CN106389341A - Penfluridol polyanhydride pellet and penfluridol long-acting controlled release tablet as well as preparation method of penfluridol long-acting controlled release tablet - Google Patents
Penfluridol polyanhydride pellet and penfluridol long-acting controlled release tablet as well as preparation method of penfluridol long-acting controlled release tablet Download PDFInfo
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- CN106389341A CN106389341A CN201610804611.0A CN201610804611A CN106389341A CN 106389341 A CN106389341 A CN 106389341A CN 201610804611 A CN201610804611 A CN 201610804611A CN 106389341 A CN106389341 A CN 106389341A
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- penfluridol
- long
- controlled release
- acting controlled
- fumaric acid
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- MDLAAYDRRZXJIF-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol Chemical compound C1CC(O)(C=2C=C(C(Cl)=CC=2)C(F)(F)F)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 MDLAAYDRRZXJIF-UHFFFAOYSA-N 0.000 title claims abstract description 102
- 229960004505 penfluridol Drugs 0.000 title claims abstract description 102
- 238000013270 controlled release Methods 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 229920002732 Polyanhydride Polymers 0.000 title abstract 5
- 239000008188 pellet Substances 0.000 title abstract 4
- 239000003814 drug Substances 0.000 claims abstract description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 10
- 239000000843 powder Substances 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 5
- 229920002472 Starch Polymers 0.000 claims abstract description 5
- 229930006000 Sucrose Natural products 0.000 claims abstract description 5
- 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 abstract description 5
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 5
- 239000008107 starch Substances 0.000 claims abstract description 5
- 235000019698 starch Nutrition 0.000 claims abstract description 5
- 150000004676 glycans Chemical class 0.000 claims abstract description 3
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 3
- 239000005017 polysaccharide Substances 0.000 claims abstract description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 84
- 239000001530 fumaric acid Substances 0.000 claims description 42
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 239000011248 coating agent Substances 0.000 claims description 28
- 238000000576 coating method Methods 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 6
- 239000004375 Dextrin Substances 0.000 claims description 5
- 229920001353 Dextrin Polymers 0.000 claims description 5
- 235000019425 dextrin Nutrition 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- 229960004793 sucrose Drugs 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 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 3
- 239000003405 delayed action preparation Substances 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 229920001730 Moisture cure polyurethane Polymers 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 239000004531 microgranule Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 6
- 201000000980 schizophrenia Diseases 0.000 abstract description 4
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 206010037218 Psychopathic personality Diseases 0.000 abstract 2
- MJRDZKSKNYIAHZ-WLHGVMLRSA-N (e)-but-2-enedioic acid;decanedioic acid Chemical compound OC(=O)\C=C\C(O)=O.OC(=O)CCCCCCCCC(O)=O MJRDZKSKNYIAHZ-WLHGVMLRSA-N 0.000 abstract 1
- 230000003247 decreasing effect Effects 0.000 abstract 1
- 239000002245 particle Substances 0.000 abstract 1
- 239000005720 sucrose Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000000463 material Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 208000028017 Psychotic disease Diseases 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000165940 Houjia Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000009231 family therapy Methods 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 239000002023 wood Substances 0.000 description 2
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 208000027776 Extrapyramidal disease Diseases 0.000 description 1
- 208000002038 Muscle Hypertonia Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 208000008630 Sialorrhea Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- 206010044074 Torticollis Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 235000015111 chews Nutrition 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 208000010118 dystonia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013350 formula milk Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 208000018197 inherited torticollis Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229920000344 molecularly imprinted polymer Polymers 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000001052 transient effect Effects 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a penfluridol polyanhydride pellet and a penfluridol long-acting controlled release tablet as well as a preparation method of the penfluridol long-acting controlled release tablet. The penfluridol long-acting controlled release tablet is prepared from the following components in percentage by weight: 50-60 % of penfluridol polyanhydride pellets, 15-20 % of starch, 10-16 % of sucrose powder, 5-10 % of polysaccharide, 0.2-1.0 % of magnesium stearate, and 1-3 % of hydroxypropylcellulose, wherein the penfluridol polyanhydride pellets are mixture particles composed of (fumaric acid--sebacic acid) polyanhydride [P(FA--SA)] (FA:SA=0.25:1) and penfluridol, and the weight percentage of penfluridol is 15-25 %. The penfluridol long-acting controlled release tablet has the long-acting controlled release effect, and is orally taken twice per month, 2 tablets each time, or the tablets are increased or decreased according to the diseases, or the administration is carried out following the doctor's advice, so that the untoward effects of penfluridol can be greatly reduced, the clinical efficacies can be improved, the home treatment for psychopaths is conveniently maintained, and the hospitalization expenses and other treatment cost of the psychopaths are reduced. Compared with the other clinical medicines for treating schizophrenia, the penfluridol long-acting controlled release tablet has better economic applicability and better clinical efficiency.
