CN109464442B

CN109464442B - Sacubitril valsartan sodium pharmaceutical composition and preparation method thereof

Info

Publication number: CN109464442B
Application number: CN201811373100.3A
Authority: CN
Inventors: 裴建梅
Original assignee: Individual
Current assignee: Individual
Priority date: 2018-11-19
Filing date: 2018-11-19
Publication date: 2020-02-28
Anticipated expiration: 2038-11-19
Also published as: CN109464442A

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a Sacubitril valsartan sodium pharmaceutical composition and a preparation method thereof. The preparation method comprises the steps of adopting acetone with a specific proportion as a solvent for independent wet granulation of raw and auxiliary materials, then mixing and granulating, and drying granules after granulation by combining a reduced pressure drying method at a lower temperature, so that a process with excellent repeatability when the scale of the proportion can be enlarged/reduced is obtained, and the medicine is prevented from being damaged in the preparation process. The obtained pharmaceutical composition has excellent stability and uniformity, and can be favorable for good popularization of the medicine in treatment of heart failure, hypertension and the like.

Description

Sacubitril valsartan sodium pharmaceutical composition and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a Sacubitril valsartan sodium pharmaceutical composition and a preparation method thereof.

Background

According to the statistics of 'report 2013 on cardiovascular diseases in China'), the cardiovascular disease patients in China are about 2.9 hundred million, and the heart failure patients are about 450 million. Angiotensin Converting Enzyme Inhibitors (ACEIs) are the first class of drugs that have been shown to reduce mortality in heart failure patients, and are the drugs that accumulate the greatest amount of evidence from the medical profession, and are the first choice drugs for the early accepted treatment of heart failure, such as enalapril.

The valsartan sodium of Sacubitril, also called LCZ696, is a heart failure resisting drug with the double effects of angiotensin receptor blocking and neutral endopeptidase inhibition developed by Nowa company, and the structure (as shown in the following formula) is disclosed in patent WO2007056546A1 for the first time. The published clinical experimental results show that the valsartan sodium of Sacubitril reduces the hospitalization rate of the subjects due to the heart failure by 21% compared with the enalapril treatment group, reduces the symptoms and physical limitations of the heart failure, and is superior to enalapril (N Engl J Med, 2014, 371(1): 993) 1004 in reducing the mortality rate and hospitalization rate of the patients with the heart failure. It can be seen that the sodium valsartan of Sacubitril is a drug with great market potential for resisting heart failure, and the product is approved to be on the market in the next half year of 2015. LCZ696 (trade name ENTRESTO) is currently commercially available^TM) Can be obtained in oral dosage forms as 200, 100 and 50mg immediate release film coated tablets。

The valsartan sodium of the Sacubitril is a special drug and has a special bonding and salifying mode, so that the valsartan sodium is unstable to moisture and heat and can be dissociated in a solution system.

The known formulation scheme for the valsartan sodium of Sacubitril comprises: patent WO2009061713 discloses a formulation of sabotara valsartan sodium and a process for its preparation by mixing a therapeutic agent with at least one pharmaceutically acceptable excipient and then either directly compressing the mixture with suitable equipment such as a tablet press or compressing the mixture with suitable equipment such as a roller compactor, however, as can be seen from the drawings of the specification, this solution has the drawback of being less reproducible after geometric magnification.

In addition, the formulation form of WO2017/134597a1, suitable for paediatric or other patients requiring low individual dosing or experiencing dysphagia (e.g. due to illness or due to age), comprising a 1:1 molar ratio of sabotarol and valsartan, preferably in the form of the so-called angiotensin receptor neutral lysozyme (ARNI) LCZ696, illustrates that small formats are also more urgently required for the use of the present medicament.

Based on the prior art, other derived prior art schemes all adopt a dry granulation technical scheme, and the stability of the product is improved by adjusting auxiliary materials and process parameters, but the problem of poor reproducibility between scale up/down is still existed, different specifications may need different generation processes, which is not beneficial to the overall performance control of the product, and the effect after the medicine is applied may be unbalanced.

