CN114096530B - Pharmaceutical composition of compound and preparation method thereof - Google Patents
Pharmaceutical composition of compound and preparation method thereof Download PDFInfo
- Publication number
- CN114096530B CN114096530B CN202180004442.1A CN202180004442A CN114096530B CN 114096530 B CN114096530 B CN 114096530B CN 202180004442 A CN202180004442 A CN 202180004442A CN 114096530 B CN114096530 B CN 114096530B
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- China
- Prior art keywords
- pharmaceutical composition
- complex
- crospovidone
- exp3174
- ahu377
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 92
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- 238000002360 preparation method Methods 0.000 title claims abstract description 36
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- 229960003953 sacubitril Drugs 0.000 claims description 43
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 32
- 229960000913 crospovidone Drugs 0.000 claims description 32
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Classifications
-
- 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
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
属于医药制剂技术领域，涉及一种复合物的药物组合物及其制备方法，特别涉及一种血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的药物组合物及其制备方法。The invention belongs to the technical field of pharmaceutical preparations, and relates to a pharmaceutical composition of a compound and a preparation method thereof, in particular to a pharmaceutical composition of a compound of an angiotensin II receptor antagonist metabolite and an NEP inhibitor and a preparation method thereof.
Description
技术领域technical field
本发明属于医药制剂技术领域，涉及一种复合物的药物组合物及其制备方法，特别涉及一种血管紧张素II受体拮抗剂代谢产物与NEP抑制剂的复合物的药物组合物及其制备方法。The invention belongs to the technical field of pharmaceutical preparations, and relates to a pharmaceutical composition of a compound and a preparation method thereof, in particular to a pharmaceutical composition of a compound of an angiotensin II receptor antagonist metabolite and an NEP inhibitor and its preparation method.
背景技术Background technique
高血压是以体循环动脉压增高为主要表现的临床综合征，是最常见的心血管疾病。高血压大多数起病缓慢，缺乏特殊临床表现，导致诊断延迟，仅在测量血压时或发生心、脑、肾等并发症时才被发现。长期的高血压与心脑血管病发病和死亡风险之间存在密切的因果关系。Hypertension is a clinical syndrome mainly manifested by increased systemic arterial pressure, and is the most common cardiovascular disease. Most hypertensions have a slow onset and lack of special clinical manifestations, leading to delayed diagnosis. They are only discovered when blood pressure is measured or complications such as heart, brain, and kidney occur. There is a close causal relationship between long-term hypertension and the risk of cardiovascular and cerebrovascular diseases and mortality.
据统计，目前全世界有超过十亿人高血压未得到控制，预计到2030年会增加到15亿。在我国，2012～2015年中国高血压调查(CHS)调查结果显示：中国≥18岁成人高血压患病率为27.9％(加权率为23.2％)，知晓率、治疗率和控制率分别为51.6％，45.8％和16.8％，治疗控制率为37.5％。高血压的发病率呈不断上升的趋势，据统计，我国心血管病患者约为2.9亿人(《中国心血管病报告2013》)。高血压如果得不到有效的控制和治疗，可以引起冠状动脉硬化，出现冠心病、心绞痛，还可能造成高血压性心脏病、心力衰竭等严重并发症。另外，长期高血压可导致肾、脑、心血管等器官损伤。According to statistics, there are currently more than one billion people with uncontrolled high blood pressure worldwide, and it is expected to increase to 1.5 billion by 2030. In my country, the survey results of the China Hypertension Survey (CHS) from 2012 to 2015 showed that the prevalence of hypertension in Chinese adults aged ≥18 years was 27.9% (weighted rate was 23.2%), and the awareness rate, treatment rate and control rate were 51.6% %, 45.8% and 16.8%, the treatment control rate was 37.5%. The incidence of hypertension is on the rise. According to statistics, there are about 290 million patients with cardiovascular disease in my country ("China Cardiovascular Disease Report 2013"). If high blood pressure is not effectively controlled and treated, it can cause coronary arteriosclerosis, coronary heart disease, angina pectoris, and serious complications such as hypertensive heart disease and heart failure. In addition, long-term high blood pressure can lead to kidney, brain, cardiovascular and other organ damage.
心衰是各种心脏疾病的严重表现或晚期阶段，是全球慢性心血管疾病防治的重要内容，死亡率和再住院率居高不下。欧美流行病学数据显示，成人心衰患病率为1.5％～2.0％，并且随着年龄增加，心力衰竭的患病率也随之增加，≥70岁人群患病率≥10％。2003年中国流行病学调查显示，我国35～74岁成人心衰患病率为0.9％。《中国心血管病报告2016》提出我国心血管病患病率处于持续上升阶段，心血管病死亡率居首位，高于肿瘤和其他疾病。我国人口老龄化加剧，冠心病、高血压、糖尿病、肥胖等慢性病的发病呈上升趋势，医疗水平的提高使心脏疾病患者生存期延长，导致我国心衰患病率呈持续升高趋势。对国内10714例住院心衰患者的调查显示：1980、1990、2000年心衰患者住院期间病死率分别为15.4％、12.3％和6.2％，主要死亡原因依次为左心衰竭(59％)、心律失常(13％)和心脏性猝死(13％)。China-HF研究显示，住院心衰患者的病死率为4.1％。Heart failure is a serious manifestation or late stage of various heart diseases, and is an important part of the prevention and treatment of chronic cardiovascular diseases worldwide, with high mortality and rehospitalization rates. European and American epidemiological data show that the prevalence of heart failure in adults is 1.5% to 2.0%, and with age, the prevalence of heart failure also increases, and the prevalence of people ≥ 70 years old is ≥ 10%. The 2003 China Epidemiological Survey showed that the prevalence of heart failure among adults aged 35-74 in my country was 0.9%. The "China Cardiovascular Disease Report 2016" pointed out that the prevalence of cardiovascular disease in my country is on the rise, and the mortality rate of cardiovascular disease ranks first, higher than that of tumors and other diseases. The aging population in my country is intensifying, and the incidence of chronic diseases such as coronary heart disease, hypertension, diabetes, and obesity is on the rise. The improvement of medical care has prolonged the survival of patients with heart disease, leading to a continuous increase in the prevalence of heart failure in my country. A survey of 10,714 hospitalized patients with heart failure in China showed that in 1980, 1990, and 2000, the mortality rates of heart failure patients during hospitalization were 15.4%, 12.3%, and 6.2%, respectively, and the main causes of death were left heart failure (59%), cardiac rhythm, etc. Arrhythmia (13%) and sudden cardiac death (13%). The China-HF study showed that the mortality rate of hospitalized patients with heart failure was 4.1%.
