Amorphous fenerenone solid dispersion tablet and preparation method thereof

Abstract

The invention provides an amorphous fenerenone solid dispersion tablet and a preparation method thereof, fenerenone exists in an amorphous form, and the solid dispersion tablet also comprises a polymer carrier, and further comprises a filler, a disintegrating agent, a lubricant and a surfactant. The amorphous finerenone solid dispersion tablet is simple in preparation process, has the advantages of high solubility, good dissolution rate, low impurity content and good stability, is simple and feasible in production process, is suitable for industrial production, and has relatively high application value.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and more particularly to an amorphous feneline solid dispersion tablet and its preparation method. Background Technology

[0002] Finerenone (BAY 94-8862) is a nonsteroidal selective mineralocorticoid receptor antagonist developed by Bayer, and its structural formula is as follows:

[0003]

[0004] Fennellone belongs to BCS Class II drugs. It has low solubility and high permeability, and the solubility of the active substance is the key factor limiting drug absorption. The original manufacturer reported crystal form I in its PCT patent application WO2016016287A1. Currently, crystal form I is the marketed pharmaceutical crystal form of fenelene. Crystal form I is thermodynamically stable, but it has poor solubility and low oral bioavailability.

[0005] Therefore, in order to meet the needs of clinical practice and patients, it is necessary to develop a fenelazol formulation with good solubility and high oral bioavailability. Summary of the Invention

[0006] One objective of this application is to provide an amorphous fenelitonee solid dispersion tablet comprising a therapeutically effective amount of amorphous fenelitonee, a filler, a disintegrant, a lubricant, and a polymeric carrier, wherein the polymeric carrier is one of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus), hydroxypropyl cellulose, copovidone, and hydroxypropyl methylcellulose.

[0007] In one or more embodiments, the weight ratio of the amorphous feneline to the polymeric carrier is 1:0.5 to 1:1.5, specifically, for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5.

[0008] In one or more embodiments, the polymeric carrier has a weight percentage of 6% to 19%.

[0009] In one or more embodiments, the filler is at least one selected from microcrystalline cellulose, mannitol, starch, lactose, sucrose, sorbitol, xylitol, and maltodextrin, and the filler has a weight percentage of 57-75%.

[0010] In one or more embodiments, the disintegrant is at least one of croscarmellose sodium, carboxymethyl starch sodium, croscarmellose or low-substituted hydroxypropyl cellulose, and the weight percentage of the disintegrant is 3 to 10%.

[0011] In one or more embodiments, the lubricant is at least one of calcium stearate, sodium fumarate stearate, or magnesium stearate, and the lubricant has a weight percentage of 0.7 to 1.5%.

[0012] In one or more embodiments, the tablet further comprises a surfactant, wherein the surfactant is Tween 80 or sodium dodecyl sulfate, and the surfactant comprises 0.75 to 1.5% by weight.

[0013] In one or more embodiments, the amorphous fenelitone solid dispersion tablet comprises: 10-15% amorphous fenelitone, 57-75% lactose, 6-19% hydroxypropyl cellulose or hydroxypropyl methylcellulose, 0.75-1.5% sodium dodecyl sulfate, 3-5% croscarmellose sodium, 3-5% croscarmellose sodium, 3-5% crospovidone, and 0.7-1.5% magnesium stearate.

[0014] In one or more embodiments, the amorphous fenelitone solid dispersion tablet comprises: 12.50% amorphous fenelitone, 7.50% hydroxypropyl cellulose, 1.25% sodium dodecyl sulfate, 68.75% lactose, 4.50% crospovidone, 4.50% crospovidone sodium carboxymethyl cellulose, and 1.00% magnesium stearate.

[0015] In one or more embodiments, the amorphous fenelitone solid dispersion tablet comprises: 12.50% amorphous fenelitone, 7.50% hydroxypropyl methylcellulose, 1.25% sodium dodecyl sulfate, 68.75% lactose, 4.50% crospovidone, 4.50% crospovidone sodium carboxymethyl cellulose, and 1.00% magnesium stearate.

