CN116036036B - Methylphenidate hydrochloride sustained-release chewable tablet as well as preparation method and application thereof - Google Patents
Methylphenidate hydrochloride sustained-release chewable tablet as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN116036036B CN116036036B CN202111504945.3A CN202111504945A CN116036036B CN 116036036 B CN116036036 B CN 116036036B CN 202111504945 A CN202111504945 A CN 202111504945A CN 116036036 B CN116036036 B CN 116036036B
- Authority
- CN
- China
- Prior art keywords
- methylphenidate hydrochloride
- coating
- sodium
- chewable tablet
- release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 229960001033 methylphenidate hydrochloride Drugs 0.000 title claims abstract description 163
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 title claims abstract description 162
- 239000007910 chewable tablet Substances 0.000 title claims abstract description 78
- 229940068682 chewable tablet Drugs 0.000 title claims abstract description 64
- 238000013268 sustained release Methods 0.000 title claims abstract description 55
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims description 47
- 239000011347 resin Substances 0.000 claims abstract description 80
- 229920005989 resin Polymers 0.000 claims abstract description 80
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000000463 material Substances 0.000 claims abstract description 39
- 239000003826 tablet Substances 0.000 claims abstract description 32
- 239000003937 drug carrier Substances 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims abstract description 8
- 230000001055 chewing effect Effects 0.000 claims abstract description 6
- 238000000576 coating method Methods 0.000 claims description 152
- 239000011248 coating agent Substances 0.000 claims description 138
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 62
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- 239000007788 liquid Substances 0.000 claims description 35
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 32
- 239000011342 resin composition Substances 0.000 claims description 31
- 239000003456 ion exchange resin Substances 0.000 claims description 23
- 229920003303 ion-exchange polymer Polymers 0.000 claims description 23
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
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- 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 claims description 16
- 235000019359 magnesium stearate Nutrition 0.000 claims description 16
- 229960001344 methylphenidate Drugs 0.000 claims description 16
- JUMYIBMBTDDLNG-UHFFFAOYSA-N methylphenidate hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(C(=O)OC)C1CCCC[NH2+]1 JUMYIBMBTDDLNG-UHFFFAOYSA-N 0.000 claims description 16
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- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 8
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- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- YWPVROCHNBYFTP-OSHKXICASA-N rubusoside Chemical compound O([C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O YWPVROCHNBYFTP-OSHKXICASA-N 0.000 claims description 2
- 235000019265 sodium DL-malate Nutrition 0.000 claims description 2
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000001509 sodium citrate Substances 0.000 claims description 2
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 229940005573 sodium fumarate Drugs 0.000 claims description 2
- 235000019294 sodium fumarate Nutrition 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 239000001540 sodium lactate Substances 0.000 claims description 2
- 235000011088 sodium lactate Nutrition 0.000 claims description 2
- 229940005581 sodium lactate Drugs 0.000 claims description 2
- 239000001394 sodium malate Substances 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000001433 sodium tartrate Substances 0.000 claims description 2
- 229960002167 sodium tartrate Drugs 0.000 claims description 2
- 235000011004 sodium tartrates Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229940013618 stevioside Drugs 0.000 claims description 2
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019202 steviosides Nutrition 0.000 claims description 2
- 235000019408 sucralose Nutrition 0.000 claims description 2
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229960004418 trolamine Drugs 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims 4
- 229940105329 carboxymethylcellulose Drugs 0.000 claims 2
- 229940068984 polyvinyl alcohol Drugs 0.000 claims 2
- 235000012239 silicon dioxide Nutrition 0.000 claims 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 claims 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 claims 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims 1
- 239000000625 cyclamic acid and its Na and Ca salt Substances 0.000 claims 1
- 229960005150 glycerol Drugs 0.000 claims 1
- LDHBWEYLDHLIBQ-UHFFFAOYSA-M iron(3+);oxygen(2-);hydroxide;hydrate Chemical compound O.[OH-].[O-2].[Fe+3] LDHBWEYLDHLIBQ-UHFFFAOYSA-M 0.000 claims 1
- 229960002160 maltose Drugs 0.000 claims 1
- 229940085605 saccharin sodium Drugs 0.000 claims 1
- 229910021487 silica fume Inorganic materials 0.000 claims 1
- 239000000741 silica gel Substances 0.000 claims 1
- 229940083542 sodium Drugs 0.000 claims 1
- 229960001462 sodium cyclamate Drugs 0.000 claims 1
- 229960002920 sorbitol Drugs 0.000 claims 1
- 235000019640 taste Nutrition 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 38
- 239000008213 purified water Substances 0.000 description 17
- 238000005507 spraying Methods 0.000 description 11
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 description 5
- 238000007599 discharging Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 2
- 235000019658 bitter taste Nutrition 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000003068 static effect Effects 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound 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 GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LRCFXGAMWKDGLA-UHFFFAOYSA-N dioxosilane;hydrate Chemical compound O.O=[Si]=O LRCFXGAMWKDGLA-UHFFFAOYSA-N 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
Classifications
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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
-
- 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
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4458—Non condensed piperidines, e.g. piperocaine only substituted in position 2, e.g. methylphenidate
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- 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
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2893—Tablet coating processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Psychology (AREA)
- Zoology (AREA)
- Psychiatry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a methylphenidate hydrochloride sustained-release chewable tablet, which comprises 0.1-10% (weight percent) methylphenidate hydrochloride, 0.1-20% (weight percent) methylphenidate hydrochloride resin compound, 1-30% (weight percent) methylphenidate hydrochloride resin compound coated with sustained-release material and pharmaceutically acceptable carrier. The invention screens and optimizes the components and the proportion of the methylphenidate hydrochloride sustained-release chewing composition, obviously improves the release speed difference between sustained-release chewing tablet batches, realizes stable and controllable product quality, improves the taste of tablets, improves the medication compliance of patients, especially children patients, and ensures the safety and effectiveness of clinical medication.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a methylphenidate hydrochloride sustained-release chewable tablet, a preparation method and application thereof.
