CN103877130A - Chinese medicinal composition for treating ischemic cerebral paralysis, application thereof to preparation of oral preparation and preparation of Chinese medicinal composition - Google Patents
Chinese medicinal composition for treating ischemic cerebral paralysis, application thereof to preparation of oral preparation and preparation of Chinese medicinal composition Download PDFInfo
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Abstract
The invention discloses a Chinese medicinal composition for treating ischemic cerebral paralysis, application thereof to preparation of an oral preparation and preparation of the Chinese medicinal composition. The composition for treating ischemic cerebral paralysis consists of a ginkgo leaf extract and borneol in the mass ratio of (1.5-2.5):1, preferably 2:1. The composition is a compound oral preparation, and comprises the components of an excipient, a flow aid, a flavoring agent and an emulsifying agent. The Chinese medicinal composition for treating ischemic cerebral paralysis is a compound oral preparation, and the compound oral preparation is tablets, granules, soft capsules or pills. The Chinese medicinal composition has a remarkable curative effect on ischemic cerebral paralysis. The composition can be used for enhancing the oral administration bioavailability of the ginkgo leaf extract while improving the medicinal effect, and has great clinical significance. The compound preparation forms of tablets, granules, soft capsules, pills and the like are convenient for patients to take.
Description
Technical field
The present invention relates to a kind of Chinese medicine composition, be specifically related to a kind of Chinese medicine composition for the treatment of the Chinese medicine composition of ischemia apoplexy, this treatment ischemia apoplexy in the application of preparing in the compound oral administration preparation for the treatment of ischemia apoplexy, and the preparation method of the Chinese medicine composition of this treatment ischemia apoplexy.
Background technology
Treatment approach and the cerebral ischemia re-pouring of brain diseases: brain is the center of human central nervous activity are also the most complicated ingredients of nervous system.But, owing to there being blood brain barrier (Blood-brainbarrier, BBB), affect the distribution of many treatment brain diseases medicines in cerebral tissue, make it be difficult to see through blood brain barrier and enter in brain, cause in brain numerous disease at aspects such as diagnosis, treatments in the clinical numerous obstacles of suffering.How to make medicine see through blood brain barrier and enter and in brain, obtain good therapeutic effect, this problem is also just perplexing domestic and international vast medicine work pursuer.At present, brain diseases treatment progress is summarized as both at home and abroad: (1) increases it through ability by transforming the structure of drug molecule and making prodrug.(2) adopt the method for nasal-cavity administration, both can avoid the first-pass metabolism of medicine, can effectively make again drug targeting brain net.(3) hyperosmotic solution such as mannitol, arabinose, fructose, glycerol are injected in carotid artery or vertebral artery, blood brain barrier endotheliocyte is got muddled, temporarily cause the increase of blood-brain barrier permeability, improve the concentration of medicine in brain.(4) Chinese medicine Herba Menthae, Borneolum Syntheticum, Moschus etc. have causing resuscitation with aromatic drugs function, can improve blood-brain barrier permeability, utilize effect of Borneolum Syntheticum " causing resuscitation with aromatic drugs, priming is up ", can improve concentration in the brain of Treatment of Central Nervous System Diseases medicine, improve medication effect.(5) in recent years find that the 26S Proteasome Structure and Function of P-glycoprotein (P-gp) on blood brain barrier capillary endothelial cell film and the P-glycoprotein (P-gp) of tumor cell are similar, its encoding gene is MDR gene, substrate is called MDR reversal agents, competitive binding MDR reversal agents can promote other medicines to see through blood brain barrier to enter in brain, therefore by with the share of multidrug resistance (MDR) inversion agent, improve the concentration of the brain of medicine.(6) on colloidal drug delivery system, particularly surface, seal the nanoparticle of surfactant (Tweens, as Tween 80).(7) receptor-mediated route of administration, by cloning the specific antibody of receptor on blood brain barrier endotheliocyte, and taking as pharmaceutical carrier, drug conveying to brain, can be realized to the active targeting of medicine transmission.Find and promote medicine by the method for blood brain barrier, significant to the treatment of cerebral disease.Research at present shows, promotes the tight connection that Blood Brain Barrier (BBB) opening, change drug blood-brain barrier permeability mainly form by change blood brain barrier endotheliocyte or the special two kinds of modes of transporter function on blood brain barrier that change to realize.
Cerebral ischemia certain hour recovers after blood supply, and its function not only fails to recover, and has but occurred more serious cerebral disturbance, is referred to as cerebral ischemia reperfusion injury (cerebral ischemia reperfusion injury, CIR).Cerebral ischemia reperfusion injury is the pathophysiological process of a kind of complexity of multifactor multimachine system participation, the number of mechanisms such as main and toxicity of excitatory amino acid effect, free radical and lipid peroxidation, heat shock protein (HSP) expression disorder, mitochondria dysfunction, intracellular calcium overload, nitric oxide and inflammatory reaction are relevant, between multiple link factor, interact.Acute cerebral ischemic reperfusion injury can cause serious delayed ischemic neurological deficits, even threat to life.
According to statistics, apoplexy has become the third-largest class cause of death in the world, and countless patients passes away because can not get effectively treatment.Survive even if having the honor, also can leave sequela in various degree.The sick clinical topmost performance of apoplexy is mind obstacle and motion, sensation and aphasis.Through treatment after a while, except conscious, all the other symptoms still can exist to some extent.These symptoms, are called sequela.The weight of sequela, because of patient's body constitution and complication different.The common sequela of apoplexy has: numbness, facial hemiparalysis, central hemiplegia, around property hemiplegia, hemiplegia, aphasia, agnosia etc., sequela is in various degree having a strong impact on patient's healthy quality of life.Find effective medicine and measure to promote post-stroke central nervous system function to recover, be one of emphasis of related discipline research always.Also more and more come into one's own about the research of Chinese medicine cerebral protection in recent years.
The brief introduction of Folium Ginkgo extract and present Research: Semen Ginkgo (Ginkgo biloba), have another name called maidenhair tree, Gong Sunshu, duck's foot tree, the high megaphanerophyte of falling leaves, is one of Relict Plant in existing ancient times, have the title of gymnosperm " living fossil ".In Folium Ginkgo extract (being called for short EGB), medicinal component contains kind more than 200, and the effective ingredient that can bring into play unique pharmacologically active of being confirmed is at present mainly ginkgetin and Folium Ginkgo terpene lactones.The glucosides that flavone compound is mainly formed by connecting with oxygen glycosidic bond by monosaccharide such as the flavone aglycone such as Quercetin, kaempferol and isorhamnetin and they and glucoses forms, and the flavone that wherein glucosides form exists accounts for the more than 95% of extract flavone total content.Folium Ginkgo terpene lactones mainly comprises bilobalide and bilobalide.Bilobalide belongs to Diterpenes, mainly comprises Ginkgolide A. B. C (being called for short GA, GB, GC), all has unique C in their molecules
20" cage modle " structure, is made up of six five-membered rings; Bilobalide belongs to sesquiterpenoids, forms (being called for short BB) by four five-membered rings.Folium Ginkgo terpene lactones is distinctive compound in Semen Ginkgo, not yet finds for it to be so far present in other any plants.Studies show that Folium Ginkgo extract has the cerebral blood flow of increasing, removes oxygen-derived free radicals, ischemia resisting anoxia, anti-platelet activating factor (platelet activating factor, the effects such as the platelet aggregation of PAF) inducing, are widely used in the treatment of ischemic cardio cerebrovascular diseases clinically.
The brief introduction of Borneolum Syntheticum and present Research: Chinese medicine Borneolum Syntheticum is the processed goods (" borneol ") of Dipterocarpaceae aiphyllium Borneolum Syntheticum Dryobalanopsaromatica Gaerta.f. resin, or the extract of feverfew Blumeabalsamifera DC. (" Blumeae preparatum Tabellae "), or taking Camphora, Oleum Terebinthinae as raw material is through the product of being processed into (being called BORNEOLUM SYNTHETICUM) of chemosynthesis, natural Broneolum Syntheticum main constituent is Borneolum Syntheticum (bomeol), synthetic borneol is racemic modification, wherein contains a large amount of isoborneols (isobomeol).
