Fnerenone oral sustained-release dry suspension and preparation method thereof

Abstract

The invention discloses a fenerenone oral sustained-release dry suspension, which comprises particles, and a coating layer and a suspending aid layer which are sequentially coated on the surfaces of the particles, the granules are prepared from the following raw materials in parts by weight: 18 to 22 parts of fenerenone, 90 to 110 parts of microcrystalline cellulose, 76 to 80 parts of lactose monohydrate, 50 to 54 parts of hydroxypropyl methylcellulose, 8 to 10 parts of croscarmellose sodium and 0.8 to 1.2 parts of lauryl sodium sulfate. The invention also discloses a preparation method of the oral slow-release dry suspension of the fenerenone. According to the invention, auxiliary materials are matched with one another, so that the oral slow-release finerenone dry suspension has good slow-release performance and stability.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a finerenone oral sustained-release dry suspension and a preparation method thereof. Background Art

[0002] Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist used to treat diabetic nephropathy and heart failure, and can reduce the risk of persistent estimated glomerular filtration rate decline, end-stage renal disease, non-fatal myocardial infarction, and hospitalization for heart failure related to type 2 diabetes in adult patients with chronic kidney disease. Finerenone can prevent excessive activation of mineralocorticoid receptors from causing multiple kidney injuries and the resulting inflammatory diseases and fibrotic processes, as well as the pathogenic factors of cardiovascular damage.

[0003] Finerenone is currently available in the form of a fast-acting oral tablet, which is taken once a day. For patients with diabetic nephropathy, heart failure and end-stage renal disease, it needs to be taken for a long time. The instructions describe that for patients who cannot swallow the whole tablet, the finerenone tablet needs to be crushed and mixed with water before oral administration, and the frequency of taking it is not low, which makes its oral compliance poor.

[0004] In addition, finerenone tablets can irritate the stomach. Patients often experience upper abdominal pain, and acid reflux and belching are also common, which affects the patient's appetite and quality of life. In addition, finerenone is unstable in light, heat, acid and other environments, so it is necessary to provide a new dosage form and maintain the quality stability of finerenone. Summary of the invention

[0005] Based on the technical problems existing in the background technology, the present invention provides a finerenone oral sustained-release dry suspension and a preparation method thereof. The present invention can make the finerenone oral sustained-release dry suspension have good sustained-release performance and stability through the coordination of auxiliary materials.

[0006] The invention provides a finerenone oral sustained-release dry suspension, comprising: particles, and a coating layer and a suspending layer sequentially coated on the surface of the particles, wherein the raw materials of the particles comprise, by weight, 18-22 parts of finerenone, 90-110 parts of microcrystalline cellulose, 76-80 parts of lactose monohydrate, 50-54 parts of hypromellose, 8-10 parts of cross-linked sodium carboxymethyl cellulose, and 0.8-1.2 parts of sodium lauryl sulfate.

[0007] Preferably, the D 90 The particle size is 100-150μm.

[0008] Preferably, the material of the coating layer is a protective coating agent.

[0009] Preferably, the materials of the coating layer include: polymer, sodium lauryl sulfate, stearic acid and pigment.

[0010] Preferably, the weight ratio of polymer, sodium lauryl sulfate, stearic acid and pigment is 38-42:3.5-4.5:5.5-6.5:37-41.

[0011] Preferably, the polymer is Eudragit® EPO, which is commercially available from Evonik.

[0012] The pigment may be at least one of talc, titanium dioxide, red iron oxide and the like.

[0013] Preferably, the materials of the suspending layer are xanthan gum and pectin.

[0014] Preferably, the weight ratio of xanthan gum to pectin is 4-5:1.

[0015] Preferably, the weight ratio of finerenone to coating layer material is 18-22:84-94.

[0016] Preferably, the weight ratio of finerenone to the suspension layer material is 18-22:2-4.

[0017] The above-mentioned hypromellose may be hypromellose K4M or the like.

