WO2022089544A1 - Bzp在治疗心脑缺血性疾病中的应用 - Google Patents

Bzp在治疗心脑缺血性疾病中的应用 Download PDF

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WO2022089544A1
WO2022089544A1 PCT/CN2021/127101 CN2021127101W WO2022089544A1 WO 2022089544 A1 WO2022089544 A1 WO 2022089544A1 CN 2021127101 W CN2021127101 W CN 2021127101W WO 2022089544 A1 WO2022089544 A1 WO 2022089544A1
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bzp
dose
once
administered
infarction
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PCT/CN2021/127101
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English (en)
French (fr)
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郑志国
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浙江奥翔药业股份有限公司
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Priority to US18/034,144 priority Critical patent/US20230398087A1/en
Publication of WO2022089544A1 publication Critical patent/WO2022089544A1/zh

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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 invention relates to the field of organic chemical drug treatment.
  • the present invention relates to compounds and methods of treatment for ischemic stroke, and more particularly, the present invention relates to the use of 5-bromo-2-( ⁇ -hydroxypentyl)benzoic acid sodium salt (BZP) in the treatment of mild, A treatment regimen for moderate acute ischemic stroke and a pharmaceutical composition comprising the BZP.
  • BZP 5-bromo-2-( ⁇ -hydroxypentyl)benzoic acid sodium salt
  • Acute brain lift is a disease with high morbidity, high disability rate, high mortality rate, high recurrence rate and many complications, which seriously endangers human health. Survivors often leave sequelae, which affect the patient's quality of life and increase the burden on the patient's family and society.
  • AIS acute ischemic stroke
  • the effective treatment of acute ischemic stroke (AIS) is to give vascular recanalization therapy within a certain time window, including recombinant tissue plasminogen activator for intravenous control and mechanical thrombectomy.
  • Chinese patent application CN101402565A discloses for the first time halogen-substituted 2-( ⁇ -hydroxypentyl) benzoate compounds and their preparation methods and their use in preventing and treating cardio-cerebral ischemic diseases, improving cardio-cerebral circulatory disorders, antithrombotics, etc.
  • PCT patent application WO2015007181A discloses 5-bromo-2-( ⁇ -hydroxypentyl)benzoic acid sodium salt (BZP) compound and its amorphous, crystal form A and crystal form B and preparation methods, and their preparation in prevention and treatment Use in cardiovascular and cerebrovascular diseases, improving cardio-cerebral circulation disorders or antithrombotic drugs.
  • BZP 5-bromo-2-( ⁇ -hydroxypentyl)benzoic acid sodium salt
  • the present invention relates to a method for preventing or treating cardio-cerebral ischemic diseases or improving cardio-cerebral circulation disorders or antithrombotics in an individual, the method comprising administering to the individual an effective amount of 5-bromo-2-( ⁇ -Hydroxypentyl)benzoic acid sodium salt (BZP) compound.
  • BZP 5-bromo-2-( ⁇ -Hydroxypentyl)benzoic acid sodium salt
  • the BZP compound has the following structure:
  • the BZP compound is in the form of amorphous, Form A or Form B, which are characterized as described in WO2015007181A, the entire content of which is incorporated herein by reference.
  • the disease is acute stroke and related diseases. In a preferred embodiment, the disease is mild to moderate acute ischemic stroke.
  • the disease is a disease characterized by:
  • Acute ischemic stroke anterior cerebral circulation infarction, non-cardiac infarction, moderate severity (NIHSS 5-15 points), age 45-85 years old; or
  • the individual is a human individual.
  • the individual is a human individual having a disease, symptom and/or characteristic of any of the above embodiments.
  • the individual suffers from a specific disease characterized by:
  • Acute ischemic stroke anterior cerebral circulation infarction, non-cardiac infarction, moderate severity (NIHSS 5-15 points), age 45-85 years old; or
  • the time from stroke onset to administration in the individual is no more than 24 hours.
  • the individual is a human patient with a time from stroke onset to administration of 6-24 hours.
  • the treatment achieves one or more of the following improvements in the individual:
  • the BZP of the present invention is formulated for administration as a liquid pharmaceutical composition.
  • Useful carriers and solvents include water, Ringer's solution, phosphate buffered saline, isotonic sodium chloride solution, and the like.
  • sterile, fixed oils may also be employed as a solvent or suspending medium, where appropriate.
  • any mixture of fixed or non-mineral oils, including synthetic mono- or diglycerides, may be utilized.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the pharmaceutical composition comprising the BZP of the present invention is a solution or dry powder formulation for injection.
  • the composition is a lyophilized powder, which can be reconstituted as an injection in a pharmaceutically acceptable liquid carrier.
  • the pharmaceutically acceptable liquid carrier can be, for example, sterile water, Ringer's solution, phosphate buffered saline, isotonic sodium chloride solution, and the like.
  • the BZPs of the present invention are administered by the parenteral route.
  • the BZPs of the present invention are administered by intravenous injection.
  • the BZPs of the present invention are administered by intravenous infusion.
  • the BZP of the invention is administered at a daily dose of 50-500 mg, eg, 100-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 325-475 mg, 350-475 mg, 350-450 mg, 375 mg -450mg, or 375-425mg, such as 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg.
  • 50-500 mg eg, 100-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 325-475 mg, 350-475 mg, 350-450 mg, 375 mg -450mg, or 500mg.
  • the single administration dose of BZP of the present invention is 25-400 mg, such as 50 mg to 400 mg, preferably 50 mg to 300 mg, more preferably 50 mg to 250 mg, more preferably 100 mg to 250 mg, such as 25 mg, 50 mg, 75 mg, 100 mg , 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg or 400mg;
  • the BZP administration frequency of the present invention is three times a day, twice a day, once a day, once every two days, every three times Once a day, twice a week, once a week, once every two weeks, once every four weeks or more.
  • the administration period of the BZP of the present invention may be one week, two weeks, three weeks, one month, two months, three months or longer, and the interval between each administration period may be the same or different.
  • the BZP dosing regimen of the present invention is 50 mg to 250 mg administered once to three times per day, eg, 50 mg administered once, twice or three times per day , 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg or 250mg.
  • the dosing regimen is 100-250 mg twice daily, eg 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg twice daily.
  • the BZP or its pharmaceutical composition of the present invention can be administered alone or in combination with other drugs.
  • the subject does not experience serious adverse events following administration.
  • the subject following administration, has an adverse event rate comparable to that of subjects receiving placebo.
  • the subject has a lower incidence of adverse events under the following dosing regimens than other dosing regimens:
  • the BZP compound is administered one to three times a day in a dose of 100-250 mg, eg, twice a day and 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg each time, preferably twice a day and 100 mg, 125 mg, 150 mg, 175 mg, 200 mg or 225 mg per administration, more preferably 200 mg twice daily.
  • the subject has a lower incidence of adverse events than other dosing regimens and achieves said improvement over other dosing regimens:
  • the BZP compound is administered one to three times a day in a dose of 100-250 mg, eg, twice a day and 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg each time, preferably twice a day and 100 mg, 125 mg, 150 mg, 175 mg, 200 mg or 225 mg per administration, more preferably 200 mg twice daily.
  • the individual is a human.
  • the time from stroke onset to administration in the individual is no more than 24 hours.
  • the individual is a human patient with a time from stroke onset to administration of 6-24 hours.
  • the present invention relates to the use of BZP in the preparation of a medicament for preventing or treating cardio-cerebral ischemic diseases or improving cardio-cerebral circulation disorders or antithrombotics in an individual.
  • the present invention relates to BZP for preventing or treating cardio-cerebral ischemic disease or improving cardio-cerebral circulatory disorder or antithrombotic in an individual.
  • the specific disease is characterized by:
  • Acute ischemic stroke anterior cerebral circulation infarction, non-cardiac infarction, moderate severity (NIHSS 5-15 points), age 45-85 years old; or
  • the individual is a human individual.
  • the individual is a human individual having a disease, symptom and/or characteristic of any of the above embodiments.
  • the individual is a human individual who is a patient of a particular disease with geographic atrophy.
  • the individual suffers from a specific disease characterized by:
  • Acute ischemic stroke anterior cerebral circulation infarction, non-cardiac infarction, moderate severity (NIHSS 5-15 points), age 45-85 years old; or
  • the treatment achieves one or more of the following effects in the individual:
  • the BZP of the invention is administered at a daily dose of 50-500 mg, eg, 100-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 325-475 mg, 350-475 mg, 350-450 mg, 375 mg -450mg, or 375-425mg, such as 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg or 500mg.
  • 50-500 mg eg, 100-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 325-475 mg, 350-475 mg, 350-450 mg, 375 mg -450mg, or 500mg.
  • the single administration dose of BZP of the present invention is 25 mg to 400 mg, preferably 50 mg to 300 mg, more preferably 50 mg to 250 mg, more preferably 100 mg to 250 mg, such as 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg or 400mg.
  • the frequency of administration of the BZP of the present invention is three times a day, twice a day, once a day, once every two days, once every three days, twice a week, once a week, once every two weeks, once every four weeks or more.
  • the administration period of the BZP of the present invention may be one week, two weeks, three weeks, one month, two months, three months or longer, and the interval between each administration period may be the same or different.
