WO2023280238A1 - 一种包含绿原酸的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途 - Google Patents

一种包含绿原酸的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途 Download PDF

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WO2023280238A1
WO2023280238A1 PCT/CN2022/104223 CN2022104223W WO2023280238A1 WO 2023280238 A1 WO2023280238 A1 WO 2023280238A1 CN 2022104223 W CN2022104223 W CN 2022104223W WO 2023280238 A1 WO2023280238 A1 WO 2023280238A1
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pharmaceutical composition
disease
acid
chlorogenic acid
alzheimer
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French (fr)
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张洁
李文斌
黄望
张飞
张雅
徐敏
张亮
黄羽佳
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四川九章生物科技有限公司
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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

Definitions

  • the invention belongs to the field of biomedicine, and in particular relates to the use of a pharmaceutical composition containing chlorogenic acid in the preparation of medicines for treating early Alzheimer's disease.
  • Alzheimer's disease is an age-related progressive neurodegenerative disease with main clinical features such as agnosia, aphasia, apraxia, impairment of visuospatial ability, and memory and cognitive dysfunction.
  • the general pathology of the patient's brain showed weight loss and volume reduction, widening and deepening of the brain sulcus, atrophy of the brain gyrus, and atrophy of the temporal lobe, especially the hippocampus.
  • the main histopathological features are senile plaques formed by argyrophilic axonal processes surrounded by ⁇ -amyloid, neurofibrillary tangles formed by hyperphosphorylated microtubule tau protein in neurons, gliosis and neuron loss in the brain. According to epidemiological survey results, it is estimated that by 2050, the total number of affected people worldwide will increase to 100 million.
  • Alzheimer's disease has been formed, such as oxidative stress theory, amyloid protein hypothesis, inflammatory mechanism, insulin-related abnormal glucose metabolism hypothesis, free radical hypothesis, etc. It has become an indisputable fact that a large number of high-density A ⁇ and its neurotoxicity in the brains of Alzheimer's patients are one of the important causes of AD.
  • the pathological changes of neuronal tau protein coexist with A ⁇ deposition, and can produce a variety of inflammatory responses.
  • oxidative stress, chronic neuroinflammatory injury, neuronal apoptosis and autophagy form a complex network with A ⁇ deposition, abnormal phosphorylation of tau protein and the resulting neurotoxicity.
  • the drugs currently on the market for the treatment of Alzheimer's disease mainly help to improve the symptoms of the disease, but cannot fundamentally prevent the deterioration of the disease.
  • the cholinesterase inhibitor drug galantamine, the antioxidant drug monoamine oxidase inhibitor, the brain metabolism activator oxiracetam, etc. are mostly used, but the effect is not satisfactory.
  • the development of new drugs in this field has almost been wiped out in the past few decades.
  • Many drugs of pharmaceutical giants such as Pfizer and AstraZeneca have failed miserably in the Phase 3 clinical stage. Natural plants contain a wealth of prodrugs and compounds with unique mechanisms of action and novel structures.
  • Chlorogenic acid also known as coffee tannin, is a phenolic acid composed of caffeic acid (CA) and quinic acid (QA), and its chemical name is 3-o-coffee Acyl quinic acid (3-o-caffeoylquinic acid, CGA).
  • Chlorogenic acid is a phenylpropanoid synthesized by plants through the intermediate product of the pentose phosphate pathway during the process of aerobic respiration. Chlorogenic acid has been developed and used in many fields such as food, health care products, cosmetics and pharmaceuticals.
  • chlorogenic acid exerts antigenic and antioxidant activities to protect nerve cells by improving memory and cognitive dysfunction, inhibiting neurotoxicity induced by ⁇ -amyloid protein, and alleviating mitochondrial damage and apoptosis. Reduce the risk of cognitive decline and neuropathy, and alleviate the clinical features of Alzheimer's disease (see, for example, Yao Yinle et al., "Chlorogenic acid improves research progress in Alzheimer's disease", Medical Herald, Vol. 36, No. 11 Issue, November 2017, pp. 1287-1290). However, there are few clinical studies on the specific role of chlorogenic acid, and there is no previous research on whether chlorogenic acid is more effective for mild, moderate or severe Alzheimer's disease.
  • the present inventors have also been working on the research of using chlorogenic acid to treat Alzheimer's disease for a long time.
  • the present inventor unexpectedly discovered a method that can significantly improve the curative effect of chlorogenic acid in the treatment of early Alzheimer's disease through a large number of screenings, and developed a method that is especially suitable for the treatment of early Alzheimer's disease.
  • Safe and highly effective pharmaceutical composition containing chlorogenic acid for Alzheimer's disease is especially suitable for the treatment of early Alzheimer's disease.
  • the present invention significantly enhances the curative effect of chlorogenic acid in treating early Alzheimer's disease by combining the main active component chlorogenic acid and the auxiliary component 3-coumaroylquinic acid in a specific dosage ratio.
  • a safe and highly effective pharmaceutical composition containing chlorogenic acid, which is especially suitable for treating early Alzheimer's disease, is disclosed.
  • the present invention provides a pharmaceutical composition for treating early Alzheimer's disease, the pharmaceutical composition comprising chlorogenic acid and 3-coumaroylquinic acid, the chlorogenic acid and The weight ratio of 3-coumaroylquinic acid is 100:(0.01-0.5), wherein the chlorogenic acid is the main active ingredient for treating early Alzheimer's disease, and the 3-coumaroylquinic acid is Adjunct ingredients for enhancing the efficacy of chlorogenic acid in the treatment of early Alzheimer's disease.
  • the weight ratio of the chlorogenic acid and 3-coumaroylquinic acid is 100:0.05.
  • the pharmaceutical composition is selected from one or more of oral formulations or non-oral formulations.
  • the oral preparation is one or more of capsules, tablets, oral liquids or granules.
