WO2017020841A1 - 一种含有lcz696的药物组合物及其制备方法 - Google Patents

一种含有lcz696的药物组合物及其制备方法 Download PDF

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WO2017020841A1
WO2017020841A1 PCT/CN2016/093126 CN2016093126W WO2017020841A1 WO 2017020841 A1 WO2017020841 A1 WO 2017020841A1 CN 2016093126 W CN2016093126 W CN 2016093126W WO 2017020841 A1 WO2017020841 A1 WO 2017020841A1
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lcz696
pharmaceutical composition
preparation
crystalline powder
amount
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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A61K9/2022—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/22—Separation; Purification; Stabilisation; Use of additives
    • C07C231/24—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—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
    • C07C233/46—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of medicine, and particularly relates to a pharmaceutical composition containing LCZ696 which can be used for the treatment of 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 is the first class of drugs that have been shown to reduce mortality in patients with heart failure. It is also the drug with the highest accumulation of evidence-based medicine. It is recognized as the drug of choice for the treatment of heart failure, enalapril. It is one of the ACEI commonly used in the treatment of clinical heart failure.
  • LCZ696 (CAS: 936623-90-4) is an anti-heart failure drug developed by Novartis, which has dual roles of angiotensin receptor blockade and neutral endopeptidase inhibition, and its structure was first disclosed in patent WO2007056546 ( The following formula).
  • This compound is a supramolecular complex (complex) trisodium salt containing 2.5 water of crystallization, which is formed by combining non-covalent bonds of valsartan and AHU377.
  • 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, in reducing heart failure patients. Mortality 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 was approved for marketing in the second half of 2015.
  • LCZ696 is a special drug with special bonding and salt formation methods, it is unstable to moisture and heat, and dissociation occurs in the solution system. Therefore, even in the conventional production environment, LCZ696 will still Because of moisture absorption The quality is degraded by other reasons. Therefore, in the production and preparation of LCZ696 clinical drugs, the contact time with air should be shortened as much as possible, and the use of heat-receiving processes (such as crushing) should be avoided.
  • Patent Example WO2007056546 Examples 1 to 3 disclose a preparation method of LCZ696.
  • the LCZ696 prepared according to the method has a very fine powder shape, so that the filtration rate in the post-treatment process is extremely slow, especially in the amplification reaction. Obviously, even if nitrogen gas is used in the whole process of suction filtration, the obtained product still has the possibility of the product becoming sticky due to moisture absorption, thereby affecting the process stability. In addition, the extremely fine powder is not conducive to the preparation of the preparation product by the subsequent preparation process.
  • Patent WO2009061713 discloses a series of preparations of LCZ696, which have the characteristics of good dissolution performance and high stability, but in the field of preparation, for a specific product having multiple specifications at the same time, from the perspective of clinical drug use and process simplification.
  • the prescribed prescriptions and processes need to achieve equal magnification/reduction at the same time, that is, under the premise of not changing the prescription and the process, the preparation specifications are doubled/reduced, and the dissolution performance of the preparation still meets the requirements for clinical use, and the dissolution performance of the preparation is not Excessive fluctuations, while the patent WO2009061713 shows that the various specifications of the formulation have not achieved equal magnification, and the prior art does not disclose a solution to achieve a proportional enlargement/reduction of the LCZ696 formulation.
  • the prior art does not provide the LCZ696 crystalline powder obtained by direct synthesis, which is advantageous for the synthesis and preparation process, and does not optimize the formulation and process of the LCZ696 formulation. Therefore, it is necessary to find a LCZ696 crystalline powder and realize the formulation of the LCZ696 formulation.
  • the optimization of the process is a technical problem that is not solved by the prior art.
  • a first object of the present invention is to overcome the deficiencies of the prior art.
  • a crystalline powder of LCZ696 prepared by direct synthesis is provided, which has the characteristics of being easy to be suctioned and filtered during the synthesis process, and can be directly used for preparation.
  • the pulverization process before the preparation can be avoided, and the preparation process is simplified (such as material mixing, etc.), and the obtained preparation can achieve equal ratio enlargement/reduction while optimizing various performances (such as dissolution performance) of the preparation.
  • a crystalline powder of LCZ696 characterized in that the crystalline powder is 20 ⁇ m ⁇ D 90 ⁇ 100 ⁇ m.
  • the powder properties (such as D 90 , D 50 , etc.) of all the LCZ696 crystalline powders in the present invention are measured after passing the dried powder through an 80 mesh sieve (pore size of about 200 ⁇ m).
  • the purpose of the screen is to remove a small amount of LCZ696 product that agglomerates during the drying process.
  • the powder with too low particle size is not conducive to product filtration, and moisture absorption is easy to occur in the filtration and drying process, while the product with too high particle size corresponds to a relatively long crystallization time, which does not conform to the synthesis process.
  • the optimal requirements, and products with too high particle size also have the problem of inhomogeneous enlargement/reduction in the formulation; when the LCZ696 crystalline powder is 20 ⁇ m ⁇ D 90 ⁇ 100 ⁇ m, preferably 25 ⁇ m ⁇ D 90 ⁇ 75 ⁇ m, it can be realized. Rapid filtration to avoid product moisture and viscosity due to excessive contact with air, affecting product quality; at the same time, avoiding product drying in the post-treatment process for a long time, and the product obtained after drying is agglomerated; more preferred
  • the LCZ696 crystalline powder is 30 ⁇ m ⁇ D 90 ⁇ 60 ⁇ m. Further, the LCZ696 crystalline powder simultaneously satisfies 5 ⁇ m ⁇ D 50 ⁇ 50 ⁇ m, preferably 8 ⁇ m ⁇ D 50 ⁇ 30 ⁇ m.
  • a second object of the present invention is to provide a method for preparing a crystalline powder of the above LCZ696, which can stably prepare a crystalline powder of LCZ696 having the foregoing powder properties, and the obtained crystalline powder can be directly used for subsequent processing without pulverization.
  • the method is suitable for industrial scale production, which uses the process route shown below.
  • the method comprises the following preparation steps:
  • reaction solution is moved to 5 to 25 ° C and stirred for 1 to 5 hours;
  • the room temperature referred to in the present invention is 20 ⁇ 5 ° C unless otherwise specified.
  • the molar ratio of free AHU377 to valsartan in reaction step 1) follows the conventional principle of setting the ratio of such reaction in the art.
  • the molar ratio of free AHU377 to valsartan is 1:0.95 to 1.05.
  • the free AHU377 and valsartan used preferably have a purity of ⁇ 99.0%.
  • the free AHU377 can be obtained by freeing the AHU377 salt, and the AHU377 salt (M) can be a common metal salt or a non-metal salt such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a zinc salt, an ammonium salt, or the like.
  • the ethylamine salt, the diethylamine salt and the like are preferably a calcium salt.
  • the free AHU377 is obtained by the following steps:
  • AHU377 salt and isopropyl acetate (IPAC) were placed in the reactor, 2N HCl was added dropwise at a temperature below 30 ° C, and stirred until clarification;
  • LCZ696 crystalline powder (such as D 90 and/or D 50, etc.) having the aforementioned powder properties can be obtained by the above method.
  • the technical key of the preparation step is the kind and proportion of the solvent in the mixed solution in the step 1), one of which is a good solvent with respect to LCZ696, the other is a poor solvent, and a certain proportion of the mixed solvent is controlled, and the temperature is decrystallized by cooling.
  • the method obtains the product, the ratio of the good solvent is increased, and/or the slow cooling and crystallization is favorable for obtaining the crystal powder having a larger particle diameter, and the ratio of the poor solvent is increased and/or the room temperature crystallization is favorable for obtaining the crystal powder having a smaller particle diameter.
  • the solvent A is a poor solvent selected from any one of acetone, tetrahydrofuran, acetonitrile, etc.
  • the solvent B is a good solvent selected from the group consisting of isopropanol, n-butanol, isobutanol and the like.
  • the solvent A is preferably acetone having relatively low toxicity; in order to maximize the yield while ensuring that the particle size of the product meets the requirements, the volume-mass ratio of the solvent A to the valsartan in the mixed solution is 6 ⁇ 10:1ml: 1g, the purpose of this step is to dissolve AHU377 and valsartan, and to ensure a certain solvent saturation to facilitate crystal precipitation.
  • the solvent A can be prepared in the subsequent process to achieve the purpose of improving the yield.
  • the solvent A in which the volume of the solvent A in the mixed solution is 1.0 to 3.0 times is added, so that the LCZ696 can be further precipitated from the solvent system, and the purpose of improving the yield can be achieved.
  • the step 4) can be further optimized: the reaction solution is moved to 5 to 25 ° C and stirred for 0.5 to 3 hours, and the solvent A is further added and stirring is continued for 0.5 to 2 hours.
  • Said step 5 is preferably filtered under the protection of an inert gas, preferably nitrogen.
  • the above method can ensure that LCZ696 is uniformly precipitated in a specific physical form, and the product yield and powder properties are also controlled optimally.
  • the speed of the LCZ696 powder in the suction filtration process is obvious, and it shows a more obvious speed advantage in mass production.
  • the faster filtration rate can effectively prevent the product from sticking due to moisture absorption during the preparation process, avoiding longer drying time, and avoiding product stagnation, avoiding the conventional pulverization process before preparation.
  • a third object of the present invention is to further optimize on the basis of the foregoing method, to control the obtained LCZ696 crystalline powder to be within a specific particle size range, and to control the hydrolysis impurities to a very low range.
  • the hydrolysis impurity is a hydrolysis impurity of AHU377, and the structure thereof is as follows:
  • hydrolysis of impurities is one of the impurities that need to be controlled in the production process.
  • Further stability experiments found that there is a certain correlation between the content of hydrolyzed impurities and its growth rate. Specifically, for the LCZ696 preparation, when the accelerated experiment (40 ° C ⁇ 2 ° C, 75% ⁇ 5% RH) 30 days, the hydrolysis impurity increased by more than 0.1%. At the time, the stability of the preparation was considered to be poor. Through experiments, we found that when the hydrolysis impurities in the preparation are controlled below 1.0%, the increment is relatively slow. The accelerated experiment (40 °C ⁇ 2 °C, 75% ⁇ 5% RH) has a low increase in hydrolysis impurities within 30 days. At 0.1%, the obtained preparation has high stability and meets the requirements for clinical use.
  • the method for preparing the low-hydrolysis impurity content LCZ696 of the present invention achieves the purpose of controlling the content of the hydrolyzed impurities by controlling the amount and concentration of the sodium hydroxide.
