TW202200123A - Pharmaceutical composition with complex and preparation method therefor having a complex of an angiotensin II receptor antagonist metabolite and an NEP inhibitor - Google Patents

Pharmaceutical composition with complex and preparation method therefor having a complex of an angiotensin II receptor antagonist metabolite and an NEP inhibitor Download PDF

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TW202200123A
TW202200123A TW110122085A TW110122085A TW202200123A TW 202200123 A TW202200123 A TW 202200123A TW 110122085 A TW110122085 A TW 110122085A TW 110122085 A TW110122085 A TW 110122085A TW 202200123 A TW202200123 A TW 202200123A
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pharmaceutical composition
complex
exp3174
ahu377
crospovidone
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TWI784575B (en
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蔡燕霞
葉冠豪
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大陸商深圳信立泰藥業股份有限公司
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    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract

The present invention belongs to the technical field of medicinal and pharmaceutical preparations, and relates to a pharmaceutical composition with a complex and a preparation method therefor. In particular, it relates to a pharmaceutical composition with a complex of an angiotensin II receptor antagonist metabolite and an NEP inhibitor and a preparation method therefor.

Description

一種複合物的藥物組合物及其製備方法A kind of compound pharmaceutical composition and preparation method thereof

本發明屬於醫藥製劑技術領域，涉及一種複合物的藥物組合物及其製備方法，特別涉及一種血管緊張素II受體拮抗劑代謝產物與NEP抑制劑的複合物的藥物組合物及其製備方法。The invention belongs to the technical field of pharmaceutical preparations, and relates to a complex pharmaceutical composition and a preparation method thereof, in particular to a complex pharmaceutical composition of an angiotensin II receptor antagonist metabolite and a NEP inhibitor and a preparation method thereof.

高血壓是以體循環動脈壓增高為主要表現的臨床綜合征，是最常見的心血管疾病。高血壓大多數起病緩慢，缺乏特殊臨床表現，導致診斷延遲，僅在測量血壓時或發生心、腦、腎等併發症時才被發現。長期的高血壓與心腦血管病發病和死亡風險之間存在密切的因果關係。Hypertension is a clinical syndrome characterized by increased systemic arterial pressure and is the most common cardiovascular disease. Most hypertension has a slow onset and lack of special clinical manifestations, which leads to a delay in diagnosis, and is 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 disease morbidity and mortality.

據統計，目前全世界有超過十億人高血壓未得到控制，預計到2030年會增加到15億。2012~2015年中國高血壓調查（CHS）調查結果顯示：中國≥18歲成人高血壓患病率為27.9%（加權率為23.2%），知曉率、治療率和控制率分別為51.6%，45.8%和16.8%，治療控制率為37.5%。高血壓的發病率呈不斷上升的趨勢，據統計，中國心血管病患者約為2.9億人（《中國心血管病報告2013》）。高血壓如果得不到有效的控制和治療，可以引起冠狀動脈硬化，出現冠心病、心絞痛，還可能造成高血壓性心臟病、心力衰竭等嚴重併發症。另外，長期高血壓可導致腎、腦、心血管等器官損傷。According to statistics, there are currently more than one billion people in the world with uncontrolled hypertension, which is expected to increase to 1.5 billion by 2030. The 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% and 45.8%, respectively. % and 16.8%, and the treatment control rate was 37.5%. The incidence of hypertension is on the rise. According to statistics, there are about 290 million people with cardiovascular disease in China ("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 hypertension can lead to kidney, brain, cardiovascular and other organ damage.

心衰是各種心臟疾病的嚴重表現或晚期階段，是全球慢性心血管疾病防治的重要內容，死亡率和再住院率居高不下。歐美流行病學資料顯示，成人心衰患病率為1.5%～2.0%，並且隨著年齡增加，心力衰竭的患病率也隨之增加，≥70歲人群患病率≥10%。2003年中國流行病學調查顯示，中國35～74歲成人心衰患病率為0.9%。《中國心血管病報告2016》提出中國心血管病患病率處於持續上升階段，心血管病死亡率居首位，高於腫瘤和其他疾病。中國人口老齡化加劇，冠心病、高血壓、糖尿病、肥胖等慢性病的發病呈上升趨勢，醫療水準的提高使心臟疾病患者生存期延長，導致中國心衰患病率呈持續升高趨勢。對國內10714例住院心衰患者的調查顯示：1980、1990、2000年心衰患者住院期間病死率分別為15.4%、12.3%和6.2%，主要死亡原因依次為左心衰竭(59%)、心律失常(13%)和心臟性猝死(13%)。China-HF研究顯示，住院心衰患者的病死率為4.1%。Heart failure is a severe manifestation or late stage of various heart diseases, and it is an important part of the prevention and treatment of chronic cardiovascular diseases in the world. The mortality rate and rehospitalization rate remain high. Epidemiological data from Europe and the United States show that the prevalence of heart failure in adults is 1.5% to 2.0%, and with the increase of age, the prevalence of heart failure also increases. A 2003 Chinese epidemiological survey showed that the prevalence of heart failure among Chinese adults aged 35 to 74 was 0.9%. "China Cardiovascular Disease Report 2016" pointed out that the prevalence of cardiovascular disease in China is in a stage of continuous increase, and the mortality rate of cardiovascular disease ranks first, higher than that of tumors and other diseases. China's population is aging, and the incidence of chronic diseases such as coronary heart disease, hypertension, diabetes, and obesity is on the rise. The improvement of medical standards has prolonged the survival period of patients with heart disease, resulting in a continuous increase in the prevalence of heart failure in China. A survey of 10,714 hospitalized patients with heart failure in China showed that in 1980, 1990, and 2000, the hospitalized mortality rates of heart failure patients were 15.4%, 12.3%, and 6.2%, respectively. The main causes of death were left heart failure (59%), heart rhythm disorders (13%) and sudden cardiac death (13%). The China-HF study showed that the fatality rate of hospitalized heart failure patients was 4.1%.

專利WO2007056546A1公開了一種纈沙坦（Valsartan）-沙庫巴曲（Sacubitril，AHU377）的鈉鹽複合物（LCZ696）及其製備方法，於2017年在中國獲批上市，商品名：諾欣妥® （國外上市商品名為ENTRESTO® ，2015年）用於心力衰竭。其分子結構單元如下：

Figure 02_image001
Figure 02_image001
Patent WO2007056546A1 discloses a sodium salt complex (LCZ696) of Valsartan-Sacubitril (AHU377) and its preparation method, which was approved for listing in China in 2017, trade name: Nuoxinto® (Foreign marketed under the trade name ENTRESTO ® , 2015) for heart failure. Its molecular structural units are as follows:
Figure 02_image001
Figure 02_image001

專利WO2009061713公開了一種沙庫巴曲纈沙坦鈉的製劑及其製備方法，通過將治療劑與至少一種可藥用賦形劑混合，公開了多種處方組成的製劑，接著將混合物用適合的設備如壓片機直接壓縮或將混合物用適合的設備如滾壓機壓制而製備。Patent WO2009061713 discloses a preparation of sacubitril and valsartan sodium and a preparation method thereof. By mixing the therapeutic agent with at least one pharmaceutically acceptable excipient, a preparation consisting of various prescriptions is disclosed, and then the mixture is mixed with suitable equipment. Such as direct compression in a tablet press or by compressing the mixture with suitable equipment such as a roller compactor.

已上市的ENTRESTO® 的處方組成含有微晶纖維素、低取代羥丙基纖維素、交聯聚維酮、硬脂酸鎂、滑石粉和膠體二氧化矽。 薄膜衣組成包含羥丙甲纖維素、二氧化鈦（E 171）、聚乙二醇4000、滑石粉和氧化鐵紅（E 172）。The marketed formulation of ENTRESTO ® contains microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, magnesium stearate, talc and colloidal silica. The film coat composition contains hypromellose, titanium dioxide (E 171), polyethylene glycol 4000, talc and red iron oxide (E 172).

另外，專利WO2017125031A1公開了一系列由血管緊張素受體拮抗劑代謝產物（EXP3174）與NEP抑制劑（Sacubitril）的複合物，且對射血分數保留的心力衰竭HFpEF表現一定效果，其分子結構單元如下：

Figure 02_image004
In addition, patent WO2017125031A1 discloses a series of complexes composed of angiotensin receptor antagonist metabolites (EXP3174) and NEP inhibitors (Sacubitril), which show a certain effect on heart failure HFpEF with preserved ejection fraction, and its molecular structural unit as follows:
Figure 02_image004

但是由於化合物組成的不同，如何尋找符合臨床使用的製劑方案至關重要，需進一步研究開發。However, due to the different composition of compounds, how to find a formulation that is suitable for clinical use is very important, and further research and development are required.

鑒於現有技術存在的問題，本發明的提供了一種新的複合物的藥物組合物及其製備方法，In view of the problems existing in the prior art, the present invention provides a new compound pharmaceutical composition and a preparation method thereof,

本發明通過以下技術方案來實現一種複合物的藥物組合物，所述複合物的結構單元如下： （aEXP3174·bAHU377）·xCa·nA 其中a:b=1:0.25~4；x為0.5~3之間的數值；A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-三級丁基醚、乙腈、甲苯、二氯甲烷；n為0~3之間的數值； 所述藥物組合物中含有低取代羥丙纖維素、交聯聚維酮、羧甲澱粉鈉、交聯羧甲基纖維素鈉、預膠化澱粉中的一種或者兩種以上任意比例的混合物，在藥物組合物中使用量為4%-50%；和一種以上的其他輔料。The present invention realizes a pharmaceutical composition of a compound through the following technical solutions, and the structural unit of the compound is as follows: (aEXP3174 bAHU377) xCa nA 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-tertiary butyl ether, Acetonitrile, toluene, dichloromethane; n is a value between 0 and 3; The pharmaceutical composition contains one of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, and pregelatinized starch, or a mixture of two or more in arbitrary proportions, The usage amount in the pharmaceutical composition is 4%-50%; and one or more other excipients.

作為本發明的一種優選技術方案，所述藥物組合物中含有低取代羥丙纖維素和交聯聚維酮，低取代羥丙纖維素在藥物組合物中使用量為優選17%-30%，交聯聚維酮在藥物組合物中使用量為優選8% -20%。As a preferred technical solution of the present invention, the pharmaceutical composition contains low-substituted hydroxypropyl cellulose and crospovidone, and the use amount of low-substituted hydroxypropyl cellulose in the pharmaceutical composition is preferably 17%-30%, The amount of crospovidone used in the pharmaceutical composition is preferably 8%-20%.

