CN103211759B - Puerarin nanocrystalline medical composition and preparation method thereof - Google Patents
Puerarin nanocrystalline medical composition and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines and relates to a puerarin nanocrystalline medical composition and a preparation method and application thereof. Specifically, the puerarin composition is a puerarin nanocrystalline composition. The puerarin composition provided by the invention remarkably improves the solubility and bioavailabilityof puerarin and reduces or eliminates the food effect of the medicine, and is good in stability and can be prepared into various common preparation forms easily, the stability and effect of the medicine are improved, so that the composition has good prospect.
Description
Technical field
The invention belongs to medical art, relate to a kind of puerarin nanocrystalline medical composition and preparation method thereof.The invention still further relates to the purposes of described puerarin nanocrystal Pharmaceutical composition.
Background technology
Puerarin (puerarin, Pue) is the main isoflavonoid extracted from the dry root of legume pueraria lobata or Radix Puerariae rattan, chemical name 8-β-D-glucopyanosyl-4',7-Dihydroxy-isoflavone.
In recent years; domestic scholars has done large quantifier elimination to the pharmacological action of puerarin and clinical practice; the pharmacological action of puerarin mainly comprises: improve microcirculation, decreasing heart rate, blood pressure lowering, Ischemic myocardium reperfusion injury, arrhythmia, anticoagulant and thrombosis, atherosclerosis, improve (the Ma Jiajia such as coronary circulation, coronary artery dilator; Li Hongmei; Dong Zhiyu; Pei Jianming. the pharmacological action of puerarin and clinical practice. Journal of the Fourth Military Medical University; 2002,23:64-66).Clinically be mainly used in angina pectoris, myocardial infarction, arrhythmia, hypertension, cerebral infarction, diabetes, the retinal artery occlusion disease (Ma Jiajia relevant with cerebrovascular microcirculation obstacle, Li Hongmei, Dong Zhiyu, Pei Jianming. the pharmacological action of puerarin and clinical practice. Journal of the Fourth Military Medical University, 2002,23:64-66; Fan little Rong. puerarin clinical pharmacology progress. time precious traditional Chinese medical science traditional Chinese medicines, 2000,11(11): 1037-1038).As the new drug improving cardiovascular and cerebrovascular circulation, puerarin has good development prospect.
But puerarin water solublity and fat-soluble all very poor, the dissolubility in water only has 1.1 × 10
-2mol/L.Oral administration infiltration rate and degree are all poor, and gastrointestinal absorption is low and bioavailability is poor, and medicine major part excretes with original shape.
At present, puerarin listing preparation has puerarin injection (its true solution formed for oil-based solvent), is applied to clinical with drug administration by injection.Although injection has that distribution is fast, distribute the feature such as wide in Radix Puerariae ferritic, but increasingly extensive along with puerarin injection clinical practice, Reporting of harms day by day increases, and mainly contain exothermic reaction, allergic rash, feeling of fullness in the head, headache etc., serious has anaphylactic shock, haemolysis etc.
In addition, puerarin nanometer (oral) preparation belongs to nano-drug transporter.But, nano-drug transporter need by means of carrier material, medicine is disperseed nanorize in the carrier, there is the shortcoming of the aspects such as such as safety: (1): carrier class nanometer formulation is as low in ubiquity envelop rates such as liposome, nanoparticle, micelle, nanocapsules, seepage, instability, and be subject to the restriction (the polyesters carrier material of current synthetic only has PLGA and PLA to include American Pharmacopeia) of toxicity and carrier material and limit it in clinical application; (2) some method needs to add organic solvent in preparation process, is difficult to remove in final formulation products, increases the risk of patient medication.
The preparation developed at present and researching and developing has solid dispersion, dropping pill formulation, tablet, capsule, granule, soft capsule, micropill, oral cavity quickly disintegrating tablet, dispersible tablet, lyophilized formulations, gel for eye use, self-emulsifying micro-emulsion oral formulations, slow releasing preparation, oral administration nanometer suspensoid, coated slow release drop pill etc.Although puerarin preparation kind is numerous, clinical practice goods are few, at present domestic and international there are no oral formulations listing, main cause or bioavailability undesirable.Therefore, improve its bioavailability particularly oral administration biaavailability be the Focal point and difficult point faced at present.
Nanotechnology effectively can improve dissolubility, the promotion stripping of insoluble drug and improve bioavailability, the particle size range of Nano medication is 1-1000 μm, Nano medication can be divided into two large classes by the form existed according to nanoparticle: nanocrystalline drug, the nanorize of medicine own; And nano-drug transporter, by means of carrier material, medicine disperses nanorize in the carrier.Nanocrystalline drug is the colloidal dispersion pure medicine being formed submicron particles, without the need to carrier material.
Compared with nano-drug transporter, the feature of nanocrystalline drug is: 1. not by the restriction of envelop rate, drug dose adjustable extent is wide: because by direct for medicine nanorize, without the need to by carrier material, so there is not the obstacle of envelop rate and drug loading, easily meet clinical demand, heavy dose of medicine (therapeutic dose >500mg) also can be prepared into nanometer formulation; 2. dosage form variation: nanocrystal suspension can be solidified further by spraying dry, lyophilization and fluid bed drying, is prepared into the solid dosage forms such as capsule, tablet, or the injection type such as freeze dried powder; 3. nanometer particle size controllable precise: size is the important parameter of nanometer formulation, closely related with solubilizing effect, oral organism-absorbing availability.Due to medicine self nanorize, measured value is the particle diameter of drug particle, truly can reflect the particle size of nanorize medicine; 4. preparation method is simple to operate, is easy to industrialized great production, and conventional equipment such as high pressure homogenizer, high pressure microjet or wet milk etc. all can prepare nanocrystalline drug.