[0016] In one or more embodiments, the amorphous fenelitone solid dispersion tablet comprises: 12.50% amorphous fenelitone, 10% soluplus, 1.25% sodium dodecyl sulfate, 66.25% lactose, 4.50% crospovidone, 4.50% crospovidone sodium carboxymethyl cellulose, and 1.00% magnesium stearate.

[0017] In one or more embodiments, the amorphous fenelitone solid dispersion tablet comprises: 12.50% amorphous fenelitone, 12.50% copovidone, 1.25% sodium dodecyl sulfate, 63.75% lactose, 4.50% crospovidone, 4.50% crospovidone sodium carboxymethyl cellulose, and 1.00% magnesium stearate.

[0018] In one or more embodiments, the amorphous felinone solid dispersion tablet has a tablet weight of 80 mg and comprises: 10 mg of amorphous felinone, 6 mg of hydroxypropyl cellulose or hydroxypropyl methylcellulose, 1 mg of sodium dodecyl sulfate, 55 mg of lactose, 3.6 mg of crospovidone, 3.6 mg of crospovidone sodium carboxymethyl cellulose, and 0.8 mg of magnesium stearate.

[0019] Another object of this application is to provide a method for preparing amorphous non-nephenone solid dispersion tablets, comprising the following steps:

[0020] a) Dissolve phenelzine in crystalline or amorphous form, with a polymeric carrier, in a suitable solvent, optionally with the addition of a surfactant, and dissolve.

[0021] b) Mix the solution obtained in step a) with 20% to 90% of the total weight of the filler to prepare wet granules, dry them, and then mix them with the remaining filler, disintegrant and lubricant, compress them into tablets to obtain amorphous non-nephenone solid dispersion tablets.

[0022] The suitable solvent is a mixture of an organic solvent and water, wherein the weight ratio of the organic solvent to water is 4 to 8:1, and the organic solvent is selected from acetone or ethanol.

[0023] In one or more embodiments, a method for preparing amorphous fenelitone solid dispersion tablets includes the following steps: adding fenelitone, a polymeric carrier, and a surfactant to a mixed solvent of acetone / water to prepare a slurry, then spraying it onto a filler accounting for 70% of the total weight of the filler in a fluidized bed, granulating, drying; granulating, then mixing with a disintegrant, lubricant, and the remaining filler, and compressing to obtain amorphous fenelitone solid dispersion tablets.

[0024] Beneficial technical effects of the present invention:

[0025] In this invention, phenelzine exists in a stable amorphous form in the solid dispersion tablets, maintaining stability over a long period. The inventors hypothesize that the uniform mixing of amorphous phenelzine within a polymeric carrier, whether in a liquid solution or solid state, prevents collisions between phenelzine molecules, thereby inhibiting crystal nucleation and achieving the goal of suppressing crystal formation. Therefore, the phenelzine solid dispersion tablets of this invention maintain long-term stability, exhibit high solubility and good dissolution rate. Furthermore, the solid dispersion of this invention offers advantages such as good tablet quality consistency and uniformity, low excipient cost, and economic viability.

[0026] The following are definitions of some of the terms used in this invention:

[0027] The crystalline form of felinone in this invention is crystalline form I of felinone, which is the crystalline form I reported in patent USRE49826E1. This crystalline form is the crystalline form of felinone tablets currently on the market.

[0028] SDS: Sodium dodecyl sulfate. Attached Figure Description

[0029] Figure 1 The XRPD spectrum of fenelone in crystal form I, which is used as a raw material in this invention, has a characteristic peak at approximately 8.3°.

[0030] Figure 2 Example 1: XRPD spectra of formulations 1-4 tablets, i.e., amorphous non-nelinone solid dispersions;

[0031] Figure 3 Example 1: XRPD spectrum of formulation 5 tablets containing phenelzine crystal form I.