Description
Technical field
The present invention relates to penfluridol preparation.
Background technology
Penfluridol is clinical conventional psychosis, and clinical at present system used is administered orally long-acting coated tablet, usual usage
Consumption is, Weekly administration 1 time, each 1--3 piece, every 20mg.There is definite treatment to treating various acute and chronic schizophrenia
Effect[1], become one of current psychiatric department one line antipsychotic drug.
It should be noted that since this medicine many decades clinical practice, many psychotics occur multiple different degrees of
Untoward reaction, its common for 1. the extrapyramidal symptoms：As occurred, hypermyotonia, face be stiff, the shake of slow movement, muscle
Quiver, the parkinson's syndrome sample symptom such as sialorrhea；2. acute dystonia：As occur mandatory dehisce, loll, torticollis, breathing
The dyskinesia and dysphagia；3. cathisophobia：As occurred being on tenterhooks, repeatedly hovering；4. tardive dyskinesia：Occur
Mouth-tongue-cheek three is levied, and such as sucks, lick, chews etc., the most common are tremble, move can not, tachycardia etc., it occurs
Rate up to more than 40%, or even the organ function injuries such as the transient heart, liver can be caused, once there is more serious untoward reaction,
To interference insane orthobiosiss greatly, severe patient to break away from also having no lack of precedents of misery with the means of committing suiside.Therefore can
The no untoward reaction reducing penfluridol, actually one of successful key factor of penfluridol clinical practice.
Content of the invention
It is an object of the invention to provide a kind of penfluridol condensing model micropill and penfluridol long-acting controlled release piece and its preparation
Method, with the defect overcoming prior art to exist, meets the needs of clinical practice.
Described penfluridol condensing model micropill, for (fumaric acid -- SA) condensing model [P (FA--SA)] (FA: SA=
0.25:1) the mixture microgranule with penfluridol, wherein：The weight percent content of penfluridol is 15～25%, preferably
For 20%；
Term：
" P (FA--SA) " refers to (fumaric acid -- SA) condensing model；
" FA: SA=0.25:1 " refer to fumaric acid: SA=0.25:1, mole；
FA is the english abbreviation of fumaric acid；SA is the english abbreviation of SA；FA: SA just refers to that fumaric acid compares SA
(weight ratio).In P (FA--SA), P is polymerization or the meaning of poly, that is, the meaning of fumaric acid and SA polymer.
Described penfluridol long-acting controlled release piece, including the component of following percentage ratio：
The percentage ratio sum of each component is 100%.
Preferably, described penfluridol long-acting controlled release piece, including the component of following percentage ratio：
The percentage ratio sum of each component is 100%.
Particularly preferred, described penfluridol long-acting controlled release piece, including the component of following percentage ratio：
Described polysaccharide is selected from one or more of dextrin, Microcrystalline Cellulose or Lactose；
Preferably, outside described penfluridol long-acting controlled release piece, also include coating, preferred coating is OPADRY coating
Powder, gain in weight 3～4%；
For ensureing clinical effective rate, and so that untoward reaction is preferably minimized, be necessary for making and be monthly administered orally 2 times it is ensured that daily
The long-acting controlled release preparation of release 3-7mg；
Calculated it is ensured that daily more than release 3mg according to lowest dose level weekly (20mg/ week), may be made as daily release
The long-acting controlled release tablet of 3.5mg, according to individual patient difference, adjusts the mesh to reach effectively treatment disease for the tablet quantity taken medicine
's.
For making daily release 3.5mg, common release 52.5mg on the 15th.It is made into 2, every penfluridol long-acting controlled release piece
Penfluridol containing principal agent is 26.25mg, and because of above-mentioned obtained penfluridol micropill pastille 25%, every penfluridol is containing above-mentioned
The penfluridol micropill of preparation is 105mg (wherein comprising penfluridol 26.25mg).Made tablet, each takes 2, often
The moon is taken 2 times, has been equivalent to daily 3.5mg penfluridol.
