Coated compound tablet

Abstract

The present invention relates to a coated compound tablet, and specifically to an immediate-release composition, comprising a first active layer, a second active layer, and a coating layer, wherein the first active layer comprises sacubitril valsartan or a salt thereof and a pharmaceutically acceptable additive thereof; the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive thereof; the coating layer comprises a coating material that is selected from a cellulose derivative, polyvinyl alcohol and waterborne acrylic resin as a main component. The immediate-release composition can achieve predicted dissolution.

Description

Coated compound tablets

[0001] This application claims priority to Chinese Patent Application No. 2024101265395, filed on January 30, 2024, and priority to Chinese Patent Application No. 2024117717299, filed on December 4, 2024. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention relates to the field of pharmaceutical preparations, and more particularly to a pharmaceutical composition containing therapeutically effective amounts of sacubitril / valsartan and amlodipine or a salt thereof. The present invention also relates to the use of the pharmaceutical composition in preparing a drug for treating cardiovascular diseases. Background Art

[0003] Sacubitril / valsartan sodium (also known as LCZ696) is a dual inhibitor of angiotensin II receptors and neprilysin, used to treat cardiovascular diseases, including hypertension and heart failure. The marketed formulation is an immediate-release tablet. The structural formula of sacubitril / valsartan sodium is as follows:

[0004] Amlodipine or its salts, such as amlodipine besylate, is a calcium channel blocker (CCB) that can be used to treat hypertension and angina pectoris. Marketed amlodipine tablets (NORVASC) contain the following excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium carboxymethyl starch, and magnesium stearate, and are usually uncoated.

[0005] The combination of angiotensin receptor inhibitors (ARBs) and calcium channel blockers (CCBs) is a common treatment for hypertension. Existing studies have shown that this combination may have a certain degree of synergy, and that different ratios of the two drugs have different synergistic effects. Furthermore, the dosage ratios required to achieve optimal synergistic effects when the same calcium channel blocker, such as amlodipine, is combined with different types of ARBs vary significantly.

[0006] Document 1 discloses a pharmaceutical composition containing sacubitril-valsartan sodium and amlodipine or its salt, wherein the ratio of sacubitril-valsartan sodium to amlodipine or its salt is 10-40:1. The specification examples disclose LCZ696-amlodipine sustained-release tablets with specifications of 200mg / 5mg.

[0007] The prior art has not reported the preparation of a compound preparation of sacubitril / valsartan sodium and amlodipine, especially a rapid-release tablet.

[0008] Document 1: CN 116211814 A. Summary of the Invention

[0009] In order to solve the problems existing in the prior art, the present invention provides a first aspect of a rapid-release composition, wherein the rapid-release composition comprises a first active layer, a second active layer and a coating layer;

[0010] The first active layer contains sacubitril / valsartan or its salt and pharmaceutically acceptable additives;

[0011] The second active layer contains amlodipine or its salt and pharmaceutically acceptable additives.

[0012] The coating layer contains a coating material selected from cellulose derivatives, polyvinyl alcohol and aqueous acrylic resin as main components. The coating material can be one or a combination of two or more.

[0013] In a preferred embodiment of the present invention, the cellulose derivative coating material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose.

[0014] In a preferred embodiment of the present invention, the water-based acrylic resin is selected from Eudragit @ EPO.

[0015] In a preferred embodiment of the present invention, the cellulose derivative coating material is selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, and methylcellulose.

[0016] In a preferred embodiment of the present invention, the coating layer contains a cellulose copolymer selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, ethylcellulose, polyvinyl alcohol and Eudragit. @ EPO coating material.

[0017] The rapid-release composition of the present invention can be a double-layer granule or a double-layer tablet; preferably a double-layer tablet; more preferably a coated double-layer tablet.

