WO2017020841A1 - Composition pharmaceutique contenant du lcz696 et son procédé de préparation - Google Patents

Composition pharmaceutique contenant du lcz696 et son procédé de préparation 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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PCT/CN2016/093126
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Chinese (zh)
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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.

Abstract

La présente invention concerne une composition pharmaceutique contenant une poudre cristalline spécifique de LCZ696. Ladite poudre cristalline de LCZ696 comprenant un élément pulvérulent spécifique satisfait à une exigence d'un procédé de préparation et peut être utilisée pour produire une composition pharmaceutique satisfaisant à une exigence d'utilisation de médicament clinique tout en réalisant une production à plus grande échelle de la composition pharmaceutique.
PCT/CN2016/093126 2015-08-03 2016-08-03 Composition pharmaceutique contenant du lcz696 et son procédé de préparation WO2017020841A1 (fr)

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CN112574132A (zh) * 2019-09-30 2021-03-30 广东东阳光药业有限公司 一种沙库必曲缬沙坦钠的制备方法
US11382866B2 (en) 2017-07-06 2022-07-12 Mankind Pharma Ltd. Fixed dose pharmaceutical composition of valsartan and sacubitril
EP4088715A1 (fr) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Formulation pharmaceutique de valsartan et sacubitril

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CN112574132B (zh) * 2019-09-30 2024-02-27 广东东阳光药业股份有限公司 一种沙库必曲缬沙坦钠的制备方法
EP4088715A1 (fr) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Formulation pharmaceutique de valsartan et sacubitril
WO2022238563A1 (fr) 2021-05-14 2022-11-17 Krka, D.D., Novo Mesto Formulation pharmaceutique de valsartan et de sacubitril

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