作為本發明的一種優選技術方案，優選低取代羥丙纖維素和交聯聚維酮的比例為1：1-3：1，二者重量之和優選在藥物組合物中使用量為25%-40%。更優選當複合物在藥物組合物中的比例為25%-30%，低取代羥丙纖維素和交聯聚維酮的比例為1.75：1-2.25：1，更優選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 weights of the two is preferably used in the pharmaceutical composition in an amount of 25%- 40%. More preferably, when the ratio of the complex in the pharmaceutical composition is 25%-30%, the ratio of low-substituted hydroxypropylcellulose and crospovidone is 1.75:1-2.25:1, more preferably 2:1.

作為本發明的一種優選技術方案，所述藥物組合物中含有羧甲澱粉鈉、交聯羧甲基纖維素鈉和交聯聚維酮，其中，羧甲澱粉鈉在藥物組合物中使用量為4%-12%，交聯羧甲基纖維素鈉在藥物組合物中使用量為4%-12%，交聯聚維酮在藥物組合物中使用量為4%-12%；三者重量之和優選在藥物組合物中使用量為15%-35%。更優選當複合物在藥物組合物中的比例為40%-50%時，羧甲澱粉鈉在藥物組合物中使用量為8-12%，交聯羧甲基纖維素鈉在藥物組合物中使用量為8-12%，交聯聚維酮在藥物組合物中使用量為8-12%。As a preferred technical solution of the present invention, the pharmaceutical composition contains sodium starch glycolate, croscarmellose sodium and crospovidone, wherein the amount of sodium starch glycolate used in the pharmaceutical composition is 4%-12%, the usage amount of croscarmellose sodium in the pharmaceutical composition is 4%-12%, and the usage amount of crospovidone in the pharmaceutical composition is 4%-12%; the weight of the three The sum 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 amount of sodium starch glycolate used in the pharmaceutical composition is 8-12%, and the croscarmellose sodium is in the pharmaceutical composition. The usage amount is 8-12%, and the usage amount of crospovidone in the pharmaceutical composition is 8-12%.

在本發明中，前述比例的低取代羥丙纖維素具有很大的表面積和孔隙率，具有很強的吸水膨脹性，展現明顯的崩解效果；而且，前述比例的交聯聚維酮在本發明中具有良好的流動性，在水中迅速表現出毛細管活性和優異的水化能力，也具有良好的崩解性能。聯合使用低取代羥丙纖維素和交聯聚維酮，可使本品在溶出介質中迅速崩解，達到快速釋放的作用。In the present invention, the low-substituted hydroxypropyl cellulose in the aforementioned proportion has a large surface area and porosity, has strong water-swelling properties, and exhibits obvious disintegration effect; The invention has good fluidity, rapidly shows 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 rapidly disintegrate this product in the dissolution medium to achieve rapid release.

作為本發明的一種優選技術方案，一種以上的其他輔料包括一種以上的填充劑、潤滑劑和包衣劑等。As a preferred technical solution of the present invention, one or more other auxiliary materials include one or more fillers, lubricants, coating agents, and the like.

作為本發明的一種優選技術方案，所述填充劑包括微晶纖維素、乳糖、甘露醇、磷酸氫鈣一種或者兩種以上任意比例的混合物，使用量為藥物組合物重量的16%-60%，優選17% -45%。As a preferred technical solution of the present invention, the filler includes one or a mixture of two or more of microcrystalline cellulose, lactose, mannitol and calcium hydrogen phosphate in any proportion, and the usage amount is 16%-60% of the weight of the pharmaceutical composition , preferably 17% -45%.

作為本發明的一種優選技術方案，所述填充劑包含微晶纖維素和乳糖的混合物，優選微晶纖維素和乳糖的質量比為1：1-5：1，優選微晶纖維素和乳糖的總質量為藥物組合物重量的16% -60%，更優選為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 the mass ratio of microcrystalline cellulose and lactose is 1:1-5:1. The total mass is 16%-60% by weight of the pharmaceutical composition, more preferably 17%-45%.

作為本發明的一種優選技術方案，所述乳糖優選無水乳糖，本發明無水乳糖和微晶纖維素構成約40%以上的總製劑部分，作為處方中的填充劑具有良好的流動性和可壓縮性，其性質穩定，製成的片劑外觀光潔，硬度、崩解較好。也可用於直壓工藝、乾法製粒工藝。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 as fillers in the prescription , its properties are stable, and the prepared tablets have smooth appearance, good hardness and disintegration. It can also be used in direct pressing process and dry granulation process.

作為本發明的一種優選技術方案，當複合物在藥物組合物中的比例為25%-30%（具體如複合物以游離酸計如60、120毫克(mg)），所述微晶纖維素和乳糖的質量比為1.5：1-5：1，優選微晶纖維素和乳糖的總質量為藥物組合物重量的17% -45%。As a preferred technical solution of the present invention, when the proportion of the complex in the pharmaceutical composition is 25%-30% (specifically, if the complex is calculated as free acid, such as 60, 120 milligrams (mg)), the microcrystalline cellulose The mass ratio to lactose is 1.5:1-5:1, preferably the total mass of microcrystalline cellulose and lactose is 17%-45% by weight of the pharmaceutical composition.

作為本發明的一種優選技術方案，當複合物在藥物組合物中的比例為40%-50%（具體如複合物以游離酸計240 mg），所述微晶纖維素和乳糖的質量比為1.8：1-2.2：1（具體如如1.9：1，2：1，2.1：1等），優選微晶纖維素和乳糖的總質量為藥物組合物重量的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, 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% by weight of the pharmaceutical composition.

作為本發明的一種優選技術方案，所述複合物（以無水游離酸C46 H50 ClN7 O7 計）的質量為藥物組合物重量的20% -50%，優選具體使用量為30 mg、60 mg、90 mg、120 mg、150 mg、180 mg、210 mg、240 mg、270 mg、300 mg等。As a preferred technical solution of the present invention, the mass of the compound (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 use amount is 30 mg, 60 mg, 90 mg, 120 mg, 150 mg, 180 mg, 210 mg, 240 mg, 270 mg, 300 mg, etc.

作為本發明的一種優選技術方案，所述潤滑劑包括二氧化矽，硬脂酸，硬脂酸鎂、聚乙二醇、氫化蓖麻油中的一種或者兩種以上的混合物，所述潤滑劑的質量為藥物組合物重量的1% -3%。As a preferred technical solution of the present invention, the lubricant includes one or a mixture of two or more selected from silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol, and hydrogenated castor oil. The mass is 1%-3% of the weight of the pharmaceutical composition.

作為本發明的一種優選技術方案，潤滑劑選擇二氧化矽和硬脂酸鎂的組合物，二氧化矽主要發揮助流劑並兼有潤滑的作用，硬脂酸鎂屬於疏水性物料，在本發明中易與顆粒混勻並附著於顆粒表面，可以減少顆粒與沖模之間的摩擦力。兩者按前述比例合用於本發明藥物組合物中，能明顯增加物料的流動性，壓片後片面光滑美觀。As a preferred technical solution of the present invention, the lubricant is a combination of silicon dioxide and magnesium stearate, silicon dioxide mainly plays a glidant and has a lubricating effect, and magnesium stearate is a hydrophobic material. In the invention, it is easy to mix with the particles and adhere to the surface of the particles, which can reduce the friction between the particles and the die. The combination of the two in the pharmaceutical composition of the present invention in the aforementioned ratio can significantly increase the fluidity of the material, and the sheet surface is smooth and beautiful after tableting.

除另有說明外，前述原輔料在藥物組合物中的百分比之和為95%-100%，所述使用量均為質量使用量。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 quality usage amounts.

作為本發明的一種優選技術方案，所述包衣劑包括任意的胃溶性包衣。具體地，例如胃溶性包衣包括85G640059-CN，所述胃溶性包衣的採用水等溶劑混合物（優選胃溶性包衣劑與純化水按質量比為1：5-1：8混合後進行包衣），包衣後增重約0.1%-4%。As a preferred technical solution of the present invention, the coating agent includes any gastric-soluble coating. Specifically, for example, the stomach-soluble coating includes 85G640059-CN, and the stomach-soluble coating is coated with a solvent mixture such as water (preferably, the stomach-soluble coating agent and purified water are mixed in a mass ratio of 1:5-1:8) Coating), the weight gain after coating is about 0.1%-4%.

本發明複合物的組成中，EXP3174的分子式為C22 H21 ClN6 O2 ，分子量約為436.9； AHU377的分子式為C24 H29 NO5 ，分子量約為411.5。In the composition of the compound 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.

所述藥物的所述複合物可以通過現有技術已知的方法獲得，其中，WO2017125031A1公開的複合物及其製備方法引入本發明。The complex of the drug can be obtained by methods known in the prior art, wherein the complex disclosed in WO2017125031A1 and the preparation method thereof are incorporated into the present invention.

作為本發明的一種更為優選技術方案，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 values of a:b include 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1 :4.

作為本發明的一種更為優選技術方案，所述複合物的結構單元如下： （EXP3174·AHU377）·xCa·nH2 O

Figure 02_image006
或者 其中x為0.5~2之間的數值；n為0~3之間的數值。As a more preferred technical solution of the present invention, the structural unit of the complex is as follows: (EXP3174·AHU377)·xCa·nH 2 O
Figure 02_image006
Or where x is a value between 0.5 and 2; n is a value between 0 and 3.

作為本發明的一種更為優選技術方案，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.

作為本發明的一種更為優選技術方案，所述複合物的結構單元如下： （EXP3174·AHU377）·1.5Ca·nH2 O 或者 （EXP3174·AHU377）·2Ca·nH2 O 其中n為1~3之間的任意數值。As a more preferred technical solution of the present invention, the structural unit of the complex is as follows: (EXP3174·AHU377)·1.5Ca·nH 2 O or (EXP3174·AHU377)·2Ca·nH 2 O wherein n is 1~3 any value in between.

作為本發明的一種更為優選技術方案，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, and 3.

作為本發明的一種更為優選技術方案，所述複合物包括： （EXP3174·AHU377）·1.5Ca·1H2 O； （EXP3174·AHU377）·1.5Ca·1.5H2 O； （EXP3174·AHU377）·1.5Ca·2H2 O； （EXP3174·AHU377）·1.5Ca·2.5H2 O； （EXP3174·AHU377）·1.5Ca·3H2 O； （EXP3174·AHU377）·2Ca·1H2 O； （EXP3174·AHU377）·2Ca·1.5H2 O； （EXP3174·AHU377）·2Ca·2H2 O； （EXP3174·AHU377）·2Ca·2.5H2 O； （EXP3174·AHU377）·2Ca·3H2 O。As a more preferred technical solution of the present invention, the complex comprises: (EXP3174·AHU377)·1.5Ca·1H 2 O; (EXP3174·AHU377)·1.5Ca·1.5H 2 O; (EXP3174·AHU377)· 1.5Ca · 2H2O; (EXP3174·AHU377)·1.5Ca·2.5H2O; (EXP3174·AHU377)·1.5Ca · 3H2O ; (EXP3174·AHU377)·2Ca · 1H2O; (EXP3174·AHU377) )·2Ca·1.5H2O; (EXP3174·AHU377)· 2Ca · 2H2O; (EXP3174·AHU377)·2Ca·2.5H2O; (EXP3174·AHU377) · 2Ca· 3H2O .

