CN110623934A - Trimetazidine hydrochloride sustained release tablet and preparation method thereof - Google Patents
Trimetazidine hydrochloride sustained release tablet and preparation method thereof Download PDFInfo
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- CN110623934A CN110623934A CN201910920683.5A CN201910920683A CN110623934A CN 110623934 A CN110623934 A CN 110623934A CN 201910920683 A CN201910920683 A CN 201910920683A CN 110623934 A CN110623934 A CN 110623934A
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- sustained
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- trimetazidine
- carbomer
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- UHWVSEOVJBQKBE-UHFFFAOYSA-N Trimetazidine Chemical compound COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 UHWVSEOVJBQKBE-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960001177 trimetazidine Drugs 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 239000007939 sustained release tablet Substances 0.000 title claims description 29
- 239000000463 material Substances 0.000 claims abstract description 64
- 238000002156 mixing Methods 0.000 claims abstract description 55
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 31
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 30
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 30
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 30
- 238000013268 sustained release Methods 0.000 claims abstract description 30
- 239000012730 sustained-release form Substances 0.000 claims abstract description 30
- 238000000576 coating method Methods 0.000 claims abstract description 28
- 239000011248 coating agent Substances 0.000 claims abstract description 27
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 25
- 229960001631 carbomer Drugs 0.000 claims abstract description 25
- 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 claims abstract description 24
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 22
- 239000011575 calcium Substances 0.000 claims abstract description 22
- 150000004683 dihydrates Chemical class 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 238000005469 granulation Methods 0.000 claims abstract description 4
- 230000003179 granulation Effects 0.000 claims abstract description 4
- 238000007873 sieving Methods 0.000 claims description 22
- 238000005303 weighing Methods 0.000 claims description 11
- 229920003134 Eudragit® polymer Polymers 0.000 claims description 7
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 7
- 229960003943 hypromellose Drugs 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229940031663 carbomer-974p Drugs 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 4
- 239000012467 final product Substances 0.000 claims 2
- 238000007907 direct compression Methods 0.000 claims 1
- 239000000945 filler Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 3
- 239000003085 diluting agent Substances 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 51
- 230000000052 comparative effect Effects 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- 239000011812 mixed powder Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000007888 film coating Substances 0.000 description 12
- 238000009501 film coating Methods 0.000 description 12
- 239000008280 blood Substances 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 229920003139 Eudragit® L 100 Polymers 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 229920003141 Eudragit® S 100 Polymers 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 206010002383 Angina Pectoris Diseases 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013065 commercial product Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- -1 Trimetazidine dihydrate Chemical class 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000005243 fluidization Methods 0.000 description 2
- 210000003194 forelimb Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- 229920003136 Eudragit® L polymer Polymers 0.000 description 1
- 229920003137 Eudragit® S polymer Polymers 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 102000002932 Thiolase Human genes 0.000 description 1
- 108060008225 Thiolase Proteins 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- VYFLPFGUVGMBEP-UHFFFAOYSA-N Trimetazidine hydrochloride Chemical compound Cl.Cl.COC1=C(OC)C(OC)=CC=C1CN1CCNCC1 VYFLPFGUVGMBEP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000004129 fatty acid metabolism Effects 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 230000003284 homeostatic effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000013563 matrix tablet Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- 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
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a trimetazidine dihydrochloride sustained-release pharmaceutical composition and a preparation method thereof. The composition comprises effective dose of trimetazidine hydrochloride and pharmaceutic adjuvant, wherein the proportion of a main drug is 10-20%, 10-45% of sustained-release material hydroxypropyl methylcellulose, 22-40% of sustained-release material carbomer, 0.2-10% of sustained-release material Uetrexed, 10-48% of diluent calcium hydrophosphate dihydrate, 0.3-1.5% of glidant colloidal silicon dioxide and 0.5-1.5% of magnesium stearate. The invention also provides a preparation method of the trimetazidine dihydrochloride composition, which comprises the steps of direct mixing technology or fluidized bed granulation, tabletting and coating. The invention overcomes the defect that the trimetazidine dihydrochloride needs to be administrated for many times because of short relative half-life period in the prior art, and can avoid side effect caused by overhigh administration initial concentration; the preparation process is simple and suitable for large-scale industrial production.
