CN1296046C - Diltiazem hydrochloride control release capsule and its preparing method - Google Patents
Diltiazem hydrochloride control release capsule and its preparing method Download PDFInfo
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- CN1296046C CN1296046C CNB2003101174746A CN200310117474A CN1296046C CN 1296046 C CN1296046 C CN 1296046C CN B2003101174746 A CNB2003101174746 A CN B2003101174746A CN 200310117474 A CN200310117474 A CN 200310117474A CN 1296046 C CN1296046 C CN 1296046C
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Abstract
The present invention relates to a diltiazem hydrochloride control release capsule and a preparing method thereof, which belongs to a pelletized medicinal preparation using an organic coating layer to constantly release medicine and a preparation method thereof. Each capsule contains a control release pellet prepared from 90 to 180 mg of diltiazem hydrochloride. The pellet is prepared from the following compounds by weight percentage: a pellet containing 50 to 75 % of medicine, a control release membranous layer accounting for 5 to 20 wt% of the pellet containing medicine, and a quick release medicine layer accounting for 5 to 35 wt% of the pellet coated with the control release membranous layer, wherein the water-fast control release membranous layer through which medicine can pass is composed of a high molecular polymer, an intestine dissolving material, a plasticizing agent and a lubricating agent and is positioned outside the pellet containing medicine; the quick release medicine layer outside the control release membranous layer is composed of diltiazem hydrochloride and a water soluble bond. The product can maintain that the concentration of diltiazem hydrochloride in blood plasma is stable in a therapeutic window in 24 hours, and is a control release formulation which is released at a constant speed.
Description
Technical field
The present invention relates to organic coatings continue to discharge medicine, pellets is pharmaceutical product of feature and preparation method thereof, specifically be to contain capsule that the controlled release coat piller of antihypertensive drugs diltiazem hydrochloride makes and preparation method thereof.
Background technology
Diltiazem hydrochloride is a kind of treatment angina pectoris and hypertensive calcium channel blocker.The most drug slow releasing preparation, the back medicine of taking medicine discharges in film control coatings, and rate of release is obeyed the Fick diffusion law, and rate of release is directly proportional, is directly proportional with the porosity of film with medication amount in retaining in preparation.For the fixed film controlled piller of porosity, its drug releasing rate must be a moderating process, very fast constantly slowing down later during beginning.This drug model is unaccommodated to eliminating short depressor (example hydrochloric acid diltiazem ) of half-life in the body, because blood drug level is too high when drug release is too fast, and it is low excessively to discharge when slow blood drug level, thereby cause fluctuation of blood pressure bigger, do not meet the requirement of treatment, also untoward reaction can take place simultaneously.
For keep in the blood plasma diltiazem hydrochloride concentration reposefully in its treatment window, reduce patient's medicining times, we are necessary to develop and only take once every day, the preparation of constant release diltiazem hydrochloride .The capsule that existing diltiazem hydrochloride slow releasing preparation has slow releasing tablet and slow-release pill to make: as U.S. Patent No. oral diltiazem hydrochloride controlled release pellets preparation once 4894240 disclosed a kind of every days, in the said preparation controlled release rete of controlled release piller with interior except ingredient diltiazem hydrochloride , also must add organic acid and could regulate medicine by the speed release of setting, the diltiazem hydrochloride pellets preparation of U.S. Patent No. 4917899 disclosed another kind of sustained release, it is filled in same hard capsule by a kind of slow-release pill and a kind of release pills and forms; CN1185104A also discloses a kind of product and preparation method of diltiazem hydrochloride controlled release preparation, take once in order to reach in its 24 hours, and make drug release approach constant speed or zero level release, its medicine also is a piller of making two kinds of different rate of releasing drug, mix and to be contained in that a single dose system realizes, the shortcoming that such preparation exists is: the piller that make two kinds of different rate of releasing drug respectively, complex process is loaded down with trivial details, and two kinds of pillers are because size, proportion, the ratio difference, can cause and mix uneven phenomenon, and make the drug action that does not reach as scheduled.
Summary of the invention
The purpose of this invention is to provide drug releasing rate and reach the diltiazem hydrochloride Extencap of taking medicine once in a day that approaches constant speed or zero level release.Another object of the present invention provides the preparation method of the Extencap of above-mentioned diltiazem hydrochloride .
In order to reach purpose of the present invention, the technical scheme that is adopted is: the controlled release piller that hydrochloric diltiazem 90～180mg makes in every capsules, said controlled release piller are that the complex by following percentage by weight is prepared from:
A, outside ball kind (1), there is the drug storing layer (2) of hydrochloric diltiazem and water-soluble binder to make the pastille piller (3) of pastille 50～75%, or makes the pastille piller (3) of pastille 50～75% by diltiazem hydrochloride , microcrystalline Cellulose and sugar and/or starch, water-soluble binder;
B, but weight that medicine permeable high molecular polymer, enteric material, plasticizer and lubricant form insoluble by one deck water is 5～20% controlled release rete (4) of pastille piller (3) outside pastille piller (3);
C, be made up of the hydrochloric diltiazem of one deck and water-soluble binder outside controlled release rete (4), weight is for having wrapped 5～35% rapid release medicine layer (5) of controlled release rete (4) piller.