But, because the puerarin nanocrystal in nanocrystal mixed liquor is easily separated out, agglomeration can be there is and be difficult to redissolve or particle diameter increase, the object improving dissolubility and bioavailability cannot be reached.Therefore, be still difficult at present obtain stable nanocrystal suspension.
Summary of the invention
The present inventor, by deep research and performing creative labour, obtains a kind of puerarin compositions particularly puerarin nanocrystalline medical composition.The present inventor is surprised to find, by the stabilizing agent prescription such as selecting suitable formula particularly suitable, obtain puerarin nanocrystalline medical composition good stability, puerarin nanocrystal is not easily separated out, the mean diameter of puerarin nanocrystal little and be less likely to occur assemble increase, puerarin dissolubility and bioavailability significantly improve.Thus provide following invention:
One aspect of the present invention relates to a kind of puerarin compositions, and it comprises as the puerarin of effective ingredient, stabilizing agent and appropriate water, and wherein, the mean diameter of puerarin is 10-1000nm.Particularly, described puerarin compositions is puerarin Pharmaceutical composition or puerarin pharmaceutical composition, more specifically, is puerarin nano molecular Pharmaceutical composition or puerarin nanocrystalline (body) Pharmaceutical composition.
Puerarin compositions according to any one of the present invention, wherein, the mean diameter of puerarin is 10-900nm; Be preferably 20-800nm, 10-250nm, 50-500nm; Be more preferably 100-300nm, such as, 100-200nm, 100-250nm, 200-300nm, 150-250nm, 150-300nm, 200-250nm, 250-300nm, 150-200nm, 150nm, 160nm, 170nm, 180nm, 190nm, 200nm, 210nm, 220nm, 230nm, 240nm, 250nm, 260nm, 270nm, 280nm, 290nm or 300nm.
Puerarin compositions according to any one of the present invention, its PDI(polydispersityindex, polydispersity index) be less than 0.5.
Puerarin compositions according to any one of the present invention, wherein, the content of puerarin is 2%-95%(W/V) or 5%-95%(W/V); Be preferably 5-50%(W/V); Be more preferably 5-30%(W/V) or 8-30%(W/V); Be particularly preferably 10-20%(W/V).Such as 10-15%(W/V), 12-15%(W/V), 15-18%(W/V), 12-18%(W/V), 15-20%(W/V), 10%(W/V), 11%(W/V), 12%(W/V), 13%(W/V), 14%(W/V), 15%(W/V), 16%(W/V), 17%(W/V), 18%(W/V), 19%(W/V) or 20%(W/V).
Puerarin compositions according to any one of the present invention, wherein, the content of stabilizing agent is 0.1-30%(W/V) or 1-30%(W/V); Be preferably 0.1-20%(W/V) or 1-20%(W/V); Be more preferably 1-10%(W/V) or 2-10%(W/V); Be particularly preferably 2-5%(W/V).Such as, 2-4%(W/V), 3-5%(W/V), 3-4%(W/V), 2.5-4%(W/V), 3.2-4%(W/V), 3.0%(W/V), 3.1%(W/V), 3.2%(W/V), 3.3%(W/V), 3.4%(W/V), 3.5%(W/V), 3.6%(W/V), 3.7%(W/V), 3.8%(W/V), 3.9%(W/V) or 4.0%(W/V).
Puerarin compositions according to any one of the present invention, wherein, described stabilizing agent comprises stabilizing agent 1,
Described stabilizing agent 1 be selected from hypromellose, pluronic, polyvidone, polysorbate, poloxamer, tween, hyprolose, polyvinyl alcohol, arabic gum, tragakanta, sodium alginate, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, glucosan, mannitol and saccharide (such as glucose, fructose or sucrose) any one or multiple;
Preferably, described stabilizing agent also comprises stabilizing agent 2, and described stabilizing agent 2 be selected from sodium lauryl sulphate, docusate sodium and arginine salt any one or multiple;
More preferably, described stabilizing agent 1 be selected from hypromellose, poloxamer, polyvidone and hyprolose any one or multiple, and described stabilizing agent 2 be selected from sodium lauryl sulphate and docusate sodium any one or multiple;
Further preferably, described stabilizing agent 1 is selected from hypromellose and/or poloxamer, and described stabilizing agent 2 is sodium lauryl sulphate.
Puerarin compositions according to any one of the present invention, wherein, the content of stabilizing agent 1 is 0.1-20%(W/V), the content of stabilizing agent 2 is 0.01-10%(W/V); Preferably, the content of stabilizing agent 1 is 0.5-15%(W/V), the content of stabilizing agent 2 is 0.01-8%(W/V); More preferably, the content of stabilizing agent 1 is 1-10%(W/V), the content of stabilizing agent 2 is 0.02-5%(W/V); Particularly preferably, the content of stabilizing agent 1 is 2-5%(W/V), the content of stabilizing agent 2 is 0.05-2%(W/V).