Description
Technical Field
The invention relates to trimetazidine hydrochloride sustained release tablets and a preparation method thereof, belonging to the technical field of pharmaceutical preparations.
Background
Trimetazidine dihydrate (TM) hydrochloride is an anti-angina drug with clinical efficacy, and has been used for the prevention and treatment of angina pectoris; unlike other classical angina pectoris resisting medicines (such as beta-receptor blocker, calcium channel antagonist and long-acting nitrate), trimetazidine hydrochloride is one kind of myocardial ischemia resisting medicine, and has the functions of inhibiting 3-keto-acyl coenzyme A thiolase, reducing free fatty acid metabolism and increasing glucose oxidation, increasing myocardial energy supply, improving cardiac function, protecting cardiac muscle and preventing angina pectoris and treating dizziness and tinnitus.
The chemical name of the trimetazidine dihydrochloride is 1- [ (2,3, 4-trimethoxyphenyl) methyl]Piperazine with structural formula shown as formula I and molecular formula C14H22N2O32HCl, molecular weight 339.26, CAS No. 13171-25-0, a white crystalline powder that is very soluble in water (solubility in water at 20 ℃ above 1 g/ml) or formic acid, slightly soluble in methanol, and poorly soluble in ethanol (99.5).
Trimetazidine dihydrochloride is rapidly absorbed after oral administration, and the half-life period is relatively short (t)1/26.0 ± 1.4h), it is therefore considered as an ideal candidate for sustained administration; in addition, trimetazidine dihydrochloride is very soluble in water, and the solubility in water at 20 ℃ is more than 1g/ml, so the development of a trimetazidine sustained release drug delivery system is a challenging task.
At present, trimetazidine dihydrochloride has the common dosage forms such as tablets, sustained-release tablets, capsules and the like on the market. The Schweiya pharmaceutical Co Ltd officially sells trimetazidine dihydrochloride sustained release tablets on the market in China, the name of English is Tr(iii) Imetazidinedihydrochloride Modified Release tables with trimetazidine hydrochloride as active ingredient, specification of 35 mg/tablet, trade name of Wangliang powder: (MR)。
The patent EP1108424/CN1166408C granted by schvea of the original research company, france, describes a matrix tablet capable of releasing trimetazidine for a long time, wherein the long-time release is realized by a single sustained-release material of hypromellose, and the initial release of the drug is faster and the maintenance time is shorter. The trimetazidine dihydrochloride sustained-release tablets can cause adverse reactions such as palpitation, extrasystole, tachycardia, orthostatic hypotension and the like by burst release, so that the control of the early-stage release rate of the preparation is particularly important.
Patent CN201110286002 adopts polyethylene Oxide (PEO) as a skeleton for controlling release of a tablet core, and the release amount of the obtained trimetazidine hydrochloride sustained release tablet reaches about 90% after 6 hours, but the strength of gel formed by PEO is not high, and the influence on the release stability of the drug is large; meanwhile, the vitrification temperature of PEO is 65-67 ℃, the thermal stability is not good, the drying temperature cannot be too high, so that problems may exist in the preparation process of the tablet, during the storage process, PEO can generate free radicals due to the oxidation effect, so that the degradation of auxiliary materials and active compounds can be caused, and the long-term storage of the product is not facilitated.
Patent EP0673649/CN1056057C describes that delayed release of trimetazidine is achieved by reservoir system using slow release pellet technology, the process is complicated, it is not suitable for industrial production, and the content difference between the preparations is relatively large because the granules are filled or tabletted after fluidized bed coating.
