CN110452156B - Co-crystal of donepezil and irbesartan and preparation method and composition and use thereof - Google Patents
Co-crystal of donepezil and irbesartan and preparation method and composition and use thereof Download PDFInfo
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- CN110452156B CN110452156B CN201810423988.0A CN201810423988A CN110452156B CN 110452156 B CN110452156 B CN 110452156B CN 201810423988 A CN201810423988 A CN 201810423988A CN 110452156 B CN110452156 B CN 110452156B
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- irbesartan
- donepezil
- crystal
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- 239000002947 C09CA04 - Irbesartan Substances 0.000 title claims abstract description 190
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 title claims abstract description 190
- 229960002198 irbesartan Drugs 0.000 title claims abstract description 190
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Abstract
本发明公开了多奈哌齐(英文名：donepezil)与厄贝沙坦(英文名：irbesartan)以非共价键相结合形成的共晶物质(如式I)及其制法和其组合物与用途。具体而言，本发明公开了多奈哌齐与厄贝沙坦形成的共晶物质固体状态形式；多奈哌齐与厄贝沙坦形成的共晶物质状态形式的制备方法；多奈哌齐与厄贝沙坦形成的共晶物质状态形式固体物质作为药物活性成分在制备各种预防和/或治疗心力衰竭、心肌缺血、高血压、血管性病变、心绞痛、高血脂症、动脉粥样硬化或糖尿病并发症等心血管疾病及其神经退行性疾病如阿尔茨海默病以及上述多种疾病并发的疾病药物中的应用。
Description
技术领域technical field
本发明涉及发现了多奈哌齐与厄贝沙坦在固体状态下存在的一种共晶固体物质状态形式；涉及发明了多奈哌齐与厄贝沙坦共晶物的制备方法；涉及发明了含有多奈哌齐与厄贝沙坦共晶物或含任意非零比例多奈哌齐与厄贝沙坦共晶物的混晶的药物组合物；本发明还涉及多奈哌齐与厄贝沙坦共晶物作为药物有效成分，在制备各种防治心力衰竭、心肌缺血、高血压、血管性病变、心绞痛、高血脂症、动脉粥样硬化或糖尿病肾病等心血管疾病及其神经退行性疾病如阿尔茨海默病以及上述多种疾病并发的疾病药物中的应用。The invention relates to the discovery of a co-crystal solid state form in which donepezil and irbesartan exist in a solid state; the invention of a preparation method for a co-crystal of donepezil and irbesartan; the invention of a co-crystal containing donepezil and irbesartan; Sartan co-crystal or a pharmaceutical composition containing any non-zero ratio of donepezil and irbesartan co-crystal mixed crystal; the present invention also relates to donepezil and irbesartan co-crystal as active ingredients of medicine, in the preparation of various Prevention and treatment of heart failure, myocardial ischemia, hypertension, vascular disease, angina pectoris, hyperlipidemia, atherosclerosis or diabetic nephropathy and other cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease and the complications of the above-mentioned diseases The application of disease medicine.
背景技术Background technique
药物共晶是指活性药物分子与共晶配体以一定比例，通过分子间非共价相互作用力形成的晶体。药物通过形成共晶，一方面可以改善其理化性质和提高临床治疗作用，另一方面共晶可以丰富其结晶形式。对于化学药物而言，通过共晶物的研究可以打破原研药企业的专利保护，提高药品的创新性和市场竞争力。Drug co-crystals refer to crystals formed by active drug molecules and co-crystal ligands in a certain ratio through intermolecular non-covalent interactions. By forming co-crystals, on the one hand, drugs can improve their physicochemical properties and improve clinical therapeutic effects, and on the other hand, co-crystals can enrich their crystalline forms. For chemical drugs, the study of co-crystals can break the patent protection of original drug companies and improve the innovation and market competitiveness of drugs.
多奈哌齐属于乙酰胆碱酯酶抑制剂，结构式如a所示，其盐酸盐是当前临床上常用的一种抗老年痴呆药物。阿尔茨海默病是一种以记忆减退为主要表现，伴有其他认知功能损害的获得性智能减退。Donepezil is an acetylcholinesterase inhibitor, the structural formula is shown in a, and its hydrochloride is an anti-senile dementia drug commonly used in clinical practice. Alzheimer's disease is an acquired intellectual impairment characterized by memory loss as the main manifestation, accompanied by other cognitive impairments.
厄贝沙坦属于血管紧张素II受体拮抗剂，通过对血管紧张素II的AT1受体产生非竞争性的抑制，从而实现减轻血管紧张素II的缩血管和促增生作用，结构式如b所示。口服生物利用度60％～80％，蛋白结合率90％，Tmax为4～6小时，t1/2为11～15小时。Irbesartan is an angiotensin II receptor antagonist, which reduces the vasoconstriction and proliferative effects of angiotensin II by non-competitive inhibition of the AT1 receptor of angiotensin II. The structural formula is shown in b. Show. Oral bioavailability is 60% to 80%, protein binding rate is 90%, Tmax is 4 to 6 hours, and t 1/2 is 11 to 15 hours.
厄贝沙坦主要用于原发性高血压的治疗，其相较其他血管紧张素受体拮抗剂的优势为降压时对心率的影响较小[1]。Irbesartan is mainly used for the treatment of essential hypertension. Compared with other angiotensin receptor antagonists, irbesartan has the advantage of less effect on heart rate during blood pressure [1] .
厄贝沙坦还具有重要的肾脏保护作用，能减缓糖尿病肾病的进展[2]。对于2型糖尿病肾病患者，若同时患有高血压，厄贝沙坦可减缓肾病的进展[3]。厄贝沙坦联合胺碘酮可对起搏器植入患者心房颤动的发生有明显的协同抑制作用[4]。Irbesartan also has an important renal protective effect, which can slow down the progression of diabetic nephropathy [2] . For patients with
关于多奈哌齐的晶型研究：Yeoojin park[5]等报道了多奈哌齐的4种晶型，并给出了其单晶结构，其中研究的所有晶型均为单一化合物的晶型，与本发明在物质成分组成上存在本质差异，本专利使用的多奈哌齐原料药为晶I型。About the crystal form research of donepezil: Yeoojin park [5] et al reported 4 crystal forms of donepezil, and gave its single crystal structure, in which all the crystal forms studied are crystal forms of a single compound, which are related to the present invention in substance There are essential differences in the composition of ingredients, and the donepezil bulk drug used in this patent is crystal I form.