本技術領域中具有通常知識者可以理解，在超分子絡合物（複合物）的單位晶胞中，所述阿利沙坦酯代謝產物（EXP3174）、AHU377、鈣離子（Ca2+ ）和溶劑分子會以數個結構單元的形式填充於其中。Those skilled in the art can understand that in the unit cell of the supramolecular complex (complex), the metabolite of allisartan medoxomil (EXP3174), AHU377, calcium ions (Ca 2+ ) and solvent molecules It will be filled in in the form of several structural units.

本發明所述超分子絡合物（複合物）區別於兩種活性成分通過簡單的物理混合得到的混合物。所述複合物分子中EXP3174和AHU377和藥學上可接受的鈣陽離子，通過非共價鍵結合得到超分子絡合物(複合物)，所述非共價鍵為本技術領域中具有通常知識者所熟知，包含但不限於氫鍵、配位鍵、離子鍵等等，所得超分子絡合物（複合物）的XRD譜圖明顯區別於EXP3174和AHU377鈣鹽的XRD譜圖，其在各溶劑（諸如水、乙醇、乙醇-水等）中的溶解性能也存在明顯區別，在其他各項理化性質諸如吸濕性、熔點、紅外譜圖等均存在明顯差異。The supramolecular complex (complex) of the present invention is distinguished from a mixture obtained by simple physical mixing of two active ingredients. EXP3174 and AHU377 and pharmaceutically acceptable calcium cations in the complex molecule are combined to obtain supramolecular complexes (complexes) through non-covalent bonds, and the non-covalent bonds are those with ordinary knowledge in the technical field. It is well known that, including but not limited to hydrogen bonds, coordination bonds, ionic bonds, etc., the XRD patterns of the obtained supramolecular complexes (complexes) are significantly different from those of EXP3174 and AHU377 calcium salts, which are in each solvent. (such as water, ethanol, ethanol-water, etc.), there are also obvious differences in solubility, and there are obvious differences in other physical and chemical properties such as hygroscopicity, melting point, and infrared spectrum.

所述藥物組合物是適於口服的固體製劑，優選口服的片劑或膠囊。The pharmaceutical composition is a solid preparation suitable for oral administration, preferably a tablet or capsule for oral administration.

本發明進一步提供了所述的藥物組合物的製備方法，所述原輔料採用直壓工藝，或者乾法製粒工藝製備後壓片，然後採用包衣劑包衣，得到包衣的藥物組合物。The present invention further provides the preparation method of the pharmaceutical composition, wherein the raw and auxiliary materials are prepared by a direct compression process or a dry granulation process and then compressed into tablets, and then coated with a coating agent to obtain a coated pharmaceutical composition.

本發明進一步提供了所述的藥物組合物可以應用於預防和/或治療高血壓、心衰、高血壓和心衰的藥物中使用。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.

本發明相對於現有技術的有益效果包括： （1）本發明實施方案可以有效保證藥物的崩解和溶出，具有良好的製粒流動性等效果。 （2）本發明獲得的藥物組合物，通過臨床驗證，可以有效的達到體內用藥濃度，應用於預防和/或治療高血壓、心衰、高血壓和心衰的藥物中使用； （3）本發明大大減少處方的原輔料組成，不僅工藝簡單，環保經濟，利於大規模產業化應用。 （4）本發明在藥物組合物活性成分占比較高的情況下，有效控制片重的情況，保證了藥物的溶出和效果，有利於該藥物的臨床使用。The beneficial effects of the present invention relative to the prior art include: (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) The pharmaceutical composition obtained by the present invention, through clinical verification, can effectively reach the drug concentration in vivo, and is used in medicines for the prevention and/or treatment of hypertension, heart failure, hypertension and heart failure; (3) The present invention greatly reduces the composition of the raw and auxiliary materials of the prescription, not only the process is simple, environmental protection and economical, but also conducive to large-scale industrial application. (4) The present invention effectively controls the weight of the tablet when the proportion of active ingredients in the pharmaceutical composition is relatively high, ensures the dissolution and effect of the drug, and is beneficial to the clinical use of the drug.

下面結合實施例對本發明作進一步詳細的描述，但發明的實施方式不限於此。The present invention will be further described in detail below with reference to the examples, but the embodiments of the invention are not limited thereto.

實施例1Example 1

AHU377游離酸的製備：Preparation of AHU377 free acid:

將2.1 g AHU377鈣鹽、40 mL醋酸異丙酯加入250mL的單口瓶中，室溫下加入2 mol/L鹽酸4.5 mL攪拌溶清。分液，收集有機層，使用20 mL水洗滌有機層兩次；35℃下減壓脫溶，得AHU377游離酸。Add 2.1 g of AHU377 calcium salt and 40 mL of isopropyl acetate into a 250-mL single-neck flask, and add 4.5 mL of 2 mol/L hydrochloric acid at room temperature to stir to dissolve. Separate the liquids, collect the organic layer, wash the organic layer twice with 20 mL of water, and remove the solution under reduced pressure at 35°C to obtain AHU377 free acid.

實施例2Example 2

複合物的製備：（按照專利WO2017125031A1的實施例2製備）

Figure 02_image008
Preparation of complex: (prepared according to Example 2 of patent WO2017125031A1)
Figure 02_image008

室溫下，將依據實施例1方法所得的AHU377游離酸2.36 g、EXP3174 2g與40 mL丙酮加入至250mL三口瓶，溶清；室溫下加入相對於AHU377 1.3當量的氫氧化鈣固體和1 mL水，室溫攪拌10h，補加40 mL丙酮，再反應8h，氮氣保護下經布氏漏斗抽濾，固體用丙酮淋洗，得白色固體，35℃下真空烘8h，烘乾得到固體3.5g（EXP3174·AHU377）3- ·1.5Ca2+ ·2.5H2 O，HPLC檢測純度為99%。重複試驗，以獲得足夠的藥效實驗用量。At room temperature, 2.36 g of AHU377 free acid, 2 g of EXP3174 and 40 mL of acetone obtained according to the method of Example 1 were added to a 250 mL there-necked flask, and dissolved; at room temperature, calcium hydroxide solid and 1 mL of 1.3 equivalents of calcium hydroxide relative to AHU377 were added. Water, stirred at room temperature for 10 h, added 40 mL of acetone, and reacted for another 8 h. Under nitrogen protection, it was filtered through a Buchner funnel. The solid was rinsed with acetone to obtain a white solid, which was dried under vacuum at 35 °C for 8 h, and dried to obtain 3.5 g of solid. (EXP3174·AHU377) 3- ·1.5Ca 2+ ·2.5H 2 O, the purity detected by HPLC was 99%. Repeat the test to obtain sufficient experimental doses for efficacy.

實施例3Example 3

複合物的製備：（按照專利WO2017125031A1的實施例3製備）

Figure 02_image011
Figure 02_image009
Preparation of complex: (prepared according to Example 3 of patent WO2017125031A1)
Figure 02_image011
Figure 02_image009

室溫下，將依據實施例1方法所得的AHU377游離酸2.36g、EXP3174 2g與40 mL丙酮加入至250mL三口瓶，溶清；室溫下加入相對於AHU377 1.6當量的氫氧化鈣固體和0.6 mL水，35℃攪拌6h，補加40 mL丙酮，再反應8h，氮氣保護下經布氏漏斗抽濾，固體用丙酮淋洗，得白色固體，50℃下真空烘8h，烘乾得到固體3.1g（EXP3174•AHU377）3- •1.5Ca2+ •2H2 O。重複試驗，以獲得足夠的藥效實驗用量。At room temperature, AHU377 free acid 2.36g, EXP3174 2g and 40 mL of acetone obtained according to the method of Example 1 were added to a 250mL there-neck flask, and dissolved; at room temperature, calcium hydroxide solid and 0.6 mL of 1.6 equivalents of calcium hydroxide relative to AHU377 were added. Water, stirred at 35 °C for 6 h, added 40 mL of acetone, reacted for 8 h, filtered through a Buchner funnel under nitrogen protection, and rinsed the solid with acetone to obtain a white solid, which was dried under vacuum at 50 °C for 8 h, and dried to obtain 3.1 g of solid (EXP3174•AHU377) 3- •1.5Ca 2+ • 2H 2 O. Repeat the test to obtain sufficient experimental doses for efficacy.

實施例4Example 4

參照實施例2和3的製備方法，分別製備得到以下複合物： （EXP3174·AHU377）·1.5Ca·1H2 O； （EXP3174·AHU377）·1.5Ca·1.5H2 O； （EXP3174·AHU377）·1.5Ca·3H2 O； （EXP3174·AHU377）·2Ca·1H2 O； （EXP3174·AHU377）·2Ca·1.5H2 O； （EXP3174·AHU377）·2Ca·2H2 O； （EXP3174·AHU377）·2Ca·2.5H2 O； （EXP3174·AHU377）·2Ca·3H2 O。Referring to the preparation methods of Examples 2 and 3, the following compounds were prepared respectively: (EXP3174·AHU377)·1.5Ca·1H 2 O; (EXP3174·AHU377)·1.5Ca·1.5H 2 O; (EXP3174·AHU377)· 1.5Ca · 3H2O ; (EXP3174·AHU377)·2Ca·1H2O; (EXP3174·AHU377)·2Ca·1.5H2O; (EXP3174·AHU377)· 2Ca · 2H2O; (EXP3174·AHU377)· 2Ca·2.5H2O; (EXP3174·AHU377) · 2Ca· 3H2O .

實施例5 崩解劑及其用量選擇Example 5 Disintegrant and its dosage selection

通過測定pH6.8介質的溶出曲線，考察不同崩解劑種類，篩選較佳崩解劑用量。處方設計內容見表1，溶出曲線結果見表2。By measuring the dissolution curve of pH6.8 medium, different types of disintegrants were investigated, and the optimal dosage of disintegrants was screened. The contents of the formulation design are shown in Table 1, and the results of the dissolution curves are shown in Table 2.