CN201410013277 and CN201510258067 adopt osmotic pump technology to realize zero-order release in vitro, but the osmotic pump preparation is also difficult to realize industrial production due to the complex process.
Disclosure of Invention
Based on the above, the invention provides a trimetazidine dihydrochloride sustained-release pharmaceutical composition and a preparation method thereof.
The invention overcomes the defects that the sustained-release tablets in the prior art have unstable quality, have large change of drug release rate in media with different pH values and can not really achieve sustained-release effect.
The trimetazidine dihydrochloride sustained-release pharmaceutical composition prepared by the invention shows more stable blood concentration fluctuation in-vivo experiments, overcomes the defects of short relative half-life period and need of multiple times of administration of trimetazidine dihydrochloride in the prior art, and avoids more side effects caused by maintaining effective blood concentration to achieve treatment effect and initial overdose at the initial administration stage.
The sustained-release pharmaceutical composition prepared by the invention can achieve the effect of multi-dose administration of common tablets for 3 times a day by administering 2 times a day, reduce the side effect in administration, improve the medication safety and add an optional medicine for patients; can reduce the times of taking medicine and improve the compliance of patients.
The sustained-release pharmaceutical composition prepared by the invention screens sustained-release materials, and the preparation method is easy to operate, high in stability, controllable in release behavior, low in production cost and suitable for large-scale industrial production.
The invention provides a trimetazidine hydrochloride sustained-release pharmaceutical composition and a preparation method thereof, wherein the composition comprises the following components in percentage by weight:
trimetazidine dihydrochloride 10-20%
10 to 45 percent of hydroxypropyl methylcellulose
22 to 40 percent of carbomer
0.2 to 10 percent of Eiteqi
10 to 48 percent of calcium hydrophosphate dihydrate
0.3 to 1.5 percent of colloidal silicon dioxide
0.5 to 1.5 percent of magnesium stearate
The framework material comprises hydroxypropyl methylcellulose, carbomer and Ettch: (A)Of the Ewing S/L series A resin).
The hydroxypropyl methylcellulose is used as a slow release framework, the viscosity range of the hydroxypropyl methylcellulose is 2000 mPas-100000 mPas, and the preferable viscosity range of the hydroxypropyl methylcellulose is 4000 mPas-15000 mPas; the content thereof is preferably 25% to 35%.
The carbomer can be selected from one or more of 934P, 971P and 974P, and can be used as a framework material together with hydroxypropyl methylcellulose and Eudragit. In this case, the content of carbomer is 22 to 40 percent, preferably 25 to 40 percent, and more preferably 25 to 35 percent of the total weight.
The Eudragit can be selected from enteric material Eudragit S/L series resin, more preferably one or more of Eudragit L100 or S100, and can be used as skeleton material together with hypromellose and carbomer. In this case, the content of Eudragit is 0.2% to 10%, preferably 3% to 8%, and more preferably 3% to 5% of the total weight.
In the invention, the Eudragit L100 and S100 are methacrylic acid and ethyl acrylate (1: 1) copolymer, the structure contains hydroxyl, and the copolymer can easily generate salt with alkali in water, the Eudragit L100 is dissolved in a solution with the pH value of more than 6, and the Eudragit S100 is dissolved in a solution with the pH value of more than 7, and is commonly used as an enteric coating material. The invention can obtain the trimetazidine dihydrochloride sustained-release tablet which can be stably released and completely released by adjusting the proportion of the hydrophilic gel sustained-release material (hydroxypropyl methylcellulose) and the pH-dependent sustained-release material (carbomer, Ewing).
The invention also provides a preparation method of the trimetazidine dihydrochloride sustained release tablet, which comprises the following steps:
1. the trimetazidine hydrochloride is mixed with a diluent, a slow release material, a glidant and a lubricant and then directly tabletted and coated to obtain the trimetazidine hydrochloride tablet.