Puerarin compositions according to any one of the present invention, wherein, the content of stabilizing agent 1 is 2-5%(W/V), 2-4.5%(W/V), 2-4%(W/V), 2.5-5%(W/V), 2.5-4.5%(W/V), 2.5-4%(W/V), 3-4%(W/V), 3-3.5%(W/V) 3.5-4%(W/V), such as 3.0%, 3.1%, 3.2%, 3.3%, 3.4%, 3.5%, 3.6%, 3.7%, 3.8%, 3.8% or 4.0%(W/V)
Puerarin compositions according to any one of the present invention, wherein, the content of stabilizing agent 2 is 0.05-2%(W/V), 0.1-2%(W/V), 0.1-1%(W/V), 0.1-0.5%(W/V), 0.5-1%(W/V), such as 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0%(W/V).
Puerarin compositions according to any one of the present invention, it is suspension.Particularly, be puerarin nanocrystal suspension.
Be not limited to theoretical restriction, the difference of nanocrystal suspension of the present invention and general suspension: (1) particle diameter is different: in puerarin nanocrystal suspension, insoluble drug exists with nm regime, scope is 1-1000nm, be generally <250nm, this suspension is colloidal dispersion system, stable homogeneous; And insoluble drug exists with micron state in general suspension, general ﹥ 5 μm, belongs to Unstable Systems, easy layering.(2) preparation method is different: equipment and the principle of preparation two kinds of suspensions are all not identical.(3) composition is different: nanocrystal suspension is primarily of water, medicine and stabilizing agent composition, and stabilizing agent mainly comprises electric charge protective agent and three-dimensional protective agent.General suspension comprises water, medicine, flocculating agent, deflocculant composition primarily of disperse medium.(4) other: puerarin nanocrystal suspension can solidify further, and dosage form and route of administration realize variation, are prepared into the solid dosage forms such as capsule, tablet, or the injection type such as freeze dried powder.
The nanocrystal suspension that the present invention prepares without crystal separate out and not stratified; Suspension good stability.Be not limited to theoretical restriction, nanocrystal suspension of the present invention, directly by for medicine nanorize own, without the need to carrier material, is the colloidal dispersion pure medicine being formed submicron particles.
Be not limited to theoretical restriction, puerarin nanocrystal is single compound, puerarin nanocrystal suspension is mixture, is made up of puerarin nanocrystal, stabilizing agent and water, and wherein the application of stabilizing agent is most important for the nanocrystal suspensoid obtaining physically stable.Stabilizing agent is mainly divided into electric charge protective agent and three-dimensional protective agent; stable nanocrystal suspension can be formed under the protection of stabilizing agent; otherwise the nanocrystal obtained easily is assembled makes particle diameter become large, even separates out, cannot reach the object improving dissolubility and bioavailability.
Puerarin compositions according to any one of the present invention, it also comprises pharmaceutically acceptable adjuvant except stabilizing agent or excipient.Such as antiseptic, its consumption is 0.2%-0.5% alternatively.Described antiseptic includes but not limited to: benzoic acid, sorbic acid, sodium benzoate, potassium sorbate etc.Suspension directly as peroral dosage form, can make oral suspensions by adding antiseptic, correctives etc., also can solidify further and make other dosage forms to use.
Particularly, described puerarin compositions makes micropill, capsule, tablet, injection, solid dispersion, granule or lyophilized injectable powder further.
According to the processing technology of different dosage form, also need some additives.These dosage forms can use puerarin mixed liquor of the present invention, and the method known by those skilled in the art is obtained, such as:
Puerarin tablet, in the preparation of puerarin capsule, also comprise filler starch, pregelatinized Starch, dextrin, sucrose, lactose, mannitol, microcrystalline Cellulose, calcium sulfate etc., disintegrating agent starch, carboxymethyl starch sodium, hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone etc., wetting agent and adhesive water, ethanol, hypromellose, polyvidone, starch slurry, syrup, rubber cement etc., lubricant stearic acid, magnesium stearate, calcium stearate, Pulvis Talci, hydrogenated vegetable oil, Polyethylene Glycol, micropowder silica gel, Stepanol MG etc., fluidizer colloidal silica, the additives such as Pulvis Talci.Puerarin tablet is obtained through tablet machine compacting containing 0.005g-1.0g by every sheet by the preparation method of tablet.Puerarin capsule loads hard capsule case by every containing 0.005g-1.0g by the preparation method of capsule to obtain.
Described micropill is obtained by extrusion―spherozation, the general method for making of coating pan, fluid bed pill method, fluidized bed coating, centrifugal fluidization comminution granulation or spraying dry pill method.
Puerarin injection is suspension type injection, and freeze-dried powder is by nanocrystal suspension obtained by freeze drying.
The example of these dosage forms of preparation is given in embodiment 7-14.
Another aspect of the present invention relates to the preparation method of the puerarin compositions according to any one of the present invention, and it comprises step puerarin, stabilizing agent and water being made suspension;
Particularly, adopt the sedimentation method, media mill method, high pressure homogenization method, high pressure microjet method or emulsion process to make puerarin in the mixture of puerarin, stabilizing agent and water and receive suspension;
Preferably, media mill method is adopted; Particularly, the rotating speed of ball mill is risen to 500-4000r/min gradually, and keep this rotating speed to mill the preferred 2h of 0.5h-20h().
Preparation method according to any one of the present invention, also comprises pre-treatment step: puerarin is crossed 40-300 mesh sieve; Be preferably 80-200 mesh sieve or 50-150 mesh sieve, be more preferably 100 mesh sieves.
Preparation method according to any one of the present invention, wherein, the mixture of described puerarin, stabilizing agent and water obtains as follows:
Stabilizing agent 1 is dissolved in suitable quantity of water, adds stabilizing agent 2 after mix homogeneously again and mix homogeneously, obtain stabiliser solution; Then merge with the mixed system of puerarin and water.
