CN1053808C - Nedepine quick releasing and slow releasing agent - Google Patents
Nedepine quick releasing and slow releasing agent Download PDFInfo
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- CN1053808C CN1053808C CN93104664A CN93104664A CN1053808C CN 1053808 C CN1053808 C CN 1053808C CN 93104664 A CN93104664 A CN 93104664A CN 93104664 A CN93104664 A CN 93104664A CN 1053808 C CN1053808 C CN 1053808C
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- nifedipine
- water slurry
- controlled release
- polymer
- hydroxypropyl methylcellulose
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a method of a controlled release preparation containing high-speed, slow-release and controlled release pellets of equal circles of Nifedipine. The aqueous polymer suspension of the medicine is mixed on a matric controlled release form (matrix type) which is selected as a coating form, and simultaneously, adhesives are added; the mixed suspension is operated by making use of a granulation cladding machine of a fluidized bed; the mixed suspension is coated on the surface of a saccharide core to be used as a circular pellet, and accordingly, the effects of delaying the release of the medicine are obtained.
Description
Recent years, pharmaceutical industry just makes great efforts to be become safer, more effective, controlled release form more easily in the solid dosage forms of original drug market more than 85% improves after finding some novel polymers always.Yet oral controlled release formulation often is subjected to the influence of some physiologic factors such as the pH-value, digestive enzyme of gastrointestinal fluid and stomach row's control time, wriggling activity, cause medicine disengage bad, can't bring into play drug effect, absorb the upper deviation, momentary dosage is crossed high phenomenon.Aktiebolaget SKF develops as far back as 1949 that a kind of be the stamen heart with sugar grain, the outer controlled release form that coats small amount of drug, these are the stamen heart with the sugar grain at present, or be the stamen heart with the medicine, coat the controlled release form of going up various polymer formation multiple dosings (multiple dose) again, be commonly referred to as ball grain (pellet).
No. 4103525 announcement of day in 1992 disclosure communique will be dissolved or be suspended in Nifedipine (nifedipine) the soln using spray pattern that contains 1.5% ethanol (EtOH) and be coated on a kind of method of making the spacetabs type powder on the lactose granule.The disclosure reported to disclose for No. 3206039 and Nifedipine, ethyl cellulose (ethylcellulose) and HYDROXY PROPYL METHYLCELLULOSE (hydroxy-propylmethylcellulose) are dissolved in the organic solution that contains ethanol utilized spray pattern to be coated on crystalline cellulose to make spacetabs type lozenge day in 1991.European patent in 1989 discloses for No. 339420 and contains the spacetabs type controlled release form that dihydropyridine (dihydropyridine) derivant and Nifedipine core are filled a prescription.Disclose Nifedipine and ethyl cellulose mixture for 1988 Deutsche Bundespatent the 3639073rd A1 number and be coated on hydroxy alkyl cellulose (hydroxyalkylcellulose), sucrose and starch and be dissolved in and contain ethanol and make spacetabs type lozenge, or the ball grain packed into make spacetabs type controlled release lozenge in the glutoid capsule.Day in 1987, the disclosure communique hydroxy propyl cellulose alcoholic solution that will contain Nifedipine for No. 62145014 was sprayed at the carrier of bulk ethyl cellulose crude granule, made spacetabs type projection preparation.No. 61148114 elder generation of day in 1986 disclosure communique coats round carrier with hydroxy propyl cellulose and Nifedipine fine crystallization mixture, and the solution material coating with similar gastric juice is prepared into the controlled release pill again.International association's patent in 1986 discloses for No. 8601717 and will contain 10% polyvinyl pyrrolidone (polyvinylpyrrolidone) alcoholic solution and be sprayed on the Nifedipine mixed crystal, coats successively with the ethanol-acetone soln of polymethacrylates (Eudragit L) and Talcum and is prepared into the controlled release medicament.