[0032] Figure 4 The XRPD spectrum of the solid dispersion tablet of the present invention was measured after 20 days of storage in Experimental Example 4. Detailed Implementation

[0033] The following detailed description of specific embodiments further illustrates the above-mentioned aspects of the present invention. However, this should not be construed as a limitation of the present invention.

[0034] Unless otherwise specified in the embodiments of the present invention, the conventional conditions shall apply. If the manufacturers of the reagents or instruments used are not specified, they can be obtained from commercially available conventional products.

[0035] In the embodiments of this invention, the active pharmaceutical ingredient used is phenelzine crystal form I, which is synthesized according to the process developed by Puji Biotechnology (Taizhou) Co., Ltd., i.e., the applicant, or prepared according to the process reported in the published literature or patents.

[0036] Examples of excipients used in this invention include lactose from Kerry Pharmaceuticals, sodium croscarmellose from JRS PHARMA Pharmaceuticals, hydroxypropyl methylcellulose from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., magnesium stearate and sodium lauryl sulfate from Beijing Fengli Pharmaceutical Co., Ltd., and hydroxypropyl cellulose from Ashland Pharmaceuticals.

[0037] The instruments used in this invention include a vortex mixer (model: vortex-2) from Tianjin Tianda Tianfa Technology Co., Ltd., a circulating vacuum pump (SHZ-DⅢ) and a lifting CNC constant temperature bath (W205B) from Taizhou Xinli Electronic Equipment Co., Ltd., a rotary evaporator from Shanghai Shensheng Technology Co., Ltd., a tablet press (ZP8) from Shanghai Xinyuan Pharmaceutical Machinery Co., Ltd., and a heat-collecting constant temperature magnetic stirrer (DF-101S) from Changzhou Jintan Chenyang Electronic Instrument Factory, etc.

[0038] All reagents (analytical grade) required in this invention were purchased from Sinopharm Reagent Co., Ltd.; silica gel (100-200 mesh) was purchased from Qingdao Ocean Chemical Plant; high performance liquid chromatograph (Agilent 1100, Zorbax SB-C18, 5μm, 250x 9.4mm i.d.), Agilent, Palo Alto, CA, USA; rotary evaporator (Digital water bath SB-1000) was purchased from EYELA Corporation, Japan; superconducting nuclear magnetic resonance spectrometer (Bruber AVANCE-400) was purchased from Bruker, Rheinstetten, Germany.

[0039] To solve the technical problem of this invention, the polymer carriers were first screened.

[0040] Example 1

[0041] Table 1: Screening of polymeric carriers

[0042]

[0043] Preparation process: Dissolve the SDS in the prescribed amount in Table 1 in 24g of purified water, then add 96g of acetone, fenelone, and polymer carrier dissolved in the above solution. Stir the solution and 70% by weight of lactose evenly to prepare a soft mass, then dry it. Mix the dry granules evenly with the remaining lactose, croscarmellose sodium, croscarmellose and magnesium stearate, and compress them in a tableting machine to obtain 80mg fenelone solid dispersion tablets.

[0044] Table 2: Detection results of different polymer carrier formulations in Table 1

[0045]

[0046] Table 2 comprehensively examines whether fenelone undergoes crystallization and its solubility. The XRPD spectra of tablets in formulations 1-5 were analyzed after being placed at 60°C for 15 days. The spectra of tablets in formulations 1-4 are shown below. Figure 2 As shown, the tablet chromatogram of formulation 5 is as follows. Figure 3 As shown, phenelzine in formulations 1-4 did not convert to its crystalline form. Figure 3 The presence of crystalline forms indicates that the tablets prepared according to formulations 1-4 are relatively stable.

