CN103417497B - Oily drug controlled-release particles and preparation method of oily drug controlled-release particles - Google Patents
Oily drug controlled-release particles and preparation method of oily drug controlled-release particles Download PDFInfo
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- CN103417497B CN103417497B CN201310394339.XA CN201310394339A CN103417497B CN 103417497 B CN103417497 B CN 103417497B CN 201310394339 A CN201310394339 A CN 201310394339A CN 103417497 B CN103417497 B CN 103417497B
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Abstract
The invention discloses oily drug controlled-release particles and a preparation method of the oily drug controlled-release particles. The preparation method comprises the following steps: (1) a silk fibroin aqueous solution and medicated mixed liquor are prepared first, wherein the medicated mixed liquor is mixed liquor of oily drugs and an emulsifying agent; (2) under the condition of ice-water bath, the medicated mixed liquor is added into the silk fibroin aqueous solution while being stirred until the solution becomes liliquoid; (3) under the condition of ice-water bath, organic solvents are added into the liliquoid while being stirred so as to disperse emulsion obtained in the step (2); then, the obtained emulsion is unfrozen after being frozen; the obtained emulsion is subjected to low speed centrifugation so as to remove redundant solvents and drugs; sediment is collected, frozen and dried to obtain the oily drug controlled-release particles. The oily drug controlled-release particles finally obtained through the preparation method comprise the emulsifying agent with the content of 0.1%-0.5% (mass concentration). The oily drug controlled-release particles can improve the drug loading capacity of the oily drugs, reduce toxic and side effects of the oily drugs, prevent the oily drugs from degeneration, and improve the bioavailability of the oily drugs.
Description
Technical field
The present invention relates to the improvement of oiliness medicine, specifically refer to a kind of oiliness medicine sustained and controlled release microgranule and preparation method thereof, belong to medical art.This preparation method is best suited for the oily traditional Chinese medicine and antitumor oiliness medicine, can obtain a kind of novel oral drug preparation and injectable drug preparation.
Background technology
Oiliness medicine generally has unique pharmacologically active, and clinical practice basis is good, but it is all liquid condition at ambient temperature, and there is hydrophobicity, volatile, oxidizable, the shortcoming of poor stability, also has special and strong stimulation or greasy abnormal smells from the patient of vomitting under normal conditions.Generally in water, dissolubility is little, dissolves in dense ethanol and most of organic solvent.All more responsive on the impact of air, light and temperature, oxidizable decomposition is gone bad, and even produces toxicity.The current method preparing oiliness pharmaceutical preparation also comparatively backwardness, the stability of preparation is also poor, and the oiliness pharmaceutical preparation making to prepare " safety, effectively, stable, controlled " seems more difficult; Oiliness medicine mostly is Multiple components organic compound composition on the other hand, analyzes and there is certain difficulty.So current oiliness pharmaceutical preparation means fall behind, dosage form is comparatively single, and poor stability of preparation.
Up to now, the dosage form of the medium oil medicine of Chinese Pharmacopoeia is mainly oral or intravenous injection emulsion and soft capsule preparation.Oral tablet is volatile loss in process of production, is difficult to effectively control content, and causes content uneven because effective ingredient moves, and easily occurs mottle or oil leakage phenomenon in tabletting, causes and is difficult to prepare stable and that oil content is high preparation.Also there is the problems such as oil impregnate, yield be low aborning in soft capsule, although its bad smell can be covered preferably, and patient is easy to carry and takes, but more important point is the ubiquity release time limit defective situation about even not discharging when discharging, and also there is the problems such as bioavailability is lower in taking; The problem of intravenous formulations is that intravenous administering mode can make some patients be difficult to bear.
Therefore, effectively controlling the stability of oiliness medicine, increase curative effect of medication, the inherent quality improving pharmaceutical preparation and exterior quality is a problem anxious to be resolved.