Borneolum Syntheticum is water white transparency or the crisp crystallization of white translucent lamellar, and molecular weight is 154.25; Gas delicate fragrance, acrid in the mouth, cool; Tool volatility, lights generation dense smoke, and has band flare up flame.Easily molten in ethanol, chloroform or ether, almost insoluble in water.The traditional Chinese medical science think Borneolum Syntheticum acrid in the mouth hardship, be slightly cold, GUIXIN, spleen, lung, have the effect such as the refreshment of having one's ideas straightened out, logical all keys." herbal guiding principle wood " is recorded, and Borneolum Syntheticum has the effect of " logical all keys, loose stagnated fire ".Chang Zuowei in many Chinese patent medicines " guiding drug ", to increase the therapeutic effect of other medicines, i.e. the traditional Chinese medical science so-called " fragrance is walked to alter, and priming is up ", " a little less than the gesture of walking alone, assistant makes to gain merit ".Research shows; Borneolum Syntheticum is rapid in gastrointestinal absorption; after being combined with glucuronic acid in vivo, excrete; because the oral rear blood brain barrier that sees through rapidly of Borneolum Syntheticum enters brain; there are some researches show; the drug matchings such as itself and ligustrazine, Moschus, SHIGEPU have certain cerebral protection; research prompting; Borneolum Syntheticum has the blood of change brain permeability; promote some active medicines to see through the effect of blood brain barrier; the bioavailability and the organ targeting that improve these medicines, increase its drug level in cerebral tissue.Borneolum Syntheticum to central nervous system's effect with and promote the mechanism of action for the treatment of central nervous system disease medicine saturating blood brain barrier, need further further investigation, this not only has certain Research Significance to illustrating the drug effect of Borneolum Syntheticum, the more important thing is and utilizes effect of Borneolum Syntheticum " priming is up " to provide a kind of favourable instrument for developing brain targeting drug delivery system.In view of increasing of current Patients with Cardiovascular/Cerebrovascular Diseases, study the key areas that corresponding countermeasure has become current drug development research, the pharmacological action of further investigation Borneolum Syntheticum, the particularly study on mechanism to cardiovascular and cerebrovascular vessel and central nervous system, if illustrated these problems, this will open up a new direction for the treatment of cardiovascular and cerebrovascular disease and central nervous system disease.In Treatment of Central Nervous System Diseases, having certain clinical development is worth.
Summary of the invention
The object of the present invention is to provide a kind of Chinese medicine composition for the treatment of the Chinese medicine composition of ischemia apoplexy, this treatment ischemia apoplexy in the application of preparing in the compound oral administration preparation for the treatment of ischemia apoplexy, for the treatment of cardiovascular and cerebrovascular disease, in improving Folium Ginkgo extract drug effect, can improve its bioavailability in vivo.Pharmacodynamic experiment proves, with the compound recipe of Folium Ginkgo extract and Borneolum Syntheticum composition not only drug effect obviously strengthen.The present invention also provides the preparation method of above-mentioned Chinese medicine composition compound oral administration preparation.
The technical scheme that completes foregoing invention task is, a kind of Chinese medicine composition for the treatment of ischemia apoplexy, is characterized in that, the mass ratio composition of described treatment ischemia apoplexy composition material is, Folium Ginkgo extract: Borneolum Syntheticum=1.5-2.5:1.
The application recommend raw materials quality than composition be, Folium Ginkgo extract: Borneolum Syntheticum=2:1.
The Chinese medicine composition for the treatment of ischemia apoplexy of the present invention is compound oral administration preparation.This compound oral administration preparation can be the dosage forms such as tablet, granule, soft capsule, drop pill.
While making compound oral administration preparation, in the component of this compositions, also have: the conventional pharmaceutic adjuvants such as excipient, fluidizer, flavoring agent, dispersant, emulsifying agent.
Wherein, excipient is selected from: starch, dextrin or carboxymethylstach sodium; Fluidizer is selected from: magnesium stearate; Flavoring agent is selected from: lactose; Dispersant is selected from: non-ionic surface active agent, for example, poloxamer; Emulsifying agent is selected from: polyglycols glyceride, Brij30 or polyoxyethylene castor oil, preferably hydrophilic and oleophilic amphoteric compound polyglycols glyceride.
In this compositions, according to the difference of dosage form, crude drug is also different from the weight ratio composition of various adjuvants.Following ratio can be for reference:
Mixture:
Folium Ginkgo extract and Borneolum Syntheticum mix powder: 20% ethanol weight ratio=1:10;
Tween 80 accounts for 2% of ethanol weight ratio;
Protein sugar accounts for 0.3% of ethanol weight ratio;
Emulsion:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: emulsifying agent: oil phase: the weight ratio=10:10:25:75 of water;
Suspensoid:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=20:10 of suspending agent;
In suspending agent, xanthan gum: low-viscosity hydroxypropylmethylc,llulose: the weight ratio=2:1:1 of sodium lauryl sulphate;
Tablet:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1～2 of adjuvant;
Granule:
Ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: Icing Sugar: CMS-Na: syrup weight ratio is 2:1:1:4:1:2;
Capsule:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:(0.5～2 of adjuvant);
Soft capsule:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=10:20 of adjuvant;
Drop pill:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=(5～25) of substrate: (50～75).
The major advantage of this compositions is that Borneolum Syntheticum can improve the distribution of Folium Ginkgo extract in brain, increases Folium Ginkgo extract effective ingredient bioavailability in vivo, improves its curative effect.The compositions of Folium Ginkgo extract and Borneolum Syntheticum is made oral formulations by the present invention, has advantages of simple and easy to do.
Folium Ginkgo extract is commercially available, meets Chinese Pharmacopoeia flavonoid of ginkgo biloba > 24%, the regulation of Folium Ginkgo terpene lactones > 6%.
Borneolum Syntheticum is the commercially available prepared slices of Chinese crude drugs that meet Chinese Pharmacopoeia standard.
The technical scheme that completes second invention task of the application is: the application of the Chinese medicine composition of above-mentioned treatment ischemia apoplexy in the compound oral administration preparation of preparation treatment ischemia apoplexy.
The technical scheme that completes the 3rd invention task of the application is: the preparation method of the Chinese medicine composition compound oral administration preparation of above-mentioned treatment ischemia apoplexy, it is characterized in that, and step is as follows:
(1). ginkgo leaf extract powder, grind to form the borneol powder of fine powder, with auxiliary materials and mixing;
(2). add soft material or fluid;
(3). film-making agent, granule processed, drop pill, or record capsule;
(4). tablet, granule, drop pill, or the needed subsequent technique of capsule.
Specifically, the preparation method of various dosage forms is as follows respectively:
Mixture:
Folium Ginkgo extract and Borneolum Syntheticum mix powder, grind to form fine powder, stirs evenly with 20% ethanol of 10 times of amounts, adds the tween 80 of weight ratio 2%, fully stirs, and leaves standstill 12h, filters, and filtrate is for subsequent use.The protein sugar that adds weight ratio 0.3%, boils 30min, lets cool, and filters, then adding distil water is quantitative, embedding, 100 DEG C, 30min, sterilizing and get final product.
Emulsion:
Selection Oleum Ricini is oil phase, and polyoxyethylene sorbitan monoleate is emulsifying agent, and oleic acid (OA) is as stabilizing agent, and glycerol is osmotic pressure regulator.Folium Ginkgo extract Borneolum Syntheticum mixture fine powder, emulsifying agent, stabilizing agent are dissolved in Oleum Ricini as oil phase, glycerol is scattered in water for injection as water, be biphasely preheated to respectively 70 DEG C, oil phase is slowly added to water, after high-speed stirred, make colostrum; After homogeneous 3 times of high pressure homogenizer 10000psi, fill is to infusion bottle, sterilizing, and lower point of hundred grades of laminar flows are filled in office preparation bottle.
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: emulsifying agent: oil phase: the weight ratio=10:10:25:75 of water.
Suspensoid:
Folium Ginkgo extract Borneolum Syntheticum mixture fine powder is appropriate, crosses 100 mesh sieves; After separately getting adjuvant and pulverizing, cross respectively 100 mesh sieves, add the rear mixer of all putting into fully to mix by the recipe quantity equivalent dilution method that progressively increases, on inspection intermediate up-to-standard after, be sub-packed in aluminum-plastic composite membrane bag heat-sealing by specification.Wherein, xanthan gum, low-viscosity hydroxypropylmethylc,llulose, sodium lauryl sulphate are suspending agent.
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=20:10 of suspending agent;
In suspending agent, xanthan gum: low-viscosity hydroxypropylmethylc,llulose: the weight ratio=2:1:1 of sodium lauryl sulphate;
Tablet:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1～2 of adjuvant;
(1). ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: starch: dextrin: CMS-Na(%) be 1:2:1:0.5:1, add lactose, starch, dextrin, CMS-Na(carboxymethyl starch sodium), mix;
(2). add 40% ethanol, soft material processed;
(3). cross 18 mesh sieves, granulation granulate;
(4). added weight, than 1% magnesium stearate, mixes tabletting and obtains plain sheet;
(5). plain sheet is poured in pot, started coating pan, after the about 5min of plain sheet preheating, control coating solution flow velocity well, start spray coating (after the about 0.15g of plain sheet average weight gain), the about 2h of coating;
(6). all wrap to plain sheet, with the alcoholic solution polishing of weight ratio 2% dimethicone, get product.
