Coated compound tablet

Abstract

The invention relates to a coated compound tablet, in particular to a quick-release composition, which comprises a first active layer, a second active layer and a coating 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, and the coating layer is coated on the first active layer. The coating layer contains a coating material that is mainly composed of a cellulose derivative, a polyvinyl alcohol, and an aqueous acrylic resin, and the immediate release composition is capable of achieving a desired elution.

Description

[0001] This application claims the priority of Chinese Patent Application No. 2024101265395 with a filing date of January 30, 2024, and Chinese Patent Application No. 2024117717299 with a filing date of December 4, 2024. This application incorporates the entire text of the above-mentioned Chinese patent applications by reference. Technical Field

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

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

[0004]

[0005] Amlodipine or its salt, such as amlodipine besylate, is a calcium channel blocker (CCB) and can be used to treat hypertension, angina pectoris, etc. The marketed amlodipine tablets (NORVASC) contain the following excipients: microcrystalline cellulose, calcium hydrogen phosphate, sodium carboxymethyl starch, and magnesium stearate, and are usually uncoated.

[0006] In the treatment of hypertension, the combined use of an angiotensin receptor inhibitor (ARB) and a calcium channel blocker (CCB) is a conventional regimen. Existing studies have shown that the combination of the two may have a certain synergistic effect, and different ratios of the combination of the two drugs have different synergistic effects. For the same calcium channel antagonist, such as amlodipine, there are also significant differences in the dosage ratios required to achieve a better synergistic effect when combined with different types of ARBs.

[0007] 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 a specification of 200 mg / 5 mg.

[0008] The prior art has not reported the preparation of a compound preparation of sacubitril / valsartan sodium and amlodipine, especially an immediate-release tablet.

[0009] Document 1: CN 116211814 A. Summary of the Invention

[0010] To solve the problems existing in the prior art, a first aspect of the present invention provides an immediate-release composition, which comprises a first active layer, a second active layer and a coating layer;

[0011] The first active layer contains sacubitril / valsartan or its salt and pharmaceutically acceptable additives;

[0012] The second active layer contains amlodipine or its salt and pharmaceutically acceptable additives.

[0013] The coating layer contains a coating material mainly composed of any one selected from cellulose derivatives, polyvinyl alcohol and aqueous acrylic resins. The coating material can be one kind, or a combination of two or more kinds.

[0014] In a preferred embodiment of the present invention, the cellulose derivative coating material is optionally selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose and ethylcellulose.

[0015] In a preferred embodiment of the present invention, the aqueous acrylic resin is selected from Eudragit @ EPO.

[0016] In a preferred embodiment of the present invention, the cellulose derivative coating material is optionally selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose and methylcellulose.

[0017] In a preferred embodiment of the present invention, the coating layer contains a coating material optionally selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, ethylcellulose, polyvinyl alcohol and Eudragit @ EPO.

[0018] The immediate-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.

[0019] In a preferred embodiment of the present invention, the immediate-release composition is a double-layer tablet, and the layer weight ratio of the first active layer to the second active layer is 0.2 - 6:1; preferably the layer weight ratio is 0.2 - 5.5:1; preferably the layer weight ratio is 0.2 - 5:1.

[0020] The immediate-release composition of the present invention contains a coating layer, and the coating is selected from film coating, preferably gastric-soluble film coating. Coating usually slows down dissolution, but the coating layer of the present invention using cellulose derivatives, polyvinyl alcohol and aqueous acrylic resins as the main coating materials has no effect on the dissolution of the immediate-release composition, especially has no effect on the dissolution of amlodipine, and can increase the total dissolution amount of amlodipine to a certain extent.

[0021] In a preferred embodiment of the present invention, the immediate-release composition is a coated bilayer tablet.

[0022] In the immediate-release composition of the present invention, in a unit dosage form, calculated as the free form, the amount of amlodipine or its salt contained in the immediate-release composition is 2.5 mg - 5 mg; the amount of sacubitril / valsartan or its salt is 200 mg - 400 mg.

[0023] In a preferred embodiment of the present invention, the immediate-release composition contains 5 mg of amlodipine or its salt.

[0024] In a preferred embodiment of the present invention, the immediate-release composition contains 200 mg or 400 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 200 mg of sacubitril / valsartan or its salt.

[0026] 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.

[0027] 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 its salt.

[0028] In a preferred embodiment of the present invention, the second active layer of the immediate-release composition contains 5 mg of amlodipine or its salt.

[0029] In a preferred embodiment of the present invention, the immediate-release composition contains a first active layer and a second active layer; the first active layer contains sacubitril / valsartan or its salt and a pharmaceutically acceptable additive; the second active layer contains amlodipine or its salt and a pharmaceutically acceptable additive, and also contains sacubitril / valsartan or its salt.