Background
Methylphenidate hydrochloride (Methylphenidate Hydrochloride, alpha-phenyl)-2-methyl piperidine acetate hydrochloride, having the structure shown in formula I), is a central nervous system stimulant and is widely used clinically for treating Attention Deficit Hyperactivity Disorder (ADHD), narcolepsy and the like. However, methylphenidate hydrochloride has a very bitter taste, which greatly increases the difficulty and compliance of children in taking the medicine. In addition, methylphenidate hydrochloride has a short half-life (t 1/2 2-3 hours), needs to be taken twice daily, and needs to be taken independently by children during school, thereby causing the phenomenon of missed taking. The preparation method comprises the steps of adopting ion exchange resin and methylphenidate hydrochloride to compound to cover the bitter taste of methylphenidate hydrochloride and regulate the release speed of methylphenidate hydrochloride, coating a slow release material on the basis of the medicine-ion exchange resin compound to realize slow release of the medicine, and then mixing the coated compound prepared by the medicine-resin compound with the rest auxiliary materials for tabletting to prepare the slow release chewable tablet. However, the preparation process is complex, the coating process is easy to generate static phenomenon, the coating is easy to fail, and the release speed and the release degree between batches are large. Therefore, the composition and the proportion of the preparation and the preparation method thereof need to be optimized, and the quality of the medicine and the dissolution and release uniformity thereof are improved.
Disclosure of Invention
The invention aims to provide a methylphenidate hydrochloride sustained-release chewable tablet, which comprises 0.1-10% (weight percent) methylphenidate hydrochloride, 0.1-20% (weight percent) methylphenidate hydrochloride resin compound, 1-30% (weight percent) methylphenidate hydrochloride resin compound coated with sustained-release materials and a pharmaceutically acceptable carrier, wherein the methylphenidate hydrochloride resin compound comprises methylphenidate hydrochloride and sodium polystyrene sulfonate ion exchange resin according to the mass ratio of 1:1-4, wherein the methylphenidate hydrochloride resin compound coated with the slow-release material consists of methylphenidate hydrochloride resin compound, povidone, polyvinyl acetate water dispersion, triethyl glycerol, talcum powder and water, and the pharmaceutically acceptable carrier is selected from any one or combination of a filling agent, a disintegrating agent, an adhesive, a lubricant, a pH regulator and a flavoring agent.
In a preferred embodiment of the present invention, the methylphenidate hydrochloride content of the chewable tablet is 0.5-5%, preferably 0.75-1%.
In a preferred embodiment of the present invention, the methylphenidate hydrochloride resin complex is contained in the chewable tablet in an amount of 1 to 8%, preferably 2.6 to 6%.
In a preferred embodiment of the present invention, the methylphenidate hydrochloride resin complex coated with the slow release material is contained in the chewable tablet in an amount of 10-25%, preferably 17-20%.
In the preferable technical scheme of the invention, the mass ratio of the methylphenidate hydrochloride resin compound methylphenidate hydrochloride to the polystyrene sodium sulfonate ion exchange resin is 1:2.5.
In a preferred embodiment of the present invention, the filler is selected from any one of mannitol, microcrystalline cellulose, guar gum, xylitol, lactose, or a combination thereof.
In a preferred embodiment of the present invention, the weight percentage of filler in the chewable tablet is 50-80%, preferably 55-70%, more preferably 60-66%.
In a preferred embodiment of the present invention, the binder is selected from one or a combination of povidone, hydroxypropyl cellulose, methylcellulose, hypromellose, sodium carboxymethylcellulose, polyvinyl alcohol, acacia, dextrin, povidone K30, povidone K25, povidone K17, povidone K90, povidone XL-10.
In a preferred embodiment of the present invention, the weight percentage of binder in the chewable tablet is 0.1-10%, preferably 0.2-5%, more preferably 0.5-1%.
In a preferred embodiment of the present invention, the disintegrant is selected from any one of carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, crospovidone, partially pregelatinized starch, or a combination thereof.
In a preferred embodiment of the present invention, the weight percentage of disintegrant in the chewable tablet is 1-20%, preferably 3-15%, more preferably 7.5-10%.
In a preferred embodiment of the present invention, the flavoring agent is selected from any one of sucrose, xylitol, aspartame, stevioside, mogrosides, glycyrrhizin, rubusoside, sodium saccharin, glycerin, sorbitol, mannitol, maltose, sucralose, cyclamate, or a combination thereof.
In a preferred embodiment of the present invention, the weight percentage of flavoring agent in the chewable tablet is 0.1-10%, preferably 1-8%, more preferably 2-5%.
In a preferred embodiment of the present invention, the pH adjustor is selected from any one of citric acid, potassium citrate, sodium citrate, malic acid, sodium malate, potassium hydroxide, sodium bicarbonate, sodium hydroxide, calcium carbonate, sodium carbonate, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, monoethanolamine, diethanolamine, triethanolamine, lactic acid, sodium lactate, potassium lactate, propionic acid, tartaric acid, sodium tartrate, sodium fumarate, potassium tartrate, potassium fumarate, and fumaric acid, or a combination thereof.
In a preferred embodiment of the present invention, the weight percentage of the pH regulator in the chewable tablet is 0.1-5%, preferably 0.5-4%, more preferably 1-2.5%.
In a preferred embodiment of the present invention, the chewable tablet optionally contains a coloring agent.
In a preferred embodiment of the present invention, the colorant is selected from any one of red iron oxide and yellow iron oxide or a combination thereof.
In a preferred embodiment of the present invention, the weight percentage of the coloring agent in the chewable tablet is 0.01% -5%, preferably 0.02% -3%, more preferably 0.04% -1%.
In a preferred embodiment of the present invention, the lubricant is selected from any one of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, silica, titanium dioxide, hydrated silica, light silicic anhydride, colloidal silica, and colloidal silica, or a combination thereof.
In a preferred embodiment of the present invention, the weight percentage of the lubricant in the chewable tablet is 0.1-5%, preferably 1-4%, more preferably 1.5-2.5%.
In a preferred embodiment of the present invention, the tablet is prepared in various possible shapes, preferably in any of an ellipsoid and a round shape with two convex sides, more preferably in any of a round tablet, an oval tablet, a capsule-shaped tablet, a triangular tablet, a rectangular tablet, a square round tablet, and a special-shaped tablet.
In a preferred embodiment of the present invention, the hardness of the chewable tablet is 5-25KP, preferably 10-16KP, more preferably 12-14KP.
In a preferred embodiment of the present invention, the chewable tablet is suitable for any of children, adults, and elderly people.