[0018] The invention also discloses a preparation method of the finerenone oral sustained-release dry suspension, comprising the following steps: dissolving sodium lauryl sulfate and hydroxypropyl methylcellulose in water, adding finerenone and mixing, to obtain suspension A; mixing microcrystalline cellulose, lactose monohydrate and cross-linked sodium carboxymethyl cellulose, spraying the suspension A, and performing fluidized bed granulation to obtain particles; coating the particles with a coating liquid, and then coating them twice with a suspending agent solution, and drying to obtain the finerenone oral sustained-release dry suspension.

[0019] Preferably, during fluidized bed granulation, the inlet air temperature is 55-65°C, the exhaust air temperature is 40-45°C, the peristaltic speed is 10-15 rpm, and the fan frequency is 25-35 Hz.

[0020] Preferably, the weight ratio of hypromellose to water is 1:4.5-4.9.

[0021] Preferably, the mass fraction of the suspending agent solution is 2-4wt%.

[0022] Preferably, the mass fraction of the coating liquid is 20-22wt%.

[0023] The water mentioned above can be deionized water, purified water, etc.

[0024] The solute of the coating solution is the coating layer material, and the suspending agent is the suspending layer material.

[0025] The present invention selects hypromellose as a sustained-release material and cooperates with microcrystalline cellulose, lactose monohydrate and cross-linked sodium carboxymethyl cellulose to prepare particles loaded with finerenone; the particles can have a narrow particle size distribution and maintain the uniformity of the particle size; and the finerenone can maintain good quality stability; and the light-shielding performance can be further improved by coating treatment, and the stability of the finerenone can be further improved;

[0026] In addition, the invention selects xanthan gum and pectin to cooperate with each other in an appropriate ratio, which can, on the one hand, enable the particles to maintain a stable suspension state in the aqueous solution, so as to facilitate administration; on the other hand, both xanthan gum and pectin contain acetyl groups, which can form a hydrogen bond cross-linking network in an acidic environment, thereby inhibiting the release of finerenone in gastric juice, and in an alkaline environment, the hydrogen bond becomes weak, and can cooperate with hydroxypropyl methylcellulose, so that finerenone can be slowly released in the intestine, thereby solving the problem of patient compliance with medication, and can allow finerenone to maintain a stable concentration in the body, thereby reducing the occurrence of toxic and side effects. DETAILED DESCRIPTION

[0027] The technical solution of the present invention is described in detail below through specific embodiments.

[0028] Example 1

[0029] A finerenone oral sustained-release dry suspension, comprising: particles, and a coating layer and a suspending layer sequentially coated on the surface of the particles, wherein the raw materials of the particles include, by weight: 20g of finerenone, 110g of microcrystalline cellulose, 76g of lactose monohydrate, 54g of hypromellose K4M, 8g of cross-linked sodium carboxymethyl cellulose, and 1.2g of sodium lauryl sulfate;

[0030] The coating layer material is composed of Eudragit EPO, sodium lauryl sulfate, stearic acid and pigment in a weight ratio of 40:4:6:39; wherein the pigment is composed of talcum powder, titanium dioxide and red iron oxide in a weight ratio of 19:10:10;

[0031] The materials of the suspension layer are xanthan gum and pectin, wherein the weight ratio of xanthan gum to pectin is 4:1;

[0032] The weight ratio of finerenone to coating material is 20:89;

[0033] The weight ratio of finerenone to the suspension layer material is 20:2.

[0034] The preparation method of the finerenone oral sustained-release dry suspension comprises the following steps: weighing the raw materials according to the above formula, dissolving sodium lauryl sulfate and hydroxypropyl methylcellulose in 500 g of water, and then adding finerenone and mixing to obtain a suspension A;

[0035] Mix microcrystalline cellulose, lactose monohydrate and cross-linked sodium carboxymethyl cellulose, put them into a fluidized bed, adjust the inlet air temperature to 55°C, the exhaust air temperature to 40°C, the peristaltic speed to 15rpm, and the fan frequency to 30Hz, spray the suspension A into the fluidized bed, and perform fluidized bed granulation to obtain D 90 Particles with a particle size of 140 μm;

[0036] The coating layer material is dissolved in water to prepare a coating solution with a total mass fraction of 21 wt%, and the particles are continuously subjected to fluidized bed coating in a fluidized bed;

[0037] Then, the suspending agent is dissolved in water to prepare a suspending solution with a mass fraction of 3 wt%, and secondary coating is performed in a fluidized bed and dried to obtain finerenone oral sustained-release dry suspension.