  • the oral preparation is an orally disintegrating tablet that is convenient for the elderly to take.
  • the non-oral formulation is one or more of injections, creams, patches, ointments, suppositories or sprays.
  • the administration of the injection is one or more of subcutaneous administration, intramuscular administration or intravenous administration.
  • the pharmaceutical composition further comprises other active ingredients selected from the following: donepezil, galantamine, rivastigmine, memantine, prednisone, rofecoxib, Nimesulide, diclonafine, rhodanine, ginkgo biloba extract, ginsenosides, huperzine A, stilbene glycosides, levodopa, carbidopa, benserazide, diphenadin, benzotrop Tropin, procyclidine, profenamine, butylphthalide, dipyridamole, low molecular weight dextran, heparin, urokininogenase, citicocholine, butylphthalide, edaravone, nimodipine or aspirin One or more.
  • active ingredients selected from the following: donepezil, galantamine, rivastigmine, memantine, prednisone, rofecoxib, Nimesulide, diclon
  • the present invention provides the use of the pharmaceutical composition described in the first aspect above in the preparation of a medicament for treating early Alzheimer's disease.
  • the drug improves the learning and memory ability of patients with early Alzheimer's disease, delays the progress of Alzheimer's disease, and improves the quality of life of patients.
  • the present invention Compared with the prior art, the present invention has the following beneficial effects: the present invention combines the main active component chlorogenic acid with the auxiliary component 3-coumaroylquinic acid in a specific dosage ratio, and the latter can effectively enhance the early treatment effect of chlorogenic acid.
  • the role of Alzheimer's disease thereby greatly reducing the dosage of chlorogenic acid, but it can achieve a better effect than using chlorogenic acid alone in the treatment of early Alzheimer's disease.
  • the present inventor unexpectedly discovered a method that can significantly improve the curative effect of chlorogenic acid in the treatment of early Alzheimer's disease through a large number of screenings, and developed a method that is especially suitable for the treatment of early Alzheimer's disease.
  • Pharmaceutical composition comprising chlorogenic acid for Alzheimer's disease. The present invention has been accomplished on this basis.
  • Alzheimer's disease or “mild Alzheimer's disease” can be diagnosed and judged as " Possible Alzheimer's disease”.
  • auxiliary ingredient generally refers to a substance that has no or almost no target pharmacological activity, but can enhance the target pharmacological activity of the main active ingredient.
  • the target pharmacological activity of the present invention is mainly the effect of treating early Alzheimer's disease.
  • 3-coumaroylquinic acid is a trace impurity that may exist in the extraction process of chlorogenic acid.
  • Niacin, 5-caffeoylquinic acid (neochlorogenic acid), 4-vinylcatechol (caffeic acid decarboxylate), 4-caffeoylquinic acid (cryptochlorogenic acid), chlorogenic acid methyl The total percentage content of compounds is not more than 1.5% (see CN105085265B).
  • the term "pharmaceutical composition” means a composition that can be administered to a mammalian host, for example, orally, topically, parenterally, by inhalation spray or rectally, in the presence of conventional nontoxic carriers, diluents, adjuvants, , vehicle, and the like in unit dosage form.
  • parenteral as used herein includes subcutaneous injection, intravenous, intramuscular injection or by infusion techniques.
  • compositions comprising compounds of the invention may be in a form suitable for oral use, for example, as tablets, troches, lozenges, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any known method and such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents and preservatives in order to provide pharmaceutically aesthetic and Palatable preparation.
  • Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binders such as starch, gelatin or gum arabic; and lubricating agents, such as magnesium stearate, stearic acid, or talc.
  • Tablets may be uncoated or they may be coated by known techniques in order to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period of time.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Osmotic therapeutic tablets may also be formed for controlled release.
  • Formulations for oral use can also be presented as hard capsules, in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft capsules, in which the active ingredient is mixed with an aqueous or oily medium, such as peanut oil. , liquid paraffin or olive oil.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • a nontoxic parenterally-acceptable diluent or solvent for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are Ringer's solution and isotonic sodium chloride solution.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the invention.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus will melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • creams, ointments, gels, solutions, lotions, impregnated dressings, aerosols, and the like, containing the compounds of the invention are contemplated.
  • These topical formulations may contain suitable conventional additives, such as preservatives, solvents to aid penetration of the drug and emollients in ointments and creams.
  • These formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Topical application shall include mouthwashes and gargles.
  • the compounds of the invention are conveniently delivered in aerosol form from pressurized packs or nebulizers using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethylene alkanes, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gases.
  • a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethylene alkanes, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gases.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of gelatin eg, for use in an inhaler or insufflator, may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • test materials used in the following examples are commercially available products unless otherwise specified.
  • Embodiment Pharmacodynamic study of the pharmaceutical composition of the present invention in the treatment of early Alzheimer's disease
  • Alzheimer's disease A large number of clinical epidemiological studies on Alzheimer's disease have found that cerebral ischemia, especially the chronic cerebral hypoperfusion common in the elderly, is closely related to the occurrence and development of Alzheimer's disease. Immediately after the death of Alzheimer's disease patients, the brain basilar artery rings were removed to detect the degree of vascular stenosis. Neuropathological changes are highly correlated. Studies on cerebral blood flow and brain metabolism in the early stage of Alzheimer's disease suggest that the occurrence of cerebral blood flow reduction and cerebral hypometabolism caused by cerebral ischemia is earlier than the neuropathological changes and dementia manifestations of Alzheimer's disease. In the case of hypoperfusion, A ⁇ is deposited in the brain, suggesting that chronic cerebral hypoperfusion is an important risk factor for the onset of Alzheimer's disease. Systematic research on the impact of chronic cerebral hypoperfusion on the pathogenesis of Alzheimer's disease has become an important target for the prevention and treatment of Alzheimer's disease.