The invention further aims at providing a preparation method of a methylphenidate hydrochloride sustained-release chewable tablet, which comprises 0.1-10% (weight percent) methylphenidate hydrochloride, 0.1-20% (weight percent) methylphenidate hydrochloride resin compound, 1-30% (weight percent) methylphenidate hydrochloride resin compound coated with sustained-release materials and a pharmaceutically acceptable carrier, wherein the methylphenidate hydrochloride resin compound comprises methylphenidate hydrochloride and polystyrene sodium sulfonate ion exchange resin according to the mass ratio of 1:1-4, wherein the methylphenidate hydrochloride resin composite coated with the slow release material consists of methylphenidate hydrochloride resin composite, povidone, polyvinyl acetate water dispersion, triethyl glycerol, talcum powder and water, and the pharmaceutically acceptable carrier is selected from any one or combination of a filling agent, a disintegrating agent, a binding agent, a lubricant, a pH regulator and a flavoring agent, and the preparation method comprises the following steps:
(1) Dissolving methylphenidate hydrochloride in water, adding sodium polystyrene sulfonate ion exchange resin under stirring of 200-300r/min, continuously stirring, centrifuging at 1000-2000rpm for 20-30min, collecting resin composition, drying at 60-80deg.C until the water content is 3-7%, grinding, and sieving with 40-60 mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Adding PVP solution accounting for 10-15% of the mass of the resin composition into the methylphenidate hydrochloride resin compound prepared in the step (1), granulating by a wet method, drying at 60-80 ℃ until the water content is 3-7%, sieving by a 40-60 mesh sieve, and finishing to prepare the methylphenidate hydrochloride resin compound PVP coating; coating the methylphenidate hydrochloride resin compound PVP coating in a fluidized bed until the coating weight is increased by 30%, drying at 60-80 ℃ for 5-10h, and sieving with a 40-60 mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with a slow-release material, wherein the coating liquid is a suspension obtained by mixing polyvinyl acetate aqueous dispersion, triethyl glycerol, talcum powder and water, the weight percentage of the polyvinyl acetate aqueous dispersion in the coating liquid is 30-40%, the weight percentage of the triethyl glycerol is 0.1-5%, and the weight percentage of the talcum powder is 0.1-1%;
(3) Weighing the rest pharmaceutically acceptable carriers with required amount, sieving, uniformly mixing with the methylphenidate hydrochloride resin compound coated with the slow-release material prepared in the step (2), tabletting to obtain a plain tablet, and coating the plain tablet until the weight of the coating is increased by 3% -5%, thus obtaining the tablet.
In a preferred embodiment of the present invention, the particle size of the sodium polystyrene sulfonate ion exchange resin is 80-200. Mu.m, preferably 110-130. Mu.m.
In the preferable technical scheme of the invention, the mixing temperature of the methylphenidate hydrochloride and the polystyrene sodium sulfonate ion exchange resin is 20-50 ℃ and the mixing time is 0.1-5h.
In the preferable technical scheme of the invention, the mixing temperature of the methylphenidate hydrochloride and the polystyrene sodium sulfonate ion exchange resin is 25-40 ℃ and the mixing time is 0.6-2h.
In a preferred embodiment of the invention, in step (2), the PVP solution has a concentration of 10-40%, preferably 20-30%.
In a preferred embodiment of the present invention, in step (2), the PVP solution is added to the resin composition 3 to 4 times, and after each addition of the PVP solution, the mixture of the PVP solution and the resin composition is wet granulated.
In the preferred technical scheme of the invention, in the step (2), the wet granulation condition is that the stirring speed is 100-500rpm, the chopping rotating speed is 500-2000rpm, the mixing is 0.5-10min, the stirring speed is 200-250rpm, the chopping rotating speed is 1000-1500rpm, and the mixing is 1-5min.
In the preferred technical scheme of the invention, the coating liquid in the step (2) comprises 32-38% of polyvinyl acetate water dispersion by weight, 0.5-4% of triethyl glycerinum by weight and 0.2-0.8% of talcum powder by weight.
In a preferred embodiment of the present invention, the solid content of the coating solution in step (2) is less than 20%, preferably 10-15%.
In a preferred embodiment of the present invention, the number of drying in step (2) is 1-3, preferably 2.
In the preferred technical scheme of the invention, the drying in the step (2) is reduced pressure drying at 60 ℃ until the drying weight loss is 15-25%, sieving with a 40-mesh sieve, granulating by a wet method, and continuing drying until the drying weight loss is 3-7%.
In a preferred embodiment of the invention, the inlet air temperature of the fluidized bed is 20-50 ℃, preferably 30-40 ℃.
In a preferred embodiment of the invention, the inlet air humidity of the fluidized bed is 20-50% RH, preferably 40-45% RH.
In a preferred embodiment of the present invention, the drying is selected from any one of reduced pressure drying, vacuum drying, spray drying, or a combination thereof.
In a preferred embodiment of the present invention, the coating solution in step (3) is a polyvinyl alcohol solution with a solid content of 10%.
In the preferred technical scheme of the invention, in the step (3), the coating condition is that the air inlet temperature is 55-65 ℃, the compressed air is 0.6-0.8 MPa, the pressure difference range is-0.1 KPa to-0.3 KPa, the tablet bed temperature is 32-42 ℃, and the rotating speed of the coating machine is 1-2.5rpm.
In the preferred technical scheme of the invention, in the step (3), other raw materials except magnesium stearate are uniformly mixed with the methylphenidate hydrochloride resin compound coated with the slow-release material prepared in the step (2) for 10-20min, and then the magnesium stearate is added for continuous mixing for 5-10min.
Another object of the present invention is to provide the use of the methylphenidate hcl sustained-release chewable tablet prepared according to the present invention for preparing a medicament for treating Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy.
Unless otherwise indicated, when the invention relates to a percentage between liquids, the percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentage between solids and liquids, the percentage being weight/volume percentage; the balance being weight/weight percent.
The present invention detects the amount of release in a sample according to the detection method of the release profile of methylphenidate hydrochloride sustained release chewable tablets described in the FDA dissolution database, unless otherwise specified. The dissolution medium is 0.4M potassium dihydrogen phosphate solution, and the volume of the medium is as follows: 900ml, rotational speed: 75rpm.
Compared with the prior art, the invention has the following beneficial technical effects:
1. the invention screens and optimizes the components and the proportion of the methylphenidate hydrochloride sustained-release chewing composition, forms a compound by the methylphenidate hydrochloride and the polystyrene sodium sulfonate ion exchange resin, covers the bad smell of the medicine, obviously improves the strong exchange capacity to adjust the release speed, scientifically screens the coating liquid and the components and the proportion thereof, scientifically screens the coating parameters (drying conditions, air inlet temperature, humidity, wet granulation and the like), obviously improves the release speed difference among sustained-release chewing tablet batches, realizes stable and controllable product quality, improves the taste of the tablet, improves the medicine compliance of patients, especially children patients, and ensures the safety and the effectiveness of clinical medicine.
2. The preparation method has the advantages of simple and convenient operation, obvious shortening of the production period, obvious cost benefit, suitability for industrial mass production and the like.
