CN114983961B - Paliperidone sustained release tablet and preparation method thereof - Google Patents
Paliperidone sustained release tablet and preparation method thereof Download PDFInfo
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- CN114983961B CN114983961B CN202210776404.4A CN202210776404A CN114983961B CN 114983961 B CN114983961 B CN 114983961B CN 202210776404 A CN202210776404 A CN 202210776404A CN 114983961 B CN114983961 B CN 114983961B
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- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 title claims abstract description 77
- 229960001057 paliperidone Drugs 0.000 title claims abstract description 74
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 239000010410 layer Substances 0.000 claims abstract description 209
- 239000003814 drug Substances 0.000 claims abstract description 173
- 229940079593 drug Drugs 0.000 claims abstract description 78
- 239000003826 tablet Substances 0.000 claims abstract description 65
- 239000011247 coating layer Substances 0.000 claims abstract description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 238000001125 extrusion Methods 0.000 claims abstract description 22
- 239000000314 lubricant Substances 0.000 claims abstract description 19
- 239000002250 absorbent Substances 0.000 claims abstract description 15
- 230000002745 absorbent Effects 0.000 claims abstract description 15
- 239000011248 coating agent Substances 0.000 claims description 44
- 238000000576 coating method Methods 0.000 claims description 44
- 239000000843 powder Substances 0.000 claims description 38
- 239000007788 liquid Substances 0.000 claims description 29
- 239000002278 tabletting lubricant Substances 0.000 claims description 27
- 238000013265 extended release Methods 0.000 claims description 26
- 239000011253 protective coating Substances 0.000 claims description 25
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 23
- 239000000463 material Substances 0.000 claims description 23
- 239000003086 colorant Substances 0.000 claims description 22
- 238000002955 isolation Methods 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000012876 carrier material Substances 0.000 claims description 19
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical group CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 11
- 229940049654 glyceryl behenate Drugs 0.000 claims description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 230000000149 penetrating effect Effects 0.000 claims description 11
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 230000004888 barrier function Effects 0.000 claims description 10
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 10
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 10
- 229960003943 hypromellose Drugs 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical group CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 9
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- -1 polyoxyethylene Polymers 0.000 claims description 9
- 239000000661 sodium alginate Substances 0.000 claims description 9
- 235000010413 sodium alginate Nutrition 0.000 claims description 9
- 229940005550 sodium alginate Drugs 0.000 claims description 9
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
- 238000005553 drilling Methods 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 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 7
- 239000004408 titanium dioxide Substances 0.000 claims description 7
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- COHYTHOBJLSHDF-UHFFFAOYSA-N Indigo Chemical compound N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 claims description 4
- 239000006096 absorbing agent Substances 0.000 claims description 4
- 239000011780 sodium chloride Substances 0.000 claims description 4
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 235000012730 carminic acid Nutrition 0.000 claims description 3
- 229920002301 cellulose acetate Polymers 0.000 claims description 3
- 229940109262 curcumin Drugs 0.000 claims description 3
- 235000012754 curcumin Nutrition 0.000 claims description 3
- 239000004148 curcumin Substances 0.000 claims description 3
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 239000011148 porous material Substances 0.000 claims description 2
- KHLVKKOJDHCJMG-QDBORUFSSA-L indigo carmine Chemical compound [Na+].[Na+].N/1C2=CC=C(S([O-])(=O)=O)C=C2C(=O)C\1=C1/NC2=CC=C(S(=O)(=O)[O-])C=C2C1=O KHLVKKOJDHCJMG-QDBORUFSSA-L 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 6
- 238000013270 controlled release Methods 0.000 abstract description 5
- 238000013268 sustained release Methods 0.000 abstract description 5
- 230000002459 sustained effect Effects 0.000 abstract description 4
- 230000000857 drug effect Effects 0.000 abstract description 3
- 230000002349 favourable effect Effects 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 229960005191 ferric oxide Drugs 0.000 description 10
- JEIPFZHSYJVQDO-UHFFFAOYSA-N ferric oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000012528 membrane Substances 0.000 description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 239000011812 mixed powder Substances 0.000 description 4
- 229960000502 poloxamer Drugs 0.000 description 4
- 229920001983 poloxamer Polymers 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 239000007916 tablet composition Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000004925 Acrylic resin Substances 0.000 description 2
- 229920000178 Acrylic resin Polymers 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000004088 foaming agent Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960005150 glycerol Drugs 0.000 description 2
- 239000001087 glyceryl triacetate Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 229940097275 indigo Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 229940083037 simethicone Drugs 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 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 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000003693 atypical antipsychotic agent Substances 0.000 description 1
- 229940127236 atypical antipsychotics Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000008316 benzisoxazoles Chemical class 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940013946 invega Drugs 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
Classifications
-
- 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
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of pharmaceutical preparations, in particular to a paliperidone sustained release tablet and a preparation method thereof. The paliperidone sustained release tablet comprises a tablet core and a semi-permeable coating layer coated outside the tablet core, wherein the tablet core comprises a first medicine containing layer and a second medicine containing layer which are positioned at two ends, and a pushing layer positioned between the first medicine containing layer and the second medicine containing layer, and a medicine release hole is formed in the semi-permeable coating layer close to the first medicine containing layer and the second medicine containing layer; wherein, water absorbent and extrusion lubricant are added in the first medicine-containing layer, a first retarder is added in the pushing layer, and a second retarder is added in the second medicine-containing layer. The paliperidone sustained release tablet can release part of paliperidone in the initial stage of medication (for example, within 2 hours after medication), can obviously improve the timeliness of paliperidone release under the condition of ensuring the sustained and controlled release effect, and is favorable for timely and rapid exertion of drug effect.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a paliperidone sustained release tablet and a preparation method thereof.
