Pharmaceutical composition containing chlorbuconazole and preparation method of pharmaceutical composition

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing chlorbuconazole and a preparation method of the pharmaceutical composition. The invention provides a pharmaceutical composition containing chlorbuconazole as well as a preparation method and application of the pharmaceutical composition. Specifically, the invention discloses a pharmaceutical composition, the pharmaceutical composition comprises chlorbuconazole or a pharmaceutically acceptable salt thereof, polyethylene glycol 400, sorbitan oleate and polysorbate 80, the chlorbuconazole or the pharmaceutically acceptable salt thereof accounts for 1-10% of the total weight of the pharmaceutical composition, and the moisture content of the pharmaceutical composition is lower than 10%. The pharmaceutical composition disclosed by the invention has good dissolution rate and relatively high stability.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a pharmaceutical composition containing chlorfenapyridine and its preparation method. Background Technology

[0002] Tafamidis is a selective stabilizer of transthyretin (TTR), with a structure shown in Formula I. The marketed product is tafamidis meglumine salt, with a structure shown in Formula II. Tafamidis meglumine soft capsules are available in Europe, the United States, and China, under the trade name [Brand Name Missing in Europe / the United States]. (20mg / capsule, equivalent to 12.2mg of chlorpromazine free acid) is used to treat adult patients with stage I symptoms of transthyretin amyloid polyneuropathy and to delay peripheral nerve function damage.

[0003]

[0004] The European Public Review Report describes the composition of chlorfenapyridine meglumine soft capsules, specifically: the capsule contents excipients are polyethylene glycol 400, sorbitan monooleate, and polysorbate 80; the capsule shell excipients are gelatin, glycerin, ferric oxide, sorbitol, dehydrated sorbitol, mannitol, titanium dioxide, and purified water. The chlorfenapyridine meglumine suspension is encapsulated into soft gelatin capsules through the preparation of a drug suspension and soft gelatin capsules.

[0005] Chinese patent CN103781770A discloses a solid form of 6-carboxy-2-(3,5-dichlorophenyl)-benzoxazole meglumine (i.e., chlorobenzoic acid meglumine). When in contact with aqueous media (such as water, phosphate buffer, and hydrochloric acid), chlorobenzoic acid easily forms a gel, which affects dissolution when administered orally.

[0006] The moisture content of the gel and contents in chlorfenapyridine soft capsules affects the stability and dissolution of chlorfenapyridine. Migration occurs within the chlorfenapyridine soft capsules, specifically the migration of moisture from the capsule shell to the contents and vice versa, leading to easy gelation of the contents and affecting dissolution. Summary of the Invention

[0007] The purpose of this invention is to provide a pharmaceutical composition containing chlorfenapyridine and its preparation method, which has good dissolution rate, high stability, simple preparation process, stable quality, and is conducive to industrial production.

[0008] This invention provides a pharmaceutical composition comprising chlorpromazine or a pharmaceutically acceptable salt thereof, polyethylene glycol 400, sorbitan oleate, and polysorbate 80, wherein the chlorpromazine or a pharmaceutically acceptable salt thereof constitutes 1% to 10% of the total weight of the pharmaceutical composition, and the water content of the pharmaceutical composition is less than 10%, preferably 5% to 8.5%, more preferably 6% to 8.5%, and even more preferably 6.8% to 8.5%. Preferably, the pharmaceutical composition consists of chlorpromazine or a pharmaceutically acceptable salt thereof, polyethylene glycol 400, sorbitan oleate, and polysorbate 80.

[0009] In some embodiments, the pharmaceutical composition contains 2% to 6% by weight of chlorpromazine or a pharmaceutically acceptable salt thereof, preferably 3% to 4%, more preferably 3% to 3.5%, and even more preferably about 3.3%.

[0010] In some embodiments, the mass ratio of chlorfenapyridine or its pharmaceutically acceptable salt, polyethylene glycol 400, sorbitan oleate, and polysorbate 80 in the pharmaceutical composition is 20:300-500:25-60:60-120, preferably 20:381-481:33-50:66-99, more preferably 20:381-481:33:66-99, and even more preferably 20:481:33:66.