Drawings
FIG. 1 comparison of the release curves of methylphenidate hydrochloride sustained-release chewable tablets prepared in examples 1-5 and reference agent
Detailed Description
The present invention is described below with reference to examples, but the present invention is not limited to the examples.
The composition of the methylphenidate hcl sustained release chewable tablet is shown in table 1.
TABLE 1
Example 1Preparation of methylphenidate hydrochloride sustained-release chewable tablet
The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet comprises the following steps:
(1) Preparation of methylphenidate hydrochloride resin composite: 100g of methylphenidate hydrochloride solution is dissolved in 750ml of purified water at 25 ℃ and 1000rpm to prepare methylphenidate hydrochloride solution, and 250g of sodium polystyrene sulfonate ion exchange resin with the particle size of 120 mu m is addedIRP 69), stirring and mixing for 1h at 25 ℃, centrifuging the prepared resin composition at 2000rpm/min for 20min, adding the centrifugally collected resin composition into 500ml deionized water, stirring and centrifuging, repeating the three washing operations of the resin composition, drying the washed resin composition at 60 ℃ under reduced pressure until the water content is 3-7%, grinding, and sieving with a 40-mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Preparation of methylphenidate hcl resin composite coated with slow-release material: placing 350g of methylphenidate hydrochloride resin complex prepared in the step (1) into a wet granulator, and stirring at 200rpm and 1000rpm, and adding 27.5g of povidone K 30 Preparing 20% PVP solution, adding three times, fully mixing for 1min, placing the prepared methylphenidate hydrochloride resin compound PVP coating at 60 ℃ for drying under reduced pressure until the weight loss on drying is 15-25%, sieving with a 40-mesh sieve, granulating by a wet method, continuously drying until the weight loss on drying is 3-7%, grinding, sieving with a 40-mesh sieve, and finishing to obtain the methylphenidate hydrochloride resin compound PVP coating;
weighing 0.75g talcum powder, 3g triethyl glycerate and 100g polyvinyl acetate water dispersionSR 30D) was added to 196.25ml of purified water, and after stirring uniformly, it was used as a coating solution for a PVP coating of methylphenidate hydrochloride resin complex. The coating process is performed in VECTOR TM Spraying the coating liquid onto the PVP coating of methylphenidate hydrochloride resin compound from the nozzle at the bottom of the fluidized bed, wherein the liquid supply speed of the coating liquid is 4-6rpm, and the initial air inlet volume is 10m 3 /h, improve advanceThe wind volume is 30m 3 And/h, the atomizing pressure of the nozzle is 1.2-1.6bar, the height of the guide cylinder is 0.5-1cm, the ambient temperature is controlled to be 30 ℃, the air inlet humidity is 20% RH, and the coating is continuously carried out until the weight of the coating is increased by 30%. The material was placed in a 60 ℃ oven and cured for 5h. Sieving with a 40-mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with the slow-release material.
(3) Preparation of methylphenidate hydrochloride sustained release chewable tablets: sieving each component in table 1 with a 40 mesh sieve, adding the rest raw materials except magnesium stearate into a hopper mixer, and mixing for 10 minutes; the magnesium stearate was then added to the hopper mixer and mixing continued for 5 minutes. And (3) after discharging, tabletting by adopting a rotary tablet press to obtain the chewable tablet. Will beDispersing in 200g of purified water, and stirring for 45 minutes to obtain a coating solution; coating is carried out in a porous coating pot by coating the coating liquid on the chewable tablets, the air inlet temperature is controlled to be 55-65 ℃, the compressed air is controlled to be 0.6-0.8 MPa, the pressure difference range is-0.1 KPa to-0.3 KPa, the rotating speed of the initial coating pot is 1.9rpm, after the first coating film is formed, the rotating speed of the coating pot can be properly increased according to the quality of the substrate, the spraying amount is reduced, but the rotating speed of the coating pot cannot exceed 2.5rpm. The temperature of the tablet bed is maintained at 32-42 ℃ during the coating process. And (3) until the weight of the coating is increased by 3%, thus obtaining the methylphenidate hydrochloride sustained-release chewable tablet.
EXAMPLE 2 preparation of methylphenidate hydrochloride sustained-release chewable tablet
The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet comprises the following steps:
(1) Preparation of methylphenidate hydrochloride resin composite: 100g of methylphenidate hydrochloride solution is dissolved in 750ml of purified water at 25 ℃ and 1000rpm to prepare methylphenidate hydrochloride solution, and 250g of sodium polystyrene sulfonate ion exchange resin with the particle size of 90 mu m is addedIRP 69), stirring and mixing at 25deg.C for 1 hr, centrifuging at 2000rpm/min for 20min, adding the centrifugally collected resin composition into 500ml deionized water, stirring, centrifuging, and repeating the above stepsAfter three washing operations of the composition, placing the washed resin composition at 60 ℃ for drying under reduced pressure until the water content is 3-7%, grinding, and sieving with a 40-mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Preparation of methylphenidate hcl resin composite coated with slow-release material: placing 350g of methylphenidate hydrochloride resin complex prepared in the step (1) into a wet granulator, and stirring at 200rpm and 1000rpm, and adding 27.5g of povidone K 30 Preparing 20% PVP solution, adding three times, fully mixing for 1min, placing the prepared methylphenidate hydrochloride resin compound PVP coating at 60 ℃ for drying under reduced pressure, carrying out primary drying weight loss to be 3-7%, grinding, sieving with a 40-mesh sieve, and granulating to obtain the methylphenidate hydrochloride resin compound PVP coating;
weighing 0.75g talcum powder, 3g triethyl glycerate and 100g polyvinyl acetate water dispersionSR 30D) was added to 196.25ml of purified water, and after stirring uniformly, it was used as a coating solution for a PVP coating of methylphenidate hydrochloride resin complex. The coating process is performed in VECTOR TM Spraying the coating liquid onto the PVP coating of methylphenidate hydrochloride resin compound from the nozzle at the bottom of the fluidized bed, wherein the liquid supply speed of the coating liquid is 4-6rpm, and the initial air inlet volume is 10m 3 And/h, improving the air inlet quantity to 30m 3 And/h, the atomizing pressure of the nozzle is 1.2-1.6bar, the height of the guide cylinder is 0.5-1cm, the ambient temperature is controlled to be 30 ℃, the air inlet humidity is 20% RH, and the coating is continuously carried out until the weight of the coating is increased by 30%. The material was placed in a 60 ℃ oven and cured for 5h. Sieving with a 40-mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with the slow-release material.
