CN104224859A - Ginkgo biloba extract sustained-release pellet preparation - Google Patents
Ginkgo biloba extract sustained-release pellet preparation Download PDFInfo
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- CN104224859A CN104224859A CN201410539436.8A CN201410539436A CN104224859A CN 104224859 A CN104224859 A CN 104224859A CN 201410539436 A CN201410539436 A CN 201410539436A CN 104224859 A CN104224859 A CN 104224859A
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Abstract
The invention relates to a Ginkgo biloba extract sustained-release preparation which is ginkgo biloba extract sustained-release pellets and is prepared by using ginkgo biloba extract, a filler, a disintegrating agent, a binder, a dissolving promoting agent and a sustained-release coating material. The sustained-release agent is prepared according to the first standard of the second appendix XD of Chinese pharmacopoeia 2010, a dissolution rate measuring method first standard (blue standard) device is adopted, 900 ml of phosphate buffered solution (which is prepared in the way that 900ml of water is added into 6.8g of monopotassium phosphate to dissolve the monopotassium phosphate, the pH value is adjusted to 4+/-0.5 through phosphoric acid, and water is added dilute the solution to 1000ml) is utilized as a releasing medium, the releasing rate is measured with the rotating speed as 100r/min, and the release amount of gingko total flavones and ginkgo terpene lactones is respectively in the range of 20-35%, 30-55%, 50-75% and more than 85% in 2 hours, 4 hours, 12 hours and 24 hours. The sustained-release preparation has good release performance.
Description
Technical field
The invention belongs to medical art, relate to the preparation that a kind of Folium Ginkgo extract is made, particularly relate to a kind of gingko leaf slow-releasing micropill, more particularly relate to a kind of gingko leaf slow-releasing micropill with Stable Release performance.The invention still further relates to the preparation method of said preparation.
Background technology
Semen Ginkgo is deciduous tree, can up to 40m.Trunk is upright, and bark is greyish white.Branch has long and short two kind, and leaf clusters on brachyplast, alternate on long shoot.Blade is fan-shaped, grows 4 ~ 8cm, wide 5 ~ 10cm, and tip centre 2 is shallow to be split, base portion wedge shape, and vein is parallel, fork-shaped difference; Long 2.5 ~ the 7cm of petiole.4 ~ May of florescence, really 7 ~ October of phase.Gather between 9 ~ October, dry.
Folium Ginkgo is at present still used for the treatment of memory by Chinese Medicine and loses, stomach pain, dysentery, hypertension, psychentonia and respiratory problems as asthma, bronchitis and poor circulation and the anxiety caused thereof.The active component of Semen Ginkgo is terpenes part, comprising bilobalide and bilobalide.These ginkgetins-glucoside composition has powerful antioxidation and Scavenging ability.
The medical value of Folium Ginkgo extract is very extensive with application.Adopt advanced technology, technology and equipment; by further extracting and developing and purification; its pharmacological action is more obvious; except there is significant antagonism paf receptor; drug effect can also be played in antiinflammatory, antiallergic, blood vessel dilating, protection cardiovascular and cerebrovascular vessel, peripheral blood circulation of improving, reduction serum cholesterol and anticancer adjuvant etc., control and the health care of the systemic disease such as cardiovascular and cerebrovascular vessel, nerve can be widely used in.
It is reported, CFDA have approved tens of kinds of Folium Ginkgo extract dosage forms at present, domestic manufacturer production comprise Folium Ginkgo, capsule, granule, soft capsule, dispersible tablet, ball, tincture, drop, oral liquid, gingko leaf extract injection etc., the sales volume of current Kang Enbei gingko leaf preparation is mainly from Folium Ginkgo and capsule.
The medical value of Folium Ginkgo extract (Ginkgo biloba P.E.) is well-known, mainly comprises following various aspects.
Promote circulation: Folium Ginkgo extract can promote the circulation of brain and body limb simultaneously.A primary healthcare function of Folium Ginkgo extract suppresses one to be called the material of platelet activating factor (PAF) exactly, and PAF is a kind of medium discharged from cell, and it can cause platelet aggregation (being deposited in together).The PAF of high-load can cause neural cell injury, and central nervous system's blood flow reduces, inflammation, and bronchoconstriction.Closely similar with free radical, high PAF level also can cause aging.Bilobalide and bilobalide can protect the neurocyte of central nervous system injury-free at ischemia (in-vivo tissue lacks oxygen) in period.This function may can have the effect of auxiliary treatment to the patient suffering from apoplexy.Except suppressing thrombocyte adhesiveness, Semen Ginkgo extrac regulates antiotasis and elastic force.In other words, it can make vascular circulation effectively.This lifting cycle efficieny effect to the trunk (tremulous pulse) in blood circulation and comparatively thin vessels (blood capillary) have same purpose.
Antioxidation: Folium Ginkgo extract at brain, may can play anti-oxidation characteristics in eyeball retina and cardiovascular system.Its antioxidation in brain and central nervous system may contribute to the brain function decline prevented because the age causes.Folium Ginkgo extract anti-oxidation function in the brain makes people interested especially.Brain and central nervous system are subject to free radical especially and attack.Free radical causes cerebral lesion to be widely regarded as causing, with the old and feeble and influence factor of various diseases that is that come, wherein even comprising Alzheimer disease.
Defying age: Folium Ginkgo extract promotes cerebral blood flow and has fabulous tonic effect to nervous system.Hundreds of the scientific researches comprising patient up to ten thousand confirm that effect of Folium Ginkgo extract is to the effect of problems of intellectual deterioration comprising the not enough and gerontal patient of cerebral blood flow.The possible symptom of Semen Ginkgo to many agings has good effect, such as: anxiety and melancholy, memory impairment, be difficult to focus one's attention on, dexterity declines, intelligence declines, dizzy, headache tinnitus (in ear ring), macula retinae portion degenerate (be grown up blind most common reason), internal ear disturbance (it can cause part to be become deaf), the bad sexual impotence caused of end poor circulation, penile blood flow
Dull-witted: such as to can be used for Alzheimer disease and memory lifting.Scientist has looked back all published high-quality to Semen Ginkgo and slight memory impairment and has studied, and reaches a conclusion: comparatively placebo is obviously more effective in lifting memory and perceptive function for Semen Ginkgo.Semen Ginkgo is widely used in treatment in Europe dull-witted.The reason that Semen Ginkgo is considered to can contribute to preventing or treat these brain disorders is that it can increase cerebral blood flow and anti-oxidation function thereof.Although many clinical trials have scientific defect, Semen Ginkgo may increase Alzheimer disease patient elaborative faculty, and the evidence of learning capacity and memory is still held very large expectation.
Premenstrual unhappy and sexual function: once evaluate Folium Ginkgo extract to there being the research of the double blinding of the premenstrual unhappy symptom women benefit of the moon controlled placebo, this test comprise 143 ages 18-45 year women, and follow the tracks of their two menstrual cycle.Receive Folium Ginkgo extract (twice daily, each 80mg) or placebo the 16th day each women of one-period, treatment continues to the 5th day of next cycle, and restarting for the 16th day in this cycle.Result impressive.Compare with placebo, Semen Ginkgo alleviates main sign, particularly mastalgia and the emotional lability of the premenstrual unhappy symptom of the moon significantly.Although at present not about the double-blind trial of this function according to, case report and the open sexual function badness improvement researched and proposed Semen Ginkgo and can make to come because flutterring Luozha gram class medicine and other antidepressant drug.
Eye problems: perhaps the flavonoid in Semen Ginkgo can stop or alleviating some retinopathy.Retina is impaired many possible causes, comprises diabetes and looks maculopathy.Be progressive degenerative eye diseases depending on maculopathy (being commonly referred to as age related macular degeneration or ARMD), and easily betide with it old people.It is that the U.S. causes blind main cause.Research and propose the vision that perhaps Semen Ginkgo contributes to keeping ARMD patient.
Hypertension.Folium Ginkgo extract can alleviate cholesterolemia, three triacetin fat, very low density lipoprotein (VLDL) to the adverse effect of human body simultaneously, and alleviate blood fat, improve microcirculation, anticoagulant, these are remarkable to hypertensive therapeutic effect.
Diabetes.Medically have at present and used Folium Ginkgo extract to replace insulin for the medicine of diabetes patient, illustrate that Folium Ginkgo possesses the function of the adjustment blood glucose of insulin, a lot of glucose tolerance tests all demonstrates Folium Ginkgo extract to regulating blood glucose, improving insulin resistant, thus the sensitivity effect of minimizing insulin antibody, enhancing insulin is obvious.