Ball grain (pellet) includes the granule of main constituent medicine, can be dispersed in the gastrointestinal tract, even under the different rate of evacuation of stomach, avoid causing the absorption upper deviation, also can reach safely effectively drug absorption simultaneously, and can reduce the undulatory property and the side effect of blood level.Owing to each granule in the ball grain only contains a spot of medicine, be not afraid of the danger that causes dosage to surpass because of come down in torrents together (dumping) for the high medicine of drug effect (potency), or cause the situation in locality high concentration stimulating gastrointestinal road in addition.Again because the more flowability of ball grain in the manufacture process of coating medicine polymer, can obtain higher productive rate and repeatability.And make in the design of ball grain controlled release form prescription except can be through coating different weight polymers, the mode of making different-thickness film clothing is to reach required dissolution rate, can also utilize the different particle diameter of sugared stamen or medicine stamen itself, form different surface areas, or utilization selects ball grain surface area mode to adjust the purpose that release rate of drugs, load (loading) dose reach the control drug release amount.Even the ball grain of different pharmaceutical can be mixed, form the controlled release form of compound recipe, get 600 coldrexs as health.As seen no matter ball grain controlled release form perhaps the allotment of processing procedure and prescription in all has suitable advantage and polytropy (flexibility) increasing safety, improving on the treatment effectiveness.
Nifedipine (Nifedipine) belongs to a kind of calcium antagonist (calcium antagonist), is used for the treatment of ischemic heart desease (ischemic heart disease) clinically, and hypertension.But the half-life of Nifedipine is very short, for effect and the antihypertensive curative effect of maintenance Nifedipine that prolongs control heart spasm, and avoid the trouble of frequently taking medicine, people such as people such as N.Kohri and A.Benita utilize organic solvent evaporation (solvent evaporaition) to obtain granule and little round shaped grain (microsphere) respectively, though have tangible controlled-release effect, product exists residual organic solvent and is difficult for the shortcoming of large-scale production.A.Hasegawa adopts Eudragit L enteric polymer to coat Nifedipine reaching the effect of controlled release, but product still exists the shortcoming of using organic solvent.
The shortcoming of residual organic solvent is arranged and reduce cost for fear of product, more existing at present water miscible polymer occur, for example polyvinyl alcohol (polyvinylalcohol), polyvinyl pyrrolidone (polyvinylpyrrolidone), methylcellulose (methylcellulose), hydroxy propyl cellulose (hydroleneglycol) etc. or its mixture, wherein preferable water-soluble polymer is polyvinyl pyrrolidone (polyvinylpyrrolidone).Insoluble polymer comprises ethyl cellulose (ethylcellulose), cellulose acetate (celluloseacetate), cellulose propionate (cellu-lose propionate), cellulose acetate propionate (cellulose acetate propionate), acetylbutyrylcellulose (cellulose acetate butyrate), acetic acid phthalic acid cellulose (cellulose acetate phthalate), Triafol T (cellulose triacetate), polymethyl methacrylate (poly methyl methacrylate), polyethyl methacrylate (polyethyl methacrylate), polybutyl methacrylate (polybutyl methacrylate), polyisobutyl methacrylate (polyisobutyl methacrylate), polymethylacrylic acid is ester (polyhexyl metharcrylaet), poly-different ten Arrcostabs of first acrylic acid (polyisodecylmethacrylate), polylauryl methacrylate (polylauryl methacrylate), polymethylacrylic acid phenylester (polyphenyl methacrylate), polymethyl acrylate (polymethylacrylate), polyacrylic acid isopropyl esters (polyisopropyl acrylate), polyacrylic acid isobutyl (polyisobutyl acrylate), polyethylene (polyethylene), polypropylene (polypropylene), polyethylene glycol oxide (polyethyleneoxide), poly-four phthalandione ethylene (poly ethylene tetrephthalate), polyvinyl isobutyl ether (poly vinyl isobutylether), polyvinyl acetate (poly vinyl acetaet), polrvinyl chloride (poly vinylchloride) and polyureas (poly urethane) etc. or its mixture.With acrylic acid and/or methacrylic acid is that the polymer of substrate is commonly referred to as EUDRAGIT, this base polymer generally is divided into several, wherein only allow the penetrating polymer of small amount of moisture