Fnerenone capsule and preparation method thereof

Abstract

The invention provides a fenerenone capsule and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The finerenone capsule provided by the invention is prepared from the following components: finerenone, a carrier, a filling agent and a disintegrating agent, the carrier is selected from at least one of hydroxypropyl methylcellulose E3 and hydroxypropyl methylcellulose E5; the carrier is divided into a slurry preparation carrier and a granulation carrier; the mass ratio of the granulation carrier to the slurry preparation carrier is (12-30): 1. The fenerenone capsule prepared by the invention has the advantages of uniform particle distribution and stable release. Compared with tablets, the capsule has the advantages that the exposure time of particles and tablets is shortened, coating is avoided technically, and the influence of moisture and a coating layer is avoided to the greatest extent.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a finerenone capsule and a preparation method thereof. Background Art

[0002] Finerenone is a new generation of non-steroidal, selective MRA developed by Bayer Healthcare Pharmaceuticals of Germany. Its chemical name is (4S) 4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide, and its chemical structure is as follows:

[0003]

[0004] Finerenone is a nonsteroidal selective antagonist of the mineralocorticoid receptor (MR), which is activated by aldosterone and cortisol and regulates gene transcription. Finerenone blocks MR-mediated sodium reabsorption and MR overactivation in epithelial (e.g., kidney) and non-epithelial (e.g., heart and blood vessels) tissues. MR overactivation is thought to contribute to fibrosis and inflammation. Finerenone is highly potent and selective for the MR, with no relevant affinity for the androgen, progesterone, estrogen, and glucocorticoid receptors.

[0005] At present, most of the related preparations of finerenone are tablets. Chinese patent CN 118319870 A discloses a finerenone tablet and a preparation method thereof, comprising finerenone, copovidone, hydrogenated lecithin, a water-soluble diluent, and a disintegrant; wherein the water-soluble diluent is one or more of mannitol, lactose, sorbitol, and sucrose. The finerenone tablet of the invention has a simple preparation process and good dissolution, and is mainly aimed at improving the dissolution stability during long-term storage to ensure the safety and effectiveness of the patient's administration.

[0006] Chinese patent CN 117618368 A relates to a solid dispersion tablet containing finerenone and a preparation method thereof, wherein the preparation comprises an active ingredient, finerenone, a water-soluble carrier, a filler, a disintegrant, and a lubricant. The finerenone solid dispersion tablet prepared by the invention has high solubility, is conducive to improving the bioavailability of the drug, has less growth of related substances in stability, has significantly improved stability, and is not prone to foreign matter during storage.

[0007] However, on the one hand, finerenone tablets have a low bulk density of particles after preparation, and the particles are fluffy, which makes them easy to absorb moisture and affects the quality of the plain tablets; on the other hand, it is film-coated, and the release in various media in vitro varies greatly, and there is a problem of RSD of the cumulative release at each time point after film coating exceeding the standard.

[0008] Based on this, in order to reduce the risk of in vitro evaluation and in vivo absorption, the particles are filled into capsules to reduce the risk. Currently, there is no commercially available finerenone capsule preparation. Therefore, the development of a finerenone capsule preparation and its preparation method is the research focus of researchers in this field. Summary of the invention

[0009] In view of the above problems, the present invention provides a finerenone capsule and a preparation method thereof. By optimizing the combination and ratio and the preparation method, the prepared finerenone capsule has the advantages of uniform particle distribution and stable release. Compared with tablets, the capsule not only reduces the exposure time of particles and plain tablets, but also avoids coating from the process, thereby avoiding the influence of moisture and coating layer to the greatest extent.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] On the one hand, the present invention provides a finerenone capsule, comprising the following components: finerenone, a carrier, a filler and a disintegrant; the carrier is selected from at least one of hypromellose E3 and hypromellose E5; the carrier is divided into a slurry carrier and a granulation carrier; the mass ratio of the granulation carrier to the slurry carrier is 12-30:1.

[0012] Preferably, the carrier is hypromellose E3.