  • the amount of sodium hydroxide does not affect the powder form of the LCZ696 crystalline powder, but it affects the product yield and impurity content.
  • the valsartan and the sodium hydroxide used are molar
  • the ratio is 1:2.5-3.0 and the concentration of the aqueous sodium hydroxide solution is in the range of 0.5-1.0 g/ml
  • the quality of the hydrolyzed impurities can be controlled to be within 1.0%.
  • the overall yield and the influence factor of the impurity content preferably, the molar ratio of valsartan to the sodium hydroxide used is 1:2.70-2.95, more preferably, when valsartan and sodium hydroxide used When the molar ratio is 1:2.80-2.90, the reaction yield and impurity content can be optimized.
  • the concentration of sodium hydroxide has a certain influence, and the lower concentration in the above concentration range corresponds to a relatively low yield.
  • the LCZ696 crystalline powder of the present invention can be directly used in the formulation process without pulverization due to its advantages in powder form and quality.
  • the pretreatment usually includes a step of pulverizing and sieving.
  • the LCZ696 product because it is unstable to moisture and heat, it needs to avoid the pulverization process in the preparation process, and the raw material medicine without pretreatment is easy to cause fluctuations in the preparation process and product quality.
  • the particle size Too coarse results in poor material mixing uniformity, which may cause a large difference in tablet weight when the tablet is pressed.
  • the particle size is too fine, resulting in poor fluidity of the material, easy sticking, and the sheet weight difference may be large when the tablet is pressed, and the sheet surface is slightly deep.
  • the inventors have surprisingly found that the LCZ696 crystalline powder in the particle size range of the present invention is more favorable to the dry granulation process than the crystalline powder outside the particle size range.
  • the LCZ696 crystalline powder has simple pretreatment and uniform particle size.
  • the process is stable, the difference between the batches is small, and the like, and more importantly, the prescription ratio can be enlarged/reduced, that is, the prescription and the process can be enlarged/reduced without changing the prescription and the process.
  • the realization of the prescription equalization enlargement/reduction is conducive to the conversion of various specifications in the production, and is the embodiment of the prescription technology content.
  • a fourth object of the present invention is to provide a LCZ696 pharmaceutical composition comprising the LCZ696 crystalline powder of the present invention.
  • the particle size range of LCZ696 crystal powder is the key to achieve the above beneficial effects. Specifically, for LCZ696 products of 50mg, 100mg, 200mg and 400mg specifications, it is required to achieve dissolution of more than 70% in 15 minutes in accordance with clinical drug requirements. Compared with the enlargement/reduction, it adopts the same prescription and process to achieve the dissolution of more than 70% of the products of all specifications in 15 minutes, and the dissolution performance fluctuates less. Through experiments, we were surprised to find that when the control drug substance is 20 ⁇ m ⁇ D 90 ⁇ 100 ⁇ m, LCZ696 products of 50mg, 100mg, 200mg and 400mg can achieve more than 70% dissolution in 15min, and the dissolution performance is less fluctuating.
  • the particle size of the drug substance is 25 ⁇ m ⁇ D 90 ⁇ 75 ⁇ m. More preferably, when the particle size of the drug substance is 30 ⁇ m ⁇ D 90 ⁇ 60 ⁇ m, the LCZ696 products of 50 mg, 100 mg, 200 mg and 400 mg can be achieved in 15 minutes. More than 70% of the dissolution, while the dissolution performance fluctuations are minimal.
  • the LCZ696 pharmaceutical composition contains a filler, a disintegrant, a binder, and the kind and amount of the adjuvant also contribute to the realization of the above-mentioned beneficial effects of the LCZ696 crystalline powder.
  • the filler is selected from the group consisting of microcrystalline cellulose, lactose, starch, pregelatinized starch, mannitol, calcium hydrogen phosphate, sorbitol, or a mixture of two or more thereof, preferably microcrystalline cellulose, mannose Alcohol, calcium hydrogen phosphate, sorbitol; when the amount of LCZ696 is 1 part by mass, the filler is used in an amount of 0.2 to 0.8 parts, preferably 0.3 to 0.7 parts.
  • the disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, carboxymethylcellulose calcium, or a mixture of two or more thereof, preferably crosslinked carboxymethyl
  • the base cellulose sodium and the crospovidone when the LCZ696 parts by mass is 1 part, the disintegrant is used in an amount of 0.04 to 0.4 parts, preferably 0.05 to 0.3 parts; the disintegrant may be selected to be added, plus And the method of adding the inside and the outside, preferably the method of adding the inside and the outside; when the method is internal and external, that is, the pharmaceutical composition comprises the inner phase particles and the external auxiliary material, the inner phase particles comprise the crystal powder of the LCZ696, the filler, the disintegrating agent, and the sticking When the mixture is mixed, the mass ratio of the internally added disintegrant to the additional disintegrant is from 0.4 to 3.8:1.
  • the binder is selected from one or a mixture of two or more of low-substituted hydroxypropylcellulose, hypromellose, sodium carboxymethylcellulose, povidone, ethylcellulose, preferably carboxymethyl Cellulose sodium, low-substituted hydroxypropylcellulose, when the amount of LCZ696 is 1 part by mass, the binder is used in an amount of 0.05 to 0.5 part, preferably 0.1 to 0.4 part.
  • the LCZ696 pharmaceutical composition may further comprise a glidant selected from the group consisting of one or a mixture of two or more of silica, talc, and the flow aid when the LCZ 696 parts by mass is 1 part.
  • the dosage of the agent is from 0.002 to 0.05 parts.
  • the LCZ696 pharmaceutical composition may further comprise a lubricant selected from one or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, stearic acid, palmitic acid, carnauba wax.
  • a lubricant selected from one or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, stearic acid, palmitic acid, carnauba wax. The mixture is used in an amount of 0.01 to 0.1 parts when the LCZ 696 parts by mass is 1 part.
  • the LCZ696 pharmaceutical composition includes, but is not limited to, tablets, granules, capsules, powders, and the like, which are common in the art.
  • the LCZ696 pharmaceutical composition may also be subjected to further coating treatment as needed, and the coating may be a coating type commonly used in the art such as a film coating, a sugar coating, etc., and the coating may be made of a coating which is common in the art.
  • Materials such as hypromellose, powdered sugar, hydroxypropylcellulose, etc., can also be used in conventional commercial coating materials, such as Opadry.
  • a crystalline powder having specific powder properties allows the pharmaceutical composition to be more optimized for proportional enlargement/reduction, that is, when the ratio of raw materials is increased/decreased by equal ratios to obtain different specifications.
  • the dissolution properties of the obtained preparation tend to be uniform, and are not affected by the increase/decrease in the ratio of the raw materials.
  • the LCZ696 formulation uses the LCZ696 crystalline powder of the present invention, and the prescription is:
  • the LCZ696 formulation uses the LCZ696 crystalline powder of the present invention, and the prescription is:
  • the LCZ696 formulation uses the LCZ696 crystalline powder of the present invention, and the prescription is:
  • a fifth object of the present invention is to provide a method for preparing the LCZ696 pharmaceutical composition of the present invention. Specifically, when the LCZ696 pharmaceutical composition is a tablet, the preparation method comprises the following steps:
  • the obtained LCZ696 core may be coated by a coating material and a coating method which are commonly used in the art, and the coating may be made of a coating material commonly used in the art, such as hypromellose.
  • a coating material commonly used in the art, such as hypromellose.
  • Sugar powder, hydroxypropyl cellulose, etc. can also be used in conventional commercial coating materials, such as Opadry
  • the present invention is advantageous in realizing the optimization of LCZ696 synthesis and preparation process, based on the fact that the LCZ696 bulk drug is unstable under wet and hot conditions, through the two technical fields of serial composition synthesis and preparation of active ingredient, through synthesis. Preparation of a specific particle size active ingredient, and optimization of the formulation process by the obtained specific particle size active ingredient. It can be seen that the present invention has the following technical features and advantages compared with the prior art:
  • a crystalline powder of LCZ696 prepared by direct synthesis is provided.
  • the crystalline powder has specific powder properties, and has the characteristics of being convenient for suction filtration and avoiding moisture absorption during the synthesis process, and the obtained product has almost no agglomeration.
  • the pulverization process can be avoided, which is beneficial to optimize the performance of the preparation (such as dissolution performance);
  • LCZ696 pharmaceutical composition comprising the LCZ696 crystalline powder of the present invention, wherein the LCZ696 crystalline powder used in the LCZ696 pharmaceutical composition has specific powder characteristics, so that it meets the formulation process requirements and is produced in accordance with Simultaneous amplification of the pharmaceutical composition can be achieved while the pharmaceutical composition is required for clinical use.
  • a method of preparing a pharmaceutical composition of the LCZ696 of the present invention which provides for the preparation of a tablet containing LCZ696.
  • Figure 1 shows the particle size distribution of the LCZ696 crystalline powder obtained in Example 1 before sieving.
  • Figure 2 is a particle size distribution diagram of the LCZ696 crystal powder obtained in Example 1 after passing through a 80 mesh sieve.
  • Figure 3 is an appearance of the LCZ696 crystal powder obtained in Example 1 after passing through a 80 mesh sieve.
  • Figure 4 is a particle size distribution of the LCZ696 crystalline powder obtained in Example 2 before sieving.
  • Figure 5 shows the particle size distribution of the LCZ696 crystal powder obtained in Example 2 after passing through a 80 mesh sieve.
  • Figure 6 is a comparison of the appearance of the LCZ696 product obtained in Example 1 before sieving.
  • Figure 7 is a comparison of the particle size distribution of the LCZ696 product obtained in Example 1 after passing through a 80 mesh sieve.
  • Figure 8 is a particle size distribution diagram of the LCZ696 crystal powder obtained in Example 4 after passing through a 80 mesh sieve.
  • Figure 9 is a particle size distribution diagram of the LCZ696 crystal powder obtained in Example 5 after passing through a 80 mesh sieve.
  • AHU377 calcium salt 1000 ml of isopropyl acetate were added to a 2 L three-necked flask, 240 ml of 2 mol/L hydrochloric acid was added dropwise under ice bath; the solution was dissolved; the organic layer was collected, and washed twice with 600 ml of water; Decomposition under reduced pressure at 38 ° C to obtain AHU377 free acid;
  • AHU377 free acid, 100g valsartan and 880ml acetone, 220ml isopropanol were added to a 3L three-necked flask, and dissolved; and a 2.78-equivalent aqueous solution of 0.9 g/ml of valsartan was added dropwise at room temperature.