表1 不同崩解劑及用量處方實驗 原輔料名稱 處方用量（mg/片） 1A 1B 1C 1D 實施例3複合物 （以無水游離酸C46 H50 ClN7 O7 計） 60 60 60 60 微晶纖維素 100 145 129 129 低取代羥丙纖維素 40 11.5 23 23 交聯聚維酮 20 4.5 9 / 二氧化矽（SH-QX1） 2.3 / / 1.1 硬脂酸鎂 2.3 2.3 2.3 2.3 片重 224.6 223.3 223.3 215.4 Table 1 Prescription experiments of different disintegrants and dosages Raw material name Prescription dosage (mg/tablet) 1A 1B 1C 1D Example 3 complex (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 60 60 60 60 microcrystalline cellulose 100 145 129 129 low substituted hydroxypropyl cellulose 40 11.5 twenty three twenty three Crospovidone 20 4.5 9 / Silica (SH-QX1) 2.3 / / 1.1 Magnesium stearate 2.3 2.3 2.3 2.3 sheet weight 224.6 223.3 223.3 215.4

表2不同崩解劑及用量溶出曲線研究結果 溶出介質   累積溶出度 10min 15min 20min 30min 45min 60min pH6.8 1A 79.7 86.5 89.9 94.1 97.1 98.5 1B 71.8 79.9 83.5 87.1 91.3 93.0 1C 72.2 77.0 80.2 84.1 87.7 90.8 1D 76.2 81.3 83.7 88.5 90.1 90.8 Table 2 Study results of different disintegrants and dosages of dissolution curves Dissolution medium cumulative dissolution 10min 15min 20min 30min 45min 60min pH6.8 1A 79.7 86.5 89.9 94.1 97.1 98.5 1B 71.8 79.9 83.5 87.1 91.3 93.0 1C 72.2 77.0 80.2 84.1 87.7 90.8 1D 76.2 81.3 83.7 88.5 90.1 90.8

由崩解劑選擇結果可知，使用低取代羥丙纖維素和交聯聚維酮比單獨使用低取代羥丙纖維素更能促進溶出，低取代羥丙纖維素和交聯聚維酮的使用量分別達17.8%和8.9%時，溶出能在15min達85%以上。From the results of disintegrant selection, it can be seen that the use of low-substituted hydroxypropyl cellulose and crospovidone can promote dissolution better than the use of low-substituted hydroxypropyl cellulose alone, and the usage of low-substituted hydroxypropyl cellulose and crospovidone When they reach 17.8% and 8.9% respectively, the dissolution energy can reach more than 85% in 15min.

所以，優選低取代羥丙纖維素在藥物組合物中使用量為17%-30%，交聯聚維酮在藥物組合物中使用量為8% -20%，優選二者在藥物組合物中使用量為25%-40%。Therefore, preferably low-substituted hydroxypropyl cellulose is used in an amount of 17%-30% in the pharmaceutical composition, and crospovidone is used in an amount of 8%-20% in the pharmaceutical composition, preferably both are in the pharmaceutical composition. The usage amount is 25%-40%.

實施例6 填充劑及其用量選擇Example 6 Filler and its dosage selection

在實施例5的基礎上，本品製劑中填充劑選擇晶纖維素（Type102）和無水乳糖（DTHV）。實驗結果發現，不同配比的填充劑可能影響片芯的崩解及溶出情況，結合崩解時間及pH6.8介質的溶出曲線篩選出適合的處方比例，具體見表3。兩者填充劑混合使用能保證片芯外觀、重量差異、脆碎度符合要求。On the basis of Example 5, crystalline cellulose (Type102) and anhydrous lactose (DTHV) were 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 formulation ratio was screened out according to the disintegration time and the dissolution curve of the pH 6.8 medium, as shown in Table 3. The mixed use of the two fillers can ensure that the appearance, weight difference and friability of the tablet cores meet the requirements.

表3 微晶纖維素/乳糖不同比例的處方設計 考察項目 2A 2B 2C 2D 2E 2F 2G 2H 微晶纖維素/ 無水乳糖配比 1：3 1：2 1：1 2：1 4：1 5：1 6：1 1.5：1 處方組成 mg/片 mg /片 mg /片 mg /片 mg /片 mg /片 mg /片 mg /片 實施例3複合物（以無水游離酸C46 H50 ClN7 O7 計） 60 60 60 60 60 60 60 60 微晶纖維素（Type102） 37.25 49.67 74.5 99.33 119.2 124.17 127.71 89.4 無水乳糖（DTHV） 111.75 99.33 74.5 49.67 29.8 24.83 21.29 59.6 羥丙甲纖維素（E5） 13 13 13 13 13 13 13 13 二氧化矽（SH-QX1） 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 硬脂酸鎂 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 Table 3 The formulation design of different ratios of microcrystalline cellulose/lactose investigation 2A 2B 2C 2D 2E 2F 2G 2H Microcrystalline cellulose/anhydrous lactose ratio 1:3 1:2 1:1 2:1 4:1 5:1 6:1 1.5:1 prescription composition mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet mg/tablet Example 3 complex (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 60 60 60 60 60 60 60 60 Microcrystalline Cellulose (Type102) 37.25 49.67 74.5 99.33 119.2 124.17 127.71 89.4 Anhydrous lactose (DTHV) 111.75 99.33 74.5 49.67 29.8 24.83 21.29 59.6 Hypromellose (E5) 13 13 13 13 13 13 13 13 Silica (SH-QX1) 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 Magnesium stearate 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3

表4微晶纖維素/乳糖不同比例的崩解時間的研究結果 考察項目 2A 2B 2C 2D 2E 2F 2G 2H 微晶纖維素/無水乳糖配比 1：3 1：2 1：1 2：1 4：1 5：1 6：1 1.5：1 崩解時間 25~37min 17~25min 6~10min 1~2min 1~2min 1~2min 1~2min 3~4min Table 4 The results of the study on the disintegration time of different ratios of microcrystalline cellulose/lactose investigation 2A 2B 2C 2D 2E 2F 2G 2H Microcrystalline cellulose/anhydrous lactose ratio 1:3 1:2 1:1 2:1 4:1 5:1 6:1 1.5:1 disintegration time 25~37min 17~25min 6~10min 1~2min 1~2min 1~2min 1~2min 3~4min

表5微晶纖維素/乳糖不同比例的溶出曲線的研究結果 溶出介質   微晶纖維素/乳糖配比 累積溶出度 10min 15min 20min 30min 45min 60min pH6.8 2B 1：2 9.9% 13.3% 17.9% 25.3% 33.5% 39.7% 2C 1：1 38.9% 47.6% 52.2% 58.6% 65.2% 70.1% 2D 2：1 72.9% 80.3% 84.3% 88.7% 92.2% 94.1% 2E 4：1 74.4% 81.5% 85.6% 88.2% 94.2% 95.4% 2F 5：1 71.6% 83.4% 87.1% 89.3% 94.8% 97.5% 2G 6：1 73.3% 82.8% 85.1% 87.3% 93.6% 96.7% 2H 1.5：1 63.6% 79.8% 81.4% 85.3% 92.7% 96.9% Table 5 Study results of the dissolution profiles of different ratios of microcrystalline cellulose/lactose Dissolution medium Microcrystalline cellulose/lactose ratio cumulative dissolution 10min 15min 20min 30min 45min 60min pH6.8 2B 1:2 9.9% 13.3% 17.9% 25.3% 33.5% 39.7% 2C 1:1 38.9% 47.6% 52.2% 58.6% 65.2% 70.1% 2D 2:1 72.9% 80.3% 84.3% 88.7% 92.2% 94.1% 2E 4:1 74.4% 81.5% 85.6% 88.2% 94.2% 95.4% 2F 5:1 71.6% 83.4% 87.1% 89.3% 94.8% 97.5% 2G 6:1 73.3% 82.8% 85.1% 87.3% 93.6% 96.7% 2H 1.5:1 63.6% 79.8% 81.4% 85.3% 92.7% 96.9%

另外，混粉流動性考察結果：採用微晶纖維素/乳糖配比為2：1，休止角（º）為40 º左右，可以滿足流動性的要求。In addition, the investigation results of the fluidity of the mixed powder: the microcrystalline cellulose/lactose ratio is 2:1, and the angle of repose (º) is about 40º, which can meet the fluidity requirements.

由於微晶纖維素/乳糖配比為6：1時，藥片厚度較厚，可能影響吞咽和依從效果。Because the microcrystalline cellulose/lactose ratio is 6:1, the thickness of the tablet is thicker, which may affect swallowing and compliance.

綜合以上結果可知，進一步優選微晶纖維素和無水乳糖的質量比為1：1-5：1，優選微晶纖維素和乳糖的總質量為藥物組合物重量的18% -60%，不僅崩解時間快，而且能得到快即溶出效果，更優選微晶纖維素和乳糖的質量比為1.5：1-5：1，溶出效果30min≥85%。Based on the above results, it is further preferred that the mass ratio of microcrystalline cellulose and anhydrous lactose is 1:1-5:1, and the preferred total mass of microcrystalline cellulose and lactose is 18%-60% of the weight of the pharmaceutical composition, not only collapse The dissolution time is fast, and the 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% in 30min.

實施例7 研究不同體外溶出的樣品在動物體內的藥動學情況。Example 7 The pharmacokinetics of different in vitro dissolution samples were studied in animals.

通過實施例5、6優選的技術方案，製備出三個具有不同的樣品，進行犬PK試驗，具體處方組成如表6中所示，溶出曲線結果見表7。Through the preferred technical solutions of Examples 5 and 6, three different samples were prepared and tested for canine PK. The specific formulation composition is shown in Table 6, and the dissolution curve results are shown in Table 7.

表6不同處方組成 原輔料名稱 處方用量（mg/片） 3A 3B 3C 實施例3複合物（以無水游離酸C46 H50 ClN7 O7 計） 60 60 60 微晶纖維素 100 77.75 77.75 無水乳糖 / 77.75 77.75 低取代羥丙纖維素 40 / / 交聯聚維酮 20 / / 羥丙甲纖維素 / 6.5 / 二氧化矽（SH-QX1） 2.3 1.1 1.1 硬脂酸鎂 2.3 2.3 2.3 腸溶包衣* / / * *腸溶包衣配方中含：Eudragit L30D-55、滑石粉、檸檬酸三乙酯，和純化水按照質量比1：6混合後進行包衣，包衣後增重約3%。Table 6 Composition of Different Prescriptions Raw material name Prescription dosage (mg/tablet) 3A 3B 3C Example 3 complex (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 60 60 60 microcrystalline cellulose 100 77.75 77.75 anhydrous lactose / 77.75 77.75 low substituted hydroxypropyl cellulose 40 / / Crospovidone 20 / / Hypromellose / 6.5 / Silica (SH-QX1) 2.3 1.1 1.1 Magnesium stearate 2.3 2.3 2.3 Enteric Coating* / / * *The enteric coating formula contains: Eudragit L30D-55, talc, triethyl citrate, and purified water in a mass ratio of 1:6 before coating, and the weight gain after coating is about 3%.