Application number be 200410022045.5 and application number be 200410100424.1 Chinese patent be take soybean oil as carrier, but find also likely can bring side effect thus, as produced heating, shiver with cold, cardiopalmus, rapid breathing, headache side reaction, long-term input easily causes the untoward reaction such as glutamate pyruvate transaminase rising.Obtaining art oil and fat breast free fatty and LPO when long-term placement and can raise containing soybean oil, cause shortened shelf life, side effect increases.In order to prevent lipid oxidation, usually need add antioxidant, but thereby increase safe uncertainty.Application number be 200510046368.2 Chinese patent use glycerol to prepare Emulsion, due to the water retention of glycerol, can blood volume be increased, likely can cause dizziness, feel sick etc. symptom.These symptoms are when the blood volumes such as gestation, hypertension, diabetes, nephropathy or blood pressure are inherently higher, just more obvious.Therefore, its safety is also uncertain.Patent CN02158898.8 adopts emulsion solvent diffusion method in liquid phase, makes oiliness Drug absorbability in porous adsorbent macromolecule.The probability of this kind of technique pharmaceutical preparation still existence and stability difference, and product grain is comparatively large, can only use as oral formulations.Application number is Chinese patent employing chitosan, sodium carboxymethyl cellulose, emulsifying agent and firming agent etc. and the oiliness drug regimen of 201210124255, and use raw material many, safety is low, complex process, and in suitability for industrialized production, difficulty is larger.
Fibroin albumen (Silk Fibroin, SF) is the natural protein material of the mankind's investigation and application the earliest extracted from Bombyx bombycis (Cocoon or wild cocoon), and it contains 18 seed amino acids comprising human body institute essential amino acids.Fibroin albumen (SF) is nontoxic, have no stimulation, and without antigen, without anaphylaxis, have good biocompatibility, in food, beauty treatment, early have application, safety is high.Along with the progress of science and technology and people are to fibroin structure, the deepening continuously of character, research in recent years based on the newtype drug slow releasing carrier material of fibroin albumen more and more receives publicity, and research category is mainly around systems such as carried medicine sustained-release film, medicament slow-release microsphere, drug releasing controlled coating and medicament slow release gels.Such as application number is 200610039191.8, the Chinese invention patent application that denomination of invention is " silk nano granular of immobilized enzyme and preparation method thereof " discloses a kind of so method, it have employed water-soluble fibroin solution with can be miscible with water proton type organic solvent or aprotic, polar type organic solvent mix, forming milky spherical particle is dispersed in organic solvent system, obtain nano wire crude granule mixed liquor or suspension, remove organic solvent, obtain silk nano granular suspension or fibroin nanometer powder, obtained nano-particle is about 35-125nm, plan is applied to immobilized enzyme field, technique is comparatively complicated, and easily there is organic solvent residual probability, do not involve medicine in technical process and enter the content becoming preparation.Separately there is the patent exploitation bio-nanotechnology that the patent No. is 200410016856.4, denomination of invention is " nano microball of shombycin protein and preparation method thereof ", make silk protein that self assembly occur under proper condition and form Nano microsphere, obtained nano-particle is about 80-3000nm, this invention is mainly applied fibroin albumen/organic solvent system and has been prepared nanometer fibroin microsphere through freeze-thaw technique, its nano wire crude granule size disparity is comparatively large and limit its scope of application, does not also design situation when medicine exists simultaneously.Application number be 200810018509.3 Chinese patent select water soluble drug directly to mix with silk fibroin solution, water soluble drug is adsorbed on the fibroin protein of macromolecule, this preparation method is used on loaded with water-soluble medicine, the method can make its medicine carrying receipts amount lower because medicine is soluble in water, add that diameter of particle is comparatively large, limit its range of application.
Summary of the invention
For prior art above shortcomings, the object of this invention is to provide a kind of oiliness medicine sustained and controlled release microgranule and preparation method thereof, this oiliness medicine sustained and controlled release microgranule can improve oiliness drug delivery amount, reduces poisonous side effect of medicine, prevent medicine degeneration, improve drug bioavailability.
