WO2022007982A2 - 一种药物组合物及其应用 - Google Patents

一种药物组合物及其应用 Download PDF

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WO2022007982A2
WO2022007982A2 PCT/CN2021/117404 CN2021117404W WO2022007982A2 WO 2022007982 A2 WO2022007982 A2 WO 2022007982A2 CN 2021117404 W CN2021117404 W CN 2021117404W WO 2022007982 A2 WO2022007982 A2 WO 2022007982A2
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pharmaceutical composition
benfotiamine
donepezil hydrochloride
donepezil
pharmaceutically acceptable
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PCT/CN2021/117404
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English (en)
French (fr)
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WO2022007982A3 (zh
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钟春玖
张寰
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上海日馨医药科技股份有限公司
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Priority to JP2023501271A priority Critical patent/JP2023534930A/ja
Priority to EP21837581.4A priority patent/EP4180040A4/en
Priority to US18/015,096 priority patent/US20230248726A1/en
Publication of WO2022007982A2 publication Critical patent/WO2022007982A2/zh
Publication of WO2022007982A3 publication Critical patent/WO2022007982A3/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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • the invention belongs to the field of medicine, in particular to a pharmaceutical composition comprising benfotiamine or a pharmaceutically acceptable salt thereof and donepezil or a pharmaceutically acceptable salt thereof, and also relates to the pharmaceutical composition Application in the preparation of medicaments for preventing or treating Alzheimer's disease.
  • Alzheimer's disease (commonly known as senile dementia, Alzheimer's disease, AD) is a progressive neurodegenerative disease with cognitive and behavioral disorders as the main clinical manifestations. Recognition impairment and rapid decay of memory function. The "World Alzheimer's Disease 2015 Report” pointed out that by 2050, the number of people with AD worldwide will increase to 130 million.
  • Donepezil molecular formula C 24 H 29 NO 3 , the common medicinal form is Donepezil hydrochloride, is the main drug for the clinical treatment of AD, it can delay the progression of AD middle and early stage and improve the clinical symptoms of early AD by inhibiting cholinesterase and increasing the level of acetylcholine. .
  • Benfotiamine molecular formula C 19 H 23 N 4 O 6 PS, chemical name S-2-[[(2-methyl-4-amino-5-pyrimidinyl)methyl]carboxamido]-5-phosphine
  • BTMP benzoylthiamineomonophosphate
  • benfotiamine can be used to prepare and prevent and treat Alzheimer's disease.
  • patent CN200710041571.X discloses a pharmaceutical composition containing benfotiamine for treating Alzheimer's disease.
  • the technical problem to be solved by the present invention is the problems of low pharmacodynamic activity and inconvenience to take when benfotiamine or donepezil is used alone.
  • the present invention provides a pharmaceutical composition comprising:
  • Donepezil or a pharmaceutically acceptable salt thereof is provided.
  • the weight ratio of benfotiamine or a pharmaceutically acceptable salt thereof to donepezil or a pharmaceutically acceptable salt thereof is (180 to 400): (3 to 6), or (180 to 400) :3, or (200 to 400):3, or 180:3, or 200:3, or 400:3.
  • the pharmaceutical composition further contains at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutically acceptable salt is hydrochloride, or hydrobromide, or sulfate, or acetate, or maleate, or tartrate.
  • the pharmaceutical composition is an oral preparation, and the oral preparation is any one of tablets, capsules, granules, powders, and pills.
  • the pharmaceutical composition comprises: benfotiamine and donepezil hydrochloride.
  • the weight ratio of benfotiamine to donepezil hydrochloride is (180 to 400): (3 to 6).
  • the weight ratio of benfotiamine to donepezil hydrochloride is 180:6, or 240:6, or 360:6, or 240:3, or 360:3.
  • the weight ratio of benfotiamine to donepezil hydrochloride is (180 to 360): (3 to 6).