have comprise acrylic acid and a small amount of season the co-polymer acrylic resin that constituted of aminomethyl esters of acrylic acid, commodity are called EUDRAGIT RL, RS, RL belongs to free permeability, and RS is a small amount of permeability.The polymer that being subject to pH value in addition influences permeability has commodity such as EUDRAGIT L, S or E.EUDRAGITL is by containing the synthetic anionic polymer of methacrylic acid and methyl methacrylate, its dissolubility belongs to insoluble in acid and pure water, form neutrality at alkali salt and in the weak base environment, have dissolubility, permeability is influenced by pH value, is that this polymer permeability strengthens more than 5.0 at pH.More famous ethylcellulose aqueous suspension commodity Aquacoat by name and Surelease.The present invention adopts Ursula department (Surelease) and excellently beats the controlled release ball grain (Pellet) that two kinds of polymer of base (Eudragit RS30D) are made Nifedipine (Nifedipine).Water tendering property of Ursula suspension greatest feature is to contain the solid ethyl cellulose of 25% (W/W) (EC), and ammonia soap. (ammonium oleate) is as stabilizing agent, 18% dibutyl suberic acid (dibutyl sebacate DBS) is as plasticizer, can the volatilization ease go and coat ammonia in the exsiccant operating process (ammonia), left oleic acid (oleic acid) still can be brought into play the function of plasticizer.The excellent base of beating then contains the solid EUDRAGIT RS of 30% (W/W), there is no any plasticizer except stabilizing agent, must add plasticizer before therefore using.Also can will contain the EUDRAGIT RS polymer of Nifedipine or Ursula department (Surelease), HYDROXY PROPYL METHYLCELLULOSE (HPMC), polyvinyl pyrrolidone (PVP) according to different proportion is in addition made up to be coated on as film clothing material and is made round shaped grain controlled release and stripping dosage form fast on the nuclear core (nonpareil seed).
Because the water solublity of Nifedipine (Nifedipine) is very poor, therefore the present invention is on the substrate controlled release form (matrix type) selecting to coat pattern, employing mixes medicine with polymer suspension, add the various suitable hydrophilic polymer that can be used as adhesive and porogen (channeling agent) effect simultaneously, directly mixing suspension is utilized fluid bed (fluid bed) operation, make it to be coated on sugared stamen surface and make ball grain (pellet) and delay the effect that medicine disengages to reach.Need to look for a kind of and medicine that adhesive than high viscosity (ahesive) is arranged before coating in the operation, to prevent that medicine from producing high speed frictional force in the coating process because of granule rolls and causing the medicine that is coated on the round shaped grain surface to come off once again.Adhesive commonly used has the HYDROXY PROPYL METHYLCELLULOSE (hydropropylmethylcellulose ' HPMC) of polyvinyl pyrrolidone (polyvinylpyrrolidone, PVP K-30) and 15cps to add directly coating after polymer and the medicament mixed.Nifedipine of the present invention (Nifedipine) prepares the method for ball grain (pellet) controlled release form, system weighs an amount of HYDROXY PROPYL METHYLCELLULOSE (HPMC) earlier to be made in its water-soluble solution, add an amount of aqueous polymer suspension and under constantly stirring, add or do not add an amount of plasticizer, will under lucifuge, add one by one to form suspension by No. 150 sieve Nifedipine medicines at last.To prepare the mixed suspension of appropriate pharmaceutical polymer and fluid bed will be warmed to 37 ℃ with the inlet temperature of setting, with the about 7.5ml/min of the spray rate of setting, the above-mentioned aqueous solution that contains Nifedipine is coated on 1 kilogram the nuclear core (nonpareil seed), leaving air temp maintains between 33-38 ℃ during the coating, sprays the back with 50 ℃ of temperature dryings 5 minutes.For the curative effect of judging Nifedipine ball grain controlled release preparation is made dissolution test with the slurry formula method (PaddleMethod) of the 21st edition (USP XXI) regulation of American Pharmacopeia, it is solution in 37～± 0.5 ℃ of 900ml 0.1N hydrochloric acid that add 0.2% tween (Tween 80) dispersant that the Nifedipine ball grain that weighs 140mg is adjusted into 100rpm with rotating speed, changed pH value to 6.8 after 2 hours, whole test is with automatic sampling mode timing sampling and the automatic light absorption value that detects wavelength 350nm.
