Pharmaceutical composition containing anisodine or salt thereof and 2-borneol

Abstract

Disclosed in the present invention is a pharmaceutical composition, comprising anisodine or a salt thereof and 2-borneol or a related substance thereof. The pharmaceutical composition provided in the present invention exhibits synergistic effects in the treatment of cardiovascular and cerebrovascular diseases, particularly central nervous system diseases such as acute ischemic stroke, and can effectively improve outcomes of patients with cerebrovascular diseases, particularly central nervous system diseases such as acute ischemic stroke, thereby enhancing the quality of life of the patients.

Description

A pharmaceutical composition comprising camphor alkaloid or its salt and 2-camphor. Technical Field

[0001] This invention relates to a pharmaceutical composition comprising camphor alkaloid or its salt and 2-camphor, and its use in the preparation of a drug for treating cerebrovascular diseases. Background Technology

[0002] Cerebrovascular diseases are a group of diseases that seriously endanger human health and have become one of the leading causes of disability and death. "Cerebral stroke," also known as "apoplexy" or "cerebrovascular accident" (CVA), is an acute cerebrovascular disease caused by the sudden rupture or blockage of blood vessels in the brain, leading to brain tissue damage. It includes ischemic and hemorrhagic strokes. Ischemic stroke has a higher incidence than hemorrhagic stroke, accounting for 60%–70% of all strokes. Occlusion and stenosis of the internal carotid artery and vertebral artery can cause ischemic stroke, which is more common in people over 40 years of age, and more prevalent in men than women; severe cases can lead to death. Hemorrhagic stroke has a higher mortality rate. Surveys show that stroke has become the leading cause of death in my country, both in urban and rural areas, and is also the leading cause of disability among Chinese adults. Stroke is characterized by high incidence, high mortality, and high disability rates. Different types of stroke require different treatments. Due to the lack of effective treatment methods, the main approach is to strengthen public education on stroke risk factors and warning signs.

[0003] Cerebrovascular diseases can be broadly classified into two categories: ischemic cerebrovascular diseases caused by reduced or interrupted blood flow, and hemorrhagic cerebrovascular diseases caused by ruptured blood vessels. Ischemic cerebrovascular diseases mainly include cerebral infarction (including cerebral thrombosis and cerebral embolism). Besides cerebral infarction, there is another type of ischemic cerebrovascular disease that can completely recover within 24 hours without any sequelae, known as transient ischemic attack (TIA) or mini-stroke. Hemorrhagic cerebrovascular diseases are also divided into two categories: one is caused by ruptured blood vessels, with blood flowing into the brain parenchyma, called cerebral hemorrhage or cerebral hemorrhage; the other is caused by ruptured blood vessels, with blood flowing into the subarachnoid space surrounding the brain, called subarachnoid hemorrhage, or SAH.

[0004] Stroke generally refers to acute cerebrovascular disease. Also known as stroke or cerebrovascular accident (CVA), it is an acute cerebrovascular disease caused by the sudden rupture or blockage of blood vessels in the brain, leading to brain tissue damage. It includes ischemic and hemorrhagic strokes.

[0005] Acute stroke is characterized by its sudden onset, severe damage, and high disability rate. Sometimes, the suddenness of the onset prevents timely medical attention, impacting the patient's treatment. Due to the increasingly high mortality and disability rates of acute stroke, it has become a significant research focus in clinical medicine. Therefore, research on improving the treatment outcomes of acute ischemic stroke is growing. Commonly used treatments include thrombolytic therapy and neuroprotective therapy, primarily aimed at eliminating free radicals in brain tissue and preventing them from reacting with proteins and nucleic acids to cause damage.

[0006] The treatment of cerebrovascular diseases, especially ischemic cerebrovascular diseases, is a major challenge in clinical practice. In the past 40 years since edaravone, no globally recognized treatment has emerged, and there is an urgent need for drugs with better efficacy.

