CN116803392A - Pharmaceutical composition of bedaquiline and preparation method thereof - Google Patents
Pharmaceutical composition of bedaquiline and preparation method thereof Download PDFInfo
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- CN116803392A CN116803392A CN202310964214.XA CN202310964214A CN116803392A CN 116803392 A CN116803392 A CN 116803392A CN 202310964214 A CN202310964214 A CN 202310964214A CN 116803392 A CN116803392 A CN 116803392A
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- Prior art keywords
- bedaquiline
- pharmaceutically acceptable
- poloxamer
- pharmaceutical composition
- composition
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- 229960000508 bedaquiline Drugs 0.000 title claims abstract description 37
- QUIJNHUBAXPXFS-XLJNKUFUSA-N bedaquiline Chemical group C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 QUIJNHUBAXPXFS-XLJNKUFUSA-N 0.000 title claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229920001983 poloxamer Polymers 0.000 claims abstract description 57
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 51
- 229960000502 poloxamer Drugs 0.000 claims abstract description 49
- 239000002245 particle Substances 0.000 claims abstract description 33
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000000463 material Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 41
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 25
- 239000011230 binding agent Substances 0.000 claims description 12
- 229960001137 bedaquiline fumarate Drugs 0.000 claims description 11
- ZLVSPMRFRHMMOY-WWCCMVHESA-N bedaquiline fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1([C@H](C2=CC3=CC(Br)=CC=C3N=C2OC)[C@@](O)(CCN(C)C)C=2C3=CC=CC=C3C=CC=2)=CC=CC=C1 ZLVSPMRFRHMMOY-WWCCMVHESA-N 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000008247 solid mixture Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
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- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 210000003918 fraction a Anatomy 0.000 claims description 4
- 238000011049 filling Methods 0.000 claims description 3
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- 238000003825 pressing Methods 0.000 claims description 3
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- GNENVASJJIUNER-UHFFFAOYSA-N 2,4,6-tricyclohexyloxy-1,3,5,2,4,6-trioxatriborinane Chemical compound C1CCCCC1OB1OB(OC2CCCCC2)OB(OC2CCCCC2)O1 GNENVASJJIUNER-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 1
- 229920002511 Poloxamer 237 Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 241000209149 Zea Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- -1 and the like Substances 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
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- 229920001531 copovidone Polymers 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
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- 229960000913 crospovidone Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
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- 230000002496 gastric effect Effects 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
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- 238000004519 manufacturing process Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 239000007935 oral tablet Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
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- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- Medicinal Preparation (AREA)
Abstract
The invention discloses a pharmaceutical composition of bedaquiline and a preparation method thereof, the pharmaceutical composition comprises an intra-particle part, wherein the intra-particle part comprises bedaquiline and pharmaceutically acceptable salts thereof, poloxamer and at least one pharmaceutically acceptable auxiliary material, and an extra-particle part comprises poloxamer and at least one pharmaceutically acceptable auxiliary material. The present invention aims to overcome the problem of poor dissolution profile of bedaquiline and provide better dissolution rate. The invention also relates to a method for preparing the pharmaceutical composition.
Description
Technical Field
The invention relates to the technical field of pharmaceutical compositions of quinolines, in particular to a pharmaceutical composition of bedaquiline and a preparation method thereof.
Background
Bedaquinoline (i.e., bedaquinoline fumarate) asOral tablets are approved in the united states. />Is anti-mycobacteriaThe medicine is suitable for the combined treatment of adult and children (5 years old and older, weight of at least 15 kg) patients with multi-drug resistant pulmonary tuberculosis. Bedapsone inhibits mycobacterial ATP (5' -adenosine triphosphate) synthase by binding to subunit-C of the enzyme necessary for energy production by Mycobacterium tuberculosis. Bedapsone is a white to almost white powder, almost insoluble in aqueous media, belonging to BCS class II, with low solubility and high permeability. It is well known that the difficulty with BCS class II drugs is that the bioavailability of these drugs is limited to their solubility. Thus, the absorption of a poorly water-soluble drug of BCS class II (e.g., bedaquiline) from an oral solid composition is controlled by its dissolution rate in gastrointestinal fluids present at the site of absorption. Since BCS class II drugs generally show low solubility, low dissolution rates and thus low bioavailability. According to the European drug administration CHMP report, bedaquiline is susceptible to significant decomposition under acidic conditions. Thus, there is a need to prepare pharmaceutical compositions of bedaquiline fumarate without acidulant to provide better dissolution profile/rate
Disclosure of Invention
The invention provides a pharmaceutical composition of bedaquiline and a preparation method thereof, and provides a pharmaceutical composition of bedaquiline and pharmaceutically acceptable salts thereof with better dissolution rate.
