CN111888477B - Bedaquinoline pharmaceutical preparation - Google Patents
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- CN111888477B CN111888477B CN202010967278.1A CN202010967278A CN111888477B CN 111888477 B CN111888477 B CN 111888477B CN 202010967278 A CN202010967278 A CN 202010967278A CN 111888477 B CN111888477 B CN 111888477B
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K9/2004—Excipients; Inactive ingredients
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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention provides a bedaquiline pharmaceutical preparation which comprises a bedaquiline solid composition and an auxiliary material, wherein the bedaquiline solid composition comprises bedaquiline or a pharmaceutically acceptable salt thereof, an acidifier and an adhesive. The bedaquiline pharmaceutical preparation prepared by the invention aims to overcome the problem of poor bedaquiline dissolution effect, has better dissolution rate, meets the standard requirement on the quality of the obtained product, and is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to a pharmaceutical preparation for treating pulmonary tuberculosis, in particular to a bedaquiline pharmaceutical preparation and a preparation method thereof.
Background
Bedaquine Fumarate (Bedaquiline Fumarate) is a novel drug developed by the pharmaceutical industry of Yangsen, a Jongsheng Qinshengzi company for treating multi-drug resistant tuberculosis. 12 months 2012, FDA approved bedaquiline fumarate tablets to be marketed in the united states. The drug is currently marketed in several countries including the united states, europe, japan, and the like. In 2016, 11 months, the Bedaquine fumarate tablet approved by the national drug administration (NMPA) is imported and marketed in China, is a diaryl quinoline antimycobacterial drug, is used as a part of combined treatment, is suitable for treating adult (more than or equal to 18 years old) multi-drug resistant tuberculosis (MDR-TB), and has a trade name of
Bedaquine fumarate has the chemical name (1R, 2S) -1- (6-bromo-2-methoxy-3-quinolinyl) -4- (dimethylamino) -2- (1-naphthyl) -1-phenyl-2-butanol fumarate (1:1) and the structural formula:
bedaquine fumarate is white or white-like powder, is insoluble in water, is an insoluble drug, belongs to BCS II class, namely low-solubility high-permeability drugs, and the dissolution of the drugs is often the rate-limiting process of absorption. As is well known, the dissolution of the medicament is the premise of playing a therapeutic role, and how to improve the dissolution of the oral solid preparation of the bedaquiline fumarate by a preparation technology ensures that the product effectively plays the therapeutic role has very important significance and value.
For the development of formulations of poorly soluble drugs, developers generally choose to prepare them as solid dispersions or add surfactants to increase their solubility, depending on the properties of the particular compound. However, the preparation of the solid dispersion needs to add operation steps and has high requirements on equipment, and the surfactant has little influence on the dissolution of the bedaquiline fumarate, so how to overcome the defect of poor water solubility of the bedaquiline fumarate and obtain a pharmaceutical preparation with good dissolution rate, simple preparation process and uniform product quality is a problem to be solved urgently.
Disclosure of Invention
The invention provides a bedaquiline pharmaceutical preparation, aiming at overcoming the problem of poor dissolution effect of bedaquiline. The bedaquiline medicinal preparation prepared by the invention has better dissolution rate, the quality of the obtained product meets the standard requirement, and the bedaquiline medicinal preparation is suitable for industrial large-scale production.
The bedaquiline pharmaceutical preparation comprises a bedaquiline solid composition and an auxiliary material, wherein the bedaquiline solid composition comprises bedaquiline or a pharmaceutically acceptable salt thereof, an acidifier and a binder.
The quality dosage of the bedaquiline solid composition is as follows: 100 parts of bedaquiline or its pharmaceutically acceptable salt, 25-50 parts of acidifier, and 5-15 parts of binder, wherein the dosage of bedaquiline pharmaceutically acceptable salt is calculated by bedaquiline.
The pharmaceutically acceptable salt of bedaquiline is bedaquiline fumarate.
Wherein the acidulant is selected from one or more of fumaric acid, sorbic acid and malic acid. The adhesive is selected from one or more of hypromellose, hydroxypropyl cellulose, sodium carboxymethylcellulose and polyvidone.