[0018] In a preferred embodiment of the present invention, the rapid-release composition is a bilayer tablet, and the layer weight ratio of the first active layer to the second active layer is 0.2-6:1; the preferred layer weight ratio is 0.2-5.5:1; and the preferred layer weight ratio is 0.2-5:1.

[0019] The rapid-release composition of the present invention comprises a coating layer selected from a film coating, preferably a gastric-soluble film coating. Coatings typically slow dissolution, but the coating layer of the present invention, which utilizes a cellulose derivative, polyvinyl alcohol, and an aqueous acrylic resin as primary coating materials, does not affect the dissolution of the rapid-release composition, particularly the dissolution of amlodipine, and can, to a certain extent, increase the total amount of amlodipine dissolved.

[0020] In a preferred embodiment of the present invention, the rapid-release composition is a coated double-layer tablet.

[0021] In the rapid-release composition of the present invention, in a unit preparation, the amount of amlodipine or its salt calculated as free form in the rapid-release composition is 2.5 mg-5 mg; the amount of sacubitril-valsartan or its salt is 200 mg-400 mg.

[0022] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt.

[0023] In a preferred embodiment of the present invention, the immediate-release composition contains 200 mg or 400 mg of sacubitril / valsartan or a salt thereof.

[0024] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt and 200 mg of sacubitril / valsartan or its salt.

[0025] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt and 400 mg of sacubitril / valsartan or its salt.

[0026] In a preferred embodiment of the present invention, the first active layer of the immediate-release composition contains 200 mg or 400 mg of sacubitril / valsartan or a salt thereof.

[0027] In a preferred embodiment of the present invention, the amount of amlodipine or its salt contained in the second active layer of the immediate-release composition is 5 mg.

[0028] In a preferred embodiment of the present invention, the rapid-release composition comprises a first active layer and a second active layer; the first active layer comprises sacubitril / valsartan or a salt thereof and a pharmaceutically acceptable additive; the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive, as well as sacubitril / valsartan or a salt thereof.

[0029] In a preferred embodiment of the present invention, a portion of sacubitril-valsartan or a salt thereof may be placed in the second active layer. When the second active layer contains sacubitril-valsartan or a salt thereof, the proportion of sacubitril-valsartan or a salt thereof in the second active layer to the total weight of sacubitril-valsartan or a salt thereof in the immediate-release composition does not exceed 80%.

[0030] In a preferred embodiment of the present invention, the proportion of sacubitril valsartan or its salt in the second active layer is 10%-80% relative to the total weight of sacubitril valsartan or its salt in the immediate-release composition, calculated as free form.

[0031] In the immediate-release composition of the present invention, the first active layer contains sacubitril / valsartan or a salt thereof and a pharmaceutically acceptable additive; the second active layer contains amlodipine or a salt thereof and a pharmaceutically acceptable additive; the additives in the first active layer or the second active layer include a filler, a binder, a disintegrant, a glidant, and a lubricant. The additives in the first active layer and the second active layer may be the same or different.

[0032] Suitable fillers of the present invention are selected from one or a combination of two or more of sucrose, lactose, glucose, starch, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, and calcium hydrogen phosphate; preferably microcrystalline cellulose and mannitol; the weight ratio of the filler in the immediate-release composition is 1.0%-70%; the preferred filler ratio is 1.0%-50%; the preferred filler ratio is 1.0%-45%, and the more preferred filler ratio is 5.0%-40%.

[0033] In a preferred embodiment of the present invention, the filler in the rapid-release composition is selected from one or a combination of two or more of microcrystalline cellulose, mannitol, and pregelatinized starch.

[0034] In a preferred embodiment of the present invention, the filler in the rapid-release composition is optionally selected from microcrystalline cellulose.

[0035] Suitable disintegrants of the present invention are selected from starch, cellulose and its derivatives, polysaccharides, guar gum, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, cross-linked calcium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose, or a combination of two or more thereof; preferred disintegrants are cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, and low-substituted hydroxypropyl cellulose; the weight ratio of the disintegrant in the rapid-release composition is 0.1-30%; preferably, the weight ratio of the disintegrant is 1-25%; and more preferably, the weight ratio of the disintegrant is 1-20%.