Background
Paliperidone is an active metabolite 9-hydroxyrisperidone of atypical antipsychotics risperidone, a derivative of benzisoxazole, with the structural formula shown below, which exerts antipsychotic effects mainly by blocking the 5-hydroxytryptamine 2A (5-HT 2A) receptor and the dopamine D2 (DA 2) receptor.
Paliperidone extended release tablets were developed by qinsheng corporation under the trade name: invega, FDA approval was obtained in 2006, specifications including 1.5mg, 3mg, 6mg and 9mg. The paliperidone sustained release tablet developed by Qiansheng company adopts OROS technology (oral osmotic pump administration controlled release system), and consists of a tablet core, an isolation coating layer, a semipermeable membrane coating layer and a coloring coating layer, wherein the tablet core consists of a boosting layer positioned at the bottom, a first drug layer positioned at the top and a second drug layer positioned in the middle, and 2 laser-perforated drug release pores are arranged on the isolation coating layer and the semipermeable membrane coating layer at one side of the first drug layer. Under the gastrointestinal tract environment, the coloring coating layer can be rapidly eroded, water enters the tablet core through the semipermeable membrane coating layer, hydrophilic materials in the tablet core and paliperidone form jelly, the medicine is pushed to be discharged from the medicine release small holes at the top end of the tablet, and insoluble components are discharged along with excrement. The semipermeable membrane coating layer can control the speed of water entering the tablet core, thereby controlling the drug release speed.
In the process of realizing the invention, the inventor finds that the drug release amount of the paliperidone extended release tablet in the initial stage of drug administration is small, and specifically, the paliperidone extended release tablet basically has no drug release in the first 2 hours after drug administration and only has a small amount of drug release in 4 hours after drug administration.
Disclosure of Invention
Therefore, the invention aims to overcome the defect of less drug release amount in the initial drug administration period in the conventional paliperidone sustained release tablet, thereby providing the paliperidone sustained release tablet and the preparation method thereof.
The invention provides a paliperidone sustained release tablet, which comprises a tablet core and a semi-permeable coating layer coated outside the tablet core, wherein the tablet core comprises a first medicine containing layer and a second medicine containing layer which are positioned at two ends, and a pushing layer positioned between the first medicine containing layer and the second medicine containing layer, and a medicine release hole is formed in the semi-permeable coating layer close to the first medicine containing layer and the second medicine containing layer;
Wherein, water absorbent and extrusion lubricant are added in the first medicine-containing layer, a first retarder is added in the pushing layer, and a second retarder is added in the second medicine-containing layer.
Optionally, the content of the water absorbing agent is 10-20wt% based on the total weight of the first medicine-containing layer, and the content of the extrusion lubricant is 1-2wt%;
The content of the first retarder is 15-20wt% based on the total weight of the pushing layer;
the content of the second retarder is 5-10wt% based on the total weight of the second drug-containing layer.
Optionally, the weight ratio of the first medicine-containing layer, the pushing layer and the second medicine-containing layer is (1-3): (2-3): (1-3).
Optionally, the water absorbent is sodium alginate; the extrusion lubricant is at least one selected from glyceryl behenate, simethicone, glycerol and hydrogenated vegetable oil, preferably glyceryl behenate; the first retarder is low-substituted hydroxypropyl cellulose; the second retarder is low-substituted hydroxypropyl cellulose.
Optionally, the particle diameter D90 of the low-substituted hydroxypropyl cellulose is 50-100 mu m;
optionally, the weight ratio of the first retarder to the second retarder is (2-4): 1.
