Sacubitril valsartan sodium tablet and preparation method thereof

Abstract

The application provides sacubitril valsartan sodium tablets and a preparation process thereof. The tablet contains sacubitril valsartan sodium, hydrogenated palm oil, trehalose, microcrystalline cellulose, crosslinked sodium carboxymethyl cellulose, colloidal silicon dioxide, magnesium stearate and film-coating premix, wherein the raw material is subjected to moisture-proof treatment by using a co-grinding technology. The preparation process is simple, no organic solvent is used, the requirement for environmental humidity is more relaxed, the time limit for temporary storage of the intermediate product is longer, and the industrialization is facilitated.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a sacubitril / valsartan sodium tablet and its preparation method. Background Technology

[0002] Sacubitril / valsartan is a combination therapy developed by Novartis for the treatment of chronic heart failure and hypertension. It is a novel single cocrystal composed of the neprilysin inhibitor sacubitril and the angiotensin receptor antagonist valsartan in a 1:1 molar ratio. Sacubitril / valsartan sodium tablets were approved by the U.S. FDA in 2015 under the brand name Entresto.

[0003] Sacubitril / valsartan sodium has a unique bonding and salt formation mechanism, which makes it highly hygroscopic under high humidity conditions, thus affecting the stability of the active pharmaceutical ingredient and the formulation. Its chemical structure is as follows:

[0004]

[0005] To avoid the introduction of moisture during the process, patent CN109464442A uses the organic solvent acetone to wet granulate the sacubitril / valsartan sodium drug composition, which poses certain safety risks.

[0006] To address the issue of the hygroscopic nature of the active ingredient in sacubitril / valsartan sodium, patent CN111358783A added a large amount of dipotassium hydrogen phosphate or disodium hydrogen phosphate to the composition. However, long-term use may lead to abnormal electrolyte metabolism in the human body, causing clinical drug risks such as hyperkalemia. CN116850150A involves low-temperature cold grinding (0~5℃) of sacubitril / valsartan sodium, sodium succinate, and valine, followed by dry granulation with other excipients. This process requires stringent conditions, which most solid dosage form workshops do not possess, and also results in high production costs, hindering industrialization. Summary of the Invention

[0007] The present invention aims to provide a method for preparing sacubitril / valsartan sodium tablets that is stable, safe and easy to produce, avoiding the introduction of moisture throughout the process and overcoming the problem of the active ingredient being easily hygroscopic.

[0008] Because sacubitril / valsartan sodium active pharmaceutical ingredient (API) is highly hygroscopic, stringent requirements are placed on environmental humidity and the storage time of intermediate products (products that have completed some processing steps, such as mixed granules and bare tablets) during formulation development and production. To address this industrialization challenge, the applicant conducted extensive formulation and process exploration research, unexpectedly discovering that grinding and mixing sacubitril / valsartan sodium API with hydrogenated palm oil (melting point 30-40℃) provided excellent moisture protection, but dissolution was not ideal. To balance moisture protection and dissolution in the formulation, the applicant screened trehalose, a high-performance excipient, from a wide variety of excipients and optimized the ratio and grinding sequence of hydrogenated palm oil, trehalose, and API, achieving the desired results.

[0009] The first objective of this invention is to disclose a sacubitril / valsartan sodium tablet composition, the composition 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 croscarmellose sodium, 0.5 parts of colloidal silica, 1.5 parts of magnesium stearate, and 6 parts of film coating premix.

[0010] Preferably, a sacubitril / valsartan sodium tablet contains 100 parts sacubitril / valsartan sodium, 6 parts hydrogenated palm oil, 60 parts trehalose, 40 parts microcrystalline cellulose, 12 parts croscarmellose sodium, 0.5 parts colloidal silica, 1.5 parts magnesium stearate, and 6 parts film coating premix.

[0011] To further enhance moisture resistance and dissolution, hydrogenated palm oil and trehalose were ground and mixed, and then sacubitril and valsartan sodium were added for co-grinding.