  • the BZP dosing regimen of the present invention is 50 mg to 250 mg administered once to three times a day, such as once, twice or three times a day, 50 mg, 75 mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg or 250mg.
  • the dosing regimen is 100-250 mg twice daily, eg 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg twice daily.
  • the BZP or its pharmaceutical composition of the present invention can be administered alone or in combination with other drugs.
  • the other drugs used in combination include, but are not limited to, edaravone, citicoline, piracetam (Naofukang), butylphthalide, and human urinary kallikrein.
  • the subject does not experience serious adverse events following administration.
  • the subject following administration, has an adverse event rate comparable to that of subjects receiving placebo.
  • the individual is a human.
  • the present invention relates to a single dosage unit, characterized in that it comprises a BZP compound.
  • the BZP compound has the following structure:
  • the BZP compound is in the form of amorphous, Form A or Form B, which are characterized as described in WO2015007181A, the entire content of which is incorporated herein by reference.
  • the single pharmaceutical dosage unit comprises the following doses of the BZP compound: 25 mg to 400 mg, such as 50 mg to 400 mg, preferably 50 mg to 300 mg, more preferably 50 mg to 250 mg, more preferably 100 mg to 250 mg, For example 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg or 400mg.
  • 25 mg to 400 mg such as 50 mg to 400 mg, preferably 50 mg to 300 mg, more preferably 50 mg to 250 mg, more preferably 100 mg to 250 mg,
  • the single pharmaceutical dosage unit may be a lyophilized powder formulation or a liquid formulation.
  • the "liquid formulation” or “liquid composition” refers to a formulation in liquid form.
  • the liquid composition of the present invention comprises (i) the BZP compound of the present invention; and (iii) a pharmaceutically acceptable liquid carrier.
  • the liquid preparation of the present invention is preferably an injection, such as an intravenous injection or instillation liquid preparation.
  • the composition of the present invention is a lyophilized powder formulation, which can be reconstituted as an injection in a pharmaceutically acceptable liquid carrier.
  • the pharmaceutically acceptable liquid carrier can be, for example, sterile water, Ringer's solution, phosphate buffered saline, isotonic sodium chloride solution, and the like.
  • the present invention relates to a complete pharmaceutical package, characterized in that it comprises one or more single-dose drug-dose units according to any one of the above-mentioned single-dose drug-dose unit embodiments.
  • the pharmaceutical kit further comprises instructions for instructing the method of use of the single pharmaceutical dosage unit.
  • the term “comprising” or “comprising” means the inclusion of stated elements, integers or steps, but not the exclusion of any other elements, integers or steps.
  • the terms “comprising” or “comprising” are used, unless otherwise indicated, combinations of the stated elements, integers or steps are also encompassed.
  • reference to an antibody variable region that "comprises” a particular sequence is also intended to encompass antibody variable regions that consist of that particular sequence.
  • “Individual” includes mammals. Mammals include, but are not limited to, domestic animals (eg, cattle, sheep, cats, dogs, and horses), primates (eg, humans and non-human primates such as monkeys), rabbits, and rodents (eg, , mice and rats). In some embodiments, the individual is a human, including a child, adolescent or adult.
  • treating refers to slowing, interrupting, retarding, alleviating, stopping, reducing, or reversing the progression or severity of an existing symptom, disorder, condition or disease.
  • prevention includes the inhibition of the occurrence or progression of a disease or disorder or symptoms of a particular disease or disorder.
  • individuals with a family history of the disease are candidates for preventive regimens.
  • prevention refers to the administration of a drug prior to the onset of signs or symptoms, particularly in individuals at risk.
  • an effective amount refers to an amount effective to achieve the desired therapeutic result, at the required dose and for the required period of time.
  • a therapeutically effective amount of a formulation, BZP compound or composition of the invention may vary depending on factors such as the disease state, the age, sex and weight of the individual and the ability of the antibody or antibody portion to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the formulation, BZP compound or composition are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective to achieve the desired prophylactic result, at the required dose and for the required period of time. Typically, a prophylactically effective amount will be less than a therapeutically effective amount because a prophylactic dose is administered in a subject prior to or at an earlier stage of the disease.
  • the term “formulation” or “pharmaceutical composition” refers to a composition comprising at least one active ingredient and at least one inactive ingredient suitable for administration to animals, preferably mammals, including humans.
  • the formulation of the present invention may be a lyophilized powder formulation or a liquid formulation.
  • "Liquid formulation” or “liquid composition” refers to a formulation in liquid form.
  • the liquid composition of the present invention comprises (i) the BZP compound of the present invention; and (iii) a pharmaceutically acceptable liquid carrier.
  • the liquid preparation of the present invention is preferably an injection, such as a liquid preparation for intravenous injection or instillation, such as a liquid preparation prepared in a 0.9% sodium chloride solution.
  • “Pharmaceutically acceptable carrier” refers to an ingredient other than the active ingredient in a pharmaceutical formulation that is not toxic to the subject.
  • Pharmaceutically acceptable carriers include, but are not limited to, solvents, buffers, excipients, stabilizers or preservatives.
  • single pharmaceutical dosage unit refers to a single pharmaceutical dosage form comprising a BZP compound of the present invention to be administered to a patient at the time of administration, eg, a vial for injection, ampoules, infusion bags, prefilled needles or A prefilled syringe containing a solution or lyophilized powder of the drug.
  • BZP at doses of 3 mg/kg, 12 mg/kg and 24 mg/kg can significantly reduce the volume of cerebral infarction and brain swelling in MCAO model rats, and improve the neurobehavior of MCAO model rats and salt-sensitive rats. , and showed a dose-dependent manner.
  • BZP can significantly restore the muscle strength and balance beam behavior of MCAO model rats, reduce the proportion of necrotic neurons and the apoptosis rate, and its improvement effect is significantly better than that of the NBPK group.
  • BZP 12mg/kg can reduce the 24-hour mortality and behavioral scores in the rat model of global cerebral ischemia-reperfusion, and significantly reduce the blood pressure of salt-sensitive rats 21 days after administration.
  • BZP has a protective effect on cerebral ischemia-reperfusion injury and is effective when administered within 4 hours after ischemia, especially within 2 hours after ischemia.
  • a single intravenous injection of BZP 50mg/kg and 100mg/kg can cause a decrease in body temperature in rats; at a high dose (100mg/kg), rats also experience decreased activity, piloerection, decreased frequency of defecation and urination, and pupillary stimulation reflex disappearance, etc. These changes all recovered within 4 hours after discontinuation of the drug.
  • the effective dose of BZP to protect against ischemia-reperfusion injury in rats (12 mg/kg) was lower than the dose that caused neurological effects in rats (50 mg/kg).
  • BZP 24,12mg/kg was better than that of NBP-K group and Br-NBP group (P ⁇ 0.01);
  • BZP can improve motor dysfunction, reduce the volume of cerebral infarction, and reduce cerebral edema.
  • the optimal treatment time window is administered within 4 hours after ischemia, especially within 2 hours after ischemia.
  • BZP can inhibit the inflammatory response of cells induced by cerebral ischemia-reperfusion injury, which is manifested by inhibiting the expression of TNF- ⁇ -IL-6-IL-1 ⁇ -NF- ⁇ B-COX-2-ICAM-1 loop.
  • BZP can reduce the loss of nerve cells and reduce the rate of apoptosis, which is manifested as inhibiting the Bax/Bcl-2-cytochrome C-Caspase-3 mitochondrial apoptosis pathway and up-regulating the PI3K-p-Akt survival signaling pathway, that is, BZP can inhibit apoptosis. effect.
  • BZP can promote nerve repair after cerebral ischemic injury and improve the recovery of motor function in rats after cerebral ischemic injury. Its mechanism of action is related to increasing the expressions of SYN, GAP-43, BDNF and GFAP in the ischemic penumbra, and down-regulating NOGO -A expression.
  • the mortality rate within 24 hours in the BZP (3,12 mg/kg) group was lower than that in the model group and NBP-K group; the behavioral score in the BZP group was significantly lower than that in the model group (P ⁇ 0.05).
  • Expression of loop factors (TNF- ⁇ , IL-1 ⁇ , IL-6, NF- ⁇ B, COX-2, ICAM-1), apoptosis pathway factors (Bax/Bcl-2, Cyt-c, Caspase-3) , neuronal necrosis rate and apoptosis rate were significantly decreased (P ⁇ 0.05), and cell survival pathways (PI3K, P-Akt) were significantly increased (P ⁇ 0.01).
  • BZP has a protective effect on acute global cerebral ischemia in rats, and its mechanism is to inhibit the inflammatory response and apoptosis of cells.
  • BZP exhibited a dose-dependent inhibitory effect on AA-induced platelet aggregation with an IC 50 of 12 ⁇ mol/L, but had no inhibitory effect on ADP and thrombin-induced platelet aggregation; in vivo experiments in rats showed that BZP at various doses
  • the group had anti-ADP (platelet aggregation inhibition rate of 23.89%, 34.42% and 44.14%, respectively), thrombin (platelet aggregation inhibition rate of 23.87%, 37.75% and 55.47%), arachidonic acid (platelet aggregation inhibition rate of 42.08%, 60.32% and 72.20%) induced platelet aggregation; and it was concentration-dependent; experimental thrombosis changes in BZP low, medium and high dose groups were 0.23 ⁇ 0.04, 0.18 ⁇ 0.02, 0.13 ⁇ 0.03, respectively.