Disclosure of Invention

In view of the problems in the prior art, the invention provides a novel pharmaceutical composition of Sacubitril and valsartan sodium and a preparation method thereof, which adopts acetone with a specific proportion as a solvent for single wet granulation of raw and auxiliary materials, then mixes the raw and auxiliary materials for granulation, and dries the granules after granulation by combining a reduced pressure drying method at a lower temperature, so that a process with excellent repeatability when the scale of the proportion can be enlarged/reduced is obtained, and the medicine is prevented from being damaged in the preparation process.

The invention realizes the beneficial effects, and is realized by the following technical scheme:

firstly, the invention provides a pharmaceutical composition of Sacubitril valsartan sodium, comprising:

(1) adding a small amount of acetone into the Sacubitril valsartan sodium to prepare wet particles of 10-20 meshes;

(2) sieving hydrophilic filler, adhesive and disintegrating agent with 80 mesh sieve, respectively, and adding small amount of acetone to obtain wet particles of 10-20 mesh;

(3) mixing the wet granules obtained in the steps (1) and (2), granulating, drying the granulated granules at a lower temperature by a reduced pressure drying method, removing acetone, adding a lubricant, uniformly mixing, tabletting, and coating with a proper auxiliary material.

As a preferred technical scheme of the invention, the usage amount of a small amount of acetone in the step (1) is as follows: LCZ 696: acetone ═ 1: 0.1-0.2 g/mL.

As a preferred technical scheme of the invention, the usage amount of the small amount of acetone in the step (2) is as follows: the sum of the quality of the hydrophilic filler, the adhesive and the disintegrant is as follows: acetone ═ 1: 0.2-0.8 g/mL.

As a preferred technical scheme of the invention, the lower temperature is 30-40 ℃, and the drying time is less than 1 h.

Through the use amount of the solvent and the drying temperature, the auxiliary materials can be uniformly mixed through a conventional wet process, the difficulty that the medicine cannot be granulated through a wet method is overcome through unexpected discovery, and the LCZ696 still exists in a special bonding and salt forming mode through detection and discovery of the obtained raw and auxiliary material mixed particles.

Through a large number of experimental methods, when the usage amount of acetone is respectively less than the usage amount, uniform mixing of raw and auxiliary materials is difficult to effectively guarantee, and when the usage amount is increased, LCZ696 is easily decomposed into individual compounds of valsartan and sabotabethan due to extension of subsequent drying time.

It has been found more surprisingly that when the above amount of solvent is used, if the raw and auxiliary materials are directly mixed and then granulated by using the solvent, rather than separately preparing wet granules in advance, it is also easy to cause the decomposition of LCZ696 into individual compounds of valsartan and sabotara, and it is possible that LCZ696 is prepared as wet granules by using acetone, so that it is in a "saturated" state, avoiding the ionic effect after directly mixing with the auxiliary materials, and reducing the possibility of drug decomposition.

In a preferred embodiment of the present invention, the hydrophilic filler is one or a mixture of two or more selected from mannitol, calcium hydrogen phosphate, sorbitol, and microcrystalline cellulose at an arbitrary ratio. The mass ratio of LCZ696 to hydrophilic filler is preferably 1: 0.7 to 0.8, sorbitol being particularly preferred.

In a preferred embodiment of the present invention, the binder is one or a mixture of two or more of povidone, low-substituted hyprolose, and hypromellose at any ratio. The mass ratio of LCZ696 to binder is preferably 1: 0.05-0.08, especially preferably hypromellose.

In a preferred embodiment of the present invention, the disintegrant is one or a mixture of two or more selected from crospovidone and croscarmellose sodium in any ratio. The mass ratio of LCZ696 to disintegrant is preferably 1: 0.05-0.08, and especially preferred is crosslinked sodium carboxymethyl starch.

As a preferred embodiment of the present invention, when the mass ratio of LCZ696 to hydrophilic filler sorbitol is preferably 1: 0.7-0.8; and the mass ratio of LCZ696 to the adhesive hypromellose is preferably 1: 0.06-0.07; and the mass ratio of LCZ696 to disintegrant sodium carboxymethyl starch is preferably 1: 0.06-0.07, the flowability in the granulation and the subsequent steps of the drug, and the uniformity of the granulation can be best ensured, and the lot-to-lot variation of the obtained pharmaceutical composition can be reduced as much as possible.