表7不同處方的體外溶出結果 介質 批號 累積溶出度 10min 15min 20min 30min 45min 60min pH1.2 3A 19.3% 26.2% 30.8% 37.3% 43.8% 48.3% 3B 8.4% 10.6% 13.2% 16.9% 21.6% 25.6% pH5.0 3A 75.9% 79.8% 82.4% 85.5% 88.4% 90.3% 3B 34.9% 47.5% 57.0% 69.1% 81.6% 88.3% pH6.8 3A 89.2% 93.1% 94.0% 95.8% 96.2% 96.4% 3B 30.0% 43.5% 50.6% 58.6% 66.0% 71.1% 3C 0.0% 0.0% 0.2% 3.1% 13.1% 22.5% Table 7 In vitro dissolution results of different formulations medium batch number cumulative dissolution 10min 15min 20min 30min 45min 60min pH1.2 3A 19.3% 26.2% 30.8% 37.3% 43.8% 48.3% 3B 8.4% 10.6% 13.2% 16.9% 21.6% 25.6% pH5.0 3A 75.9% 79.8% 82.4% 85.5% 88.4% 90.3% 3B 34.9% 47.5% 57.0% 69.1% 81.6% 88.3% pH6.8 3A 89.2% 93.1% 94.0% 95.8% 96.2% 96.4% 3B 30.0% 43.5% 50.6% 58.6% 66.0% 71.1% 3C 0.0% 0.0% 0.2% 3.1% 13.1% 22.5%

結果：由於3C批次選擇了腸溶包衣，在pH5.5以下的酸性介質中腸溶衣膜不會被破壞，因此，未檢測3C批次片劑在pH1.2及pH5.0中的溶出曲線。Results: Since the enteric coating was selected for batch 3C, the enteric coating film would not be destroyed in acidic media below pH 5.5. Therefore, the tablets of batch 3C in pH 1.2 and pH 5.0 were not tested. Dissolution profile.

以原料藥的混懸液作為對照，採用這3A、3B和3C三批樣品進行犬PK試驗，考察不同體外溶出行為的處方在比格犬體內的藥動學情況，結果如表8所示。Taking the suspension of the API as a control, the three batches of samples 3A, 3B and 3C were used to conduct a dog PK test 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不同處方樣品在比格犬的體內藥動學結果 待測物 組別 均值與 標準差 AUC0-last (hr*ng/mL) AUC0-∞ (hr*ng/mL) F (%) 沙庫巴曲 3A Mean 439 452 126.61% SD 121 131 / 3B Mean 353 362 101.40% SD 121 123 / 3C Mean 334 326 91.32% SD 138 159 / 原料混懸液 Mean 349 357 / SD 206 207 / EXP3174 3A Mean 811 839 99.53% SD 500 506 / 3B Mean 749 759 90.04% SD 275 280 / 3C Mean 425 478 56.70% SD 42.7 21.9 / 原料混懸液 Mean 836 843 / SD 247 253 / LBQ657   3A Mean 853 874 114.10% SD 141 124 / 3B Mean 734 742 96.87% SD 261 262 / 3C Mean 468 506 66.06% SD 150 166 / 原料混懸液 Mean 749 766 / SD 236 232 / 註：LBQ657為沙庫巴曲活性代謝產物。Table 8 In vivo pharmacokinetic results of different prescription samples in beagle dogs Analyte group mean and standard deviation AUC0-last (hr*ng/mL) AUC0-∞ (hr*ng/mL) F (%) Shakuba Qu 3A Mean 439 452 126.61% SD 121 131 / 3B Mean 353 362 101.40% SD 121 123 / 3C Mean 334 326 91.32% SD 138 159 / Raw material suspension Mean 349 357 / SD 206 207 / EXP3174 3A Mean 811 839 99.53% SD 500 506 / 3B Mean 749 759 90.04% SD 275 280 / 3C Mean 425 478 56.70% SD 42.7 21.9 / Raw material suspension Mean 836 843 / SD 247 253 / LBQ657 3A Mean 853 874 114.10% SD 141 124 / 3B Mean 734 742 96.87% SD 261 262 / 3C Mean 468 506 66.06% SD 150 166 / Raw material suspension Mean 749 766 / SD 236 232 / Note: LBQ657 is the active metabolite of sacubitril.

由以上結果可知，與混懸液比較，沙庫巴曲三種處方片劑F值均有90%以上，說明沙庫巴曲主要在小腸遠端吸收，而EXP3174腸溶包衣片劑與混懸液相比生物利用度只有混懸液的60%左右，其他2組別沒有包腸溶衣片劑F值均有90%以上，說明而EXP3174在小腸近端及遠端均有吸收。It can be seen from the above results 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 the EXP3174 enteric-coated tablet and the suspension are absorbed. The bioavailability of the liquid phase is only about 60% of that of the suspension, and the F values of the other two groups without enteric-coated tablets are above 90%, indicating that EXP3174 is absorbed in the proximal and distal small intestines.

上述實驗顯示腸溶包衣樣品與混懸液比較吸收降低，因此本發明選擇胃溶包衣。具體地，例如胃溶性包衣包括85G640059-CN，所述胃溶性包衣的採用水等溶劑混合物，包衣後增重約0.1%-4%。The above experiments show that the absorption of the enteric-coated samples is reduced compared to the suspension, so the gastro-coated coating was selected for the present invention. Specifically, for example, the stomach-soluble coating includes 85G640059-CN, and the stomach-soluble coating adopts a solvent mixture such as water, and the weight gain after coating is about 0.1%-4%.

在前述實驗例5-7的技術方案的基礎上，本發明進一步得到以下優選的實施例。On the basis of the technical solutions of the foregoing experimental examples 5-7, the present invention further obtains the following preferred embodiments.

實施例8Example 8

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 60 微晶纖維素 80 無水乳糖 20 低取代羥丙纖維素 40 交聯聚維酮XL 20 二氧化矽 2.3 硬脂酸鎂 2.3 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 60 microcrystalline cellulose 80 anhydrous lactose 20 low substituted hydroxypropyl cellulose 40 Crospovidone XL 20 silica 2.3 Magnesium stearate 2.3

製備方法為：將前述原輔料進行混粉直壓。The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed.

將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：7混合後，包衣混粉直壓得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。After mixing the coating material film coating premix (gastric soluble type 295F640025-CN) and purified water in a mass ratio of 1:7, the tablets 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 coated tablets, and the weight gain after coating is about 3%.

實施例9Example 9

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 60 微晶纖維素 80 無水乳糖 20 低取代羥丙纖維素 40 交聯聚維酮XL 20 二氧化矽 2.3 硬脂酸鎂 2.3 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 60 microcrystalline cellulose 80 anhydrous lactose 20 low substituted hydroxypropyl cellulose 40 Crospovidone XL 20 silica 2.3 Magnesium stearate 2.3

生產工藝：製備方法為：將前述原輔料進行乾法製粒，然後壓片；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：7混合後，包衣製粒壓片得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。Production process: The preparation method is as follows: dry granulation of the aforementioned raw and auxiliary materials, and then tableting; after mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water in a mass ratio of 1:7, The tablets obtained by coating granulation and tableting (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%.

實施例10Example 10

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 120 微晶纖維素 160 無水乳糖 40 低取代羥丙纖維素 80 交聯聚維酮XL 40 二氧化矽 4.6 硬脂酸鎂 4.6 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 120 microcrystalline cellulose 160 anhydrous lactose 40 low substituted hydroxypropyl cellulose 80 Crospovidone XL 40 silica 4.6 Magnesium stearate 4.6

生產工藝：製備方法為：將前述原輔料進行混粉直壓；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：6混合後，包衣混粉直壓得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed; the coating material film coating premix (gastric soluble type 295F640025-CN) and purified water are mixed in a mass ratio of 1:6, and the coating is mixed. The tablets obtained by direct compression of the powder (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%.

實施例11Example 11

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 120 微晶纖維素 160 無水乳糖 40 低取代羥丙纖維素 80 交聯聚維酮XL 40 二氧化矽 4.6 硬脂酸鎂 4.6 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 120 microcrystalline cellulose 160 anhydrous lactose 40 low substituted hydroxypropyl cellulose 80 Crospovidone XL 40 silica 4.6 Magnesium stearate 4.6

生產工藝：製備方法為：將前述原輔料進行乾法製粒，然後壓片；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：6混合後，包衣製粒壓片得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。Production process: The preparation method is as follows: dry granulation of the aforementioned raw materials and auxiliary materials, and then tableting; after mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water in a mass ratio of 1:6, The tablets obtained by coating granulation and tableting (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%.

實施例12Example 12

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 240 微晶纖維素 83 無水乳糖 53 羧甲澱粉鈉 27 交聯羧甲基纖維素鈉 33 交聯聚維酮 33 二氧化矽 8 硬脂酸鎂 5.5 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 240 microcrystalline cellulose 83 anhydrous lactose 53 Sodium starch glycolate 27 Croscarmellose sodium 33 Crospovidone 33 silica 8 Magnesium stearate 5.5

生產工藝：製備方法為：將前述原輔料進行混粉直壓；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：6混合後，包衣混粉直壓得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。Production process: The preparation method is as follows: the aforementioned raw and auxiliary materials are mixed and directly pressed; the coating material film coating premix (gastric soluble type 295F640025-CN) and purified water are mixed in a mass ratio of 1:6, and the coating is mixed. The tablets obtained by direct compression of the powder (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%.

實施例13Example 13

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 240 微晶纖維素 83 無水乳糖 53 羧甲澱粉鈉 27 交聯羧甲基纖維素鈉 33 交聯聚維酮 33 二氧化矽 8 硬脂酸鎂 5.5 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 240 microcrystalline cellulose 83 anhydrous lactose 53 Sodium starch glycolate 27 Croscarmellose sodium 33 Crospovidone 33 silica 8 Magnesium stearate 5.5

生產工藝：製備方法為：將前述原輔料進行乾法製粒，然後壓片；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：6混合後，包衣製粒壓片得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。Production process: The preparation method is as follows: dry granulation of the aforementioned raw materials and auxiliary materials, and then tableting; after mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water in a mass ratio of 1:6, The tablets obtained by coating granulation and tableting (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%.

實施例14Example 14

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 240 微晶纖維素 70 無水乳糖 36 羧甲澱粉鈉 50 交聯羧甲基纖維素鈉 60 交聯聚維酮 60 二氧化矽 24 硬脂酸鎂 11 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 240 microcrystalline cellulose 70 anhydrous lactose 36 Sodium starch glycolate 50 Croscarmellose sodium 60 Crospovidone 60 silica twenty four Magnesium stearate 11

生產工藝：製備方法為：將前述原輔料進行乾法製粒，然後壓片；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：6混合後，包衣製粒壓片得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。Production process: The preparation method is as follows: dry granulation of the aforementioned raw materials and auxiliary materials, and then tableting; after mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water in a mass ratio of 1:6, The tablets obtained by coating granulation and tableting (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%.

