WO2023065071A1 - Utilisation de bornéol dans la préparation d'un médicament pour le traitement d'un accident vasculaire ischémique cérébral - Google Patents

Utilisation de bornéol dans la préparation d'un médicament pour le traitement d'un accident vasculaire ischémique cérébral Download PDF

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WO2023065071A1
WO2023065071A1 PCT/CN2021/124428 CN2021124428W WO2023065071A1 WO 2023065071 A1 WO2023065071 A1 WO 2023065071A1 CN 2021124428 W CN2021124428 W CN 2021124428W WO 2023065071 A1 WO2023065071 A1 WO 2023065071A1
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stroke
injection
ischemic stroke
drug
administration
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PCT/CN2021/124428
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English (en)
Chinese (zh)
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鱼刚
江传亮
邓世平
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苏州沪云新药研发股份有限公司
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Priority to PCT/CN2021/124428 priority Critical patent/WO2023065071A1/fr
Publication of WO2023065071A1 publication Critical patent/WO2023065071A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present application relates to the field of biomedicine, in particular to the use of borneol in the preparation of medicines for treating ischemic stroke.
  • Stroke is the second leading cause of human death and the leading cause of death in my country. It is also listed as the third leading cause of death along with ischemic heart disease and malignant tumors.
  • the current number of stroke patients aged 40 and above in my country It has reached 12.42 million, and it is showing an increasing trend year by year. On average, one person has a stroke every 7 seconds, and one person dies of a stroke every 21 seconds.
  • the mortality rate of hospitalized stroke patients in my country is 2.3% to 3.2% within 1 month after onset, 9% to 9.6% in 3 months, 34.5% to 37.1% in 3 months, and 14.4% in 1 year ⁇ 15.4%, 1-year death/disability rate 33.4% ⁇ 33.8%.
  • Ischemic stroke has the characteristics of high morbidity, high disability and high mortality. It is one of the main causes of death for adults in my country. It is also the disease with the highest disability rate of a single disease, which brings heavy burdens to society and families (Stroke-1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders [J]. Stroke, 1989, 20(10): 1407-1431; Acute ischemia in China Guidelines for Diagnosis and Treatment of Acute Stroke 2018; China Cardiovascular Disease Report 2018).
  • Stroke includes ischemic stroke and hemorrhagic stroke.
  • Cerebral ischemic stroke is the localized ischemic necrosis or softening of brain tissue caused by cerebral blood circulation disorder and ischemia and hypoxia. The main causes include: large artery atherosclerosis, small artery sclerosis and occlusion due to factors such as high blood pressure, blood-derived embolism, increased blood viscosity, and vasospasm.
  • Acute ischemic stroke generally refers to stroke within two weeks of onset, accounting for 69.6%-70.8% of all strokes. In my country, there are more than 2 million new patients with acute ischemic stroke each year (Wang W, Jiang B, Sun H , et al.
  • thrombolysis In addition to effective secondary prevention and stroke rehabilitation for ischemic stroke, there are currently very limited treatment options in the acute phase, mainly including thrombolysis, endovascular interventional therapy, and neuroprotection. Due to the limited treatment time window ( ⁇ 4.5h) and many contraindications, only a small number of patients ( ⁇ 3%) benefited from thrombolysis.
  • 3Animal model The animals used in preclinical tests are generally young and healthy male animals with uniform body weight and age, a single model of cerebral ischemia, and generally no other concurrent diseases; There is no significant difference, and generally accompanied by a variety of chronic diseases (such as arteriosclerosis, hypertension, diabetes and previous stroke history, etc.), these concomitant diseases will not only affect the functional recovery of patients, but also affect the efficacy, metabolism and safety of drugs .
  • chronic diseases such as arteriosclerosis, hypertension, diabetes and previous stroke history, etc.
  • 4Drug treatment time window Preclinical animal experiments can carry out drug treatment or prevention at any time point after ischemia, and the method and route of administration can also be determined and adjusted according to requirements; however, when cerebral ischemia occurs in clinical patients is unpredictable It is estimated that medication in advance is not feasible at all, and it will take some time from the occurrence of cerebral ischemia to the treatment of the doctor. In clinical practice, the possibility of drug treatment within 2 hours after the occurrence of cerebral ischemia is very small. The treatment time window for most patients is 6 hours or longer after stroke. 5Other factors (Chin J Clin Pharmacol2013, 29(11), 869-871).
  • Huang Ruxun a famous neurology expert in my country, proposed the principle of individualized treatment based on classification and staging.
  • TOAST analysis standards include five categories:
  • LAA Large-artery atherosclerosis
  • Cardioembolism cardiac embolism, CE: This category includes cerebral embolism caused by a variety of diseases that can produce cardioembolism. High and moderate risk factors for embolism.
  • Small arterial (sex) stroke (lacunar infarction, SAA): it can be diagnosed if one of the following three criteria is met: (1) It has a typical lacunar infarction syndrome, and the imaging findings are consistent with Stroke with consistent clinical manifestations and lesions with the largest diameter ⁇ 1.5cm; (2) stroke with typical lacunar infarction syndrome, but no corresponding lesion found in imaging; (3) atypical lacunar infarction Syndrome, but the imaging examination found a stroke with a lesion of ⁇ 1.5 cm consistent with the clinical manifestations.
  • Ischemic stroke caused by other causes This category includes cerebral infarction caused by other clear causes (hypercoagulable state, blood system disease, drug use, etc.).
  • NIHSS National Institutes of Health Stroke Scale
  • the NIHSS score has a total of 42 points and 11 items. It has been widely used in international multi-center randomized controlled studies. It is a recognized scoring system for stratifying the severity of stroke patients.
  • the scoring items and scoring standards are as follows:
  • ischemic stroke with NIHSS score ⁇ 5 points is “mild ischemic stroke”
  • ischemic stroke with 6 ⁇ NIHSS score ⁇ 15 points is “moderate ischemic stroke”.
  • Stroke "ischemic stroke with 15 ⁇ NIHSS score ⁇ 20 points” as “moderate-severe ischemic stroke” or “severe ischemic stroke”
  • ischemic stroke with NIHSS score > 20 Stroke is "very critical ischemic stroke”.
  • NIHSS score In clinical practice, using the NIHSS score to classify ischemic stroke is used to select the treatment population, which is conducive to finding accurate and effective populations.
