A kind of sacubitril-valsartan sodium tablet composition and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically relates to a sacubitril-valsartan sodium tablet composition and a preparation method thereof. The composition contains 100g of sacubitril-valsartan sodium, 30-40g of Tristar NF stearate, 6-10g of taro gum, 2-4g of sodium caseinate, 28-44g of microcrystalline cellulose, 16g of cross-linked sodium carboxymethyl cellulose, 2g of magnesium stearate, and 6g of gastric film coating premix per 1000 tablets. The present invention provides a process for fluidized bed granulation using an aqueous solvent after compounding a molten lipid excipient with a sacubitril-valsartan sodium raw material. No organic reagent is used in the preparation process of the process, which greatly reduces the production cost, reduces the harm to operators and the pollution to the environment; the process is simple and feasible, and is suitable for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a sacubitril-valsartan sodium tablet composition and a preparation method thereof. Background Art

[0002] Sacubitril-valsartan sodium is an angiotensin receptor neprilysin inhibitor (ARNI) developed by Novartis. On the one hand, it inhibits neprilysin (neutral endopeptidase; NEP) through the active metabolite LBQ657 of sacubitril, which plays a role in sodium excretion, diuresis, vasodilation and heart protection. On the other hand, valsartan blocks the type 1 receptor (AT1) of angiotensin II to dilate blood vessels and reduce the heart load. This drug is mainly used to treat chronic heart failure and hypertension.

[0003] Sacubitril-valsartan sodium is a new type of salt complex eutectic synthesized from two active pharmaceutical ingredients, sacubitril and valsartan. Its chemical structure is as follows:

[0004]

[0005] Sacubitril-valsartan sodium releases sacubitril and valsartan simultaneously in the body to exert its effects, and its therapeutic effect is much higher than the simple combination of valsartan and sacubitril. Its melting point is 138°C, and it is unstable under hot and humid conditions, especially when the humidity is above 65%, it is very easy to absorb moisture, accompanied by a decrease in content and an increase in impurities; limited by the properties of the raw materials, the preparation of sacubitril-valsartan sodium preparations in the prior art usually adopts dry granulation, direct tableting and organic reagent wet granulation.

[0006] Patent CN105748420B uses hydroxypropyl methylcellulose and raw materials to prepare sustained-release skeleton tablets using a powder direct compression process. Powder direct tableting has the disadvantages of poor powder fluidity and large differences in tablet weight. In addition, the raw materials account for a large proportion and are easily hygroscopic, which makes direct compression very prone to sticking risks.

[0007] Patent CN116850152A invented a technology that dissolves waxy materials in acetone and sprays them on the sacubitril valsartan sodium raw material to form a binary complex, and then dry granulates them with hydroxypropyl methylcellulose to improve the hygroscopicity of the raw material. Patent CN105935358B uses hydroxypropyl methylcellulose as a sustained-release skeleton material and adopts dry granulation to prepare sustained-release tablets. Patent CN111358783B adds one or two of the stabilizers dipotassium hydrogen phosphate and disodium hydrogen phosphate to the prescription to improve the hygroscopicity problem, and adopts dry granulation to prepare granules; the above patent processes all use dry granulation, which has a low yield and is prone to waste, and has a lot of dust and is prone to pollution, and has poor compressibility and reproducibility.

[0008] Patent CN109464442B invented a wet granulation process with good reproducibility when the scale can be enlarged / reduced, and granulation is carried out using acetone; Patent CN113456607B invented a sacubitril-valsartan sodium osmotic pump controlled-release tablet, in which the raw material, the permeation enhancer and the suspending agent are evenly mixed and then wet granulated with anhydrous ethanol, and the semipermeable membrane is coated with an acetone-water solution after tableting; Patent CN115444829B granulates the sacubitril-valsartan sodium raw material, the hydrophilic gel skeleton material and the swelling agent with anhydrous ethanol, and oven-drying to prepare a gastric retention sustained-release tablet; The granulation process in the above patents all adopts wet granulation. Although wet granulation has a simple process, good reproducibility, and is most commonly used in large-scale production, the above wet granulation processes all use organic solvents acetone or anhydrous ethanol, which has safety hazards in the process, greatly increases the production cost, and also has a certain impact on operators and the environment.