WO2007056546A1公开了一种缬沙坦(Valsartan)-沙库巴曲(Sacubitril，AHU377)的钠盐复合物(LCZ696)及其制备方法，于2017年在中国获批上市，商品名：
专利WO2009061713公开了一种沙库巴曲缬沙坦钠的制剂及其制备方法，通过将治疗剂与至少一种可药用赋形剂混合，公开了多种处方组成的制剂，接着将混合物用适合的设备如压片机直接压缩或将混合物用适合的设备如滚压机压制而制备。Patent WO2009061713 discloses a preparation of sacubitril-valsartan sodium and its preparation method. By mixing the therapeutic agent with at least one pharmaceutically acceptable excipient, it discloses a preparation composed of various prescriptions, and then mixes the mixture with It is prepared by direct compression in suitable equipment, such as a tablet press, or by compressing the mixture in suitable equipment, such as a roller compactor.
已上市的
另外，WO2017125031A1公开了一系列由血管紧张素受体拮抗剂代谢产物(EXP3174)与NEP抑制剂(Sacubitril)的复合物，且对射血分数保留的心力衰竭HFpEF表现一定效果，其分子结构单元如下：In addition, WO2017125031A1 discloses a series of complexes of metabolites of angiotensin receptor antagonist (EXP3174) and NEP inhibitor (Sacubitril), which have certain effects on heart failure HFpEF with preserved ejection fraction, and its molecular structural units are as follows :
但是由于化合物组成的不同，如何寻找符合临床使用的制剂方案至关重要，需进一步研究开发。However, due to the different composition of the compounds, how to find a preparation scheme suitable for clinical use is very important, and further research and development are needed.
发明内容Contents of the invention
鉴于现有技术存在的问题，本发明的提供了一种新的复合物药物组合物及其制备方法，In view of the problems existing in the prior art, the present invention provides a new compound pharmaceutical composition and its preparation method,
本发明通过以下技术方案来实现，一种复合物的药物组合物，所述复合物的结构单元如下：The present invention is achieved through the following technical scheme, a pharmaceutical composition of a complex, the structural unit of the complex is as follows:
(aEXP3174·bAHU377)·xCa·nA(aEXP3174 bAHU377) xCa nA
其中a∶b＝1∶0.25～4；x为0.5～3之间的数值；A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-叔-丁基醚、乙腈、甲苯、二氯甲烷；n为0～3之间的数值；Where a:b=1:0.25～4; x is a value between 0.5～3; A refers to water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, methyl-tert-butyl ether, Acetonitrile, toluene, dichloromethane; n is a value between 0 and 3;
所述药物组合物中含有低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠、交联羧甲基纤维素钠、预胶化淀粉中的一种或者两种以上任意比例的混合物，在药物组合物中使用量为4％-50％；和一种以上的其他辅料。The pharmaceutical composition contains one of low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, croscarmellose sodium, and pregelatinized starch, or a mixture of two or more in any proportion , the amount used in the pharmaceutical composition is 4%-50%; and more than one other auxiliary materials.
作为本发明的一种优选技术方案，所述药物组合物中含有低取代羟丙纤维素和交联聚维酮，低取代羟丙纤维素在药物组合物中使用量为优选17％-30％，交联聚维酮在药物组合物中使用量为优选8％-20％。As a preferred technical solution of the present invention, the pharmaceutical composition contains low-substituted hydroxypropyl cellulose and crospovidone, and the amount of low-substituted hydroxypropyl cellulose in the pharmaceutical composition is preferably 17%-30%. , The dosage of crospovidone in the pharmaceutical composition is preferably 8%-20%.
作为本发明的一种优选技术方案，优选低取代羟丙纤维素和交联聚维酮的比例为1∶1-3∶1，二者重量之和优选在药物组合物中使用量为25％-40％。更优选当复合物在药物组合物中的比例为25％-30％，低取代羟丙纤维素和交联聚维酮的比例为1.75∶1-2.25∶1，更优选2∶1。As a preferred technical solution of the present invention, the ratio of low-substituted hydroxypropyl cellulose and crospovidone is preferably 1:1-3:1, and the sum of the weight of the two is preferably 25% in the pharmaceutical composition. -40%. More preferably, when the ratio of the complex in the pharmaceutical composition is 25%-30%, the ratio of low-substituted hydroxypropyl cellulose and crospovidone is 1.75:1-2.25:1, more preferably 2:1.
作为本发明的一种优选技术方案，所述药物组合物中含有羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮，其中，羧甲淀粉钠在药物组合物中使用量为4％-12％，交联羧甲基纤维素钠在药物组合物中使用量为4％-12％，交联聚维酮在药物组合物中使用量为4％-12％；三者重量之和优选在药物组合物中使用量为15％-35％。更优选当复合物在药物组合物中的比例为40％-50％时，羧甲淀粉钠在药物组合物中使用量为8-12％，交联羧甲基纤维素钠在药物组合物中使用量为8-12％，交联聚维酮在药物组合物中使用量为8-12％。As a preferred technical solution of the present invention, the pharmaceutical composition contains sodium carboxymethyl starch, croscarmellose sodium and crospovidone, wherein the dosage of sodium carboxymethyl starch in the pharmaceutical composition is 4%-12%, the amount of croscarmellose sodium in the pharmaceutical composition is 4%-12%, and the amount of crospovidone in the pharmaceutical composition is 4%-12%; the three The sum of weights is preferably used in an amount of 15%-35% in the pharmaceutical composition. More preferably when the ratio of the compound in the pharmaceutical composition is 40%-50%, the sodium starch glycolate used in the pharmaceutical composition is 8-12%, and the croscarmellose sodium in the pharmaceutical composition The usage amount is 8-12%, and the usage amount of the crospovidone in the pharmaceutical composition is 8-12%.
在本发明中，前述比例的低取代羟丙纤维素具有很大的表面积和孔隙率，具有很强的吸水膨胀性，展现明显的崩解效果；而且，前述比例的交联聚维酮在本发明中具有良好的流动性，在水中迅速表现出毛细管活性和优异的水化能力，也具有良好的崩解性能。联合使用低取代羟丙纤维素和交联聚维酮，可使本品在溶出介质中迅速崩解，达到快速释放的作用。In the present invention, the low-substituted hydroxypropyl cellulose of the aforementioned ratio has a large surface area and porosity, has strong water absorption swelling property, and exhibits obvious disintegration effect; moreover, the crospovidone of the aforementioned ratio is used in this invention The invention has good fluidity, rapidly exhibits capillary activity and excellent hydration ability in water, and also has good disintegration performance. The combined use of low-substituted hydroxypropyl cellulose and crospovidone can make this product disintegrate rapidly in the dissolution medium and achieve rapid release.
作为本发明的一种优选技术方案，一种以上的其他辅料包括一种以上的填充剂、润滑剂和包衣剂等。As a preferred technical solution of the present invention, more than one other adjuvant includes more than one filler, lubricant and coating agent.