Granule:
(1). ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: Icing Sugar: CMS-Na(%): syrup weight ratio is 2:1:1:4:1:2;
(2). in pot, prepare weight ratio 50% syrup sizing mixing, weight ratio 15% starch slurry, lets cool, stand-by;
(3). get the supplementary material of having got ready, granulate with wet granulation and oscillating granulator, in trough type mixing machine, add successively Icing Sugar, medicine, starch, lactose, CMS-Na to be first dry mixed 10 minutes, then add 50% cold syrup and 15% cold starch slurry granulation;
The disposable solution that adds 50% cold syrup and 15% starch slurry mix homogeneously, stirs and is granulation into suitable soft material;
Granulate with oscillating granulator, granulation screen cloth 16 orders, are dried;
(4). by dry granule, by 14 eye mesh screen granulate, magnesium stearate joins in the granule of whole good grain in always mixed, to obtain final product.
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1～2 of adjuvant.
Capsule:
Folium Ginkgo extract Borneolum Syntheticum mixture fine powder is appropriate, all crosses 80 mesh sieves with adjuvant, and mix homogeneously, adds appropriate wetting agent, granulates with 18 mesh sieves, and 50 DEG C of oven dry, arrange, and fill capsule No. 1.
Soft capsule:
(1). ginkgo leaf extract powder and grind to form the borneol powder of fine powder, adds decentralized photo and the continuous phase of recipe quantity;
(2). under room temperature, stir 10-20min and become fluid;
(3). mixing speed is 1500-3000rpm/min, pours into capsule and get final product.
Continuous phase used is polyglycols glyceride, Brij30 or polyoxyethylene castor oil, preferably hydrophilic and oleophilic amphoteric compound polyglycols glyceride, and decentralized photo used is poloxamer.
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=10:20 of adjuvant.
Drop pill:
Through prerun, the optimised process optimizing is that coolant is methyl-silicone oil, and PEG4000 is 1:1 with PEG6000 ratio, medicine and substrate ratio 1:4, and 85 DEG C of feed temperatures, 10 ± 2 DEG C of coolant temperatures, dripping distance is 4cm.Take a certain amount of PEG4000 and PEG6000 is placed in the thermostat water bath of uniform temperature in prescription ratio, after the complete melting of substrate mixes, add a certain amount of ginkgo leaf extract powder and the borneol powder that grinds to form fine powder, stir until the complete melting of medicine rapidly, splash in condensing agent methyl-silicone oil with certain speed by fixing bore drop pill, after its condensation molding, collect drop pill and wipe surperficial liquid paraffin with oil-Absorbing Sheets, under room temperature, naturally dry and obtain drop pill finished product.
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=5～25:50～75 of substrate.
Pharmacodynamic experiment of the present invention:
1. experiment material
1.1. reagent
Folium Ginkgo extract (flavonoid of ginkgo biloba 26.01%, bilobalide content 7.32%, Xuzhou Heng Kai Semen Ginkgo Products Co., Ltd); Borneolum Syntheticum (Nanjing University of Traditional Chinese Medicine's traditional Chinese medical science hall); Red tetrazolium (TTC), nimodipine tablet (the large pharmacy of Nanjing Yi Feng).
1.2 instrument
PA1204B electronic balance (Shanghai Precision Scientific Apparatus Co., Ltd); HH-6 digital display thermostat water bath (high honour instrument manufacturing company limited of Jintan City of Jiangsu Province); Canon camera.
1.3 laboratory animal
Clean level SD rat, male, body weight 300～500g.
2 statistical methods
Each group experimental data with
represent, adopt SPSS11.5 statistical package to carry out variance analysis, between many groups, relatively adopt between two q inspection.
3. method
The preparation of 3.1 fishing lines
Reference literature method, nylon wire one end of a long 50mm, diameter 0.30mm is sticked into all-purpose adhesive smooth spherical, and apart from 18.0mm place, pommel labelling, for subsequent use after alcohol wipe.
The preparation of 3.2 models
Rat is divided into 7 groups at random, i.e. model control group, sham operated rats, Folium Ginkgo extract group, Folium Ginkgo extract compatibility Borneolum Syntheticum group (Borneolum Syntheticum low dosage), Folium Ginkgo extract compatibility Borneolum Syntheticum group (dosage in Borneolum Syntheticum), Folium Ginkgo extract compatibility Borneolum Syntheticum group (Borneolum Syntheticum high dose), positive drug group (nimodipine).Above-mentioned each group of medicine is all configured to desired concn with normal saline, gastric infusion, and 7d continuously, operation in the 7th day, postoperative 30min is administered once again.The method of Longa is improved, and prepares this model with internal carotid artery bolt collimation method.Rat 10% chloral hydrate anesthesia, face upward position fixing, cervical region median incision, cut after skin, blunt separation, find out right carotid (CCA), continue to separate downwards and ligation external carotid artery (ECA) and the each branch of external carotid artery (occipital artery, superior thyroid artery, lingual artery and facial artery), peel off gently vagus nerve, isolate internal carotid artery (ICA) and arteria pterygopalatina, ECA proximal part is for line, press from both sides and close ICA and CCA with bulldog clamp, cut an osculum at ECA apart from ICA2mm place, the line bolt preparing is inserted to ECA and enters CCA, light bundle for line, prevent hemorrhage, cut off ECA, unclamp the bulldog clamp of ICA, traction ECA, make itself and ICA approximately in line, pumpback fishing line gently, make it along entering ICA, (attention avoids fishing line to enter arteria pterygopalatina to continue propelling downwards, until there is slight resistance).Now visible ICA stretches, fishing line insertion depth is about 18mm, show that fishing line is through middle cerebral artery (MCA) the initial segment, arrive anterior cerebral artery (ACA) near-end, block all blood of MCA for source, comprised the blood supply from ICA and ACA and posterior cerebral artery.Unclamp CCA bulldog clamp, tighten standby line, stay the long the end of a thread of 1cm outward, blacking, skin suture, steams again and raises.After ischemia 4h, pull out loop line bolt and pour into again, steam again nature and feed.Above process is all carried out in room temperature constant (24～25 DEG C) situation.
3.3 rat experiment cerebral ischemia behavior scoring methods
While pouring into again 4h, 24h, press.With reference to neuroethology standards of grading: (1) carry overhead approximately 1 chi of Mus tail, observe forelimb situation.Normal rat two forelimbs stretch to ground symmetrically.Have left shoulder inward turning, receipts person in left fore, is chosen as 4 points.Otherwise 0 point; (2) by sliding animal horizontalization floor, push away respectively a left side (or right) shoulder and, to side shifting, check the resistance that opposing promotes.Normal rat bilateral resistance is obviously symmetrical.When right shoulder moves to the left, find resistance descender, according to the difference of decline degree, be chosen as 1～3 point; (3) animal two forelimbs are put on a wire netting, observed the muscular tension of two forelimbs, normal rat two muscle of anterior limb tension force are obviously symmetrical.The obvious descender of left fore muscular tension according to the weight declining, be chosen as 1～3 point as found.
According to above standard scoring, 10 points of full marks, mark is higher, illustrates that the behavior disorder of animal is more serious.Scoring adopts single blind method.
Cerebral infarct size is measured in 3.4TTC dyeing
Each experimental group Mus is poured into 24h in ischemia 4h again and breaks end and get brain rapidly, cut after antinion, interval 2mm does 5 crown sections of brain continuously, put immediately stripping and slicing in 1%TTC normal saline, 37 DEG C of lucifuge constant-temperature incubation 30min by cerebral tissue piece turn-over, cut ischemia part in the time of 15min after dyeing, divide the weight of the total brain of another name and ischemia part, calculate cerebral infarction rate (%).(TTC is reduced by mitochondrion catalase, can make normal structure dyeing take on a red color, and slough is white in color).
The mensuration of 3.5 brain water contents
Get brain and claim that cerebral tissue being placed in to 115 DEG C of electrically heated drying cabinets after weight in wet base dries to constant weight, claim dry weight, calculate brain water content: water content (%)=[(weight in wet base-dry weight)/weight in wet base] × 100%, cerebral index=(cutaneous horn weight/body weight) × 100.
