WO2023065071A1 - Use of borneol in preparation of drug for treating cerebral ischemic stroke - Google Patents

Use of borneol in preparation of drug for treating cerebral ischemic stroke Download PDF

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Publication number
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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French (fr)
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/en
Publication of WO2023065071A1 publication Critical patent/WO2023065071A1/en

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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

The present application relates to a use of (+)-2-borneol in preparation of a drug for treating a cerebral ischemic stroke, wherein an NIHSS score of the cerebral ischemic stroke is greater than or equal to 6. The drug can effectively reduce or avoid serious adverse reactions generated during the prevention and/or treatment of the cerebral ischemic stroke, and improve the prevention and/or treatment effect of the cerebral ischemic stroke.

Description

莰醇在制备治疗缺血性脑卒中的药物中的用途Application of camphenol in preparation of medicine for treating ischemic stroke 技术领域technical field
本申请涉及生物医药领域，具体的涉及莰醇在制备治疗缺血性脑卒中的药物中的用途。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.
背景技术Background technique
脑卒中是导致人类死亡的第二位原因，在我国是第一大死亡原因，且与缺血性心脏病、恶性肿瘤并列为三大致死性疾病，我国40岁及以上人群脑卒中现患人数达1242万，且呈现逐年上升趋势，平均每7秒就有1人发生卒中，每21秒就有1人死于卒中。我国住院脑卒中患者发病后1个月内死亡率2.3％～3.2％，3个月死亡率9％～9.6％，3个月致死/致残率34.5％～37.1％，1年死亡率14.4％～15.4％，1年致死/致残率33.4％～33.8％。缺血性脑卒中具有高发病率、高致残率和高死亡率的特点，是我国成年人主要死亡原因之一，同时也是单病种致残率最高的疾病，给社会和家庭带来沉重的负担(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；中国急性缺血性脑卒中诊治指南2018；中国心血管病报告2018)。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).
脑卒中包括缺血性卒中和出血性卒中。缺血性脑卒中(cerebral ischemic stroke)为脑部血液循环障碍、缺血缺氧所致的局限性脑组织缺血性坏死或软化。其主要病因包括：大动脉粥样硬化，因高血压等因素导致小动脉硬化闭塞、血源性栓塞、血液黏度增高和血管痉挛等。急性缺血性脑卒中一般指发病两周内的脑卒中，约占全部卒中的69.6％-70.8％，我国每年新发急性缺血性脑卒中患者超过200万(Wang W，Jiang B，Sun H，et al.Prevalence，Incidence，and Mortality of Stroke in China:Results from a Nationwide Population-Based Survey of 480687Adults[J].Circulation，2017，135(8):759-771；中国急性缺血性脑卒中诊治指南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. Prevalence, Incidence, and Mortality of Stroke in China: Results from a Nationwide Population-Based Survey of 480687 Adults[J]. Circulation, 2017, 135(8):759-771; Diagnosis and Treatment of Acute Ischemic Stroke in China Guidelines 2018).
缺血性脑卒中除有效的二级预防和卒中康复治疗外，急性期的治疗手段目前非常有限，主要有溶栓、血管内介入治疗和神经保护。溶栓因其治疗时间窗的限制(≤4.5h)和诸多禁忌症等原因，仅少数患者(＜3％)受益，尽管目前临床上存在超窗溶栓趋势(至9h)，但受益患者仍然有限；血管内治疗(机械取栓)目前可将时间窗延长至24h，但血管内介入治疗禁忌症较多、手术实施难度较高、价格昂贵；神经保护剂理论上可抢救缺血半暗带，扩大治疗时间窗(理论上可达72h)，使临床患者明显获益，目前市场上神经保护剂品种众多，但尚无具有循证医学证据、疗效确切的神经保护剂(中国心血管病报告2018；中国急性缺血性脑卒中诊治指南2018；急性缺血性卒中血管内治疗中国指南2018；Thrombolysis Guided by Perfusion  Imaging up to 9 Hours after Onset of Stroke[J].N Engl J Med.2019,380(19):1795-1803)。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. Although there is a clinical trend of over-window thrombolysis (up to 9h), the benefited patients still Limited; endovascular treatment (mechanical thrombectomy) can currently extend the time window to 24 hours, but there are many contraindications for endovascular interventional treatment, the operation is difficult and expensive; neuroprotective agents can theoretically rescue the ischemic penumbra , expand the treatment time window (theoretically up to 72h), so that clinical patients can obviously benefit, there are many kinds of neuroprotective agents on the market, but there is no neuroprotective agent with evidence-based medical evidence and definite curative effect (China Cardiovascular Disease Report 2018; Chinese guidelines for diagnosis and treatment of acute ischemic stroke 2018; Chinese guidelines for endovascular treatment of acute ischemic stroke 2018; Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke[J].N Engl J Med.2019,380 (19):1795-1803).
当前有超过1000个神经保护剂在动物实验中有效，超过100种药物进行了临床试验，然而所有以随机、双盲、安慰剂对照进行严格临床研究的神经保护剂在临床全部失败(O'Collins VE，Macleod MR，Donnan GA，et al.1，026 experimental treatments in acute stroke[J].Ann Neurol,2006；59:467-477)。故以临床前动物药效或体外药效的数据，难以推测临床的有效性。Currently, more than 1,000 neuroprotective agents are effective in animal experiments, and more than 100 drugs have undergone clinical trials. However, all neuroprotective agents that have been subjected to randomized, double-blind, placebo-controlled clinical studies have all failed clinically (O'Collins VE, Macleod MR, Donnan GA, et al. 1, 026 experimental treatments in acute stroke [J]. Ann Neurol, 2006; 59:467-477). Therefore, it is difficult to predict the clinical effectiveness based on the data of preclinical animal efficacy or in vitro efficacy.
总结神经保护剂类药物从基础研究(临床前研究)转化至临床研究普遍失败，主要原因可能是：①种属差异：目前临床前试验应用最多的动物是鼠类，少数会用到灵长类动物，这两类动物的脑组织结构和人脑结构不管在解剖学上和组织学上都存在较大差异；临床前研究的实验动物卒中模型都是同质的，而人类卒中则是异质的、千差万别的，存在多种的其他影响因素(如年龄、发作次数、发作部位、伴随疾病、严重程度、并发症、联合用药等)差别，所以临床前动物试验有效的药物对人类不一定有效。②评价标准：在大多数临床前试验中，神经保护剂的有效性是通过观察组织学上梗死体积的变化，或者是否能够挽救梗死半暗带来评价；而在临床试验中，药物的有效性是通过减少死亡率及残障率、改善生活质量(功能)的目的来评价。事实上梗死体积与功能缺失并无直接、必然的联系。③动物模型：现今在临床前试验的动物一般为年轻健康的雄性动物，体重年龄较均一，脑缺血造模方式单一，且一般无其他并发疾病；而临床上脑卒中患者多年老年人，性别亦无明显差异，且一般伴有多种慢性病(如动脉硬化、高血压、糖尿病和既往卒中史等)，这些伴发疾病既会影响患者机能恢复，又影响药物的药效、代谢和安全性。④药物治疗时间窗：临床前动物实验可以在缺血后任意时间点进行药物治疗或预防，给药的方法和途径也可以根据要求确定和调整；而临床患者何时发生脑缺血是不可预估的，提前用药根本不可行，而从发生脑缺血到就诊用药也需要一段时间，临床上在脑缺血发生后2h内进行药物治疗的可能性都很小，大部分患者的治疗时间窗为卒中发生后6h或更长。⑤其他因素(Chin J Clin Pharmacol2013，29(11)，869-871)。In conclusion, the transformation of neuroprotective agents from basic research (preclinical research) to clinical research generally fails. The main reasons may be: ① species differences: currently the most used animals in preclinical tests are mice, and a few use primates Animals, the brain tissue structure of these two types of animals is quite different from the human brain structure in both anatomy and histology; experimental animal stroke models in preclinical studies are homogeneous, while human stroke is heterogeneous There are many other influencing factors (such as age, attack frequency, attack site, concomitant diseases, severity, complications, combined medication, etc.) differences, so drugs that are effective in preclinical animal tests may not be effective in humans . ②Evaluation criteria: In most preclinical trials, the effectiveness of neuroprotective agents is evaluated by observing the changes in infarct volume on histology, or whether they can save the infarct penumbra; while in clinical trials, the effectiveness of drugs It is evaluated by the purpose of reducing the mortality and disability rate and improving the quality of life (function). In fact, there is no direct and inevitable relationship between infarct volume and functional loss. 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 . 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).
我国著名神经内科专家黄如训在1998年就提出以分型、分期为核心治疗个体化原则。经过长期临床实践的反复思考而形成的一个重要理念：脑卒中是一大类疾病的总称，基于多病因、不同发病机制、多种病理和临床类型，各有相应的治疗方法和治疗效果。临床上有轻、中、重、极危重等的病情分型(如广泛使用的NIHSS评分)；有以临床征象为据，基本反映病变部位及范围OCSP分型；以临床病因为据的TOAST分型(大动脉粥样硬化、心源性、小血管、其他原因、原因不明)；以临床结构影像进行分型，如大、中、小、腔隙、多发等分型。1992年提出重视脑卒中的个体化治疗，其后分型研究，多方面论述，形成“以分型、分期为核心治疗的个体化原则”理念。治疗个体化原则的基本内含是针对性强的方案和有效措施， 同近年兴起的精准医疗有异曲同工之处(Chin J Clin Neurosci 2017,25(1),119～124)In 1998, Huang Ruxun, a famous neurology expert in my country, proposed the principle of individualized treatment based on classification and staging. An important concept formed after repeated thinking in long-term clinical practice: Stroke is a general term for a large class of diseases, based on multiple etiologies, different pathogenesis, various pathologies and clinical types, each with corresponding treatment methods and therapeutic effects. Clinically, there are mild, moderate, severe, and critical disease classifications (such as the widely used NIHSS score); there is OCSP classification based on clinical signs, which basically reflects the location and extent of the lesion; TOAST classification based on clinical etiology Types (large artery atherosclerosis, cardiogenic, small vessels, other causes, unknown causes); classification based on clinical structural images, such as large, medium, small, lacunar, and multiple. In 1992, he proposed to attach importance to the individualized treatment of cerebral apoplexy. Afterwards, the classification research was discussed in many aspects, and the concept of "individualized treatment with classification and staging as the core treatment principle" was formed. The basic content of the principle of individualized treatment is highly targeted programs and effective measures, which are similar to the precision medicine that has emerged in recent years (Chin J Clin Neurosci 2017,25(1),119～124)
在国际上广泛应用的几种分型方法中，TOAST法侧重于缺血性卒中的病因学分型,因其具有满意的效度和信度，在临床工作中得到广泛应用。TOAST分析标准包含五大类：Among the several typing methods widely used in the world, the TOAST method focuses on the etiological typing of ischemic stroke, and is widely used in clinical work because of its satisfactory validity and reliability. TOAST analysis standards include five categories:
1.大动脉粥样硬化型(性)卒中(large-artery atherosclerosis,LAA)：这一类别要求颈动脉超声波扫描或多普勒扫描确认颈内动脉闭塞或狭窄达到血管横截面面积的50％，通过血管造影或磁共振血管造影(MRA)发现的颈动脉、大脑前、中、后动脉、椎基底动脉狭窄达到血管横截面面积的50％。1. Large-artery atherosclerosis (LAA): This category requires carotid artery ultrasound scan or Doppler scan to confirm that the internal carotid artery is occluded or narrowed to 50% of the cross-sectional area of the vessel, and passed Carotid arteries, anterior, middle, and posterior cerebral arteries, and vertebrobasilar arteries found by angiography or magnetic resonance angiography (MRA) stenosis up to 50% of the cross-sectional area of the vessels.
2.心源型(性)脑栓塞(cardioembolism,CE)：这一类别包括由多种可以产生心源性栓子的疾病引发的脑栓塞，在TOAST型法中，列出了造成心源性栓子的高度、中度危险因素。2. Cardioembolism (cardioembolism, CE): This category includes cerebral embolism caused by a variety of diseases that can produce cardioembolism. High and moderate risk factors for embolism.
心源型(性)栓子的来源Source of cardiogenic (sexual) emboli
Figure PCTCN2021124428-appb-000001
Figure PCTCN2021124428-appb-000001
3.小动脉型(性)卒中(腔隙性脑梗死，SAA)：具备以下三项标准之一者即可确诊：(1)具有典型的腔隙性梗死综合征，且影像学检查发现与临床表现相符的、最大径＜1.5cm的病灶的卒中；(2)具有典型的腔隙性梗死综合征，但影像学未发现相应病灶的卒中；(3)具有非典型的腔隙性脑梗死综合征，但影像学检查发现与临床表现相符的、最大径＜1.5cm的病灶的卒中。3. 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.