Well-known, Folium Ginkgo is the dried leaves of Ginkgoaceae plant Ginkgo biloba (Ginkgo biloba L.), there is astringing the lung, relieving asthma, activating blood circulation to dissipate blood stasis, pain relieving effect.Gingko leaf preparation is mainly used in the disease such as coronary blood supply insufficiency, angina pectoris, myocardial infarction, cerebral thrombosis, cerebral vasospasm of arteriosclerosis and caused by hypertension, has become the ideal medicament improving brain and peripheral blood circulation obstacle at present.It has been generally acknowledged that its effective ingredient is flavonoid (>=24%) (WANG M, GUZILINUER T.Clinical efficacy of Yinxingdamo Injection combined with antithrombotic therapy for treating the patients with acute coronary syndrome [J] .Chin J Mod Appl Pharm (Chinese Journal of Modern Applied Pharmacy), 2011, 28 (13): 1379-1381) and lactone compound (>=6%) (Mauri P, Palma A D, Pozzi F, et al.LC-MS characterization of terpene lactones in plasma of experimental animals treated with Ginkgo biloba extracts correlation with pharmacological activity [J] .J Pharm Biomed Anal, 2006, 40:763-768, Wang Xuan, Gu Zhenlun, Qin Zhenhong, etc. ginkalide A and B mixture are to the protective effect [J] of rat permanent focal cerebral ischemia. Chinese herbal medicine, 2007,38 (2): 241-244).The flavonol glycosides constituents being aglycon with Quercetin, kaempferol and isorhamnetin is the most important ingredient of ginkgetin, mainly exists with the form being combined into glucosides with glucose, rhamnose etc.; Lactone composition mainly comprises ginkalide A (ginkgolideA, GLA), ginkalide B (ginkgolideB, GLB), ginkalide C (ginkgolideC, GLC) and bilobalide (bilobalide, BLL).So mainly with this two large constituents as index composition, carry out the Internal pharmacokinetics research of Folium Ginkgo and related preparations, thus medicine absorbing state in vivo after reflection administration.
Due to one of main hydrolytic glycone that Quercetin is ginkgetin, therefore the content mainly with this composition in research represents total flavones, in biological sample, the assay method of Quercetin mainly comprises LC-MS (WANG L, MORRIS M E.Liquid chromatography – tandem mass spectroscopy assay for quercetin and conjugated quercetin metabolites in human plasma and urine [J] .J Chromatogr B, 2005,821 (2): 194-201, HONG Y J, MITCHELL A E.Metabolic profiling of flavonol metabolites in human urine by liquid chromatography and tandem mass spectrometry [J] .J Agric Food Chem, 2004, 52 (22): 6794-6801), HPLC-UV (SALKA E, NIELSEN, LARS O D.Column-switching high-performance liquid chromatographic assay for the determination of quercetin in human urine with ultraviolet absorbance detection [J] .J Chromatogr B Biomed Sci, 1998, 707 (1/2): 81-89), , HPLC-ECD (ERLUND I, ALFTHAN G, SIREN H, et al.Validated method for the quantitation of quercetin from human plasma using high-performance liquid chromatography with electrochemical detection [J] .J Chromatogr B Biomed Sci, 1999, 727 (1/2): 179-189) and HPLC-electrochemical detector (Wang great Li, Di Bin, Li Long, Cheng Mingchuan. the pharmacokinetic studies [J] of ginkgetin in Beagle dog body in Folium Ginkgo. Chinese Journal of Modern Applied Pharmacy, 2012, 29 (06): 483-486) etc. multiple.Pharmacokinetic study results shows, take Quercetin as index composition, (dosage: every animals administer 2 after Beagle dog oral administration Folium Ginkgo, be roughly equal to total flavonoids 19.2mg), the highest blood drug level is reached greatly about 1.5 hours, peak concentration is about 15.9ng/mL, and occurs Double-peak Phenomenon at 8 hours; In another study (Cui Haizhen. the research [D] of Folium Ginkgo nasal in-situ gel. Yanbian University, 2010), researcher devises Folium Ginkgo extract situ-gel, and compared for the relative bioavailability of itself and Folium Ginkgo, result shows, and gel peak concentration higher than tablet, but is eliminated very fast, namely cannot detect after 3 hours, its relative bioavailability is about about 80% as calculated.
In recent years some research displays, bilobalide is a kind of natural platelet activating factor (PAF) receptor antagonist, has significant curative effect to cardio-cerebrovascular, and the antagonism wherein especially produced PAF with ginkalide B is the strongest.So along with the continuous renewal of detection means, in the quality evaluation and pharmacokinetic of Folium Ginkgo or other ginkgo leaf extract preparation, bilobalide more and more causes the attention of people.Zhang Fu such as to be continued at (the Zhang Fugeng, Liu Zhenguo, Liu Changxiao. the comparison [J] of domestic and imported Terpene Lactones in Ginkgo Tablet. drug evaluation is studied, 2011,34 (01): 35-38) adopt HPLC-ECD method to measure and compared for the content of various lactone in domestic and imported Folium Ginkgo, (the Wang Changhong such as Wang Changhong, Li Hong, CHOU osmanthus is new, Cheng Xuemei, Zhang Fang, Wang Zhengtao. the pharmacokinetics of folium ginkgo dripping pill agent and tablet and evaluation of bioequivalence [J]. Chinese Journal of New Drugs and Clinical Remedies, 2005, 12:946-950) prepare Folium Ginkgo extract drop pill, and be experimental animal with rabbit, compared for the pharmacokinetic difference of itself and Folium Ginkgo, with ginkalide A, ginkalide B, the blood drug level of ginkalide C and bilobalide is as index, result shows, rabbit is GLA after oral folium ginkgo dripping pill agent and tablet respectively, GLB, GLC and BLL all meets a compartment model.After oral administration dripping pill agent, GLA, GLB, GLC and BLL are respectively 104%, 109%, 112% and 110% relative to the bioavailability of oral tablet.The pharmacokinetic parameters of two kinds of preparations is without significant difference.Along with the progress of detection means, in Simultaneously test biological specimen, the content of Multiple components becomes possibility.Wu Caisheng etc. (relative bioavailability [J] of .HPLC-MS/MS method mensuration Semen Ginkgo 7 kinds of effective ingredient concentration and Folium Ginkgo tinctures in dog plasma such as Wu Caisheng. Chinese Journal of New Drugs, 2013,22 (01): 93-99) adopt HPLC-MS-MS coupling method to carry out Simultaneously test to 7 kinds of compositions such as the ginkalide A in plasma sample after administration, ginkalide B, ginkalide C, bilobalide, Quercetin, kaempferol and isorhamnetins, and compared for the relative bioavailability of Folium Ginkgo tincture and Folium Ginkgo, drop pill.In different preparation, the absorption difference of 7 effective ingredient is comparatively large, and the relative bioavailability of each composition disunity.
Except animal experiment, also there is report about the pharmacokinetics after the oral Folium Ginkgo extract of healthy volunteer.(the Fourtillan JB such as Fourtillan, Brisson AM, Girault J, Ingrand I, Decourt JP, Drieu K, et al.Pharmacokinetic properties of Bilobalide and Ginkgolides A and B in healthy subjects after intravenous and oral administration of Ginkgo biloba extract (EGb 761) .Therapie.1995; 50 (2): 137-44) healthy volunteer is studied on an empty stomach or after the meal after oral and intravenously administrable Folium Ginkgo extract, the Pharmacokinetic Characteristics of main active GLA, GLB and BLL.Research finds, after giving Folium Ginkgo extract on an empty stomach, the mean absolute bioavailability of GLA, GLB and BLL is respectively 80%, 88% and 79%.Major part medicine is discharged from urine with original shape, and GLA, GLB and BLL are respectively 72.3%, 41.4% and 31.2%, and the oral rear elimination half-life is respectively 4.50,10.57 and 3.21 hours.The pharmacokinetic characteristic impact of food on GLA, GLB and BLL is very little.
Current spendable gingko leaf preparation clinically mainly tablet, capsule and drop pill, these preparations are all conventional formulations, usually need every day to take three times, for preventing cardiovascular and cerebrovascular disease, use for many years clinically, have Duo Jia pharmaceutical factory to produce, the huge market demand, market prospect is good, but it is frequent to take number of times, general people only take once, be for twice very general, thus affect preventive effect after often missing.
Therefore, provide a kind of gingko leaf preparation with long-acting, be still the research of technique focus that this area pharmacy circle is paid close attention to.But because this extract effective ingredient is complicated, content is low, and dosage is large, and the difficulty of dosage form design is large.The complexity of effective ingredient brings challenges to realizing single active ingredient purification, complex process, cost intensive.Such as can every day once oral, to improving the compliance of patient medication and preventive effect, be still the work that those skilled in the art make great efforts to study.