According to a preferable technical scheme, the pharmaceutical composition adopts the above proportion combination, adopts magnesium stearate as a lubricant, preferably uses the usage amount of the pharmaceutical composition lubricant which is 1-3% of the weight of LCZ696, performs tabletting after uniform mixing, and increases the weight of the coating by 0.3-1.5% after coating by Opadry after tabletting.

The obtained pharmaceutical composition has similar dissolution to that of a commercial product, further improved stability and reduced impurity limit as much as possible, and is expected to meet the relevant requirements of consistency evaluation.

The invention also aims to provide a preparation method of the Sacubitril valsartan sodium pharmaceutical composition, which comprises the following steps:

The preparation method of the pharmaceutical composition further comprises various preferred technical schemes of the pharmaceutical composition.

Specifically, as a preferred technical scheme of the present invention, the usage amount of the small amount of acetone in step (1) is: LCZ 696: acetone ═ 1: 0.1-0.2 g/mL.

The dissolution of the pharmaceutical composition obtained by the method is similar to that of a product sold in the market, the stability is further improved, the limited amount of impurities is reduced as far as possible, and the pharmaceutical composition is expected to meet the relevant requirements of consistency evaluation.

The pharmaceutical composition can be applied to medicines for preventing and/or treating hypertension, heart failure, hypertension and heart failure.

The obtained medicinal composition greatly reduces the types of auxiliary materials, has simple preparation process, excellent scale amplification/scale reduction reproducibility of products due to different specifications, reduces production cost, is easy for industrialized application, and effectively ensures the balance of medicament action after patients with different diseases take medicaments with different specifications.

Note that: the invention unless otherwise specifically indicated, the valsartan sodium of Sacubitril refers to a compound with the following structure:

the beneficial effects of the invention compared with the prior art comprise:

(1) the invention adopts acetone with a specific proportion as a solvent for independent wet granulation of raw and auxiliary materials, then mixes the raw and auxiliary materials for granulation, and dries the granules after granulation by combining a reduced pressure drying method with a lower temperature, thereby obtaining a process with excellent repeatability when the scale of the raw and auxiliary materials can be enlarged/reduced, ensuring that the medicine is not damaged in the preparation process, and leading the wet granulation to be possible to be applied to the medicine.

(2) Through the preparation method, the obtained pharmaceutical composition has stable quality, and is characterized in that the granulation particles have good fluidity and good uniformity, the pharmaceutical composition has good stability, and the difference between tablets is reduced as much as possible, so that the effectiveness and the balance of clinical application are improved;

(3) the invention greatly reduces the raw and auxiliary material composition of the prescription, not only reduces the process cost, but also has simple process and is beneficial to large-scale industrialized application.

Drawings

FIG. 1 shows the X-ray spectrum of a Sacubitril raw material;

FIG. 2, X-ray spectrum of valsartan starting material;

FIG. 3 shows the X-ray spectrum of the raw material of Sacubitril sodium valsartan.

Detailed Description

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

Example 1

A Sacubitril valsartan sodium pharmaceutical composition and a preparation method thereof comprise the following steps:

(1) adding a small amount of acetone into the sabotara valsartan sodium to prepare 20-mesh wet particles, wherein the weight ratio of LCZ 696: acetone ═ 1: 0.15 g/mL;

(2) respectively sieving hydrophilic filler-sorbitol, adhesive-hydroxypropyl methylcellulose, disintegrant-crosslinked carboxymethyl starch sodium with 80 mesh sieve, adding a small amount of acetone to obtain 20 mesh wet granules, wherein the total mass of the hydrophilic filler, the adhesive and the disintegrant is as follows: acetone ═ 1: 0.5 g/mL;

(3) and (3) uniformly mixing the wet granules obtained in the steps (1) and (2), granulating, drying the granulated granules at 30-40 ℃ under reduced pressure for 30min, removing acetone, adding a lubricant, uniformly mixing, tabletting according to the required specification of the medicine, and coating with Opadry to increase the weight by 1%.

