Pharmaceutical composition containing anisodine or salt thereof and 2-borneol

Abstract

The invention discloses a pharmaceutical composition which comprises anisodine or salt thereof and 2-borneol or related substances thereof. The pharmaceutical composition provided by the invention has a synergistic effect in treatment of cardia-cerebrovascular diseases, especially central nervous diseases such as acute ischemic stroke, can effectively improve the effect of patients with cerebrovascular diseases, especially central diseases such as acute ischemic stroke, and improves the quality of life.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising anisodine or a salt thereof and borneol, and to the use thereof in the preparation of a medicament for treating cerebrovascular diseases. Background Art

[0002] Cerebrovascular diseases are a group of diseases that seriously endanger human health and have currently become one of the important causes of disability and death in humans. "Cerebral stroke" is also known as "stroke" and "cerebrovascular accident" (CVA). It is an acute cerebrovascular disease, which is a group of diseases caused by sudden rupture of blood vessels in the brain or blockage of blood vessels leading to the inability of blood to flow into the brain, resulting in brain tissue damage, including ischemic and hemorrhagic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% - 70% of the total number of strokes. Occlusion and stenosis of the internal carotid artery and vertebral artery can cause ischemic stroke, mostly in people over 40 years old, more common in men than in women, and severe cases can cause death. The mortality rate of hemorrhagic stroke is relatively high. Investigations show that stroke has become the leading cause of death in both urban and rural areas in China and the primary cause of disability in Chinese adults. Stroke is characterized by high incidence, high mortality, and high disability rate. Different types of stroke have different treatment methods. Due to the lack of effective treatment means, it is necessary to popularize the education of stroke risk factors and early warning symptoms among the whole population to truly prevent and treat stroke.

[0003] Cerebrovascular diseases can be simply divided into two categories. One is ischemic cerebrovascular diseases caused by reduced or interrupted blood flow, and the other is hemorrhagic cerebrovascular diseases caused by blood vessel rupture. Ischemic cerebrovascular diseases mainly include cerebral infarction (including cerebral thrombosis and cerebral embolism). In addition to cerebral infarction, there is also an ischemic cerebrovascular disease that can completely recover within 24 hours without any sequelae, called transient ischemic attack or transient ischemic attack, which doctors usually simply call TIA, also known as mini-stroke. Hemorrhagic cerebrovascular diseases are also divided into two categories. One is that the blood vessel ruptures and the blood flows into the brain parenchyma, called cerebral hemorrhage or intracerebral hemorrhage. The other is that the blood vessel ruptures and the blood flows into the subarachnoid space around the brain, called subarachnoid hemorrhage, which doctors simply call SAH.

[0004] A stroke generally refers to an acute cerebrovascular disease. "Cerebral stroke" is also known as "stroke" and "cerebrovascular accident" (CVA). It is an acute Cerebrovascular diseases disease, which is a group of diseases caused by sudden rupture of blood vessels in the brain or blockage of blood vessels leading to the inability of blood to flow into the brain, resulting in brain tissue damage, including ischemic and hemorrhagic strokes.

[0005] Acute stroke is characterized by sudden onset, great harm, and high disability rate. Sometimes, due to the sudden onset and lack of advance preparation, medical treatment is not timely, which affects the patient's treatment to a certain extent. Due to the increasing mortality and disability rates of acute stroke, it has become one of the important research objects in clinical medicine. Therefore, there are more and more studies on how to improve the treatment effect of acute cerebral infarction. The commonly used treatment methods are thrombolytic therapy, neuroprotective therapy, etc., which are mainly to eliminate free radicals in brain tissue and prevent them from reacting with proteins, nucleic acids, etc. to cause physical damage.

[0006] The treatment of cerebrovascular disease, especially ischemic cerebrovascular disease, is a major problem in current clinical treatment. After edaravone, there has been no world-recognized therapeutic drug in this field for nearly 40 years worldwide, and there is an urgent need for the emergence of better effective drugs.