Experimental result sees the following form:
The impact of table 1 on MACO cerebral infarction rate, brain water content, cerebral index
Note: represent P < 0.05 with model group comparison: *, * * represents P < 0.01.With the comparison of Folium Ginkgo group: # represents P < 0.05, and ## represents P < 0.01.
Experimental result by statistics Epidemiological Analysis shows, compared with model group, the cerebral infarction rate of each group and its have significant difference, show rat MACO modeling success, compared with Folium Ginkgo group, each Borneolum Syntheticum compatibility administration group and positive drug group and its all have significant difference, show compared with independent Folium Ginkgo extract, and compatibility Borneolum Syntheticum has significant superiority to treatment Ischemia Injury apoplexy.
For rat brain water content, compatibility Borneolum Syntheticum high dose group has also demonstrated good superiority.
Anxious poison experiment of the present invention:
1. experiment material
Folium Ginkgo extract (flavonoid of ginkgo biloba 26.01%, bilobalide content 7.32%, Xuzhou Heng Kai Semen Ginkgo Products Co., Ltd); Borneolum Syntheticum (Nanjing University of Traditional Chinese Medicine's traditional Chinese medical science hall); 0.5%CMC-Na.
SPF level kunming mice, body weight 18-22g, male and female half and half.
2. test method
The maximal dose of determining gastric infusion through a large amount of trial tests, each sample is configured to respectively the Cmax (37 DEG C) of response, and administration volume is 0.4ml/10g, blank group gavage equal-volume 0.5%CMC-Na.Get 36 KM mices, body weight 18～22g, male and female half and half, be divided at random 3 groups by body weight, every group 12, one night of fasting before experiment, freely drink water, give each group of mouse stomach administration, fasting 2h after administration by aforementioned dosage, tight mice reaction and the death condition of observing, and observe day by day the situations such as mice activity, feed, record dead animal number, Continuous Observation 14 days, in the 15th day, tested mice is put to death, dissect the pathological change of the major organs such as rear its heart of perusal, liver, spleen, lung, kidney, brain, gastrointestinal.
3. result of the test
With the comparison of blank group, administration group mice is comparatively peace and quiet of performance in 2h after medicine, and movable less, animal regular reflection exists, and has no the Novel presentation of other neural psychiatric systems.Test the 2nd day to the 14th day, the mental status of respectively organizing mice is good, and hair color is bright and clean, and freely, food ration, feces show no obvious abnormalities in activity, and in mouth and nose, without abnormal secretions, mucosa, without hyperemia, does not occur other poisoning symptoms and death condition.After putting to death animal, dissect macroscopy, the main organs such as the heart, liver, spleen, lung, kidney, brain, gastrointestinal are not all found pathological change.It is 20.46g/kg to the day maximum dosage-feeding of Folium Ginkgo extract that this experiment records mice, and after compatibility Borneolum Syntheticum, the day maximum dosage-feeding of Folium Ginkgo extract is 15.03g/kg.
4. discuss
Result of the test demonstration, than Folium Ginkgo extract group, after compatibility Borneolum Syntheticum, mice decreases to a day maximum dosage-feeding for Folium Ginkgo extract.This may have necessarily relevantly with Borneolum Syntheticum dosage is excessive, makes to stimulate each organ so that causes deadly, and the dose that this also points out us should note controlling well Borneolum Syntheticum in the time of clinical application improves therapeutic effect under the prerequisite of medication that ensures safety.Bioavailability experiment of the present invention:
1. experiment material
1.1 instrument
Agilent LC-MS/MS liquid phase GC-MS (HPLC1290/MS6460); Vortex mixer (XW-80A, Qingpu Shanghai Hu Xi instrument plant); Anke TGL-16G high speed centrifuge (Anting Scientific Instrument Factory, Shanghai); Adjustable Nitrogen evaporator (DCY-24G, Qingdao Hai Ke Instrument Ltd.); 100000/analytical balance (Nanjing is with Ma Neili instrument and equipment company limited); HH-6 digital display thermostat water bath (high honour instrument manufacturing company limited of Jintan City of Jiangsu Province).
1.2 medicines, reagent and animal
Folium Ginkgo extract (flavonoid of ginkgo biloba 26.01%, bilobalide content 7.32%, Xuzhou Heng Kai Semen Ginkgo Products Co., Ltd); Borneolum Syntheticum (Nanjing University of Traditional Chinese Medicine's traditional Chinese medical science hall); Domperidone (interior mark), Ginkgo total lactones reference substance GA, GB, GC, BB(are purchased from food and medicine inspection institute of Jiangsu Province); Ammonium acetate, ethyl acetate, methanol (chromatographically pure); Water is pure water heartily; Other reagent are analytical pure.
Clean level SD rat, Quan Xiong, body weight 200～220g.The quality certification number: scxk (Soviet Union) 2008-0033.
2 methods and result
The preparation of 2.1 reference substance solution
The preparation of series concentration bilobalide reference substance solution: precision weighing bilobalide GA, GB, GC, the each 10mg of BB reference substance are placed in 10mL volumetric flask respectively, add appropriate dissolve with methanol, after supersonic cooling, add methanol to graduation mark, four kinds of mark liquid are mixed, after shaking up, obtain the mixed mark of 250 μ g/ml storing solution, put refrigerator cold-storage, treat that the used time is diluted to desired concn by mobile phase.
The preparation of mark liquid in domperidone: precision weighing domperidone reference substance, 10mg is placed in 10ml volumetric flask, adds appropriate dissolve with methanol, after supersonic cooling, add methanol to graduation mark, after shaking up, obtain mark storing solution in 1mg/ml, put refrigerator cold-storage, treat that the used time is diluted to desired concn by mobile phase.
2.2 dosage regimens and plasma sample processing method
Each six the SD rats of Folium Ginkgo extract group and compatibility group, male, gastric infusion, dosage is Folium Ginkgo extract 1000mg/kg, compatibility group content of bornyl alcohol is 1000mg/kgGBE+500mg/kg Borneolum Syntheticum.Medicine dissolution is in 0.5% CMC-Na, and dosage is 1ml/100g.In 5,10,20,30,45,60,90,120,180,240,300,360,600,1440min gets respectively blood 0.5ml, join (blood plasma of 0.5ml adds the heparin sodium of 10 μ l) in the sub warhead that contains heparin sodium the centrifugal 6min of 5000rpm, separated plasma, get supernatant, be stored in-20 DEG C of Refrigerator stores, for subsequent use.
The plasma sample vortex mixed of thawing, adds mark liquid (50 μ g/ml domperidone) in 10 μ l, vortex 1min in each 100 μ l samples, add again 1ml ethyl acetate, vortex 3min, the centrifugal 5min of 12000rpm, gets upper strata organic layer, nitrogen dries up, with 100 μ l mobile phases redissolution, vortex 90s, the centrifugal 5min of 12000rpm, get supernatant, sample introduction.
The foundation of Folium Ginkgo terpene lactones blood drug level HPLC-MS/MS analytical method in 2.3 plasma containing drugs
2.3.1 chromatographic condition:
Adopt C
8chromatographic column (m), mobile phase is methanol-6mM ammonium acetate (70:30) to 4.6mm × 250mm × 5 μ, flow velocity: 0.7ml/min, and column temperature: 40 DEG C, sample size: 20 μ l.
2.3.2 mass spectrum condition:
Electron spray ionisation (ESI); Gas temp:250 DEG C, Gas folw:5.0L/min, Nebulizer:20PSI, Sheath gas flow:250 DEG C, Capillary:3500V.Select ion detection (MRM) pattern, adopt anion mode to detect, m/z is GA:467.0-351.0, GB:423.0-367.0, GC:439.0-383.0, BB:325.0-163.0, IS:424.0-166.9.
2.3.3 methodological study:
2.3.3.1 specificity test
Get rat blank plasma, blank plasma adds Ginkgo total lactones mixed mark reference substance and interior mark reference substance, Folium Ginkgo extract experimental group blood plasma, and each 5 parts of Borneolum Syntheticum compatibility group blood plasma, by plasma sample disposal methods, measures.Under above-mentioned chromatographic condition, bilobalide GA, GB, GC, BB and domperidone all can well separate with the assorted peak of albumen in blood plasma, endogenous material, other compositions in Folium Ginkgo extract and the cylinder metabolism-ure of these compositions and associativity composition are all noiseless, its retention time is all consistent with reference substance, see Fig. 1 and Fig. 2-1,2-2,2-3,2-4,2-5, and Fig. 3-1,3-2,3-3,3-4,3-5.Therefore this method has good specificity.
