CN1265785C - Chrono-slow-releasing prepn. hydrochloride verapamil - Google Patents
Chrono-slow-releasing prepn. hydrochloride verapamil Download PDFInfo
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- CN1265785C CN1265785C CNB2004100143001A CN200410014300A CN1265785C CN 1265785 C CN1265785 C CN 1265785C CN B2004100143001 A CNB2004100143001 A CN B2004100143001A CN 200410014300 A CN200410014300 A CN 200410014300A CN 1265785 C CN1265785 C CN 1265785C
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Abstract
本发明涉及药物制剂领域，具体涉及盐酸维拉帕米的择时释药制剂。它由两种或两种以上不同释药规律的盐酸维拉帕米微丸按一定比例混合后制成。本发明依据疾病发作的时辰节律性和药物的时辰药理学特性，能够达到择时释放再缓释的效果，将使病人受药后心率和血压全天处于平稳较低的状态，对于心绞痛高血压病人的长期治疗具有十分有益的临床意义。The invention relates to the field of pharmaceutical preparations, in particular to a time-selected drug release preparation of verapamil hydrochloride. It is prepared by mixing two or more verapamil hydrochloride pellets with different drug release laws in a certain proportion. Based on the chronological rhythm of disease onset and the chronopharmacological characteristics of the drug, the present invention can achieve the effect of time-selected release and then sustained release, and will keep the patient's heart rate and blood pressure in a stable and low state throughout the day after receiving the drug, which is effective for angina pectoris and hypertension. The long-term treatment of patients has very beneficial clinical significance.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, disclose the pharmaceutical composition that contains verapamil hydrochloride, is verapamil hydrochloride slow release release preparation when selecting specifically.
Background technology
Verapamil hydrochloride, English name: verapamil hydrochloride, chemical name: α-[3-[[2-(3, the 4-dimethoxy phenyl) ethyl] methylamino] propyl group]-3,4-dimethoxy-α-cumene acetonitrilehydrochlorate, molecular formula: C27H38N2O4HCl, structural formula is as follows:
This product is the crystallization or the crystalline powder of white or off-white color, odorless, and bitter in the mouth, easily molten in water, methanol or chloroform, insoluble in ether or benzene; Verapamil hydrochloride is a calcium ion antagonist, can be used for treating variant angina pectoris and unstable angina pectoris and hypertension.The biological half-life of verapamil hydrochloride is short, and liver first-pass effect is big, and ordinary preparation needs repeatedly take every day.That sells on market at present has verapamil hydrochloride slow releasing tablet, oral cavity disintegration tablet, capsule and a verapamil hydrochloride injection, and CN02156851 discloses the preparation method of verapamil hydrochloride disintegrating tablet.
The anginal morbidity of hypertension has the division of day and night rhythmicity, the result of study of chronopharmacology shows, human blood-pressure presents tangible physiological rhythm undulatory property, when the hypertensive patient wakes up, catecholamine discharges and increases sharply in the body, heart rate is accelerated, hypertension, angina pectoris hypertension is higher than other period at the sickness rate of this time period, if can synchronously keep certain blood drug level peak value in the blood this moment, then can effectively prevent and reduce the outbreak of cardiovascular disease, common slow releasing preparation does not reach such therapeutic effect.Domesticly do not see have when verapamil hydrochloride is oral to be selected slow release release preparation sell as yet.(the development of verapamil hydrochloride pulse controlled release micro pill such as Zhang Yu, Chinese Journal of Pharmaceuticals, 2003.34 (5) p236-237) reported the part Study of verapamil hydrochloride pulse controlled release micro pill, the micropill of its report is formed by three layers: swell layer, block layer and outer clothing film, article has only reported that the release time lag of pulse controlled release micro pill is influenced by block layer and outer clothing film thickness, and several adjuvants have been carried out the test of different-thickness to the influence of release time lag respectively.Only mention in the article and use a kind of micropill, and do not provide in the article and have the treatment meaning, reach the weight range and the ratio of several adjuvants of pulse controlled-release effect, also do not provide the prescription of preparation verapamil hydrochloride pulse controlled release agent, those of ordinary skill can't be prepared the micropill that reaches the pulse controlled-release effect by the technology that provides in the article.