In one embodiment of the invention, stabilizing agent 2 is dissolved in suitable quantity of water, adds stabilizing agent 1 after mix homogeneously again and mix homogeneously, obtain stabiliser solution; Then merge with the mixed system of puerarin and water.
The puerarin compositions that another aspect of the invention relates to according to any one of the present invention improves microcirculation in preparation, decreasing heart rate, blood pressure lowering, Ischemic myocardium reperfusion injury, arrhythmia, anticoagulant and thrombosis, atherosclerosis, improve coronary circulation, purposes in the medicine of coronary artery dilator, or treating and/or preventing and/or auxiliary treatment angina pectoris, myocardial infarction, arrhythmia, hypertension, cerebral infarction, diabetes, purposes in the medicine of retinal artery occlusion or the disease relevant with cerebrovascular microcirculation obstacle, particularly, described retinal artery occlusion is that central retinal artery occlusion and/or Branch Retinal Artery block, the disease relevant with cerebrovascular microcirculation obstacle is ischemic encephalopathy.
Another aspect of the invention relates to a kind ofly to be improved microcirculation, decreasing heart rate, blood pressure lowering, Ischemic myocardium reperfusion injury, arrhythmia, anticoagulant and thrombosis, atherosclerosis, improves the method for coronary circulation, coronary artery dilator, comprises the step of the puerarin compositions according to any one of the present invention using effective dose.
Another aspect of the invention relates to a kind of method with/auxiliary treatment angina pectoris, myocardial infarction, arrhythmia, hypertension, cerebral infarction, diabetes, retinal artery occlusion or the disease relevant with cerebrovascular microcirculation obstacle that treats and/or prevents, and comprises the step of the puerarin compositions according to any one of the present invention using effective dose; Particularly, described retinal artery occlusion is that central retinal artery occlusion and/or Branch Retinal Artery block; The disease relevant with cerebrovascular microcirculation obstacle is ischemic encephalopathy.
The route of administration of described medicine can be oral administration, drug administration by injection, transdermal administration or per rectum administration.The factors such as concrete dosage can be advised according to doctor, patient's state of an illness, age, body weight, sex determine.
Particle diameter in the present invention or mean diameter can the method known of those skilled in the art measure, such as, recorded by Malvern nano particle size instrument and/or ZETA potentiometer (NANO-ZS90).
In the present invention, the content of each composition, if not otherwise specified, all refers to weight/volume (w/v) (g/100ml).
In the present invention, term " nanocrystalline (body) " is free translation, is translated by nanocrystal, emphasize " nanometer " state, but not emphasize " crystal " form, just occurring in nature major part medicine exists with crystal form, but do not get rid of amorphous form, as amorphous state.Domesticly also be translated into nano molecular medicine, this title may have more comparative relative to nano-drug transporter.
In the present invention, the object of administration is experimenter, such as mammal, includes but not limited to: people, monkey, pig, cattle, sheep, etc.
In the present invention, term " effective dose " refers to the dosage that can realize treating, prevent, alleviate and/or alleviating disease of the present invention or disease in experimenter.
The beneficial effect of the invention
Puerarin compositions of the present invention significantly improves dissolubility and the bioavailability of puerarin, reduce or eliminate the food effect of medicine, have good stability, be easy to be prepared into multiple common preparation formulation, add the stability of medicine and improve drug effect, there is good prospect.
In addition, compared with nano-drug transporter, the feature of nanocrystalline drug is: I. not by the restriction of envelop rate, drug dose adjustable extent is wide: because by direct for medicine nanorize, without the need to by carrier material, so there is not the obstacle of envelop rate and drug loading, easily meet clinical demand, heavy dose of medicine (therapeutic dose >500mg) also can be prepared into nanometer formulation; II. dosage form variation: nanocrystal suspension can be solidified further by spraying dry, lyophilization and fluid bed drying, is prepared into the solid dosage forms such as capsule, tablet, or the injection type such as freeze dried powder; III. nanometer particle size controllable precise: due to medicine self nanorize, measured value is the particle diameter of drug particle, truly can reflect the particle size of nanorize medicine; IV. preparation method is simple to operate, is easy to industrialized great production, and between different batches, variability is less, makes to have great advantage in suitability for industrialized production.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
embodiment 1: the preparation of puerarin nanocrystal suspension (1)
Prescription forms:
Preparation method:
By said ratio, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then tens microns.Be dispersed in water by medicine, then add hypromellose, sodium lauryl sulphate, benzoic acid, make thick suspension, then pass through media mill legal system for nanocrystal suspension, rotating speed is 4000rpm, grinding time 2h, and particle diameter can reach 250.4nm.
embodiment 2: the preparation of puerarin nanocrystal suspension (2)
Prescription forms:
Preparation method:
By said ratio, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then tens microns.Be dispersed in water by medicine, then add hyprolose, docusate sodium, sodium benzoate, make thick suspension, then prepare nanocrystal suspension by high pressure homogenization method, high pressure is 1.5 × 10
5kPa, through 15 circulations, particle diameter can reach 358.4nm.
embodiment 3: puerarin nanocrystal suspension (3) and preparation method thereof
Prescription forms:
Preparation method:
By said ratio, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then tens microns.Be dispersed in water by medicine, then add poloxamer, polyvinyl alcohol, sorbic acid, make thick suspension, then pass through high pressure microjet legal system for nanocrystal suspension, cycle-index is 80 times, and particle diameter can reach 385.9nm.
