CN113842376A - Risperidone-containing pharmaceutical composition, oral dissolving film agent and preparation method - Google Patents
Risperidone-containing pharmaceutical composition, oral dissolving film agent and preparation method Download PDFInfo
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- CN113842376A CN113842376A CN202010599317.7A CN202010599317A CN113842376A CN 113842376 A CN113842376 A CN 113842376A CN 202010599317 A CN202010599317 A CN 202010599317A CN 113842376 A CN113842376 A CN 113842376A
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- Prior art keywords
- coating
- risperidone
- pharmaceutical composition
- film
- mannitol
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- 229960001534 risperidone Drugs 0.000 title claims abstract description 93
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 238000000576 coating method Methods 0.000 claims abstract description 229
- 239000011248 coating agent Substances 0.000 claims abstract description 221
- 239000000463 material Substances 0.000 claims abstract description 49
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 32
- 229930195725 Mannitol Natural products 0.000 claims abstract description 32
- 239000000594 mannitol Substances 0.000 claims abstract description 32
- 235000010355 mannitol Nutrition 0.000 claims abstract description 32
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 18
- 230000008569 process Effects 0.000 claims abstract description 15
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 14
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 14
- 239000000758 substrate Substances 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000000796 flavoring agent Substances 0.000 claims abstract description 9
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 9
- 239000004014 plasticizer Substances 0.000 claims abstract description 9
- 239000000945 filler Substances 0.000 claims abstract description 8
- 239000008139 complexing agent Substances 0.000 claims abstract description 7
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 7
- 239000004480 active ingredient Substances 0.000 claims abstract description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000002131 composite material Substances 0.000 claims description 13
- 239000004376 Sucralose Substances 0.000 claims description 11
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 11
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 11
- 235000019408 sucralose Nutrition 0.000 claims description 11
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical group [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 10
- 239000004698 Polyethylene Substances 0.000 claims description 10
- 229910052782 aluminium Inorganic materials 0.000 claims description 10
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 10
- 238000005520 cutting process Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 229920000728 polyester Polymers 0.000 claims description 10
- -1 polyethylene Polymers 0.000 claims description 10
- 229920000573 polyethylene Polymers 0.000 claims description 10
- 238000007789 sealing Methods 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 229960001855 mannitol Drugs 0.000 claims description 8
- 238000010008 shearing Methods 0.000 claims description 8
- 210000000214 mouth Anatomy 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 235000005976 Citrus sinensis Nutrition 0.000 claims description 6
- 240000002319 Citrus sinensis Species 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
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- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 239000004148 curcumin Substances 0.000 claims description 3
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- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- YTUUEOBZXXUZJL-UHFFFAOYSA-N 2,3-diethylpentane-1,2,3-triol Chemical compound CCC(O)(CC)C(O)(CC)CO YTUUEOBZXXUZJL-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 235000006679 Mentha X verticillata Nutrition 0.000 claims description 2
- 235000002899 Mentha suaveolens Nutrition 0.000 claims description 2
- 235000001636 Mentha x rotundifolia Nutrition 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- UEAVLBXLOZNDHT-UHFFFAOYSA-K calcium;sodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Ca+2].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEAVLBXLOZNDHT-UHFFFAOYSA-K 0.000 claims description 2
- 235000019219 chocolate Nutrition 0.000 claims description 2
- 235000013399 edible fruits Nutrition 0.000 claims description 2
- 239000001341 hydroxy propyl starch Substances 0.000 claims description 2
- 235000013828 hydroxypropyl starch Nutrition 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 238000007873 sieving Methods 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229920003134 Eudragit® polymer Polymers 0.000 claims 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 23
- 235000019658 bitter taste Nutrition 0.000 abstract description 14
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 235000019640 taste Nutrition 0.000 description 13
- 239000012535 impurity Substances 0.000 description 11
- 229920003149 Eudragit® E 100 Polymers 0.000 description 10
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 10
- 238000005507 spraying Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000001856 Ethyl cellulose Substances 0.000 description 5
- 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 5
- 229920001249 ethyl cellulose Polymers 0.000 description 5
- 235000019325 ethyl cellulose Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 206010037218 Psychopathic personality Diseases 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 229940124274 edetate disodium Drugs 0.000 description 4
- 238000007689 inspection Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 229940100688 oral solution Drugs 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 210000003296 saliva Anatomy 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 210000001779 taste bud Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010013911 Dysgeusia Diseases 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 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
- 210000004027 cell Anatomy 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
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- 239000007884 disintegrant Substances 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005243 fluidization Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 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
- 238000011835 investigation Methods 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229920003168 pharmaceutical polymer Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a pharmaceutical composition containing risperidone, an oral dissolving film agent and a preparation method, and belongs to the technical field of pharmaceutical preparations. The invention provides a pharmaceutical composition containing risperidone, which comprises an active ingredient risperidone, coating substrate mannitol, a coating material and a solvent, wherein the weight percentage of the risperidone in the pharmaceutical composition is 6.3% -20.5%. The invention also provides an oral instant film agent, which comprises the pharmaceutical composition containing risperidone, a film-forming material, a plasticizer, a filler, a metal ion complexing agent and a flavoring agent, wherein the film-forming material is selected from polyvinyl alcohol. The invention also provides a preparation method of the pharmaceutical composition and the orally disintegrating film agent. The oral instant film agent finally prepared by the invention can completely cover the bitter taste of the risperidone raw material, and the process is mature and simple, thus being suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and relates to a pharmaceutical composition containing risperidone, a preparation method of the pharmaceutical composition, an oral instant film agent taking the pharmaceutical composition as a main raw material, and a preparation method of the oral instant film agent.