[0007] Anisodine is an alkaloid M receptor antagonist and a scopolamine drug (chemical structure shown in Formula 1). It is an alkaloid M receptor antagonist separated and extracted from Solanaceae plants such as belladonna, datura and scopolamine. In addition to anisodine, there are also atropine, scopolamine and anisodamine. As early as 1981, it was reported that scopolamine drugs can promote the recovery of brain nerve function. Literature reports that the mechanism of anisodine hydrobromide against cerebral ischemia-reperfusion injury mainly includes the following aspects: anti-oxidative damage and anti-calcium overload, Na + -K + -Influence on AT enzyme activity and energy metabolism, regulating neurotransmitters, and inhibiting the release of excitatory amino acids.

[0008] At present, most studies believe that anisodine hydrobromide, as an M receptor blocker, improves microcirculation, which is the basis for its prevention and treatment of ischemic stroke. In the process of screening and studying ischemic stroke therapeutic drugs, the inventors focused on the in-depth development of non-clinical research on anisodine in this treatment field, and unexpectedly found that anisodine achieved unexpectedly better effects when used in combination with (+)-2-borneol or borneol-like substances.

[0009] (+)-2-Borneolum is the main component of borneol, which is a commonly used Chinese medicine. The 2020 edition of the "Pharmacopoeia of the People's Republic of China" includes natural borneol (dextrorotatory borneol), mugwort tablets (levorotatory borneol), and borneol (synthetic borneol).

[0010] Natural borneol is extracted from fresh branches and leaves of Cinnamomum camphora (L.) Presl, a plant of the Lauraceae family. Its main component is d-borneol, and its d-borneol content is not less than 96%.

[0011] Borneol is the crystal of the leaf extract of Blumea balsamifera (L.) DC., a plant of the Compositae family. Its main component is (-)-borneol, and the content of (-)-borneol is not less than 85% calculated as borneol. Borneol synthetic is also called synthetic borneol, and its borneol content is not less than 55%.

[0012] In addition, (+)-borneol is also known as (+)-2-camphanol (see Chemical Structural Formula 2), (-)-borneol is also known as (-)-2-camphanol (see Chemical Structural Formula 3), and both (+)-borneol and (-)-borneol can be derived from natural extraction sources or obtained through chemical synthesis.

[0013] Borneol is pungent and bitter in taste, slightly cold in nature, and belongs to the heart, spleen, and lung meridians. It has the functions of resuscitating the consciousness and clearing heat and relieving pain, and is used for symptoms such as coma due to febrile diseases, convulsions, syncope due to wind-phlegm in stroke, sore throat, toothache, oral ulcers, carbuncles, and red eyes. Natural borneol has the best effect among borneols. In addition, since the minimum content of (+)-borneol in natural borneol is 96%, and there are still certain amounts of impurities, which may affect the safety of drug use. Therefore, natural borneol has been purified, and currently, commercially available (+)-2-camphanol with a purity

[0014] ≥98% is available.

[0015] The present invention is expected to provide a safer and more effective drug for the treatment of stroke, meeting the clinical needs that have not been satisfactorily solved globally in this field.

[0016] SUMMARY OF THE INVENTION

[0017] The object of the present invention is to provide a drug that has a better therapeutic effect on cardiovascular and cerebrovascular diseases, especially ischemic cerebrovascular diseases and their related diseases, compared with existing standard treatment methods. Specifically, it is a pharmaceutical composition comprising anisodine or its salt and 2-camphanol or its homologs, which has a synergistic effect in the treatment of cardiovascular and cerebrovascular diseases, especially acute ischemic stroke, effectively improves the effect of patients with cerebrovascular diseases, especially acute ischemic stroke, and improves the quality of life.

