WO2017000864A1 - 一种用于心衰治疗的药物组合物及其制备方法 - Google Patents

一种用于心衰治疗的药物组合物及其制备方法 Download PDF

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WO2017000864A1
WO2017000864A1 PCT/CN2016/087391 CN2016087391W WO2017000864A1 WO 2017000864 A1 WO2017000864 A1 WO 2017000864A1 CN 2016087391 W CN2016087391 W CN 2016087391W WO 2017000864 A1 WO2017000864 A1 WO 2017000864A1
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pharmaceutical composition
lcz696
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mass
parts
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French (fr)
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宋科
周红
叶冠豪
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深圳信立泰药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition for treating heart failure and a preparation method thereof.
  • Heart failure (referred to as heart failure) is a complex clinical syndrome in which ventricular filling or impaired ejection capacity is impaired by any abnormal cardiac structure or function.
  • the main clinical manifestations of heart failure are dyspnea and fatigue (limited activity tolerance), as well as fluid retention (pulmonary congestion and peripheral edema).
  • Heart failure is a serious and terminal stage of various heart diseases, and its incidence is high. It is one of the most important cardiovascular diseases today (Guide to Diagnosis and Treatment of Heart Failure in China 2014).
  • Angiotensin-converting enzyme inhibitor (ACEI) is the first class of drugs that has been shown to reduce the mortality rate of patients. It is also the drug with the highest accumulation of evidence-based medicine. It is the drug of choice for workers to treat heart failure. Elapril is the drug. One of the ACEI commonly used in the treatment of clinical heart failure.
  • LCZ696 (CAS: 936623-90-4) is a drug developed by Novartis for anti-heart failure, the structure of which was first disclosed in patent WO2007056546.
  • the compound is a supramolecular complex (complex) composed of valsartan and AHU377 through non-covalent bonding, and has an dual action of angiotensin receptor blockade and neutral endopeptidase inhibition.
  • LCZ696 reduces the hospitalization rate of heart failure by 21% compared with the enalapril-treated group, and reduces the symptoms and physical limitations of heart failure, reducing mortality in heart failure patients and Hospitalization rates are superior to enalapril (N Engl J Med, 2014, 371(1): 993-1004). It can be seen that LCZ696 is a market-leading anti-heart failure drug, and the product is expected to be approved for marketing in 2015.
  • LCZ696 is unstable to moisture and dissociates in the solution system, the use of solvents should be avoided as much as possible during the formulation process.
  • Chinese patent CN200880114940.6 discloses a solid oral preparation containing LCZ696, which has the characteristics of good dissolution performance and meets the requirements for clinical administration.
  • the preparation method adopts a dry granulation process, which has many processes and is cumbersome, which is not conducive to the cost control of the preparation.
  • the powder direct pressure process is one of the solutions to the above problems.
  • the first object of the present invention is to overcome the deficiencies of the prior art and to provide a pharmaceutical composition containing LCZ696, which has the characteristics of moderate flowability, good compatibility of raw materials and the like, and is suitable for preparing LCZ696 by powder direct pressing process. Solid oral preparations.
  • a pharmaceutical composition comprising LCZ696, the pharmaceutical composition comprising LCZ696, a filler, a binder, a disintegrant, characterized in that the filler is a hydrophilic filler.
  • the hydrophilic filler is selected from the group consisting of lactose, mannitol, starch, pregelatinized starch, sucrose, dextrin, calcium hydrogen phosphate, sorbitol, or a mixture of two or more thereof in any ratio. Since fillers usually account for a large proportion of excipients, the selection of fillers in the powder direct compression process requires a comprehensive consideration of the effects on the formulation process (such as fluidity) and product quality (such as dissolution properties). Specifically, for a specific LCZ696 drug substance, the hydrophilic filler is preferably lactose, mannitol, pregelatinized starch, calcium hydrogen phosphate, sorbitol.