  • BZP can selectively inhibit AA-induced platelet aggregation
  • in vivo experiments show that BZP can inhibit ADP, thrombin, AA-induced platelet aggregation
  • BZP can inhibit the formation of experimental thrombus in rats.
  • BZP was higher in lung tissue within 50 minutes of administration, with the highest fat content at 110 minutes.
  • the concentration of BZP in the brain is relatively low, and the elimination is fast, and it can no longer be detected after 50 minutes.
  • BZP is rapidly converted to BNBP in vivo (not via NADPH coenzyme/CYP450).
  • liver tissue has the strongest ability to transform BZP in vitro, and spleen has the lowest ability to transform BZP.
  • BNBP was higher in kidney, liver, and lung tissue at 1 minute of administration.
  • BNBP-OH is the major metabolite of BNBP (via NADPH coenzyme/CYP450).
  • the results showed that the cumulative excretion of BZP, BNBP and BNBP-OH was only 3.12% of the administered dose of BZP, suggesting that BNBP-OH may be further metabolized in vivo.
  • BZP has completed two Phase I clinical trials investigating its single-dose (BZP1601 trial) and multiple-dose (BZP1702 trial) pharmacokinetics in 48 and 29 healthy subjects, respectively.
  • BZP1601 trial single-dose
  • BZP1702 trial multiple-dose
  • pharmacokinetics in 48 and 29 healthy subjects, respectively.
  • the AUC 0-t and C max of BZP in plasma have a linear relationship with the dose; however, the linear relationship between the AUC 0-t and C max of BNBP and the administered dose has not been determined.
  • the pharmacokinetic parameters of BZP and BNBP were not significantly different in subjects of different genders, and there was no obvious drug accumulation after multiple intravenous infusions. No meaningful metabolites other than BNBP were found in two human trials.
  • BZP has completed two Phase I clinical trials exploring its safety and tolerability in single dose (BZP1601 trial) and multiple doses (BZP1702 trial) in 50 and 30 healthy subjects, respectively.
  • a single intravenous infusion of BZP in the range of 25-400 mg or multiple intravenous infusions in the dose range of 50-200 mg have good safety and tolerability, and the incidence of AE does not increase with the increase in dose.
  • This table contains data as of June 21, 2019
  • This table contains data as of June 21, 2019
  • the PK main exposure parameters AUC 0-t and C max of BZP and BNBP did not differ significantly between subjects of different genders.
  • the total cumulative excretion rate of BZP and metabolite BNBP in the 200mg group through urine and feces was 0.5%, and no debrominated metabolites were found in the metabolites.
  • BZP1601 trial Same as BZP1601 trial.
  • the study contained 4 BZP groups (50 mg, 100 mg, 200 m, respectively) and a placebo group.
  • the number of participants in each group was 10, 10, 10, and 6, respectively, for a total of 36 cases.
  • One subject in the 50mg group took the drug two days before administration, among which the drug aminocaxanil may affect drug metabolism, and the subject was taken out of the group after collecting a 24-hour blood sample on the second day of administration, and the drug could not be fully calculated. Therefore, this subject was not included in the pharmacokinetic analysis data set, and the other 29 subjects who were given BZP were all included in the pharmacokinetic analysis data set.
  • BZP and BNBP basically reached a steady state on the 5th day after continuous intravenous infusion of BZP.
  • the AUC 0-t and C max of BZP were linearly related to the dose after the first dose and after administration at steady state, but the linear relationship of AUC 0-t and C max of BNBP to the dose could not be determined.
  • the accumulation ratio of BZP was 1.10-1.18
  • the accumulation ratio of BNBP was 1.60-1.78.
  • the main pharmacokinetic exposure parameters (AUC 0-t and C max ) of BZP and BNBP were not significantly different among subjects of different sexes (the mean ratio range of BZP was 0.797-1.01 and 0.799-1.01, respectively, and the mean of BNBP was The ratios ranged from 0.845-1.20 and 0.851-1.12, respectively). No other meaningful metabolites other than BNBP were found.
  • BZP has completed 2 Phase I clinical trials.
  • the AUC 0-t and Cmax of BZP in plasma were linearly related to dose in the range of 25-400 mg by a single intravenous infusion (BZP1601 trial) or by multiple intravenous infusions in the 50-200 mg dose range (BZP1702 trial).
  • BZP1601 trial a single intravenous infusion
  • BZP1702 trial multiple intravenous infusions in the 50-200 mg dose range
  • the linear relationship between the AUC 0-t and C max of BNBP and the administered dose cannot be determined.
  • the only difference in geometric mean T 1/2 between BZP and BNBP was observed between the two trials.
  • the geometric mean T 1/2 of BZP and BNBP were approximately 8 hours and 15 hours after a single dose of BZP, and 5.34-5.57 hours and 7.78-10.3 hours in the BZP1702 trial. It is speculated that the difference between the two trials may be related to the time of blood sample collection.
  • BZP1601 test at 0 minutes, 20 minutes, 40 minutes, 60 minutes (at the end of instillation), 1.25 hours, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours after administration , 16 hours, 24 hours, 36 hours, 48 hours, blood samples were collected, but in the BZP1702 test, blood samples were collected only 24 hours after administration on the first day of administration.
  • BZP was shown to have a good safety profile and tolerability in healthy subjects. In the two clinical trials, only one case of moderate hypotension (100 mg group) occurred in the multiple-dose trial, and the remaining AEs were all mild. There was no statistical difference in the proportion of AEs between the BZP group and the placebo group, and the incidence did not increase with dose increase.
  • AEs determined by the investigator to be related to study drug included mild bradycardia (single doses of 25 mg and 200 mg without any clinically meaningful ECG QTc abnormalities), decreased white blood cell count (single dose of 50 mg), neutrophil count/ Percent reduction (single dose of 50 mg, multiple doses of placebo), first-degree AV block (single dose of 100 mg), proteinuria (single dose of 200 mg), coagulopathy (single dose of 200 mg), administration site pain (multiple doses of 200 mg) , hypotension (multiple doses of 100 mg), hypokalemia (multiple doses of 200 mg) and decreased diastolic blood pressure (multiple doses of 200 mg).
  • AEs related to study drug occurred from minutes to day 9 after dosing and resolved without any clinical intervention. There were no deaths, SAEs, AEs leading to withdrawal or other important AEs in either clinical trial, and no pregnancy was reported. No dose-limiting toxicity (DLT) occurred.
  • the BZP1703 clinical trial is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial.
  • the purpose of the trial is to evaluate the safety and feasibility of different doses of BZP for injection versus placebo in the treatment of acute ischemic stroke, and to preliminarily explore its effectiveness, so as to provide a basis for the design of phase III clinical trials.
  • the subjects participating in the trial will be randomly assigned to the following three treatment groups according to the ratio of 2:2:1: BZP low-dose experimental group (100mg bid, intravenous infusion, each administration of 2 vials of BZP and 2 vials of BZP simulant) , BZP high-dose test group (200mg bid, intravenous drip, 4 bottles of BZP each time), placebo control group (bid, intravenous drip, 4 bottles of BZP simulant each time).
  • Subjects will receive the trial drug twice daily for 14 consecutive days and then enter a follow-up period with safety follow-up on days 45 and 90, and NIHSS and Modified Rankin Scale (mRS) )evaluation of. Each subject is expected to participate in the trial for approximately 91 days.
  • mRS Modified Rankin Scale
  • the primary safety endpoint of the BZP1703 trial was SAE, and the primary efficacy endpoint was the difference between the NIHSS score at day 14 and the baseline NIHSS score.
  • Secondary safety endpoints included all-cause death, fatal and symptomatic intracranial hemorrhage, hemorrhagic transformation of cerebral infarction detected by head magnetic resonance imaging (MRI) on day 14, various adverse events; other bleeding events, AEs, AEs of particular interest (seizure, bradycardia, atrioventricular block, coagulation abnormalities, proteinuria, leukopenia), number and incidence of new vascular events (ischemic stroke/hemorrhagic Stroke/myocardial infarction/vascular death), vital signs, physical examination, laboratory tests (blood routine, blood biochemistry, urine routine, stool routine, coagulation function, etc.), abnormal conditions of 12-lead electrocardiogram (ECG) and other indicators.
  • ECG 12-lead electrocardiogram
  • Secondary efficacy endpoints included change from baseline in NIHSS score on days 7 and 90, reduction rate from baseline in NIHSS score on days 7, 14 and 90, and NIHSS score of 0-1 on days 7, 14 and 90 Proportion of subjects with score or loss of ⁇ 4 points, incidence of neurological worsening NIHSS score increase of ⁇ 4 points on days 7 and 14, ordinal analysis of distribution of mRS scores on days 7, 14 and 90, days 7, The proportion of subjects with mRS scores of 0-1, 0-2, and 0-3 at 14 and 90 days, the incidence of new cerebral infarction shown by head MRI-DWI at day 14, etc.