When forming film clothing (film) with the polymer suspension of aqueous since waterborne polymeric institute water content reduce, and between solids, produce cohesiveness (capillary force), cause polymer/solid particle distortion (deform), coagulation (coalesce) to form even film clothing.People such as Shirley T. are at nineteen ninety Int.J.Pharm. the 60th phase 109-124 page or leaf, and people such as G.P.Millili must add plasticizer when the report of nineteen ninety DrugDev.Ind.Pharm. the 16th volume the 16th phase 2383-2407 page or leaf forms the film clothing with the waterborne polymeric suspension, the glass transition temperature (Glass TransitionTemperature Tg) of moulding compound is reduced, it is mobile fully at temperature of plate polymer particle to be produced, and particle wood body can spread and reach the effect that particle resets and form complete successive film clothing.Make in the ball grain control drug prescription and add plasticizer dosage and kind, the difference along with employed polymer, according to the report of people such as R.Bodmeier, be used for Eudragit RS with 10～30% triethyl group citrates (Triethyl Citrate ' TEC) and can produce best bating effect in nineteen ninety Int.J.Pharm. the 59th phase 197-204 page or leaf.According to people such as F.C.Masilungan in Int.J.Pharm. the 20th phase 295-305 page or leaf in 1984, and people such as B.H.Lippld in 1989 in the report of Int.J.Pharm. the 54th phase 12-25 page or leaf, order for 16% dibutyl sebacate (DBS) that adds total solid in the Ursula department (Surelease) be the plasticizer of ethyl cellulose (EC) the best.The Eudragit RS and the Ursula department polymer suspension of same concentration shown in figure (1), the resulting ball grain of Eudragit RS obtains film clothing more complete, continuous bosom, even it is also identical to add hydrophilic HYDROXY PROPYL METHYLCELLULOSE (HPMC) result.
Increase the concentration of Eudragit RS and Ursula department coated polymer at fixing Nifedipine consumption, cause increasing medicine and justify the curvature (tortuosity) that discharges in the spherolite dosage form by oneself, therefore delay disengaging of medicine, medicine is justified the speed that spherolite disengages by oneself shown in figure (2,3), reduce along with the recruitment of adding polymer concentration, the ball grain that wherein adds Eudragit RS again is more remarkable.Though form the ball grain controlled release form of multiple dosing (multiple dose) with the insoluble polymer carrier, usually can utilize adding hydrophilic or water-soluble substances to revise its rate of release, as HYDROXY PROPYL METHYLCELLULOSE (HPMC), insoluble polymer adds the penetration that HYDROXY PROPYL METHYLCELLULOSE can increase moisture content, influence the quality of film clothing, can also reduce the interparticle cohesiveness of insoluble drug (cohesive), shown in figure (4), utilize 5% HYDROXY PROPYL METHYLCELLULOSE to make adhesive directly pharmaceutical pack to be overlying on ball grain (Pellet) and can to help the Nifedipine particle to disperse, promote the dissolution rate of Nifedipine (Nifedipine) when having only.
The important goal of true upslide and controlled release form, be to reach an ideal treatment concentration, and the blood level of the treatment of remaining valid, need a load doses (loadingdose) when therefore design is write out a prescription, an and lasting amount (maintain dose), therefore the present invention prepared contain 5% HYDROXY PROPYL METHYLCELLULOSE fast, the stable dosage form of disengaging, with contain 5% HYDROXY PROPYL METHYLCELLULOSE, the different polymer mixed of 3% proper proportion delay to disengage dosage form, this two classes controlled release ball grain and commercially available Nifedipine controlled release ball granule type compare, and are shown under the proper proportion as figure (5) and can obtain the stripping curve identical with standard substance.Embodiment
Example 1
Weigh 5g hydroxypropyl methyl silvalin (HPMC) and be dissolved in an amount of aqueous solution, add 1g EudragitRS aqueous polymer suspension, add or do not add an amount of plasticizer, and constantly stir, to add the formation suspension one by one through No. 150 sieve Nifedipines at last, organize in contrast not add Eudragit RS polymer in addition.
Example 2
Weigh 5g HYDROXY PROPYL METHYLCELLULOSE (HPMC) and be dissolved in an amount of aqueous solution, add 1g Ursula department (Surelease) aqueous polymer suspension, add or do not add suitable plasticizer, and constantly stir, to add the formation suspension one by one through No. 150 sieve Nifedipines at last, organize in contrast not add Ursula department in addition.
Example 3-7
Weigh 5-0g HYDROXY PROPYL METHYLCELLULOSE (HPMC) according to example 1 and be dissolved in an amount of aqueous solution, add 3-5g Eudragit RS aqueous polymer suspension, added No. 150 sieve Nifedipines and form suspension.