Optionally, the first drug-containing layer further comprises paliperidone, a carrier material and a tabletting lubricant, wherein the content of paliperidone is 2-4wt%, the content of the carrier material is 72-86 wt% and the content of the tabletting lubricant is 1-2wt% based on the total weight of the first drug-containing layer;
The pushing layer also contains pushing materials, penetrating agents and tabletting lubricants, the content of the pushing materials is 56.5-63.5 wt% based on the total weight of the pushing layer, the content of the penetrating agents is 10-30 wt%, and the content of the tabletting lubricants is 1-2 wt%;
the second drug-containing layer also contains paliperidone, a carrier material and a tabletting lubricant, the content of the paliperidone is 2-4wt%, the content of the carrier material is 83-91.5wt% and the content of the tabletting lubricant is 1-2wt% based on the total weight of the second drug-containing layer;
Optionally, for the single paliperidone extended release tablet, the total weight of paliperidone in the first drug-containing layer and the second drug-containing layer is 1.5-12 mg;
Optionally, the carrier material is selected from at least one of polyoxyethylene, hypromellose, and poloxamer having a molecular weight 100000 ～ 400000; the tabletting lubricant is at least one of stearic acid, magnesium stearate and sodium stearyl fumarate; the pushing material is selected from at least one of polyoxyethylene, hypromellose, hydroxypropyl cellulose and poloxamer with molecular weight 4000000 ～ 7000000; the penetrating agent is at least one of sodium chloride, potassium chloride, glucose and sodium citrate;
optionally, the pushing layer further contains 0.5-1.5 wt% of a first colorant, and the second drug-containing layer further contains 0.5-1.0 wt% of a second colorant, wherein the first colorant is different from the second colorant, and each of the first colorant and the second colorant is independently selected from any one of iron oxide red, iron oxide yellow, brilliant blue, indigo, carmine and curcumin.
Optionally, the weight of the semi-permeable coating layer is 18-22% of the weight of the tablet core, the semi-permeable coating layer contains a semi-permeable material and a pore-forming agent, and the content of the semi-permeable material is 98-99% by weight and the content of the pore-forming agent is 1-2% by weight based on the total weight of the semi-permeable coating layer;
Optionally, the semi-permeable material is selected from at least one of cellulose acetate, ethyl cellulose and acrylic resin; the pore-forming agent is at least one selected from polyethylene glycol, triethyl citrate and triacetin;
Optionally, the paliperidone extended release tablet further comprises an isolation coating layer, wherein the isolation coating layer is positioned between the tablet core and the semi-permeable coating layer, and the drug release holes penetrate through the isolation coating layer; the weight of the isolation coating layer is 8-12% of the weight of the tablet core, the isolation coating layer contains hydroxypropyl cellulose and povidone, the content of the hydroxypropyl cellulose is 50-90% by weight, and the content of the povidone is 10-50% by weight based on the total weight of the isolation coating layer;
Optionally, the paliperidone extended release tablet further comprises a protective coating layer, wherein the protective coating layer is coated on the outer surface of the semi-permeable coating layer; the weight of the protective coating layer is 5-10% of the weight of the tablet core, the protective coating layer contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder, and the weight of the protective coating layer is taken as a reference, the content of the hypromellose is 52-79 wt%, the content of the polyethylene glycol is 10-20 wt%, the content of the titanium dioxide is 5-15 wt%, the content of the iron oxide red is 1-3 wt%, and the content of the talcum powder is 5-10 wt%.
Optionally, the number of the drug release holes near one end of the first drug containing layer is 1-3, the number of the drug release holes near one end of the second drug containing layer is 1-3, and the aperture of the drug release holes is 0.5-0.7 mm.
The invention also provides a method for preparing the paliperidone extended release tablet of any one of the above, which comprises the following operations:
Layering and tabletting the first medicine-containing layer premix powder, the pushing layer premix powder and the second medicine-containing layer premix powder to form a first medicine-containing layer, a pushing layer and a second medicine-containing layer respectively, wherein the first medicine-containing layer and the second medicine-containing layer are positioned at two ends, and the pushing layer is positioned between the first medicine-containing layer and the second medicine-containing layer to obtain a tablet core; wherein, the water absorbent and the extrusion lubricant are added in the first medicine-containing layer premix powder, the first retarder is added in the pushing layer premix powder, and the second retarder is added in the second medicine-containing layer premix powder;
coating the tablet core by using a semi-permeable coating liquid, and forming a semi-permeable coating layer outside the tablet core;
and laser drilling the semi-permeable coating layer close to the first medicine containing layer and the second medicine containing layer.
Optionally, the content of the water absorbing agent is 10 to 20 weight percent and the content of the extrusion lubricant is 1 to 2 weight percent based on the total weight of the premixed powder of the first medicine-containing layer; the content of the first retarder is 15-20wt% based on the total weight of the pushing layer premixed powder; the content of the second retarder is 5-10wt% based on the total weight of the second medicine-containing layer premix powder.
Optionally, the weight ratio of the first medicine-containing layer premix powder, the pushing layer premix powder and the second medicine-containing layer premix powder is (1-3): (2-3): (1-3).
