WO2017000864A1 - Pharmaceutical composition for treating heart failure and preparation method therefor - Google Patents

Abstract

A pharmaceutical composition comprising LCZ696 comprises LCZ696, a hydrophilic filling agent, a binder and a disintegrant. When the pharmaceutical composition comprises 1 pts. wt. LCZ696, it comprises 0.5-2.75 pts. wt. hydrophilic filling agent. A method for preparing LCZ696 formulation by powder direct pressing.

Description

Medicine composition for heart failure treatment and preparation method thereof Technical field

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition for treating heart failure and a preparation method thereof.

Background technique

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).

Since 2005, due to the prevalence of cardiovascular risk factors, the number of cardiovascular diseases in China has continued to increase. According to statistics, there are about 290 million cardiovascular patients in China, and there are about 4.5 million patients with central failure (China Cardiovascular Disease Report 2013). Angiotensin-converting enzyme inhibitor (ACEI) is the first class of drugs that has been shown to reduce the mortality rate of patients. It is also the drug with the highest accumulation of evidence-based medicine. It is the drug of choice for workers to treat heart failure. Elapril is the drug. One of the ACEI commonly used in the treatment of clinical heart failure.

LCZ696 (CAS: 936623-90-4) is a drug developed by Novartis for anti-heart failure, the structure of which was first disclosed in patent WO2007056546. The compound is a supramolecular complex (complex) composed of valsartan and AHU377 through non-covalent bonding, and has an dual action of angiotensin receptor blockade and neutral endopeptidase inhibition. Clinical trials have shown that LCZ696 reduces the hospitalization rate of heart failure by 21% compared with the enalapril-treated group, and reduces the symptoms and physical limitations of heart failure, reducing mortality in heart failure patients and Hospitalization rates are superior to enalapril (N Engl J Med, 2014, 371(1): 993-1004). It can be seen that LCZ696 is a market-leading anti-heart failure drug, and the product is expected to be approved for marketing in 2015.

Since LCZ696 is unstable to moisture and dissociates in the solution system, the use of solvents should be avoided as much as possible during the formulation process. Chinese patent CN200880114940.6 discloses a solid oral preparation containing LCZ696, which has the characteristics of good dissolution performance and meets the requirements for clinical administration. However, the preparation method adopts a dry granulation process, which has many processes and is cumbersome, which is not conducive to the cost control of the preparation. The powder direct pressure process is one of the solutions to the above problems.

Due to the poor fluidity of the LCZ696 product itself, the proportion in the preparation is large, and it is difficult to prepare a powder suitable for direct pressure powder. The prior art does not disclose the prescription and process for preparing the LCZ696 solid oral preparation by direct powder compaction. It is a technical problem to be solved in the prior art to find a pharmaceutical composition suitable for the preparation of a solid oral preparation of LCZ696 suitable for clinical use.

Summary of the invention

The first object of the present invention is to overcome the deficiencies of the prior art and to provide a pharmaceutical composition containing LCZ696, which has the characteristics of moderate flowability, good compatibility of raw materials and the like, and is suitable for preparing LCZ696 by powder direct pressing process. Solid oral preparations.

The above advantageous effects of the present invention are achieved by the following technical solutions:

A pharmaceutical composition comprising LCZ696, the pharmaceutical composition comprising LCZ696, a filler, a binder, a disintegrant, characterized in that the filler is a hydrophilic filler.

The hydrophilic filler is selected from the group consisting of lactose, mannitol, starch, pregelatinized starch, sucrose, dextrin, calcium hydrogen phosphate, sorbitol, or a mixture of two or more thereof in any ratio. Since fillers usually account for a large proportion of excipients, the selection of fillers in the powder direct compression process requires a comprehensive consideration of the effects on the formulation process (such as fluidity) and product quality (such as dissolution properties). Specifically, for a specific LCZ696 drug substance, the hydrophilic filler is preferably lactose, mannitol, pregelatinized starch, calcium hydrogen phosphate, sorbitol. When the mass fraction of the LCZ696 is 1, the hydrophilic filler is used in an amount of 0.5 to 2.75 parts by mass. Since the common specifications of the LCZ696 are 100 mg and 200 mg, the use of the excessive filler makes the final tablet weight too large. The compliance of the patient is lowered, and the use of too little filler is disadvantageous for tableting. Preferably, the hydrophilic filler is used in an amount of 0.6 to 2 parts, more preferably 0.6 to 1 part by mass.