[0038] Example 2

[0039] A finerenone oral sustained-release dry suspension, comprising: particles, and a coating layer and a suspending layer sequentially coated on the surface of the particles, wherein the raw materials of the particles include, by weight: 20g of finerenone, 90g of microcrystalline cellulose, 80g of lactose monohydrate, 50g of hypromellose K4M, 10g of cross-linked sodium carboxymethyl cellulose, and 0.8g of sodium lauryl sulfate;

[0040] The coating layer material is composed of Eudragit EPO, sodium lauryl sulfate, stearic acid and pigment in a weight ratio of 40:4:6:39; wherein the pigment is composed of talcum powder, titanium dioxide and red iron oxide in a weight ratio of 19:10:10;

[0041] The materials of the suspension layer are xanthan gum and pectin, wherein the weight ratio of xanthan gum to pectin is 5:1;

[0042] The weight ratio of finerenone to coating material is 20:89;

[0043] The weight ratio of finerenone to the suspension layer material was 20:4.

[0044] The preparation method of the finerenone oral sustained-release dry suspension comprises the following steps: weighing the raw materials according to the above formula, dissolving sodium lauryl sulfate and hydroxypropyl methylcellulose in 500 g of water, and then adding finerenone and mixing to obtain a suspension A;

[0045] Mix microcrystalline cellulose, lactose monohydrate and cross-linked sodium carboxymethyl cellulose, put them into a fluidized bed, adjust the inlet air temperature to 65°C, the exhaust air temperature to 45°C, the peristaltic speed to 12 rpm, and the fan frequency to 25 Hz, spray the suspension A into the fluidized bed, and perform fluidized bed granulation to obtain D 90 Particles with a particle size of 110 μm;

[0046] The coating layer material is dissolved in water to prepare a coating solution with a total mass fraction of 21 wt%, and the particles are continuously subjected to fluidized bed coating in a fluidized bed;

[0047] Then, the suspending agent is dissolved in water to prepare a suspending solution with a mass fraction of 3 wt%, and secondary coating is performed in a fluidized bed and dried to obtain finerenone oral sustained-release dry suspension.

[0048] Example 3

[0049] A finerenone oral sustained-release dry suspension, comprising: particles, and a coating layer and a suspending layer sequentially coated on the surface of the particles, wherein the raw materials of the particles include, by weight: 20g of finerenone, 100g of microcrystalline cellulose, 78g of lactose monohydrate, 52g of hypromellose K4M, 9g of cross-linked carboxymethyl cellulose sodium, and 1g of sodium lauryl sulfate;

[0050] The coating layer material is composed of Eudragit EPO, sodium lauryl sulfate, stearic acid and pigment in a weight ratio of 40:4:6:39; wherein the pigment is composed of talcum powder, titanium dioxide and red iron oxide in a weight ratio of 19:10:10;

[0051] The materials of the suspension layer are xanthan gum and pectin, wherein the weight ratio of xanthan gum to pectin is 4.5:1;

[0052] The weight ratio of finerenone to coating material is 20:89;

[0053] The weight ratio of finerenone to the suspension layer material is 20:3.

[0054] The preparation method of the finerenone oral sustained-release dry suspension comprises the following steps: weighing the raw materials according to the above formula, dissolving sodium lauryl sulfate and hydroxypropyl methylcellulose in 500 g of water, and then adding finerenone and mixing to obtain a suspension A;

[0055] Mix microcrystalline cellulose, lactose monohydrate and cross-linked sodium carboxymethyl cellulose, put them into a fluidized bed, adjust the inlet air temperature to 60°C, the exhaust air temperature to 45°C, the peristaltic speed to 11rpm, and the fan frequency to 25Hz, spray the suspension A into the fluidized bed, and perform fluidized bed granulation to obtain D 90 Particles with a particle size of 115 μm;

[0056] The coating layer material is dissolved in water to prepare a coating solution with a total mass fraction of 21 wt%, and the particles are continuously subjected to fluidized bed coating in a fluidized bed;

[0057] Then, the suspending agent is dissolved in water to prepare a suspending solution with a mass fraction of 3 wt%, and secondary coating is performed in a fluidized bed and dried to obtain finerenone oral sustained-release dry suspension.