It is it desired to daily release 7mg penfluridol, as long as monthly taking 2 times, each taking 4, clinically may be used
According to insane various symptoms and its occurring degree, by adjusting medication number, ideal result can be obtained.
The preparation method of described penfluridol long-acting controlled release piece, comprises the steps：
(1) penfluridol crude drug is dissolved in ethanol, (fumaric acid -- SA) condensing model is heated to melting, then
Add 65-70 DEG C of penfluridol ethanol solution, in 70-75 DEG C of stirring mixing 20～40 minutes, 70-75 DEG C of vacuum distilling removed
Ethanol, vacuum is drained, cooling and solidifying, pulverizes, vacuum drying, then pulverizes, and obtains penfluridol condensing model micropill；
(2) starch, cane sugar powder, dextrin and described penfluridol condensing model micropill are mixed, addition volumetric concentration is
50% ethanol, then adopts method well known in the art, pelletizes, is subsequently adding magnesium stearate and Hydroxypropyl Cellulose tabletting, that is,
Penfluridol long-acting controlled release piece can be obtained；
The weight consumption of 50% ethanol is the 10～35% of penfluridol condensing model micropill；
Further, coating steps are also included：
OPADRY coating powder and ethanol are heated to 40 DEG C, mixing, obtain coating solution (A), set aside for use；
In coating solution (A), the weight content of OPADRY coating powder is 13% about.
Then described penfluridol long-acting controlled release piece is adopted known method, with described coating solution (A bag
Clothing, increase weight 3-4%, you can obtains penfluridol long-acting controlled release coated tablet.
Wherein：The preparation method of described poly- (fumaric acid -- SA) [P (FA--SA)] (FA: SA=20: 80), including
Following steps：
1. fumaric acid prepolymer (A) preparation：
By fumaric acid, under nitrogen protection, it is heated to 135～140 DEG C of interior temperature, back flow reaction 1～2 hour, preferably 1.5 is little
When；
Reaction is finished, and vacuum distilling reclaims reaction dissolvent, and (acetic acid that predominantly acetic anhydride generates with reaction is vacuum dried get Fu Ma
Sour prepolymer (A)；
Fumaric acid with the mol ratio of acetic anhydride is：0.25mol: 3.07mol=1: 12～13；
2. the preparation of SA prepolymer (B)：
By SA and acetic anhydride, under nitrogen protection, 135 DEG C～140 DEG C back flow reaction 30～50 minutes, preferably 40 points
Clock, then collects SA prepolymer (B) from product；
SA with the mol ratio of acetic anhydride is：1.5mol: 9.63mol=1: 6～7；
3. the preparation of poly- (fumaric acid -- SA)：
By fumaric acid prepolymer (A) and SA prepolymer (B), under vacuo, 170～190 DEG C, preferably 180 DEG C are reacted
80～100 minutes, preferably 90 minutes, then from using product, collect described [P (FA--SA)] (FA: SA=20: 80),
mp:70 DEG C about.
Fumaric acid prepolymer (A) is 0.25 with the mol ratio of SA prepolymer (B):1；
Penfluridol is made and is monthly taken secondary long-acting controlled release piece it is ensured that daily release 7mg (can be made into every by the present invention
The secondary long-acting controlled release preparation taken a piece of or each take two, each take multi-disc also dependent on the state of an illness and individual variation), can
Greatly reduce clinical drug untoward reaction, improve clinical effective rate.
Medicinal macromolecular sustained-release material has multiple, such as polylactic acid, polyurethane, poly-aspartate, liposome etc., but all
Cannot be used for the preparation of oral controlled-release tablet, only only fumaric acid -- SA) condensing model can be used for the preparation of oral controlled-release tablet.
Compared with other medicinal macromolecule controlled-release materials, fumaric acid -- SA) condensing model：1. there is excellent biology
The compatibility and surface eroding；2. can be used for preparing oral controlled-release tablet, promote drug dissolution and bioavailability；3. rich horse
Acid -- SA) condensing model press zero order kineticses resolution of velocity (at the uniform velocity decomposition), is well suited for the preparation of controlled release tablet；4. prepare relatively
Simply, modifiable reaction temperature and dispensing change condensing model performance, are readily applicable to the preparation of oral controlled-release piece, other medicinal height
Molecularly Imprinted Polymer does not possess These characteristics.