4.其他原因引发的缺血性卒中(SOE)：这一类别包括由其他明确原因引发的脑梗死(高凝状态、血液***疾病、吸食毒品等)。4. Ischemic stroke caused by other causes (SOE): This category includes cerebral infarction caused by other clear causes (hypercoagulable state, blood system disease, drug use, etc.).
5.原因不明的缺血性卒中(SUE)：这一类别包括不能归于以上类别的缺血性脑卒中。5. Unexplained ischemic stroke (SUE): This category includes ischemic strokes that cannot be assigned to the above categories.
国际上，缺血性脑卒中患者的严重程度还广泛采用美国国立卫生研究院卒中量表(NIH Stroke Scale，NIHSS)进行量化，根据NIHSS总分对卒中患者严重程度进行判断，分值越大，代表病情越严重。NIHSS评分共42分11项，在国际多中心随机对照研究中被广泛应用，是公认的对卒中患者严重程度分层的评分体系，各评分项目和评分标准如下：Internationally, the severity of ischemic stroke patients is also widely quantified by the National Institutes of Health Stroke Scale (NIHSS), and the severity of stroke patients is judged according to the NIHSS total score. It means that the condition is more serious. 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:
Figure PCTCN2021124428-appb-000002
Figure PCTCN2021124428-appb-000002
Figure PCTCN2021124428-appb-000003
Figure PCTCN2021124428-appb-000003
Figure PCTCN2021124428-appb-000004
Figure PCTCN2021124428-appb-000004
Figure PCTCN2021124428-appb-000005
Figure PCTCN2021124428-appb-000005
一般认为，“NIHSS评分≤5分的缺血性脑卒中”为“轻度缺血性脑卒中”，“6≤NIHSS评分≤15分的缺血性脑卒中”为“中度缺血性脑卒中”，“15≤NIHSS评分≤20分的缺血性脑卒中”为“中-重度缺血性脑卒中”或“重度缺血性脑卒中”，“NIHSS评分＞20分的缺血性脑卒中”为“极危重缺血性脑卒中”。It is generally believed that "ischemic stroke with NIHSS score ≤ 5 points" is "mild ischemic stroke", and "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".
临床实践中，以NIHSS评分进行缺血性脑卒中的分型用于治疗人群的选择，有利于找到精准的有效人群。如对于血管内治疗，在《急性大血管闭塞性缺血性卒中血管内治疗中国专家共识(2019年修订版)》中明确指出，对于NIHSS评分≥6分的前循环急性大血管闭塞性缺血性卒中(AIS-LVO)患者行血管内治疗获益明确，但对于NIHSS评分＜6分的患者行血管内治疗可能是合理的。对于NIHSS评分＜6分的患者是否获益仍有待于进一步评价，可能获益，也可能不获益，甚至更差。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. For example, for 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. Whether patients with NIHSS score < 6 points benefit still needs to be further evaluated. They may benefit, or may not benefit, or even worse.
综上，对缺血性脑卒中治疗，目前临床上尚无有效的预防或治疗脑卒中疾病的神经保护 剂类药物；体外药效或动物药效难以推测临床的有效性；以TOAST分型或以NIHSS评分分型或其他分型进行精准化治疗，“以分型、分期为核心治疗的个体化原则”理念已形成广泛共识，有利于获得药物的真实有效人群，提高药物的疗效，避免无效患者选择错误的药物进行治疗而延误病情、增加安全性风险并带来经济损失。In summary, for the treatment of ischemic stroke, there is no clinically effective neuroprotective drug for the prevention or treatment of stroke; it is difficult to predict the clinical effectiveness from the in vitro drug effect or animal drug effect; TOAST classification or Precise treatment based on NIHSS classification or other classifications, the concept of "individualized treatment with classification and staging as the core principle" has formed a broad consensus, which is conducive to obtaining the real and effective population of drugs, improving the efficacy of drugs, and avoiding ineffectiveness Patients choose the wrong drug for treatment, which will delay their treatment, increase safety risks and bring economic losses.
发明内容Contents of the invention
现有技术中通常将(+)-2-莰醇作为药物佐剂用于治疗脑卒中等疾病，如与依达拉奉等活性成分联用用于治疗脑卒中，但是尚无将(+)-2-莰醇单独作为活性成分用于治疗缺血性脑卒中患者的报道。In the prior art, (+)-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.
此外，申请人令人惊讶的发现单一组分的(+)-2-莰醇对缺血性脑卒中患者人群具有高度的选择性，在部分类型或分型的缺血性脑卒中患者治疗中有优异的治疗效果(如心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、复发性脑卒中，NIHSS评分≥6分的脑卒中)，而在另一部分类型或分型的缺血性脑卒中患者中效果相对较差或者没有效果(如大动脉粥样硬化型脑卒中、NIHSS评分≤5分的脑卒中)。在我国超过千万缺血性脑卒中现存患者及每年超过200万新发卒中患者中，在严重缺乏有效的药物治疗措施的背景下，药物组比安慰剂组(不用药的情况下)显示出的绝对效应差值(第90天恢复至mRS 0-1分的患者代表恢复至完全康复或无残疾状态)意义重大。In addition, the applicant surprisingly found that 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). Among the more than 10 million patients with ischemic stroke and more than 2 million new stroke patients each year in my country, in the context of a serious lack of effective drug treatment measures, the drug group showed significantly higher The difference in absolute effect (patients returning to mRS 0-1 at day 90 representing recovery to full recovery or no disability) was significant.
并且，(+)-2-莰醇具有良好的人体安全性，(+)-2-莰醇单独作为活性成分治疗脑卒中能够有效的避免联用其他活性成分在缺血性脑卒中预防和/或治疗过程中产生的不良反应(如联用依达拉奉使用，因依达拉奉成分的加入带来严重的肝肾毒性)。此外，(+)-2-莰醇单独作为活性成分可提高(+)-2-莰醇的人体用药剂量(如与依达拉奉联用受依达拉奉毒性的限制，(+)-2-莰醇单次使用剂量限制在7.5mg)，进而提高缺血性脑卒中预防和/或治疗效果。Moreover, (+)-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). In addition, (+)-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.
本申请的目的之一是提供(+)-2-莰醇作为唯一的活性成分在制备治疗特定的缺血性脑卒中亚型或分型患者药物中的应用。One of the purposes of this application is to provide the use of (+)-2-camphorol as the only active ingredient in the preparation of a medicament for treating patients with specific ischemic stroke subtypes or types.
本申请的另一个目的在于提供一种治疗特定的缺血性脑卒中亚型或分型患者的药物，其包含唯一的活性成分(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合。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.
本发明的另一个目的在于提供一种治疗缺血性脑卒中的方法，包括向由此需要的受试者施用(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合。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. One or a combination of drugs, their metabolites, and solvates.
一方面，本申请提供了(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途， 其中所述缺血性脑卒中选自心源型(性)栓塞型脑卒中、小动脉闭塞型(性)脑卒中、非高血压型(性)脑卒中、和复发型(性)脑卒中的任一种或其组合，和/或所述缺血性脑卒中的NIHSS评分≥6分。In one aspect, 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.
一方面，本申请提供了(+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血性脑卒中的NIHSS评分≥6分。In one aspect, 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.
在某些实施方式中，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述(+)-2-莰醇的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。In some embodiments, 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.
一方面，本申请提供了(+)-2-莰醇在制备用于降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血性脑卒中的NIHSS评分≥6分。In one aspect, 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.
在某些实施方式中，所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。In some embodiments, 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.
在某些实施方式中，所述缺血性脑卒中选自6≤NIHSS评分≤20分的缺血性脑卒中。In some embodiments, the ischemic stroke is selected from ischemic stroke with 6≤NIHSS score≤20 points.
一方面，本申请提供了(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中选自中度、中-重度或重度型缺血性脑卒中患者的任一种。In one aspect, 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.
在某些实施方式中，所述药物仅包含(+)-2-莰醇作为活性成分。In certain embodiments, the medicament comprises (+)-2-borneol as the active ingredient only.
在某些实施方式中，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。In certain embodiments, the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
在某些实施方式中，所述药物中(+)-2-莰醇的含量为约5mg，或约10mg，或约20mg，或约30mg，或约40mg。In certain embodiments, 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.
在某些实施方式中，所述(+)-2-莰醇还包括其药学上可接受的盐或酯，其代谢物，其前药，或其溶剂合物。In certain embodiments, the (+)-2-camphor also includes pharmaceutically acceptable salts or esters thereof, metabolites thereof, prodrugs thereof, or solvates thereof.
在某些实施方式中，所述药物中含有药学上可接受的赋形剂。In certain embodiments, the medicament contains pharmaceutically acceptable excipients.
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂、糖浆剂。In some embodiments, 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.
另一方面，本申请提供一种药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合；所述活性成分的剂量为约5mg至约40mg。In another aspect, 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.
在某些实施方式中，其中所述药物还包括地一种或多种药学上可接受的赋形剂。In certain embodiments, the medicament further includes one or more pharmaceutically acceptable excipients.
在某些实施方式中，其中所述活性成分从药物中快释或缓释，例如延迟或脉冲式地释放。In certain embodiments, wherein the active ingredient is released from the medicament rapidly or sustainably, eg, delayed or pulsed.
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂、糖浆剂。In some embodiments, 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.
在某些实施方式中，其中所述药物被配制为经以下方式施用：静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。In certain embodiments, wherein 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.
在某些实施方式中，其中所述施用通过肠胃外施用，且所述药物以注射剂、粉针剂、或溶液剂的形式存在。In some embodiments, the administration is by parenteral administration, and the drug is in the form of injection, powder injection, or solution.
在某些实施方式中，其中所述活性成分的浓度为约0.01mg/mL至约5mg/mL，优选约0.1mg/mL至约2.5mg/mL。In some embodiments, 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.
在某些实施方式中，其中所述药物被配制为约5mL至约500mL的注射液或粉针剂，其中所述活性成分的含量为约5mg至40mg。In some embodiments, 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.
在某些实施方式中，当药物为注射液剂时，所述活性成分的剂量被配制为约5mg至最大日剂量。In certain embodiments, when the medicament is an injection solution, the dose of the active ingredient is formulated from about 5 mg to the maximum daily dose.
在某些实施方式中，当药物为注射液剂时，所述活性成分的剂量被配制为约5mg至约40mg。In certain embodiments, when the drug is an injection solution, the dose of the active ingredient is formulated to be about 5 mg to about 40 mg.
另一方面，本申请提供一种药盒，其包含前述的药物。In another aspect, the present application provides a kit, which comprises the aforementioned medicine.
另一方面，本申请提供一种预防和/或治疗缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代 谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In another aspect, 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.
在某些实施方式中，还包括将所述药物与静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂中的任一种或其组合联合使用。In some embodiments, 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.
另一方面，本申请提供一种提高缺血性脑卒中预防和/或治疗效果的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In another aspect, 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.
在某些实施方式中，，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。In certain embodiments, wherein 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.
在某些实施方式中，所述活性成分的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。In some embodiments, 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.
另一方面，本申请提供一种降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In another aspect, 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.
在某些实施方式中，其中所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。In some embodiments, 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.
在某些实施方式中，所述药物的给药途径包括静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和/或涂抹给药。In some embodiments, 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.
在某些实施方式中，所述药物通过胃肠外方式施用。In certain embodiments, the drug is administered parenterally.
在某些实施方式中，所述药物通过静脉注射方式施用。In certain embodiments, the medicament is administered intravenously.
在某些实施方式中，所述活性成分以至少约5mg至最大日剂量施用。In certain embodiments, the active ingredient is administered at a dose of at least about 5 mg up to a maximum daily dose.
在某些实施方式中，所述活性成分以至少约5mg至约40mg的日剂量施用。In certain embodiments, the active ingredient is administered in a daily dose of at least about 5 mg to about 40 mg.
在某些实施方式中，所述活性成分以约10mg/天至约20mg/天的日剂量施用。In certain embodiments, the active ingredient is administered at a daily dose of about 10 mg/day to about 20 mg/day.
在某些实施方式中，其中所述日剂量作为一次性剂量或以多次单剂量施用。In certain embodiments, wherein said daily dose is administered as a single dose or in multiple single doses.
在某些实施方式中，其中所述药物制剂经长期使用，优选长达数天，数周或数月。In certain embodiments, wherein the pharmaceutical formulation is used for a long period of time, preferably up to several days, weeks or months.
在某些实施方式中，所述药物可在以下阶段给药，包括脑梗期、手术或其他药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。In certain embodiments, 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 .