作为本发明的一种优选技术方案，所述填充剂包括微晶纤维素、乳糖、甘露醇、磷酸氢钙一种或者两种以上任意比例的混合物，使用量为药物组合物重量的16％-60％，优选17％-45％。As a preferred technical solution of the present invention, the filler includes microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate or a mixture of two or more in any proportion, and the usage amount is 16%- 60%, preferably 17%-45%.
作为本发明的一种优选技术方案，所述填充剂包含微晶纤维素和乳糖的混合物，优选微晶纤维素和乳糖的质量比为1∶1-5∶1，优选微晶纤维素和乳糖的总质量为药物组合物重量的16％-60％，更优选为17％-45％。As a preferred technical solution of the present invention, the filler comprises a mixture of microcrystalline cellulose and lactose, preferably the mass ratio of microcrystalline cellulose and lactose is 1:1-5:1, preferably microcrystalline cellulose and lactose The total mass of the pharmaceutical composition is 16%-60%, more preferably 17%-45%.
作为本发明的一种优选技术方案，所述乳糖优选无水乳糖，本发明无水乳糖和微晶纤维素构成约40％以上的总制剂部分，作为处方中的填充剂具有良好的流动性和可压缩性，其性质稳定，制成的片剂外观光洁，硬度、崩解较好。也可用于直压工艺、干法制粒工艺。As a preferred technical solution of the present invention, the lactose is preferably anhydrous lactose, and the anhydrous lactose and microcrystalline cellulose of the present invention constitute more than 40% of the total preparation part, and have good fluidity and Compressibility, its properties are stable, and the tablets made have smooth appearance, good hardness and disintegration. It can also be used in direct compression process and dry granulation process.
作为本发明的一种优选技术方案，当复合物在药物组合物中的比例为25％-30％(具体如复合物以游离酸计如60、120mg)，所述微晶纤维素和乳糖的质量比为1.5∶1-5∶1，优选微晶纤维素和乳糖的总质量为药物组合物重量的17％-45％。As a preferred technical solution of the present invention, when the ratio of the compound in the pharmaceutical composition is 25%-30% (specifically, such as the compound is calculated as 60, 120 mg in terms of free acid), the content of the microcrystalline cellulose and lactose The mass ratio is 1.5:1-5:1, preferably the total mass of microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.
作为本发明的一种优选技术方案，当复合物在药物组合物中的比例为40％-50％(具体如复合物以游离酸计240mg)，所述微晶纤维素和乳糖的质量比为1.8∶1-2.2∶1(具体如如1.9∶1，2∶1，2.1∶1等)，优选微晶纤维素和乳糖的总质量为药物组合物重量的17％-45％。As a preferred technical solution of the present invention, when the proportion of the compound in the pharmaceutical composition is 40%-50% (specifically, as the compound is 240 mg in terms of free acid), the mass ratio of the microcrystalline cellulose and lactose is 1.8:1-2.2:1 (specifically such as 1.9:1, 2:1, 2.1:1, etc.), preferably the total mass of microcrystalline cellulose and lactose is 17%-45% of the weight of the pharmaceutical composition.
作为本发明的一种优选技术方案，所述复合物(以无水游离酸C46H50ClN7O7计)的质量为药物组合物重量的20％-50％，优选具体使用量为30mg、60mg、90mg、120mg、150mg、180mg、210mg、240mg、270mg、300mg等。As a preferred technical solution of the present invention, the mass of the complex (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) is 20%-50% of the weight of the pharmaceutical composition, and the preferred specific usage amount is 30mg , 60mg, 90mg, 120mg, 150mg, 180mg, 210mg, 240mg, 270mg, 300mg, etc.
作为本发明的一种优选技术方案，所述润滑剂包括二氧化硅，硬脂酸，硬脂酸镁、聚乙二醇、氢化蓖麻油中的一种或者两种以上的混合物，所述润滑剂的质量为药物组合物重量的1％-3％。As a preferred technical solution of the present invention, the lubricant includes silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol, hydrogenated castor oil or a mixture of two or more, the lubricant The quality of the agent is 1%-3% of the weight of the pharmaceutical composition.
作为本发明的一种优选技术方案，润滑剂选择二氧化硅和硬脂酸镁的组合物，二氧化硅主要发挥助流剂并兼有润滑的作用，硬脂酸镁属于疏水性物料，在本发明中易与颗粒混匀并附着于颗粒表面，可以减少颗粒与冲模之间的摩擦力。两者按前述比例合用于本发明药物组合物中，能明显增加物料的流动性，压片后片面光滑美观。As a preferred technical solution of the present invention, the lubricant is selected from the composition of silicon dioxide and magnesium stearate, silicon dioxide mainly plays the role of glidant and lubricating, and magnesium stearate belongs to hydrophobic materials. In the present invention, it is easy to mix with the granule and adhere to the surface of the granule, which can reduce the friction between the granule and the die. The two are used together in the pharmaceutical composition of the present invention according to the aforementioned ratio, which can obviously increase the fluidity of the material, and the tablet surface is smooth and beautiful after being compressed.
除另有说明外，前述原辅料在药物组合物中的百分比之和为95％-100％，所述使用量均为质量使用量。Unless otherwise specified, the sum of the percentages of the aforementioned raw and auxiliary materials in the pharmaceutical composition is 95%-100%, and the usage amounts are all mass usage amounts.
作为本发明的一种优选技术方案，所述包衣剂包括任意的胃溶性包衣。具体地，例如胃溶性包衣包括85G640059-CN，所述胃溶性包衣的采用水等溶剂混合物(优选胃溶性包衣剂与纯化水按质量比为1∶5-1∶8混合后进行包衣)，包衣后增重约0.1％-4％。As a preferred technical solution of the present invention, the coating agent includes any gastric soluble coating. Specifically, for example, the gastric-soluble coating includes 85G640059-CN, and the gastric-soluble coating is coated with a solvent mixture such as water (preferably mixing the gastric-soluble coating agent and purified water at a mass ratio of 1:5-1:8) Coating), the weight gain after coating is about 0.1%-4%.
本发明复合物的组成中，EXP3174的分子式为C22H21ClN6O2，分子量约为436.9；AHU377的分子式为C24H29NO5，分子量约为411.5。In the composition of the complex of the present invention, the molecular formula of EXP3174 is C 22 H 21 ClN 6 O 2 , and the molecular weight is about 436.9; the molecular formula of AHU377 is C 24 H 29 NO 5 , and the molecular weight is about 411.5.
所述药物的所述复合物可以通过现有技术已知的方法获得，其中，WO2017125031A1公开的复合物及其制备方法引入本发明。The compound of the drug can be obtained by methods known in the prior art, wherein the compound disclosed in WO2017125031A1 and its preparation method are introduced into the present invention.