Example 8-12
Weigh the 5-0g HYDROXY PROPYL METHYLCELLULOSE according to example 2 and be dissolved in an amount of aqueous solution, add 3-5g Ursula department aqueous polymer suspension, added No. 150 sieve Nifedipines and form suspension.
Example 13-19
Weigh the 5-0g HYDROXY PROPYL METHYLCELLULOSE according to example 1 and be dissolved in an amount of aqueous solution, add 0-5g Ursula department's polymer or Eudragit RS aqueous polymer suspension, added No. 150 sieve Nifedipines and form suspension.Graphic explanation:
The stripping situation of the various film clothing of Fig. 1
Fig. 2 adds the ethyl cellulose amount influences stripping
Fig. 3 adds the excellent base unit weight of beating influences stripping
Fig. 4 coats the stripping of HYDROXY PROPYL METHYLCELLULOSE
The stripping of Fig. 5 mixing prescription
Claims (8)
1, a kind of round shaped grain controlled release agent that contains Nifedipine, be to constitute, it is characterized in that described coatings is by Nifedipine, 5% hydroxypropyl methylcellulose be selected from 3%Eudragit RS or water slurry that Ursula department and optional plasticizer are formed sprays and forms by nuclear core that does not contain active ingredient and the coatings that contains Nifedipine; The water slurry that wherein said Ursula department is made up of 25% solid ethyl cellulose, 18% dibutyl sebacate and ammonia soap..
2,, it is characterized in that described coatings is to be formed by the water slurry spraying that contains Nifedipine, hydroxypropyl methylcellulose and Eudragit RS according to the described round shaped grain controlled release agent of claim 1.
3, according to the described round shaped grain controlled release agent of claim 1, it is characterized in that described coatings is by containing Nifedipine, the water slurry spraying of hydroxypropyl methylcellulose and Ursula department forms.
4, a kind of method for preparing the described round shaped grain controlled release agent of claim 1 is characterized in that the coating water slurry uses fluidized-bed spraying.
5, in accordance with the method for claim 4, it is characterized in that described coating water slurry is the water slurry that contains Nifedipine, hydroxypropyl methylcellulose and Eudragit RS.
6,, it is characterized in that described coating water slurry is the water slurry that contains Nifedipine, hydroxypropyl methylcellulose and Ursula department according to the described method of claim 4.
7, a kind of quick stripping dosage form that contains Nifedipine is made up of nuclear core that does not contain active ingredient and the coatings that contains Nifedipine, it is characterized in that the water slurry spraying that described coatings is made up of Nifedipine and 5% hydroxypropyl methylcellulose forms.
8, a kind of preparation method of quick stripping dosage form as claimed in claim 7 is characterized in that the coating water slurry uses the spraying of sulfuration bed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93104664A CN1053808C (en) | 1993-04-24 | 1993-04-24 | Nedepine quick releasing and slow releasing agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93104664A CN1053808C (en) | 1993-04-24 | 1993-04-24 | Nedepine quick releasing and slow releasing agent |
Publications (2)
| Publication Number | Publication Date |
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| CN1094282A CN1094282A (en) | 1994-11-02 |
| CN1053808C true CN1053808C (en) | 2000-06-28 |
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| CN93104664A Expired - Fee Related CN1053808C (en) | 1993-04-24 | 1993-04-24 | Nedepine quick releasing and slow releasing agent |
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| NZ619857A (en) | 2010-03-29 | 2015-05-29 | Ferring Bv | A fast dissolving pharmaceutical composition |
| JO3112B1 (en) | 2010-03-29 | 2017-09-20 | Ferring Bv | A fast dissolving pharmaceutical composition |
| CN108853044B (en) * | 2018-07-06 | 2020-11-06 | 郑州明泽医药科技有限公司 | Nifedipine sustained release tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6248618A (en) * | 1985-08-27 | 1987-03-03 | Zeria Shinyaku Kogyo Kk | Slow-releasing drug preparation and production thereof |
| CN1058533A (en) * | 1990-06-28 | 1992-02-12 | 田边制药株式会社 | Controlled-release pharmaceutical formulation |
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1993
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6248618A (en) * | 1985-08-27 | 1987-03-03 | Zeria Shinyaku Kogyo Kk | Slow-releasing drug preparation and production thereof |
| CN1058533A (en) * | 1990-06-28 | 1992-02-12 | 田边制药株式会社 | Controlled-release pharmaceutical formulation |
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