[0036] In a preferred embodiment of the present invention, in the rapid-release composition, the disintegrant is selected from cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, and carboxymethylcellulose calcium.

[0037] Suitable binders of the present invention are selected from one or more of starch, cellulose and its derivatives, polysaccharides, low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, etc.; preferred binders are low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, and ethyl cellulose; the weight ratio of the binder in the rapid-release composition is 0-30%; the preferred binder ratio is 1-25%, and the more preferred binder ratio is 1-20%.

[0038] In a preferred embodiment of the present invention, in the rapid-release composition, the binder is selected from low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and ethyl cellulose.

[0039] The glidant and / or lubricant of the present invention is arbitrarily selected from one or more of colloidal silicon dioxide, magnesium stearate, calcium stearate, stearic acid, talc, calcium phosphate, magnesium carbonate, polyethylene glycol, glyceryl behenate, glyceryl monostearate, sodium stearyl fumarate, and the like; preferably, the lubricant is colloidal silicon dioxide, magnesium stearate, or talc; preferably, the glidant is talc, magnesium stearate, or colloidal silicon dioxide. The weight ratio of the glidant or lubricant in the immediate-release composition is 0.1-15%; preferably, the weight ratio of the glidant or lubricant is 0.5-10%, and more preferably, the weight ratio of the glidant or lubricant is 0.5-5%.

[0040] In another aspect, the present invention provides a use of sacubitril / valsartan or a salt thereof and amlodipine or a salt thereof in preparing a medicament for treating cardiovascular diseases. The cardiovascular diseases described herein include, but are not limited to, hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular disease, thrombosis, and the like.

[0041] In a further preferred embodiment of the present invention, the use contains 400 mg or 200 mg of sacubitril / valsartan and 5 mg of amlodipine, calculated as free form.

[0042] In another aspect, the present invention provides a use of any of the above-mentioned rapid-release compositions in the preparation of a medicament for treating cardiovascular diseases, including but not limited to hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular disease, thrombosis, and the like.

[0043] In another aspect, the present invention provides a method for preparing a bilayer rapid-release formulation, particularly a bilayer rapid-release tablet containing sacubitril / valsartan or a salt thereof and amlodipine or a salt thereof. The method comprises the following steps:

[0044] Step 1: mixing sacubitril / valsartan or its salt with required additives and then granulating;

[0045] Step 2: mixing amlodipine or its salt with required additives and then granulating;

[0046] Step 3: compressing the granules from step 1 and step 2 into a double-layer tablet;

[0047] Step 4: coating the double-layer tablet.

[0048] In a preferred embodiment of the present invention, the granulation method of the preparation method is preferably dry granulation.

[0049] In a preferred embodiment of the present invention, in step 2, part of sacubitril / valsartan or its salt and amlodipine or its salt and required additives are mixed and then granulated.

[0050] In a preferred embodiment of the present invention, the double-layer tablet is coated with a coating premix in step 4, and the coating material of the coating premix is ​​optionally selected from one or a combination of two or more of cellulose derivatives, polyvinyl alcohol and aqueous acrylic resins.

[0051] When sacubitril-valsartan sodium and amlodipine or its salt are prepared into an immediate-release composition, the dissolution of amlodipine or its salt is restricted and slowed when the composition is a single-layer tablet. The immediate-release composition of the present invention, particularly a bilayer tablet, effectively avoids the problem of amlodipine not being released within the prescribed time due to the high viscosity of sacubitril-valsartan or its salt.