[0013] Preferably, the mass ratio of the granulation carrier to the slurry carrier is 14-25:1.

[0014] Further preferably, the mass ratio of the granulation carrier to the slurry preparation carrier is 15.7-24:1.

[0015] Preferably, the mass ratio of finerenone to carrier is 1:3-4.5;

[0016] More preferably, the mass ratio of finerenone to carrier is 1:4.

[0017] Preferably, the filler is selected from at least one of anhydrous lactose, microcrystalline cellulose 102, microcrystalline cellulose 302, mannitol 160C and mannitol 100SD.

[0018] Further preferably, the filler is selected from anhydrous lactose and mannitol 160C; more preferably, the filler is selected from anhydrous lactose.

[0019] Preferably, the disintegrant is selected from at least one of croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

[0020] More preferably, the disintegrant is selected from at least one of croscarmellose sodium and crospovidone.

[0021] More preferably, the disintegrant is selected from croscarmellose sodium.

[0022] Preferably, the finerenone capsule comprises the following components in parts by mass: 60-100 parts of finerenone, 300-340 parts of a carrier, 50-110 parts of a filler and 110-160 parts of a disintegrant.

[0023] Further preferably, the finerenone capsule comprises the following components in parts by mass: 70-90 parts of finerenone, 310-330 parts of a carrier, 60-105 parts of a filler and 120-160 parts of a disintegrant.

[0024] More preferably, the finerenone capsule comprises the following components in parts by mass: 70-80 parts of finerenone, 310-320 parts of a carrier, 64-96 parts of a filler and 153-122 parts of a disintegrant.

[0025] Preferably, the finerenone capsule further comprises a pore-forming agent, a lubricant and a solvent.

[0026] Preferably, the porogen is lactose.

[0027] Preferably, the lubricant is at least one of magnesium stearate, silicon dioxide, polyethylene glycol, talcum powder, and micro-powdered silica gel. Further preferably, the lubricant is magnesium stearate.

[0028] Preferably, the solvent is water.

[0029] Preferably, the mass ratio of the porogen, lubricant and finerenone is 10-20:5-8:70-90; further preferably, the mass ratio of the porogen, lubricant and finerenone is 15-18:5-7:70-80.

[0030] On the other hand, the present invention provides a method for preparing the above-mentioned finerenone capsules, comprising the following steps:

[0031] S1: mixing the slurry carrier, porogen and solvent to obtain a mixture 1;

[0032] S2: Mixture 1 and finerenone are mixed, homogenized, and stirred to obtain mixture 2;

[0033] S3: Add mixture 2 to the granulation carrier for granulation, crush, mix with filler, disintegrant and lubricant, and fill into capsules.

[0034] Preferably, in S1, the mixing is stirring for a time of >10 min;

[0035] Preferably, in S2, the mixing is stirring, and the time is >20 min;

[0036] Preferably, in S2, the homogenization time is 1-10 min. More preferably, in S2, the homogenization time is 5-10 min.

[0037] Preferably, in S2, the stirring time is greater than 20 min, and the slurry is placed for no more than 24 h after preparation.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The present invention optimizes the combination and ratio, optimizes the preparation method, and prepares the phenerenone capsules, which have the advantages of uniform particle distribution and stable release. Compared with tablets, the capsules not only reduce the exposure time of particles and plain tablets, but also avoid coating from the process, thereby avoiding the influence of moisture and coating layer to the greatest extent. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is the release curve of fenarezone capsules prepared in Example 1 at 0 days and accelerated for 3 months in a pH 1.2 medium.

[0041] Figure 2 The release curve of phenerenone tablets prepared in Example 1 at 0 days and accelerated for 3 months in pH 1.2 medium DETAILED DESCRIPTION

[0042] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0043] Embodiment 1:

[0044]

[0045] Add Hydroxypropyl Methylcellulose E3 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring, stir for more than 10 minutes; then add the raw materials to the above mixture while stirring, stir for more than 20 minutes, homogenize with a homogenizer for 5-10 minutes, and continue stirring for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the granules after granulation, add anhydrous lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate. Fill the mixed granules into capsules.

