CN102512392A - Manidipine hydrochloride solid dispersion, preparation and preparation method of above - Google Patents
Manidipine hydrochloride solid dispersion, preparation and preparation method of above Download PDFInfo
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- CN102512392A CN102512392A CN2011104494280A CN201110449428A CN102512392A CN 102512392 A CN102512392 A CN 102512392A CN 2011104494280 A CN2011104494280 A CN 2011104494280A CN 201110449428 A CN201110449428 A CN 201110449428A CN 102512392 A CN102512392 A CN 102512392A
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Abstract
The invention discloses a manidipine hydrochloride solid dispersion, which comprises manidipine hydrochloride and a dispersing medium PEG6000, wherein a weight ratio of the manidipine hydrochloride to the PEG6000 is 10:90-40:60. The invention further discloses a manidipine hydrochloride solid dispersion preparation, which comprises the manidipine hydrochloride solid dispersion, lactose, microcrystalline cellulose, magnesium stearate, and PVPK30. The invention further discloses preparation methods for the solid dispersion and the solid dispersion preparation. According to the present invention, the manidipine hydrochloride is prepared into the manidipine hydrochloride solid dispersion to accelerate the drug release so as to provide an effective method, such that the dissolution of the manidipine hydrochloride can be improved, the bioavailability of the manidipine hydrochloride can be improved, the stability of the manidipine hydrochloride can be increased, and the drug is easily stored; the manidipine hydrochloride solid dispersion preparation prepared by using the manidipine hydrochloride solid dispersion has characteristics of high dissolution rate, high bioavailability, easy storage, and convenient large-scale application.
Description
Technical field
The present invention relates to a kind of medicine and preparation method thereof, be specifically related to a kind of CV-4093 solid dispersion and preparation and preparation method thereof.
Background technology
Hypertension is one of modal cardiovascular disease in the world today; Current hypertensive Drug therapy is based on uses the different drug kind; Comprise Angiotensin-Converting (ACE) inhibitor, ARB (ARBs), diuretic, beta-blocker and calcium channel blocker (also claiming calcium antagonist); CV-4093 is a third generation dihydropyridine calcium ion antagonist, can suppress stream in the smooth muscle cell voltage-dependent calcium ion, causes systematic vasodilation; Thereby bring high blood pressure down, pharmacology, toxicological experiment show that all CV-4093 has clear and definite drug effect and less toxic and side effects.
Calcium ion antagonist belongs to long-acting antihypertensive drugs, and through the selective exclusion voltage dependent channel, lax vascular smooth muscle brings high blood pressure down.Pass through for many years clinical exploration and innovation after going on the market, it is high to have possessed the blood vessel selectivity, stable in properties, determined curative effect, long half time, clinical advantage such as persistent.The characteristics of calcium antagonist hypotensive effect are: 1. the blood pressure lowering amplitude to the hyperpietic is big, and normal arterial pressure patient is not obvious to the reaction of calcium antagonist.2. drug effect is rapid, blood pressure lowering is steady, side effect is little, and the compliance of taking medicine is good.3. blood pressure lowering does not reduce the blood flow of brain, arteria coronaria and kidney simultaneously, and drug withdrawal suddenly can not cause hypertension rebound.4. also effective to hypertensive patients coronary heart disease, heart failure, peripheral angiopathy.5. short-term and long-term treatment are all effective, and long-term treatment can make left ventricular hypertrophy disappear, and prevent that atherosclerosis from taking place.6. the long-acting calcium antagonist action period of new generation is long, and medicining times is few, and is easy to use.7. because of not increasing heart rate,, do not produce postural hypotension so do not increase myocardial oxygen consumption.8. metabolism there is not influence: blood fat, blood glucose and electrolyte are had no adverse effects.
CV-4093 has following distinguishing feature:
(1) acting duration is longer
(2) the blood vessel selectivity of height
(3) renal artery had higher selectivity
(4) untoward reaction is few, and patient dependence is good.
At present; Research to CV-4093 mainly concentrates on the technical study of synthetic hydrochloric acid Manidipine; Like the Chinese patent publication number is that the Chinese invention patent of CN101575313A discloses a kind of new method and removes the impurity in the Manidipine alkali bullion, improves the purity and the yield of CV-4093 finished product.