  • the obtained product was passed through an 80 mesh sieve to obtain 184.2 g of a crystalline powder having a D 90 of 43.90 ⁇ m and a D 50 of 10.14 ⁇ m.
  • the particle size distribution of the obtained crystalline powder is shown in Fig. 2, and the external appearance is shown in Fig. 3.
  • AHU377 calcium salt 1000 ml of isopropyl acetate were added to a 2 L three-necked flask, 230 ml of 2 mol/L hydrochloric acid was added dropwise under ice bath; the solution was dissolved and dissolved; the organic layer was separated, and washed twice with 600 ml of water; Decomposition under reduced pressure at 38 ° C to obtain AHU377 free acid, dissolved in 250 ml of isopropanol, and then decomposed again under reduced pressure and repeated once;
  • AHU377 free acid, 100g valsartan and 800ml of acetone, 220ml of isopropanol were added to a 3L three-necked flask, and dissolved; and a 2.95-equivalent aqueous solution of sodium hydroxide at a concentration of 0.85 g/ml relative to valsartan was added dropwise at room temperature.
  • the temperature is raised to 53 ° C for 30 min; then the external temperature is reduced to 30 ° C at a rate of 1.0 ° C / 10 min, about 1.0 g of seed crystals are added, the reaction solution is moved to a temperature of 20 ° C for 2 h; then dropped into the system 1200ml of acetone was added, and the temperature was stirred for 2 hours. Under vacuum protection, the mixture was filtered through a Buchner funnel to obtain a white solid. The mixture was dried under vacuum at 35 ° C for 8 hours, and dried to obtain a solid 191.3 g. The yield was 85.6%. The purity by HPLC was 99.33%. The impurity content was 0.58%, and the particle size distribution was as shown in FIG.
  • the obtained product was passed through an 80 mesh sieve to obtain 188.0 g of a crystalline powder having a D 90 of 48.07 ⁇ m and a D 50 of 10.26 ⁇ m.
  • the particle size distribution of the obtained crystalline powder is shown in Fig. 5 .
  • Example 1 Since the crystal powders obtained in Example 1 and Example 2 have a moderate particle size morphology, rapid filtration can be achieved during the reaction. In order to reflect its advantages compared with the prior art in filtration, the reaction scales of Example 1 and Example 2 are magnified 20 times, and it is combined with Patent CN200680001733.0 Example 3 (hereinafter referred to as "contrast implementation” Example 1") relative ratio, the results are as follows:
  • the crystalline powder obtained in Comparative Example 1 had a more serious agglomeration due to moisture absorption during the filtration process (appearance is shown in FIG. 6), and the passage rate through the 80 mesh sieve was only about 25%.
  • the particle size distribution of the crystalline powder is shown in Fig. 7.
  • Example 1 and Example 2 can achieve faster filtration, which is more obvious in larger scale production.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 80ml acetone, 15ml isobutanol was added to the reaction flask; 2.9 equivalents relative to valsartan was added at room temperature, the concentration was 0.85 G/ml aqueous sodium hydroxide solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 ° C at a rate of 1.5 ° C / 10 min.
  • the reaction solution was stirred to a temperature of 15 ° C and stirred for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; filtered under a nitrogen atmosphere through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h and dried.
  • the solid was 19.2 g, the purity was 99.83%, and the hydrolysis impurity content was 0.12%.
  • the obtained product was passed through an 80 mesh sieve to obtain 18.5 g of a crystalline powder having a D 90 of 31.60 ⁇ m and a D 50 of 8.40 ⁇ m.
  • the particle size distribution of the obtained crystalline powder is shown in Fig. 8 .
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 85ml tetrahydrofuran, 17ml isopropanol was added to the reaction bottle and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is 0.85 g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 1.5 ° C/10 min.
  • the reaction solution was stirred to a temperature of 20 ° C for 3 h; then 135 ml of THF was added dropwise to the system, and the temperature was stirred for 2 h; under a nitrogen atmosphere, suction filtration through a Buchner funnel to obtain a white solid, and vacuum drying at 40 ° C for 8 h. Drying gave a solid of 18.9 g, a purity of 99.83%, and a hydrolyzed impurity content of 0.12%.
  • the obtained product was passed through an 80 mesh sieve to obtain 18.1 g of a crystalline powder having a D 90 of 32.95 ⁇ m and a D 50 of 8.71 ⁇ m.
  • the particle size distribution of the obtained crystalline powder is shown in Fig. 9 .
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 70ml acetone, 12ml n-butanol was added to the reaction flask and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is 0.85 g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 1.5 ° C/10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 3 h; then 150 ml of acetone was added dropwise to the system, and the temperature was stirred for 1 h; under a nitrogen atmosphere, filtered through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h. Drying gave 19.5 g of a solid with a purity of 99.78% and a hydrolyzed impurity content of 0.13%.
  • the obtained product was passed through an 80 mesh sieve to obtain 18.7 g of a crystalline powder having a D 90 of 31.16 ⁇ m and a D 50 of 8.28 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 88ml acetone, 40ml isopropanol was added to the reaction flask and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is a 0.85 g/ml aqueous sodium hydroxide solution, and the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 0.5 ° C/10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 2 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 3 h; under a nitrogen atmosphere, suction filtration through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h. Drying gave 18.5 g of a solid with a purity of 99.80% and a hydrolyzed impurity content of 0.12%.
  • the obtained product was passed through an 80 mesh sieve to obtain 17.6 g of a crystalline powder having a D 90 of 87.23 ⁇ m and a D 50 of 46.23 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetonitrile, 25ml isopropanol was added to the reaction flask and stirred to dissolve; at room temperature, 2.9 equivalent concentration relative to valsartan was added dropwise It is 0.85 g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25 min; the temperature is lowered to 45 ° C, about 0.3 g of seed crystals are added, the solution is turbid after stirring, and then the external temperature is lowered to 30 at a rate of 1.0 ° C / 10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 2 h; then, 130 ml of acetonitrile was added dropwise to the system, and the temperature was stirred for 2 h. Under a nitrogen atmosphere, the mixture was filtered through a Buchner funnel to obtain a white solid, which was vacuum dried at 40 ° C for 8 h. Drying gave a solid of 19.0 g, a purity of 99.81%, and a hydrolyzed impurity content of 0.10%.
  • the obtained product was passed through an 80 mesh sieve to obtain 18.6 g of a crystalline powder having a D 90 of 50.75 ⁇ m and a D 50 of 11.03 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isopropanol was added to the reaction bottle and stirred to dissolve; at room temperature, 2.6 equivalent concentration relative to valsartan was added dropwise It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 1 h; suction filtration through a Buchner funnel under nitrogen to obtain a white solid, vacuum drying at 35 ° C for 12 h Drying gave 16.5 g of solid with a purity of 99.92% and a hydrolyzed impurity content of 0.03%.
  • the obtained product was passed through an 80 mesh sieve to obtain 15.8 g of a crystalline powder having a D 90 of 45.74 ⁇ m and a D 50 of 16.34 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml C at 25 °C
  • the ketone and 20 ml of n-butanol were added to the reaction flask and stirred and dissolved; a 2.8 equivalent aqueous solution of 0.9 g/ml of valsartan was added dropwise at room temperature, and the temperature was raised to 50 ° C for 25 min; the temperature was lowered to 45 ° C.
  • the obtained product was passed through an 80 mesh sieve to obtain 17.0 g of a crystalline powder having a D 90 of 40.86 ⁇ m and a D 50 of 11.79 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isobutanol was added to the reaction flask and stirred to dissolve; at room temperature, add 2.95 equivalent concentration relative to valsartan It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 2 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; under a nitrogen atmosphere, suction filtration through a Buchner funnel gave a white solid, and vacuum drying at 35 ° C for 12 h. Drying gave a solid of 18.9 g, a purity of 99.38%, and a hydrolyzed impurity content of 0.53%.
  • the obtained product was passed through an 80 mesh sieve to obtain 18.1 g of a crystalline powder having a D 90 of 44.48 ⁇ m and a D 50 of 14.54 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isopropanol was added to the reaction bottle and stirred to dissolve; at room temperature, add 2.4 equivalent concentration relative to valsartan It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; suction filtration through a Buchner funnel under nitrogen to obtain a white solid, vacuum drying at 35 ° C for 12 h Drying gave a solid of 12.5 g, a purity of 99.90%, and a hydrolyzed impurity content of 0.02%.
  • the obtained product was passed through an 80 mesh sieve to obtain only 11.8 g of a crystalline powder having a D 90 of 42.35 ⁇ m and a D 50 of 13.01 ⁇ m.
  • AHU377 free acid (10g AHU377 calcium salt free), 10g valsartan and 90ml acetone, 20ml isopropanol was added to the reaction flask and stirred to dissolve; at room temperature, 3.1 equivalent concentration relative to valsartan was added dropwise It is 0.9g/ml sodium hydroxide aqueous solution, the temperature is raised to 50 ° C for 25min; the temperature is lowered to 45 ° C, the seed crystal is added about 0.3g, the solution is turbid after stirring, and then the external temperature is reduced to 30 at a rate of 1.0 ° C / 10 min.
  • the reaction solution was moved to a temperature of 25 ° C for 3 h; then 120 ml of acetone was added dropwise to the system, and the temperature was stirred for 2 h; suction filtration through a Buchner funnel under nitrogen to obtain a white solid, vacuum drying at 35 ° C for 12 h Drying gave 18.5 g of solid, purity of 96.75%, and hydrolysis impurity content of 1.87%, and the obtained product was pale yellow.
  • the obtained product was passed through an 80 mesh sieve to obtain 17.9 g of a crystalline powder having a D 90 of 43.66 ⁇ m and a D 50 of 12.52 ⁇ m.
  • the amount of sodium hydroxide only affects the yield and impurity content, but has little effect on the powder morphology.
  • the yield gradually decreases with the decrease of the amount of sodium hydroxide.
  • the amount of sodium hydroxide is less than 2.5 equivalents, although the particle size and impurities are satisfactory, the yield is The sharp drop to below 60% can not meet the requirements of industrial production; when the amount of sodium hydroxide is more than 3.0 equivalents (relative to valsartan), the content of hydrolyzed impurities exceeds 1.0%, after the product is subsequently prepared into a preparation, Does not meet the requirements for stability of the formulation.
  • the concentration of sodium hydroxide has a slight effect on the preparation process, as shown by the fact that when the concentration of sodium hydroxide is lowered, with more water being introduced, the reaction yield is lowered.