Summary of the invention
The invention discloses new preparation of verapamil hydrochloride and preparation method thereof, slow release release preparation when being the selecting of verapamil hydrochloride, it is a kind of multiple unit type preparation, dosage is dispersed in a plurality of miniature compartments, each unitary drug release behavior difference, can design different dosing time and dosage according to the disease treatment needs, this dosage form is suitable for once a day administration at the appointed time, with diseases such as treatment hypertension, angina pectoris and brain soldiers.Design considerations of the present invention is the division of day and night rhythmicity of seizure of disease and the chronopharmacology characteristic of medicine, can reach the effect that discharges again slow release when selecting, 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, have very useful clinical meaning for angina pectoris hypertensive patient's long-term treatment.
Major technique characteristics of the present invention are: 1. preparation characteristic: slow release release preparation was to make after verapamil hydrochloride micropill by two or more different release rules mixes by a certain percentage when verapamil hydrochloride was selected.The structural similarity of several micropills is 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.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.2. release pattern: this preparation release behavior discharges slow release again when selecting, and promptly reaches treatment concentration and keeps a period of time at the initial stage of disease incidence, meets the hypertensive pathogeny of angina pectoris, makes the therapeutic effect of preparation reach best.
Concrete technical scheme of the present invention is as follows:
Slow release release preparation when verapamil hydrochloride of the present invention is selected contains the micropill of two kinds or two to four kinds different drug release behaviors, is mixed in proportion the back.
Can be made into two kinds, three kinds, four kinds different micropills according to different release needs, also more kinds of micropills can be arranged as required, 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 34～52%
Medicated layer 19～35%
Swell layer 11～21%
Controlled release layer 11～19%
Second kind of micropill: celphere 29～46%
Medicated layer 21～32%
Swell layer 4～15%
Controlled release layer 19～29%
More than each component be weight percentage, all in the gross weight of this kind micropill.
First kind of micropill and the second kind of used weight ratio of micropill preferred 1: 0.5-10 when two kinds of micropills mix, further preferred 1: 1-2.
In above-mentioned celphere preferably sucrose, starch, microcrystalline Cellulose or the dextrin one or more.
Hydrochloric verapamil of medicated 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 Tweens of described surfactant, 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 preferably.
The pellet preparations of release when verapamil hydrochloride of the present invention is selected, preferred following two kinds of micropills are in 1: the ratio of 1-2 is packed into and is made pellet capsule in the hard capsule:
First kind of micropill:
Celphere: sucrose and starch/sucrose and dextrin 38～48%
Medicated layer: verapamil hydrochloride 22～32%
Hydroxypropyl methylcellulose E3 and/or methylcellulose 1～3%
Swell layer: hydroxypropyl methylcellulose E5 10～17%
Polysorbas20 or sodium lauryl sulphate 2～4%
Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 11～18%
Second kind of micropill:
Celphere: sucrose and starch or sucrose and dextrin 34～43%
Medicated layer: verapamil hydrochloride 21～29%
Hydroxypropyl methylcellulose E3 and/or methylcellulose 0.5～3%
Swell layer: hydroxypropyl methylcellulose E5 or low-substituted hydroxypropyl cellulose 7～12%
Polysorbas20 or sodium lauryl sulphate 1～3%
Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 19～27%
Below all be weight percentage.
Two kinds of preferred weight ratios of micropill are 3 when the preparation pellet capsule: 4.
Above-mentioned micropill also can be pressed into tablet by adding pharmaceutic adjuvant after the required mixed, and described pharmaceutic adjuvant comprises one or more in binding agent, disintegrating agent, diluent, the lubricant etc.