[0011] Preferably, the pharmaceutically acceptable salt of chlorpromazine is chlorpromazine meglumine.

[0012] A soft capsule comprising the pharmaceutical composition of chlorpromazine and a capsule shell. Preferably, the pharmaceutical composition consists of the pharmaceutical composition of chlorpromazine and a capsule shell.

[0013] In some embodiments, the capsule shell comprises the following components: gelatin, plasticizer, colorant, light-blocking agent, and water, wherein the weight ratio of gelatin to water is 1:0.7 to 1.2, preferably 1:0.8 to 1.2, more preferably 1:0.8 to 1, and even more preferably 1:0.8 to 0.9. Preferably, the capsule shell is composed of gelatin, plasticizer, colorant, light-blocking agent, and water.

[0014] In some embodiments, the soft capsule comprises a pharmaceutical composition and a shell; the pharmaceutical composition comprises chlorpromazine or a pharmaceutically acceptable salt thereof, polyethylene glycol 400, sorbitan oleate, and polysorbate 80; the chlorpromazine or a pharmaceutically acceptable salt thereof comprises 1% to 10% of the total weight of the pharmaceutical composition, and the moisture content of the pharmaceutical composition is less than 10%; the shell comprises gelatin, plasticizer, colorant, opacifier, and water, wherein the weight ratio of gelatin to water is 1:0.7 to 1.2.

[0015] In some embodiments, the pharmaceutical composition in the soft capsule is the contents of the soft capsule dosage form. In some embodiments, the plasticizer is selected from one or more of glycerol, sorbitol, dehydrated sorbitol, partially dehydrated sorbitol liquid, 1,3-propanediol, 1,2-propanediol, polyethylene glycol, or maltitol, preferably glycerol and partially dehydrated sorbitol liquid.

[0016] In some embodiments, the colorant is one or more of yellow iron oxide, red iron oxide, or indigo, preferably yellow iron oxide.

[0017] In some embodiments, the light-blocking agent is titanium dioxide.

[0018] In some embodiments, the plasticizer is glycerol and partially dehydrated sorbitol liquid, wherein the weight ratio of glycerol to partially dehydrated sorbitol liquid is 0.5 to 14:1, preferably 0.5 to 2:1, and more preferably 2:1.

[0019] In some embodiments, the weight ratio of gelatin to plasticizer is 1 to 4:1, preferably 1 to 2:1, and more preferably 1.3 to 1.5:1.

[0020] In some embodiments, the capsule contains 20% to 60% gelatin by weight, preferably 30% to 45%, more preferably 34% to 40%, and even more preferably 38% to 40%.

[0021] In some embodiments, the capsule contains 20% to 50% water by weight, preferably 25% to 45%, more preferably 30% to 42%, and even more preferably 30% to 35%.

[0022] In some embodiments, the shell contains 15% to 50% plasticizer by weight, preferably 20% to 35%, more preferably 23% to 28%, and even more preferably 26% to 28%.

[0023] In some embodiments, the shell contains 0.05% to 2% colorant by weight, preferably 0.05% to 0.5%, more preferably 0.1% to 0.2%.

[0024] In some embodiments, the shell contains 0.1% to 2% light-blocking agent by weight, preferably 0.2% to 1%, more preferably 0.3% to 0.4%.

[0025] In some specific embodiments, the capsule shell comprises the following components by weight percentage: about 39.6% gelatin, about 32.4% water, about 27.4% plasticizer, about 0.2% colorant, and about 0.4% light-blocking agent.

[0026] In some embodiments, the soft capsule comprises a pharmaceutical composition and a shell; the pharmaceutical composition comprises chlorfenapyridine, polyethylene glycol 400, sorbitan oleate, and polysorbate 80; the pharmaceutical composition has a water content of 6.8% to 8.5%; the mass ratio of chlorfenapyridine, polyethylene glycol 400, sorbitan oleate, and polysorbate 80 in the pharmaceutical composition is 20:481:33:66; and the shell, by weight percentage, comprises about 39.6% gelatin, about 27.4% plasticizer, about 0.2% colorant, about 0.4% opacifier, and about 32.4% water.