  • the powder properties of the LCZ696 crystalline powder are greatly affected by the solvent system; in addition, in the synthesis process, the smaller the particle size of the crystalline powder, the longer the filtration time required. Especially in large-scale reactions, which makes the product moisture absorption caused by excessive exposure to the air for a long time, and the resulting product has a more serious compaction, which is not conducive to the subsequent preparation process; The rate and the content of hydrolyzed impurities, which are affected by the amount and concentration of sodium hydroxide; and the LCZ696 crystalline powder with specific powder properties and low hydrolyzed impurities, and the optimization of the synthesis process requires a comprehensive solvent system. A number of factors affecting the amount and concentration of sodium hydroxide.
  • the inner phase particles are mixed with the added crospovidone and magnesium stearate, and after mixing, the resulting mixture is tableted.
  • the resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity, and the chip surface obtained by tableting is smooth, and the difference in tablet weight is small.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity, and the chip surface obtained by tableting is smooth, and the difference in tablet weight is small.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the tablet obtained by tableting has a smooth surface and a small difference in tablet weight.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity. Since no lubricant is added, the core of the tablet obtained by pressing is slightly burred, but the overall appearance conforms to the requirements of the pharmacopoeia.
  • the preparation method is the same as that in the embodiment 12, but in the preparation process, since the particle size of the raw material is too small, the sticking phenomenon occurs in the dry granulation process, but the subsequent process is not affected, and the surface color of the obtained core is slightly uneven, compared with the embodiment.
  • the surface of the chip obtained in 12 to 16 was slightly darker, but the overall condition was still satisfactory.
  • the LCZ696 core was prepared in the same manner as in Example 12. The resulting core was coated with an Opadry coating polymer to give a coated tablet.
  • the obtained internal phase particles have good fluidity, and the obtained tablets have a smooth surface and a small difference in tablet weight.
  • the core color is slightly darker and white-like.
  • Example 17 32.95 84.77 96.82 99.87
  • Example 18 32.95 85.54 97.34 99.50
  • Comparative Example 4 16.80 64.73 87.43 98.12
  • Comparative Example 5 43.66 83.45 96.35 98.43
  • the prescriptions and processes of Examples 12-18 and Comparative Example 5 can also achieve the equal reduction of the prescription and the process, while the Comparative Example 4 is also effective because the tablet is effective within 15 minutes.
  • the dissolution of the ingredients was less than 70%, and the ratio of the formulation was not reduced.
  • the solid oral preparation (100 mg) obtained in the examples was allowed to stand under accelerated conditions (40 ° C ⁇ 2 ° C, RH 75% ⁇ 5%) for 30 days to examine changes in hydrolysis impurities and appearance, and the results were as follows:
  • the content of the hydrolyzed impurities has a great influence on the quality of the preparation.
  • the hydrolysis impurities in the examples 12-18 and the comparative example 4 are less than 1.0%, and the preparation is hydrolyzed in the accelerated test. Incremental comparison Small, 60-day increment is below 0.10%, and the appearance of the preparation is still not white when the accelerated experiment is completed, and no significant change has occurred.
  • the raw material medicines with different powder properties and impurity contents were obtained by adjusting the solvent system, the feed ratio, the reaction conditions and the like, and the solid oral preparations were prepared by the same prescription and preparation process as in Example 12, respectively, using Example 17 and Examples.
  • the method of 18 studies the effect of the powder properties and impurity content of the raw material on the enlargement/reduction of the preparation ratio and the stability of the preparation.
  • the specific performance is that the ratio of enlargement/reduction of the preparation is mainly related to the particle size of the drug substance.
  • the particle size D90 of the drug substance is 20-100 ⁇ m
  • the formulation and process of the preparation can be scaled up/down, when the particle size of the drug substance is D90.
  • the temperature is ⁇ 60 ⁇ m
  • the dissolution property of the obtained preparation is the best, and the effect of the enlargement/reduction ratio of the prescription is optimal.
  • the stability of the preparation is mainly related to the content of hydrolysis impurities in the raw material medicine.
  • the content of hydrolysis impurities in the preparation is less than 1.0%
  • the increase of hydrolysis impurities in the accelerated experiment for 30 days is less than 0.10%, which is in line with the quality requirements of LCZ696 preparation. .
  • the particle size of the drug substance is controlled to be 20 to 100 ⁇ m
  • the problem of enlargement/reduction of the prescription ratio can be solved, and controlling the content of the hydrolysis impurity in the drug substance to be 1.0% or less is advantageous for solving the problem of improving the stability of the preparation.
  • Test articles solid oral preparations obtained in Examples 12 and 13 and Comparative Example 5 (day 0); negative control: using a vehicle control substance - deionized water (laboratory preparation).
  • ICR mice SPF grade, sex and number of animals used for testing, females: 25, males: 25.