In order to achieve the above purpose, the present invention provides the following technical solutions:
the invention provides a pharmaceutical composition of bedaquiline, comprising: the pharmaceutical composition comprises an intra-particle part, wherein the intra-particle part comprises bedaquiline and pharmaceutically acceptable salts thereof, poloxamer and at least one pharmaceutically acceptable auxiliary material; and b an extra-granular portion comprising a poloxamer and at least one pharmaceutically acceptable excipient.
Optionally, the intra-particle portion a comprises 30-50% of bedaquiline and pharmaceutically acceptable salts thereof, 1-3% of poloxamer and at least one pharmaceutically acceptable auxiliary material; the extra-granular fraction comprising 1-3% poloxamer and at least one pharmaceutically acceptable excipient, wherein the percentages are based on the total weight of the composition.
Optionally, the intra-particle fraction a comprises 35-40% bedaquiline fumarate, 1-3% poloxamer and at least one pharmaceutically acceptable excipient; the extra-granular fraction comprising 1-3% poloxamer and at least one pharmaceutically acceptable excipient, wherein the percentages are based on the total weight of the composition.
Optionally, the intra-particle fraction a comprises 30-50% bedaquiline fumarate, 1-3% poloxamer, 1-10% binder, and 20-35% diluent; b an extra-granular portion comprising 1-3% poloxamer, 15% to 25% diluent, 1% to 10% disintegrant, 1% to 5% glidant, and 1% to 5% lubricant, wherein the percentages are based on the total weight of the composition.
Alternatively, the pharmaceutical composition is a solid composition, and pharmaceutically acceptable excipients of the solid composition may be used.
The invention provides a preparation method of a pharmaceutical composition of bedaquiline, which comprises the following steps:
firstly, preparing a solution of poloxamer and a binder in a solvent;
secondly, mixing the solution prepared in the first step with the bedaquiline, pharmaceutically acceptable salts thereof and optionally at least one pharmaceutically acceptable auxiliary material to prepare particles;
third, drying the granules obtained in the second step;
fourth, mixing the particles dried in the third step with poloxamer and at least one pharmaceutically acceptable auxiliary material to obtain a mixture;
and fifth, pressing the mixture obtained in the fourth step into tablets or filling capsules.
Alternatively, the solution prepared in the first step is a solution of 1-3% poloxamer and a binder, the solution is sprayed in the second step onto 30-50% bedaquiline fumarate and optionally at least one pharmaceutically acceptable excipient placed on a fluid bed to prepare particles, and in the fourth step 1-3% poloxamer and at least one pharmaceutically acceptable excipient are mixed with the particles after drying in the third step.
Alternatively, the drying of the particles may be carried out at a temperature of 50.+ -. 15 ℃.
Optionally, the solvent is selected from the group consisting of water, ethanol, isopropanol, and mixtures thereof.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The main object of the present invention is to provide a pharmaceutical composition of bedaquiline and its pharmaceutically acceptable salts with better dissolution rate, wherein the composition comprises poloxamers in the intra-and extra-granular parts.
The term "composition" as used in the present invention is meant to include tablets, granules, capsules, minitablets or pellets. Immediate release tablets are preferred.
The invention provides a technical scheme that: a pharmaceutical composition of bedaquiline, said pharmaceutical composition comprising an intra-granular fraction comprising bedaquiline and pharmaceutically acceptable salts thereof, poloxamer and at least one pharmaceutically acceptable excipient; and b an extra-granular portion comprising a poloxamer and at least one pharmaceutically acceptable excipient.
The term "intra-granular fraction" as used in the present invention refers to a granule comprising bedaquiline and pharmaceutically acceptable salts thereof, poloxamer and at least one pharmaceutically acceptable adjuvant. The granules may be obtained by granulation, preferably wet granulation, more preferably fluid bed granulation.
The term "extra-granular fraction" as used in the present invention refers to one or more pharmaceutically acceptable excipients, including poloxamers, mixed with the intra-granular fraction.
The term "%" as used in mass standards refers to the percentage of the total weight of the composition, unless otherwise specified.
Further, the intra-particle part a comprises 30-50% of bedaquiline and pharmaceutically acceptable salts thereof, 1-3% of poloxamer and at least one pharmaceutically acceptable auxiliary material; the extra-granular fraction comprising 1-3% poloxamer and at least one pharmaceutically acceptable excipient, wherein the percentages are based on the total weight of the composition. In the present invention, bedaquiline may be used as a base or in the form of a pharmaceutically acceptable salt, preferably in the form of a fumarate salt. The amount of bedaquiline fumarate is 30-50% of the total weight of the composition, preferably 35-40% of the total weight of the composition.
Further, the intra-particle portion a comprises 35-40% of bedaquiline fumarate, 1-3% of poloxamer and at least one pharmaceutically acceptable excipient; the extra-granular fraction comprising 1-3% poloxamer and at least one pharmaceutically acceptable excipient, wherein the percentages are based on the total weight of the composition.