  • endovascular treatment it is clearly stated in the "Chinese Expert Consensus on Endovascular Therapy for Acute Large Vessel Occlusive Ischemic Stroke (Revised 2019)" that acute large vessel occlusive ischemia in the anterior circulation with NIHSS score ⁇ 6 points
  • Patients with acute stroke (AIS-LVO) benefit from endovascular therapy, but endovascular therapy may be reasonable for patients with NIHSS score ⁇ 6.
  • patients with NIHSS score ⁇ 6 points benefit still needs to be further evaluated. They may benefit, or may not benefit, or even worse.
  • (+)-2-camphor is usually used as a drug adjuvant for the treatment of stroke and other diseases, such as in combination with active ingredients such as edaravone for the treatment of stroke, but there is no (+) - A report of 2-borneol alone as an active ingredient in the treatment of patients with ischemic stroke.
  • the (+)-2-camphorol of a single component has a high degree of selectivity to the ischemic stroke patient population, and in the treatment of some types or subtypes of ischemic stroke patients Excellent therapeutic effect (such as cardioembolic stroke, small artery occlusion stroke, non-hypertensive stroke, recurrent stroke, stroke with NIHSS score ⁇ 6 points), while in another part of the type or The effect is relatively poor or not effective in patients with type of ischemic stroke (such as large artery atherosclerotic stroke, stroke with NIHSS score ⁇ 5 points).
  • (+)-2-borneol has good human safety, and (+)-2-borneol alone as an active ingredient in the treatment of stroke can effectively avoid the use of other active ingredients in ischemic stroke prevention and/or Or adverse reactions during treatment (such as combined use of edaravone, because the addition of edaravone will cause serious liver and kidney toxicity).
  • (+)-2-camphor alone can improve the dosage of (+)-2-camphor as an active ingredient in human body (such as combined use with edaravone is limited by edaravone toxicity, (+)- The single dose of 2-camphorol is limited to 7.5mg), so as to improve the prevention and/or treatment effect of ischemic stroke.
  • (+)-2-camphorol as the only active ingredient in the preparation of a medicament for treating patients with specific ischemic stroke subtypes or types.
  • Another object of the present application is to provide a medicine for treating patients with specific ischemic stroke subtype or type, which comprises the only active ingredient (+)-2-camphor, its pharmaceutically acceptable salt or One or a combination of esters, prodrugs thereof, metabolites thereof, and solvates thereof.
  • Another object of the present invention is to provide a method for treating ischemic stroke, comprising administering (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, or its precursor to a subject in need thereof.
  • the application provides the use of (+)-2-camphorol in the preparation of drugs for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from cardiogenic (sexual) Any one or combination of embolism stroke, arteriolar occlusion (sex) stroke, non-hypertensive (sex) stroke, and recurrent (sex) stroke, and/or the ischemic stroke NIHSS score ⁇ 6 points for stroke.
  • the application provides the use of (+)-2-camphor in the preparation of a drug for improving the effect of ischemic stroke prevention and/or treatment, wherein the ischemic stroke is selected from cardiogenic Any one or combination of embolic stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the preventive and/or therapeutic effects are selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the daily activity of patients.
  • the effect of (+)-2-camphor is selected from the group consisting of regulating energy metabolism and redox metabolism, improving the survival rate of ischemic injured neurons, and reducing the size of cerebral infarction caused by ischemic stroke , improving any one or combination of neurobehavioral features of ischemic stroke.
  • the application provides the use of (+)-2-camphorol in the preparation of drugs for reducing or avoiding adverse reactions in the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke Stroke is selected from any one or combination of cardioembolic stroke, arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the ischemic stroke NIHSS score ⁇ 6 points.
  • the way of reducing or avoiding the adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, and improving the brain function of patients. Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the other drugs are selected from any one of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents, or a combination thereof use.
  • the ischemic stroke is selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points.
  • the present application provides the use of (+)-2-camphor in the preparation of a medicament for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from moderate, moderate-severe Or any of the patients with severe ischemic stroke.
  • the medicament comprises (+)-2-borneol as the active ingredient only.
  • the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  • the content of (+)-2-camphor in the medicament is about 5 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg.
  • the (+)-2-camphor also includes pharmaceutically acceptable salts or esters thereof, metabolites thereof, prodrugs thereof, or solvates thereof.
  • the medicament contains pharmaceutically acceptable excipients.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome Agents, suspensions, ointments, creams, transdermal absorption agents, transmucosal absorption agents, lozenges, drops, drop pills, pills, capsules, powders, powders, liniments, fine granules, syrups.
  • the present application provides a drug, the active ingredient of which is selected from the group consisting of (+)-2-borneol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate one or a combination thereof; the dosage of the active ingredients is from about 5 mg to about 40 mg.
  • the medicament further includes one or more pharmaceutically acceptable excipients.
  • the active ingredient is released from the medicament rapidly or sustainably, eg, delayed or pulsed.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome Agents, suspensions, ointments, creams, transdermal absorption agents, transmucosal absorption agents, lozenges, drops, drop pills, pills, capsules, powders, powders, liniments, fine granules, syrups.
  • the medicament is formulated to be administered by intravenous injection, intraarterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional Any one or a combination of drug delivery, implant drug delivery, patch drug delivery and smear drug delivery.
  • the administration is by parenteral administration, and the drug is in the form of injection, powder injection, or solution.
  • the concentration of the active ingredient is about 0.01 mg/mL to about 5 mg/mL, preferably about 0.1 mg/mL to about 2.5 mg/mL.
  • the drug is prepared as an injection or powder injection of about 5 mL to about 500 mL, and the content of the active ingredient is about 5 mg to 40 mg.
  • the dose of the active ingredient is formulated from about 5 mg to the maximum daily dose.
  • the dose of the active ingredient is formulated to be about 5 mg to about 40 mg.
  • the present application provides a kit, which comprises the aforementioned medicine.
  • the present application provides a method for preventing and/or treating ischemic stroke, comprising administering to a subject in need only an effective amount of a drug, the active ingredient of which is selected from (+)-2 - one or a combination of camphenol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate, the ischemic stroke is selected from cardioembolic stroke Any one or combination of stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • it also includes combining the drug with any one or a combination of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents Combined use.
  • the present application provides a method for improving the effect of preventing and/or treating ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the active ingredient of which is selected from (+) - one or a combination of 2-borneol, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the ischemic stroke is selected from cardiogenic embolism Any one or combination of acute stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the preventive and/or therapeutic effect is selected from any one or a combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the patient's ability to perform daily activities.