  • the weight ratio of benfotiamine to donepezil hydrochloride is (200 to 400): (3 to 6).
  • the weight ratio of benfotiamine to donepezil hydrochloride is (200 to 400):3.
  • the weight ratio of benfotiamine to donepezil hydrochloride is 200:3, or 400:3.
  • the pharmaceutical composition comprises 3 mg to 10 mg of donepezil hydrochloride.
  • 150 mg to 600 mg of benfotiamine is included in the pharmaceutical composition.
  • the present invention also provides the application of the above-mentioned pharmaceutical composition in preparing a medicine for preventing or treating Alzheimer's disease.
  • the present invention has the following advantages:
  • a pharmaceutical composition provided by the present invention comprises benfotiamine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof.
  • the results of the water maze experiment showed that the combined administration of benfotiamine and donepezil hydrochloride achieved a good synergistic effect, which could better improve the spatial learning and memory ability of AD mice, and the effect was significantly better than benfotiamine or hydrochloric acid.
  • the effect of donepezil when administered alone shows that the pharmaceutical composition of the present invention has better pharmaceutical activity in the treatment of Alzheimer's disease.
  • the present invention prepares benfotiamine and donepezil hydrochloride into a compound preparation, which is convenient to take and can better improve the compliance of patients.
  • Fig. 1 is the influence of each compound on animal incubation period in the embodiment
  • Fig. 2 is the influence of each compound in the embodiment on the number of times of animal crossing
  • Figure 3 shows the effect of each compound in the examples on the time of the animal's target quadrant.
  • donepezil or benfotiamine can be used alone in the treatment of Alzheimer's disease
  • the combination of the above two drugs may be used in the preparation of drugs for the prevention or treatment of Alzheimer's disease more beneficial.
  • the inventor's study found that there is a synergistic effect between donepezil and benfotiamine that is significantly better than that of the active ingredients alone.
  • the present invention provides a pharmaceutical composition comprising benfotiamine or a pharmaceutically acceptable salt thereof; and donepezil or a pharmaceutically acceptable salt thereof.
  • the results of the water maze experiment showed that the combined administration of benfotiamine and donepezil hydrochloride achieved a good synergistic effect, which could better improve the spatial learning and memory ability of AD mice, and the effect was significantly better than benfotiamine or hydrochloric acid.
  • the effect of donepezil when administered alone shows that the pharmaceutical composition of the present invention has better pharmaceutical activity in the treatment of Alzheimer's disease.
  • the present invention prepares benfotiamine and donepezil hydrochloride into a compound preparation, which is convenient to take and can better improve the compliance of patients.
  • the present invention generally does not have any special restrictions on the sources of materials or reagents used, for example, commercially available ones can be used.
  • the effective components contained in the composition are: benfotiamine 150 mg; donepezil hydrochloride 5 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 200 mg; donepezil hydrochloride 5 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 300 mg; donepezil hydrochloride 5 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 400 mg; donepezil hydrochloride 5 mg.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 600 mg; donepezil hydrochloride 5 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 400 mg; donepezil hydrochloride 3 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 400 mg; donepezil hydrochloride 6 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • the effective components contained in the composition are: benfotiamine 200 mg; donepezil hydrochloride 6 mg.
  • the raw materials of benfotiamine and donepezil hydrochloride are weighed according to the prescription amount, and at least one pharmaceutically acceptable carrier or excipient is added to prepare an oral preparation.
  • the oral preparation can be any one of tablets, capsules, granules, powders, and pills.
  • Rodents have a strong motivation to escape the water environment in water, and can escape from the water environment in the fastest and most direct way.
  • the process of learning to escape from the water environment reflects the animal's learning ability.
  • Spatial positioning according to the surrounding environment and purposefully swimming to a safe place in the water (such as a platform) can reflect the animal's spatial learning and memory ability.
  • mice Male APP/PS1/Tau mice and C57BL/6 wild-type mice.
  • the mice were 8 months old and weighed 250-300 g, purchased from The Jackson laboratory.