2.3.3.2 standard curve and the range of linearity
Get mixed mark storing solution, make the mixed mark reference substance of variable concentrations by multiple dilution method, join in rat blank plasma, process by " sample treatment ".Obtain ultimate density and be respectively 2,5,10,25,50,100,250,500,1000,2000 and the QC sample of 5000ng/ml, low middle high level is respectively 5ng/ml, 50,1000ng/ml.
LC-MS/MS analyzes mensuration, concentration (X) with bilobalide in blood plasma is weighted least square regression to bilobalide and interior target peak area ratio (Y), the standard curve that obtains bilobalide GA in blood plasma is Y=0.000321X+0.006625, range of linearity 2-1000ng/ml, detectability 2ng/ml, R
2=0.9955; The standard curve of GB is Y=0.0045X+0.0248, range of linearity 2-100ng/ml, detectability 2ng/ml, R
2=0.9929; The standard curve of GC is Y=0.0023X+0.0171, range of linearity 2-100ng/ml, detectability 2ng/ml, R
2=0.9903; The standard curve of BB is Y=0.001485X+0.315734, range of linearity 100-2000ng/ml, detectability 2ng/ml, R
2=0.9870.
2.3.3.3 precision and accuracy test
2.3.3.3.1 accuracy test
Select the mixed mark quality-control sample of a low middle Senior Three concentration, sample introduction 6 times, accuracy in computation RSD (%) value.In Table
Table 2 bilobalide extracts accuracy test
2.3.3.3.2 precision test
Calculate respectively withinday precision and the day to day precision of sample, in Table.
Table 3 bilobalide extracts precision test
2.3.3.4 sample stability is investigated
Prepare each 5 parts of basic, normal, high 3 kinds of concentration plasma containing drug samples, investigate respectively it under room temperature, freezing and Freezing-Melting Condition and place the stability of depositing 7d under-20 DEG C of freezing conditions, measure with LC-MS/MS after treatment, investigate the concordance of chromatographic peak peak area ratio.Result shows, the content of bilobalide GA, GB, GC and BB is original content between 90.8%～102.7%.Under DEG C freezing condition of bilobalide GA, GB, GC and BB plasma sample-20, deposit 7d stable.
2.3.3.5 extraction recovery test
Prepare the bilobalide plasma sample of concentration in basic, normal, high 3, after processing by " sample treatment ", measure its absolute recovery through LC-MS/MS, in Table.
The extraction recovery test of table 4 bilobalide and domperidone
2.4 result of the test
After the isodose Folium Ginkgo extract of rat oral gavage and Folium Ginkgo compatibility Borneolum Syntheticum, 5,10,20,30,45,60,90,120,180,240,300,360,600, each curve while getting the blood drug level medicine of blood point of 1440min, see Fig. 4-1,4-2,4-3,4-4.
2.5 pharmacokinetic parameters are calculated
Blood drug level-the time data recording is analyzed to matching with Dass2.0 statistical package, relatively adopt between two t inspection between many groups, main pharmacokinetic parameters is in table 4.
Table 5 pharmacokinetic parameters (n=6)
Result of the test shows, after single oral administration, compatibility Borneolum Syntheticum has certain influence to the pharmacokinetic parameters of bilobalide in Folium Ginkgo extract, wherein, with the most remarkable on the impact of active component GB, plasma concentration significantly raises, especially post-drug period, compared with Folium Ginkgo extract group, AUC
(0-∞), MRT
(0-t)and CLz/F has significant difference (P<0.01), AUC
(0-∞)improve approximately 50%.Borneolum Syntheticum can increase the absorption of bilobalide as can be seen here, improves bilobalide bioavailability.
3 discuss
The biological sample processing method that this experiment adopts is organic reagent extraction, investigate respectively the index composition extraction ratio after methyl tert-butyl ether, ethyl acetate, ether processing plasma sample, result of the test shows, during using ethyl acetate as extractant, the extraction yield of bilobalide index composition is higher, and blood plasma disturbs less.
Pass through By consulting literatures, herein with reference to the research method of Jia Shu Xie etc., adopt HPLC-MS/MS multiple techniques, under MRM pattern simultaneously to Folium Ginkgo extract in Ginkgo total lactones four kinds of index composition GA, GB, GC, BB and interior marks carry out quantitatively, the method is highly sensitive through investigating, favorable reproducibility, easy and simple to handle, result is accurate, has higher specificity, meets the correlation analysis requirement of pharmacopeia to biological sample.
After single oral administration, the impact of the pharmacokinetic parameters of compatibility Borneolum Syntheticum on bilobalide in Folium Ginkgo extract, may be that Borneolum Syntheticum reduces bilobalide elimination behavior in vivo, but the absorption behavior of alone group and compatibility group medicine is without significant difference, about improving machine-processed process in the body of bilobalide bioavailability in Folium Ginkgo extract, Borneolum Syntheticum compatibility awaits further discussion.
Brain of the present invention distributes and tests:
1. experiment material
1.1 instrument
Agilent LC-MS/MS liquid phase GC-MS (HPLC1290/MS6460); Vortex mixer (XW-80A, Qingpu Shanghai Hu Xi instrument plant); Anke TGL-16G high speed centrifuge (Anting Scientific Instrument Factory, Shanghai); Adjustable Nitrogen evaporator (DCY-24G, Qingdao Hai Ke Instrument Ltd.); 100000/analytical balance (Nanjing is with Ma Neili instrument and equipment company limited); XHF-D high speed disperser (Xin Yi biotech inc, Ningbo).
1.2 medicines, reagent and animal
Folium Ginkgo extract (flavonoid of ginkgo biloba 26.01%, bilobalide content 7.32%, Xuzhou Heng Kai Semen Ginkgo Products Co., Ltd); Borneolum Syntheticum (Nanjing University of Traditional Chinese Medicine's traditional Chinese medical science hall); Domperidone (interior mark), Ginkgo total lactones reference substance GA, GB, GC, BB(are purchased from food and medicine inspection institute of Jiangsu Province); Ammonium acetate, ethyl acetate, methanol (chromatographically pure); Water is pure water heartily; Other reagent are analytical pure.
Clean level SD rat, Quan Xiong, body weight 200～220g, the quality certification number: scxk (Soviet Union) 2008-0033.
2 methods and result
The preparation of 2.1 reference substance solution
The preparation of series concentration bilobalide reference substance solution: precision weighing bilobalide GA, GB, GC, the each 10mg of BB reference substance are placed in 10mL volumetric flask respectively, add appropriate dissolve with methanol, after supersonic cooling, add methanol to graduation mark, four kinds of mark liquid are mixed, after shaking up, obtain the mixed mark of 250 μ g/ml storing solution, put refrigerator cold-storage, treat that the used time is diluted to desired concn by mobile phase.
The preparation of mark liquid in domperidone: precision weighing domperidone reference substance, 10mg is placed in 10ml volumetric flask, adds appropriate dissolve with methanol, after supersonic cooling, add methanol to graduation mark, after shaking up, obtain mark storing solution in 1mg/ml, put refrigerator cold-storage, treat that the used time is diluted to desired concn by mobile phase.
2.2 dosage regimens and brain tissue sample's processing method
Each 16 the SD rats of Folium Ginkgo extract group and compatibility group, male, establish 30,60,120 and 360min time point, four of every time points, gastric infusion, dosage is Folium Ginkgo extract 1000mg/kg, compatibility group content of bornyl alcohol is 1000mg/kgGBE+500mg/kg Borneolum Syntheticum.Medicine dissolution is in 0.5% CMC-Na, and dosage is 1ml/100g.In 30,60,120 and the de-cervical vertebra of 360min put to death rat, get brain, brain is separated from brain stem, cold PBS buffer carefully rinses, filter paper blots, and is stored in-20 DEG C of Refrigerator stores, for subsequent use.
The 0.3g that weighs of the brain tissue sample of thawing, the homogenate of 1ml normal saline, adds mark liquid (50 μ g/ml domperidone) in 20 μ l, vortex 1min, then add 3ml ethyl acetate, vortex 3min, the centrifugal 5min of 12000rpm, get upper strata organic layer 1.5ml, nitrogen dries up, with 100 μ l mobile phases redissolution, vortex 3min, the centrifugal 5min of 12000rpm, gets supernatant, sample introduction.
The foundation of Folium Ginkgo terpene lactones blood drug level HPLC-MS/MS analytical method in 2.3 pastille cerebral tissue
2.3.1 chromatographic condition:
Adopt C
8chromatographic column (m), mobile phase is methanol-6mM ammonium acetate (70:30) to 4.6mm × 250mm × 5 μ, flow velocity: 0.7ml/min, and column temperature: 40 DEG C, sample size: 20 μ l.
