CN101491509B - Cyclovirobuxine-D sustained-release micro-pill capsules and preparation method thereof - Google Patents
Cyclovirobuxine-D sustained-release micro-pill capsules and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a buxine slow-release micro-pill capsule and a method for preparing the same. A slow-release micro-pill consisting of a hollow pill core, a main drug layer using Cyclovirobuxine D as an active ingredient and slow-release preparation auxiliary material layer is encapsulated into a capsule to prepare the buxine slow-release micropill capsule; the hollow pill core, the Cyclovirobuxine D as a main drug and the slow-release preparation auxiliary materials comprise the following weight percent: 70 to 95 percent of the hollow pill core, 1 to 5 percent of the Cyclovirobuxine D and the 4 to 25 percent of the slow-release preparation auxiliary materials; and the slow-release preparation auxiliary materials comprise acrylic resin as an adhesive, ethyl cellulose as a coating material, dibutyl sebacate as a plasticizer and talcum powder as a lubricant for encapsulation. The method has good repeatability; and the buxine slow-release micro-pill capsule has even products, good slow release effect and high bioavailability.
Description
(1) technical field:
The present invention relates to a kind of oral chemicals slow releasing preparation, be specifically related to cyclovirobuxine-D sustained-release micro-pill capsules that contains cyclovirobuxinum D and preparation method thereof.
(2) background technology:
Main Ingredients and Appearance in the Buxine is a cyclovirobuxinum D (molecular formula: C
26H
46N
2O), cyclovirobuxinum D is the effective monomer that extracts from Ramulus Buxi Sinicae, is used for the treatment of the pain in the chest due to obstruction of QI of caused by energy stagnation and blood stasis clinically, irregularly intermittent and regularly intermittent pulse, and the coronary heart disease and arrhythmia person especially generally receives publicity as a kind of non-glycoside cardiac tonic.Very clear and definite to its cardiovascular pharmacological effect and drug efficacy study thereof.Ramulus Buxi Sinicae is just on the books in Ming Dynasty's Compendium of Material Medica, and Buxine is mainly used in promoting flow of QI and blood, treatment of arthritis and promoting collateral and channels etc.
Buxine confirms to have heart tonifying clinically to patients with arrhythmia, increases coronary flow and increases the animal hypoxia-bearing capability, and arrhythmia, the blood vessel dilating effect, especially to coronary disease ward property, ventricular premature contraction has good curative effect.Clinical observation by Buxine Tablet treatment angina pectoris proves that further this medical instrument has the effect of remarkable alleviation angina pectoris in addition, reduce seizure frequency and persistent period, the electrocardiogram of ischemia is obviously improved, and its curative effect further improves with the prolongation of treatment time.
Along with the deep development to the pharmacological research of cyclovirobuxinum D, it is more and more approved in the good effectiveness of (as: angina pectoris, arrhythmia, cardiac insufficiency, cerebral blood supply insufficiency etc.) aspect the treatment cardiovascular disease.Clinical practice at present is the most extensive promptly to angina pectoris and ARR treatment.This type of disease is common cardiovascular disease, is one of most important disease that influences human health.In recent years along with the quickening of social life rhythm, changes in diet, this type of disease have become the No.1 killer of human health.The cardiovascular drugs that has gone on the market mostly is chemical synthetic drug, and toxic and side effects is big.And by the cyclovirobuxine-D sustained-release capsule of Chinese medicine proved recipe and modern Chinese medicine preparation process development, evident in efficacy, side effect is low.Buxine Tablet has been put into national basic medical insurance medicine catalogue.According to the vital statistics data that Ministry of Public Health is announced, the death of nineteen fifty-seven urbanite cardiovascular and cerebrovascular disease accounts for 12%, 1989 year of total death and rises to 16.6%, and cause of the death cis-position rises to prosposition by the 5th, 6.China unreasonable along with the raising diet structure of living standards of the people, the blue-collar minimizing of crowd, body weight rises, and serum cholesterol raises, factors such as hypertension, evidence of coronary heart diseases raises year by year.The acute coronary sickness rate 1974 was 21.6/10 ten thousand, to 2000 then up to 47.9/10 ten thousand, the average annual growth rate of heart infarction has reached 4.32%.Therefore this medicine has vast market prospect.
Is ordinary preparation at present, exists and take often that problems such as patient compliance difference directly influence the clinical efficacy of medicine at the Buxine preparation of producing.