Background
Risperidone is a novel atypical antipsychotic that selectively inhibits the mesolimbic dopaminergic nervous system without producing the severe extrapyramidal responses that conventional anti-schizophrenia drugs do. The traditional Chinese medicine composition has few adverse reactions in clinical administration, high safety and low price, and is one of the first-choice medicines for resisting schizophrenia at present.
Risperidone preparations on the market at present mainly comprise risperidone tablets, capsules, orally disintegrating tablets, oral liquid and the like. The common tablets and capsules need to be taken with water, and are inconvenient to take especially for children and old patients with dysphagia, and the psychopath often refuses to take the medicine and vomits the medicine. Although the orally disintegrating tablets solve the problems to a certain extent, the orally disintegrating tablets have unpleasant sandy feeling in oral cavity when being taken, and in addition, the orally disintegrating tablets are easy to be broken in the transportation process, easily cause inaccurate administration dosage and have higher requirements on production, packaging and storage; the oral liquid needs to be taken by a special quantitative cup, is inconvenient to carry, and influences the wide application of the oral liquid in clinic.
In order to improve the medication compliance of the psychotic, patent CN101632651A discloses an oral instant film of risperidone, which comprises risperidone, water-soluble pharmaceutical polymer auxiliary materials, additives (flavoring agent, coloring agent, opacifier, plasticizer, preservative, pH regulator and disintegrant) and water. However, the invention ignores one property of the risperidone raw material, namely the risperidone raw material has strong bitter taste, although the flavoring agent is arranged in the prescription, the strong bitter taste of the risperidone is not enough to be covered, and the drug can be directly contacted with oral taste buds and maintained for a period of time when being taken, so the bitter taste can greatly influence the compliance of psychopath patients when taking the drug, and further can influence the clinical application of the psychopath patients to a certain extent.
Patent CN103349657A discloses a risperidone film preparation, in order to mask the bitter taste of risperidone, a plurality of composite films are invented, including an acid strip film belt and an alkaline strip film belt, when the composite film is taken, an effervescent film is formed when the composite film is in contact with water, a large number of bubbles are generated, and the smell is paralyzed to mask the taste. However, the invention needs to prepare a plurality of membrane belts during production, has complex production process and higher cost, and is not suitable for industrial production.
Patent CN108685876A discloses an oral film-like pharmaceutical composition containing risperidone. Risperidone has low solubility in water, exists in granular form, and is bitter in taste. According to the invention, the acidic substance is added to dissolve risperidone, and then povidone is added to mask the taste, so that the prepared orally dissolving film has almost no bitter taste. Based on examples 2 and 3 in the invention, repeated verification experiments are carried out, and although the prepared oral solution film is hardly bitter, under a new analysis method optimized by the inventor, the oral solution film is poor in stability when placed at a high temperature of 60 ℃ for 10 days, and the single impurity exceeding limit (actually measured by 0.59% in 5 days, 0.94% in 10 days and 0.2% in the limit) is not known, so that the medication safety of a patient is influenced to a certain extent.