  • the effect of the active ingredient is selected from the group consisting of regulating energy metabolism and redox metabolism, increasing the survival rate of neurons injured by ischemia, reducing the size of cerebral infarction caused by ischemic stroke, and improving ischemic cerebral infarction. Any one or combination of neurobehavioral features of stroke.
  • the present application provides a method for reducing or avoiding adverse reactions during the prevention and/or treatment of ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the drug's
  • the active ingredient is selected from one or a combination of (+)-2-camphor, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the ischemic brain
  • the stroke is selected from any one or combination of cardioembolic stroke, arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS of the ischemic stroke Score ⁇ 6 points.
  • the way of reducing or avoiding adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, providing patients with Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the other drugs are selected from any one of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents, or a combination thereof use.
  • the administration route of the drug includes intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional administration, implant Injection administration, patch administration and/or smear administration.
  • the drug is administered parenterally.
  • the medicament is administered intravenously.
  • the active ingredient is administered at a dose of at least about 5 mg up to a maximum daily dose.
  • the active ingredient is administered in a daily dose of at least about 5 mg to about 40 mg.
  • the active ingredient is administered at a daily dose of about 10 mg/day to about 20 mg/day.
  • said daily dose is administered as a single dose or in multiple single doses.
  • the pharmaceutical formulation is used for a long period of time, preferably up to several days, weeks or months.
  • the drug may be administered during periods including cerebral infarction, surgery or other drug therapy, stroke rehabilitation, before thrombectomy, after thrombectomy, before thrombolysis and/or after thrombolysis .
  • stroke is well known in the art.
  • a stroke can be occlusive (due to a closed blood vessel) or hemorrhagic (due to bleeding from a blood vessel).
  • ischemia refers to the lack of blood supply and oxygen that occurs when autoregulatory dilation of resistive blood vessels fails to compensate for reduced perfusion pressure distal to abnormal narrowing (coarctation) of blood vessels.
  • strokes of either type can occur at any age for a variety of reasons, These causes include heart disease, trauma, infection, tumors, blood dyscrasias, vascular malformations, immune disorders, and exogenous toxins.
  • stroke generally refers to ischemic stroke, usually due to decreased blood flow to the brain or parts thereof, which results in insufficient oxygen supply to brain cells.
  • a stroke causes irreversible tissue damage due to the death of brain cells.
  • the symptoms of stroke are well known in the art. For example, stroke symptoms include sudden numbness or weakness in the face, arm, or leg (especially on one side of the body), sudden confusion, trouble speaking or understanding, sudden loss of vision in one or both eyes, and sudden trouble walking , dizziness, loss of balance or coordination.
  • Ischemic stroke may result from atherothrombosis or cerebral aortic embolism, from coagulopathy or nonneoplastic vascular disease, or from cardiac ischemia that results in a decrease in total blood flow. Examples include atherothrombotic stroke, cardioembolic stroke, and lacunar stroke. Atrial fibrillation can also cause cardioembolic stroke (also often called embolic or thromboembolic stroke).
  • (+)-2-borneol also known as d-borneol or ((+)-borneol)
  • (+)-2-borneol is the main component of natural borneol (the 2015 edition of Chinese Pharmacopoeia stipulates that the content of d-borneol in natural borneol should not be less than 96%) .
  • Dextamphalol is a bicyclic monoterpenoid compound, which exists in the volatile oil of many Chinese herbal medicines, and exhibits various biological activities, such as anti-inflammatory, anti-oxidation and enhancing GABA receptor function, etc. (Euro J Pharma 2017,811:1 -11).
  • the structural formula of D-borneol is as follows:
  • the term "pharmaceutically acceptable salt” generally means suitable for use in contact with the tissues of the subject without undue toxicity, irritation, allergic reaction, etc. within the scope of sound medical judgment, and with Take those with a reasonable benefit/risk ratio with a grain of salt.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.
  • prodrug generally refers to a compound that is readily converted in vivo (eg, by enzymes in the blood) by enzymatic hydrolysis to yield the parent compound.
  • a comprehensive discussion is provided in T. Higuchi and V. Stella in the A.C.S. Proceedings series, Prodrugs as Novel Delivery Systems, Volume 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Permagon Press, 1987 , both of which are incorporated herein by reference.
  • the term "metabolite” generally refers to a derivative of any formula that is produced in an individual following administration of a parent compound (eg, (+)-2-borneol).
  • parent compound eg, (+)-2-borneol
  • These derivatives can be produced from the parent compound by various biochemical transformations in the body of an individual such as oxidation, reduction, hydrolysis or conjugation, and include, for example, oxide and demethylated derivatives.
  • Metabolites of the compounds of the invention can be identified using routine techniques known in the art. See, eg, Bertolini, G. et al., J. Med. Chem. 40: 2011-2016 (1997); Shan, D. et al., J. Pharm. Sci. 86(7): 765-767; Bagshawe K. , Drug Dev. Res.
  • solvate is used in a conventional sense, generally referring to a complex of a solute (eg, an active compound, a salt of an active compound) and a solvent. If the solvent is water, the solvate may conveniently be referred to as a hydrate.
  • the term "pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), Isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc., and combinations thereof (See e.g. Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carriers are incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
  • prevention and/or treatment includes not only preventing and/or treating a disease, but also generally preventing the onset of a disease, slowing or reversing the progression of a disease, preventing or slowing down one or more symptoms associated with a disease onset, reduction and/or alleviation of one or more symptoms associated with the disease, reduction of the severity and/or duration of the disease and/or any symptoms associated therewith and/or prevention of the disease and/or any symptoms associated therewith prevent, reduce or reverse any physiological impairment caused by the disease, and generally any pharmacological effect that is beneficial to the patient being treated.
  • disease or “condition” are used interchangeably and generally refer to any deviation from the normal state of a subject, such as any change in the state of the body or certain organs that prevents or disrupts the performance of function , and/or cause symptoms such as malaise, dysfunction, suffering or even death in those who are sick or come into contact with it.
  • a disease or condition may also be called a disorder, ailing, ailment, malady, disorder, sickness, illness, complaint, inderdisposion or affectation.
  • the term "administration" generally refers to introducing the pharmaceutical formulation of the present application into the body of a subject by any route of introduction or delivery. Any method known to those skilled in the art for contacting cells, organs or tissues with the drug may be used. Such administration may include, without limitation, intravenous, intraarterial, intranasal, intraperitoneal, intramuscular, subcutaneous transdermal or oral.
  • the daily dose may be divided into one, two or more doses of suitable form to be administered at one, two or more times during a certain period of time.