关于厄贝沙坦的晶型和共晶研究有报道，并在专利CN201310446196.2中[6]公开了一个厄贝沙坦瑞格列奈共无定型物。在中国专利CN201510175133.7中，苏州朗科生物技术有限公司的张健[7]等人公开了一个厄贝沙坦与沙库必曲的共晶复合物.There are reports on the crystal form and co-crystal research of irbesartan, and in patent CN201310446196.2 [6] , an irbesartan repaglinide co-amorph is disclosed. In Chinese patent CN201510175133.7, Zhang Jian [7] of Suzhou Netac Biotechnology Co., Ltd. disclosed a co-crystal complex of irbesartan and sacubitril.
在上述公开报道中，所涉及的厄贝沙坦共晶物质成分中除厄贝沙坦外的另一组分，均与本专利采用的多奈哌齐存在结构和性质上的明显差异。In the above-mentioned public reports, the other component of the irbesartan co-crystal material involved, except for irbesartan, has obvious differences in structure and properties from the donepezil used in this patent.
多奈哌齐为目前应用最广泛的抗阿尔茨海默病药物，厄贝沙坦是目前抗高血压一线用药，与多奈哌齐与其他药物联用和厄贝沙坦与其他药物联用公开报道较多，但未见多奈哌齐与厄贝沙坦二者的联用，且更无二者形成共晶固体物质的研究报道。Donepezil is currently the most widely used anti-Alzheimer's disease drug, and irbesartan is the current first-line antihypertensive drug. There is no research report on the combination of donepezil and irbesartan, and there is no research report on the formation of a co-crystal solid substance.
综上所述，迄今未见多奈哌齐与厄贝沙坦形成共晶或共无定型合物的研究报道，在物质形态、物质状态、组合比例、制备方法以及用途等方面，也未见与本发明相似或冲突研究内容。To sum up, so far, there is no research report on the formation of co-crystal or co-amorphous compound between donepezil and irbesartan, and there is no report on the formation of co-crystal or co-amorphous compound of donepezil and irbesartan. Similar or conflicting research content.
本发明通过将多奈哌齐与厄贝沙坦制备成为在特定晶格内共存的特定共晶固体物质，从而形成有别于多奈哌齐、厄贝沙坦及二者简单联合应用的新物质，进而发现本发明的新共晶固体物质在前述的心血管及神经系统障碍疾病中的特殊优势。In the present invention, donepezil and irbesartan are prepared into a specific co-crystal solid substance coexisting in a specific crystal lattice, thereby forming a new substance that is different from donepezil, irbesartan and their simple combined application, and further discovers the present invention The special advantages of the new co-crystal solid substances in the aforementioned cardiovascular and neurological disorders.
发明内容SUMMARY OF THE INVENTION
本发明要解决的技术问题之一：提供多奈哌齐与厄贝沙坦共晶物存在状态和表征方式。One of the technical problems to be solved by the present invention is to provide the existence state and characterization method of the cocrystal of donepezil and irbesartan.
本发明要解决的技术问题之二：提供多奈哌齐与厄贝沙坦共晶物的制备方法。The second technical problem to be solved by the present invention is to provide a preparation method of a co-crystal of donepezil and irbesartan.
本发明要解决的技术问题之三：提供含有多奈哌齐与厄贝沙坦共晶物纯品、或含有任意非零比例多奈哌齐与厄贝沙坦共晶物的混合固体物质及其组合物。The third technical problem to be solved by the present invention is to provide a mixed solid substance containing pure cocrystal of donepezil and irbesartan, or a cocrystal of donepezil and irbesartan in any non-zero ratio and its composition.
本发明要解决的技术问题之四：提供使用多奈哌齐与厄贝沙坦共晶物作为药物活性成分的药物组合物，其每次用药剂量在5-1000mg范围内。所述的药物组合物包括片剂、胶囊、丸剂、注射用制剂、缓释或控释制剂药物。The fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition using the co-crystal of donepezil and irbesartan as a pharmaceutical active ingredient, and the dosage of each drug is in the range of 5-1000 mg. The pharmaceutical compositions include tablets, capsules, pills, injection preparations, sustained-release or controlled-release preparations.
本发明要解决的技术问题之五：是提供多奈哌齐与厄贝沙坦共晶物质，与单独的厄贝沙坦相比，溶出速率和溶出量都具有成药优势。The fifth technical problem to be solved by the present invention is to provide a co-crystal material of donepezil and irbesartan, and compared with the single irbesartan, both the dissolution rate and the dissolution amount have the advantages of finished medicine.
本发明要解决的技术问题之六：是提供多奈哌齐与厄贝沙坦共晶物，由于二者非共价作用力的结合而改善了药物生物利用度，更好发挥药物治疗作用。The sixth technical problem to be solved by the present invention is to provide a co-crystal of donepezil and irbesartan, which improves the bioavailability of the drug due to the combination of the two non-covalent forces, and better exerts the therapeutic effect of the drug.
本发明要解决的技术问题之七：是提供了多奈哌齐与厄贝沙坦共晶物作为药物有效成分，在制备各种预防和/或治疗心力衰竭、心肌缺血、高血压、血管性病变、心绞痛、高血脂症、动脉粥样硬化或糖尿病肾病等心血管疾病及其神经退行性疾病如阿尔茨海默病以及上述多种疾病并发的疾病药物中的应用。The seventh technical problem to be solved by the present invention is to provide the co-crystal of donepezil and irbesartan as the active ingredient of the medicine, which is used in the preparation of various prevention and/or treatment of heart failure, myocardial ischemia, hypertension, vascular disease, Cardiovascular diseases such as angina pectoris, hyperlipidemia, atherosclerosis or diabetic nephropathy and their neurodegenerative diseases such as Alzheimer's disease as well as the application of the drugs for the diseases complicated by the above-mentioned various diseases.
为解决上述技术问题，本发明采用如下技术方案：In order to solve the above-mentioned technical problems, the present invention adopts the following technical solutions:
1.多奈哌齐与厄贝沙坦共晶物样品形态特征：1. Morphological characteristics of the co-crystal of donepezil and irbesartan:
1.1本发明涉及的多奈哌齐与厄贝沙坦共晶物，是多奈哌齐与厄贝沙坦以1:1摩尔比形成共晶物。1.1 The co-crystal of donepezil and irbesartan involved in the present invention is a co-crystal formed by donepezil and irbesartan in a molar ratio of 1:1.
