CN1215845C - Sustained releasing minipills of diltiazem hydrochloride and its preparation - Google Patents
Sustained releasing minipills of diltiazem hydrochloride and its preparation Download PDFInfo
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- CN1215845C CN1215845C CN 200310112634 CN200310112634A CN1215845C CN 1215845 C CN1215845 C CN 1215845C CN 200310112634 CN200310112634 CN 200310112634 CN 200310112634 A CN200310112634 A CN 200310112634A CN 1215845 C CN1215845 C CN 1215845C
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- micropill
- medicine
- diltiazem hydrochloride
- controlled release
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- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960005316 diltiazem hydrochloride Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 230000002459 sustained effect Effects 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 53
- 239000007902 hard capsule Substances 0.000 claims abstract description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 32
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 32
- 238000013270 controlled release Methods 0.000 claims description 31
- 229940079593 drug Drugs 0.000 claims description 28
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 22
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 22
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 20
- 239000008188 pellet Substances 0.000 claims description 18
- 229930006000 Sucrose Natural products 0.000 claims description 16
- 239000005720 sucrose Substances 0.000 claims description 16
- 239000006185 dispersion Substances 0.000 claims description 15
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 14
- 239000001856 Ethyl cellulose Substances 0.000 claims description 13
- 239000011248 coating agent Substances 0.000 claims description 13
- 238000000576 coating method Methods 0.000 claims description 13
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 13
- 229920001249 ethyl cellulose Polymers 0.000 claims description 13
- -1 carboxy-propyl Chemical group 0.000 claims description 10
- 239000006187 pill Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
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- 238000005303 weighing Methods 0.000 claims description 9
- 229920001353 Dextrin Polymers 0.000 claims description 8
- 239000004375 Dextrin Substances 0.000 claims description 8
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- 235000019425 dextrin Nutrition 0.000 claims description 8
- 229920000609 methyl cellulose Polymers 0.000 claims description 8
- 239000001923 methylcellulose Substances 0.000 claims description 8
- 235000019698 starch Nutrition 0.000 claims description 8
- 239000008107 starch Substances 0.000 claims description 8
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 7
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 7
- 239000000463 material Substances 0.000 claims description 7
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 7
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- 239000004925 Acrylic resin Substances 0.000 claims description 6
- 229920000178 Acrylic resin Polymers 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 229930195729 fatty acid Natural products 0.000 claims description 6
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 4
- 241000220324 Pyrus Species 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 3
- 235000010603 pastilles Nutrition 0.000 claims description 3
- 239000007787 solid Substances 0.000 claims description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 claims description 2
- 235000014443 Pyrus communis Nutrition 0.000 claims description 2
- 229920002125 Sokalan® Polymers 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 229920005601 base polymer Polymers 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229960004166 diltiazem Drugs 0.000 claims description 2
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 125000005456 glyceride group Chemical group 0.000 claims description 2
- 239000010410 layer Substances 0.000 claims description 2
- 235000021017 pears Nutrition 0.000 claims description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 239000000344 soap Substances 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 230000008961 swelling Effects 0.000 claims description 2
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 13
- 206010020772 Hypertension Diseases 0.000 abstract description 12
- 230000006399 behavior Effects 0.000 abstract description 8
- 230000036772 blood pressure Effects 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 3
- 230000003111 delayed effect Effects 0.000 abstract description 2
- QMBJSIBWORFWQT-DFXBJWIESA-N Chlormadinone acetate Chemical compound C1=C(Cl)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 QMBJSIBWORFWQT-DFXBJWIESA-N 0.000 abstract 3
- 238000004090 dissolution Methods 0.000 description 10
- 230000001186 cumulative effect Effects 0.000 description 9
- 229940026380 diltiazem hydrochloride 90 mg Drugs 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 230000001631 hypertensive effect Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- WVVSZNPYNCNODU-CJBNDPTMSA-N Ergometrine Natural products C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-CJBNDPTMSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- WVVSZNPYNCNODU-XTQGRXLLSA-N Lysergic acid propanolamide Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@H](CO)C)C2)=C3C2=CNC3=C1 WVVSZNPYNCNODU-XTQGRXLLSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229960001405 ergometrine Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000005213 imbibition Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
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- YFNCATAIYKQPOO-UHFFFAOYSA-N thiophanate Chemical compound CCOC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OCC YFNCATAIYKQPOO-UHFFFAOYSA-N 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention discloses a sustained releasing minipill of diltiazem hydrochloride and a preparation method thereof, which belongs to the field of medicinal preparations. The present invention is characterized in that two or more than two diltiazem hydrochloride minipills with different medicine releasing behaviors are mixed according to a certain proportion and are filled in hard capsules or pressed into tablets. After the minipill is used, the medicine release begins after the time is delayed for 4 to 6 hours; after the medicine release reaches a peak, the peak level is maintained for 10 to 16 hours, and the medicine effect is slowly released after the medicine is taken for 24 hours. The minipill can prevent and treat patient's hypertension and angina pectoris caused by the increase of blood pressure and heart rates in several hours after the patients wake up in the morning.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, the delay that is specifically related to diltiazem hydrochloride discharges the dosage form of slow release again, and promptly diltiazem hydrochloride postpones the spacetabs type pellet.