The grain diameter d0.9 of the bedaquiline or the pharmaceutically acceptable salt thereof disclosed by the invention is less than 50 microns, and the grain diameter of more than 60% of the bedaquiline solid composition in percentage by mass is less than 150 microns. More preferably, the beraquiline or the pharmaceutically acceptable salt thereof has a particle size d0.9 of 35 μm or less, and 80% or more by mass of the beraquiline solid composition has a particle size of 150 μm or less.
The invention discloses a bedaquiline medicinal preparation, which comprises the following components in part by mass: 100 parts of bedaquiline or pharmaceutically acceptable salt thereof, 25-50 parts of acidifier, 5-15 parts of binder, 80-160 parts of diluent, 6-18 parts of disintegrant and 3-8 parts of lubricant, wherein the dosage of the bedaquiline pharmaceutically acceptable salt is calculated by the bedaquiline.
Wherein the diluent is selected from one or more of microcrystalline cellulose, corn starch, lactose and pregelatinized starch; the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; the lubricant is one or more selected from pulvis Talci, magnesium stearate, sodium stearyl fumarate, and silica gel.
The invention also discloses a method for preparing the bedaquiline medicinal preparation. In particular, the invention discloses a method for preparing the bedaquiline solid composition, which comprises the following steps:
(1) Adding an acidifier and an adhesive into an ethanol aqueous solution containing 50-90% of ethanol, and dissolving to prepare a mixed solution;
(2) And (3) adding the mixed solution into the bedaquiline or the pharmaceutically acceptable salt thereof in a spraying way, granulating, drying and finishing to obtain the bedaquiline solid composition.
Mixing the bedaquiline solid composition with a diluent, a disintegrating agent and a lubricant, and tabletting to obtain the bedaquiline pharmaceutical preparation.
The invention provides a Bedaquin medicinal preparation with simple preparation method and high dissolution rate, and the preparation contains a Bedaquin solid composition. The bedaquiline solid composition is a medicine particle containing bedaquiline or a pharmaceutically acceptable salt thereof, a weak acid auxiliary material (namely an acidifier) and an adhesive, the bedaquiline or the pharmaceutically acceptable salt thereof is wrapped by the weak acid auxiliary material to form the medicine particle, and the medicine particle and other auxiliary materials are prepared into a bedaquiline medicine preparation, so that the dissolution effect can be obviously improved, and the bioavailability is increased. In some embodiments, the same batch of the bedaquiline fumarate is wrapped by weakly acidic auxiliary materials and the bedaquiline fumarate is not wrapped by the weakly acidic auxiliary materials to respectively prepare the bedaquiline solid composition, and the same other auxiliary materials are added for tabletting, so that the dissolution experiment result shows that the preparation wrapped by the weakly acidic auxiliary materials has a good dissolution effect.
In particular, in some embodiments, when the particle size d0.9 of the bedaquiline or the pharmaceutically acceptable salt thereof is below 35 μm, and the particle size of more than 80% of the bedaquiline solid composition is below 150 μm, the bedaquiline preparation has a fast dissolution speed and a better dissolution effect.
Detailed Description
Example 1
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding fumaric acid and hypromellose into 220mL ethanol water solution containing 80% ethanol, and dissolving to obtain mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 38 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 60% (w/w).
(2) Preparation of a bedaquiline formulation:
and mixing the solid composition of the bedaquiline with lactose, sodium carboxymethyl starch and magnesium stearate, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 2
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding sorbic acid and sodium carboxymethyl cellulose into 240mL of ethanol aqueous solution containing 50% ethanol in proportion to dissolve to prepare mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 50 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 63.6% (w/w).
(2) Preparation of a bedaquiline formulation:
and mixing the bedaquiline solid composition with microcrystalline cellulose, lactose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and magnesium stearate, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 3
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding malic acid and hydroxypropyl cellulose into 250mL of ethanol water solution containing 70% ethanol, and dissolving to obtain mixed solution;
(ii) And (3) spraying the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 46 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 68.9% (w/w).