Patent CN104546806A discloses an oral instant film containing risperidone and a preparation method thereof. The invention achieves the taste masking effect by cyclodextrin inclusion, and the auxiliary materials comprise cyclodextrin, a film forming material, a plasticizer and a flavoring agent. The preparation method comprises preparing risperidone clathrate by saturated aqueous solution-ultrasonic cell pulverization method, mixing cyclodextrin and risperidone solution, performing ultrasonic action for 100 times, refrigerating at 4 deg.C for 24 hr, filtering under reduced pressure, drying at 40 deg.C for 4 hr to constant weight, and grinding. The preparation process is complicated, the efficiency is low, the automation degree is not high, the industrial production is not easy to realize, the inclusion rate is not controlled definitely, the step of removing free medicines is avoided, and if the inclusion rate is low and the risperidone which is not included is existed, the prepared oral instant membrane is still bitter.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a pharmaceutical composition containing risperidone, an oral instant film agent and a preparation method thereof. Aims to provide an oral instant film agent containing risperidone, which has good taste, is easy to be accepted and used by patients, has low production cost and is suitable for industrialized production.
The invention achieves the taste masking effect in a coating form, and povidone and tartaric acid are not used in the prescription for taste masking.
The invention provides a pharmaceutical composition containing risperidone, which comprises active ingredients of risperidone, coating substrate mannitol and a coating material, wherein the weight percentage of the risperidone in the pharmaceutical composition is 6.3% -20.5%.
In some preferred embodiments, the weight ratio of risperidone to mannitol as a coating substrate is 1: 2-1: 6.
The pharmaceutical composition of the invention, in some embodiments, the coating material accounts for 3% -6% of the sum of the mass of the risperidone and the mannitol as the coating substrate; preferably, the coating material is ewing; a more preferred coating material is ewt E100.
The pharmaceutical composition of the present invention, in some embodiments, further comprises a coating solvent selected from ethanol, acetone, or isopropanol, preferably ethanol (95%, v/v), wherein the coating solvent is eventually removed.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:
(1) adding the coating material Utex into the coating solvent, and stirring until the coating material is completely dissolved to obtain a coating solution;
(2) taking part of the coating solution, adding risperidone into the coating solution, and dispersing for 5-10 min by a shearing machine to form uniform suspension serving as coating solution I;
(3) sieving mannitol with 40 mesh sieve, adding into fluidized bed to serve as coating substrate;
(4) carrying out fluidized coating on the mannitol serving as the coating substrate by using the coating solution I obtained in the step (2) to obtain a coating intermediate I;
(5) and taking the rest coating solution as a coating solution II, and continuously performing fluidized coating on the coating intermediate I to obtain a coating intermediate II, namely the risperidone-containing pharmaceutical composition.
In some embodiments, the coating solvent in step (1) is selected from ethanol, acetone or isopropanol, preferably ethanol (95%, v/v).
In other embodiments, step (3), i.e., the step of preparing the coated substrate, described above may also be performed before step (1).
In some embodiments, the coating solution taken in step (2) is the same as the coating solution taken in step (5), i.e.: the volume ratio of the coating solution in the coating solution I to the coating solution in the coating solution II is 1: 1-4: 1, and preferably 3: 1.
Another aspect of the present invention, i.e. the main object, is to provide an oral instant film formulation comprising the pharmaceutical composition containing risperidone, i.e. the coating intermediate II, as described above, and a film-forming material, a plasticizer, a filler, a metal ion complexing agent, and a flavoring agent. In some preferred embodiments, the film-forming material is selected from polyvinyl alcohol, with polyvinyl alcohol EG-05P or EG-18P being more preferred.
In some embodiments, the plasticizer is selected from glycerol, triethylglycerol or polyvinyl alcohol 400, preferably glycerol.
The filler is selected from one or more of mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, starch and lactose, and preferably mannitol or low-substituted hydroxypropyl cellulose.
The metal ion complexing agent is selected from disodium edetate or calcium sodium edetate.
The flavoring agent is one or more selected from sucrose, sucralose, sweet orange essence, chocolate essence, mixed fruit essence and mint essence.
The invention also provides a preparation method of the oral instant film agent, which comprises the following steps:
(1) dispersing the film forming material in water, heating and dissolving at the temperature of 70-95 ℃, and cooling to room temperature;
(2) adding plasticizer, filler, metal ion complexing agent, correctant and the pharmaceutical composition containing risperidone, namely the coating intermediate II, and stirring uniformly;
(3) defoaming, coating in a coating dryer with the coating thickness of 200 +/-50 mu m, the drying temperature of 70-80 ℃ and the drying time of 8-10 min;
(4) cutting into pieces, and sealing in the polyester/aluminum/cast polyethylene medicinal composite membrane.