Background technology
Diltiazem hydrochloride [chemical name: suitable-(+)-5-[(2-Dimethoxyphenyl)-3-acetoxyl group-2,3-dihydro-1,5-benzimidazole thiophanate nitrogen Zhuo-4 (5H)-keto hydrochloride], crystallization or crystalline powder for white or off-white color, odorless, bitter in the mouth, easily molten in water, methanol or chloroform, insoluble in ether or benzene.Diltiazem hydrochloride is as a kind of calcium ion antagonist, and it is relevant that its effect suppresses flow of calcium ions during with cardiac muscle and vascular smooth muscle depolarization, can make vascular smooth muscle relaxation, and peripheral vascular resistance descends, and blood pressure reduces; The amplitude of its blood pressure lowering is relevant with hypertensive degree, and the normotensive only makes blood pressure slightly descend.Can effectively expand visceral pericardium and subendocardial coronary artery, alleviate spontaneous angina pectoris or bring out angina pectoris due to the coronary vasospasm by ergometrine, by decreased heart rate and bringing high blood pressure down, reduce myocardium requirementing keto quantity, increase exercise tolerance and also alleviate exertional angina pectoris.Diltiazem hydrochloride be a kind of safe, effectively treat the hypertensive medicine of angina pectoris, side effect is slight, takes for a long time to have no drug resistance.
That sells on market at present has diltiazem hydrochloride slow releasing tablet, a slow releasing capsule, and Shang Weijian has diltiazem hydrochloride to postpone the spacetabs type dosage form.CN1133709 discloses the preparation method of diltiazem hydrochloride controlled release tablet, the diltiazem hydrochloride controlled release tablet is a unit dosage form, has heavy dose of prominent probability of releasing, may cause great danger for patient's body, safety aspect to preparation is influential greatly, and the diltiazem hydrochloride controlled release tablet is not considered the division of day and night rhythmicity of hypertension angina pectoris morbidity, this dosage form just reaches the purpose of traditional slow release,, do not reach the purpose of delayed release in conjunction with the rhythmicity of seizure of disease and the chronopharmacology feature of medicine.
Summary of the invention
The object of the invention provides diltiazem hydrochloride and postpones spacetabs type pellet preparations and preparation technology thereof, mode of administration when aiming to provide a kind of novel selecting, treatment when being used for that angina pectoris is hypertensive to be selected.
The present invention's design has certain pharmacology's foundation, promptly be to show according to the result of study of chronopharmacology in recent years, people's heart rate and blood pressure night is all at a low ebb, therefore the probability of angina pectoris hypertensive episode during this period of time is lower, substantially do not need provide medicine in the blood this moment, and people's heart rate and blood pressure all raise in the back several hrs of waking up in the morning, so angina pectoris hypertension mostly occurs during this period of time, this moment is if can keep certain blood drug level peak value synchronously in the blood, then can effectively prevent and reduce the outbreak of cardiovascular disease, the present invention promptly meets above-mentioned division of day and night rhythmicity, it is a kind of delay sustained-release pellet preparation with novel release pattern, medicine-releasing system when being a kind of selecting, the design considerations of said preparation is the division of day and night rhythmicity of seizure of disease and the chronopharmacology characteristic of medicine, satisfy division of day and night therapeutics requirement clinically, so the present invention is comparatively ideal controlled release agent type, to make patient be subjected to that heart rate and blood pressure whole day are in steadily lower state behind the medicine, angina pectoris hypertensive patient's long-term treatment is had very useful clinical meaning.