  • the BZP1703 trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial.
  • the subjects participating in the trial will be randomly assigned to the following three treatment groups according to the ratio of 2:2:1: BZP low-dose experimental group (100mg bid), BZP high-dose experimental group (200mg bid), and placebo control group (bid). ).
  • the trial used a central randomization system to randomize subjects to reduce potential bias. After the investigator confirms that the subject meets all the requirements for participating in the trial, the subject will be randomized through the interactive web response system before the first administration of the trial drug. Subjects will be randomly assigned to three groups A/B/C with a unique random number in a ratio of 2:2:1. The investigators, sponsors, and subjects were unaware of the correspondence between the three groups A/B/C and the low-dose experimental group, the high-dose experimental group, and the placebo control group. The specific groups of A/B/C were only known at the time of unblinding.
  • the trial will be blinded to subjects, investigators, other investigators at the site, and sponsors (including monitors and contract research organization companies) to ensure that there is no bias in the analysis and assessment of safety and efficacy.
  • the packaging form and administration method of the lyophilized powder injection of the simulant used in the dosing regimen are the same as those of the test drug.

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Abstract

涉及5-溴-2-(α-羟基戊基)苯甲酸钠盐(BZP)在治疗心脑缺血性疾病中的应用。尤其涉及治疗缺血性脑卒中的BZP化合物和治疗方法，更具体而言，涉及使用BZP治疗轻、中度急性缺血性脑卒中的治疗方案以及包含所述BZP的药物组合物。

Description

BZP在治疗心脑缺血性疾病中的应用 技术领域
本发明涉及有机化学药物治疗领域。具体而言，本发明涉及治疗缺血性脑卒中的化合物和治疗方法，更具体而言，本发明涉及使用5-溴-2-(α-羟基戊基)苯甲酸钠盐(BZP)治疗轻、中度急性缺血性脑卒中的治疗方案以及包含所述BZP的药物组合物。
背景技术
急性脑举中是一种发病率高、致残率高、死亡率高、复发率高及并发症多的疾病，严重危害人类健康。幸存者往往留下后遗症，影响患者生活质量，也增加患者家庭和社会的负担。目前，急性缺血性脑卒中(Acute ischemic stroke，AIS)的有效的治疗方法是在一定时间窗内给予血管再通治疗包括重组组织型纤溶酶原激活剂进行静脉溶控和机械取栓，虽收到较好效果，但远未满足临床需求。因此寻找有效治疗急性缺血性脑卒中的药物一直是本领域中需要解决的问题。
中国专利申请CN101402565A首次公开了卤素取代2-(α-羟基戊基)苯甲酸盐类化合物和其制备方法及其在预防和治疗心脑缺血性疾病及改善心脑循环障碍、抗血栓等方面的应用，其中提到制备易溶于水的一价金属离子、二价金属离子、三价金属离子或有机碱基的盐，并具体提到了钾盐、钙盐和苯乙胺盐等。
PCT专利申请WO2015007181A公开了5-溴-2-(α-羟基戊基)苯甲酸钠盐(BZP)化合物以及其无定型物、晶型A和晶型B和制备方法，以及它们在制备预防和治疗心脑血管性疾病、改善心脑循环障碍或抗血栓的药物中的用途。
然而，上述专利申请在预防和治疗心脑缺血性疾病及改善心脑循环障碍、抗血栓的药物用途方面，仅验证了在动物体内的活性，考虑到人类的相关疾病的复杂性和特殊性，仍然需要对使用此类药物的给药方法和剂量方案等进行深入的研究和改进。
发明内容
一、治疗方法
第一方面，本发明涉及在个体中预防或治疗心脑缺血性疾病或改善心脑循环障碍或抗血栓的方法，该方法包括向所述个体施用有效量的5-溴-2-(α-羟基戊基)苯甲酸钠盐(BZP)化合 物。
所述BZP化合物具有以下结构：
Figure PCTCN2021127101-appb-000001
在一个实施方案中，所述BZP化合物为无定形物、晶型A或晶型B的形式，它们的特征如WO2015007181A所述，该专利申请的全部内容通过引用并入本文。
在一个实施方案中，所述的疾病为急性脑卒中及相关疾病。在一个优选的实施方案中，所述的疾病为轻、中度急性缺血性脑卒中。
在一个实施方案中，所述的疾病为具有以下特征的疾病：
(1)急性缺血性卒中；
(2)急性缺血性脑卒中，脑部前循环梗死；
(3)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死；
(4)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)
(5)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁；或
(6)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁，BZP需要在卒中发病24小时内给药。
在一个实施方案中，所述个体为人类个体。
在一个优选的实施方案中，所述个体为人类个体，其具有上述实施方案任一项所述的疾病、症状和/或特征。
在一个优选的实施方案中，所述个体患有具备以下特征的特定疾病：
(1)急性缺血性卒中；
(2)急性缺血性脑卒中，脑部前循环梗死；
(3)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死；
(4)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)
(5)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁；或
(6)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁，BZP需要在卒中发病24小时内给药。
在一个优选的实施方案中，所述个体从卒中发病到给药的时间不超过24小时。在一个更优选的实施方案中，所述个体为卒中发病到给药的时间为6-24小时的人类患者。
在一个优选的实施方案中，所述治疗可在个体中实现以下一种或多种改善效果：
(1)改善神经功能评分，降低NIHSS分值；
(2)改善神经功能结局，降低mRS分值；
(3)减少脑梗死体积；
(4)减少缺血性脑卒中的复发率；
(5)减少缺血性卒中的出血转化率，包括症状性颅内出血和无症状性出血转化；和/或
(6)降低缺血性卒中的死亡率。
在一些实施方案中，本发明的BZP配制为液体药物组合物形式施用。可用的载体和溶剂包括水、林格液、磷酸缓冲盐溶液和等渗氯化钠溶液等。此外，在适宜时也可用无菌、不挥发的油作为溶剂或悬浮介质。为了此目的，可以利用任意混合的非挥发性矿物油或非矿物油，包括合成的甘油单酯或甘油二酯。此外，诸如油酸的脂肪酸也可用于制备注射剂。
在一些实施方案中，包含本发明的BZP的药物组合物为注射用溶液剂或干粉制剂。例如，所述组合物为冻干粉，其可在可药用的液体载体中复配为注射液。所述可药用的液体载体可以是例如无菌的水、林格液、磷酸缓冲盐溶液和等渗氯化钠溶液等。
在一些实施方案中，本发明的BZP通过胃肠外途径施用。
在一些实施方案中，本发明的BZP通过静脉内注射施用。
在一些实施方案中，本发明的BZP通过静脉内滴注施用。
在一些实施方案中，本发明的BZP给药的日剂量为50-500mg，例如100-500mg、200-500mg、250-500mg、300-500mg，325-475mg、350-475mg、350-450mg、375-450mg、或375-425mg，例如50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg。