In some specific embodiments, the method comprises the following steps: dispersing polyvinyl alcohol in a formula amount in water at normal temperature, heating to 70-95 ℃, heating for dissolving, cooling to room temperature, adding glycerol, disodium edetate, filler mannitol, sucralose, sweet orange essence, low-substituted hydroxypropyl cellulose and a coating intermediate II, uniformly stirring, defoaming for 5-10 min, coating in a coating dryer with the coating thickness of 200 +/-50 mu m, the drying temperature of 70-80 ℃, the drying time of 8-10 min, then taking down, cutting into pieces, and sealing in the polyester/aluminum/cast polyethylene medicinal composite film.
The invention further provides a risperidone oral instant film agent, which comprises the following components in percentage by weight:
the invention has the beneficial effects that:
(1) the risperidone is dispersed in a coating solvent with certain viscosity, mannitol is used as a coating substrate to coat to form a coating intermediate I, and then the coating solvent is used to coat the coating intermediate I. In addition, after coating, the risperidone can be isolated from being contacted with oxygen and certain auxiliary materials incompatible with the risperidone, the generation of oxidation impurities and other impurities can be effectively reduced, the preparation stability is excellent, and the medication safety of patients is higher. In addition, the test result shows that the raw materials are basically not lost after the coating by the coating method, the yield of the raw materials in the pan body is over 95 percent and is far higher than that of the conventional coating method, namely the risperidone is directly coated by the coating liquid, and the yield of the raw materials is only 86 percent.
(2) The coating material is Eudragit E100, an acid soluble substance, which can be dissolved below pH5.0 and can swell in other pH medium. The pH value of saliva in the oral cavity is generally 6.0-7.0, and the Eudragit E100 is not dissolved in the saliva and only slowly swells, so that taste buds can not feel bitter completely when a patient takes the coated risperidone oral dissolving film agent, the oral dissolving film agent can be accepted by the patient more easily, and the compliance of a psychopath patient in taking medicine is effectively improved.
(3) The risperidone oral instant film agent prepared by the invention does not need water when being taken by a patient, can be dispersed and dissolved in the oral cavity when meeting saliva, can effectively prevent the phenomenon of spitting of the mental patient, and is more acceptable to the patient who swallows foreign matters and has discomfort and the old patient. In addition, the oral dissolving film disclosed by the invention is fine and smooth in mouth feel, has no sand feeling and discomfort, and can improve the administration compliance of patients to a certain extent.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that: the embodiments of the present invention are given for illustration only, and not for limitation, and the simple modifications of the present invention based on the technical solutions of the present invention belong to the protection scope of the present invention.
Example 1 preparation of an oral fast dissolving film after coating Eudragit E100
The first step is as follows: preparation of risperidone coating-coating intermediate II (risperidone content 9.3%)
Prescription:
the process comprises the following steps:
1) preparing a coating solution: the weighed 95% ethanol was added to a 2000ml beaker and stirred at high speed using an overhead mechanical stirrer, followed by slow addition of Eudragit E100 with constant stirring until a clear and clear coating solution (5% solids) was dissolved. Taking out 540g of the dissolved coating solution, adding risperidone according to the prescription amount, shearing and dispersing for 10min, rotating at 4000rpm to form uniform risperidone suspension serving as coating liquid I for later use; the rest 180g of coating solution is used as coating solution II for standby;
2) fluidized coating: installing GPCG 2LabSystem fluidized bed (top spraying coating) as required, preheating the empty machine to about 30 ℃, adding mannitol screened by a 40-mesh sieve into the fluidized bed (serving as a coating substrate), and spraying coating liquid I to perform powder coating on the mannitol. And ensuring that the coating liquid is in a continuous stirring state in the coating process. And after coating, obtaining a coating intermediate I, continuously coating the coating intermediate I with a coating solution II, stopping the machine, respectively collecting the materials in the air bag and the pot body of the fluidized bed, weighing, and fully mixing 30% of the materials to obtain the coating intermediate II. And respectively taking the coating intermediate I, the air bag, the materials in the pot body and the coating intermediate II for content inspection.