[0027] Another aspect of the present invention provides a method for preparing a soft capsule containing chlorfenapyridine, comprising the following steps:

[0028] (1) Preparation of the pharmaceutical composition: Mix chlorfenapyridine or its pharmaceutically acceptable salt, polysorbate 80, sorbitan oleate and polyethylene glycol 400 evenly;

[0029] (2) Preparation of adhesive solution: Mix gelatin, water, plasticizer, colorant and opacifier, heat to above 60°C, swell until the gelatin solution is free of bubbles, and obtain adhesive solution;

[0030] (3) Pelletizing: The drug composition obtained in step (1) and the gelatinous liquid obtained in step (2) are pelletized using a soft capsule machine to obtain the initial soft capsule product;

[0031] (4) Dry the soft capsules obtained in step (3) to obtain soft capsules containing chlorpheniramine.

[0032] In some embodiments, after the drying step in step (4), the moisture content of the contents is controlled to be less than 10%, preferably 5% to 8.5%, more preferably 6% to 8.5%, and even more preferably 6.8% to 8.5%.

[0033] In some embodiments, the soft capsule contains 9 mg to 15 mg of chlorpromazine per unit dose, preferably 12.2 mg per unit dose.

[0034] In another aspect, the present invention provides the use of the pharmaceutical composition comprising chlorpromazine or its soft capsules as described herein in the preparation of a drug for transthyretin amyloidosis polyneuropathy.

[0035] Technical effect

[0036] The pharmaceutical composition and its soft capsule formulation of the present invention have good dissolution and stability. The preparation process of the present invention is simple and feasible, with stable quality, which is conducive to industrial production.

[0037] definition

[0038] In this invention, sorbitan oleate may be named Span 80 or sorbitan monooleate.

[0039] In this invention, polysorbate 80 may be referred to as Tween 80.

[0040] In this instruction manual, capsule skin, capsule shell, or rubber skin have the same meaning.

[0041] In this invention, the contents refer to the substance enclosed within the capsule shell.

[0042] The partially dehydrated sorbitol solution in this invention is the sorbitol-sorbitan solution described in the 2020 Pharmacopoeia as an excipient. It is a sorbitol solution partially dehydrated internally via acid catalysis. The anhydrous content is 68.0%–85.0% (g / g). The anhydrous content mainly includes D-sorbitol and 1,4-dehydrated sorbitol (i.e., 1,4-sorbitan), and may also contain mannitol, hydrogenated oligosaccharides and disaccharides, and other dehydrated sorbitols. Based on anhydrous content, it contains D-sorbitol (C6H... 14 O6) not less than 25%, 1,4-sorbitol (C6H) 12 O5) shall not be less than 15.0% (g / g).

[0043] The term "room temperature" refers to a temperature between 15°C and 30°C.

[0044] In this invention, the word “approximately” used before weight percentages indicates a range of ±10%. Detailed Implementation

[0045] The present invention will now be described in more detail through embodiments. However, these specific descriptions are only for illustrating the technical solutions of the present invention and do not constitute any limitation on the present invention.

[0046] All reagents and raw materials used in this invention are commercially available. Experimental methods without specific conditions are generally performed under standard conditions.

[0047] The method for detecting the moisture content of the contents in the embodiment is as follows: extract the contents of the soft capsules and determine the moisture content by means of the Fischer method, according to the method for moisture determination (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0832, Method 1).

