A solid formulation containing a solid dispersion of finerenone and a method for its preparation

Abstract

The present application relates to the technical field of medicine, in particular to a solid preparation containing a solid dispersion of finerenone and a preparation method thereof, which comprises a solid dispersion of finerenone and at least one pharmaceutically acceptable excipient; the solid dispersion of finerenone is prepared by using a hot melt extrusion method with finerenone and a matrix. In the hot melt extrusion method, polyethylene glycol and copolymerized povidone are used as solubilizers and plasticizers, so that the hot melt temperature can be reduced to below 160 DEG C, which not only reduces energy consumption, but also ensures the stability of the drug.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a solid dosage form containing phenelzine solid dispersion and its preparation method. Background Technology

[0002] Fennellone is a nonsteroidal, highly selective mineralocorticoid receptor antagonist that has been shown in preclinical studies to block the harmful effects of excessive activation of mineralocorticoid receptors. It is indicated for adult patients with type 2 diabetes-associated chronic kidney disease (with proteinuria) to reduce the risk of persistent decline in estimated glomerular filtration rate (eGFR), end-stage renal disease, cardiovascular death, and hospitalization due to heart failure.

[0003] Finelendone was originally developed by Bayer, approved by the US FDA in July 2021, and registered and approved for import into China in June 2022. Its structural formula is as follows:

[0004]

[0005] Fennellone belongs to the BCS2 class of drugs (low solubility, high permeability). Its solubility in water is only 0.02 mg / ml, making it almost insoluble. This poor water solubility leads to poor solubility and dissolution rate, potentially resulting in unsatisfactory dissolution and bioavailability in formulations. Therefore, improving the dissolution of fenelrenone is a key issue that needs to be addressed in formulation research.

[0006] Common methods to improve the bioavailability of poorly soluble drugs include micronization and solid dispersion techniques. However, after micronization, the drug exhibits strong electrostatic effects, reducing the effectiveness of micronization and resulting in low yields. Common solid dispersion formulation methods include melt processing and solvent processing, but these methods are difficult to scale up for production due to complex processes and residual organic solvents.

[0007] Chinese patents CN115916197A and CN112237573B both utilize micronization to improve dissolution. However, during the pulverization process, the active pharmaceutical ingredient (API) tends to agglomerate, making it difficult to achieve the target particle size, and the process is energy-intensive. Furthermore, the solid dosage forms in these patents all use SDS as a solubilizer and phenelzine dispersion suspensions for granulation. This preparation method is complex and prone to producing products with low content.

[0008] CN117618368A describes a process for preparing fenelone solid dispersions that uses organic solvents. However, the solvent method requires addressing the issue of solvent recovery, resulting in higher production costs and hindering large-scale production. Summary of the Invention

[0009] The purpose of this invention is to provide a solid dosage form containing phenelzine solid dispersion and its preparation method, providing a safe, effective, and highly soluble phenelzine solid dispersion, as well as a phenelzine solid dosage form with rapid dissolution and high long-term stability.

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

[0011] A solid dosage form containing a fenelinone solid dispersion, comprising a fenelinone solid dispersion and at least one pharmaceutically acceptable excipient;

[0012] The fenelitone solid dispersion is prepared by hot melt extrusion of fenelitone technical and matrix. The matrix of the fenelitone solid dispersion is one or more of copovidone, povidone, hydroxypropyl methylcellulose, and polyethylene glycol.

[0013] As a preferred technical solution, the matrix of the non-nelitone solid dispersion is polyethylene glycol and copolyvinyl ketone, with a ratio of 1:1 to 1:5, preferably 1:3.

[0014] The pharmaceutically acceptable excipients are fillers, disintegrants, and lubricants.

[0015] The fillers are mannitol and microcrystalline cellulose in a ratio of 1:0.5 to 1:2; the disintegrant is sodium croscarmellose; and the lubricant is magnesium stearate.

[0016] As a preferred technical solution, the solid dosage form containing fenelinone solid dispersion comprises, by weight: 25%–70% fenelinone solid dispersion, 25%–70% filler, 2%–5% disintegrant, and 0.5%–2% lubricant.

[0017] A method for preparing a solid dosage form containing fenelitone solid dispersion, wherein fenelitone technical material is mixed with a matrix and then melted and extruded to obtain a fenelitone solid dispersion; the fenelitone solid dispersion is pulverized and ground into particles; the particles are mixed with a filler, a disintegrant, and a lubricant, then compressed into tablets and coated to obtain a solid dosage form containing fenelitone solid dispersion.

[0018] Furthermore, the preparation method includes the following steps:

[0019] 1) Mix phenelzine technical grade drug with matrix in a certain proportion to obtain a physical mixture, melt and extrude the mixture, cool it down to obtain a solid dispersion;

[0020] 2) Grind the solid dispersion obtained in step 1) using a 60-100 mesh sieve to form solid dispersion particles;

[0021] 3) Mix the solid dispersion particles, filler, disintegrant, and lubricant obtained in step 2) evenly;

[0022] 4) Tableting;

[0023] 5) Prepare the coating solution and perform coating to obtain fenelazol film-coated tablets.