  • rats were subjected to bilateral common carotid artery ligation to simulate the occurrence of mild Alzheimer's disease in humans after chronic cerebral hypoperfusion, and to observe the intervention of the pharmaceutical composition of the present invention on the learning and memory functions of these rats, thereby Investigate the curative effect of the pharmaceutical composition of the present invention in treating early Alzheimer's disease.
  • Chlorogenic acid and 3-coumaroylquinic acid (extracted and purified from leaves of Eucommia ulmoides with a purity of over 99.5%) are made by Sichuan Jiuzhang Biotechnology Co., Ltd. Mannate Sodium Capsules (150 mg, Zhunzi H20190031) were purchased from Shanghai Lvgu Pharmaceutical Co., Ltd.
  • the chronic cerebral hypoperfusion model was established by bilateral common carotid artery ligation. Rats were acclimated to the environment for 1 week before operation, fasted for 12 hours and water for 4 hours before operation. Anesthetized with 0.4% sodium pentobarbital (0.5mL/100g i.p.), fixed on the operating table in the supine position, the skin in front of the neck was depilated, disinfected with povidone iodine, the anterior median incision was made, and the superficial subcutaneous fascia was bluntly dissected.
  • each group of therapeutic drugs was given intraperitoneal injection to the rats in each group, and the blank group and the model group were given the solvent saline solution by intraperitoneal injection.
  • Each dosing group started to dosing one week after modeling, and the experiment started after 20 days of continuous dosing, and the dosing continued during the experiment.
  • the blank group and the model group were given the same amount of normal saline solution at the same time.
  • the composition and dosage of each group of therapeutic drugs are as follows:
  • Chlorogenic acid treatment group chlorogenic acid 60 mg/kg/d, with normal saline as solvent, administered by intraperitoneal injection.
  • 3-coumaroylquinic acid treatment group 3-coumaroylquinic acid 0.03mg/kg/d, with normal saline as solvent, intraperitoneal injection.
  • Chlorogenic acid + 3-coumaroylquinic acid (100:0.01) treatment group chlorogenic acid 60mg/kg/d+3-coumaroylquinic acid 0.006mg/kg/d, with normal saline As a solvent, administered by intraperitoneal injection.
  • Chlorogenic acid + 3-coumaroylquinic acid (100:0.05) treatment group chlorogenic acid 60mg/kg/d+3-coumaroylquinic acid 0.03mg/kg/d, with normal saline As a solvent, administered by intraperitoneal injection.
  • Chlorogenic acid + 3-coumaroylquinic acid (100:0.5) treatment group chlorogenic acid 60mg/kg/d+3-coumaroylquinic acid 0.3mg/kg/d, with normal saline As a solvent, administered by intraperitoneal injection.
  • Chlorogenic acid + 3-coumaroylquinic acid (100:1) treatment group chlorogenic acid 60mg/kg/d+3-coumaroylquinic acid 0.6mg/kg/d, with normal saline As a solvent, administered by intraperitoneal injection.
  • Mannlute sodium treatment group 100 mg/kg/d of Mannlute Na, with normal saline as a solvent, administered by intragastric administration.
  • the Morris water maze behavior test was performed.
  • the water maze consists of a circular pool, an automatic camera and a computer analysis system.
  • a camera above the pool synchronously records the movement trajectories of the rats.
  • water was injected into the pool, the water depth was 30cm, and the water surface was 1cm higher than the surface of the platform. Milk powder was put in to make it milky white, so that the rats could not see the platform, and the water temperature was controlled between 22-25°C.
  • the head of each rat was dyed black, and each animal was trained twice on the first day to make it learn and generate memory. Place the animal's head into the water towards the pool wall, and if the platform is not found within 120s, lead it to the platform and place it for 30s to guide its learning and memory.
  • the environment remains quiet and the reference object remains unchanged.
  • the underwater platform was removed, and the rats were put into the water with their heads facing the pool wall at the same water entry point, and the rats were allowed to find the platform in memory without the platform, and the activity time of the rats in the quadrant of the original platform was recorded.
  • the data was statistically analyzed using SPSS 18.0 statistical software, and the measurement data were expressed as mean ⁇ standard deviation.
  • the comparison between groups was performed by one-way analysis of variance, and the data obtained from the water maze positioning and navigation experiment was analyzed by two-factor repeated measures analysis of variance, two-two multiple LSD test was used for comparison, and p ⁇ 0.05 was considered statistically significant.
  • the effect is better than that of manlute sodium.
  • the weight ratio of chlorogenic acid to 3-coumaroylquinic acid in the composition is 100:0.01 or 100:0.5, although the synergistic effect of 3-coumaroylquinic acid on chlorogenic acid It is not as good as when the weight ratio of the two is 100:0.05, but during the experiment, as time goes by, the escape latency and search distance of the rats are also significantly shorter than those of the model group (p ⁇ 0.05).
  • Table 1 The influence (s) of pharmaceutical composition of the present invention on Morris water maze test average escape latency
  • Table 2 The influence (cm) of pharmaceutical composition of the present invention on Morris water maze experiment search distance
  • Table 3 The influence of the pharmaceutical composition of the present invention on the space exploration ability of Morris water maze experiment
  • chlorogenic acid is used as the main active ingredient
  • 3-coumaroylquinic acid is used as an auxiliary ingredient, and the latter can effectively enhance the efficacy of chlorogenic acid in treating early Alzheimer's disease. Efficacy. Therefore, the research and development of the pharmaceutical composition of the present invention is of great significance for intervening in the early stages of Alzheimer's disease, delaying the progress of Alzheimer's disease, and improving the quality of life of patients.