In order to solve the problems of the technologies described above, present invention employs following technical scheme:
A kind of oiliness medicine sustained and controlled release microgranule preparation method, preparation process is:
1) silk fibroin water solution and pastille mixed liquor is prepared, silk fibroin water solution concentration is 1.0% ~ 5.0% (W/V), pastille mixed liquor is the mixed liquor of oiliness medicine and emulsifying agent, and its medium oil medicine and emulsifying agent volume ratio are 20:1 ~ 50:1, and emulsifier hlb value is 8 ~ 18; The preferred tween 80 of described emulsifying agent or PLURONICS F87;
2) under ice-water bath condition, add described pastille mixed liquor while stirring in silk fibroin water solution, mixing speed is 100-800rpm, until solution becomes emulsion liquid; Wherein silk fibroin water solution and pastille mixed liquor consumption volume ratio are 20:1 ~ 8:1;
3) by silk fibroin protein solution: organic solvent volume adds organic solvent while stirring to disperse the 2nd than the amount being 1 ~ 5:10 under ice-water bath condition) emulsion of step gained, mixing speed is greater than 800rpm, add after terminating and continue stirring 5 ~ 30min, then by freezing under-18 ~-30 DEG C of conditions for the emulsion obtained, take out after 24h and thaw; Low-speed centrifugal is to remove unnecessary solvent and medicine, and namely the lyophilization of collecting precipitation thing obtains oiliness medicine sustained and controlled release microgranule.In the oiliness medicine sustained and controlled release microgranule that this method finally obtains, emulsifier content is 0.1% ~ 0.5% (mass concentration).
Described oiliness medicine should be water insoluble, can dissolve each other with emulsifying agent.
The preparation method of described silk fibroin water solution is: soak with removing waxy substance, carbohydrate and ash impurities wherein through ethers, alcohol organic solvent successively by useless light defective cocoon shell or silk, come unstuck through water boil and obtain fibrous fibroin albumen, fibrous fibroin albumen is dissolved in CaC1
2/ C
2h
5oH/ H
2in the organic-inorganic mixed solvent that O is formed, lysate is dialysed successively, sucking filtration, the concentrated silk fibroin water solution that can obtain needing concentration.
Compared with prior art, the present invention has the following advantages:
(1) the oiliness drug microparticles particle size distribution of gained of the present invention is homogeneous, the microgranule of different-grain diameter is obtained by the volume ratio of adjustment organic solvent and silk fibroin protein solution, thus the different medicine of passive target can be prepared according to the therapeutic purposes of medicine, easilier than existing micropill to absorb, can various ways administration.
(2) contain the solubility natural silk fibroin of function admirable in medicine carrying microgranule of the present invention, its good biocompatibility, safety non-toxic, and be the necessary aminoacid of human body, can be absorbed by the body.
(3) this method preparation technology is unique, make use of the self-assembly property carrying oiliness medicine emulsifying agent and fibroin albumen especially, oil-in-water emulsion can be formed fast in water, microgranule is solidified under the shearing force of stirring and the effect of organic solvent, do not need to add oleaginous base or the larger reagent of other toxicity, reduce the toxic and side effects of medicine, also reduce cost simultaneously.Haemolysis does not occur in hemolytic test result display 4h, toxicity assessment also demonstrates and which reduces the toxicity of medicine to cell.
(4) the oiliness medicine sustained and controlled release microgranule that obtains of this method, can not affect and change the drug effect of oiliness medicine self.
(5) reaction condition is gentle, and technique is simple, low raw-material cost, is suitable for amplifying producing.And the conditions such as material proportion can be regulated as required, thus obtain size tunable, discharge controlled microgranule.
(6) this preparation method can be applicable to the more oiliness medicine of kind, as Oleum Curcumae, Oleum Bulbus Allii, coix seed oil, safflower oil, Fructus Perillae oil, Fructus Evodiae oil, Fructus Forsythiae oil, patchouli oil, Semen Armeniacae Amarum wet goods; Animal oil is as unsaturated fatty acids such as fish oil etc. and vitamin E, triglyceride, oleic acid.
