CN116036036A - 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
- CN116036036A CN116036036A CN202111504945.3A CN202111504945A CN116036036A CN 116036036 A CN116036036 A CN 116036036A CN 202111504945 A CN202111504945 A CN 202111504945A CN 116036036 A CN116036036 A CN 116036036A
- Authority
- CN
- China
- Prior art keywords
- methylphenidate hydrochloride
- methylphenidate
- release
- coating
- sustained
- 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 154
- 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 153
- 239000007910 chewable tablet Substances 0.000 title claims abstract description 73
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- 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 24
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- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
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- 229940043237 diethanolamine Drugs 0.000 description 1
- LRCFXGAMWKDGLA-UHFFFAOYSA-N dioxosilane;hydrate Chemical compound O.O=[Si]=O LRCFXGAMWKDGLA-UHFFFAOYSA-N 0.000 description 1
- WPUMTJGUQUYPIV-JIZZDEOASA-L disodium (S)-malate Chemical compound [Na+].[Na+].[O-]C(=O)[C@@H](O)CC([O-])=O WPUMTJGUQUYPIV-JIZZDEOASA-L 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L disodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 206010020765 hypersomnia Diseases 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 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
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 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
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- SHPKCSFVQGSAJU-SEPHDYHBSA-L potassium fumarate Chemical compound [K+].[K+].[O-]C(=O)\C=C\C([O-])=O SHPKCSFVQGSAJU-SEPHDYHBSA-L 0.000 description 1
- 235000019295 potassium fumarate Nutrition 0.000 description 1
- PHZLMBHDXVLRIX-UHFFFAOYSA-M potassium lactate Chemical compound [K+].CC(O)C([O-])=O PHZLMBHDXVLRIX-UHFFFAOYSA-M 0.000 description 1
- 239000001521 potassium lactate Substances 0.000 description 1
- 235000011085 potassium lactate Nutrition 0.000 description 1
- 229960001304 potassium lactate Drugs 0.000 description 1
- 239000001472 potassium tartrate Substances 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 235000011005 potassium tartrates Nutrition 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 229940095574 propionic acid Drugs 0.000 description 1
- 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 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 229960004029 silicic acid Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019265 sodium DL-malate Nutrition 0.000 description 1
- 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 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940005573 sodium fumarate Drugs 0.000 description 1
- 235000019294 sodium fumarate Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000001394 sodium malate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Images
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- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
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- 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
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- 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
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- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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-piperidineacetic acid methyl ester hydrochloride, with the structure shown as formula I) is a central nervous system stimulant, and is widely applied to the clinic for treating Attention Deficit Hyperactivity Disorder (ADHD), hypersomnia 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 added
IRP 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 thoroughly for 1min, and making into final productDrying the methylphenidate hydrochloride resin compound 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, 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 dispersion
SR 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 be
Dispersing 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. Coating processThe temperature of the middle tablet bed is kept at 32-42 ℃. 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 added
IRP 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, 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 dispersion
SR 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 The coating liquid is processed on a fluidized bed processorSpraying the liquid into 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 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 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 be
Dispersing 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 added
IRP 69), stirring and mixing at 25 ℃After 1h, the prepared resin composition is placed in 2000rpm/min for centrifugation for 20min, the centrifugally collected resin composition is added into 500ml of deionized water, stirring and centrifugation are carried out, three washing operations of the resin composition are repeated, the washed resin composition is placed in 60 ℃ for decompression and drying until the water content is 3-7%, and then is ground and screened by a 40-mesh sieve, thus obtaining the 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 dispersion
SR 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 40 mesh sieve, adding other raw materials except magnesium stearate into hopperMixing for 10 minutes in a mixer; 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 be
Dispersing 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 added
IRP 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 Is prepared into the concentration ofAdding 20% PVP solution for 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 is 15-25%, sieving with a 40-mesh sieve, granulating by a wet method, continuously drying until the weight loss 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 dispersion
SR 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 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 be
Dispersing in 200ml purified water, stirring for 45 min to obtain coating solution; coating the chewable tablet in a porous coating pan by coating the coating liquid on the chewable tablet, controlling the air inlet temperature to 55-65 ℃, controlling the compressed air to 0.6-0.8 MPa, controlling the pressure difference to be-0.1 KPa to-0.3 KPa, and increasing the rotating speed of the coating pan according to the quality of the substrate after the first coating film is formed, wherein the rotating speed of the initial coating pan is 1.9rpmThe spray rate was reduced but the coating pan rotation speed was not allowed to 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 added
IRP 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 dispersion
SR 30D) is added into 196.25ml of purified water, and the mixture is stirred uniformly to obtain the final productCoating liquid of methylphenidate hydrochloride resin compound PVP coating. 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; 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 be
Dispersing 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 added
IRP 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 1.9g of triethyl glycerol and 127g of polyvinyl acetate aqueous dispersion
SR 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 (10)
1. The methylphenidate hydrochloride sustained-release chewable tablet is characterized by comprising 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 consists of 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.