embodiment 4: puerarin nanocrystal suspension (4) and preparation method thereof
Prescription forms:
Preparation method:
By said ratio, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then tens microns.Be dispersed in water by medicine, then add pluronic, sodium lauryl sulphate, benzoic acid, make thick suspension, then prepare nanocrystal suspension by high pressure homogenization method, high pressure is 1.5 × 10
5kPa, through 10 circulations, particle diameter can reach 576.5nm.
embodiment 5: puerarin nanocrystal suspension (5) and preparation method thereof
Prescription forms:
Preparation method:
By said ratio, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then tens microns.Be dispersed in water by medicine, then add methylcellulose, docusate sodium, sodium benzoate, make thick suspension, then pass through media mill legal system for nanocrystal suspension, rotating speed is 3500rpm, grinding time 1h, and particle diameter can reach 365.7nm.
embodiment 6: puerarin nanocrystal suspension (6) and preparation method thereof
Prescription forms:
Preparation method:
By said ratio, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, and particle diameter is then tens microns.Be dispersed in water by medicine, then add polyvidone, arginine salt, benzoic acid, make thick suspension, then pass through media mill legal system for nanocrystal suspension, rotating speed is 4000rpm, grinding time 1.5h, and particle diameter can reach 336.7nm.
embodiment 7: puerarin tablet and preparation method thereof (1)
Preparation method:
As described in Example 1, obtained nanocrystal suspensoid, obtains freeze-dried powder by lyophilization.30g starch and freeze-dried powder are mixed, then adds 20g lactose and appropriate carboxymethyl starch sodium, make adhesive with 10% appropriate starch slurry, make soft material, cross 12-14 mesh sieve and granulate, 80 DEG C of dryings, granulate, add the rear tabletting of 0.5g magnesium stearate mixing.Tablet is pressed into containing 0.005g-1.0g puerarin by every sheet.
Wherein, cryodesiccated flow process is: drop to-70 DEG C from room temperature 25 DEG C and carry out the pre-freeze stage to nanocrystal suspensoid, the pre-freeze time is 3h, open vacuum pump forvacuum afterwards, to make in freeze drying box Stress control between 13pa-130pa, heating distils to pre-freeze sample, and rate of sublimation is that the sample that makes per hour declines the thickness of 1 millimeter, obtains freeze-dried powder after 40h.
Relate to cryodesiccated in the following examples, its step is identical with the present embodiment.
embodiment 8: puerarin tablet and preparation method thereof (2)
As described in Example 1, obtained nanocrystal suspensoid, obtains freeze-dried powder by lyophilization.25g microcrystalline Cellulose and 30g lactose are crossed 80 mesh sieve mix homogeneously respectively, adds appropriate polyvinylpolypyrrolidone mix homogeneously, then add freeze-dried powder mix homogeneously, finally add 0.2g micropowder silica gel and the rear direct compression of 0.3g magnesium stearate mixing.Tablet is pressed into containing 0.005g-1.0g puerarin by every sheet.
embodiment 9: puerarin tablet and preparation method thereof (3)
As described in Example 1, obtained nanocrystal suspensoid.By 30g pregelatinized Starch, 20g lactose, the mixing of 2g carboxymethyl starch sodium, make soft material, cross 20 mesh sieve wet granulars, 60 DEG C of dryings, granulate with 50% appropriate amount of ethanol as wetting agent, after adding the mixing of 0.5g magnesium stearate, tabletting obtains the sheet heart.The sheet heart is placed in fluid bed, passes into air-flow, make tablet be suspended in spatially stirring down of coating room and be in fluidized state, by nanocrystal suspension atomization input fluid bed, obtained the tablet of packaging medicine clothing layer by fluidized coating.Every sheet is containing 0.005g-1.0g puerarin.
embodiment 10: puerarin capsule and preparation method thereof
Preparation method:
As described in Example 1, obtained nanocrystal suspensoid, obtains freeze-dried powder by lyophilization.20g starch and 50g lactose are first carried out drying, cross 80 mesh sieve mix homogeneously and obtain mixture, freeze-dried powder is mixed homogeneously with mixture, cross 80 mesh sieve twice, mix homogeneously, then add 0.3g magnesium stearate, mixture crosses 80 mesh sieve twice, abundant mixing, finally loads hard capsule case by every containing 0.005g-1.0g puerarin by powder and obtains puerarin capsule.
embodiment 11: puerarin micropill and preparation method thereof
Preparation method:
As described in Example 1, obtained nanocrystal suspension, obtains freeze-dried powder by lyophilization.Freeze-dried powder and microcrystalline Cellulose are sieved and mixes, then add appropriate stearic acid and lactose, add and make wet feed with quality of material than for the water of 1:1, through extruding-round as a ball comminutor makes micropill.Extrude rotating speed 300r/min, round as a ball rotating speed 1000r/min, round as a ball time 4min.Take out micropill in 50 DEG C of oven dry, the micropill between screening 18-24 order, makes pellet preparations of the present invention.Micropill diameter is less than 2.5mm, and it is 93% that result records yield, and micropill roundness is good.
Also the puerarin micropill in the present embodiment can be made capsule: containing 0.005g-1.0g puerarin, pellet preparations is distributed into hard capsule case by every seed lac softgel shell and obtains puerarin capsule.
embodiment 12: puerarin micropill and preparation method thereof
Preparation method:
As described in Example 5, obtained nanocrystal suspension, obtains freeze-dried powder by lyophilization.The previously prepared good microcrystalline Cellulose blank pill heart, is placed in coating pan by the blank pill heart, the rotating speed 200r/min of coating pan, sprays appropriate adhesive starch slurry, roll and be sprinkled into freeze-dried powder.Under the effect of adhesive starch slurry, freeze-dried powder is attached to blank pill in the heart, repeatedly carries out this operation, obtain the micropill of a certain size and content of dispersion at 50 DEG C after drying.Take out micropill in 50 DEG C of oven dry, the micropill between screening 18-24 order, makes pellet preparations of the present invention.Micropill diameter is less than 2.5mm, and it is 95% that result records yield, and micropill roundness is good.