[0047] Regarding solubility, the tablets prepared from formulations 1-4 were of superior quality, indicating that Soluplus, hydroxypropyl cellulose, copovidone, and hydroxypropyl methylcellulose are optimal choices as polymeric carriers. The solubility determination conditions for phenelzine were as follows: 50 mL of pH 4.5 acetate buffer was heated in a water bath at 37°C, and an excess of the total mixed particles from each formulation was added. The mixture was shaken every 15 minutes, and after 2 hours, samples were taken, filtered, and the solubility of phenelzine was measured.

[0048] Example 2

[0049] This embodiment screens the weight ratio of polymeric carriers and phenelzine.

[0050] Table 3: Screening by weight ratio of hydroxypropyl cellulose and fenetonil

[0051]

[0052]

[0053] The preparation process of tablets with formulations 6 to 10 in Table 3 is based on Example 1.

[0054] Table 4: Test results of tablets prepared with different weight ratios of hydroxypropyl cellulose and fenelone

[0055]

[0056] The methods for determining whether fenelazol undergoes crystallization and its solubility are the same as in Example 1. Table 4 shows the evaluation indicators, indicating that a specific weight ratio of fenelazol to hydroxypropyl cellulose is required to achieve the effects of improved solubility and formulation stability of fenelazol. To achieve these effects, the weight ratio of hydroxypropyl cellulose to fenelazol must be at least 0.5:1.

[0057] Table 5: Soluplus and fenelazol weight ratio screening

[0058]

[0059] The methods for determining whether fenelazol undergoes crystallization and its solubility are the same as in Example 1. It was found that tablets prepared according to formulations 13-15 did not undergo crystallization, and the solubility of fenelazol in these tablets was 1.39-1.41 mg / mL. The solubility of formulations 11-12 was less than 0.30 mg / mL. This indicates that solid dispersion tablets using Soluplus as the polymer carrier exhibit reduced stability and crystallization when the weight ratio of Soluplus to fenelazol is 0.45:1 or lower, resulting in lower solubility. Stable amorphous fenelazol solid dispersion tablets can be obtained when the weight ratio of Soluplus to fenelazol is 0.7:1 or higher.

[0060] Table 6: Screening by weight ratio of copovidone and fenelone

[0061]

[0062] The methods for determining whether fenelazol undergoes crystallization and its solubility are the same as in Example 1. It was found that fenelazol did not undergo crystallization in the tablets prepared with formulations 17-20, and the solubility of fenelazol in the tablets was 1.38-1.43 mg / mL. The tablets prepared with formulation 16 underwent crystallization, with a solubility of 0.22 mg / mL. This example demonstrates that tablets using copovidone as a polymer carrier do not undergo crystallization when the weight ratio of copovidone to fenelazol exceeds 1:1, while the solubility is significantly increased.

[0063] Example 3

[0064]

[0065]

[0066] Preparation method of amorphous fenelitone solid dispersion tablets: Dissolve SDS in 24g of purified water, then add 96g of acetone, fenelitone and soluplus are dissolved in the above solution, stir the solution and 70% lactose evenly to prepare soft material, and then dry it. Mix the dry granules evenly with the remaining lactose, croscarmellose sodium, croscarmellose and magnesium stearate, and compress them in a tableting machine to obtain 80mg fenelitone solid dispersion tablets.

[0067] Example 4

[0068] Element weight / mg Fennedone 10 Hydroxypropyl cellulose 15 SDS 1 lactose 46 Cross-linked carboxymethyl cellulose sodium 3.6 Cross-linked polyvinylpyrrolidone 3.6 magnesium stearate 0.8 total 80

[0069] Preparation method of amorphous fenelitone solid dispersion tablets: Dissolve SDS in 24g of purified water, then add 96g of acetone. Dissolve fenelitone and hydroxypropyl cellulose in the above solution. Stir the solution and 70% lactose evenly to prepare a soft mass, then dry it. Mix the dry granules evenly with the remaining lactose, croscarmellose sodium, croscarmellose and magnesium stearate, and compress in a tableting machine to obtain 80mg fenelitone solid dispersion tablets.

