Sacubitril and valsartan sodium tablet and preparation method thereof

Abstract

The invention provides a sacubitril and valsartan sodium tablet and a preparation process thereof. The sacubitril valsartan sodium tablet contains sacubitril valsartan sodium, hydrogenated palm oil, trehalose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and a film coating premix, wherein the raw material medicines are subjected to moisture-proof treatment by adopting a co-grinding technology. The preparation process is simple, no organic solvent is used, the requirement for environment humidity is lower, the temporary storage time limit of an intermediate product is longer, and industrialization is facilitated.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a sacubitril-valsartan sodium tablet and a preparation method thereof. Background Art

[0002] Sacubitril-valsartan is a combination drug developed by Novartis for the treatment of chronic heart failure and hypertension. It is a new single co-crystal composed of the enkephalinase inhibitor sacubitril and the angiotensin receptor antagonist valsartan in a molar ratio of 1:1. Sacubitril-valsartan sodium tablets were approved for marketing by the US FDA in 2015 under the trade name Entresto. In 2017, they were approved to enter the Chinese market under the trade name Notosin, and were later included in the 2020 National Medical Insurance Catalogue.

[0003] Sacubitril-valsartan sodium has a special bonding and salt-forming mode, which makes it very easy to absorb moisture under high humidity conditions, thus affecting the stability of the raw materials and preparations. Its chemical structure is as follows:

[0004] In order to avoid the introduction of moisture during the process, patent CN109464442A uses organic solvent acetone to wet granulate the sacubitril-valsartan sodium pharmaceutical composition, which poses certain safety hazards.

[0005] In order to solve the problem that the active ingredient of sacubitril-valsartan sodium is easily hygroscopic, patent CN111358783A adds a large amount of dipotassium hydrogen phosphate or disodium hydrogen phosphate to the components. However, long-term use may cause abnormal electrolyte metabolism in the human body and induce clinical medication risks such as hyperkalemia. CN116850150A grinds sacubitril-valsartan sodium, sodium succinate, and valine at low temperature (0~5℃), and then dry granulates them with other excipients. This condition is relatively demanding and most solid preparation workshops do not have this condition. At the same time, the production cost is high, which is not conducive to industrialization. Summary of the invention

[0006] The present invention aims to provide a method for preparing sacubitril-valsartan sodium tablets which are stable in nature, safe and easy to produce, avoiding the introduction of moisture throughout the process and overcoming the problem that the active ingredient is easy to absorb moisture.

[0007] Since the sacubitril valsartan sodium API is very easy to absorb moisture, relatively strict requirements are placed on the environmental humidity and the temporary storage time limit of intermediate products (referring to products that have completed some processing steps, such as total mixed particles, bare chips, etc.) during the preparation research and development and production process. In response to this industrialization problem, the applicant has conducted a lot of prescription and process exploration research, and unexpectedly discovered that the sacubitril valsartan sodium API and hydrogenated palm oil (melting point 30~40℃) can play a good moisture-proof effect after grinding and mixing, but the dissolution is not ideal. In order to take into account the moisture-proof and dissolution of the preparation, the applicant selected trehalose with excellent performance from a wide variety of excipients, and optimized the ratio and grinding order of hydrogenated palm oil, trehalose and APIs, achieving the expected effect.

[0008] The first invention object of the present invention is to disclose a sacubitril-valsartan sodium tablet composition, the combination formula of which includes 100 parts of sacubitril-valsartan sodium, 5-7 parts of hydrogenated palm oil, 50-70 parts of trehalose, 29-51 parts of microcrystalline cellulose, 12 parts of cross-linked sodium carboxymethyl cellulose, 0.5 parts of colloidal silicon dioxide, 1.5 parts of magnesium stearate, and 6 parts of film coating premix.

[0009] Preferably, a sacubitril-valsartan sodium tablet contains 100 parts of sacubitril-valsartan sodium, 6 parts of hydrogenated palm oil, 60 parts of trehalose, 40 parts of microcrystalline cellulose, 12 parts of croscarmellose sodium, 0.5 parts of colloidal silicon dioxide, 1.5 parts of magnesium stearate, and 6 parts of film coating premix.

[0010] In order to further achieve moisture-proof and dissolution effects, hydrogenated palm oil and trehalose are further ground and mixed, and then sacubitril valsartan sodium is added for co-grinding.