2. Mixing trimetazidine hydrochloride and diluent, granulating with fluidized bed to obtain granules, mixing with sustained release material, glidant and lubricant, tabletting, and coating.
The coating process uses a gastric-soluble film coating premix which is a common gastric-soluble film coating.
Drawings
FIG. 1 shows examples 1 to 7 and commercially available productsRelease profile control (ph1.2 hydrochloric acid solution);
FIG. 2 is an embodiment 8E11. Comparative examples 1 and 2 and commercial products (A)MR) release profile comparison graph (ph1.2 hydrochloric acid solution);
FIG. 3 shows examples 1, 9, and 3, and their commercial products (A)MR) release profile comparison plot (pH6.8 phosphate buffer);
FIG. 4 shows a commercially available productComparative graph of time curve of MR, example 9 and comparative example 1 (days 1-4)
FIG. 5 isComparative graph of time curve of MR, example 9 and comparative example 1 (day 4)
Detailed Description
The present invention is further described below with reference to the following drawings and examples, but is not limited thereto.
Example 1 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve; mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 974P and Eudragit L100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide by a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 2 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve; mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 934P and Uttzs 100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide with a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 3 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve; mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 974P and Eudragit S100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide by a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 4 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 971P and Eudragit L100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide by a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 5 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 974P and Eudragit L100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide by a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 6 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 974P and Eudragit S100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide by a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 7 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 934P and Eiteqi L100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide with a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 8 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
fluid bed granulation: weighing formula amounts of trimetazidine hydrochloride, calcium hydrophosphate dihydrate, hydroxypropyl methylcellulose, carbomer 934P and Ewing L100, placing the materials in a fluidized bed granulation pot for fluidization for 10min, spraying sufficient purified water in a atomization manner under a fluidization condition, adjusting the air inlet temperature to 60 ℃ after the liquid spraying is finished, and drying until the water content is less than 3% to obtain a dried material;
finishing and total mixing: sieving the dried material and the prescribed amount of colloidal silicon dioxide through a sieve with the aperture of 1.5mm to obtain dry particles; putting the dry granules and the magnesium stearate in the prescription amount into a hopper mixer to be uniformly mixed to obtain total mixed powder;
tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets;
coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Example 9 trimetazidine hydrochloride sustained release tablet formula composition: the specification is 35mg, and the prescription amount is 1000 tablets.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer 934P and Eiteqi L100 into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide with a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Comparative examples 1 to 3. trimetazidine dihydrochloride sustained release tablets are formulated as follows: the specification is 35mg, the prescription amount is 1000 tablets, and hydroxypropyl methylcellulose is independently used as a slow-release material.
The preparation method comprises the following steps:
pretreatment: pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
mixing: weighing trimetazidine hydrochloride and calcium hydrophosphate dihydrate according to the prescription amount, placing the trimetazidine hydrochloride and the calcium hydrophosphate dihydrate into a hopper mixer, uniformly mixing, adding hydroxypropyl methylcellulose, carbomer and Utex into the materials, uniformly mixing, sieving the materials and colloidal silicon dioxide by a 30-mesh sieve, mixing for 2 times, placing the materials into the hopper mixer, adding magnesium stearate, and uniformly mixing to obtain total mixed powder; tabletting: putting the total mixed powder into a rotary tablet machine for tabletting to obtain plain tablets; coating: the plain tablets are placed in a high-efficiency coating machine for film coating.
Trimetazidine hydrochloride sustained-release tablets of examples 1 to 11 and comparative examples 1 to 3 and a commercially available product (((R) ()MR)) release curves are shown in FIGS. 1-3.