The binder is selected from one or a mixture of two or more of povidone, high-substituted hydroxypropylcellulose, and hypromellose in any ratio. The use of a binder consists in facilitating the shaping of the pharmaceutical composition during the preparation process. Preferably, the binder is selected from one or a mixture of two or more of high-substituted hydroxypropylcellulose and hypromellose in any ratio. When the mass fraction of LCZ696 is 1, the mass fraction of the binder is 0.02 to 0.2 parts. There is a choice of the amount of the binder to be used. The use of too much binder makes the pharmaceutical composition too rigid to be disintegrated after preparation, and too little binder can not achieve adhesion, It is advantageous for tablet molding. In addition, the use of too little binder can cause the formulation to disintegrate too quickly, which is not conducive to clinical administration. Preferably, the binder is used in an amount of from 0.02 to 0.14 parts by mass.

The disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, croscarmellose sodium, low-substituted hydroxypropylcellulose, or a mixture of two or more thereof in any ratio. . The use of the disintegrant is to achieve effective dissolution after the product is successfully disintegrated after entering the body to achieve a therapeutic effect. Preferably, the disintegrating agent is selected from one or a mixture of two or more of crospovidone, croscarmellose sodium, and croscarmellose sodium in an arbitrary ratio. When the mass fraction of LCZ696 is 1, the mass fraction of the disintegrant is from 0.03 to 0.2 parts. The use of the excessive disintegrant makes the pharmaceutical composition easy to absorb moisture, and the excessive disintegration after preparation into a preparation is not conducive to achieving clinical therapeutic purposes, and the use of too little disintegrant cannot guarantee complete release of the drug, which is disadvantageous for For the purpose of clinical treatment, it is preferred that the disintegrant is used in an amount of from 0.04 to 0.15 parts by mass.

The LCZ696 pharmaceutical composition may further comprise a glidant selected from the group consisting of dioxide One or a mixture of two or more of silicon and talc is mixed in an arbitrary ratio. The purpose of using a glidant is to further improve the powder flow properties to better achieve the powder direct compression process of the LCZ696 pharmaceutical composition. When the mass fraction of LCZ696 is 1, the mass fraction of the glidant is 0.002 to 0.05 parts. Preferably, the flow aid is used in an amount of 0.01 to 0.04 parts.

The pharmaceutical composition of the LCZ696 of the present invention may further comprise a lubricant depending on the prescription. The lubricant is selected from one or a mixture of two or more of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, stearic acid, palmitic acid, and carnauba wax in any ratio. The purpose of the lubricant is to prevent sticking of the pharmaceutical composition during subsequent stamping, the amount of lubricant being based on the ability to achieve lubrication as is known in the art. Preferably, the amount of lubricant used is 0.01 to 0.1 parts.

In summary, for the pharmaceutical composition of the LCZ696, in addition to the dissolution property, stability, and the like of the further obtained preparation, the powder properties of the total mixed powder should be controlled in the art for the powder direct pressing process. Within a reasonable range, after the powder is pressed, the difference in tablet weight is in accordance with the relevant requirements of the Chinese Pharmacopoeia (2010 Edition), and it can be seen that the fluidity of the mixed powder meets the requirements and the process is stable.

In addition, since the pharmaceutical composition of the LCZ696 has better flow properties, the pharmaceutical composition of the LCZ696 can also be prepared into other dosage forms other than the tablet by utilizing the advantage of the total mixed powder, such as dispensing. After the capsule is obtained, it can also be prepared into a tablet or a capsule by a conventional dry granulation process.

A preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:

name Parts by mass LCZ696 1 lactose 0.78 Cross-linked povidone 0.1 Highly substituted hydroxypropyl cellulose 0.06 Silica 0.02 Magnesium stearate 0.04

A preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:

name Parts by mass LCZ696 1

lactose 1.56 Cross-linked povidone 0.2 Highly substituted hydroxypropyl cellulose 0.12 Silica 0.04 Magnesium stearate 0.08

A preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:

name Parts by mass LCZ696 1 Mannitol 0.78 Cross-linked povidone 0.1 Highly substituted hydroxypropyl cellulose 0.06 Silica 0.02 Magnesium stearate 0.04

A preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:

name Parts by mass LCZ696 1 lactose 0.74 Cross-linked povidone 0.1 Hypromellose 0.10 Colloidal silica 0.02 Magnesium stearate 0.04

A preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:

A preferred pharmaceutical composition containing LCZ696 of the present invention is as follows:

name Parts by mass LCZ696 1 Sorbitol 0.72 Cross-linked sodium carboxymethyl starch 0.12 Hypromellose 0.10 Silica 0.02 Magnesium stearate 0.04

A second object of the present invention is to provide a method for preparing a pharmaceutical composition of LCZ696 based on the aforementioned prescription characteristics and further preparing the pharmaceutical composition into a tablet by a process of powder direct pressing. The LCZ696 prepared by the method has the advantages of high mixing uniformity and good fluidity, and is suitable for the powder direct pressing process.