  • Vehicle control group 0mg/kg, compound 1 solid oral preparation powder, according to the active ingredient low dose group 1.0mg/kg, medium dose group 10mg/kg, high dose group 110mg/kg intragastric administration, the administration time was One week (7 days).
  • Climbing rod test operation Vertically erected with a smooth metal rod (approximately 0.9 cm in diameter and approximately 72 cm in length).
  • the aerial pole reflex operation was performed after the end of the climbing rod test operation: the tail of the mouse was lifted, and the mouse was thrown after 4 rotations to observe the abnormal posture of the landing of the mouse (side or back landing) ), repeated 5 times in a row, and scored according to Irwin's behavioral grading scale.
  • Climbing rods and aerial righting reflexes were observed at 2, 4, 8 and 24 hours before and immediately after the last dose. After the end of the experiment, the surviving animals used in this test were sacrificed by anesthesia with excess CO 2 . Behavioral scores are expressed in terms of frequency. The above data should be statistically analyzed using SAS 9.1.
  • Level 1 1 to 2 times out of 5 times
  • the solid oral preparations obtained in Examples 12 and 13 showed that the content of the hydrolyzed impurities in the preparation was less than 1.0%, and the observation results of the rods and the aerial righting reflexes at the observation time points of the animals in the active ingredients of 1.0, 10 and 110 mg/kg were compared with the vehicle. There was no significant difference between the groups (0mg/kg) (P>0.05).
  • the solid oral preparations obtained in Examples 12 and 13 have a hydrolyzed impurity content of 1.0% or less, and the incidence of adverse reactions of the solid oral preparation is very small; and the content of the hydrolyzed impurities in the solid oral preparation obtained in Comparative Example 5 is obtained. Above 1.0%, the incidence of adverse reactions is significantly increased. However, the specific cause of the adverse reaction in mice is unknown. It is speculated that the solid oral preparation may produce other specific impurities due to excessive hydrolysis of impurities, or due to the synergistic effect between the drug and the impurities. It is known that the control of the drug substance and Impurity levels are important for reducing adverse drug reactions.

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Abstract

公开了一种含有特定LCZ696结晶粉末的LCZ696药物组合物，由于所采用的LCZ696结晶粉末具有特定的粉体特征，使得其在满足制剂工艺要求并制得符合临床用药要求的药物组合物的同时，可以实现药物组合物的等比放大。

Description

一种含有LCZ696的药物组合物及其制备方法 技术领域
本发明属于医药领域，特别涉及一种可用于心衰治疗的含有LCZ696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)是被证实能降低心力衰竭患者死亡率的第一类药物，也是循证医学证据积累最多的药物，是公认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具有血管紧张素受体阻断和中性内肽酶抑制双重作用的抗心衰药物，其结构在专利WO2007056546中首次公开(如下式)。该化合物为含有2.5个结晶水的超分子络合物(复合物)三钠盐，由缬沙坦和AHU377通过非共价键结合而成。
Figure PCTCN2016093126-appb-000001
已经公开的临床实验结果表明，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，产品于2015年下半年获批上市。
由于LCZ696是一种特殊的药物，其具有特殊的键合及成盐方式，使得其对湿、热不稳定，并且在溶液体系中会发生离解，因此，即便在常规生产环境下，LCZ696依然会因为吸潮 等原因导致质量下降。所以，在LCZ696临床用药的生产、制剂等过程中要尽量缩短其与空气的接触时间，并避免受热工艺(如粉碎等)的使用。
专利WO2007056546实施例1～实施例3公开了LCZ696的制备方法，依据该方法制备得到的LCZ696呈极细粉末状，使得其在后处理过程中的抽滤速度极慢，在放大反应中表现得尤为明显，即便是抽滤过程中全程采用氮气保护，所得产品依然存在因吸潮而导致产品变粘的可能，从而影响工艺稳定性，另外，极细的粉末也不利于后续制剂工艺制备制剂产品。
专利WO2009061713公开了一系列LCZ696的制剂，该系列制剂具有溶出性能好，稳定性高等特点，但是在制剂领域中，对于特定的、同时拥有多个规格的产品，从临床用药及工艺简化的角度出发，已定的处方及工艺需要同时实现等比放大/缩小，即在不改变处方、工艺的前提下，实现制剂规格等倍放大/缩小而制剂溶出性能依然符合临床用药要求，同时制剂溶出性能无过大波动，而专利WO2009061713附图显示其各规格制剂并未实现等比放大，现有技术也未公开实现LCZ696制剂等比放大/缩小的解决方案。
综上可知，现有技术并没有提供直接合成获得的、有利于合成及制剂工艺的LCZ696结晶粉末，亦未实现LCZ696制剂处方及工艺的最优化，因此寻找一种LCZ696结晶粉末且实现LCZ696制剂处方、工艺的最优化是现有技术没有解决的技术问题。
发明内容
本发明的第一个目的在于克服现有技术的不足，首次提供一种通过合成直接制备得到的LCZ696结晶粉末，所述结晶粉末在合成过程中具有便于抽滤等特点，且可直接用于制剂过程中，可避免制剂前的粉碎工序，有利于制剂工艺简化(如物料混合等)，所得制剂在实现制剂各项性能(如溶出性能等)最优化的同时，实现等比放大/缩小。
本发明的上述有益效果通过如下技术方案实现：
一种LCZ696的结晶粉末，其特征在于所述结晶粉末20μm≤D90≤100μm。
具体的，如未作特别说明，本发明中所有LCZ696结晶粉末的粉体性质(如D90、D50等)均为将干燥所得粉体过80目筛(孔径约200μm)后测得，过筛的目的在于除去少量在干燥过程中结块的LCZ696产品。在合成过程中，过低粒径的粉体不利于产品过滤，且在过滤、烘干过程易发生吸潮，而过高粒径的产品则对应相对更长的析晶时间，不符合合成工艺最优的要求，且过高粒径的产品也存在在制剂中无法实现等比放大/缩小的问题；当LCZ696结晶粉末在20μm≤D90≤100μm，优选25μm≤D90≤75μm时，可以实现迅速过滤，避免产品因与空气接触时间过长而吸潮变粘而影响产品质量；同时，也避免产品在后处理工艺中长时间烘干，且烘干后所得产品出现结块现象；更优选的，所述LCZ696结晶粉末30μm≤D90≤60μm。进一步的，所述LCZ696结晶粉末同时满足5μm≤D50≤50μm，优选8μm≤D50≤30μm。
本发明的第二个目的在于提供一种上述LCZ696结晶粉末的制备方法，该方法可以稳定制备具有前述粉体性质的LCZ696结晶粉末，所得结晶粉末无需粉碎即可以直接用于后续制 剂工艺中，该方法适用于工业化放大生产，所述方法采用如下所示工艺路线。
Figure PCTCN2016093126-appb-000002
所述方法包含如下制备步骤：
1)在低于30℃的温度下，将游离的AHU377与缬沙坦一同溶清于溶剂A/溶剂B的混合溶液；
2)在低于30℃的温度下缓慢滴入氢氧化钠水溶液，升温至50～55℃反应20-30min；
3)降温至40～45℃，补加相当于缬沙坦0.1～5.0wt％的LCZ696晶种，溶液变浑浊，随后按0.5～1.5℃/10min的速率降温至30℃～35℃；
4)将反应液移至5～25℃搅拌1～5h；
5)过滤，真空干燥后得到LCZ696结晶粉末。
如无特别说明，本发明所述室温指代20±5℃。反应步骤1)中游离的AHU377与缬沙坦的摩尔比遵循本领域常规对此类反应投料比的设定原则，优选的，游离的AHU377与缬沙坦的摩尔比为1：0.95～1.05，所采用游离的AHU377及缬沙坦优选纯度≥99.0％。所述游离的AHU377可以将AHU377盐游离得到，所述AHU377盐(M)可为常见的金属盐或非金属盐，如钠盐、钾盐、钙盐、镁盐、锌盐、铵盐、三乙胺盐、二乙胺盐等等，优选钙盐。本发明的一个优选的方案，所述游离的AHU377采用如下步骤得到：
a)将AHU377盐和醋酸异丙酯(IPAC)置于反应器中，在低于30℃的温度下，滴加2N HCl，搅拌至澄清；
b)分液并收集有机相，洗涤、干燥、脱溶后得到游离的AHU377。
对于不同有效成分，其影响晶习的条件存在差异，而对于LCZ696，采用以上方法即可制得具有前述粉体性质的LCZ696结晶粉末(如D90和/或D50等)。该制备步骤的技术关键在于步骤1)中混合溶液中溶剂的种类及配比，其中一种相对于LCZ696为良溶剂，另一种为不良溶剂，且控制一定的混合溶剂比例，采用降温析晶法得到产物，良溶剂的比例升高和/或缓慢降温析晶有利于得到粒径较大的结晶粉末，不良溶剂比例升高和/或室温析晶有利于得到粒径较小的结晶粉末。具体的，所述溶剂A为不良溶剂，选自丙酮、四氢呋喃、乙腈等中的任意一种，所述溶剂B为良溶剂，选自异丙醇、正丁醇、异丁醇等中的任意一种，所述溶剂A优 选毒性相对较低的丙酮；为了在保证产品粒径符合要求的同时实现产率最大化，所述步骤1)混合溶液中溶剂A与缬沙坦的体积质量比为6～10:1ml:1g，该步骤的目的在于将AHU377及缬沙坦溶清，并保证一定的溶剂饱和度以利于晶体析出，优选的，所述混合溶液中溶剂A与缬沙坦的体积质量比为7～9:1ml:1g；在步骤1)所述混合溶液中，所述溶剂A与溶剂B的体积比VA:VB＝1-7:1，同样，特定比例的溶剂可以保证一定的溶剂饱和度，有利于晶体析出，优选的，所述溶剂A与溶剂B的体积比VA:VB＝4-6:1。
为使LCZ696尽可能多的从体系中析出，可以制备工艺后续补加溶剂A，以达到提高产率的目的。具体的，在步骤4)中补充加入混合溶液中溶剂A体积1.0～3.0倍的溶剂A，可以使得LCZ696进一步从溶剂体系中析出，并达到提高产率的目的。优选的，步骤4)可进一步优化为：将反应液移至5～25℃搅拌0.5～3h，补加溶剂A后继续搅拌0.5～2h。
所述步骤5)优选在惰性气体保护下过滤，所述惰性气体优选氮气。
研究发现，在上述方法的范围内，产品仅存在粒径的波动，而杂质含量波动较小，因此上述方法可以保证LCZ696以特定物理形态均匀析出，产品产率、粉体性质亦控制在最优状态，该LCZ696粉体在抽滤过程的速度优势明显，并在大规模生产中体现出更为明显的速度优势。更快的抽滤速度可以有效避免产品在制备过程中因吸潮而发粘，避免更长的烘干时间，并避免产品发生板结，避免了制剂前的常规粉碎工艺。
本发明的第三个目的在于在前述方法的基础上进一步优化，将所得LCZ696结晶粉末控制在特殊粒径范围内之外，还将水解杂质控制在很低的范围。具体的，所述水解杂质为AHU377的水解杂质，其结构如下式：