  • APP/PS1/Tau mice are APP/PS1/tau triple-transgenic Alzheimer's disease (3 ⁇ Tg-AD) model mice, and their A ⁇ deposition appeared several months earlier than the pathological changes of tau protein, which can more realistically simulate Clinical course and pathological changes of Alzheimer's disease.
  • CMC-Na sodium carboxymethyl cellulose
  • BTMP bisenfotiamine
  • Shanghai Rixin Biotechnology Co., Ltd. batch number 1908002
  • Donepezil hydrochloride Eisai (China) Manufactured by Pharmaceutical Co., Ltd. Lot 1704019.
  • Preparation of 20mg/ml BTMP suspension (administration dose 400mg/kg): Weigh 500mg BTMP, add 0.7% m/v CMC-Na to 25ml, to obtain 20mg/ml BTMP suspension.
  • Preparation of 10mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension (dosage 200mg/kg BTMP suspension + 1.5mg/kg donepezil hydrochloride suspension): prepare 20mg/ml BTMP suspension respectively 10mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension.
  • Preparation of 5mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension (dosage 100mg/kg BTMP suspension + 1.5mg/kg donepezil hydrochloride suspension): prepare 10mg/ml BTMP suspension respectively 5mg/ml BTMP suspension + 0.075mg/ml donepezil hydrochloride suspension was obtained by mixing the same volume before administration.
  • mice in the blank control group, the model group and the experimental group were given continuous intragastric administration for 8 weeks according to the dosage/specification of 2.2.
  • the water maze training and testing began in the last week of administration.
  • the training and testing period of the water maze was 6 days, the training period was 5 days, and the testing period was 1 day.
  • the training and testing period of the water maze (a total of 6 days), keep the indoor lighting and other conditions consistent, keep the indoor quiet, and eliminate the interference of the environment and personnel.
  • the mice did not need to be placed on the platform for 15 s before training.
  • the two quadrants of each mouse were trained 10-15 minutes apart. Do this for 5 days in a row.
  • Test period (6th day) 24 hours after the last training, the platform was removed, the mice were dropped at the opposite side of the original platform quadrant (that is, the farthest position from the platform), and the mice were recorded in the target quadrant (the original platform).
  • the time of the quadrant where the platform is located, the number of times of crossing the original platform position (the number of times of crossing the platform) and the time of first crossing the original platform position (latency period) were used as the indicators of the spatial learning and memory ability of mice.
  • mice in the model group increased significantly, the number of times of crossing the platform was less, and the time in the target quadrant was significantly reduced, and there were significant differences. It shows that the transgenic model mice and normal mice have differences in spatial learning and memory ability, which is suitable for spatial learning and memory training. Compared with the model group, the positive control group and the experimental group had significant improvements in the incubation period, the number of times of crossing the platform, and the target quadrant time, and there were significant differences. The results are shown in Table 1.
  • results of the water maze test of the present invention show that after the combined administration of benfotiamine and donepezil hydrochloride, a good synergistic effect is obtained, which can better improve the spatial learning and memory ability of AD mice, and the effect is significantly better than that of benfotiamine Or the effect of donepezil hydrochloride when administered alone is also better than that of vitamin B1, and the pharmaceutical composition of the present invention has better pharmaceutical activity in treating Alzheimer's disease.
  • ADAS-cog scale including 11 items (word recall, naming, executive instruction, structural practice, intentional practice, orientation, word recognition, recall test instruction, oral language ability, word finding ability, language comprehension ability) ), used to assess the cognitive function level of patients, with a score ranging from 0 to 70 points, with higher scores indicating more severe cognitive impairment), and patients were scored after 12, 24, 36, and 52 weeks of administration. Group differences in change from baseline in patient scores are shown in the table below.
  • the ADAS-cog score improvement of the patients in the treatment group is better than that in the placebo group.