Example 2

(2) respectively sieving hydrophilic filler-mannitol, adhesive-hypromellose, disintegrant-crosslinked carboxymethyl starch sodium with 80 mesh sieve, adding small amount of acetone to obtain 20 mesh wet granules, wherein the total mass of hydrophilic filler, adhesive and disintegrant is as follows: acetone ═ 1: 0.5 g/mL;

Example 3

(2) respectively sieving hydrophilic filler-microcrystalline cellulose, adhesive-hypromellose, disintegrant-crosslinked carboxymethyl starch sodium with 80 mesh sieve, adding small amount of acetone to obtain 20 mesh wet granules, wherein the total mass of hydrophilic filler, adhesive and disintegrant is as follows: acetone ═ 1: 0.5 g/mL;

Example 4

(2) respectively sieving hydrophilic filler-sorbitol, adhesive-polyvidone, disintegrant-crosslinked carboxymethyl starch sodium with 80 mesh sieve, adding small amount of acetone to obtain 20 mesh wet granules, wherein the mass sum of the hydrophilic filler, adhesive and disintegrant is as follows: acetone ═ 1: 0.5 g/mL;

Examples 5 to 20

By adopting the technical schemes of the examples 1, 2, 3 and 4, the following medicaments are prepared according to the required specifications respectively to obtain the examples 5 to 20 respectively,

comparative example 1

Referring to the formulation and preparation method of example 3 of WO2009/061713, the following formulation was followed:

magnesium stearate, talc, colloidal silicon dioxide and microcrystalline cellulose were first sieved through a 30 mesh sieve. The above mixture, LCZ696, crospovidone, and low substituted hydroxypropylcellulose were then mixed in a hopper mixer for about 120 revolutions. The resulting mixture was then sieved through a 30 mesh sieve. The sieved mixture was then mixed in a hopper mixer for about 120 revolutions. The mixture was pressed with a roller press at a pressure of 30 kN. After pressing, the mixture was ground and sieved through an 18 mesh sieve to obtain the final internal phase particles. The granules were mixed with crospovidone and talc (plus granules) sieved through a 30 mesh screen for about 50 revolutions in a hopper mixer. The resulting mixture was then mixed with magnesium stearate (plus granules) sieved through a 30 mesh screen for about 50 revolutions in a hopper mixer. The resulting final mixture was then compressed into tablets using a Fette3090 apparatus. Coating weight gain of 1% is carried out by using an Opadry coating polymer, and a coated tablet is obtained.

Comparative examples 2 to 5

By adopting the technical scheme of the comparative example 1, the preparation is respectively prepared according to the required specifications of the following medicaments to respectively obtain the comparative examples 2-5,

example 21

Dissolution testing

The dissolution of the LCZ696 direct compression tablets obtained in examples 6, 10, 14 and 18 and comparative example 3 was measured by the second paddle method, which is an addition to the chinese pharmacopoeia (2010 version) and is shown in the following table:

item	15min	30min	45min
				Example 6	83.71	93.65	99.49
Example 10	80.71	91.36	99.12
				Example 14	81.51	92.82	98.72
Example 18	79.29	92.71	98.85
				Comparative example 3	78.94	86.21	96.63

It can be seen that the preparations obtained in examples 6, 10, 14 and 18 and comparative example 3 have better dissolution performance and more consistent dissolution characteristics, and are dissolved by about 80% within 15min, thereby meeting the clinical medication requirements.

Example 22

Stability test

The solid oral formulations (100mg) obtained in examples 6, 10, 14 and 18 and comparative example 3 were allowed to stand under accelerated conditions (40 ℃ ± 2 ℃ and RH 75% ± 5%) for 30 days, and the change of impurity a in the pharmaceutical composition was measured by the HPLC method described in the appendix of the chinese pharmacopoeia (2010 version), and the following results were obtained:

it can be seen from the stability tests that examples 6, 10, 14, 18 have significantly better quality stability than example 3.