[0048] The dissolution rate was determined according to the Dissolution and Release Rate Determination Method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II (Paddle Method)). The dissolution rate of the preparations obtained in the examples was determined. Specifically, 900 mL of 0.05 mol / L sodium dihydrogen phosphate solution (pH 6.8) was used as the dissolution medium. The dissolution method was the paddle method, with a rotation speed of 75 rpm and a medium temperature of 37℃ ± 0.5℃. Sampling times were 10, 15, 20, 30, 45 min, and 60 min. The drug concentration in the filtrate was determined by HPLC, and the dissolution rate was calculated. The chromatographic conditions were as follows: octadecylsilane-bonded silica gel was used as the packing material [Waters Atlantis T3 (4.6 mm × 150 mm, 3 μm) or a column with equivalent performance]; 0.1% phosphoric acid solution was used as mobile phase A, and acetonitrile was used as mobile phase B, with gradient conditions shown in the table below; the flow rate was 1.2 mL per minute; the column temperature was 45 °C; the detection wavelength was 220 nm; and the injection volume was 25 μL.

[0049]

[0050]

[0051] Example 1: Preparation of Chlorfenapyridine Dimeglumine Soft Capsules

[0052] (1) Preparation of contents: Weigh the prescribed amounts of polysorbate 80, sorbitan oleate, polyethylene glycol 400 and chlorfenapyridine, and mix and disperse them evenly;

[0053] (2) Preparation of the gelatin solution: Weigh the prescribed amounts of gelatin, glycerin, partially dehydrated sorbitol solution, yellow iron oxide, titanium dioxide and water, heat to a temperature above 60°C, and let it swell until there are no bubbles in the gelatin solution to obtain the gelatin solution.

[0054] (3) Pelletizing: The prepared gel and contents are pelletized using a soft capsule machine to obtain the initial soft capsule product;

[0055] (4) Dry the soft capsules obtained in step (3) to obtain chlorpheniramine digluconate soft capsules.

[0056] Example 2: Effect of different ratios of gelatin and water in the capsule shell on the flowability of the adhesive solution

[0057] Prepared according to the preparation method of the adhesive solution in Example 1, the different formulations are shown in Table 1 below.

[0058] Table 1. Effect of different ratios of gelatin and water in the capsule shell on the fluidity of the adhesive solution.

[0059]

[0060] The results showed that the ratio of gelatin to water directly affected the viscosity and fluidity of the gelatin solution, thus affecting the feasibility of gelling and pelleting. When the ratio of gelatin to water was 1:0.5, the gelatin solution was too viscous, with poor fluidity, resulting in thick and uneven capsules; when the ratio was 1:1.5, the gelatin solution was too thin, making it difficult to form the capsules; when the ratio of gelatin to water was between 1:0.8 and 1:1.2, the fluidity of the resulting gelatin solution was moderate.

[0061] Example 3: Effect of different ratios of glycerol and partially dehydrated sorbitol solution on the hardness and softness of capsule shells

[0062] Table 2. Proportions of different glycerol and partially dehydrated sorbitol solutions

[0063]

[0064]

[0065] The preparation method is the same as in Example 1. The plasticizer has a good moisturizing effect, preventing the soft capsules from drying out and aging. Results showed that when glycerin and partially dehydrated sorbitol were mixed as a plasticizer, and the ratio of glycerin to partially dehydrated sorbitol was 1:14, the dried capsules became hard and brittle, which was detrimental to stable storage and transportation.

[0066] Example 4: Effect of different gelatin-to-water ratios on the dissolution of chlorfenapyridine

[0067] Table 3 Composition of each embodiment

[0068]

[0069]

[0070] The preparation method is the same as in Example 1. The moisture content of the contents in each example is controlled by different drying times.

[0071] Table 4. Effect of different gelatin-to-water ratios on the dissolution of chlorfenapyridine soft capsules

[0072]

[0073] Example 5: Effect of different moisture contents on dissolution

[0074] Table 5 Composition of each embodiment

[0075]

[0076] The preparation method was the same as in Example 1. The moisture content of the contents in each example was controlled by varying the drying time. Dissolution behavior was investigated after 0 hours and after 1 month of accelerated drying (40 degrees Celsius, 75% humidity).