本领域技术人员能够从下文的详细描述中容易地洞察到本申请的其它方面和优势。下文的详细描述中仅显示和描述了本申请的示例性实施方式。如本领域技术人员将认识到的，本申请的内容使得本领域技术人员能够对所公开的具体实施方式进行改动而不脱离本申请所涉及发明的精神和范围。相应地，本申请的说明书中的描述仅仅是示例性的，而非为限制性的。Those skilled in the art can easily perceive other aspects and advantages of the present application from the following detailed description. In the following detailed description, only exemplary embodiments of the present application are shown and described. As those skilled in the art will appreciate, the content of the present application enables those skilled in the art to make changes to the specific embodiments which are disclosed without departing from the spirit and scope of the invention to which this application relates. Accordingly, the descriptions in the specification of the present application are only exemplary and not restrictive.
具体实施方式Detailed ways
以下由特定的具体实施例说明本申请发明的实施方式，熟悉此技术的人士可由本说明书所公开的内容容易地了解本申请发明的其他优点及效果。The implementation of the invention of the present application will be described in the following specific examples, and those skilled in the art can easily understand other advantages and effects of the invention of the present application from the content disclosed in this specification.
术语定义Definition of Terms
术语“脑卒中”在本领域是众所周知的。脑卒中可以是闭塞性的(由于血管闭合)或出血性的(由于血管出血)。本文所用的术语“缺血”是指当阻力血管的自动调整性扩张不能代偿血管异常狭窄(缩窄)的远端减少的灌注压而发生的血液供给和氧的缺乏。虽然大部分闭塞性脑卒中是由动脉粥样硬化和血栓形成引起，以及大部分出血性脑卒中与高血压或动脉瘤相关，任一类型的脑卒中可能在任何年龄由于多种原因而发生，这些原因包括心脏病、外伤、感染、肿瘤、血液恶液质、血管畸形、免疫失调、以及外源毒素。The term "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). As used herein, the term "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. Although most occlusive strokes are caused by atherosclerosis and thrombosis, and most hemorrhagic strokes are associated with hypertension or aneurysm, 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.
除非另有说明，在本申请中，术语“脑卒中”一般指缺血性脑卒中，通常是由于流向大脑或其部分的血流量减少所致，该血流量减少导致脑细胞供氧不足。特别地，由于脑细胞死亡，脑卒中会导致不可逆转的组织损伤。脑卒中的症状在本领域是众所周知的。例如，脑卒中症状包括面部、手臂或腿部突然麻木或无力(特别是在身体的一侧)、突然意识混乱、说话或理解困难、一只或两只眼睛突然看不到，以及突然行走困难、头晕、失去平衡或协调。缺血性脑卒中可能是由动脉粥样硬化血栓形成或大脑主动脉栓塞、由凝血障碍或非肿瘤性血管疾病、或由导致总血流量减少的心脏缺血引起的。例如，动脉粥样硬化性血栓性脑卒中、心源性脑卒中和腔隙性脑卒中，心房颤动也可引起心源性脑卒中(通常也称为栓塞性或血栓栓塞性 脑卒中)。Unless otherwise stated, in this application the term "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. In particular, 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).
在本申请中，术语“莰醇”，又名片脑、龙脑香、冰片脑、梅冰等，可以由菊科艾纳香茎叶或樟科植物龙脑樟枝叶经水蒸汽蒸馏并重结晶而得。(+)-2-莰醇，又称右旋莰醇或((+)-borneol)，是天然冰片的主要成分(2015版中国药典规定天然冰片中右旋莰醇含量不低于96％)。右旋莰醇是一种双环单萜类化合物，存在于许多中草药的挥发油中，表现出多种生物活性，如抗炎、抗氧化以及增强GABA受体功能等(Euro J Pharma 2017,811:1-11)。右旋莰醇的结构式如下：In this application, the term "Bamphol", also known as Pianol, Borneoxiang, Borneolum, Meibing, etc., can be obtained by steam distillation and recrystallization from the stems and leaves of Ainaxiang of Asteraceae or borneol camphor branches of Lauraceae. have to. (+)-2-borneol, also known as d-borneol or ((+)-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:
Figure PCTCN2021124428-appb-000006
Figure PCTCN2021124428-appb-000006
右旋莰醇(分子式C 10H 18O；分子量154.25) D-acyl alcohol (molecular formula C 10 H 18 O; molecular weight 154.25)
在本申请中，术语“药学上可接受的盐”通常是指在合理的医学判断的范围内适合用于与受试者的组织接触而没有不适当的毒性，刺激，过敏反应等，并且与合理的利益/风险比相称的那些盐。药学上可接受的盐是本领域公知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1–19详细描述了药学上可接受的盐。In this application, 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.
在本申请中，术语“前药”通常是指易于在体内(例如通过血液中的酶)通过酶促水解转化产生母体化合物的化合物。在A.C.S.论文集系列的T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，第14卷和Edward B.Roche编辑的Bioreversible Carriers in Drug Design，American Pharmaceutical Associtation and Permagon Press，1987中提供了全面的讨论，这两个文献通过引用结合到本文中。In this application, the term "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.
在本申请中，术语“代谢物”通常是指在施用母体化合物(如(+)-2-莰醇)后在个体体内产生的任何结构式的衍生物。这些衍生物可以通过个体体内的各种生物化学转化例如氧化、还原、水解或结合由母体化合物产生，并且包括例如氧化物和去甲基衍生物。可以用现有技术中已知的常规技术鉴定本发明化合物的代谢物。参见例如，Bertolini，G.等人，J.Med.Chem.40：2011-2016(1997)；Shan，D.等人，J.Pharm.Sci.86(7)：765-767；Bagshawe K.，Drug Dev.Res.34：220-230(1995)；Bodor，N.，Advances in Drug Res.13：224-331(1984)；Bundgaard，H.，Design of Prodrugs(Elsevier Press1985)；和Larsen，I.K.，Design and Application of Prodrugs，Drug Design and Development(Krogsgaard-Larsen等人，编辑，Harwood Academic Publishers，1991)。In this application, 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). 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. 34: 220-230 (1995); Bodor, N., Advances in Drug Res. 13: 224-331 (1984); Bundgaard, H., Design of Prodrugs (Elsevier Press 1985); and Larsen, I.K., Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
在本申请中，术语“溶剂化物”按照常规意义使用，通常是指溶质(例如，活性化合物， 活性化合物的盐)和溶剂的配合物。如果溶剂是水，则溶剂化物可以方便地称为水合物。In the present application, the term "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.
在本申请中，术语“药学上可接受的赋形剂”包括任意和所有的溶剂、分散介质、包衣、表面活性剂、抗氧化剂、防腐剂(例如，抗细菌剂、抗真菌剂)、等张剂(isotonic agent)、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、甜味剂、矫味剂、染料等以及它们的组合(参见例如Remington's Pharmaceutical Sciences,第18版,Mack Printing Company,1990,第1289-1329页)。除非任何常规载体与活性成分不相容，否则其在治疗或药物组合物中的应用将被考虑。As used herein, 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.
在本申请中，术语“预防和/或治疗”不仅包括预防和/或治疗疾病，还通常包括预防疾病的发作，减缓或逆转疾病的进展，预防或减缓与疾病相关的一种或多种症状的发作，减少和/或减轻与疾病相关的一种或多种症状，降低疾病和/或与其相关的任何症状的严重程度和/或持续时间和/或预防疾病和/或与其相关的任何症状的严重程度的进一步增加，预防、减少或逆转由疾病引起的任何生理损伤，以及通常对正在治疗的患者有益的任何药理学作用。In this application, the term "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.
在本申请中，术语“疾病”或“病症”可以互换使用，通常是指受试者与正常状态的任意偏离，例如身体或某些器官的状态的任何变化，妨碍或扰乱了功能的履行，和/或在患病或与其接触的人中引起症状例如不适、机能障碍、痛苦或甚至死亡。疾病或病症还可以称为失调(distemper)、不适(ailing)、小病(ailment)、疾病(malady)、紊乱(disorder)、疾病(sickness)、生病(illness)、身体不适(complaint)、inderdisposion或affectation。In this application, the terms "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.
本申请中，术语“施用”通常是指通过任意引入或递送途径将本申请药物制剂引入受试者的身体中。可以采用本领域技术人员已知的用于使细胞、器官或组织与所述药物接触的任何方法。所述施用可以包括而不限于静脉内、动脉内、鼻内、腹内、肌内、皮下透皮或口服。每日剂量可以划分成一个、两个或更多个合适形式的剂量以在某个时间段期间的一个、两个或更多个时间施用。In the present application, 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.
在本申请中，术语“有效量”或“有效剂量”通常是指足以实现或至少部分实现所需效果的量。药物或治疗剂的“治疗有效量”或“治疗有效剂量”通常是当单独使用或与另一种治疗剂组合使用时促进疾病消退(这通过疾病症状严重程度的降低、疾病无症状期的频度和持续时间的增加、或者由于罹患疾病而引起的损害或残疾的预防来证明)的任何药物量。药物的“预防有效量”或“预防有效剂量”通常是指当单独或与另一种治疗剂组合给有疾病发展或疾病复发的风险的受试者施用时抑制疾病的发展或复发的药物量。可以使用本领域技术人员已知的多种方法对治疗剂或预防剂促进疾病消退或抑制疾病发展或复发的能力进行评估，比如在处于临床试验期间的人类受试者中、在动物模型***中预测对人类的功效、或者通过在 体外测定中测定药剂的活性。In this application, 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.
在本申请中，术语“受试者”通常是指需要诊断、预后、改善、预防和/或治疗疾病的人或非人动物(包括哺乳动物)，诸如人、非人灵长类动物(猿、长臂猿、大猩猩、黑猩猩、猩猩、猕猴)、家畜(狗和猫)、农场动物(家禽如鸡和鸭、马、牛、山羊、绵羊、猪)和实验动物(小鼠、大鼠、兔、豚鼠)。人受试者包括胎儿、新生儿、婴儿、青少年和成人受试者。受试者包括动物疾病模型。In this application, 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.
在本申请中，术语“包括”、“包含”、“具有”、“可以”、“含有”及其变体通常旨在是开放式过渡性短语、术语或词语，其不排除额外行为或结构的可能性。术语“由……组成”通常表示不能存在别的组分(或同样地，特征、整数、步骤、等)。除非上下文另有明确规定，单数形式如英文的“a”，“an”，“the”，中文的“一个”、“一种”和“所述/该”一般包括所指代事物的复数形式。In this application, the terms "comprises," "comprises," "has," "may," "containing," and variations thereof are generally intended to be open-ended transitional phrases, terms, or words that do not exclude additional acts or structures possibility. The term "consisting of" generally means that no other components (or likewise, features, integers, steps, etc.) can be present. Unless the context clearly stipulates otherwise, singular forms such as "a", "an" and "the" in English, "一", "一个" and "解说/这" in Chinese generally include plural forms of the things referred to .
在本申请中，术语“约”通常意指大约(approximately)、在......的附近(intheregionof)、粗略地(roughly)、或左右(around)。当术语“约”当用于指涉数值范围时，截值或特定数值用于指示所载明的数值可与该列举数值有多达10％的差异。因此，术语“约”可用于涵盖自特定值±10％或更少的变异、±5％或更少的变异、±1％或更少的变异、±0.5％或更少的变异、或±0.1％或更少的变异。In this application, the term "about" generally means approximately, in the vicinity of, roughly, or around. When the term "about" is used in reference to a numerical range, 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. Thus, 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.
应理解，数字或一系列数字之前的术语“至少”包括与该术语“至少”相邻的数字，及逻辑上包括在内的所有后续数字或整数，如从上下文中明确的。当“至少”出现在一系列数字或范围之前时，应理解“至少”可修饰该系列或范围中每一个数字。It will be understood that the term "at least" preceding a number or series of numbers includes the number adjacent to that term "at least", and all subsequent numbers or integers logically included, as clear from the context. When "at least" precedes a list of numbers or a range, it is understood that "at least" modifies each number in the list or range.
在本申请中，对于疾病分型或亚型，术语“型”与“性”的含义相同，或者省略“型”或“性”后意义等同，如“心源性栓塞型脑卒中”意义同“心源型栓塞性脑卒中”、“小动脉闭塞型脑卒中”同“小动脉闭塞性脑卒中”、“非高血压性脑卒中”同“非高血压型脑卒中”、“复发性脑卒中”同“复发型脑卒中”。In this application, for disease classification or subtype, 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".
在本申请中，对于疾病的称呼，术语“脑卒中”与“卒中”的含义相同。In this application, the term "stroke" has the same meaning as "stroke" for the name of the disease.