Optionally, the water absorbent is sodium alginate; the extrusion lubricant is at least one selected from glyceryl behenate, simethicone, glycerol and hydrogenated vegetable oil, preferably glyceryl behenate; the first retarder is low-substituted hydroxypropyl cellulose; the second retarder is low-substituted hydroxypropyl cellulose.
Optionally, the particle diameter D90 of the low-substituted hydroxypropyl cellulose is 50-100 μm.
Optionally, the weight ratio of the first retarder to the second retarder is (2-4): 1.
Optionally, the first drug-containing layer pre-mixed powder further comprises paliperidone, a carrier material and a tabletting lubricant, wherein the content of the paliperidone is 2-4wt%, the content of the carrier material is 72-86 wt% and the content of the tabletting lubricant is 1-2wt% based on the total weight of the first drug-containing layer pre-mixed powder.
Optionally, the pushing layer premixed powder further comprises a pushing material, a penetrating agent and a tabletting lubricant, wherein the pushing material accounts for 56.5-63.5 wt% of the total weight of the pushing layer premixed powder, the penetrating agent accounts for 10-30 wt% of the total weight of the pushing layer premixed powder, and the tabletting lubricant accounts for 1-2 wt%.
Optionally, the second drug-containing layer pre-mixed powder further comprises paliperidone, a carrier material and a tabletting lubricant, wherein the content of the paliperidone is 2-4wt%, the content of the carrier material is 83-91.5wt% and the content of the tabletting lubricant is 1-2wt% based on the total weight of the second drug-containing layer pre-mixed powder.
Optionally, the carrier material is selected from at least one of polyoxyethylene, hypromellose, and poloxamer having a molecular weight 100000 ～ 400000; the tabletting lubricant is at least one of stearic acid, magnesium stearate and sodium stearyl fumarate; the pushing material is selected from at least one of polyoxyethylene, hypromellose, hydroxypropyl cellulose and poloxamer with molecular weight 4000000 ～ 7000000; the penetrating agent is at least one selected from sodium chloride, potassium chloride, glucose and sodium citrate.
Optionally, the push layer premix powder further comprises 0.5-1.5 wt% of a first colorant, the second medicated layer premix powder further comprises 0.5-1.0 wt% of a second colorant, the first colorant is different from the second colorant, and the first colorant and the second colorant are each independently selected from any one of iron oxide red, iron oxide yellow, brilliant blue, indigo, carmine and curcumin.
Optionally, before coating the tablet core with the semi-permeable coating liquid, the method further comprises an operation of coating the tablet core with a barrier coating liquid to form a barrier coating layer on the surface of the tablet core, and then coating the surface of the barrier coating layer with the semi-permeable coating liquid to form a semi-permeable coating layer;
Laser drilling the barrier coating layer and the semi-permeable coating layer close to the first drug-containing layer and the second drug-containing layer when laser drilling is performed;
Optionally, the method further comprises the operation of coating the surface of the semi-permeable coating layer after laser drilling with a protective coating liquid to form a protective coating layer;
Optionally, the semi-permeable coating liquid contains a semi-permeable material and a pore-forming agent;
Optionally, the isolating coating liquid contains hydroxypropyl cellulose and povidone;
Optionally, the protective coating liquid contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder.
Optionally, the isolation coating solution contains hydroxypropyl cellulose and povidone, wherein the content of the hydroxypropyl cellulose is 50-90 wt% and the content of the povidone is 10-50 wt% based on the dry weight of the isolation coating solution. The dry weight of the isolation coating liquid is 8-12% of the total weight of the first medicine-containing layer premix powder, the pushing layer premix powder and the second medicine-containing layer premix powder.
Optionally, the semi-permeable coating liquid contains a semi-permeable material and a pore-foaming agent, wherein the content of the semi-permeable material is 98-99 wt% based on the dry weight of the semi-permeable coating liquid, and the content of the pore-foaming agent is 1-2 wt%; the semi-permeable material is at least one selected from cellulose acetate, ethyl cellulose and acrylic resin; the pore-forming agent is at least one selected from polyethylene glycol, triethyl citrate and triacetin. The dry weight of the semi-permeable coating liquid is 18-22% of the total weight of the first medicine-containing layer premix powder, the pushing layer premix powder and the second medicine-containing layer premix powder.
Optionally, the protective coating liquid contains 52-79wt% of hydroxypropyl methylcellulose, 10-20wt% of polyethylene glycol, 5-15wt% of titanium dioxide, 1-3wt% of iron oxide red and 5-10wt% of talcum powder based on the dry weight of the protective coating liquid. The dry weight of the protective coating liquid is 5-10% of the total weight of the first medicine-containing layer premix powder, the pushing layer premix powder and the second medicine-containing layer premix powder.
Alternatively, the solvent of the barrier coating solution may be selected within a certain range, for example, the solvent of the barrier coating solution may be selected from at least one of ethanol, acetone and water, preferably ethanol.