Summary of the invention
Can not be synchronous for the ginkgetin existed in prior art and bilobalide slow release effect, slow release effect is poor, and blood concentration fluctuation is large, the shortcomings such as bioavailability is low.The object of the present invention is to provide a kind of gingko leaf sustained release formulation with elegant formulations character, particularly there is the sustained-release micro-pill capsules agent of gingko leaf slow-releasing pellet preparations such as this micropill hard capsule case sealing of elegant formulations character as described herein.Have been found that ginkgetin of the present invention and bilobalide have the performance of synchronous slow.Particularly, the present invention has been surprisingly found that, the gingko leaf slow-releasing pellet preparations with formula feature of the present invention is a kind of gingko leaf slow-releasing pellet preparations with Stable Release performance, especially can substantially discharge by original scale at its flavones ingredient after Long-term Storage in pellet preparations.The present invention is based on this find and be accomplished.
In the present invention, if not otherwise indicated, obtained gingko leaf sustained release formulation measures its release in different time points in the following manner: with Chinese Pharmacopoeia version in 2010 two annex XD first methods, dissolution method first method (blue laws) device is adopted (to get potassium dihydrogen phosphate 6.8g with phosphate buffered solution, the 900ml that adds water makes dissolving, with phosphoric acid adjust ph to 4 ± 0.5, being diluted with water to 1000ml) 900ml is release medium, at 2 hours, 4 hours, release percentage amounts (the % of the total flavonoids that 12 hours and 24 hours measure and terpene lactone, the percent basis of the amount of total flavonoids and terpene lactone in preparation is accounted for respectively) with burst size.Total flavonoids (and Quercetin, kaempferol, isorhamnetin and proportionate relationship thereof) in preparation and terpene lactone (and bilobalide, ginkalide A, ginkalide B, ginkalide C) content and the burst size of these materials in release liquid are carried out according to the method under [assay] item in Chinese Pharmacopoeia 2010 version one 1079 pages contained " Folium Ginkgo ".
The invention provides and a kind ofly can maintain the effective blood drug concentration of 24 hours and slow-release micro-pill of a kind of novel composition containing ginkgo leaf extract of the Accumulation dissolution of total flavonol glycosides and Terpene lactones all more than 85% and preparation method thereof.
In a first aspect of the present invention, provide a kind of slow releasing preparation of Folium Ginkgo extract, it is ginkgo biloba extract sustained-release pellet, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent, Sustained release coating materials.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, comprising: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion, Sustained release coating materials 25-48 weight portion.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, comprising: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion, Sustained release coating materials 35 weight portion.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described filler is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described disintegrating agent is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described binding agent is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described chaotropic agent is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP).
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, the composition of described Sustained release coating materials comprises: filmogen, stabilizing agent, antiplastering aid, plasticizer, porogen.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, the composition of described Sustained release coating materials comprises: filmogen 10-30 weight portion, stabilizing agent 0.5-4 weight portion, antiplastering aid 1-4 weight portion, plasticizer 5-15 weight portion, porogen 3.5-10 weight portion.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, the composition of described Sustained release coating materials comprises: filmogen 16 weight portion, stabilizing agent l weight portion, antiplastering aid 3 weight portion, plasticizer 8 weight portion, porogen 7 weight portion.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, the composition of described Sustained release coating materials comprises: filmogen, stabilizing agent, antiplastering aid, plasticizer.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, the composition of described Sustained release coating materials comprises: filmogen 10-30 weight portion, stabilizing agent 0.5-2 weight portion, antiplastering aid 1-4 weight portion, plasticizer 6-12 weight portion.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, the composition of described Sustained release coating materials comprises: filmogen is 30 weight portions, stabilizing agent 2 weight portion, antiplastering aid 2.5 weight portion, plasticizer 7.2 weight portion.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described filmogen be in polyacrylic resin, ethyl cellulose and stearic acid any one or its arbitrarily than mixture.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described porogen be in hydroxypropyl emthylcellulose, Polyethylene Glycol and polyvinylpyrrolidone any one or its arbitrarily than mixture.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described plasticizer be in dibutyl sebacate, triethyl citrate, propylene glycol, polyethylene glycols, dimethyl phthalate and triacetin any one or its arbitrarily than mixture.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described stabilizing agent be in oleic acid, hexadecanol and sodium lauryl sulphate any one or its arbitrarily than mixture.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, described antiplastering aid be in Pulvis Talci and micropowder silica gel any one or its arbitrarily than mixture.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, it is prepared by the method comprised the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill.
Ginkgo biloba extract sustained-release pellet according to a first aspect of the present invention, wherein also comprises alkalescence material.In one embodiment, described alkalescence material is selected from arginine, meglumine, Tris, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate etc.Have been surprisingly found that, when add specified quantitative certain/some alkalescence material time, slow releasing preparation is in keeping sample for a long time, its Quercetin is consistent with kaempferol stripping ratio and original state, and when not adding the specific alkalescence material of this feature amount, can there is significant change with kaempferol stripping ratio at Quercetin after Long-term Storage in slow releasing preparation compared with original state.In one embodiment, in every 160 parts of Folium Ginkgo extract in slow releasing preparation of the present invention, described alkalescence amount of substance is 5 ~ 50 parts, such as 6 ~ 30 parts, such as 7 ~ 20 parts.Have been found that the above-mentioned alkalescence material of too high or too low amount all can not realize above-mentioned effect or can cause other unacceptable problem.Although these flavone compounds do not have typical soda acid variation characteristic, but surprisingly they are not when adding the alkalescence material of particular types of the present invention and specified quantitative, along with the prolongation of preparation storage, the Dissolution behaviours of some flavone compound can change; And use during alkalescence material of the present invention and can overcome this problem.In one embodiment, described alkalescence material adds in described slow-release micro-pill together with described Folium Ginkgo extract.
Further, second aspect present invention provides the method preparing ginkgo biloba extract sustained-release pellet described in the arbitrary embodiment of first aspect present invention, and it comprises the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, optional alkalescence material, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill.
Further, third aspect present invention provides a kind of ginkgo biloba extract sustained-release capsule, and it comprises hard capsule case and is sealed in the micropill in this hard capsule case.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, wherein said micropill at least comprises the ginkgo biloba extract sustained-release pellet described in the arbitrary embodiment of first aspect present invention.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, wherein said micropill also optionally comprises Folium Ginkgo extract and often releases micropill, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent.As well known to those skilled in the art, it is with the routine release i.e. micropill of the medicine of delivery mode release immediately that term " often releases micropill ", to be different from slow-release micro-pill.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, wherein said Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, wherein said Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, the filler that wherein said Folium Ginkgo extract often releases micropill is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, the disintegrating agent that wherein said Folium Ginkgo extract often releases micropill is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, the binding agent that wherein said Folium Ginkgo extract often releases micropill is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, the chaotropic agent that wherein said Folium Ginkgo extract often releases micropill is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP).
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention; it is prepared by the method comprised the following steps that wherein said Folium Ginkgo extract often releases micropill: get Folium Ginkgo extract, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously; adding water or concentration is that the ethanol of 30-80% is prepared into soft material; then obtain 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator, to obtain final product.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, wherein said Folium Ginkgo extract is often released in micropill and is also comprised alkalescence material.In one embodiment, described alkalescence material is selected from arginine, meglumine, Tris, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate etc.In one embodiment, often release in every 160 parts of Folium Ginkgo extract in micropill, described alkalescence amount of substance is 5 ~ 50 parts, such as 6 ~ 30 parts, such as 7 ~ 20 parts.
Ginkgo biloba extract sustained-release capsule according to a third aspect of the present invention, the weight ratio that wherein said Folium Ginkgo extract often releases the Folium Ginkgo extract in micropill and ginkgo biloba extract sustained-release pellet is 1:2 ~ 5, such as 1:2 ~ 4, such as 1:3.
Further, fourth aspect present invention provides a kind of ginkgo biloba extract sustained-release capsule, and it comprises hard capsule case and is sealed in the micropill in this hard capsule case.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, wherein said micropill comprises: release micropill in ginkgo biloba extract sustained-release pellet, Folium Ginkgo extract and Folium Ginkgo extract often releases micropill three kinds of micropills.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, as described in wherein said ginkgo biloba extract sustained-release pellet embodiment as arbitrary in first aspect present invention.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, wherein said Folium Ginkgo extract often releases micropill, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, wherein said Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, wherein said Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, wherein said Folium Ginkgo extract is often released in micropill and is also comprised alkalescence material.In one embodiment, described alkalescence material is selected from arginine, meglumine, Tris, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate etc.In one embodiment, often release in every 160 parts of Folium Ginkgo extract in micropill, described alkalescence amount of substance is 5 ~ 50 parts, such as 6 ~ 30 parts, such as 7 ~ 20 parts.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, releases micropill in wherein said Folium Ginkgo extract and comprises: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion, Sustained release coating materials 10-20 weight portion.As well known to those skilled in the art, term " in release micropill " is the micropill with medium slow speed release and middling speed delivery mode release medicine, to be different from slow-release micro-pill and often to release micropill.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, releases micropill in wherein said Folium Ginkgo extract and comprises: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion, Sustained release coating materials 15 weight portion.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, releases in wherein said Folium Ginkgo extract in micropill and also comprises alkalescence material.In one embodiment, described alkalescence material is selected from arginine, meglumine, Tris, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate etc.In one embodiment, in release in every 160 parts of Folium Ginkgo extract in micropill, described alkalescence amount of substance is 5 ~ 50 parts, such as 6 ~ 30 parts, such as 7 ~ 20 parts.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, release in wherein said Folium Ginkgo extract in micropill Sustained release coating materials composition and method for making embodiment as arbitrary in first aspect present invention as described in.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, releasing micropill in wherein said Folium Ginkgo extract is prepared by the method comprised the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, the filler released micropill in wherein said Folium Ginkgo extract and often release micropill is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, the disintegrating agent released micropill in wherein said Folium Ginkgo extract and often release micropill is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, the binding agent released micropill in wherein said Folium Ginkgo extract and often release micropill is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions.