Advantage of the present invention is: 1. on formulation characteristic, the prepared diltiazem hydrochloride of the present invention postpones the spacetabs type pellet preparations, it is a kind of multiple unit type preparation, dosage is dispersed in a plurality of miniature compartments, releases or technologic defective can not influence the release behavior of whole preparation to some extent yet even indivedual junior unit preparation is prominent; 2. the more important thing is on the design philosophy of dosage form, it is a kind of novel pellet according to the chronopharmacology characteristic Design of the division of day and night rhythmicity of hypertension angina pectoris morbidity and medicine that the prepared diltiazem hydrochloride of the present invention postpones the spacetabs type pellet, has great importance for the treatment of hypertension patient with angina pectoris.
Technology main feature of the present invention is: it is to be filled in the hard capsule or to be pressed into tablet after diltiazem hydrochloride micropill by two or more different release rules mixes by a certain percentage to form that diltiazem hydrochloride postpones the spacetabs type pellet.The structural similarity of several micropills, be followed successively by celphere, medicine layer, swell layer and controlled release layer from inside to outside, the drug release behavior of medicine is mainly controlled by the material category and the weightening finish level thereof of swell layer, additive and controlled release layer, select the used ratio of several micropills and micropill as required, reach therapeutic purposes.Swell layer is to be main clothing membrane material with hydrophilic inert excipients and low quantity of surfactant, and controlled release layer mainly forms for the material coating with the aqueous dispersion.This diltiazem hydrochloride postpones the main release mechanism of spacetabs type micropill, and to be moisture enter swell layer by the micropore permeation of outer controlled release layer, the swell layer imbibition, after the expansive force of internal layer had surpassed the critical tensile strength of controlled release layer, controlled release layer was broken and is triggered drug release and come out.
Concrete technical scheme of the present invention is as follows:
Diltiazem hydrochloride of the present invention postpones the spacetabs type pellet preparations, contains the micropill of two or more different drug release behaviors, is filled in the hard capsule after mixing by a certain percentage or is pressed into tablet.
Can be made into two kinds, three kinds, four or more different micropills according to different release needs, make after mixing by a certain percentage again.Preferably contain two kinds of micropills and mix by a certain percentage, two kinds of micropills are formed and weight is:
First kind of micropill: celphere 35～50%
Medicine layer 20～35%
Swell layer 10～20%
Controlled release layer 10～18%
Second kind of micropill: celphere 30～45%
Medicine layer 20～32%
Swell layer 9～20%
Controlled release layer 20～30%
First kind of micropill and second kind of used ratio of micropill are preferably: 1: 1～3
In above-mentioned celphere preferably sucrose, starch, microcrystalline Cellulose or the dextrin one or more.
Hydrochloric diltiazem of medicine layer and binding agent, binding agent is one or more in hydroxypropyl methylcellulose, methylcellulose, carboxy-propyl cellulose, sodium carboxymethyl cellulose, carbopol, polyvidone preferably.
Swell layer contains pharmaceutic adjuvant and the surfactant with swelling behavior or disintegrating property, one or more in the preferred hydroxypropyl methylcellulose of described pharmaceutic adjuvant, low-substituted hydroxypropyl cellulose or the polyvinylpolypyrrolidone; The preferred soap kind of described surfactant, hydrosulphate, azochlorosulfonate acid compound, fatty glyceride, sucrose fatty acid ester, smooth, poly-three pear esters of fatty acid three pears, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether or polyoxyethylene-polyoxypropylene copolymer.
Controlled release layer contains the water-insoluble high molecular polymer, preferably ethyl cellulose and/or acrylic resin base polymer.
Diltiazem hydrochloride of the present invention postpones the spacetabs type pellet, and the component of preferred following two kinds of micropills and content are packed in 1: 1～2 ratio and made pellet capsule in the hard capsule:
First kind of micropill:
Celphere: sucrose and starch/sucrose and dextrin 37～46%
Medicine layer: diltiazem hydrochloride 23～31%
Hydroxypropyl methylcellulose E3 and/or methylcellulose 1～2%
Swell layer: hydroxypropyl methylcellulose E5 10～16%
Polysorbas20 or sodium lauryl sulphate 2～4%
Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 16～18%
Second kind of micropill:
Celphere: sucrose and starch or sucrose and dextrin 34～43%
Medicine layer: diltiazem hydrochloride 21～29%
Hydroxypropyl methylcellulose E3 and/or methylcellulose 0.5～2%
Swell layer: hydroxypropyl methylcellulose E5 or low-substituted hydroxypropyl cellulose 9～15%
Polysorbas20 or sodium lauryl sulphate 1～2%
Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 20%～28%
Below all be weight percentage.