Alternatively, the solvent of the semi-permeable coating solution may be selected within a certain range, for example, the solvent of the semi-permeable coating solution may be selected from at least one of acetone, water, ethanol and methylene chloride, preferably a mixed solvent of acetone and water.
Alternatively, the solvent of the protective coating solution may be selected within a certain range, for example, the solvent of the protective coating solution may be selected from water and/or ethanol, preferably water.
The technical scheme of the invention has the following advantages:
1. The paliperidone sustained release tablet provided by the invention can release part of paliperidone in the initial period of medication (for example, within 2 hours after medication), can obviously improve the timeliness of paliperidone release under the condition of ensuring the sustained and controlled release effect, and is favorable for timely and rapid exertion of the drug effect.
Specifically, the tablet core of the paliperidone sustained release tablet comprises a first drug-containing layer and a second drug-containing layer which are positioned at two ends, and a pushing layer which is positioned between the first drug-containing layer and the second drug-containing layer, wherein a water absorbent and an extrusion lubricant are added in the first drug-containing layer, a first retarder is added in the pushing layer, and a second retarder is added in the second drug-containing layer; the water absorbing agent and the extrusion lubricant contained in the first medicine-containing layer can soften the first medicine-containing layer after water absorption and reduce the friction force between the first medicine-containing layer and the medicine release holes, so that the release speed of the first medicine-containing layer is accelerated, and the paliperidone sustained release tablet can start to release medicines in the initial stage of medicine application; the first retarder contained in the pushing layer can delay the extrusion of the pushing layer from the drug release hole after the first drug containing layer is completely extruded from the drug release hole, so that the pushing layer can still generate enough pushing force to push the second drug containing layer to extrude; the second retarder contained in the second medicine-containing layer can delay the extrusion of the second medicine-containing layer from the medicine release holes, so that the second medicine-containing layer is not released in the initial stage after the medicine is taken, and is released in the middle and later stages after the medicine is taken.
2. The paliperidone sustained release tablet provided by the invention further optimizes the extrusion effect of the pushing layer on the second drug-containing layer and the sustained release effect of the second drug-containing layer by optimizing the relative dosage of the first retarder and the second retarder.
3. The paliperidone sustained release tablet provided by the invention selects the low-substituted hydroxypropyl cellulose as the first retarder and the second retarder, and optimizes the particle size of the low-substituted hydroxypropyl cellulose, so that the sustained and controlled release effect of the paliperidone sustained release tablet is further optimized.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
Fig. 1 is a graph showing the release profile of several paliperidone extended release tablets in experimental examples of the present invention.
Detailed Description
The following examples are provided for a better understanding of the present invention and are not limited to the preferred embodiments described herein, but are not intended to limit the scope of the invention, any product which is the same or similar to the present invention, whether in light of the present teachings or in combination with other prior art features, falls within the scope of the present invention.
The specific experimental procedures or conditions are not noted in the examples and may be followed by the operations or conditions of conventional experimental procedures described in the literature in this field. The reagents or apparatus used were conventional reagent products commercially available without the manufacturer's knowledge.
Example 1
4000 Paliperidone extended release tablets were prepared as follows:
(1) Paliperidone, polyoxyethylene (carrier material, molecular weight 200000), sodium alginate (water absorbent), glyceryl behenate (extrusion lubricant) and magnesium stearate (tabletting lubricant) were taken according to the prescription shown in table 1, and were mixed after passing through a 20 mesh sieve to obtain a first drug-containing layer premix powder;
(2) Polyoxyethylene (pushing material, molecular weight 7000000, sodium chloride (penetrating agent), low-substituted hydroxypropyl cellulose (first retarder, particle size D90 of 83.2 μm), ferric oxide red (first colorant) and magnesium stearate (tabletting lubricant) are taken according to the prescription shown in Table 1, and are mixed after passing through a 20-mesh sieve, so as to obtain pushing layer premixed powder;
(3) Paliperidone, polyoxyethylene (carrier material, molecular weight 200000), low-substituted hydroxypropyl cellulose (second retarder, particle size D90 of 83.2 μm), iron oxide yellow (second colorant) and magnesium stearate (tabletting lubricant) were taken according to the prescription shown in table 1, and mixed after passing through a 20-mesh sieve to obtain a second drug-containing layer premix powder;
(4) Tabletting the first medicine-containing layer premixed powder, the pushing layer premixed powder and the second medicine-containing layer premixed powder obtained in the steps (1) - (3) by using a three-layer tablet press, so that the first medicine-containing layer and the second medicine-containing layer are positioned at two ends, and the pushing layer is positioned between the first medicine-containing layer and the second medicine-containing layer to obtain a tablet core;
(5) Preparing an isolation coating liquid according to a prescription shown in table 1, coating the tablet core obtained in the step (4) at 40-50 ℃ by using the isolation coating liquid to form an isolation coating layer on the surface of the tablet core, and drying at 60 ℃ after coating until the water content is less than 3%;
(6) Preparing a semi-permeable coating liquid according to a prescription shown in a table 1, coating the dried coating product obtained in the step (5) at 25-35 ℃ by using the semi-permeable coating liquid to form a semi-permeable coating layer on the surface of the isolation coating layer, and drying at 60 ℃ after coating until the moisture is less than 3%;
(7) Carrying out laser drilling on the isolation coating layer and the semi-permeable coating layer which are close to the first drug containing layer and the second drug containing layer in the dried coating product obtained in the step (6), and punching a drug release hole with the aperture of 0.6mm at each end;
(8) Preparing protective coating liquid according to the prescription shown in table 1, coating the perforated product in the step (7) at 40-50 ℃ by using the protective coating liquid to form a protective coating layer on the surface of the semi-permeable coating layer, and drying at 60 ℃ after coating until the water content is less than 3%, thus obtaining the paliperidone sustained release tablet.