[0009] Due to the special properties of the raw materials, there are no reports on the use of purified water for wet granulation or fluidized bed granulation. Therefore, it is of great significance to develop a sacubitril / valsartan sodium pharmaceutical composition that uses purified water instead of organic reagents for granulation to reduce production costs, reduce harm to the human body, and reduce environmental pollution. Summary of the invention

[0010] Purpose of the invention: In view of the problems existing in the prior art, the present invention provides an oral preparation of sacubitril / valsartan sodium and a preparation method thereof. The raw material is first dispersed in Tristar NF stearic acid to prepare small particles, and then granulated with a purified aqueous solution of tsara gum and sodium caseinate. No organic reagent is used in the preparation process, which is safe and pollution-free, and greatly saves production costs.

[0011] Inventive concept: Limited by the properties of the raw material of sacubitril valsartan sodium, there is currently no pharmaceutical composition that can be granulated using purified water. The study found that ordinary stearic acid is a waxy crystal with a large particle size, which is difficult to mix evenly with the raw material in the process; its melting point is high, and the dispersion of the raw material in it needs to be exposed to higher temperature conditions, which increases the risk of degradation of the raw material and the generation of impurities; ordinary stearic acid has a high water content (3%~4%), which cannot effectively isolate the raw material from the binder aqueous solution; therefore, ordinary stearic acid is not suitable for this technical solution. The stearic acid Tristar NF selected in the technical solution of the present invention has the following advantages: (1) Most of its particle size is 75~150μm, which is close to the particle size of the raw material, and can be mixed more evenly with the raw material; (2) The melting temperature is only 55℃, and it can be completely melted at 60℃, which can better disperse the raw material evenly. Under this temperature condition, the raw material is stable; (3) It has a low water content (0.1%) and does not absorb water. The raw material wrapped by it can be better isolated from water, and can be directly granulated with purified water later. It should be further explained that, in the study, it was found that after the sacubitril valsartan sodium raw material was placed at 60°C for 30 days, the content and related substances hardly changed. Therefore, in the present technical solution, the heating extrusion temperature was set to 60°C.

[0012] In addition, the adhesive solution prepared by gum tsugara and sodium caseinate can wrap and further granulate the small particles of sacubitril valsartan and Tristar NF stearate. The composite particles formed after drying further protect the raw materials from the influence of humidity during storage.

[0013] The technical solution of the present invention is a sacubitril-valsartan sodium tablet composition, wherein each 1000 tablets contain 100g of sacubitril-valsartan sodium, 30-40g of Tristar NF stearate, 6-10g of taro gum, 2-4g of sodium caseinate, 28-44g of microcrystalline cellulose, 16g of cross-linked sodium carboxymethyl cellulose, 2g of magnesium stearate, and 6g of gastric film coating premix. Among them, sacubitril-valsartan sodium is uniformly dispersed in Tristar NF stearate in a crystalline state, and taro gum and sodium caseinate are used to prepare an adhesive solution.

[0014] As a preferred technical solution of the present invention, the sacubitril valsartan sodium tablet composition of the present invention contains 100g of sacubitril valsartan sodium, 35g of Tristar NF stearate, 8g of tara gum, 3g of sodium caseinate, 36g of microcrystalline cellulose, 16g of cross-linked sodium carboxymethyl cellulose, 2g of magnesium stearate, and 6g of gastric-soluble film coating premix per 1000 tablets.

[0015] Another aspect of the present invention is a method for preparing a sacubitril-valsartan sodium tablet composition, comprising the following steps:

[0016] Step 1: grind sacubitril / valsartan sodium and pass through a 100-mesh sieve;

[0017] Step 2: Mix Tristar NF stearate and sacubitril valsartan sodium using a three-dimensional mixer;

[0018] Step 3: adding the mixture obtained in step 2 into a hot melt extrusion granulator to obtain granules A;

[0019] Step 4: Add taro gum and sodium caseinate into purified water to dissolve as an adhesive solution for later use;

[0020] Step 5: using the binder solution prepared in step 4 to perform fluidized bed granulation on particles A, microcrystalline cellulose and croscarmellose sodium to obtain particles B;

[0021] Step 6: Add magnesium stearate to granules B and mix using a three-dimensional mixer;

[0022] Step 7: Punch out tablets with φ8 mm circular shallow depressions and apply film coating.

[0023] As a preferred technical solution of the present invention, the particle size distribution of sacubitril / valsartan in step 1 is 80 μm≤D90≤150 μm.

[0024] As a preferred technical solution of the present invention, the mixing speed of the three-dimensional mixer in step 2 is 10 to 20 Hz, and the mixing time is 15 to 30 minutes.

[0025] As a preferred technical solution of the present invention, the heating temperature of the hot melt extrusion granulation in step 3 is 60°C and the extrusion temperature is 15°C.