Figure PCTCN2016093126-appb-000003
水解杂质含量过高可能引起药物不良反应，因此水解杂质属于产品生产过程中需要重点控制的杂质之一。进一步的稳定性实验发现，水解杂质含量与其增长速率存在一定关联，具体的，对于LCZ696制剂，当加速实验(40℃±2℃，75％±5％RH)30天水解杂质增量超过0.1％时，则认为制剂稳定性不佳。通过实验我们惊喜的发现，当制剂中水解杂质控制在1.0％以下时，其增量相对较缓，加速实验(40℃±2℃，75％±5％RH)30天内水解杂质增量远低于0.1％，所得制剂稳定性较高，符合临床用药要求。
具体的，本发明所述低水解杂质含量LCZ696的制备方法通过控制氢氧化钠的量及浓度以达到控制水解杂质含量的目的。具体的，氢氧化钠的用量不影响LCZ696结晶粉末的粉体形态，但会影响产品产率及杂质含量，在前述溶剂体系及制备步骤下，当缬沙坦与所使用的氢氧化钠的摩尔比为1:2.5-3.0，且氢氧化钠水溶液浓度范围为0.5-1.0g/ml时，可以将水解杂质量控制在1.0％以内。具体的，在保证前述LCZ696结晶粉末性质的基础上进一步控制水解杂质含量存在技术困难，当氢氧化钠使用量过多，会导致水解杂质含量增多；当氢氧化钠使用量过少会导致终产物产率降低，也会影响晶体的析出。因此，综合产率及杂质含量的影响因素，优选的，缬沙坦与所使用的氢氧化钠的摩尔比为1:2.70-2.95，更优选的，当缬沙坦与所使用的氢氧化钠的摩尔比为1:2.80-2.90时，反应产率及杂质含量情况可以达到最优化。另外，氢氧化钠的浓度对存在一定影响，在上述浓度范围内较低的浓度对应相对较低的产率。
本发明所述的LCZ696结晶粉末由于其粉体形态及质量等方面的优势，可以不经粉碎而直接用于制剂工艺中。具体的，对于常规的产品的制剂，制剂前通常需要根据制剂工艺、制剂处方的需要及产品特性将原料药预处理到所需的状态，预处理通常包括粉碎和过筛的步骤。而对于LCZ696产品，由于其对湿、热不稳定，使得其在制备过程中需要避免粉碎的工艺，而不加预处理的原料药则容易造成制剂工艺、产品质量的波动，具体的，粒径过粗导致物料混合均匀性差，压片时可能引起片重差异较大，粒径过细导致物料流动性差，易粘冲，且压片时亦可引起片重差异较大，且片面略深。
发明人惊奇的发现，本发明所述的粒径范围内LCZ696结晶粉末较粒径范围外的结晶粉末更有利于干法制粒工艺，具体的，所述LCZ696结晶粉末具有预处理简单、粒径均匀、工艺稳定、批间差异性小等有优点，更重要的是还可以实现处方等比放大/缩小，即不改变处方及工艺，即可实现制剂规格的放大/缩小。处方实现等比放大/缩小有利于生产中各规格产品的转换，是处方技术含量的体现。
基于以上，本发明第四个目的在于提供一种含有本发明所述LCZ696结晶粉末的LCZ696药物组合物。
LCZ696结晶粉末的粒径范围内是实现上述有益效果的关键，具体的，对于50mg、100mg、200mg及400mg规格的LCZ696产品，其符合临床用药要求需要实现15min达到70％以上的溶出，而实现等比放大/缩小则是采用完全相同的处方、工艺实现各规格产品均在15min达到70％以上的溶出，且溶出性能波动较小。通过实验我们惊奇的发现，当控制原料药在20μm≤D90≤100μm时，50mg、100mg、200mg及400mg规格的LCZ696产品均可实现15min达到70％以上的溶出，且溶出性能波动较小，优选的，原料药的粒径为25μm≤D90≤75μm，更优选的，当原料药的粒径为30μm≤D90≤60μm时，50mg、100mg、200mg及400mg规格的LCZ696产品均可实现15min达到70％以上的溶出，同时溶出性能波动最小。
所述LCZ696药物组合物含有填充剂、崩解剂、粘合剂，辅料的种类、用量也有助于LCZ696结晶粉末的上述有益效果的实现。
具体的，所述填充剂选自微晶纤维素、乳糖、淀粉、预胶化淀粉、甘露醇、磷酸氢钙、山梨醇中的一种或两种以上的混合物，优选微晶纤维素、甘露醇、磷酸氢钙、山梨醇；当LCZ696质量份为1份时，所述填充剂的用量为0.2～0.8份，优选0.3～0.7份。
所述崩解剂选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠、羧甲基纤维素钙中的一种或两种以上的混合物，优选交联羧甲基纤维素钠、交联聚维酮，当LCZ696质量份为1份时，所述崩解剂的用量为0.04～0.4份，优选0.05～0.3份；所述崩解剂可以选择内加、外加及内外加的方式，优选内外加的方式；当采用内外加的方式，即药物组合物包含内相颗粒和外加辅料，所述内相颗粒包含LCZ696的结晶粉末、填充剂、崩解剂、粘合剂时，内加崩解剂与外加崩解剂的质量比为0.4～3.8:1。
所述粘合剂选自低取代羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠、聚维酮、乙基纤维素中的一种或两种以上的混合物，优选羧甲基纤维素钠、低取代羟丙纤维素，当LCZ696质量份为1份时，所述粘合剂的用量为0.05～0.5份，优选0.1～0.4份。
所述LCZ696药物组合物可以进一步包含助流剂，所述助流剂选自二氧化硅、滑石粉中的一种或两种以上的混合物，当LCZ696质量份为1份时，所述助流剂的用量为0.002～0.05份。
所述LCZ696药物组合物可以进一步包含润滑剂，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的混合物，当LCZ696质量份为1份时，所述润滑剂的用量为0.01～0.1份。
所述LCZ696药物组合物包括但不限于片剂、颗粒剂、胶囊剂、散剂等本领域常见的药物制剂。所述LCZ696药物组合物也可以视需要进行进一步包衣处理，所述包衣可为薄膜衣、糖衣等本领域常见的包衣类型，所述包衣采用的材料可采用本领域常见的包衣材料，如羟丙甲纤维素、糖粉、羟丙纤维素等，亦可以采用常规的市售包衣材料，如欧巴代
Figure PCTCN2016093126-appb-000004
采用具有特定粉体性质的结晶粉末，并在上述处方的辅助下，所述药物组合物可以实现等比放大/缩小的更优化，即当通过将原辅料用量等比递增/递减从而得到不同规格的制剂时，所得制剂的溶出性能趋于一致，不会受到原辅料等比递增/递减的影响。
本发明的一个优选的技术方案，所述LCZ696制剂采用本发明所述的LCZ696结晶粉末，其处方为：
Figure PCTCN2016093126-appb-000005
本发明的一个优选的技术方案，所述LCZ696制剂采用本发明所述的LCZ696结晶粉末，其处方为：
Figure PCTCN2016093126-appb-000006
本发明的一个优选的技术方案，所述LCZ696制剂采用本发明所述的LCZ696结晶粉末，其处方为：
Figure PCTCN2016093126-appb-000007
本发明第五个目的在于提供了本发明所述LCZ696药物组合物的制备方法，具体的，当所述LCZ696药物组合物为片剂时，所述制备方法包含如下制备步骤：
(1)将原、辅料过40目筛，备用；
(2)将处方中内加成分进行预混合，使用干法制粒机压制预混合之后的混合物，整粒之后得到内相颗粒；
(3)将内相颗粒与外加辅料进行混合，混合之后将所得的混合物进行压片得到LCZ696片芯。
可以视需要采用本领域常用的包衣材料及包衣方法，对所得LCZ696片芯进行包衣处理，所述包衣采用的材料可采用本领域常见的包衣材料，如羟丙甲纤维素、糖粉、羟丙纤维素等，亦可以采用常规的市售包衣材料，如欧巴代
Figure PCTCN2016093126-appb-000008
综上，本发明从利于实现LCZ696合成、制剂工艺最优化出发，基于LCZ696原料药在湿、热下不稳定的实际，通过有效成分的粒径串联合成和制剂两大技术领域，通过合成实现了特定粒径有效成分的制备，并通过所得特定粒径有效成分实现制剂工艺最优化。可知，与现有技术相比，本发明具有如下技术特点及优势：
1、首次提供一种通过合成直接制备得到的LCZ696结晶粉末，所述结晶粉末具有特定的粉体性质，其在合成过程中具有便于抽滤，避免吸潮等特点，所得产品几乎没有结块现象，在制剂过程中可避免粉碎工序，有利于实现制剂各项性能(如溶出性能等)最优化；
2、提供一种LCZ696结晶粉末的制备方法，该方法可以稳定制备所述具有特定粉体性质的LCZ696结晶粉末，所得结晶粉末可以直接用于后续制剂工艺中，该方法适用于所述LCZ696 结晶粉末的工业化生产；
3、提供一种低水解杂质含量LCZ696结晶粉末的制备方法，所述LCZ696结晶粉末在之前制备方法的基础上，通过控制氢氧化钠的用量，进一步将所得LCZ696结晶粉末中的水解杂质控制在相对较低的范围，保证了产品质量；
4、提供一种含有本发明所述LCZ696结晶粉末的LCZ696药物组合物，由于所述LCZ696药物组合物所采用的LCZ696结晶粉末具有特定的粉体特征，使得其在满足制剂工艺要求并制得符合临床用药要求的药物组合物的同时，可以实现药物组合物的等比放大。
5、提供了一种本发明所述LCZ696药物组合物的制备方法，该方法可以实现制备含有LCZ696的片剂。
附图说明
图1实施例1所得LCZ696结晶粉末过筛前粒径分布图
图2实施例1所得LCZ696结晶粉末过80目筛后粒径分布图
图3实施例1所得LCZ696结晶粉末过80目筛后外观图
图4实施例2所得LCZ696结晶粉末过筛前粒径分布图
图5实施例2所得LCZ696结晶粉末过80目筛后粒径分布图
图6对比实施例1所得LCZ696产品过筛前外观图
图7对比实施例1所得LCZ696产品过80目筛后粒径分布图
图8实施例4所得LCZ696结晶粉末过80目筛后粒径分布图
图9实施例5所得LCZ696结晶粉末过80目筛后粒径分布图
具体实施方式
下面结合实施例和附图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。
一、合成研究部分
通过调整溶剂体系、投料比、反应条件等工艺参数，对溶剂体系及投料比对产品粉体性质、水解杂质含量的影响情况进行研究。
实施例1
AHU377游离酸的制备：
将100g AHU377钙盐、1000ml醋酸异丙酯加入2L的三口瓶中，冰浴下滴加2mol/L盐酸240ml；搅拌溶清；分液，收集有机层，并将其用600ml水洗涤两次；38℃下减压脱溶，得AHU377游离酸；
LCZ696的制备：
室温下，AHU377游离酸、100g缬沙坦与880ml丙酮、220ml异丙醇加入至3L三口瓶，溶清；室温下滴加相对于缬沙坦2.85当量浓度为0.9g/ml的氢氧化钠水溶液，升温至50℃ 反应20min；降温至45℃，补加晶种约2.0g，搅拌后溶液浑浊，后按1.0℃/10min的速率将外温降至35℃，然后将反应液移至15℃温度下搅拌2h；随后再向体系中滴入丙酮1120ml，15℃下搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘8h，烘干得到固体188.0g，HPLC检测纯度为99.91％，水解杂质含量为0.02％，其粒径分布如图1所示。
将所得产品过80目筛，得184.2g结晶粉末，其D90为43.90μm，D50为10.14μm，所得结晶粉末的粒径分布图如图2所示，外观图如图3所示。
实施例2
AHU377游离酸的制备：
将100g AHU377钙盐、1000ml醋酸异丙酯加入2L的三口瓶中，冰浴下滴加2mol/L盐酸230ml；搅拌溶清；分液，收集有机层，并将其用600ml水洗涤两次；38℃下减压脱溶，得AHU377游离酸，加入250ml异丙醇溶解后再次减压脱溶并重复一次；
LCZ696的制备：
室温下，AHU377游离酸、100g缬沙坦与800ml丙酮、220ml异丙醇加入至3L三口瓶，溶清；室温下滴加相对于缬沙坦2.95当量浓度为0.85g/ml的氢氧化钠水溶液，升温至53℃反应30min；随后按1.0℃/10min的速率将外温降至30℃，补加晶种约1.0g，将反应液移至20℃温度下搅拌2h；随后再向体系中滴入丙酮1200ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘8h，烘干得到固体191.3g，收率85.6％，HPLC检测纯度为99.33％，水解杂质含量为0.58％，其粒径分布如图4所示。
将所得产品过80目筛，得188.0g结晶粉末，其D90为48.07μm，D50为10.26μm，所得结晶粉末的粒径分布图如图5所示。
实施例3
由于实施例1和实施例2所得结晶粉末粒径形态适中，在反应过程中可以实现快速过滤。为体现其在过滤方面与现有技术相比所存在的优势，特将实施例1和实施例2的反应规模放大20倍，并将其与专利CN200680001733.0实施例3(下称“对比实施例1”)相对比，结果如下：
项目 抽虑时间(min) D90(μm)
实施例1 约20min 44.68
实施例2 <20min 47.36
对比实施例1 约55min 16.80
特别的，对比实施例1所得结晶粉末由于在过滤过程中吸潮而存在较严重的结块现象(外观如图6所示)，表现为通过80目筛的通过率仅为约25％，所得结晶粉末的粒径分布如图7所示。
而对比之下，实施例1、实施例2产品则可以实现较快过滤，在更大规模生产中体现的更为明显。
实施例4
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与80ml丙酮、15ml异丁醇加入反应瓶中；室温下滴加相对于缬沙坦2.9当量，浓度为0.85g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.5℃/10min的速率将外温降至30℃，将反应液移至15℃温度下搅拌3h；随后再向体系中滴入丙酮120ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，40℃下真空烘8h，烘干得到固体19.2g，纯度99.83％，水解杂质含量为0.12％。
