CN113018274A - Pharmaceutical composition containing hydroxypropyl methylcellulose and preparation method thereof - Google Patents
Pharmaceutical composition containing hydroxypropyl methylcellulose and preparation method thereof Download PDFInfo
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- CN113018274A CN113018274A CN202110258836.1A CN202110258836A CN113018274A CN 113018274 A CN113018274 A CN 113018274A CN 202110258836 A CN202110258836 A CN 202110258836A CN 113018274 A CN113018274 A CN 113018274A
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- hydroxypropyl methylcellulose
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 title claims abstract description 51
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 title claims abstract description 51
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 title claims abstract description 47
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 239000000463 material Substances 0.000 claims abstract description 35
- 239000007962 solid dispersion Substances 0.000 claims abstract description 32
- 239000002138 L01XE21 - Regorafenib Substances 0.000 claims abstract description 29
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 229960004836 regorafenib Drugs 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 21
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 17
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 14
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 14
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940069328 povidone Drugs 0.000 claims abstract description 6
- 239000011259 mixed solution Substances 0.000 claims description 29
- 238000005507 spraying Methods 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 20
- 239000002245 particle Substances 0.000 claims description 20
- 239000008187 granular material Substances 0.000 claims description 18
- 238000002156 mixing Methods 0.000 claims description 17
- 239000000243 solution Substances 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 16
- 229960003943 hypromellose Drugs 0.000 claims description 12
- 238000012216 screening Methods 0.000 claims description 12
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000011248 coating agent Substances 0.000 claims description 6
- 238000000576 coating method Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 5
- 230000008961 swelling Effects 0.000 claims description 5
- 238000004090 dissolution Methods 0.000 abstract description 14
- 239000007787 solid Substances 0.000 abstract description 13
- 239000003814 drug Substances 0.000 abstract description 6
- 238000002425 crystallisation Methods 0.000 abstract description 4
- 230000008025 crystallization Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 229940022682 acetone Drugs 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000007888 film coating Substances 0.000 description 5
- 238000009501 film coating Methods 0.000 description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000011978 dissolution method Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229940083466 soybean lecithin Drugs 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- -1 4-chloro-3-trifluoromethyl-phenyl Chemical group 0.000 description 1
- 206010055114 Colon cancer metastatic Diseases 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000004031 devitrification Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940124303 multikinase inhibitor Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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Abstract
The invention discloses a pharmaceutical composition containing hydroxypropyl methylcellulose and a preparation method thereof, wherein the pharmaceutical composition is prepared from the following raw and auxiliary materials: regorafenib, povidone, croscarmellose sodium, microcrystalline cellulose, acetone, absolute ethyl alcohol and hydroxypropyl methyl cellulose are prepared by utilizing the raw and auxiliary materials, so that the stability of the regorafenib amorphous solid dispersion can be improved, and the problem of crystallization of the raw material medicine in the solid component and preparation dissolution process is solved.
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a pharmaceutical composition containing hydroxypropyl methylcellulose and a preparation method thereof.
Background
Regorafenib (Regorafenib), a novel oral multi-kinase inhibitor, is approved by the FDA in 2012 and 2013 for the treatment of metastatic colon cancer, rectal cancer and gastrointestinal stromal tumors, respectively, and its chemical name is 4- {4- [3- (4-chloro-3-trifluoromethyl-phenyl) -ureide ] -3-fluorophenoxy } -pyridine-2-carboxylic acid methylamine, but the existing Regorafenib amorphous solid dispersion needs to have improved stability and is prone to the problem of drug devitrification during the dissolution of solid components and formulations.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition containing hydroxypropyl methylcellulose and a preparation method thereof, and aims to increase the stability of regorafenib amorphous solid dispersion and solve the problem of crystallization of a crude drug in the dissolution process of a solid component and a preparation.
In order to achieve the purpose, the pharmaceutical composition containing hydroxypropyl methylcellulose adopted by the invention is prepared from the following raw materials:
40mg of regorafenib, 160mg of povidone, 154mg of croscarmellose sodium, 100mg of microcrystalline cellulose, 432mg of acetone, 108mg of absolute ethyl alcohol and 2mg of hydroxypropyl methylcellulose.
Wherein the povidone is polyvinylpyrrolidone K25.
The hydroxypropyl methylcellulose is one or more of hydroxypropyl methylcellulose E4M, hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E50, hydroxypropyl methylcellulose K100 and hydroxypropyl methylcellulose K100M.