1.2本发明的多奈哌齐与厄贝沙坦共晶物，不含有结晶溶剂或结晶水成分，当使用粉末X射线衍射分析，CuKα辐射实验条件时，表现为衍射峰位置：2-Theta值(°)或d值
表1多奈哌齐与厄贝沙坦共晶物的粉末X射线衍射峰值Table 1 Powder X-ray diffraction peaks of co-crystals of donepezil and irbesartan
表2多奈哌齐原料和厄贝沙坦原料的物理混合物的粉末X射线衍射峰值Table 2 Powder X-ray Diffraction Peaks of Physical Mixtures of Donepezil Raw Materials and Irbesartan Raw Materials
1.3本发明涉及的多奈哌齐与厄贝沙坦共晶物，使用衰减全反射傅立叶红外光谱法进行分析时，在3613、3424、3052、2948、2870、2331、1723、1690、1625、1605、1592、1500、1455、1440、1404、1344、1317、1286、1266、1219、1199、1157、1124、1111、1072、1038、1011、949、928、907、835、820、770、753、707cm-1的吸收峰为多奈哌齐与厄贝沙坦共晶物所呈现的红外光谱特征峰位置。其中红外光谱特征峰的允许偏差为±2cm-1(图3)。1.3 When the co-crystal of donepezil and irbesartan involved in the present invention is analyzed by attenuated total reflection Fourier transform infrared spectroscopy, the results are 1500, 1455, 1440, 1404, 1344, 1317, 1286, 1266, 1219, 1199, 1157, 1124, 1111, 1072, 1038, 1011, 949, 928, 907, 835, 820, 770, 753, 707cm -1 The absorption peak is the characteristic peak position of the infrared spectrum presented by the co-crystal of donepezil and irbesartan. The allowable deviation of the characteristic peaks of the infrared spectrum is ±2cm -1 (Fig. 3).
1.4本发明涉及的多奈哌齐与厄贝沙坦共晶物，使用差示扫描量热技术分析时，表现为在30～210℃范围内，升温速率为每分钟10℃时，其DSC图谱中在152℃±3℃处含有1个吸热峰(图4)。多奈哌齐、厄贝沙坦、共晶物、物理混合物的DSC比较图谱见图5。多奈哌齐与厄贝沙坦共晶物与多奈哌齐、厄贝沙坦、及二者的物理混合物的DSC图谱在吸/放热峰数量、位置等方面均存在明显差异，表明多奈哌齐与厄贝沙坦形成了新的物质。1.4 When the co-crystal of donepezil and irbesartan involved in the present invention is analyzed by differential scanning calorimetry, it is in the range of 30 to 210°C and the heating rate is 10°C per minute, and the DSC spectrum is at 152°C. There is an endothermic peak at °C ± 3 °C (Figure 4). Figure 5 shows the comparative DSC spectra of donepezil, irbesartan, co-crystal and physical mixture. The DSC spectra of the co-crystals of donepezil and irbesartan, donepezil, irbesartan, and their physical mixtures have obvious differences in the number and position of the absorption/exothermic peaks, indicating the formation of donepezil and irbesartan. new substance.
2.多奈哌齐与厄贝沙坦共晶物和混合固体物质的制备方法特征：2. Characteristics of the preparation method of donepezil and irbesartan co-crystal and mixed solid substance:
2.1本发明涉及的多奈哌齐与厄贝沙坦共晶物的制备方法，按照多奈哌齐与厄贝沙坦1:1的摩尔比例投料，采用控制压力与温度的机械化学方法制备多奈哌齐与厄贝沙坦共晶物。所述的机械化学方法为手动研磨或球磨法，优选加液球磨法，其中加液球磨法的球料比为1:1～10:1，优选为6:1～10:1；球磨转速20r/min～400r/min；加液的有机溶剂种类为任意一种或多种经不同配比组合制成的混合溶剂；所述的有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、戊醇、异戊醇、正己醇、乙二醇、乙腈、丙酮、乙酸乙酯、二氧六环、四氢呋喃、氯仿、二氯甲烷、二氯乙烷、乙醚、石油醚、水；研磨时间为0.1～10小时。2.1 The preparation method of the co-crystal of donepezil and irbesartan involved in the present invention, feeds according to the molar ratio of donepezil and irbesartan 1:1, adopts the mechanochemical method of controlling pressure and temperature to prepare the co-crystal of donepezil and irbesartan. crystals. The mechanochemical method is manual grinding or ball milling, preferably liquid ball milling, wherein the ball-to-material ratio of liquid addition ball milling is 1:1 to 10:1, preferably 6:1 to 10:1; the ball milling speed is 20r /min～400r/min; the type of organic solvent to be added is any one or more mixed solvents prepared by combining different ratios; the organic solvent is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, dioxane, tetrahydrofuran, chloroform, dichloromethane, dichloroethane, diethyl ether, Petroleum ether, water; grinding time is 0.1 to 10 hours.
2.2本发明涉及的多奈哌齐与厄贝沙坦共晶物的制备方法，将多奈哌齐与厄贝沙坦按摩尔比例1:1投料放入洁净容器中，加入有机溶剂制成混悬液，室温搅拌6小时～4天，所获得的混悬液通过溶剂蒸发干燥、过滤自然干燥或过滤真空干燥获得多奈哌齐与厄贝沙坦共晶物。所述的有机溶剂优选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、叔丁醇、戊醇、异戊醇、正己醇、乙二醇、乙腈、丙酮、乙酸乙酯、氯仿、二氯甲烷、二氯乙烷、二氧六环、四氢呋喃、正己烷、环己烷、石油醚中的任意一种或多种经不同配比组合制成的混合溶剂；保持多奈哌齐与厄贝沙坦总质量与有机溶剂固液比为1mg/ml～1000mg/ml范围内。2.2 The preparation method of the co-crystal of donepezil and irbesartan involved in the present invention, put the donepezil and irbesartan in a molar ratio of 1:1 into a clean container, add an organic solvent to make a suspension, and stir at room temperature for 6 Hours to 4 days, the obtained suspension is dried by solvent evaporation, natural drying by filtration or vacuum drying by filtration to obtain the co-crystal of donepezil and irbesartan. Described organic solvent is preferably selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, n-hexanol, ethylene glycol, acetonitrile, acetone, ethyl acetate, chloroform , dichloromethane, dichloroethane, dioxane, tetrahydrofuran, n-hexane, cyclohexane, petroleum ether, any one or more mixed solvents made by different ratio combinations; keep donepezil and irbe The total mass of sartan and the solid-liquid ratio of the organic solvent are in the range of 1 mg/ml to 1000 mg/ml.
2.3本发明的多奈哌齐与厄贝沙坦共晶物的混合固体物质，是将上述方法制备获得的多奈哌齐与厄贝沙坦共晶物成分，与其他化学物质按照任意非零比例和常规的方法进行混合。2.3 The mixed solid matter of donepezil and irbesartan co-crystal of the present invention is the donepezil and irbesartan co-crystal components prepared by the above-mentioned method, and is carried out with other chemical substances according to any non-zero ratio and conventional method. mix.