The second step is that: preparation of oral instant film agent
Prescription:
the process comprises the following steps: dispersing polyvinyl alcohol in water, heating to 70-95 ℃ for dissolving, cooling to room temperature, adding the prescribed amount of glycerol, edetate disodium, mannitol, sucralose, orange essence, low-substituted hydroxypropyl cellulose and a coating intermediate II containing risperidone, uniformly stirring, defoaming, coating in a coating dryer, coating with the thickness of 200 +/-50 mu m, drying at 70-80 ℃ for 8-10 min, then taking down, cutting into pieces, and sealing in a polyester/aluminum/cast polyethylene pharmaceutical composite film.
Example 2 preparation of an oral fast dissolving film after coating Eudragit E100
The first step is as follows: preparation of risperidone coating-coating intermediate II (risperidone content 20.5%)
Prescription:
the process comprises the following steps:
1) preparing a coating solution: the weighed 95% ethanol was added to a 2000ml beaker and stirred at high speed using an overhead mechanical stirrer, followed by slow addition of Eudragit E100 with constant stirring until a clear and clear coating solution (5% solids) was dissolved. Taking out 226.8g of dissolved coating solution, adding risperidone according to the prescription amount, shearing and dispersing for 10min, rotating at 4000rpm to form uniform risperidone suspension serving as coating solution I for later use; the remaining 56.7g of coating solution is used as coating solution II for standby;
2) fluidized coating: installing GPCG 2LabSystem fluidized bed (top spraying coating) as required, preheating the empty machine to about 30 ℃, adding mannitol screened by a 40-mesh sieve into the fluidized bed (serving as a coating substrate), and spraying coating liquid I to perform powder coating on the mannitol. And ensuring that the coating liquid is in a continuous stirring state in the coating process. And after coating, obtaining a coating intermediate I, continuously coating the coating intermediate I with a coating solution II, stopping the machine, respectively collecting the materials in the air bag and the pot body of the fluidized bed, weighing, and fully mixing 30% of the materials to obtain the coating intermediate II. And respectively taking the coating intermediate I, the air bag, the materials in the pot body and the coating intermediate II for content inspection.
The second step is that: preparation of oral instant film agent
Prescription:
the process comprises the following steps: dispersing polyvinyl alcohol in water, heating to 70-95 ℃ for dissolving, cooling to room temperature, adding the prescribed amount of glycerol, edetate disodium, mannitol, sucralose, orange essence, low-substituted hydroxypropyl cellulose and a coating intermediate II containing risperidone, uniformly stirring, defoaming, coating in a coating dryer, coating with the thickness of 200 +/-50 mu m, drying at 70-80 ℃ for 8-10 min, then taking down, cutting into pieces, and sealing in a polyester/aluminum/cast polyethylene pharmaceutical composite film.
Example 3 preparation of an oral fast dissolving film after coating Eudragit E100
The first step is as follows: preparation of risperidone coating-coating intermediate II (risperidone content 6.3%)
Prescription:
the process comprises the following steps:
1) preparing a coating solution: the weighed 95% ethanol was added to a 2000ml beaker and stirred at high speed using an overhead mechanical stirrer, followed by slow addition of Eudragit E100 with constant stirring until a clear and clear coating solution (5% solids) was dissolved. Taking out 661.5g of the dissolved coating solution, adding risperidone according to the prescription amount, shearing and dispersing for 10min at the rotation speed of 4000rpm to form uniform risperidone suspension serving as coating solution I for later use; the rest 661.5g of coating solution is used as coating solution II for standby;
2) fluidized coating: installing GPCG 2LabSystem fluidized bed (top spraying coating) as required, preheating the empty machine to about 30 ℃, adding mannitol screened by a 40-mesh sieve into the fluidized bed (serving as a coating substrate), and spraying coating liquid I to perform powder coating on the mannitol. And ensuring that the coating liquid is in a continuous stirring state in the coating process. And after coating, obtaining a coating intermediate I, continuously coating the coating intermediate I with a coating solution II, stopping the machine, respectively collecting the materials in the air bag and the pot body of the fluidized bed, weighing, and fully mixing 30% of the materials to obtain the coating intermediate II. And respectively taking the coating intermediate I, the air bag, the materials in the pot body and the coating intermediate II for content inspection.
The second step is that: preparation of oral instant film agent
Prescription:
the process comprises the following steps: dispersing polyvinyl alcohol in water, heating to 70-95 ℃ for dissolving, cooling to room temperature, adding the prescribed amount of glycerol, edetate disodium, mannitol, sucralose, orange essence, low-substituted hydroxypropyl cellulose and a coating intermediate II containing risperidone, uniformly stirring, defoaming, coating in a coating dryer, coating with the thickness of 200 +/-50 mu m, drying at 70-80 ℃ for 8-10 min, then taking down, cutting into pieces, and sealing in a polyester/aluminum/cast polyethylene pharmaceutical composite film.