The invention also provides a preparation method of the pharmaceutical composition containing hypromellose, which comprises the following steps:
preparing a mixture from acetone and absolute ethyl alcohol according to a preset proportion, slowly adding polyvinylpyrrolidone K25 into the mixture under a stirring state, adding a certain amount of regorafenib into the mixture after the polyvinylpyrrolidone K25 is fully dissolved, and keeping the stirring state until the solution is clear to obtain a first mixed solution;
adding a certain amount of hydroxypropyl methylcellulose into purified water, continuously stirring and swelling until the hydroxypropyl methylcellulose is completely dissolved, and adding the completely dissolved solution into the first mixed solution to obtain a second mixed solution;
uniformly mixing the microcrystalline cellulose and a certain amount of the croscarmellose sodium according to a ratio, placing the mixture in a fluidized bed granulator after uniform mixing, and preheating the materials;
spraying the second mixed solution on the preheated material, and drying the preheated material after the spraying is finished to obtain a solid dispersion;
after drying is completed, screening the solid dispersion, and screening out large particles;
dry granulating the screened particles of the solid dispersion by using a dry granulator to obtain dry pressed particles;
fully mixing the residual amount of the croscarmellose sodium with the dry-pressed granules to obtain mixed granules;
and tabletting the mixed granules to obtain an plain tablet, and coating the plain tablet to obtain the regorafenib tablet.
Wherein, in the step of adding the completely dissolved solution to the first mixed solution: the solution that dissolves completely needs to be added slowly and needs to be kept under constant stirring.
Wherein, in the step of spraying the second mixed solution on the preheated material, drying the preheated material after the spraying is finished to obtain the solid dispersion: the pump flow speed of spraying the second mixed solution to the preheated material is 5-15rpm, and the temperature of the preheated material is controlled at 35-50 ℃.
Wherein, in the step of spraying the second mixed solution on the preheated material, drying the preheated material after the spraying is finished to obtain the solid dispersion: drying the liquid after the liquid spraying is finished, wherein the drying temperature is controlled to be 50-90 ℃.
The invention has the beneficial effects that: preparing a mixture from acetone and absolute ethyl alcohol according to a preset proportion, slowly adding polyvinylpyrrolidone K25 into the mixture under a stirring state, adding a certain amount of regorafenib into the mixture after the polyvinylpyrrolidone K25 is fully dissolved, and keeping the stirring state until the solution is clear to obtain a first mixed solution; adding a certain amount of hydroxypropyl methylcellulose into purified water, continuously stirring and swelling until the hydroxypropyl methylcellulose is completely dissolved, and adding the completely dissolved solution into the first mixed solution to obtain a second mixed solution; uniformly mixing the microcrystalline cellulose and a certain amount of the croscarmellose sodium according to a ratio, placing the mixture in a fluidized bed granulator after uniform mixing, and preheating the materials; spraying the second mixed solution on the preheated material, and drying the preheated material after the spraying is finished to obtain a solid dispersion; after drying is completed, screening the solid dispersion, and screening out large particles; dry granulating the screened particles of the solid dispersion by using a dry granulator to obtain dry pressed particles; fully mixing the residual amount of the croscarmellose sodium with the dry-pressed granules to obtain mixed granules; and tabletting the mixed granules to obtain an plain tablet, and coating the plain tablet to obtain the regorafenib tablet. Therefore, the stability of the regorafenib amorphous solid dispersion is improved, and the problem of crystallization of the crude drug in the solid dispersion and preparation dissolution process is solved.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
Fig. 1 is a flow chart of the steps of the method of preparing a hypromellose-containing pharmaceutical composition of the present invention.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are illustrative and intended to be illustrative of the invention and are not to be construed as limiting the invention.
In the description of the present invention, it is to be understood that the terms "length", "width", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", and the like, indicate orientations or positional relationships based on the orientations or positional relationships illustrated in the drawings, and are used merely for convenience in describing the present invention and for simplicity in description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed in a particular orientation, and be operated, and thus, are not to be construed as limiting the present invention. Further, in the description of the present invention, "a plurality" means two or more unless specifically defined otherwise.
Referring to fig. 1, the present invention provides a method for preparing a pharmaceutical composition containing hypromellose,
s1: preparing a mixture from acetone and absolute ethyl alcohol according to a preset proportion, slowly adding polyvinylpyrrolidone K25 into the mixture under a stirring state, adding a certain amount of regorafenib into the mixture after the polyvinylpyrrolidone K25 is fully dissolved, and keeping the stirring state until the solution is clear to obtain a first mixed solution;
s2: adding a certain amount of hydroxypropyl methylcellulose into a proper amount of purified water, continuously stirring and swelling until the hydroxypropyl methylcellulose is completely dissolved, and adding the completely dissolved solution into the first mixed solution to obtain a second mixed solution;
s3: uniformly mixing the microcrystalline cellulose and a certain amount of the croscarmellose sodium according to a ratio, placing the mixture in a fluidized bed granulator after uniform mixing, and preheating the materials;
s4: spraying the second mixed solution on the preheated material, and drying the preheated material after the spraying is finished to obtain a solid dispersion;
s5: after drying is completed, screening the solid dispersion, and screening out large particles;
s6: dry granulating the screened particles of the solid dispersion by using a dry granulator to obtain dry pressed particles;
s7: fully mixing the residual amount of the croscarmellose sodium with the dry-pressed granules to obtain mixed granules;
s8: and tabletting the mixed granules to obtain an plain tablet, and coating the plain tablet to obtain the regorafenib tablet.