[0018] The inventors of the present invention have been engaged in the discovery and development of drugs for the treatment of cerebrovascular diseases for a long time. It was unexpectedly found in the animal pharmacodynamic experiments for screening and researching drugs for the treatment of ischemic stroke that the combination of anisodine or its salt and (+)-2-camphanol can significantly improve the infarct area of brain tissue, and the pharmacodynamic effect on the ischemic stroke model is significantly better than that of the commercially available edaravone dexborneol injection, and the efficacy of the drug has been fully verified.

[0019] These unexpected test results unexpectedly suggest that anisodine or its salts and borneol in the treatment of cerebrovascular diseases, especially ischemic stroke, have an obvious synergistic effect, and the effect will be better when the ratio of the two active ingredients is within a suitable range. In particular, when the ratio of anisodine or its salts to borneol is between 1:1 and 1:15, it can effectively improve multiple indicators of the animal cerebrovascular disease model, suggesting that it will have an obvious therapeutic effect on patients with acute ischemic stroke and improve the quality of life.

[0020] The pharmaceutical composition of the present invention contains anisodine or its salts and borneol or its analogs as active ingredients, and the weight ratio is 1:1 to 1:25, preferably 1:1 to 1:15, and further preferably 1:3 to 1:10. It is characterized by having obvious advantages in the treatment of cardiovascular and cerebrovascular diseases, especially central nervous system diseases, thrombosis-related diseases, and cerebrovascular diseases such as stroke and their related diseases.

[0021] The pharmaceutical composition also includes various pharmaceutically relevant excipients.

[0022] The anisodine salt is preferably anisodine hydrobromide. Based on medical common sense, hydrobromides, hydrochlorides, sulfates, bisulfates, hydrogen phosphates, etc. all have the same effect, and hydrobromide is preferred.

[0023] The pharmaceutical composition of the present invention contains anisodine hydrobromide and borneol or its related substances as active ingredients, and the weight ratio is 1:1 to 1:25, preferably 1:1 to 1:15, and further preferably 1:3 to 1:10.

[0024] The borneol or its related substances are preferably natural borneol and (+)-borneol with a purity of ≥98%. Based on medical and traditional Chinese medicine common sense, one of natural borneol, borneol syntheticum, synthetic borneol, (+)-borneol and (-)-borneol with a purity of ≥98% is preferred, and natural borneol and (+)-borneol with a purity of ≥98% are preferred.

[0025] According to the administration route and experimental results of the animal test model, the drug can be administered by injection or orally. Based on medical common sense, it can be generalized that the dosage form of the drug combination can be injection, tablet, capsule, oral liquid, sublingual tablet, orally disintegrating tablet, sublingual film, sublingual rapidly disintegrating tablet, buccal film, buccal tablet, granule, infusion, pill, powder, plaster, nasal spray, suspension, powder, suppository, cream, nasal drops, spray, drop or patch.

[0026] Another object of the present invention is to provide an application of the above-mentioned pharmaceutical composition in the preparation of drugs for treating oxidative stress injuries and thrombus-related diseases such as cardiovascular and cerebrovascular diseases, neurological diseases, vascular headache, retinal vasospasm, central retinopathy, ischemic optic neuropathy, Parkinson's disease, motion sickness, bronchial asthma, organophosphorus pesticide poisoning, retinopathy, diabetic peripheral neuropathy, neurodegenerative diseases, etc., especially in the preparation of drugs for acute ischemic stroke and its related diseases.

[0027] In some embodiments, the present invention provides an injection of anisodine or its salt and (+)-2-borneol. In addition to the active ingredients, the injection further comprises one or more of a cosolvent, an antioxidant, an osmotic pressure regulator, and a pH regulator.

[0028] The cosolvent is one or more of ethanol, propylene glycol, isopropanol, or polyethylene glycol.

[0029] The osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, glucose, sorbitol, or xylitol.

[0030] The antioxidant is one or more of sodium bisulfite, sodium metabisulfite, sodium sulfate, or sodium sulfite.

[0031] The pH regulator is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium dihydrogen phosphate, or potassium dihydrogen phosphate.

[0032] The injection also needs to be protected by filling with an inert gas, and the inert gas is one of nitrogen and carbon dioxide.

