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 PDF

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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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CN106389341B (en
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申玉良
曹春宇
郑良彬
舒志坚
申玉军
肖云生
刘红
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Hunan Zhongnan Pharmaceutical Co Ltd
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Hunan Zhongnan Pharmaceutical Co Ltd
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1641Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic 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
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • A61K31/451Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

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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

Penfluridol condensing model micropill and penfluridol long-acting controlled release piece and preparation method thereof
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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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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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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