[0026] As a preferred technical solution of the present invention, the air inlet temperature of the fluidized bed granulation in step 5 is 45-55°C, and the air inlet volume is 15-20m 3 / h, the atomization pressure is 0.5~1.0Bar.

[0027] As a preferred technical solution of the present invention, the mixing speed of the three-dimensional mixer in step 6 is 10 Hz and the mixing time is 5 min.

[0028] As a preferred technical solution of the present invention, the hardness of the tablet in step 7 is 60~100N.

[0029] The present invention can achieve the following beneficial effects:

[0030] (1) The present invention overcomes the limitation of the preparation process caused by the instability of the raw material when exposed to water. By combining hot melt extrusion and fluidized bed granulation, a tablet with superior performance is designed. The dissolution rate within 30 minutes is greater than 85%, which is beneficial to the release and absorption in the body. The content and related substances change little under accelerated conditions of six months, and the stability is good.

[0031] (2) In the preparation process of the present invention, no organic reagents are used, thus avoiding the impact of large-scale use of organic reagents on operators and the environment. In addition, the preparation process is simple and feasible, low in cost, and suitable for large-scale production. DETAILED DESCRIPTION

[0032] The present invention will be further explained and illustrated by the following examples, but are not intended to be limiting of the present invention.

[0033] Example 1

[0034]

[0035] Preparation method:

[0036] Step 1: grind sacubitril / valsartan sodium and pass through a 100-mesh sieve;

[0037] Step 2: Mix Tristar NF stearate and sacubitril valsartan sodium evenly using a three-dimensional mixer at a mixing speed of 20 Hz for 20 min;

[0038] Step 3: continuously add the mixture of step 2 into a hot melt extrusion granulator, set the heating melting temperature to 60°C and the extrusion temperature to 15°C, to obtain particles A;

[0039] Step 4: Add taro gum and sodium caseinate into purified water to dissolve as an adhesive solution for later use;

[0040] Step 5: Use the binder solution prepared in step 4 to perform fluidized bed granulation on particles A, microcrystalline cellulose and cross-linked carboxymethyl cellulose sodium, set the inlet air temperature to 45-55°C, and the inlet air volume to 15-20m 3 / h, atomization pressure is 0.5~1.0Bar, and particle B is obtained;

[0041] Step 6: Add magnesium stearate to granules B and mix using a three-dimensional mixer, setting the mixing speed to 10 Hz and the mixing time to 5 min;

[0042] Step 7: Use φ8mm round shallow concave punching tablet, control the hardness to 60-100N, and apply film coating.

[0043] Example 2

[0044]

[0045] Preparation method: Prepare according to the preparation method of Example 1.

[0046] Example 3

[0047]

[0048] Preparation method: Prepare according to the preparation method of Example 1.

[0049] Example 4

[0050]

[0051] Preparation method: Prepare according to the preparation method of Example 1.

[0052] Example 5

[0053]

[0054] Preparation method: Prepare according to the preparation method of Example 1.

[0055] Comparative Example 1 The amount of stearic acid Tristar NF is below the lower limit

[0056]

[0057] Preparation method: Prepare according to the preparation method of Example 1.

[0058] Comparative Example 2 The amount of Tristar NF stearate is higher than the upper limit

[0059]

[0060] Preparation method: Prepare according to the preparation method of Example 1.

[0061] Comparative Example 3 The amount of taro gum and sodium caseinate is below the lower limit

[0062]

[0063] Preparation method: Prepare according to the preparation method of Example 1.

[0064] Since the concentration of the binder solution is too low, too much fine powder is prepared and the particles stick to the wall seriously.

[0065] Comparative Example 4 The amount of taro gum and sodium caseinate is higher than the upper limit

[0066]

[0067] Preparation method: Prepare according to the preparation method of Example 1.

[0068] Test Example 1 Content and related substances investigation

[0069] The samples were placed under accelerated conditions of 40°C ± 2°C and 75% ± 5% RH for 6 months. The content of sacubitril valsartan sodium and related substances were detected by high performance liquid chromatography. The experimental results are as follows:

[0070]

[0071] From the data of Examples 1-3 and Comparative Examples 1 and 2, it can be seen that the more Tristar NF stearate is used, the smaller the change of content and related substances under the accelerated six-month condition, while the amount below the protection limit will lead to a decrease in content and an increase in related substances. From the data of Examples 1, 4, 5 and Comparative Examples 3 and 4, it can be seen that too low an amount of taro gum and sodium caseinate affects the granulation effect, causing content loss, resulting in a significant decrease in the content at day 0.