[0011] The second invention object of the present invention is to disclose a method for preparing sacubitril-valsartan sodium tablets, which specifically comprises the following steps: Step 1: Grinding: Grinding and mixing hydrogenated palm oil and trehalose, and then adding sacubitril valsartan sodium for co-grinding; Step 2: Mixing: The material obtained in step 1 is mixed with microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide using a mixing granulator, the stirring speed is set to 200 rpm, and the mixing is performed for 3 minutes; Step 3 Dry granulation: The material obtained in step 2 is granulated by a dry granulator, and the feed speed is set to 15 rpm, the roller speed is 10 rpm, the roller pressure is 5 MPa, and the granulation screen is 20 mesh; Step 4: Total mixing: Mix the material obtained in step 3 with magnesium stearate using a hopper mixer, set the speed to 10 rpm, and mix for 5 minutes; Step 5: tabletting: the material obtained in step 4 is tabletted, and the hardness is not less than 50N; Step 6: Coating: Coat the tablets obtained in step 5.

[0012] The present invention can achieve the following beneficial effects: (1) The disadvantage of sacubitril / valsartan sodium API being highly hygroscopic and unstable is overcome. The resulting tablets have low moisture absorption and weight gain under high humidity conditions, good stability of related substances, and meet the requirements of very fast dissolution. Therefore, the humidity control of the production environment is more relaxed, the temporary storage time is longer, and the production cost is reduced; (2) The preparation process is simple to operate, does not use organic solvents, is safe and pollution-free, and is conducive to industrialization. DETAILED DESCRIPTION

[0013] The prescription composition of Examples 1 to 5 is:

[0014] The preparation method of embodiments 1 to 5: Step 1: Grinding: Grinding and mixing hydrogenated palm oil and trehalose, and then adding sacubitril valsartan sodium for co-grinding; Step 2: Mixing: The material obtained in step 1 is mixed with microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide using a mixing granulator, the stirring speed is set to 200 rpm, and the mixing is performed for 3 minutes; Step 3 Dry granulation: The material obtained in step 2 is granulated by a dry granulator, and the feed speed is set to 15 rpm, the roller speed is 10 rpm, the roller pressure is 5 MPa, and the granulation screen is 20 mesh; Step 4: Total mixing: Mix the material obtained in step 3 with magnesium stearate using a hopper mixer, set the speed to 10 rpm, and mix for 5 minutes; Step 5: tabletting: the material obtained in step 4 is tabletted, and the hardness is not less than 50N; Step 6: Coating: Coat the tablets obtained in step 5.

[0015] The prescription composition of comparative examples 1 to 6 is:

[0016] Preparation method of comparative example 1: Step 1: Grind and sieve sacubitril-valsartan sodium for later use; Step 2-6: refer to the preparation method of step 2-6 in Example 1-5.

[0017] The preparation method of comparative examples 2 to 5 is as follows: refer to the preparation method of embodiments 1 to 5.

[0018] Preparation method of comparative example 6: Step 1: Grind and mix hydrogenated palm oil and sacubitril / valsartan sodium, and then add trehalose for co-grinding; Step 2-6: refer to the preparation method of step 2-6 in Example 1-5. Test Example 1: Process Smoothness Inspection

[0019] The smoothness of each process of Examples 1 to 5 and Comparative Examples 1 to 6 was observed and recorded as follows: Examples 1-5, Comparative Examples 1 to 2 and 4 to 6 had smooth processes; Comparative Example 3 had sticking of the pressing wheel in the dry granulation process, and sticking and loose tablets in the tableting process, so Comparative Example 3 was not investigated subsequently. Test Example 2: Hygroscopic Weight Gain and Appearance Shape Examination

[0020] The unpackaged sacubitril-valsartan sodium bulk drug, samples of Examples 1 to 5, Comparative Examples 1 to 2 and 4 to 6 were placed in a high humidity test chamber (25°C / 75%RH), and samples were taken on the 1st, 3rd and 7th days, respectively, to measure the moisture absorption and weight gain, and the results were recorded as follows:

[0021] It can be seen from Table 1 that under the conditions of 25°C / 75%RH, the raw material is very easy to absorb moisture. After being placed for 1 day, the appearance and properties change significantly; the samples of Examples 1 to 5 and Comparative Example 4 have a moisture absorption weight gain of less than 5% after being placed for 7 days, and the appearance and properties do not change significantly; the moisture absorption weight gain of Comparative Example 1 exceeded 5% after being placed for 3 days, and a slight waist crack appeared, and the moisture absorption weight gain exceeded 10% after being placed for 7 days, and the waist crack was completely formed; the moisture absorption weight gain of Comparative Examples 2 and 5 samples exceeded 5% after being placed for 7 days, and a slight waist crack appeared; the moisture absorption weight gain of Comparative Example 6 sample after being placed for 7 days did not exceed 5%, but some spots appeared.