(3) Preparation of methylphenidate hydrochloride sustained release chewable tablets: sieving each component in table 1 with a 40 mesh sieve, adding the rest raw materials except magnesium stearate into a hopper mixer, and mixing for 10 minutes; the magnesium stearate was then added to the hopper mixer and mixing continued for 5 minutes. And (3) after discharging, tabletting by adopting a rotary tablet press to obtain the chewable tablet. Will beDispersing in 200ml purified water, stirring for 45 min to obtain coating solution; coating is carried out in a porous coating pot by coating the coating liquid on the chewable tablets, the air inlet temperature is controlled to be 55-65 ℃, the compressed air is controlled to be 0.6-0.8 MPa, the pressure difference range is-0.1 KPa to-0.3 KPa, the rotating speed of the initial coating pot is 1.9rpm, after the first coating film is formed, the rotating speed of the coating pot can be properly increased according to the quality of the substrate, the spraying amount is reduced, but the rotating speed of the coating pot cannot exceed 2.5rpm. The temperature of the tablet bed is maintained at 32-42 ℃ during the coating process. And (3) until the weight of the coating is increased by 3%, thus obtaining the methylphenidate hydrochloride sustained-release chewable tablet.
EXAMPLE 3 preparation of methylphenidate hydrochloride sustained-release chewable tablet
The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet comprises the following steps:
(1) Preparation of methylphenidate hydrochloride resin composite: 100g of methylphenidate hydrochloride solution is dissolved in 750ml of purified water at 25 ℃ and 1000rpm to prepare methylphenidate hydrochloride solution, and 250g of sodium polystyrene sulfonate ion exchange resin with the particle size of 90 mu m is addedIRP 69), stirring and mixing for 1h at 25 ℃, centrifuging the prepared resin composition at 2000rpm/min for 20min, adding the centrifugally collected resin composition into 500ml deionized water, stirring and centrifuging, repeating the three washing operations of the resin composition, drying the washed resin composition at 60 ℃ under reduced pressure until the water content is 3-7%, grinding, and sieving with a 40-mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Preparation of methylphenidate hcl resin composite coated with slow-release material: placing 350g of methylphenidate hydrochloride resin complex prepared in the step (1) into a wet granulator, and stirring at 200rpm and 1000rpm, and adding 27.5g of povidone K 30 Preparing 20% PVP solution, adding three times, mixing for 1min, vacuum drying at 60deg.C until the weight loss is 15-25%, sieving with 40 mesh sieve, wet granulating, drying until the weight loss is 3-7%,grinding, sieving with a 40-mesh sieve, and finishing to obtain a methylphenidate hydrochloride resin compound PVP coating;
weighing 0.75g talcum powder, 3g triethyl glycerate and 100g polyvinyl acetate water dispersionSR 30D) was added to 196.25ml of purified water, and after stirring uniformly, it was used as a coating solution for a PVP coating of methylphenidate hydrochloride resin complex. The coating process is performed in VECTOR TM Spraying the coating liquid onto the PVP coating of methylphenidate hydrochloride resin compound from the nozzle at the bottom of the fluidized bed, wherein the liquid supply speed of the coating liquid is 4-6rpm, and the initial air inlet volume is 10m 3 And/h, improving the air inlet quantity to 30m 3 And/h, the atomizing pressure of the nozzle is 1.2-1.6bar, the height of the guide cylinder is 0.5-1cm, the ambient temperature is controlled to be 25 ℃, and the air inlet humidity is 36% RH. The coating was continued until the coating increased weight by 30%. The material was placed in a 60 ℃ oven and cured for 5h. Sieving with a 40-mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with the slow-release material.
(3) Preparation of methylphenidate hydrochloride sustained release chewable tablets: sieving each component in table 1 with a 40 mesh sieve, adding the rest raw materials except magnesium stearate into a hopper mixer, and mixing for 10 minutes; the magnesium stearate was then added to the hopper mixer and mixing continued for 5 minutes. And (3) after discharging, tabletting by adopting a rotary tablet press to obtain the chewable tablet. Will beDispersing in 200ml purified water, stirring for 45 min to obtain coating solution; coating is carried out in a porous coating pot by coating the coating liquid on the chewable tablets, the air inlet temperature is controlled to be 55-65 ℃, the compressed air is controlled to be 0.6-0.8 MPa, the pressure difference range is-0.1 KPa to-0.3 KPa, the rotating speed of the initial coating pot is 1.9rpm, after the first coating film is formed, the rotating speed of the coating pot can be properly increased according to the quality of the substrate, the spraying amount is reduced, but the rotating speed of the coating pot cannot exceed 2.5rpm. The temperature of the tablet bed is maintained at 32-42 ℃ during the coating process. And (3) until the weight of the coating is increased by 3%, thus obtaining the methylphenidate hydrochloride sustained-release chewable tablet.
EXAMPLE 4 preparation of methylphenidate hydrochloride sustained-release chewable tablet
The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet comprises the following steps:
(1) Preparation of methylphenidate hydrochloride resin composite: 100g of methylphenidate hydrochloride solution is dissolved in 750ml of purified water at 25 ℃ and 1000rpm to prepare methylphenidate hydrochloride solution, and 250g of sodium polystyrene sulfonate ion exchange resin with the particle size of 90 mu m is addedIRP 69), stirring and mixing for 1h at 25 ℃, centrifuging the prepared resin composition at 2000rpm/min for 20min, adding the centrifugally collected resin composition into 500ml deionized water, stirring and centrifuging, repeating the three washing operations of the resin composition, drying the washed resin composition at 60 ℃ under reduced pressure until the water content is 3-7%, grinding, and sieving with a 40-mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Preparation of methylphenidate hcl resin composite coated with slow-release material: placing 350g of methylphenidate hydrochloride resin complex prepared in the step (1) into a wet granulator, and stirring at 200rpm and 1000rpm, and adding 27.5g of povidone K 30 Preparing 20% PVP solution, adding three times, fully mixing for 1min, placing the prepared methylphenidate hydrochloride resin compound PVP coating at 60 ℃ for drying under reduced pressure until the weight loss on drying is 15-25%, sieving with a 40-mesh sieve, granulating by a wet method, continuously drying until the weight loss on drying is 3-7%, grinding, sieving with a 40-mesh sieve, and finishing to obtain the methylphenidate hydrochloride resin compound PVP coating;
weighing 0.75g talcum powder, 3g triethyl glycerate and 100g polyvinyl acetate water dispersionSR 30D) was added to 196.25ml of purified water, and after stirring uniformly, it was used as a coating solution for a PVP coating of methylphenidate hydrochloride resin complex. The coating process is performed in VECTOR TM Spraying the coating liquid onto the PVP coating of methylphenidate hydrochloride resin compound via nozzle at the bottom of the fluidized bedThe liquid speed is 4-6rpm, and the initial air inlet quantity is 10m 3 And/h, improving the air inlet quantity to 30m 3 And/h, the atomizing pressure of the nozzle is 1.2-1.6bar, the height of the guide cylinder is 0.5-1cm, the ambient temperature is controlled to be 27 ℃, and the air inlet humidity is 40% RH. The coating was continued until the coating increased weight by 30%. The material was placed in a 60 ℃ oven and cured for 5h. Sieving with a 40-mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with the slow-release material.
