CN101612140B - Preparation method of diclofenac potassium sustained-release pellet capsule - Google Patents
Preparation method of diclofenac potassium sustained-release pellet capsule Download PDFInfo
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- CN101612140B CN101612140B CN200910100649XA CN200910100649A CN101612140B CN 101612140 B CN101612140 B CN 101612140B CN 200910100649X A CN200910100649X A CN 200910100649XA CN 200910100649 A CN200910100649 A CN 200910100649A CN 101612140 B CN101612140 B CN 101612140B
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Abstract
The invention relates to a preparation method of diclofenac potassium sustained-release pellet capsule. The preparation method sequentially comprises: preparing diclofenac potassium hormone pill by an extrusion-spheronization mothod, packing an isolation layer, packing a sustained-release layer and encapsulating the capsule, extruding the capsule into a stick on the condition that the set frequency of an extruder is 10-100Hz, and spheronizing the capsule for 3-30min on the condition that the frequency of a spheronization machine is 20-150Hz. In the invention, flying dust does not occur, the pollution is little and the production process meets the requirement of GMP; after the prepared diclofenac potassium sustained-release capsule is taken orally, the plasma concentration of the drug is gentle with small fluctuation and the capsule has good sustained-release effect.
Description
(1) technical field: the present invention relates to a kind of preparation method of oral chemicals slow releasing preparation, be specially a kind of method that spheronization prepares diclofenac potassium sustained-release pellet capsule of extruding.
(2) background technology: diclofenac potassium is the potent anthranilic acid of third generation non-steroidal anti-inflammatory analgesics, and its mechanism of action transforms prostaglandin for suppressing the Cycloxygenase activity thereby block arachidonic acid.Simultaneously, it also can promote arachidonic acid to combine with triglyceride (triacylglycerol), reduces the arachidonic acid concentration of endocellular liberation, and suppresses the synthetic of leukotriene indirectly.The peroral dosage form of this medicine of domestic and international market is mainly diclofenac potassium tablet at present, and usage and dosage is 100～150mg every day, divides and takes for 2～3 times, and is very inconvenient.
Diclofenac potassium sustained-release pellet capsule is compared characteristics such as to have an effective blood drug concentration steady, and medicining times is few with conventional tablet.Compare with enteric coatel tablets; patient's doing well,improving is more stable; can also avoid the diclofenac potassium enteric coatel tablets to absorb the too high blood peak concentration of drug that the back occurs; minimizing is too high by blood drug level; suppressed strong and the destruction to gastrointestinal mucosa protection barrier that may occur to prostaglandin; reduce gastric mucosal erosion or ulcer incidence rate, improved the safety and the toleration of diclofenac potassium.
Its content of diclofenac potassium sustained-release pellet capsule agent is spherical slow-release micro-pill, be day clothes slow releasing agent once, this sustained-release micro-pill capsules is the polyploid slow-released system simultaneously, compare the sustained-release micro-pill capsules product with slow releasing tablet (unit medicine-releasing system) following characteristics are arranged: (1) can be distributed in whole gastrointestinal tract rapidly, and absorption is stable and local irritation is little; (2) because the set of site-specific drug delivery mini-pill has constituted whole dosage form and release shape is, so the out of control of individual elements can not cause coming down in torrents of whole dosage, so safety is higher; (3) influenced by gastric emptying little for polynary release dosage form, and individual variation is less, stable curative effect.
Therefore the oral non_steroidal anti_inflammatory drug field of opening up another safe, effective, low toxicity of diclofenac potassium sustained-release pellet capsule with succeeding in developing.
Extrude spheronization and be widely regarded as comparatively novel, superior micropill technology of preparing so far, it is compared with traditional coating pan pill, centrifugal granulating pill has the operating time of reduction and cost, flexible operation, and coating is even, but characteristics such as automation mechanized operation.
Consult document, pertinent literature seldom, the Piclofenac potassium sustained release capsule patent of existing at present Hainan Baina Pharmaceutical Development Co., Ltd. application comes forth, its application number is 200810134825.7, publication number is CN 101322695A.But the present invention and above-mentioned patent have a great difference, the preparation method of the diclofenac potassium sustained-release pellet of above-mentioned patent disclosure is a lamination method on celphere, production cycle is long and can cause dust from flying, and spheronization is extruded in the present invention's employing, do not contain celphere, with short production cycle and can avoid dust from flying, have higher efficient and GMP compatible more.
(3) summary of the invention: task of the present invention provide a kind of technology simple, do not have dust from flying, be easy to suitability for industrialized production and have the preparation method of the diclofenac potassium sustained-release pellet capsule of good slow release effect.