在一些实施方案中，本发明的BZP单次给药剂量为25-400mg，例如50mg至400mg，优选50mg至300mg，更优选50mg至250mg，更优选100mg至250mg，例如25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg或400mg；本发明的BZP给药频率为每天三次、每天两次、每天一次、每两天一次、每三天一次、每周两次、每周一次、每两周一次、每四周一次或更长时间。本发明的BZP的给药周期可以为一周、二周、三周、一月、两月、三月或更长时间，而且每个给药周期之间的间隔可以相同或不同。
在一个优选的实施方案中，本发明的BZP给药方案为每天给药一次到三次，每次给药剂量为50mg至250mg，例如，每天给药一次、两次或三次且每次给药50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg或250mg。优选地，所述给药方案为每天给药两次，每次给药剂量为100-250mg，例如每天两次，每次给药100mg、125mg、150mg、175mg、200mg、225mg或250mg。
在一些实施方案中，本发明的BZP或其药物组合物可以单独施用，也可以联合其他药物共同施用。
在上述方法的一些实施方案中，在给药后，所述个体不发生严重不良事件。
在上述方法的一些实施方案中，在给药后，所述个体的不良事件发生率与接受安慰剂的个体相当。
在一个优选的实施方案中，所述个体在以下给药方案下的不良事件发生率低于其他给药方案：
所述BZP化合物每天给药一至三次，每次给药剂量为100-250mg，例如每天给药两次且每次给药100mg、125mg、150mg、175mg、200mg、225mg或250mg，优选每天两次且每次给药100mg、125mg、150mg、175mg、200mg或225mg，更优选每天两次且每次给药200mg。
在一个更优选的实施方案中，所述个体在以下给药方案下的不良事件发生率低于其他给药方案并且实现的所述改善效果优于其他给药方案：
所述BZP化合物每天给药一至三次，每次给药剂量为100-250mg，例如每天给药两次且每次给药100mg、125mg、150mg、175mg、200mg、225mg或250mg，优选每天两次且每次给药100mg、125mg、150mg、175mg、200mg或225mg，更优选每天两次且每次给药200mg。
在上述方法的一些实施方案中，所述个体是人。在一个优选的实施方案中，所述个体从卒中发病到给药的时间不超过24小时。在一个更优选的实施方案中，所述个体为卒中发病到给药的时间为6-24小时的人类患者。
二、用途
第二方面，本发明涉及BZP在制备用于在个体中预防或治疗心脑缺血性疾病或改善心脑循环障碍或抗血栓的药物中的用途。
第三方面，本发明涉及BZP，其用于在个体中预防或治疗心脑缺血性疾病或改善心脑循环障碍或抗血栓。
对于第二和第三方面，对它们的进一步限定如下：
在一个实施方案中，所述的特定疾病为具有以下特征：
(1)急性缺血性卒中；
(2)急性缺血性脑卒中，脑部前循环梗死；
(3)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死；
(4)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)
(5)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁；或
(6)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁，BZP需要在卒中发病24小时内给药。
在一个实施方案中，所述个体为人类个体。
在一个优选的实施方案中，所述个体为人类个体，其具有上述实施方案任一项所述的疾病、症状和/或特征。
在一个优选的实施方案中，所述个体为人类个体，其为特定疾病患者并伴有地图样萎缩。
在一个优选的实施方案中，所述个体患有具备以下特征的特定疾病：
(1)急性缺血性卒中；
(2)急性缺血性脑卒中，脑部前循环梗死；
(3)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死；
(4)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)
(5)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁；或
(6)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁，BZP需要在卒中发病24小时内给药。
在一个优选的实施方案中，所述治疗可在个体中实现以下一种或多种效果：
(7)改善神经功能评分，降低NIHSS分值；
(8)改善神经功能结局，降低mRS分值；
(9)减少脑梗死体积；
(10)减少缺血性脑卒中的复发率；
(11)减少缺血性卒中的出血转化率，包括症状性颅内出血和无症状性出血转化；和/或
(12)降低缺血性卒中的死亡率。
在一些实施方案中，本发明的BZP给药的日剂量为50-500mg，例如100-500mg、200-500mg、250-500mg、300-500mg，325-475mg、350-475mg、350-450mg、375-450mg、或375-425mg，例如50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg。
在一些实施方案中，本发明的BZP单次给药剂量为25mg至400mg，优选50mg至300mg，更优选50mg至250mg，更优选100mg至250mg，例如25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg或400mg。本发明的BZP给药频率为每天三次、每天两次、每天一次、每两天一次、每三天一次、每周两次、每周一次、每两周一次、每四周一次或更长时间。本发明的BZP的给药周期可以为一周、二周、三周、一月、两月、三月或更长时间，而且每个给药周期之间的间隔可以相同或不同。
在一个优选的实施方案中，本发明的BZP给药方案为每天给药一次到三次，每次给药剂量为50mg至250mg，例如每天一次、两次或三次，每次给药50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg或250mg。优选地，所述给药方案为每天给药两次，每次给药剂量为100-250mg，例如每天两次，每次100mg、125mg、150mg、175mg、200mg、225mg或250mg。
在一些实施方案中，本发明的BZP或其药物组合物可以单独施用，也可以联合其他药物共同施用。所述的联合使用的其他药物包括但不限于依达拉奉、胞二磷胆碱、吡拉西坦(脑复康)、丁基苯酞、人尿激肽原酶。
在一些实施方案中，在给药后，所述个体不发生严重不良事件。
在一些实施方案中，在给药后，所述个体的不良事件发生率与接受安慰剂的个体相当。
在一些实施方案中，所述个体是人。
应当理解，上文第二至三方面记载的任何技术特征与第一方面中记载的技术方案的任何技术特征的任意组合得到的技术方案也包括在本申请中。
三、单次药物剂量单元或成套药物包装盒
在第四方面，本发明涉及一种单次药物剂量单元，其特征在于包含BZP化合物。
所述BZP化合物具有以下结构：
Figure PCTCN2021127101-appb-000002
在一个实施方案中，所述BZP化合物为无定形物、晶型A或晶型B的形式，它们的特征如WO2015007181A所述，该专利申请的全部内容通过引用并入本文。
在一个优选的实施方案中，所述单次药物剂量单元包含以下剂量的所述BZP化合物：25mg至400mg，例如50mg至400mg，优选50mg至300mg，更优选50mg至250mg，更优选100mg至250mg，例如25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg或400mg。
在一个进一步优选的实施方案中，所述单次药物剂量单元可以是冻干粉制剂或液体制剂。所述“液体制剂”或“液体组合物”是指液体形式的制剂。本发明的液体组合物包含(i)本发明所述的BZP化合物；和(iii)可药用的液体载体。本发明的液体制剂优选为注射剂，例如经静脉注射或滴注的液体制剂。或者，本发明的组合物为冻干粉制剂，其可在可药用的液体载体中复配为注射液。所述可药用的液体载体可以是例如无菌的水、林格液、磷酸缓冲盐溶液和等渗氯化钠溶液等。
在第五方面，本发明涉及一种成套药物包装盒，其特征在于，包含一个或多个上述单次药物剂量单元实施方案中任意一项所述的单次药物剂量单元。在优选的实施方案中，所述成套药物包装盒还包含用于指导所述单次药物剂量单元的使用方法的说明书。
应当理解，上文第四至五方面记载的任何技术特征与第一至三方面中记载的技术方案的任何技术特征的任意组合得到的技术方案也包括在本申请中。
定义
为了解释本说明书，将使用以下定义，并且只要适当，以单数形式使用的术语也可以包括复数，并且反之亦然。要理解，本文所用的术语仅是为了描述具体的实施方案，并且不意欲是限制性的。
如本文所用，术语“包含”或“包括”是指包括所述的要素、整数或步骤，但是不排除任意其他要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组合的情形。例如，当提及“包含”某个具体序列的抗体可变区时，也旨在涵盖由该具体序列组成的抗体可变区。
“个体”包括哺乳动物。哺乳动物包括但不限于，家养动物(例如，牛，羊，猫，狗和马)，灵长类动物(例如，人和非人灵长类动物如猴)，兔，以及啮齿类动物(例如，小鼠和大鼠)。在一些实施方案中，个体是人，包括儿童、青少年或成人。
用于本文时，“治疗”指减缓、中断、阻滞、缓解、停止、降低、或逆转已存在的症状、 病症、病况或疾病的进展或严重性。
用于本文时，“预防”包括对疾病或病症或特定疾病或病症的症状的发生或发展的抑制。在一些实施方式中，具有家族病史的个体是预防性方案的候选。通常，术语“预防”是指在病征或症状发生前，特别是在具有风险的个体中发生前的药物施用。