Summary of the invention
One of the object of the invention be to provide a kind of have can increase medicine dissolution rate and dissolution, improve the CV-4093 solid dispersion of bioavailability.
The present invention is achieved in that
A kind of CV-4093 solid dispersion is made up of CV-4093 and disperse medium PEG6000, and the weight ratio of CV-4093 and PEG6000 is 10: 90～40: 60.
The invention also discloses the method for preparing of said CV-4093 solid dispersion:
It is liquid that PEG6000 is heated to 60～80 ℃ of one-tenth; Under constantly stirring, add CV-4093; Dispersed with stirring 20 to 50 minutes is poured over straticulation solid on the metal decking, and is positioned over quenching below-10 ℃ 0.5 to 2 hour immediately; Take out and pulverize, promptly make the CV-4093 solid dispersion.
Scheme further is: 30 minutes dispersed with stirring time.
Scheme further is: thin solid is positioned over quenching below-20 ℃ 1 hour immediately.
The mean molecule quantity 5500～7000 of PEG6000.
Another object of the present invention is to provide a kind of CV-4093 solid dispersion preparation, comprises following composition:
Described CV-4093 solid dispersion 30 to 80 weight portions
Lactose 30 to 85 weight portions
Microcrystalline Cellulose 60 to 160 weight portions
Magnesium stearate 0.5 to 2 weight portion
PVPK303 to 8 weight portion.
Described CV-4093 solid dispersion preparation is tablet or capsule.
In the said CV-4093 solid dispersion preparation, the hydrochloric Manidipine of every or every capsules 5 is to 20mg, and the best is 10mg.
The method for preparing of described CV-4093 solid dispersion preparation is:
CV-4093 solid dispersion and pharmaceutic adjuvant lactose, microcrystalline Cellulose are crossed mixed 3 mix homogeneously of 100 mesh sieves sieve; Add the 5%PVPK30 aqueous solution, process granule with 18 mesh sieves, in 50～60 ℃ of dryings; Add the magnesium stearate mix homogeneously, suppress in flakes or incapsulate.
Compared with prior art, the invention has the beneficial effects as follows:
Because CV-4093 is almost insoluble in water, belong to insoluble drug, the present invention processes the CV-4093 solid dispersion with CV-4093, and to accelerate drug release be a kind of effective method, can improve the stripping of CV-4093; Improve the bioavailability of CV-4093; Increase the stability of CV-4093, be beneficial to the storage of medicine.Through the CV-4093 solid dispersion preparation that the CV-4093 solid dispersion is prepared from, have the characteristics that dissolution height, bioavailability are high, be easy to store equally, make things convenient for large-scale application.
The sample of getting embodiment of the invention preparation is according to two X C of Chinese Pharmacopoeia version in 2010, the first method dissolution method; 500ml is a solvent with 0.1mol/l hydrochloric acid solution (containing 0.5% sodium lauryl sulphate); Rotating speed is per minute 75 commentaries on classics/min; Measure through 45 minutes the time, the medicine stripping quantity is not less than 90%, than adopt common wet method/or the sample (average out to 75%) of dry granulation preparation exceed 15%.
The specific embodiment
Do further elaboration in the face of the present invention down.
Embodiment one
A kind of CV-4093 solid dispersion is made up of CV-4093 and disperse medium PEG6000, and the weight ratio of CV-4093 and PEG6000 is 10: 90, and wherein the mean molecule quantity of PEG6000 is 5500～7000.
It is liquid that the method for preparing of CV-4093 solid dispersion: PEG6000 is heated to 60～80 ℃ of one-tenth; Under constantly stirring, add CV-4093; Dispersed with stirring 30 minutes is poured over straticulation solid on the metal decking rapidly, is positioned over quenching below-20 ℃ 1 hour immediately; 100 mesh sieves were pulverized in taking-up, promptly made the CV-4093 solid dispersion.
Embodiment two
A kind of CV-4093 solid dispersion is made up of CV-4093 and disperse medium PEG6000, and the weight ratio of CV-4093 and PEG6000 is 25: 75, and wherein the mean molecule quantity of PEG6000 is 5500～7000.