In this embodiment, the hypromellose-containing pharmaceutical composition further comprises 2.4mg of colloidal silicon dioxide, 3.6mg of magnesium stearate, and 13.86mg of a film-coating premix. And after the step of fully mixing the residual amount of the croscarmellose sodium and the dry-pressed granules, adding a certain amount of colloidal silicon dioxide, magnesium stearate and a film-coating premix, and fully mixing again to obtain the mixed granules. The film coating premix is prepared from titanium dioxide, soybean lecithin, talcum powder, polyethylene glycol, polyvinyl alcohol and allure red aluminum lake. After the drying is finished, screening the solid dispersion to screen out large particles: and screening out large particles by using a screen with 40-80 meshes. In the step of tabletting the mixed granules to obtain an plain tablet, and then coating the plain tablet to obtain a regorafenib tablet: the hardness of the plain tablet is controlled to be 80N-200N.
The method specifically comprises the following steps: mixing 432mg of acetone and 108mg of absolute ethyl alcohol according to a ratio of 4:1 to form a mixture, adding 160mg of polyvinylpyrrolidone K25 into the mixture to serve as a carrier, slowly adding 40mg of regorafenib after the carrier is completely dissolved to enable the ratio of the regorafenib to the carrier to be 1:4, and completely dissolving the regorafenib to obtain a clear and transparent solution; adding 2mg of hydroxypropyl methylcellulose into purified water, and continuously stirring for swelling until the hydroxypropyl methylcellulose is completely dissolved, wherein the proportion of the hydroxypropyl methylcellulose in the solid dispersion is as follows: 0.1% -5.0%, more preferably 0.3% -3.0%, slowly adding the completely dissolved solution into the first mixed solution, and continuously stirring in the adding process to obtain a second mixed solution; uniformly mixing 100mg of microcrystalline cellulose and a certain amount of 100mg of croscarmellose sodium according to a ratio of 1:1, placing the mixture in a fluidized bed granulator after uniform mixing, heating the materials at an air inlet temperature of 50-90 ℃, more preferably at a temperature of 38-45 ℃, and preheating the materials; spraying the second mixed solution on the preheated material, and drying the preheated material after the liquid spraying is finished to obtain a solid dispersion, wherein the pump flow speed of the second mixed solution sprayed on the preheated material is 5-15rpm, the temperature of the preheated material is controlled to be 35-50 ℃, and the second mixed solution is dried after the liquid spraying is finished, the drying temperature is controlled to be 50-90 ℃, and the air inlet temperature of 60-70 ℃ is preferred; after drying is finished, screening the solid dispersion to remove large particles, and screening the large particles by using a 40-80-mesh screen, preferably a 60-mesh screen; dry granulating the screened particles of the solid dispersion by using a dry granulator to obtain dry pressed particles; the remaining 54mg of the croscarmellose sodium was thoroughly mixed with the dry-pressed granules, after which 2.4mg of colloidal silicon dioxide, 3.6mg of magnesium stearate and 13.86mg of a film-coating premix were added and thoroughly mixed again to obtain the mixed granules. And (3) obtaining mixed particles, wherein the film coating premix is prepared from titanium dioxide, soybean lecithin, talcum powder, polyethylene glycol, polyvinyl alcohol and allure red aluminum lake. Then tabletting the mixed particles to obtain plain tablets, wherein the hardness of the plain tablets is controlled to be 80-200N, preferably 160-190N; and coating the plain tablets to obtain the regorafenib tablets.
The comparative table for the above examples is given in example 1:
example 1:
example 2 (comparative):
the regorafenib tablet prepared from the solid matrix containing a proper amount of hydroxypropyl methylcellulose in the embodiment 1 is subjected to dissolution curve determination, and the dissolution method comprises the following steps: chinese pharmacopoeia 2015 edition four 0931 second method (paddle method), medium: water (0.1% SDS), volume of medium: 900ml, rotation speed: 75 r/min. The dissolution results are summarized in the following table:
example 1 koji dissolution in different media
And (3) carrying out dissolution curve determination on the regorafenib tablets prepared by adopting single povidone as a solid matrix according to the comparative example, wherein the dissolution method comprises the following steps: chinese pharmacopoeia 2015 edition four 0931 second method (paddle method), medium: water (0.1% SDS), volume of medium: 900ml, rotation speed: 75 r/min. The dissolution results are summarized in the following table:
example 2 koji dissolution in aqueous Medium
After 0.3% -3.0% of preferred HPMC auxiliary materials are added into the prescription, the stability of the solid components is remarkably improved, the supersaturated state of the solid components is kept for a long time, and the solid components can be maintained for 4 hours without reduction. The dissolution rate of the regorafenib tablet reaches over 85% within 30min, and no phenomenon that the dissolution rate is obviously reduced within 240min is found.