[0046] Embodiment 2:

[0047]

[0048]

[0049] Add Hydroxypropyl Methylcellulose E5 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring, stir for more than 10 minutes; then add the raw materials to the above mixture while stirring, stir for more than 20 minutes, homogenize with a homogenizer for 5-10 minutes, and continue stirring for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the granules after granulation, add anhydrous lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate. Fill the mixed granules into capsules.

[0050] Embodiment 3:

[0051]

[0052] Add Hydroxypropyl Methylcellulose E3 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring, stir for more than 10 minutes; then add the raw materials to the above mixture while stirring, stir for more than 20 minutes, homogenize with a homogenizer for 5-10 minutes, and continue stirring for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the granules after granulation, add anhydrous lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate. Fill the mixed granules into capsules.

[0053] Table 1. Comparison of dissolution data of different types of carriers and different amounts of carriers used in slurry preparation in pH 1.2 medium

[0054]

[0055] Table 2. Comparison of dissolution data of different types of carriers and different amounts of carriers used in slurry preparation in pH 4.5 medium

[0056]

[0057] From the data in Table 1-2, it can be seen that the release of both media of E5 is slower than that of E3, and the increase of HPMC in the slurry slows down the release, and the RSD of the existing process is qualified, while the RSD of finerenone tablets does not meet the requirements. Based on the values ​​of the tablet fit in the two media, the formulation of HPMC E3, that is, Example 1, is most similar to the release of finerenone tablets.

[0058] Embodiment 4:

[0059]

[0060]

[0061] Add Hydroxypropyl Methylcellulose E3 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring and stir for more than 10 minutes; then add the raw materials to the above mixture while stirring and stir for more than 20 minutes, then use a homogenizer to homogenize for 5-10 minutes, and continue to stir for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the particles after granulation, add anhydrous lactose, cross-linked polyvinylpyrrolidone and magnesium stearate. Fill the mixed particles into capsules.

[0062] Embodiment 5:

[0063]

[0064] Add Hydroxypropyl Methylcellulose E3 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring, stir for more than 10 minutes; then add the raw materials to the above mixture while stirring, stir for more than 20 minutes, homogenize with a homogenizer for 5-10 minutes, and continue stirring for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the granules after granulation, add anhydrous lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate. Fill the mixed granules into capsules.

[0065] Table 3. Comparison of dissolution data of different disintegrants and different dosages of disintegrants in pH 1.2 medium

[0066]

[0067] Table 4. Comparison of dissolution data of different disintegrants and different dosages of disintegrants in pH 4.5 medium

[0068]

[0069] From the data in Tables 3-4, it can be seen that the in vitro release of the formulation described in Example 1 is closer to that of finerenone tablets based on the comprehensive fit values ​​of the two media. Therefore, croscarmellose sodium was selected as the disintegrant, and the effect was better under a specific ratio.

[0070] Embodiment 6:

[0071]

[0072]

[0073] Add Hydroxypropyl Methylcellulose E3 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring and stir for more than 10 minutes; then add the raw materials to the above mixture while stirring and stir for more than 20 minutes, then use a homogenizer to homogenize for 5-10 minutes, and continue to stir for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the granules after granulation, add mannitol 160C, cross-linked carboxymethyl cellulose sodium and magnesium stearate. Fill the mixed granules into capsules.

[0074] Table 5. Comparison of dissolution data of different external fillers in pH 1.2 & pH 4.5 media

[0075]

[0076] From the data in Table 5, it can be seen that Example 1 has a better fit with the finerenone tablets.

[0077] In summary, considering the fit between the pH 1.2 medium and the pH 4.5 medium of Examples 1 to 6 and the finerenone tablets, Example 1 has a higher fit with the finerenone tablets. It can be seen that under the conditions of the same specifications and the same medium, using the prescription and existing process of Example 1, and changing the preparation process of the granules to capsules, there is no effect on the release of the product.