  • the term “effective amount” or “effective dose” generally refers to an amount sufficient to achieve, or at least partially achieve, the desired effect.
  • a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is typically one that, when used alone or in combination with another therapeutic agent, promotes regression of disease (by reducing the severity of disease symptoms, frequency of asymptomatic periods of disease), any amount of drug that is evidenced by an increase in the degree and duration of the disease, or by the prevention of impairment or disability due to the presence of a disease.
  • a “prophylactically effective amount” or “prophylactically effective dose” of a drug generally refers to the amount of the drug that, alone or in combination with another therapeutic agent, inhibits the development or recurrence of the disease when administered to a subject at risk of disease development or disease recurrence .
  • the ability of a therapeutic or prophylactic agent to promote disease regression or inhibit disease progression or recurrence can be assessed using a variety of methods known to those skilled in the art, such as in human subjects during clinical trials, in animal model systems Efficacy in humans is predicted, or by assaying the activity of the agent in an in vitro assay.
  • the term "subject” generally refers to a human or non-human animal (including mammals), such as a human, a non-human primate (ape, or , gibbons, gorillas, chimpanzees, orangutans, macaques), domestic animals (dogs and cats), farm animals (poultry such as chickens and ducks, horses, cows, goats, sheep, pigs) and laboratory animals (mice, rats, rabbits , guinea pig).
  • Human subjects include fetal, neonatal, infant, adolescent and adult subjects.
  • Subjects include animal disease models.
  • the term “about” generally means approximately, in the vicinity of, roughly, or around.
  • a cut-off or a specific value is used to indicate that the stated value may vary by as much as 10% from the recited value.
  • the term “about” may be used to encompass a variation of ⁇ 10% or less, ⁇ 5% or less, ⁇ 1% or less, ⁇ 0.5% or less, or ⁇ 0.5% or less from the specified value. 0.1% or less variation.
  • the term “type” and “sex” have the same meaning, or the meaning is equivalent after omitting "type” or “sex”, such as “cardiogenic embolism stroke” has the same meaning "Cardiogenic embolic stroke”, “small artery occlusive stroke” is the same as “small artery occlusive stroke”, “non-hypertensive stroke” is the same as “non-hypertensive stroke”, “recurrent stroke” Stroke” is the same as “recurrent stroke”.
  • stroke has the same meaning as "stroke” for the name of the disease.
  • ischemic stroke usually refers to "ischemic stroke with NIHSS score ⁇ 5 points”
  • moderate ischemic stroke usually refers to "6 ⁇ NIHSS score ⁇ 15
  • Score ischemic stroke "severe ischemic stroke” or “moderate-severe ischemic stroke” usually refers to "ischemic stroke with 15 ⁇ NIHSS score ⁇ 20 points”
  • critically ill ischemic stroke Hemorrhagic stroke
  • the present application provides the use of (+)-2-camphor in the preparation of a medicament for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from cardiogenic embolism Any one or combination of stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the ischemic stroke may be selected from any one of cardiogenic embolic stroke, arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, or combination.
  • the ischemic stroke may be cardioembolic stroke or arteriolar occlusive stroke.
  • the ischemic stroke may be cardioembolic stroke combined with non-hypertensive stroke (no history of hypertension).
  • the ischemic stroke may be arteriolar occlusive stroke combined with non-hypertensive stroke (no history of hypertension) and recurrent stroke (with history of stroke).
  • the ischemic stroke can be selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points. In other embodiments, the ischemic stroke can be selected from ischemic stroke with NIHSS score>20.
  • the ischemic stroke score may be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.
  • the ischemic stroke may be cardioembolic stroke or arteriolar occlusion stroke, and the score of the ischemic stroke may be 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the medicament comprises only one of (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, a metabolite thereof, a prodrug thereof, and a solvate thereof, or Combination as active ingredient.
  • the medicament contains only (+)-2-borneol as active ingredient.
  • the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  • the content of (+)-2-camphor in the medicament may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg.
  • the medicament contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include, but are not limited to: for example, fats, beeswax, semi-solid and liquid polyols, natural or hydrogenated oils, etc.; water (for example, distilled water, especially distilled water for injection, etc.) , physiological saline, alcohol (for example, ethanol), glycerin, polyol, dextrose aqueous solution, mannitol, vegetable oil, etc.); additives [for example, expander, disintegrant, binder, lubricant, wetting agent, stabilizer , emulsifiers, dispersants, preservatives, sweeteners, colourants, flavoring or perfuming agents, concentrates, diluents, buffer substances, solvents or solubilizers, chemicals for effect storage, for regulating osmotic Compressed salt, coating agent or antioxidant] etc.
  • water for example, distilled water, especially distilled water for injection, etc.
  • physiological saline for example, alcohol (
  • the pharmaceutically acceptable excipient may be a form of water that is suitable for pharmaceutical or biological preparation and that is different from water that occurs in nature, including purified water, water for injection, Sterile purified water, bacteriostatic water for injection, and sterile water for injection (which is a sterile, bacterium-free, solute-free preparation of distilled water for injection).
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome formulation, suspension, ointment, cream, percutaneous absorption, transmucosal absorption, lozenge, drop, drop pill, pill, capsule, powder, powder, liniment, fine granule or syrup.
  • the dosage form of the drug may be an injection, a powder injection or a solution suitable for intravenous injection or intracranial injection.
  • the administration route of the drug includes intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional administration, implant Any one or combination of injection administration, patch administration and smear administration.
  • the drug can be administered in the following stages, including the period of cerebral infarction, the period of surgery or drug treatment, the period of stroke rehabilitation, before thrombectomy, after thrombectomy, before thrombolysis and/or after thrombolysis.
  • the drug can be administered at the stage of cerebral infarction, operation or drug treatment, before thrombectomy, and before thrombolysis.
  • the drug can be administered during stroke rehabilitation, after thrombectomy, and after thrombolysis.
  • the drug can be administered at all stages, for example, before thrombectomy, during surgery or drug treatment and after thrombectomy, before thrombolysis, during surgery or drug treatment and after thrombolysis.
  • the present application provides the use of (+)-2-camphor in the preparation of a drug for improving the effect of ischemic stroke prevention and/or treatment, wherein the ischemic stroke is selected from cardiogenic Any one or combination of thromboembolic stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the preventive and/or therapeutic effects are selected from any one or combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the daily activity of patients.