Comparative example 1 preparation of an oral fast dissolving film after coating Eudragit E100 Utty (conventional coating means)
The first step is as follows: risperidone direct coating
Prescription:
the process comprises the following steps:
1) preparing a coating solution: the weighed 95% ethanol was added to a 2000ml beaker and stirred at high speed using an overhead mechanical stirrer, followed by slow addition of Eudragit E100 with constant stirring until a clear and clear coating solution (5% solids) was dissolved.
2) Fluidized coating: installing GPCG 2LabSystem fluidized bed (top spraying coating) as required, preheating the empty machine to about 30 ℃, adding the premixed risperidone and mannitol into the fluidized bed, and spraying coating liquid for powder coating. And (3) sampling a 20g sample when the theoretical coating weight is increased by 3 percent to be used as an intermediate I, continuously coating the rest materials to 4 percent, then blanking, respectively collecting the materials in the air bag of the fluidized bed and the pot body, weighing, and fully mixing 30 percent of the materials respectively to be used as a coating intermediate II. And respectively taking the intermediate I, the air bag and the materials in the pot body and the intermediate II for content detection.
The second step is that: preparation of risperidone oral instant film
Prescription:
the process comprises the following steps: dispersing polyvinyl alcohol in water, heating to 70-95 ℃ for dissolving, cooling to room temperature, adding glycerol, disodium edetate, mannitol, sucralose, sweet orange essence, low-substituted hydroxypropyl cellulose and risperidone coating intermediate, uniformly stirring, defoaming, coating in a coating dryer with the coating thickness of 200 +/-50 mu m, the drying temperature of 70-80 ℃, the drying time of 8-10 min, then taking down, cutting into pieces, and sealing in the polyester/aluminum/cast polyethylene pharmaceutical composite film.
Comparative example 2 preparation of an oral fast dissolving film after coating with an aqueous ethylcellulose dispersion
The first step is as follows: risperidone coating
Prescription:
remarking: the ethyl cellulose solids content in the aqueous dispersion was 30%.
The process comprises the following steps:
1) preparing a coating solution: adding 90g of weighed ethyl cellulose aqueous dispersion into a beaker, adding 260g of purified water, shearing at 3000rpm for 10min, adding the risperidone in the amount of the prescription, and shearing at 3000rpm until the risperidone is uniformly dispersed to serve as coating liquid I for later use; weighing 30g of ethyl cellulose aqueous dispersion, adding 87g of purified water, and shearing at 3000rpm for 10min to obtain coating liquid II for later use;
2) fluidized coating: installing GPCG 2LabSystem fluidized bed (top spraying coating) as required, preheating the empty machine to about 30 ℃, adding mannitol which is sieved by a 40-mesh sieve into the fluidized bed, and spraying coating liquid I for powder coating. And ensuring that the coating liquid is in a continuous stirring state in the coating process. And after coating is finished, obtaining a coating intermediate I, continuously coating the intermediate I by using a coating liquid II, stopping the machine, respectively collecting materials in the air bag of the fluidized bed and the pot body, weighing, and fully mixing 30% of the materials to obtain the coating intermediate II. And respectively taking the intermediate I, the air bag, the materials in the pot body and the coating intermediate II for content inspection.
The second step is that: preparation of risperidone oral instant film
Prescription:
the process comprises the following steps: dispersing polyvinyl alcohol in water, heating to 70-95 ℃ for dissolving, cooling to room temperature, adding glycerol, disodium edetate, mannitol, sucralose, sweet orange essence, low-substituted hydroxypropyl cellulose and risperidone coating intermediate, uniformly stirring, defoaming, coating in a coating dryer with the coating thickness of 200 +/-50 mu m, the drying temperature of 70-80 ℃, the drying time of 8-10 min, then taking down, cutting into pieces, and sealing in the polyester/aluminum/cast polyethylene pharmaceutical composite film.
Comparative example 3 preparation of uncoated Risperidone oral fast dissolving film pharmaceutical composition
Prescription:
the process comprises the following steps:
dispersing polyvinyl alcohol in water, heating to 70-95 ℃ for dissolving, cooling to room temperature, adding glycerol, disodium edetate, mannitol, sucralose, sweet orange essence, low-substituted hydroxypropyl cellulose, microcrystalline cellulose and risperidone, uniformly stirring, defoaming, coating in a coating dryer, coating with the thickness of 200 +/-50 mu m, drying at 70-80 ℃ for 8-10 min, then taking down, cutting into pieces, and sealing in a polyester/aluminum/cast polyethylene pharmaceutical composite film.