2.3.2 mass spectrum condition:
Electron spray ionisation (ESI); Gas temp:250 DEG C, Gas folw:5.0L/min, Nebulizer:20PSI, Sheath gas flow:250 DEG C, Capillary:3500V.Select ion detection (MRM) pattern, adopt anion mode to detect, m/z is GA:467.0-351.0, GB:423.0-367.0, GC:439.0-383.0, BB:325.0-163.0, IS:424.0-166.9.
2.3.3 methodological study:
2.3.3.1 specificity test
Get the blank brain homogenate of rat, in blank brain homogenate, add Ginkgo total lactones mixed mark reference substance and interior mark reference substance, Folium Ginkgo extract experimental group brain homogenate, each 5 parts of Borneolum Syntheticum compatibility group brain homogenate, by the processing of brain homogenate sample treatment, measures.Under above-mentioned chromatographic condition, bilobalide GA, GB, GC, BB and domperidone all can well separate with the assorted peak of albumen in brain homogenate, endogenous material, other compositions in Folium Ginkgo extract and the cylinder metabolism-ure of these compositions and associativity composition are all noiseless, its retention time is all consistent with reference substance, see Fig. 5 and Fig. 6-1,6-2,6-3,6-4,6-5, and Fig. 7-1,7-2,7-3,7-4,7-5.Therefore this method has good specificity.
2.3.3.2 standard curve and the range of linearity
Get mixed mark storing solution, make the mixed mark reference substance of variable concentrations by multiple dilution method, join in the blank brain homogenate of rat, process by " sample treatment ".Obtain ultimate density and be respectively 2,5,10,25,50,100,250,500,1000,2000 and the QC sample of 5000ng/ml, low middle high level is respectively 5ng/ml, 50,1000ng/ml.
LC-MS/MS analyzes mensuration, concentration (X) with bilobalide in cerebral tissue is weighted least square regression to bilobalide and interior target peak area ratio (Y), the standard curve that obtains bilobalide GA in cerebral tissue is Y=0.0003X+0.0037, range of linearity 2-5000ng/ml, detectability 2ng/ml, R
2=0.9988; The standard curve of GB is Y=0.002X+0.0243, range of linearity 2-250ng/ml, detectability 2ng/ml, R
2=0.9923; The standard curve of GC is Y=0.0007X+0.0138, range of linearity 2-2000ng/ml, detectability 2ng/ml, R
2=0.9968; The standard curve of BB is Y=0.0015X+0.0083, range of linearity 2-2000ng/ml, detectability 2ng/ml, R
2=0.9985.
2.3.3.3 precision and accuracy test
2.3.3.3.1 accuracy test
Select the mixed mark quality-control sample of a low middle Senior Three concentration, sample introduction 6 times, accuracy in computation RSD (%) value.In Table
Table 6 bilobalide extracts accuracy test
2.3.3.3.2 precision test
Calculate the withinday precision of sample in Table.
Table 7 bilobalide extracts precision test
2.3.3.4 sample stability is investigated
Prepare each 5 parts of basic, normal, high 3 kinds of concentration pastille brain tissue homogenate samples, investigate respectively it under room temperature, freezing and Freezing-Melting Condition and place the stability of depositing 7d under-20 DEG C of freezing conditions, measure with LC-MS/MS after treatment, investigate the concordance of chromatographic peak peak area ratio.Result shows, the content of bilobalide GA, GB, GC and BB is original content between 90.8%～102.7%.Under bilobalide GA, GB, GC and BB brain tissue homogenate sample-20 DEG C freezing condition, deposit 7d stable.
2.3.3.5 extraction recovery test
Prepare the bilobalide brain tissue homogenate sample of concentration in basic, normal, high 3, after processing by " sample treatment ", measure its absolute recovery through LC-MS/MS, in Table.
The extraction recovery test of table 8 bilobalide and domperidone
2.4 result of the test
After the isodose Folium Ginkgo extract of rat oral gavage and Folium Ginkgo compatibility Borneolum Syntheticum, 30,60,120, the brain distribution situation of each time point of 360min, see Fig. 8-1,8-2,8-3,8-4.
Result of the test shows, after single oral administration, compatibility Borneolum Syntheticum is distributed with certain influence to the rat cerebral tissue of bilobalide in Folium Ginkgo extract, wherein, with comparatively remarkable on the impact of active component GB and GC, has significant difference.
3 discuss
Borneolum Syntheticum usually uses as " priming " and other drug compatibility in Chinese traditional treatment, to increase the curative effect of other drug, brings into play the effect of its " assistant makes ".Modern pharmacological research proves, Borneolum Syntheticum can be by affect the links such as absorption, distribution and the metabolism of body to medicine, thus the pharmacokinetics of change other drug.The impact of Borneolum Syntheticum on bilobalide constituents content in rat cerebral tissue in Folium Ginkgo extract after oral administration studied in this research first, result show Borneolum Syntheticum can increase bilobalide in IC distribution, this also provides strong foundation for Borneolum Syntheticum compatibility Folium Ginkgo extract improves its treatment ischemia apoplexy drug action.Borneolum Syntheticum can promote blood brain barrier physiological open, improves the concentration of other drug in cerebrospinal fluid, and its mechanism may relate to the expression of induction brain microvessel endothelial cells in vitro nitricoxide synthase; Change and participate in the cellular morphology structure of composition blood brain barrier and mutual connected mode, induce it to gulp down drink function, suppress P-glycoprotein etc., await further discussion.
Brief description of the drawings
Fig. 1 is blank brain homogenate chromatogram;
Fig. 2-1,2-2,2-3,2-4,2-5 are that blank brain homogenate adds GA, GB, GC, BB and IS reference substance chromatogram;
Fig. 3-1,3-2,3-3,3-4,3-5 are brain tissue sample (GA, GB, GC, BB, IS);
Fig. 4-1,4-2,4-3,4-4 are the blood drug level of bilobalide after Folium Ginkgo extract and Borneolum Syntheticum compatibility oral administration;
Fig. 5 is blank brain homogenate chromatogram;
Fig. 6-1,6-2,6-3,6-4,6-5 are that blank brain homogenate adds GA, GB, GC, BB and IS reference substance chromatogram;
Fig. 7-1,7-2,7-3,7-4,7-5 are brain tissue sample (GA, GB, GC, BB, IS);
Fig. 8-1,8-2,8-3,8-4 are the blood drug level of bilobalide after Folium Ginkgo extract and Borneolum Syntheticum compatibility oral administration.
Detailed description of the invention
Folium Ginkgo extract and Borneolum Syntheticum mix powder, grind to form fine powder, carries out percolation with 75% ethanol of 10 times of amounts by fluid extract under " Chinese Pharmacopoeia " version annex IO in 2010 and extractum percolation.Collect percolate, filter, filtrate recycling ethanol is to the ratio of weight ratio 1:1(medicinal liquid with crude drug, as follows), add the tween 80 of weight ratio 2%, fully stir, leave standstill 12h, filter, filtrate is for subsequent use.The protein sugar that adds weight ratio 0.3%, boils 30min, lets cool, and filters, then adding distil water is quantitative, embedding, 100 DEG C, 30min, sterilizing and get final product.
Selection Oleum Ricini is oil phase, and polyoxyethylene sorbitan monoleate is emulsifying agent, and oleic acid (OA) is as stabilizing agent, and glycerol is osmotic pressure regulator.Folium Ginkgo extract Borneolum Syntheticum mixture fine powder, emulsifying agent, stabilizing agent are dissolved in Oleum Ricini as oil phase, glycerol is scattered in water for injection as water, be biphasely preheated to respectively 70 DEG C, oil phase is slowly added to water, after high-speed stirred, make colostrum; After homogeneous 3 times of high pressure homogenizer 10000psi, fill is to infusion bottle, sterilizing, and lower point of hundred grades of laminar flows are filled in office preparation bottle.
Wherein, Folium Ginkgo extract Borneolum Syntheticum mixture fine powder: emulsifying agent: oil phase: the weight ratio=10:10:25:75 of water.
Folium Ginkgo extract Borneolum Syntheticum mixture fine powder is appropriate, crosses 100 mesh sieves; After separately getting adjuvant and pulverizing, cross respectively 100 mesh sieves, add the rear mixer of all putting into fully to mix by the recipe quantity equivalent dilution method that progressively increases, on inspection intermediate up-to-standard after, be sub-packed in aluminum-plastic composite membrane bag heat-sealing by specification.Wherein, xanthan gum, low-viscosity hydroxypropylmethylc,llulose, sodium lauryl sulphate are suspending agent.