  • the effect of (+)-2-camphor is selected from the group consisting of regulating energy metabolism and redox metabolism, improving the survival rate of ischemic injured neurons, and reducing the size of cerebral infarction caused by ischemic stroke , improving any one or combination of neurobehavioral features of ischemic stroke.
  • the medicament comprises only one of (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, a metabolite thereof, a prodrug thereof, and a solvate thereof, or Combination as active ingredient.
  • the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  • the content of (+)-2-camphor in the medicament may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg.
  • the medicament contains pharmaceutically acceptable excipients.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome formulation, suspension, ointment, cream, percutaneous absorption, transmucosal absorption, lozenge, drop, drop pill, pill, capsule, powder, powder, liniment, fine granule or syrup.
  • the dosage form of the drug can be injection, powder injection, solution and other dosage forms suitable for intravenous injection or intracranial injection.
  • the administration route of the drug includes intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional administration, implant Any one or combination of injection administration, patch administration and smear administration.
  • the drug can be administered in the following stages, including the period of cerebral infarction, the period of surgery or drug treatment, the period of stroke rehabilitation, before thrombectomy, after thrombectomy, before thrombolysis and/or after thrombolysis.
  • the present application provides the use of (+)-2-camphorol in the preparation of medicines for reducing or avoiding adverse reactions in the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke
  • the stroke is selected from any one or a combination of cardioembolic stroke, arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the ischemic stroke NIHSS score ⁇ 6 points.
  • the way of reducing or avoiding the adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, and improving the brain function of patients. Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the other drugs are selected from any one of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents, or a combination thereof use.
  • the medicament comprises only one of (+)-2-borneol, a pharmaceutically acceptable salt or ester thereof, a metabolite thereof, a prodrug thereof, and a solvate thereof, or Combination as active ingredient.
  • the medicament contains only (+)-2-borneol as active ingredient.
  • the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  • the content of (+)-2-camphor in the medicament can be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, or about 40 mg.
  • the medicament contains pharmaceutically acceptable excipients.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome Agents, suspensions, ointments, creams, transdermal absorption agents, transmucosal absorption agents, lozenges, drops, drop pills, pills, capsules, powders, powders, liniments, fine granules, syrups.
  • the administration route of the drug includes intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional administration, implant Any one or combination of injection administration, patch administration and smear administration.
  • the drug can be administered in the following stages, including the period of cerebral infarction, the period of surgery or drug treatment, the period of stroke rehabilitation, before thrombectomy, after thrombectomy, before thrombolysis and/or after thrombolysis.
  • the present application provides a drug, the active ingredient of which is selected from the group consisting of (+)-2-borneol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate one or a combination of them.
  • the active ingredient of the medicament may be (+)-2-borneol only.
  • the medicament further includes one or more pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients include, but are not limited to: for example, fats, beeswax, semi-solid and liquid polyols, natural or hydrogenated oils, etc.; water (for example, distilled water, especially Distilled water for injection, etc.), physiological saline, alcohol (for example, ethanol), glycerin, polyol, glucose aqueous solution, mannitol, vegetable oil, etc.); additives [for example, expander, disintegrant, binder, lubricant, Wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colourants, flavoring or perfuming agents, concentrates, diluents, buffer substances, solvents or solubilizers, chemical agents for effect storage products, salts for adjusting osmotic pressure, coating agents or antioxidants], etc.
  • water for example, distilled water, especially Distilled water for injection, etc.
  • physiological saline for example, alcohol (for
  • the pharmaceutically acceptable excipient may be a form of water that is suitable for pharmaceutical or biological preparation and that is different from water that occurs in nature, including purified water, water for injection, Sterile purified water, bacteriostatic water for injection, and sterile water for injection (which is a sterile, bacterium-free, solute-free preparation of distilled water for injection).
  • the active ingredient is released from the medicament rapidly or sustainably, eg, delayed or pulsed.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome Agents, suspensions, ointments, creams, transdermal absorption agents, transmucosal absorption agents, lozenges, drops, drop pills, pills, capsules, powders, powders, liniments, fine granules, syrups.
  • the medicament is formulated to be administered by intravenous injection, intraarterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional Any one or a combination of drug delivery, implant drug delivery, patch drug delivery and smear drug delivery.
  • the administration is by parenteral administration, and the drug is in the form of injection, powder injection, or solution.
  • the drug may be in the form of a sterile solution or suspension.
  • the dose of the active ingredient is from about 5 mg to about 40 mg.
  • the dosage of the active ingredient may be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg.
  • the concentration of the active ingredient can be about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, about 0.07 mg/mL mL, about 0.08mg/mL, about 0.09mg/mL, about 0.1mg/mL, about 0.12mg/mL, about 0.14mg/mL, about 0.16mg/mL, about 0.18mg/mL, about 0.2mg/mL, About 0.3mg/mL, about 0.4mg/mL, about 0.5mg/mL, about 0.6mg/mL, about 0.7mg/mL, about 0.8mg/mL, about 0.9mg/mL, about 1.0mg/mL, about 2.0 mg/mL, about 3.0 mg/mL, about 4.0 mg/mL, or about 5 mg/mL.
  • the drug is prepared as an injection or powder injection of about 5 mL to about 500 mL, and the content of the active ingredient is about 5 mg to 20 mg.
  • the dose of the active ingredient is formulated from about 5 mg to the maximum daily dose.
  • the dose of the active ingredient is formulated to be about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg or about 40 mg.
  • the drug can be formulated as a 20mL/10mg injection solution, or a 10mL/5mg injection solution.
  • the present application provides a method for preventing and/or treating ischemic stroke, comprising administering to a subject in need only an effective amount of a drug, the active ingredient of which is selected from (+)-2 - one or a combination of camphenol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate, the ischemic stroke is selected from cardioembolic stroke Any one or combination of stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the ischemic stroke may be cardioembolic stroke or arteriolar occlusive stroke.
  • the ischemic stroke may be cardioembolic stroke combined with non-hypertensive stroke (no history of hypertension).
  • the ischemic stroke may be arteriolar occlusive stroke combined with non-hypertensive stroke (no history of hypertension) and recurrent stroke (with history of stroke).
  • the ischemic stroke can be selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points. In other embodiments, the ischemic stroke can be selected from ischemic stroke with NIHSS score>20.
  • the ischemic stroke score can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.
  • the ischemic stroke may be cardioembolic stroke or arteriolar occlusion stroke, and the score of the ischemic stroke may be 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 or 20.
  • the medicament comprises (+)-2-borneol as the active ingredient only.