To achieve these goals, the technical solution used in the present invention is: a kind of to extrude the method that spheronization prepares diclofenac potassium sustained-release pellet capsule, described method comprises adopting successively to be extruded spheronization and prepares the plain ball of diclofenac potassium, bag contagion gown, wraps sustained-release coating layer again, diclofenac potassium sustained-release pellet capsule is made in last fill, these preparation method process following steps:
(1) preparation of the plain ball of diclofenac potassium: get diclofenac potassium and filler, weight ratio by diclofenac potassium and filler is 1: 0.5～10, mix homogeneously gets dry mixture, reuse binding agent wet method system soft material, the weight (g) of the volume of adhesive therefor (ml) and above-mentioned dry mixture is than being 0.3～0.8: 1, above-mentioned soft material is extruded through extruder, and the setting extruded velocity is 10～100Hz, is extruded as bar; The gained bar is round as a ball in spheronizator, and setting round as a ball rotating speed is 20～150Hz, round as a ball time 3～30min, through baking oven or fluid bed drying, cross 18～40 mesh sieves and the plain ball of diclofenac potassium;
Above-mentioned used filler is a kind of or its mixture in microcrystalline Cellulose, amylum pregelatinisatum, starch, octadecanol, polyvinylpyrrolidone (PVP K30), Glyceryl Behenate, sodium carboxymethyl cellulose, hypromellose, carbomer, stearic acid, ethyl cellulose, lactose, the mannitol;
The used binding agent of above-mentioned system soft material is a water, or 0.5%～10% polyvinylpyrrolidone (PVP K30) aqueous solution, or 0.5%～10% hydroxypropyl emthylcellulose (HPMC) E5 aqueous solution;
(2) bag contagion gown: get the plain ball of above-mentioned steps (1) gained, with fluid bed or coating pan or fusion method bag contagion gown, ball is isolated in preparation, and blast temperature is 10～80 ℃, and the weightening finish of bag contagion gown is 1%～10% of plain ball weight;
Adopting fluid bed or the used contagion gown material of coating pan bag contagion gown is the ethanol-water solution or the alcoholic solution of ethyl cellulose and polyvinylpyrrolidone (PVP K30), the compound method of this solution is that ethyl cellulose and polyvinylpyrrolidone (PVP K30) weight ratio (g/g) are 7～2: 1, and with 50%～95% ethanol water or anhydrous alcohol solution, be prepared in ethyl cellulose 1%～10% (weight ratio, solution g/g); Used contagion gown material or be 1%～10% hydroxypropyl emthylcellulose (HPMC) E5 aqueous solution; Blast temperature is 10～80 ℃, and the weightening finish of bag contagion gown is 1%～10% (pressing ethyl cellulose calculates) of plain ball weight;
Adopting the used contagion gown material of fusion method bag contagion gown is stearic acid, plain ball is placed coating pan, be heated to 60 ℃ in the coating pan rotation process, be sprinkled into stearic acid and make it evenly be melted in plain ball surface, the weightening finish of bag contagion gown is 1%～10% (pressing stearic acid calculates) of plain ball weight, stop heating after all stearic acid add, treat cold slightly after, be sprinkled into the stearic acid weight ratio be that 0.1～2 Pulvis Talci prevents the piller adhesion;
(3) bag sustained-release coating layer: the isolation ball of getting above-mentioned steps (2) gained, with fluid bed or centrifugal granulator or coating pan bag sustained-release coating layer, use the aqueous dispersion of extended release coatings material, blast temperature is 10～50 ℃, bag extended release coatings weightening finish is for isolating 1%～20% of ball weight, through fluid bed or oven drying, sieving promptly gets diclofenac potassium sustained-release pellet;
Used extended release coatings material is a kind of or its mixture in Eudragit NE30D, Eudragit RL30D, Eudragit RS30D, the Sulisi;
The preparation of the aqueous dispersion of extended release coatings material: with a kind of or its mixture in the above-mentioned extended release coatings material with suitable quantity of water dilution or dissolving and 10%～20% (weight ratio, extended release coatings solution g/g);
(4) fill capsule: above-mentioned diclofenac potassium sustained-release pellet No. 0 softgel shell of packing into is promptly got diclofenac potassium sustained-release pellet capsule, and every capsules contains principal agent diclofenac potassium 100mg.
The present invention wraps contagion gown, bag extended release coatings, filled capsules to extrude after spheronization prepares the fragrant sour potassium micropill of chlorine more successively, reaches the purpose of slow release.The development of sustained-release micro-pill capsules of the present invention is reduced to once a day administration number of times, and medicine blood drug level is mild, and it is little to fluctuate, and untoward reaction is little.
Preparation method of the present invention, reduce operating time and cost, flexible operation, coating is even, but automation mechanized operation, technology is simple, be easy to suitability for industrialized production, dust from flying can not occur, pollute little, the production process GMP compatible, and the diclofenac potassium sustained-release pellet capsule that makes has the good slow release effect.