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, the chaotropic agent released micropill in wherein said Folium Ginkgo extract and often release micropill is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP).
Ginkgo biloba extract sustained-release capsule according to a fourth aspect of the present invention, wherein said Folium Ginkgo extract often release micropill, in the weight ratio of Folium Ginkgo extract released in micropill, slow-release micro-pill three kinds of micropills be 1:0.5 ~ 2:2 ~ 5, such as 1:0.8 ~ 1.2:2 ~ 4, such as 1:1:3.
According to the present invention, described gingko leaf sustained release formulation has the formula composition described in any embodiment of the present invention.Because the present invention adopts conventional method to prepare slow releasing preparation, and obtain technique effect of the present invention, therefore formula composition of the present invention can independently can not exist because of preparation technology.
Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.
Be further described to various aspects of the present invention below.
According to the present invention, the Folium Ginkgo extract used in the various preparation of the present invention, if not otherwise indicated, refer to the Folium Ginkgo extract meeting Chinese Pharmacopoeia version in 2010 one 392 pages contained " Folium Ginkgo extract " standards, such as, the main total flavonoids that contains (also can be described as ginkgetin, Ginkgo total flavones, total flavones etc. in the present invention, it is normally in Quercetin, kaempferol, isorhamnetin three) >24%, Quercetin and kaempferol peak area ratio 0.8-1.2, the peak area ratio of isorhamnetin and Quercetin is greater than 0.15; Composition containing ginkgo total lactones (also can be described as terpene lactone, Folium Ginkgo terpene lactones, terpene lactones etc. in the present invention, it is normally in bilobalide, ginkalide A, ginkalide B, ginkalide C) >6%; Ginkgoic acid <10ppm.
In the present invention, when mentioning aquiferous ethanol, if not otherwise indicated, the ethanol of 30% ~ 80% is all referred to.
According to the present invention, described gingko leaf sustained release formulation has the formula composition described in any embodiment of the present invention.Because the present invention adopts conventional method to prepare slow releasing preparation, and obtain technique effect of the present invention, therefore formula composition of the present invention can independently can not exist because of preparation technology.
According to arbitrary embodiment of either side of the present invention, the micropill of described coating or non-coating can also prepare in the following manner: by filler, disintegrating agent, binding agent mix homogeneously, add water or 30 ~ 80% ethanol (such as about 50% ethanol) soft material processed, make the ganoid spheroidal celphere of 24-40 order with extruding ball blast comminutor, dry; Folium Ginkgo extract and chaotropic agent are dissolved in 20 ~ 40% ethanol (such as about 30% ethanol) and make solution; Make celphere in fluid bed, the temperature keeping ball core is 30 DEG C, is sprayed on celphere then by this dissolution homogeneity, and obtained ganoid spheroidal pastille micropill, to obtain final product.
Ginkgo leaf extract preparation of the present invention can control Ginkgo total flavones simultaneously, the release of Folium Ginkgo terpene lactones, with Chinese Pharmacopoeia version in 2010 two annex XD first methods, adopt dissolution method first method (blue laws) device, (potassium dihydrogen phosphate 6.8g is got with phosphate buffered solution, the 900ml that adds water makes dissolving, with phosphoric acid adjust ph to 4 ± 0.5, being diluted with water to 1000ml) 900ml is release medium, rotating speed is 100 turns per minute and measures release, at 2 hours, 4 hours, the Ginkgo total flavones of 12 hours and 24 hours and the burst size of Folium Ginkgo terpene lactones are respectively within the scope of 20-35%, within the scope of 30-55%, with more than 85% (such as in 85 ~ 98% scopes) within the scope of 50-75%.Gingko leaf preparation of the present invention can control the synchronous release of Ginkgo total flavones, Folium Ginkgo terpene lactones, has the advantage that administration number of times is few, blood concentration fluctuation is little, and can realize medication once a day for clinical treatment.
It is simple that preparation method of the present invention has technique, is suitable for suitability for industrialized production.
Detailed description of the invention
Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.
In following instantiation part, as do not mentioned in addition, be prepared with the inventory of every 100000 unit formulations when preparing preparation compositions.Raw material Folium Ginkgo extract used in example below, after measured, its Quercetin and kaempferol peak area ratio are 0.97, the peak area ratio of isorhamnetin and Quercetin is 0.231, total flavonoids 30.4%, terpene lactone 8.6%, ginkgoic acid <2ppm, all the other features meet standards of pharmacopoeia.
embodiment 1:prepare ginkgo biloba extract sustained-release pellet preparation:
1, ball core composition:
Folium Ginkgo extract 160 weight portion,
Starch (filler) 170 weight portion,
Low-substituted hydroxypropyl cellulose (disintegrating agent) 20 weight portion,
Microcrystalline Cellulose (binding agent) 20 weight portion,
Polyvinylpyrrolidone (PVP K-30, chaotropic agent) 3 weight portions,
Sustained release coating materials 25 weight portion.
2, Sustained release coating materials composition:
Ethyl cellulose (filmogen) 10 weight portion,
Dibutyl sebacate (plasticizer) 10 weight portion,
Hydroxypropyl emthylcellulose (porogen) 3.5 weight portion,
Hexadecanol (stabilizing agent) 0.5 weight portion,
Pulvis Talci (antiplastering aid) 1 weight portion.
3, the preparation of slow-release micro-pill:
Step (1): by Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent mix homogeneously, add water and prepare soft material, throw circle comminutor with extruding and make 20-35 object circle containing principal agent micropill, dry, sieve gets best 20-30 order piller, is pastille micropill;
Step (2): each component water in Sustained release coating materials is mixed with the aqueous dispersion that solids content is 18%, and uniform stirring becomes suspension, makes to make sustained release coating liquid, for subsequent use;
Step (3): loaded in fluid bed by pastille micropill obtained for step (1), temperature controls at 25-40 DEG C, then adopts spray coating at the bottom of fluid bed to obtain slow-release micro-pill by sustained release coating liquid obtained for step (2);
Step (4): the slow-release micro-pill that step (3) is obtained is sub-packed in hard capsule case, and make the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
4, vitro release checks: get this product, according to drug release determination method (Chinese Pharmacopoeia version in 2000 two annex XD first methods), adopt dissolution method first method device, (potassium dihydrogen phosphate 6.8g is got with phosphate buffered solution, the 900ml that adds water makes dissolving, with phosphoric acid adjust ph to 4 ± 0.5, being diluted with water to 1000ml) 900ml is release medium, rotating speed is 100 turns per minute, operate in accordance with the law, respectively at 2 hours, 4 hours, within 12 hours and 24 hours, sample 5ml respectively and (and instant in stripping rotor, supplement same volume, the water of identical temperature), filter, get subsequent filtrate, as need testing solution, according to the total flavonoids concentration/stripping quantity (comprising Quercetin, kaempferol, isorhamnetin three concentration/stripping quantity) in official method mensuration solution and terpene lactone concentration/stripping quantity (comprising bilobalide, ginkalide A, ginkalide B, ginkalide C concentration/stripping quantity).
Another according to the total flavonoids content (comprising Quercetin, kaempferol, isorhamnetin three content) in official method mensuration preparation and terpene lactone contents (comprising bilobalide, ginkalide A, ginkalide B, ginkalide C content).Calculate at the total flavonoids Accumulation dissolution (%) of different time and terpene lactone Accumulation dissolution (%).
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 31.8 | 30.3 | 20-35％ |
| 4 | 53.1 | 54.4 | 30-55％ |
| 12 | 72.7 | 74.6 | 50-75％ |
| 24 | 97.3 | 97.6 | 85～98％ |
In a supplementary test, change the wetting agent water used during soft material processed in above step (1) into 30% ethanol, 50% ethanol or 80% ethanol to prepare slow releasing preparation, result uses the Accumulation dissolution of two constituents of each time point of different wetting agent gained slow releasing preparation in 24 hours and uses the slow releasing preparation that water is wetting agent suitable, without obviously distinguishing.