People such as Ma Fengyu (" Chinese medicine Chinese medicine magazine ", in April, 2008) prepared cyclovirobuxine-D sustained-release microsphere sheet, but its technology only is suitable for prepared in laboratory, and preparation microsphere after needing in acetone and chloroform, to dissolve, in preparation, can produce organic solvent residual, have a strong impact on drug safety, simultaneously because a large amount of uses of chloroform make preparation method can not be applied to the big production of industry; And this process coating in solution can not all be sealed into all medicines, influences the yield of preparation, because each envelop rate is all different, product quality can't be guaranteed simultaneously.
(3) summary of the invention:
Task of the present invention is the shortcoming that overcomes Buxine conventional tablet and the existence of above-mentioned slow releasing preparation, a kind of had good sustained release effect is provided, the bioavailability height, the product homogeneity is good, be fit to the big cyclovirobuxine-D sustained-release micro-pill capsules of producing, and the preparation method of this sustained-release micro-pill capsules is provided.
Cyclovirobuxine-D sustained-release micro-pill capsules of the present invention, be that the principal agent layer of active component and slow-release micro-pill that slow releasing preparation adjuvant layer is formed are made behind the fill capsule by celphere, with the cyclovirobuxinum D, celphere is as parent nucleus, cyclovirobuxinum D principal agent layer is coated on the celphere, the percentage by weight of celphere, cyclovirobuxinum D principal agent and slow releasing preparation adjuvant is, g/g: celphere 70%-95%, cyclovirobuxinum D 1%-5%, slow releasing preparation adjuvant 4%-25%; Described slow releasing preparation adjuvant comprises binding agent acroleic acid resin, coating material ethyl cellulose, plasticizer certain herbaceous plants with big flowers two dibutyl phthalates and fill capsule Pulvis Talci with lubricator, and the weight ratio of each component is an acroleic acid resin in the slow releasing preparation adjuvant: ethyl cellulose: certain herbaceous plants with big flowers two dibutyl phthalates: Pulvis Talci=1-3: 6-10: 1.5-3: 0.3-1.
Described celphere is commercially available, and as parent nucleus usefulness, its diameter is controlled at 0.5～1.8mm, and the cyclovirobuxine-D sustained-release micro-pill diameter is controlled at 0.5～2mm.
Cyclovirobuxinum D adopts the street drug meet one one of Chinese Pharmacopoeia version in 2000.
The preparation method of cyclovirobuxine-D sustained-release micro-pill capsules of the present invention comprises the steps:
1) takes by weighing the binding agent acroleic acid resin by formula ratio, add an amount of dehydrated alcohol to its whole dissolvings, getting celphere puts in the coating pan, with joining solution evenly be sprayed on the celphere with spray gun, the method of reuse hydrojet dusting evenly sprays the recipe quantity cyclovirobuxinum D around above-mentioned and contains on the celphere of binding agent, sieve, hot air drying 8 hours is made the piller that contains cyclovirobuxinum D;
2) take by weighing ethyl cellulose by formula ratio, make the coating material Aquacoat; Taking by weighing plasticizer certain herbaceous plants with big flowers two dibutyl phthalates by formula ratio joins in the above-mentioned Aquacoat of making, stir, under stirring, evenly be sprayed on the above-mentioned piller that contains cyclovirobuxinum D with spray gun, sieve, hot air drying 8 hours, make slow-release micro-pill, the slow-release micro-pill diameter is controlled at 0.5～2mm; Aquacoat concentration is advisable with 5%～10%.
3) slow-release micro-pill is mixed with the Pulvis Talci of formula ratio, fill becomes capsule.
Cyclovirobuxine-D sustained-release micro-pill capsules of the present invention, every capsules contains cyclovirobuxinum D 1～6mg; Usage every day 1 time, each 1-2 grain.
Cyclovirobuxine-D sustained-release micro-pill capsules of the present invention, simple to operate, be fit to the big production of industry, and preparation yield height, the product homogeneity is good, is not affected by the external environment good reproducibility; Relatively this product slow release effect is better, bioavailability is high, uses convenient with existing slow releasing preparation.
Fig. 1 is the cumulative release of cyclovirobuxine-D sustained-release micro-pill capsules of the present invention and 03141370 the cyclovirobuxine-D sustained-release preparation line chart of writing music.
Fig. 2 is cyclovirobuxine-D sustained-release micro-pill capsules cumulative release degree homogeneity figure of the present invention.
(5) specific embodiments:
The present invention can be further understood by embodiment, but content of the present invention can not be limited.