For the shelf-life that makes pharmaceutical preparation prolongs, medicine is not subjected to the influence of light and humidity, can be guaranteed the quality of preparation outside rapid release medicine layer (5) by the protective layer (6) that one deck water-soluble binder is formed.
The composition of controlled release rete is the key factor that influences drug release rate in the technical scheme of the present invention, and we preferably are made up of the material of following percentage by weight by controlled release rete (4) after repeated tests:
Insoluble but the permeable high molecular polymer 60～90% of medicine of water
Enteric material 0.5～15%
Plasticizer 2～30%
Lubricant 0.5～6%
Here the insoluble but permeable high molecular polymer of medicine of said water can for ethyl cellulose (pharmaceutical grade, 4～25mPaS), methyl methacrylate: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is with the copolymer of 2: 1: 0.1～0.2 ratio; Said enteric-coating material can be used methacrylic acid and Polymerization of Methyl thing, and/or cellulose acetate-phthalate (CAP), hydroxypropyl emthylcellulose succinate (HPMCAS), hydroxypropylmethyl cellulose phthalate (HPMCP) etc., with preferable methyl acrylic acid: the polymer of methyl methacrylate (with 1: 1～2 ratios) is good; Said plasticizer can adopt dibutyl sebacate and/or triethyl citrate and/or diethyl phthalate, or their homologue etc., be good with preferred dibutyl sebacate and/or triethyl citrate;
Said water-soluble binder has synthetic polymer such as cellulose derivative: hydroxypropyl emthylcellulose, methylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose, Polyethylene Glycol, polyvinyl acetate, polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate co-polymer etc., or natural product such as saccharide, gelatin, arabic gum etc.; With preferred hydroxypropyl emthylcellulose or polyvinylpyrrolidone is good.
Rapid release medicine layer 5 preferably is made up of following materials in weight portion:
Diltiazem hydrochloride 8～10
Water-soluble binder 1
The preparation method of diltiazem hydrochloride Extencap of the present invention is to take by weighing with the controlled release piller that the prepares 1 kilogram of diltiazem hydrochloride raw material by following weight:
Diltiazem hydrochloride 500～750g
Ball kind 0～380g
Microcrystalline Cellulose 0～310g
Icing Sugar 0～35g
Starch 0～35g
Insoluble but the permeable high molecular polymer 35～95g of medicine of water
Enteric-coating material 0.3～12.5g
Plasticizer 1.0～25g
Water-soluble binder 30～80g
Lubricant 0.8～3.5g
Concrete operations step: a. prepares pastille piller (3): one of method is 80～95% of diltiazem hydrochloride total amount is dissolved in or is suspended in the water or ethanol liquid that contains water-soluble binder, above-mentioned medicinal liquid is sprayed onto ball kind (1) surface, forms drug storing layer (2) and make pastille piller (3); Two of method is that diltiazem hydrochloride powder is sprayed under the condition of the water that contains water-soluble binder or ethanol liquid at the same time, spreads to ball kind (1) and coated on above-mentioned ball kind (1) surface, forms drug storing layer (2) and makes pastille piller (3); Three of method is that diltiazem hydrochloride powder, microcrystalline Cellulose and sugar and/or starch are mixed, and adds the water or the ethanol liquid system soft material of water-soluble binder, and required pastille piller (3) is extruded-be rounded to soft material.
B. wrap controlled release rete (4): method is by behind the dosage preparation release-controlled film liquid, carries out coating by the organic solvent coating method or the use coating method technology of pharmaceuticals industry routine;
C. wrap rapid release medicine layer (5): method is to make solution or suspension in water-soluble soluble adhesive water of the diltiazem hydrochloride of surplus or the ethanol liquid, carries out coated with the organic solvent coating method or the use coating method technology of pharmaceuticals industry routine.
Ready-made controlled release piller is measured medicament contg, by every capsules contain 90 120 or 150 or 180mg diltiazem hydrochloride encapsulated.
Then be made into the aqueous solution that contains 1%～5% water-soluble binder when need be and make coating solution, carry out coating with the coating method technology of pharmaceuticals industry routine at rapid release medicine layer (5) bag protective layer, make the bag protective layer after piller increase weight 0.5%～5%.
In order to guarantee the quality of controlled release piller, to making the controlled release piller, preferred bottom spraying type boiling packaging technique is operated from preparation pastille piller.