将所得产品过80目筛，得18.5g结晶粉末，其D90为31.60μm，D50为8.40μm，所得结晶粉末的粒径分布如图8所示。
实施例5
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与85ml四氢呋喃、17ml异丙醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.9当量浓度为0.85g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.5℃/10min的速率将外温降至30℃，将反应液移至20℃温度下搅拌3h；随后再向体系中滴入THF 135ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，40℃下真空烘8h，烘干得到固体18.9g，纯度99.83％，水解杂质含量为0.12％。
将所得产品过80目筛，得18.1g结晶粉末，其D90为32.95μm，D50为8.71μm，所得结晶粉末的粒径分布如图9所示。
实施例6
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与70ml丙酮、12ml正丁醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.9当量浓度为0.85g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.5℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌3h；随后再向体系中滴入丙酮150ml，保持温度搅拌1h；氮气保护下经布氏漏斗抽滤，得白色固体，40℃下真空烘8h，烘干得到固体19.5g，纯度99.78％，水解杂质含量为0.13％。
将所得产品过80目筛，得18.7g结晶粉末，其D90为31.16μm，D50为8.28μm。
实施例7
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与88ml丙酮、40ml异丙醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.9当量浓度为0.85g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按0.5℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌2h；随后再向体系中滴入丙酮120ml，保持温度搅拌3h；氮气保护下经布氏漏斗抽滤，得白色固体，40℃下真空烘8h，烘干得到固体18.5g，纯度99.80％，水解杂质含量为0.12％。
将所得产品过80目筛，得17.6g结晶粉末，其D90为87.23μm，D50为46.23μm。
实施例8
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与90ml乙腈、25ml异丙醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.9当量浓度为0.85g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.0℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌2h；随后再向体系中滴入乙腈130ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，40℃下真空烘8h，烘干得到固体19.0g，纯度99.81％，水解杂质含量为0.10％。
将所得产品过80目筛，得18.6g结晶粉末，其D90为50.75μm，D50为11.03μm。
影响因素研究1
采用实施例1的投料量、投料比、补加不良溶剂的量及反应条件，通过改变混合溶剂中良溶剂及不良溶剂的种类和/或比例，以研究不同溶剂体系所得结晶粉末粉体情况，结果如下表：
Figure PCTCN2016093126-appb-000009
可知，当其余因素不变时，混合溶剂中不良溶剂比例越高，所得LCZ696产品粒径减小，过滤速度也逐渐递减，在约20μm处快速递减，其中第1组在60min以上，而相同过滤条件下，第2组则为约35min。发明人还发现溶剂体系及溶剂比例对于水解杂质含量几乎没有影响。
另外，为达到大粒径产品，需要延长析晶时间，具体的，第7组反应，除降低混合溶剂中不良溶剂用量降低外，在补加不良溶剂后还需要延长析晶时间至12h以上，才可以达到该大粒径产品，因此对于LCZ696产品，制备太大粒径的产品并不经济。
实施例9
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与90ml丙酮、20ml异丙醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.6当量浓度为0.9g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.0℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌3h；随后再向体系中滴入丙酮120ml，保持温度搅拌1h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘料12h，烘干得到固体16.5g，纯度99.92％，水解杂质含量为0.03％。
将所得产品过80目筛，得15.8g结晶粉末，其D90为45.74μm，D50为16.34μm。
实施例10
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与90ml丙 酮、20ml正丁醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.8当量浓度为0.9g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.0℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌3h；随后再向体系中滴入丙酮120ml，保持温度搅拌1h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘料12h，烘干得到固体17.8g，纯度99.89％，水解杂质含量为0.03％。
将所得产品过80目筛，得17.0g结晶粉末，其D90为40.86μm，D50为11.79μm。
实施例11
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与90ml丙酮、20ml异丁醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.95当量浓度为0.9g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.0℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌2h；随后再向体系中滴入丙酮120ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘料12h，烘干得到固体18.9g，纯度99.38％，水解杂质含量为0.53％。
将所得产品过80目筛，得18.1g结晶粉末，其D90为44.48μm，D50为14.54μm。
对比实施例2
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与90ml丙酮、20ml异丙醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦2.4当量浓度为0.9g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.0℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌3h；随后再向体系中滴入丙酮120ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘料12h，烘干得到固体12.5g，纯度99.90％，水解杂质含量为0.02％。
将所得产品过80目筛，仅得11.8g结晶粉末，其D90为42.35μm，D50为13.01μm。
对比实施例3
25℃条件下，将AHU377游离酸(10g AHU377钙盐游离得到)、10g缬沙坦与90ml丙酮、20ml异丙醇加入反应瓶中搅拌溶清；室温下滴加相对于缬沙坦3.1当量浓度为0.9g/ml的氢氧化钠水溶液，升温至50℃反应25min；降温至45℃，补加晶种约0.3g，搅拌后溶液混浊，随后按1.0℃/10min的速率将外温降至30℃，将反应液移至25℃温度下搅拌3h；随后再向体系中滴入丙酮120ml，保持温度搅拌2h；氮气保护下经布氏漏斗抽滤，得白色固体，35℃下真空烘料12h，烘干得到固体18.5g，纯度96.75％，水解杂质含量为1.87％，所得产品呈淡黄色。
将所得产品过80目筛，得17.9g结晶粉末，其D90为43.66μm，D50为12.52μm。
影响因素研究2
采用实施例1的投料量、投料比、溶剂体系等反应条件，通过改变氢氧化钠用量及浓度，以研究氢氧化钠用量及浓度对水解产物量的影响，如下表：
编号 当量(相对于缬沙坦) 浓度(g/ml) 水解杂质(％) D90(μm) 产率
1 2.90 0.6 0.13 42.67 82.5％
2 2.90 0.9 0.12 44.93 86.7％
3 3.00 0.9 0.85 43.48 87.1％
4 3.00 0.7 0.87 42.16 84.3％
5 2.60 0.9 0.02 43.73 69.8％
6 2.30 0.9 0.02 41.46 51.4％
7 3.20 0.9 2.74 42.59 84.5％
由上表可知，氢氧化钠用量仅对产率和杂质含量存在影响，而对于粉体形态影响不大。具体的，在本发明保护的范围内随着氢氧化钠用量的降低，产率逐渐降低，当氢氧化钠用量低于2.5当量时，尽管其粒径及杂质情况符合要求，但其产率却急剧下降至60％以下，不能满足工业化生产的要求；而当氢氧化钠用量在大于3.0当量(相对于缬沙坦)时，其水解杂质含量则超过1.0％，产品在后续制备成制剂后，不符合制剂稳定性的要求。
另外，在本发明要求保护的范围内，氢氧化钠的浓度对制备工艺略有影响，表现为当氢氧化钠浓度降低时，伴随更多水的带入，使得反应产率有所降低。
综合可以看出，在合成工艺中，对于LCZ696结晶粉末的粉体性质，其受到溶剂体系影响较大；另外，在合成工艺中，当结晶粉末的粒径越小，其所需过滤时间越长，在大规模反应中尤为明显，这使得产品因过长时间暴露在空气中而吸潮导致产品水份随之上升，所得产品出现较为严重的板结，不利于后续制剂工艺的进行；而对于产率和水解杂质的含量，其受到氢氧化钠用量及浓度的影响；而得到具有特定粉体性质的，且水解杂质较低的LCZ696结晶粉末，并且实现合成工艺最优，需要由综合溶剂体系、氢氧化钠用量及浓度等多个影响因素。
二、制剂研究部分
使用合成研究部分制备得到的不同批次的产品，通过对原料药性质、制剂处方及工艺等参数的调整，了解原料药性质、水解杂质含量等因素对制剂质量的影响情况。
实施例12
LCZ696片剂(100mg)
采用实施例1方法所得的LCZ696结晶粉末(D90＝43.90μm，水解杂质：0.02％)为原料药。
Figure PCTCN2016093126-appb-000010
制备方法：
1、将原、辅料过40目筛，备用；
2、将处方中内相颗粒成分进行预混合，使用干法制粒机压制预混合之后的混合物，整粒之后得到内相颗粒；
3、将内相颗粒与外加交联聚维酮和硬脂酸镁进行混合，混合之后将所得的混合物进行压片。
使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。制备过程中，所得内相颗粒流动性好，所得片剂片面光滑，片重差异小。
实施例13
LCZ696片剂(100mg)
采用实施例1方法所得的LCZ696结晶粉末(D90＝43.07μm，水解杂质：0.58％)为原料药。
Figure PCTCN2016093126-appb-000011
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，所得内相颗粒流动性好，压片所得片芯片面光滑，片重差异小。
实施例14
LCZ696片剂(100mg)
采用实施例4方法所得的LCZ696结晶粉末(D90＝31.60μm，水解杂质：0.12％)为原料药。
Figure PCTCN2016093126-appb-000012
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，所得内相颗粒流动性好，所得片剂片面光滑，片重差异小。
实施例15
LCZ696片剂(100mg)
采用实施例4方法所得的LCZ696结晶粉末(D90＝31.60μm，水解杂质：0.12％)为原料药。
Figure PCTCN2016093126-appb-000013
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，所得内相颗粒流动性好，所得片剂片面光滑，片重差异小。
实施例16
LCZ696片剂(100mg)
采用实施例7方法所得的LCZ696结晶粉末(D90＝87.23μm，水解杂质：0.13％)为原料药。
Figure PCTCN2016093126-appb-000014