  • the medicament contains pharmaceutically acceptable excipients.
  • the administration route of the drug includes intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration, intracranial injection, interventional administration, implant Any one or combination of injection administration, patch administration and smear administration.
  • the drug is administered parenterally.
  • the medicament is administered intravenously and/or intraarterially.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microneedle, effervescent tablet, solution, emulsion, liposome formulation, suspension, ointment, cream, percutaneous absorption, transmucosal absorption, lozenge, drop, drop pill, pill, capsule, powder, powder, liniment, fine granule or syrup.
  • the dosage form of the drug can be injection, powder injection, solution and other dosage forms suitable for intravenous injection or intracranial injection.
  • the drug can be administered in the following stages, including the period of cerebral infarction, the period of surgery or drug treatment, the period of stroke rehabilitation, before thrombectomy, after thrombectomy, before thrombolysis and/or after thrombolysis.
  • the drug can be administered at the stage of cerebral infarction, operation or drug treatment, before thrombectomy, and before thrombolysis.
  • the drug can be administered during stroke rehabilitation, after thrombectomy, and after thrombolysis.
  • the active ingredient is administered at a dose of at least about 5 mg up to a maximum daily dose.
  • the active ingredient is present at about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19mg, about 20mg, about 21mg, about 22mg, about 23mg, about 24mg, about 25mg, about 26mg, about 27mg, about 28mg, about 29mg, about 30mg, about 31mg, about 32mg, about 33mg, about 34mg, about 35mg, About 36mg, about 37mg, about 338mg, about 39mg, about 40mg, about 41mg, about 42mg, about 43mg, about 44mg, about 45mg, about 46mg, about 47mg, about 48mg, about 49mg, about 50mg, about 60mg, about 70mg , at a daily dose of about 80 mg, about 70 mg, about 90 mg,
  • the active ingredient is administered at a dose of about 10 mg/day to about 40 mg/day.
  • the active ingredient is administered at a dose of about 10 mg/day, about 15 mg/day, about 20 mg/day, 30 mg/day, or about 40 mg/day.
  • the active ingredient is used in a daily dose of at least about 0.05 mg/kg body weight to 5 mg/kg body weight or higher for parenteral administration.
  • the active ingredient is administered parenterally (such as intravenous injection) at a daily dose of about 0.05 mg/kg body weight, about 0.06 mg/kg body weight, about 0.07 mg/kg body weight, about 0.08 mg/kg body weight, about 0.09 mg/kg body weight, about 0.1 mg/kg body weight, about 0.2 mg/kg body weight, about 0.3 mg/kg body weight, about 0.4 mg/kg body weight, about 0.5 mg/kg body weight, about 0.6 mg/kg body weight, about 0.7 mg /kg body weight, about 0.8mg/kg body weight, about 0.9mg/kg body weight, to about 1mg/kg body weight, about 1.1mg/kg body weight, about 1.2mg/kg body weight, about 1.3mg/kg body weight, about 1.4mg/kg body weight kg body weight, about 1.5 mg/kg body weight, about 1.6 mg/kg body weight, about 1.7 mg/kg body weight, about 1.8 mg/kg body weight, about 1.9 mg/kg body weight, up to about 2
  • said daily dose is administered as a single dose or in multiple single doses.
  • the above-mentioned daily dose can be administered 1 to 3 times a day.
  • the pharmaceutical formulation is used for a long period of time, preferably up to several days, weeks or months.
  • the indicated drug administration may be for 1 to 7 days, or for 2-4 weeks, or for 1 to 3 months, or for 3 to 12 months or longer.
  • the drug may be administered during periods including cerebral infarction, surgery or other drug therapy, stroke rehabilitation, before thrombectomy, after thrombectomy, before thrombolysis and/or after thrombolysis .
  • it also includes combining the drug with any one or a combination of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, neuroprotective agents Combined use.
  • the present application provides a method for improving the effect of preventing and/or treating ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the active ingredient of which is selected from (+) - one or a combination of 2-borneol, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the ischemic stroke is selected from cardiogenic embolism Any one or combination of acute stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke.
  • the preventive and/or therapeutic effect is selected from any one or a combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the patient's ability to perform daily activities.
  • the effect of the active ingredient is selected from the group consisting of regulating energy metabolism and redox metabolism, increasing the survival rate of neurons injured by ischemia, reducing the size of cerebral infarction caused by ischemic stroke, and improving ischemic cerebral infarction. Any one or combination of neurobehavioral features of stroke.
  • the present application provides a method for reducing or avoiding adverse reactions during the prevention and/or treatment of ischemic stroke, comprising administering only an effective amount of a drug to a subject in need, the drug's
  • the active ingredient is selected from one or a combination of (+)-2-camphor, its pharmaceutically acceptable salt or ester, its prodrug, its metabolite, and its solvate, and the ischemic brain
  • the stroke is selected from any one or combination of cardioembolic stroke, arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS of the ischemic stroke Score ⁇ 6 points.
  • the way of reducing or avoiding adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, providing patients with Provide any one or combination of continuous and stable treatments throughout the stroke prevention and treatment.
  • the other drugs are selected from any one or combination of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, and neuroprotective agents Combined use.
  • (+)-2-camphor in the preparation of drugs for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from cardiogenic embolism stroke, arteriolar occlusion Any one or combination of stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • (+)-2-camphor in the preparation of medicines for improving the effect of ischemic stroke prevention and/or treatment, wherein the ischemic stroke is selected from cardiogenic embolism stroke, Any one or combination of arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the effect of the (+)-2-camphor is selected from: regulating energy metabolism and redox metabolism, improving the survival rate of ischemic damaged neurons, reducing the risk of ischemic stroke Any one or combination of causing cerebral infarction size and improving the neurobehavioral characteristics of ischemic stroke.
  • (+)-2-camphorol in the preparation of medicines for reducing or avoiding adverse reactions in the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from heart Any one or a combination of thromboembolic stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points .
  • the way of reducing or avoiding adverse reactions in the prevention and treatment of ischemic stroke is selected from: replacing other drugs, reducing the type and/or dosage of other drugs used by patients, Provide any one or combination of continuous and stable treatments for patients throughout the stroke prevention and treatment.
  • the other drugs are selected from any of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, and neuroprotective agents or a combination thereof.
  • ischemic stroke is selected from ischemic stroke with 6 ⁇ NIHSS score ⁇ 20 points.