The present invention is polymer or the ethyl cellulose based on water-insoluble methacrylic acid and esters and acrylic acid and esters thereof, be equipped with an amount of enteric macromolecular material, make solution or suspension or latex, in suitable coating machine, carry out coating to form film control coated pellets to the pastille piller.The release-controlled film of these coated pellets is under the environment that the gastrointestinal tract pH value constantly raises, because enteric material constantly dissolving constantly increases the permeability of release-controlled film, generation has the factor of impelling drug release to speed, thereby overcome that the medication amount that retains in piller reduces and the influence of the opposite factor of the drug releasing rate that slows down that produces, the result is nearly constant speed ground medicine longer time in gastrointestinal tract to discharge, help controlling blood drug level and physiological effect thereof, simultaneously product can reach drug releasing rate and approaches to take medicine once in one day that constant speed or zero level discharge.The diltiazem hydrochloride Extencap that provides with preparation method of the present invention carries out the test of release in vitro degree and human bioavailability is tested and can be confirmed.
One, release in vitro degree test
Test method: get this product and adopt the oar subtraction unit, rotating speed is 100 rev/mins, with 900ml water is solvent, and 10ml solution is regularly got in operation in accordance with the law respectively, filter, and supplementing water 10ml in process container immediately, it is an amount of that precision is measured subsequent filtrate, and dilute with water is made every 1ml and is contained 8 μ g solution approximately, other precision takes by weighing through 2 hours diltiazem hydrochloride reference substance of 105 ℃ of dryings an amount of, and being dissolved in water and quantitatively being diluted to every 1ml contains 8 μ g solution approximately.Get above-mentioned two kinds of solution, measure trap respectively at the wavelength place of 236nm according to spectrophotography; Calculate the burst size of every capsules at different time.
Test specimen: sample 1 is the sample of embodiment 1, specification: the 180mg/ grain
Sample 2 is the sample of embodiment 2, specification: the 180mg/ grain
Sample 3 is the sample of embodiment 3, specification: the 150mg/ grain
Sample 4 is the sample of embodiment 4, specification: the 120mg/ grain
Sample 5 is the sample of embodiment 5, specification: the 90mg/ grain
Result of the test:
| Time (h) | Release % | |||||
| The USP-26 standard | Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | |
| 1 2 3 4 6 8 10 15 | 5～20 30～50 70～90 ≥80 | 15.9 23.2 32.3 44.8 66.6 79.3 88.0 99.1 | 10.5 18.7 29.4 42.6 64.5 77.7 86.8 95.8 | 13.6 21.2 30.1 45.6 65.5 80.2 89.7 97.5 | 8.6 16.7 27.9 43.6 65.4 79.2 87.5 96.9 | 18.9 25.8 35.2 48.8 70.7 85.6 93.3 98.1 |
The result shows: the release scope was 5～20%, 4 hours to be 30～50%, 10 hours to be to be not less than 80% in 70～90%, 15 hours at 1 hour.
Two, human bioavailability test
1. material
1.1 medicine and reagent
Be subjected to test preparation: diltiazem hydrochloride (DiltiazemHydrochloride) controlled release capsule (specification of making by above-mentioned method of inventing: every 180mg).Diltiazem hydrochloride chemical reference substance (lot number DZ90201, purity 100.04%, Guangzhou Medicine Industry Inst); N-demethyl diltiazem (N-monodesmethyldiltiazem) chemical reference substance (content 99.9%, Sigma company).Verapamil (Verapamil) chemical reference substance (lot number 20000113, content 99.9% is as internal standard substance).
Acetonitrile, methanol (U.S. Fisher Scientific, HPLC level); Sodium acetate (Guangzhou chemical reagent two factories, chemical pure); Glacial acetic acid (Shanghai chemical reagent one factory, analytical pure); Test water is fresh distilled water.
1.2 instrument and equipment
High performance liquid chromatograph system: by Waters M510 pump, Waters 717plus Autosampler, Waters
TM486 detectors, Waters Millennium
TMChromatographic work station is formed.
2. method:
2.1HPLC measure plasma sample diltiazem concentration
2.1.1 chromatographic condition chromatographic column: HYPERSIL BDS C
18Post (Dalian Yi Lite scientific instrument company limited, 5 μ m, 200mm * 4.6mm, lot number 1222267).Mobile phase: 0.01molL
-1Sodium-acetate buffer (PH5.8)-acetonitrile (55: 45); Flow velocity: 1.0mLmin
-1Room temperature: 25～28 ℃; Autosampler temperature: 18 ℃; Ultraviolet detection wavelength: 236nm; Sensitivity: 0.002AUFS.