[0007] Hyoscyamine hydrobromide belongs to the class of alkaloid M receptor antagonists and is a hyoscyamine drug (chemical structure shown in Formula 1). It is an alkaloid M receptor antagonist successively isolated and extracted from plants of the Solanaceae family, including belladonna, datura, and hyoscyamine. Besides hyoscyamine hydrobromide, other alkaloid M receptor antagonists include atropine, scopolamine, and hyoscyamine alkaloid. As early as 1981, it was reported that hyoscyamine drugs can promote the recovery of brain nerve function. Literature reports that the mechanism of hyoscyamine hydrobromide in combating cerebral ischemia-reperfusion injury mainly includes the following aspects: anti-oxidative damage and anti-calcium overload, and Na+... + -K + Effects of AT enzyme activity and energy metabolism, regulation of neurotransmitters, and inhibition of excitatory amino acid release.

[0008] Most current research suggests that, as an M-receptor blocker, the improvement of microcirculation is the basis for the prevention and treatment of ischemic stroke by camphor hydrobromide. During the screening and research of drugs for ischemic stroke, the inventors focused on the in-depth development of non-clinical studies of camphor hydrobromide in this therapeutic field. Unexpectedly, they discovered that camphor hydrobromide, when used in combination with (+)-2-borneol or borneol-like substances, achieved unexpectedly better results.

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

[0010] Natural borneol is made from the fresh branches and leaves of the camphor tree (Cinnamomum camphora) Presl, a plant of the Lauraceae family, through extraction and processing. Its main component is dextrorotatory borneol, and its dextrorotatory borneol content is not less than 96%.

[0011] Artemisia argyi is a crystallized extract of the leaves of Blumea balsamifera (L.) DC., a plant in the Asteraceae family. Its main component is L-borneol, and its L-borneol content is not less than 85% (calculated as borneol). Borneol, also known as synthetic borneol, has a borneol content of not less than 55%.

[0012] In addition, dextrorotatory borneol is also known as (+)-2-camphenol (chemical structural formula shown in Formula 3), and levorotatory borneol is also known as (-)-2-camphenol (chemical structural formula shown in Formula 2). Levorotatory and dextrorotatory borneol can be obtained from natural sources or through chemical synthesis.

[0013] 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 refreshing the mind, clearing heat and relieving pain. It is used for symptoms such as delirium due to febrile diseases, convulsions, stroke with phlegm syncope, sore throat and toothache, oral ulcers and carbuncles, and red eyes. Among borneol, natural borneol has the best effect. In addition, since the lower limit of dextrorotatory borneol content in natural borneol is 96%, it still contains a certain amount of impurities, which may affect the safety of medication. Therefore, people have purified natural borneol. Currently, (+)-2-borneol with a purity of ≥98% is available on the market.

[0014] This invention is expected to provide safer and more effective drugs for the treatment of stroke, meeting a clinical need that has not yet been satisfactorily resolved globally. Summary of the Invention

[0015] The purpose of this invention is to provide a drug that has a better therapeutic effect on cardiovascular and cerebrovascular diseases, especially ischemic cerebrovascular diseases and related diseases than existing standard treatments. Specifically, it is a pharmaceutical composition comprising camphor and willow alkaloid or its salt and 2-camphor or its analogues, which has a synergistic effect in the treatment of cardiovascular and cerebrovascular diseases, especially acute ischemic stroke, effectively improving the efficacy of treatment for patients with cerebrovascular diseases, especially acute ischemic stroke, and improving their quality of life.

[0016] The inventors have long been engaged in the discovery and development of drugs for the treatment of cerebrovascular diseases. In the process of screening and studying the efficacy of drugs for the treatment of ischemic stroke, they unexpectedly discovered that the combination of camphor-salicylic acid or its salt with (+)-2-borneol can significantly improve the infarct area of ​​cerebral tissue, and the efficacy of the drug in the ischemic stroke model is significantly better than that of commercially available edaravone dexborneol injection. The efficacy of the drug has been fully verified.