作为本发明的一种更为优选技术方案，a∶b的值包括1∶0.25，1∶0.5，1∶1，1∶1.5，1∶2，1∶2.5，1∶3，1∶3.5，1∶4。As a more preferred technical solution of the present invention, the value of a:b includes 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4.
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：As a more preferred technical solution of the present invention, the structural units of the complex are as follows:
(EXP3174·AHU377)·xCa·nH2O(EXP3174·AHU377)·xCa·nH 2 O
或者or
其中x为0.5～2之间的数值；n为0～3之间的数值。Wherein, x is a value between 0.5 and 2; n is a value between 0 and 3.
作为本发明的一种更为优选技术方案，x包括0.5、1、1.5、2。As a more preferred technical solution of the present invention, x includes 0.5, 1, 1.5, and 2.
作为本发明的一种更为优选技术方案，所述复合物的结构单元如下：As a more preferred technical solution of the present invention, the structural units of the complex are as follows:
(EXP3174·AHU377)·1.5Ca·nH2O(EXP3174·AHU377)·1.5Ca·nH 2 O
或者or
(EXP3174·AHU377)·2Ca·nH2O(EXP3174·AHU377)·2Ca·nH 2 O
其中n为1～3之间的任意数值。Where n is any value between 1 and 3.
作为本发明的一种更为优选技术方案，n包括0.5、1、1.5、2、2.5、3。As a more preferred technical solution of the present invention, n includes 0.5, 1, 1.5, 2, 2.5, 3.
作为本发明的一种更为优选技术方案，所述复合物包括：As a more preferred technical solution of the present invention, the complex includes:
(EXP3174·AHU377)·1.5Ca·1H2O；(EXP3174·AHU377)·1.5Ca·1H 2 O;
(EXP3174·AHU377)·1.5Ca·1.5H2O；(EXP3174·AHU377)·1.5Ca·1.5H 2 O;
(EXP3174·AHU377)·1.5Ca·2H2O；(EXP3174·AHU377)·1.5Ca·2H 2 O;
(EXP3174·AHU377)·1.5Ca·2.5H2O；(EXP3174·AHU377)·1.5Ca·2.5H 2 O;
(EXP3174·AHU377)·1.5Ca·3H2O；(EXP3174·AHU377)·1.5Ca·3H 2 O;
(EXP3174·AHU377)·2Ca·1H2O；(EXP3174·AHU377)·2Ca·1H 2 O;
(EXP3174·AHU377)·2Ca·1.5H2O；(EXP3174·AHU377)·2Ca·1.5H 2 O;
(EXP3174·AHU377)·2Ca·2H2O；(EXP3174 AHU377) 2Ca 2H 2 O;
(EXP3174·AHU377)·2Ca·2.5H2O；(EXP3174·AHU377)·2Ca·2.5H 2 O;
(EXP3174·AHU377)·2Ca·3H2O。(EXP3174·AHU377)·2Ca·3H 2 O.
本领域的技术人员可以理解，在超分子络合物(复合物)的单位晶胞中，所述阿利沙坦酯代谢产物(EXP3174)、AHU377、钙离子(Ca2+)和溶剂分子会以数个结构单元的形式填充于其中。Those skilled in the art can understand that in the unit cell of the supramolecular complex (complex), the metabolites of alisartan medoxomil (EXP3174), AHU377, calcium ions (Ca 2+ ) and solvent molecules will be in the form of several It is filled in the form of structural units.
本发明所述超分子络合物(复合物)区别于两种活性成分通过简单的物理混合得到的混合物。所述复合物分子中EXP3174和AHU377和药学上可接受的钙阳离子，通过非共价键结合得到超分子络合物(复合物)，所述非共价键为本领域普通技术人员所熟知，包含但不限于氢键、配位键、离子键等等，所得超分子络合物(复合物)的XRD谱图明显区别于EXP3174和AHU377钙盐的XRD谱图，其在各溶剂(诸如水、乙醇、乙醇-水等)中的溶解性能也存在明显区别，在其他各项理化性质诸如吸湿性、熔点、红外谱图等均存在明显差异。The supramolecular complexes (complexes) of the present invention are distinguished from mixtures obtained by simple physical mixing of two active ingredients. EXP3174 and AHU377 and pharmaceutically acceptable calcium cations in the complex molecule are combined by non-covalent bonds to obtain a supramolecular complex (complex), and the non-covalent bonds are well known to those of ordinary skill in the art, Including but not limited to hydrogen bonds, coordination bonds, ionic bonds, etc., the XRD spectrum of the obtained supramolecular complex (complex) is obviously different from the XRD spectrum of EXP3174 and AHU377 calcium salt, which is in each solvent (such as water , ethanol, ethanol-water, etc.) are also significantly different in solubility, and there are obvious differences in other physical and chemical properties such as hygroscopicity, melting point, infrared spectrum, etc.
所述药物组合物是适于口服的固体制剂，优选口服的片剂或胶囊。The pharmaceutical composition is a solid preparation suitable for oral administration, preferably an oral tablet or capsule.
本发明进一步提供了所述的药物组合物的制备方法，所述原辅料采用直压工艺，或者干法制粒工艺制备后压片，然后采用包衣剂包衣，得到包衣的药物组合物。The present invention further provides a method for preparing the pharmaceutical composition. The raw materials are prepared by direct compression or dry granulation and then compressed into tablets, and then coated with a coating agent to obtain a coated pharmaceutical composition.
本发明进一步提供了所述的药物组合物可以应用于预防和/或治疗高血压、心衰、高血压和心衰的药物中使用。The present invention further provides that the pharmaceutical composition can be used in medicines for preventing and/or treating hypertension, heart failure, hypertension and heart failure.
本发明相对于现有技术的有益效果包括：The beneficial effect of the present invention with respect to prior art comprises:
(1)本发明实施方案可以有效保证药物的崩解和溶出，具有良好的制粒流动性等效果。(1) The embodiment of the present invention can effectively ensure the disintegration and dissolution of the drug, and has good granulation fluidity and other effects.
(2)本发明获得的药物组合物，通过临床验证，可以有效的达到体内用药浓度，应用于预防和/或治疗高血压、心衰、高血压和心衰的药物中使用；(2) The pharmaceutical composition obtained in the present invention can effectively reach the drug concentration in the body through clinical verification, and can be used in the prevention and/or treatment of hypertension, heart failure, hypertension and heart failure;
(3)本发明大大减少处方的原辅料组成，不仅工艺简单，环保经济，利于大规模产业化应用。(3) The present invention greatly reduces the composition of raw and auxiliary materials of the prescription, not only has simple process, is environmentally friendly and economical, and is beneficial to large-scale industrial application.
