Pharmaceutical Composition

Abstract

This invention relates to a sacubitril / valsartan sodium tablet composition and its preparation method, belonging to the field of pharmaceutical formulation technology. The technical solution of this invention is: a tablet composition containing sacubitril / valsartan sodium, comprising 50 parts of sacubitril / valsartan sodium, 4-16 parts of chitosan, 30-45 parts of microcrystalline cellulose, 3-8 parts of croscarmellose sodium, and 0.7-2 parts of magnesium stearate. This invention provides a stable sacubitril / valsartan sodium tablet and its preparation method. The tablets obtained by the preparation method have advantages such as rapid dissolution, smooth surface, and good stability, solving the sticking and punching problem in the preparation process of sacubitril / valsartan sodium tablets, and are suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a sacubitril / valsartan sodium tablet composition and its preparation method, belonging to the field of pharmaceutical formulation technology. Background Technology

[0002] Sacubitril / valsartan sodium is an angiotensin receptor neprilysin inhibitor (ARNI) developed by Novartis and marketed under the brand name ENTRESTO. It is used to reduce the risk of death and hospitalization in patients with certain types of long-term (chronic) heart failure.

[0003] Sacubitril / valsartan sodium, chemically named (3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl)propionic acid-(S)-3'-methyl-2'-(pentanoyl(2'-(tetrazol-5-yl)biphenyl-4'-ylmethyl)amino)butyric acid)trisodium hemipentahydrate, molecular formula C 48 H 55 N6O8 Na3·2.5H2O, structural formula is: .

[0004] When the relative humidity (RH) is below 20%, sacubitril / valsartan sodium will reversibly lose most of its water of crystallization; when the relative humidity (RH) exceeds 60%, sacubitril / valsartan sodium is highly hygroscopic and unstable, and the higher the temperature, the faster the decomposition and the lower the content, and the more impurities, which poses a great challenge to the formulation process.

[0005] Chinese patent CN103251587A discloses an oral tablet of sacubitril / valsartan sodium, using conventional excipients. However, to improve hygroscopicity, it significantly uses large amounts of lubricants and flow aids in its formulation, which is detrimental to the compressibility of the material, as well as the stability and dissolution of the product. No stability studies were conducted. Chinese patent CN111358783A discloses a sacubitril / valsartan sodium pharmaceutical formulation. To address the hygroscopicity of the active pharmaceutical ingredient (API), it adds large amounts of stabilizers dipotassium hydrogen phosphate and disodium hydrogen phosphate (2-10%) to the formulation. The use of large amounts of inorganic salts can easily cause electrolyte imbalances in the human body, posing a significant risk to clinical use. However, it does not effectively solve the hygroscopicity problem during tableting. Patent CN116850152A improves the hygroscopicity of the API by dissolving a waxy material in acetone and then spraying it onto the sacubitril / valsartan sodium API to form a binary complex, followed by dry granulation with hydroxypropyl methylcellulose.

[0006] Therefore, it is essential to develop a formulation preparation process that is stable and suitable for industrial production. Summary of the Invention

[0007] The purpose of this invention is to provide a tablet containing sacubitril / valsartan sodium, based on existing technology, and to solve the problems of sticking and stability during tablet preparation.

[0008] The technical solution of the present invention is as follows: A tablet composition containing sacubitril / valsartan sodium contains 50 parts of sacubitril / valsartan sodium, 4-16 parts of chitosan, 30-45 parts of microcrystalline cellulose, 3-8 parts of croscarmellose sodium, and 0.7-2 parts of magnesium stearate.

[0009] Preferably, the tablet composition containing sacubitril / valsartan sodium described in this application contains 50g of sacubitril / valsartan sodium, 4-16g of chitosan, 30-45g of microcrystalline cellulose, 3-8g of croscarmellose sodium, and 0.7-2g of magnesium stearate per 1000 tablets.

[0010] Preferably, the tablet composition containing sacubitril / valsartan sodium described in this application contains 50g of sacubitril / valsartan sodium, 6-15g of chitosan, 35-40g of microcrystalline cellulose, 4-6g of croscarmellose sodium, and 1-1.5g of magnesium stearate per 1000 tablets.