Table 1 example 1 paliperidone extended release tablet formulation
The paliperidone sustained release tablet prepared by the embodiment comprises a tablet core, and an isolation coating layer, a semi-permeable coating layer and a protective coating layer which are coated outside the tablet core in sequence; the tablet core comprises a first medicine-containing layer and a second medicine-containing layer which are positioned at two ends, and a pushing layer which is positioned between the first medicine-containing layer and the second medicine-containing layer, wherein the first medicine-containing layer is added with a water absorbent (sodium alginate) and an extrusion lubricant (glyceryl behenate), the pushing layer is added with a first retarder (low-substituted hydroxypropyl cellulose), and the second medicine-containing layer is added with a second retarder (low-substituted hydroxypropyl cellulose); and drug release holes are formed on the isolation coating layer and the semi-permeable coating layer which are close to the first drug containing layer and the second drug containing layer.
Wherein, the weight ratio of the first medicine-containing layer, the pushing layer and the second medicine-containing layer is 50:100:50; the content of the water absorbent (sodium alginate) is 10wt% and the content of the extrusion lubricant (glyceryl behenate) is 1wt% based on the total weight of the first medicine-containing layer; the content of the first retarder (low substituted hydroxypropylcellulose) was 15wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropylcellulose) is 5wt% based on the total weight of the second drug-containing layer; the weight of the first retarder is 6 times that of the second retarder.
Example 2
4000 Paliperidone extended release tablets were prepared as in example 1, except that: the formulation of the paliperidone extended release tablet of this example is shown in table 2.
Table 2 example 2 paliperidone extended release tablet formulation
The weight ratio of the first drug-containing layer, the pushing layer and the second drug-containing layer of the paliperidone sustained release tablet prepared in the embodiment is 50:100:50; the content of the water absorbent (sodium alginate) is 20wt% and the content of the extrusion lubricant (glyceryl behenate) is 2wt% based on the total weight of the first medicine-containing layer; the content of the first retarder (low substituted hydroxypropylcellulose) was 20wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropylcellulose) is 10wt% based on the total weight of the second drug-containing layer; the weight of the first retarder is 4 times that of the second retarder.
Example 3
4000 Paliperidone extended release tablets were prepared as in example 1, except that: the formulation of the paliperidone extended release tablet of this example is shown in table 3.
Table 3 example 3 paliperidone extended release tablet formulation
The weight ratio of the first drug-containing layer, the pushing layer and the second drug-containing layer of the paliperidone sustained release tablet prepared in the embodiment is 50:100:75; the content of the water absorbent (sodium alginate) is 20wt% and the content of the extrusion lubricant (glyceryl behenate) is 2wt% based on the total weight of the first medicine-containing layer; the content of the first retarder (low substituted hydroxypropylcellulose) was 15wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropylcellulose) is 10wt% based on the total weight of the second drug-containing layer; the weight of the first retarder is 2 times that of the second retarder.
Example 4
4000 Paliperidone extended release tablets were prepared as in example 1, except that: the formulation of the paliperidone extended release tablet of this example is shown in table 4.
Table 4 example 4 paliperidone extended release tablet formulation
The weight ratio of the first drug-containing layer, the pushing layer and the second drug-containing layer of the paliperidone sustained release tablet prepared in the embodiment is 50:100:50; the content of the water absorbent (sodium alginate) is 20wt% and the content of the extrusion lubricant (glyceryl behenate) is 2wt% based on the total weight of the first medicine-containing layer; the content of the first retarder (low substituted hydroxypropylcellulose) was 15wt% based on the total weight of the push layer; the content of the second retarder (low-substituted hydroxypropylcellulose) is 10wt% based on the total weight of the second drug-containing layer; the weight of the first retarder is 3 times that of the second retarder.