[0030] In a preferred embodiment of the present invention, part of the sacubitril / valsartan or its salt can be placed in the second active layer. When the second active layer contains sacubitril / valsartan or its salt, the proportion of sacubitril / valsartan or its salt in the second active layer in the total weight of sacubitril / valsartan or its salt in the immediate-release composition does not exceed 80%.

[0031] In a preferred embodiment of the present invention, the proportion of sacubitril / valsartan or its salt in the second active layer, calculated as the free form, relative to the total weight of sacubitril / valsartan or its salt in the immediate-release composition, is 10% - 80%.

[0032] In the immediate-release composition of the present invention, the first active layer contains sacubitril / valsartan or its salt and pharmaceutically acceptable additives; the second active layer contains amlodipine or its salt and pharmaceutically acceptable additives; the additives in the first active layer or the second active layer include fillers, binders, disintegrants, glidants, and lubricants. The additives in the first active layer and the additives in the second active layer can be the same or different.

[0033] Suitable fillers of the present invention are optionally selected from one or more combinations of sucrose, lactose, glucose, starch, pregelatinized starch, microcrystalline cellulose, mannitol, sorbitol, calcium hydrogen phosphate; preferably microcrystalline cellulose, 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%.

[0034] In a preferred embodiment of the present invention, the filler in the immediate-release composition is optionally selected from one or more combinations of microcrystalline cellulose, mannitol, and pregelatinized starch.

[0035] In a preferred embodiment of the present invention, the filler in the immediate-release composition is optionally selected from microcrystalline cellulose.

[0036] Suitable disintegrants of the present invention are optionally selected from one or more combinations of starch, cellulose and its derivatives, polysaccharides, guar gum, crospovidone, sodium carboxymethyl starch, calcium carboxymethyl cellulose, sodium cross-linked carboxymethyl cellulose, calcium cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; the preferred disintegrants are crospovidone, sodium cross-linked carboxymethyl cellulose, low-substituted hydroxypropyl cellulose; the weight ratio of the disintegrant in the immediate-release composition is 0.1-30%; the preferred weight ratio of the disintegrant is 1-25%; the further preferred weight ratio of the disintegrant is 1-20%.

[0037] In a preferred embodiment of the present invention, in the immediate-release composition, the disintegrant is optionally selected from crospovidone, sodium cross-linked carboxymethyl cellulose, and calcium carboxymethyl cellulose.

[0038] Suitable binders of the present invention are optionally 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.; the preferred binders are low-substituted hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose; the weight ratio of the binder in the immediate-release composition is 0-30%; the preferred binder ratio is 1-25%, and the more preferred binder ratio is 1-20%.

[0039] In a preferred embodiment of the present invention, in the immediate-release composition, the binder is optionally selected from low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and ethyl cellulose.

[0040] The glidant and / or lubricant of the present invention is optionally selected from one or more of colloidal silicon dioxide, magnesium stearate, calcium stearate, stearic acid, talc powder, calcium phosphate, magnesium carbonate, polyethylene glycol, glyceryl behenate, glycerol monostearate, sodium stearyl fumarate, etc.; the preferred lubricant is colloidal silicon dioxide, magnesium stearate or talc powder; the preferred glidant is talc powder, magnesium stearate or colloidal silicon dioxide. The weight ratio of the glidant or lubricant in the immediate-release composition is 0.1-15%; the preferred 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%.

[0041] On the other hand, the present invention provides the use of sacubitril / valsartan or its salt and amlodipine or its salt in the preparation of a drug for treating cardiovascular diseases. The cardiovascular diseases described in the present invention include but are not limited to hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular disease, thrombosis, etc.

[0042] In a further preferred embodiment of the present invention, in the above use, calculated as the free form, it contains 400 mg or 200 mg of sacubitril / valsartan and 5 mg of amlodipine.

[0043] On the other hand, the present invention provides the use of any of the above immediate-release compositions in the preparation of a drug for treating cardiovascular diseases. The cardiovascular diseases described above include but are not limited to hypertension, heart disease, heart failure, angina pectoris, arrhythmia, cerebrovascular disease, thrombosis, etc.

[0044] On the other hand, the present invention provides a method for preparing a bilayer immediate-release preparation, especially for preparing a bilayer immediate-release tablet containing sacubitril / valsartan or its salt and amlodipine or its salt. The method includes the following steps:

[0045] Step 1: Mix sacubitril / valsartan or its salt with the required additives and then granulate;

[0046] Step 2: Mix amlodipine or its salt with the required additives and then granulate;

[0047] Step 3: Compress the granules from Step 1 and Step 2 into a bilayer tablet;

[0048] Step 4: Coating the bilayer tablet.