The invention has the beneficial effects as follows：
There is long-acting controlled release effect, be monthly administered orally 2 times, each take 2 or according to state of an illness increase and decrease or follow the doctor's advice, can be significantly
Reduce penfluridol untoward reaction, improve clinical efficacy, the insane family therapy of convenient maintenance, reduces psychotic
Hospitalization cost and other treatment expense.Compare with clinical other treatment schizophrenia drug, have more preferable economic serviceability
With more preferable clinical effective rate.Prolonged application penfluridol maintains insane family therapy, and its effective percentage is up to
100%.
Specific embodiment
Embodiment 1
The preparation of poly- (fumaric acid -- SA) [P (FA--SA)] (FA: SA=20: 80)：
1. fumaric acid prepolymer (A) preparation：
Anti- in tetra- mouthfuls of the 1000ml equipped with mechanical agitator, thermometer, return duct, heater, vacuum tube and charging hopper
Answer in bottle, add fumaric acid 29g (0.25mol), fine vacuum extracts air in reaction bulb, finish, after closing vacuum, be slowly passed through nitrogen
Make pressure of the inside of a bottle consistent with atmospheric pressure, repeat operation once.From separatory funnel add acetic anhydride 250ml (313.2g,
3.07mol), under nitrogen protection, it is stirred and heated to 135 DEG C of back flow reaction of interior temperature 1.5 hours.Reaction is finished, and vacuum distilling reclaims
Reaction dissolvent (acetic acid of predominantly acetic anhydride and reaction generation controls not higher than 80 DEG C of distillation interior temperature).Distillation is finished, in alembic
It is vacuum dried to obtain fumaric acid prepolymer (A), Room-temperature seal is placed stand-by.
2. the preparation of SA prepolymer (B)：
Anti- in tetra- mouthfuls of the 3000ml equipped with mechanical agitator, thermometer, return duct, heater, vacuum tube and charging hopper
Answer in bottle, add SA 303g (1.5mol), fine vacuum extracts air in reaction bulb, finish, after closing vacuum, be slowly passed through nitrogen
Make pressure of the inside of a bottle consistent with atmospheric pressure, repeat operation once.From separatory funnel add acetic anhydride 909ml (982g,
9.63mol), under nitrogen protection, it is stirred and heated to and be stirred at reflux 40 points of reaction between 135 DEG C of interior temperature (160 DEG C about of temperature outward)
Clock.Reaction is finished, and vacuum distilling reclaims reaction dissolvent, and (acetic acid that predominantly acetic anhydride generates with reaction controls distillation interior temperature to be not higher than
80℃).Distillation is finished, and adds 600ml dichloromethane, and being stirred and heated to micro- backflow (40 DEG C) makes product dissolve, and stirring is as cold as
Room temperature, coarse vacuum filters.Filtrate is stirred down and is added drop-wise to 2500ml mixed solvent [petroleum ether (60-90 DEG C): ether=1: 1 (v/
V) precipitation in], rate of crossing collects white solid, and this white solid is added to 500ml mixed solvent [petroleum ether (60-90 DEG C): ether
=1: 1 (v/v)] one night of middle immersion.Filter, filter cake is washed with a small amount of absolute ether, is vacuum dried constant weight and obtains SA pre-polymerization
Thing (A) 386g, mp：48-50 DEG C, yield 90%, Room-temperature seal is placed stand-by.
3. the preparation of poly- (fumaric acid -- SA)：
In above-mentioned tetra- mouthfuls of reaction bulbs of 1000ml being equipped with fumaric acid prepolymer (A) (0.25mol), add SA pre-
Polymers 286g (1mol), room temperature fine vacuum is taken out air in most reaction bulb, is filled with nitrogen, and this process repeats secondary, to ensure to remove
Air in reaction bulb to the greatest extent.It is stirred and heated to 180 DEG C of outer temperature under a high vacuum, react 90 minutes.Stop heating, vacuum cooled to 70 DEG C
Hereinafter, stop vacuum, add 600ml chloroform, being stirred and heated to micro- backflow (65 DEG C) makes reactant dissolve.It is as cold as 40 DEG C about, stir
Mix lower slowly pouring chloroformic solution in 1500ml petroleum ether (60-90 DEG C) to precipitate, filter, washed with a small amount of ether.In 50 DEG C
It is vacuum dried constant weight, obtain product：Poly- (fumaric acid -- SA) [P (FA--SA)] (FA: SA=0.25:1, mp:70 DEG C of left sides
Right.