3.多奈哌齐与厄贝沙坦共晶的晶型成分、给药剂量及药物制剂组合物特征：3. The crystal composition, dosage and pharmaceutical composition characteristics of the co-crystal of donepezil and irbesartan:
3.1本发明涉及的药物组合物，含有多奈哌齐与厄贝沙坦共晶物和药学上可接受的载体。3.1 The pharmaceutical composition involved in the present invention comprises a co-crystal of donepezil and irbesartan and a pharmaceutically acceptable carrier.
3.2本发明涉及的药物组合物，含有多奈哌齐与厄贝沙坦共晶物的混合固体物质和药学上可接受的载体。3.2 The pharmaceutical composition involved in the present invention comprises a mixed solid substance of the co-crystal of donepezil and irbesartan and a pharmaceutically acceptable carrier.
3.3本发明涉及的药物组合物，多奈哌齐与厄贝沙坦共晶物的每日用药剂量在5mg～1000mg范围内。3.3 In the pharmaceutical composition involved in the present invention, the daily dosage of the co-crystal of donepezil and irbesartan is in the range of 5 mg to 1000 mg.
3.4本发明涉及的组合物，所述药物组合物的剂型是各种片剂、胶囊、丸剂、注射用制剂、缓释制剂或控释制剂。3.4 For the composition of the present invention, the dosage form of the pharmaceutical composition is various tablets, capsules, pills, injection preparations, sustained-release preparations or controlled-release preparations.
3.5本发明涉及的多奈哌齐与厄贝沙坦共晶物、多奈哌齐与厄贝沙坦共晶物的混合固体物质或药物组合物在制备各种预防和/或治疗心力衰竭、心肌缺血、高血压、血管性病变、心绞痛、高血脂症、动脉粥样硬化或糖尿病并发症等心血管疾病及其神经退行性疾病如阿尔茨海默病以及上述多种疾病并发的疾病药物中的应用。3.5 The mixed solid substance or pharmaceutical composition of the co-crystal of donepezil and irbesartan, the co-crystal of donepezil and irbesartan involved in the present invention is used in the preparation of various prevention and/or treatment of heart failure, myocardial ischemia, hypertension , vascular disease, angina pectoris, hyperlipidemia, atherosclerosis or diabetes complications and other cardiovascular diseases and neurodegenerative diseases such as Alzheimer's disease and the application of the above-mentioned diseases complicated by various diseases.
3.6本发明涉及一种对慢性心力衰竭治疗的基于多奈哌齐与厄贝沙坦共晶物的治疗新策略，其特征为通过减轻心脏后负荷和抑制心脏超负荷运转两个方面的综合效应达到改善心脏功能的目的，其实现的基础是多奈哌齐与厄贝沙坦共晶物可以同时发挥两方面的作用，而且由于本发明对吸收和血药浓度的改变，达到最佳的治疗效果。3.6 The present invention relates to a new treatment strategy based on the co-crystal of donepezil and irbesartan for the treatment of chronic heart failure, which is characterized by reducing cardiac afterload and inhibiting the combined effect of cardiac overload operation to improve cardiac performance. The purpose of the function is based on the fact that the co-crystal of donepezil and irbesartan can play two roles at the same time, and the best therapeutic effect can be achieved due to the change of absorption and blood concentration of the present invention.
3.7本发明涉及的对慢性心力衰竭的治疗新策略，其特征为厄贝沙坦通过拮抗血管紧张素Ⅱ(AT)受体，发挥扩张血管，降低血压，减轻心脏后负荷；多奈哌齐通过抑制乙酰胆碱酯酶，提高副交感神经活性，改善衰竭心脏交感神经功能亢进，副交感神经功能低下的失衡状态，促进心脏功能修复，达到治疗心力衰竭中其他措施不能达到的治疗效果。3.7 The new strategy for the treatment of chronic heart failure involved in the present invention is characterized in that irbesartan acts to dilate blood vessels, lower blood pressure, and relieve cardiac afterload by antagonizing angiotensin II (AT) receptors; donepezil inhibits acetylcholinester Enzymes can improve parasympathetic nerve activity, improve the unbalanced state of sympathetic nerve hyperfunction and low parasympathetic nerve function in the heart failure, promote the repair of heart function, and achieve therapeutic effects that cannot be achieved by other measures in the treatment of heart failure.
3.8本发明涉及的对慢性心力衰竭的治疗新策略，其特征为包括厄贝沙坦在内的其他能够减轻后负荷的同类药物与包括多奈哌齐在内的能够抑制乙酰胆碱酯酶提高副交感神经活性的药物形成共晶物在治疗心力衰竭中的应用。3.8 The new treatment strategy for chronic heart failure involved in the present invention is characterized by other similar drugs that can reduce afterload including irbesartan and drugs that can inhibit acetylcholinesterase and improve parasympathetic nerve activity including donepezil Use of co-crystal formation in the treatment of heart failure.
本发明涉及以本发明多奈哌齐与厄贝沙坦共晶成分、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明多奈哌齐与厄贝沙坦共晶成分、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明多奈哌齐与厄贝沙坦共晶成分、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质在其药物组合物中的含量通常为0.1-95重量％。The present invention relates to a pharmaceutical composition using the co-crystal components of donepezil and irbesartan of the present invention and the solid substance of the mixed crystal form of the co-crystal of donepezil and irbesartan of the present invention as active ingredients. The pharmaceutical composition can be prepared according to methods known in the art. It can be obtained by mixing the components of the co-crystal of donepezil and irbesartan of the present invention, the solid substance of the mixed crystal form of the co-crystal of donepezil and irbesartan of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or Adjuvants are combined to make any dosage form suitable for human or animal use. The content of the co-crystal component of donepezil and irbesartan of the present invention and the mixed crystal form solid substance of the co-crystal of donepezil and irbesartan of the present invention is usually 0.1-95% by weight in the pharmaceutical composition.
本发明多奈哌齐与厄贝沙坦共晶物、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。The co-crystal of donepezil and irbesartan of the present invention, the mixed crystal form solid substance of the co-crystal of donepezil and irbesartan of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dose, and the route of administration can be enteral or non- Intestinal, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.
本发明的给药剂型优选是固体剂型。固体剂型可以是片剂(包括普通片、肠溶片、缓释片、控释片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等。The dosage form for administration of the present invention is preferably a solid dosage form. Solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, sustained-release tablets, controlled-release tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft Capsules, enteric-coated capsules), granules, powders, pellets, drop pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.