[0022] Test Example 3 Dissolution curve investigation The dissolution of samples of Examples 1 to 5, Comparative Examples 1 to 2 and 4 to 6 in a pH 6.8 phosphate buffer and a paddle method at 50 rpm was measured respectively.

[0023] Chromatographic conditions: octadecylsilane bonded silica gel as filler (ZORBAX SB-C18, 4.6mm×150mm, 5μm or chromatographic column with equivalent performance); acetonitrile-water-trifluoroacetic acid (45:55:0.1) as mobile phase; flow rate of 1.8mL per minute; column temperature of 30℃; detection wavelength of 254nm; injection volume of 10μL.

[0024] The results are recorded as follows:

[0025] It can be seen from Table 2 that the dissolution amounts of Examples 1 to 5 and Comparative Examples 1, 2, and 5 in 15 min are all not less than 85%, which meets the "very rapid dissolution" requirement of ICH, while Comparative Examples 4 and 6 do not meet the requirement. Test Example 4 Investigation of the stability of related substances

[0026] Examples 1 to 5 and Comparative Examples 1 to 2 and 4 to 6 were respectively packaged in ordinary PVC aluminum-plastic packaging and placed under accelerated conditions (40°C ± 2°C / 75% RH ± 5% RH) for 6 months. Samples were taken at the end of the 3rd month and the 6th month during the test, and the total content of related substances was determined according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules 0512).

[0027] Chromatographic conditions: Use octadecylsilane bonded silica gel as filler (ZORBAX SB-C18, 3.0mm×150mm, 3.5μm or chromatographic column with equivalent performance); use water-trifluoroacetic acid (100:0.1) as mobile phase A, and acetonitrile-trifluoroacetic acid (100:0.1) as mobile phase B, and perform gradient elution according to the table below; the flow rate is 1.0mL per minute; the column temperature is 50℃; the detection wavelength is 254nm; the injection volume is 10μL.

[0028]

[0029] The results are recorded as follows:

[0030] From the results in Table 3, it can be seen that: based on the comprehensive analysis of the accelerated 3-month and 6-month stability test data, the related substances in Examples 1 to 5 have good stability.

Claims

1. A sacubitril-valsartan sodium tablet, characterized in that It contains 100 parts of sacubitril valsartan sodium, 5-7 parts of hydrogenated palm oil, 50-70 parts of trehalose, 29-51 parts of microcrystalline cellulose, 12 parts of cross-linked carboxymethyl cellulose sodium, 0.5 part of colloidal silicon dioxide, 1.5 parts of magnesium stearate, and 6 parts of film coating premix, wherein the raw material sacubitril valsartan sodium is processed by co-grinding technology.

2. The sacubitril-valsartan sodium tablets according to claim 1, characterized in that Contains 100 parts of sacubitril / valsartan sodium, 6 parts of hydrogenated palm oil, 60 parts of trehalose, 40 parts of microcrystalline cellulose, 12 parts of croscarmellose sodium, 0.5 parts of colloidal silicon dioxide, 1.5 parts of magnesium stearate and 6 parts of film coating premix.

3. The sacubitril-valsartan sodium tablets according to claim 1, characterized in that The hydrogenated palm oil and trehalose are ground and mixed, and then sacubitril valsartan sodium is added and co-grinded.

4. A method for preparing the sacubitril-valsartan sodium tablets according to claim 1, characterized in that The following steps are involved: Step 1: Grinding: Grinding and mixing hydrogenated palm oil and trehalose, and then adding sacubitril valsartan sodium for co-grinding; Step 2: Mixing: Mix the material obtained in step 1 with microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide using a mixing granulator; Step 3: Dry granulation: The material obtained in step 2 is granulated using a dry granulator; Step 4: Total mixing: Mix the material obtained in step 3 with magnesium stearate using a hopper mixer; Step 5: tableting: tableting the material obtained in step 4; Step 6: Coating: Coat the tablets obtained in step 5.

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