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=20:10 of suspending agent;
In suspending agent, xanthan gum: low-viscosity hydroxypropylmethylc,llulose: the weight ratio=2:1:1 of sodium lauryl sulphate.
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1～2 of adjuvant;
(1). ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: starch: dextrin: CMS-Na(%) be 1:2:1:0.5:1, add lactose, starch, dextrin, CMS-Na(carboxymethyl starch sodium), mix;
(2). add 40% ethanol, soft material processed;
(3). cross 18 mesh sieves, granulation granulate;
(4). added weight, than 1% magnesium stearate, mixes tabletting and obtains plain sheet;
(5). plain sheet is poured in pot, started coating pan, after the about 5min of plain sheet preheating, control coating solution flow velocity well, start spray coating (after the about 0.15g of plain sheet average weight gain), the about 2h of coating;
(6). all wrap to plain sheet, with the alcoholic solution polishing of weight ratio 2% dimethicone, get product.
(1). ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: Icing Sugar: CMS-Na(%): syrup weight ratio is 2:1:1:4:1:2;
(2). in pot, prepare weight ratio 50% syrup sizing mixing, weight ratio 15% starch slurry, lets cool, stand-by;
(3). get the supplementary material of having got ready, granulate with wet granulation and oscillating granulator, in trough type mixing machine, add successively Icing Sugar, medicine, starch, lactose, CMS-Na to be first dry mixed 10 minutes, then add 50% cold syrup and 15% cold starch slurry granulation;
The disposable solution that adds 50% cold syrup and 15% starch slurry mix homogeneously, stirs and is granulation into suitable soft material;
Granulate with oscillating granulator, granulation screen cloth 16 orders, are dried;
(4). by dry granule, by 14 eye mesh screen granulate, magnesium stearate joins in the granule of whole good grain in always mixed, to obtain final product.
Wherein, Folium Ginkgo extract Borneolum Syntheticum mixture fine powder: weight ratio=1:1～3 of adjuvant.
Folium Ginkgo extract Borneolum Syntheticum mixture fine powder is appropriate, all crosses 80 mesh sieves with adjuvant, and mix homogeneously, adds appropriate wetting agent, granulates with 18 mesh sieves, and 50 DEG C of oven dry, arrange, and fill capsule No. 1.
Embodiment 11, soft capsule:
(1). ginkgo leaf extract powder and grind to form the borneol powder of fine powder, adds decentralized photo and the continuous phase of recipe quantity;
(2). under room temperature, stir 10-20min and become fluid;
(3). mixing speed is 1500-3000rpm/min, pours into capsule and get final product.
Continuous phase used is polyglycols glyceride, Brij30 or polyoxyethylene castor oil, preferably hydrophilic and oleophilic amphoteric compound polyglycols glyceride, and decentralized photo used is poloxamer.
Wherein, Folium Ginkgo extract Borneolum Syntheticum mixture fine powder: the weight ratio=1:2 of adjuvant.
Embodiment 12, drop pill:
Through prerun, the optimised process optimizing is that coolant is methyl-silicone oil, and PEG4000 is 1:1 with PEG6000 ratio, medicine and substrate ratio 1:4, and 85 DEG C of feed temperatures, 10 ± 2 DEG C of coolant temperatures, dripping distance is 4cm.Take a certain amount of PEG4000 and PEG6000 is placed in the thermostat water bath of uniform temperature in prescription ratio, after the complete melting of substrate mixes, add a certain amount of ginkgo leaf extract powder and the borneol powder that grinds to form fine powder, stir until the complete melting of medicine rapidly, splash in condensing agent methyl-silicone oil with certain speed by fixing bore drop pill, after its condensation molding, collect drop pill and wipe surperficial liquid paraffin with oil-Absorbing Sheets, under room temperature, naturally dry and obtain drop pill finished product.
Wherein, Folium Ginkgo extract Borneolum Syntheticum mixture fine powder: weight ratio=5～25:50～75 of adjuvant.
Wherein, excipient is selected from: starch, dextrin or carboxymethylstach sodium; Fluidizer is selected from: magnesium stearate; Flavoring agent is selected from: lactose; Dispersant is selected from: non-ionic surface active agent, for example, poloxamer; Emulsifying agent is selected from: polyglycols glyceride, Brij30 or polyoxyethylene castor oil, preferably hydrophilic and oleophilic amphoteric compound polyglycols glyceride.
Embodiment 13, basic identical with above each embodiment, but according to the difference of dosage form, crude drug is also different from the weight ratio composition of various adjuvants; Each dosage form adjuvant ratio is as follows,
Mixture:
Folium Ginkgo extract and Borneolum Syntheticum mix powder: 20% ethanol weight ratio=1:10;
Protein sugar accounts for 0.3% of ethanol weight ratio;
Emulsion:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: emulsifying agent: oil phase: the weight ratio=10:10:25:75 of water;
Suspensoid:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=20:10 of suspending agent;
In suspending agent, xanthan gum: low-viscosity hydroxypropylmethylc,llulose: the weight ratio=2:1:1 of sodium lauryl sulphate;
Tablet:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1～2 of adjuvant;
Granule:
Ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: Icing Sugar: CMS-Na: syrup weight ratio is 2:1:1:4:1:2;
Capsule:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:0.5～2 of adjuvant;
Soft capsule:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=10:20 of adjuvant;
Drop pill:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=5～25:50～75 of substrate.
Claims (9)
1. a Chinese medicine composition for the treatment of ischemia apoplexy, is characterized in that, the mass ratio composition of described treatment ischemia apoplexy composition material is
,folium Ginkgo extract: Borneolum Syntheticum=1.5-2.5: 1.
2. the Chinese medicine composition for the treatment of ischemia apoplexy according to claim 1, is characterized in that, described raw materials quality compares composition and is, Folium Ginkgo extract: Borneolum Syntheticum=2: 1.
3. the Chinese medicine composition for the treatment of ischemia apoplexy according to claim 1, is characterized in that, the Chinese medicine composition of described treatment ischemia apoplexy is compound oral administration preparation, and this compound oral administration preparation is tablet, granule, soft capsule or drop pill.
4. the Chinese medicine composition for the treatment of ischemia apoplexy according to claim 3, is characterized in that, also has: excipient, fluidizer, flavoring agent, dispersant, emulsifying agent in the component of described compositions.
5. the Chinese medicine composition for the treatment of ischemia apoplexy according to claim 4, is characterized in that, wherein, excipient is selected from: starch, dextrin or carboxymethylstach sodium; Fluidizer is selected from: magnesium stearate; Flavoring agent is selected from: lactose; Dispersant is selected from: non-ionic surface active agent, for example, poloxamer; Emulsifying agent is selected from: polyglycols glyceride, Brij30 or polyoxyethylene castor oil, preferably hydrophilic and oleophilic amphoteric compound polyglycols glyceride.
6. the Chinese medicine composition for the treatment of ischemia apoplexy according to claim 4, is characterized in that, in this compositions, according to the difference of dosage form, crude drug is also different from the weight ratio composition of various adjuvants; Each dosage form adjuvant ratio is as follows,
Mixture:
Folium Ginkgo extract and Borneolum Syntheticum mix powder: 20% ethanol weight ratio=1:10;
Tween 80 accounts for 2% of ethanol weight ratio;
Protein sugar accounts for 0.3% of ethanol weight ratio;
Emulsion:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: emulsifying agent: oil phase: the weight ratio=10:10:25:75 of water;
Suspensoid:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=20:10 of suspending agent;
In suspending agent, xanthan gum: low-viscosity hydroxypropylmethylc,llulose: the weight ratio=2:1:1 of sodium lauryl sulphate;
Tablet:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1 ~ 2 of adjuvant;
Granule:
Ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: Icing Sugar: CMS-Na: syrup weight ratio is 2:1:1:4:1:2;
Capsule:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:0.5 ~ 2 of adjuvant;
Soft capsule:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=10:20 of adjuvant;
Drop pill:
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=5 ~ 25:50 ~ 75 of substrate.
7. the application of the Chinese medicine composition for the treatment of ischemia apoplexy claimed in claim 1 in the compound oral administration preparation of preparation treatment ischemia apoplexy.
8. the preparation method for the treatment of the Chinese medicine composition compound oral administration preparation of ischemia apoplexy described in claim 1, is characterized in that, step is as follows:
(1). ginkgo leaf extract powder, grind to form the borneol powder of fine powder, with auxiliary materials and mixing;
(2). add soft material or fluid;
(3). film-making agent, granule processed, drop pill, or record capsule;
(4). tablet, granule, drop pill, or the needed subsequent technique of capsule.