本发明多奈哌齐与厄贝沙坦共晶物、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质可以制成普通制剂、也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。The co-crystals of donepezil and irbesartan of the present invention, and the mixed crystal form solid substances of the co-crystals of donepezil and irbesartan of the present invention can be made into common preparations, slow-release preparations, controlled-release preparations, targeted preparations and various preparations. A microparticle drug delivery system.
为了将本发明多奈哌齐与厄贝沙坦共晶物、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。In order to prepare the solid substance of the co-crystal of donepezil and irbesartan of the present invention and the mixed crystal form of the co-crystal of donepezil and irbesartan of the present invention into tablets, various excipients known in the art can be widely used, including diluents , binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; Propanol, etc.; the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, acacia mucilage, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polymer Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfonate, etc.; lubricants and flow aids The agent may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。The tablets can also be further prepared as coated tablets, such as sugar-coated, film-coated, enteric-coated, or bilayer and multi-layer tablets.
为了将给药单元制成胶囊剂，可以将有效成分本发明多奈哌齐与厄贝沙坦共晶物、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明多奈哌齐与厄贝沙坦共晶成分、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质先与稀释剂、粘合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明多奈哌齐与厄贝沙坦共晶成分、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质片剂的各种稀释剂、粘合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明多奈哌齐与厄贝沙坦共晶物、本发明多奈哌齐与厄贝沙坦共晶混合晶型固体物质的胶囊剂。In order to make the dosing unit into a capsule, the active ingredients of the co-crystal of donepezil and irbesartan of the present invention, the mixed crystal form of the co-crystal of donepezil and irbesartan of the present invention can be mixed with a diluent and a glidant, Place the mixture directly in hard or soft capsules. The active ingredient of the present invention, the co-crystal component of donepezil and irbesartan, and the solid substance of the mixed crystal form of the present invention's donepezil and irbesartan co-crystal can also be made into granules or pellets with diluents, binders and disintegrating agents. , and then placed in hard or soft capsules. Various diluents, binders, wetting agents, disintegrating agents, various diluents, binders, wetting agents, disintegrants, The variety of glidant can also be used to prepare the capsules of the co-crystal of donepezil and irbesartan of the present invention and the mixed crystal form of the co-crystal of donepezil and irbesartan of the present invention.
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。In addition, colorants, preservatives, fragrances, flavors, or other additives can also be added to the pharmaceutical preparations, if desired.
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。In order to achieve the purpose of medication and enhance the therapeutic effect, the medicament or pharmaceutical composition of the present invention can be administered by any known administration method.
本发明多奈哌齐与厄贝沙坦共晶物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。The dosage of the pharmaceutical composition of the co-crystal of donepezil and irbesartan of the present invention can vary widely according to the nature and severity of the disease to be prevented or treated, individual conditions of patients or animals, administration routes and dosage forms. The above doses may be administered in a single dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosing regimen including the use of other therapeutic means.
本发明多奈哌齐与厄贝沙坦共晶物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明多奈哌齐与厄贝沙坦共晶物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。The co-crystal or composition of donepezil and irbesartan of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the co-crystal of donepezil and irbesartan of the present invention has a synergistic effect with other therapeutic drugs, its dosage should be adjusted according to the actual situation.
4.本发明的有益技术效果：多奈哌齐与厄贝沙坦共晶物的安全性、溶解性和生物活性优势特征。4. Beneficial technical effects of the present invention: the advantages of safety, solubility and biological activity of the co-crystal of donepezil and irbesartan.
4.1本发明的多奈哌齐与厄贝沙坦共晶物不含任何结晶溶剂，具有良好的安全性成药优势。4.1 The co-crystal of donepezil and irbesartan of the present invention does not contain any crystallization solvent, and has the advantages of good safety as a medicine.
4.2本发明的多奈哌齐与厄贝沙坦共晶物在水和0.5％十二烷基硫酸钠溶出体系中表现出优于厄贝沙坦的成药优势(图6)。4.2 The co-crystal of donepezil and irbesartan of the present invention showed the advantages over irbesartan in the dissolution system of water and 0.5% sodium dodecyl sulfate (Fig. 6).
4.3本发明涉及的多奈哌齐与厄贝沙坦共晶物(简称：共晶)，有区别于多奈哌齐、厄贝沙坦单独使用及混合使用在动物体内的代谢特性；与多奈哌齐和厄贝沙坦的物理混合物(简称：物理混合物)相比，相同的给药剂量下，有更高的生物利用度和血药浓度；与多奈哌齐原料和厄贝沙坦原料的物理混合物相比，其动物体内生物利用度等药动学性质提高，体内可达到更高的血药浓度和AUC(图7、图8)，更有利于心血管和神经退行性疾病的治疗和预防；与多奈哌齐和厄贝沙坦单体化合物相比，其动物体内代谢半衰期，达峰时间等药动学参数均显著改善，其中多奈哌齐半衰期显著延长，可更有效提升副交感神经兴奋性，改善衰竭心脏交感神经功能亢进，副交感神经功能低下的失衡状态；厄贝沙坦半衰期显著延长，可更有效控制体内肾素—血管紧张素系统兴奋性，减轻心血管系统压力，有利保护体内心血管系统组织和器官，有利于心血管和神经退行性疾病的治疗和预防。4.3 The co-crystal of donepezil and irbesartan involved in the present invention (abbreviation: co-crystal) is different from the metabolic characteristics of donepezil and irbesartan used alone and mixed in animals; Compared with the physical mixture (abbreviation: physical mixture), it has higher bioavailability and plasma concentration under the same dosage; compared with the physical mixture of donepezil raw materials and irbesartan raw materials, its bioavailability in animals Pharmacokinetic properties such as degree of improvement, higher blood concentration and AUC can be achieved in vivo (Figure 7, Figure 8), which is more conducive to the treatment and prevention of cardiovascular and neurodegenerative diseases; with donepezil and irbesartan alone Compared with other compounds, the pharmacokinetic parameters such as metabolic half-life and time to peak in animals were significantly improved. Among them, the half-life of donepezil was significantly prolonged, which could more effectively enhance the excitability of parasympathetic nerves, improve the hyperfunction of sympathetic nerves in the heart failure, and reduce the function of parasympathetic nerves. The imbalanced state of irbesartan; the half-life of irbesartan is significantly prolonged, which can more effectively control the excitability of the renin-angiotensin system in the body, reduce the pressure on the cardiovascular system, protect the tissues and organs of the cardiovascular system in the body, and benefit cardiovascular and neurodegeneration Treatment and prevention of sexually transmitted diseases.