2.1.2 sample process is got in plasma sample 1mL and the 10mL centrifuge tube-1 with sample injector, adds 20ng μ L
-1Interior mark standard solution 10 μ L, fully vortex 30s leaves standstill 5min, adds normal hexane-ether (5: 1) 4mL, and fully vortex 60s leaves standstill 5min, 4000rmin
-1Centrifugal 10 minutes, fully draw supernatant and go in the 10mL centrifuge tube-2, add 0.01molL
-1HCL200 μ L goes into centrifuge tube-2, and fully vortex 60s leaves standstill 5min, in 4000rmin
-1Centrifugal 10 minutes, following clear liquid sucked the automatic sampler tubule again behind centrifugal purification, and sample introduction 10 μ L analyze.
2.1.3 standard curve and chromatographic behavior prepare, and Diltiazem concentration is respectively 2,10,25,50,100,150,200,250, the 1ml human normal plasma sample of 300ng/ml is the standard curve sample.This sample is handled the sample introduction analysis according to said method, with the normal concentration is abscissa (X), the ratio of gained Diltiazem and interior target chromatographic peak area is vertical coordinate (Y), draw standard curve, rectilinear regression get regression equation, correlation coefficient: Y=0.0126X-0.0042 (r=0.9996, n=9).The minimum 2ng/ml that quantitatively is limited in blood plasma.Retention time: N-monodesmethyldiltiazem is about 2.85min, Desacetyldiltiazem and is about 2.99min, Diltiazem and is about 4.10min, Verapamil (interior mark) and is about 5.78min.Diltiazem, Verapamil two peaks are all noiseless, and peak shape is separated good.
2.1.4 the Diltiazem standard plasma sample of basic, normal, high 3 concentration of precision and accuracy carries out precision and accuracy is investigated: sample in a few days RSD is 2.5～6.5%, and RSD is 2.9～5.4% in the daytime; Average extraction recovery is 66.9～77.8%, and average relative recovery is 96.5～99.3%.Show that this assay method can satisfy the requirement of Diltiazem bioavailability study.
2.1.5 the Diltiazem quality-control sample of basic, normal, high 3 concentration of stability carries out study on the stability: the quality-control sample of basic, normal, high 3 concentration is deposited 24h under room temperature (25 ℃) condition can keep stable (irrelevance is-0.6～4.0%); Under freeze thawing 3 times (30 ℃) condition, can keep stable (irrelevance-4.7～3.9%); Under freezing (30 ℃) condition, deposit and to keep stable (irrelevance-6.5～-3.0%) in 15 days.
2.2 EXPERIMENTAL DESIGN
2.2.1 the experimenter selects
Single-dose: select 20 routine young adult healthy male volunteers to be experimenter, age 22.1 ± 1.5, height 170.7 ± 3.4cm, body weight 60.7 ± 5.3kg.All experimenters all confirm no gastroenteropathy through health check-up, and the heart, liver, renal function are normal, and test in the previous moon and do not take any medicine.12h and duration of test fasting before taking medicine, ban on opium-smoking and the opium trade wine, prohibit the beverage that contains caffeine, avoid strenuous exercise, the back fasting 4h that takes medicine, the unified low-fat diet that gives.Duration of test is not taken other medicines.
Multiple dosing: select 20 routine young adult healthy male volunteers to be experimenter, age 22.5 ± 0.8, height 169.6 ± 3.8cm, body weight 59.7 ± 3.5kg.All experimenters all confirm no gastroenteropathy through health check-up, and the heart, liver, renal function are normal, and test in the previous moon and do not take any medicine.12h and duration of test fasting before taking medicine, ban on opium-smoking and the opium trade wine, prohibit the beverage that contains caffeine, avoid strenuous exercise, the preceding 5d back fasting 2h that takes medicine, the 6d back fasting 4h that takes medicine, the unified low-fat diet that gives.Duration of test is not taken other medicines.
2.2.2 testing program
Single-dose: 7:30 single in early morning oral drugs 180mg on an empty stomach, use the 250ml warm water delivery service., take medicine back 0.5h, 1h, 2h, 3h preceding in taking medicine, 4h, 5h, 6h, 8h, 12h, 24h, 36h, 48h, 60h time point are got blood, each 5ml successively.Blood sample is placed the heparinization test tube, and centrifugal (4000rpm 10min), isolates blood plasma, and-30 ℃ keep in Dark Place to mensuration.
Multiple dosing: 7:30 single in early morning oral drugs 180mg on an empty stomach, use the 250ml warm water delivery service, continuous 6 days.Before 1d, 4d, 5d, 6d take medicine, and take medicine back 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 14h, 24h of 6d gets blood from veins of upper extremity, each 5ml.Blood sample is placed the heparinization test tube, and centrifugal (4000rpm 10min), isolates blood plasma, and-30 ℃ keep in Dark Place to mensuration.