Wherein the chemical structural formula of the impurity A is as follows:

example 23

The granules of examples 6, 10, 14, 18 and comparative example 3 were taken before final compression, and the angle of repose and the mixing uniformity were measured by the granule distribution test method described in the "GMP guidelines for pharmaceuticals" 2010 (oral solid preparations) 5.2.4, with the following results:

	angle of repose (degree) of granules	Mixing uniformity (%)
			Example 6	24.6	1.4
Example 10	28.8	1.7
			Example 14	29.3	1.9
Example 18	27.6	2.1
			Comparative example 3	42.3	4.8

It is understood that examples 6, 10, 14 and 18 are significantly more excellent in fluidity and content uniformity than example 3, and have more balanced quality.

Example 24:

the dissolution conditions of 6 tablets of the LCZ696 direct compression tablet obtained in examples 6, 10, 14 and 18 and comparative example 3 were respectively measured by a second paddle method, a dissolution measuring method XC in appendix of Chinese pharmacopoeia (2010 version).

It is understood that examples 6, 10, 14 and 18 have significantly better uniformity among sheets, smaller variation among sheets and more uniform quality than example 3.

Example 25:

the following determination method is adopted for X-ray detection, and no separate characteristic peak of Sacubitril and strong valsartan is found in granulation, and a characteristic peak of Sacubitril and strong valsartan sodium is found in granulation, so that the method can confirm that no obvious compound bond breakage exists in the granulation process of the embodiments 1-20 of the invention, and the Sacubitril and valsartan sodium is completely reserved, so that the wet granulation by using a solvent is possible to be applied to the medicine of the invention.

Specifically, refer to FIG. 1-X-ray spectrum of Sacubitril raw material, FIG. 2-X-ray spectrum of Valsartan raw material, and FIG. 3-X-ray spectrum of sodium Valsartan raw material.

X-ray diffraction detection conditions:

x-ray diffraction is carried out by adopting an acute image (Empyrean) X-ray diffractometer, and measuring the 2 theta range of 2-40 degrees under the conditions of Cu target K α rays, voltage of 40.0kV, current of 40.0mA, divergence slit of 1/32 degrees, anti-divergence slit of 1/16 degrees, anti-divergence slit of 7.5mm, step length of 0.02 degrees and residence time of 40s in each step.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A Sacubitril valsartan sodium pharmaceutical composition, which is characterized by comprising:

(1) adding a small amount of acetone into the Sacubitril valsartan sodium to prepare wet particles of 10-20 meshes, wherein the using amount of the acetone is as follows: sodium valsartan from Sacubitril: acetone = 1: 0.1-0.2 g/mL;

(2) respectively sieving the hydrophilic filler, the adhesive and the disintegrant by a sieve of 80 meshes, wherein the mass ratio of the sabotara valsartan sodium to the hydrophilic filler sorbitol is 1: 0.7-0.8; and the mass ratio of the sarkobatra valsartan sodium to the adhesive hydroxypropyl methylcellulose is 1: 0.06-0.07; and the mass ratio of the sabotara valsartan sodium to the disintegrant sodium carboxymethyl starch is 1: 0.06-0.07, adding a small amount of acetone to prepare wet particles of 10-20 meshes, wherein the use amount of the acetone is as follows: the sum of the quality of the hydrophilic filler, the adhesive and the disintegrant is as follows: acetone = 1: 0.2-0.8 g/mL;

(3) mixing the wet granules obtained in the steps (1) and (2), granulating, drying the granulated granules by a reduced pressure drying method at a lower temperature of 30-40 ℃, removing acetone, adding a lubricant, uniformly mixing, tabletting, and coating with proper auxiliary materials.

2. The pharmaceutical composition of claim 1, wherein the drying time is less than 1 hour.

3. The pharmaceutical composition according to claim 1, wherein magnesium stearate is used as a lubricant, the amount of the lubricant used in the pharmaceutical composition is 1-3% of the weight of the sodium valsartan from sabotara, the mixture is uniformly mixed and tabletted, and the coating is coated by Opadry after tabletting, so that the coating weight is increased by 0.3-1.5%.

4. A process for the preparation of a pharmaceutical composition of valsartan sodium from claims 1 to 3 comprising:

5. Use of a pharmaceutical composition according to any one of claims 1 to 3 for the preparation of a medicament for the prevention and/or treatment of hypertension, heart failure, hypertension and heart failure.