附图说明Description of drawings
图1多奈哌齐与厄贝沙坦共晶物的粉末X射线衍射图谱Fig.1 Powder X-ray diffraction pattern of the co-crystal of donepezil and irbesartan
图2多奈哌齐和厄贝沙坦的物理混合物的粉末X射线衍射图谱Fig. 2 Powder X-ray diffraction pattern of the physical mixture of donepezil and irbesartan
图3多奈哌齐与厄贝沙坦共晶物的红外吸收光谱图Figure 3 Infrared absorption spectrum of the co-crystal of donepezil and irbesartan
图4多奈哌齐与厄贝沙坦共晶物的差示扫描量热图谱Figure 4 Differential scanning calorimetry of the co-crystal of donepezil and irbesartan
图5多奈哌齐与厄贝沙坦共晶物及多奈哌齐、厄贝沙坦、二者物理混合物的差示扫描量热对比图谱Fig. 5 Differential scanning calorimetry contrast map of the co-crystal of donepezil and irbesartan and the physical mixture of donepezil, irbesartan and the two
图6多奈哌齐与厄贝沙坦共晶物及厄贝沙坦的溶出曲线图Fig. 6 Dissolution curves of donepezil and irbesartan co-crystal and irbesartan
图7多奈哌齐与厄贝沙坦共晶物及物理混合物在大鼠体内的血药浓度-时间曲线Fig.7 Plasma concentration-time curve of donepezil and irbesartan co-crystal and physical mixture in rats
图8多奈哌齐与厄贝沙坦共晶物及物理混合物在大鼠体内药时曲线下面积Figure 8 Area under the curve of donepezil and irbesartan co-crystal and physical mixture in rats
具体实施方式Detailed ways
为更好说明本发明的技术方案，特给出以下实施例，但本发明并不仅限于此。In order to better illustrate the technical solutions of the present invention, the following examples are given, but the present invention is not limited thereto.
实施例1Example 1
多奈哌齐与厄贝沙坦共晶物制备方法1：Preparation method of donepezil and irbesartan co-crystal 1:
按照表3所示，取多奈哌齐与厄贝沙坦适量按照摩尔比为1:1放入研钵中，加入适量溶剂，人工研磨适当时间。对其进行粉末X射线衍射分析，其衍射图谱与图1一致，表明所得样品为多奈哌齐与厄贝沙坦共晶物。As shown in Table 3, take an appropriate amount of donepezil and irbesartan into a mortar according to the molar ratio of 1:1, add an appropriate amount of solvent, and manually grind for an appropriate time. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, indicating that the obtained sample was a co-crystal of donepezil and irbesartan.
表3多奈哌齐与厄贝沙坦共晶物制备方法1的条件参数Table 3 Condition parameters of
多奈哌齐与厄贝沙坦共晶物制备方法2：
按照表4所示，取多奈哌齐与厄贝沙坦适量按照摩尔比为1:1放入球磨罐中，加入适量有机溶剂，选择适当球料比，设定适当转速，研磨适当时间。对其进行粉末X射线衍射分析，其衍射图谱与图1一致，表明所得样品为多奈哌齐与厄贝沙坦共晶物。As shown in Table 4, take an appropriate amount of donepezil and irbesartan according to the molar ratio of 1:1 and put it into a ball mill tank, add an appropriate amount of organic solvent, select an appropriate ball-to-material ratio, set an appropriate rotational speed, and grind an appropriate time. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, indicating that the obtained sample was a co-crystal of donepezil and irbesartan.
表4多奈哌齐与厄贝沙坦共晶物制备方法2的条件参数Table 4 Condition parameters of
多奈哌齐与厄贝沙坦共晶物制备方法3：
按照表5所示，取多奈哌齐与厄贝沙坦适量按照摩尔比为1:1放入洁净的容器内，加入适量有机溶剂，于室温条件下搅拌适当时间，将所得的混悬液溶剂蒸发干燥、过滤自然干燥或过滤真空干燥。对其进行粉末X射线衍射分析，其衍射图谱与图1一致，表明所得样品为多奈哌齐与厄贝沙坦共晶物。As shown in Table 5, take an appropriate amount of donepezil and irbesartan and put them in a clean container according to the molar ratio of 1:1, add an appropriate amount of organic solvent, stir for an appropriate time at room temperature, and evaporate the obtained suspension solvent to dryness , filter natural drying or filter vacuum drying. The powder X-ray diffraction analysis was carried out, and the diffraction pattern was consistent with Fig. 1, indicating that the obtained sample was a co-crystal of donepezil and irbesartan.
表5多奈哌齐与厄贝沙坦共晶物制备方法3的条件参数Table 5 Conditional parameters of
实施例2Example 2
多奈哌齐与厄贝沙坦共晶物的体外溶出释放特征In vitro dissolution and release characteristics of co-crystals of donepezil and irbesartan
考察了多奈哌齐与厄贝沙坦共晶物与厄贝沙坦原料药在水溶液和0.5％SDS水溶液2个系统中的溶解性特征。参照《普通口服固体制剂溶出度试验技术指导原则》测定，溶解曲线比较采用模型非依赖性相似因子(f2)方法，通过f2值的计算比较原料及物理混合物和多奈哌齐与厄贝沙坦共晶物样品在2种溶媒系统中溶解曲线的相似性，当f2值高于50，则认为两条曲线相似，当f2值低于50则认为二者存在差异。实验以厄贝沙坦样品作为参照，计算模型非依赖性相似因子f2值。溶解百分含量采用用高效液相法，以外标法计算其溶解百分含量。以时间为横坐标，溶解百分含量为纵坐标分别绘制溶解曲线(图6)。数据见表6、7。The solubility characteristics of donepezil-irbesartan co-crystal and irbesartan API in aqueous solution and 0.5% SDS aqueous solution were investigated. Referring to the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Preparations", the dissolution curves were compared using the model-independent similarity factor (f2) method, and the raw materials and physical mixtures and co-crystals of donepezil and irbesartan were compared by calculating the f2 value The similarity of the dissolution curves of the samples in the two solvent systems. When the f2 value is higher than 50, the two curves are considered to be similar, and when the f2 value is lower than 50, the two curves are considered to be different. In the experiment, the irbesartan sample was used as a reference, and the model-independent similarity factor f2 value was calculated. The dissolved percentage was calculated by the high-performance liquid phase method and the external standard method. Taking the time as the abscissa and the dissolution percentage as the ordinate, the dissolution curves were drawn respectively (Fig. 6). The data are shown in Tables 6 and 7.
检测条件：检测系统：Aligent 1200，色谱柱：Agilent Eclipse XDB-C18(4.6×250mm,5μm)；流动相：乙腈-0.1％磷酸水(40:60，v/v)；流速：1mL·min-1；柱温：25℃；检测波长：厄贝沙坦：220nm；进样量：10μl。Detection conditions: detection system: Aligent 1200, chromatographic column: Agilent Eclipse XDB-C18 (4.6×250mm, 5μm); mobile phase: acetonitrile-0.1% phosphoric acid water (40:60, v/v); flow rate: 1mL·min - 1 ; column temperature: 25°C; detection wavelength: irbesartan: 220 nm; injection volume: 10 μl.