  • the results showed that the combination therapy of benfotiamine and donepezil hydrochloride could significantly delay the progression of Alzheimer's disease.

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Abstract

本发明公开了一种药物组合物，所述药物组合物包含苯磷硫胺或其药学上可接受的盐；和多奈哌齐或其药学上可接受的盐。实验结果表明，苯磷硫胺和盐酸多奈哌齐联合给药后，取得了较好的协同效果，可较好改善AD小鼠的空间学习记忆能力，且效果显著优于苯磷硫胺或盐酸多奈哌齐在单独用药时的效果，表明本发明药物组合物在治疗阿尔茨海默病方面有较好的药物活性。

Description

一种药物组合物及其应用 发明领域
本发明属于医药领域，具体涉及一种药物组合物，所述药物组合物包含苯磷硫胺或其药学上可接受的盐和多奈哌齐或其药学上可接受的盐，还涉及所述药物组合物在制备预防或治疗阿尔茨海默病药物中的应用。
发明背景
阿尔茨海默病(俗称老年性痴呆，Alzheimer’s disease，AD)是一种以认知、行为失常为主要临床表现的进行性神经退行性疾病，也是一种最常见的老年期痴呆，主要表现为识别能力障碍与记忆功能的迅速衰减。《世界阿尔茨海默病2015报告》指出，到2050年，全球AD的患病人数将增加至1.3亿。
多奈哌齐，分子式C 24H 29NO 3，常见药用形式为盐酸多奈哌齐，为临床上治疗AD主要药物，其通过抑制胆碱酯酶增加乙酰胆碱水平而延缓AD中、早期病状进展和改善早期AD临床病状。
苯磷硫胺，分子式C 19H 23N 4O 6PS，化学名S-2-[[(2-甲基-4-氨基-5-嘧啶基)甲基]甲酰胺基]-5-膦酰氧基-2，3-戊烯-3-硫醇苯甲酸酯，benzoylthiamineomonophosphate，简称BTMP，可以改善水溶性维生素B1生物利用度低的缺点，提高血液和组织中维生素B1的浓度，从而提高疗效。近来有研究表明，苯磷硫胺可以用于制备预防和治疗阿尔茨海默病，如专利CN200710041571.X公开提供了一种包含苯磷硫胺治疗阿尔茨海默病的药物组合物。
虽然现有技术已披露上述治疗阿尔茨海默病的药物，但迄今尚无逆转或阻止病情进展的有效药物。因此尚缺乏一种更为有效且能够提高患者依从性的药物。
发明概述
本发明要解决的技术问题是苯磷硫胺或多奈哌齐在单独用药时存在的药效活动性低以及服用不方便的问题。
为了解决上述技术问题，本发明提供一种药物组合物，所述药物组合物包含：
苯磷硫胺或其药学上可接受的盐；和
多奈哌齐或其药学上可接受的盐。
可选地，所述苯磷硫胺或其药学上可接受的盐与多奈哌齐或其药学上可接受的盐的重量比为(180至400)∶(3至6)，或(180至400)∶3，或(200至400)∶3，或180∶3，或200∶3，或400∶3。
可选地，所述药物组合物还含有至少一种药物上可接受的载体或赋形剂。
可选地，所述药学上可接受的盐为盐酸盐、或氢溴酸盐、或硫酸盐、或醋酸盐、或马来酸盐、或酒石酸盐。
可选地，所述药物组合物为口服制剂，所述口服制剂为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
可选地，所述药物组合物包含：苯磷硫胺和盐酸多奈哌齐。
可选地，所述苯磷硫胺与盐酸多奈哌齐的重量比为(180至400)∶(3至6)。
可选地，所述苯磷硫胺与盐酸多奈哌齐的重量比为180∶6，或240∶6，或360∶6，或240∶3，或360∶3。
可选地，所述苯磷硫胺与盐酸多奈哌齐的重量比为(180至360)∶(3至6)。