[0012] The second objective of this invention is to disclose a method for preparing sacubitril / valsartan sodium tablets, specifically including the following steps:

[0013] Step 1 Grinding: After grinding and mixing hydrogenated palm oil and trehalose, add sacubitril and valsartan sodium for co-grinding.

[0014] Step 2 Mixing: The material obtained in Step 1 is mixed with microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and colloidal silica using a mixing granulator. The stirring speed is set to 200 rpm and the mixture is mixed for 3 minutes.

[0015] Step 3 Dry Granulation: Granulate the material obtained in Step 2 using a dry granulation machine. Set the conveying speed to 15 rpm, the pressure roller speed to 10 rpm, the pressure roller pressure to 5 MPa, and the granulation screen to 20 mesh.

[0016] Step 4: 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.

[0017] Step 5: Compress the material obtained in Step 4 into tablets with a hardness of not less than 50N.

[0018] Step 6: Coating: Coat the tablets obtained in Step 5 to obtain the final product.

[0019] The present invention can achieve the following beneficial effects:

[0020] (1) It overcomes the disadvantage of sacubitril valsartan sodium raw material being extremely hygroscopic and unstable. The resulting tablets have low moisture gain under high humidity conditions, good stability of related substances, and meet the requirements for very rapid dissolution. Therefore, the humidity control of the production environment is more relaxed, the storage time is longer, and the production cost is reduced.

[0021] (2) The preparation process is simple to operate, does not use organic solvents, is safe and pollution-free, and is conducive to industrialization. Detailed Implementation

[0022] The prescription composition of Examples 1-5:

[0023]

[0024] Preparation methods of Examples 1-5:

[0025] Step 1 Grinding: After grinding and mixing hydrogenated palm oil and trehalose, add sacubitril and valsartan sodium for co-grinding.

[0026] Step 2 Mixing: The material obtained in Step 1 is mixed with microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and colloidal silica using a mixing granulator. The stirring speed is set to 200 rpm and the mixture is mixed for 3 minutes.

[0027] Step 3 Dry Granulation: Granulate the material obtained in Step 2 using a dry granulation machine. Set the conveying speed to 15 rpm, the pressure roller speed to 10 rpm, the pressure roller pressure to 5 MPa, and the granulation screen to 20 mesh.

[0028] Step 4: 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.

[0029] Step 5: Compress the material obtained in Step 4 into tablets with a hardness of not less than 50N.

[0030] Step 6: Coating: Coat the tablets obtained in Step 5 to obtain the final product.

[0031] The prescription composition of comparative examples 1-6:

[0032]

[0033] Preparation method of Comparative Example 1:

[0034] Step 1: Crush and sieve the sacubitril / valsartan sodium, and set aside;

[0035] Steps 2-6: Refer to the preparation method in Steps 2-6 of Examples 1-5.

[0036] Preparation methods for comparative examples 2-5: refer to the preparation methods of examples 1-5.

[0037] Preparation method of Comparative Example 6:

[0038] Step 1: Grind and mix hydrogenated palm oil and sacubitril / valsartan sodium, then add trehalose and co-grind.

[0039] Steps 2-6: Refer to the preparation method in Steps 2-6 of Examples 1-5.

[0040] Experimental Example 1: Process Smoothness Assessment

[0041] The smoothness of each process in Examples 1-5 and Comparative Examples 1-6 was observed and recorded as follows: The processes in Examples 1-5, Comparative Examples 1-2 and 4-6 were smooth; Comparative Example 3 showed sticking of the pressure roller in the dry granulation process and sticking and loosening of the tablets in the tableting process, so Comparative Example 3 was not further investigated.