It is liquid that the method for preparing of CV-4093 solid dispersion: PEG6000 is heated to 60～80 ℃ of one-tenth; Under constantly stirring, add CV-4093; Dispersed with stirring 50 minutes is poured over straticulation solid on the metal decking rapidly, is positioned over-30 ℃ of quenchings 0.5 hour immediately; 80 mesh sieves were pulverized in taking-up, promptly made the CV-4093 solid dispersion.
Embodiment three
A kind of CV-4093 solid dispersion is made up of CV-4093 and disperse medium PEG6000, and the weight ratio of CV-4093 and PEG6000 is 40: 60, and wherein the mean molecule quantity of PEG6000 is 5500～7000.
It is liquid that the method for preparing of CV-4093 solid dispersion: PEG6000 is heated to 60～80 ℃ of one-tenth; Under constantly stirring, add CV-4093; Dispersed with stirring 20 minutes is poured over straticulation solid on the metal decking rapidly, is positioned over-20 ℃ of quenchings 2 hours immediately; 100 mesh sieves were pulverized in taking-up, promptly made the CV-4093 solid dispersion.
Embodiment four
CV-4093 solid dispersion with embodiment one preparation prepares CV-4093 sheet and CV-4093 capsule.Formula proportion is following:
Annotate: be equivalent to the hydrochloric Manidipine 5mg of every/capsules in the present embodiment.
Method for preparing is:
CV-4093 solid dispersion and pharmaceutic adjuvant lactose, microcrystalline Cellulose are crossed 100 mesh sieves sieve and are mixed 3 mix homogeneously; Add 5%PVPK30 aqueous solution 100g, process granule with 18 mesh sieves, in 50～60 ℃ of dryings; Add the magnesium stearate mix homogeneously, suppress in flakes or incapsulate.
Embodiment five
CV-4093 solid dispersion with embodiment two preparations prepares CV-4093 sheet and capsule.
Annotate: be equivalent to the hydrochloric Manidipine 10mg of every/capsules in the present embodiment.
Method for preparing is with embodiment four.
Embodiment six
CV-4093 solid dispersion with embodiment one preparation prepares CV-4093 sheet and capsule.
Annotate: be equivalent to the hydrochloric Manidipine 20mg of every/capsules in the present embodiment.
Method for preparing is with embodiment four.
Tablet and capsule sample difference six tablets of tablets of picked at random or six seed lac wafers with the sample of getting embodiment of the invention preparation and common wet granulation; According to two X C of Chinese Pharmacopoeia version in 2010, the first method dissolution method; 500ml is a solvent with 0.1mol/l hydrochloric acid solution (containing 0.5% sodium lauryl sulphate); Rotating speed is per minute 75 commentaries on classics/min, in the time of 45 minutes, measures the medicine stripping quantity and sees the following form:
| Sample | Test film 1 | Test film 2 | Test film 3 | Test film 4 | Test film 5 | Test film 6 | On average |
| Embodiment 1 tablet | ?91.2％ | ?91.8％ | ?91.6％ | ?90.7％ | ?91.0％ | ?90.3％ | 90.9％ |
| Embodiment 1 capsule | ?91.5％ | ?91.9％ | ?92.1％ | ?91.3％ | ?91.7％ | ?92.3％ | 91.8％ |
| Embodiment 2 tablets | ?91.5％ | ?91.4％ | ?92.1％ | ?92.7％ | ?91.3％ | ?91.2％ | 91.7％ |
| Embodiment 2 capsules | ?92.3％ | ?91.9％ | ?92.7％ | ?93.3％ | ?92.2％ | ?91.8％ | 92.4％ |
| Embodiment 3 tablets | ?91.5％ | ?91.7％ | ?91.4％ | ?92.1％ | ?92.3％ | ?92.4％ | 91.9％ |
| Embodiment 3 capsules | ?92.8％ | ?92.4％ | ?92.5％ | ?91.9％ | ?92.7％ | ?92.6％ | 92.5％ |
| Common wet granulation sheet | ?75.8％ | ?76.7％ | ?75.7％ | ?75.3％ | ?76.4％ | ?76.2％ | 76.0％ |
| Common wet granulation capsule | ?76.1％ | ?75.4％ | ?75.9％ | ?75.1％ | ?75.7％ | ?75.6％ | 75.6％ |
According to last table institute column data; Can find out, the tablet or the capsule sample of embodiment of the invention preparation, its medicine stripping quantity is significantly higher than the tablet and the capsule sample of common wet granulation; Tablet has on average exceeded 19.6% to 20.9%, and capsule has on average exceeded 21.4% to 22.4%.