[0033] In some embodiments, the present invention provides a sublingual tablet of anisodine or its salt and (+)-2-borneol. In addition to the active ingredients, the sublingual tablet further comprises one or more of the following types of excipients: filler, binder, disintegrant, lubricant, and flavoring agent, and the excipients for preventing the volatilization of borneol are one or more of glyceryl behenate, stearic acid, crospovidone, or povidone. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 Summary chart of the effect of intravenous injection of the test substance on the balance beam passing time of MCAO rats

[0035] Figure 2 Summary chart of the effect of intravenous injection of the test substance on the cerebral infarction area ratio of MCAO rats DETAILED DESCRIPTION OF THE EMBODIMENTS

[0036] The present invention will be further described below in conjunction with embodiments, but these embodiments do not constitute any limitation to the present invention.

[0037] In the examples, (+)-2-borneol is obtained by purifying or synthesizing natural borneol, with a purity of ≥98%, also known as dextrorotatory borneol.

[0038] Example 1

[0039] Weigh 2 g of (+)-2-borneol, add it to 300 ml of propylene glycol, stir to completely dissolve it, slowly add water for injection to 90% of the total volume, add 2 g of anisodine hydrobromide to dissolve it, and adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 1000 ml to obtain the product.

[0040] Example 2

[0041] Weigh 2.5 g of (+)-2-borneol, add it to 300 ml of propylene glycol, stir to completely dissolve it, slowly add water for injection to 90% of the total volume, add 0.1 g of anisodine hydrobromide and 1 g of sodium metabisulfite to dissolve them, and adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 1000 ml to obtain the product.

[0042] Example 3

[0043] Weigh 4 g of (+)-2-borneol, add it to 300 ml of propylene glycol, stir to completely dissolve it, slowly add water for injection to 90% of the total volume, add 0.5 g of anisodine hydrobromide and 1 g of sodium metabisulfite to dissolve them, and adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 1000 ml to obtain the product.

[0044] Example 4

[0045] Weigh 3 g of (+)-2-borneol, add it to 500 ml of propylene glycol, stir to completely dissolve it, slowly add water for injection to 90% of the total volume, add 1 g of anisodine hydrobromide to dissolve it, and adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 2000 ml to obtain the product.

[0046] Example 5

[0047] Weigh 7.5 g of (+)-2-borneol, add it to 1200 ml of propylene glycol, stir to completely dissolve it, slowly add water for injection to 90% of the total volume, add 1 g of anisodine hydrobromide to dissolve it, and adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 5000 ml to obtain the product.

[0048] Example 6

[0049] Weigh 10 g of (+)-2-borneol, add it to 2000 ml of propylene glycol, stir to completely dissolve it, slowly add water for injection to 90% of the total volume, add 1 g of anisodine hydrobromide to dissolve it, and adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 5000 ml to obtain the product.

[0050] The preparation process of the injection in the above Examples 1-6 further includes conventional steps such as liquid medicine filtration, sterilization, nitrogen filling, and filling. During the filling process, nitrogen filling protection operation needs to be carried out on the product.

[0051] Example 7

[0052] Weigh 2 g of (+)-2-borneol, add an appropriate amount of ethanol to dissolve it, and use it as a solvent reserve. Add it to the mixed material containing 0.5 g of anisodine hydrobromide, 5 g of crospovidone, 66 g of mannitol, and 3 g of hypromellose, granulate, add 1 g of magnesium stearate after drying and mix, and press into 1000 tablets of anisodine hydrobromide and borneol sublingual tablets.

[0053] Example 8

[0054] Weigh 2 g of (+)-2-borneol, melt and granulate 5 g of glyceryl behenate, crush and pass through a 60-mesh sieve, then add it to the mixed material containing 0.5 g of anisodine hydrobromide, 4 g of sodium carboxymethylcellulose, 66 g of mannitol, and 3 g of povidone, add 1 g of stearic acid and mix, and press into 1000 tablets of anisodine hydrobromide and borneol sublingual tablets.