In a supplementary test, in step (2), each component water in Sustained release coating materials is mixed with solids content is that the aqueous dispersion of 10% or 25% is to prepare slow releasing preparation, result uses the slow releasing preparation of the Accumulation dissolution of two constituents of each time point of different Sustained release coating materials solution gained slow releasing preparation in 24 hours and embodiment 1 suitable, without obviously distinguishing.
In a supplementary test, in step (3), use coating pan and carry out coating of pellets without fluid bed, prepare slow releasing preparation, result uses the slow releasing preparation of the Accumulation dissolution of two constituents of each time point of coating pan coating gained slow releasing preparation in 24 hours and embodiment 1 suitable, without obviously distinguishing.
embodiment 2:prepare ginkgo biloba extract sustained-release pellet preparation:
1, ball core composition:
Folium Ginkgo extract 160 weight portion,
Microcrystalline Cellulose (filler) 120 weight portion,
Starch (disintegrating agent) 40 weight portion,
Sucrose (binding agent) 30 weight portion,
Polyethylene Glycol (chaotropic agent) 3 weight portion,
Sustained release coating materials 48 weight portion.
2, Sustained release coating materials composition:
Polyacrylic resin (filmogen) 30 weight portion,
Triethyl citrate (plasticizer) 12 weight portion,
Oleic acid (stabilizing agent) 2 weight portion,
Micropowder silica gel (antiplastering aid) 4 weight portion.
3, the preparation of slow-release micro-pill:
Step (1): by Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent mix homogeneously, add water and prepare soft material, throw circle comminutor with extruding and make 20-35 object circle containing principal agent micropill, dry, sieve gets best 20-30 order piller, is pastille micropill;
Step (2): each component water in Sustained release coating materials is mixed with the aqueous dispersion that solids content is 20%, and uniform stirring becomes suspension, makes to make sustained release coating liquid, for subsequent use;
Step (3): loaded in fluid bed by pastille micropill obtained for step (1), temperature controls at 25-40 DEG C, then adopts spray coating at the bottom of fluid bed to obtain slow-release micro-pill by sustained release coating liquid obtained for step (2);
Step (4): the slow-release micro-pill that step (3) is obtained is sub-packed in hard capsule case, and make the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
4, vitro release inspection: the method according to embodiment 1 is carried out, and the present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 21.2 | 20.5 | 20-35％ |
| 4 | 35.3 | 33.7 | 30-55％ |
| 12 | 53.7 | 54.3 | 50-75％ |
| 24 | 86.7 | 85.6 | 85～98％ |
embodiment 3:prepare ginkgo biloba extract sustained-release pellet preparation:
1, ball core composition:
Folium Ginkgo extract 160 weight portion,
Microcrystalline Cellulose (filler) 158 weight portion,
Polyvinylpolypyrrolidone (disintegrating agent) 45 weight portion,
Hydroxypropyl methylcellulose (binding agent) 26 weight portion,
Polyvinylpyrrolidone (PVPK-30 chaotropic agent) 3 weight portions,
Sustained release coating materials 42.9 weight portion.
2, Sustained release coating materials composition:
Ethyl cellulose (filmogen) 28 weight portion,
Triethyl citrate (plasticizer) 10 weight portion,
Sodium lauryl sulphate (stabilizing agent) 0.9 weight portion,
Pulvis Talci (antiplastering aid) 4 weight portion.
3, the preparation of slow-release micro-pill:
Step (1): by filler, disintegrating agent, binding agent mix homogeneously, adds 50% ethanol soft material, makes the ganoid spheroidal celphere of 24-40 order with extruding ball blast comminutor, dry, sieve gets best 24-35 order piller, is Blank Pellets, for subsequent use;
Step (2): above-mentioned Folium Ginkgo extract, chaotropic agent are joined respectively in the alcoholic solution of 30% of 50 DEG C of continuous stirrings, stir into uniform solution; Celphere is in fluid bed, and the temperature keeping ball core is 30 DEG C, then by ganoid spheroidal pastille micropill obtained on the celphere being sprayed on step (1) gained of this dissolution homogeneity;
Step (3): the pastille micropill that step (2) is obtained puts into fluid bed, temperature controls at 25-40 DEG C, again using with the Sustained release coating materials dispersion suspension of solids content 20% of 50% ethanol preparation as sustained release coating liquid, adopt spray coating at the bottom of fluid bed to make slow-release micro-pill, to obtain final product;
Step (4): the slow-release micro-pill that step (3) is obtained is sub-packed in hard capsule case, and make the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
4, vitro release inspection: the method according to embodiment 1 is carried out, and the present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 24.1 | 25.3 | 20-35％ |
| 4 | 37.1 | 35.8 | 30-55％ |
| 12 | 56.7 | 58.3 | 50-75％ |
| 24 | 88.7 | 86.8 | 85～98％ |
embodiment 4:prepare ginkgo biloba extract sustained-release pellet preparation:
1, ball core composition:
Folium Ginkgo extract 160 weight portion,
Lactose (filler) 120 weight portion,
Carboxylic Yue base Starch Sodium (disintegrating agent) 50 weight portion,
Polyvidone (binding agent) 40 weight portion,
Polyethylene Glycol (chaotropic agent) 1 weight portion,
Sustained release coating materials 41 weight portion.
2, Sustained release coating materials composition:
Polyacrylic resin (filmogen) 20 weight portion,
Dibutyl sebacate (plasticizer) 5 weight portion,
Oleic acid (stabilizing agent) 4 weight portion,
Hydroxypropyl emthylcellulose (porogen) 10 weight portion,
Micropowder silica gel (antiplastering aid) 2 weight portion.
3, the preparation of slow-release micro-pill: the method with reference to embodiment 1 prepares the pellet preparations in capsule shape, and every capsules comprises Folium Ginkgo extract 160mg.In the present invention, if not otherwise specified, the Polyethylene Glycol mentioned is all Polyethylene Glycol of molecular weight 1000.
4, vitro release inspection: the method according to embodiment 1 is carried out, and the present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 28.4 | 26.7 | 20-35％ |
| 4 | 45.7 | 44.3 | 30-55％ |
| 12 | 60.6 | 62.3 | 50-75％ |
| 24 | 91.7 | 93.2 | 85～98％ |
embodiment 5:prepare ginkgo biloba extract sustained-release pellet preparation:
1, ball core composition:
Folium Ginkgo extract 160 weight portion,
Microcrystalline Cellulose/lactose (1:1, filler) 155 weight portions,
Low-substituted hydroxypropyl cellulose (disintegrating agent) 30 weight portion,
Carboxymethyl cellulose sodium (binding agent) 35 weight portion,
Polyethylene Glycol (chaotropic agent) 3 weight portion,
Sustained release coating materials 35 weight portion.
2, Sustained release coating materials composition:
Polyacrylic resin (filmogen) 16 weight portion,
Triethyl citrate (plasticizer) 8 weight portion,
Sodium lauryl sulphate (stabilizing agent) 1 weight portion,
Polyethylene Glycol (porogen) 7 weight portion,
Micropowder silica gel (antiplastering aid) 3 weight portion.
3, the preparation of slow-release micro-pill: the method with reference to embodiment 1 prepares the pellet preparations in capsule shape, and every capsules comprises Folium Ginkgo extract 160mg.
4, vitro release inspection: the method according to embodiment 1 is carried out, and the present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 26.6 | 27.9 | 20-35％ |
| 4 | 45.8 | 44.3 | 30-55％ |
| 12 | 65.3 | 64.1 | 50-75％ |
| 24 | 96.1 | 95.4 | 85～98％ |
embodiment 6:prepare ginkgo biloba extract sustained-release pellet preparation (two kinds of micropills):
1, Example 2 step (1) gained pastille micropill (namely often releasing micropill) 1 weight portion, with embodiment 2 step (3) gained slow-release micro-pill 3 weight portion, the two mix homogeneously; Be sub-packed in hard capsule case by gained mixing micropill, make the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.It comprises the preparation often releasing micropill and slow-release micro-pill two kinds of micropills described in a kind of typical third aspect present invention.
2, vitro release inspection: the method according to embodiment 1 is carried out, and the present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 30.5 | 32.1 | 20-35％ |
| 4 | 50.1 | 48.5 | 30-55％ |
| 12 | 65.3 | 66.9 | 50-75％ |
| 24 | 96.8 | 95.5 | 85～98％ |
Also can mix the obtained pellet preparations in capsule shape by often releasing micropill and slow-release micro-pill with the ratio of the weight ratio 1:2 of the Folium Ginkgo extract wherein comprised, 1:4 or 1:5, the preparation obtaining three kinds of ratios mixing at the Accumulation dissolution of 2,4,12,24 little two class chemical substances constantly respectively in 20-35%, 30-55%, 50-75% and 85 ~ 98% scopes.
embodiment 7:prepare ginkgo biloba extract sustained-release pellet preparation (three kinds of micropills):
1, with reference to formula and the method for embodiment 1, different is only the Sustained release coating materials using 15 weight portions in ball core composition, the proportioning of Sustained release coating materials is still with embodiment 1, reduce the consumption of Sustained release coating materials when being only coating of pellets in step (3), obtain a kind of micropill (releasing micropill namely) with medium rate of release;
2, Example 1 step (1) gained pastille micropill (namely often releasing micropill) 1 weight portion, above-mentioned in release micropill 1 weight portion, embodiment 2 step (3) gained slow-release micro-pill 3 weight portion, three's mix homogeneously; Be sub-packed in hard capsule case by gained mixing micropill, make the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.It is comprise described in a kind of typical fourth aspect present invention often release micropill, in release the preparation of micropill and slow-release micro-pill three kinds of micropills.