(4) specific embodiments:
The following examples are used to further specify and describe the present invention, but and do not mean that the present invention only limits to this.Value is the arbitrary concrete numerical value of scope of the present invention among the embodiment, is and can implements.
Embodiment 1: the preparation diclofenac potassium sustained-release pellet capsule
(1) preparation of the plain ball of diclofenac potassium: get diclofenac potassium 100g, microcrystalline Cellulose 200g and mix homogeneously, mixture is made soft material with 2% hydroxypropyl emthylcellulose (HPMC) E5 aqueous solution 160ml, extrude with frequency 30Hz at extruder then and make bar, the gained bar places in the spheronizator, with the round as a ball 3min of 30Hz, again with the round as a ball 5min of 60Hz, 40 ℃ of dry 12h, cross 18～32 mesh sieves and plain ball;
(2) bag contagion gown: with above-mentioned plain ball bag contagion gown, the contagion gown material is: ethyl cellulose (10cp) restrains by weight with polyvinylpyrrolidone (PVP K30) and mixed than 5: 1, and dissolve with 95% ethanol water, or use anhydrous alcohol solution, be prepared into concentration and be calculated as 3% solution with the ethyl cellulose weight in grams, adopt fluid bed bag contagion gown, blast temperature is 30 ℃; Bag contagion gown weightening finish is calculated as 4% of plain ball weight by ethyl cellulose weight, and is dry, sieve and must isolate ball.
(3) bag sustained-release coating layer: with above-mentioned isolation ball bag sustained-release coating layer, getting formula ratio EudragitNE30D, to be diluted with water to concentration be 15% (weight ratio, g/g) extended release coatings solution, stirring 0.5h makes evenly, with fluidized bed coating, blast temperature is 20 ℃, and coating increases weight and is 6.5% of piller behind the above-mentioned bag contagion gown layer, 40 ℃ of oven drying 24h, sieve and diclofenac potassium sustained-release pellet.
(4) fill capsule: the above-mentioned diclofenac potassium sustained-release pellet that makes is filled into capsule No. 0, promptly gets diclofenac potassium sustained-release pellet capsule, every capsules contains principal agent diclofenac potassium 100mg.
To change the dissolution that the basket method is measured above-mentioned diclofenac potassium sustained-release pellet capsule, rotating speed is 100rpm, is dissolution medium with the phosphate buffer of pH6.8, and water temperature is 37.5 ℃.After measured, 2h stripping 40%, 6h stripping 65%, 12h stripping are complete.
Embodiment 2:
(1) preparation of the plain ball of diclofenac potassium: get diclofenac potassium 100g, mannitol 150g, lactose 50g, and mix homogeneously, mixture is made soft material with 3% polyvinylpyrrolidone (PVP K30) aqueous solution 150ml, then extruder with frequency 50Hz extrude bar, the gained bar places in the spheronizator, with the round as a ball 3min of frequency 25Hz, again with the round as a ball 10min of 60Hz, 40 ℃ of dry 12h, cross 24～40 mesh sieves and the plain ball of diclofenac potassium;
(2) plain ball bag contagion gown layer: with above-mentioned plain ball bag contagion gown, adopt coating pan with stearic acid fusion bag contagion gown, plain ball in the coating pan is heated to 60 ℃, adding stearic acid makes it evenly be melted in plain ball surface, calculating the weightening finish of bag contagion gown with stearic acid is 3% of plain ball weight, stearic acid adds postcooling, and the Pulvis Talci that adds in cooling procedure with stearic acid equivalent prevents the piller adhesion, sieves and must isolate ball;
(3) bag sustained-release coating layer: with above-mentioned isolation ball bag sustained-release coating layer, the formula ratio Sulisi is diluted to solid content 15% (weight ratio with water, g/g) Sulisi solution, stirring 0.5h makes evenly, with fluidized bed coating, blast temperature is 20 ℃, and the coating weightening finish is 20% of above-mentioned isolation ball weight, 40 ℃ of oven drying 24h, sieve and diclofenac potassium sustained-release pellet;
(4) fill capsule: the above-mentioned diclofenac potassium sustained-release pellet that makes is filled into capsule No. 0, promptly gets diclofenac potassium sustained-release pellet capsule, every capsules contains principal agent diclofenac potassium 100mg.
To change the dissolution that the basket method is measured above-mentioned diclofenac potassium sustained-release pellet capsule, rotating speed is 100rpm, is dissolution medium with the phosphate buffer of pH6.8, and water temperature is 37.5 ℃.After measured, 2h stripping 37%, 6h stripping 62%, 12h stripping are complete.