Embodiment 1: the preparation of cyclovirobuxine-D sustained-release micro-pill capsules
1. the composition of cyclovirobuxine-D sustained-release micro-pill capsules and prescription:
Cyclovirobuxinum D 3.0g
Celphere 110.0g
Acroleic acid resin RS100 1.34g
Ethyl cellulose 9.15g (dry weight)
Certain herbaceous plants with big flowers two dibutyl phthalate 2.20g
Pulvis Talci 0.63g
Make 1000
2. preparation method:
1) get 1.34g binding agent acroleic acid resin RS100, add ethanol, get celphere 110.0g and put in the coating pan to its whole dissolvings, with joining binder solution evenly be sprayed on the celphere with spray gun; Get cyclovirobuxinum D 3.0g, with the method for hydrojet dusting cyclovirobuxinum D (powder) is evenly sprayed around above-mentioned and contain on the celphere of binding agent, sieve, hot air drying 8 hours is made the piller that contains cyclovirobuxinum D;
2) get ethyl cellulose 9.15g, add water and be mixed with the 5%-10% Aquacoat, the concentration and the viscosity relationship that the present invention is directed to Aquacoat (ethyl cellulose aqueous solution) are studied, and the result thinks that 8% aqueous dispersion has the viscosity of appropriateness; Getting plasticizer certain herbaceous plants with big flowers two dibutyl phthalate 2.20g joins in the above-mentioned Aquacoat, stir, and under stirring, evenly be sprayed on the piller that contains cyclovirobuxinum D that step 1) makes with spray gun, sieve, hot air drying 8 hours, make slow-release micro-pill, the slow-release micro-pill diameter is controlled at 0.5～2mm;
3) get Pulvis Talci 0.63g, slow-release micro-pill is mixed with Pulvis Talci, 1000 capsules are made in fill.
The cyclovirobuxine-D sustained-release micro-pill capsules of the described composition and method of making the same preparation of this embodiment, wherein smooth, the rounding of cyclovirobuxine-D sustained-release micro-pill; Art for coating is feasible, and the densification of slow-release micro-pill, toughness, intensity and slow release degree all reach requirement, and active ingredient release from microgranule is even, stable.
Embodiment 2: the preparation of cyclovirobuxine-D sustained-release micro-pill capsules
1. the composition of cyclovirobuxine-D sustained-release micro-pill capsules and prescription:
Cyclovirobuxinum D 1.5g
Celphere 130.0g
Acroleic acid resin RS100 1.95g
Ethyl cellulose 10.0g (dry weight)
Certain herbaceous plants with big flowers two dibutyl phthalate 1.50g
Pulvis Talci 0.8g
Make 1000
2. preparation method: with embodiment 1.
Embodiment 3: the preparation of cyclovirobuxine-D sustained-release micro-pill capsules
1. the composition of cyclovirobuxine-D sustained-release micro-pill capsules and prescription:
Cyclovirobuxinum D 5.0g
Celphere 100.0g
Acroleic acid resin RS100 3.8g
Ethyl cellulose 6.5g (dry weight)
Certain herbaceous plants with big flowers two dibutyl phthalate 3.00g
Pulvis Talci 0.95g
Make 1000
2. preparation method: with embodiment 1.
Embodiment 4: the release test of the cyclovirobuxine-D sustained-release micro-pill capsules of the present invention's preparation
Get the sample of the embodiment of the invention 1 preparation, the cyclovirobuxine-D sustained-release preparation for preparing with embodiment in the Chinese patent 03,141,370 1 carries out the cumulative release degree relatively.3 in the cyclovirobuxine-D sustained-release preparation of embodiment 1 preparation in 5 in cyclovirobuxine-D sustained-release preparation getting the embodiment of the invention 1 preparation and the Chinese patent 03141370, with changeing slurry method mensuration cumulative release degree, data and curves is seen Fig. 1.
As seen the present invention has better release than Chinese patent 03141370 prepared cyclovirobuxine-D sustained-release preparation.
Embodiment 5: the determination of recovery rates of the cyclovirobuxine-D sustained-release micro-pill capsules of the present invention's preparation
The cyclovirobuxine-D sustained-release capsule 's content of getting embodiment 1 preparation is an amount of, measures its content according to method in the Chinese Pharmacopoeia.
Get this sample an amount of (measured quantities when being equivalent to drug release determination approximately in the time of 1 hour, 4 hours, 8 hours) respectively, and the cyclovirobuxinum D reference substance that adds about equivalent respectively is an amount of, make the solution of series concentration, measure in accordance with the law, calculate its response rate (%) and relative standard deviation RSD%, see the following form:
According to above-mentioned detection, the average recovery rate of cyclovirobuxinum D reaches 98.50% among the present invention, and relative standard deviation is 3.39%, and the cyclovirobuxine-D sustained-release preparation of more water-soluble method preparation has a clear superiority in.