在本申请中，“轻度缺血性脑卒中”通常是指“NIHSS评分≤5分的缺血性脑卒中”，“中度缺血性脑卒中”通常是指“6≤NIHSS评分≤15分的缺血性脑卒中”，“重度缺血性脑卒中”或“中-重度缺血脑卒中”通常是指“15≤NIHSS评分≤20分的缺血性脑卒中”，“极危重缺血性脑卒中”通常是指“NIHSS评分＞20分的缺血性脑卒中”。In this application, "mild ischemic stroke" usually refers to "ischemic stroke with NIHSS score ≤ 5 points", and "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" usually refers to "ischemic stroke with NIHSS score > 20 points".
发明详述Detailed description of the invention
用途use
一方面，本申请提供了(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中选自心源型栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In one aspect, 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.
在某些实施方式中，所述缺血性脑卒中可以选自心源型栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合。In certain embodiments, the ischemic stroke may be selected from any one of cardiogenic embolic stroke, arteriolar occlusive stroke, non-hypertensive stroke, and recurrent stroke, or combination.
例如，所述缺血性脑卒中可以是心源性栓塞型脑卒中或小动脉闭塞型脑卒中。For example, the ischemic stroke may be cardioembolic stroke or arteriolar occlusive stroke.
例如，所述缺血性脑卒中可以是心源性栓塞型脑卒中合并非高血压性脑卒中(无高血压既往史)。For example, the ischemic stroke may be cardioembolic stroke combined with non-hypertensive stroke (no history of hypertension).
例如，所述缺血性脑卒中可以是小动脉闭塞型脑卒中合并非高血压性脑卒中(无高血压既往史)及复发性脑卒中(有脑卒中既往史)。For example, the ischemic stroke may be arteriolar occlusive stroke combined with non-hypertensive stroke (no history of hypertension) and recurrent stroke (with history of stroke).
在某些实施方式中，所述缺血性脑卒中可以选自6≤NIHSS评分≤20分的缺血性脑卒中。在另一些实施方式中，所述缺血性脑卒中可以选自NIHSS评分＞20分的缺血性脑卒中。In some embodiments, 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.
例如所述缺血性脑卒中的评分可以为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更高。For example, the ischemic stroke score may be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.
又例如，所述缺血性脑卒中可以是心源性栓塞型脑卒中或小动脉闭塞型脑卒中，且所述缺血性脑卒中的评分可以为6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。For another example, 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.
在某些实施方式中，所述药物仅包含(+)-2-莰醇、其药学上可接受的盐或酯，其代谢物，其前药，和其溶剂合物中的一种或其组合作为活性成分。In certain embodiments, 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.
例如，所述药物仅包含(+)-2-莰醇作为活性成分。For example, the medicament contains only (+)-2-borneol as active ingredient.
在某些实施方式中，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。例如，所述药物中(+)-2-莰醇的含量可以为约5mg、约10mg，约15mg、约20mg、约30mg或约40mg。In certain embodiments, the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg. For example, 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.
在某些实施方式中，所述药物中含有药学上可接受的赋形剂。In certain embodiments, the medicament contains pharmaceutically acceptable excipients.
所述药学上可接受的赋形剂可以包括但不限于：例如，脂肪、蜂蜡、半固体和液体多元醇、天然的或氢化的油等；水(例如，蒸馏水、特别是注射用蒸馏水等)、生理盐水、醇(例如，乙醇)、甘油、多元醇、葡萄糖水溶液、甘露醇、植物油等)；添加剂[例如，扩张剂、崩解剂、粘合剂、润滑剂、润湿剂、稳定剂、乳化剂、分散剂、防腐剂、甜味剂、着色剂、调味剂或芳香剂、浓缩剂、稀释剂、缓冲物质、溶剂或增溶剂、用于实现储存效果的化学品、用于调节渗透压的盐、包衣剂或抗氧化剂]等。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.
在某些实施方式中，所述药学上可接受的赋形剂可以是水的一种形式，其适合于药学或生物学制备并且与自然界中出现的水不同，包括纯化的水、注射用水、无菌纯化的水、注射 用抑菌水、和注射用无菌水(其为注射用蒸馏水的无菌、无细菌、无溶质制剂)。In certain embodiments, 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).
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂或糖浆剂。In some embodiments, 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.
例如，所述药物的剂型可以为注射剂，粉针剂或溶液剂等适合静脉注射或颅内注射方式给药的剂型。For example, the dosage form of the drug may be an injection, a powder injection or a solution suitable for intravenous injection or intracranial injection.
在某些实施方式中，所述药物的给药途径包括静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述药物可在以下阶段给药，包括脑梗期、手术或药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。In some embodiments, 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.
例如，所述药物可以在脑梗期、手术或药物治疗期，取栓前，溶栓前等阶段给药。For example, the drug can be administered at the stage of cerebral infarction, operation or drug treatment, before thrombectomy, and before thrombolysis.
例如，所述药物可以在卒中康复期，取栓后，溶栓后等阶段给药。For example, the drug can be administered during stroke rehabilitation, after thrombectomy, and after thrombolysis.
例如，所述药物可以在全阶段给药，例如在取栓前、手术或药物治疗期和取栓后，溶栓前、手术或药物治疗期和溶栓后的全程施用。For example, 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.
另一方面，本申请提供了(+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In another aspect, 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.
在某些实施方式中，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述(+)-2-莰醇的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述药物仅包含(+)-2-莰醇、其药学上可接受的盐或酯，其代谢物，其前药，和其溶剂合物中的一种或其组合作为活性成分。In certain embodiments, 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.
在某些实施方式中，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。例如，所述药物中(+)-2-莰醇的含量可以为约5mg、约10mg，约15mg、约20mg、约30mg或约40mg。In certain embodiments, the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg. For example, 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.
在某些实施方式中，所述药物中含有药学上可接受的赋形剂。In certain embodiments, the medicament contains pharmaceutically acceptable excipients.
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂或糖浆剂。In some embodiments, 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.
例如，所述药物的剂型可以为注射剂，粉针剂，溶液剂等适合静脉注射或颅内注射方式给药的剂型。For example, the dosage form of the drug can be injection, powder injection, solution and other dosage forms suitable for intravenous injection or intracranial injection.
在某些实施方式中，所述药物的给药途径包括静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述药物可在以下阶段给药，包括脑梗期、手术或药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。In some embodiments, 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.
另一方面，本申请提供了(+)-2-莰醇在制备用于降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。On the other hand, 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.
在某些实施方式中，所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。In some embodiments, 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.
在某些实施方式中，所述药物仅包含(+)-2-莰醇、其药学上可接受的盐或酯，其代谢物，其前药，和其溶剂合物中的一种或其组合作为活性成分。In certain embodiments, 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.
例如，所述药物仅包含(+)-2-莰醇作为活性成分。For example, the medicament contains only (+)-2-borneol as active ingredient.
在某些实施方式中，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。例如，所述药物中(+)-2-莰醇的含量可以为约5mg、约10mg,、约15mg、约20mg，约30mg，或约40mg。In certain embodiments, the amount of (+)-2-borneol in the medicament is about 5 mg to about 40 mg. For example, 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.
在某些实施方式中，所述药物中含有药学上可接受的赋形剂。In certain embodiments, the medicament contains pharmaceutically acceptable excipients.
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂、糖浆剂。In some embodiments, 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.
在某些实施方式中，所述药物的给药途径包括静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述药物可在以下阶段给药，包括脑梗期、手术或药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。In some embodiments, 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.
药物drug
另一方面，本申请提供一种药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合。In another aspect, 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.
例如，所述药物的活性成分可以仅为(+)-2-莰醇。For example, the active ingredient of the medicament may be (+)-2-borneol only.
在某些实施方式中，其中所述药物还包括地一种或多种药学上可接受的赋形剂。In certain embodiments, the medicament further includes one or more pharmaceutically acceptable excipients.
在某些实施方式中，所述药学上可接受的赋形剂包括但不限于：例如，脂肪、蜂蜡、半固体和液体多元醇、天然的或氢化的油等；水(例如，蒸馏水、特别是注射用蒸馏水等)、生理盐水、醇(例如，乙醇)、甘油、多元醇、葡萄糖水溶液、甘露醇、植物油等)；添加剂[例如，扩张剂、崩解剂、粘合剂、润滑剂、润湿剂、稳定剂、乳化剂、分散剂、防腐剂、甜味剂、着色剂、调味剂或芳香剂、浓缩剂、稀释剂、缓冲物质、溶剂或增溶剂、用于实现储存效果的化学品、用于调节渗透压的盐、包衣剂或抗氧化剂]等。In certain embodiments, 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.
在某些实施方式中，所述药学上可接受的赋形剂可以是水的一种形式，其适合于药学或生物学制备并且与自然界中出现的水不同，包括纯化的水、注射用水、无菌纯化的水、注射用抑菌水、和注射用无菌水(其为注射用蒸馏水的无菌、无细菌、无溶质制剂)。In certain embodiments, 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).
在某些实施方式中，其中所述活性成分从药物中快释或缓释，例如延迟或脉冲式地释放。In certain embodiments, wherein the active ingredient is released from the medicament rapidly or sustainably, eg, delayed or pulsed.
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂、糖浆剂。In some embodiments, 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.
在某些实施方式中，其中所述药物被配制为经以下方式施用：静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。In certain embodiments, wherein 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.
在某些实施方式中，其中所述施用通过肠胃外施用，且所述药物以注射剂、粉针剂、或溶液剂的形式存在。例如，所述药物可以以灭菌溶液或悬浮液的形式存在。In some embodiments, the administration is by parenteral administration, and the drug is in the form of injection, powder injection, or solution. For example, the drug may be in the form of a sterile solution or suspension.
在某些实施方式中，其中所述活性成分的剂量为约5mg至约40mg。In certain embodiments, the dose of the active ingredient is from about 5 mg to about 40 mg.
例如，所述活性成分的剂量可以为约5mg、约10mg、约15mg、约20mg、约30mg或约40mg。For example, 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.
例如，所述活性成分的浓度可以为约0.01mg/mL、约0.02mg/mL、约0.03mg/mL、约0.04mg/mL、约0.05mg/mL、约0.06mg/mL、约0.07mg/mL、约0.08mg/mL、约0.09mg/mL、约0.1mg/mL、约0.12mg/mL、约0.14mg/mL、约0.16mg/mL、约0.18mg/mL、约0.2mg/mL、约0.3mg/mL、约0.4mg/mL、约0.5mg/mL、约0.6mg/mL、约0.7mg/mL、约0.8mg/mL、约0.9mg/mL、约1.0mg/mL、约2.0mg/mL、约3.0mg/mL、、约4.0mg/mL、或约5mg/mL。For example, 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.
在某些实施方式中，其中所述药物被配制为约5mL至约500mL的注射液或粉针剂，其中所述活性成分的含量为约5mg至20mg。In certain embodiments, 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.
在某些实施方式中，当药物为注射液剂时，所述活性成分的剂量被配制为约5mg至最大日剂量。In certain embodiments, when the medicament is an injection solution, the dose of the active ingredient is formulated from about 5 mg to the maximum daily dose.
例如，当药物为注射液剂时，所述活性成分的剂量被配制为约5mg、约10mg、约15mg、约20mg、约30mg或约40mg。For example, when the drug is an injection solution, 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.
又例如，所述药物可以被配制为20mL/10mg的注射液剂，或10mL/5mg的注射液剂。For another example, the drug can be formulated as a 20mL/10mg injection solution, or a 10mL/5mg injection solution.
治疗方法treatment method
另一方面，本申请提供一种预防和/或治疗缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In another aspect, 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.
例如，所述缺血性脑卒中可以是心源性栓塞型脑卒中或小动脉闭塞型脑卒中。For example, the ischemic stroke may be cardioembolic stroke or arteriolar occlusive stroke.
例如，所述缺血性脑卒中可以是心源性栓塞型脑卒中合并非高血压性脑卒中(无高血压既往史)。For example, the ischemic stroke may be cardioembolic stroke combined with non-hypertensive stroke (no history of hypertension).
例如，所述缺血性脑卒中可以是小动脉闭塞型脑卒中合并非高血压性脑卒中(无高血压既往史)及复发性脑卒中(有脑卒中既往史)。For example, the ischemic stroke may be arteriolar occlusive stroke combined with non-hypertensive stroke (no history of hypertension) and recurrent stroke (with history of stroke).
在某些实施方式中，所述缺血性脑卒中可以选自6≤NIHSS评分≤20分的缺血性脑卒中。在另一些实施方式中，所述缺血性脑卒中可以选自NIHSS评分＞20分的缺血性脑卒中。In some embodiments, 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.
例如，所述缺血性脑卒中的评分可以为6、7、8、9、10、11、12、13、14、15、16、17、18、19、20或更高。For example, the ischemic stroke score can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or higher.
又例如，所述缺血性脑卒中可以是心源性栓塞型脑卒中或小动脉闭塞型脑卒中，且所述 缺血性脑卒中的评分可以为6、7、8、9、10、11、12、13、14、15、16、17、18、19或20。For another example, 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.