[0011] Preferably, the tablet composition containing sacubitril / valsartan sodium described in this application contains 50g of sacubitril / valsartan sodium, 10g of chitosan, 38g of microcrystalline cellulose, 5g of croscarmellose sodium, and 1g of magnesium stearate per 1000 tablets.

[0012] This application obtains a tablet composition of sacubitril / valsartan sodium with satisfactory dissolution and stability by rationally combining chitosan with other excipients and using the preparation method described in this application.

[0013] If the amount of chitosan in the sacubitril / valsartan sodium tablet composition described in this application is below the lower limit, sticking and punching problems will occur during the preparation process, and the tablets will become loose due to moisture absorption during storage.

[0014] The method for preparing the sacubitril / valsartan sodium tablet composition of the present invention includes the following steps: Step 1. Mix the prescribed amount of sacubitril / valsartan sodium with one-third of the prescribed amount of croscarmellose sodium.

[0015] Step 2. Mix the mixture obtained in Step 1 with half of the prescribed amount of chitosan until homogeneous.

[0016] Preferably, the uniform mixing described in steps 1 and 2 is achieved by mixing in a hopper mixer at a speed of 15 rpm for at least 20 minutes.

[0017] Step 3. Mix the mixture obtained in Step 2 with two-thirds of the prescribed amount of croscarmellose sodium, half of the prescribed amount of chitosan, and the prescribed amount of microcrystalline cellulose until homogeneous.

[0018] Preferably, the uniform mixing described in this step is achieved by mixing in a hopper mixer at a speed of 15 rpm for at least 10 minutes.

[0019] Step 4. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 3 and mix well.

[0020] Preferably, the uniform mixing described in this step is achieved by mixing in a hopper mixer at a speed of 15 rpm for at least 10 minutes.

[0021] Step 5. Compress the mixture obtained in Step 4 into tablets, controlling the core hardness to 60-90 N, to obtain the final product.

[0022] The preparation method described in this invention, by separately mixing sacubitril / valsartan sodium with one-third of the prescribed amount of croscarmellose sodium and chitosan, ensures that the tablets have suitable dissolution and stability.

[0023] If mixing at 15 rpm for less than 20 minutes in steps 1 and 2 results in tablets with stability issues during storage.

[0024] Beneficial effects: This invention provides a stable sacubitril / valsartan sodium tablet and a preparation method thereof. The tablets obtained by the preparation method have the advantages of rapid dissolution, smooth surface, and good stability, and solve the sticking and punching problem in the preparation process of sacubitril / valsartan sodium tablets, making it suitable for large-scale industrial production.

[0025] Example 1. 50g of sacubitril / valsartan sodium, 4g of chitosan, 45g of microcrystalline cellulose, 3g of croscarmellose sodium, and 0.7g of magnesium stearate were used to prepare 1000 tablets according to the preparation method described in the technical solution section of this application. During the tableting process, there were no sticking or punching problems, and some of the resulting tablets were smooth.

[0026] Example 2. 50g of sacubitril / valsartan sodium, 16g of chitosan, 30g of microcrystalline cellulose, 8g of croscarmellose sodium, and 2g of magnesium stearate were used to prepare 1000 tablets according to the preparation method described in the technical solution section of this application. During the tableting process, there were no sticking or punching problems, and some of the resulting tablets were smooth.

[0027] Example 3. 50g of sacubitril / valsartan sodium, 10g of chitosan, 38g of microcrystalline cellulose, 5g of croscarmellose sodium, and 1g of magnesium stearate were used to prepare 1000 tablets according to the preparation method described in the technical solution section of this application. During the tableting process, there were no sticking or punching problems, and some of the resulting tablets were smooth.

[0028] Compared with the formulation of Example 1. Example 3, microcrystalline cellulose was used instead of chitosan, as follows: Prepare 1000 tablets using the following method: 50g of sacubitril / valsartan sodium, 48g of microcrystalline cellulose, 5g of croscarmellose sodium, and 1g of magnesium stearate.