Experimental example
The paliperidone extended release tablets prepared in examples 1 to 4 and the commercially available paliperidone extended release tablets (name: ruida; manufacturer: janssen Cilag Manufacturing L.L.C.; lot number: 19AD 4321) were tested for release by a paddle method at 50rpm, the release medium was aqueous hydrochloric acid at pH 1.0, the volume of the release medium was 500ml, 10ml of the solution was taken at 1,2, 4,6,8, 12, 14, 18 and 24 hours after the start of the test, 3ml of the primary filtrate was removed by filtration with a 0.45 μm filter membrane, the secondary filtrate was used as a sample solution, and then the chromatographic conditions were determined by high performance chromatography: c18 column (ACE C18 4.6X150 mm column), mobile phase is ammonium formate buffer solution (ammonium formate 4.2g, water is added to dissolve, formic acid 5ml, water is added to dilute to 4000 ml) -acetonitrile, volume ratio is 70:30, flow rate is 1.0ml/min, column temperature is 35 ℃, detection wavelength is 275nm, sample injection amount is 10 μl, test result is shown in Table 5 and figure 1.
Table 5 degree of release of several paliperidone extended release tablets
As can be seen from table 1 and fig. 1, compared with the commercial products, the paliperidone sustained release tablet of the invention releases part of paliperidone within 2 hours after administration, and obviously improves the timeliness of paliperidone release under the condition of ensuring the sustained and controlled release effect, thereby being beneficial to timely and rapid exertion of the drug effect.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (5)
1. The paliperidone sustained release tablet is characterized by comprising a tablet core, a semi-permeable coating layer coated outside the tablet core, an isolation coating layer and a protective coating layer; the tablet core comprises a first medicine containing layer and a second medicine containing layer which are positioned at two ends, and a pushing layer which is positioned between the first medicine containing layer and the second medicine containing layer, wherein a medicine release hole is formed in a semi-permeable coating layer which is close to the first medicine containing layer and the second medicine containing layer;
The weight of the semi-permeable coating layer is 18-22% of the weight of the tablet core, the semi-permeable coating layer contains a semi-permeable material and a pore-forming agent, the content of the semi-permeable material is 98-99% by weight based on the total weight of the semi-permeable coating layer, and the content of the pore-forming agent is 1-2% by weight;
the semi-permeable material is cellulose acetate; the pore-forming agent is polyethylene glycol;
Wherein, the weight ratio of the first medicine-containing layer, the pushing layer and the second medicine-containing layer is 1:2:1 or 1:2:1.5; the first drug-containing layer is added with a water absorbent, an extrusion lubricant, paliperidone, a carrier material and a tabletting lubricant, the pushing layer is added with a first retarder, a pushing material, a penetrating agent and a tabletting lubricant, and the second drug-containing layer is added with a second retarder, paliperidone, a carrier material and a tabletting lubricant;
the content of the water absorbing agent is 10-20wt% based on the total weight of the first medicine-containing layer, and the content of the extrusion lubricant is 1-2wt%; the paliperidone content is 2-4wt%, the carrier material content is 72-86 wt%, and the tabletting lubricant content is 1-2wt%;
The content of the first retarder is 15-20wt% based on the total weight of the pushing layer; the content of the pushing material is 56.5 to 63.5 weight percent, the content of the penetrating agent is 10 to 30 weight percent, and the content of the tabletting lubricant is 1 to 2 weight percent;
The content of the second retarder is 5-10wt% based on the total weight of the second drug-containing layer; the paliperidone content is 2-4wt%, the carrier material content is 83-91.5wt%, and the tabletting lubricant content is 1-2wt%;
The weight ratio of the first retarder to the second retarder is (2-4): 1, a step of;
the water absorbent is sodium alginate;
the extrusion lubricant is selected from glyceryl behenate;
the first retarder is low-substituted hydroxypropyl cellulose;
the second retarder is low-substituted hydroxypropyl cellulose;
The carrier material is polyoxyethylene with molecular weight 100000 ～ 400000;
the pushing material is polyoxyethylene with molecular weight 4000000 ～ 7000000;
The penetrating agent is sodium chloride;
The isolating coating layer is positioned between the tablet core and the semi-permeable coating layer, and the drug release holes penetrate through the isolating coating layer; the weight of the isolation coating layer is 8-12% of the weight of the tablet core, the isolation coating layer contains hydroxypropyl cellulose and povidone, the content of the hydroxypropyl cellulose is 50-90% by weight, and the content of the povidone is 10-50% by weight based on the total weight of the isolation coating layer;
The protective coating layer is coated on the outer surface of the semi-permeable coating layer; the weight of the protective coating layer is 5-10% of the weight of the tablet core, the protective coating layer contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder, and the weight of the protective coating layer is taken as a reference, the content of the hypromellose is 52-79 wt%, the content of the polyethylene glycol is 10-20 wt%, the content of the titanium dioxide is 5-15 wt%, the content of the iron oxide red is 1-3 wt%, and the content of the talcum powder is 5-10 wt%;
The particle diameter D90 of the low-substituted hydroxypropyl cellulose is 50-100 mu m.