[0017] These unexpected experimental results all suggest that camphor alkaloids or their salts and 2-borneol have a significant synergistic effect in the treatment of cerebrovascular diseases, especially ischemic stroke. Moreover, the effect is better when the ratio of the two active ingredients is within an appropriate range. In particular, the ratio of camphor alkaloids or their salts to 2-borneol is between 1:1 and 1:15, which can effectively improve multiple indicators in animal models of cerebrovascular diseases, suggesting that it will have a significant therapeutic effect on patients with acute ischemic stroke and improve their quality of life.

[0018] The pharmaceutical composition of the present invention comprises camphor alkaloid or its salt and 2-camphor or its analogues as active ingredients, in a weight ratio of 1:1 to 1:25, preferably 1:1 to 1:15, more preferably 1:3 to 1:10, and even more preferably 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. It is characterized by its significant advantages in treating cardiovascular and cerebrovascular diseases, especially central nervous system diseases, thrombosis-related diseases, and cerebrovascular diseases such as stroke and related diseases.

[0019] The pharmaceutical composition also includes various pharmaceutically relevant excipients.

[0020] The camphor-willow salt is preferably camphor-willow hydrobromide. Based on common medical knowledge, hydrobromide, hydrochloride, sulfate, hydrogen sulfate, hydrogen phosphate, etc. all have the same effect, with hydrobromide being the preferred choice.

[0021] The pharmaceutical composition of the present invention comprises camphor hydrobromide and 2-camphor or related compounds in a weight ratio of 1:1 to 1:25, preferably 1:1 to 1:15, more preferably 1:3 to 1:10, and even more preferably 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10.

[0022] The pharmaceutical composition of the present invention, comprising camphor alkaloid or its salt and 2-camphor, can be packaged as a single drug combination or in the form of a compound preparation, and can be administered separately or in the form of a compound oral preparation.

[0023] The 2-camphenol or its related compounds are preferably derived from natural borneol and (+)-2-camphenol with a purity ≥98%. Based on common sense in medicine and traditional Chinese medicine, the preferred alternatives are natural borneol, mugwort tablets, synthetic borneol, (+)-2-camphenol with a purity ≥98%, and (-)-2-camphenol.

[0024] Based on the administration routes and experimental results of animal models, the drug can be administered by injection or orally. According to common medical knowledge, this can be extended to include dosage forms such as injections, tablets, capsules, oral liquids, sublingual tablets, orally disintegrating tablets, sublingual films, sublingually disintegrating tablets, buccal films, lozenges, granules, powders, pills, powders, ointments, nasal sprays, suspensions, powders, suppositories, creams, nasal drops, sprays, drops, or patches.

[0025] Another object of the present invention is to provide an application of the above-mentioned pharmaceutical composition in the preparation of drugs for treating cardiovascular and cerebrovascular diseases, neurological diseases, vascular headaches, retinal vasospasm, central retinopathy, ischemic optic neuropathy, Parkinson's disease, motion sickness, bronchial asthma, organophosphorus pesticide poisoning, retinopathy, diabetic peripheral neuropathy, neurodegenerative diseases and other oxidative stress damage and thrombosis-related diseases, especially in drugs for acute ischemic stroke and related diseases.

[0026] In some embodiments, the present invention provides an injection of camphor alkaloid or its salt and (+)-2-camphor alcohol, wherein, in addition to the active ingredient, the injection also includes one or more of a solubilizer, antioxidant, osmotic pressure regulator, and pH regulator.

[0027] The co-solvent is one or more of ethanol, propylene glycol, isopropanol, or polyethylene glycol.

[0028] The osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, glucose, sorbitol, and xylitol.

[0029] The antioxidant is one or more of sodium bisulfite, sodium metabisulfite, sodium sulfate, and sodium sulfite.

[0030] The pH adjuster is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

[0031] The injection solution also needs to be protected with an inert gas, which is either nitrogen or carbon dioxide.