(3) Preparation of methylphenidate hydrochloride sustained release chewable tablets: sieving each component in table 1 with a 40 mesh sieve, adding the rest raw materials except magnesium stearate into a hopper mixer, and mixing for 10 minutes; the magnesium stearate was then added to the hopper mixer and mixing continued for 5 minutes. And (3) after discharging, tabletting by adopting a rotary tablet press to obtain the chewable tablet. Will beDispersing in 200ml purified water, stirring for 45 min to obtain coating solution; coating is carried out in a porous coating pot by coating the coating liquid on the chewable tablets, the air inlet temperature is controlled to be 55-65 ℃, the compressed air is controlled to be 0.6-0.8 MPa, the pressure difference range is-0.1 KPa to-0.3 KPa, the rotating speed of the initial coating pot is 1.9rpm, after the first coating film is formed, the rotating speed of the coating pot can be properly increased according to the quality of the substrate, the spraying amount is reduced, but the rotating speed of the coating pot cannot exceed 2.5rpm. The temperature of the tablet bed is maintained at 32-42 ℃ during the coating process. And (3) until the weight of the coating is increased by 3%, thus obtaining the methylphenidate hydrochloride sustained-release chewable tablet.
EXAMPLE 5 preparation of methylphenidate hydrochloride sustained-release chewable tablet
The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet comprises the following steps:
(1) Preparation of methylphenidate hydrochloride resin composite: 100g of methylphenidate hydrochloride solution is dissolved in 750ml of purified water at 25 ℃ and 1000rpm to prepare methylphenidate hydrochloride solution, and 250g of sodium polystyrene sulfonate ion exchange resin with the particle size of 90 mu m is addedIRP 69), stirring and mixing at 25deg.C for 1 hr, centrifuging at 2000rpm/min for 20min, and collecting resin groupAdding the compound into 500ml deionized water, stirring, centrifuging, repeating the three washing operations of the resin composition, then placing the washed resin composition at 60 ℃ for drying under reduced pressure until the water content is 3-7%, grinding, and sieving with a 40-mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Preparation of methylphenidate hcl resin composite coated with slow-release material: placing 350g of methylphenidate hydrochloride resin complex prepared in the step (1) into a wet granulator, and stirring at 200rpm and 1000rpm, and adding 27.5g of povidone K 30 Preparing 20% PVP solution, adding three times, fully mixing for 1min, placing the prepared methylphenidate hydrochloride resin compound PVP coating at 60 ℃ for drying under reduced pressure until the weight loss on drying is 15-25%, sieving with a 40-mesh sieve, granulating by a wet method, continuously drying until the weight loss on drying is 3-7%, grinding, sieving with a 40-mesh sieve, and finishing to obtain the methylphenidate hydrochloride resin compound PVP coating;
weighing 0.75g talcum powder, 3g triethyl glycerate and 100g polyvinyl acetate water dispersionSR 30D) was added to 196.25ml of purified water, and after stirring uniformly, it was used as a coating solution for a PVP coating of methylphenidate hydrochloride resin complex. The coating process is performed in VECTOR TM Spraying the coating liquid onto the PVP coating of methylphenidate hydrochloride resin compound from the nozzle at the bottom of the fluidized bed, wherein the liquid supply speed of the coating liquid is 4-6rpm, and the initial air inlet volume is 10m 3 And/h, improving the air inlet quantity to 30m 3 And/h, the atomizing pressure of the nozzle is 1.2-1.6bar, the height of the guide cylinder is 0.5-1cm, the ambient temperature is controlled to be 26 ℃, the air inlet humidity is 56% RH, and the coating is continuously carried out until the weight of the coating is increased by 30%. The material was placed in a 60 ℃ oven and cured for 5h. Sieving with a 40-mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with the slow-release material.
(3) Preparation of methylphenidate hydrochloride sustained release chewable tablets: sieving each component in table 1 with a 40 mesh sieve, adding the rest raw materials except magnesium stearate into a hopper mixer, and mixing for 10 minutes; adding magnesium stearate into the hopper mixer, and continuously mixing for 5 minutes. And (3) after discharging, tabletting by adopting a rotary tablet press to obtain the chewable tablet. Will beDispersing in 200ml purified water, stirring for 45 min to obtain coating solution; coating is carried out in a porous coating pot by coating the coating liquid on the chewable tablets, the air inlet temperature is controlled to be 55-65 ℃, the compressed air is controlled to be 0.6-0.8 MPa, the pressure difference range is-0.1 KPa to-0.3 KPa, the rotating speed of the initial coating pot is 1.9rpm, after the first coating film is formed, the rotating speed of the coating pot can be properly increased according to the quality of the substrate, the spraying amount is reduced, but the rotating speed of the coating pot cannot exceed 2.5rpm. The temperature of the tablet bed is maintained at 32-42 ℃ during the coating process. And (3) until the weight of the coating is increased by 3%, thus obtaining the methylphenidate hydrochloride sustained-release chewable tablet.