在某些实施方式中，所述药物仅包含(+)-2-莰醇作为活性成分。In certain embodiments, the medicament comprises (+)-2-borneol as the active ingredient only.
在某些实施方式中，所述药物中含有药学上可接受的赋形剂。In certain embodiments, the medicament contains pharmaceutically acceptable excipients.
在某些实施方式中，所述药物的给药途径包括静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述药物通过胃肠外方式施用。In certain embodiments, the drug is administered parenterally.
在某些实施方式中，所述药物通过静脉注射和/或动脉注射方式施用。In certain embodiments, the medicament is administered intravenously and/or intraarterially.
在某些实施方式中，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂或糖浆剂。In some embodiments, 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.
例如，所述药物的剂型可以为注射剂，粉针剂，溶液剂等适合静脉注射或颅内注射方式给药的剂型。For example, the dosage form of the drug can be injection, powder injection, solution and other dosage forms suitable for intravenous injection or intracranial injection.
在某些实施方式中，所述药物可在以下阶段给药，包括脑梗期、手术或药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。In some embodiments, 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.
例如，所述药物可以在脑梗期、手术或药物治疗期，取栓前，溶栓前等阶段给药。For example, the drug can be administered at the stage of cerebral infarction, operation or drug treatment, before thrombectomy, and before thrombolysis.
例如，所述药物可以在卒中康复期，取栓后，溶栓后等阶段给药。For example, the drug can be administered during stroke rehabilitation, after thrombectomy, and after thrombolysis.
在某些实施方式中，所述活性成分以至少约5mg至最大日剂量施用。In certain embodiments, the active ingredient is administered at a dose of at least about 5 mg up to a maximum daily dose.
例如，所述活性成分以约5mg、约6mg、约7mg、约8mg、约9mg、约10mg、约11mg、约12mg、约13mg、约14mg、约15mg、约16mg、约17mg、约18mg、约19mg、约20mg、约21mg、约22mg、约23mg、约24mg、约25mg、约26mg、约27mg、约28mg、约29mg、约30mg、约31mg、约32mg、约33mg、约34mg、约35mg、约36mg、约37mg、约338mg、约39mg、约40mg、约41mg、约42mg、约43mg、约44mg、约45mg、约46mg、约47mg、约48mg、约49mg、约50mg、约60mg、约70mg、约80mg、约70mg、约90mg、或约100mg的日剂量施用。For example, 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, or about 100 mg.
在某些实施方式中，所述活性成分以约10mg/天至约40mg/天的剂量施用。In certain embodiments, the active ingredient is administered at a dose of about 10 mg/day to about 40 mg/day.
例如，所述活性成分以约10mg/天、约15mg/天、约20mg/天、30mg/天、或约40mg/天的剂量施用。For example, 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.
在某些实施方式中，其中所述活性成分对于胃肠外方式施用以日剂量至少约0.05mg/kg 体重到5mg/kg体重或更高应用。In certain embodiments, wherein 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.
例如，所述活性成分对于胃肠外方式施用(如静脉注射)以日剂量约0.05mg/kg体重、约0.06mg/kg体重、约0.07mg/kg体重、约0.08mg/kg体重、约0.09mg/kg体重、约0.1mg/kg体重、约0.2mg/kg体重、约0.3mg/kg体重、约0.4mg/kg体重、约0.5mg/kg体重、约0.6mg/kg体重、约0.7mg/kg体重、约0.8mg/kg体重、约0.9mg/kg体重、到约1mg/kg体重、约1.1mg/kg体重、约1.2mg/kg体重、约1.3mg/kg体重、约1.4mg/kg体重、约1.5mg/kg体重、约1.6mg/kg体重、约1.7mg/kg体重、约1.8mg/kg体重、约1.9mg/kg体重、到约2mg/kg体重、约2.1mg/kg体重、约2.2mg/kg体重、约2.3mg/kg体重、约2.4mg/kg体重、约2.5mg/kg体重、约2.6mg/kg体重、约2.7mg/kg体重、约2.8mg/kg体重、约2.9mg/kg体重、到约3mg/kg体重、约3.1mg/kg体重、约3.2mg/kg体重、约3.3mg/kg体重、约3.4mg/kg体重、约3.5mg/kg体重、约3.6mg/kg体重、约3.7mg/kg体重、约3.8mg/kg体重、约3.9mg/kg体重、到约4mg/kg体重、约4.1mg/kg体重、约4.2mg/kg体重、约4.3mg/kg体重、约4.4mg/kg体重、约4.5mg/kg体重、约4.6mg/kg体重、约4.7mg/kg体重、约4.8mg/kg体重、约4.9mg/kg体重、到约5mg/kg体重应用。For example, 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 mg/kg body weight, about 2.1 mg/kg body weight Body weight, about 2.2 mg/kg body weight, about 2.3 mg/kg body weight, about 2.4 mg/kg body weight, about 2.5 mg/kg body weight, about 2.6 mg/kg body weight, about 2.7 mg/kg body weight, about 2.8 mg/kg body weight , about 2.9 mg/kg body weight, up to about 3 mg/kg body weight, about 3.1 mg/kg body weight, about 3.2 mg/kg body weight, about 3.3 mg/kg body weight, about 3.4 mg/kg body weight, about 3.5 mg/kg body weight, About 3.6 mg/kg body weight, about 3.7 mg/kg body weight, about 3.8 mg/kg body weight, about 3.9 mg/kg body weight, up to about 4 mg/kg body weight, about 4.1 mg/kg body weight, about 4.2 mg/kg body weight, about 4.3 mg/kg body weight, about 4.4 mg/kg body weight, about 4.5 mg/kg body weight, about 4.6 mg/kg body weight, about 4.7 mg/kg body weight, about 4.8 mg/kg body weight, about 4.9 mg/kg body weight, to about 5mg/kg body weight application.
在某些实施方式中，其中所述日剂量作为一次性剂量或以多次单剂量施用。例如，可以在一天施用1至3次上述日剂量。In certain embodiments, wherein said daily dose is administered as a single dose or in multiple single doses. For example, the above-mentioned daily dose can be administered 1 to 3 times a day.
在某些实施方式中，其中所述药物制剂经长期使用，优选长达数天，数周或数月。例如，所示药物施用可以是1至7天，也可以是2-4周，也可以是1至3个月，也可以是3至12个月或更长。In certain embodiments, wherein the pharmaceutical formulation is used for a long period of time, preferably up to several days, weeks or months. For example, 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.
在某些实施方式中，所述药物可在以下阶段给药，包括脑梗期、手术或其他药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。In certain embodiments, 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 .
在某些实施方式中，还包括将所述药物与静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂中的任一种或其组合联合使用。In some embodiments, 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.
另一方面，本申请提供一种提高缺血性脑卒中预防和/或治疗效果的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合。In another aspect, 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.
在某些实施方式中，，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。In certain embodiments, wherein 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.
在某些实施方式中，所述活性成分的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特 征的任一种或其组合。In some embodiments, 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.
另一方面，本申请提供一种降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。In another aspect, 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.
在某些实施方式中，其中所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。In some embodiments, 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.
在某些实施方式中，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、和神经保护剂的任一种或其组合联合使用。In some embodiments, 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.
本申请还提供了一下具体实施方式：This application also provides the following specific implementation methods:
1.(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。1. Use of (+)-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.(+)-2-莰醇在制备用于提高缺血性脑卒中预防和/或治疗效果的药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。2. The use of (+)-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.
3.根据实施方式2所述的用途，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。3. The use according to Embodiment 2, wherein 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 patient's ability to perform daily activities.
4.根据实施方式2所述的用途，所述(+)-2-莰醇的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。4. According to the use described in embodiment 2, 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.
5.(+)-2-莰醇在制备用于降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的药物中的用途，其中所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。5. 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 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 .
6.根据实施方式5所述的用途，所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。6. The use according to embodiment 5, 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.
7.根据实施方式5所述的用途，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。7. The use according to embodiment 5, 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.
8.根据实施方式1-7中任一项所述的用途，其中所述缺血性脑卒中选自6≤NIHSS评分≤20分的缺血性脑卒中。8. The use according to any one of embodiments 1-7, wherein the ischemic stroke is selected from ischemic stroke with 6≤NIHSS score≤20 points.
9.(+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中选自中度、中-重度或重度型缺血性脑卒中患者的任一种。9. 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 severe ischemia Any type of stroke patient.
10.根据实施方式1-9中任一项所述的用途，所述药物仅包含(+)-2-莰醇作为活性成分。10. Use according to any one of embodiments 1-9, the medicament comprising (+)-2-borneol as active ingredient only.
11.根据实施方式1-10中任一项所述的用途，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。11. The use according to any one of embodiments 1-10, the content of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
12.根据实施方式1-11中任一项所述的用途，所述药物中(+)-2-莰醇的含量为约5mg，或约10mg，或约20mg，或约30mg，或约40mg。12. The use according to any one of embodiments 1-11, 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 .
13.根据实施方式1-12中任一项所述的用途，所述(+)-2-莰醇还包括其药学上可接受的盐或酯，其代谢物，其前药，或其溶剂合物。13. The use according to any one of embodiments 1-12, the (+)-2-borneol also includes its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, or its solvent compound.
14.根据实施方式1-13中任一项所述的用途，所述药物中含有药学上可接受的赋形剂。14. The use according to any one of embodiments 1-13, wherein the medicine contains pharmaceutically acceptable excipients.
15.根据实施方式1-14中任一项所述的用途，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂或糖浆剂。15. The use according to any one of embodiments 1-14, 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.
16.药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合；所述活性成分的剂量为约5mg至约40mg。16. 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.
17.根据实施方式16所述的药物，其中所述药物还包括地一种或多种药学上可接受的赋形剂。17. The medicament according to embodiment 16, wherein the medicament further comprises one or more pharmaceutically acceptable excipients.
18.根据实施方式16-17中任一项所述的药物，其中所述活性成分从药物中快释或缓释，例如延迟或脉冲式地释放。18. The medicament according to any one of embodiments 16-17, wherein the active ingredient is released from the medicament rapidly or slowly, eg delayed or pulsed.
19.根据实施方式16-18中任一项所述的药物，所述药物的剂型包括注射剂、粉针剂、滴剂、贴剂、片剂、颗粒剂、舌下片剂、微针剂、泡腾片、溶液剂、乳剂、脂质体制剂、悬浮剂、软膏剂、霜剂、经皮吸收剂、经粘膜吸收剂、锭剂、滴剂、滴丸剂、丸剂、胶囊剂、散剂、粉末剂、擦剂、细粒剂或糖浆剂。19. The medicine according to any one of embodiments 16-18, 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.
20.根据实施方式16-19中任一项所述的药物，其中所述药物被配制为经以下方式施用：静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介 入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。20. 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.
21.根据实施方式20所述的药物，其中所述施用通过肠胃外施用，且所述药物以注射剂、粉针剂、或溶液剂的形式存在。21. The medicament according to embodiment 20, wherein the administration is by parenteral administration, and the medicament is in the form of injection, powder injection, or solution.
22.根据实施方式16-21中任一项所述的药物，其中所述活性成分的浓度为约0.05mg/mL至约5mg/mL，优选约0.1mg/mL至约2.5mg/mL。22. The medicament according to any one of embodiments 16-21, wherein the concentration of the active ingredient is from about 0.05 mg/mL to about 5 mg/mL, preferably from about 0.1 mg/mL to about 2.5 mg/mL.
23.根据实施方式16-22中任一项所述的药物，其中所述药物被配制为约5mL至约500mL的小容量注射液或大容量注射液或粉针剂，其中所述活性成分的含量为约5mg至40mg。23. The medicament according to any one of embodiments 16-22, wherein the medicament is formulated as a small-volume injection or a large-volume injection or powder injection of about 5 mL to about 500 mL, wherein the content of the active ingredient is From about 5 mg to 40 mg.
24.根据实施方式16-23中任一项所述的药物，其中所述药物被配制为约10mL至约500mL的小容量注射液或大容量注射液或粉针剂，其中所述活性成分的含量为约5mg至40mg。24. The medicament according to any one of embodiments 16-23, wherein the medicament is formulated as a small-volume injection or a large-volume injection or powder injection from about 10 mL to about 500 mL, wherein the content of the active ingredient is From about 5 mg to 40 mg.
25.根据实施方式16-24中任一项所述的药物，其中所述药物被配制为5mg活性成分/10mL或10mg活性成分/20mL的注射剂。25. The medicament according to any one of embodiments 16-24, wherein the medicament is formulated as an injection of 5 mg active ingredient/10 mL or 10 mg active ingredient/20 mL.
26.根据实施方式16-25中任一项所述的药物，当药物为溶液剂时，所述活性成分的剂量被配制为约5mg至最大日剂量。26. 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.