(4)本发明在药物组合物活性成分占比较高的情况下，有效控制片重的情况，保证了药物的溶出和效果，有利于该药物的临床使用。(4) In the case where the proportion of active ingredients in the pharmaceutical composition is relatively high, the present invention effectively controls the tablet weight, ensures the dissolution and effect of the drug, and is beneficial to the clinical use of the drug.
具体实施方式Detailed ways
下面结合实施例对本发明作进一步详细的描述，但发明的实施方式不限于此。The present invention will be further described in detail below in conjunction with the examples, but the embodiments of the invention are not limited thereto.
实施例1Example 1
AHU377游离酸的制备：Preparation of AHU377 free acid:
将2.1g AHU377钙盐、40mL醋酸异丙酯加入250mL的单口瓶中，室温下加入2mol/L盐酸4.5mL搅拌溶清。分液，收集有机层，使用20mL水洗涤有机层两次；35℃下减压脱溶，得AHU377游离酸。Add 2.1g of AHU377 calcium salt and 40mL of isopropyl acetate into a 250mL single-necked bottle, add 4.5mL of 2mol/L hydrochloric acid at room temperature and stir to dissolve. Separate the liquid, collect the organic layer, and wash the organic layer twice with 20 mL of water; desolvate under reduced pressure at 35°C to obtain the free acid of AHU377.
实施例2Example 2
复合物的制备：(按照专利WO2017125031A1的实施例2制备)Preparation of the complex: (prepared according to Example 2 of patent WO2017125031A1)
室温下，将依据实施例1方法所得的AHU377游离酸2.36g、EXP31742g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU3771.3当量的氢氧化钙固体和1mL水，室温搅拌10h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，35℃下真空烘8h，烘干得到固体3.5g(EXP3174·AHU377)3-·1.5Ca2+·2.5H2O，HPLC检测纯度为99％。重复试验，以获得足够的药效实验用量。At room temperature, add 2.36g of AHU377 free acid, EXP31742g and 40mL of acetone obtained according to the method of Example 1 into a 250mL three-necked flask, and dissolve; add 1.3 equivalents of calcium hydroxide solid and 1mL of water relative to AHU377 at room temperature, and stir at room temperature 10h, add 40mL of acetone, react for another 8h, filter through a Buchner funnel under nitrogen protection, rinse the solid with acetone to obtain a white solid, dry in vacuum at 35°C for 8h, and dry to obtain 3.5g of solid (EXP3174·AHU377) 3 - · 1.5Ca 2+ · 2.5H 2 O, the purity by HPLC is 99%. Repeat the test to obtain sufficient dosage for the drug effect test.
实施例3Example 3
复合物的制备：(按照专利WO2017125031A1的实施例3制备)Preparation of the complex: (prepared according to Example 3 of patent WO2017125031A1)
室温下，将依据实施例1方法所得的AHU377游离酸2.36g、EXP31742g与40mL丙酮加入至250mL三口瓶，溶清；室温下加入相对于AHU3771.6当量的氢氧化钙固体和0.6mL水，35℃搅拌6h，补加40mL丙酮，再反应8h，氮气保护下经布氏漏斗抽滤，固体用丙酮淋洗，得白色固体，50℃下真空烘8h，烘干得到固体3.1g(EXP3174·AHU377)3-·1.5Ca2+·2H2O。重复试验，以获得足够的药效实验用量。At room temperature, add 2.36g of AHU377 free acid, EXP31742g and 40mL of acetone obtained according to the method of Example 1 into a 250mL three-necked flask, and dissolve; Stir at ℃ for 6 hours, add 40 mL of acetone, react for another 8 hours, filter through Buchner funnel under nitrogen protection, rinse the solid with acetone to obtain a white solid, dry in vacuum at 50 °C for 8 hours, and dry to obtain 3.1 g of solid (EXP3174·AHU377 ) 3- · 1.5Ca 2+ · 2H 2 O. Repeat the test to obtain sufficient dosage for the drug effect test.
实施例4Example 4
参照实施例2和3的制备方法，分别制备得到以下复合物：With reference to the preparation methods of Examples 2 and 3, the following complexes were prepared respectively:
(EXP3174·AHU377)·1.5Ca·1H2O；(EXP3174·AHU377)·1.5Ca·1H 2 O;
(EXP3174·AHU377)·1.5Ca·1.5H2O；(EXP3174·AHU377)·1.5Ca·1.5H 2 O;
(EXP3174·AHU377)·1.5Ca·3H2O；(EXP3174·AHU377)·1.5Ca·3H 2 O;
(EXP3174·AHU377)·2Ca·1H2O；(EXP3174·AHU377)·2Ca·1H 2 O;
(EXP3174·AHU377)·2Ca·1.5H2O；(EXP3174·AHU377)·2Ca·1.5H 2 O;
(EXP3174·AHU377)·2Ca·2H2O；(EXP3174 AHU377) 2Ca 2H 2 O;
(EXP3174·AHU377)·2Ca·2.5H2O；(EXP3174·AHU377)·2Ca·2.5H 2 O;
(EXP3174·AHU377)·2Ca·3H2O。(EXP3174·AHU377)·2Ca·3H 2 O.
实施例5崩解剂及其用量选择Embodiment 5 disintegrant and consumption selection thereof
通过测定pH6.8介质的溶出曲线，考察不同崩解剂种类，筛选较佳崩解剂用量。处方设计内容见表1，溶出曲线结果见表2。By measuring the dissolution curve of the pH6.8 medium, different types of disintegrants were investigated, and the optimal dosage of disintegrants was screened. The content of the formulation design is shown in Table 1, and the results of the dissolution curve are shown in Table 2.
表1不同崩解剂及用量处方实验Table 1 Different disintegrants and dosage prescription experiments
表2不同崩解剂及用量溶出曲线研究结果Table 2 Different disintegrants and dosage dissolution curve research results
由崩解剂选择结果可知，使用低取代羟丙纤维素和交联聚维酮比单独使用低取代羟丙纤维素更能促进溶出，低取代羟丙纤维素和交联聚维酮的使用量分别达17.8％和8.9％时，溶出能在15min达85％以上。According to the results of disintegrant selection, the use of low-substituted hydroxypropyl cellulose and crospovidone can promote dissolution more than that of low-substituted hydroxypropyl cellulose alone, and the dosage of low-substituted hydroxypropyl cellulose and crospovidone When reaching 17.8% and 8.9% respectively, the dissolution can reach more than 85% in 15 minutes.
所以，优选低取代羟丙纤维素在药物组合物中使用量为17％-30％，交联聚维酮在药物组合物中使用量为8％-20％，优选二者在药物组合物中使用量为25％-40％。Therefore, the preferred low-substituted hydroxypropyl cellulose used in the pharmaceutical composition is 17%-30%, and the crospovidone used in the pharmaceutical composition is 8%-20%, preferably both in the pharmaceutical composition The usage amount is 25%-40%.