2.3 pharmacokinetic parameters is calculated
2.3.1. single-dose
Reach the equal treating excess syndrome measured value of peak concentration Cmax, peak time Tmax; t
1/2=0.693/ λ
Zλ
ZSlope for the terminal straight line portion of logarithm blood drug level-time graph; AUC
0-t
nThe employing trapezoidal method is calculated; AUC
0 → ∞=AUC
0-t
n+ Ct
n/ λ
zAbsorbance Fa=(Ct+0.693 * AUC
0-t/t
1/2)/(0.693 * AUC
0 → ∞/ t
1/2) * 100%, t
1/2Value is 3.7h.
2.3.2 multiple dosing
Cmax, Tmax are actual measurement peak concentration, the peak time of last dosage during the stable state administration; Cmin is the meansigma methods of surveying paddy concentration before last dosage is taken medicine at interval with the τ time; AUC
SSThe employing trapezoidal method is calculated; C
AV=AUC
SS/ τ; DF=(Cmax-Cmin)/C
AV* 100%, Cmin is the actual measurement paddy concentration of last dosage during the stable state administration.
3. result:
Single-dose: the Cmax that is subjected to test preparation is 89.0 ± 25.6ng/ml; Tmax is 6.00 ± 2.55h; t
1/2Be 10.80 ± 1.44h; AUC
0 → tBe 1610.5 ± 311.7ng/mlh; AUC
0 → ∞Be 1648.8 ± 312.1ng/mlh.
Multiple dosing: the Cmax that is subjected to test preparation is 164.3 ± 36.8ng/ml; Cmin is 40.3 ± 14.7ng/ml; Tmax is 3.73 ± 2.20h; t
1/2Be 10.73 ± 2.72h; AUC
SSBe 2168.8 ± 544.5ng/mlh; C
AVBe 90.4 ± 22.7ng/ml; DF is 139.5 ± 31.3ng/ml.
4. conclusion:
Above-mentioned test shows, the diltiazem hydrochloride controlled release capsule (specification: after 180mg) continuous oral is subjected to test preparation to reach stable state that meets above-mentioned release standard, diltiazem hydrochloride blood drug level all (in 50～200ng/ml), met the requirement of this product controlled release preparation at internationally recognized treatment window in 24 hours.
Advantage of the present invention:
Diltiazem hydrochloride Extencap provided by the present invention can be kept in the blood plasma diltiazem hydrochloride concentration reposefully in its treatment window in 24 hours, be a kind of controlled release preparation of constant release; Reduced patient's medicining times, only need take once every day; Have only a kind of piller just can reach the requirement of controlled release preparation in product one capsules of the present invention, so preparation technology of the present invention is simple, the good evenness of product has guaranteed the quality of product.
Further set forth technical scheme of the present invention below in conjunction with specific embodiment.
Specific embodiments:
Embodiment 1:
Operating procedure a, system pastille piller 3
1, take by weighing the 500g ball kind 1 of commercially available 30～36 order specifications, throw in bottom spraying type ebullated bed coating machine, start and adjusting intake make the ball kind be suitable fluidized state;
2, spray into the suspension that is made into by 1100g diltiazem hydrochloride , 100g hydroxypropyl emthylcellulose (HPMC 6mPaS), 3000g 50% ethanol in the surface of ball kind 1 with the speed of 5～15ml/min, form drug storing layer 2,40～60 ℃ of this process control inlet temperature, atomizing pressure 1.5 * 10
5Pa;
3, continue to feed hot-air dry, discharging;
4, sieve, get pastille piller 1632g.
B, bag controlled release rete 4
1, gets above-mentioned pastille piller 700g and be dosed in the bottom spraying type ebullated bed coating machine, feed hot-air and make it into suitable fluidized state;
2, spray into and contain methyl methacrylate: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is aqueous dispersion (the containing 30% solid) 17.0g of 2: 1: 0.2 copolymer, methyl methacrylate: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is aqueous dispersion (the containing 30% solid) 141.2g of 2: 1: 0.1 copolymer, triethyl citrate 23.5g, contain methacrylic acid: methyl methacrylate is aqueous dispersion (the containing 30% solid) 39.5g of 1: 1 polymer, micropowder silica gel 1.7g, the suspension of water 350g.55 ℃ of this process control inlet temperature, atomizing pressure 1.3 * 10
5Pa;
3, after drying, discharging have been sprayed;
4, sieve, get piller 777g.
C, bag rapid release medicine layer 5
1, the above-mentioned piller 777g that has wrapped release-controlled film is dropped in the end spray ebullated bed coating machine, feed hot blast and make it into suitable fluidized state;
2, spray into the solution that contains 150g diltiazem hydrochloride , 17g HPMC, 400g water, the control inlet temperature is 48～52 ℃, atomizing pressure 1.5 * 10
5Pa;
3, after drying, discharging have been sprayed;
4, sieve, get piller 915g.Survey the content of diltiazem hydrochloride with the method for Chinese Pharmacopoeia (version in 2000), content is 61% as a result
5, encapsulated, the loading amount of every capsules is above-mentioned 0.302g piller, and it is 180mg that product specification is equivalent to hydrochloric diltiazem .