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Abstract

本发明提供了一种包含绿原酸的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途，属于生物医药领域。在本发明的药物组合物中采用绿原酸作为主要活性成分，并且采用3-香豆酰奎尼酸作为辅助成分，后者能够有效增强绿原酸治疗早期阿尔茨海默病的疗效。本发明药物组合物的研究和开发，对于从阿尔茨海默病的早期进行干预，延缓阿尔茨海默病的进展，提高患者的生活质量具有非常重要的意义。

Description

一种包含绿原酸的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途 技术领域
本发明属于生物医药领域，具体涉及包含绿原酸的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途。
背景技术
阿尔茨海默病是一种与年龄相关的进行性发展的神经系统退行性疾病，以失认、失语、失用、视空间能力损害、记忆和认知功能障碍等表现为主要临床特征。患者脑的大体病理表现为重量减轻和体积缩小，脑沟变宽，加深，脑回萎缩，颞叶特别是海马区萎缩。其主要组织病理学特征为嗜银神经轴索突起包绕β淀粉样蛋白形成的老年斑、神经元内微管tau蛋白高度磷酸化形成的神经纤维缠结、大脑内胶质增生和神经元缺失。流行病学调查结果显示，预计到2050年世界范围内受影响的人口总数将增加到1亿。
目前，形成了许多关于阿尔茨海默病病理特征的推测，如氧化应激学说、淀粉样蛋白假说、炎症机制、与胰岛素相关的糖代谢异常假说、自由基假说等。阿尔茨海默病患者脑内出现的大量高密度的Aβ及其神经毒性作用是导致AD的重要原因之一，已经成为不争的事实。而神经元tau蛋白的病理变化与Aβ沉积共存，并可产生多种炎症反应。同时，许多证据显示，氧化应激、慢性神经炎症损伤、神经元凋亡和自噬与Aβ沉积和tau蛋白异常磷酸化及其产生的神经毒性形成了复杂的网络。
目前已经上市治疗阿尔茨海默病的药物主要以辅助改善疾病症状为主，但不能从根本上阻止病情恶化。临床上对于阿尔茨海默病的治疗，多采用胆碱酯酶抑制药物加兰他敏、抗氧化药物单胺氧化酶抑制剂、脑代谢赋活剂奥拉西坦等，但效果并不令人满意。实质上，过去几十年以来，这一领域新药研发几乎 全军覆没。辉瑞、阿斯利康等制药巨头的多个药物均在3期临床阶段惨遭失败。天然植物中蕴含着丰富的具有独特作用机理和新颖结构的药物前体及化合物，众多研究发现，天然药物中的某些成分具有促进Aβ消除、减少Aβ生成、抗凋亡、抗氧化、促进神经修复等作用。因此，在阿尔茨还海默病药物的研发过程中，天然产物因其生物活性及结构的多样性受到国内外研究学者的广泛关注。2019年，我国药监部门有条件批准甘露特钠上市用于治疗轻度至中度阿尔茨海默症，甘露特钠的成功为我国学者从天然产物中寻找预防或治疗神经退行性疾病药物的研发思路带来了鼓舞。
绿原酸(chlorogenic acid,CGA)又名咖啡鞣酸，是由咖啡酸(caffeic acid,CA)和奎尼酸(quinic acid,QA)组成的缩酚酸，其化学名为3-o-咖啡酰奎尼酸(3-o-caffeoylquinic acid,CGA)。绿原酸是植物在进行有氧呼吸的过程中，经磷酸戊糖途径中间产物合成的一种苯丙素类物质。绿原酸已经被开发应用于食品，保健品，化妆品和药品等多个领域。其广泛的存在于常见的各种蔬菜水果中，具有多种生物活性，如心血管保护作用、抗氧化作用、抗紫外及抗辐射作用、抗诱变及抗癌作用、抗菌作用、抗病毒作用、降脂降糖作用、免疫调节作用等。在医药化工和食品等领域都具有广泛的应用。
此前，已有研究表明，绿原酸通过改善记忆和认知功能障碍、抑制β淀粉样蛋白诱导的神经毒性、缓解线粒体损伤和凋亡作用等途径发挥抗原、抗氧化等活性，保护神经细胞，减轻认知功能下降和神经病变的风险，缓解阿尔茨海默病的临床特征(参见，例如，姚银乐等，“绿原酸改善阿尔茨海默病研究进展”，医药导报，第36卷第11期，2017年11月，第1287-1290页)。但是，临床上对于绿原酸的具体作用研究较少，此前也没有绿原酸究竟是针对轻度、中度和重度哪一阶段的阿尔茨海默病更加有效的研究。
本发明人“四川九章生物科技有限公司”团队从2000年开始对绿原酸进行系统研发，2013年8月获得了绿原酸原料药和注射剂的临床批件(批件号：2013L01855、2013L01856)。2016年12月“首创1类新药注射用绿原酸的I/II 期临床研究”被国家卫计委及科技部列入十三五国家科技重大专项重大新药创制课题，也是四川省重大科技支撑项目。
本发明人长期以来也一直致力于使用绿原酸治疗阿尔茨海默病方面的研究。本发明人在对绿原酸药理作用的深入研究中，通过大量筛选，意外地发现了能够显著提高绿原酸治疗早期阿尔茨海默病疗效的方法，研制出了一种特别适于治疗早期阿尔茨海默病的安全、高效的包含绿原酸的药物组合物。
发明内容
为了解决上述技术问题，本发明通过以特定用量比例将主要活性成分绿原酸与辅助成分3-香豆酰奎尼酸组合，显著增强了绿原酸治疗早期阿尔茨海默病的疗效，研制出了一种特别适于治疗早期阿尔茨海默病的安全、高效的包含绿原酸的药物组合物。