From the results, it can be seen that after a certain amount of HPMC series auxiliary materials are added into the solid components, the solid components reach more than 85% in an aqueous medium within 20min, and no obvious dissolution reduction is found within 240min, so that the stability of the solid components is remarkably improved compared with that of a comparative example. In addition, the regorafenib solid preparation containing the HPMC auxiliary material comprises but is not limited to common oral solid preparations such as regorafenib tablets, granules, capsules, sustained-release preparations and the like, and the regorafenib solid dispersion containing the HPMC auxiliary material is mainly prepared by but is not limited to methods such as a solvent method, a hot-melt extrusion method, a spray drying method, a grinding method and the like.
In conclusion, the application of hypromellose and series of pharmaceutical excipients thereof in Regorafenib preparations is used for increasing the stability of the amorphous solid dispersion (hereinafter referred to as solid dispersion or solid dispersion), inhibiting crystallization of the raw material medicine in the process of preparing the solid dispersion and dissolving out the preparation and solving the problem of dissolution reduction of the solid dispersion and the preparation.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (7)
1. The hypromellose-containing pharmaceutical composition is characterized by being prepared from the following raw and auxiliary materials:
40mg of regorafenib, 160mg of povidone, 154mg of croscarmellose sodium, 100mg of microcrystalline cellulose, 432mg of acetone, 108mg of absolute ethyl alcohol and 2mg of hydroxypropyl methylcellulose.
2. The hypromellose-containing pharmaceutical composition of claim 1,
the povidone is polyvinylpyrrolidone K25.
3. The hypromellose-containing pharmaceutical composition according to claim 2,
the hydroxypropyl methylcellulose is one or more of hydroxypropyl methylcellulose E4M, hydroxypropyl methylcellulose E15, hydroxypropyl methylcellulose E5, hydroxypropyl methylcellulose E50, hydroxypropyl methylcellulose K100 and hydroxypropyl methylcellulose K100M.
4. A process for the preparation of a hypromellose-containing pharmaceutical composition according to claim 3, comprising the steps of:
preparing a mixture from acetone and absolute ethyl alcohol according to a preset proportion, slowly adding polyvinylpyrrolidone K25 into the mixture under a stirring state, adding a certain amount of regorafenib into the mixture after the polyvinylpyrrolidone K25 is fully dissolved, and keeping the stirring state until the solution is clear to obtain a first mixed solution;
adding a certain amount of hydroxypropyl methylcellulose into purified water, continuously stirring and swelling until the hydroxypropyl methylcellulose is completely dissolved, and adding the completely dissolved solution into the first mixed solution to obtain a second mixed solution;
uniformly mixing the microcrystalline cellulose and a certain amount of the croscarmellose sodium according to a ratio, placing the mixture in a fluidized bed granulator after uniform mixing, and preheating the materials;
spraying the second mixed solution on the preheated material, and drying the preheated material after the spraying is finished to obtain a solid dispersion;
after drying is completed, screening the solid dispersion, and screening out large particles;
dry granulating the screened particles of the solid dispersion by using a dry granulator to obtain dry pressed particles;
fully mixing the residual amount of the croscarmellose sodium with the dry-pressed granules to obtain mixed granules;
and tabletting the mixed granules to obtain an plain tablet, and coating the plain tablet to obtain the regorafenib tablet.
5. The method of preparing a hypromellose-containing pharmaceutical composition according to claim 4, wherein in the step of adding a completely dissolved solution to the first mixed solution:
the solution that dissolves completely needs to be added slowly and needs to be kept under constant stirring.
6. The method for preparing a hypromellose-containing pharmaceutical composition according to claim 4, wherein the step of spraying the second mixed solution onto the preheated material, and drying the sprayed solution after completion to obtain a solid dispersion comprises:
the pump flow speed of spraying the second mixed solution to the preheated material is 5-15rpm, and the temperature of the preheated material is controlled at 35-50 ℃.
7. The method for preparing a hypromellose-containing pharmaceutical composition according to claim 4, wherein the step of spraying the second mixed solution onto the preheated material, and drying the sprayed solution after completion to obtain a solid dispersion comprises:
drying the liquid after the liquid spraying is finished, wherein the drying temperature is controlled to be 50-90 ℃.
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