Comparative example 1 preparation of methylphenidate hcl sustained-release chewable tablet
The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet comprises the following steps:
(1) Preparation of methylphenidate hydrochloride resin composite: 100g of methylphenidate hydrochloride solution is dissolved in 750ml of purified water at 25 ℃ and 1000rpm to prepare methylphenidate hydrochloride solution, and 250g of sodium polystyrene sulfonate ion exchange resin with the particle size of 120 mu m is addedIRP 69), stirring and mixing for 1h at 25 ℃, centrifuging the prepared resin composition at 2000rpm/min for 20min, adding the centrifugally collected resin composition into 500ml deionized water, stirring and centrifuging, repeating the three washing operations of the resin composition, drying the washed resin composition at 60 ℃ under reduced pressure until the water content is 3-7%, grinding, and sieving with a 40-mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Preparation of methylphenidate hcl resin composite coated with slow-release material: placing 350g of methylphenidate hydrochloride resin complex prepared in the step (1) into a wet granulator, and stirring at 200rpm and 1000rpm, and adding 27.5g of povidone K 30 Preparing 20% PVP solution, adding three times, mixing for 1min, and compounding to obtain methylphenidate hydrochloride resinDrying the PVP coating at 60 ℃ under reduced pressure until the weight loss on drying is 15-25%, sieving with a 40-mesh sieve, granulating by a wet method, continuing drying until the weight loss on drying is 3-7%, grinding, sieving with a 40-mesh sieve, and finishing to obtain the methylphenidate hydrochloride resin compound PVP coating;
weighing 1.9g of triethyl glycerol and 127g of polyvinyl acetate aqueous dispersionSR 30D) was added to 71ml of purified water, and after stirring uniformly, it was used as a coating solution for a PVP coating of methylphenidate hydrochloride resin complex. The coating process is performed in VECTOR TM Spraying the coating liquid onto the PVP coating of methylphenidate hydrochloride resin compound from the nozzle at the bottom of the fluidized bed, wherein the liquid supply speed of the coating liquid is 4-6rpm, and the initial air inlet volume is 10m 3 And/h, improving the air inlet quantity to 30m 3 And/h, the atomizing pressure of the nozzle is 1.2-1.6bar, the height of the guide cylinder is 0.5-1cm, the ambient temperature is controlled to be 30 ℃, the air inlet humidity is 20% RH, and the coating is continued.
The results show that the materials are hard due to the fact that the materials are rubbed and static electricity is extremely high in the coating process, and the materials cannot be blown up even if the air inlet quantity is regulated to the maximum value, so that the coating process fails.
Test example 1Dissolution and release of methylphenidate hydrochloride sustained release chewable tablets
Dissolution and release of the methylphenidate hcl sustained-release chewable tablets prepared in examples 1-5 were examined according to the method of the present invention and compared with the reference agent methylphenidate hcl sustained-release chewable tablet (trade name quillicaw ER, manufacturer: tris Pharma, inc.) and the results are shown in fig. 1. It can be seen that the slow release effect of each example is relatively uniform, and that examples 4-5 have similar release effects to the original reference reagent.
The above description of the embodiments of the present invention is not intended to limit the present invention, and those skilled in the art can make various changes or modifications according to the present invention without departing from the spirit of the present invention, and shall fall within the scope of the claims of the present invention.
Claims (24)
1. The methylphenidate hydrochloride sustained-release chewable tablet is characterized by comprising, by weight, 0.75-1% of methylphenidate hydrochloride, 2.6-6% of methylphenidate hydrochloride resin compound, 17-20% of methylphenidate hydrochloride resin compound coated with sustained-release materials and a pharmaceutically acceptable carrier, wherein the methylphenidate hydrochloride resin compound consists of methylphenidate hydrochloride and sodium polystyrene sulfonate ion exchange resin according to a mass ratio of 1:1-4, the methylphenidate hydrochloride resin compound coated with sustained-release materials consists of methylphenidate hydrochloride resin compound, povidone, polyvinyl acetate water dispersion, triethyl glycerol, talcum powder and water, the pharmaceutically acceptable carrier is selected from any one or combination of a filler, a disintegrating agent, an adhesive, a lubricant, a pH regulator and a flavoring agent,
the preparation method of the methylphenidate hydrochloride resin compound coated with the slow-release material comprises the following steps: adding PVP solution accounting for 10-15% of the mass of the resin composition into the methylphenidate hydrochloride resin composition, granulating by a wet method, drying at 60-80 ℃ until the water content is 3-7%, sieving by a 40-60 mesh sieve, and finishing to obtain the methylphenidate hydrochloride resin composition PVP coating; coating the methylphenidate hydrochloride resin compound PVP coating in a fluidized bed until the coating weight is increased by 30%, drying at 60-80 ℃ for 5-10h, and sieving with a 40-60 mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with a slow-release material, wherein the coating liquid is a suspension obtained by mixing polyvinyl acetate aqueous dispersion, triethyl glycerol, talcum powder and water, the weight percentage of the polyvinyl acetate aqueous dispersion in the coating liquid is 30-40%, the weight percentage of the triethyl glycerol is 0.1-5%, and the weight percentage of the talcum powder is 0.1-0.25%;
the filler is selected from any one or combination of mannitol, microcrystalline cellulose, guar gum and xylitol, the weight percentage of the filler in the chewable tablet is 60-66%,
the adhesive is selected from one or a combination of povidone, hydroxypropyl cellulose, methylcellulose, hypromellose, carboxymethylcellulose sodium, carboxymethylcellulose, polyvinyl alcohol, acacia, dextrin, povidone K30, povidone K25, povidone K17, povidone K90, povidone XL and povidone XL-10,
the weight percentage of the binder in the chewing tablet is 0.5-1%,
the disintegrating agent is selected from carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, cross-linked povidone, and a combination of partially pregelatinized starch,
the weight percentage of the disintegrating agent in the chewing tablet is 7.5-10%,
the flavoring agent is selected from any one or combination of sucrose, xylitol, aspartame, stevioside, mogroside, glycyrrhizin, rubusoside, saccharin sodium, glycerol, sorbitol, mannitol, maltose, sucralose and sodium cyclamate, wherein the weight percentage of the flavoring agent in the chewable tablet is 2-5%,
the pH regulator is selected from any one or combination of citric acid, potassium citrate, sodium citrate, malic acid, sodium malate, potassium hydroxide, sodium bicarbonate, sodium hydroxide, calcium carbonate, sodium carbonate, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, monoethanolamine, diethanolamine, triethanolamine, lactic acid, sodium lactate, potassium lactate, propionic acid, tartaric acid, sodium tartrate, sodium fumarate, potassium tartrate, potassium fumarate and fumaric acid, wherein the weight percentage of the pH regulator in the chewable tablet is 1-2.5%,
the lubricant is selected from any one or combination of sodium stearyl fumarate, stearic acid, magnesium stearate, calcium stearate, talcum powder, sucrose fatty acid ester, silicon dioxide, titanium dioxide, hydrated silicon dioxide, light silicic anhydride, colloidal silicon dioxide and micro silica gel, and the weight percentage of the lubricant in the chewable tablet is 1.5-2.5%.
2. The methylphenidate hcl sustained-release chewable tablet of claim 1, wherein the chewable tablet optionally comprises a colorant selected from the group consisting of red iron oxide, yellow iron oxide, and combinations thereof, the weight percentage of colorant in the chewable tablet being between 0.04% and 1%.
3. The methylphenidate hcl sustained release chewable tablet of claim 1, wherein the hardness of the chewable tablet is between 5KP and 25KP.
