CN103120643A - Curcumin dicaprate suspension injection and preparation method and application thereof - Google Patents
Curcumin dicaprate suspension injection and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses curcumin dicaprate and a derivative nano suspension agent, a preparation method of freeze-dried powder thereof and an application in the treatment of depression and tumor. A surfactant serves as a main pharmaceutical adjunct, particularly poloxamer, and curcumin dicaprate nano granulation is successfully realized by employing the wet grinding combined freeze drying technology. The curcumin dicaprate is prepared into a pharmaceutically acceptable oil diluent, and the reconstructed curcumin dicaprate and derivative nano suspension agent can be prepared into a nano suspension agent for injection with the particle size of about 500nm. The nano suspension agent consists of the following components: curcumin dicaprate and/or derivatives thereof and the surfactant. The nano suspension agent preparation can be applied to treating depression and tumors. The nano suspension agent preparation is simple in composition, high in stability, high in needle penetration, economic and reliable in preparation method and easy to industrialize.
Description
Technical field
The present invention relates to medical technical field, be specifically related to play a kind of curcumin dicaprate suspensoid injectio, preparation method and the application thereof of long-acting slow-release effect.
Background technology
Nano suspension refers to that the medicine mean diameter is dispersed in less than the nanoparticle of 1 μ m the suspensoid that forms in liquid medium.Nano suspension is mainly used in slightly water-soluble, especially all application of insoluble medicine of water and organic solvent, and nano suspension has the effect of long-acting targeting simultaneously.The method for preparing at present both at home and abroad nanosuspension can be divided into two large classes according to the difference of particle generation type: bottom-up method and top-down method, and bottom-up mainly refers to be gathered into again nanoparticle after medicine dissolution, as the sedimentation method etc.; Top-down is ground into nanoparticle to oarse-grained medicine by mechanical force, as medium milling method, high pressure homogenization method etc.Be not both at home and abroad a lot of to adopting single flat planetary type ball-milling instrument to prepare the report that the nanometer suspension particle is applied to medicine, main method has wet grinding and dry grinding method, and the ratio of the ratio of different parameters such as milling time, grinding rate, grinding bead and medicine, medicine and grinding medium (only for wet grinding) all can have influence on drug particle crystalline state, size and dispersion.The medium milling technology by the invention of Nanosystem company, now belongs to Elan Drug Delivery company the earliest.Medium grinder is comprised of grinding chamber, milling bar and recirculation chamber, water, abrasive media, medicine and corresponding adjuvant are housed in grinding chamber, the high-speed motion of milling bar makes between drug particle, between drug particle and abrasive media, and produce fierce collision between drug particle and grinding chamber inwall, thereby drug particle is crushed to Nano grade.Main and the rate of charge (being the ratio of medicine and liquid, the volume of medicine etc.) of the size of particle diameter, grinding rate, milling time, abrasive media are relevant.This method speed is fast, simple to operate, applicable to the medicine of slightly water-soluble or water, the equal indissoluble of organic solvent, can control the temperature of grinding in process of lapping, therefore also is applicable to the thermal instability medicine.Nano suspension has multiple advantage: the dissolution rate that has increased medicine; Increased the saturation solubility of medicine; Have bioadhesive, extended the medicine holdup time in vivo, improved the bioavailability of medicine; Can change the crystal formation of medicine, increase the ratio of unformed shape crystal formation in medicine or convert unformed shape fully to, improve the dissolubility of medicine; Can by the finishing to drug particle, reach the purpose of site specific delivery; Increased physical stability; Can be cured by aftertreatment technologys such as lyophilization or spray dryinges, further be prepared into multiple dosage form according to different way of administration, as tablet, pill, capsule, suppository, gel and aerosol; Applied widely, be applicable to multiple insoluble drug and can realize industrialized great production.
Curcumin be Rhizoma Curcumae Longae main component it, curcumin is widely used as pigment, food additive and flavoring agent, various experimental models proof curcumins have antitumor, antiinflammatory, antioxidation, protect the liver the pharmacologically active such as kidney; Precious kind grade the in Beijing University's medical board storehouse is in the depression alleviating pills of main component Radix Curcumae, find and take the lead in reporting that curcumin has obvious antidepressant activity, and carried out deep research, think and select curcumin to have great research potential and using value as research treatment antitumor and with the drug candidate of depression.Problems such as but due to the curcumin poor stability, be insoluble in water, bioavailability is low, and internal metabolism is fast, and absorption process transforms, and the half-life is short and limited use.How to solve its stability, improve its bioavailability, improve emphasis and difficult point that internal metabolism and dynamics problem become research.Therefore the people such as Yu Fenghua has synthesized the esters prodrug of curcumin-curcumin dicaprate (CurDD), and after CurDD absorbs, enzymolysis is that curcumin is brought into play activity.The curcumin dicaprate is that the curcumin dicaprate that synthesizes by esterification on two hydroxyls of curcumin is seen (Fig. 1).Be yellow crystal, volatile flavor arranged, non-hygroscopic.