The penfluridol condensing model being embodiment 1 that following examples adopt.
Embodiment 2
Prescription：(weight)
In 105g penfluridol condensing model micropill, 26.25g containing penfluridol.
Make 1000 altogether, shallow arc punch diePiece weight 189mg, every 26.25mg containing penfluridol.
Preparation process：
Penfluridol crude drug is dissolved in ethanol, (fumaric acid -- SA) condensing model is heated to melting, Ran Houjia
Enter 65 DEG C of penfluridol ethanol solution, in 70 DEG C of stirring mixing 40 minutes, 70 DEG C of vacuum distillinges removed ethanol, and vacuum is drained,
Cooling and solidifying, pulverizes, vacuum drying, then pulverizes, and obtains penfluridol condensing model micropill；
1. pelletize：By above-mentioned formula middle dosage, successively by starch, cane sugar powder (taking the Icing Sugar crossing 80 mesh sieves after pulverizing), paste
Essence and penfluridol micropill mix homogeneously, add 21g volumetric concentration 50% ethanol, and side edged mixes, and makes moist wood, uses 20 mesh sieves
Net is pelletized.Made wet grain is put in baking oven, in 65 DEG C of normal pressure aeration-dryings, controls dry particl aqueous 3.5%, rewinding, use 20
Eye mesh screen granulate obtains material (G).
2. tabletting：
Measure by above-mentioned formula, magnesium stearate and Hydroxypropyl Cellulose are added in above-mentioned prepared material (G), are sufficiently mixed
Uniformly, tabletting obtains penfluridol long-acting controlled release piece plain piece.
3. film coating：
1. the preparation of coating solution：Equipped with mechanical agitator, thermometer, three mouthfuls of reaction bulbs of heater, add 100ml
Ethanol, is stirred and heated to 40 DEG C, and accelerating stirring makes liquid form vortex, adds white stomach dissolution type OPADRY coating powder 12g (in 5
Add in minute), in 40 DEG C about quick stirrings 45 minutes.Stop heating, sealing stirring is as cold as room temperature and obtains coating solution (A), standing
Stand-by.
2. coating operations：1000 penfluridol long-acting controlled release piece plain pieces of above-mentioned preparation are added experiment to use small-sized coating
In pot, with Hot-blast Heating to 40 DEG C, adjust coating pan rotating speed 20--30r./min., slowly spray into the coating solution (A) of above-mentioned preparation
(45ml about), make penfluridol long-acting controlled release piece plain piece weightening 3% (during coating, tablet temperature will be maintained at 40 DEG C about).
After the completion of coating, continue out hot blast drying.Discharging obtains white penfluridol long-acting controlled release coated tablet.
Embodiment 3
Prescription：
The common 200g of material, makes 1000 altogether, shallow arc punch diePiece weight 200mg, every contains penfluridol
26.25mg.
Embodiment 4
Prescription：
Amount to 357g, make 1000 altogether, shallow arc punch die, φ 10mm, piece weight 357mg, every contains penfluridol
52.5mg, every first quarter moon is administered orally once, each takes 1-2 piece, is equivalent to and 3.5-7mg penfluridol is administered orally daily, and such as patient needs
Larger quantities, can disposably take several pieces, to reach good clinical effectiveness.
Preparation process：
Penfluridol crude drug is dissolved in ethanol, (fumaric acid -- SA) condensing model is heated to melting, Ran Houjia
Enter 65 DEG C of penfluridol ethanol solution, in 75 DEG C of stirring mixing 20 minutes, 75 DEG C of vacuum distillinges removed ethanol, and vacuum is drained,
Cooling and solidifying, pulverizes, vacuum drying, then pulverizes, and obtains penfluridol condensing model micropill；
1. pelletize：
By above-mentioned formula middle dosage, successively by starch, cane sugar powder (taking the Icing Sugar crossing 80 mesh sieves after pulverizing), Lactose, crystallite
Cellulose, dextrin, Hydroxypropyl Cellulose and penfluridol micropill mix homogeneously, are slowly added into 50g50% ethanol (v/w), side edged
Mixing, makes moist wood, is pelletized with 20 eye mesh screens.Made wet grain is put in baking oven, in 60 DEG C of normal pressure aeration-dryings, controls dry
Between grain aqueous 3.5%, rewinding, obtain material (G) with 20 eye mesh screen granulate.
