Determination of the infarct area: Results showed that the brain tissue of rats in the sham-operated group was normal, with no infarction. The brain tissue of rats in the model group showed significant ischemia and a clearly defined infarct area, with a highly significant difference compared to the sham-operated group (p<0.01), indicating successful model establishment; and honokiol (50.0 μg·kg⁻¹) -1 The dosage group significantly improved the cerebral infarction area after ischemia-reperfusion in rats, showing a highly significant difference compared with the model group (p<0.01), and magnolol (10.0 μg·kg) also improved the infarction area. -1 The dosage group significantly improved the infarct size after ischemia-reperfusion in rats, showing a significant difference compared to the model group (p<0.05). The combination of magnolol and natural borneol was also observed at magnolol dosages of 50, 10, and 2.0 μg / kg. -1 All doses improved the cerebral infarction range in rats after ischemia-reperfusion, showing highly significant differences (p<0.01) or significant differences (p<0.05) compared with the model group. Moreover, compared with honokiol alone, at the same dosage, the combined administration of honokiol and borneol enhanced the improvement of the cerebral infarction range in rats after ischemia-reperfusion by honokiol, thereby reducing the effective dose of honokiol and enhancing the therapeutic effect.

Claims

1. A pharmaceutical composition comprising magnolol and borneol.

2. The pharmaceutical composition according to claim 1, characterized in that: The magnolol mentioned includes magnolol isolated from Magnolia officinalis or chemically synthesized magnolol, preferably magnolol isolated from Magnolia officinalis with a purity of ≥90%, more preferably natural magnolol with a purity of ≥99.0%.

3. The pharmaceutical composition according to claim 1, characterized in that: The borneol includes natural borneol or synthetic borneol, preferably natural borneol, and (+)-2-borneol with a purity of ≥98% and (-)-2-borneol with a purity of ≥98%, more preferably natural borneol and (+)-2-borneol with a purity of ≥98%.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that: The weight ratio of magnolol and borneol is 100.0-1.0:1.0-100.0, preferably 20.0-1.0:1.0-20.0, more preferably 10.0-1.0:1.0-10.0, and most preferably 5.0-1.0:1.0-5.

0.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that: The pharmaceutical composition also contains pharmaceutically acceptable excipients.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that: The pharmaceutical composition is prepared as a solid dispersion, a cyclodextrin inclusion complex, a self-emulsifying microemulsion, or a liposome; preferably a cyclodextrin inclusion complex, a self-emulsifying microemulsion, or a liposome.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that: The dosage forms of the pharmaceutical composition include oral formulations and injections; the oral formulations include tablets, capsules, granules, solutions, emulsions, and suspensions, preferably tablets, capsules, and granules; the injections include intramuscular injections, subcutaneous injections, intradermal injections, and intravenous injections, preferably intravenous injections.

8. Use of the pharmaceutical composition according to any one of claims 1-7 in the preparation of a medicament for treating cerebrovascular diseases, especially a medicament for treating ischemic cerebrovascular diseases or a medicament for treating cerebral infarction.

9. The use of the combination of magnolol and borneol in the preparation of drugs for the treatment of cerebrovascular diseases, especially drugs for the treatment of ischemic cerebrovascular diseases or drugs for the treatment of cerebral infarction.

10. The application as described in claim 8 or 9, wherein the weight ratio of magnolol to borneol is 100.0–1.0:1.0–100.0, preferably 20.0–1.0:1.0–20.0, and more preferably 10.0–1.0:1.0–10.0.

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