[0058] Comparative Example 1-2

[0059] Hydroxypropyl methylcellulose K4M was replaced with hydroxypropyl cellulose and polylactic acid-glycolic acid copolymer in sequence, and the other particles were prepared according to the method of Example 3. It was found that the particles prepared in Comparative Examples 1-2 had different particle sizes, uneven particle size distribution, and the particles were easy to stick together.

[0060] Comparative Example 3

[0061] The microcrystalline cellulose was replaced with pregelatinized starch, and the granules were prepared according to the method of Example 3. It was found that the granules were relatively hard.

[0062] Comparative Example 4

[0063] Lactose monohydrate was replaced with corn starch, and granules were prepared according to the method of Example 3. It was found that there was a lot of fine powder and the particle size distribution of the granules was uneven.

[0064] It can be seen from the above results that the use of microcrystalline cellulose, lactose monohydrate, and hypromellose K4M in combination can make the particles have a narrower particle size distribution and maintain the uniformity of the particle size.

[0065] Comparative Example 5

[0066] The material of the suspending layer was xanthan gum, and the other procedures were carried out according to the method of Example 3 to prepare finerenone oral sustained-release dry suspension.

[0067] Comparative Example 6

[0068] The material of the suspending layer was pectin, and the other procedures were carried out according to the method of Example 3 to prepare finerenone oral sustained-release dry suspension.

[0069] Comparative Example 7

[0070] The xanthan gum in the suspending layer material was replaced with sodium alginate, and the finerenone oral sustained-release dry suspension was prepared according to the method of Example 3.

[0071] Comparative Example 8

[0072] The finerenone oral sustained-release dry suspension was prepared according to the method of Example 3 except that the pectin in the suspending layer material was replaced with sodium alginate.

[0073] Example 3 and Comparative Examples 5-8 were taken to test the sedimentation volume ratio and dispersibility of each group.

[0074] It was found that: the sedimentation volume ratio of Example 3 was 0.98, it was quickly dispersed after adding water and shaking, it did not form cakes after sedimentation, and it was quickly dispersed after shaking; while the sedimentation volume ratios of Comparative Examples 5-8 were all less than 0.9, and they could be quickly dispersed after adding water and shaking, but they were easy to form cakes after sedimentation and could not be evenly dispersed after shaking.

[0075] It can be seen from the above results that the combination of xanthan gum and pectin can make the particles maintain good dispersibility and stability in water.

[0076] Comparative Examples 9-10

[0077] Sodium dodecyl sulfate was replaced with poloxamer and polyvinyl alcohol in sequence, and finerenone oral sustained-release dry suspension was prepared according to the method of Example 3 for other preparations.

[0078] Comparative Example 11

[0079] Finerenone oral sustained-release dry suspension was prepared according to the method of Example 3 except that cross-linked sodium carboxymethyl cellulose was replaced by sodium carboxymethyl starch.

[0080] The finerenone oral sustained-release dry suspension prepared in Examples 1-3 and Comparative Examples 9-11 was subjected to a dissolution test.

[0081] The dissolution method is: paddle method 50rpm, sampling time is 1, 2, 3, 4, 6, 8, 10, 12, 16, 20h, dissolution medium is pH 6.8 phosphate aqueous solution, medium volume is 900ml, temperature is 37°C. The timing starts when the sample is added, 10ml is sampled at the set time point, and the dissolution medium is supplemented with isothermal and equal volume. The sample is filtered to obtain the test solution, and the finerenone content is detected. The results are described in Table 1.