Embodiment 6: the homogeneity of the release of the cyclovirobuxine-D sustained-release micro-pill capsules of the present invention's preparation is measured
Get embodiment of the invention 1-3 sample (wherein embodiment 1 has got 4 batches), operate in accordance with the law, sampling 10ml during respectively at 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, fluid infusion 10ml according to the drug release determination method.Calculate its release and cumulative release degree, the result is as follows:
Its accumulative total release curve is seen Fig. 2, and it is good to illustrate that sample prepared in accordance with the present invention discharges homogeneity.
Embodiment 7: the medicine stability test of the cyclovirobuxine-D sustained-release micro-pill capsules of the present invention's preparation
(1) medicine stability test:
Get 3 batches of medicines of embodiment 1 preparation,, carry out accelerated test under humidity 75% ± 5% condition, the results are shown in following table 40 ℃ of temperature:
Conclusion: under the accelerated test condition, kept sample 6 months, content and release no significant difference, each detects index all in acceptability limit.
(2) room temperature keeps sample and investigates test
Get 3 batches of medicines of embodiment 1 preparation,, carry out accelerated test under the normal humidity condition, the results are shown in following table 25 ℃ ± 2 ℃ of temperature:
Conclusion: at room temperature, kept sample 6 months, content and release no significant difference, each detects index all in acceptability limit.
Claims (4)
1. cyclovirobuxine-D sustained-release micro-pill capsules, it is characterized in that: described cyclovirobuxine-D sustained-release micro-pill capsules is that the principal agent layer of active component and slow-release micro-pill that slow releasing preparation adjuvant layer is formed are made behind the fill capsule by celphere, with the cyclovirobuxinum D, cyclovirobuxinum D principal agent layer is coated on the celphere, the percentage by weight of celphere, cyclovirobuxinum D principal agent and slow releasing preparation adjuvant is, g/g: celphere 70%-95%, cyclovirobuxinum D 1%-5%, slow releasing preparation adjuvant 4%-25%; Described slow releasing preparation adjuvant comprises binding agent acroleic acid resin, coating material ethyl cellulose, plasticizer certain herbaceous plants with big flowers two dibutyl phthalates and fill capsule Pulvis Talci with lubricator, and the weight ratio of each component is an acroleic acid resin in the slow releasing preparation adjuvant: ethyl cellulose: certain herbaceous plants with big flowers two dibutyl phthalates: Pulvis Talci=1-3: 6-10: 1.5-3: 0.3-1.
2. cyclovirobuxine-D sustained-release micro-pill capsules according to claim 1 is characterized in that described celphere diameter is controlled at 0.5～1.8mm, and the cyclovirobuxine-D sustained-release micro-pill diameter is 0.5～2mm.
3. the preparation method of cyclovirobuxine-D sustained-release micro-pill capsules according to claim 1 and 2, it is characterized in that: 1) take by weighing the binding agent acroleic acid resin by formula ratio, add an amount of dehydrated alcohol to its whole dissolvings, getting celphere puts in the coating pan, with joining solution be sprayed on the celphere with spray gun, the method for powder is sprayed the recipe quantity cyclovirobuxinum D on the reuse hydrojet, after sieving, hot air drying 8 hours is made and is contained the cyclovirobuxinum D piller; 2) take by weighing ethyl cellulose by formula ratio, make the coating material Aquacoat; Take by weighing plasticizer certain herbaceous plants with big flowers two dibutyl phthalates by formula ratio and join in the Aquacoat, stir, be sprayed on the piller with spray gun under stirring, hot air drying is 8 hours after sieving, and makes slow-release micro-pill; Then slow-release micro-pill is mixed with the Pulvis Talci of formula ratio, capsule preparations is made in fill.
4. the preparation method of cyclovirobuxine-D sustained-release micro-pill capsules according to claim 3, it is characterized in that: the concentration of Aquacoat is 5%～10%.
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Effective date of registration: 20180326 Address after: Hangzhou City, Zhejiang province Binjiang District 310052 River Street No. 568 bin Kang Road Patentee after: Hangzhou Conba Pharmaceutical Co., Ltd. Address before: No. 568, Binjiang District Road, Binjiang District, Hangzhou, Zhejiang Co-patentee before: Hangzhou Conba Pharmaceutical Co., Ltd. Patentee before: Hangzhou Ethypharm-Conba Chinese Traditional Medicine R&D Center Co., Ltd. |
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Application publication date: 20090729 Assignee: Guizhou Baite Pharmaceutical Co., Ltd. Assignor: Hangzhou Conba Pharmaceutical Co., Ltd. Contract record no.: 2018330000033 Denomination of invention: Cyclovirobuxine-D sustained-release micro-pill capsules and preparation method thereof Granted publication date: 20110504 License type: Exclusive License Record date: 20180410 |