可选地，所述苯磷硫胺与盐酸多奈哌齐的重量比为(200至400)∶(3至6)。
可选地，所述苯磷硫胺与盐酸多奈哌齐的重量比为(200至400)∶3。
可选地，所述苯磷硫胺与盐酸多奈哌齐的重量比为200∶3，或400∶3。
可选地，所述药物组合物包含3mg至10mg的盐酸多奈哌齐。
可选地，所述药物组合物中包含150mg至600mg的苯磷硫胺。
本发明还提供了上述所述药物组合物在制备预防或治疗阿尔茨海默病药物中的应用。
与现有技术相比本发明具有以下优点：
本发明提供的一种药物组合物包含苯磷硫胺或其药学上可接受的盐；和多奈哌齐或其药学上可接受的盐。水迷宫实验结果表明，苯磷硫胺和盐酸多奈哌齐联合给药后，取得了较好的协同效果，可较好改善AD小鼠的空间学习记忆能力，且效果显著优于苯磷硫胺或盐酸多奈哌齐在单独用药时的效果，表明本发明药物组合物在治疗阿尔茨海默病方面有较好的药物活性。
进一步地，本发明通过将苯磷硫胺和盐酸多奈哌齐制备成复方制剂，服用方便，能较好提高患者的依从性。
附图简要说明
图1为实施例中各化合物对动物潜伏期的影响；
图2为实施例中各化合物对动物穿台次数的影响；
图3为实施例中各化合物对动物目标象限时间的影响。
发明详述
虽然现有技术中已经披露多奈哌齐或苯磷硫胺可单独应用于治疗阿尔茨海默病，但尚未有人披露或认识到上述两种药物的组合可能在制备预防或治疗阿尔茨海默病药物时更为有益。而发明人研究发现，多奈哌齐和苯磷硫胺之间存在显著优于单独活性成分的协同作用。
本发明提供的一种药物组合物，所述药物组合物包含苯磷硫胺或其药学上可接受的盐；和多奈哌齐或其药学上可接受的盐。水迷宫实验结果表明，苯磷硫胺和盐酸多奈哌齐联合给药后，取得了较好的协同效果，可较好改善AD小鼠的空间学习记忆能力，且效果显著优于苯磷硫胺或盐酸多奈哌齐在单独用药时的效果，表明本发明药物组合物在治疗阿尔茨海默病方面有较好的药物活性。另外，本发明通过将苯磷硫胺和盐酸多奈哌齐制备成复方制剂，服用方便，能较好提高患者的依从性。
为使本发明的上述目的、特征和优点能够更为明显易懂，下面具体对本发明的具体实施方式做详细的说明。
除特殊注明外，本发明对所用材料或试剂的来源通常没有特殊限制，例如可以采用市售即可。
第一实施例
所述组合物包含的有效组分为：苯磷硫胺150mg；盐酸多奈哌齐5mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第二实施例
所述组合物包含的有效组分为：苯磷硫胺200mg；盐酸多奈哌齐5mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第三实施例
所述组合物包含的有效组分为：苯磷硫胺300mg；盐酸多奈哌齐5mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第四实施例
所述组合物包含的有效组分为：苯磷硫胺400mg；盐酸多奈哌齐5mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物 上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第五实施例
所述组合物包含的有效组分为：苯磷硫胺600mg；盐酸多奈哌齐5mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第六实施例
所述组合物包含的有效组分为：苯磷硫胺400mg；盐酸多奈哌齐3mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第七实施例
所述组合物包含的有效组分为：苯磷硫胺400mg；盐酸多奈哌齐6mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