[0078] Comparative Example 1:

[0079]

[0080] Add lactose to purified water and stir for more than 10 minutes; then add the raw materials to the above mixture while stirring, stir for more than 20 minutes, and then use a homogenizer to homogenize for 5-10 minutes. No magnetic stirring is performed during the slurry transfer process. The raw materials are observed to be obviously stratified by naked eyes, and the stratification is fast. Failure to add hydroxypropyl methylcellulose to the slurry solution will cause the material in the slurry to stratify. Even if the spraying process continues to stir, there is still a risk of stratification leading to unqualified content uniformity. From the perspective of process feasibility, this formula is not applicable.

[0081] Comparative Example 2:

[0082] There is no phenarene capsule preparation in the market. After searching, the patent CN118662470A describes the preparation method of phenarene capsule. The excipients and preparation processes of the embodiments in this article are inconsistent with those in the patent, but the specifications are consistent. All the embodiments in this article use a one-step granulation process, while the patent uses a direct mixing process without granulation.

[0083]

[0084] Finerenone and propylene glycol alginate are mixed through a 40-mesh sieve and set aside; the above materials are mixed with lactose powdered cellulose, pregelatinized starch, povidone, and half of the cross-linked sodium carboxymethyl cellulose in a mixer for 30 minutes; hard sodium fumarate and the remaining half of the cross-linked sodium carboxymethyl cellulose are added to the mixer and mixed for 15 minutes; the above total mixed powder is used for capsule filling.

[0085] Table 6. Comparison of dissolution data of preparations with different preparation processes and formulations in pH 1.2 & pH 4.5 media

[0086]

[0087] It can be seen from the data in Table 6 that the direct mixing process in Comparative Example 2 results in rapid release at pH 1.2, and the degree of fit in the pH 4.5 medium is much lower than that of the technical solution in the present invention. The embodiments of the present invention are intended to maintain the product release curve and the degree of fit, and on this basis, optimize the dissolution RSD and product stability, etc., so Comparative Example 2 does not meet the expected goal.

[0088] Comparative Example 3

[0089]

[0090]

[0091] Add Hydroxypropyl Methylcellulose E3 (slurry preparation) to purified water and stir until completely dissolved; add lactose to the above mixture while stirring, stir for more than 10 minutes; then add the raw materials to the above mixture while stirring, stir for more than 20 minutes, homogenize with a homogenizer for 5-10 minutes, and continue stirring for more than 20 minutes; then granulate with Hydroxypropyl Methylcellulose E3 (granulation) by top spraying, dry granulate (crush) the granules after granulation, add anhydrous lactose, cross-linked sodium carboxymethyl cellulose and magnesium stearate. Fill the mixed granules into capsules.

[0092] Table 7. Comparison of dissolution data of preparations with different total carrier dosage in pH 1.2 & pH 4.5 media

[0093]

[0094] From the data in Table 7, it can be seen that the in vitro release of the formulation described in Example 1 is closer to that of finerenone tablets, based on the fitting values ​​of the two media and the two preparations. Therefore, the release is significantly slowed down after the same slurry carrier is maintained and the granulation carrier is added, and the fitting degree decreases. The products prepared by the formulation process of the technical solution of Examples 1-6 of the present invention meet the requirements for each key quality attribute, and the detailed results are as follows:

[0095] Table 7. Test results of finerenone capsules

[0096] project Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 content 101.1％ 101.3％ 100.4％ 102.0％ 101.3％ 100.8％ Related substances 0.09％ 0.13％ 0.14％ 0.09％ 0.12％ 0.10％ Moisture content 2.0％ 2.4％ 2.1％ 2.4％ 2.0％ 3.5％

[0097] According to Appendix 9001 "Guidelines for Stability Testing of Raw Materials and Preparations" of the 2020 edition of the Chinese Pharmacopoeia, the samples prepared in Example 1 of the optimal combination were subjected to stability testing, including accelerated testing (temperature 40°C ± 2°C, relative humidity 75% ± 5%, placed for 6 months, sampling at the 1st, 3rd, and 6th months) and long-term testing (temperature 25°C ± 2°C, relative humidity 60% ± 5%, placed for 24 months, sampling at the 6th, 12th, 18th, and 24th months), and tested according to the inspection items and compared with the data of October. The results of the stability test are as follows:

[0098] Table 8. Results of accelerated stability test of finerenone capsules

[0099] project Day 0 January March June content 101.1％ 101.0％ 100.8％ 100.2％ Related substances 0.09％ 0.11％ 0.12％ 0.09％ Moisture content 2.0％ 2.3％ 2.6％ 2.2％

[0100] Table 9. Results of long-term stability test of finerenone capsules

[0101] project Day 0 June December 18 months 24 months content 101.1％ 99.9％ 100.2％ 99.8％ 100.1％ Related substances 0.09％ 0.12％ 0.14％ 0.16％ 0.14％ Moisture content 2.0％ 2.2％ 2.0％ 2.5％ 2.5％

[0102] The stability test results show that compared with the commercially available phenareninone tablets (water content 5.0%), the phenareninone capsules prepared by the present invention have stable quality.

[0103] like Figure 1-2 As shown, the experiment compared the pH 1.2 medium dissolution curves of finerenone capsules and commercial finerenone tablets (trade name Kerendia) after 3 months of acceleration (water content of finerenone tablets after 3 months of acceleration was 5.4%), and the comparison results are as follows:

[0104] Table 10. Accelerated 3-month stability dissolution results of finerenone capsules and finerenone tablets

[0105]

[0106]

[0107] The test results showed that the release of phenerenone tablets slowed down after 3 months under accelerated conditions compared with 0 days, while phenerenone capsules showed better moisture and release stability.

[0108] Therefore, the capsules prepared according to the present invention can improve the influence of moisture and reduce the instability of release to a great extent.

[0109] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A finerenone capsule, characterized in that: The invention comprises the following components: finerenone, a carrier, a filler and a disintegrant; the carrier is selected from at least one of hypromellose E3 and hypromellose E5; the carrier is divided into a slurry carrier and a granulation carrier; the mass ratio of the granulation carrier to the slurry carrier is 12-30:

1.

2. The fenarezone capsule according to claim 1, characterized in that The mass ratio of the granulation carrier to the slurry preparation carrier is 14-25:

1.

3. The fenarezone capsule according to claim 1, characterized in that: The mass ratio of finerenone to the carrier is 1:3-4.

5.

4. The fenarezone capsule according to claim 1, characterized in that: The filler is selected from at least one of anhydrous lactose, microcrystalline cellulose 102, microcrystalline cellulose 302, mannitol 160C and mannitol 100SD; the disintegrant is selected from at least one of cross-linked carboxymethyl cellulose sodium, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch and low-substituted hydroxypropyl cellulose.

5. The finerenone capsule according to claim 1, characterized in that: The finerenone capsule comprises the following components in parts by weight: 60-100 parts of finerenone, 300-340 parts of a carrier, 50-110 parts of a filler and 110-160 parts of a disintegrant.

6. The finerenone capsule according to claim 5, characterized in that: The finerenone capsule comprises the following components, calculated by weight: 70-90 parts of finerenone, 310-330 parts of a carrier, 60-105 parts of a filler and 120-160 parts of a disintegrant.

7. The finerenone capsule according to claim 1, characterized in that: The finerenone capsule further comprises a pore former, a lubricant and a solvent.

8. The finerenone capsule according to claim 7, characterized in that: The porogen is lactose.

9. The finerenone capsule according to claim 7, characterized in that: The mass ratio of the porogen, the lubricant and finerenone is 10-20:5-8:70-90.

10. The method for preparing finerenone capsules according to any one of claims 1 to 9, characterized in that: The following steps are involved: S1: mixing the slurry carrier, porogen and solvent to obtain a mixture 1; S2: Mixture 1 and finerenone are mixed, homogenized, and stirred to obtain mixture 2; S3: Add mixture 2 to the granulation carrier for granulation, crush, mix with filler, disintegrant and lubricant, and fill into capsules.

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