The above beneficial effects of the method are achieved by the following technical solutions:

A method of preparing a pharmaceutical composition suitable for powder direct pressure LCZ696, the method comprising the steps of:

1) The original and auxiliary materials are passed through a 40 mesh sieve, and the preparation is prepared according to the prescription amount;

2) taking a prescription amount of a binder, a disintegrant and a 1/2 prescription filler to uniformly mix the powder A;

3) taking a prescribed amount of raw materials, a flow aid, and a filler to uniformly mix the mixed powder B;

The mixed powder A obtained in the step 2 is added to the mixed powder B obtained in the step 3, and a predetermined amount of the lubricant is added and uniformly mixed to obtain a total mixed powder.

The total mixed powder obtained by the above method can be further prepared by a powder direct pressing method, and the direct pressing process of the powder follows the common knowledge in the art. Preferably, the tablet specifications are 100 mg, 200 mg, and 400 mg. The process of direct powder pressing needs to control the hardness of the tablet below 10 kgf.

A third object of the present invention is to provide an LCZ696 tablet which is prepared by the powder direct compression process of the LCZ696 pharmaceutical composition of the present invention, and the LCZ696 tablet has the characteristics of high yield, and various indexes such as tablets The difference in weight, dissolution performance, stability, etc. are in line with the quality requirements of clinical drugs.

Compared with the prior art, the present invention has the following technical features and advantages:

1. For the first time, a pharmaceutical composition of LCZ696 suitable for powder direct pressing process is provided. The pharmaceutical composition has the characteristics of moderate flowability, good compatibility of raw materials and the like, and is suitable for preparing LCZ696 solid preparation by a simpler powder direct pressing process.

2. A method for preparing a pharmaceutical composition of LCZ696, which is combined with a specific LCZ696 pharmaceutical composition formulation, is suitable for industrial large-scale production, and is advantageous for obtaining a LCZ696 pharmaceutical composition conforming to a powder direct compression process.

3. Providing a preparation of LCZ696, which is prepared by a powder direct pressing process, and various indexes such as dissolution performance and stability are in compliance with clinical drug quality requirements.

detailed description

The present invention will be further described in detail below with reference to the embodiments, but the embodiments of the invention are not limited thereto.

Example 1

Preparation of LCZ696 pharmaceutical composition

1, lactose, high-substituted hydroxypropyl cellulose, crospovidone, silica, magnesium stearate over 40 mesh sieve Use, according to the amount of prescription to weigh the preparation;

2, taking a prescription amount of crospovidone, high-substituted hydroxypropyl cellulose and 1/2 prescription amount of lactose mixed evenly mixed powder A;

3, taking the prescription amount of raw materials, silicon dioxide, 1/2 prescription amount of lactose mixed evenly mixed powder B;

4. Add the mixed powder A to the mixed powder B, and add a prescription amount of magnesium stearate to obtain a total mixed powder.

Preparation of tablets

The total mixed powder was prepared into a tablet having a specification of 100 mg by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 2

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in the weight difference of the obtained tablet tablets was small, and it met the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition), but the tablet tablets obtained in Example 2 were relatively heavier.

Example 3

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 4

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 5

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 6

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 7

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

Due to the absence of a flow aid in the formulation of Example 7, the variation in tablet weight was too large, which was greater than that of Examples 1 to 6, but still met the relevant requirements of the Chinese Pharmacopoeia (2010 edition).

Example 8

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 9

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Comparative Example 1

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in tablet weight obtained is in line with the relevant requirements of Appendix IA of the Second Edition of the Chinese Pharmacopoeia (2010 Edition).

Comparative Example 2

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg tablet was prepared by a powder direct pressing process. However, since the amount of the filler was too small, the tablet weight was only 162 mg, the sheet thickness was thin, and the hardness range was 3~5kgf; In addition, the difference in tablet weight of the obtained tablets does not meet the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Comparative Example 3

The LCZ696 total mixed powder was prepared in the same manner as in Example 1, and a 100 mg-sized tablet was prepared by a powder direct pressing process, and the hardness of the tablet was controlled to 5 to 10 kgf.

The difference in weight of the tablets obtained was less fluctuating and complied with the relevant requirements of the second appendix IA of the Chinese Pharmacopoeia (2010 edition).

Example 10

Dissolution test

The dissolution rate of the LCZ696 direct-pressed tablets obtained in Examples 1 to 9 and Comparative Examples 1 to 3 was respectively measured by the Chinese Pharmacopoeia (2010 edition) Appendix XC Dissolution Measurement Method Second Method Paddle Method, and the obtained data are shown in the following table:

project 15min 30min 45min Example 1 87.24 99.35 99.13 Example 2 83.71 99.76 98.42 Example 3 80.31 95.34 98.56 Example 4 80.71 93.76 98.42 Example 5 83.21 96.24 98.83 Example 6 81.25 92.34 98.01 Example 7 81.51 92.12 98.32 Example 8 79.29 90.71 98.45 Example 9 75.45 87.51 97.84 Comparative Example 1 62.70 89.82 93.99 Comparative Example 2 53.94 84.21 96.63 Comparative Example 3 90.16 ^* 96.72 98.75

^* This data is detected when it is 10min.