2. tabletting：
Measure by above-mentioned formula, magnesium stearate is added in above-mentioned prepared material (G), be sufficiently mixed uniformly, tabletting obtains
Penfluridol long-acting controlled release blade.
3. film coating：
1. the preparation of coating solution：Equipped with mechanical agitator, thermometer, three mouthfuls of reaction bulbs of heater, add 100ml
Ethanol, is stirred and heated to 40 DEG C, and accelerating stirring makes liquid form vortex, and portion is a to add white stomach dissolution type OPADRY coating powder
12g (added) in 5 minutes, in 40 DEG C about quick stirrings 45 minutes.Stop heating, sealing stirring is as cold as room temperature and obtains coating solution
(A), set aside for use.
2. coating operations：1000 penfluridol long-acting controlled release piece plain pieces of above-mentioned preparation are added experiment to use small-sized coating
In pot, with Hot-blast Heating to 40 DEG C, adjust coating pan rotating speed 20--30r./min., slowly spray into the coating solution (A) of above-mentioned preparation
(45ml about), make penfluridol long-acting controlled release piece plain piece weightening 4% (during coating, tablet temperature will be maintained at 40 DEG C about).
After the completion of coating, continue out hot blast drying.Discharging obtains white penfluridol long-acting controlled release coated tablet.
Embodiment 5
Containing penfluridol (fumaric acid -- SA) condensing model degradation experiment：
Made micropill moisture content 2%, containing penfluridol 25%, granularity 80 mesh
Penfluridol (fumaric acid -- SA) the condensing model micropill of Example 1, with the compacting of infrared spectrum compression mold
One-tenth (20MPa, room temperature, 3min) disk (185mg,Thick 1mm about), take two panels to be placed in the isotonic phosphoric acid of 50ml PH7.4
In salt buffer solution, degrade in 37 DEG C of constant temperature oscillators, change buffer daily, spend n days and take out sample, use distilled water wash sample
It is vacuum dried after product and weighs, according to the mass loss of sample how much representing, its calculating formula is as follows for degraded situation：
Its experimental result is as shown in the table：
Above-mentioned as shown by data, penfluridol (fumaric acid -- SA) condensing model micropill, daily with 3.5% about speed
Degraded, it is sufficient to prove, penfluridol (fumaric acid -- SA) the condensing model micropill of the present invention, has good controlled-release effect.
Explanation：PH7.4 isotonic phosphate buffer solution [0.01mol/L, PH7.4 (PBS)] is prepared：
Formula：Sodium chloride 8g, potassium dihydrogen phosphate 0.2g, disodium hydrogen phosphate .12H2O 2.9g,
Potassium chloride 0.2g.
Formulation operations：
In 1000ml volumetric bottle, add 500ml water, sequentially add by under the shaking of above-mentioned formula, shake well has dissolved
Entirely, add water 960ml, adjusts PH to 7.4, adds water scale, and autoclave sterilization sterilizes to obtain PH7.4 isotonic phosphate buffer
Liquid.It is saved in standby in 4 DEG C of refrigerator.
Embodiment 6
Penfluridol (fumaric acid -- SA) the condensing model micropill of Example 2, is entered using embodiment 3 identical method
Row test, result is as follows：
Its experimental result is as shown in the table：
Above-mentioned as shown by data (take two panels to test, material weight 714mg about) penfluridol (fumaric acid -- SA) polyacids
Acid anhydride micropill, is degraded with 3.5% about speed daily it is sufficient to prove, the penfluridol (fumaric acid -- SA) of the present invention gathers
Anhydride micropill, has good controlled-release effect.
Claims (11)
1. penfluridol condensing model micropill is it is characterised in that be (fumaric acid -- SA) condensing model [P (FA--SA)] (FA: SA
=0.25:1) the mixture microgranule with penfluridol.
2. penfluridol condensing model micropill according to claim 1 is it is characterised in that the percentage by weight of penfluridol contains
Measure as 15～25%.
3. penfluridol condensing model micropill according to claim 1 is it is characterised in that the percentage by weight of penfluridol contains
Measure as 20%.
4. penfluridol long-acting controlled release piece is it is characterised in that include the component of following percentage ratio：
The percentage ratio sum of each component is 100%.
5. penfluridol long-acting controlled release piece according to claim 4 is it is characterised in that include the component of following percentage ratio：
The percentage ratio sum of each component is 100%.