Accompanying drawing explanation
Fig. 1 is that this method prepares the Oleum Curcumae microgranule of gained and the infrared spectrum comparison diagram of pure silk element and blank microparticles.Wherein a pure silk fibroin, b blank microparticles, c medicine carrying microgranule.
Fig. 2 is that Oleum Curcumae microgranule prepared by this method takes gained surface topography photo (amplifying 20000 times) through scanning electron microscope.
Fig. 3 is the grain size distribution of Oleum Curcumae microgranule laser fineness gage gained prepared by this method.
Fig. 4 is the 4h haemolysis result photo of Oleum Curcumae microgranule prepared by this method.
Fig. 5 is that the Oleum Curcumae and commercially available Oleum Curcumae preparation injection that discharge in the Oleum Curcumae microgranule prepared of this method are to the inhibition comparison diagram of Hela Growth of Cells.
Detailed description of the invention
Oiliness medicine sustained and controlled release microgranule preparation method of the present invention, its preparation process is:
1) silk fibroin water solution and pastille mixed liquor is prepared, silk fibroin water solution concentration is 1.0% ~ 5.0% (W/V), pastille mixed liquor is the mixed liquor of oiliness medicine and emulsifying agent, and its medium oil medicine and emulsifying agent volume ratio are 20:1 ~ 50:1, and emulsifier hlb value is 8 ~ 18; The preferred tween 80 of described emulsifying agent or PLURONICS F87.
2) under ice-water bath condition, add described pastille mixed liquor while stirring in silk fibroin water solution, mixing speed is 100-800rpm, until solution becomes emulsion liquid; Silk fibroin water solution and pastille mixed liquor amount ratio are 20:1 ~ 8:1.
3) by silk fibroin water solution: organic solvent volume stirs (stirring to produce shearing force) limit than the amount being 1 ~ 5:10 below in ice-water bath condition and adds organic solvent to disperse the 2nd) emulsion of step gained, mixing speed is greater than 800rpm, add after terminating and continue to stir 5-30min, then by freezing under-18 DEG C ~-30 DEG C conditions for the emulsion obtained, take out after 24h and thaw; Low-speed centrifugal is to remove unnecessary solvent and medicine, and collecting precipitation thing adopts normal freeze-drying method namely to obtain oiliness medicine sustained and controlled release microgranule.Silk fibroin water solution: organic solvent volume is than preferred 1:10,2:10,3:10,4:10,5:10.The preferred dehydrated alcohol of described organic solvent.In gained oiliness medicine sustained and controlled release microgranule, emulsifier content is 0.1% ~ 0.5% (mass concentration).
Oiliness medicine of the present invention should be water insoluble, can dissolve each other with emulsifying agent.Can be: Oleum Curcumae, Oleum Bulbus Allii, coix seed oil, safflower oil, Fructus Perillae oil, Fructus Evodiae oil, Fructus Forsythiae oil, patchouli oil, Semen Armeniacae Amarum wet goods; Animal oil is as unsaturated fatty acids such as fish oil etc. and vitamin E, triglyceride, oleic acid.
The preparation method of described silk fibroin water solution is: soak with removing waxy substance, carbohydrate and ash impurities wherein through ethers, alcohol organic solvent successively by useless light defective cocoon shell or silk, come unstuck through water boil and obtain fibrous fibroin albumen, fibrous fibroin albumen is dissolved in CaC1
2/ C
2h
5oH/ H
2in the organic-inorganic mixed solvent that O is formed, lysate is dialysed successively, sucking filtration, the concentrated silk fibroin water solution that can obtain needing concentration.
Under the specific process conditions that the present invention stirs at ice bath and certain speed, silk fibroin water solution is mixed with oiliness medicament mixed liquid, under the effect of shearing force and organic solvent, fibroin albumen and emulsifying agent self assembly form emulsion and are embedded wherein by medicine, prepare uniform particle diameter, drug loading medicine carrying that is high, controllable rate of release delays controlled release microparticle.The oiliness medicine sustained and controlled release microgranule that the present invention prepares, its particulate form is irregular spherical or ellipticalness, and the microgranule of size between 800 ~ 5911nm accounts for 92% of total particulate loading, and granule is small, and particle size distribution is comparatively even, and drug loading is 10% ~ 20.51%.Oiliness medicine is embedded in interparticle by fibroin albumen, can reduce oiliness drug side effect, cover abnormal smells from the patient, prevents air and medicament contact, improves oiliness medicine oxidation resistance.