[0049] In a preferred embodiment of the present invention, the granulation method of the preparation method is preferably dry granulation.

[0050] In a preferred embodiment of the present invention, in step two, part of sacubitril / valsartan or its salt and amlodipine or its salt and the required additives are mixed and then granulated.

[0051] In a preferred embodiment of the present invention, in step four, the double-layer tablets are coated with a coating premix, and the coating material of the coating premix is arbitrarily selected from one or two or more combinations of cellulose derivatives, polyvinyl alcohol, and aqueous acrylic resins.

[0052] When sacubitril / valsartan sodium and amlodipine or its salt are prepared into an immediate-release composition, when the composition is a single-layer tablet, the dissolution of amlodipine or its salt is restricted and the dissolution becomes slower. When preparing the immediate-release composition of the present invention, especially a double-layer tablet, the problem that amlodipine cannot be released within the specified time due to the high viscosity of sacubitril / valsartan or its salt can be effectively avoided.

[0053] Since the common dosage of amlodipine or its salt is 2.5 mg or 5 mg, while the common dosage of sacubitril / valsartan or its salt is 200 mg or 400 mg, and the dosage difference between the two is large. When preparing a double-layer preparation, such as a double-layer tablet, there may be difficulties such as large differences in tablet weight and poor uniformity of the content of the drug active ingredient. In the present invention, by controlling the layer weight of the double-layer tablet within a certain ratio, or placing part of sacubitril / valsartan or its salt in the two layers of the double-layer tablet, the above problems can be effectively solved, and the problem of difficult swallowing caused by too large tablet weight can be avoided.

[0054] The present invention uses a coating material selected from cellulose derivatives, polyvinyl alcohol, and aqueous acrylic resins to coat the double-layer tablets, which can effectively reduce the water absorption and increase in impurity content in the double-layer tablets, especially in the amlodipine layer, and the coating material does not hinder the dissolution of amlodipine. Detailed implementation mode

[0055] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0056] The "sacubitril / valsartan or its salt" described in the present invention includes sacubitril / valsartan sodium salt and its hydrate, sacubitril / valsartan potassium salt and its hydrate.

[0057] The "amlodipine or its salt" described in the present invention includes p-toluenesulfonate and benzenesulfonate of amlodipine; the amlodipine includes levamlodipine.

[0058] Example 1 - Preparation of plain tablets

[0059] Refer to the following prescription to prepare double-layer tablets of sacubitril / valsartan sodium and amlodipine p-toluenesulfonate

[0060]

[0061]

[0062] Preparation of bilayer tablets:

[0063] Step 1) Preparation of the first-layer granules: Mix sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked povidone, talc, and magnesium stearate; perform dry granulation, and mix thoroughly with the additional excipients for later use.

[0064] Step 2) Preparation of the second-layer granules: Mix sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, amlodipine besylate, low-substituted hydroxypropyl cellulose, cross-linked povidone, talc, and magnesium stearate; perform dry granulation, and mix thoroughly with the additional excipients for later use.

[0065] Step 3) Perform bilayer tabletting on the first layer and the second layer.

[0066] Example 2 - Preparation of plain tablets

[0067] Prepare bilayer tablets of sacubitril / valsartan sodium and amlodipine tosylate with reference to the prescription in the following table

[0068]

[0069]

[0070] Preparation of bilayer tablets:

[0071] Step 1) Preparation of the first-layer granules: Mix sacubitril / valsartan sodium, colloidal silicon dioxide, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked povidone, talc, and magnesium stearate; perform dry granulation, and mix thoroughly with the additional excipients for later use.

[0072] Step 2) Preparation of the second-layer granules: Mix amlodipine besylate, mannitol, microcrystalline cellulose, hydroxypropyl cellulose, carboxymethylcellulose calcium, and magnesium stearate for later use.

[0073] Step 3) Perform bilayer tabletting on the first layer and the second layer.

[0074] Example 3 - Preparation of coated tablets

[0075] Step 1) Preparation of the coating solution: Weigh the gastric-soluble film coating premix (containing: hydroxypropyl methylcellulose (main component), titanium dioxide, polyethylene glycol, talc, red iron oxide, black iron oxide), add it to purified water under stirring conditions and stir until it is completely dispersed, stir for more than 45 minutes, and set aside for later use.

[0076] Step 2) Coating the double-layer plain tablets to obtain coated tablets, with a coating weight gain of about 2.25%.

[0077] Referring to the above method, the double-layer plain tablets 1-1 were coated with different film coating premixes as follows:

[0078]

[0079]

[0080] Stability test

[0081] Stability test method for tablets: The samples were placed in an open condition under light of 4500 lx ± 500 lx for 30 days, and the related substances were examined at 0 day and 30 days respectively. The test results are as follows:

[0082]

[0083] Note: " / " represents not detected.