27.根据实施方式16-26中任一项所述的药物，当药物为溶液剂时，所述活性成分的剂量被配制为约5mg至约40mg。27. The medicament according to any one of embodiments 16-26, when the medicament is a solution, the active ingredient is formulated in a dose of about 5 mg to about 40 mg.
28.药盒，其包含实施方式16-27中任一项所述的药物。28. A kit comprising the medicament of any one of embodiments 16-27.
29.一种预防和/或治疗缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。29. 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.
30.根据实施方式29所述的方法，还包括将所述药物与静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂中的任一种或其组合联合使用。30. The method according to embodiment 29, further comprising combining the drug with any one of intravenous thrombolytic drugs, antiplatelet drugs, anticoagulant drugs, defibrosis drugs, volume expansion drugs, microcirculation improving drugs, and neuroprotective agents. species or combinations thereof.
31.一种提高缺血性脑卒中预防和/或治疗效果的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。31. 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.
32.根据实施方式31所述的方法，其中所述预防和/或治疗效果选自缓解症状、改善预后、减轻神经功能缺损程度、提高患者日常活动能力的任一种或其组合。32. The method according to embodiment 31, wherein 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.
33.根据实施方式31所述的方法，所述活性成分的效果选自：调节能量代谢与氧化还原代谢，提高缺血损伤神经元存活率，降低缺血性脑卒中所致脑梗死面积，改善缺血性脑卒中神经行为学特征的任一种或其组合。33. The method according to embodiment 31, 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.
34.一种降低或避免缺血性脑卒中预防和/或治疗过程中产生的不良反应的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其前药、其代谢物、和其溶剂合物中的一种或其组合，所述缺血性脑卒中选自心源性栓塞型脑卒中、小动脉闭塞型脑卒中、非高血压性脑卒中、和复发性脑卒中的任一种或其组合，和/或所述缺血型脑卒中的NIHSS评分≥6分。34. 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.
35.根据实施方式34所述的方法，其中所述的降低或避免缺血性脑卒中防治过程中的不良反应的方式选自：替代其他药物、减少患者使用其他药物的种类和/或使用剂量、为患者在脑卒中防治全程中提供持续稳定治疗的任一种或其组合。35. The method according to embodiment 34, wherein 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.
36.根据实施方式34所述的用途，所述的其他药物选自静脉溶栓药、抗血小板药、抗凝药、降纤药、扩容药、改善微循环药、神经保护剂的任一种或其组合联合使用。36. The use according to embodiment 34, 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.
37.根据实施方式29-36中任一项所述的方法，所述药物的给药途径包括静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药、涂抹给药。37. The method according to any one of embodiments 29-36, 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.
38.根据实施方式29-37中任一项所述的方法，所述药物通过胃肠外方式施用。38. The method of any one of embodiments 29-37, wherein the medicament is administered parenterally.
39.根据实施方式29-38中任一项所述的方法，所述药物通过静脉注射方式施用。39. The method of any one of embodiments 29-38, wherein the medicament is administered intravenously.
40.根据实施方式29-39中任一项所述的方法，所述活性成分以至少约5mg至最大日剂量施用。40. The method according to any one of embodiments 29-39, the active ingredient being administered in a dose of at least about 5 mg up to a maximum daily dose.
41.根据实施方式29-40中任一项所述的方法，所述活性成分以约10mg/天至约20mg/天的日剂量施用。41. The method according to any one of embodiments 29-40, wherein the active ingredient is administered at a daily dose of about 10 mg/day to about 20 mg/day.
42.根据实施方式29-41中任一项所述的方法，其中所述日剂量作为一次性剂量或以多次单剂量施用。42. The method according to any one of embodiments 29-41, wherein the daily dose is administered as a single dose or in multiple single doses.
43.根据实施方式29-42中任一项所述的方法，其中所述药物经长期使用，优选长达数天，数周或数月。43. The method according to any one of embodiments 29-42, wherein the medicament is used chronically, preferably up to days, weeks or months.
44.根据实施方式29-43中任一项所述的方法，所述药物可在以下阶段给药，包括脑梗期、手术或其他药物治疗期、卒中康复期、取栓前、取栓后、溶栓前和/或溶栓后。44. The method according to any one of embodiments 29-43, 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.
不欲被任何理论所限，下文中的实施例仅仅是为了阐释本申请的药物、制备方法和用途等，而不用于限制本申请发明的范围。Not intending to be limited by any theory, the following examples are only for explaining the medicine, preparation method and application of the present application, and are not intended to limit the scope of the invention of the present application.
实施例Example
实施例1(+)-2-莰醇抗急性脑缺血剂量与效应关系Embodiment 1 (+)-2-camphorol anti-acute cerebral ischemia dose and effect relationship
本试验采用大鼠局灶性脑缺血模型(MCAO)，选用120只SD大鼠，雄性，随机分为12个组，分别为溶剂对照组(60％的1,2-丙二醇，静脉注射，5mL/kg)，阳性对照组(尼莫地平注射液，尾静脉注射，25、50、100、500、1000μg/kg)及(+)-2-莰醇注射液剂量组(剂量分别为0.5、1、2、4、6、8mg/kg，静脉注射)，每组10只SD大鼠，全雄。溶剂对照组、阳性对照组及(+)-2-莰醇注射液组SD大鼠按上述剂量设计MCAO脑缺血后分别给药1次。观察给药后脑梗死面积及脑梗后24h神经学行为评分。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, 1000μg/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.
结果显示(见表1)，溶剂对照组大鼠脑梗死面积为39.7％，行为学评分为2.5±0.53；(+)-2-莰醇起始剂量为0.5mg/kg，脑梗死面积为33.8％，与溶剂对照组比较，梗死面积减少了15.0％，随着剂量的增加，脑梗死面积进一步缩小，行为学评分也相应降低，与溶剂对照组比较其减少梗死面积的百分比逐渐增大，显示出在剂量与效应之间有良好的量效关系存在。但当剂量达到6mg/kg和8mg/kg时，脑梗面积不再随着剂量的增加而降低，6mg/kg和8mg/kg两个剂量组的脑梗死面积均为20.3％。因此，(+)-2-莰醇用1mg/kg、2mg/kg和4mg/kg作为大鼠的低、中、高剂量进行其他试验较为合适。The results show (see Table 1), the cerebral infarction area of solvent control group rats is 39.7%, and the behavioral score is 2.5 ± 0.53; %, compared with the solvent control group, the infarct size was reduced by 15.0%. With the increase of the dose, the cerebral infarct size was further reduced, and the behavioral score was also reduced accordingly. Compared with the solvent control group, the percentage of the infarct size reduction increased gradually, showing There is a good dose-effect relationship between dose and effect. But when the dose reached 6mg/kg and 8mg/kg, the cerebral infarction area no longer decreased with the increase of the dose, and the cerebral infarction area of the two dose groups of 6mg/kg and 8mg/kg was 20.3%. Therefore, it is more appropriate to carry out other experiments with (+)-2-camphorol using 1 mg/kg, 2 mg/kg and 4 mg/kg as low, medium and high doses in rats.
同时阳性对照药尼莫地平5个给药剂量组结果显示，阳性对照药的最大效应出现在1000μg/kg，再增加剂量，脑梗死面积将无显著降低，在该剂量，大鼠脑梗死面积为25.3％，与溶剂对照组比较，脑梗死面积减少最大效应为36.2％，所有治疗组的行为学评分也明显低于溶剂对照组。Simultaneously positive control drug nimodipine 5 dosage group results show that the maximum effect of positive control drug appears at 1000 μ 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.
对(+)-2-莰醇与阳性对照药进行比较发现，(+)-2-莰醇抗大鼠急性脑缺血的药物效价强度较尼莫地平注射液略低，但最大效应明显优于尼莫地平注射液。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.
表1(+)-2-莰醇注射液对大鼠脑梗死的影响(单位：脑梗死面积
Figure PCTCN2021124428-appb-000007
n＝10) The impact of table 1 (+)-2-camphor injection on rat cerebral infarction (unit: cerebral infarction area
Figure PCTCN2021124428-appb-000007
n=10)
组别group 剂量dose 行为学评分behavioral score 脑梗面积(％)Cerebral infarction area (%) 脑梗面积减少(％)Cerebral infarction area reduction (%)
溶剂对照组solvent control group 溶剂5ml/kgSolvent 5ml/kg 2.5±0.532.5±0.53 39.7±3.339.7±3.3 //
(+)-2-莰醇组(+)-2-borneol group 0.5mg/kg0.5mg/kg 2.1±0.882.1±0.88 33.8±4.4**33.8±4.4** 15.015.0
(+)-2-莰醇组(+)-2-borneol group 1mg/kg1mg/kg 2.1±0.572.1±0.57 30.2±2.3***30.2±2.3*** 24.024.0
(+)-2-莰醇组(+)-2-borneol group 2mg/kg2mg/kg 2.0±0.82*2.0±0.82* 26.2±2.0***26.2±2.0*** 33.933.9
(+)-2-莰醇组(+)-2-borneol group 4mg/kg4mg/kg 1.9±0.57*1.9±0.57* 21.8±2.0***21.8±2.0*** 45.245.2
(+)-2-莰醇组(+)-2-borneol group 6mg/kg6mg/kg 1.8±0.79*1.8±0.79* 20.3±2.2***20.3±2.2*** 48.948.9
(+)-2-莰醇组(+)-2-borneol group 8mg/kg8mg/kg 1.7±0.48**1.7±0.48** 20.3±2.5***20.3±2.5*** 48.948.9
阳性对照组positive control group 25μg/kg25μg/kg 2.2±0.632.2±0.63 34.0±5.7*34.0±5.7* 14.314.3
阳性对照组positive control group 50μg/kg50μg/kg 1.9±0.57*1.9±0.57* 32.2±4.5**32.2±4.5** 19.019.0
阳性对照组positive control group 100μg/kg100μg/kg 1.8±0.42**1.8±0.42** 27.3±4.1***27.3±4.1*** 31.331.3
阳性对照组positive control group 500μg/kg500μg/kg 1.4±0.52***1.4±0.52*** 26.2±3.2***26.2±3.2*** 33.933.9
阳性对照组positive control group 1000μg/kg1000μg/kg 1.5±0.53***1.5±0.53*** 25.3±3.3***25.3±3.3*** 36.236.2
*P<0.05，**P<0.01,***P<0.001vs溶剂对照组*P<0.05, **P<0.01, ***P<0.001vs solvent control group
实施例2(+)-2-莰醇对局灶性缺血再灌注脑损伤的保护作用Example 2 Protective effect of (+)-2-camphor on focal ischemia-reperfusion brain injury
本试验采用颈内动脉线栓法制备大鼠脑缺血再灌注模型，于缺血再灌注后2h尾静脉注射给药1次。(+)-2-莰醇设4个给药剂量组，分别为0.25、0.5、1.0、2.0mg/kg；依达拉奉也设4个给药剂量组，分别为0.75、1.5、3.0、6.0mg/kg。脑缺血再灌注48h后观察所试药物对脑缺血大鼠的神经缺陷症状、脑梗死面积及死亡率的影响。结果显示(见表2-1至表2-3)，依达拉奉均呈剂量依赖性减少脑缺血再灌注损伤，起效剂量为6mg/kg，(+)-2-莰醇在0.25～2.0mg/kg剂量范围内呈剂量依赖性减少脑缺血再灌注损伤，起效剂量为1.0mg/kg，且(+)-2-莰醇药效强度优于依达拉奉。In this experiment, 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. After 48 hours of cerebral ischemia-reperfusion, 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. Within the dose range of ~2.0 mg/kg, it can reduce cerebral ischemia-reperfusion injury in a dose-dependent manner, and the effective dose is 1.0 mg/kg, and the efficacy of (+)-2-camphor is better than that of edaravone.
表2-1.(+)-2-莰醇对神经缺陷症状的影响Table 2-1. Effect of (+)-2-camphor on neurological deficit symptoms
Figure PCTCN2021124428-appb-000008
Figure PCTCN2021124428-appb-000008
均值±标准误。 *P<0.05，与模型组比较。 Mean ± standard error. * P<0.05, compared with model group.
表2-2依达拉奉对神经缺陷症状的影响Table 2-2 Effect of Edaravone on Neurological Deficiency Symptoms
Figure PCTCN2021124428-appb-000009
Figure PCTCN2021124428-appb-000009
Figure PCTCN2021124428-appb-000010
Figure PCTCN2021124428-appb-000010
均值±标准误。 *P<0.05，与模型组比较。 Mean ± standard error. * P<0.05, compared with model group.