Claims (8)
1. CV-4093 solid dispersion, it is characterized in that: said solid dispersion is made up of CV-4093 and disperse medium PEG6000, and the weight ratio of CV-4093 and PEG6000 is 10: 90～40: 60.
2. according to the said CV-4093 solid dispersion of claim 1, it is characterized in that: the mean molecule quantity 5500～7000 of said PEG6000.
3. the method for preparing of claim 1 or 2 said CV-4093 solid dispersion; It is characterized in that: it is liquid that PEG6000 is heated to 60～80 ℃ of one-tenth, constantly stirring adding CV-4093 down, dispersed with stirring 20 to 50 minutes; Be poured over straticulation solid on the metal decking; And be positioned over quenching below-20 ℃ 0.5 to 2 hour immediately, and take out and pulverize, promptly make the CV-4093 solid dispersion.
4. according to the said method of claim 3, it is characterized in that: 30 minutes dispersed with stirring time.
5. according to the said method of claim 3, it is characterized in that: thin solid is positioned over quenching below-20 ℃ 1 hour immediately.
6. CV-4093 solid dispersion preparation is characterized in that comprising following composition:
CV-4093 solid dispersion 30 to 80 weight portions of claim 1 or 2 preparations
Lactose 30 to 85 weight portions
Microcrystalline Cellulose 60 to 160 weight portions
Magnesium stearate 0.5 to 2 weight portion
PVPK30 3 to 8 weight portions.
7. according to the said CV-4093 solid dispersion preparation of claim 6, it is characterized in that: described CV-4093 solid dispersion preparation is tablet or capsule.
8. the method for preparing of claim 6 or 7 described CV-4093 solid dispersion preparations is characterized in that:
Said CV-4093 solid dispersion and pharmaceutic adjuvant lactose, microcrystalline Cellulose are crossed mixed 3 mix homogeneously of 100 mesh sieves sieve; Add the 5%PVPK30 aqueous solution, process granule with 18 mesh sieves, in 50～60 ℃ of dryings; Add the magnesium stearate mix homogeneously, suppress in flakes or incapsulate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103784411A (en) * | 2012-11-01 | 2014-05-14 | 齐鲁制药(海南)有限公司 | Erlotinib hydrochloride medicinal composition and preparation method thereof |
| CN104224786A (en) * | 2014-09-28 | 2014-12-24 | 苏州普罗达生物科技有限公司 | Manidipine hydrochloride composition and preparation method thereof |
| CN113662922A (en) * | 2020-10-29 | 2021-11-19 | 北京莱瑞森医药科技有限公司 | Mirabegron sustained-release composition and preparation method and application thereof |
-
2011
- 2011-12-29 CN CN2011104494280A patent/CN102512392B/en active Active
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| 《中国新药杂志》 20110130 于波涛 等 "马尼地平缓释片的制备及释药机制考察" 第177-179、192页 1-8 第20卷, 第2期 * |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103784411A (en) * | 2012-11-01 | 2014-05-14 | 齐鲁制药(海南)有限公司 | Erlotinib hydrochloride medicinal composition and preparation method thereof |
| CN103784411B (en) * | 2012-11-01 | 2016-03-23 | 齐鲁制药(海南)有限公司 | A kind of erlotinid hydrochloride Pharmaceutical composition and preparation method thereof |
| CN104224786A (en) * | 2014-09-28 | 2014-12-24 | 苏州普罗达生物科技有限公司 | Manidipine hydrochloride composition and preparation method thereof |
| CN104224786B (en) * | 2014-09-28 | 2016-09-07 | 顾玉奎 | A kind of CV-4093 composition and preparation method thereof |
| CN113662922A (en) * | 2020-10-29 | 2021-11-19 | 北京莱瑞森医药科技有限公司 | Mirabegron sustained-release composition and preparation method and application thereof |
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| CN102512392B (en) | 2013-11-27 |
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