[0029] Step 1. Place the prescribed amount of sacubitril / valsartan sodium and one-third of the prescribed amount of croscarmellose sodium in a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0030] Step 2. Place the mixture obtained in Step 1, along with two-thirds of the prescribed amount of cross-linked carboxymethyl cellulose sodium and the prescribed amount of microcrystalline cellulose, into a hopper mixer and mix at a speed of 15 rpm for at least 10 minutes.

[0031] Step 3. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 2 and place it in a hopper mixer. Mix at a speed of 15 rpm for at least 10 minutes.

[0032] Step 4. Compress the mixture obtained in Step 3 into tablets, controlling the core hardness to 80N, to obtain the final tablet.

[0033] During the tablet compression process, there was a sticking problem, and 24% of the resulting tablets had pitting and were not smooth.

[0034] Comparative Example 2. The prescription is the same as in Example 3, and 1000 tablets are prepared according to the following preparation method.

[0035] Step 1. Place the prescribed amounts of sacubitril / valsartan sodium, chitosan, microcrystalline cellulose, and croscarmellose sodium into a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0036] Step 2. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 1, and mix at a speed of 15 rpm for at least 10 minutes. Compress into tablets with a tablet hardness of 80 N.

[0037] During the tablet compression process, there was a sticking problem, and 12% of the resulting tablets had pitting and were not smooth.

[0038] Comparative Example 3. The prescription is the same as in Example 3, and 1000 tablets are prepared according to the following preparation method.

[0039] Step 1. Place the prescribed amount of sacubitril / valsartan sodium and half the prescribed amount of chitosan into a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0040] Step 2. Place the mixture obtained in Step 1, along with two-thirds of the prescribed amount of croscarmellose sodium, the prescribed amount of chitosan, and microcrystalline cellulose, into a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0041] Step 3. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 2, and mix in a hopper mixer at a speed of 15 rpm for no less than 10 minutes.

[0042] Step 4. Compress the mixture obtained in Step 3 into tablets, controlling the core hardness to 80N, to obtain the final tablet.

[0043] There is no sticking or punching problem during the tablet compression process, and the resulting tablets are smooth.

[0044] Comparative Example 4. The prescription is the same as in Example 3, and 1000 tablets are prepared according to the following preparation method.

[0045] Step 1. Place the prescribed amount of sacubitril / valsartan sodium, half the prescribed amount of chitosan, and one-third the prescribed amount of croscarmellose sodium in a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0046] Step 2. Place the mixture obtained in Step 1, along with half the prescribed amount of chitosan, two-thirds of the prescribed amount of croscarmellose sodium, and the prescribed amount of microcrystalline cellulose, into a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0047] Step 3. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 2, and mix in a hopper mixer at a speed of 15 rpm for no less than 10 minutes.

[0048] Step 4. Compress the mixture obtained in Step 3 into tablets, controlling the core hardness to 80N, to obtain the final tablet.

[0049] There is no sticking or punching problem during the tablet compression process, and the resulting tablets are smooth.

[0050] Compared with Example 5, the formulation of Example 3 uses 5g of microcrystalline cellulose instead of croscarmellose sodium. Specifically, it consists of: 50g of sacubitril / valsartan sodium, 10g of chitosan, 43g of microcrystalline cellulose, and 1g of magnesium stearate. 1000 tablets are prepared according to the preparation method described in the technical solution section of this application. During tablet compression, there are no sticking or punching problems, and some of the resulting tablets are smooth.

[0051] Step 1. Mix the prescribed amount of sacubitril / valsartan sodium with half the prescribed amount of chitosan at a speed of 15 rpm for at least 20 minutes.

[0052] Step 2. Place the mixture obtained in Step 1, along with half the prescribed amount of chitosan, two-thirds of the prescribed amount of croscarmellose sodium, and the prescribed amount of microcrystalline cellulose, into a hopper mixer and mix at a speed of 15 rpm for at least 20 minutes.

[0053] Step 3. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 2, and mix in a hopper mixer at a speed of 15 rpm for no less than 10 minutes.

[0054] Step 4. Compress the mixture obtained in Step 3 into tablets, controlling the core hardness to 80N, to obtain the final tablet.

[0055] There is no sticking or punching problem during the tablet compression process, and the resulting tablets are smooth.