  • (+)-2-camphor in the preparation of a medicament for the prevention and/or treatment of ischemic stroke, wherein the ischemic stroke is selected from moderate, moderate-severe or severe ischemia Any type of stroke patient.
  • the content of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  • the content of (+)-2-borneol in the medicine is about 5 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 40 mg .
  • the (+)-2-borneol also includes its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, or its solvent compound.
  • the dosage form of the drug includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microinjection, effervescent Tablets, solutions, emulsions, liposome preparations, suspensions, ointments, creams, transdermal absorption agents, transmucosal absorption agents, lozenges, drops, drop pills, pills, capsules, powders, powders, Liniments, granules or syrups.
  • a medicine the active ingredient of which is selected from one of (+)-2-borneol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate or its Combinations; the dosage of said active ingredient is from about 5 mg to about 40 mg.
  • the dosage form of the medicine includes injection, powder injection, drop, patch, tablet, granule, sublingual tablet, microinjection, effervescent Tablets, solutions, emulsions, liposome preparations, suspensions, ointments, creams, transdermal absorption agents, transmucosal absorption agents, lozenges, drops, drop pills, pills, capsules, powders, powders, Liniments, granules or syrups.
  • the medicament according to any one of embodiments 16-19, wherein the medicament is formulated to be administered via: intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, Any one of sublingual administration, intracranial injection, interventional administration, implantation administration, sticking administration and smear administration or a combination thereof.
  • the medicament according to any one of embodiments 16-25 when the medicament is a solution, the dose of the active ingredient is formulated from about 5 mg up to the maximum daily dose.
  • the active ingredient is formulated in a dose of about 5 mg to about 40 mg.
  • a kit comprising the medicament of any one of embodiments 16-27.
  • a method for preventing and/or treating ischemic stroke comprising administering to a subject in need only an effective amount of a drug whose active ingredient is selected from (+)-2-borneol, its One or a combination of pharmaceutically acceptable salts or esters, metabolites, prodrugs, and solvates thereof, the ischemic stroke is selected from cardioembolic stroke, arteriolar occlusion Any one or combination of stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • a method for improving the effect of preventing and/or treating ischemic stroke comprising administering only an effective amount of a drug whose active ingredient is selected from (+)-2-borneol to a subject in need , a pharmaceutically acceptable salt or ester thereof, a prodrug thereof, a metabolite thereof, and a solvate thereof, or one or a combination thereof, the ischemic stroke is selected from cardioembolic stroke, small Any one or combination of arterial occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • preventive and/or therapeutic effect is selected from any one or a combination of alleviating symptoms, improving prognosis, reducing the degree of neurological deficit, and improving the patient's ability to perform daily activities.
  • the effect of the active ingredient is selected from: regulating energy metabolism and redox metabolism, improving the survival rate of ischemic damaged neurons, reducing the size of cerebral infarction caused by ischemic stroke, improving Any one or combination of neurobehavioral features of ischemic stroke.
  • a method for reducing or avoiding adverse reactions during the prevention and/or treatment of ischemic stroke comprising administering only an effective amount of a drug to a subject in need, the active ingredient of which is selected from ( +)-2-camphor, a pharmaceutically acceptable salt or ester thereof, a prodrug thereof, a metabolite thereof, and a solvate thereof, or a combination thereof, wherein the ischemic stroke is selected from cardiac sources Any one or combination of thromboembolic stroke, small artery occlusive stroke, non-hypertensive stroke, and recurrent stroke, and/or the NIHSS score of the ischemic stroke ⁇ 6 points.
  • the other drugs are selected from any of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, and neuroprotective agents or a combination thereof.
  • the route of administration of the drug includes intravenous injection, arterial injection, intramuscular injection, intraperitoneal injection, oral administration, nasal drop administration, sublingual administration , intracranial injection, interventional drug delivery, implant drug delivery, patch drug delivery, and smear drug delivery.
  • the active ingredient being administered in a dose of at least about 5 mg up to a maximum daily dose.
  • the drug can be administered in the following stages, including cerebral infarction period, surgery or other drug treatment period, stroke rehabilitation period, before thrombectomy, and after thrombectomy , before and/or after thrombolysis.
  • Embodiment 1 (+)-2-camphorol anti-acute cerebral ischemia dose and effect relationship
  • This experiment adopts rat focal cerebral ischemia model (MCAO), selects 120 SD rats, male, is divided into 12 groups randomly, is respectively solvent control group (60% 1,2-propanediol, intravenous injection, 5mL/kg), positive control group (nimodipine injection, tail vein injection, 25, 50, 100, 500, 1000 ⁇ g/kg) and (+)-2-camphor injection dosage groups (doses were 0.5, 1, 2, 4, 6, 8mg/kg, intravenous injection), 10 SD rats in each group, all male.
  • the SD rats in the solvent control group, the positive control group and the (+)-2-camphor injection group were administered once after MCAO cerebral ischemia according to the above dose design.
  • the area of cerebral infarction after administration and the neurological behavior score 24 hours after cerebral infarction were observed.
  • Simultaneously positive control drug nimodipine 5 dosage group results show that the maximum effect of positive control drug appears at 1000 ⁇ g/kg, increase dose again, cerebral infarction area will not significantly reduce, and at this dose, rat cerebral infarction area is 25.3%, compared with the solvent control group, the maximum effect of reducing cerebral infarct size was 36.2%, and the behavioral scores of all treatment groups were also significantly lower than the solvent control group.
  • (+)-2-borneol Comparing (+)-2-borneol with the positive control drug, it was found that the drug potency of (+)-2-borneol against acute cerebral ischemia in rats was slightly lower than that of nimodipine injection, but the maximum effect was obvious Superior to nimodipine injection.
  • the cerebral ischemia-reperfusion model of rats was prepared by internal carotid artery suture method, and the drug was administered once by tail vein injection 2 hours after ischemia-reperfusion.
  • (+)-2-camphor has 4 dosage groups, which are respectively 0.25, 0.5, 1.0, and 2.0mg/kg; Edaravone also has 4 dosage groups, which are respectively 0.75, 1.5, 3.0, 6.0 mg/kg.
  • the effects of the tested drugs on neurological deficit symptoms, cerebral infarct size and mortality of cerebral ischemia rats were observed. The results showed (see Table 2-1 to Table 2-3), edaravone reduced cerebral ischemia-reperfusion injury in a dose-dependent manner.
  • Clinical trial design multicenter, randomized, double-blind, placebo-controlled, parallel trial design.