2. The paliperidone extended release tablet of claim 1, wherein for a monolithic paliperidone extended release tablet, the total weight of paliperidone in the first drug-containing layer and the second drug-containing layer is 1.5-12 mg; the tabletting lubricant is at least one of stearic acid, magnesium stearate and sodium stearyl fumarate;
The pushing layer further comprises 0.5-1.5 wt% of a first colorant, the second drug-containing layer further comprises 0.5-1.0 wt% of a second colorant, the first colorant is different from the second colorant, and each of the first colorant and the second colorant is independently selected from any one of iron oxide red, iron oxide yellow, brilliant blue, indigo blue, carmine and curcumin.
3. The paliperidone extended release tablet of claim 1, wherein the number of drug release holes near one end of the first drug-containing layer is 1-3, the number of drug release holes near one end of the second drug-containing layer is 1-3, and the pore diameter of the drug release holes is 0.5-0.7 mm.
4. A method of preparing a paliperidone extended release tablet of any one of claims 1-3, comprising the operations of:
Layering and tabletting the first medicine-containing layer premix powder, the pushing layer premix powder and the second medicine-containing layer premix powder to form a first medicine-containing layer, a pushing layer and a second medicine-containing layer respectively, wherein the first medicine-containing layer and the second medicine-containing layer are positioned at two ends, and the pushing layer is positioned between the first medicine-containing layer and the second medicine-containing layer to obtain a tablet core; wherein, the water absorbent, the extrusion lubricant, the paliperidone, the carrier material and the tabletting lubricant are added in the first medicine-containing layer premix powder, the first retarder, the pushing material, the penetrating agent and the tabletting lubricant are added in the pushing layer premix powder, and the second retarder, the paliperidone, the carrier material and the tabletting lubricant are added in the second medicine-containing layer premix powder;
coating the tablet core by using a semi-permeable coating liquid, and forming a semi-permeable coating layer outside the tablet core;
Before coating the tablet core with the semi-permeable coating liquid, the method comprises the operation of coating the tablet core with a barrier coating liquid to form a barrier coating layer on the surface of the tablet core, and then coating the surface of the barrier coating layer with the semi-permeable coating liquid to form a semi-permeable coating layer;
Laser drilling the barrier coating layer and the semi-permeable coating layer close to the first drug-containing layer and the second drug-containing layer when laser drilling is performed;
the method comprises the operation of coating the surface of the semi-permeable coating layer subjected to laser drilling by using a protective coating liquid to form a protective coating layer;
the semi-permeable coating liquid contains a semi-permeable material and a pore-forming agent;
The isolating coating liquid contains hydroxypropyl cellulose and povidone;
The protective coating liquid contains hypromellose, polyethylene glycol, titanium dioxide, iron oxide red and talcum powder.
5. The method of claim 4 wherein the push layer premix further comprises a first colorant and the second medicated layer premix further comprises a second colorant.
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| CN104857515A (en) * | 2014-02-25 | 2015-08-26 | 中国科学院上海药物研究所 | Controlled release dosing medicine core composition and osmotic pump preparation comprising medicine core composition |
| CN107281151A (en) * | 2016-04-01 | 2017-10-24 | 天津市汉康医药生物技术有限公司 | Paliperidone osmotic pump type controlled release tablets |
| CN114601813A (en) * | 2022-03-30 | 2022-06-10 | 深圳市泛谷药业股份有限公司 | Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof |
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2022
- 2022-06-30 CN CN202210776404.4A patent/CN114983961B/en active Active
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| WO2015001488A1 (en) * | 2013-07-01 | 2015-01-08 | Ranbaxy Laboratories Limited | Extended-release tablets of paliperidone and processes of preparation thereof |
| CN104857515A (en) * | 2014-02-25 | 2015-08-26 | 中国科学院上海药物研究所 | Controlled release dosing medicine core composition and osmotic pump preparation comprising medicine core composition |
| CN107281151A (en) * | 2016-04-01 | 2017-10-24 | 天津市汉康医药生物技术有限公司 | Paliperidone osmotic pump type controlled release tablets |
| CN114601813A (en) * | 2022-03-30 | 2022-06-10 | 深圳市泛谷药业股份有限公司 | Paliperidone double-layer osmotic pump sustained-release preparation and preparation method thereof |
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| Box-Behnken 法优化盐酸氨溴索夹芯渗透泵片的处方;马银玲等;《中国药学杂志》;第51卷(第12期);第1006-1013页 * |
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| CN114983961A (en) | 2022-09-02 |
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