  • the hydrophilic filler is used in an amount of 0.5 to 2.75 parts by mass. Since the common specifications of the LCZ696 are 100 mg and 200 mg, the use of the excessive filler makes the final tablet weight too large. The compliance of the patient is lowered, and the use of too little filler is disadvantageous for tableting.
  • the hydrophilic filler is used in an amount of 0.6 to 2 parts, more preferably 0.6 to 1 part by mass.
  • the binder is selected from one or a mixture of two or more of povidone, high-substituted hydroxypropylcellulose, and hypromellose in any ratio.
  • the use of a binder consists in facilitating the shaping of the pharmaceutical composition during the preparation process.
  • the binder is selected from one or a mixture of two or more of high-substituted hydroxypropylcellulose and hypromellose in any ratio.
  • the mass fraction of LCZ696 is 1, the mass fraction of the binder is 0.02 to 0.2 parts. There is a choice of the amount of the binder to be used.
  • the binder is used in an amount of from 0.02 to 0.14 parts by mass.
  • the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, or a mixture of two or more thereof in any ratio. .
  • the use of the disintegrant is to achieve effective dissolution after the product is successfully disintegrated after entering the body to achieve a therapeutic effect.
  • the disintegrating agent is selected from one or a mixture of two or more of crospovidone, croscarmellose sodium, and croscarmellose sodium in an arbitrary ratio.
  • the mass fraction of LCZ696 is 1, the mass fraction of the disintegrant is from 0.03 to 0.2 parts.
  • the use of the excessive disintegrant makes the pharmaceutical composition easy to absorb moisture, and the excessive disintegration after preparation into a preparation is not conducive to achieving clinical therapeutic purposes, and the use of too little disintegrant cannot guarantee complete release of the drug, which is disadvantageous for For the purpose of clinical treatment, it is preferred that the disintegrant is used in an amount of from 0.04 to 0.15 parts by mass.
  • the LCZ696 pharmaceutical composition may further comprise a glidant selected from the group consisting of dioxide One or a mixture of two or more of silicon and talc is mixed in an arbitrary ratio.
  • a glidant selected from the group consisting of dioxide
  • One or a mixture of two or more of silicon and talc is mixed in an arbitrary ratio.
  • the purpose of using a glidant is to further improve the powder flow properties to better achieve the powder direct compression process of the LCZ696 pharmaceutical composition.
  • the mass fraction of LCZ696 is 1, the mass fraction of the glidant is 0.002 to 0.05 parts.
  • the flow aid is used in an amount of 0.01 to 0.04 parts.
  • the pharmaceutical composition of the LCZ696 of the present invention may further comprise a lubricant depending on the prescription.
  • the lubricant is selected from one or a mixture of two or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, stearic acid, palmitic acid, and carnauba wax in any ratio.
  • the purpose of the lubricant is to prevent sticking of the pharmaceutical composition during subsequent stamping, the amount of lubricant being based on the ability to achieve lubrication as is known in the art.
  • the amount of lubricant used is 0.01 to 0.1 parts.
  • the powder properties of the total mixed powder should be controlled in the art for the powder direct pressing process.
  • the difference in tablet weight is in accordance with the relevant requirements of the Chinese Pharmacopoeia (2010 Edition), and it can be seen that the fluidity of the mixed powder meets the requirements and the process is stable.
  • the pharmaceutical composition of the LCZ696 can also be prepared into other dosage forms other than the tablet by utilizing the advantage of the total mixed powder, such as dispensing. After the capsule is obtained, it can also be prepared into a tablet or a capsule by a conventional dry granulation process.
  • a preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:
  • a preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:
  • lactose 1.56 Cross-linked povidone 0.2 Highly substituted hydroxypropyl cellulose 0.12 Silica 0.04 Magnesium stearate 0.08
  • a preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:
  • a preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:
  • a preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:
  • a preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:
  • a second object of the present invention is to provide a method for preparing a pharmaceutical composition of LCZ696 based on the aforementioned prescription characteristics and further preparing the pharmaceutical composition into a tablet by a process of powder direct pressing.