具体地，通过以下几个方面的技术方案实现了本发明：
在第一个方面中，本发明提供了一种治疗早期阿尔茨海默病的药物组合物，所述药物组合物包含绿原酸和3-香豆酰奎尼酸，所述绿原酸和3-香豆酰奎尼酸的重量比为100：(0.01-0.5)，其中所述绿原酸是治疗早期阿尔茨海默病的主要活性成分，所述3-香豆酰奎尼酸是用于增强绿原酸治疗早期阿尔茨海默病的疗效的辅助成分。
作为可选方式，在上述药物组合物中，所述绿原酸和3-香豆酰奎尼酸的重量比为100：0.05。
作为可选方式，在上述药物组合物中，所述药物组合物选自口服制剂或非口服制剂中的一种或者多种。
作为可选方式，在上述药物组合物中，所述口服制剂是胶囊剂、片剂、口服液或颗粒剂中的一种或者多种。
优选地，所述口服制剂是便于老年人服用的口腔崩解片。
作为可选方式，在上述药物组合物中，所述非口服制剂是注射剂、霜剂、 贴剂、软膏剂、栓剂或喷雾剂中的一种或者多种。
作为可选方式，在上述药物组合物中，所述注射剂的给药方式是皮下给药、肌内给药或静脉内给药中的一种或多种。
作为可选方式，在上述药物组合物中，所述药物组合物还包含选自以下的其他活性成分：多奈哌齐、加兰他敏、卡巴拉汀、美金刚、强的松、罗非考西、尼美舒利、双氯奈芬、罗丹宁、银杏叶提取物、人参皂苷、石杉碱甲、二苯乙烯苷、左旋多巴、卡比多巴、苄丝肼、苯海萦、苯托托品、丙环定、普罗吩胺、丁苯酞、潘生丁、低分子右旋糖酐、肝素、尿激肽原酶、胞二磷胆、丁苯酞、依达拉奉、尼莫地平或阿司匹林中的一种或者多种。
在第二个方面中，本发明提供了上述第一个方面所述的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途。
作为可选方式，在上述用途中，所述药物改善早期阿尔茨海默病患者的学习记忆能力，延缓阿尔茨海默病的进展，提高患者的生活质量。
本发明相对于现有技术，具有以下有益效果：本发明以特定用量比例将主要活性成分绿原酸与辅助成分3-香豆酰奎尼酸组合，后者能够有效增强绿原酸的治疗早期阿尔茨海默病的作用，从而极大地降低绿原酸用量，但是却能够达到比单独使用绿原酸更好的治疗早期阿尔茨海默病的效果。
具体实施方式
本发明人在对绿原酸药理作用的深入研究中，通过大量筛选，意外地发现了能够显著提高绿原酸治疗早期阿尔茨海默病疗效的方法，研制出了一种特别适于治疗早期阿尔茨海默病的包含绿原酸的药物组合物。在此基础上完成了本发明。
为了更好的理解本发明，下面对本发明中涉及的一些术语进行进一步的解释说明。
“早期阿尔茨海默病”或“轻度阿尔茨海默病”可以通过诊断，根据国家 卫健委发布的“阿尔茨海默病的诊疗规范(2020年版)”中的评价标准判定为“可能的阿尔茨海默病”。
如本文所用，“辅助成分”通常指不具有或几乎不具有目标药理活性，但是能够增强主要活性成分目标药理活性的物质。本发明的目标药理活性主要是治疗早期阿尔茨海默病的作用。
如本文所用，“3-香豆酰奎尼酸”是绿原酸提取过程中可能存在的一种微量杂质，采用我公司此前开发的提取方法提取的绿原酸原料中3-香豆酰奎尼酸、5-咖啡酰奎尼酸(新绿原酸)、4-乙烯基邻苯二酚(咖啡酸脱羧物)、4-咖啡酰奎尼酸(隐绿原酸)、绿原酸甲基化物的总百分含量不超过1.5％(参见CN105085265B)。我公司此前已创造性地尝试将“绿原酸”与“香豆酰奎尼酸”联合使用发挥协同抗肿瘤作用，具体涉及用于制备治疗肿瘤多药耐药药物(CN108159028B)、制备治疗肉瘤的药物(CN108653263B)、制备治疗鳞状细胞癌的药物(CN108685892B)和制备治疗肾癌的药物(CN108498497B)，均获得了成功。但是，目前尚无将绿原酸与3-香豆酰奎尼酸联用治疗早期阿尔茨海默病的报道。
本文所用的术语“药物组合物”表示可以施用于哺乳动物宿主的组合物，例如通过口服、局部、胃肠外、通过吸入喷雾剂或通过直肠，以包含常用无毒性载体、稀释剂、佐剂、媒介物等的单位剂型的形式。本文所用的术语"胃肠外"包括皮下注射、静脉内、肌内注射或通过输注技术。
包含本发明化合物的药物组合物可以是适合于口服应用的形式，例如，为片剂、药片、锭剂、可分散粉末或颗粒、乳剂、硬胶囊或软胶囊或糖浆剂或酏剂。
欲用于口服应用的组合物可以根据任意公知方法制备且这样的组合物可以包含选自甜味剂、矫味剂、着色剂和防腐剂的一种或多种试剂，以便提供药学上美观和适口的制剂。片剂可以包含活性成分与适合于制备片剂的无毒性药学上可接受的赋形剂的混合物。这些赋形剂可以是，例如惰性稀释剂，例如碳 酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；成粒剂和崩解剂，例如玉米淀粉或藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是不包衣的或可以通过公知技术将它们包衣，以延缓在胃肠道中崩解和吸收，且由此在较长期限内提供持续作用。例如，可以使用延时材料，例如单硬脂酸甘油酯或二硬脂酸甘油酯。还可以形成用于控释的渗透治疗片剂。