2. The methylphenidate hcl sustained-release chewable tablet according to claim 1, characterized in that the methylphenidate hcl content in the chewable tablet is 0.5-5%, preferably 0.75-1%.
3. A sustained release methylphenidate hcl chewable tablet according to any one of claims 1-2, characterized in that the methylphenidate hcl resin complex content in the chewable tablet is 1-8%, preferably 2.6-6%.
4. A methylphenidate hcl sustained release chewable tablet according to any one of claims 1-3, wherein the methylphenidate hcl resin complex has a mass ratio of methylphenidate hcl to sodium polystyrene sulfonate ion exchange resin of 1:2.5.
5. The methylphenidate hcl sustained-release chewable tablet according to any one of claims 1-4, wherein the bulking agent is selected from any one of mannitol, microcrystalline cellulose, guar gum, xylitol, lactose, or a combination thereof.
6. The methylphenidate hcl sustained-release chewable tablet of any one of claims 1-5, wherein the binder is selected from any one or combination of povidone, hydroxypropyl cellulose, methylcellulose, hypromellose, sodium carboxymethylcellulose, carboxymethyl cellulose, polyvinyl alcohol, acacia, dextrin, povidone K30, povidone K25, povidone K17, povidone K90, povidone XL-10.
7. The methylphenidate hcl sustained-release chewable tablet according to any one of claims 1-6, wherein the disintegrant is selected from any one of carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, crospovidone, partially pregelatinized starch, or a combination thereof.
8. The methylphenidate hcl sustained-release chewable tablet of any one of claims 1-7, wherein 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.
9. The preparation method of the methylphenidate hydrochloride sustained-release chewable tablet is characterized in that the chewable tablet 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 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 5-15% 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%, curing for 5-10 hours at 60-80 ℃, 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.
10. Use of a methylphenidate hcl sustained release chewable tablet according to any one of claims 1-8 or as prepared by the method of preparation according to claim 9 for the preparation of a medicament for the treatment of Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy.
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Citations (3)
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| CN102429884A (en) * | 2011-12-29 | 2012-05-02 | 天津市嵩锐医药科技有限公司 | Methylphenidate hydrochloride oral cavity disintegrating pharmaceutical composition |
| US20120207824A1 (en) * | 2011-02-15 | 2012-08-16 | Tris Pharma, Inc. | Orally effective methylphenidate extended release powder and aqueous suspension product |
| US20140287041A1 (en) * | 2012-08-15 | 2014-09-25 | Tris Pharma Inc | Methylphenidate Extended Release Chewable Tablet |
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2021
- 2021-12-10 CN CN202111504945.3A patent/CN116036036B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120207824A1 (en) * | 2011-02-15 | 2012-08-16 | Tris Pharma, Inc. | Orally effective methylphenidate extended release powder and aqueous suspension product |
| CN102429884A (en) * | 2011-12-29 | 2012-05-02 | 天津市嵩锐医药科技有限公司 | Methylphenidate hydrochloride oral cavity disintegrating pharmaceutical composition |
| US20140287041A1 (en) * | 2012-08-15 | 2014-09-25 | Tris Pharma Inc | Methylphenidate Extended Release Chewable Tablet |
Non-Patent Citations (1)
| Title |
|---|
| 颜耀东: "《缓释控释制剂的设计与开发》", 中国医药科技出版社, pages: 218 - 219 * |
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