3, vitro release inspection: the method according to embodiment 1 is carried out, and the present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 27.4 | 25.8 | 20-35％ |
| 4 | 37.5 | 38.4 | 30-55％ |
| 12 | 60.4 | 58.9 | 50-75％ |
| 24 | 95.2 | 93.4 | 85～98％ |
In the present embodiment, also can by often release micropill, in release micropill, slow-release micro-pill three kinds of micropills with the obtained pellet preparations in capsule shape of the ratio of the weight ratio 1:0.5:5 of the Folium Ginkgo extract wherein comprised, 1:2:2,1:2:5,1:0.5:2,1:0.8:2,1:0.8:4,1:1.2:2 or 1:1.2:4 mixing, the preparation obtaining 8 kinds of ratios mixing at the Accumulation dissolution of 2,4,12,24 little two class chemical substances constantly respectively in 20-35%, 30-55%, 50-75% and 85 ~ 98% scopes.
embodiment 11:
The formula of reference example 1 and method, different is only also be added with 12 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 32.4 | 30.9 | 20-35％ |
| 4 | 53.8 | 53.2 | 30-55％ |
| 12 | 71.4 | 73.9 | 50-75％ |
| 24 | 97.8 | 97.9 | 85～98％ |
embodiment 12:
The formula of reference example 1 and method, different is only also be added with 10 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 21.5 | 21.2 | 20-35％ |
| 4 | 35.7 | 34.3 | 30-55％ |
| 12 | 53.1 | 53.7 | 50-75％ |
| 24 | 86.2 | 86.3 | 85～98％ |
embodiment 13:
The formula of reference example 1 and method, different is only also be added with 15 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 24.6 | 25.0 | 20-35％ |
| 4 | 37.6 | 36.5 | 30-55％ |
| 12 | 56.2 | 58.8 | 50-75％ |
| 24 | 88.5 | 87.6 | 85～98％ |
embodiment 14:
The formula of reference example 1 and method, different is only also be added with 12 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 28.7 | 26.5 | 20-35％ |
| 4 | 45.1 | 44.8 | 30-55％ |
| 12 | 61.5 | 62.1 | 50-75％ |
| 24 | 92.2 | 93.0 | 85～98％ |
embodiment 15:
The formula of reference example 1 and method, different is only also be added with 12 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 26.7 | 27.4 | 20-35％ |
| 4 | 46.4 | 44.7 | 30-55％ |
| 12 | 65.5 | 63.6 | 50-75％ |
| 24 | 95.3 | 95.9 | 85～98％ |
embodiment 16:
The formula of reference example 1 and method, different is only also be added with 12 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 30.2 | 31.4 | 20-35％ |
| 4 | 51.3 | 49.4 | 30-55％ |
| 12 | 65.7 | 66.3 | 50-75％ |
| 24 | 97.1 | 95.6 | 85～98％ |
embodiment 17:
The formula of reference example 1 and method, different is only also be added with 12 weight portion alkalescence material Tris together with every 160 weight portion Folium Ginkgo extract, prepare the pellet preparations in capsule shape, every capsules comprises Folium Ginkgo extract 160mg.
The present embodiment gained preparation Accumulation dissolution is as follows:
| Time (hour) | The Accumulation dissolution (%) of total flavones | The Accumulation dissolution (%) of terpene lactones | Scope |
| 2 | 27.1 | 26.4 | 20-35％ |
| 4 | 37.7 | 38.3 | 30-55％ |
| 12 | 60.1 | 58.2 | 50-75％ |
| 24 | 95.5 | 93.6 | 85～98％ |
embodiment 18:
Formula is substantially with embodiment 11, but the addition of alkalescence material is respectively 1,3,7,15,20,30,50 part; Method for making is with embodiment 11; Obtain seven preparations be designated as respectively embodiment 181, embodiment 182 ... embodiment 187.
These seven preparations carry out vitro release inspection, result according to embodiment 1 method:
Seven kinds of preparations 2,4,12,24 little total flavones Accumulation dissolution (%) constantly respectively within the scope of 23-34%, within the scope of 34-52%, within the scope of 54-71% and within the scope of 88-96%;
The preparation that these five alkalescence material additions of embodiment 181 to embodiment 185 are less than or equal to 20 parts 2,4,12,24 little terpene lactoness constantly Accumulation dissolution (%) respectively within the scope of 24-32%, within the scope of 33-54%, within the scope of 55-70% and within the scope of 88-95%; But
The preparation that these two alkalescence material additions of embodiment 186 to embodiment 187 are more than or equal to 20 parts at the Accumulation dissolution (%) of 2,4,12,24 little terpene lactoness constantly respectively within the scope of 5-11%, within the scope of 12-19%, within the scope of 21-43% and within the scope of 44-62%, when the alkalescence material of higher amount is added in display, terpene lactones burst size is not enough.
embodiment 19:
The alkalescence substitution of materials wherein substantially with embodiment 11, but is arginine, meglumine, sodium bicarbonate, sodium carbonate, the sodium hydrogen phosphate of equivalent by formula; Method for making is with embodiment 11; Obtain five preparations be designated as respectively embodiment 191, embodiment 192 ... embodiment 195.
These five preparations carry out vitro release inspection, result according to embodiment 1 method:
Five kinds of preparations 2,4,12,24 little total flavones Accumulation dissolution (%) constantly respectively within the scope of 25-34%, within the scope of 36-51%, within the scope of 55-70% and within the scope of 88-95%;
Five kinds of preparations 2,4,12,24 little terpene lactones Accumulation dissolution (%) constantly respectively within the scope of 23-32%, within the scope of 37-51%, within the scope of 54-68% and within the scope of 89-93%.
test example 1: preparation nature is investigated
The whole preparations prepared in above embodiment 1 to embodiment 19, measure their total flavonoids content (and wherein Quercetin, kaempferol, isorhamnetin content and proportionate relationship thereof), terpene lactone contents (and wherein bilobalide, ginkalide A, ginkalide B, ginkalide C content) etc. with reference to official method.Result shows, these parameters peak area ratio etc. of kaempferol peak area ratio, isorhamnetin and Quercetin (the such as Quercetin with) are with raw materials used consistent, or these parameters (such as total flavonoids content, terpene lactone contents etc.) are consistent with the theoretical amount that feeds intake.Such as, the whole preparations obtained, after measured, Quercetin and kaempferol peak area ratio are all in 0.96 ~ 0.99 scope, and the peak area ratio of isorhamnetin and Quercetin is all in 0.213 ~ 0.245 scope.
In addition, the whole preparations prepared in above embodiment 1 to embodiment 19, when carrying out release test, carrying out release test 12 hours, in release liquid, Quercetin and kaempferol peak area ratio are all in 0.93 ~ 1.01 scope, show this parameter in dissolution fluid and preparation measured result and crude drug result suitable.In addition, in the release liquid of carry out release test 2 hours, 4 hours and 24 hours, Quercetin and kaempferol peak area ratio are all in 0.90 ~ 1.05 scope.Visible, these preparations have good release performance in an initial condition, and not only total flavones has consistent releasing properties with terpene lactones two class material, and the main chemical compositions of flavonoid also discharges pari passu.
test example 2: study on the stability
The whole preparations prepared in above embodiment 1 to embodiment 19, under the state of plastic-aluminum combined film phonograph seal, place 6 months at being placed in 40 DEG C.
Measure total flavonoids content, the terpene lactone contents of these samples 6 months time, and the remaining percent of total flavonoids and terpene lactone when calculating June with results contrast during respective samples 0 month.Result shows, and the remaining percent of whole sample total flavonoids after high-temperature treatment June is all in 96 ~ 98% scopes, and the remaining percent of terpene lactone, all in 96 ~ 99% scopes, shows these samples and all has excellent chemical stability.
In addition, measure whole sample Quercetin and kaempferol peak area ratio after high-temperature treatment June, result is all in 0.92 ~ 0.99 scope, and the peak area ratio of isorhamnetin and Quercetin, also all in 0.202 ~ 0.254 scope, shows this parameter and has no significant change.