[0055] Experimental study on the pharmacodynamic effects of different combinations of anisodine and 2-borneol on rats with ischemic stroke

[0056] Objective: The experiment is intended to adopt the intravenous injection administration method, and use the balance beam passing time, cerebral blood flow difference, and cerebral infarction area as indicators to investigate the protective effects of different drug combinations on rats with focal cerebral ischemia-reperfusion (MCAO).

[0057] Experimental animals:

[0058] SD rats, SPF grade, male, sourced from Shanghai Slack Experimental Animal Co., Ltd., experimental animal quality certificate number: 20220004067557, experimental animal production license number: SCXK(Shanghai)2022-0004, experimental animal use license number: SYXK(Shanghai)2022-0022.

[0059] Number of enrolled animals: 72, animal body weight at the start of the experiment: about 180-200 g.

[0060] Experimental method:

[0061] Grouping: After 4 days of adaptive feeding of rats, behavioral training (balance beam, rotarod) was performed on all rats in each group starting three days before surgery. SD rats were evenly divided into 9 groups according to body weight, namely the sham operation group, the model group, the positive drug Xanboni group (Xanboni is edaravone dexborneol injection), the anisodine hydrobromide group, the dexborneol group ((+)-2-borneol), the anisodine hydrobromide-dexborneol compound group 1, the anisodine hydrobromide-dexborneol compound group 2, the anisodine hydrobromide-dexborneol compound group 3, and the anisodine hydrobromide-dexborneol compound group 4. There were 8 rats in each group, and appropriate spare animals were reserved.

[0062] Model establishment: Rats were fasted for 12 h before surgery and allowed free access to water. Before surgery, animals in each group were anesthetized with isoflurane, with spontaneous respiration maintained. They were fixed in the supine position on a rat board, the hair on the midline of the neck was removed, and disinfected with 75% alcohol. A surgical incision was made in the midline of the ventral neck of the rats, and the muscles and fascia were separated along the inner edge of the sternocleidomastoid muscle. The right common carotid artery, external carotid artery, and internal carotid artery were separated. A small inclined incision was made with a vascular scissors about 0.5 cm proximal to the ligation site of the external carotid artery. The proximal end of the external carotid artery was pulled to form a straight line with the internal carotid artery. The rat suture was slowly advanced 1.8 cm into the cranial direction of the internal carotid artery through the incision of the main trunk of the right external carotid artery. Marked by the bifurcation of the common carotid artery, when a slight resistance was felt during the advancement, the middle cerebral artery was blocked. The suture was removed 2 h after infarction to complete the model of cerebral ischemia-reperfusion injury. The sham operation group only underwent vascular separation. 20 minutes after infarction, a Doppler flowmeter was used to examine the cerebral blood flow, and when the difference in cerebral blood flow between the left and right brains (ROI%) was higher than 48%, the model was considered successful and the rats were included in the experiment. During the operation, an incandescent lamp was used to heat to maintain the rectal temperature.

[0063] Drug administration: The drugs in each group were intravenously injected at 0.5 h after cerebral infarction and 12 h after reperfusion of the animals. The sham operation group and the model group were given the same volume of blank solvent; the blank solvent was 8% propylene glycol + 92% normal saline, and all samples were dissolved or diluted to the target concentration with the blank solvent; the sham operation group and the model group were given the blank solvent; the positive drug Xanboni group was given edaravone dexborneol injection; the anisodine hydrobromide group was given anisodine hydrobromide solution; the dexborneol group was given dexborneol solution; the anisodine hydrobromide-dexborneol compound group was given a mixed solution of anisodine hydrobromide and dexborneol. The grouping and detailed drug administration information are shown in Table 1.