Slow release release preparation when verapamil hydrochloride of the present invention is selected, medicine lag behind during through certain release, and medicine discharges with the speed slow release that is similar to zero level.
Pharmaceutical composition of the present invention, slow releasing preparation when also being applicable to the selecting of verapamil or other officinal salt of verapamil.
It below is the preparation method of verapamil hydrochloride of the present invention slow release release preparation when selecting, may further comprise the steps: step 1, verapamil hydrochloride and binding agent are dissolved in the distilled water, can heat in case of necessity or ultrasonic, dissolving back is as the pastille solution for standby, and other takes by weighing celphere and places fluid bed preheating number minute, will contain drug solns then and be sprayed onto on the celphere, as ground floor is medicine layer, prepares to contain pill core; Step 2, measuring swell layer material and surfactant is dissolved in the distilled 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, place fluid bed preheating number minute, then the swell layer coating solution is sprayed onto and contains on the pill core, as the second layer is swell layer: step 3, take by weighing the controlled release layer material, and 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.To make up promptly by a certain percentage with the micropill that the difference that makes with quadrat method is formed.Can directly pack in the hard capsule, also can add pharmaceutic adjuvant and be pressed into tablet, also can be made into the dosage form that other is fit to.
Slow release release preparation hysteresis rate of releasing drug peaking when the release in 4-5 hour when verapamil hydrochloride of the present invention is selected, and this rate of releasing drug peak value kept 4-5 hour, 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, after taking this product, there is medicine to have the outbreak that then can effectively prevent and reduce this type of cardiovascular disease in the blood synchronously.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.
Following examples are intended to further specify, and the scope of the invention are not limited.
The specific embodiment
Embodiment 1
First kind of micropill:
Consumption
Celphere: sucrose and starch (1: 1) 220mg
Medicated layer: verapamil hydrochloride 120mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 7mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 56mg
Sodium lauryl sulphate 13.3mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 55.6mg
Second kind of micropill:
Celphere: sucrose and starch (1: 1) 220mg
Medicated layer: verapamil hydrochloride 120mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 7mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 56mg
Sodium lauryl sulphate 13.3mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 104.5mg
Above weight is every weight that capsule is contained.
Preparation method: feed intake by 1000 capsular amounts.Step 1 is dissolved in verapamil hydrochloride in the distilled water that contains 3% (g/ml) HPMCE3, and 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 blank pill in the heart, be medicine layer as ground floor, prepares to contain pill core; Step 2, measure 6% (g/ml) HPMC E5, the distilled water that adds half amount, add sodium lauryl sulphate then, ultrasonic dissolution 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 takes by weighing ethylcellulose aqueous dispersion (surelease ), adding distil water, being mixed with solid content is the 10%w/w aqueous dispersion, as the controlled release layer coating solution, other takes by weighing, and the gained micropill places the fluid bed preheating in the step 2, then coating solution is sprayed onto on the micropill.Kind of the micropill of promptly winning.
With second kind of micropill of method preparation, be to pack at 1: 1 in No. 0 hard capsule case promptly by weight with first kind of micropill and second kind of micropill.
Result of the test:
First kind of micropill dissolution:
Time: 6 hours 10 hours 14 hours 16 hours
Cumulative release percent: 1.9% 53.6% 83.6% 96.8%
Second kind of micropill dissolution:
Time: 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 3.0% 56.4% 79.6% 93.2%
Mix back micropill dissolution:
Time: 5 hours 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 2.1% 19.5% 66.3% 83.1% 94.1%
Embodiment 2
First kind of micropill:
Consumption
Celphere: microcrystalline Cellulose 200mg
Medicated layer: verapamil hydrochloride 120mg
Polyvinylpyrrolidone (PVP K-30) 7.0mg
Methylcellulose 2.5mg
Swell layer: hydroxyl methylcellulose sodium (CMS-Na) 75mg
Polysorbas20 11.3mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 71.6mg
Second kind of micropill:
Celphere: sucrose and starch (1: 1) 200mg
Medicine layer: verapamil hydrochloride 120mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 7.0mg
Methylcellulose 2.5mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 65mg
Polysorbas20 16.6mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 140.5mg
Preparation method is with embodiment 1.Two kinds of blended ratios of micropill are 1: 1, and packing promptly.