Diltiazem hydrochloride of the present invention postpones the spacetabs type pellet, and medicine lags behind during through certain release, and prominent the disengaging of medicine reaches the rate of releasing drug peak value and keep some hrs, then disengages medicine and continues the long period.
It below is the preparation method that diltiazem hydrochloride of the present invention postpones the spacetabs type pellet, may further comprise the steps: step 1, diltiazem hydrochloride is dissolved in the distilled water that contains binding agent, the dissolving back is as the pastille solution for standby, other takes by weighing celphere and places the fluid bed preheating, to contain drug solns then and be sprayed onto on the celphere, be medicine layer as ground floor, prepares to contain pill core; Step 2, measure swell layer material and proper amount of surfactant adding distil water, dissolving also makes solution even, as the swell layer coating solution, other takes by weighing the pill core that contains that step 1 prepares, placing the fluid bed preheating, the swell layer coating solution is sprayed onto contains on the pill core then, is swell layer as the second layer; Step 3, take by weighing the controlled release layer material, adding distil water is mixed with the aqueous dispersion with suitable solid content, as the controlled release layer coating solution, get the micropill that step 2 obtains and place the fluid bed preheating, then coating solution is sprayed onto on the micropill, promptly get final micropill, to make up in the hard capsule of packing into by a certain percentage with the micropill that the difference that makes with quadrat method is formed or to add compressed with adhesive in blocks, promptly.
According to the present invention, the diltiazem hydrochloride micropill of preferred two kinds of drug release behaviors in the micropill of multiple different release rule combinations, its external release time lag was respectively 4-6 hour and 8-9 hour, wherein release time lag is that 4-6 hour micropill can discharge in 18-19 hour fully substantially, but shows 7-8 hour rate of releasing drug peaking in external rate of releasing drug-time graph; And the release time lag to be micropill drug release in 24 hours of 8-9 hour can reach more than 80%, can discharge substantially in 30 hours fully, show that in external rate of releasing drug-time graph the dispensing back can keep higher rate of releasing drug in 10-16 hour.Diltiazem hydrochloride postpones the micropill that the spacetabs type pellet contains above-mentioned two kinds of different drug release behaviors, combination back drug release behavior shows as by a certain percentage: the beginning release lagged behind in the time of 4-6 hour, kept behind the peaking this horizontal 10-16 hour, and then steadily disengaged medicine up to back 24 hours of dispensing.
Release pattern provided by the invention, its pharmacology's foundation is the research according to chronopharmacology, blood pressure and heart rate all raise to some extent in the several hrs after the patient wakes up in the morning, be easy to trigger hypertension angina pectoris disease, this moment is if there is medicine to have the outbreak that then can effectively prevent and reduce this type of cardiovascular disease synchronously in the blood.Look the type and the order of severity of the state of an illness when this product is used and formulate dosage regimen, one time maximal dose is no more than 360mg.
The specific embodiment
Embodiment 1:
Diltiazem hydrochloride postpones spacetabs type pellt capsule and preparation method thereof:
First kind of micropill:
Consumption (dosage)
Celphere: sucrose and starch (1: 1) 115mg
Medicine layer: diltiazem hydrochloride 90mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 40.9mg
Sodium lauryl sulphate 10mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 34mg
Second kind of micropill:
Celphere: sucrose and starch (1: 1) 115mg
Medicine layer: diltiazem hydrochloride 90mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 40.9mg
Sodium lauryl sulphate 5mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 78.5mg
Preparation method is as follows: step 1, diltiazem hydrochloride 16g is dissolved among the distilled water 30ml that contains 3% (g/ml) HPMC E3, the dissolving back is as the pastille solution for standby, other takes by weighing celphere 20g and placed the fluid bed preheating ten minutes, to contain drug solns then and be sprayed onto blank pill in the heart, as ground floor is medicine layer, prepares to contain pill core; Step 2, measure 6% (g/ml) HPMC E5 24ml, adding distil water 12ml, sodium lauryl sulphate 180mg, ultrasonic dissolution also makes solution even, as the swell layer coating solution, other takes by weighing that step 1 prepares contains pill core 5g, placing the fluid bed preheating ten minutes, and the swell layer coating solution was sprayed onto contains on the pill core then, is swell layer as the second layer; Step 3 takes by weighing ethylcellulose aqueous dispersion (surelease ), and adding distil water is an amount of, being mixed with solid content is the 8%w/w aqueous dispersion, as the controlled release layer coating solution, places the fluid bed preheating ten minutes, then coating solution is sprayed onto on the micropill kind of the micropill of promptly winning.