[0064] Table 1: Experimental grouping and drug administration information

[0065]

[0066]

[0067] At the end of the experiment (24 h after reperfusion), the cerebral blood flow changes of all animals were measured using a Doppler flowmeter to evaluate the improvement effect of the test substance on ischemic stroke; the balance beam passage time function test was performed; and the whole brain was sectioned coronally continuously for TTC staining and photography. The infarct area was measured using Image-J software, and the percentage of the infarct area in the whole brain area was calculated. The infarct improvement rate was calculated, and the synergistic effect was preliminarily evaluated using the King's formula.

[0068] Note: (1) Infarct area ratio = total infarct area ÷ total area of whole brain sections × 100%;

[0069] Infarct improvement rate = (infarct area ratio of the model group - infarct area ratio of the drug administration group) ÷ infarct area ratio of the model group × 100%;

[0070] (2) King's formula: q = E (A+B) / (E A + E B -E A ·E B ), where E A , E B and E (A+B) are the infarct protection rates of single agent A, single agent B, and the compound, respectively.

[0071] (3) Experimental data are expressed as Mean±SD, and corresponding statistical analysis was performed using SPSS 21.0 software. If p < 0.05, it is considered to have a statistically significant difference, and if p < 0.01, it is considered to have a highly statistically significant difference.

[0072] Experimental results:

[0073] (1) The summary of the results of the balance beam passage time test for MCAO rats is shown in Table 2:

[0074] Table 2 Effects of intravenous injection of the test substance on the balance beam passage time of MCAO rats (x±SD, n = 8)

[0075]

[0076]

[0077] ## p < 0.01 vs. sham operation group; *p < 0.05, **p < 0.01 vs. model group

[0078] (2) The summary of the results of the effects on the cerebral infarct area of MCAO rats is shown in Table 3:

[0079] Table 3 Effects of intravenous injection of the test substance on the infarct area ratio of MCAO rats (x±SD, n = 8)

[0080]

[0081] ## p < 0.01 vs. sham operation group; *p < 0.05, **p < 0.01 vs. model group

[0082] Experimental conclusion:

[0083] The test substances anisodine hydrobromide and (+)-borneol can effectively improve the passing time of the balance beam in MCAO rats when administered alone; both can significantly reduce the cerebral infarction area in MCAO rats and improve the improvement rate of cerebral infarction in rats.

[0084] The combined administration group of the test substances anisodine hydrobromide and (+)-borneol can effectively improve the passing time of the balance beam in MCAO rats; both can significantly reduce the cerebral infarction area in MCAO rats and improve the improvement rate of cerebral infarction in rats.

[0085] The combined compound of anisodine hydrobromide and (+)-borneol is superior to the administration of the test substance anisodine hydrobromide or (+)-borneol alone or the positive drug Xanthan

[0086] In the MACO rat model, the efficacy of anisodine hydrobromide does not increase with the increase of the dose, which has been reported in many literatures. In the present invention, when the compound ratio of anisodine hydrobromide and (+)-borneol increases from 1:1 to 1:10, the effect gradually increases, but at the ratio of 1:15, the effect decreases. Generally, the combined compound group 3 of anisodine hydrobromide and (+)-borneol (ratio 1:10) shows the best performance.

[0087] Calculated according to the King formula, the infarction improvement rates of the anisodine hydrobromide (0.30 mg / kg) group, (+)-borneol (0.9 mg / kg) and the combined compound of anisodine hydrobromide and (+)-borneol (0.3 + 0.9 mg / kg) are q = 1.19, which indicates that the combined use of anisodine hydrobromide and (+)-borneol can play a synergistic effect in the treatment of ischemic stroke.

[0088] The above is only the preferred embodiment of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and refinements can be made, and these improvements and refinements should also be regarded as the protection scope of the present invention.

Claims

1. A pharmaceutical composition, the active ingredients of which include anisodine or its salt and 2-borneol or its related substances, characterized in that: The weight ratio of anisodine or its salt to 2-borneol or its related substances is 1:1 to 1:

25.