Also the puerarin micropill in the present embodiment can be made capsule: containing 0.005g-1.0g puerarin, pellet preparations is distributed into hard capsule case by every seed lac softgel shell and obtains puerarin capsule.
embodiment 13: puerarin injection and preparation method thereof
Preparation method:
Under cleaning condition, according to the recipe quantity described in embodiment 1, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, medicine is dispersed in 100ml water for injection, add hypromellose, sodium lauryl sulphate again, antioxidant mannitol 0.5g makes thick suspension, then passes through media mill legal system for nanocrystal suspension, through coarse filtration, ultrafiltration, obtain apyrogenic solution, be placed in ampoule bottle, liquid drugs injection technique makes the product of 0.1g/ bottle routinely.
embodiment 14: puerarin freeze-drying powder pin and preparation method thereof
Preparation method:
Under cleaning condition, according to the recipe quantity described in embodiment 2, principal agent puerarin crosses 100 mesh sieves, and 80 mesh sieves crossed by adjuvant, medicine is dispersed in 100ml water for injection, add hyprolose, docusate sodium again, antioxidant mannitol 0.5g makes thick suspension, then passes through media mill legal system for nanocrystal suspension, through coarse filtration, ultrafiltration, obtain apyrogenic solution, be placed in control antibiotic bottle, freeze-dry process makes the product of 0.1g/ bottle routinely.
experimental example 1: puerarin nanocrystal suspension interior evaluating is studied
1. experiment material
Test sample:
(1) the puerarin nanocrystal suspension of embodiment 1;
(2) the general suspension of puerarin:
Prescription forms:
Preparation method:
Sodium benzoate, methyl hydroxybenzoate are dissolved in pure water, make rubber cement with sodium carboxymethyl cellulose and microcrystalline Cellulose, the above-mentioned rubber cement of puerarin is ground well, add Fructus Citri Limoniae essence and mix and get final product.
Laboratory animal: SD rat, male, body weight 180-220g, 20.
2. experimental technique:
1) dosage regimen and blood specimen collection
Male SD rat 20 (180-220g), is divided into four groups at random, often organizes five.The order of administration of according to the form below, dosage is 50mg/kg.After gastric infusion, 0.1h, 0.2h, 0.5h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h eye socket is got blood and is about in the dry EP pipe that 0.5ml puts with 1% anticoagulant heparin, 12000rmin
-1centrifugal 5min, is separated and obtains rat plasma, in-20 DEG C of freezen protective.
Table 1:SD rat dosage regimen
2) plasma treatment process
Get rat blank plasma 0.1ml, add 0.4ml methanol extraction albumen, vortex 1min mixes, 12000rmin afterwards
-1centrifugal 5min.Get supernatant 0.5ml, N
2dry up, after residue dissolves with 200 μ L mobile phases, vortex 1min, full dose is transferred in EP pipe, 12000rmin
-1centrifugal 5min, supernatant is transferred in EP pipe, carries out HPLC analysis.
3) blood plasma puerarin method for measurement of concentration
Adopt high performance liquid chromatography, be interior mark with hydroxy benzaldehyde, mobile phase is 0.1% citric acid soln-methanol (70:30), and flow velocity is 1.0ml/min; Determined wavelength is 250nm, and sample size is 20 μ l.
3. experimental result
After the administration of SD Oral Administration in Rats, measure the blood drug level of each time point, in body, drug-time curve is shown in Fig. 1.
Rat Internal pharmacokinetics result of study shows: puerarin nanocrystal suspension can improve the bioavailability of puerarin, reduction or eliminate the food effect of medicine, improves drug effect.
experimental example 2: grain diameter measurement experiment (1)
1. experiment material
Sample: nanocrystal suspension, pure water prepared by embodiment 1.
Instrument: Malvern nano particle size instrument and ZETA potentiometer.
2. experimental technique
Get nanocrystal suspension prepared by 0.2ml in cillin bottle, add 1.8ml pure water and dilute ten times, obtain the settled solution of blue-opalescent, measure particle diameter (mean diameter) and PDI with Malvern nano particle size instrument and ZETA potentiometer.
3. experimental result
The particle diameter that nanocrystal suspension prepared by embodiment 1 records is shown in Fig. 2 A-B.
Result shows, and the particle diameter of puerarin nanocrystal suspension of the present invention is 250.4nm, PDI is 0.151, and obtained puerarin nanocrystal suspension is more stable.
experimental example 3: grain diameter measurement experiment (2)
1. experiment material
Sample: puerarin freeze-drying powder pin, pure water prepared by embodiment 9.
Instrument: Malvern nano particle size instrument and ZETA potentiometer.
2. experimental technique
Get one bottle of puerarin freeze-drying powder pin product, specification is 0.1g/ bottle, and add 2ml pure water and redissolve, ultrasonic making is uniformly dispersed, and obtains the settled solution of blue-opalescent, measures particle diameter and PDI with Malvern nano particle size instrument and ZETA potentiometer.
3. experimental result
The particle diameter that puerarin freeze-drying powder pin prepared by embodiment 9 records after adding water and redissolving is shown in Fig. 3 A-B.