Comparative experiment of effects
1. Degree of release test
The tablets were subjected to in vitro tests and the cumulative release was measured for 1, 2,3,4, 5, 6, 8 h. In order to ensure that the trimetazidine dihydrochloride sustained-release tablets can be stably released, according to the guiding principle of sustained-release preparations in the 'Chinese pharmacopoeia' 2015 edition and the sustained-release requirements of the product, the release degrees of the trimetazidine dihydrochloride sustained-release tablets at various time points are respectively set to be 1h 20-35%, 2h 40-50%, 4h 65-75%, 6h 85-90% and 8h>90 percent, in the prescription screening process, after trimetazidine hydrochloride sustained-release tablets are prepared according to each prescription, the cumulative release degree of the trimetazidine hydrochloride sustained-release tablets at each time point is measured, and the release curves of the examples 1-11, the comparative examples 1 and the comparative examples 2 in a hydrochloric acid medium with pH1.2 are examined; and for example 1, example 9, comparative example 3 andMR performed release profile determination in phosphate buffer at pH 6.8.
The self-prepared products prepared in examples 1 to 11 and comparative examples 1 to 3 were mixed with commercially available trimetazidine hydrochloride sustained release tablets (b)MR) were subjected to the comparison of the release rate experiments to investigate the in vitro release profile, and the results are shown in fig. 1 to 3 and tables 1 to 3.
TABLE 1 Release degree of tablets obtained in examples 1 to 7 and commercial products (MR) results (pH1.2 hydrochloric acid solution)
TABLE 2 Release Rate and commercial products of tablets obtained in examples 7 to 11 and comparative examples 1 to 2: (MR) results (pH1.2 hydrochloric acid solution)
Table 3 release rates of tablets obtained in example 9 and comparative example 3 and commercial products (c)MR) results (pH6.8 phosphate buffer)
As shown in FIG. 1-2 and Table 1-2, it can be used in combination with commercially available trimetazidine dihydrochloride sustained-release tablets (b)MR) compared with the prior art, after hydroxypropyl methylcellulose is used together with carbomer 934P, 974P or 971P and Ewing S100 or L100, the release degree is smaller than that of a product (I) sold in the market in hydrochloric acid medium with the pH value of 1.2 within 1-4 h at the early stageMR) and release rates of 5h to 8h with commercially available products (MR) was nearly close and the 8h final dissolution was above 90%. In the comparative example, carbomer or Ewing is absent in the sustained-release material, and the early-stage release degree is higher than that in the example.
As shown in FIG. 3 and Table 3, commercially available product (A) was dissolved in phosphate buffer at pH6.8MR) and comparative example 3 released earlier (before 4h) faster than example 1 and example 9.
The above results show that the product is comparable to the commercial product (A)MR), the self-prepared sustained-release material adopts hydroxypropyl methylcellulose, carbomer and Eudragit to be used together, and can ensure that the preparation can avoid the burst release of the drug in both acidic and alkaline media, thereby achieving the ideal sustained-release effect.
2. In vivo assay
Example 9, comparative example 1 and commercial productsPharmacokinetic experiments were performed to compare the homeostatic conditions. The specific test method is as follows:
selecting 18 healthy male Beagle dogs with body weight of 10 + -1.0 kg, dividing into 3 groups, and respectively taking commercially available productsExample 9, comparative example 1. No drug was administered within 14 days prior to the experiment, compared to 20: 00 fasting was started, with the day of the experiment 6: 00 and night 18: 1 tablet (35mg) is taken at the time of 00 meals, and the medicine is continuously taken for 4 days. 3.0ml of blood is taken from forelimb veins before each administration on days 1-3, and is placed in an anticoagulation tube for blood concentration analysis to confirm whether the steady state is achieved, and on day 4 of a multiple administration steady state test, 6 in the morning: 00 taking 3.0ml of blood from forelimb vein after 1h, 2h, 3h, 4h, 6h, 8h, 12h, 13h, 14h, 15h, 16h, 18h, 20h and 24h, placing in anticoagulation tube, and analyzing blood concentration. The time curve of the day 1 to day 4 of the example 9, the comparative example 1 and the commercial product is shown in FIG. 4, and the time curve of the day 4 is shown in FIG. 5.