[0032] In some embodiments, the present invention provides a sublingual tablet of camphor alkaloid or its salt and (+)-2-borneol, wherein, in addition to the active ingredient, the sublingual tablet further includes one or more of the following types of excipients: fillers, binders, disintegrants, lubricants, and flavoring agents, wherein the excipient for preventing the volatilization of dexborneol is one or more of glyceryl behenate, stearic acid, crospovidone, and povidone. Detailed Implementation

[0033] The present invention will be further described below with reference to embodiments, but these embodiments do not constitute any limitation on the present invention.

[0034] In the examples, (+)-2-camphenol was obtained by purification or synthesis of natural borneol, with a purity of ≥98%, and is also known as dextrocamphenol.

[0035] Example 1:

[0036] Weigh 2g of (+)-2-camphenol, add 300ml of propylene glycol, stir until completely dissolved, slowly add water for injection to 90% of the total volume, add 2g of camphor hydrobromide to dissolve, adjust the pH to 3.0-6.0 with hydrochloric acid or sodium hydroxide and add to 1000ml to obtain the final product.

[0037] Example 2:

[0038] Weigh 2.5g of (+)-2-camphenol, add 300ml of propylene glycol, stir until completely dissolved, slowly add water for injection to 90% of the total volume, add 0.1g of camphor hydrobromide and 1g of sodium metabisulfite, dissolve, adjust the pH to 3.0-6.0 with hydrochloric acid or sodium hydroxide and add to 1000ml to obtain the final product.

[0039] Example 3:

[0040] Weigh 4g of (+)-2-camphenol, add 300ml of propylene glycol, stir until completely dissolved, slowly add water for injection to 90% of the total volume, add 0.5g of camphor hydrobromide and 1g of sodium metabisulfite, dissolve, adjust the pH to 3.0-6.0 with hydrochloric acid or sodium hydroxide and add to 1000ml to obtain the final product.

[0041] Example 4:

[0042] Weigh 3g of (+)-2-camphenol, add 500ml of propylene glycol, stir until completely dissolved, slowly add water for injection to 90% of the total volume, add 1g of camphor hydrobromide and dissolve, adjust the pH to 3.0-6.0 with hydrochloric acid or sodium hydroxide and add to 2000ml to obtain the final product.

[0043] Example 5:

[0044] Weigh 7.5g of (+)-2-camphenol, add 1200ml of propylene glycol, stir until completely dissolved, slowly add water for injection to 90% of the total volume, add 1g of camphor hydrobromide and dissolve it, adjust the pH to 3.0-6.0 with hydrochloric acid or sodium hydroxide and add to 5000ml to obtain the final product.

[0045] Example 6:

[0046] Weigh 10 g of (+)-2-borneol, add 2000 ml of propylene glycol, stir to dissolve completely, slowly add water for injection until the total volume reaches 90%, add scopoletin hydrobromide 1 g and dissolve it, adjust the pH to 3.0 - 6.0 with hydrochloric acid or sodium hydroxide and make up to 5000 ml to obtain the product.

[0047] The preparation process of the injection in the above Examples Ⅰ - Ⅵ also includes conventional steps such as filtration of the medicinal liquid, sterilization, nitrogen filling, and filling. During the filling process, nitrogen filling protection operation is required for the product.

[0048] Example 7:

[0049] Weigh 2 g of (+)-2-borneol, dissolve it in an appropriate amount of ethanol as a solvent for standby, add it to the mixed material containing 0.5 g of scopoletin 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 scopoletin hydrobromide and borneol sublingual tablets.

[0050] Example 8:

[0051] Weigh 2 g of (+)-2-borneol, melt and granulate 5 g of glyceryl behenate, crush and sieve through a 60-mesh sieve, then add it to the mixed material containing 0.5 g of scopoletin hydrobromide, 4 g of sodium carboxymethylcellulose, 66 g of mannitol, and 3 g of polyvinylpyrrolidone, add 1 g of stearic acid and mix, and press into 1000 tablets of scopoletin hydrobromide and borneol sublingual tablets.