  • the LCZ696 prepared by the method has the advantages of high mixing uniformity and good fluidity, and is suitable for the powder direct pressing process.
  • the mixed powder A obtained in the step 2 is added to the mixed powder B obtained in the step 3, and a predetermined amount of the lubricant is added and uniformly mixed to obtain a total mixed powder.
  • the total mixed powder obtained by the above method can be further prepared by a powder direct pressing method, and the direct pressing process of the powder follows the common knowledge in the art.
  • the tablet specifications are 100 mg, 200 mg, and 400 mg.
  • the process of direct powder pressing needs to control the hardness of the tablet below 10 kgf.
  • a third object of the present invention is to provide an LCZ696 tablet which is prepared by the powder direct compression process of the LCZ696 pharmaceutical composition of the present invention, and the LCZ696 tablet has the characteristics of high yield, and various indexes such as tablets The difference in weight, dissolution performance, stability, etc. are in line with the quality requirements of clinical drugs.
  • the present invention has the following technical features and advantages:
  • a pharmaceutical composition of LCZ696 suitable for powder direct pressing process is provided.
  • the pharmaceutical composition has the characteristics of moderate flowability, good compatibility of raw materials and the like, and is suitable for preparing LCZ696 solid preparation by a simpler powder direct pressing process.
  • a method for preparing a pharmaceutical composition of LCZ696, which is combined with a specific LCZ696 pharmaceutical composition formulation, is suitable for industrial large-scale production, and is advantageous for obtaining a LCZ696 pharmaceutical composition conforming to a powder direct compression process.
  • the total mixed powder was prepared into a tablet having a specification of 100 mg by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • Example 7 Due to the absence of a flow aid in the formulation of Example 7, the variation in tablet weight was too large, which was greater than that of Examples 1 to 6, but still met the relevant requirements of the Chinese Pharmacopoeia (2010 edition).