Comparative example 4 oral fast dissolving film of risperidone based on examples 2 and 3 of patent CN108685876A (No povidone was included in example 1 of this application, the pharmaceutical composition was bitter and had a poor mouth feel, so no comparison was made)
Prescription:
the process comprises the following steps: dispersing risperidone in water, adding L-tartaric acid, edetate disodium, orange essence and sucralose, stirring for dissolving, adding povidone K30, stirring for dissolving, adding hydroxypropyl methylcellulose E3 and E15, stirring for dispersing uniformly, adding glycerol, stirring uniformly, defoaming, coating in a coating dryer with the coating thickness of 200 +/-50 mu m, the drying temperature of 70-80 ℃, the drying time of 8-10 min, taking down, cutting into pieces, and sealing in the polyester/aluminum/cast polyethylene pharmaceutical composite film.
Test results and comparative analysis
1. The oral fast dissolving films of each example and comparative example were tasted and scored, the scoring results are shown in table 1.
TABLE 1 comparison of the raw material yield and the oral instant film taste prepared therefrom in different coating modes
Remarking: bitterness score, 10 points for the oral film prepared from the uncoated material, with higher scores indicating a higher taste and 0 points indicating no bitterness.
Comparative example 3 the results show that uncoated risperidone was prepared as an orally fast dissolving film, which was bitter in taste and had a longer aftertaste in the mouth, although sucralose and orange flavor were added to correct the taste.
In the embodiment of the invention, after the raw materials are coated by adopting a two-layer coating mode and are prepared into the oral instant membrane, the medicinal membrane has no bitter taste completely, and the raw material yield in the pot body of the fluidized bed is over 95 percent.
The coating method of comparative example 1, however, is not only low in raw material yield but also bitter. The risperidone/mannitol mixed powder coating has the advantages that the risperidone is low in density, air enters the bottom of the fluidized bed, the risperidone dry powder is blown into an air bag at the top of the fluidized bed and cannot fall down in time, and accordingly the coated risperidone is few, the coating effect is poor, and the taste is bitter. In addition, risperidone is blown into the air pocket, which results in a low yield of raw materials in the pan body.
Comparative example 2, which employs the same two-layer coating method as in example, but uses a coating material of an aqueous medium in which ethylcellulose is suspended, and it does not form a dense coating layer when coated, so the coating effect is not good as in the example of the present invention, and the yield of raw material is low because the raw material is not completely coated, and the raw material has a light weight after fluidized drying, and is easily blown to the top of the fluidized bed and adsorbed, and thus cannot be obtained.
The coating material Ettqi E100 in the embodiment of the invention is dissolved in ethanol, has certain viscosity, the risperidone is dispersed in the coating medium, is coated with a layer of compact sugar coating similar to the sugarcoated haws, and is fluidized and dried, the risperidone is not easily blown to the top of a fluidized bed except good coating effect, the raw material yield is high, meanwhile, the coating intermediate I with certain weight has good fluidization effect, a layer of coating liquid is sprayed on the basis, the coating effect is strengthened, the bitter taste of the raw material is completely covered, the coated raw material is prepared into glue solution and is coated and dried after being placed for 8 hours, the medicine film still has no bitter taste, the requirement of production time can be completely met, and the taste of the medicine film is ensured.
2. And (3) placing the prepared oral solution film at a high temperature of 60 ℃ for stability investigation. The results are shown in Table 2.
TABLE 2 Risperidone oral fast dissolving film stability at 60 deg.C
The results show that the oral instant films of examples 1-3 have better stability at 60 ℃ for 15 days, and compared with uncoated comparative example 3, the cis-N-oxide is lower, and the impurity is generated by oxidation of risperidone.
Comparative example 1 no single impurity exceeded the limit at 60 ℃ for 10 days, presumably because the raw material was incompatible with some auxiliary material in the presence of the coating material, because the raw material was not completely coated in the coating manner of comparative example 1, and there was a gap in the raw material coating layer, just allowing risperidone, the coating material and the auxiliary material to be in close contact, thereby generating unknown impurities.