With second kind of micropill of method preparation, with first kind of micropill and second kind of micropill by the dose ratio be in 1: 1 hard capsule case of packing into promptly.Result of the test:
First kind of micropill dissolution:
Time: 6 hours 10 hours 14 hours 16 hours
Cumulative release percent: 2.2% 54.4% 84.0% 97.6%
Second kind of micropill dissolution:
Time: 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 2.8% 57.5% 78.6% 91.4%
Mix back micropill dissolution:
Time: 5 hours 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 2.4% 18.3% 65.0% 82.8% 91.1%
Embodiment 2:
First kind of micropill:
Celphere: sucrose and dextrin (1: 1) 167mg
Medicine layer: diltiazem hydrochloride 90mg
Methylcellulose 2.5mg
Hydroxypropyl methylcellulose E3 2.5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 51.4mg
Polysorbas20 12.9mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 61.7mg
Second kind of micropill:
Celphere: sucrose and dextrin (1: 1) 167mg
Medicine layer: diltiazem hydrochloride 90mg
Methylcellulose 2.5mg
Hydroxypropyl methylcellulose E3 2.5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 51.4mg
Polysorbas20 6.4mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 98.7mg
Preparation method is 1: 1 with 1, two kind of blended ratio of micropill of embodiment.
Result of the test:
First kind of micropill dissolution:
Time: 6 hours 10 hours 14 hours 16 hours
Cumulative release percent: 3.9% 66.2% 95.3% 100%
Second kind of micropill dissolution:
Time: 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 1.2% 57.5% 77.8% 85.8%
Mix back micropill dissolution:
Time: 5 hours 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 3.5% 28.6% 82.7% 89.9% 97.3%
Embodiment 3
First kind of micropill:
Celphere: microcrystalline Cellulose 115mg
Medicine layer: diltiazem hydrochloride 90mg
Polyvidone 5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 20mg
Low-substituted hydroxypropyl cellulose 20mg
Tween 80 10mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 34mg
Second kind of micropill:
Celphere: microcrystalline Cellulose 115mg
Medicine layer: diltiazem hydrochloride 90mg
Polyvidone 5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 20mg
Low-substituted hydroxypropyl cellulose 20mg
Tween 80 5mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 78.5mg
Preparation method is 3: 4 with 1, two kind of blended ratio of micropill of embodiment.
First kind of micropill dissolution:
Time: 6 hours 10 hours 14 hours 16 hours
Cumulative release percent: 4.8% 61.5% 88.0% 92.3%
Second kind of micropill dissolution:
Time: 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 2.8% 59.0% 78.5% 91.4%
Mix back micropill dissolution:
Time: 5 hours 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 2.1% 26.7% 76.8% 88.8% 96.8%
Claims (3)
1, diltiazem hydrochloride postpones the spacetabs type pellet preparations, it is characterized in that: contain two kinds of micropills, two kinds of micropills are formed and percentage by weight is:
First kind of micropill: celphere 35～50%
Medicine layer 20～35%
Swell layer 10～20%
Controlled release layer 10～18%
Second kind of micropill: celphere 30～45%
Medicine layer 20～32%
Swell layer 9～20%
Controlled release layer 20～30%
First kind of micropill and second kind of used part by weight of micropill are: 1: 1～3;
Wherein celphere is selected from one or more in sucrose, starch, microcrystalline Cellulose or the dextrin:
Hydrochloric diltiazem of medicine layer and binding agent, binding agent is selected from one or more in hydroxypropyl methylcellulose, methylcellulose, carboxy-propyl cellulose, sodium carboxymethyl cellulose, carbopol, the polyvidone;
Swell layer contains pharmaceutic adjuvant and the surfactant with swelling behavior or disintegrating property, and described pharmaceutic adjuvant is selected from one or more in hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose or the polyvinylpolypyrrolidone; Described surfactant is selected from soap kind, hydrosulphate, azochlorosulfonate acid compound, fatty glyceride, sucrose fatty acid ester, smooth, poly-three pear esters of fatty acid three pears, polyoxyethylene fatty acid ester, polyoxyethylene aliphatic alcohol ether or polyoxyethylene-polyoxypropylene copolymer;
Controlled release layer is ethyl cellulose and/or acrylic resin base polymer.