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg tablet was prepared by a powder direct pressing process. However, since the amount of the filler was too small, the tablet weight was only 162 mg, the sheet thickness was thin, and the hardness range was 3 ⁇ 5kgf; In addition, the difference in tablet weight of the obtained tablets does not meet the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).
  • the LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.
  • Example 2 83.71 99.76 98.42
  • Example 3 80.31 95.34 98.56
  • Example 4 80.71 93.76 98.42
  • Example 5 83.21 96.24 98.83
  • Example 6 81.25 92.34 98.01
  • Example 7 81.51 92.12 98.32
  • Example 8 79.29 90.71 98.45
  • Example 9 75.45 87.51 97.84

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Abstract

一种含有LCZ696的药物组合物，其包含LCZ696、亲水性填充剂、粘合剂、崩解剂，当LCZ696的质量份为1时，亲水性填充剂质量份为0.5-2.75份。一种采用粉末直压工艺制备LCZ696制剂的方法。

Description

一种用于心衰治疗的药物组合物及其制备方法 技术领域
本发明属于药物制剂领域，特别涉及一种用于治疗心衰的药物组合物及其制备方法。
背景技术
心力衰竭(简称心衰)，是由于任何心脏结构或功能异常导致心室充盈或射血能力受损的一组复杂临床综合征。心力衰竭主要临床表现为呼吸困难和乏力(活动耐量受限)，以及液体潴留(肺淤血和外周水肿)。心衰为各种心脏疾病的严重和终末阶段，发病率高，是当今最重要的心血管疾病之一(《中国心力衰竭诊断和治疗指南2014》)。
自2005年以来，由于心血管病危险因素的流行，我国心血管病的发病人数呈持续增加的态势。据统计，我国心血管病患者约为2.9亿人，其中心力衰竭病患约有450万人(《中国心血管病报告2013》)。血管紧张素转化酶抑制剂(ACEI)是被证实能降低患者病死率的第一类药物，也是循证医学证据积累最多的药物，是工人的治疗心衰的首选药物，依拉普利即为常用于临床心衰治疗的ACEI之一。
LCZ696(CAS：936623-90-4)是由诺华公司研发的一种用于抗心衰的药物，其结构在专利WO2007056546中首次公开。该化合物由缬沙坦和AHU377通过非共价键结合而成的超分子络合物(复合物)，具有血管紧张素受体阻断和中性内肽酶抑制双重作用。临床实验结果表明，与依拉普利治疗组相比，LCZ696使受试者因心力衰竭住院率下降了21％，并减少了心力衰竭的症状和身体限制，在降低心力衰竭患者的死亡率和住院率方面优于依拉普利(N Engl J Med，2014，371(1)：993-1004)。可以看出，LCZ696是一种极具市场潜力抗心衰药物，产品预计将于2015年获批上市。
Figure PCTCN2016087391-appb-000001
由于LCZ696对湿不稳定，且在溶液体系中会发生离解，因此在制剂过程中应尽量避免溶剂的使用。中国专利CN200880114940.6公开了一种含有LCZ696的固体口服型制剂，该制剂具有溶出性能好的特点，符合临床给药要求。但是该制备方法采用干法制粒工艺，该方法工序较多，工艺较为繁琐，不利于制剂成本控制。而粉末直压工艺则是解决以上问题的方案之一。
由于LCZ696产品本身的流动性不佳，在制剂中占的比例较大，制备成适合粉末直压粉体存在困难，现有技术未有公开粉末直压制备LCZ696固体口服制剂的处方及工艺，因此寻找适用于粉末直压制备符合临床使用的LCZ696固体口服制剂的药物组合物，是现有技术需要解决的技术问题。
发明内容
本发明的第一个目的在于克服现有技术的不足，提供一种含有LCZ696的药物组合物，该药物组合物具有流动性能适中、原辅料兼容性好等特点，适合采用粉末直压工艺制备LCZ696固体口服制剂。
本发明的上述有益效果通过如下技术方案实现：
一种含有LCZ696的药物组合物，所述药物组合物包含LCZ696、填充剂、粘合剂、崩解剂，其特征在于所述填充剂为亲水性填充剂。