还可以将用于口服应用的制剂制成硬胶囊，其中将活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合；或制成软胶囊，其中将活性成分与水或油介质例如花生油、液体石蜡或橄榄油混合。可以用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制糖浆剂和酏剂。这样的制剂还可以包含缓和剂、防腐剂和矫味剂和着色剂。
无菌可注射制剂还可以是在无毒性胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或混悬液，例如，为在1,3-丁二醇中的溶液。在可接受的媒介物和溶剂中，可以使用的有林格氏液和等渗氯化钠溶液。
组合物还可以是用于本发明化合物直肠施用的栓剂形式。可以通过混合药物于适合的无刺激性赋形剂制备这些组合物，其在常温下为固体，而在直肠温度下为液体，且由此可以在直肠中熔化以释放药物。例如，这样的材料包括可可脂和聚乙二醇。
对于局部应用而言，关注包含本发明化合物的霜剂、软膏剂、凝胶剂、溶液、洗剂、浸渍的敷料和气雾剂等。这些局部用制剂可以包含适合的常用添加剂，例如防腐剂、辅助药物渗透的溶剂和在软膏剂和霜剂中的软化剂。这些制剂还可以包含相容性常用载体，例如霜剂或软膏剂基质和用于洗剂的乙醇或油醇。局部施用应包括口腔洗剂和含漱液。
为了通过吸入施用，便利地以气雾剂形式从加压药包或喷雾器中递送本发明的化合物，其中使用适合的抛射剂，例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、四氟乙烷、七氟丙烷、二氧化碳或其它适合的气体。
在加压气雾剂的情况中，可以通过安装阀门以递送计量的用量确定剂量单位。可以配制包含本发明化合物和适合的粉末基质例如乳糖或淀粉的粉末混合物的例如用于吸入器或吹入器的明胶胶囊和药筒。
上述各种剂型可以根据药物制剂领域的常规工艺制备而成。
下面参照具体的实施例对本发明做进一步说明。应当理解，此处所描述的具体实施例仅用于解释本发明，并不用于限定本发明的范围。
实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。所用试剂或仪器未注明生产厂商者，均为可通过正规渠道购买得到的常规产品。
下面实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的试验材料，如无特殊说明，均为市售产品。
除非另外说明，否则本发明中涉及的百分比和份数均为重量百分比和重量份数。
实施例：本发明药物组合物治疗早期阿尔茨海默病的药效学研究
临床上对阿尔茨海默病所作的大量临床流行病学研究发现，脑缺血，尤其是老年人普遍存在的慢性脑低灌注与阿尔茨海默病的发生发展有着极为密切的关联性。在阿尔茨海默病患者死亡后即刻取出脑基底动脉环，检测血管管腔狭窄程度，结果显示动脉粥样硬化改变明显重于年龄匹配对照组，且血管狭窄指数与阿尔茨海默病特征性的神经病理改变高度相关。在阿尔茨海默病前期的脑血流和脑代谢研究提示，脑缺血导致的脑血流降低和脑低代谢的发生早于阿尔茨海默病的神经病理改变和痴呆表现，在慢性脑低灌注的情况下，脑内Aβ发生沉积，这表明慢性脑低灌注是启动阿尔茨海默病发病的重要危险因素。系统研究慢性脑低灌注对阿尔茨海默病发病的影响，成为了预防和治疗阿尔茨海默病的重要靶点。
1.实验目的
本研究通过对大鼠实施双侧颈总动脉结扎术，模拟人类慢性脑低灌注后轻 度阿尔茨海默病的发生，观察本发明药物组合物对这些大鼠学习记忆功能的干预情况，从而考察本发明药物组合物治疗早期阿尔茨海默病的疗效。
2.实验材料
2.1.实验动物：健康的6-8周龄SPF级雄性Sprague-Dawley(SD)大鼠，体重280-300g。
2.2.受试药物：
绿原酸和3-香豆酰奎尼酸(系由杜仲叶中提取、纯化得到，纯度为99.5％以上)四川九章生物科技有限公司自制。甘露特钠胶囊(150mg，国药准字H20190031)购自上海绿谷制药有限公司。
3.实验方法
3.1.慢性脑低灌注模型的制备
采用双侧颈总动脉结扎术制备慢性脑低灌注模型。大鼠术前适应环境1周，术前12h禁食，4h禁水。0.4％的戊巴比妥钠(0.5mL/100g i.p.)麻醉，仰卧位固定于手术台上，颈前皮肤去毛，碘伏消毒，颈前正中切开，钝性分离皮下浅筋膜，沿气管双侧仔细分离胸锁乳突肌和胸骨舌骨肌，见动脉鞘；用玻璃分针分离暴露双侧颈总动脉并埋线，用丝线分别双重结扎两侧颈总动脉，并于两结扎点之间剪断血管，逐层缝合切口，消毒待醒。术中白炽灯照射保持大鼠肛温在36.5℃-37.5℃。术后单笼放置，防止窒息。
3.2.实验动物分组和给药
随机选取体重在要求范围内的健康SD大鼠10只，作为正常对照组。选择建模成功的80只大鼠随机平均分为8组，每组10只大鼠，分别命名为：模型对照组(n＝10)、绿原酸治疗组(n＝10)、3-香豆酰奎尼酸治疗组(n＝10)、绿原酸+3-香豆酰奎尼酸(100：0.01)治疗组(n＝10)、绿原酸+3-香豆酰奎尼酸(100：0.05)治疗组(n＝10)、绿原酸+3-香豆酰奎尼酸(100：0.5)治疗组(n＝10)、绿原酸+3-香豆酰奎尼酸(100：1)治疗组(n＝10)、甘露特纳治疗组(n＝10)，连同正常对照组(n＝10)，共9个实验组，共90只。