[0024] The phenelzine technical grade is non-micronized phenelzine, D 90 ≤150μm;

[0025] The hot melt extrusion temperature for preparing the solid dispersion is 120–240°C; preferably, the hot melt extrusion temperature for preparing the solid dispersion is 120–160°C.

[0026] The coating powder is a gastrointestinal soluble film coating premix, with a coating weight gain of 2-4%.

[0027] The solid formulation containing phenelzine solid dispersion described in this invention has the following advantages compared with the prior art:

[0028] 1. In this invention, polyethylene glycol and copovidone are used as solubilizers and plasticizers in the hot melt extrusion method, which can reduce the hot melt temperature to below 160°C, thereby reducing energy consumption and ensuring the stability of the drug.

[0029] 2. The present invention uses hot melt extrusion to make the fenelone technical material more uniformly dispersed. At the same time, without the use of surfactant sodium dodecyl sulfate, it can achieve rapid dissolution in the dissolution medium, and the dissolution efficiency is significantly better than that of the original formulation, thus improving the bioavailability of poorly soluble drugs.

[0030] 3. The preparation process provided by this invention is simple, consumes little energy, leaves no residual solvent, does not introduce other impurities during the entire process, and the product has good stability during long-term storage. Detailed Implementation

[0031] The present invention will be further described below with reference to embodiments. The following description is only for explaining the present invention and does not limit its content in any way.

[0032] The following describes in detail the tablets containing non-nephenone solid dispersions and their preparation methods according to embodiments of the present invention.

[0033] Examples 1-3

[0034] Table 1 Solid Dispersion Formulation

[0035]

[0036] The preparation of fenelazol solid dispersion according to the above formulation includes the following steps:

[0037] The various prescription components are mixed evenly to prepare a physical mixture. The extruder temperature is set at 150°C. After the temperature rises to the set value and stabilizes, the physical mixture is added, and the temperature is raised until it is completely melted. The mixture is then extruded to obtain strip-shaped material, which is cooled to room temperature to obtain a solid dispersion.

[0038] Examples 4-7

[0039] Table 2 Tablet Prescription (1000 tablets)

[0040]

[0041] Preparation method:

[0042] 1. The solid dispersions of Examples 1 to 3 were pulverized using a 60-mesh sieve to obtain phenelzine solid dispersion particles;

[0043] 2. Place phenelzine solid dispersion particles, mannitol, microcrystalline cellulose, and croscarmellose sodium in a mixing hopper and mix for 5 minutes. Then add magnesium stearate and mix for 2 minutes.

[0044] 3. Compress the above-mentioned total mixture of granules into tablets using a Φ7mm shallow concave die, with a tablet hardness of 30-80N;

[0045] 4. The coating premix was prepared into a coating solution with a solid content of 12% using purified water for coating. The weight gain of the coating ranged from 2% to 4%, resulting in the solid formulation containing phenelzine solid dispersions as described in Examples 4-7.

[0046] Comparative Example 1

[0047] The difference from Example 5 is that: fenelazol technical grade drug and excipient are directly mixed, specifically:

[0048] 1. Place fenelone raw material, mannitol, microcrystalline cellulose, and croscarmellose sodium in a mixing hopper and mix for 5 minutes. Then add magnesium stearate and mix for 2 minutes.

[0049] 2. Compress the above-mentioned total mixture of granules into tablets using a Φ7mm shallow concave die, with a tablet hardness of 30-80N;

[0050] 3. The coating premix is ​​prepared into a coating solution with a solid content of 12% using purified water for coating. The weight gain of the coating ranges from 2% to 4%, resulting in a solid dosage form.

[0051] Comparative Example 2

[0052] The tablet was prepared according to the formulation disclosed in Table 1-1 of Chinese Patent CN115916197A, Tablet 5.

[0053] Table 3 Prescription Composition (g / 1000 tablets)

[0054] Prescription composition Comparative Example 2 <![CDATA[Finerenone (D 90 about 7 μm)]]> 10g microcrystalline cellulose 64.7g Lactose monohydrate 45g Sodium croscarmellose 4.5g Hydroxypropyl methylcellulose 4.5g Sodium dodecyl sulfate 0.4g magnesium stearate 0.9g Coating powder 6g

[0055] Preparation method: A granular suspension of phenelzine, hydroxypropyl methylcellulose, and sodium dodecyl sulfate in water is prepared. Microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium are mixed in a container or fluidized bed granulator (premix). The premix and granule solution are granulated in a fluidized bed granulator. After drying and sieving the granules, magnesium stearate is added as a lubricant to form a mixture to be compressed. The mixture is then compressed into tablets using a rotary tablet press. A uniform coating suspension is prepared using coating powder and purified water. Coating is then performed in a suitable coating device.

[0056] Comparative Example 3

[0057] The difference from Example 2 is that the solid dispersion particles were prepared by hot melt extrusion at a temperature of 260°C, while other conditions were the same as in Example 2, and a solid dispersion was obtained.