Measure the release conditions of whole sample after high-temperature treatment June, result but presents and forms relevant difference with formula:
(1) the whole preparation of embodiment 1 to embodiment 7 gained, after high-temperature treatment June, 2,4,12,24 little total flavones Accumulation dissolution (%) constantly respectively within the scope of 24-33%, within the scope of 37-50%, within the scope of 55-72% and within the scope of 88-96%, at 2,4,12,24 little terpene lactones Accumulation dissolution (%) constantly respectively within the scope of 26-32%, within the scope of 35-48%, within the scope of 56-70% and within the scope of 87-98%, show that these preparations all show and have the release mode suitable with original state;
(2) the whole preparation of embodiment 11 to embodiment 19 gained, after high-temperature treatment June, 2,4,12,24 little total flavones Accumulation dissolution (%) constantly respectively within the scope of 26-33%, within the scope of 35-52%, within the scope of 56-71% and within the scope of 89-97%, at 2,4,12,24 little terpene lactones Accumulation dissolution (%) constantly respectively within the scope of 26-30%, within the scope of 36-51%, within the scope of 58-71% and within the scope of 89-98%, show that these preparations all show and have the release mode suitable with original state;
(3) embodiment 1 to embodiment 7, embodiment 181, embodiment 182, the whole preparation of embodiment 19 gained, they are after high-temperature treatment June, carry out release test 2,4,12,24 constantly little, in release liquid, Quercetin and kaempferol peak area ratio are all in 2.02 ~ 2.93 scopes, this character is that this area is completely unacceptable, because this release in vitro reflects medicine release in vivo and absorption, such release will cause the absorption of active component unbalanced, thus affects biology effect.
(4) the whole preparation of embodiment 11 to embodiment 17 gained, and embodiment 183 to embodiment 187 sample, they are after high-temperature treatment June, carry out release test 2,4,12,24 constantly little, in release liquid, Quercetin and kaempferol peak area ratio are all in 0.91 ~ 1.07 scope, show that these samples are still keeping the stripping release performance of excellent monomer chemistries component ratio relation after high-temperature treatment.
Above to invention has been detailed description, generally speaking, the invention provides following aspect:
[1]. a kind of slow releasing preparation of Folium Ginkgo extract, it is ginkgo biloba extract sustained-release pellet, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent, Sustained release coating materials.
[2]. the ginkgo biloba extract sustained-release pellet of [1], comprising: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion, Sustained release coating materials 25-48 weight portion; Or comprising: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion, Sustained release coating materials 35 weight portion.
[3]. the ginkgo biloba extract sustained-release pellet of [1], wherein:
Described filler is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions;
Described disintegrating agent is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions;
Described binding agent is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions;
Described chaotropic agent is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP);
The composition of described Sustained release coating materials comprises: filmogen, stabilizing agent, antiplastering aid, plasticizer, porogen;
The composition of described Sustained release coating materials comprises: filmogen 10-30 weight portion, stabilizing agent 0.5-4 weight portion, antiplastering aid 1-4 weight portion, plasticizer 5-15 weight portion, porogen 3.5-10 weight portion;
The composition of described Sustained release coating materials comprises: filmogen 16 weight portion, stabilizing agent l weight portion, antiplastering aid 3 weight portion, plasticizer 8 weight portion, porogen 7 weight portion;
The composition of described Sustained release coating materials comprises: filmogen, stabilizing agent, antiplastering aid, plasticizer;
The composition of described Sustained release coating materials comprises: filmogen 10-30 weight portion, stabilizing agent 0.5-2 weight portion, antiplastering aid 1-4 weight portion, plasticizer 6-12 weight portion;
The composition of described Sustained release coating materials comprises: filmogen is 30 weight portions, stabilizing agent 2 weight portion, antiplastering aid 2.5 weight portion, plasticizer 7.2 weight portion;
Described filmogen be in polyacrylic resin, ethyl cellulose and stearic acid any one or its arbitrarily than mixture;
Described porogen be in hydroxypropyl emthylcellulose, Polyethylene Glycol and polyvinylpyrrolidone any one or its arbitrarily than mixture;
Described plasticizer be in dibutyl sebacate, triethyl citrate, propylene glycol, polyethylene glycols, dimethyl phthalate and triacetin any one or its arbitrarily than mixture;
Described stabilizing agent be in oleic acid, hexadecanol and sodium lauryl sulphate any one or its arbitrarily than mixture; And/or
Described antiplastering aid be in Pulvis Talci and micropowder silica gel any one or its arbitrarily than mixture.
[4]. the ginkgo biloba extract sustained-release pellet of [1], it is prepared by the method comprised the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill; Enter further, described ginkgo biloba extract sustained-release pellet, wherein also comprise alkalescence material; Such as, described alkalescence material is selected from arginine, meglumine, Tris, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate etc.; Such as, in every 160 parts of Folium Ginkgo extract, described alkalescence amount of substance is 5 ~ 50 parts, such as 6 ~ 30 parts, such as 7 ~ 20 parts.
[5]. the method for the ginkgo biloba extract sustained-release pellet of any one of [1]-[4], it comprises the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, optional alkalescence material, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill.
[6]. a kind of ginkgo biloba extract sustained-release capsule, it comprises hard capsule case and is sealed in the micropill in this hard capsule case; Further, described micropill comprises the ginkgo biloba extract sustained-release pellet of any one of [1]-[5], and Folium Ginkgo extract often releases micropill.
[7]. the ginkgo biloba extract sustained-release capsule of [6], wherein:
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion;
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion;
The filler that described Folium Ginkgo extract often releases micropill is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions;
The disintegrating agent that described Folium Ginkgo extract often releases micropill is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions;
The binding agent that described Folium Ginkgo extract often releases micropill is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions;
The chaotropic agent that described Folium Ginkgo extract often releases micropill is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP);
Described Folium Ginkgo extract is often released in micropill and is also comprised alkalescence material; And/or
The weight ratio that described Folium Ginkgo extract often releases the Folium Ginkgo extract in micropill and ginkgo biloba extract sustained-release pellet is 1:2 ~ 5, such as 1:2 ~ 4, such as 1:3.
[8]. a kind of ginkgo biloba extract sustained-release capsule, it comprises hard capsule case and is sealed in the micropill in this hard capsule case; Further, described micropill comprises: release micropill in ginkgo biloba extract sustained-release pellet, Folium Ginkgo extract and Folium Ginkgo extract often releases micropill three kinds of micropills.
[9]. the ginkgo biloba extract sustained-release capsule of [8], wherein:
Described ginkgo biloba extract sustained-release pellet is as described in any one of [1]-[4];
Described Folium Ginkgo extract often releases micropill, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent;
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion;
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion;
Described Folium Ginkgo extract is often released in micropill and is also comprised alkalescence material;
Release micropill in described Folium Ginkgo extract to comprise: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion, Sustained release coating materials 10-20 weight portion;
Release micropill in described Folium Ginkgo extract to comprise: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion, Sustained release coating materials 15 weight portion;
Release in described Folium Ginkgo extract in micropill and also comprise alkalescence material;
Release in described Folium Ginkgo extract in micropill Sustained release coating materials composition and method for making as described in any one of claim 1-4;
The filler released micropill in described Folium Ginkgo extract and often release micropill is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions;
The disintegrating agent released micropill in described Folium Ginkgo extract and often release micropill is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions;
The binding agent released micropill in described Folium Ginkgo extract and often release micropill is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions;
The chaotropic agent released micropill in described Folium Ginkgo extract and often release micropill is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP);
Wherein said Folium Ginkgo extract often release micropill, in the weight ratio of Folium Ginkgo extract released in micropill, slow-release micro-pill three kinds of micropills be 1:0.5 ~ 2:2 ~ 5, such as 1:0.8 ~ 1.2:2 ~ 4, such as 1:1:3.
[10]. the ginkgo biloba extract sustained-release pellet of any one of [1]-[5], the ginkgo biloba extract sustained-release capsule of [6]-[7], the ginkgo biloba extract sustained-release capsule of [8]-[9], it is with Chinese Pharmacopoeia version in 2010 two annex XD first methods, adopt dissolution method first method (blue laws) device, (potassium dihydrogen phosphate 6.8g is got with phosphate buffered solution, the 900ml that adds water makes dissolving, with phosphoric acid adjust ph to 4 ± 0.5, being diluted with water to 1000ml) 900ml is release medium, rotating speed is 100 turns per minute and measures release, at 2 hours, 4 hours, the Ginkgo total flavones of 12 hours and 24 hours and the burst size of Folium Ginkgo terpene lactones are respectively within the scope of 20-35%, within the scope of 30-55%, with more than 85% (such as in 85 ~ 98% scopes) within the scope of 50-75%.
Claims (10)
1. a slow releasing preparation for Folium Ginkgo extract, it is ginkgo biloba extract sustained-release pellet, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent, Sustained release coating materials.