Embodiment 2
A, system pastille piller 3
1. take by weighing the 500g ball kind 1 of commercially available 30～36 order specifications, drop in the lateral spray type ebullated bed, start and adjusting intake make the ball kind be suitable rotation status;
2. the speed with 5～15ml/min sprays into the solution that is made into by 100gHPMC, 2500g water, is sprinkled into the mixed powder of being made up of 1800g diltiazem hydrochloride powder simultaneously and forms drug storing layer 2,40～60 ℃ of this process control inlet temperature, atomizing pressure 1.6 * 10
5Pa;
3. continue to feed hot-air dry, discharging;
4. sieve, get piller 2304g.
B, bag controlled release rete 4
With above-mentioned pastille piller 1230g by carrying out coating with following prescription feed liquid:
Aquacoat (containing 30% solid) 607g, methyl methacrylate: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is aqueous dispersion (containing 30% solid) 60g, triethyl citrate 42g, the micropowder silica gel 1.7g of 2: 1: 0.2 copolymer, the suspension of water 1000g.
The technology of coating is similar to embodiment 1.Get piller 1460g.
C, bag rapid release medicine layer 5
1, the above-mentioned piller 1460g that has wrapped release-controlled film is dropped in the end spray ebullated bed coating machine, feed hot blast and make it into suitable fluidized state;
2, spray into the solution that contains 440g diltiazem hydrochloride , 44g HPMC, 1200g water, the control inlet temperature is 48～52 ℃, atomizing pressure 1.5 * 10
5Pa;
3, sprayed after drying, discharging, sieve, piller 1885g, piller is surveyed the content of diltiazem hydrochloride , content is 67% as a result.
4, encapsulated, the loading amount of every capsules is above-mentioned 0.275g piller, and it is 180mg that product specification is equivalent to hydrochloric diltiazem .
Embodiment 3
A, system pastille piller 3
1,, adds the about 2100g of 3%HPMC aqueous solution and be mixed and made into soft material with 1400g diltiazem hydrochloride powder, 900g microcrystalline Cellulose, 100g cane sugar powder, 100g starch mix homogeneously in mixer granulator;
2, soft material extruding-extrude, be rounded to piller in the sphering machine; Extruder mesh size 0.8mm, extruded velocity 30～70rpm, sphering machine rotating speed 600～1100rpm, 3～9 minutes sphering time;
3 pillers are at 45～65 ℃ of temperature dryings;
4, sieve, get pastille piller 2489g.
B, bag controlled release rete 4
Take by weighing above-mentioned pastille piller 1000g by carrying out coating with following prescription feed liquid:
(pharmaceutical grade, 12mPaS) 45.5g, methacrylic acid: methyl methacrylate is 1: 1 polymer 0.2g, a methacrylic acid: methyl methacrylate is 1: 2 polymer 0.1g, dibutyl sebacate 3.15g, the suspension of Pulvis Talci 3.35g, 75% ethanol 800g to ethyl cellulose;
The technology of coating is similar to embodiment 1.Get piller 1040g.
C, bag rapid release medicine layer 5
1, the above-mentioned piller 1040g that has wrapped release-controlled film is dropped in the end spray ebullated bed coating machine, feed hot blast and make it into suitable fluidized state;
2, spray into the solution that contains 80g diltiazem hydrochloride , 10g HPMC, 250g water, the control inlet temperature is 48～52 ℃, atomizing pressure 1.5 * 10
5Pa;
3, sprayed after drying, discharging, sieve, piller 1100g, survey the content of diltiazem hydrochloride , content is 53% as a result.
4, encapsulated, the loading amount of every capsules is above-mentioned 0.290g piller, and it is 150mg that product specification is equivalent to hydrochloric diltiazem .
Embodiment 4
A, system pastille piller 3
Get piller 2300g with embodiment 2..
B, bag controlled release rete 4
1, above-mentioned pastille piller 1500g is added in the lateral spray type ebullated bed coating machine, feed hot-air and make it into suitable fluidized state;
2, spray into and contain ethyl acrylate: methyl methacrylate is aqueous dispersion (containing 30% solid) 33.3g, diethyl phthalate 3g, the micropowder silica gel 1.7g of aqueous dispersion (containing 30% solid) 400g, Aquacoat (containing 30% solid) 170g, methacrylic acid and methyl methacrylate (1: the 1) polymer of 2: 1 copolymer, the suspension of water 1000g.This process control inlet temperature is lower than 40 ℃, atomizing pressure 1.5 * 10
5Pa;
3, after drying, discharging have been sprayed.Get piller 1670g.