表6多奈哌齐与厄贝沙坦共晶物厄贝沙坦的溶出曲线数据(溶出介质：水)Table 6 Dissolution curve data of donepezil and irbesartan co-crystal irbesartan (dissolution medium: water)
表7多奈哌齐与厄贝沙坦共晶物的溶出曲线数据(溶出介质：0.5％十二烷基硫酸钠)Table 7 Dissolution curve data of donepezil and irbesartan co-crystal (dissolution medium: 0.5% sodium lauryl sulfate)
溶出实验结果表明：多奈哌齐与厄贝沙坦共晶物在上述两种溶出系统中均表现出较快的溶出速率，在水中还较厄贝沙坦原料药具有更大的溶出量，具有明显的溶解性成药优势。The results of the dissolution test showed that the co-crystals of donepezil and irbesartan showed a faster dissolution rate in the above two dissolution systems, and also had a larger dissolution amount in water than the irbesartan API, with obvious advantages. Solubility of over-the-counter medicines.
实施例3多奈哌齐与厄贝沙坦共晶物在大鼠体内吸收特征和血药浓度特征：Example 3 Absorption characteristics and plasma concentration characteristics of the co-crystal of donepezil and irbesartan in rats:
本发明所涉及的的多奈哌齐与厄贝沙坦共晶物的动物体内代谢特点，包括如下过程：The animal body metabolism characteristics of the donepezil and irbesartan co-crystals involved in the present invention include the following process:
将9只SD大鼠，随机分为3组，每组3只。于给药前12h禁食不禁水。称取大鼠体重，按100mg·kg-1的厄贝沙坦给药剂量计算，将多奈哌齐与厄贝沙坦的物理混合物及厄贝沙坦原料、多奈哌齐与厄贝沙坦共晶物样品装入固体给药器内，通过口腔将药粉直接置入大鼠胃中。分别于给药后5分钟、15分钟、30分钟、45分钟、1小时、1.5小时、2小时、3小时、4小时、6小时、9小时、12小时及24小时眼龇静脉丛采血置肝素化管中，4℃、4000rpm离心10min，冻存于-40℃冰箱内待测。精密量取大鼠血浆100μL，加内标溶液100μL、乙酸乙酯1.2mL，振荡5分钟使样品充分混合，12800rpm离心10分钟，取上清液，以N2气吹干，加100μL乙酸乙酯复溶样品，离心后取上清90μL，进样检测。Nine SD rats were randomly divided into 3 groups with 3 rats in each group. Fasting without food or
色谱条件：以乙腈-0.1％磷酸水溶液作为流动相，梯度洗脱，洗脱条件如表8所示：Chromatographic conditions: use acetonitrile-0.1% phosphoric acid aqueous solution as mobile phase, gradient elution, elution conditions are shown in Table 8:
表8 HPLC法的洗脱条件Table 8 Elution conditions of HPLC method
不同样品在大鼠体内的多奈哌齐药代动力学数据见表9所示，厄贝沙坦药代动力学参数见表10所示，血药浓度-时间曲线见图7所示，药时曲线下面积(AUC)比较图谱见图8所示。多奈哌齐与厄贝沙坦共晶物在大鼠体内生物利用度较物理混合物均有提高。具有达峰时间长，血药浓度高、作用平台延长的优势生物学特征。The pharmacokinetic data of donepezil in rats of different samples are shown in Table 9, the pharmacokinetic parameters of irbesartan are shown in Table 10, and the plasma concentration-time curve is shown in Figure 7. The area (AUC) comparison map is shown in Figure 8. The bioavailability of the co-crystal of donepezil and irbesartan in rats was higher than that of the physical mixture. It has the advantages of long peak time, high blood drug concentration and prolonged action platform.
表9多奈哌齐药代动力学参数表Table 9 Pharmacokinetic parameters of donepezil
表10厄贝沙坦药代动力学参数表Table 10 Pharmacokinetic parameters of irbesartan
实施例4Example 4
组合药物制剂的制备方法1(片剂)：Preparation method 1 (tablet) of combined pharmaceutical preparation:
一种组合药物片剂的制备方法，其特征是使用多奈哌齐与厄贝沙坦共晶物纯品、或含有任意比例晶Ⅱ型的混晶固体物质作为组合药物的原料药、使用几种赋形剂作为制备组合药物片剂的辅料成分，按照一定比例配比制成每片含药量在5～500mg的片剂样品，表11给出片剂配方比例：A preparation method of a combination drug tablet, which is characterized by using the pure co-crystal of donepezil and irbesartan, or a mixed crystal solid substance containing any proportion of crystal form II as the raw material drug of the combination drug, using several excipients Table 11 shows the tablet formulation ratio:
表11多奈哌齐与厄贝沙坦共晶物组合药物片剂的制备配方Table 11 Preparation formula of donepezil and irbesartan co-crystal combination drug tablet
将多奈哌齐与厄贝沙坦共晶物作为原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，直接压片；或辅料混合干法制粒再与原料药混合均匀后压片，即得。The method for preparing a tablet preparation from a co-crystal of donepezil and irbesartan as a raw material drug is as follows: mixing several excipients with the raw material drug uniformly, and directly compressing it; After pressing, you can get it.
组合药物制剂的制备方法2(片剂)：Preparation method 2 (tablet) of combined pharmaceutical preparation:
一种组合药物片剂的制备方法，其特征是使用多奈哌齐与厄贝沙坦共晶物、使用几种赋形剂作为制备组合药物片剂的辅料成分，按照一定比例配比制成每片含共晶在5～500mg的片剂样品，表12给出片剂配方比例：A preparation method of a combination drug tablet, which is characterized in that a co-crystal of donepezil and irbesartan is used, and several excipients are used as auxiliary components for preparing the combination drug tablet, and each tablet is prepared according to a certain proportion and proportioned. Table 12 shows the tablet formulation ratio for the tablet samples with co-crystals ranging from 5 to 500 mg:
表12多奈哌齐与厄贝沙坦共晶物组合药物片剂的制备配方The preparation formula of table 12 Donepezil and Irbesartan co-crystal combination drug tablet
将多奈哌齐与厄贝沙坦共晶作为原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，加入1％羟甲基纤维素钠溶液适量，制成软料，过筛制粒，湿粒烘干，过筛整粒，加入硬脂酸镁和滑石粉混合均匀，压片，即得。The method for preparing a tablet preparation by using the co-crystal of donepezil and irbesartan as a raw material drug is as follows: mixing several excipients with the raw material drug uniformly, adding an appropriate amount of 1% sodium hydroxymethyl cellulose solution to prepare a soft material, Sieve and granulate, dry the wet granules, sieve and granulate, add magnesium stearate and talc, mix evenly, and press into tablets.