所述亲水性填充剂选自乳糖、甘露醇、淀粉、预胶化淀粉、蔗糖、糊精、磷酸氢钙、山梨醇中的一种或两种以上以任意比例的混合。由于填充剂通常在辅料中所占比例较大，因此对于粉末直压工艺中填充剂的选择，需要综合考量其对制剂工艺(如流动性)和产品质量(如溶出性能等)的影响。具体的，对于特定的LCZ696原料药，所述亲水性填充剂优选乳糖、甘露醇、预胶化淀粉、磷酸氢钙、山梨醇。当LCZ696的质量份为1时，所述亲水性填充剂的质量份用量为0.5～2.75份，由于LCZ696的常用规格为100mg和200mg，过多填充剂的使用使得最终制剂片重过大，降低了患者服用的顺应性，而过少填充剂的使用则不利于压片成型，优选的，所述亲水性填充剂的质量份用量为0.6～2份，更优选0.6～1份。
所述粘合剂选自聚维酮、高取代羟丙纤维素、羟丙甲纤维素中的一种或两种以上以任意比例的混合。粘合剂的使用在于使所述药物组合物在制备过程中利于成型。优选的，所述粘合剂选自高取代羟丙纤维素、羟丙甲纤维素中的一种或两种以上以任意比例的混合。当LCZ696的质量份为1时，所述粘合剂的质量份用量为0.02～0.2份。粘合剂的使用量存在选择，过多粘合剂的使用使得所述药物组合物制备成制剂后硬度过大而不易崩解，而过少粘合剂的使用则无法达到粘合作用，不利于压片成型，另外，过少粘合剂的使用也会使制剂崩解过快，不利于临床给药。优选的，所述粘合剂的质量份用量为0.02～0.14份。
所述崩解剂选自交联聚维酮、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素中的一种或两种以上以任意比例的混合。崩解剂的使用在于使得产品进入体内后顺利崩解后实现有效溶出，以达到治疗效果。优选的，所述崩解剂选自交联聚维酮、交联羧甲基淀粉钠、交联羧甲基纤维素钠中的一种或两种以上以任意比例的混合。当LCZ696的质量份为1时，所述崩解剂的质量份用量为0.03～0.2份。过多崩解剂的使用使得所述药物组合物容易吸潮，制备成制剂后过快崩解也不利于实现临床治疗目的，而过少崩解剂的使用则不能保证药物完全释放，不利于实现临床治疗目的，优选的，所述崩解剂的质量份用量为0.04～0.15份。
所述LCZ696药物组合物可以进一步含有助流剂，所述助流剂选自二氧化 硅、滑石粉中的一种或两种以上以任意比例的混合。使用助流剂的目的在于进一步改善粉体流动性能，以更好的实现LCZ696药物组合物的粉末直压工艺。当LCZ696的质量份为1时，所述助流剂的质量份用量为0.002～0.05份。优选的，所述助流剂的用量为0.01～0.04份。
本发明所述LCZ696的药物组合物还可以视处方需要进一步包含润滑剂。所述润滑剂选自硬脂酸镁、氢化植物油、聚乙二醇类、硬脂酸、棕榈酸、巴西棕榈蜡中的一种或两种以上以任意比例的混合。润滑剂的目的在于防止所述药物组合物在后续冲压过程中发生粘冲，所述润滑剂的量以本领域公知的能实现润滑效果为准，优选的，所述润滑剂的质量份用量为0.01～0.1份。
综上所述，对于所述LCZ696的药物组合物，除了需要考虑进一步所得制剂溶出性能、稳定性等外，对于粉末直压工艺，其总混粉体的粉体性质均应控制在本领域公知的合理范围内，所述粉体压片之后，其片重差异均符合《中国药典(2010版)》相关要求，可见其混粉流动性符合要求，且工艺稳定。
此外，由于所述LCZ696的药物组合物具有较好的流动性能，因此还可以利用所述总混粉体的该优势将所述LCZ696的药物组合物制备成片剂外的其他剂型，如分装后得到胶囊剂；也可以采用传统干法制粒工艺制备成片剂、胶囊剂。
本发明一个优选的含有LCZ696的药物组合物，其处方如下：
名称 质量份
LCZ696 1
乳糖 0.78
交联聚维酮 0.1
高取代羟丙纤维素 0.06
二氧化硅 0.02
硬脂酸镁 0.04
本发明一个优选的含有LCZ696的药物组合物，其处方如下：
名称 质量份
LCZ696 1
乳糖 1.56
交联聚维酮 0.2
高取代羟丙纤维素 0.12
二氧化硅 0.04
硬脂酸镁 0.08
本发明一个优选的含有LCZ696的药物组合物，其处方如下：
名称 质量份
LCZ696 1
甘露醇 0.78
交联聚维酮 0.1
高取代羟丙纤维素 0.06
二氧化硅 0.02
硬脂酸镁 0.04
本发明一个优选的含有LCZ696的药物组合物，其处方如下：
名称 质量份
LCZ696 1
乳糖 0.74
交联聚维酮 0.1
羟丙甲纤维素 0.10
胶态二氧化硅 0.02
硬脂酸镁 0.04
本发明一个优选的含有LCZ696的药物组合物，其处方如下：
Figure PCTCN2016087391-appb-000002
Figure PCTCN2016087391-appb-000003
本发明一个优选的含有LCZ696的药物组合物，其处方如下：
名称 质量份
LCZ696 1
山梨醇 0.72
交联羧甲基淀粉钠 0.12
羟丙甲纤维素 0.10
二氧化硅 0.02
硬脂酸镁 0.04
本发明的第二个目的在于提供一种基于前述处方特点制备LCZ696药物组合物，并采用粉末直压的工艺将所述药物组合物进一步制备成片剂的方法。该方法制备得到的LCZ696具有混合均匀度高、流动性好等有益效果，适合采用粉末直压工艺。
该方法的上述有益效果通过如下技术方案实现：