[0056] Experimental Example 1. Determination of dissolution.

[0057] Take the products of Examples 1-3 and Control Examples 1-5 respectively, and perform high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512) using 900 ml of pH 6.8 acid salt buffer as the dissolution medium, paddle method, and a rotation speed of 50 rpm. Take appropriate amounts of the dissolution solution at 5 min, 15 min, 30 min and 45 min respectively, and add the same volume of dissolution medium at the same temperature. Filter, and take the filtrate as the test solution for determination.

[0058] Chromatographic conditions: Column: Octadecylsilane-bonded silica gel; Mobile phase: Water (containing 0.05% trifluoroacetic acid) - Acetonitrile (containing 0.05% trifluoroacetic acid) (40:60); Column temperature: 35℃; Detection wavelength: 254nm. Results are shown in Table 1.

[0059] Table 1 .

[0060] Table 1 shows that the rational combination of chitosan and other excipients in the technical solution of this invention, along with the preparation method described in this application, yields tablets with high dissolution rates. This is beneficial for improving the bioavailability of the tablets for users.

[0061] Test Example 2. Stability Test One hundred tablets each of Examples 1-3 and Control Examples 1-5 were taken (Note: Smooth tablets were selected for the control examples; tablets with pitting were not included in the stability test). They were packaged in ordinary PVC aluminum-plastic packaging and placed in a constant temperature and humidity chamber at 40℃±2℃ and 75%RH±5%RH for 6 months. Samples were taken at the end of the 3rd and 6th months of the test period, and the contents of related substances were determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). The appearance was also observed. The results are shown in Table 2.

[0062] Table 2 .

[0063] Table 2 shows that the reasonable combination of chitosan and other excipients in the technical solution of this invention solves the stability problem of sacubitril / valsartan sodium tablets.

[0064] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications may still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions may be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A tablet composition containing sacubitril / valsartan sodium, comprising 50 parts of sacubitril / valsartan sodium, 4-16 parts of chitosan, 30-45 parts of microcrystalline cellulose, 3-8 parts of croscarmellose sodium, and 0.7-2 parts of magnesium stearate.

2. The tablet composition of claim 1, wherein each 1000 tablets contains 50 g of sacubitril / valsartan sodium, 4-16 g of chitosan, 30-45 g of microcrystalline cellulose, 3-8 g of croscarmellose sodium, and 0.7-2.0 g of magnesium stearate.

3. The tablet composition of claim 1, wherein each 1000 tablets contains 50 g of sacubitril / valsartan sodium, 6-15 g of chitosan, 35-40 g of microcrystalline cellulose, 4-6 g of croscarmellose sodium, and 1-1.5 g of magnesium stearate.

4. The tablet composition of claim 1, wherein each 1000 tablets contains 50 g of sacubitril / valsartan sodium, 10 g of chitosan, 38 g of microcrystalline cellulose, 5 g of croscarmellose sodium, and 1 g of magnesium stearate.

5. A method for preparing the tablet composition according to any one of claims 1-4, comprising the following steps: Step 1. Mix the prescribed amount of sacubitril / valsartan sodium with one-third of the prescribed amount of croscarmellose sodium until homogeneous. Step 2. Mix the mixture obtained in Step 1 with half the prescribed amount of chitosan until homogeneous. Preferably, the uniform mixing described in steps 1 and 2 is achieved by mixing in a hopper mixer at a speed of 15 rpm for at least 20 minutes. Step 3. Mix the mixture obtained in Step 2 with two-thirds of the prescribed amount of croscarmellose sodium, half the prescribed amount of chitosan, and the prescribed amount of microcrystalline cellulose until homogeneous. Preferably, the uniform mixing described in this step is achieved by mixing in a hopper mixer at a speed of 15 rpm for at least 10 minutes. Step 4. Add the prescribed amount of magnesium stearate to the mixture obtained in Step 3, and mix well. Preferably, the uniform mixing described in this step is achieved by mixing in a hopper mixer at a speed of 15 rpm for at least 10 minutes. Step 5. Compress the mixture obtained in Step 4 into tablets, controlling the core hardness to 60-90 N, to obtain the final tablet.