[0052] Example 9: Pharmacodynamic experiment of the different compatibility of scopolamine and 2-borneol on rats with ischemic stroke

[0053] Objective: The experiment intends to adopt the intravenous injection administration method, and take the balance beam passing time, cerebral blood flow difference, and cerebral infarction area as indexes to investigate the protective effects of different drug compatibilities on rats with focal cerebral ischemia-reperfusion (MCAO).

[0054] Experimental animals:

[0055] 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.

[0056] Number of animals included in the group: 72, animal body weight at the start of the experiment: about 180 - 200 g. Experimental method:

[0057] Grouping: After 4 days of acclimatization, all rats in each group underwent behavioral training (balance beam, tumbling bar) three days before surgery. SD rats were evenly divided into 9 groups according to body weight: sham operation group, model group, positive control drug group (Edaravone Dexborneol injection), camphor hydrobromide group, Dexborneol group ((+)-2-camphorol), camphor hydrobromide and Dexborneol compound group 1, camphor hydrobromide and Dexborneol compound group 2, camphor hydrobromide and Dexborneol compound group 3, and camphor hydrobromide and Dexborneol compound group 4, with a total of 8 rats in each group, and appropriate reserve animals were kept in reserve.

[0058] Model Establishment: Rats were fasted for 12 hours before surgery but had free access to water. Animals in all groups were anesthetized with isoflurane before surgery, maintaining spontaneous respiration. They were fixed in a supine position on a rat board, with hair removed from the midline of the neck and disinfected with 75% alcohol. A surgical incision was made on the ventral side of the neck midline, separating the muscle and fascia along the inner edge of the sternocleidomastoid muscle. The right common carotid artery, external carotid artery, and internal carotid artery were then isolated. A small oblique incision was made on the external carotid artery approximately 0.5 cm proximal to the ligation site using vascular scissors. The external carotid artery was pulled proximal to the heart until it was aligned with the internal carotid artery. The suture occluded the rat and slowly advanced 1.8 cm towards the internal carotid artery through the incision on the right external carotid artery, marking the bifurcation of the common carotid artery. Slight resistance was felt during advancement, indicating that the middle cerebral artery had been blocked. The suture occluded 2 hours after infarction, completing the cerebral ischemia-reperfusion injury model. The sham-operated group only underwent vascular dissection. Twenty minutes after infarction, cerebral blood flow was assessed using Doppler flowmetry. A model was considered successful and enrolled in the experiment if the difference in blood flow between the left and right hemispheres (ROI%) was greater than 48%. Incandescent lamps were used to maintain rectal temperature during the procedure.

[0059] Administration: The drugs in each group were administered intravenously 0.5 h after cerebral infarction and 12 h after reperfusion. The sham-operated group and the model group were given the same volume of blank solvent. The blank solvent was 8% propylene glycol + 92% physiological saline. All samples were dissolved or diluted to the target concentration with the blank solvent. The sham-operated group and the model group were given blank solvent. The positive control group was given edaravone dexborneol injection. The camphor hydrobromide group was given camphor hydrobromide solution. The dexborneol group was given dexborneol solution. The camphor hydrobromide and dexborneol compound group was given a mixed solution of camphor hydrobromide and dexborneol. The grouping and detailed administration information are shown in Table 1.

[0060] Table 1: Experimental Groups and Drug Administration Information

[0061] At the end of the experiment (24 hours after reperfusion), changes in cerebral blood flow were measured in all animals using Doppler flowmeter to assess the ameliorative effect of the test substance on ischemic stroke; a balance beam time-passing function test was performed; and continuous coronal sections of the whole brain were stained with TTC and photographed. The infarct area was measured using Image-J software, the percentage of the infarct area to the whole brain area was calculated, the infarct improvement rate was calculated, and the synergistic effect was preliminarily assessed using the King's formula.