一种制备适合粉末直压LCZ696药物组合物的方法，所述方法包含如下步骤：
1)将原、辅料过40目筛，并按处方量进行称量备料；
2)取处方量粘合剂、崩解剂与1/2处方量填充剂混合均匀得混粉A；
3)取处方量原料药、助流剂、填充剂混合均匀得混粉B；
将步骤2所得混粉A加入步骤3所得混粉B中，并加入处方量润滑剂混合均匀，得总混粉末。
采用上述方法所得的总混粉末可以进一步采用粉末直压法制备得到LCZ696片剂，所述粉末直压的工艺遵从本领域公知常识，优选的，所述片剂规格为100mg、200mg、400mg，所述粉末直压的工艺需将片剂硬度控制在10kgf以下。
本发明的第三个目的在于提供一种LCZ696片剂，该制剂由本发明所述LCZ696药物组合物通过粉末直压工艺制备得到，所述LCZ696片剂具有合格率高的特点，各项指标如片重差异、溶出性能、稳定性等均符合临床用药质量要求。
与现有技术相比，本发明具有如下技术特点及优势：
1、首次提供一种适合粉末直压工艺的LCZ696药物组合物，该药物组合物流动性能适中、原辅料兼容性好等特点，适合采用更简单的粉末直压工艺制备LCZ696固体制剂。
2、提供一种LCZ696药物组合物的制备方法，该方法结合特定的LCZ696药物组合物处方，适合工业化大生产使用，有利于得到符合粉末直压工艺的LCZ696药物组合物。
3、提供一种LCZ696制剂，该制剂采用粉末直压工艺制备得到，其各项指标如溶出性能、稳定性等均符合临床用药质量要求。
具体实施方式
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。
实施例1
Figure PCTCN2016087391-appb-000004
LCZ696药物组合物的制备
1、乳糖、高取代羟丙纤维素、交联聚维酮、二氧化硅、硬脂酸镁过40目筛备 用，按照处方量进行称量备料；
2、取处方量交联聚维酮、高取代羟丙纤维素与1/2处方量乳糖混合均匀得混粉A；
3、取处方量原料药、二氧化硅、1/2处方量乳糖混合均匀得混粉B；
4、将混粉A加入混粉B中，另加入处方量硬脂酸镁混合，得总混粉末。
片剂的制备
将总混粉末采用粉末直压工艺制备成规格为100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例2
Figure PCTCN2016087391-appb-000005
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求，但实施例2所得片剂片重相对更重。
实施例3
Figure PCTCN2016087391-appb-000006
Figure PCTCN2016087391-appb-000007
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例4
Figure PCTCN2016087391-appb-000008
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例5
Figure PCTCN2016087391-appb-000009
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例6
Figure PCTCN2016087391-appb-000010
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例7
Figure PCTCN2016087391-appb-000011
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
由于实施例7处方中未加助流剂，其片重差异波动偏大，大于实施例1～6，但仍符合《中国药典》(2010版)相关要求。
实施例8
Figure PCTCN2016087391-appb-000012
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例9
Figure PCTCN2016087391-appb-000013
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
对比实施例1
Figure PCTCN2016087391-appb-000014
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异符合《中国药典》(2010版)第二部附录IA的相关要求。
对比实施例2
Figure PCTCN2016087391-appb-000015
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，但是由于填充剂用量过少，片重仅有162mg，片厚较薄，硬度范围为3～5kgf；另外，所得片剂的片重差异不符合《中国药典》(2010版)第二部附录IA的相关要求。
对比实施例3
Figure PCTCN2016087391-appb-000016
采用与实施例1相同的方法制备LCZ696总混粉末，并采用粉末直压工艺制备成规格100mg的片剂，所述片剂的硬度控制在5～10kgf。