The known impurities of comparative example 2, which were out of limits at 60 ℃ for 10 days, show that, in addition to the poor coating effect of this coating material, the compatibility with the raw materials was also poor.
Comparative example 3 is an orally dissolving film prepared from uncoated raw materials, and the preparation has good stability after being left at 60 ℃ for 15 days, but the orally dissolving film has extremely bitter taste, and the bitter taste is regained after being taken, and is relieved after about 5 hours.
Comparative example 4 although the prepared orodispersible film has no bitter taste, the single impurity and the total impurity are not obviously increased after being placed for 5 days and 10 days at the high temperature of 60 ℃, and the dosage safety of patients is influenced to a certain extent if the single impurity and the total impurity are exceeded.
Claims (10)
1. A pharmaceutical composition containing risperidone comprises an active ingredient risperidone, coating substrate mannitol, a coating material and a solvent, wherein the weight percentage of the risperidone in the pharmaceutical composition is 6.3% -20.5%.
2. The pharmaceutical composition according to claim 1, wherein the weight ratio of risperidone to mannitol is 1: 2-1: 6.
3. The pharmaceutical composition of claim 1, wherein the coating material accounts for 3% -6% of the sum of the mass of risperidone and mannitol; preferably, the coating material is ewing; a more preferred coating material is ewt E100.
4. The pharmaceutical composition according to claim 1, further comprising a coating solvent selected from ethanol, acetone, or isopropanol, preferably ethanol (95%, v/v), wherein the coating solvent is finally removed.
5. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 4, comprising the steps of:
(1) adding the coating material Eudragit into coating solvent ethanol (95%, v/v), and stirring to completely dissolve to obtain a coating solution;
(2) taking part of the coating solution, adding risperidone into the coating solution, and dispersing for 5-10 min by a shearing machine to form uniform suspension serving as coating solution I;
(3) sieving mannitol with 40 mesh sieve, adding into fluidized bed to serve as coating substrate;
(4) carrying out fluidized coating on the mannitol serving as the coating substrate by using the coating solution I obtained in the step (2) to obtain a coating intermediate I;
(5) and taking the rest coating solution as a coating solution II, and continuously performing fluidized coating on the coating intermediate I to obtain a coating intermediate II, namely the risperidone-containing pharmaceutical composition.
6. The preparation method according to claim 5, wherein the volume ratio of the coating solution in the coating solution I to the coating solution in the coating solution II is 1: 1-4: 1, preferably 3: 1.
7. An oral instant film agent, comprising the pharmaceutical composition containing risperidone of any one of claims 1-4, a film-forming material, a plasticizer, a filler, a metal ion complexing agent, and a flavoring agent, wherein the film-forming material is selected from polyvinyl alcohol, preferably polyvinyl alcohol EG-05P or EG-18P.
8. An oral fast dissolving film according to claim 7, the plasticizer is selected from glycerol, triethylglycerol or polyvinyl alcohol 400, preferably glycerol;
the filler is selected from one or more of mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, starch and lactose, and preferably mannitol or low-substituted hydroxypropyl cellulose;
the metal ion complexing agent is selected from disodium edetate or calcium sodium edetate;
the flavoring agent is one or more selected from sucrose, sucralose, sweet orange essence, chocolate essence, mixed fruit essence and mint essence.
9. A method of preparing an orally fast dissolving film of any one of claims 7-8 comprising the steps of:
(1) dispersing the film forming material in water, heating and dissolving at the temperature of 70-95 ℃, and cooling to room temperature;
(2) adding a plasticizer, a filler, a metal ion complexing agent, a flavoring agent and the pharmaceutical composition containing risperidone of any one of claims 1-4, and uniformly stirring;
(3) defoaming, coating in a coating dryer with the coating thickness of 200 +/-50 mu m, the drying temperature of 70-80 ℃ and the drying time of 8-10 min;
(4) cutting into pieces, and sealing in the polyester/aluminum/cast polyethylene medicinal composite membrane.
10. An oral cavity instant film agent of risperidone comprises the following components by percentage:
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| KR101943270B1 (en) * | 2018-07-17 | 2019-01-28 | 코오롱제약주식회사 | Taste-masking Cinacalcet Orally Disintegrating Tablet and producing method thereof |
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| US20060159758A1 (en) * | 2002-12-11 | 2006-07-20 | Rajesh Gandhi | Coating composition for taste masking coating and methods for their application and use |
| US20120035216A1 (en) * | 2006-01-06 | 2012-02-09 | Pamela Palmer | Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain |
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