表2-3不同效应水平两药的脑梗死面积影响和量效关系Table 2-3 Effect of two drugs with different effect levels on cerebral infarction size and dose-effect relationship
Figure PCTCN2021124428-appb-000011
Figure PCTCN2021124428-appb-000011
实施例3(+)-2-莰醇在缺血性脑卒中患者中的临床试验研究Example 3 Clinical Trial Research of (+)-2-Bornyl Alcohol in Patients with Ischemic Cerebral Stroke
临床试验设计：多中心、随机、双盲、安慰剂对照、平行试验设计。Clinical trial design: multicenter, randomized, double-blind, placebo-controlled, parallel trial design.
临床试验方法clinical trial method
受试人群：18岁(最小年龄)至85岁(最大年龄)，男女均可；根据《中国急性缺血性脑卒中诊治指南2018》诊断为急性缺血性脑卒中患者；从“最后看起来正常的时间”到开始研究药物治疗≤24小时，对于醒后卒中或因失语、意识障碍等原因无法准确获得症状出现时间时，应以患者最后表现正常的时间为准；首次发病或上次发病后愈后良好(mRS评分0-1分)再次发病(复发)的患者；就诊时5分≤NIHSS评分≤20分，且NIHSS第五项上肢和第六项下肢评分之和≥2分；理解并遵守研究流程，自愿参加，并签署知情同意书(知情同意书由本人或法定代理人自愿签署)。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).
试验药组：(+)-2-莰醇，低剂量10mg(单次给药剂量)和高剂量20mg(单次给药剂量)。Test drug group: (+)-2-camphor, low dose 10 mg (single administration dose) and high dose 20 mg (single administration dose).
安慰剂组：与试验药组区别在于其不含活性成分(+)-2-莰醇。Placebo group: the difference from the test drug group is that it does not contain the active ingredient (+)-2-camphor.
给药方式：与250ml生理盐水配伍后静脉滴注Administration method: Intravenous infusion after mixing with 250ml normal saline
给药次数及间隔：1天给药2次，每次间隔12小时。Dosing frequency and interval: 2 times a day, with an interval of 12 hours each time.
治疗周期：连续给药7天Treatment cycle: continuous administration for 7 days
主要疗效终点指标：第90±7天mRS 0-1比例。The main efficacy endpoint index: mRS 0-1 ratio at day 90±7.
注：脑卒中临床试验的主要目的是判断特定干预措施的疗效，已有多种功能评估量表可供选择使用，其中被大力推荐作为脑卒中临床试验终点指标的是改良Rankin评分量表(modified Rankin scale，mRS)。在国内外脑卒中临床试验中，mRS是现今最常使用的功能结局评估量表。Note: The main purpose of stroke clinical trials is to judge the efficacy of specific interventions. There are a variety of functional assessment scales available for use, among which the modified Rankin Scale (modified Rankin scale, mRS). In stroke clinical trials at home and abroad, mRS is the most commonly used functional outcome assessment scale.
mRS评分又称为改良Rankin评分量表(表3)，是用来评价脑卒中患者神经功能恢复状态的量表，共分为七级。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.
表3 mRS评分量表Table 3 mRS scoring scale
症状symptom 评分score
完全无症状completely asymptomatic 00
尽管有症状，但无明显功能障碍，能完成所有日常职责和活动Ability to perform all daily duties and activities without significant functional impairment despite symptoms 11
轻度残疾，不能完成病前所有活动，但不需要帮助，能照顾自己的事务Mildly disabled, unable to perform all premorbid activities, but able to look after self without assistance 22
中度残疾，要求一些帮助，但行走不需要帮助Moderately disabled, requires some assistance, but walks without assistance 33
重度残疾，不能独立行走，无他人帮助不能满足自身需求Severely disabled, unable to walk independently, unable to meet their own needs without help from others 44
严重残疾，不能独立行走，无他人帮助不能满足自身需求Severely disabled, unable to walk independently, unable to meet their own needs without help from others 55
死亡die 66
“第90±7天mRS 0-1比例”代表卒中患者从入院时基线mRS评分≥2(即轻度残疾或中度残疾或重度残疾或严重残疾)经治疗在90±7天后恢复至mRS评分为0-1(即完全无症状或无明显功能障碍)的比例，通常以百分比表示。"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.
结果result
一项共入组240例受试者(低剂量组、高剂量组和安慰剂组均入组80例受试者)的(+)-2-莰醇临床试验研究。204(85.00％)例受试者完成治疗期试验，三组均有68(85.00％)例受试者完成治疗期试验。36(15.00％)例受试者提前退出试验，三组均有12(15.00％)例受试者未完成试验。A clinical trial study of (+)-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.
3.1(+)-2-莰醇在不同TOAST亚型中的治疗效果3.1(+)-2-Bornyl alcohol treatment effect in different TOAST subtypes
表4受试者TOAST分型基线情况(FAS)Table 4 Subject TOAST classification baseline situation (FAS)
Figure PCTCN2021124428-appb-000012
Figure PCTCN2021124428-appb-000012
Figure PCTCN2021124428-appb-000013
Figure PCTCN2021124428-appb-000013
注：表中“n”代表相应组成部分的人数，“％”代表率，计算方式为：相应组成部分的人数/各组人数*100％。Note: "n" in the table represents the number of people in the corresponding component, and "%" represents the rate. The calculation method is: number of people in the corresponding component/number of people in each group*100%.
FAS：即Full analysis set，全分析集FAS: Full analysis set, full analysis set
表5治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(TOAST＝大动脉粥样硬化型)Table 5 Analysis of the proportion of patients with mRS score 0-1 points on the 90th ± 7th day of treatment (FAS)-subgroup (TOAST=large artery atherosclerosis type)
Figure PCTCN2021124428-appb-000014
Figure PCTCN2021124428-appb-000014
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
表6治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(TOAST＝心源性栓塞型)Table 6 Analysis of the proportion of patients with mRS score 0-1 points on the 90th ± 7th day of treatment (FAS)-subgroup (TOAST=cardiogenic embolism type)
Figure PCTCN2021124428-appb-000015
Figure PCTCN2021124428-appb-000015
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
表7治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(TOAST＝小动脉闭塞型)Table 7 Treatment of the first 90 ± 7 days mRS score 0-1 points patient proportion analysis (FAS) - subgroup (TOAST = small artery occlusion type)
Figure PCTCN2021124428-appb-000016
Figure PCTCN2021124428-appb-000016
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
通过试验药组与安慰剂组的绝对效应差值结果分析(见表中“低剂量组vs安慰剂组组间差异”及“高剂量组vs安慰剂组组间差异”)，表5-7中的结果显示(+)-2-莰醇在治疗心源性栓塞型脑卒中与小动脉闭塞型脑卒中的效果明显优于大动脉粥样硬化型脑卒中(在心源性栓塞型脑卒中结果中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值分别为42.9％和80.0％；在小动脉闭塞型脑卒中结果中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值分别为19.6％和16.0％；但在大动脉粥样硬化型脑卒中结果中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值为负值，分别为-1.9％和-12.1％，说明无效或效果更差)，其中在心源性栓塞型脑卒中高剂量治疗组中，mRS评分为0或1分(即预后良好)的患者比例高达80％，与安慰剂组比较具有统计学差异；而在小动脉闭塞型脑卒中(+)-2-莰醇治疗组也优于安慰剂组；而(+)-2-莰醇在治疗大动脉粥样硬化型脑卒中的效果不明显，或效果更差，以上表明(+)-2-莰醇并非 在所有的脑卒中亚型中均能产生治疗效果，并且本申请也发现(+)-2-莰醇对于心源性栓塞型脑卒中和小动脉闭塞型脑卒中在治疗效果上有高度的选择性，提示在上述类型的患者中具有良好的治疗效果。Through the analysis of the absolute effect difference between the test drug group and the placebo group (see the "low dose group vs placebo group group difference" and "high dose group vs placebo group group difference" in the table), table 5-7 The results in the study showed that (+)-2-camphorol was significantly more effective in the treatment of cardioembolic stroke and small artery occlusive stroke than large artery atherosclerotic stroke (in cardioembolic stroke results , the absolute effect differences between the low-dose and high-dose test drug groups and the placebo group were 42.9% and 80.0% respectively; The difference in effect was 19.6% and 16.0%, respectively; however, in the outcome of large artery atherosclerotic stroke, the absolute difference in effect between the low-dose and high-dose test drug groups and the placebo group was negative, being -1.9% and -1.9% respectively. -12.1%, indicating no effect or worse effect), among them, in the high-dose treatment group of cardioembolic stroke, the proportion of patients with mRS score of 0 or 1 (that is, good prognosis) was as high as 80%, compared with the placebo group There are statistical differences; and in the small artery occlusive stroke (+)-2-borneol treatment group is also better than the placebo group; and the effect of (+)-2-borneol in the treatment of large artery atherosclerotic stroke It is not obvious, or the effect is worse, the above shows that (+)-2-borneol does not all produce therapeutic effects in all stroke subtypes, and the application also finds that (+)-2-borneol is effective for cardiogenic Embolic stroke and arteriolar occlusive stroke were highly selective in the treatment effect, suggesting a good treatment effect in these types of patients.
3.2(+)-2-莰醇在有(或无)高血压史的卒中患者中的治疗效果3.2(+)-2-Bornhalol Therapeutic effect in stroke patients with (or without) history of hypertension
表8治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(高血压史＝有)Table 8 Treatment of the first 90 ± 7 days mRS score 0-1 points patient proportion analysis (FAS) - subgroup (hypertension history = have)
Figure PCTCN2021124428-appb-000017
Figure PCTCN2021124428-appb-000017
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
表9治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(高血压史＝无)Table 9 Treatment of the first 90 ± 7 days mRS score 0-1 points patient proportion analysis (FAS) - subgroup (hypertension history = no)
Figure PCTCN2021124428-appb-000018
Figure PCTCN2021124428-appb-000018
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
通过试验药组与安慰剂组的绝对效应差值结果分析(见表中“低剂量组vs安慰剂组组间差异”及“高剂量组vs安慰剂组组间差异”)，表8-9中的结果显示(+)-2-莰醇在无高血压病史的脑卒中患者中的治疗效果明显优于有高血压病史的脑卒中患者(在无高血压病史的脑卒中患者中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值分别为34.7％和8.6％；但在有高血压史的脑卒中患者中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值仅分别为5.1％和7.8％)，且低剂量组治疗无高血压史的患者较安慰剂具有统计学差异。Through the analysis of the absolute effect difference between the test drug group and the placebo group (see the "low dose group vs placebo group group difference" and "high dose group vs placebo group group difference" in the table), table 8-9 The results in showed that (+)-2-camphor in stroke patients without history of hypertension was significantly better than stroke patients with history of hypertension (in stroke patients without history of hypertension, low dose The absolute effect difference between the high-dose test drug group and the placebo group was 34.7% and 8.6% respectively; but in stroke patients with a history of hypertension, the absolute effect of the low-dose and high-dose test drug groups and the placebo group The differences were only 5.1% and 7.8%, respectively), and the low-dose group treated patients with no history of hypertension had a statistical difference compared with the placebo.
3.3(+)-2-莰醇在有(或无)脑卒中史的卒中患者中的治疗效果3.3 Therapeutic effect of (+)-2-borneol in stroke patients with (or without) stroke history
表10治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(卒中史＝再次发病)Table 10 Analysis of the proportion of patients with mRS score 0-1 points on the 90th ± 7th day of treatment (FAS)-subgroup (stroke history=recurrence)
Figure PCTCN2021124428-appb-000019
Figure PCTCN2021124428-appb-000019
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
表11治疗第90±7天mRS评分0-1分和0-2分患者比例分析(FAS)-亚组(卒中史＝首次发病)Table 11 Proportion analysis of patients with mRS score 0-1 and 0-2 on day 90 ± 7 of treatment (FAS) - subgroup (stroke history = first onset)
Figure PCTCN2021124428-appb-000020
Figure PCTCN2021124428-appb-000020
注：百分比的计算基于各治疗组疗效可评价人群。Note: The calculation of the percentage is based on the evaluable population of each treatment group.