第八实施例
所述组合物包含的有效组分为：苯磷硫胺200mg；盐酸多奈哌齐6mg。
制备方法：
按照处方量称取苯磷硫胺和盐酸多奈哌齐原料药，加入至少一种药物上可接受的载体或赋形剂，制备成口服制剂。所述口服制剂可以为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
以下通过Morris水迷宫实验，将本发明所提供的药物组合物与苯磷硫胺、盐酸多奈哌齐、维生素B1单独给药后的效果进行对比。
测试例1：Morris水迷宫实验
1.实验原理
啮齿类动物在水中有强烈的逃避水环境的动机，并能以最快、最直接的途径逃离水环境。学会逃避水环境的过程体现动物的学习能力，根据周围环境进行空间定位，有目的地游往水中安全的地方(如平台)，可以体现动物的空间学习记忆能力。
2.实验内容
2.1.材料
(1)实验动物
实验动物为雄性APP/PS1/Tau小鼠和C57BL/6野生型小鼠。鼠龄8个月，体重250-300g，购自The Jackson laboratory。
APP/PS1/Tau小鼠为APP/PS1/tau三转基因阿尔茨海默病(3×Tg-AD)模型小鼠，其Aβ沉积的出现早于tau蛋白病理改变数月，能够更真实地模拟阿尔茨海默病临床过程和病理改变。
(2)主要制剂
CMC-Na(羧甲基纤维素钠)，上海国药集团化学试剂有限公司，批号20181203；BTMP(苯磷硫胺)，上海日馨生物科技有限公司，批号1908002；盐酸多奈哌齐，卫材(中国)药业有限公司制造，批号1704019。
2.2.药物配制及给药信息
(1)药物配制
0.7％m/v CMC-Na(羧甲基纤维素钠)的配制：称取0.7g羧甲基纤维素钠溶解于100ml纯净水，即得0.7％m/v CMC-Na。
10mg/ml维生素B1溶液(给药剂量200mg/kg)的配制：称取500mg维生素B1，加0.7％m/v CMC-Na至50ml，即得10mg/ml溶液。
10mg/ml BTMP混悬液(给药剂量200mg/kg)的配制：称取500mg BTMP，加0.7％m/v CMC-Na至50ml，即得10mg/ml BTMP混悬液。
20mg/ml BTMP混悬液(给药剂量400mg/kg)的配制：称取500mg BTMP，加0.7％m/v CMC-Na至25ml，即得20mg/ml BTMP混悬液。
0.075mg/ml盐酸多奈哌齐混悬液(给药剂量1.5mg/kg)的配制：1片盐酸多奈哌齐片(含5mg盐酸多奈哌齐)研碎加0.7％m/v CMC-Na至66.67ml，即得0.075mg/ml盐酸多奈哌齐混悬液。
0.15mg/ml盐酸多奈哌齐混悬液(给药剂量3.0mg/kg)的配制：1片盐酸多奈哌齐片(含5mg盐酸多奈哌齐)研碎加0.7％m/v CMC-Na至33.33ml，即得0.15mg/ml盐酸多奈哌齐混悬液。
10mg/ml BTMP混悬液+0.075mg/ml盐酸多奈哌齐混悬液(给药剂量200mg/kg BTMP混悬液+1.5mg/kg盐酸多奈哌齐混悬液)的配制：分别配制20mg/ml BTMP混悬液及0.15mg/ml盐酸多奈哌齐混悬液，给药前等体积混匀，即得10mg/ml BTMP混悬液+0.075mg/ml盐酸多奈哌齐混悬液。
5mg/ml BTMP混悬液+0.075mg/ml盐酸多奈哌齐混悬液(给药剂量100mg/kg BTMP混悬液+1.5mg/kg盐酸多奈哌齐混悬液)的配制：分别配制10mg/ml BTMP混悬液及0.15mg/ml盐酸多奈哌齐混悬液，给药前等体积混匀，即得5mg/ml BTMP混悬液+0.075mg/ml盐酸多奈哌齐混悬液。
(2)给药信息
Figure PCTCN2021117404-appb-000001