实施例6填充剂及其用量选择Embodiment 6 filler and its consumption selection
在实施例5的基础上，本品制剂中填充剂选择晶纤维素(Type102)和无水乳糖(DTHV)。实验结果发现，不同配比的填充剂可能影响片芯的崩解及溶出情况，结合崩解时间及pH6.8介质的溶出曲线筛选出适合的处方比例，具体见表3。两者填充剂混合使用能保证片芯外观、重量差异、脆碎度符合要求。On the basis of Example 5, crystalline cellulose (Type 102) and anhydrous lactose (DTHV) are selected as fillers in the preparation of this product. The experimental results found that different proportions of fillers may affect the disintegration and dissolution of the tablet core, and the appropriate prescription ratio was selected based on the disintegration time and the dissolution curve of the pH 6.8 medium. See Table 3 for details. The mixed use of the two fillers can ensure that the appearance, weight difference and friability of the tablet core meet the requirements.
表3微晶纤维素/乳糖不同比例的处方设计Table 3 Prescription design of different ratios of microcrystalline cellulose/lactose
表4微晶纤维素/乳糖不同比例的崩解时间的研究结果Table 4 The research results of the disintegration time of different ratios of microcrystalline cellulose/lactose
表5微晶纤维素/乳糖不同比例的溶出曲线的研究结果Table 5 The results of the dissolution profile of different ratios of microcrystalline cellulose/lactose
另外，混粉流动性考察结果：采用微晶纤维素/乳糖配比为2∶1，休止角(°)为40°左右，可以满足流动性的要求。In addition, the test results of the fluidity of the mixed powder: the ratio of microcrystalline cellulose/lactose is 2:1, and the angle of repose (°) is about 40°, which can meet the fluidity requirements.
由于微晶纤维素/乳糖配比为6∶1时，药片厚度较厚，可能影响吞咽和依从效果。When the ratio of microcrystalline cellulose/lactose is 6:1, the tablet is thicker, which may affect swallowing and compliance.
综合以上结果可知，进一步优选微晶纤维素和无水乳糖的质量比为1∶1-5∶1，优选微晶纤维素和乳糖的总质量为药物组合物重量的18％-60％，不仅崩解时间快，而且能得到快速溶出效果，更优选微晶纤维素和乳糖的质量比为1.5∶1-5∶1，溶出效果30min≥85％。Based on the above results, it can be seen that the mass ratio of microcrystalline cellulose and anhydrous lactose is further preferably 1:1-5:1, and the total mass of microcrystalline cellulose and lactose is preferably 18%-60% of the weight of the pharmaceutical composition, not only The disintegration time is fast, and a rapid dissolution effect can be obtained. More preferably, the mass ratio of microcrystalline cellulose and lactose is 1.5:1-5:1, and the dissolution effect is ≥85% within 30 minutes.
实施例7研究不同体外溶出的样品在动物体内的药动学情况。Example 7 studies the pharmacokinetics of different samples dissolved in vitro in animals.
通过实施例5、6优选的技术方案，制备出三个具有不同的样品，进行犬PK试验，具体处方组成如表6中所示，溶出曲线结果见表7。Through the preferred technical scheme of Examples 5 and 6, three samples with different characteristics were prepared, and the dog PK test was carried out. The specific prescription composition is shown in Table 6, and the dissolution curve results are shown in Table 7.
表6不同处方组成Table 6 Different prescription composition
*肠溶包衣配方中含：Eudragit L30D-55、滑石粉、柠檬酸三乙酯，和纯化水按照质量比1∶6混合后进行包衣，包衣后增重约3％。*The enteric coating formula contains: Eudragit L30D-55, talcum powder, triethyl citrate, and purified water are mixed at a mass ratio of 1:6 for coating, and the weight gain after coating is about 3%.
表7不同处方的体外溶出结果Table 7 The in vitro dissolution results of different formulations
结果：由于3C批次选择了肠溶包衣，在pH5.5以下的酸性介质中肠溶衣膜不会被破坏，因此，未检测3C批次片剂在pH1.2及pH5.0中的溶出曲线。Results: Since the enteric coating was selected for the 3C batch, the enteric coating film will not be destroyed in the acidic medium below pH 5.5. Therefore, the 3C batch of tablets at pH 1.2 and pH 5.0 were not tested. Dissolution profile.
以原料药的混悬液作为对照，采用这3A、3B和3C三批样品进行犬PK试验，考察不同体外溶出行为的处方在比格犬体内的药动学情况，结果如表8所示。Taking the suspension of the raw material drug as a control, the three batches of samples 3A, 3B and 3C were used for the PK test in dogs to investigate the pharmacokinetics of the formulations with different in vitro dissolution behaviors in Beagle dogs. The results are shown in Table 8.
表8不同处方样品在比格犬的体内药动学结果Table 8 The pharmacokinetic results of different prescription samples in Beagle dogs
注：LBQ657为沙库巴曲活性代谢产物。Note: LBQ657 is the active metabolite of sacubitril.
由以上结果可知，与混悬液比较，沙库巴曲三种处方片剂F值均有90％以上，说明沙库巴曲主要在小肠远端吸收，而EXP3174肠溶包衣片剂与混悬液相比生物利用度只有混悬液的60％左右，其他2组别没有包肠溶衣片剂F值均有90％以上，说明而EXP3174在小肠近端及远端均有吸收。From the above results, it can be seen that compared with the suspension, the F values of the three prescription tablets of sacubitril are all above 90%, indicating that sacubitril is mainly absorbed in the distal small intestine, while EXP3174 enteric-coated tablets and mixed Compared with the suspension, the bioavailability is only about 60% of that of the suspension, and the F values of the other 2 groups of uncoated tablets are above 90%, indicating that EXP3174 is absorbed in both the proximal and distal small intestines.
上述实验显示肠溶包衣样品与混悬液比较吸收降低，因此我们选择胃溶包衣。具体地，例如胃溶性包衣包括85G640059-CN，所述胃溶性包衣的采用水等溶剂混合物，包衣后增重约0.1％-4％。The above experiments showed that the absorption of enteric coated samples was reduced compared to suspension, so we chose gastric coating. Specifically, for example, the gastric soluble coating includes 85G640059-CN, the gastric soluble coating is made of a solvent mixture such as water, and the weight gain after coating is about 0.1%-4%.
在前述实验例5-7的技术方案的基础上，本发明进一步得到以下优选的实施例。On the basis of the technical solutions of the foregoing experimental examples 5-7, the present invention further obtains the following preferred embodiments.