[0062] Note: (1) Infarct area ratio = total infarct area ÷ total area of ​​whole brain slice × 100%;

[0063] Infarction improvement rate = (infarction area ratio in the model group - infarction area ratio in the treatment group) ÷ infarction area ratio in the model group × 100%;

[0064] (2) King's formula: q = E (A+B) / (E A +E B -E A ·E B E A E B and E (A+B) The infarct protection rates were calculated for single-agent A, single-agent B, and combination therapy, respectively.

[0065] (3) Experimental data are expressed as Mean±SD. SPSS21.0 software was used for corresponding statistical analysis. If p<0.05, it is considered to be statistically significant; if p<0.01, it is considered to be statistically extremely significant.

[0066] Experimental results:

[0067] (1) The results of the effect on the balance beam time test of MCAO rats are summarized in Table 2:

[0068] Table 2. Effect of intravenous injection of the test substance on the balance beam crossing time of MCAO rats (x±SD, n=8) ## p<0.01 vs. sham surgery group; *p<0.05, **p<0.01 vs. model group

[0069] (2) The results of the effect on the cerebral infarction area of ​​MCAO rats are summarized in Table 3:

[0070] Table 3. Effect of intravenous injection of the test substance on the ratio of cerebral infarction area in MCAO rats (x±SD, n=8) ## p<0.01 vs. sham surgery group; *p<0.05, **p<0.01 vs. model group

[0071] Experimental conclusion:

[0072] Both the test substances, camphor hydrobromide and dextromethorphan, when administered alone, effectively improved the balance beam passage time in MCAO rats; both significantly reduced the cerebral infarction area in MCAO rats and increased the improvement rate of cerebral infarction in rats.

[0073] Both the test substance camphor hydrobromide and dextromethorphan were administered in combination to effectively improve the balance beam passage time of MCAO rats; both significantly reduced the cerebral infarction area of ​​MCAO rats and increased the improvement rate of cerebral infarction in rats.

[0074] The combination of camphor hydrobromide and dextroborneol is superior to the administration of the test substance camphor hydrobromide or dextroborneol or the positive control drug succinate alone.

[0075] In the MACO rat model, the efficacy of camphor hydrobromide does not increase with increasing dosage, as reported in numerous studies. In this invention, the combined ratio of camphor hydrobromide and dextroborneol gradually increased from 1:1 to 1:10, but the effect decreased at a ratio of 1:15. Overall, the best performance was observed in group 3 (1:10 ratio) of the combined camphor hydrobromide and dextroborneol.

[0076] The infarct improvement rate of the group treated with camphor hydrobromide (0.30 mg / kg), dexborneol (0.9 mg / kg), and the combination of camphor hydrobromide and dexborneol (0.3 + 0.9 mg / kg) was calculated according to the King's formula, q = 1.19. This indicates that the combined use of camphor hydrobromide and dexborneol can exert a synergistic effect in the treatment of ischemic stroke.

[0077] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

[0078] Attached image:

[0079] Figure 1: Summary of the effects of intravenous injection of the test substance on the balance beam time of MCAO rats

[0080] Figure 2: Summary of the effects of intravenous injection of the test substance on the infarct area ratio in MCAO rats

Claims

1. A pharmaceutical composition comprising camphor alkaloid or its salt and 2-camphor or its related compounds as active ingredients, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:1 to 1:

25.

2. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:1 to 1:

15.

3. The pharmaceutical composition according to claim 2, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:3 to 1:

10.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

3.

5. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

4.

6. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

5.

7. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

6.

8. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

7.

9. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

8.

10. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

9.

11. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that, The weight ratio of camphor alkaloid or its salt to 2-camphor or its related compounds is 1:

10.

12. The pharmaceutical composition according to any one of claims 1 to 11, characterized in that, Camphor-salicylic acid or its salts and 2-camphor can be available in single-drug combination packaging or in combination formulations, and can be administered individually or in combination formulations.

13. The pharmaceutical composition according to any one of claims 1 to 12, characterized in that, The camphor-willow alkaloid salt is selected from hydrobromide, hydrochloride, sulfate, hydrogen sulfate, hydrogen phosphate and other pharmaceutically acceptable salts, with hydrobromide being preferred.