C, bag rapid release medicine layer 5
1, takes by weighing the above-mentioned piller 1680g that has wrapped release-controlled film and drop in the end spray ebullated bed coating machine, feed hot blast and make it into suitable fluidized state;
2, spray into the solution that contains 410g diltiazem hydrochloride , 44g HPMC, 1200g water, the control inlet temperature is 48～52 ℃, atomizing pressure 1.5 * 10
5Pa;
3, sprayed after drying, discharging, sieve, piller 2060g, survey the content of diltiazem hydrochloride , content is 69% as a result.
4, encapsulated, the loading amount of every capsules is above-mentioned 0.178g piller, and it is 120mg that product specification is equivalent to hydrochloric diltiazem .
Embodiment 5
A, system pastille piller 3
The technology of system pastille piller is identical with embodiment 1.Get piller 1632g.
B, bag controlled release rete 4
Take by weighing above-mentioned pastille piller 900g by with following prescription coating:
Get methyl methacrylate: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is 2: 1: 0.2 copolymer 20g, methyl methacrylate: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is 2: 1: 0.1 copolymer 30g, methacrylic acid and methyl methacrylate (1: 1) polymer 5g, methacrylic acid and methyl methacrylate (1: 2) polymer 3g, dibutyl sebacate 9g, micropowder silica gel 3.3g, water 250g, the suspension of ethanol 750g;
The technology of coating is similar to embodiment 1.Get piller 960g.
C, bag rapid release medicine layer 5
1, the above-mentioned about 970g of piller that has wrapped release-controlled film is dropped in the end spray ebullated bed coating machine, feed hot blast and make it into suitable fluidized state;
2, spray into the solution that contains 150g diltiazem hydrochloride , 15g hydroxypropyl emthylcellulose HPMC, 400g water, the control inlet temperature is 48～52 ℃, atomizing pressure 1.5 * 10
5Pa;
3, sprayed after drying, discharging, sieve, piller 1090g.
D, bag protective layer 6
1, the above-mentioned piller 1090g that has wrapped release-controlled film is dropped in the end spray ebullated bed coating machine, feed hot blast and make it into suitable fluidized state;
2, spray into the solution that contains 22g hydroxypropyl emthylcellulose HPMC, 438g water, the control inlet temperature is 48～52 ℃, atomizing pressure 1.5 * 10
5Pa;
3, sprayed after drying, discharging, sieve, piller 1100g, survey the content of diltiazem hydrochloride , content is 60% as a result.
4, encapsulated, the loading amount of every capsules is above-mentioned 0.153g piller, and it is 90mg that product specification is equivalent to hydrochloric diltiazem .
Claims (4)
1, a kind of Extencap for the treatment of hypertensive hydrochloric diltiazem is characterized in that: the controlled release piller that hydrochloric diltiazem 90～180mg makes in every capsules, said controlled release piller are that the complex by following percentage by weight is prepared from:
A, outside ball kind (1), there is the drug storing layer (2) of hydrochloric diltiazem and hydroxypropyl emthylcellulose to make the pastille piller (3) of pastille 50～75%; Or make the pastille piller (3) of pastille 50～75% by diltiazem hydrochloride , microcrystalline Cellulose and sugar and/or starch and hydroxypropyl emthylcellulose;
B, but weight that medicine permeable high molecular polymer, enteric material, plasticizer and lubricant form insoluble by one deck water is 5～20% controlled release rete (4) of pastille piller (3) outside pastille piller (3), and controlled release rete (4) is made up of the material of following percentage by weight
Insoluble but the permeable high molecular polymer 60～90% of medicine of water
Enteric material 0.5～15%
Plasticizer 2～30%
Lubricant 0.5～6%
Said water is insoluble but the permeable high molecular polymer of medicine is ethyl cellulose, the methyl methacrylate of 4～25mPaS pharmaceutical grade: ethyl acrylate: the trimethylammonio ethyl ester of methacrylic acid chlorination is with the copolymer or the ethyl acrylate of 2: 1: 0.1～0.2 ratio: methyl methacrylate is 2: 1 a copolymer; Said enteric material is a methacrylic acid: methyl methacrylate is with 1: 1～2 ratio of polymer; Said plasticizer is dibutyl sebacate and/or triethyl citrate;
C, be made up of the hydrochloric diltiazem of one deck and hydroxypropyl emthylcellulose outside controlled release rete (4), weight is for having wrapped 5～35% rapid release medicine layer (5) of controlled release rete (4) piller, and rapid release medicine layer (5) is made up of following materials in weight portion:
Diltiazem hydrochloride 8～10
Hydroxypropyl emthylcellulose 1
2, according to the Extencap of the said hydrochloric diltiazem of claim 1, it is characterized in that: the protective layer of outside rapid release medicine layer (5), forming (6) by one deck hydroxypropyl emthylcellulose.