[0070] Example 5

[0071]

[0072]

[0073] Preparation method of amorphous fenelitone solid dispersion tablets: Dissolve SDS in 24g of purified water, then add 96g of acetone. Dissolve fenelitone and hydroxypropyl methylcellulose in the above solution. Stir the solution and 70% lactose evenly to prepare a soft mass, then dry it. Mix the dry granules evenly with the remaining lactose, croscarmellose sodium, croscarmellose and magnesium stearate, and compress in a tableting machine to obtain 80mg fenelitone solid dispersion tablets.

[0074] Experimental Example 1: Solubility Determination

[0075] The solubility determination method was the same as in Example 1. The solubility of phenelzine crystal form I was measured to be 0.03 mg / mL. The solubilities of phenelzine in the tablets of Examples 3-5 were 1.40 mg / L, 1.42 mg / mL, and 1.43 mg / mL, respectively. The solubility of phenelzine in the tablets of Examples 3-5 is close to that of the tablets prepared from the formulations in the aforementioned examples that did not undergo crystal transformation, and shows a significant improvement compared to the solubility of phenelzine crystal form I.

[0076] Experimental Example 2: Determination of Content Uniformity

[0077] The uniformity of the two tablets was examined according to the content uniformity test method in Chapter 0941 of the General Section IV of the 2020 edition of the Chinese Pharmacopoeia:

[0078] Tablets of formulations 8, 13, and 17 in Example 2;

[0079] Comparative tablets: The active ingredients in formulations 8, 13, and 17 of Example 2 were replaced with phenelzine crystal form I. The excipients and their contents were kept the same. Phenelzine crystal form I was dry-mixed with the excipients and tableted. The tableting process did not include the step of dissolving the active ingredient in a solvent. Comparative tablets 8, 13, and 17 were obtained respectively.

[0080] Table 7: Results of Tablet Content Uniformity Test

[0081] sample Average content (%) RSD Example 2 Formula 8 99.68 1.59 Example 2 Formula 13 99.75 1.48 Example 2 Formula 17 99.93 1.41 Comparison Tablet 8 101.55 6.53 Comparison of tablets 13 103.27 5.89 Comparison of tablets 17 102.50 5.37

[0082] The average content values ​​and RSD values ​​in Table 7 show that the tablets of formulations 8, 13, and 17 in Example 2 have better content uniformity. The content uniformity A+2s values ​​in Table 7 are 3.816, 3.712, and 3.688, respectively, all less than L, which meets the requirements of Chinese Pharmacopoeia 2020 Edition 0941. The content uniformity A+2s values ​​in Table 6 are 16.144, 15.553, and 15.375, respectively, all greater than L, which does not meet the requirements of Chinese Pharmacopoeia 2020 Edition 0941.

[0083] Experimental Example 3: Dissolution Determination

[0084] Six tablets each of the samples from formulations 8, 13, and 17 of Example 2, and six tablets each of the comparative tablets 8, 13, and 17 of Test Example 2 were taken. Dissolution and release were determined according to the second method (paddle method) of the Chinese Pharmacopoeia 2020 edition, 0931, using 0.1N hydrochloric acid solution (900 mL volume), a rotation speed of 50 r / min, and sampling times of 10, 15, 20, 30, and 45 min. The drug content was determined using ultraviolet detection, and the dissolution rate was calculated. The results are shown in the table below:

[0085]

[0086] The results in the table above show that the tablets prepared by formulations 8, 13 and 17 in Example 2 of the present invention have significantly better release rates than the comparative tablets with phenelzine crystal form I as the active ingredient.