The Oleum Curcumae that the oiliness medicine sustained and controlled release microgranule that the present invention obtains discharges, warp and general zedoary oil injection are to the inhibition comparison of Hela Growth of Cells, and this oiliness medicine sustained and controlled release microgranule can not affect and change the property of medicine of oiliness medicine self.
Below in conjunction with concrete preparation example to help to understand the present invention.
1. first adopt the molten technique of salt to prepare micromolecule silk fibroin water solution: the light defective cocoon shell ether that will give up soaks 48h and removes waxiness, at room temperature soaks 24h remove portion Organic substance and impurity with after distilled water cleaning, drying with dehydrated alcohol, clean, dry.Use 0.5%(mass concentration) Na
2cO
3clean cocoon shell is boiled three times by aqueous solution, each 30min, obtains fibrous fibroin albumen (SF) with distilled water wash drying.Fibroin fiber is dissolved in CaC1
2/ C
2h
5oH/ H
2o(mol ratio 1:2:8) organic-inorganic mixed solvent in, by the 3d that dialyses in lysate bag filter, take out sucking filtration, then the concentrated silk fibroin water solution obtaining 1.0% ~ 5.0% (W/V).
2. the preparation of Oleum Curcumae microgranule: get Oleum Curcumae 2.5ml, with Oleum Curcumae: tween 80 volume ratio is that 20:1 ~ 50:1 adds tween 80 and stirs, and obtains pastille mixed liquor; It is 3%(W/V that the silk fibroin water solution obtained above is adjusted concentration); Get 50ml silk fibroin solution in beaker, under ice-water bath condition, adjustment mixing speed is 800rpm, the pastille mixed liquor of aforementioned arrangements is all joined in silk fibroin aqueous solution, under test speed stirs, drip 125mL dehydrated alcohol subsequently, stir after 20min has reacted product to be put into-20 DEG C freezing, thaw after 24h, in 3000rpm centrifugal collecting precipitation, normal freeze-drying method is then adopted to be drying to obtain fibroin embedding Oleum Curcumae microgranule.
Fig. 1 is that this method prepares the Oleum Curcumae microgranule of gained and the infrared spectrum comparison diagram of pure silk element and blank microparticles.Wherein a pure silk fibroin, b blank microparticles, c medicine carrying microgranule.Carry as seen from the figure Oleum Curcumae microgranule from pure silk fibroin, do not have the blank microparticles infrared absorption peak of medicine carrying different, this microgranule detects at infrared spectrum the characteristic peak finding that there is Oleum Curcumae to be existed, and illustrates that it is inner containing Oleum Curcumae.Recording particle drug-loaded amount by ultraviolet spectrophotometer is 20.51%.