14. The pharmaceutical composition according to any one of claims 1 to 12, characterized in that... The active ingredient 2-camphenol or its related compounds are selected from one or more of natural borneol, (+)-2-camphenol, borneol, artemisia, synthetic borneol, and artificially synthesized (+)-2-camphenol and (-)-2-camphenol with a purity ≥98%, preferably natural borneol, (+)-2-camphenol, and artificially synthesized (+)-2-camphenol with a purity ≥98%.

15. The pharmaceutical composition according to any one of claims 1 to 14, characterized in that, It also includes pharmaceutically acceptable excipients.

16. The pharmaceutical composition of claim 15, characterized in that, The dosage form of the pharmaceutical composition is selected from: injections, tablets, capsules, oral liquids, sublingual tablets, orally disintegrating tablets, sublingual films, sublingually disintegrating tablets, buccal films, lozenges, granules, powders, pills, powders, ointments, nasal sprays, suspensions, powders, suppositories, creams, nasal drops, sprays, drops, or patches.

17. The pharmaceutical composition of claim 16, characterized in that, The pharmaceutical composition is an injectable preparation, and the pharmaceutically acceptable excipients include one or more of the following: solubilizers, antioxidants, osmotic pressure regulators, and pH regulators.

18. The injectable formulation as described in claim 17, characterized in that, The co-solvent is one or more of ethanol, propylene glycol, isopropanol, or polyethylene glycol.

19. The injectable formulation as described in claim 17, characterized in that, The osmotic pressure regulator is one or more of sodium chloride, potassium chloride, magnesium chloride, glucose, sorbitol, and xylitol.

20. The injectable formulation as described in claim 17, characterized in that, The antioxidant is one or more of sodium bisulfite, sodium metabisulfite, sodium sulfate, and sodium sulfite.

21. The injectable formulation as described in claim 17, characterized in that, The pH adjuster is one or more of hydrochloric acid, sulfuric acid, sodium hydroxide, sodium dihydrogen phosphate, and potassium dihydrogen phosphate.

22. The injectable formulation as described in claim 17, characterized in that, It requires filling the headspace with an inert gas to suppress the volatilization of dextromethorphan, wherein the inert gas is one of nitrogen or carbon dioxide.

23. The pharmaceutical composition of claim 16, characterized in that... In addition to the active ingredient, the oral solid dosage forms such as sublingual tablets and tablets also include the following types of excipients: fillers, binders, disintegrants, lubricants, flavoring agents, and excipients to prevent the volatilization of 2-camphor or its related compounds.

24. The sublingual tablet as described in claim 23, characterized in that, The oral solid dosage forms such as sublingual tablets and tablets are characterized in that the excipients used to prevent the volatilization of 2-camphor or its related compounds are one or more of glyceryl behenate, stearic acid, crospovidone, and povidone.

25. The use of the pharmaceutical composition according to any one of claims 1-24 in the preparation of a medicament for treating cardiovascular diseases, cerebrovascular diseases, neurological diseases, vascular headaches, retinal vasospasm, central retinopathy, ischemic optic neuropathy, Parkinson's disease, motion sickness, bronchial asthma, organophosphorus pesticide poisoning, retinopathy, diabetic peripheral neuropathy, neurodegenerative diseases, and other oxidative stress-related diseases and thrombosis-related diseases.

26. The application as described in claim 25, characterized in that, The cerebrovascular disease referred to ischemic stroke or its resulting neurological symptoms, activities of daily living, and functional impairments.

27. The application as described in claims 25-26, characterized in that, The cerebrovascular disease referred to is hemorrhagic stroke or the resulting neurological symptoms, activities of daily living, and functional impairments.

28. The application as described in claims 25-26, characterized in that, The ischemic stroke refers to acute ischemic stroke or the resulting neurological symptoms, activities of daily living, and functional impairments.

29. The application as described in claims 25-26, characterized in that, The cerebrovascular disease mentioned refers to acute paralysis caused by acute ischemic stroke.

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