2. the ginkgo biloba extract sustained-release pellet of claim 1, comprising: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion, Sustained release coating materials 25-48 weight portion; Or comprising: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion, Sustained release coating materials 35 weight portion.
3. the ginkgo biloba extract sustained-release pellet of claim 1, wherein:
Described filler is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions;
Described disintegrating agent is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions;
Described binding agent is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions;
Described chaotropic agent is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP);
The composition of described Sustained release coating materials comprises: filmogen, stabilizing agent, antiplastering aid, plasticizer, porogen;
The composition of described Sustained release coating materials comprises: filmogen 10-30 weight portion, stabilizing agent 0.5-4 weight portion, antiplastering aid 1-4 weight portion, plasticizer 5-15 weight portion, porogen 3.5-10 weight portion;
The composition of described Sustained release coating materials comprises: filmogen 16 weight portion, stabilizing agent l weight portion, antiplastering aid 3 weight portion, plasticizer 8 weight portion, porogen 7 weight portion;
The composition of described Sustained release coating materials comprises: filmogen, stabilizing agent, antiplastering aid, plasticizer;
The composition of described Sustained release coating materials comprises: filmogen 10-30 weight portion, stabilizing agent 0.5-2 weight portion, antiplastering aid 1-4 weight portion, plasticizer 6-12 weight portion;
The composition of described Sustained release coating materials comprises: filmogen is 30 weight portions, stabilizing agent 2 weight portion, antiplastering aid 2.5 weight portion, plasticizer 7.2 weight portion;
Described filmogen be in polyacrylic resin, ethyl cellulose and stearic acid any one or its arbitrarily than mixture;
Described porogen be in hydroxypropyl emthylcellulose, Polyethylene Glycol and polyvinylpyrrolidone any one or its arbitrarily than mixture;
Described plasticizer be in dibutyl sebacate, triethyl citrate, propylene glycol, polyethylene glycols, dimethyl phthalate and triacetin any one or its arbitrarily than mixture;
Described stabilizing agent be in oleic acid, hexadecanol and sodium lauryl sulphate any one or its arbitrarily than mixture; And/or
Described antiplastering aid be in Pulvis Talci and micropowder silica gel any one or its arbitrarily than mixture.
4. the ginkgo biloba extract sustained-release pellet of claim 1, it is prepared by the method comprised the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill; Enter further, described ginkgo biloba extract sustained-release pellet, wherein also comprise alkalescence material; Such as, described alkalescence material is selected from arginine, meglumine, Tris, sodium bicarbonate, sodium carbonate, sodium hydrogen phosphate etc.; Such as, in every 160 parts of Folium Ginkgo extract, described alkalescence amount of substance is 5 ~ 50 parts, such as 6 ~ 30 parts, such as 7 ~ 20 parts.
5. prepare the method for the ginkgo biloba extract sustained-release pellet of any one of claim 1-4, it comprises the following steps:
(1) each pastille micropill is made: get Folium Ginkgo extract, optional alkalescence material, filler, disintegrating agent, binding agent and chaotropic agent mix homogeneously, adding water or concentration is that the ethanol of 30-80% is prepared into soft material, then obtains 20-30 object ganoid spheroidal pastille micropill with Squeezinggranulator;
(2) with Sustained release coating materials preparation sustained release coating liquid: filmogen is distributed in water containing plasticizer or aquiferous ethanol solution, then porogen, stabilizing agent, antiplastering aid is added, last to add water again or aquiferous ethanol stirs into suspension, forming solids content is the aqueous dispersion of 10-25%, cross 120 mesh sieves, obtain sustained release coating liquid;
(3) pastille micropill obtained for step (1) is loaded in coating pan or fluid bed, temperature controls at 25-40 DEG C, then spray at the bottom of coating pan or fluid bed is adopted to carry out coating to described pastille micropill sustained release coating liquid obtained for step (2), obtained slow-release micro-pill.
6. a ginkgo biloba extract sustained-release capsule, it comprises hard capsule case and is sealed in the micropill in this hard capsule case; Further, described micropill comprises the ginkgo biloba extract sustained-release pellet of any one of claim 1-5, and Folium Ginkgo extract often releases micropill.
7. the ginkgo biloba extract sustained-release capsule of claim 6, wherein:
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion;
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion;
The filler that described Folium Ginkgo extract often releases micropill is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions;
The disintegrating agent that described Folium Ginkgo extract often releases micropill is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions;
The binding agent that described Folium Ginkgo extract often releases micropill is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions;
The chaotropic agent that described Folium Ginkgo extract often releases micropill is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP);
Described Folium Ginkgo extract is often released in micropill and is also comprised alkalescence material; And/or
The weight ratio that described Folium Ginkgo extract often releases the Folium Ginkgo extract in micropill and ginkgo biloba extract sustained-release pellet is 1:2 ~ 5, such as 1:2 ~ 4, such as 1:3.
8. a ginkgo biloba extract sustained-release capsule, it comprises hard capsule case and is sealed in the micropill in this hard capsule case; Further, described micropill comprises: release micropill in ginkgo biloba extract sustained-release pellet, Folium Ginkgo extract and Folium Ginkgo extract often releases micropill three kinds of micropills.
9. the ginkgo biloba extract sustained-release capsule of claim 8, wherein:
Described ginkgo biloba extract sustained-release pellet is as described in any one of claim 1-4;
Described Folium Ginkgo extract often releases micropill, and it is made up of Folium Ginkgo extract, filler, disintegrating agent, binding agent, chaotropic agent;
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion;
Described Folium Ginkgo extract is often released micropill and is comprised: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion;
Described Folium Ginkgo extract is often released in micropill and is also comprised alkalescence material;
Release micropill in described Folium Ginkgo extract to comprise: Folium Ginkgo extract 160 weight portion, filler 120-170 weight portion, disintegrating agent 20-50 weight portion, binding agent 20-40 weight portion, chaotropic agent 1-5 weight portion, Sustained release coating materials 10-20 weight portion;
Release micropill in described Folium Ginkgo extract to comprise: Folium Ginkgo extract 160 weight portion, filler 155 weight portion, disintegrating agent 30 weight portion, binding agent 35 weight portion, chaotropic agent 3 weight portion, Sustained release coating materials 15 weight portion;
Release in described Folium Ginkgo extract in micropill and also comprise alkalescence material;
Release in described Folium Ginkgo extract in micropill Sustained release coating materials composition and method for making as described in any one of claim 1-4;
The filler released micropill in described Folium Ginkgo extract and often release micropill is any one in starch, sucrose, lactose and microcrystalline Cellulose, or the mixture of wherein several or whole arbitrary proportions;
The disintegrating agent released micropill in described Folium Ginkgo extract and often release micropill is any one in starch, carboxymethyl starch, modified starch, carboxylic Yue base Starch Sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, sodium alginate, carboxymethyl starch and polyvinylpolypyrrolidone, or the mixture of wherein several or whole arbitrary proportions;
The binding agent released micropill in described Folium Ginkgo extract and often release micropill is any one in microcrystalline Cellulose, Carboxymethyl cellulose sodium, methylcellulose, polyvidone, hydroxypropyl cellulose, ethyl cellulose and hydroxypropyl emthylcellulose, or the mixture of wherein several or whole arbitrary proportions;
The chaotropic agent released micropill in described Folium Ginkgo extract and often release micropill is the mixture of any one or the two any ratio in Polyethylene Glycol (PEG) and polyvinylpyrrolidone (PVP);
Wherein said Folium Ginkgo extract often release micropill, in the weight ratio of Folium Ginkgo extract released in micropill, slow-release micro-pill three kinds of micropills be 1:0.5 ~ 2:2 ~ 5, such as 1:0.8 ~ 1.2:2 ~ 4, such as 1:1:3.
10. the ginkgo biloba extract sustained-release pellet of any one of claim 1-5, the ginkgo biloba extract sustained-release capsule of claim 6-7, the ginkgo biloba extract sustained-release capsule of claim 8-9, it is with Chinese Pharmacopoeia version in 2010 two annex XD first methods, adopt dissolution method first method (blue laws) device, (potassium dihydrogen phosphate 6.8g is got with phosphate buffered solution, the 900ml that adds water makes dissolving, with phosphoric acid adjust ph to 4 ± 0.5, being diluted with water to 1000ml) 900ml is release medium, rotating speed is 100 turns per minute and measures release, at 2 hours, 4 hours, the Ginkgo total flavones of 12 hours and 24 hours and the burst size of Folium Ginkgo terpene lactones are respectively within the scope of 20-35%, within the scope of 30-55%, with more than 85% (such as in 85 ~ 98% scopes) within the scope of 50-75%.
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| CN1631395A (en) * | 2003-12-23 | 2005-06-29 | 天津米克莱特生物技术有限公司 | Gingko leaf sustained release formulation and preparation process thereof |
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