[0082] Table 1 Cumulative dissolution of finerenone oral sustained-release dry suspension

[0083] Cumulative dissolution % Example 1 Example 2 Example 3 Comparative Example 9 Comparative Example 10 Comparative Example 11 1h 10.83 23.25 14.67 28.43 29.37 36.60 2h 19.87 48.83 24.86 46.58 45.57 50.49 3h 32.34 59.91 39.71 63.64 65.36 70.68 4h 42.30 68.69 51.02 82.37 84.76 82.11 6h 52.32 82.01 60.14 90.56 91.37 90.57 8h 62.84 91.12 73.64 93.44 95.37 95.60 10h 70.66 96.89 82.95 96.68 98.65 97.43 12h 81.65 97.37 88.59 98.37 98.96 98.56 16h 86.59 98.25 92.20 98.50 99.37 99.37 20h 90.37 98.37 96.14 99.05 99.56 99.26

[0084] It can be seen from Table 1 that the finerenone oral sustained-release dry suspension prepared by the present invention has no burst release phenomenon. From the perspective of cumulative release, the release curve is relatively gentle, close to "zero-order release"; the overall release time is about 20 hours, and the drug release period is significantly extended compared with the finerenone oral tablets; while Comparative Examples 9-11 have a burst release phenomenon, and the release curve is steep, which is not "zero-order release".

[0085] The finerenone oral sustained-release dry suspension prepared in Example 3 was tested for influencing factors according to the requirements of the Chinese Pharmacopoeia. The results are shown in Table 2.

[0086] Table 2 Test results of influencing factors

[0087]

[0088] It can be seen from Table 2 that the finerenone oral sustained-release dry suspension prepared in the present invention has good quality stability.

[0089] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A finerenone oral sustained-release dry suspension, characterized in that: include: The particles and the coating layer and the suspension layer sequentially coated on the surface of the particles, wherein the raw materials of the particles include, by weight: 18-22 parts of finerenone, 90-110 parts of microcrystalline cellulose, 76-80 parts of lactose monohydrate, 50-54 parts of hypromellose, 8-10 parts of cross-linked sodium carboxymethyl cellulose, and 0.8-1.2 parts of sodium lauryl sulfate.

2. The finerenone oral sustained-release dry suspension according to claim 1, characterized in that: Particle D 90 The particle size is 100-150μm.

3. The finerenone oral sustained-release dry suspension according to claim 1 or 2, characterized in that: The material of the coating layer is a protective coating agent; preferably, the material of the coating layer includes: polymer, sodium lauryl sulfate, stearic acid and pigment; preferably, the weight ratio of polymer, sodium lauryl sulfate, stearic acid and pigment is 38-42:3.5-4.5:5.5-6.5:37-41; preferably, the polymer is Eudragit EPO.

4. The finerenone oral sustained-release dry suspension according to any one of claims 1 to 3, characterized in that: The materials of the suspension layer are xanthan gum and pectin; preferably, the weight ratio of xanthan gum to pectin is 4-5:

1.

5. The finerenone oral sustained-release dry suspension according to any one of claims 1 to 4, characterized in that: The weight ratio of finerenone to coating layer material is 18-22:84-94.

6. The finerenone oral sustained-release dry suspension according to any one of claims 1 to 5, characterized in that: The weight ratio of finerenone to the suspension layer material is 18-22:2-4.

7. A method for preparing the finerenone oral sustained-release dry suspension according to any one of claims 1 to 6, characterized in that: The method comprises the following steps: dissolving sodium lauryl sulfate and hydroxypropyl methylcellulose in water, adding finerenone and mixing evenly to obtain suspension A; mixing microcrystalline cellulose, lactose monohydrate and cross-linked sodium carboxymethyl cellulose evenly, spraying the suspension A into the suspension, and performing fluidized bed granulation to obtain particles; coating the particles with a coating liquid, and then coating them twice with a suspending agent solution, and drying to obtain finerenone oral sustained-release dry suspension.

8. The method for preparing finerenone oral sustained-release dry suspension according to claim 5, characterized in that: During fluidized bed granulation, the inlet air temperature is 55-65°C, the exhaust air temperature is 40-45°C, the peristaltic speed is 10-15rpm, and the fan frequency is 25-35Hz; preferably, the weight ratio of hypromellose to water is 1:9.2-10.

9. The method for preparing finerenone oral sustained-release dry suspension according to claim 5, characterized in that: The mass fraction of the suspending agent solution is 2-4wt%.

10. The method for preparing finerenone oral sustained-release dry suspension according to claim 5, characterized in that: The mass fraction of the coating liquid is 20-22wt%.

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