[0052] Since the common dosage of amlodipine or its salts is 2.5 mg or 5 mg, while the common dosage of sacubitril / valsartan or its salts is 200 mg or 400 mg, the significant difference in dosage between the two can lead to difficulties in preparing bilayer formulations, such as bilayer tablets, such as large differences in tablet weight and poor uniformity of the active pharmaceutical ingredient content. The present invention effectively addresses these issues by controlling the weight of the bilayer tablets within a certain ratio, or by placing a portion of sacubitril / valsartan or its salts in both layers of the bilayer tablets, thereby avoiding swallowing difficulties caused by excessive tablet weight.

[0053] The present invention uses a coating material selected from cellulose derivatives, polyvinyl alcohol and aqueous acrylic resin to coat the double-layer tablet, which can effectively reduce the water absorption and impurity content increase of the double-layer tablet, especially the amlodipine layer, and the coating material will not hinder the dissolution of amlodipine. DETAILED DESCRIPTION

[0054] The present invention is further described in detail below with reference to the examples, but the embodiments of the invention are not limited thereto. Unless otherwise specified, the experimental materials, reagents, and experimental animals used in the examples of the present invention can be obtained by conventional methods in the art.

[0055] The "sacubitril valsartan or its salt" mentioned in the present invention includes sacubitril valsartan sodium salt and its hydrate, sacubitril valsartan potassium salt and its hydrate.

[0056] The "amlodipine or its salt" described in the present invention includes p-toluenesulfonate and benzenesulfonate of amlodipine; the amlodipine described includes levoamlodipine.

[0057] Example 1 - Preparation of plain tablets

[0058] Refer to the following table for the preparation of bilayer tablets of sacubitril valsartan sodium and amlodipine p-toluenesulfonate

[0059] Preparation of bilayer tablets:

[0060] Step 1) Preparation of first layer granules: sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate are mixed; dry granulated, and mixed with external excipients for later use;

[0061] Step 2) Preparation of the second layer of granules: sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, amlodipine besylate, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate are mixed; dry granulation is performed, and the mixture is mixed with the added excipients and set aside;

[0062] Step 3) performing double-layer tableting on the first layer and the second layer;

[0063] Example 2 - Preparation of plain tablets

[0064] Refer to the following table for the preparation of bilayer tablets of sacubitril valsartan sodium and amlodipine p-toluenesulfonate

[0065] Preparation of bilayer tablets:

[0066] Step 1) Preparation of first layer granules: sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, talc, and magnesium stearate are mixed; dry granulated, and mixed with external excipients for later use;

[0067] Step 2) Preparation of the second layer of granules: Mix amlodipine besylate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethylcellulose calcium, and magnesium stearate and set aside;

[0068] Step 3) performing double-layer tableting on the first layer and the second layer;

[0069] Example 3 - Preparation of coated tablets

[0070] Step 1) Preparation of coating solution: Weigh a gastric soluble film coating premix (comprising hydroxypropyl methylcellulose (main ingredient), titanium dioxide, polyethylene glycol, talc, red iron oxide, and black iron oxide) and add it to purified water under stirring until completely dispersed. Stir for at least 45 minutes and set aside.

[0071] Step 2) coating the double-layer plain tablets to obtain coated tablets, with the coating weight gain being about 2.25%.

[0072] Referring to the above method, the double-layer plain tablet 1-1 was coated with different film coating premixes as follows:

[0073] Stability test

[0074] Tablet stability test method: Place the sample under light conditions of 4500lx±500lx and leave it open for 30 days. The relevant substances are tested at 0 day and 30 days respectively. The test results are as follows:

[0075] Note: “ / ” means not detected.

[0076] The results showed that the coated tablets could significantly reduce the content of degradation impurities and unknown total impurities of amlodipine compared with the plain tablets. Among the different coating materials, compared with Eudragit@L30D-55 coating, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, Eudragit @ EPO coating provides better stability.