Claims (3)
1. the preparation method of a diclofenac potassium sustained-release pellet capsule, described preparation method comprises the plain ball of preparation diclofenac potassium, plain ball bag contagion gown successively, wraps sustained-release coating layer and fill capsule again, it is characterized in that adopting and extrude spheronization and prepare the plain ball of diclofenac potassium, described preparation method is through following step:
(1) preparation of the plain ball of diclofenac potassium: get diclofenac potassium and filler, weight ratio by diclofenac potassium and filler is 1: 0.5～10, mix homogeneously and dry mixture, with binding agent wet method system soft material, the volume of adhesive therefor and the weight ratio of above-mentioned dry mixture, ml: g, be 0.3～0.8: 1, soft material is extruded as bar through extruder, and the gained bar is round as a ball in spheronizator, through baking oven or fluid bed drying, cross 18～40 mesh sieves and plain ball;
Described filler is a kind of or its mixture in microcrystalline Cellulose, amylum pregelatinisatum, starch, octadecanol, 30 POVIDONE K 30 BP/USP 30, Glyceryl Behenate, sodium carboxymethyl cellulose, hypromellose, carbomer, stearic acid, ethyl cellulose, lactose, the mannitol;
Adhesive therefor is a water, or 0.5%～10% polyvinylpyrrolidone aqueous solution, or 0.5%～10% hydroxypropyl emthylcellulose E5 aqueous solution;
(2) plain ball bag contagion gown: get the plain ball that step (1) makes, adopt fluid bed or coating pan bag contagion gown, use ethanol-water solution or the alcoholic solution of contagion gown material, or be 1%～10% hydroxypropyl emthylcellulose E5 aqueous solution as ethyl cellulose and polyvinylpyrrolidone; Perhaps adopt fusion method bag contagion gown, use the contagion gown material to be stearic acid; Bag contagion gown weightening finish is 1%～10% of plain ball weight, sieves at last and makes coating and isolate ball;
(3) bag sustained-release coating layer: get the isolation ball that step (2) makes, adopt fluid bed bag sustained-release coating layer, or adopt centrifugal granulator bag sustained-release coating layer, or adopt coating pan bag sustained-release coating layer; Use the aqueous dispersion of extended release coatings material, the coating weightening finish is for isolating 1%～20% of ball weight, through fluid bed or oven drying, sieving promptly gets diclofenac potassium sustained-release pellet;
Used extended release coatings material is a kind of or its mixture in Eudragit NE30D, Eudragit RL30D, Eudragit RS30D, the Sulisi;
(4) fill capsule: the diclofenac potassium sustained-release pellet that step (3) is made No. 0 softgel shell of packing into promptly gets diclofenac potassium sustained-release pellet capsule, and every capsules contains principal agent diclofenac potassium 100mg.
2. preparation method according to claim 1 is characterized in that setting extruded velocity in the step (1) is 10～100Hz, and setting round as a ball rotating speed is 20～150Hz, round as a ball time 3～30min.
3. preparation method according to claim 1, it is characterized in that middle contagion gown material ethyl cellulose of step (2) and polyvinylpyrrolidone weight ratio are 7～2: 1, its compound method: ethanol water with 50%～95% or anhydrous alcohol solution, make solution in ethyl cellulose weight 1%～10%.
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| CN102266292B (en) * | 2011-07-14 | 2013-03-13 | 浙江金华康恩贝生物制药有限公司 | Matrix diclofenac potassium sustained-release pellet capsules and production process thereof |
| CN115317464B (en) * | 2022-09-01 | 2023-08-08 | 苏州弘森药业股份有限公司 | Potassium diclofenac microcapsule and preparation method thereof |
Citations (4)
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| JP2005075830A (en) * | 2003-09-01 | 2005-03-24 | Jordanian Pharmaceutical Manufacturing Co | Universal release control composition |
| EP1855647A1 (en) * | 2005-03-04 | 2007-11-21 | Intelgenx Corporation | Delayed release pharmaceutical oral dosage form and method of making same |
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101322695A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Piclofenac potassium sustained release capsule and preparing technique thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005075830A (en) * | 2003-09-01 | 2005-03-24 | Jordanian Pharmaceutical Manufacturing Co | Universal release control composition |
| EP1855647A1 (en) * | 2005-03-04 | 2007-11-21 | Intelgenx Corporation | Delayed release pharmaceutical oral dosage form and method of making same |
| CN101288659A (en) * | 2007-04-18 | 2008-10-22 | 王雷波 | Floating type pellets in stomach and preparation method thereof |
| CN101322695A (en) * | 2008-08-01 | 2008-12-17 | 海南百那医药发展有限公司 | Piclofenac potassium sustained release capsule and preparing technique thereof |
Non-Patent Citations (2)
| Title |
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| 刘耀等.挤出-滚圆法制备微丸的研究进展.《中国药学杂志》.2008,第43卷(第6期),第401-405页. * |
| 王文刚等.挤出-滚圆制微丸工艺的进展.《中国新药杂志》.2001,第10卷(第9期),第661-664页. * |
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