术语“有效量”指以需要的剂量并持续需要的时间段，有效实现所需治疗结果的量。本发明的制剂、BZP化合物或组合物的治疗有效量可以根据多种因素如疾病状态、个体的年龄、性别和重量和抗体或抗体部分在个体中激发所需反应的能力而变动。治疗有效量也是这样的一个量，其中制剂、BZP化合物或组合物的任何有毒或有害作用低于治疗有益作用。
“预防有效量”指以需要的剂量并持续需要的时间段，有效实现所需预防结果的量。通常，由于预防性剂量在对象中在疾病较早阶段之前或在疾病较早阶段使用，故预防有效量将小于治疗有效量。
如文中所用，术语“制剂”或“药物组合物”指适合于向动物优选哺乳动物(包括人)施用的包含至少一种活性成分和至少一种非活性成分的组合物。本发明的制剂可以是冻干粉制剂或液体制剂。“液体制剂”或“液体组合物”是指液体形式的制剂。本发明的液体组合物包含(i)本发明所述的BZP化合物；和(iii)可药用的液体载体。本发明的液体制剂优选为注射剂，例如经静脉注射或滴注的液体制剂，例如配制在0.9％氯化钠溶液中的液体制剂。
“可药用载体”指药物制剂中除活性成分以外的成分，其对对象无毒性。可药用载体包括但不限于溶剂、缓冲剂、赋形剂、稳定剂或防腐剂。
术语“约”在与数字数值联合使用时意为涵盖具有比指定数字数值小10％的下限和比指定数字数值大10％的上限的范围内的数字数值。
如文中所用，术语“单次药物剂量单元”是指在给药时待施用于患者的包含本发明的BZP化合物的单次药物剂型，例如注射用的小瓶、安瓿、输液袋、预充针或预充式注射器，其中含有药物的溶液或冻干粉。
具体实施方式
以下结合实施例进一步说明本发明，下列实施例不应被理解为对本发明范围的限制。
缩写
AE    不良反应
DLT   剂量限制性毒性
EC50 半数有效浓度
SAE  严重不良反应
TEAE 治疗期间不良反应
实施例1：动物体内药理学研究
与模型组相比，BZP在3mg/kg，12mg/kg和24mg/kg剂量下可以显著降低MCAO模型大鼠的脑梗死及脑肿胀体积，改善MCAO模型大鼠和对盐敏感大鼠的神经行为，并呈现剂量依赖性。在12mg/kg剂量下，BZP可以显著恢复MCAO模型大鼠肌力与平衡木行为能力，降低坏死神经元占比和细胞凋亡率，且其改善效果均显著优于NBPK组。此外，BZP 12mg/kg可以降低大鼠全脑缺血再灌注模型的24小时内死亡率和行为学评分，并于用药21后天显著降低对盐敏感大鼠的血压。BZP对脑缺血再灌注损伤有保护作用在缺血后4小时内给药有效，尤其缺血后2小时以内给药效果更佳。
在呼吸系统方面，单次静脉注射BZP 25-100mg/kg未见其对大鼠影响。
在神经行为方面，单次静脉注射BZP 50mg/kg和100mg/kg可致大鼠体温降低；高剂量下(100mg/kg)大鼠亦出现活动降低，竖毛，排便排尿次数降低及瞳孔刺激反射的消失等。这些改变皆在停药后4小时内恢复。BZP对大鼠体内缺血再灌注损伤保护的有效剂量(12mg/kg)低于在大鼠上造成神经系统影响的剂量(50mg/kg)。
在心血管系统方面，静脉注射50mg/kg BZP后0.25小时犬出现收缩压，舒张压，平均动脉一过性小幅升高，有一定剂量相关性。这些改变皆在给药后0.5小时内恢复。BZP 5-50mg剂量范围内未见其对II导联心电图有影响。
实施例2：动物体内药效学研究
2.1 BZP对大鼠局灶性脑缺血再灌注损伤的保护作用:
(1)神经行为学评分变化：与模型组相比，BZP 3,12,24mg/kg组在2.5h时和6h时评分显著降低(P<0.05，P<0.01)，呈剂量依赖性，说明BZP可以显著改善脑缺血再灌注损伤大鼠的运动功能障碍；
(2)脑梗死体积变化：与模型组相比，BZP 0.75,3,12,24mg/kg组脑梗死体积显著降低(P<0.01)，并呈剂量依赖性，BZP12,24mg/kg效果优于NBP-K和Br-NBP组(P<0.01)，BZP 3mg/kg效果优于Br-NBP组(P<0.01)。说明BZP可显著减小脑梗死体积。对BZP 0.75,3,12mg/kg组剂量组分别对皮层和纹状体梗死体积进行分析，BZP 0.75mg/kg组可以显著减小皮层的体积(P<0.01)，发现BZP 3,12mg/kg组均显著减小纹状体和皮层的梗死体积(P<0.01)。
(3)脑水肿变化：与模型组相比，BZP 3,12,24mg/kg组脑水肿体积显著减小(P<0.01)，并呈现剂量依赖性。
BZP 24,12mg/kg效果优于NBP-K组和Br-NBP组(P<0.01)；
(4)治疗时间窗：与模型组相比，BZP 12mg/kg组在缺血后0.5h或2h或4h给药均可显著减小脑梗死体积(P<0.01，P<0.05)。且0.5h和2h的效果优于4h(P<0.01)，在后续实验中，选择在缺血2h给药。
BZP可改善运动功能障碍，减小脑梗死体积，减轻脑水肿，最佳治疗时间窗在缺血后4h以内给药，尤其缺血后2h以内给药效果更佳。
2.2 BZP对大鼠局灶性脑缺血再灌注损伤所致炎症反应的影响:
TNF-α,IL-6,IL-1β,NF-κB,Cox-2,ICAM-1免疫组化染色结果免疫组化染色光密度值结果显示：与模型组相比，BZP低中高剂量组TNF-α，IL-6，IL-1β，NF-κB，COX-2，ICAM-1表达显著减少(P<0.05,P<0.01)，且BZP 12mg/kg组优于NBP-K 9.6mg/kg组与Br-NBP 10.5mg/kg组(P<0.05,P<0.01)。
免疫组化阳性细胞数目结果显示：与模型组相比，BZP低中高剂量组TNF-α,IL-6,IL-1β,NF-κB,COX-2,ICAM-1表达显著减少(P<0.05,P<0.01)，且BZP 12mg/kg组优于NBP-K 9.6mg/kg组与Br-NBP 10.5mg/kg组(P<0.05,P<0.01)。
BZP可抑制脑缺血再灌注损伤诱导的细胞炎症反应作用，表现为抑制TNF-α—IL-6—IL-1β—NF-κB—COX-2—ICAM-1环路的表达。
2.3 BZP对大鼠局灶性脑缺血再灌注损伤后神经细胞凋亡的保护作用：
BZP可减少神经细胞缺失，降低细胞凋亡率，表现为抑制Bax/Bcl-2—细胞色素C—Caspase-3线粒体凋亡通路，上调PI3K—p-Akt生存信号通路，即BZP有抑制凋亡作用。
2.4 BZP对大鼠局灶性脑缺血再灌注损伤后神经可塑性的影响：
BZP可促进脑缺血损伤后神经修复作用，改善大鼠脑缺血损伤之后运动功能的康复，其作用机制与增加缺血半暗带区域SYN，GAP-43，BDNF，GFAP的表达，下调NOGO-A的表达有关。
2.5 BZP对大鼠全脑缺血再灌注损伤的保护作用：
BZP(3,12mg/kg)组24h内死亡率低于模型组和NBP-K组；行为学评分BZP组较模型组显著降低(P<0.05)；与模型组比较，BZP组海马CA1区炎症环路因子(TNF-α、IL-1β、IL-6、NF-κB、COX-2、ICAM-1)、凋亡通路因子(Bax/Bcl-2、Cyt-c、Caspase-3)的表达，神经元坏死率、凋亡率均显著降低(P<0.05)，细胞生存通路(PI3K、P-Akt)显著增加(P<0.01)。
BZP对大鼠急性全脑缺血具有保护作用，其机制为抑制细胞的炎症反应和凋亡。
2.6 BZP抗血小板聚集作用及抗血栓作用：
离体实验证明，BZP对AA诱导的血小板聚集呈现剂量依赖性抑制作用，IC 50为12μmol/L，但对ADP、凝血酶诱导的血小板聚集无抑制作用；大鼠在体实验表明，BZP各剂量组具有抗ADP(血小板聚集抑制率分别为23.89％、34.42％和44.14％)、凝血酶(血小板聚集抑制率23.87％、37.75％和55.47％)、花生四烯酸(血小板聚集抑制率42.08％、60.32％和72.20％)诱导的血小板聚集的作用；并呈浓度依赖性；实验性血栓形成变化BZP低、中、高剂量组实验性血栓结果分别为0.23±0.04，0.18±0.02，0.13±0.03，较模型组明显降低(P<0.01),并呈现剂量依赖性。其中高剂量组的BZP与同摩尔剂量ASA组相比无统计学差异(P>0.05),但弱于Br-NBP组(P<0.01)。结果显示，BZP具有抗血栓形成的作用。
离体实验证明，BZP可选择性抑制AA诱导的血小板聚集；在体实验证明，BZP可抑制ADP、凝血酶、AA诱导的血小板聚集；BZP可抑制大鼠实验性血栓的形成。
2.7 BZP对大鼠急性全脑缺血的保护作用：
与假手术组相比，模型组大鼠出现较大脑梗死体积，而BZP 0.75,3,12,24mg/kg组均可显著减小脑梗死体积(P<0.05,P<0.01)；Br-NBP 10.5mg/kg组和NBP-K 9.6mg/kg组也可显 著减小脑梗死体积(P<0.01)，但BZP 12,24mg/kg组减小脑梗死体积优于Br-NBP组和NBP-K组(P<0.01)。BZP对大鼠脑梗死体积的改善呈明显的量效关系，随剂量的增加，大鼠脑梗死体积逐渐减小，具有较高相关性(R 2＝0.9739)。
核磁共振结果表明：BZP对大鼠局灶性脑缺血再灌注损伤具有保护作用。
实施例3：动物体内药代动力学研究
BZP单次静脉注射于大鼠(0.75-12.0mg/kg)和犬(1.0-4.0mg/kg)后，BZP和BNBP的C max和AUC 0-t均随剂量增加而增加，基本符合线性动力学。除BZP雌鼠体内的AUC 0-t显著高于雄鼠外，犬BZP和BNBP，鼠BNBP在雌雄之间无显著差异。
连续7天静脉注射BZP于大鼠(6.0mg/kg)和犬(2.0mg/kg)时，BZP和BNBP在体内均没有累积。在大鼠中，末次给药后的BZP其AUC 0-t显著高于首次，但C max在单次和多次给药之间无差异，表明在大鼠中多次用药后可能存在BZP与BNBP代谢的变化。此一代谢变化并未见于犬中(首次与末次给药的BZP和BNBP的C max和AUC 0-t皆无明显显著的统计学差异)。