Result of the test:
First kind of micropill dissolution:
Time: 6 hours 10 hours 14 hours 16 hours
Cumulative release percent: 4.1% 66.8% 98.4% 100%
Second kind of micropill dissolution:
Time: 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 1.8% 58.1% 78.2% 86.5%
Mix back micropill dissolution:
Time: 5 hours 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 3.8% 29.5% 85.4% 91.3% 98.5%
Embodiment 3:
First kind of micropill:
Consumption
Celphere: microcrystalline Cellulose 170mg
Medicine layer: verapamil hydrochloride 120mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 9mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 45mg
Tween 80 11.6mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 70.6mg
Second kind of micropill:
Consumption
Celphere: microcrystalline Cellulose 190mg
Medicine layer: verapamil hydrochloride 120mg
Hydroxypropyl methylcellulose E3 (HPMC E3) 6mg
Swell layer: hydroxypropyl methylcellulose E5 (HPMC E5) 35mg
Tween 80 9.5mg
Controlled release layer: ethylcellulose aqueous dispersion (surelease ) 89.8mg
Preparation method is 3: 4 with 1, two kind of blended ratio of micropill of embodiment, in No. 0 hard capsule of packing into.
First kind of micropill dissolution:
Time: 6 hours 10 hours 14 hours 16 hours
Cumulative release percent: 5.1% 63.2% 89.2% 94.3%
Second kind of micropill dissolution:
Time: 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 3.2% 62.1% 79.1% 92.0%
Mix back micropill dissolution:
Time: 5 hours 8 hours 16 hours 20 hours 24 hours
Cumulative release percent: 2.6% 27.4% 77.2% 89.2% 97.1%
Claims (7)
- The pellet preparations of release when 1, verapamil hydrochloride is selected is characterized in that: by two kinds of different micropills, make after being mixed in proportion, the composition of two kinds of micropills and each components contents are:First kind of micropill: celphere 34～52%Medicated layer 19～35%Swell layer 11～21%Controlled release layer 11～19%Second kind of micropill: celphere 29～46%Medicated layer 21～32%Swell layer 4～15%Controlled release layer 19～29%More than each component percentages all in the gross weight of this kind micropill;Hydrochloric verapamil of medicated 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; Wherein swell layer contains pharmaceutic adjuvant and the surfactant with swelling behavior or disintegrating property, and described pharmaceutic adjuvant is selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose or polyvinylpolypyrrolidone; Described surfactant is selected from Tweens, 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 contains ethyl cellulose and/or acrylic resin base polymer.
- 2, the pellet preparations of claim 1, wherein celphere is selected from one or more of sucrose, starch, microcrystalline Cellulose or dextrin.
- 3, claim 1 or 2 pellet preparations, the weight ratio of wherein contained first kind of micropill and second kind of micropill is 1: 0.5-10.
- 4, the pellet preparations of claim 3, the weight ratio of wherein contained first kind of micropill and second kind of micropill is 1: 1-2.