所得片剂片重差异波动较小，且符合《中国药典》(2010版)第二部附录IA的相关要求。
实施例10
溶出度检测
采用中国药典(2010版)附录XC溶出度测定方法第二法桨法分别检测实施例1～9及对比实施例1～3所得LCZ696直压片剂的溶出度情况，所得数据如下表所示：
项目 15min 30min 45min
实施例1 87.24 99.35 99.13
实施例2 83.71 99.76 98.42
实施例3 80.31 95.34 98.56
实施例4 80.71 93.76 98.42
实施例5 83.21 96.24 98.83
实施例6 81.25 92.34 98.01
实施例7 81.51 92.12 98.32
实施例8 79.29 90.71 98.45
实施例9 75.45 87.51 97.84
对比实施例1 62.70 89.82 93.99
对比实施例2 53.94 84.21 96.63
对比实施例3 90.16* 96.72 98.75
*该数据为10min时检测得到
可以看出，实施例1～9所得制剂具有较好的溶出性能，符合临床用药要求。
对于对比实施例1，其未采用本发明保护的填充剂，尽管所述处方适合粉末直压工艺，但是所得制剂溶出性能明显不如实施例1～9所得产品。
对于对比实施例2，其处方中填充剂的用量过少，使得一方面因总混粉末流动性不佳而导致其片重差异较大，另一方面，所得制剂的溶出性能也不及实施例1～9所得产品。
对于对比实施例3，尽管处方符合粉末直压工艺需求，但是由于其粘合剂用量过少，使得其溶出过快，在10min中即溶出90％以上，不利于临床治疗效果的实现。
实施例11
稳定性检测
将实施例1～9所得制剂在加速条件(40℃±2℃，RH75％±5％)下放置1个月，检测其有效成分含量及单杂、总杂含量，所得结果如下：
Figure PCTCN2016087391-appb-000017
由上表可知，在加速实验中，实施例1～9所得制剂的单杂、总杂含量变化较小，符合临床用药相关质量法规的要求，可知实施例1～9所得制剂稳定性较高。
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。

Claims (10)

  1. 一种含有LCZ696的药物组合物，所述药物组合物包含LCZ696、填充剂、粘合剂、崩解剂，其特征在于所述填充剂为亲水性填充剂，当LCZ696的质量份为1时，所述亲水性填充剂的质量份用量为0.5～2.75份。
  2. 根据权利要求1所述的药物组合物，其特征在于所述亲水性填充剂的质量份用量为0.6～2份。
  3. 根据权利要求1或2任意一项所述的药物组合物，其特征在于所述亲水性填充剂选自乳糖、甘露醇、淀粉、预胶化淀粉、蔗糖、糊精、磷酸氢钙、山梨醇中的一种或两种以上以任意比例的混合。
  4. 根据权利要求1-3任意一项所述的药物组合物，其特征在于所述粘合剂选自聚维酮、高取代羟丙纤维素、羟丙甲纤维素中的一种或两种以上以任意比例的混合，所述粘合剂的质量份用量为0.02～0.2份。
  5. 根据权利要求1-4任意一项所述的药物组合物，其特征在于所述崩解剂选自交联聚维酮、交联羧甲基淀粉钠、交联羧甲基纤维素钠、低取代羟丙基纤维素中的一种或两种以上以任意比例的混合，所述崩解剂的质量份用量为0.03～0.2份。
  6. 根据权利要求1-5任意一项所述的药物组合物，其特征在于所述亲水性填充剂的质量份用量为0.6～1份，所述粘合剂的质量份用量为0.02～0.14份，所述崩解剂的质量份用量为0.04～0.15份。
  7. 根据权利要求1-6任意一项所述的药物组合物，其特征在于所述药物组合物进一步含有助流剂，所述助流剂选自二氧化硅、滑石粉中的一种或两种以上以任意比例的混合，所述助流剂的质量份用量为0.002～0.05份，优选0.01～0.04份。
  8. 根据权利要求1-7任意一项所述的药物组合物，其特征在于所述药物组合物进一步包含润滑剂，所述润滑剂选自硬脂酸镁、氢化植物油、聚乙二醇类、硬脂酸、棕榈酸、巴西棕榈蜡中的一种或两种以上以任意比例的混合，所述润滑剂的质量份用量为0.01～0.1份。
  9. 一种LCZ696片剂，其特征在于将权利要求1-8所述含有LCZ696的药物组合物采用粉末直压工艺制备得到。
  10. 一种制备如权利要求9所述LCZ696片剂的方法，所述方法包含如下步骤：
    1)将原、辅料过40目筛，并按处方量进行称量备料；
    2)取处方量粘合剂、崩解剂与1/2处方量填充剂混合均匀得混粉A；
    3)取处方量原料药、助流剂、填充剂混合均匀得混粉B；
    4)将步骤2)所得混粉A加入步骤3)所得混粉B中，并加入处方量润滑剂混合均匀，得总混粉末。
PCT/CN2016/087391 2015-06-30 2016-06-28 一种用于心衰治疗的药物组合物及其制备方法 WO2017000864A1 (zh)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018178295A1 (en) 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Stable hot-melt extrudate containing valsartan and sacubitril