BZP在给药50分钟内在肺组织较高，在110分钟时脂肪的含量最高。BZP在脑内的浓度相对较低，且消除较快，50分钟后已不能检测。BZP在体内迅速转化为BNBP(非经由NADPH辅酶/CYP450)。其中肝脏组织体外转化BZP的能力最强，脾脏转化能力最低。BNBP在给药1分钟时在肾，肝，肺组织较高。BNBP-OH是BNBP的主要代谢产物(经由NADPH辅酶/CYP450)。但是研究结果显示BZP，BNBP和BNBP-OH的累积排泄量仅为BZP给药剂量的3.12％，提示BNBP-OH可能在体内进行了进一步的代谢。
实施例4：动物体内毒理学研究
急毒实验中，给予大鼠和犬BZP单次静脉注射，其MTD为200mg/kg和300mg/kg。BZP在神经系统和呼吸系统产生的毒性反应在15分钟至4小时间均可恢复。
大鼠连续13周每日1次BZP静脉注射的长毒实验中，150mg/kg组所有大鼠每次给药结束即可见呼吸急促，俯卧，间或可见流涎，翻正反射消失，约在1小时内逐渐恢复正常，部分大鼠间或可见软便/稀便，血液学，血生化，眼科检查，尿常规等未见明显异常。犬连续13周，每日1次BZP静脉注射的长毒实验中，150mg/kg组全部犬在每次给药过程中陆续出现呕吐白色泡沫样物质，流涎，头部及全身震颤，痉挛/抽搐，间或可见呼吸急促，部分犬间或可见稀便。150mg/kg尚可致轻微贫血及肝脏损害(肝脏重量及系数升高，肝细胞肥大)。50mg/kg组部分犬在给药中后期间或可见头部及四肢震颤，稀便，呕吐，流涎。上述症状在停药28天后均可恢复。大鼠和犬长毒实验显示BZP的NOAEL剂量为50mg/kg。长毒中出现的神经和呼吸系统反应为一过性反应，产生的轻微贫血和对肝脏的损害也都在观察期内恢复。
实施例5：单次给药的I期临床研究(BZP1601试验)以及多次给药的I期临床研究(BZP1702试验)
BZP已完成两个一期临床试验，探讨其单剂量(BZP1601试验)和多剂量(BZP1702试验)分別在48名和29名健康受试者上的药代动力学。单次或多次静脉注射BZP后，血浆中BZP的AUC 0-t和C max与剂量成线性相关；但BNBP的AUC 0-t和C max与给药剂量的线性关系尚无法确定。BZP和BNBP的药动参数于不同性别受试者未见明显的差异，多次静脉滴注后未出现明显的药物蓄积。两次人体试验未发现除BNBP之外其他有意义的代谢产物。
试验药物的有效性和安全性
BZP已完成2个一期临床试验，分别探索其单剂量(BZP1601试验)和多剂量(BZP1702试验)在50名和30名健康受试者上的安全性和耐受性。BZP在25-400mg范围内单次静脉滴注或是在50-200mg剂量范围内进行多次静脉滴注皆具有良好的安全性和耐受性，AE发生率不随剂量增长而增加。
表1:布罗佐喷钠(BZP)临床研究列表
Figure PCTCN2021127101-appb-000003
此表包含截至2019年6月21日
人体药代动力学与产品代谢
表2:布罗佐喷钠(BZP)临床研究列表
Figure PCTCN2021127101-appb-000004
Figure PCTCN2021127101-appb-000005
此表包含截至2019年6月21日
缩略语:SD：标准差
药代动力学和代谢
BZP1601试验
分析人群：任何接受过BZP并进行了生物样本采集，可以进行药动分析的受试者均被纳入药动特性分析(未包含预研究12.5mg组)。研究分析含6个BPZ组别(分别为25mg，50mg，100mg，200mg，300mg，400mg)和安慰剂组，各组入组受试者例数分别为8例，8例，8例，8例，8例，8例，12例，共60例。正式研究入组的60例受试者均纳入药动分析集。
分析结果：BZP单次给药后，BZP及其代谢产物BNBP在健康受试者中的T 1/2的几何平均值约为8小时和15小时；各剂量组的T max的中位值相近，提示在给药结束后BZP和BNBP基本达到血药浓度峰值。各剂量组的尿液累积排泄率基本一致。单次静脉滴注不同剂量的BZP，在25-400mg剂量范围内血浆中BZP的主要暴露参数AUC 0-t和C max与剂量成线性相关；BNBP的AUC 0-t和C max与剂量的线性关系不能得出明确的结论。在25-400mg剂量范围内BZP和BNBP的PK主要暴露参数AUC 0-t和C max于不同性别受试者未见明显的差异。200mg组BZP及代谢产物BNBP经尿和粪便的总累计排泄率为0.5％，代谢产物中暂未发现脱溴代谢产物。
BZP1702试验
分析人群：同BZP1601试验。研究含4个BZP组(分别为50mg，100mg，200m)和安慰剂组。各组入组人数分别为10例，10例，10例和6例，共36例。50mg组1例受试者因给药前两天服用了药物，其中氨咖黄敏药物可能影响药物代谢，且该受试者给药第2天采集24小时血样之后出组，无法完整计算药动学参数，故该受试者不予纳入药动学分析数据集，其他给予了BZP的29例受试者全部纳入药动学分析数据集中。
分析结果：在50-200mg剂量范围内，连续多次静脉滴注BZP后第5天BZP和BNBP已基本达稳态。在首次给药及稳态下给药后，BZP的AUC 0-t和C max与剂量大小成线性关系，但BNBP的AUC 0-t和C max与剂量的线性关系不能确定。连续给药7天后，BZP的蓄积比为1.10-1.18，BNBP的蓄积比为1.60-1.78。BZP和BNBP的主要药动学暴露参数(AUC 0-t和C max)于不同性别受试者中未见明显的差异(BZP的均值比值范围分别为0.797-1.01和0.799-1.01，BNBP的均值比值范围分别为0.845-1.20和0.851-1.12)。未发现除BNBP之外其他有意义的代谢产物。
安全性及耐受性
暴露患者人数和暴露持续时间
BZP1601试验
分析人群：任何接受过研究药物并至少有一次安全性数据采集的受试者均将被纳入安全性分析(未包含预研究12.5mg组)。正式研究入组的60例受试者全部纳入安全性数据集，BZP组48例和安慰剂组12例。
所有受试者均按照方案要求完成静脉滴注给药。BZP总用药量见下表。
表3:布罗佐喷钠(BZP)总用药量
Figure PCTCN2021127101-appb-000006
数据来源：BZP1601临床试验报告表12-1
BZP1702试验
分析人群：同BZP1601试验。入组的36例受试者全部纳入安全性分析数据集，BZP组30例和安慰剂组6例。
除50mg组1例受试者因中途退出只完成首次给药以外，其他受试者均按照方案要求完成了特定剂量下的12次给药。BZP总用药量见下表。
表4:布罗佐喷钠(BZP)总用药量
Figure PCTCN2021127101-appb-000007
数据来源：BZP1702临床试验报告表12-1
I期临床试验总结：
BZP已完成2个I期临床试验。BZP在25-400mg范围内单次静脉滴注(BZP1601试验)或是在50-200mg剂量范围内多次静脉滴注(BZP1702试验)血浆中BZP的AUC 0-t和C max与剂量成线性相关；但BNBP的AUC 0-t和C max与给药剂量的线性关系尚无法确定。多次静脉滴注后未出现明显的药物蓄积。唯两次试验观察到的BZP和BNBP的T 1/2几何平均值有所差异。在BZP1601试验中，BZP给药一次后，BZP和BNBP的T 1/2几何平均值约为8小时和15小时；而在BZP1702试验中为5.34-5.57小时和7.78-10.3小时。推测两次试验间的差异可能与血液样本采集时间相关。BZP1601试验于给药后0分钟，20分钟，40分钟，60分钟(滴注结束时)，1.25小时，1.5小时，2小时，2.5小时，3小时，4小时，6小时，8小时，12小时，16小时，24小时，36小时，48小时采集血样，而在BZP1702试验中给药第1天血样只收集到了给药后24小时。
BZP在健康受试者内显示具有良好的安全性和耐受性。在两次临床试验中，仅在多剂量试验发生1例中度低血压(100mg组)，其余AE皆为轻度。AE发生比例在BZP组与安慰剂组之间无统计学差异，且发生率不随剂量增长而增加。研究者判定与研究药物相关的AE包括轻度心动过缓(单剂量25mg和200mg，未出现任何心电图QTc异常有临床意义的情况)，白细胞计数降低(单剂量50mg)，中性粒细胞计数/百分比降低(单剂量50mg，多剂量安慰剂)，一度房室传导阻滞(100mg单剂量)，蛋白尿(单剂量200mg)，凝血障碍(单剂量200mg)，给药部位疼痛(多剂量200mg)，低血压(多剂量100mg)，低钾血症(多剂量200mg)和舒张压降低(多剂量200mg)。与研究药物相关的AE发生于给药后数分钟至第9天，并在未经任何临床干预下症状转归为消失。两次临床试验均未发生死亡事件，SAE，导致退出的AE或其他重要AE，亦无妊娠报告。无剂量限制性毒性(DLT)发生。
实施例6：II期临床试验
BZP1703临床试验为多中心，随机，双盲，安慰剂平行对照的II期临床试验。试验目的在于评价不同剂量注射用BZP对比安慰剂治疗急性缺血性卒中的安全性和可行性，并初步探讨其有效性，为Ⅲ期临床试验设计提供依据。
该试验计划在中国入选375例年龄在45至75周岁之间急性缺血性卒中患者。参加试验的受试者将按照2:2:1的比例随机分配入以下三个治疗组：BZP低剂量试验组(100mg bid，静脉滴注，每次给予2瓶BZP以及2瓶BZP模拟剂)，BZP高剂量试验组(200mg bid，静脉滴注，每次给予4瓶BZP)，安慰剂对照组(bid，静脉滴注，每次给予4瓶BZP模拟剂)。受试者将接受每日两次、连续14天的试验药物治疗，随后进入随访期，受试者将于第45天和第90天进行安全性随访，并进行NIHSS和改良Rankin量表(mRS)的评估。每位受试者参与试验的时间预计约为91天。