(2) Preparation of a bedaquiline formulation:
and mixing the bedaquiline solid composition with microcrystalline cellulose, lactose, crospovidone, croscarmellose sodium and sodium stearyl fumarate, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 4
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Dissolving fumaric acid, sorbic acid, polyvidone and hydroxypropyl cellulose in 200mL ethanol water solution containing 80% ethanol to obtain mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 40 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 72.4% (w/w).
(2) Preparation of bedaquiline formulation:
and mixing the solid composition of the bedaquiline with lactose, corn starch, crospovidone, magnesium stearate and aerosil, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 5
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding fumaric acid, malic acid, sodium carboxymethylcellulose and hydroxypropyl cellulose into 250mL of ethanol aqueous solution containing 50% ethanol, and dissolving to obtain mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 45 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 76.5% (w/w).
(2) Preparation of bedaquiline formulation:
mixing the solid composition of the bedaquiline with lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate and talcum powder, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 6
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding fumaric acid and hydroxypropyl methylcellulose into 150mL of ethanol water solution containing 90% ethanol, and dissolving to obtain a mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 35 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 80.3% (w/w).
(2) Preparation of a bedaquiline formulation:
and mixing the solid composition of the bedaquiline with lactose, sodium carboxymethyl starch and magnesium stearate, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 7
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding sorbic acid and sodium carboxymethyl cellulose into 150mL ethanol water solution containing 60% ethanol to dissolve to prepare mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 23 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of the particles with the particle size less than 150 mu m in the solid composition is 86.6% (w/w).
(2) Preparation of a bedaquiline formulation:
and mixing the bedaquiline solid composition with microcrystalline cellulose, lactose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and magnesium stearate, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Example 8
The preparation method comprises the following steps:
(1) Preparation of a bedaquiline solid composition:
(i) Adding malic acid and hydroxypropyl cellulose into 200mL of ethanol water solution containing 50% ethanol, and dissolving to obtain mixed solution;
(ii) And (3) spraying and adding the mixed solution into the bedaquiline fumarate with the particle size d0.9 of 18 mu m in a fluidized bed, granulating, drying and finishing to obtain the bedaquiline solid composition, wherein the weight proportion of particles with the particle size of less than 150 mu m in the solid composition is 82.5% (w/w).
(2) Preparation of a bedaquiline formulation:
and mixing the bedaquiline solid composition with microcrystalline cellulose, lactose, crospovidone, croscarmellose sodium and sodium stearyl fumarate, and tabletting to obtain the bedaquiline pharmaceutical preparation.
Comparative example
The preparation method comprises the following steps:
1. formulations 1, 3 and 5 were prepared in the same manner as in example 1, wherein the solid composition had a weight proportion of particles having a particle size of less than 150 μm of 60% (w/w).
2. Formulations 2, 4 and 6 were prepared by mixing bedaquiline fumarate, lactose, sodium carboxymethyl starch and magnesium stearate uniformly and tabletting by direct compression, wherein the solid composition had a weight proportion of 60% (w/w) of granules having a particle size of less than 150 μm.
Dissolution study
The samples prepared in examples 1 to 8 and comparative recipes 1 to 6 were taken and the eluates were taken at 5, 10, 15, 20, 30, 45 and 60min for HPLC measurements using 0.01mol/L hydrochloric acid solution as dissolution medium and at 50 rpm in accordance with the dissolution method (slurry method), and the experimental results were as follows:
according to the experimental results, the bedaquiline fumarate, the acidifier and the binder form a bedaquiline solid composition, and the bedaquiline fumarate is mixed with other auxiliary materials for tabletting, so that the dissolution rate of the bedaquiline fumarate can be obviously improved. Further, the dissolution effect is more excellent when the particle diameter d0.9 of the pharmaceutically acceptable salt of beraquiline is 35 μm or less and the particle size 80% w/w or more in the beraquiline solid composition is 150 μm or less.