6. penfluridol long-acting controlled release piece according to claim 5 is it is characterised in that include the component of following percentage ratio：
7. the penfluridol long-acting controlled release piece according to any one of claim 4～6 is it is characterised in that described polysaccharide selects
From one or more of dextrin, Microcrystalline Cellulose or Lactose.
8. penfluridol long-acting controlled release piece according to claim 7 is it is characterised in that in the described long-acting control of penfluridol
Release outside piece, also include coating.
9. penfluridol long-acting controlled release piece according to claim 7 it is characterised in that make monthly is administered orally 2 times it is ensured that every
The long-acting controlled release preparation of day release 3-7mg, every penfluridol long-acting controlled release piece penfluridol containing principal agent is 26.25mg.
10. the preparation method of the penfluridol long-acting controlled release piece according to any one of claim 4～6 is it is characterised in that wrap
Include following steps：
(1) penfluridol crude drug is dissolved in ethanol, (fumaric acid -- SA) condensing model is heated to melting, is subsequently adding
65-70 DEG C of penfluridol ethanol solution, in 70-75 DEG C of stirring mixing 20～40 minutes, 70-75 DEG C of vacuum distilling removed second
Alcohol, vacuum is drained, cooling and solidifying, pulverizes, vacuum drying, then pulverizes, and obtains penfluridol condensing model micropill；
(2) starch, cane sugar powder, dextrin and described penfluridol condensing model micropill are mixed, add volumetric concentration to be 50%
Ethanol, then pelletizes, and adds magnesium stearate and Hydroxypropyl Cellulose tabletting, you can obtain described penfluridol long-acting controlled release piece.
The preparation method of 11. penfluridol long-acting controlled release pieces according to claim 10 is it is characterised in that described is poly-
The preparation method of (fumaric acid -- SA) [P (FA--SA)] (FA: SA=20: 80), comprises the steps：
(1) fumaric acid prepolymer (A) preparation：
By fumaric acid, under nitrogen protection, it is heated to 135～140 DEG C of interior temperature, back flow reaction 1～2 hour；
Reaction finish, vacuum distilling reclaim reaction dissolvent (predominantly acetic anhydride and reaction generate acetic acid, be vacuum dried fumaric acid is pre-
Polymers (A)；
Fumaric acid is 1: 12～13 with the mol ratio of acetic anhydride；
(2) preparation of SA prepolymer (B)：
By SA and acetic anhydride, under nitrogen protection, 135 DEG C～140 DEG C back flow reaction 30～50 minutes, preferably 40 minutes, so
SA prepolymer (B) is collected afterwards from product；
SA is 1: 6～7 with the mol ratio of acetic anhydride；
(3) preparation of poly- (fumaric acid -- SA)：
By fumaric acid prepolymer (A) and SA prepolymer (B), under vacuo, 170～190 DEG C, 80～100 minutes are reacted, so
Described [P (FA--SA)] (FA: SA=20: 80) are collected afterwards from using product；
Fumaric acid prepolymer (A) is 0.25 with the mol ratio of SA prepolymer (B):1.
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| CN201610804611.0A CN106389341B (en) | 2016-09-06 | 2016-09-06 | Penfluridol polyanhydride pellet, penfluridol long-acting controlled-release tablet and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134012A (en) * | 2006-08-30 | 2008-03-05 | 王永峰 | Method for producing injectable drug administration preparations using mixed polyacid anhydride as the carrier for middle-size or small molecule medicament and application thereof |
| CN101732311A (en) * | 2009-12-15 | 2010-06-16 | 苏春华 | Penfluridol-containing oral preparation and application thereof |
| CN104546784A (en) * | 2014-12-31 | 2015-04-29 | 康普药业股份有限公司 | Penfluridol tablet composition and preparation method thereof |
-
2016
- 2016-09-06 CN CN201610804611.0A patent/CN106389341B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134012A (en) * | 2006-08-30 | 2008-03-05 | 王永峰 | Method for producing injectable drug administration preparations using mixed polyacid anhydride as the carrier for middle-size or small molecule medicament and application thereof |
| CN101732311A (en) * | 2009-12-15 | 2010-06-16 | 苏春华 | Penfluridol-containing oral preparation and application thereof |
| CN104546784A (en) * | 2014-12-31 | 2015-04-29 | 康普药业股份有限公司 | Penfluridol tablet composition and preparation method thereof |
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