BZP1703试验主要安全性终点为SAE，主要有效性终点为第14天的NIHSS评分与基线NIHSS评分之间的差值。次要安全性终点包括全因死亡，致命性出血及症状性颅内出血，第14天的头部核磁共振成像(MRI)检测出的脑梗死出血转化，各种不良事件；其他出血事件，AE，特别关注的AE(痫性发作、心动过缓，房室传导阻滞，凝血功能异常，蛋白尿，白细胞降低)，新发血管性事件患者的例数和发生率(缺血性卒中/出血性卒中/心肌梗死/血管性死亡)，生命体征，体格检查，实验室检查(血常规，血生化，尿常规，便常规，凝血功能等)，12导联心电图(ECG)等指标的异常情况。次要有效性终点包括第7和90天的NIHSS评分自基线的改变，第7，14和90天的NIHSS评分自基线的减分率，第7，14和90天的NIHSS评分为0-1分或减分≥4分的受试者比例，第7和14天的神经功能恶化NIHSS评分增加≥4分的发生率，第7，14和90天mRS评分分布的有序分析，第7，14和90天的mRS评分为0-1分、0-2分、0-3分的受试者比例，第14天的头部MRI-DWI显示的新发脑梗死的发生率等。
二期试验设计示意图
Figure PCTCN2021127101-appb-000008
1.1设计特点
BZP1703试验是一项多中心、随机、双盲、安慰剂平行对照临床试验。参加试验的受试 者将按照2:2:1的比例随机分配入以下三个治疗组：BZP低剂量试验组(100mg bid)，BZP高剂量试验组(200mg bid)，安慰剂对照组(bid)。
该试验采用中央随机化系统对受试者进行随机分组，以减少潜在的偏倚。研究者在确认受试者符合所有参加试验要求后，将在首次给予试验药物前通过交互式网络应答系统对该受试者进行随机。受试者将以2:2:1的比例按唯一的随机号随机分配到A/B/C三组。研究者、申办方及受试者均不知道A/B/C这三组与低剂量试验组、高剂量试验组和安慰剂对照组的对应关系。在揭盲时才知晓A/B/C的具体组别。
该试验将对受试者、研究者、研究中心的其他研究人员及申办方(包括监查员及合同研究组织公司)进行设盲，以保证对安全性、有效性分析评估没有偏倚。为保证盲态，给药方案中使用的模拟剂冻干粉针剂的包装形式、给药方式与试验药物相同。当所有数据录入数据库并确认无误后，数据库将按照流程启动锁定。数据库一旦锁定，即可启动揭盲程序。按照流程由随机化独立统计师释放受试者随机表给项目统计人员进行揭盲后的数据统计分析。
1.2结果与讨论
该试验的初步结果表明，单次剂量200mg效果明显优于单次剂量100mg；单次剂量200mg、每日两次的给药方案的效果明显优于单次剂量100mg、每日两次的给药方案。

Claims (25)

  1. 在个体中预防或治疗心脑缺血性疾病或改善心脑循环障碍或抗血栓的方法，该方法包括向所述个体施用有效量的5-溴-2-(α-羟基戊基)苯甲酸钠盐(BZP)化合物，其中所述BZP化合物具有以下结构：
    Figure PCTCN2021127101-appb-100001
  2. 根据权利要求1的方法，其中BZP施用的日剂量为50-500mg，例如100-500mg、200-500mg、250-500mg、300-500mg，325-475mg、350-475mg、350-450mg、375-450mg、或375-425mg，例如50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg。
  3. 根据权利要求1的方法，其中BZP单次施用剂量为25mg至400mg，例如50mg至400mg，优选50mg至300mg，更优选50mg至250mg，更优选100mg至250mg，例如25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg或400mg，和/或BZP的施用频率为每天三次、每天两次、每天一次、每两天一次、每三天一次、每周两次、每周一次、每两周一次或每四周一次施用。
  4. 根据权利要求1的方法，其中BZP每天施用一次到三次，每次施用剂量为50mg至250mg，例如，每天施用一次、两次或三次且每次施用50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg或250mg。
  5. 根据权利要求1的方法，其中BZP每天施用两次，每次施用剂量为100-250mg，例如每天两次且每次施用100mg、125mg、150mg、175mg、200mg、225mg或250mg，优选每天两次且每次给药200mg。
  6. 根据权利要求1-5任一项的方法，其中所述的疾病为急性脑卒中及相关疾病，优选地，所述的疾病为轻、中度急性缺血性脑卒中。
  7. 根据权利要求6的方法，其中所述的疾病为具有以下特征的疾病：
    (1)急性缺血性卒中；
    (2)急性缺血性脑卒中，脑部前循环梗死；
    (3)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死；
    (4)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)
    (5)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁；或
    (6)急性缺血性脑卒中，脑部前循环梗死，非心源性梗死，严重程度中等(NIHSS 5-15分)，年龄45-85岁，BZP需要在卒中发病24小时内给药。
  8. 根据上述权利要求任一项的方法，其中所述个体为人。
  9. 根据上述权利要求任一项的方法，其中所述个体从卒中发病到给药的时间不超过24小时，优选地，所述个体为卒中发病到给药的时间为6-24小时的人类患者。
  10. 根据上述权利要求任一项的方法，所述治疗在个体中实现以下一种或多种改善效果：
    (1)改善神经功能评分，降低NIHSS分值；
    (2)改善神经功能结局，降低mRS分值；
    (3)减少脑梗死体积；
    (4)减少缺血性脑卒中的复发率；
    (5)减少缺血性卒中的出血转化率，包括症状性颅内出血和无症状性出血转化；和/或
    (6)降低缺血性卒中的死亡率。
  11. 根据上述权利要求任一项的方法，其中所述给药方案的不良事件发生率低于其他给药方案并且实现的所述改善效果优于其他给药方案。
  12. 根据上述权利要求任一项的方法，其中BZP通过胃肠外途径施用，优选通过静脉内注射施用或静脉内滴注施用。
  13. 根据上述权利要求任一项的方法，其中BZP以药物组合物例如无菌冻干粉或由无菌冻干粉在可药用的液体载体中复配得到的注射液形式施用。
  14. 如权利要求1所述的BZP在制备用于在个体中预防或治疗心脑缺血性疾病或改善心脑循环障碍或抗血栓的药物中的用途。
  15. 根据权利要求14的用途，其中BZP施用的日剂量为50-500mg，例如100-500mg、200-500mg、250-500mg、300-500mg，325-475mg、350-475mg、350-450mg、375-450mg、或375-425mg，例如50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、 275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg或500mg。
  16. 根据权利要求14的用途，其中BZP单次施用剂量为25mg至400mg，例如50mg至400mg，优选50mg至300mg，更优选50mg至250mg，更优选100mg至250mg，例如25mg、50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg或400mg，和/或BZP的施用频率为每天三次、每天两次、每天一次、每两天一次、每三天一次、每周两次、每周一次、每两周一次或每四周一次施用。
  17. 根据权利要求14的用途，其中BZP每天施用一次到三次，每次施用剂量为50mg至250mg，例如，每天施用一次、两次或三次且每次施用50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg或250mg。
  18. 根据权利要求14的用途，其中BZP每天施用两次，每次施用剂量为100-250mg，例如每天两次且每次施用100mg、125mg、150mg、175mg、200mg、225mg或250mg，优选每天两次且每次给药200mg。
  19. 根据权利要求14-18任一项的用途，其中所述的疾病为急性脑卒中及相关疾病，优选地，所述的疾病为轻、中度急性缺血性脑卒中。
  20. 根据权利要求14-19任一项的用途，其中所述药物为无菌冻干粉或由无菌冻干粉在可药用的液体载体中复配得到的注射液的形式。
  21. 一种单次药物剂量单元，其特征在于包含5-溴-2-(α-羟基戊基)苯甲酸钠盐(BZP)化合物，其中所述单次药物剂量单元包含以下剂量的所述BZP化合物：25mg至400mg，例如50mg至400mg，优选50mg至300mg，更优选50mg至250mg，更优选100mg至250mg，例如50mg、75mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg或400mg。
  22. 根据权利要求21的单次药物剂量单元，其中所述BZP化合物为无菌冻干粉或由无菌冻干粉在可药用的液体载体中复配得到的注射液的形式。
  23. 根据权利要求21或22的单次药物剂量单元，其中所述可药用的液体载体是无菌的水、林格液、磷酸缓冲盐溶液或等渗氯化钠溶液。
  24. 根据权利要求21-23任一项的单次药物剂量单元，其为注射用的小瓶、安瓿、输液袋、预充针或预充式注射器的形式，其中含有权利要求22所述的BZP化合物的溶液或无菌冻干粉。
  25. 成套药物包装盒，其包含一个或多个如权利要求21-24任一项所述的单次药物剂量单元，以及任选的用于指导所述单次药物剂量单元的使用方法的说明书。
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