Claims (5)
1. The bedaquiline pharmaceutical preparation comprises a bedaquiline solid composition and an auxiliary material, wherein the bedaquiline solid composition comprises bedaquiline or a pharmaceutically acceptable salt thereof, an acidifier and a binder, and the auxiliary material is selected from a diluent, a disintegrant and a lubricant, and is characterized in that the grain diameter d0.9 of the bedaquiline or the pharmaceutically acceptable salt thereof is less than 50 mu m, and the grain diameter of more than 60% of the bedaquiline solid composition by mass is less than 150 mu m; the acidulant is selected from one or more of fumaric acid, sorbic acid and malic acid; the adhesive is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose and povidone; the diluent is selected from one or more of microcrystalline cellulose, corn starch, lactose and pregelatinized starch; the disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone and croscarmellose sodium; the lubricant is selected from one or more of talcum powder, magnesium stearate, sodium stearyl fumarate and superfine silica gel powder; and the mass dosage of the pharmaceutical preparation is as follows: 100 parts of bedaquiline or pharmaceutically acceptable salt thereof, 25-50 parts of acidifier, 5-15 parts of binder, 80-160 parts of diluent, 6-18 parts of disintegrant and 3-8 parts of lubricant, wherein the dosage of the bedaquiline pharmaceutically acceptable salt is calculated by the bedaquiline.
2. The bedaquiline pharmaceutical preparation according to claim 1, wherein the bedaquiline or the pharmaceutically acceptable salt thereof has a particle size d0.9 of 35 μm or less, and 80% by mass or more of the bedaquiline solid composition has a particle size of 150 μm or less.
3. The pharmaceutical formulation of bedaquiline according to any one of claims 1 to 2, wherein the pharmaceutically acceptable salt of bedaquiline is bedaquiline fumarate.
4. A process for preparing a pharmaceutical preparation of bedaquiline according to any one of claims 1 to 2, comprising the steps of preparing a solid composition of bedaquiline:
(1) Adding an acidifying agent and an adhesive into an ethanol water solution containing 50-90% of ethanol, and dissolving to prepare a mixed solution;
(2) And (3) adding the mixed solution into bedaquiline or pharmaceutically acceptable salt thereof in a fluidized bed in a spraying way, granulating, drying and finishing to obtain the bedaquiline solid composition.
5. The method for preparing a bedaquiline pharmaceutical preparation according to claim 4, wherein the bedaquiline solid composition is mixed with a diluent, a disintegrant and a lubricant and compressed into tablets to obtain the bedaquiline pharmaceutical preparation.
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| CN101547904A (en) * | 2006-12-05 | 2009-09-30 | 詹森药业有限公司 | Fumarate salt of (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol |
| CN103784412A (en) * | 2014-01-15 | 2014-05-14 | 青岛市肿瘤医院 | Icotinib hydrochloride dispersible tablet and preparation method thereof |
| CN103860497A (en) * | 2014-03-14 | 2014-06-18 | 王志刚 | Meloxicam dispersible tablet and preparation method thereof |
| WO2017030605A2 (en) * | 2014-12-04 | 2017-02-23 | Thomas Manning | Tablet composition for anti-tuberculosis antibiotics |
| CN107205945A (en) * | 2015-01-27 | 2017-09-26 | 詹森药业有限公司 | Dispersible composition |
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2020
- 2020-09-15 CN CN202010967278.1A patent/CN111888477B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101547904A (en) * | 2006-12-05 | 2009-09-30 | 詹森药业有限公司 | Fumarate salt of (alpha S, beta R)-6-bromo-alpha-[2-(dimethylamino)ethyl]-2-methoxy-alpha-1-naphthalenyl-beta-phenyl-3-quinolineethanol |
| CN103784412A (en) * | 2014-01-15 | 2014-05-14 | 青岛市肿瘤医院 | Icotinib hydrochloride dispersible tablet and preparation method thereof |
| CN103860497A (en) * | 2014-03-14 | 2014-06-18 | 王志刚 | Meloxicam dispersible tablet and preparation method thereof |
| WO2017030605A2 (en) * | 2014-12-04 | 2017-02-23 | Thomas Manning | Tablet composition for anti-tuberculosis antibiotics |
| CN107205945A (en) * | 2015-01-27 | 2017-09-26 | 詹森药业有限公司 | Dispersible composition |
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