  • Subject population 18 years old (minimum age) to 85 years old (maximum age), both male and female; patients diagnosed with acute ischemic stroke according to the "Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke in China 2018"; "Normal time” to the start of study drug treatment ⁇ 24 hours, for stroke after waking up or when the symptom onset time cannot be accurately obtained due to aphasia, disturbance of consciousness and other reasons, the time when the patient's last normal performance should prevail; Patients with good recovery (mRS score 0-1 points) relapse (relapse); 5 points ⁇ NIHSS score ⁇ 20 points at the time of consultation, and the sum of NIHSS fifth upper limb and sixth lower limb score ⁇ 2 points; understanding And abide by the research process, participate voluntarily, and sign the informed consent (the informed consent is voluntarily signed by the person or legal representative).
  • Test drug group (+)-2-camphor, low dose 10 mg (single administration dose) and high dose 20 mg (single administration dose).
  • Placebo group the difference from the test drug group is that it does not contain the active ingredient (+)-2-camphor.
  • Dosing frequency and interval 2 times a day, with an interval of 12 hours each time.
  • Treatment cycle continuous administration for 7 days
  • the main efficacy endpoint index mRS 0-1 ratio at day 90 ⁇ 7.
  • mRS modified Rankin scale
  • the mRS score also known as the modified Rankin scale (Table 3), is a scale used to evaluate the neurological recovery status of stroke patients and is divided into seven levels.
  • symptom score completely asymptomatic 0
  • Ability to perform all daily duties and activities without significant functional impairment despite symptoms 1 Mildly disabled, unable to perform all premorbid activities, but able to look after self without assistance 2 Moderately disabled, requires some assistance, but walks without assistance 3 Severely disabled, unable to walk independently, unable to meet their own needs without help from others 4 Severely disabled, unable to walk independently, unable to meet their own needs without help from others 5 die 6
  • Day 90 ⁇ 7 mRS 0-1 ratio means that stroke patients recover to mRS score 90 ⁇ 7 days after treatment from baseline mRS score ⁇ 2 (i.e. mild disability or moderate disability or severe disability or severe disability) after treatment On a scale of 0-1 (i.e. completely asymptomatic or no apparent dysfunction), usually expressed as a percentage.
  • (+)-2-camphorol with a total of 240 subjects enrolled (80 subjects were enrolled in the low-dose group, high-dose group and placebo group). 204 (85.00%) subjects completed the treatment period test, and 68 (85.00%) subjects in the three groups completed the treatment period test. 36 (15.00%) subjects quit the trial early, and 12 (15.00%) subjects in the three groups did not complete the trial.
  • n in the table represents the number of people in the corresponding component
  • % represents the rate.
  • the calculation method is: number of people in the corresponding component/number of people in each group*100%.
  • NIHSS score The severity of stroke is usually defined by NIHSS score, which affects the evaluation of efficacy.
  • N represents the number of samples
  • n represents the number of patients with an mRS score of 0-1 on the 90th ⁇ 7th day of treatment
  • % represents the proportion of patients with an mRS score of 0-1 on the 90th ⁇ 7th day of treatment.
  • (+)-2-camphor has selective efficacy in patients with different NIHSS scores.
  • NIHSS the more severe the stroke
  • this treatment effect means that stroke patients with NIHSS score Score ⁇ 2 (i.e. mild disability or moderate disability or severe disability or severe disability) recovered to an mRS score of 0-1 (i.e.
  • test drug group completely asymptomatic or no apparent dysfunction after 90 ⁇ 7 days of treatment with the test drug compared to placebo ) is higher.
  • the absolute effect difference between the test drug group and the placebo group ranges from 3.3% to 16.0%, which has significant clinical value and significantly reduces the occurrence of disability in patients.
  • (+)-2-borneol alone as the active ingredient in the treatment of stroke can effectively avoid the serious adverse reactions (such as combined use of ida
  • the use of ravone is caused by the liver and kidney toxicity caused by the ingredients of edaravone).
  • (+)-2-camphor alone can improve the dose of (+)-2-camphor as an active ingredient in human body (such as combined use with edaravone is limited by edaravone toxicity
  • (+)- The single dose of 2-camphorol is limited to 7.5 mg), such as a single 10 mg or a single 20 mg, so as to improve the effect of ischemic stroke prevention and/or treatment.

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Abstract

La présente invention concerne une utilisation de (+)-2-bornéol dans la préparation d'un médicament pour le traitement d'un accident vasculaire ischémique cérébral, un score NIHSS de l'accident vasculaire ischémique cérébral étant supérieur ou égal à 6. Le médicament peut réduire ou éviter efficacement des réactions indésirables graves générées pendant la prévention et/ou le traitement de l'accident vasculaire ischémique cérébral, et améliorer l'effet de prévention et/ou de traitement de l'accident vasculaire ischémique cérébral.
PCT/CN2021/124428 2021-10-18 2021-10-18 Utilisation de bornéol dans la préparation d'un médicament pour le traitement d'un accident vasculaire ischémique cérébral WO2023065071A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019006734A1 (fr) * 2017-07-07 2019-01-10 苏州沪云肿瘤研究中心股份有限公司 Utilisation de (+)-2-bornéol dans la préparation d'un médicament visant à favoriser la régulation à la hausse de l'expression de la sphingosine kinase-1 et/ou du bdnf
CN113845424A (zh) * 2021-10-14 2021-12-28 南京医科大学 右崁醇酯类化合物及其药物用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019006734A1 (fr) * 2017-07-07 2019-01-10 苏州沪云肿瘤研究中心股份有限公司 Utilisation de (+)-2-bornéol dans la préparation d'un médicament visant à favoriser la régulation à la hausse de l'expression de la sphingosine kinase-1 et/ou du bdnf
CN113845424A (zh) * 2021-10-14 2021-12-28 南京医科大学 右崁醇酯类化合物及其药物用途

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"Master's Thesis", 1 March 2018, TAISHAN MEDICAL COLLEGE, CN, article LI, YUAN: "Research on Mechanism of Natural Right-Handed Borneol in Treatment of Ischemic Cerebral Stroke", pages: 1 - 56, XP009545050, DOI: 10.27353/d.cnki.gtsyc.2018.000151 *
LEI CHANG, ET AL: "(+)-Borneol is neuroprotective against permanent cerebral ischemia in rats by suppressing production of proinflammatory cytokines", JOURNAL OF BIOMEDICAL RESEARCH, vol. 31, no. 4, pages 306 - 314, XP055731347, ISSN: 1674-8301, DOI: 10.7555/JBR.31.20160138 *
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