实施例8Example 8
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
制备方法为：将前述原辅料进行混粉直压。The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed with powder and directly pressed.
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶7混合后，包衣混粉直压得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water according to the mass ratio of 1:7, the tablet obtained by direct compression of the coating mixed powder (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例9Example 9
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；Production process: The preparation method is: dry granulate the aforementioned raw and auxiliary materials, and then compress into tablets;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶7混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water according to the mass ratio of 1:7, the tablets obtained by coating, granulating and tabletting (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例10Example 10
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行混粉直压；Production process: the preparation method is: the above-mentioned raw and auxiliary materials are mixed with powder and directly pressed;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶6混合后，包衣混粉直压得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (gastric solution type 295F640025-CN) and purified water according to the mass ratio of 1:6, the tablet obtained by direct compression of the coating mixed powder (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例11Example 11
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；Production process: The preparation method is: dry granulate the aforementioned raw and auxiliary materials, and then compress into tablets;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (gastric solution type 295F640025-CN) and purified water according to the mass ratio of 1:6, the tablet obtained by coating, granulating and tabletting (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例12Example 12
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行混粉直压；Production process: the preparation method is: the above-mentioned raw and auxiliary materials are mixed with powder and directly pressed;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶6混合后，包衣混粉直压得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water according to the mass ratio of 1:6, the tablet obtained by direct compression of the coating mixed powder (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例13Example 13
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；Production process: The preparation method is: dry granulate the aforementioned raw and auxiliary materials, and then compress into tablets;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water according to the mass ratio of 1:6, the tablets obtained by coating, granulating and tabletting (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例14Example 14
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；Production process: The preparation method is: dry granulate the aforementioned raw and auxiliary materials, and then compress into tablets;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (gastric solution type 295F640025-CN) and purified water according to the mass ratio of 1:6, the tablet obtained by coating, granulating and tabletting (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
实施例15Example 15
采用实施例3获得复合物作为原料药，一种复合物药物组合物及其制备方法，包括：Using Example 3 to obtain the compound as a bulk drug, a compound pharmaceutical composition and a preparation method thereof, comprising:
生产工艺：制备方法为：将前述原辅料进行干法制粒，然后压片；Production process: The preparation method is: dry granulate the aforementioned raw and auxiliary materials, and then compress into tablets;
将包衣材料薄膜包衣预混剂(胃溶型295F640025-CN)和纯化水按照质量比1∶6混合后，包衣制粒压片得到的片剂(其中，包衣所用的纯化水在包衣后经干燥最终去除)，得到包衣片，包衣后增重约3％。After mixing the coating material film coating premix (gastric solution type 295F640025-CN) and purified water according to the mass ratio of 1:6, the tablet obtained by coating, granulating and tabletting (wherein, the purified water used for coating is in After coating, it is finally removed by drying) to obtain a coated tablet, with a weight gain of about 3% after coating.
注：a表示实施例8-15所述复合物的用量以无水游离酸C46H50ClN7O7计。Note: a represents the amount of the compound described in Examples 8-15 in terms of anhydrous free acid C 46 H 50 ClN 7 O 7 .
前述部分实施例的溶出效果如下：The stripping effect of foregoing part embodiment is as follows:
各实施例的溶出符合标准要求，并在动物实验中体现足够的药物暴露量。The dissolution of each embodiment meets the requirements of the standard, and shows sufficient drug exposure in animal experiments.
实施例16-23Examples 16-23
实施例16-23分别与实施例8-15的处方一致，所不同的是，所使用的原料药为实施例2的复合物a。Examples 16-23 are consistent with the prescriptions of Examples 8-15, except that the raw material drug used is the compound a of Example 2.
注：a表示所述复合物的用量以无水游离酸C46H50ClN7O7计。Note: a represents the amount of the complex in terms of anhydrous free acid C 46 H 50 ClN 7 O 7 .
实施例24采用实施例8的药物组合物进行临床I期试验Embodiment 24 adopts the pharmaceutical composition of embodiment 8 to carry out clinical phase I test
本发明复合物片已完成在健康受试者中单中心、随机、双盲、安慰剂对照的多剂量、单次、多次给药的耐受性、药代动力学I期临床试验。单次给药设置60mg、180mg、360mg、540mg、720mg、960mg、1080mg，共7个剂量组；多次给药设置180mg、360mg、540mg、720mg，共4个剂量组；在480mg剂量组开展食物影响试验，同时在食物影响试验第一周期采集尿样和粪样，用于回收率和药物代谢转化研究；以评价本发明复合物片在健康受试者中单次、多次给药的耐受性、药代动力学、药物代谢转化及回收率以及食物对其药代动力学的影响，并初步评价药效学。The compound tablet of the present invention has completed single-center, randomized, double-blind, placebo-controlled multiple-dose, single-dose, multiple-dose tolerance, and pharmacokinetic phase I clinical trials in healthy subjects. 60mg, 180mg, 360mg, 540mg, 720mg, 960mg, 1080mg for a single administration, 7 dosage groups in total; 180mg, 360mg, 540mg, 720mg for multiple administrations, 4 dosage groups in total; food in the 480mg dosage group Influence test, collect urine sample and excrement sample in the first cycle of food influence test at the same time, be used for recovery rate and drug metabolism conversion research; Receptivity, pharmacokinetics, drug metabolic transformation and recovery rate, and the influence of food on its pharmacokinetics, and preliminary evaluation of pharmacodynamics.
根据单次给药和多次给药的PK结果进行推算，口服本发明复合物240mg后，人体内EXP3174暴露量不低于口服氯沙坦100mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 200mg后人体内LBQ657暴露量；口服本发明复合物480mg后，人体内EXP3174暴露量不低于口服氯沙坦200mg后人体内总活性成分暴露量，人体内LBQ657暴露量不低于口服LCZ696 400mg后人体内LBQ657暴露量。According to the PK results of single administration and multiple administrations, after oral administration of 240 mg of the complex of the present invention, the exposure of EXP3174 in the human body is no less than the exposure of the total active ingredients in the human body after oral administration of 100 mg of losartan, and the exposure of LBQ657 in the human body The exposure amount of EXP3174 in the human body is not lower than the exposure amount of LBQ657 in the human body after oral administration of 200 mg of LCZ696; the exposure amount of EXP3174 in the human body is not lower than the exposure amount of the total active ingredients in the human body after oral administration of 200 mg of losartan, and the exposure amount of LBQ657 in the human body is not lower than that in the human body. Lower than the exposure of LBQ657 in humans after oral administration of LCZ696 400mg.
所以，本发明复合物在应用于心衰和高血压疾病患者后，从体内药代和药效上均表现符合预期的临床治疗效果。Therefore, after the complex of the present invention is applied to patients with heart failure and hypertensive diseases, it shows expected clinical therapeutic effects in terms of pharmacokinetics and efficacy in vivo.