组合药物制剂的制备方法3(胶囊)：Preparation method 3 (capsule) of combined pharmaceutical preparation:
一种组合药物胶囊的制备方法，其特征是使用多奈哌齐与厄贝沙坦共晶物物质纯品、或含有任意比例晶Ⅱ型的混晶固体物质作为组合药物的原料药、使用几种赋形剂作为制备组合药物胶囊的辅料成分，按照一定比例配比制成每片含药量在10～500mg的胶囊样品，表13给出胶囊配方比例：A preparation method of a combined medicine capsule, which is characterized in that the pure product of the co-crystal material of donepezil and irbesartan, or the mixed crystal solid material containing any proportion of crystal type II is used as the raw material medicine of the combined medicine, and several excipients are used. As the adjuvant ingredients for the preparation of combined drug capsules, the capsule samples each containing 10-500 mg of drug are prepared according to a certain proportion. Table 13 gives the capsule formula ratio:
表13多奈哌齐与厄贝沙坦共晶物组合药物胶囊制剂的原料药和辅料配方Table 13 API and excipient formula of donepezil and irbesartan co-crystal combination drug capsule preparation
将多奈哌齐与厄贝沙坦共晶物物质纯品或含有任意比例晶Ⅱ型的混晶原料药制备成片剂制剂的方法是：将几种赋形剂与原料药混合均匀，加入1％羟甲基纤维素钠溶液适量，制成湿粒烘干过筛整粒，加入硬脂酸镁混合均匀，插入胶囊制得；或不使用制粒步骤，而直接将多奈哌齐与厄贝沙坦共晶物物质原料药与几种赋形剂辅料混合均匀，过筛后，直接装入胶囊制得。The method for preparing the pure product of the co-crystal material of donepezil and irbesartan or the mixed crystal bulk drug containing any proportion of crystal form II into a tablet preparation is as follows: mixing several excipients with the bulk drug uniformly, adding 1% hydroxyl A suitable amount of sodium methylcellulose solution is prepared into wet granules, dried, sieved and sized, added with magnesium stearate, mixed evenly, and inserted into capsules to prepare; or directly co-crystal of donepezil and irbesartan without using the granulation step Substances and raw materials are mixed evenly with several excipients and auxiliary materials, sieved, and directly packed into capsules to prepare.
实施例5Example 5
多奈哌齐与厄贝沙坦共晶物组合药物的给药剂量1(片剂)：Dosage of Donepezil and Irbesartan Cocrystal Combination Drug 1 (tablet):
使用多奈哌齐与厄贝沙坦共晶物样品作为药物活性成分制备开发的药物组合物，其特征是使用多奈哌齐与厄贝沙坦共晶物作为药物的活性成分，每日给药剂量为900mg，可分别制备成每日3次/每次3片100mg普通片剂，或每日3次/每次1片300mg的片剂类。The pharmaceutical composition prepared and developed using the co-crystal sample of donepezil and irbesartan as the active ingredient of the medicine, is characterized in that the co-crystal of donepezil and irbesartan is used as the active ingredient of the medicine, and the daily dosage is 900 mg, which can be It is respectively prepared into 3 100mg
多奈哌齐与厄贝沙坦共晶物组合药物的给药剂量2(胶囊)：Dosage of Donepezil and Irbesartan Cocrystal Combination Drug 2 (capsule):
使用多奈哌齐与厄贝沙坦共晶物样品作为药物活性成分制备开发的药物组合物，其特征是使用多奈哌齐与厄贝沙坦共晶物作为药物的活性成分，每日给药剂量为1200mg，可分别制备成每日3次/每次4粒100mg胶囊，或者每日2次/每次2粒300mg胶囊。The pharmaceutical composition prepared and developed by using the co-crystal sample of donepezil and irbesartan as the active ingredient of the medicine is characterized in that the co-crystal of donepezil and irbesartan is used as the active ingredient of the medicine, and the daily administration dose is 1200 mg, which can be It is prepared as 4 capsules of 100
需要说明的问题：本发明涉及的多奈哌齐与厄贝沙坦共晶物药物组合物在有效成分的给药剂量上存在有许多因素影响，例如：患者年龄、体表面积的不同，给药途径、给药次数、治疗目的不同而造成每次用药剂量的不同；晶型样品间存在的吸收和血药浓度不同等，亦造成本发明在使用多奈哌齐与厄贝沙坦共晶物成分的每次合适剂量范围为0.1-10mg/kg体重，优选为0.2-5mg/kg体重。使用时应根据实际的治疗不同情况需求制定不同的多奈哌齐与厄贝沙坦共晶物物质有效成分总剂量方案，并可分为多次或一次给药方式完成。Problems that need to be explained: the pharmaceutical composition of donepezil and irbesartan co-crystals involved in the present invention is affected by many factors on the administration dose of the active ingredient, such as: the age of the patient, the difference in body surface area, the route of administration, the dosage of Different times of medication and different therapeutic purposes result in different doses of each medication; different absorption and blood drug concentrations exist between crystal form samples, etc., which also causes the present invention to use each appropriate dose of the co-crystal of donepezil and irbesartan. The range is 0.1-10 mg/kg body weight, preferably 0.2-5 mg/kg body weight. During use, different total dosage regimens of the active ingredients of the co-crystal of donepezil and irbesartan should be formulated according to the actual needs of treatment, and can be divided into multiple or one-time administrations.
参考文献references
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[3]Lewis EJ，Hunsicker LG，Clarke WR，Berl T，Pohl MA，Lewis JB，Ritz E，Atkins RC，Rohde R，Raz I；Collaborative Study Group.Renoprotective effect ofthe angiotensin-receptor antagonist irbesartan in patients with nephropathydue to type 2diabetes.N Engl J Med.2001，345(12):851–60.[3] Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathydue to type 2diabetes. N Engl J Med. 2001, 345(12):851–60.
[4]方昱，严激.胺碘酮与厄贝沙坦联用对病态窦房结综合征人工心脏起搏后的疗效.中国临床保健杂志.2008，11(1):25–26.[4] Fang Yu, Yan Ji. The efficacy of amiodarone combined with irbesartan in patients with sick sinus syndrome after artificial cardiac pacing. China Journal of Clinical Health. 2008, 11(1): 25–26.
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