2, the described pellet preparations of claim 1, following two kinds of micropills are packed into by 1: 1～2 part by weight make pellet capsule in the hard capsule:
First kind of micropill:
Celphere: sucrose and starch/sucrose and dextrin 37～46%
Medicine layer: diltiazem hydrochloride 23～31%
Hydroxypropyl methylcellulose E3 and/or methylcellulose 1～2%
Swell layer: hydroxypropyl methylcellulose E5 10～16%
Polysorbas20 or sodium lauryl sulphate 2～4%
Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 16～18%
Second kind of micropill:
Celphere: sucrose and starch or sucrose and dextrin 34～43%
Medicine layer: diltiazem hydrochloride 21～29%
Hydroxypropyl methylcellulose E3 and/or methylcellulose 0.5～2%
Swell layer: hydroxypropyl methylcellulose E5 or low-substituted hydroxypropyl cellulose 9～15%
Polysorbas20 or sodium lauryl sulphate 1～2%
Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 20～28%
Below all be weight percentage.
3, the preparation method of claim 1 or 2 described pellet preparations, may further comprise the steps: step 1, diltiazem hydrochloride is dissolved in the distilled water that contains binding agent, the dissolving back is as the pastille solution for standby, other takes by weighing celphere and places the fluid bed preheating, to contain drug solns then and be sprayed onto on the celphere, be medicine layer as ground floor, prepares to contain pill core; Step 2 is measured swell layer material and surfactant adding distil water, dissolves and makes solution even, as the swell layer coating solution, other takes by weighing the pill core that contains that step 1 prepares, and places the fluid bed preheating, then the swell layer coating solution being sprayed onto and containing on the pill core, is swell layer as the second layer; Step 3, take by weighing the controlled release layer material, adding distil water is mixed with the aqueous dispersion with suitable solid content, as the controlled release layer coating solution, get the micropill that step 2 obtains and place the fluid bed preheating, then coating solution is sprayed onto on the micropill, promptly get final micropill, to make up in the hard capsule of packing into by a certain percentage with the micropill that the difference that makes with quadrat method is formed or to add compressed with adhesive in blocks, promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310112634 CN1215845C (en) | 2003-12-15 | 2003-12-15 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 200310112634 CN1215845C (en) | 2003-12-15 | 2003-12-15 | Sustained releasing minipills of diltiazem hydrochloride and its preparation |
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| CN1215845C true CN1215845C (en) | 2005-08-24 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100420437C (en) * | 2006-09-30 | 2008-09-24 | 中国药科大学 | Tetramethylpyrazine phosphate slow-release micro-pill and its preparing method |
| CN101766581B (en) * | 2008-12-30 | 2012-08-15 | 北京科信必成医药科技发展有限公司 | Diltiazem hydrochloride timing controlled release tablet in group-hole released way and preparation method thereof |
| CN102091053B (en) * | 2009-12-14 | 2017-02-08 | 常州善美药物研究开发中心有限公司 | Particle composite controlled-release tablets |
| CN102485219A (en) * | 2010-12-03 | 2012-06-06 | 沈阳药科大学 | Diltiazem hydrochloride delayed release bilayer osmotic pump controlled released tablet and its preparation method |
| CN102319220B (en) * | 2011-09-30 | 2013-06-05 | 孙卫东 | Preparation method of oral sustained controlled-release particle system |
| CN103091308A (en) * | 2011-11-01 | 2013-05-08 | 新乡医学院 | Diltiazem hydrochloride delayed sustained-release pellet capsule quality standard identification method |
| 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 |
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