實施例15Example 15

採用實施例3獲得複合物作為原料藥，一種複合物的藥物組合物及其製備方法，包括： 物料名稱 處方量mg/片 實施例3複合物a 240 微晶纖維素 70 無水乳糖 36 羧甲澱粉鈉 50 交聯羧甲基纖維素鈉 60 交聯聚維酮 60 二氧化矽 24.4 硬脂酸鎂 12.77 Adopt embodiment 3 to obtain compound as raw material drug, a kind of compound pharmaceutical composition and preparation method thereof, comprising: Material name Prescription amount mg/tablet Example 3 Complex a 240 microcrystalline cellulose 70 anhydrous lactose 36 Sodium starch glycolate 50 Croscarmellose sodium 60 Crospovidone 60 silica 24.4 Magnesium stearate 12.77

生產工藝：製備方法為：將前述原輔料進行乾法製粒，然後壓片；將包衣材料薄膜包衣預混劑（胃溶型295F640025-CN）和純化水按照質量比1：6混合後，包衣製粒壓片得到的片劑（其中，包衣所用的純化水在包衣後經乾燥最終去除），得到包衣片，包衣後增重約3%。 註：a 表示實施例8-15所述複合物的用量以無水游離酸C46 H50 ClN7 O7 計。Production process: The preparation method is as follows: dry granulation of the aforementioned raw materials and auxiliary materials, and then tableting; after mixing the coating material film coating premix (stomach-soluble type 295F640025-CN) and purified water in a mass ratio of 1:6, The tablets obtained by coating granulation and tableting (wherein, the purified water used for coating is finally removed by drying after coating) to obtain coated tablets, and the weight gain after coating is about 3%. Note: a represents the amount of the complexes described in Examples 8-15 in terms of anhydrous free acid C 46 H 50 ClN 7 O 7 .

前述部分實施例的溶出效果如下： 介質 批號 累積溶出度 10min 15min 20min 30min 45min 60min pH6.8 實施例8 88.4% 91.7% 93.7% 95.6% 96.8% 97.2% 實施例11 88.2% 92.1% 94.0% 95.3% 97.2% 97.3% 實施例14 52.2% 72.3% 88.0% 94.9% 96.2% 96.4% The dissolution effect of the foregoing part of the embodiment is as follows: medium batch number cumulative dissolution 10min 15min 20min 30min 45min 60min pH6.8 Example 8 88.4% 91.7% 93.7% 95.6% 96.8% 97.2% Example 11 88.2% 92.1% 94.0% 95.3% 97.2% 97.3% Example 14 52.2% 72.3% 88.0% 94.9% 96.2% 96.4%

各實施例的溶出符合標準要求，並在動物實驗中體現足夠的藥物暴露量。The dissolution of each example complies with the standard requirements and reflects sufficient drug exposure in animal experiments.

實施例16-23Examples 16-23

實施例16-23分別與實施例8-15的處方一致，所不同的是，所使用的原料藥為實施例2的複合物a 。 註：a 表示所述複合物的用量以無水游離酸C46 H50 ClN7 O7 計。The formulations of Examples 16-23 are respectively the same as those of Examples 8-15, the difference is that the API used is the compound a of Example 2. Note: a indicates that the amount of the complex is based on anhydrous free acid C 46 H 50 ClN 7 O 7 .

實施例24採用實施例8的藥物組合物進行臨床I期試驗Embodiment 24 uses the pharmaceutical composition of embodiment 8 to carry out clinical phase I trial

本發明複合物片已完成在健康受試者中單中心、隨機、雙盲、安慰劑對照的多劑量、單次、多次給藥的耐受性、藥代動力學Ⅰ期臨床試驗。單次給藥設置60mg、180mg、360mg、540mg、720mg、960mg、1080mg，共7個劑量組；多次給藥設置180mg、360mg、540mg、720mg，共4個劑量組；在480mg劑量組開展食物影響試驗，同時在食物影響試驗第一週期採集尿樣和糞樣，用於回收率和藥物代謝轉化研究；以評價本發明複合物片在健康受試者中單次、多次給藥的耐受性、藥代動力學、藥物代謝轉化及回收率以及食物對其藥代動力學的影響，並初步評價藥效學。The compound tablet of the present invention has completed a single-center, random, double-blind, placebo-controlled multi-dose, single and multiple administration tolerance and pharmacokinetic phase I clinical trials in healthy subjects. Single-dose 60mg, 180mg, 360mg, 540mg, 720mg, 960mg, 1080mg, a total of 7 dose groups; multiple doses set 180mg, 360mg, 540mg, 720mg, a total of 4 dose groups; in the 480mg dose group, food In the impact test, urine samples and fecal samples were collected in the first cycle of the food impact test for recovery and drug metabolism transformation studies; to evaluate the resistance of the compound tablet of the present invention to single and multiple administration in healthy subjects. Acceptability, pharmacokinetics, drug metabolism and recovery, and the effect of food on its pharmacokinetics, and preliminary evaluation of pharmacodynamics.

根據單次給藥和多次給藥的PK結果進行推算，口服本發明複合物240mg後，人體內EXP3174暴露量不低於口服氯沙坦100mg後人體內總活性成分暴露量，人體內LBQ657暴露量不低於口服LCZ696 200mg後人體內LBQ657暴露量；口服本發明複合物480mg後，人體內EXP3174暴露量不低於口服氯沙坦200mg後人體內總活性成分暴露量，人體內LBQ657暴露量不低於口服LCZ696 400mg後人體內LBQ657暴露量。According to the PK results of single administration and multiple administration, after oral administration of 240 mg of the compound of the present invention, the exposure of EXP3174 in human body is not lower than that of total active ingredient exposure in human body after oral administration of 100 mg of losartan, and the exposure of LBQ657 in human body After oral administration of 200 mg of LCZ696, the exposure of LBQ657 in human body; after oral administration of 480 mg of the compound of the present invention, the exposure of EXP3174 in human body is not lower than the exposure of total active components in human body after oral administration of 200 mg of losartan, and the exposure of LBQ657 in human body is not lower than that of 200 mg of losartan. Lower than the LBQ657 exposure in humans after oral administration of LCZ696 400 mg.

所以，本發明複合物在應用於心衰和高血壓疾病患者後，從體內藥代和藥效上均表現符合預期的臨床治療效果。Therefore, after the compound of the present invention is applied to patients with heart failure and hypertensive diseases, both in vivo pharmacokinetics and pharmacodynamics show the expected clinical therapeutic effect.

對比實施例1 名稱型號 mg/片 1 實施例3複合物 60 2 微晶纖維素乳糖複合物 100 3 低取代羥丙纖維素 60 4 泊洛沙姆188 18 5 二氧化矽 3 6 硬脂酸鎂 3 Comparative Example 1 name model mg/tablet 1 Example 3 Complex 60 2 Microcrystalline Cellulose Lactose Complex 100 3 low substituted hydroxypropyl cellulose 60 4 Poloxamer 188 18 5 silica 3 6 Magnesium stearate 3

製粒工藝：乾法製粒。Granulation process: dry granulation.

該處方測定pH1.2的溶出結果，溶出緩慢，具體如下表所示： 溶出 介質 批號 累積溶出度 10min 15min 20min 30min 45min 60min pH1.2   10% 15% 18% 22% 30% 35% The dissolution results of pH 1.2 were determined for this prescription, and the dissolution was slow, as shown in the following table: Dissolution medium batch number cumulative dissolution 10min 15min 20min 30min 45min 60min pH1.2 10% 15% 18% twenty two% 30% 35%

對比實施例2 名稱型號 mg/片 1 實施例3複合物 66.6 2 泊洛沙姆188 90 3 交聯聚維酮XL 60 4 微晶纖維素 18 5 二氯甲烷（溶劑最終去除） 400 6 硬脂酸鎂 3 Comparative Example 2 name model mg/tablet 1 Example 3 Complex 66.6 2 Poloxamer 188 90 3 Crospovidone XL 60 4 microcrystalline cellulose 18 5 Dichloromethane (solvent final removal) 400 6 Magnesium stearate 3

製粒工藝：將實施例3複合物和泊洛沙姆188溶於二氯甲烷，將交聯聚維酮XL和微晶纖維素置於流化床控制進風溫度50-70℃，物料溫度40-50℃，進行噴霧乾燥，然後與硬脂酸鎂混合後壓片。Granulation process: The compound of Example 3 and poloxamer 188 were dissolved in dichloromethane, and crospovidone XL and microcrystalline cellulose were placed in a fluidized bed to control the inlet air temperature of 50-70 °C, and the material temperature of 40 °C. -50°C, spray-dried, then mixed with magnesium stearate and compressed into tablets.

所得片劑進行40℃±2℃，75%±5%RH下保存2個月，採用HPLC法進行雜質檢測，結果如下，可見該處方工藝的產品的穩定性較差。 批號 有關物質增加量 ZZ-001 其他單個雜質 其他總雜質 總雜質 實施例8 ＜0.01% ＜0.1% ＜0.1% ＜0.1% 實施例11 ＜0.01% ＜0.1% ＜0.1% ＜0.1% 對比實施例2 0.02% 0.3% 0.5% 0.9%

Figure 02_image014
The obtained tablets were stored at 40°C ± 2°C and 75% ± 5% RH for 2 months, and the HPLC method was used for impurity detection. batch number Relevant substance increase ZZ-001 Other individual impurities Other total impurities total impurities Example 8 <0.01% <0.1% <0.1% <0.1% Example 11 <0.01% <0.1% <0.1% <0.1% Comparative Example 2 0.02% 0.3% 0.5% 0.9%
Figure 02_image014

對比實施例3Comparative Example 3

採用以下處方與實施例處方進行對比，採用本發明處方，在pH1.2下的溶出明顯好於301-305的對比例，並且，實施例9和實施例11的溶出性質接近，並通過犬pK實驗發現，其體內代謝物的效果AUClast 接近，可以有效保證藥效。The following formulations are compared with the formulations of the examples. Using the formulation of the present invention, the dissolution at pH 1.2 is significantly better than that of the comparative examples of 301-305. Moreover, the dissolution properties of Example 9 and Example 11 are similar, and can pass the canine pK Experiments have found that the effect of its metabolites in the body is close to AUC last , which can effectively ensure the efficacy of the drug.