2.3.实验方法
空白对照组小鼠、模型组及实验组小鼠按2.2.给药剂量/规格连续灌胃给药8周，给药最后一周开始水迷宫训练及测试。水迷宫训练及测试为期6天，训练期5天，测试期1天。另外，在水迷宫训练及测试期内(共6天时间)，保持室内灯光等条件一致，保持室内安静，排除环境、人员等干扰。
(1)实验前准备：水迷宫池内放入适量水，水温保持22+3℃，将平台放置固定位置(目标象限)且低于水面1cm，加入钛白粉至水颜色混白，平台看不清。
(2)训练期(第1天至第5天)：每天进行第一个象限训练前，将每只小鼠置于平台15s(增加小鼠对平台的安全感)，随后小鼠从平台所在象限放入水池(头朝池壁)，设置游泳时间为60s。若60s内其找到平台，停留5s，视为成功找到平台。若未能找到平台，记录时间为60s，将小鼠引导至平台停留20s，小鼠拿出，结束此只小鼠此象限训练。
第一象限训练后，依次进行余下三个象限训练，训练前不需提前将小 鼠置于平台停留15s。每只小鼠两个象限训练时间间隔10-15分钟。以此训练方式，连续训练5天。
(3)测试期(第6天)：最后一次训练结束24小时后，将平台撤除，小鼠于原平台象限对侧位置(即距离平台最远位置)投下，记录小鼠在目标象限(原平台所在象限)时间、穿过原平台位置次数(穿台次数)及首次穿过原平台位置时间(潜伏期)，并以此作为小鼠空间学习记忆能力的考察指标。
3.实验结果
与空白对照组相比，模型组小鼠潜伏期时间明显增长，穿台次数少，在目标象限时间明显减少，且具有显著性差异。表明该转基因模型小鼠与正常小鼠在空间学习记忆能力方面存在差异，适用于空间学习记忆训练。与模型组相比，阳性对照组及实验组在潜伏期、穿台次数、目标象限时间均有明显改善，且均有显著性差异，结果见表1。
表1各化合物组小鼠Morris水迷宫测试结果(n＝10)
Figure PCTCN2021117404-appb-000002
备注：P＜0.05为差异显著； *P＜0.05-与空白对照组相比； #P＜0.05-与模型组相比； &P＜0.05-与BTMP相比
以潜伏期、穿台次数、目标象限时间为化合物药效考察指标，排序依次为空白对照组、BTMP+盐酸多奈哌齐、1/2BTMP+盐酸多奈哌齐、BTMP、 盐酸多奈哌齐、VB1、模型组(表现优的在前)。结果如图1至图3所示，结果表明VB1对AD小鼠学习记忆改善不明显，BTMP、盐酸多奈哌齐、BTMP+盐酸多奈哌齐、1/2BTMP+盐酸多奈哌齐对AD小鼠的空间记忆学习能力有明显改善，且BTMP和盐酸多奈哌齐联合给药改善效果最佳，效果明显优于单独使用BTMP、盐酸多奈哌齐的效果。
本发明水迷宫实验结果表明，苯磷硫胺和盐酸多奈哌齐联合给药后，取得了较好的协同效果，可较好改善AD小鼠的空间学习记忆能力，且效果显著优于苯磷硫胺或盐酸多奈哌齐在单独用药时的效果，也优于维生素B1的效果，本发明药物组合物在治疗阿尔茨海默病方面有较好的药物活性。
测试例2：临床试验
在中度阿尔茨海默病患者(筛查时MMSE为10～19)中进行为期52周的临床试验研究。研究分组和给药方案如下：
Figure PCTCN2021117404-appb-000003
基于ADAS-cog量表(共包含11项(语词回忆、命名、执行指令、结构性练习、意向性练习、定向力、词语辨认、回忆测验指令、口头语言表达能力、找词能力、语言理解能力)，用于评估患者的认知功能水平，评分范围为0～70分，分数越高表明认知受损越重)，在给药12、24、36、52周后对患者进行评分。患者评分相对于基线变化的组间差异如下表中所示。
Figure PCTCN2021117404-appb-000004
Figure PCTCN2021117404-appb-000005