It can be seen that the preparations obtained in Examples 1 to 9 have good dissolution properties and meet the requirements for clinical use.

For Comparative Example 1, which did not employ the filler protected by the present invention, although the formulation was suitable for the powder direct pressing process, the resulting formulation had significantly lower dissolution properties than the products obtained in Examples 1-9.

For Comparative Example 2, the amount of the filler used in the formulation was too small, so that the difference in tablet weight was large due to the poor fluidity of the total mixed powder on the one hand, and the dissolution performance of the obtained formulation was not as good as in Example 1 on the other hand. ~9 products.

For Comparative Example 3, although the prescription meets the requirements of the powder direct pressing process, since the amount of the binder is too small, the dissolution thereof is too fast, and 90% or more is dissolved in 10 minutes, which is disadvantageous for the realization of the clinical therapeutic effect.

Example 11

Stability test

The preparations obtained in Examples 1 to 9 were allowed to stand under accelerated conditions (40 ° C ± 2 ° C, RH 75% ± 5%) for 1 month, and the contents of the active ingredients and the single and total impurities were measured. The results were as follows:

As can be seen from the above table, in the accelerated experiment, the preparations of Examples 1 to 9 had small changes in the amount of single and total impurities, which met the requirements of the relevant clinical quality regulations, and it was found that the preparations obtained in Examples 1 to 9 had high stability.

The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and combinations thereof may be made without departing from the spirit and scope of the invention. Simplifications should all be equivalent replacements and are included in the scope of the present invention.

Claims (10)

A pharmaceutical composition comprising LCZ696, the pharmaceutical composition comprising LCZ696, a filler, a binder, a disintegrant, characterized in that the filler is a hydrophilic filler, when the mass fraction of LCZ696 is 1. The hydrophilic filler is used in an amount of 0.5 to 2.75 parts by mass. The pharmaceutical composition according to claim 1, wherein the hydrophilic filler is used in an amount of from 0.6 to 2 parts by mass. The pharmaceutical composition according to any one of claims 1 to 2, wherein the hydrophilic filler is selected from the group consisting of lactose, mannitol, starch, pregelatinized starch, sucrose, dextrin, calcium hydrogen phosphate, and sorbus One or more of the alcohols are mixed in any ratio. The pharmaceutical composition according to any one of claims 1 to 3, wherein the binder is one or more selected from the group consisting of povidone, high-substituted hydroxypropylcellulose, and hypromellose. The amount of the binder is 0.02 to 0.2 parts by mass in any ratio. The pharmaceutical composition according to any one of claims 1 to 4, wherein the disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, croscarmellose sodium, and low One or a mixture of two or more of the substituted hydroxypropylcelluloses is used in an arbitrary ratio, and the dispersing agent is used in an amount of 0.03 to 0.2 parts by mass. The pharmaceutical composition according to any one of claims 1 to 5, wherein the hydrophilic filler is used in an amount of from 0.6 to 1 part by mass, and the binder is used in an amount of from 0.02 to 0.14 parts by mass. The disintegrating agent is used in an amount of from 0.04 to 0.15 parts by mass. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutical composition further contains a glidant selected from one or both of silica and talc. The above mixing amount is in an arbitrary ratio, and the amount of the glidant is from 0.002 to 0.05 parts, preferably from 0.01 to 0.04 parts. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition further comprises a lubricant selected from the group consisting of magnesium stearate, hydrogenated vegetable oil, polyethylene glycol, and hard One or a mixture of two or more of fatty acid, palmitic acid, and carnauba wax is mixed in an arbitrary ratio, and the lubricant is used in an amount of 0.01 to 0.1 parts by mass. An LCZ696 tablet characterized in that the pharmaceutical composition containing LCZ696 according to claims 1-8 is prepared by a powder direct compression process. A method of preparing a LCZ696 tablet according to claim 9, the method comprising the steps of: 1) The original and auxiliary materials are passed through a 40 mesh sieve, and the preparation is prepared according to the prescription amount; 2) taking a prescription amount of a binder, a disintegrant and a 1/2 prescription filler to uniformly mix the powder A; 3) taking a prescribed amount of raw materials, a flow aid, and a filler to uniformly mix the mixed powder B; 4) The mixed powder A obtained in the step 2) is added to the mixed powder B obtained in the step 3), and a predetermined amount of the lubricant is added and uniformly mixed to obtain a total mixed powder.