9. the preparation method for the treatment of the Chinese medicine composition compound oral administration preparation of ischemia apoplexy described in claim 8, is characterized in that, the concrete preparation method of various dosage forms is as follows respectively:
Mixture:
Folium Ginkgo extract and Borneolum Syntheticum mix powder, grind to form fine powder, and 20% ethanol that adds mixed-powder weight ratio 1:10 stirs; Add the tween 80 of 20% ethanol weight ratio 2%, fully stir, leave standstill 12h, filter, filtrate is for subsequent use; The protein sugar that adds weight ratio 0.3%, boils 30min, lets cool, and filters, then adding distil water is quantitative, embedding, 100 DEG C, 30min, sterilizing and get final product;
Emulsion:
Selection Oleum Ricini is oil phase, and polyoxyethylene sorbitan monoleate is emulsifying agent, and oleic acid is as stabilizing agent, and glycerol is osmotic pressure regulator; Folium Ginkgo extract Borneolum Syntheticum mixture fine powder, emulsifying agent, stabilizing agent are dissolved in Oleum Ricini as oil phase, glycerol is scattered in water for injection as water, be biphasely preheated to respectively 70 DEG C, oil phase is slowly added to water, after high-speed stirred, make colostrum; After homogeneous 3 times of high pressure homogenizer 10000psi, fill is to infusion bottle, sterilizing, and lower point of hundred grades of laminar flows are filled in office preparation bottle;
Wherein, Folium Ginkgo extract Borneolum Syntheticum mixture fine powder: emulsifying agent: oil phase: the weight ratio=10:10:25:75 of water;
Suspensoid:
Folium Ginkgo extract Borneolum Syntheticum mixture fine powder is appropriate, crosses 100 mesh sieves; After separately getting adjuvant and pulverizing, cross respectively 100 mesh sieves, add the rear mixer of all putting into fully to mix by the recipe quantity equivalent dilution method that progressively increases, on inspection intermediate up-to-standard after, be sub-packed in aluminum-plastic composite membrane bag heat-sealing by specification; Wherein, xanthan gum, low-viscosity hydroxypropylmethylc,llulose, sodium lauryl sulphate are suspending agent;
Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: the weight ratio=20:10 of suspending agent;
In suspending agent, xanthan gum: low-viscosity hydroxypropylmethylc,llulose: the weight ratio=2:1:1 of sodium lauryl sulphate;
Tablet: Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1 ~ 2 of adjuvant;
(1). ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: starch: dextrin: CMS-Na is 1:2:1:0.5:1, add lactose, starch, dextrin, carboxymethyl starch sodium, mix;
(2). add 40% ethanol, soft material processed;
(3). cross 18 mesh sieves, granulation granulate;
(4). added weight, than 1% magnesium stearate, mixes tabletting and obtains plain sheet;
(5). plain sheet is poured in pot, started coating pan, after plain sheet preheating approximately 5 min, control coating solution flow velocity well, start spray coating, after the about 0.15g of plain sheet average weight gain, coating 2h;
(6). all wrap to plain sheet, with the alcoholic solution polishing of weight ratio 2% dimethicone, get product;
Granule:
(1). ginkgo leaf extract powder: the borneol powder that grinds to form fine powder: lactose: Icing Sugar: CMS-Na: syrup weight ratio is 2:1:1:4:1:2;
(2). in pot, prepare weight ratio 50% syrup sizing mixing, weight ratio 15% starch slurry, lets cool, stand-by;
(3). get the supplementary material of having got ready, granulate with wet granulation and oscillating granulator, in trough type mixing machine, add successively Icing Sugar, medicine, starch, lactose, CMS-Na to be first dry mixed 10 minutes, then add 50% cold syrup and 15% cold starch slurry granulation;
The disposable solution that adds 50% cold syrup and 15% starch slurry mix homogeneously, stirs and is granulation into suitable soft material;
Granulate with oscillating granulator, granulation screen cloth 16 orders, are dried;
(4). by dry granule, by 14 eye mesh screen granulate, magnesium stearate joins in the granule of whole good grain in always mixed, to obtain final product;
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=10:1 ~ 2 of adjuvant;
Capsule:
Folium Ginkgo extract Borneolum Syntheticum mixture fine powder is appropriate, all crosses 80 mesh sieves with adjuvant, and mix homogeneously, adds appropriate wetting agent, granulates with 18 mesh sieves, and 50 DEG C of oven dry, arrange, and fill capsule No. 1;
Soft capsule:
(1). ginkgo leaf extract powder and grind to form the borneol powder of fine powder, adds decentralized photo and the continuous phase of recipe quantity;
(2). under room temperature, stir 10-20min and become fluid;
(3). mixing speed is 1500-3000rpm/min, pours into capsule and get final product;
Continuous phase used is polyglycols glyceride, Brij30 or polyoxyethylene castor oil, preferably hydrophilic and oleophilic amphoteric compound polyglycols glyceride, and decentralized photo used is poloxamer;
Wherein, Folium Ginkgo extract Borneolum Syntheticum mixture fine powder: the weight ratio=10:20 of adjuvant;
Drop pill:
Coolant is methyl-silicone oil, and PEG4000 is 1:1 with PEG6000 ratio, medicine and substrate ratio 1:4, and 85 DEG C of feed temperatures, 10 ± 2 DEG C of coolant temperatures, dripping distance is 4cm; Take a certain amount of PEG4000 and PEG6000 is placed in the thermostat water bath of uniform temperature in prescription ratio, after the complete melting of substrate mixes, add a certain amount of ginkgo leaf extract powder and the borneol powder that grinds to form fine powder, stir until the complete melting of medicine rapidly, splash in condensing agent methyl-silicone oil with certain speed by fixing bore drop pill, after its condensation molding, collect drop pill and wipe surperficial liquid paraffin with oil-Absorbing Sheets, under room temperature, naturally dry and obtain drop pill finished product;
Wherein, Folium Ginkgo extract and Borneolum Syntheticum mixture fine powder: weight ratio=5 ~ 25:50 ~ 75 of substrate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108938672A (en) * | 2018-09-27 | 2018-12-07 | 延边大学 | A kind of Chinese medicine composition and Chinese materia medica preparation for ischemia apoplexy rehabilitation |
| CN111166774A (en) * | 2019-12-13 | 2020-05-19 | 南京中医药大学翰林学院 | Composition for preventing and treating cerebral ischemia diseases and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1476832A (en) * | 2002-08-23 | 2004-02-25 | 江苏康缘药业股份有限公司 | Bilobalide soft capsule and its preparation method |
| CN1778318A (en) * | 2004-11-26 | 2006-05-31 | 秦引林 | Compound injection from ice tablet and ginkgo leaf extract and its making method thereof |
| CN1792366A (en) * | 2004-11-15 | 2006-06-28 | 贵阳云岩西创药物科技开发有限公司 | Ginkgo leaves dispersion tablets, and its preparing method |
| CN101439059A (en) * | 2007-11-20 | 2009-05-27 | 马杰 | Ginkgo leaf extract drop and preparation method thereof |
| CN101502539A (en) * | 2009-03-21 | 2009-08-12 | 山西振东泰盛制药有限公司 | Method for preparing ginkgo leaf extract cyclodextrin inclusion compound and preparation |
-
2013
- 2013-09-17 CN CN201310424211.3A patent/CN103877130A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1476832A (en) * | 2002-08-23 | 2004-02-25 | 江苏康缘药业股份有限公司 | Bilobalide soft capsule and its preparation method |
| CN1792366A (en) * | 2004-11-15 | 2006-06-28 | 贵阳云岩西创药物科技开发有限公司 | Ginkgo leaves dispersion tablets, and its preparing method |
| CN1778318A (en) * | 2004-11-26 | 2006-05-31 | 秦引林 | Compound injection from ice tablet and ginkgo leaf extract and its making method thereof |
| CN101439059A (en) * | 2007-11-20 | 2009-05-27 | 马杰 | Ginkgo leaf extract drop and preparation method thereof |
| CN101502539A (en) * | 2009-03-21 | 2009-08-12 | 山西振东泰盛制药有限公司 | Method for preparing ginkgo leaf extract cyclodextrin inclusion compound and preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108938672A (en) * | 2018-09-27 | 2018-12-07 | 延边大学 | A kind of Chinese medicine composition and Chinese materia medica preparation for ischemia apoplexy rehabilitation |
| CN111166774A (en) * | 2019-12-13 | 2020-05-19 | 南京中医药大学翰林学院 | Composition for preventing and treating cerebral ischemia diseases and application thereof |
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