[0084] The results show that the coated tablets can significantly reduce the content of degradation impurities and unknown total impurities of amlodipine compared with the plain tablets. And among different coating materials, compared with coating with Eudragit@L30D-55, coating with hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, Eudragit @ EPO has better stability.

[0085] Dissolution test

[0086] Using 900 ml of pH 4.5 acetate buffer solution as the dissolution medium (37 °C), the rotation speed was 75 revolutions per minute, and the operation was carried out according to the law. At 45 minutes, 5 ml of the solution was taken and filtered to determine the total dissolution amount of amlodipine. The test results are as follows (%):

[0087]

[0088] Using 900 ml of pH 6.8 phosphate buffer solution as the dissolution medium (37 °C), the rotation speed was 75 revolutions per minute, and the operation was carried out according to the law. At 45 minutes, 5 ml of the solution was taken and filtered to determine the total dissolution amount of amlodipine. The test results are as follows (%):

[0089]

[0090] Under acidic or neutral pH conditions, coating with hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, Eudragit @ EPO, etc., amlodipine has a more excellent dissolution amount, while Eudragit @L30D-55 has no obvious effect on dissolution.

[0091] Hygroscopicity test

[0092] Hygroscopicity test method for tablets: Place each sample in an environment with 70% RH humidity for 1 h, 8 h, and 24 h, and then detect the weight gain of the sample due to moisture absorption. The weight gain due to moisture absorption = (weight of the sample after moisture absorption - initial weight of the sample) / initial weight of the sample. The test results are as follows:

[0093]

[0094] In the hygroscopicity test, when coated with hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, ethylcellulose, polyvinyl alcohol, Eudragit @ EPO, etc., the tablets have excellent non-hygroscopic properties.

[0095] Example 4

[0096] Prepare the following bilayer tablets by referring to the same preparation method as in the reference example.

[0097]

[0098] Determination of content uniformity:

[0099] Take 10 test samples, and according to the methods specified in each variety item, respectively determine the relative content x1, x2,..., xn of each single dose with the labeled amount as 100, calculate the content mean value and standard deviation S, and the absolute value of the difference between the labeled amount 100 and the calculated value is A. Judgment criterion: A + 2.2S ≤ 15.

[0100] A + 2.2S Sacubitril and valsartan sodium Amlodipine besylate Tablet 4-1 5.5 18.2 Tablet 4-2 6.0 14.1 Tablet 4-3 5.8 9.5 Tablet 4-4 5.6 14.8

[0101] Judging from the content uniformity data, when the content of sacubitril / valsartan sodium is 400 mg or 200 mg and the content of amlodipine is 5 mg, the weight ratio of the two drug active ingredients is relatively large. When the proportion of sacubitril / valsartan sodium in this layer remains unchanged, the layer weight ratio of the sacubitril / valsartan sodium layer to the amlodipine layer reaches 8:1. During the tablet preparation process, the large layer weight difference will significantly affect the process stability of the tablets. In particular, the content uniformity of the amlodipine layer cannot meet the requirements and has an adverse effect on dissolution. When the bilayer weight ratio is controlled within 5:1 (sacubitril / valsartan sodium layer: amlodipine layer), satisfactory content uniformity (A + 2.2S not higher than 15) can be obtained.

Claims

1. A rapid-release composition, characterized in that, The immediate-release composition contains a first active layer, a second active layer and a coating layer. The first active layer contains sacubitril / valsartan or its salt and a pharmaceutically acceptable additive. The second active layer contains amlodipine or its salt and a pharmaceutically acceptable additive. The coating layer contains a coating material mainly composed of a cellulose derivative, polyvinyl alcohol and an aqueous acrylic resin.

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

3. The immediate 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, wherein the immediate-release composition comprises a first active layer, a second active layer, and a coating layer. The first active layer contains sacubitril / valsartan or its salt and a pharmaceutically acceptable additive. The second active layer contains amlodipine or its salt and a pharmaceutically acceptable additive. The coating layer contains a coating material selected from hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, ethylcellulose, polyvinyl alcohol, and Eudragit @ EPO.

5. The immediate-release composition according to claim 1, wherein the immediate-release composition contains 200 mg or 400 mg of sacubitril / valsartan or its salt.

6. The immediate-release composition according to claim 1, wherein the immediate-release composition contains 2.5 mg or 5 mg of amlodipine or its salt.

7. The immediate-release composition according to claim 1, which is a coated double-layer tablet.

8. The immediate-release composition according to claim 1, wherein the layer weight ratio of the first active layer to the second active layer is 0.2-6:

1.

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

1.

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

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