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，所得内相颗粒流动性好，压片所得片芯片面光滑，片重差异小。
实施例17
LCZ696片剂(100mg)
采用实施例5方法所得的LCZ696结晶粉末(D90＝32.95μm水解杂质：0.14％)为原料药。
Figure PCTCN2016093126-appb-000015
Figure PCTCN2016093126-appb-000016
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，由于内相缺少助流剂，原辅料的混合效果相对于处方中有助流剂的实施例略差，使得所需混合时间相对更长，但所得内相颗粒流动性基本无差异，压片所得片芯片面光滑，片重差异小。
实施例18
LCZ696片剂(100mg)
采用实施例5方法所得的LCZ696结晶粉末(D90＝32.95μm，水解杂质：0.14％)为原料药。
Figure PCTCN2016093126-appb-000017
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，所得内相颗粒流动性好，由于未加入润滑剂，压片所得片芯极少部分片面略有毛刺，但外观总体符合药典要点要求。
对比实施例4
LCZ696片剂(100mg)
采用对比实施例1所得的LCZ696结晶粉末(D90＝16.80μm，水解杂质：0.04％)为原料药，使用与实施例12相同的处方。
Figure PCTCN2016093126-appb-000018
制备方法同实施例12，但是制备过程中，由于原料粒径过小，在干法制粒过程中曾经出现粘冲现象，但不影响后续工艺，所得片芯的片面颜色略不均匀，较实施例12～实施例16所得片芯片面颜色略深，但整体仍符合要求。
对比实施例5
LCZ696片剂(100mg)
采用对比实施例3所得的LCZ696结晶粉末(D90＝43.66μm，水解杂质：1.87％)为原料药，使用与实施例12相同的处方。
Figure PCTCN2016093126-appb-000019
采用与实施例12相同的方法制备得到LCZ696片芯。使用欧巴代包衣聚合物对所得片芯进行包衣，得到包衣片。
制备过程中，所得内相颗粒流动性好，所得片剂片面光滑，片重差异小。但是，由于原料药中水解杂质含量较高，使得片芯颜色略暗，呈类白色。
实施例19
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，检测实施例12～16及对比实施例4～5所得LCZ696干法制粒的片剂溶出度情况，所得数据如下表所示：
项目 粒径(μm) 15min 30min 45min
实施例12 43.90 85.50 97.37 98.87
实施例13 48.07 85.73 98.55 99.55
实施例14 31.60 86.21 97.13 99.91
实施例15 31.60 85.20 98.26 99.46
实施例16 87.23 81.62 94.50 98.91
实施例17 32.95 85.54 97.35 99.61
实施例18 32.95 86.45 98.20 99.43
对比实施例4 16.80 85.31 95.94 99.64
对比实施例5 43.66 85.53 96.50 99.97
可以看出，实施例12-18，对比实施例4-5所得片剂均在15min内实现70％以上的溶出，并在45min溶出接近实现全部溶出，符合LCZ696产品临床用药要求。
等比放大检测(200mg)
将对应将实施例12～16及对比实施例4-5的原辅料用量增大一倍，并采用相同的工艺参数压制成200mg规格的片剂。
采用中国药典(2010版)附录XC溶出度测定方法第二法桨法，对应检测200mg规格片剂溶出度情况，所得数据如下表所示：
项目 粒径(μm) 15min 30min 45min
实施例12 43.09 83.45 96.24 99.17
实施例13 48.07 85.37 97.61 99.72
实施例14 31.60 85.80 96.72 99.45
实施例15 31.60 84.23 94.43 99.28
实施例16 87.23 74.92 93.07 99.58
实施例17 32.95 84.77 96.82 99.87
实施例18 32.95 85.54 97.34 99.50
对比实施例4 16.80 64.73 87.43 98.12
对比实施例5 43.66 83.45 96.35 98.43
可以看出，在等比放大制备成200mg规格的片剂后，各处方所得片剂溶出性能均有一定程度下降，其中实施例12-18及对比实施例5处方、工艺所得片剂仍可以实现在15min内有效成分70％以上的溶出，并在45min溶出接近实现全部溶出，符合LCZ696产品临床用药要求，可以实现制剂等比放大。
而对于对比实施例4，由于其所使用原料药粒径过小，使得其在等比放大后所得片剂在15min内有效成分溶出低于70％，不符合LCZ696产品临床用药要求，无法实现制剂等比放大。
在进一步进行的等比缩小实验验中，实施例12-18及对比实施例5的处方、工艺同样可以实现处方、工艺的等比缩小，而对比实施例4则同样因为片剂在15min内有效成分溶出低于70％，而无法实现制剂等比缩小。
在等比缩小实验(50mg)及进一步的等比放大实验中(400mg)，我们发现实施例12-18及对比实施例5的处方仍然可以实现等比缩小/放大。
实施例20
稳定性实验
将实施例所得固体口服型制剂(100mg)在加速条件(40℃±2℃，RH75％±5％)下放置30天，检测水解杂质及外观的变化情况，所得结果如下：
Figure PCTCN2016093126-appb-000020
通过稳定性实验可以看出，水解杂质含量对于制剂质量存在较大影响，具体的，实施例12-18及对比实施例4中水解杂质含量低于1.0％，制剂在加速试验中体现为水解杂质增量较 小，60天增量在0.10％以下，加速实验完成时制剂外观仍未白色，未发生明显变化。
而对于对比实施例5，由于其水解杂质含量高于1.0％，使得其在加速试验过程中水解杂质增量较大，60天增量远高于0.10％，并呈加速上升趋势，加速实验完成时制剂外观由类白色变成淡黄色，外观变化明显。
影响因素实验4
通过调整溶剂体系、投料比、反应条件等工艺参数获得不同粉体性质及杂质含量的原料药，使用与实施例12相同的处方及制剂工艺制备得到固体口服制剂，分别采用实施例17及实施例18的方法研究原料药粉体性质及杂质含量对制剂等比放大/缩小、制剂稳定性的影响，
结果如下表：
Figure PCTCN2016093126-appb-000021
通过以上影响因素实验可知，原料药粒径及水解杂质含量分别影响制剂的等比放大/缩小与制剂稳定性。
具体表现为，制剂等比放大/缩小主要与原料药粒径相关，当原料药粒径D90在20～100μm时，制剂处方、工艺可以实现等比放大/缩小，当原料药粒径D90在30～60μm时，所得制剂溶出性能最佳，且处方等比放大/缩小效果最佳。
而制剂的稳定性则主要与原料药中水解杂质的含量相关，当制剂中水解杂质含量低于1.0％时，其加速实验中30天的水解杂质增量低于0.10％，符合LCZ696制剂质量要求。
综上可知，将原料药粒径控制在20～100μm时可以解决处方等比放大/缩小的问题，而控制原料药中水解杂质含量在1.0％以下则有利于解决提高制剂稳定性的问题。
实施例21
不良反应考察实验(行为学实验)
实验样品：
供试品：实施例12、13及对比实施例5所得固体口服型制剂(0天)；阴性对照品：采用溶媒对照品——去离子水(实验室制备)。
实验动物：
ICR小鼠，SPF级，用于试验的动物性别和数量，雌性动物：25只，雄性动物：25只。购入时体重及年龄范围，雌性动物：9.6～13.5g，3周龄；雄性动物：10.0～13.0g，3周龄。
给药剂量：
溶媒对照组0mg/kg，化合物1固体口服型制剂磨粉，按活性成分低剂量组1.0mg/kg，中剂量组10mg/kg，高剂量组110mg/kg灌胃给药，给药时间均为一周(7天)。
试验步骤：
爬杆试验操作：用一根表面光滑的金属棒(直径约为0.9cm，长度约为72cm)，垂直竖立。于给药前和给药后不同时间点爬杆试验操作结束后进行空中翻正反射操作：提起小鼠尾巴，旋转4圈后抛出小鼠，观察小鼠落地的异常姿态(侧面或背面着地)，连续重复5次，并根据Irwin’s行为分级评分标准进行评分。分别于给药前及最后一次给药后第2、4、8、24小时各观察一次爬杆和空中翻正反射。实验结束后，采用过量CO2麻醉处死本试验所用存活动物。行为学评分结果均以频数表示。上述数据应采用SAS 9.1进行统计分析。
评分标准，Irwin’s行为分级评分标准：
0级：正常站立
1级：5次中有1～2次呈侧卧
2级：5次中有3～4次呈侧卧
3级：5次全呈侧卧
4级：5次中有1～2次呈背着地
5级：5次中有3～4次呈背着地
6级：5次全呈背着地
7级：背着地且翻正迟缓
8级：不能翻正
结果及讨论：
实施例12、13所得固体口服型制剂，由于制剂中水解杂质含量在1.0％以下，采用活性成分1.0、10和110mg/kg组动物各观察时间点爬杆和空中翻正反射观察结果与溶媒对照组(0mg/kg)相比均无明显差异(P>0.05)。
对比实施例5所得固体口服型制剂10和110mg/kg组的检测结果在3级-5级之间分布，部分动物观察到异常表现。
由上述统计结果可知，实施例12、13所得固体口服型制剂中水解杂质含量在1.0％以下，固体口服型制剂不良反应发生率非常小；而对比实施例5所得固体口服型制剂中水解杂质含量高于1.0％，从而使不良反应发生率明显增高。但是，造成小鼠不良反应的具体原因未知，推测可能因过多水解杂质含量杂质引起固体口服型制剂产生其他特异性杂质或者由于药物-杂质之间的协同制约作用引起，可知，控制原料药及杂质含量对于降低药物不良反应意义重大。
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 (12)

  1. 一种含有LCZ696的药物组合物，含有LCZ696的结晶粉末、填充剂、崩解剂、粘合剂，其特征在于所述药物组合物采用的LCZ696的结晶粉末20μm≤D90≤100μm。
  2. 根据权利要求1所述的LCZ696的药物组合物，其特征在于所述LCZ696的结晶粉末25μm≤D90≤75μm，优选30μm≤D90≤60μm。
  3. 根据权利要求1或2任意一项所述的LCZ696的药物组合物，其特征在于所述LCZ696的结晶粉末5μm≤D50≤50μm，优选8μm≤D50≤30μm。
  4. 根据权利要求1-3任意一项所述的LCZ696的药物组合物，其特征在于所述LCZ696的结晶粉末水解杂质含量低于1.0％。
  5. 根据权利要求1-4任意一项所述的LCZ696的药物组合物，其特征在于所述填充剂选自微晶纤维素、乳糖、淀粉、预胶化淀粉、甘露醇、磷酸氢钙、山梨醇中的一种或两种以上的混合物；当LCZ696质量份为1份时，所述填充剂的用量为0.2～0.8份。
  6. 根据权利要求1-5任意一项所述的LCZ696的药物组合物，其特征在于所述崩解剂选自交联聚维酮、羧甲基淀粉钠、交联羧甲基纤维素钠、羧甲基纤维素钙中的一种或两种以上的混合物，当LCZ696质量份为1份时，所述崩解剂的用量为0.04～0.4份，所述崩解剂可采用内加、外加及内外加的方式。
  7. 根据权利要求6所述的LCZ696的药物组合物，其特征在于所述LCZ696的药物组合物包含内相颗粒和外加辅料，所述内相颗粒包含LCZ696的结晶粉末、填充剂、崩解剂、粘合剂，所述崩解剂采用内外加的方式，所述外加辅料包含崩解剂，内加崩解剂与外加崩解剂的质量比为0.4～3.8:1。
  8. 根据权利要求1-7任意一项所述的LCZ696的药物组合物，其特征在于所述粘合剂选自低取代羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠、聚维酮、乙基纤维素中的一种或两种以上的混合物，当LCZ696质量份为1份时，所述粘合剂的用量为0.05～0.5份。
  9. 根据权利要求1-8任意一项所述的LCZ696的药物组合物，其特征在于所述的LCZ696的药物组合物中填充剂的用量为0.3～0.7份，崩解剂的用量为0.05～0.3份；粘合剂的用量为0.1～0.4份。
  10. 根据权利要求1-9任意一项所述的LCZ696的药物组合物，其特征在于所述LCZ696的药物组合物进一步包含助流剂和/或润滑剂，所述助流剂选自二氧化硅、滑石粉中的一种或两种以上的混合物，当LCZ696质量份为1份时，所述助流剂的用量为0.002～0.05份；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的混合物，当LCZ696质量份 为1份时，所述润滑剂的用量为0.01～0.1份。
  11. 根据权利要求1所述的LCZ696的药物组合物，其特征在于所述LCZ696的药物组合物的处方为以下任意一种：
    处方1：
    Figure PCTCN2016093126-appb-100001
    处方2：
    Figure PCTCN2016093126-appb-100002
    处方3：
    Figure PCTCN2016093126-appb-100003
  12. 一种权利要求1-11任意一项所述的LCZ696的药物组合物的制备方法，其特征在于所述制备方法包含如下制备步骤：
    (1)将原、辅料过40目筛，备用；
    (2)将处方中内加成分进行预混合，使用干法制粒机压制预混合之后的混合物，整粒之后得到内相颗粒；
    (3)将内相颗粒与外加辅料进行混合，混合之后将所得的混合物进行压片得到LCZ696片芯，
    所述片剂进一步经过包衣处理，所述包衣采用羟丙甲纤维素、糖粉、羟丙纤维素或欧巴代中的任意一种。
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