[0077] Dissolution test

[0078] 900 ml of pH 4.5 acetate buffer was used as the dissolution medium (37°C) at a rotation speed of 75 rpm. The procedure was followed. After 45 minutes, 5 ml of the solution was filtered and the total amount of amlodipine dissolved was determined. The test results (%) are as follows:

[0079] 900 ml of pH 6.8 phosphate buffer was used as the dissolution medium (37°C) at 75 rpm. The dissolution was performed according to the procedure. After 45 minutes, 5 ml of the solution was filtered and the total amount of amlodipine dissolved was determined. The test results are as follows (%):

[0080] Under acidic or neutral pH conditions, use hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, Eudragit @ EPO coating, amlodipine has a better dissolution rate, while Eudragit @ L30D-55 had no significant effect on dissolution.

[0081] Hygroscopicity test

[0082] Tablet hygroscopicity test method: Each sample was placed in a 70% RH environment and the sample weight gain after 1 hour, 8 hours, and 24 hours was measured. The weight gain after hygroscopicity = (sample weight after hygroscopicity - initial sample weight) / initial sample weight. The test results are as follows:

[0083] In the hygroscopicity test, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, Eudragit @ EPO coating, etc., the tablets have excellent non-hygroscopic properties.

[0084] Example 4

[0085] The following double-layer tablets were prepared by the same preparation method as in Example 1.

[0086] Content uniformity determination:

[0087] Take 10 test samples and determine the relative content x1, x2, ..., xn of each single dose based on the labeled amount as 100 according to the method specified under each variety. Calculate the content mean and standard deviation S. The absolute value of the difference between the labeled amount and 100 is A. Judgment standard: A + 2.2S ≤ 15.

[0088] Judging from the content uniformity data, when the sacubitril-valsartan sodium content is 400mg or 200mg and the amlodipine content is 5mg, the weights of the two active pharmaceutical ingredients are relatively large. When the proportion of sacubitril-valsartan sodium in the layer remains unchanged, the layer weight ratio of the sacubitril-valsartan sodium layer to the amlodipine layer reaches 8:1. During tablet preparation, large layer weight differences will significantly affect the tablet's process stability, especially the content uniformity of the amlodipine layer will not meet requirements and will adversely affect dissolution. When the double-layer weight ratio is controlled within 5:1 (sacubitril-valsartan sodium layer:amlodipine layer), satisfactory content uniformity (A+2.2S no greater than 15) can be achieved.

Claims

1. A rapid-release composition, characterized in that The rapid-release composition comprises a first active layer, a second active layer and a coating layer, wherein the first active layer comprises sacubitril / valsartan or a salt thereof and a pharmaceutically acceptable additive, the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive, and the coating layer comprises a coating material mainly composed of cellulose derivatives, polyvinyl alcohol and aqueous acrylic resin.

2. The immediate-release composition according to claim 1, wherein the cellulose derivative is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and ethylcellulose.

3. The rapid-release composition according to claim 1, wherein the aqueous acrylic resin is selected from Eudragit @ EPO.

4. The immediate-release composition according to claim 1, comprising a first active layer, a second active layer and a coating layer, wherein the first active layer comprises sacubitril / valsartan or a salt thereof and a pharmaceutically acceptable additive, the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive, and the coating layer comprises a cellulose copolymer selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, ethylcellulose, polyvinyl alcohol and Eudragit. @ EPO coating material. The rapid-release composition according to claim 1 , comprising 200 mg or 400 mg of sacubitril / valsartan or a salt thereof. The immediate-release composition according to claim 1 , comprising 2.5 mg or 5 mg of amlodipine or a salt thereof. The rapid-release composition according to claim 1 , which is a coated double-layer tablet. 8 . The rapid-release composition according to claim 1 , wherein the weight ratio of the first active layer to the second active layer is 0.2-6:

1. 9 . The rapid-release composition according to claim 8 , wherein the weight ratio of the first active layer to the second active layer is 0.2-5.5:

1.

10. Use of the rapid-release composition according to any one of claims 1 to 9 in the preparation of a medicament for treating cardiovascular diseases; preferably, the cardiovascular diseases include hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular disease, and thrombosis.

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