- 5, claim 1 or 2 pellet preparations, by following two kinds of micropills by 1: the weight ratio of 1-2 is packed into and is made pellet capsule in the hard capsule:First kind of micropill:Celphere: sucrose and starch or sucrose and dextrin 38～48%Medicine layer: verapamil hydrochloride 22～32%Hydroxypropyl methylcellulose E3 and/or methylcellulose 1～3%Swell layer: hydroxypropyl methylcellulose E5 10～17%Polysorbas20 or sodium lauryl sulphate 2～4%Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 11～18%Second kind of micropill:Celphere: sucrose and starch or sucrose and dextrin 34～43%Medicated layer: verapamil hydrochloride 21～29%Hydroxypropyl methylcellulose E3 and/or methylcellulose 0.5～3%Swell layer: hydroxypropyl methylcellulose E5 or low-substituted hydroxypropyl cellulose 7～12%Polysorbas20 or sodium lauryl sulphate 1～3%Controlled release layer: ethylcellulose aqueous dispersion or acrylic resin 19～27%More than each component percentages all in the gross weight of this kind micropill.
- 6, the pellet preparations of claim 5, wherein the weight ratio of two kinds of micropills is 3: 4.
- 7, the preparation method of each pellet preparations in the claim 1 to 6 may further comprise the steps:A) verapamil hydrochloride is dissolved in the distilled water that contains binding agent, the dissolving back is as the pastille solution for standby, and other takes by weighing celphere and places the fluid bed preheating, will contain drug solns then and be sprayed onto on the celphere, as ground floor is medicated layer, prepares to contain pill core;B) measure swell layer material adding distil water, dissolve and make solution even, as the swell layer coating solution, other takes by weighing the pill core that contains that a) prepares, and places the fluid bed preheating, the swell layer coating solution is sprayed onto to contain on the pill core then, and be swell layer as the second layer;C) 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, gets b) micropill that obtains places the fluid bed preheating, then coating solution is sprayed onto on the micropill, promptly gets final micropill;D) micropill that will form with the difference that makes with quadrat method by required mixed promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100143001A CN1265785C (en) | 2004-03-12 | 2004-03-12 | Chrono-slow-releasing prepn. hydrochloride verapamil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100143001A CN1265785C (en) | 2004-03-12 | 2004-03-12 | Chrono-slow-releasing prepn. hydrochloride verapamil |
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| Publication Number | Publication Date |
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| CN1559397A CN1559397A (en) | 2005-01-05 |
| CN1265785C true CN1265785C (en) | 2006-07-26 |
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| CNB2004100143001A Expired - Fee Related CN1265785C (en) | 2004-03-12 | 2004-03-12 | Chrono-slow-releasing prepn. hydrochloride verapamil |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100420437C (en) * | 2006-09-30 | 2008-09-24 | 中国药科大学 | Ligustrazine phosphate sustained-release pellets and preparation method |
| CN102205130A (en) * | 2011-05-18 | 2011-10-05 | 杭州高成生物营养技术有限公司 | Low-friability medicinal micro-pill core and preparation method thereof |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422453B (en) * | 2008-11-10 | 2011-04-13 | 河南新帅克制药股份有限公司 | Verapamil hydrochloride delayed-release capsule and preparation method thereof |
| CN102319220B (en) * | 2011-09-30 | 2013-06-05 | 孙卫东 | Preparation method of oral sustained controlled-release particle system |
| CN102973515B (en) * | 2012-11-28 | 2016-12-21 | 康普药业股份有限公司 | One treats hypertension, anginal slow releasing preparation |
| CN107260718A (en) * | 2017-06-26 | 2017-10-20 | 中国科学院心理研究所 | Verapamil is used to prepare the purposes for suppressing to relapse medicine after drug rehabilitation |
-
2004
- 2004-03-12 CN CNB2004100143001A patent/CN1265785C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100420437C (en) * | 2006-09-30 | 2008-09-24 | 中国药科大学 | Ligustrazine phosphate sustained-release pellets and preparation method |
| CN102205130A (en) * | 2011-05-18 | 2011-10-05 | 杭州高成生物营养技术有限公司 | Low-friability medicinal micro-pill core and preparation method thereof |
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| Publication number | Publication date |
|---|---|
| CN1559397A (en) | 2005-01-05 |
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