[1]精确Pearson-Clopper双侧95％置信区间[1] Exact Pearson-Clopper two-sided 95% confidence interval
[2]渐近双侧95％置信区间[2] Asymptotic two-sided 95% confidence interval
[3]基于卡方检验[3] Based on chi-square test
通过试验药组与安慰剂组的绝对效应差值结果分析(见表中“低剂量组vs安慰剂组组间差异”及“高剂量组vs安慰剂组组间差异”)，表10-11中的结果显示(+)-2-莰醇在有卒中史的脑卒中患者中的治疗效果明显优于无卒中病史的脑卒中患者(在有卒中史即再次发病或复发的脑卒中患者中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值分别为31.9％和22.4％，；但在无卒中史即首次发病的脑卒中患者中，低剂量和高剂量试验药组与安慰剂组的绝对效应差值仅分别为3.3％和2.1％)，且低剂量组治疗再次发病患者较安慰剂具有统计学差异。Through the analysis of the absolute effect difference results between the test drug group and the placebo group (see "low dose group vs placebo group group difference" and "high dose group vs placebo group group difference" in the table), table 10-11 The results in the study showed that the therapeutic effect of (+)-2-camphorol in stroke patients with stroke history was significantly better than that in stroke patients without stroke history (in stroke patients with stroke history, that is, recurrent or recurrent stroke patients, The absolute effect differences between the low-dose and high-dose test drug groups and the placebo group were 31.9% and 22.4%, respectively; The difference in absolute effect of the low-dose group was only 3.3% and 2.1%, respectively), and the low-dose group had a statistical difference compared with the placebo in the treatment of relapsed patients.
3.4(+)-2-莰醇在不同NIHSS评分的卒中患者中的治疗效果3.4(+)-2-Bornhalol Therapeutic Effects in Stroke Patients with Different NIHSS Scores
表12治疗第90±7天mRS评分0-1分患者比例分析(FAS)-亚组(不同NIHSS评分)Table 12 Analysis of the proportion of patients with mRS score 0-1 points on the 90th ± 7th day of treatment (FAS) - subgroup (different NIHSS scores)
Figure PCTCN2021124428-appb-000021
Figure PCTCN2021124428-appb-000021
Figure PCTCN2021124428-appb-000022
Figure PCTCN2021124428-appb-000022
注：脑卒中严重程度通常采用NIHSS评分界定，卒中严重程度影响疗效评估。Note: The severity of stroke is usually defined by NIHSS score, which affects the evaluation of efficacy.
N代表样本人数，n代表治疗第90±7天mRS评分0-1分的患者人数，％代表治疗第90±7天mRS评分0-1分的患者比例。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, and % represents the proportion of patients with an mRS score of 0-1 on the 90th ± 7th day of treatment.
通过试验药组与安慰剂组在不同NIHSS卒中患者中的绝对效应差值结果分析(见表中“试验药组与安慰剂组的绝对效应差值”)，表12结果显示(+)-2-莰醇在NIHSS评分＝5分型卒中患者中的治疗效果不明显，甚至较安慰剂更差(试验药组与安慰剂组的绝对效应差值为负值，即-7.6％)；但当NIHSS评分＝6分，(+)-2-莰醇注射液疗效显现(试验药组与安慰剂组的绝对效应差值为3.3％)，并呈现出患者NIHSS越大(卒中程度越严重)治疗效果越显著(如在NIHSS评分≥6分型卒中患者中试验药组与安慰剂组的绝对效应差值为10.3％；在NIHSS评分≥7分型卒中试验药组与安慰剂组的绝对效应差值为11.0％；在NIHSS评分≥8分型卒中患者中试验药组与安慰剂组的绝对效应差值为16.0％)。Through the analysis of the absolute effect difference between the test drug group and the placebo group in different NIHSS stroke patients (see "The absolute effect difference between the test drug group and the placebo group" in the table), the results in Table 12 show that (+)-2 -The treatment effect of camphenol in stroke patients with NIHSS score = 5 was not obvious, even worse than placebo (the absolute effect difference between the test drug group and the placebo group was negative, i.e. -7.6%); but when NIHSS score = 6 points, (+)-2-camphorinol injection showed curative effect (the absolute effect difference between the test drug group and the placebo group was 3.3%), and showed that the greater the NIHSS of the patient (the more severe the stroke) the treatment The more significant the effect (for example, the absolute effect difference between the test drug group and the placebo group in stroke patients with NIHSS score ≥ 6 is 10.3%; the absolute effect difference between the test drug group and the placebo group in stroke patients with NIHSS score ≥ 7 11.0%; the absolute effect difference between the test drug group and the placebo group was 16.0% in stroke patients with NIHSS score ≥ 8).
以上结果说明，(+)-2-莰醇在不同NIHSS评分的患者中，疗效具有选择性。具体的，(+)-2-莰醇对NIHSS评分＝5分的卒中患者无效或效果不明显或效果更差，而在NIHSS评分为6分的患者中开始起效/获益，且呈现患者NIHSS越大(卒中程度越严重)治疗效果越显著(体现在试验药组与安慰剂组的绝对效应差值越大)，这种治疗效果也就是NIHSS评分≥6的卒中患者从入院时基线mRS评分≥2(即轻度残疾或中度残疾或重度残疾或严重残疾)经试验药治疗比安慰剂治疗在90±7天后恢复至mRS评分为0-1(即完全无症状或无明显功能障碍)的比例更高。试验药组与安慰剂组的绝对效应差值从3.3％至16.0％，具有重大的临床价值，明显减少了患者残疾的发生。The above results show that (+)-2-camphor has selective efficacy in patients with different NIHSS scores. Specifically, (+)-2-camphorol is ineffective or insignificant or worse for stroke patients with NIHSS score = 5 points, but it starts to work/benefit in patients with NIHSS score of 6 points, and it appears that patients The greater the NIHSS (the more severe the stroke), the more significant the treatment effect (reflected in the greater the absolute effect difference between the test drug group and the placebo group), 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. 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.
3.5(+)-2-莰醇在卒中患者中的安全性3. Safety of 5(+)-2-borneol in stroke patients
表13严重不良反应按***器官分类及首选术语汇总列表(SS)Table 13 Summary list of serious adverse reactions by system organ class and preferred terms (SS)
Figure PCTCN2021124428-appb-000023
Figure PCTCN2021124428-appb-000023
安全性统计结果显示，三个组别受试者在服药后发生的不良事件和与药物相关的不良事件，在发生例数、严重程度、症状上均无明显差别，三个组别均未见严重不良反应，也未见本品具有肝肾毒性，说明本品人体安全性良好。The results of safety statistics showed that there was no significant difference in the number of cases, severity, and symptoms of adverse events and drug-related adverse events that occurred after the three groups of subjects took the medicine, and no significant difference was found in the three groups. Severe adverse reactions, and no liver and kidney toxicity of this product has been found, indicating that this product has good human safety.
依达拉奉右莰醇(依达拉奉30mg与(+)-2-莰醇7.5mg联用)药品说明书中，明确指出：“重度肾功能衰竭的患者禁忌使用(有致自功能表竭加重的可能)”、“轻、中度肾功能损害的患者慎用”、“肝功能损害患者慎用”、“心脏疾病患者慎用”、“高龄患者恨用”。“因有使用本品有效成分之一依达拉奉，加重急性肾功能不全或肾功能衰竭而致死的病例，因此在本品给药过程中应进行多次肾功能检测，同时在给药结束后继续留切观察，出现肾功能下降的表现或少原等症状的情况下，立即停止给药，进行适当处理。”Edaravone dexborneol (edaravone 30mg combined with (+)-2-borneol 7.5mg) drug instructions, clearly pointed out: "Patients with severe renal failure are contraindicated (there are cases of exacerbation of self-function Possibility)", "Use with caution in patients with mild to moderate renal impairment", "Use with caution in patients with liver impairment", "Use with caution in patients with heart disease", "Use with caution in elderly patients". "Due to the use of edaravone, one of the active ingredients of this product, there have been cases of death due to acute renal insufficiency or renal failure. Therefore, multiple renal function tests should be performed during the administration of this product. Afterwards, we will continue to stay and observe, and if symptoms such as decreased renal function or less original symptoms appear, the drug should be stopped immediately and appropriate treatment should be carried out."
可见，单独(+)-2-莰醇作为活性成分治疗脑卒中能够有效的避免联用其他活性成分在缺血性脑卒中预防和/或治疗过程中产生的严重不良反应(如联用依达拉奉使用因依达拉奉成分带来的肝肾毒性)。此外，(+)-2-莰醇单独作为活性成分可提高(+)-2-莰醇的人体用药剂量(如与依达拉奉联用受依达拉奉毒性的限制，(+)-2-莰醇单次使用剂量限制在7.5mg)，如单次10mg或单次20mg，进而提高缺血性脑卒中预防和/或治疗效果。It can be seen that (+)-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). In addition, (+)-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.

Claims (10)

  1. (+)-2-莰醇在制备用于预防和/或治疗缺血性脑卒中药物中的用途，其中所述缺血性脑卒中的NIHSS评分≥6分。Use of (+)-2-camphor in the preparation of a medicament for preventing and/or treating ischemic stroke, wherein the NIHSS score of the ischemic stroke is more than or equal to 6 points.
  2. 根据权利要求1所述的用途，其中所述缺血性脑卒中选自6≤NIHSS评分≤20分的缺血性脑卒中。The use according to claim 1, wherein the ischemic stroke is selected from ischemic stroke with 6≤NIHSS score≤20 points.
  3. 根据权利要求1-2中所述的用途，所述药物仅包含(+)-2-莰醇作为活性成分。According to the use described in claims 1-2, the medicament comprises only (+)-2-borneol as active ingredient.
  4. 根据权利要求1-3中所述的用途，所述药物中(+)-2-莰醇的含量为约5mg至约40mg。According to the use described in claims 1-3, the content of (+)-2-borneol in the medicament is about 5 mg to about 40 mg.
  5. 根据权利要求1-4中所述的用途，所述(+)-2-莰醇还包括其药学上可接受的盐或酯，其代谢物，其前药，或其溶剂合物。According to the use described in claims 1-4, the (+)-2-borneol also includes its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, or its solvate.
  6. 药物，所述药物的活性成分仅选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合；所述活性成分的剂量为约5mg至约40mg。A drug, the active ingredient of which is selected from only one or a combination of (+)-2-borneol, its pharmaceutically acceptable salt or ester, its metabolite, its prodrug, and its solvate ; the dose of the active ingredient is from about 5 mg to about 40 mg.
  7. 根据权利要求6所述的药物，其中所述药物被配制为经以下方式施用：静脉注射、动脉注射、肌肉注射、腹腔注射、口服给药、滴鼻给药、舌下给药、颅内注射、介入给药、植入给药、贴敷给药和涂抹给药的任一种或其组合。The medicament according to claim 6, wherein 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 administration, implant administration, patch administration and smear administration, or any combination thereof.
  8. 根据权利要求6-7中任一项所述的药物，其中所述施用通过肠胃外施用，且所述药物以注射剂、粉针剂、或溶液剂的形式存在。The medicament according to any one of claims 6-7, wherein the administration is by parenteral administration, and the medicament is in the form of injection, powder injection, or solution.
  9. 根据权利要求6-8中任一项所述的药物，其中所述药物被配制为约5mL至约500mL的注射液或粉针剂，其中所述活性成分的含量为约5mg至40mg。The medicament according to any one of claims 6-8, wherein the medicament is prepared as an injection or powder injection of about 5mL to about 500mL, wherein the content of the active ingredient is about 5mg to 40mg.
  10. 一种预防和/或治疗缺血性脑卒中的方法，包括向有需要的受试者仅施用有效量的药物，所述药物的活性成分选自(+)-2-莰醇、其药学上可接受的盐或酯、其代谢物、其前药、和其溶剂合物中的一种或其组合，所述缺血型脑卒中的NIHSS评分≥6分。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 pharmaceutical Acceptable salts or esters, metabolites thereof, prodrugs thereof, and solvates thereof, or one or a combination thereof, and the NIHSS score of the ischemic stroke is ≥ 6 points.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019006734A1 (en) * 2017-07-07 2019-01-10 苏州沪云肿瘤研究中心股份有限公司 Use of (+)-2-borneol in preparation of drug for promoting upregulation of expression of sphingosine kinase-1 and/or bdnf
CN113845424A (en) * 2021-10-14 2021-12-28 南京医科大学 Right camphol ester compound and pharmaceutical application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019006734A1 (en) * 2017-07-07 2019-01-10 苏州沪云肿瘤研究中心股份有限公司 Use of (+)-2-borneol in preparation of drug for promoting upregulation of expression of sphingosine kinase-1 and/or bdnf
CN113845424A (en) * 2021-10-14 2021-12-28 南京医科大学 Right camphol ester compound and pharmaceutical application thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"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 *
LI YONG, REN MIHONG, WANG JIAJUN, MA RONG, CHEN HAI, XIE QIAN, LI HONGYAN, LI JINXIU, WANG JIAN: "Progress in Borneol Intervention for Ischemic Stroke: A Systematic Review", FRONTIERS IN PHARMACOLOGY, vol. 12, XP093057876, DOI: 10.3389/fphar.2021.606682 *
WANG, WEICONG ET AL.: "Pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of single and continuous intravenous infusion of SPT-07A in healthy volunteers.", EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY., vol. 76, no. 6, 9 March 2020 (2020-03-09), XP037143584, DOI: 10.1007/s00228-020-02851-x *

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