Result shows, and the particle diameter of puerarin nanocrystal suspension of the present invention is 261.8nm, PDI is 0.145, and obtained puerarin nanocrystal suspension is more stable.
Visible, when being prepared into solid preparation, puerarin remains the form of nanocrystal.
experimental example 4: stability experiment
1. experiment material
Puerarin nanocrystal suspension, pure water prepared by test sample: embodiment 1-6.
Instrument: Malvern nano particle size instrument and ZETA potentiometer.
2. experimental technique
Puerarin nanocrystal suspension prepared by embodiment 1-6, places 0 day, 2 days, 4 days, 7 days respectively under room temperature condition, measure particle diameter and PDI with Malvern nano particle size instrument and ZETA potentiometer.
Before measurement, get nanocrystal suspension prepared by puerarin nanocrystal suspension prepared by 0.2ml embodiment 1-6 respectively in cillin bottle, add 1.8ml pure water and dilute ten times, obtain the settled solution of blue-opalescent, measure particle diameter and PDI with Malvern nano particle size and ZETA potentiometer.
3. experimental result
As shown shown in 2-7.
Table 2: puerarin nanocrystal suspension stability experiment data prepared by embodiment 1
| Standing time (d) | Particle diameter (nm) | PDI |
| 0 | 234.5 | 0.156 |
| 2 | 241.2 | 0.143 |
| 4 | 237.8 | 0.167 |
| 7 | 247.6 | 0.178 |
Table 3: puerarin nanocrystal suspension stability experiment data prepared by embodiment 2
| Standing time (d) | Particle diameter (nm) | PDI |
| 0 | 356.7 | 0.235 |
| 2 | 378.6 | 0.226 |
| 4 | 369.0 | 0.256 |
| 7 | 380.8 | 0.237 |
Table 4: puerarin nanocrystal suspension stability experiment data prepared by embodiment 3
| Standing time (d) | Particle diameter (nm) | PDI |
| 0 | 325.7 | 0.178 |
| 2 | 332.8 | 0.189 |
| 4 | 345.3 | 0.176 |
| 7 | 356.1 | 0.173 |
Table 5: puerarin nanocrystal suspension stability experiment data prepared by embodiment 4
| Standing time (d) | Particle diameter (nm) | PDI |
| 0 | 552.7 | 0.532 |
| 2 | 576.8 | 0.457 |
| 4 | 574.3 | 0.489 |
| 7 | 620.5 | 0.496 |
Table 6: puerarin nanocrystal suspension stability experiment data prepared by embodiment 5
| Standing time (d) | Particle diameter (nm) | PDI |
| 0 | 385.6 | 0.278 |
| 2 | 394.8 | 0.299 |
| 4 | 410.3 | 0.304 |
| 7 | 427.1 | 0.283 |
Table 7: puerarin nanocrystal suspension stability experiment data prepared by embodiment 6
| Standing time (d) | Particle diameter (nm) | PDI |
| 0 | 336.7 | 0.212 |
| 2 | 339.8 | 0.231 |
| 4 | 346.3 | 0.245 |
| 7 | 367.3 | 0.278 |
Result shows: puerarin nanocrystal suspension room temperature prepared by embodiment 1-6 is placed all more stable, and the particle diameter of the puerarin nanocrystal suspension of particularly embodiment 1 preparation is minimum, is optimum prescription and preparation method.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Accompanying drawing explanation
Fig. 1: nanometer formulation improves the bioavailability of insoluble drug and reduces food effect.
Fig. 2: A-B, the particle size determination result of puerarin nanocrystal suspension.
Fig. 3: A-B, the particle size determination result after puerarin nanocrystal solids preparation water redissolves.
Claims (30)
1. a puerarin nanocrystalline medical composition, it comprises as the puerarin of effective ingredient, stabilizing agent and appropriate water, and wherein, the mean diameter of puerarin is 210-300nm; Described stabilizing agent comprises stabilizing agent 1 and stabilizing agent 2; Wherein,
Described stabilizing agent 1 is hypromellose;
Described stabilizing agent 2 is sodium lauryl sulphate;
The content of stabilizing agent 1 is 0.1-20% (W/V), and the content of stabilizing agent 2 is 0.01-10% (W/V).
2. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of puerarin is 2%-95% (W/V).
3. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of puerarin is 5-50% (W/V).
4. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of puerarin is 8-30% (W/V).
5. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of puerarin is 10-20% (W/V).
6. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent is 1-30% (W/V).
7. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent is 1-20% (W/V).
8. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent is 1-10% (W/V).
9. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent is 2-5% (W/V).
10. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent 1 is 0.5-15% (W/V), and the content of stabilizing agent 2 is 0.01-8% (W/V).
11. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent 1 is 1-10% (W/V), and the content of stabilizing agent 2 is 0.02-5% (W/V).
12. puerarin nanocrystalline medical composition according to claim 1, wherein, the content of stabilizing agent 1 is 2-5% (W/V), and the content of stabilizing agent 2 is 0.05-2% (W/V).
13. puerarin nanocrystalline medical composition according to any one of claim 1 to 12, it is suspension.
14. puerarin nanocrystalline medical composition according to any one of claim 1 to 12, it also comprises the pharmaceutically acceptable adjuvant except stabilizing agent.
15. puerarin nanocrystalline medical composition according to claim 14, described adjuvant is excipient.
16. puerarin nanocrystalline medical composition according to claim 13, it also comprises the pharmaceutically acceptable adjuvant except stabilizing agent.