實驗處方及結果如下： 原輔料名稱 處方用量（mg/片） 301 302 303 304 305 306 實施例3 複合物 133.2 （按以無水游離酸C46 H50 ClN7 O7 計為120mg） 微晶纖維素 41.67 76 105 130 100 100 乳糖 41.67 50 30 33 30 30 交聯羧甲基纖維素鈉 23.33 30 / 33 / / 低取代羥丙纖維素 / / 80 65 50 75 交聯聚維酮 26.67 31 / / 40 25 羧甲澱粉鈉 / 25 / / / / 二氧化矽 2.67 3.5 3 4 3 3 硬脂酸鎂 2.67 3.5 3 4 3 3 溶出 介質 批號 累積溶出度 10min 15min 20min 30min 45min 60min pH1.2 301 2% 3% 3% 4% 6% 7% 302 7% 11% 13% 15% 19% 22% 303 11% 15% 18% 22% 26% 28% 304 13% 16% 19% 22% 26% 29% 305 / 17% / 26% / 36% 306 15% 18% 21% 27% 30% 33% 實施例9 20% 26% 31% 38% 46% 51% 實施例11 / 27% / 37% / 46% The experimental prescription and results are as follows: Raw material name Prescription dosage (mg/tablet) 301 302 303 304 305 306 Example 3 Complex 133.2 (120 mg calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) microcrystalline cellulose 41.67 76 105 130 100 100 lactose 41.67 50 30 33 30 30 Croscarmellose sodium 23.33 30 / 33 / / low substituted hydroxypropyl cellulose / / 80 65 50 75 Crospovidone 26.67 31 / / 40 25 Sodium starch glycolate / 25 / / / / silica 2.67 3.5 3 4 3 3 Magnesium stearate 2.67 3.5 3 4 3 3 Dissolution medium batch number cumulative dissolution 10min 15min 20min 30min 45min 60min pH1.2 301 2% 3% 3% 4% 6% 7% 302 7% 11% 13% 15% 19% twenty two% 303 11% 15% 18% twenty two% 26% 28% 304 13% 16% 19% twenty two% 26% 29% 305 / 17% / 26% / 36% 306 15% 18% twenty one% 27% 30% 33% Example 9 20% 26% 31% 38% 46% 51% Example 11 / 27% / 37% / 46%

比格犬體內pk數據 PK parameters   實施例9*2 305 實施例11 EXP3174 Unit Mean Mean Mean AUClast h*ng/mL 4644.9 3729.2 4271.1 LBQ657 Unit Mean Mean Mean AUClast h*ng/mL 4002.5 3473.5 3827.8 備註：LBQ657為沙庫巴曲活性代謝產物，*2為2片。Beagle in vivo pk data PK parameters Example 9*2 305 Example 11 EXP3174 Unit Mean Mean Mean AUC last h*ng/mL 4644.9 3729.2 4271.1 LBQ657 Unit Mean Mean Mean AUC last h*ng/mL 4002.5 3473.5 3827.8 Remarks: LBQ657 is the active metabolite of sacubitril, *2 is 2 tablets.

從上述實驗結果可見，在本發明處方中，當複合物a 在藥物組合物中為60mg或者120mg時，選擇微晶纖維素和乳糖作為支援劑的情況下，優選低取代羥丙纖維素和交聯聚維酮的組合，其溶出效果優於交聯羧甲基纖維素鈉、低取代羥丙纖維素、交聯聚維酮、羧甲澱粉鈉單一使用或者其他比例組合；並且從批次305、306和實施例9、11的對比結果，優選低取代羥丙纖維素和交聯聚維酮質量比為1.75-2.25:1，更優選2:1。a 表示所述複合物的用量以無水游離酸C46 H50 ClN7 O7 計It can be seen from the above experimental results that in the formulation of the present invention, when the compound a is 60 mg or 120 mg in the pharmaceutical composition, and when microcrystalline cellulose and lactose are selected as supporting agents, low-substituted hydroxypropyl cellulose and cross-linked cellulose are preferred. The combination of crospovidone, its dissolution effect is better than that of croscarmellose sodium, low-substituted hydroxypropyl cellulose, crospovidone, sodium starch glycolate, or a combination of other ratios; and from batch 305 , 306 and the comparative results of Examples 9 and 11, preferably the mass ratio of low-substituted hydroxypropyl cellulose and crospovidone is 1.75-2.25:1, more preferably 2:1. a represents the amount of the complex in terms of anhydrous free acid C 46 H 50 ClN 7 O 7

對比實施例4Comparative Example 4

採用以下處方與實施例9通過猴pK實驗發現，其體內代謝物的效果AUClast 接近，可以有效保證相應藥效。Using the following prescription and Example 9, it was found through monkey pK experiment that the effect of its metabolites in vivo was close to AUC last , which can effectively ensure the corresponding drug efficacy.

實驗處方及結果如下： 原輔料名稱 用量 比例% 批次 401   實施例3複合物 266.4 （按以無水游離酸C46 H50 ClN7 O7 計為240mg） 44.58 微晶纖維素 70 11.71 無水乳糖 36 6.02 羧甲澱粉鈉 50 8.37 交聯羧甲基纖維素鈉 60 10.04 交聯聚維酮 60 10.04 二氧化矽 24.4 4.08 硬脂酸鎂 12.77 2.14 動物（猴）體內pk數據 PK parameters   實施例9*4 60mg*4 401 240mg EXP3174 Unit Mean Mean AUClast h*ng/mL 21193.5 21173.5 備註：LBQ657為沙庫巴曲活性代謝產物，*4為4片。The experimental prescription and results are as follows: Raw material name Dosage Proportion% batch 401 Example 3 Complex 266.4 (240 mg calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) 44.58 microcrystalline cellulose 70 11.71 anhydrous lactose 36 6.02 Sodium starch glycolate 50 8.37 Croscarmellose sodium 60 10.04 Crospovidone 60 10.04 silica 24.4 4.08 Magnesium stearate 12.77 2.14 Animal (monkey) in vivo pk data PK parameters Example 9*4 60mg*4 401 240mg EXP3174 Unit Mean Mean AUC last h*ng/mL 21193.5 21173.5 Remarks: LBQ657 is the active metabolite of sacubitril, *4 is 4 tablets.

動物的體內PK資料結果表明，401批EXP3174暴露量和4片實施例9工藝60mg樣品更接近。The results of the in vivo PK data of animals showed that the exposure of the 401 batches of EXP3174 was closer to that of the 4 tablets of the 60 mg sample of the Example 9 process.

對比實施例5Comparative Example 5

實驗處方及結果如下： 402 比例% 403 比例% 實施例3複合物 266.4 52.35 266.4 52.35 微晶纖維素 83 16.31 83 16.31 無水乳糖 53 10.41 53 10.41 羧甲澱粉鈉 27 5.31 / / 交聯羧甲基纖維素鈉 33 6.48 / / 交聯聚維酮 33 6.48 33 6.48 低取代羥丙纖維素 / / 60 11.79 二氧化矽 8 1.57 8 1.57 硬脂酸鎂 5.5 1.08 5.5 1.08 溶出介質 批號 累積溶出度 10min 15min 20min 30min 45min 60min pH1.2 402 4% 6% 6% 8% 9% 10% 403 - 6% - 10% 13% 15% The experimental prescription and results are as follows: 402 Proportion% 403 Proportion% Example 3 Complex 266.4 52.35 266.4 52.35 microcrystalline cellulose 83 16.31 83 16.31 anhydrous lactose 53 10.41 53 10.41 Sodium starch glycolate 27 5.31 / / Croscarmellose sodium 33 6.48 / / Crospovidone 33 6.48 33 6.48 low substituted hydroxypropyl cellulose / / 60 11.79 silica 8 1.57 8 1.57 Magnesium stearate 5.5 1.08 5.5 1.08 Dissolution medium batch number cumulative dissolution 10min 15min 20min 30min 45min 60min pH1.2 402 4% 6% 6% 8% 9% 10% 403 - 6% - 10% 13% 15%

綜合對比實施例4和5的效果，基於實施例14和15（批次401）、以及402和403的處方，本發明申請人研究發現，當複合物a 在藥物組合物中為240mg，微晶纖維素和乳糖的1.8：1-2.2：1（具體如1.9：1，2：1，2.1：1）時，優選含有羧甲澱粉鈉、交聯羧甲基纖維素鈉和交聯聚維酮，羧甲澱粉鈉在藥物組合物中使用量為8-12%，交聯羧甲基纖維素鈉在藥物組合物中使用量為優選8-12%，交聯聚維酮在藥物組合物中使用量為8-12%，相對於選擇其他比例的羧甲澱粉鈉、交聯羧甲基纖維素鈉和交聯聚維酮的組合，或者交聯聚維酮和低取代羥丙纖維素的組合，以及在此基礎上微晶纖維素和乳糖的其他比例，難以達到相應的溶出，預期難以達到相應的體內溶出效果。a 表示所述複合物的用量以無水游離酸C46 H50 ClN7 O7 計Comprehensively comparing the effects of Examples 4 and 5, based on the formulations of Examples 14 and 15 (batch 401), and 402 and 403, the applicant of the present invention has found that when the compound a in the pharmaceutical composition is 240 mg, the microcrystalline When the ratio of cellulose and lactose is 1.8:1-2.2:1 (specifically, 1.9:1, 2:1, 2.1:1), it is preferable to contain sodium starch glycolate, croscarmellose sodium and crospovidone , the amount of sodium starch glycolate used in the pharmaceutical composition is 8-12%, the amount of croscarmellose sodium used in the pharmaceutical composition is preferably 8-12%, and the amount of crospovidone in the pharmaceutical composition is preferably 8-12%. The usage amount is 8-12%, compared to the combination of sodium starch glycolate, croscarmellose sodium and crospovidone in other proportions, or the combination of crospovidone and low-substituted hydroxypropyl cellulose. Combination, 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 dissolution effect in vivo. a represents the amount of the complex in terms of anhydrous free acid C 46 H 50 ClN 7 O 7

上述實施例為本發明較佳的實施方式，但本發明的實施方式並不受上述實施例的限制，其他的任何未背離本發明的精神實質與原理下所作的改變、修飾、替代、組合、簡化，均應為等效的置換方式，都包含在本發明的保護範圍之內。The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

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Claims (16)