4. A methylphenidate hcl sustained release chewable tablet according to claim 3, wherein the hardness of the chewable tablet is between 10 KP and 16KP.
5. The methylphenidate hcl sustained release chewable tablet of claim 4, wherein the hardness of the chewable tablet is between 12 KP and 14KP.
6. The methylphenidate hcl sustained-release chewable tablet according to any one of claims 1-5, wherein the chewable tablet is suitable for any one of children, adults, and geriatric use.
7. The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet according to any one of claims 1 to 6, which comprises, by weight, 0.75 to 1% of methylphenidate hydrochloride, 2.6 to 6% of methylphenidate hydrochloride resin complex, 17 to 20% of methylphenidate hydrochloride resin complex coated with sustained-release material and a pharmaceutically acceptable carrier, wherein the methylphenidate hydrochloride resin complex is composed of methylphenidate hydrochloride and sodium polystyrene sulfonate ion exchange resin according to a mass ratio of 1:1 to 4, the methylphenidate hydrochloride resin complex coated with sustained-release material is composed of methylphenidate hydrochloride resin complex, povidone, polyvinyl acetate aqueous dispersion, triethyl glycerol, talc and water, and the pharmaceutically acceptable carrier is selected from any one or a combination of fillers, disintegrants, binders, lubricants, pH adjusters and flavoring agents, and comprises the following steps:
(1) Dissolving methylphenidate hydrochloride in water, adding sodium polystyrene sulfonate ion exchange resin under stirring of 200-300r/min, continuously stirring, centrifuging at 1000-2000rpm for 20-30min, collecting resin composition, drying at 60-80deg.C until the water content is 3-7%, grinding, and sieving with 40-60 mesh sieve to obtain methylphenidate hydrochloride resin compound;
(2) Adding PVP solution accounting for 10-15% of the mass of the resin composition into the methylphenidate hydrochloride resin compound prepared in the step (1), performing wet granulation, drying at 60 ℃ under reduced pressure until the weight loss on drying is 15-25%, sieving with a 40-mesh sieve, performing wet granulation, continuously drying until the weight loss on drying is 3-7%, sieving with a 40-60-mesh sieve, and finishing to obtain the methylphenidate hydrochloride resin compound PVP coating; coating the methylphenidate hydrochloride resin compound PVP coating in a fluidized bed until the coating weight is increased by 30%, drying at 60-80 ℃ for 5-10h, and sieving with a 40-60 mesh sieve to obtain the methylphenidate hydrochloride resin compound coated with a slow-release material, wherein the coating liquid is a suspension obtained by mixing polyvinyl acetate aqueous dispersion, triethyl glycerol, talcum powder and water, the weight percentage of the polyvinyl acetate aqueous dispersion in the coating liquid is 30-40%, the weight percentage of the triethyl glycerol is 0.1-5%, and the weight percentage of the talcum powder is 0.1-0.25%;
(3) Weighing the rest pharmaceutically acceptable carriers with required amount, sieving, uniformly mixing with the methylphenidate hydrochloride resin compound coated with the slow-release material prepared in the step (2), tabletting to obtain a plain tablet, coating the plain tablet until the weight of the coating is increased by 3% -5%, thus obtaining the tablet,
the particle size of the polystyrene sodium sulfonate ion exchange resin is 80-200 mu m,
the mixing temperature of the methylphenidate hydrochloride and the polystyrene sodium sulfonate ion exchange resin is 20-50 ℃, the mixing time is 0.1-5h,
the inlet air temperature of the fluidized bed is 30-40 ℃, and the inlet air humidity of the fluidized bed is 40-45% RH.
8. The process according to claim 7, wherein the particle size of the sodium polystyrene sulfonate ion exchange resin is 110 to 130. Mu.m.
9. The preparation method of claim 7, wherein the mixing temperature of the methylphenidate hydrochloride and the polystyrene sodium sulfonate ion exchange resin is 25-40 ℃ and the mixing time is 0.6-2h.
10. The method of claim 7, wherein the PVP solution is at a concentration of 10-40% in step (2).
11. The method of claim 10, wherein the PVP solution is present in the range of 20-30% in step (2).
12. The method of claim 7, wherein in step (2), the PVP solution is added to the resin composition 3 to 4 times, and the mixture of the PVP solution and the resin composition is wet granulated after each addition of the PVP solution.
13. The process according to claim 7, wherein in the step (2), the wet granulation is carried out at a stirring speed of 100 to 500rpm, a chopping speed of 500 to 2000rpm, and mixing for 0.5 to 10 minutes.
14. The preparation method according to claim 13, wherein in the step (2), the wet granulation is carried out at a stirring speed of 200-250rpm and a chopping speed of 1000-1500rpm, and the mixture is mixed for 1-5min.
15. The process according to claim 7, wherein the coating liquid in step (2) comprises 32 to 38% by weight of the aqueous polyvinyl acetate dispersion, 0.5 to 4% by weight of triethyl glycerol and 0.2 to 0.8% by weight of talc.
16. The method of claim 7, wherein the coating in step (2) has a solids content of less than 20%.
17. The method of claim 16, wherein the coating solution in step (2) has a solids content of 10-15%.
18. The process according to claim 7, wherein the number of drying in step (2) is 1 to 3.
19. The method of claim 18, wherein the number of drying steps in step (2) is 2.
20. The method of claim 7, wherein the drying is selected from any one of reduced pressure drying, vacuum drying, spray drying, or a combination thereof.
21. The method according to claim 7, wherein the coating liquid in the step (3) is a polyvinyl alcohol solution having a solid content of 10%.
22. The process according to claim 7, wherein in step (3), the coating conditions are that the inlet air temperature is 55-65 ℃, the compressed air is 0.6-0.8 MPa, the pressure difference is-0.1 KPa to-0.3 KPa, the tablet bed temperature is 32-42 ℃, and the rotational speed of the coating machine is 1-2.5rpm.
23. The preparation method according to claim 7, wherein in the step (3), the other raw materials except magnesium stearate are uniformly mixed with the methylphenidate hydrochloride resin composite coated with the slow release material prepared in the step (2) for 10-20min, and then magnesium stearate is added for further mixing for 5-10min.
24. Use of a methylphenidate hydrochloride sustained-release chewable tablet prepared by a preparation method according to any one of claims 1-6 or a methylphenidate hydrochloride sustained-release chewable tablet prepared by a preparation method according to any one of claims 7-23 for the preparation of a medicament for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy.
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| 颜耀东.《缓释控释制剂的设计与开发》.中国医药科技出版社,2006,第218-219页. * |
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