17. puerarin nanocrystalline medical composition according to claim 16, described adjuvant is excipient.
18. puerarin nanocrystalline medical composition according to claim 14, wherein, described puerarin compositions makes micropill, capsule, tablet, injection, solid dispersion, granule or lyophilized injectable powder further.
19. puerarin nanocrystalline medical composition according to claim 16, wherein, described puerarin compositions makes micropill, capsule, tablet, injection, solid dispersion, granule or lyophilized injectable powder further.
The preparation method of the puerarin nanocrystalline medical composition according to any one of 20. claim 1 to 13, it comprises step puerarin, stabilizing agent and water being made suspension.
21. preparation methoies according to claim 20, wherein, adopt the sedimentation method, media mill method, high pressure homogenization method, high pressure microjet method or emulsion process to make puerarin nanosuspension in the mixture of puerarin, stabilizing agent and water.
22. preparation methoies according to claim 20, wherein, adopt media mill method to make puerarin nanosuspension in the mixture of puerarin, stabilizing agent and water.
23. preparation methoies according to claim 22, wherein, rise to 500-4000r/min gradually by the rotating speed of ball mill, and keep this rotating speed to mill 0.5h-20h.
24. preparation methoies according to claim 20, wherein, also comprise pre-treatment step: puerarin is crossed 40-300 mesh sieve.
25. preparation methoies according to claim 20, wherein, also comprise pre-treatment step: puerarin is crossed 80-200 mesh sieve.
26. preparation methoies according to claim 20, wherein, also comprise pre-treatment step: puerarin is crossed 50-150 mesh sieve.
27. preparation methoies according to claim 20, wherein, also comprise pre-treatment step: puerarin is crossed 100 mesh sieves.
28. preparation methoies according to claim 21 or 22, wherein, the mixture of described puerarin, stabilizing agent and water obtains as follows:
Stabilizing agent 1 is dissolved in suitable quantity of water, adds stabilizing agent 2 after mix homogeneously again and mix homogeneously, obtain stabiliser solution; Then the mixed system of puerarin and water is merged; Or stabilizing agent 2 is dissolved in suitable quantity of water, adds stabilizing agent 1 after mix homogeneously again and mix homogeneously, obtain stabiliser solution; Then the mixed system of puerarin and water is merged.
Puerarin compositions according to any one of 29. claim 1 to 19 improves microcirculation, decreasing heart rate, blood pressure lowering, Ischemic myocardium reperfusion injury, arrhythmia, anticoagulant and thrombosis, atherosclerosis, the purposes improved in the medicine of coronary circulation, coronary artery dilator in preparation, or treat and/or prevent and/or auxiliary treatment angina pectoris, myocardial infarction, arrhythmia, hypertension, cerebral infarction, diabetes, retinal artery occlusion or the disease relevant with cerebrovascular microcirculation obstacle medicine in purposes; The described disease relevant with cerebrovascular microcirculation obstacle is ischemic encephalopathy.
30. purposes according to claim 29, wherein, described retinal artery occlusion is that central retinal artery occlusion and/or Branch Retinal Artery block.
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| CN103860764A (en) * | 2014-03-12 | 2014-06-18 | 逄增容 | Traditional Chinese medicine for treating central retinal artery obstruction and preparation method thereof |
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| WO2016119114A1 (en) * | 2015-01-27 | 2016-08-04 | 上海秀新臣邦医药科技有限公司 | Puerarin nanocrystalline capsule and preparation method therefor |
| CN105982877B (en) * | 2015-01-27 | 2021-05-28 | 上海秀新臣邦医药科技有限公司 | Puerarin nano crystal capsule and preparation method thereof |
| CN104906038A (en) * | 2015-06-24 | 2015-09-16 | 万特制药(海南)有限公司 | Aripiprazole nanocrystal and preparation method thereof |
| CN105560226A (en) * | 2016-01-04 | 2016-05-11 | 河北工业大学 | Pharmaceutical composition containing puerarin and applications thereof |
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| CN107184554B (en) * | 2017-06-18 | 2020-07-28 | 北京中医药大学 | A puerarin liquid crystal nanoparticle for nasal cavity nanometer preparation and its preparation method |
| CN107987065A (en) * | 2017-12-20 | 2018-05-04 | 中国药科大学 | A kind of common amorphous substance of Puerarin niacinamide |
| WO2019141204A1 (en) * | 2018-01-17 | 2019-07-25 | Nano And Advanced Materials Institute Limited | Nano-crystallized herbal ingredient-containing package and method of preparing herbal decoction |
| CN108815129A (en) * | 2018-07-12 | 2018-11-16 | 天津双硕医药科技有限公司 | A kind of miscellaneous Shandong amine nanocrystal oral solid drug composition of grace |
| CN108836947A (en) * | 2018-07-12 | 2018-11-20 | 天津双硕医药科技有限公司 | It is a kind of dimension how appropriate drawing nanocrystal oral solid drug composition |
| CN108853017B (en) * | 2018-09-17 | 2021-03-02 | 西安力邦医药科技有限责任公司 | Prescription and preparation process of estriol nano oral preparation |
| CN111991355B (en) * | 2019-12-30 | 2023-06-23 | 云南汉盟制药有限公司 | Solid nano powder composition containing nano cannabidiol, preparation method and application |
| CN112426427B (en) * | 2020-06-24 | 2022-07-12 | 中国人民解放军军事科学院军事医学研究院 | Application of midazolam nanocrystal in preparation of medicine for improving blood brain barrier permeability |
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