[0077] Table 6. Effect of dissolution of chlorfenapyridine soft capsules

[0078]

[0079]

[0080] The results showed that when the moisture content of the contents was 10.3%, the dissolution rate decreased significantly after one month of accelerated dissolution.

[0081] Example 6: Effect of different proportions of contents on sedimentation volume ratio

[0082] Example 6-1 Moisture content of different contents

[0083] Table 7 Composition of contents

[0084] composition Content (mg) Chlorfenapyridine meglumine 20 Polyethylene glycol 400 481 Polysorbate 80 66 Sorbitan oleate 33

[0085] Weigh out the prescribed amounts of polysorbate 80, sorbitan oleate, polyethylene glycol 400, and chlorfenapyridine, mix them, and disperse them evenly.

[0086] After adding different amounts of water to the contents, the sedimentation volume ratio in the contents was determined. For specific methods, refer to the sedimentation volume ratio test method under the item 0123 Oral Suspension in Part IV of the 2020 Chinese Pharmacopoeia.

[0087] Table 8 Moisture content of different contents

[0088]

[0089] The results are shown in Table 8. The results indicate that when the moisture content of the contents exceeds 10%, the sedimentation volume is relatively low, and the active ingredient, chlorfenapyridine, cannot be evenly dispersed, resulting in an unstable suspension. When the moisture content of the contents is below 8%, the suspension is stable.

[0090] Example 6-2 Different polyethylene glycol 400 contents

[0091] Table 9 Different Polyethylene Glycol 400 Contents

[0092] composition Example 6-2-1 Example 6-2-2 Example 6-2-3 Chlorfenapyridine meglumine (mg) 20 20 20 Polyethylene glycol 400 (mg) 381 481 581 Polysorbate 80 (mg) 66 66 66 Sorbitan oleate (mg) 33 33 33 Let stand at room temperature No settlement No settlement 0.92

[0093] Weigh the prescribed amounts of polysorbate 80, sorbitan oleate, polyethylene glycol 400, and chlorfenapyridine, mix them, and disperse them evenly. Measure the sedimentation volume ratio in the contents. The results are shown in Table 9.

[0094] Examples 6-3: Different polysorbate 80 contents

[0095] Table 10 Different Polysorbate 80 Contents

[0096] composition Example 6-3-1 Example 6-3-2 Example 6-3-3 Chlorfenapyridine meglumine (mg) 20 20 20 Polyethylene glycol 400 (mg) 481 481 481 Polysorbate 80 (mg) 33 66 99 Sorbitan oleate (mg) 33 33 33 Let stand at room temperature 0.85 No settlement No settlement

[0097] Weigh the prescribed amounts of polysorbate 80, sorbitan oleate, polyethylene glycol 400, and chlorfenapyridine, mix them, and disperse them evenly. Measure the sedimentation volume ratio in the contents. The results are shown in Table 10.

[0098] Example 7 Stability Experiment

[0099] Table 11 Prescription Composition

[0100] Prescription composition Chlorfenapyridine meglumine (mg) 20 Polyethylene glycol 400 (mg) 481 Polysorbate 80 (mg) 66 Sorbitan oleate (mg) 33 Gelatin (mg) 216.6 Water (mg) 177.6 Partially dehydrated sorbitol solution (mg) 50 Glycerin (mg) 100 Yellow iron oxide (mg) 1 Titanium dioxide (mg) 2.1

[0101] The preparation method is the same as in Example 1, and a pilot production of 100,000 capsules was conducted. Stability was assessed by placing the capsules under conditions of 40 degrees Celsius and 75% high humidity.

[0102] Table 12 Stability test results

[0103]

Claims

1. A pharmaceutical composition comprising chlorpromazine or a pharmaceutically acceptable salt thereof, polyethylene glycol 400, sorbitan oleate, and polysorbate 80, wherein the chlorpromazine or a pharmaceutically acceptable salt thereof comprises 1% to 10% of the total weight of the pharmaceutical composition, preferably 2% to 6%, more preferably 3% to 4%, and even more preferably 3% to 3.5%; wherein the moisture content of the pharmaceutical composition is less than 10%, preferably 5% to 8.5%, more preferably 6% to 8.5%, and even more preferably 6.8% to 8.5%; preferably, the pharmaceutically acceptable salt of chlorpromazine is chlorpromazine meglumine.

2. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of chlorfenapyridine or its pharmaceutically acceptable salt, polyethylene glycol 400, sorbitan oleate, and polysorbate 80 in the pharmaceutical composition is 20:300-500:25-60:60-120, preferably 20:381-481:33-50:66-99, and more preferably 20:381-481:33: 66 to 99, with a further preferred ratio of 20:481:33:

66.

3. A soft capsule comprising the pharmaceutical composition of claim 1 or 2 and a shell, wherein the pharmaceutical composition in the soft capsule is the contents of the soft capsule dosage.

4. The soft capsule according to claim 3, characterized in that, The shell comprises the following components: gelatin, plasticizer, colorant, opacifier and water; wherein the weight ratio of gelatin to water is 1:0.7 to 1.2, preferably 1:0.8 to 1.2, more preferably 1:0.8 to 1, and even more preferably 1:0.8 to 0.

9.

5. The soft capsule according to claim 4, characterized in that, The plasticizer is selected from one or more of glycerol, sorbitol, dehydrated sorbitol, partially dehydrated sorbitol liquid, 1,3-propanediol, 1,2-propanediol, polyethylene glycol or maltitol, preferably glycerol and partially dehydrated sorbitol liquid; And / or, the colorant is one or more of yellow iron oxide, red iron oxide or indigo, preferably yellow iron oxide; And / or, the light-blocking agent is titanium dioxide.

6. The soft capsule according to claim 5, wherein the plasticizer is glycerin and partially dehydrated sorbitol liquid, wherein the weight ratio of glycerin to partially dehydrated sorbitol liquid is 0.5 to 14:1, preferably 0.5 to 2:1, more preferably 2:

1.

7. The soft capsule according to claim 4, characterized in that, The weight ratio of gelatin to plasticizer is 1 to 4:1, preferably 1 to 2:1, and more preferably 1.3 to 1.5:

1.

8. The soft capsule according to claim 4, characterized in that, The capsule contains 20% to 60% gelatin by weight, preferably 30% to 45%, more preferably 34% to 40%, and even more preferably 38% to 40%; and / or the capsule contains 20% to 50% water, preferably 25% to 45%, more preferably 30% to 42%, and even more preferably 30% to 35%. And / or, the shell contains 15% to 50% plasticizer, preferably 20% to 35%, more preferably 23% to 28%, and even more preferably 26% to 28%; And / or, the capsule contains 0.05% to 2% of a colorant, preferably 0.05% to 0.5%, more preferably 0.1% to 0.2%; And / or, the shell contains 0.1% to 2% of a light-blocking agent, preferably 0.2% to 1%, more preferably 0.3% to 0.4%.

9. A method for preparing the soft capsules according to any one of claims 3-8, comprising the following steps: (1) Preparation of the pharmaceutical composition: Mix chlorfenapyridine or its pharmaceutically acceptable salt, polysorbate 80, sorbitan oleate and polyethylene glycol 400 evenly; (2) Preparation of adhesive solution: Mix gelatin, water, plasticizer, colorant and opacifier, heat to above 60°C, swell until the gelatin solution is free of bubbles, and obtain adhesive solution; (3) Pelletizing: The drug composition obtained in step (1) and the gelatin obtained in step (2) are pelletized using a soft capsule machine to obtain the initial soft capsule product; (4) Dry the soft capsules obtained in step (3) to obtain soft capsules containing chlorfenapyridine; Preferably, after the drying step in step (4), the moisture content of the pharmaceutical composition is controlled to be less than 10%, preferably 5% to 8.5%, more preferably 6% to 8.5%, and even more preferably 6.8% to 8.5%.

10. The soft capsule according to claim 3, characterized in that, The unit dose is 9 mg to 15 mg, preferably 12.2 mg, based on chlorpromazine.

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