对比实施例1Comparative Example 1
制粒工艺：干法制粒。Granulation process: dry granulation.
该处方测定pH1.2的溶出结果，溶出缓慢，具体如下表所示：The dissolution results of this prescription were measured at pH 1.2, and the dissolution was slow, as shown in the following table:
对比实施例2Comparative Example 2
制粒工艺：将实施例3复合物和泊洛沙姆188溶于二氯甲烷，将交联聚维酮XL和微晶纤维素置于流化床控制进风温度50-70℃，物料温度40-50℃，进行喷雾干燥，然后与硬脂酸镁混合后压片。Granulation process: dissolve the compound of Example 3 and poloxamer 188 in dichloromethane, place crospovidone XL and microcrystalline cellulose in a fluidized bed to control the inlet air temperature at 50-70°C, and the material temperature at 40°C -50°C, spray-dried, then mixed with magnesium stearate and compressed into tablets.
所得片剂进行40℃±2℃，75％±5％RH下保存2个月，采用HPLC法进行杂质检测，结果如下，可见该处方工艺的产品的稳定性较差。Gained tablet carries out 40 ℃ ± 2 ℃, preserves under 75% ± 5% RH for 2 months, adopts HPLC method to carry out impurity detection, the result is as follows, it can be seen that the stability of the product of this prescription process is relatively poor.
对比实施例3Comparative Example 3
采用以下处方与实施例处方进行对比，采用本发明处方，在pH1.2下的溶出明显好于301-305的对比例，并且，实施例9和实施例11的溶出性质接近，并通过犬pK实验发现，其体内代谢物的效果AUClast接近，可以有效保证药效。Adopt the following prescription to compare with the embodiment prescription, adopt the prescription of the present invention, the stripping under pH1.2 is obviously better than the comparative example of 301-305, and the stripping properties of embodiment 9 and embodiment 11 are close, and pass dog pK Experiments have found that the effect of its metabolites in the body is close to AUC last , which can effectively guarantee the efficacy of the drug.
实验处方及结果如下：The experimental prescription and results are as follows:
比格犬体内pk数据pk data in beagle dogs
备注：LBQ657为沙库巴曲活性代谢产物，*2为2片。Remarks: LBQ657 is the active metabolite of sacubitril, *2 is 2 tablets.
从上述实验结果可见，在本发明处方中，当复合物a在药物组合物中为60mg或者120mg时，选择微晶纤维素和乳糖作为支持剂的情况下，优选低取代羟丙纤维素和交联聚维酮的组合，其溶出效果优于交联羧甲基纤维素钠、低取代羟丙纤维素、交联聚维酮、羧甲淀粉钠单一使用或者其他比例组合；并且从批次305、306和实施例9、11的对比结果，优选低取代羟丙纤维素和交联聚维酮质量比为1.75-2.25∶1，更优选2∶1。From the above experimental results, it can be seen that in the prescription of the present invention, when complex a is 60 mg or 120 mg in the pharmaceutical composition, and microcrystalline cellulose and lactose are selected as support agents, low-substituted hydroxypropyl cellulose and cross-linked hydroxypropyl cellulose are preferred. The combination of polyvidone, its dissolution effect is better than croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, carboxymethyl starch sodium single use or other ratio combination; and from batch 305 , 306 and the comparative results of Examples 9 and 11, the mass ratio of low-substituted hydroxypropyl cellulose to crospovidone is preferably 1.75-2.25:1, more preferably 2:1.
a表示所述复合物的用量以无水游离酸C46H50ClN7O7计 a represents the amount of the complex in terms of anhydrous free acid C 46 H 50 ClN 7 O 7
对比实施例4Comparative Example 4
采用以下处方与实施例9通过猴pK实验发现，其体内代谢物的效果AUClast接近，可以有效保证相应药效。Using the following prescription and Example 9, it was found through the monkey pK experiment that the effect AUC last of the metabolites in the body is close, which can effectively guarantee the corresponding drug effect.
实验处方及结果如下：The experimental prescription and results are as follows:
动物(猴)体内pk数据pk data in animals (monkeys)
备注：LBQ657为沙库巴曲活性代谢产物，*4为4片。Note: LBQ657 is the active metabolite of sacubitril, *4 is 4 tablets.
动物的体内PK数据结果表明，401批EXP3174暴露量和4片实施例9工艺60mg样品更接近。The results of animal PK data showed that the exposure of 401 batches of EXP3174 was closer to that of 4 tablets of the 60 mg sample of the process of Example 9.
对比实施例5Comparative Example 5
实验处方及结果如下：The experimental prescription and results are as follows:
综合对比实施例4和5的效果，基于实施例14和15(批次401)、以及402和403的处方，本发明申请人研究发现，当复合物a在药物组合物中为240mg，微晶纤维素和乳糖的1.8∶1-2.2∶1(具体如1.9∶1，2∶1，2.1∶1)时，优选含有羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮，羧甲淀粉钠在药物组合物中使用量为8-12％，交联羧甲基纤维素钠在药物组合物中使用量为优选8-12％，交联聚维酮在药物组合物中使用量为8-12％，相对于选择其他比例的羧甲淀粉钠、交联羧甲基纤维素钠和交联聚维酮的组合，或者交联聚维酮和低取代羟丙纤维素的组合，以及在此基础上微晶纤维素和乳糖的其他比例，难以达到相应的溶出，预期难以达到相应的体内溶出效果。Comprehensively comparing the effects of Examples 4 and 5, based on the prescriptions of Examples 14 and 15 (batch 401), and 402 and 403, the applicant of the present invention has found that when Compound a is 240 mg in the pharmaceutical composition, microcrystalline When the ratio of cellulose and lactose is 1.8:1-2.2:1 (specifically such as 1.9:1, 2:1, 2.1:1), it is preferred to contain sodium carboxymethyl starch, croscarmellose sodium and crospovidone The dosage of sodium carboxymethyl starch in the pharmaceutical composition is 8-12%, the dosage of croscarmellose sodium in the pharmaceutical composition is preferably 8-12%, and the dosage of crospovidone in the pharmaceutical composition The amount used is 8-12%, relative to the combination of sodium starch glycolate, croscarmellose sodium and crospovidone, or crospovidone and low-substituted hydroxypropyl cellulose in other proportions Combinations, and other ratios of microcrystalline cellulose and lactose on this basis, it is difficult to achieve the corresponding dissolution, and it is expected that it is difficult to achieve the corresponding in vivo dissolution effect.
a表示所述复合物的用量以无水游离酸C46H50ClN7O7计 a represents the amount of the complex in terms of anhydrous free acid C 46 H 50 ClN 7 O 7
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.
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