[0087] Experimental Example 4: Stability Determination

[0088] Ten tablets each of the tablets prepared from formulations 8, 13, and 17 in Example 2, and the control tablets 8, 13, and 17 in Test Example 2 were placed at 60°C for 20 days. The impurity content was measured as follows:

[0089]

[0090]

[0091] After 20 days of storage, 8 tablets of formulation 2 from Example 2 were subjected to XRPD spectral analysis, and the results are as follows. Figure 4 As shown, the amorphous fenelazol in formulation 8 of Example 2 did not transform into its crystalline form. Similarly, formulations 13 and 17 of Example 2 were subjected to XRPD spectral analysis, and the obtained spectra were consistent with... Figure 4Similarly, amorphous fenelone did not transform into crystals, indicating that the amorphous fenelone solid dispersion tablets prepared by this invention are relatively stable. In terms of total impurity content, compared to tablets made with crystalline fenelone I, the increase in impurities in the solid dispersion tablets of formulations 8, 13, and 17 in Example 2 was between 0.6% and 0.65%, while the increase in impurities in the control tablets of Experimental Example 2 was between 0.8% and 0.95%. From the perspective of the increase in total impurity content, the solid dispersion tablets of this invention are relatively stable.

[0092] Equivalent schemes and scope

[0093] Some non-limiting preferred embodiments of the present invention have been described above. Those skilled in the art can make various changes and modifications to this description without departing from the essential scope of the invention as defined by the claims. These changes and modifications should also be considered within the scope of protection of this invention.

Claims

1. An amorphous nonelinone solid dispersion tablet, characterized in that, It contains a therapeutically effective amount of amorphous fenelitonee, a filler, a disintegrant, a lubricant, and a polymeric carrier, said polymeric carrier being selected from one of polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (soluplus), hydroxypropyl cellulose, copovidone, and hydroxypropyl methylcellulose.

2. The tablet according to claim 1, characterized in that, The weight ratio of the amorphous felinone to the polymeric carrier is 1:0.5 to 1:1.5, preferably 1:0.7 to 1:1.5, and more preferably 1:1 to 1:1.

5.

3. The tablet according to any one of claims 1 to 2, characterized in that, The polymer carrier has a weight percentage of 6-19%.

4. The tablet according to any one of claims 1 to 3, characterized in that, The filler is at least one selected from microcrystalline cellulose, mannitol, starch, lactose, sucrose, sorbitol, xylitol, and maltodextrin, and the filler has a weight percentage of 57-75%.

5. The tablet according to any one of claims 1 to 4, characterized in that, The disintegrant is at least one of croscarmellose sodium, carboxymethyl starch sodium, croscarmellose or low-substituted hydroxypropyl cellulose, and the weight percentage of the disintegrant is 3-10%.

6. The tablet according to any one of claims 1 to 5, characterized in that, The lubricant is at least one of calcium stearate, sodium fumarate stearate, or magnesium stearate, and the weight percentage of the lubricant is 0.7% to 1.5%.

7. The tablet according to any one of claims 1 to 6, characterized in that, The tablets also contain a surfactant, which is Tween 80 or sodium dodecyl sulfate, and the surfactant is present in a weight percentage of 0.75 to 1.5%.

8. The tablet according to any one of claims 1 to 7, characterized in that, The fenelitone tablets comprise: 10-15% amorphous fenelitone, 57-75% lactose, 6-19% hydroxypropyl cellulose or hydroxypropyl methylcellulose, 0.75-1.5% sodium dodecyl sulfate, 3-5% crostomeric sodium cellulose, 3-5% crospovidone, and 0.7-1.5% magnesium stearate.

9. A method for preparing the amorphous fenelinone solid dispersion tablets according to any one of claims 1 to 8, characterized in that, Includes the following steps: a) Dissolve phenelzine in crystalline or amorphous form, with the polymeric carrier, in a suitable solvent, optionally with the addition of a surfactant, and dissolve. b) Mix the solution obtained in step a) with 20% to 90% of the total weight of the filler to prepare wet granules, dry them, and then mix them with the remaining filler, disintegrant and lubricant, compress them into tablets to obtain amorphous non-nephenone solid dispersion tablets. The suitable solvent is a mixture of an organic solvent and water, wherein the weight ratio of the organic solvent to water is 4 to 8:1, and the organic solvent is selected from acetone and ethanol.

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