WO2019073062A1 (en) 2017-10-13 2019-04-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) TABLET CONTAINING VALSARTAN AND SACUBITRIL
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
EP4088715A1 (en) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Pharmaceutical formulation of valsartan and sacubitril

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108379232A (zh) * 2018-03-21 2018-08-10 宁波蒙曼生物科技有限公司 一种含有lcz-696的分散片及其制备工艺

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101848700A (zh) * 2007-11-06 2010-09-29 诺瓦提斯公司 基于血管紧张素受体拮抗剂/阻断剂(arb)和中性内肽酶(nep)抑制剂的超结构的双重作用的药物组合物
WO2015028941A1 (en) * 2013-08-26 2015-03-05 Novartis Ag New use
CN104557600A (zh) * 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 沙库比曲的制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102204907A (zh) * 2011-03-31 2011-10-05 北京赛科药业有限责任公司 一种含缬沙坦的药物组合物及其制备方法
CA2882771C (en) * 2012-08-24 2021-02-23 Novartis Ag Nep inhibitors for treating diseases characterized by atrial enlargement or remodeling
CN105362239A (zh) * 2014-09-01 2016-03-02 深圳信立泰药业股份有限公司 一种含有盐酸厄洛替尼的药物组合物及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101848700A (zh) * 2007-11-06 2010-09-29 诺瓦提斯公司 基于血管紧张素受体拮抗剂/阻断剂(arb)和中性内肽酶(nep)抑制剂的超结构的双重作用的药物组合物
WO2015028941A1 (en) * 2013-08-26 2015-03-05 Novartis Ag New use
CN104557600A (zh) * 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 沙库比曲的制备方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018178295A1 (en) 2017-03-31 2018-10-04 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Stable hot-melt extrudate containing valsartan and sacubitril
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
US11819577B2 (en) 2017-07-06 2023-11-21 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
WO2019073062A1 (en) 2017-10-13 2019-04-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) TABLET CONTAINING VALSARTAN AND SACUBITRIL
EP4088715A1 (en) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Pharmaceutical formulation of valsartan and sacubitril
WO2022238563A1 (en) 2021-05-14 2022-11-17 Krka, D.D., Novo Mesto Pharmaceutical formulation of valsartan and sacubitril

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