Further, the intra-particle fraction a comprises 30-50% bedaquiline fumarate, 1-3% poloxamer, 1-10% binder, and 20-35% diluent; b an extra-granular portion comprising 1-3% poloxamer, 15% to 25% diluent, 1% to 10% disintegrant, 1% to 5% glidant, and 1% to 5% lubricant, wherein the percentages are based on the total weight of the composition.
Further, the pharmaceutical composition is a solid composition, and pharmaceutically acceptable excipients of the solid composition may be used.
Poloxamers are also known as polyoxyethylene-polyoxypropylene block copolymers. In the present invention, a particular class of poloxamers may be used, such as poloxamer 108, poloxamer 188, poloxamer 237 or poloxamer 288. The amount of poloxamer in the intra-granular fraction is 1-3% of the total weight of the composition, and the amount of poloxamer in the extra-granular fraction is 1-3% of the total weight of the composition.
Pharmaceutically acceptable excipients which may be used according to the invention are well known for the preparation of pharmaceutical compositions. Preferably, the pharmaceutical composition of the present invention is a solid composition, and pharmaceutically acceptable excipients for the solid composition may be selected from, but not limited to, diluents, binders, disintegrants, lubricants, glidants/anti-adherent agents and solvents.
The diluent is selected from microcrystalline cellulose (MCC), powdered cellulose, lactose monohydrate, lactose anhydrous, sucrose, sorbitol, xylitol, mannitol, maltodextrin, modified starches such as pregelatinized starch, corn flour, corn starch and mixtures thereof. The present invention comprises a diluent in an amount of about 35% to about 55% by weight of the total pharmaceutical composition.
The binder is selected from the group comprising povidone, copovidone, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, propylene glycol, polyvinyl alcohol and mixtures thereof. The present invention comprises a binder in an amount of from about 1% to about 10% by weight of the total composition, preferably from 1% to 5% by weight of the total composition.
The disintegrant is selected from the group comprising crospovidone, croscarmellose sodium (CCS), hydroxypropyl cellulose (L-HPC), and mixtures thereof. The present invention comprises a disintegrant in an amount of about 1% to about 10% by weight of the total composition, preferably 1% to 5% by weight of the total composition.
The glidant is selected from the group consisting of talc, colloidal silicon dioxide, magnesium stearate and mixtures thereof. The present invention comprises a glidant in an amount of about 1% to about 5% by weight of the total composition, preferably 1% to 3% by weight of the total composition.
The lubricant is selected from the group comprising sodium stearyl fumarate, calcium stearate, stearic acid, polyethylene glycol, and mixtures thereof. The present invention comprises a lubricant in an amount of from about 1% to about 5% by weight of the total composition, preferably from 1% to 3% by weight of the total composition.
Pharmaceutically acceptable solvents may include, but are not limited to, water, ethanol, isopropanol, and the like, or mixtures thereof. Solvents or solvent mixtures may be used for wet granulation and film coating.
The composition of the present invention may be a coating composition, preferably a film coating composition. The film coating may comprise one or more film-forming polymers and suitable coating adjuvants. Suitable film-forming polymers are selected from the group of hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol or mixtures thereof. Suitable coating excipients may also contain opacifiers such as titanium dioxide, glidants such as talc and pigments such as yellow iron oxide.
The pharmaceutical compositions of the present invention are for oral administration and may be in the form of tablets, capsules, minitablets, granules or pellets. Preferably, the pharmaceutical composition of the present invention is an immediate release tablet.
The inventors of the present invention have surprisingly found that the use of poloxamers with bedaquiline and pharmaceutically acceptable salts thereof in the intra-granular fraction and the use of poloxamers in the extra-granular fraction provides better dissolution rates.
The following examples are intended to illustrate the scope of the invention, but are not limited thereto.
Examples (poloxamer containing) and comparative examples (poloxamer free)
The preparation method of the pharmaceutical composition of the bedaquiline is characterized by comprising the following steps: the method comprises the following steps:
firstly, preparing a solution of poloxamer and a binder in a solvent;
secondly, mixing the solution prepared in the first step with the bedaquiline, pharmaceutically acceptable salts thereof and optionally at least one pharmaceutically acceptable auxiliary material to prepare particles;
third, drying the granules obtained in the second step;
fourth, mixing the particles dried in the third step with poloxamer and at least one pharmaceutically acceptable auxiliary material to obtain a mixture;
and fifth, pressing the mixture obtained in the fourth step into tablets or filling capsules.
Further, the solution prepared in the first step is a solution of 1-3% poloxamer and a binder, the solution is sprayed on 30-50% bedaquiline fumarate and optionally at least one pharmaceutically acceptable excipient placed on a fluidized bed in the second step to prepare particles, and 1-3% poloxamer and at least one pharmaceutically acceptable excipient are mixed with the particles dried in the third step in the fourth step.