[0042] Experimental Example 2: Moisture Absorption Weight Gain and Appearance Examination

[0043] Sacubitril / valsartan sodium raw material without any packaging, samples from Examples 1-5, Comparative Examples 1-2 and 4-6 were placed in a high humidity test chamber (25℃ / 75%RH). Samples were taken on days 1, 3, and 7, and the moisture gain was measured. The results are recorded below:

[0044]

[0045] As can be seen from Table 1, under the conditions of 25℃ / 75%RH, the active pharmaceutical ingredient is extremely hygroscopic, and its appearance changes significantly after one day. The moisture absorption weight gain of samples 1-5 and Comparative Example 4 after 7 days is less than 5%, and the appearance does not change significantly. Comparative Example 1 has a moisture absorption weight gain of more than 5% after 3 days and has developed slight waist cracks. After 7 days, the moisture absorption weight gain exceeds 10% and it has completely cracked. Comparative Examples 2 and 5 have a moisture absorption weight gain of more than 5% after 7 days and have developed slight waist cracks. Although the moisture absorption weight gain of Comparative Example 6 after 7 days is less than 5%, some mottled spots have appeared.

[0046] Experimental Example 3: Dissolution Curve Investigation

[0047] The dissolution of samples from Examples 1-5, Comparative Examples 1-2, and 4-6 was determined under pH 6.8 phosphate buffer and paddle method at 50 rpm.

[0048] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (ZORBAX SB-C18, 4.6 mm × 150 mm, 5 μm or equivalent column); acetonitrile-water-trifluoroacetic acid (45:55:0.1) was used as the mobile phase; the flow rate was 1.8 mL per minute; the column temperature was 30 °C; the detection wavelength was 254 nm; and the injection volume was 10 μL.

[0049] The results are recorded as follows:

[0050]

[0051] As can be seen from Table 2, the dissolution rate of Examples 1-5 and Comparative Examples 1, 2, and 5 was not less than 85% within 15 minutes, which meets the ICH requirement of "very rapid dissolution", while Comparative Examples 4 and 6 did not meet the requirement.

[0052] Experimental Example 4: Investigation of the Stability of Related Substances

[0053] Examples 1-5, Comparative Examples 1-2 and 4-6 were packaged in ordinary PVC aluminum-plastic packaging and placed under accelerated conditions (40℃±2℃ / 75%RH±5%RH) for 6 months. Samples were taken at the end of the 3rd month and the end of the 6th month during the test period, and the total content of related substances was determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0054] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (ZORBAX SB-C18, 3.0 mm × 150 mm, 3.5 μm or equivalent column); water-trifluoroacetic acid (100:0.1) was used as mobile phase A, and acetonitrile-trifluoroacetic acid (100:0.1) was used as mobile phase B, with gradient elution according to the table below; the flow rate was 1.0 mL per minute; the column temperature was 50 °C; the detection wavelength was 254 nm; and the injection volume was 10 μL.

[0055]

[0056] The results are recorded as follows:

[0057]

[0058] As can be seen from the results in Table 3, the related substances in Examples 1-5 show good stability after comprehensive analysis of the stability test data after 3 months and 6 months of accelerated testing.

Claims

1. A sacubitril / valsartan sodium tablet, characterized in that... The tablets contain 100 parts sacubitril / valsartan sodium, 5-7 parts hydrogenated palm oil, 50-70 parts trehalose, 29-51 parts microcrystalline cellulose, 12 parts croscarmellose sodium, 0.5 parts colloidal silica, 1.5 parts magnesium stearate, and 6 parts film-coating premix. The active pharmaceutical ingredient, sacubitril / valsartan sodium, is processed using a co-grinding technique. The specific steps for preparing sacubitril / valsartan sodium tablets are as follows: Step 1 Grinding: After grinding and mixing hydrogenated palm oil and trehalose, add sacubitril and valsartan sodium for co-grinding. Step 2 Mixing: The material obtained in Step 1 is mixed with microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, and colloidal silica using a mixing granulator; Step 3: Dry granulation: Granulate the material obtained in Step 2 using a dry granulation machine; Step 4: Mixing: Mix the material obtained in Step 3 with magnesium stearate using a hopper mixer; Step 5: Tableting: Compress the material obtained in Step 4 into tablets; Step 6: Coating: Coat the tablets obtained in Step 5 to obtain the final product.

2. The sacubitril / valsartan sodium tablets according to claim 1, characterized in that... It 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 silica, 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... Hydrogenated palm oil and trehalose are ground and mixed, and then sacubitril and valsartan sodium are added for co-grinding.

Images