Fig. 2 is that Oleum Curcumae microgranule prepared by this method takes gained surface topography photo (amplifying 20000 times) through scanning electron microscope (SEM), and Oleum Curcumae microgranule is spherical particle closely as can be seen from Figure 2, and particle diameter is below 10 μm, and particle size distribution is homogeneous.Part microsphere surface has duct, gap, ovalize, infers that its drug release may be passing hole channel release, corrosion, cracking separation.Fig. 3 is the grain size distribution of Oleum Curcumae microgranule laser fineness gage gained prepared by this method, can account for 92% of total particulate loading by the microgranule of principal dimensions between 800 ~ 5911nm.Fig. 4 is the 4h haemolysis result photo of Oleum Curcumae microgranule under each concentration prepared by this method.In Fig. 4, the rightest test tube is positive control, the most left test tube is negative control, from left to right namely 2nd ~ 6 test tubes are Oleum Curcumae particulate products prepared by this method, 7th ~ 11 is the contrasts of commercially available Oleum Curcumae preparation injection, upper as can be seen from figure, not there is haemolysis in the Oleum Curcumae microgranule 4h that the present invention obtains.Fig. 5 is the growing state of Hela cell in each group of sample, the Hela cellular morphology observed from inverted microscope.Fig. 5 (a) is blank group, and Fig. 5 (b) is commercially available Oleum Curcumae preparation injection, and Fig. 5 (c) is the Rhizoma Curcumae line of oils of the Oleum Curcumae microgranule release that the present invention obtains.Found by contrast cellular morphology and quantity, cellular control unit form is substantially identical, and major part is rounded, and part is fusiformis or triangle, and well adherent, grows vigorous.The slow release Rhizoma Curcumae line of oils Growth of Cells that commercially available Oleum Curcumae injection and the present invention obtain is subject to obvious suppression, cell number is few compared with matched group, show inhibitory action, show as cell pyknosis, spacing increases, and cell is in the state of independent dispersion, cell rupture time serious, occur coagulation, the slow release Oleum Curcumae that known the present invention obtains and commercially available Oleum Curcumae are prepared injection and are shown the equal inhibitory action to cancerous cell.
The present invention is at minimizing oiliness poisonous side effect of medicine, and the basis increasing its absorption efficiency proposes.Utilize the good protein characteristic of fibroin protein, a kind of preparation method of inventing for oiliness medicine specially.Method uses emulsifying agent as after the solubilisings such as tween 80, silk fibroin protein solution that ease of solubility fibroin albumen makes mixes with utilizing the molten Process of salt to prepare again, after adopting specified conditions that the structure of fibroin albumen is changed, System forming emulsion again by the embedding of oiliness medicine wherein, prepares the oiliness drug microparticles that high, the slow controlled release releasing effect of uniform particle diameter, drug loading is good under the effect of shearing force etc.
What finally illustrate is, above embodiment is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to technical scheme of the present invention or equivalent replacement, and not departing from aim and the scope of technical solution of the present invention, it all should be encompassed in the middle of right of the present invention.
Claims (3)
1. an oiliness medicine sustained and controlled release microgranule preparation method, is characterized in that: preparation process is:
1) prepare silk fibroin water solution, silk fibroin water solution concentration is 1.0% ~ 5.0% (W/V);
2) preparation of Oleum Curcumae microgranule: get Oleum Curcumae 2.5ml, with Oleum Curcumae: tween 80 volume ratio is that 20:1 ~ 50:1 adds tween 80 and stirs, and obtains pastille mixed liquor; By the 1st) step obtain silk fibroin water solution adjustment concentration be 3%(W/V); Get 50ml silk fibroin water solution in beaker, under ice-water bath condition, adjustment mixing speed is 800rpm, the pastille mixed liquor of aforementioned arrangements is all joined in silk fibroin water solution, 125mL dehydrated alcohol is dripped subsequently under test speed stirs, described test speed is greater than 800rpm, stir after 20min has reacted product to be put into-20 DEG C freezing, thaw after 24h, in 3000rpm centrifugal collecting precipitation, then adopt normal freeze-drying method to be drying to obtain fibroin embedding Oleum Curcumae microgranule, this fibroin embedding Oleum Curcumae microgranule is oiliness medicine sustained and controlled release microgranule.
2. oiliness medicine sustained and controlled release microgranule preparation method according to claim 1, it is characterized in that: the preparation method of described silk fibroin water solution is: useless light defective cocoon shell or silk are soaked with removing waxy substance, carbohydrate and ash impurities wherein through ethers, alcohol organic solvent successively, come unstuck through water boil and obtain fibrous fibroin albumen, fibrous fibroin albumen is dissolved in CaC1
2/ C
2h
5oH/ H
2in the organic-inorganic mixed solvent that O is formed, lysate is dialysed successively, sucking filtration, the concentrated silk fibroin water solution that can obtain needing concentration.
3. an oiliness medicine sustained and controlled release microgranule, is characterized in that: prepared by the arbitrary described method of claim 1-2.
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