一種複合物的藥物組合物，其特徵在於，所述複合物的結構單元如下： （aEXP3174·bAHU377）·xCa·nA 其中a:b=1:0.25~4；x為0.5~3之間的數值；A指代水、甲醇、乙醇、2-丙醇、丙酮、乙酸乙酯、甲基-三級丁基醚、乙腈、甲苯、二氯甲烷；n為0~3之間的數值； 所述藥物組合物中含有低取代羥丙纖維素、交聯聚維酮、羧甲澱粉鈉、交聯羧甲基纖維素鈉、預膠化澱粉中的一種或者兩種以上任意比例的混合物，在所述藥物組合物中使用量為4%-50%；和一種以上的其他輔料。A pharmaceutical composition of a complex, wherein the structural unit of the complex is as follows: (aEXP3174 bAHU377) xCa nA 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-tertiary butyl ether, Acetonitrile, toluene, dichloromethane; n is a value between 0 and 3; The pharmaceutical composition contains one of low-substituted hydroxypropyl cellulose, crospovidone, sodium carboxymethyl starch, croscarmellose sodium, and pregelatinized starch, or a mixture of two or more in arbitrary proportions, The usage amount in the pharmaceutical composition is 4%-50%; and one or more other adjuvants. 根據請求項1所述的複合物的藥物組合物，其中所述藥物組合物中含有低取代羥丙纖維素和交聯聚維酮，低取代羥丙纖維素在所述藥物組合物中使用量為17%-30%，交聯聚維酮在所述藥物組合物中使用量為8% -20%；或者所述藥物組合物中含有羧甲澱粉鈉、交聯羧甲基纖維素鈉和交聯聚維酮，羧甲澱粉鈉在所述藥物組合物中使用量為4%-12%，交聯羧甲基纖維素鈉在所述藥物組合物中使用量為4%-12%，交聯聚維酮在所述藥物組合物中使用量為4%-12%。The pharmaceutical composition of the compound according to claim 1, wherein the pharmaceutical composition contains low-substituted hydroxypropyl cellulose and crospovidone, and the amount of low-substituted hydroxypropyl cellulose used in the pharmaceutical composition is 17%-30%, and the usage amount of crospovidone in the pharmaceutical composition is 8%-20%; or the pharmaceutical composition contains sodium starch glycolate, croscarmellose sodium and Crospovidone, sodium starch glycolate used in the pharmaceutical composition in an amount of 4%-12%, and croscarmellose sodium in the pharmaceutical composition in an amount of 4%-12%, Crospovidone is used in an amount of 4%-12% in the pharmaceutical composition. 根據請求項2所述的複合物的藥物組合物，其中低取代羥丙纖維素和交聯聚維酮的比例為1：1-3：1，二者重量之和優選在所述藥物組合物中使用量為25%-40%；或者羧甲澱粉鈉、交聯羧甲基纖維素鈉和交聯聚維酮三者重量之和在所述藥物組合物中使用量為15%-35%。The pharmaceutical composition of the compound according to claim 2, wherein the ratio of low-substituted hydroxypropyl cellulose and crospovidone is 1:1-3:1, and the sum of the weights of the two is preferably in the pharmaceutical composition The amount used is 25%-40%; or the total weight of sodium starch glycolate, croscarmellose sodium and crospovidone is 15%-35% in the pharmaceutical composition . 根據請求項3所述的複合物的藥物組合物，其中當所述複合物在所述藥物組合物中的比例為25%-30%，優選低取代羥丙纖維素和交聯聚維酮的比例為1.75：1-2.25：1，更優選2：1；或者當所述複合物在所述藥物組合物中的比例為40%-50%，所述藥物組合物中含有羧甲澱粉鈉、交聯羧甲基纖維素鈉和交聯聚維酮，羧甲澱粉鈉在所述藥物組合物中使用量為8-12%，交聯羧甲基纖維素鈉在所述藥物組合物中使用量為優選8-12%，交聯聚維酮在所述藥物組合物中使用量為8-12%。The pharmaceutical composition of the complex according to claim 3, wherein when the proportion of the complex in the pharmaceutical composition is 25%-30%, preferably a combination of low-substituted hydroxypropyl cellulose and crospovidone The ratio is 1.75:1-2.25:1, more preferably 2:1; or when the ratio of the complex in the pharmaceutical composition is 40%-50%, the pharmaceutical composition contains sodium starch glycolate, Croscarmellose sodium and crospovidone, sodium starch glycolate is used in the pharmaceutical composition in an amount of 8-12%, and croscarmellose sodium is used in the pharmaceutical composition The amount is preferably 8-12%, and the amount of crospovidone used in the pharmaceutical composition is 8-12%. 根據請求項1-4任一項所述的複合物的藥物組合物，其中所述一種以上的其他輔料包括一種以上的填充劑、潤滑劑和包衣劑； 所述填充劑包括微晶纖維素、乳糖、甘露醇、磷酸氫鈣一種或者兩種以上任意比例的混合物，使用量為所述藥物組合物重量的16% -60%； 所述潤滑劑包括二氧化矽，硬脂酸，硬脂酸鎂、聚乙二醇、氫化蓖麻油中的一種或者兩種以上的混合物，所述潤滑劑的質量為所述藥物組合物重量的1% -3%； 所述包衣劑包括胃溶型包衣劑。The pharmaceutical composition of the complex according to any one of claims 1-4, wherein the one or more other excipients include one or more fillers, lubricants and coating agents; Described filler includes microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate one or a mixture of two or more arbitrary proportions, and the usage amount is 16%-60% of the weight of the pharmaceutical composition; Described lubricant comprises silicon dioxide, stearic acid, magnesium stearate, polyethylene glycol, hydrogenated castor oil in one or the mixture of two or more, and the quality of described lubricant is the weight of described pharmaceutical composition. 1% -3%; The coating agent includes a stomach-soluble coating agent. 根據請求項5所述的複合物的藥物組合物，其中所述填充劑包括微晶纖維素和乳糖的混合物，微晶纖維素和乳糖的質量比為1：1-5：1，微晶纖維素和乳糖的總質量為所述藥物組合物重量的16% -60%。The pharmaceutical composition of the complex according to claim 5, wherein the filler comprises a mixture of microcrystalline cellulose and lactose, the mass ratio of microcrystalline cellulose and lactose is 1:1-5:1, and the microcrystalline fiber is The total mass of lactose and lactose is 16%-60% of the weight of the pharmaceutical composition. 根據請求項5所述的複合物的藥物組合物，其中當所述複合物在所述藥物組合物中的比例為25%-30%，微晶纖維素和乳糖的質量比為1.5：1-5：1，優選微晶纖維素和乳糖的總質量為所述藥物組合物重量的17% -45%。The pharmaceutical composition of the complex according to claim 5, wherein when the ratio of the complex in the pharmaceutical composition is 25%-30%, the mass ratio of microcrystalline cellulose and lactose is 1.5:1- 5:1, preferably the total mass of microcrystalline cellulose and lactose is 17%-45% by weight of the pharmaceutical composition. 根據請求項5所述的複合物的藥物組合物，其中當所述複合物在所述藥物組合物中的比例為40%-50%，微晶纖維素和乳糖的質量比為1.8：1-2.2：1，優選微晶纖維素和乳糖的總質量為所述藥物組合物重量的17% -45%。The pharmaceutical composition of the complex according to claim 5, wherein when the ratio of the complex in the pharmaceutical composition is 40%-50%, the mass ratio of microcrystalline cellulose and lactose is 1.8:1- 2.2:1, preferably the total mass of microcrystalline cellulose and lactose is 17%-45% by weight of the pharmaceutical composition. 根據請求項1-8任一項所述的複合物的藥物組合物，其中所述複合物（以無水游離酸C46 H50 ClN7 O7 計）的質量為所述藥物組合物重量的20% -50%。The pharmaceutical composition of the complex according to any one of claims 1-8, wherein the mass of the complex (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) is 20% of the weight of the pharmaceutical composition % -50%. 根據請求項1-8任一項所述的複合物的藥物組合物，其中所述複合物（以無水游離酸C46 H50 ClN7 O7 計）的使用量為30mg、60mg、90mg、120mg、150mg、180mg、210mg、240mg、270mg、300mg。The pharmaceutical composition of the complex according to any one of claims 1-8, wherein the used amount of the complex (calculated as anhydrous free acid C 46 H 50 ClN 7 O 7 ) is 30 mg, 60 mg, 90 mg, 120 mg , 150mg, 180mg, 210mg, 240mg, 270mg, 300mg. 根據請求項1-10任一項所述的複合物的藥物組合物，其中 所述藥物組合物是適於口服的固體製劑，優選口服的片劑或膠囊。The pharmaceutical composition of the complex according to any one of claims 1-10, wherein the pharmaceutical composition is a solid preparation suitable for oral administration, preferably a tablet or capsule for oral administration. 根據請求項1-11任一項所述的複合物的藥物組合物，其中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； 進一步優選所述複合物的結構單元如下： （EXP3174·AHU377）·xCa·nH2 O 或者
Figure 03_image006
其中x為0.5~2之間的數值；n為0~3之間的數值；進一步優選x包括0.5、1、1.5、2。The pharmaceutical composition of the complex according to any one of claims 1-11, wherein the values of a:b include 1:0.25, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4; further preferably, the structural unit of the complex is as follows: (EXP3174·AHU377)·xCa·nH 2 O or
Figure 03_image006
Wherein, x is a value between 0.5 and 2; n is a value between 0 and 3; further preferably, x includes 0.5, 1, 1.5, and 2. 根據請求項1-11任一項所述的複合物的藥物組合物，其中所述複合物的結構單元如下： （EXP3174·AHU377）·1.5Ca·nH2 O 或者 （EXP3174·AHU377）·2Ca·nH2 O 其中n為1~3之間的任意數值，進一步優選：n包括0.5、1、1.5、2、2.5、3。The pharmaceutical composition of the complex according to any one of claims 1-11, wherein the structural unit of the complex is as follows: (EXP3174·AHU377)·1.5Ca·nH 2 O or (EXP3174·AHU377)·2Ca· nH 2 O wherein n is any value between 1 and 3, more preferably: n includes 0.5, 1, 1.5, 2, 2.5, and 3. 根據請求項1-11任一項所述的複合物的藥物組合物，其中所述複合物包括： （EXP3174·AHU377）·1.5Ca·1H2 O； （EXP3174·AHU377）·1.5Ca·1.5H2 O； （EXP3174·AHU377）·1.5Ca·2H2 O； （EXP3174·AHU377）·1.5Ca·2.5H2 O； （EXP3174·AHU377）·1.5Ca·3H2 O； （EXP3174·AHU377）·2Ca·1H2 O； （EXP3174·AHU377）·2Ca·1.5H2 O； （EXP3174·AHU377）·2Ca·2H2 O； （EXP3174·AHU377）·2Ca·2.5H2 O； （EXP3174·AHU377）·2Ca·3H2 O。The pharmaceutical composition of the complex according to any one of claims 1-11, wherein the complex comprises: (EXP3174·AHU377)·1.5Ca·1H 2 O; (EXP3174·AHU377)·1.5Ca·1.5H 2O; ( EXP3174 ·AHU377)·1.5Ca · 2H2O; (EXP3174·AHU377)·1.5Ca·2.5H2O; (EXP3174·AHU377)·1.5Ca · 3H2O ; (EXP3174·AHU377)·2Ca · 1H 2 O; (EXP3174 · AHU377) · 2Ca · 1.5H 2 O; (EXP3174 · AHU377) · 2Ca · 2H 2 O; (EXP3174 · AHU377) · 2Ca · 2.5H 2 O; (EXP3174 · AHU377) · 2Ca 3H2O . 根據請求項1-11任一項所述的複合物的藥物組合物，其中所述藥物組合物採用直壓工藝，或者乾法製粒工藝製備。The pharmaceutical composition of the compound according to any one of claims 1-11, wherein the pharmaceutical composition is prepared by a direct compression process or a dry granulation process. 一種藥物組合物的用途，其特徵在於，根據請求項1-15任一項所述的藥物組合物在製備預防和/或治療高血壓、心衰、高血壓和心衰的藥物中的應用。A use of a pharmaceutical composition, characterized in that the pharmaceutical composition according to any one of claims 1-15 is used in the preparation of a medicament for preventing and/or treating hypertension, heart failure, hypertension and heart failure.
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