[0058] Using the above-mentioned solid dispersion, a solid formulation containing phenelzine solid dispersion was obtained according to the formulation and preparation method of Example 5.

[0059] Experimental Example 1: Dissolution Determination

[0060] Examples 4-7, Comparative Examples 1-2, and Reference Preparation (commercially available fenelazone tablets, trade name: [Brand Name Missing]) Dissolution was determined according to the 2020 edition of the Chinese Pharmacopoeia, Part IV, 0931, Dissolution and Release Determination Method (Method II), using 900 ml of pH 4.5 acetate buffer as the dissolution medium, rotating at 75 rpm, and following the prescribed procedure. The detection method was high performance liquid chromatography.

[0061] Table 4. Dissolution rates of Samples from Examples 4-7 and Comparative Examples 1-2 in standard media.

[0062]

[0063] As shown in Table 4, the dissolution rates of Examples 4-7 of this invention in the standard medium at pH 4.5 were consistent with the dissolution behavior of the reference formulation, all exceeding 85% at 15 min. In Comparative Example 1, controlling the particle size of the active pharmaceutical ingredient according to the original patent formulation process had limited effect on improving solubility. In Comparative Example 2, the active pharmaceutical ingredient was micronized, resulting in a significantly lower dissolution rate than the examples. Compared to Comparative Examples 1-2, Examples 4-7 used a hot-melt extrusion method to prepare solid dispersions, which greatly improved the poor solubility of the active ingredient, and the dissolution rates were superior to those of the original formulation process product. The above results indicate that the fenelazol formulation prepared by this invention has good dissolution performance.

[0064] Test Example 2: Stability Test

[0065] Example 5 and the reference formulation were investigated under accelerated conditions of 40±2℃ / 75%±5% RH. The results are shown in Table 5.

[0066] Table 5 Results of Related Substance Detection

[0067]

[0068] As shown in Table 5, the solid dispersion formulations prepared in the embodiments of the present invention, under accelerated conditions, showed no significant changes in content and related substances after 3 months compared to 0 months. Comparative Example 3, however, exhibited poor stability due to excessively high melting temperature. Therefore, the solid formulations containing phenelzine provided by the present invention, and the finished products prepared by the preparation method, demonstrate good stability.

Claims

1. A solid dosage form containing phenelzine solid dispersion, characterized in that, Includes felindone solid dispersion and at least one pharmaceutically acceptable excipient; The fenelitone solid dispersion is prepared by hot melt extrusion of fenelitone technical and matrix.

2. The solid dosage form containing phenelzine solid dispersion according to claim 1, characterized in that, The matrix of the non-nelitone solid dispersion is one or more of copovidone, povidone, hydroxypropyl methylcellulose, and polyethylene glycol.

3. The solid dosage form containing phenelzine solid dispersion according to claim 1, characterized in that, The matrix content in the felinone solid dispersion is approximately 50% to 80%.

4. The solid dosage form containing phenelzine solid dispersion according to claim 2, characterized in that, The matrix of the non-nelitone solid dispersion is polyethylene glycol and copolyvinyl ketone in a ratio of 1:1 to 1:

5.

5. The solid dosage form containing phenelzine solid dispersion according to claim 1, characterized in that, The pharmaceutically acceptable excipients are fillers, disintegrants, and lubricants.

6. The solid dosage form containing phenelzine solid dispersion according to claim 1, characterized in that, The solid dosage form containing felinone solid dispersion comprises, by weight: 25%–70% felinone solid dispersion, 25%–70% filler, 2%–5% disintegrant, and 0.5%–2% lubricant.

7. The solid dosage form containing phenelzine solid dispersion according to claim 1, characterized in that, The filler is mannitol and microcrystalline cellulose in a ratio of 1:0.5 to 1:2; the disintegrant is sodium croscarmellose; and the lubricant is magnesium stearate.

8. A method for preparing a solid dosage form containing phenelzine solid dispersion as described in claim 1, characterized in that, Finelendone technical material is mixed with a matrix and then melted and extruded to obtain a finelendone solid dispersion. The finelendone solid dispersion is then pulverized and ground into granules. The granules are mixed with fillers, disintegrants, and lubricants, then compressed into tablets and coated to obtain a solid dosage form containing finelendone solid dispersion.

9. The method for preparing a solid dosage form containing phenelzine solid dispersion according to claim 8, characterized in that, Includes the following steps: 1) Mix phenelzine technical grade drug with matrix to obtain a uniform mixture, melt and extrude the mixture, cool it down, and obtain a solid dispersion; 2) Grind the solid dispersion obtained in step 1) using a 60-100 mesh sieve to form solid dispersion particles; 3) Mix the solid dispersion particles, filler, disintegrant, and lubricant obtained in step 2) evenly; 4) Tableting; 5) Prepare a coating solution, perform coating, and obtain a solid formulation containing phenelzine solid dispersion.

10. The method for preparing a solid dosage form containing phenelzine solid dispersion according to claim 9, characterized in that, The phenelzine technical grade is non-micronized phenelzine, D 90 ≤150μm; the hot melt extrusion temperature for preparing the solid dispersion is 120~240℃.

Images