本实验除了甘露特纳治疗组为灌胃给药外，其余各治疗组均采用腹腔注射给药的方式对各组大鼠进行给药，空白组和模型组腹腔注射给予溶剂生理盐水溶液。各给药组分别于造模术后1周开始给药，连续给药20天后开始进行实验，实验过程中继续给药。空白组和模型组同时给予等量的生理盐水溶液。各组治疗药物的组成和用量如下所示：
(1)绿原酸治疗组：绿原酸60mg/kg/d，以生理盐水作为溶剂，腹腔注射给药。
(2)3-香豆酰奎尼酸治疗组：3-香豆酰奎尼酸0.03mg/kg/d，以生理盐水作为溶剂，腹腔注射给药。
(3)绿原酸+3-香豆酰奎尼酸(100：0.01)治疗组：绿原酸60mg/kg/d+3-香豆酰奎尼酸0.006mg/kg/d，以生理盐水作为溶剂，腹腔注射给药。
(4)绿原酸+3-香豆酰奎尼酸(100：0.05)治疗组：绿原酸60mg/kg/d+3-香豆酰奎尼酸0.03mg/kg/d，以生理盐水作为溶剂，腹腔注射给药。
(5)绿原酸+3-香豆酰奎尼酸(100：0.5)治疗组：绿原酸60mg/kg/d+3-香豆酰奎尼酸0.3mg/kg/d，以生理盐水作为溶剂，腹腔注射给药。
(6)绿原酸+3-香豆酰奎尼酸(100：1)治疗组：绿原酸60mg/kg/d+3-香豆酰奎尼酸0.6mg/kg/d，以生理盐水作为溶剂，腹腔注射给药。
(7)甘露特钠治疗组：甘露特纳100mg/kg/d，以生理盐水作为溶剂，灌胃给药。
3.3.观察指标
给药结束后进行Morris水迷宫行为测试。水迷宫由圆形水池和自动摄像及电脑分析系统组成。水池上方的摄像机同步记录大鼠的运动轨迹。测试前将水注入池中，水深30cm，水面高出站台表面1cm，放入奶粉使之成为乳白色，使大鼠不能见到站台，水温控制在22-25℃之间。实验前1天，将每只大鼠头部染黑，每只动物第1天训练2次使之学习并产生记忆，入池位置为站台的对象限及邻象限，于象限边1/2弧度处将动物头朝池壁入水，120s未找到站台者， 将其引至站台，放置30s引导其学习与记忆，训练期环境保持安静与参照物不变。
(1)定位航行实验
实验共进行5天。数据采集及图像分析均由图像自动监视和处理系统完成。实验结束后记录各动物的到达站台的游动时间及距离、初始角度、搜索站台的轨迹及逃避潜伏期，设定逃避潜伏期的时限为120s。
(2)空间探索实验
定位航行实验结束后将水下平台撤除，在同一入水点将大鼠头朝池壁放入水中，让大鼠在无平台情况下寻找记忆中的平台，记录大鼠在原平台象限的活动时间。
3.4.统计学方法
数据采用SPSS 18.0统计软件进行相关统计学分析，计量资料以均数±标准差表示，组间比较采用单因素方差分析，其中水迷宫定位航行实验所得数据采用双因素重复测量方差分析，两两多重比较采用LSD检验，p＜0.05为差异有统计学意义。
4.实验结果
4.1.本发明药物组合物对大鼠Morris水迷宫定位航行实验的影响
如下表1和表2所示，双因素重复测量方差分析和两两多重比较的统计学分析结果表明，模型组大鼠与空白对照组大鼠相比，逃避潜伏期显著延长(p<0.01)，搜索距离显著增加(p<0.01)，表明慢性脑低灌注模型能够模拟早期阿尔茨海默病时的学习记忆功能减退。
对各给药组的实验结果进行分析后发现，绿原酸单用组和3-香豆酰奎尼酸单用组与模型组相比，大鼠的逃避潜伏期和搜索距离几乎没有任何改善，提示绿原酸单用和3-香豆酰奎尼酸单用对实验大鼠的学习记忆功能基本上没有改善作用。但是，绿原酸单用的作用效果略微好于3-香豆酰奎尼酸单用的效果。
对于不同重量比例的绿原酸与3-香豆酰奎尼酸联用组的实验结果进行分 析后发现，与预期结果不同，并非3-香豆酰奎尼酸的用量越大，其对于绿原酸的增效作用越强。当在组合物中绿原酸与3-香豆酰奎尼酸的重量比为100：0.05时，3-香豆酰奎尼酸对绿原酸的协同增效作用最强，在实验期间，随着时间的推移，大鼠的逃避潜伏期和搜索距离均较模型组明显缩短(p<0.01)，其作用效果与阳性对照药物甘露特钠(p<0.01)相当，甚至在某些时间点的作用效果优于甘露特钠。此外，当在组合物中绿原酸与3-香豆酰奎尼酸的重量比为100：0.01或100：0.5时，尽管3-香豆酰奎尼酸对绿原酸的协同增效作用不及两者重量比100：0.05时，但是在实验期间，随着时间的推移，大鼠的逃避潜伏期和搜索距离也均较模型组显著缩短(p<0.05)。但是，令人吃惊的是，当进一步增加组合物中3-香豆酰奎尼酸的用量，使得绿原酸与3-香豆酰奎尼酸的重量比为100：1时，3-香豆酰奎尼酸反而未表现出对绿原酸明显的增效作用。
表1：本发明药物组合物对Morris水迷宫实验平均逃避潜伏期的影响(s)
Figure PCTCN2022104223-appb-000001
注释： #，p<0.05， ##，p<0.01，模型组与空白组比较；*，p<0.05，**，p<0.01，给药组与模型组比较。
表2：本发明药物组合物对Morris水迷宫实验搜索距离的影响(cm)
Figure PCTCN2022104223-appb-000002
Figure PCTCN2022104223-appb-000003
注释： #，p<0.05， ##，p<0.01，模型组与空白组比较；*，p<0.05，**，p<0.01，给药组与模型组比较。
4.2.本发明药物组合物对大鼠Morris水迷宫空间探索实验的影响