[0072] Test Example 2 Investigation of Cumulative Dissolution

[0073] According to the second method of dissolution and release determination method 0931 of the fourth volume of the Chinese Pharmacopoeia 2020 edition, sacubitril valsartan sodium tablets were placed in a dissolution cup with 900 mL of degassed pH 6.8 phosphate buffer as the release medium, the rotation speed was 50 rpm, and the temperature was (37±0.5)°C, and the cumulative dissolution was determined.

[0074] The dissolution results of the embodiments and comparative examples are as follows:

[0075]

[0076]

[0077] From the cumulative dissolution results in Table 2 and Table 3, it can be seen that the dissolution of sacubitril and valsartan in Examples 1-5 all reached more than 85% in 30 min, indicating that Tristar NF stearate, tara gum, and sodium caseinate have good solubility within the scope of the present invention.

[0078] From the dissolution results of Examples 1-3 and Comparative Examples 1 and 2, it can be seen that the amount of Tristar NF stearate affects the dissolution rate of the composition. The higher the amount, the slower the dissolution. When it is higher than the protection limit, the dissolution becomes slower and the 45-min dissolution rate does not reach 85%. From Examples 1, 4, 5 and Comparative Examples 3 and 4, it can be seen that the amount of tara gum and sodium caseinate affects the speed of dissolution. The more the amount, the slower the dissolution. When the amount exceeds the protection limit, the dissolution rate is significantly inhibited. When the amount is too little, the content will be partially lost during the preparation process, and the final dissolution rate is only 90%.

[0079] From the results of the content and related substances investigation in Test Example 1 and the cumulative dissolution investigation results in Test Example 2, it can be seen that the dosage of Tristar NF stearate, taro gum and sodium caseinate plays an important role in the stability of the composition. A dosage below the protection range will lead to a decrease in content and an increase in related substances, but a dosage exceeding the protection range will limit dissolution.

Claims

1. A sacubitril-valsartan sodium tablet composition, characterized in that: Each 1000 tablets contain 100g of sacubitril / valsartan sodium, 30-40g of Tristar NF stearate, 6-10g of taro gum, 2-4g of sodium caseinate, 28-44g of microcrystalline cellulose, 16g of cross-linked sodium carboxymethyl cellulose, 2g of magnesium stearate, and 6g of gastric soluble film coating premix. The preparation steps of the composition include the following steps: Step 1: grind sacubitril / valsartan sodium and pass through a 100-mesh sieve; Step 2: Mix Tristar NF stearate and sacubitril valsartan sodium using a three-dimensional mixer; Step 3: Add the mixture obtained in step 2 into a hot melt extrusion granulator, the heating temperature for granulation is 60°C, the extrusion temperature is 15°C, and granules A are obtained; Step 4: Add taro gum and sodium caseinate into purified water to dissolve as an adhesive solution for later use; Step 5: using the binder solution prepared in step 4 to perform fluidized bed granulation on particles A, microcrystalline cellulose and croscarmellose sodium to obtain particles B; Step 6: Add magnesium stearate to granules B and mix using a three-dimensional mixer; Step 7: Punch out tablets with φ8 mm circular shallow depressions and apply film coating.

2. The sacubitril-valsartan sodium tablet composition according to claim 1, characterized in that Each 1,000 tablets contains 100g of sacubitril / valsartan sodium, 35g of Tristar NF stearate, 8g of taro gum, 3g of sodium caseinate, 36g of microcrystalline cellulose, 16g of cross-linked sodium carboxymethyl cellulose, 2g of magnesium stearate, and 6g of gastric film coating premix.

3. The sacubitril-valsartan sodium tablet composition according to claim 1, characterized in that: In step 2, the rotation speed of the three-dimensional mixer is 10 to 20 Hz, and the mixing time is 15 to 30 minutes.

4. The sacubitril-valsartan sodium tablet composition according to claim 1, characterized in that: In step 5, the inlet air temperature of the fluidized bed granulation is 45-55°C, and the inlet air volume is 15-20m 3 / h, the atomization pressure is 0.5~1.0Bar, and particles B are obtained.

5. The sacubitril-valsartan sodium tablet composition according to claim 1, characterized in that: In step 6, the mixing speed of the three-dimensional mixer is 10 Hz, and the mixing time is 5 min.

6. The sacubitril-valsartan sodium tablet composition according to claim 1, characterized in that: The hardness of the tablet in step 7 is 60~100N.

Images