3, a kind of preparation method of the Extencap as the said hydrochloric diltiazem of claim 1 is characterized in that, the controlled release piller of 1 kilogram of diltiazem hydrochloride of preparation takes by weighing by the raw material of following weight:
Diltiazem hydrochloride 500～750g
Ball kind 0～380g
Microcrystalline Cellulose 0～310g
Icing Sugar 0～35g
Starch 0～35g
Insoluble but the permeable high molecular polymer 35～95g of medicine of water
Enteric-coating material 0.3～12.5g
Plasticizer 1.0～25g
Hydroxypropyl emthylcellulose 30～80g
Lubricant 0.8～3.5g
Operating procedure: a. prepares pastille piller (3): one of method is 80～95% of diltiazem hydrochloride total amount is dissolved in or is suspended in the water or ethanol liquid that contains hydroxypropyl emthylcellulose, above-mentioned medicinal liquid is sprayed onto ball kind (1) surface, forms drug storing layer (2) and make pastille piller (3); Two of method is that diltiazem hydrochloride powder is sprayed under the condition of the water that contains hydroxypropyl emthylcellulose or ethanol liquid at the same time, spreads to ball kind (1) and coated on above-mentioned ball kind (1) surface, forms drug storing layer (2) and makes pastille piller (3); Three of method is that diltiazem hydrochloride powder, microcrystalline Cellulose and sugar and/or starch are mixed, and adds the water or the ethanol liquid system soft material of hydroxypropyl emthylcellulose, and required pastille piller (3) is extruded-be rounded to soft material;
B. wrap controlled release rete (4): method is by behind the dosage preparation release-controlled film liquid, carries out coating by the organic solvent coating method or the use coating method technology of pharmaceuticals industry routine;
C. wrap rapid release medicine layer (5): method is that the diltiazem hydrochloride with surplus is dissolved in the water of hydroxypropyl emthylcellulose or the ethanol liquid and makes solution or suspension, carries out coated with the organic solvent coating method or the use coating method technology of pharmaceuticals industry routine.
4, according to the preparation method of the Extencap of the said hydrochloric diltiazem of claim 3; it is characterized in that: the method for bread protective layer (5) is hydroxypropyl emthylcellulose to be made into 1%～5% aqueous solution make coating solution outside immediate release drug layer (4); organic solvent solution coating method technology with the pharmaceuticals industry routine is carried out coating, weightening finish 0.5～5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101174746A CN1296046C (en) | 2003-12-23 | 2003-12-23 | Diltiazem hydrochloride control release capsule and its preparing method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2003101174746A CN1296046C (en) | 2003-12-23 | 2003-12-23 | Diltiazem hydrochloride control release capsule and its preparing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1554346A CN1554346A (en) | 2004-12-15 |
| CN1296046C true CN1296046C (en) | 2007-01-24 |
Family
ID=34337818
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2003101174746A Expired - Fee Related CN1296046C (en) | 2003-12-23 | 2003-12-23 | Diltiazem hydrochloride control release capsule and its preparing method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1296046C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100398122C (en) * | 2005-01-28 | 2008-07-02 | 北京北大药业有限公司 | Enteric coated Chinese medicine composition for treating cervical and lumbar spondylopathy |
| US20130171199A1 (en) * | 2009-12-22 | 2013-07-04 | Abbott Healthcare Private Limited | Controlled release pharmaceutical composition |
| CN102106842B (en) * | 2009-12-24 | 2014-03-05 | 杭州赛利药物研究所有限公司 | A kind of levofloxacin hydrochloride pellet capsule and preparation method thereof |
| CN113171351A (en) * | 2021-04-02 | 2021-07-27 | 海南锦瑞制药有限公司 | Diltiazem hydrochloride controlled-release pill and preparation method thereof |
| CN114129541B (en) * | 2022-01-05 | 2023-05-30 | 南通联亚药业股份有限公司 | Diltiazem hydrochloride sustained-release capsule and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1033007A (en) * | 1987-11-06 | 1989-05-24 | 田边制药株式会社 | Protracted effective preparation |
| CN1133709A (en) * | 1995-04-18 | 1996-10-23 | 上海延安制药厂 | Process for preparing controlled-release tablet of diltiazem hydrochloride |
-
2003
- 2003-12-23 CN CNB2003101174746A patent/CN1296046C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1033007A (en) * | 1987-11-06 | 1989-05-24 | 田边制药株式会社 | Protracted effective preparation |
| CN1133709A (en) * | 1995-04-18 | 1996-10-23 | 上海延安制药厂 | Process for preparing controlled-release tablet of diltiazem hydrochloride |
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| Publication number | Publication date |
|---|---|
| CN1554346A (en) | 2004-12-15 |
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