如下表3所示，双因素重复测量方差分析和两两多重比较的统计学分析结果表明，模型组大鼠与空白对照组大鼠相比，模型组大鼠在原平台所在象限搜索时间显著缩短(p<0.01)，表明慢性脑低灌注模型能够模拟早期阿尔茨海默病时的学习记忆功能减退。
对各给药组的实验结果进行分析后发现，绿原酸单用组和3-香豆酰奎尼酸单用组与模型组相比，大鼠在原平台所在象限搜索时间几乎没有任何延长，提示绿原酸单用和3-香豆酰奎尼酸单用对实验大鼠的学习记忆功能基本上没有改善作用。但是，绿原酸单用的作用效果略微好于3-香豆酰奎尼酸单用的效果。
对于不同重量比例的绿原酸与3-香豆酰奎尼酸联用组的实验结果进行分析后发现，与预期结果不同，并非3-香豆酰奎尼酸的用量越大，其对于绿原酸的增效作用越强。当在组合物中绿原酸与3-香豆酰奎尼酸的重量比为100：0.05时，3-香豆酰奎尼酸对绿原酸的协同增效作用最强，在实验期间，大鼠在原平台所在象限搜索时间较模型组明显延长(p<0.01)，其作用效果与阳性对照药物甘露特钠(p<0.01)相当。此外，当在组合物中绿原酸与3-香豆酰奎尼酸的重量比为100：0.01或100：0.5时，尽管3-香豆酰奎尼酸对绿原酸的协同增效作用不及两者重量比100：0.05时，但是在实验期间，大鼠在原平台所在象 限所搜时间较模型组也显著延长(p<0.05)。但是，令人吃惊的是，当进一步增加组合物中3-香豆酰奎尼酸的用量，使得绿原酸与3-香豆酰奎尼酸的重量比为100：1时，3-香豆酰奎尼酸反而未表现出对绿原酸明显的增效作用。
表3：本发明药物组合物对Morris水迷宫实验空间探索能力的影响
组别 原平台象限活动时间(s)
空白组 60.2±10.1
模型组 29.4±8.9 ##
绿原酸组 32.6±8.5
3-香豆酰奎尼酸组 30.2±7.8
绿原酸+3-香豆酰奎尼酸组(100：0.01) 40.7±8.6*
绿原酸+3-香豆酰奎尼酸组(100：0.05) 46.3±9.5**
绿原酸+3-香豆酰奎尼酸组(100：0.5) 41.5±9.1*
绿原酸+3-香豆酰奎尼酸组(100：1) 34.3±9.2
甘露特钠组 48.5±9.4**
注释： #，p<0.05， ##，p<0.01，模型组与空白组比较；*，p<0.05，**，p<0.01，给药组与模型组比较。
5.实验结论
上述实验结果表明，包含特定重量比例的绿原酸和3-香豆酰奎尼酸的本发明药物组合物能够显著提高慢性脑低灌注模型大鼠的空间学习记忆能力。
由此可见，在本发明的药物组合物中采用绿原酸作为主要活性成分，并且采用3-香豆酰奎尼酸作为辅助成分，后者能够有效增强绿原酸治疗早期阿尔茨海默病的疗效。因而，对本发明药物组合物的研究和开发，对于从阿尔茨海默病的早期进行干预，延缓阿尔茨海默病的进展，提高患者的生活质量具有非常重要的意义。
显然，本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。

Claims (9)

  1. 一种治疗早期阿尔茨海默病的药物组合物，其特征在于：所述药物组合物包含绿原酸和3-香豆酰奎尼酸，所述绿原酸和3-香豆酰奎尼酸的重量比为100：(0.01-0.5)，其中所述绿原酸是治疗早期阿尔茨海默病的主要活性成分，所述3-香豆酰奎尼酸是用于增强绿原酸治疗早期阿尔茨海默病的疗效的辅助成分。
  2. 根据权利要求1所述的药物组合物，其特征在于：所述绿原酸和3-香豆酰奎尼酸的重量比为100：0.05。
  3. 根据权利要求1或权利要求2所述的药物组合物，其特征在于：所述药物组合物选自口服制剂或非口服制剂中的一种或者多种。
  4. 根据权利要求3所述的药物组合物，其特征在于：所述口服制剂是胶囊剂、片剂、口服液或颗粒剂中的一种或者多种，优选地，所述口服制剂是口腔崩解片。
  5. 根据权利要求3所述的药物组合物，其特征在于：所述非口服制剂是注射剂、霜剂、贴剂、软膏剂、栓剂或喷雾剂中的一种或者多种。
  6. 根据权利要求5所述的药物组合物，其特征在于：所述注射剂的给药方式是皮下给药、肌内给药或静脉内给药中的一种或多种。
  7. 根据权利要求1-6中任一项所述的药物组合物，其特征在于：所述药物组合物还包含选自以下的其他活性成分：多奈哌齐、加兰他敏、卡巴拉汀、美金刚、强的松、罗非考西、尼美舒利、双氯奈芬、罗丹宁、银杏叶提取物、人参皂苷、石杉碱甲、二苯乙烯苷、左旋多巴、卡比多巴、苄丝肼、苯海萦、苯托托品、丙环定、普罗吩胺、丁苯酞、潘生丁、低分子右旋糖酐、肝素、尿激肽原酶、胞二磷胆、丁苯酞、依达拉奉、尼莫地平或阿司匹林中的一种或者多种。
  8. 权利要求1-7中任一项所述的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途。
  9. 根据权利要求8所述的用途，其特征在于：所述药物改善早期阿尔茨海默病患者的学习记忆能力，延缓阿尔茨海默病的进展，提高患者的生活质量。
PCT/CN2022/104223 2021-07-07 2022-07-06 一种包含绿原酸的药物组合物在制备治疗早期阿尔茨海默病的药物中的用途 WO2023280238A1 (zh)

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