Further, the drying of the particles may be performed at a temperature of 50±15 ℃.
Comparison (no poloxamer) tablets were prepared with the same process without poloxamer.
Dissolution data of the above examples and comparative examples:
the tablets in the above examples and comparative examples were taken and analyzed at 50rpm in 0.01N hydrochloric acid solution as a dissolution medium using a paddle method. Samples were collected at 5, 15, 30, 45 and 60 minute intervals and evaluated using HPLC methods. The experimental results are shown in the following Table-2:
as is apparent from the results given in the above table, the dissolution rates of poloxamers with intra-particle and extra-particle poloxamers in the examples of the present invention are superior to those of the comparative examples without poloxamer.
Accordingly, the present invention provides pharmaceutical compositions of bedaquiline that exhibit better dissolution rates with poloxamer in the intra-granular fraction and poloxamer in the extra-granular fraction.
From the foregoing it will be observed that numerous modifications and variations can be effectuated without departing from the true spirit and scope of the novel concepts of the present invention. It is to be understood that no limitation with respect to the specific embodiments illustrated is intended or should be inferred.
Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (9)
1. A pharmaceutical composition of bedaquiline, characterized in that: the pharmaceutical composition comprises an intra-particle part, wherein the intra-particle part comprises bedaquiline and pharmaceutically acceptable salts thereof, poloxamer and at least one pharmaceutically acceptable auxiliary material; and b an extra-granular portion comprising a poloxamer and at least one pharmaceutically acceptable excipient.
2. The pharmaceutical composition of bedaquiline according to claim 1, characterized in that: the intra-particle part a comprises 30-50% of bedaquiline and pharmaceutically acceptable salts thereof, 1-3% of poloxamer and at least one pharmaceutically acceptable auxiliary material; the extra-granular fraction comprising 1-3% poloxamer and at least one pharmaceutically acceptable excipient, wherein the percentages are based on the total weight of the composition.
3. The pharmaceutical composition of bedaquiline according to claim 1, characterized in that: the intra-particle part a comprises 35-40% of bedaquiline fumarate, 1-3% of poloxamer and at least one pharmaceutically acceptable auxiliary material; the extra-granular fraction comprising 1-3% poloxamer and at least one pharmaceutically acceptable excipient, wherein the percentages are based on the total weight of the composition.
4. The pharmaceutical composition of bedaquiline according to claim 1, characterized in that: the intra-particle fraction a comprising 30-50% bedaquiline fumarate, 1-3% poloxamer, 1-10% binder, and 20-35% diluent; b an extra-granular portion comprising 1-3% poloxamer, 15% to 25% diluent, 1% to 10% disintegrant, 1% to 5% glidant, and 1% to 5% lubricant, wherein the percentages are based on the total weight of the composition.
5. The pharmaceutical composition of bedaquiline according to any one of claims 1-4, wherein: the pharmaceutical composition is a solid composition, and pharmaceutically acceptable excipients of the solid composition may be used.
6. A process for the preparation of a pharmaceutical composition of bedaquiline according to any one of claims 1 to 5, characterized in that: the method comprises the following steps:
firstly, preparing a solution of poloxamer and a binder in a solvent;
secondly, mixing the solution prepared in the first step with the bedaquiline, pharmaceutically acceptable salts thereof and optionally at least one pharmaceutically acceptable auxiliary material to prepare particles;
third, drying the granules obtained in the second step;
fourth, mixing the particles dried in the third step with poloxamer and at least one pharmaceutically acceptable auxiliary material to obtain a mixture;
and fifth, pressing the mixture obtained in the fourth step into tablets or filling capsules.
7. The pharmaceutical composition of bedaquiline and the preparation method thereof according to claim 6, wherein: the solution prepared in the first step is a solution of 1-3% poloxamer and a binder, the solution is sprayed on 30-50% bedaquiline fumarate and optionally at least one pharmaceutically acceptable excipient placed on a fluid bed in the second step to prepare particles, and 1-3% poloxamer and at least one pharmaceutically acceptable excipient are mixed with the particles dried in the third step in the fourth step.
8. The pharmaceutical composition of bedaquiline and the preparation method thereof according to claim 6 or 7, wherein: the drying of the particles may be carried out at a temperature of 50.+ -. 15 ℃.
9. The pharmaceutical composition of bedaquiline and the preparation method thereof according to claim 8, wherein: wherein the solvent is selected from the group consisting of water, ethanol, isopropanol, and mixtures thereof.
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| CN202310964214.XA CN116803392A (en) | 2023-08-02 | 2023-08-02 | Pharmaceutical composition of bedaquiline and preparation method thereof |
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