由以上结果可见，治疗组患者的ADAS-cog分值改善优于安慰剂组。特别地，36周时治疗组患者的ADAS-cog分值改善达2.116分，具有统计学差异(p＝0.077)，52周治疗组患者的ADAS-cog分值改善达3.331分，具有统计学差异(p＝0.029)。结果表明，苯磷硫胺与盐酸多奈哌齐的联合疗法可显著延缓阿尔茨海默病的病情进展。
同时，在给药期间，在治疗组患者中未观察到明显的药物相关不良反应，表明苯磷硫胺与盐酸多奈哌齐的联合疗法具有良好的安全性，患者对于该疗法的耐受性良好。
虽然本发明披露如上，但本发明并非限定于此。任何本领域技术人员，在不脱离本发明的精神和范围内，均可作各种更动与修改，因此本发明的保护范围应当以权利要求所限定的范围为准。

Claims (15)

  1. 一种药物组合物，其特征在于，所述药物组合物包含：
    苯磷硫胺或其药学上可接受的盐；和
    多奈哌齐或其药学上可接受的盐。
  2. 如权利要求1所述的药物组合物，其特征在于，所述苯磷硫胺或其药学上可接受的盐与多奈哌齐或其药学上可接受的盐的重量比为(180至400)∶(3至6)，或(180至400)∶3，或(200至400)∶3，或180∶3，或200∶3，或400∶3。
  3. 如权利要求1所述的药物组合物，其特征在于，所述药物组合物还含有至少一种药物上可接受的载体或赋形剂。
  4. 如权利要求1所述的药物组合物，其特征在于，所述药学上可接受的盐为盐酸盐、或氢溴酸盐、或硫酸盐、或醋酸盐、或马来酸盐、或酒石酸盐。
  5. 如权利要求1所述的药物组合物，其特征在于，所述药物组合物为口服制剂，所述口服制剂为片剂、胶囊剂、颗粒剂、粉剂、丸剂中的任意一种。
  6. 如权利要求1所述的药物组合物，其特征在于，所述药物组合物包含：苯磷硫胺和盐酸多奈哌齐。
  7. 如权利要求6所述的药物组合物，其特征在于，所述苯磷硫胺与盐酸多奈哌齐的重量比为(180至400)∶(3至6)。
  8. 如权利要求7所述的药物组合物，其特征在于，所述苯磷硫胺与盐酸多奈哌齐的重量比为180∶6，或240∶6，或360∶6，或240∶3，或360∶3。
  9. 如权利要求7所述的药物组合物，其特征在于，所述苯磷硫胺与盐酸多奈哌齐的重量比为(180至360)∶(3至6)。
  10. 如权利要求7所述的药物组合物，其特征在于，所述苯磷硫胺与盐酸多奈哌齐的重量比为(200至400)∶(3至6)。
  11. 如权利要求10所述的药物组合物，其特征在于，所述苯磷硫胺与盐酸多奈哌齐的重量比为(200至400)∶3。
  12. 如权利要求11所述的药物组合物，其特征在于，所述苯磷硫胺与盐酸多奈哌齐的重量比为200∶3，或400∶3。
  13. 如权利要求1至12任一项所述的药物组合物，其特征在于，所述药物组合物包含3mg至10mg的盐酸多奈哌齐。
  14. 如权利要求1至12任一项所述的药物组合物，其特征在于，所述药物组合物中包含150mg至600mg的苯磷硫胺。
  15. 如权利要求1所述的药物组合物在制备预防或治疗阿尔茨海默病药物中的应用。
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CN101317849A (zh) * 2007-06-20 2008-12-10 复旦大学附属中山医院 一种防治阿尔茨海默病或衰老的药物组合物
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CN108904739A (zh) * 2018-09-13 2018-11-30 陕西中医药大学 一种治疗老年痴呆病的中西复方制剂及其制备方法

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