2. A pharmaceutical composition, the active ingredients of which include anisodine or its salt and 2-borneol or its related substances, characterized in that: The weight ratio of anisodine or its salt to 2-borneol or its related substances is 1:1 to 1:

15.

3. A pharmaceutical composition, the active ingredients of which include anisodine or its salt and 2-borneol or its related substances, characterized in that: The weight ratio of anisodine or its salt to 2-borneol or its related substances is 1:3 to 1:

10.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The anisodine salt is selected from hydrobromide, hydrochloride, sulfate, hydrogen sulfate, hydrogen phosphate and other pharmaceutically acceptable salts, among which hydrobromide is preferred.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The active ingredient 2-borneol or its related substances are selected from natural borneol, (+)-2-borneol, borneol, moxa slices, synthetic borneol, artificially synthesized borneol, etc. One or more of (+)-2-borneol and (-)-2-borneol with a purity of ≥98%, preferably natural borneol, (+)-2-borneol, and artificially synthesized (+)-2-borneol with a purity of ≥98%.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that Pharmaceutically acceptable excipients are also included.

7. The pharmaceutical composition according to claim 6, characterized in that The dosage form of the pharmaceutical composition is selected from: injection, tablet, capsule, oral liquid, sublingual tablet, orally disintegrating tablet, sublingual film, sublingual rapidly disintegrating tablet, buccal film, lozenge, granule, granule, pill, powder, ointment, nasal spray, suspension, powder, suppository, cream, nasal drops, spray, drops or patch.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition is an injection, and the pharmaceutically acceptable excipients include one or more of a cosolvent, an antioxidant, an osmotic pressure regulator, and a pH regulator.

9. The injection according to claim 8, characterized in that The cosolvent is one or more of ethanol, propylene glycol, isopropanol, or polyethylene glycol.

10. The injection according to claim 8, characterized in that The osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, glucose, sorbitol and xylitol.

11. The injection according to claim 8, characterized in that The antioxidant is one or more of sodium bisulfite, sodium pyrosulfite, sodium sulfate and sodium sulfite.

12. The injection according to claim 8, characterized in that The pH adjuster is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

13. The injection according to claim 8, characterized in that It needs to fill the headspace with inert gas to suppress the volatilization of dextroborneol, and the inert gas is one of nitrogen and carbon dioxide.

14. The pharmaceutical composition according to claim 7, characterized in that In addition to the active ingredients, the oral solid preparations such as sublingual tablets and tablets also include the following types of auxiliary materials: fillers, adhesives, disintegrants, lubricants, flavoring agents and auxiliary materials for preventing the volatilization of 2-borneol or its related substances.

15. The sublingual tablet according to claim 14, characterized in that The oral solid preparations such as sublingual tablets and tablets are characterized in that the auxiliary material for preventing the volatilization of 2-borneol or its related substances is one or more of glyceryl behenate, stearic acid, cross-linked polyvinylpyrrolidone and polyvinylpyrrolidone.

16. Use of the pharmaceutical composition according to any one of claims 1 to 15 in the preparation of a medicament for treating oxidative stress damage and thrombosis-related diseases such as cardiovascular disease, cerebrovascular disease, neurological disease, vascular headache, retinal vasospasm, central retinopathy, ischemic optic neuropathy, Parkinson's disease, motion sickness, bronchial asthma, organophosphorus pesticide poisoning, retinopathy, diabetic peripheral neuropathy, neurodegenerative disease, etc.

17. The use according to claim 16, characterized in that The cerebrovascular disease is ischemic stroke or the neurological symptoms, daily living activities and functional disorders caused by it.

18. The use according to claim 16, characterized in that The cerebrovascular disease is hemorrhagic stroke or the neurological symptoms, daily living activities and functional disorders caused by it.

19. The use according to claim 17, characterized in that The ischemic stroke is acute ischemic stroke or the neurological symptoms, daily living activities and functional disorders caused by it.

20. The use according to claim 16, characterized in that The cerebrovascular disease is acute paralysis caused by acute ischemic stroke.

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