And (3) test results:
as can be seen from FIG. 4, example 9 of the present invention, comparative example 1 (sustained-release material is hypromellose only) and a commercially available productAfter the MR is taken for 60 hours, the blood concentration of the Beagle dog in vivo reaches steady state; comparative example 1 and commercial productsThe MR blood concentration was significantly lower than in example 9.
As can be seen from figure 5, after the medicines in example 9 and comparative example 1 are taken for 3-4 hours, the blood concentration of the Beagle dog reaches the peak value, the peak concentration is 90-93 mug/ml, and the peak concentrations are basically close to each other; while the blood concentration of the comparative example 1 before taking the medicine is obviously lower than that of the example 9; compared with comparative example 1 and a commercial productMR, example 9 plasma concentration varied more smoothly.
The results show that the sustained-release material adopts hydroxypropyl methylcellulose, carbomer and Eudragit for use, the preparation method is direct mixing tabletting coating or fluidized bed granulating tabletting coating, and the release of the self-product is superior to that of the product on the marketThe slow sustained release property of MR and the ability to maintain the blood drug level at a higher level.
Claims (7)
1. The trimetazidine dihydrochloride sustained-release pharmaceutical composition is characterized by comprising the following components in percentage by weight:
trimetazidine dihydrochloride 10-20%
10 to 45 percent of hydroxypropyl methylcellulose (HPMC)
22 to 40 percent of carbomer
0.2 to 10 percent of Eiteqi
10 to 48 percent of calcium hydrophosphate dihydrate
0.3 to 1.5 percent of colloidal silicon dioxide
0.5 to 1.5 percent of magnesium stearate.
2. Trimetazidine dihydrochloride sustained-release pharmaceutical composition according to claim 1, wherein the viscosity of hypromellose ranges from 2000mPas to 100000mPas, preferably from 4000mPas to 15000 mPas; preferably, the content of the hypromellose is 25 to 35 percent of the total weight of the composition.
3. The trimetazidine dihydrochloride sustained-release pharmaceutical composition according to claim 1, wherein the sustained-release material is hypromellose combined with carbomer and ewing, wherein carbomer is one of carbomer 974P, carbomer 934P and carbomer 971P, and ewing is one of ewing L100 and ewing S100.
4. Trimetazidine dihydrochloride sustained-release pharmaceutical composition according to claims 1 to 3, wherein the content of carbomer is 22 to 40 percent of the total weight, preferably the content of carbomer is 25 to 35 percent of the total weight.
5. A trimetazidine dihydrochloride sustained release pharmaceutical composition according to claim 1-3, wherein the amount of Eudragit is 0.2-10% by weight, preferably the amount of Eudragit is 3-8% by weight, further preferably 3-5% by weight.
6. A preparation method for preparing trimetazidine dihydrochloride sustained release tablets as claimed in claims 1-5, which is characterized by using a direct compression process and comprising the following steps:
(1) pre-treating the raw materials and the auxiliary materials by a 40-mesh sieve;
(2) premixing trimetazidine hydrochloride, carbomer, Ewing and hydroxypropyl methylcellulose;
(3) adding colloidal silicon dioxide, sieving with 30 mesh sieve, mixing for 2 times, mixing with three-dimensional mixer for 15min, adding magnesium stearate, and mixing for 3min to obtain total mixture;
(4) tabletting and coating to obtain the final product.
7. A preparation method for preparing trimetazidine dihydrochloride sustained release tablets as claimed in claims 1-5, which is characterized in that a fluidized bed granulation and tabletting process is used, and comprises the following steps:
(1) pre-treating the raw and auxiliary materials by sieving with a 40-mesh sieve;
(2) weighing trimetazidine hydrochloride, a sustained-release material and a filler according to the amount, uniformly mixing, then performing one-step granulation, granulating the granules together with colloidal silicon dioxide, adding magnesium stearate, and mixing;
(3) tabletting and coating to obtain the final product.
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