Curcumin dicaprate dissolubility in water, oil, organic solvent is not very high, belongs to all medicines of indissoluble of water and oil.By the physicochemical property of curcumin dicaprate as can be known, the dissolubility of curcumin dicaprate in water is more much lower than curcumin dissolubility in water, dissolubility neither be very high in each organic solvent for the curcumin dicaprate simultaneously, and this just brings very large difficulty for making injection.Be head it off, the present invention is prepared into the nanometer suspension dosage form with the curcumin dicaprate, through constantly studying, design, and finally creates the present invention with practical value through repeatedly test and after improving.
Summary of the invention
The purpose of this invention is to provide a kind of curcumin dicaprate suspensoid injectio.The inventor finds, when drug particle adds appropriate lipophilic surfactant, the water of particle during in lyophilizing show good dispersibility, and can directly disperse in oil for injection after lyophilizing; And be surprised to find, after being prepared as the lyophilizing suspensoid, to compare with the suspended particles of conventional micropowder preparation, suspensoid of the present invention dispersibility, dispersion stabilization, slow release characteristic and brain targeting in oil all are significantly higher than the former.
Especially, the inventor finds through test, research, the dispersibility receipts surface-active contents in water and oil and the kind impact of medicine grain particle.
Particularly, when containing the surfactant components such as phospholipid, tween in pharmaceutical formulation, be unfavorable for that dispersibility, thereafter the freeze dried powder of medicine in water can't disperse in oil.When containing the surfactant components such as poloxamer in pharmaceutical formulation, being conducive to dispersibility, thereafter the freeze dried powder of medicine in water can directly disperse in oil, and has good syringeability.In addition, the inventor also finds, by weight percentage, lipotropy poloxamer addition affects dispersion and the rate of release of medicine, content be less than the curcumin dicaprate 5% the time, have a strong impact on the dispersibility of drug particle, and when surpassing 80%, drug releasing rate is too fast, can not reach the effect of long-acting slow-release.Therefore its use amount is preferably the 5-80% of curcumin dicaprate weight, preferred 5-20%.
The inventor also finds, the particle size distribution of drug particle affects the syringeability of suspensoid.Add above-mentioned surface-active particle during preparation, mean diameter has better syringeability during less than 5 microns, in the time of especially below 1 micron, and the equal tool significant advantage of syringeability and cleansing pin resistance.Surprisingly, the suspendible particle of 100-1000 nanometer also has significant brain targeting.
In general, the prepared curcumin dicaprate of the present invention nano suspension has following advantage:
1) the inventive method prepares insoluble drug nano suspension prescription simply, and technique is easily gone, and is easy to amplify chemical industry production.Simultaneously, the present invention has well solved the restricted problem that many curcumins are used, so the present invention has larger practical value and wide application prospect;
2) the long-acting slow-release effect is arranged and can penetrate that blood brain barrier works in brain can targeting antidepressant and antitumor for the curcumin dicaprate nano suspension of the present invention preparation;
3) to add adjuvant few, safe and effective in the present invention.
The derivant demethyl curcumin dicaprate of curcumin dicaprate and two nor-curcumin dicaprate have close structure and medicine voltinism matter, also can be applied to the present invention.Nor-curcumin dicaprate and two nor-curcumin dicaprate also have same effect with the suspensoid injectio of appropriate lipophilic surfactant's preparation.
Description of drawings
Fig. 1 is curcumin dicaprate structural formula.
Fig. 2 is curcumin dicaprate nano freeze-dried powder scanning electron microscope (SEM) photograph.
Fig. 3 is the injection site medicine remaining quantity of curcumin dicaprate nano suspension after the rat muscle injection.
Fig. 4 is curcumin dicaprate nanometer and common suspensoid curve chart when the cerebral tissue Chinese medicine is dense.
Fig. 5 is the mensuration of outstanding tail dead time.
The best mode that invention realizes
The specific embodiment of form is described in further detail foregoing of the present invention more by the following examples, but should not be interpreted as at this point that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away from the above-mentioned technological thought situation of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means and the modification of change include within the scope of the invention.For the curcumin dicaprate nano suspension that the present invention obtains according to above-mentioned preparation method is investigated in progress, the inventor has carried out the experiment of series of physicochemical character and interior evaluating, surveys stability, settling volume ratio, syringeability, the release of intramuscular injection site, brain assay under fusing point, high light, high temperature, super-humid conditions comprising form, differential scanning calorimeter under the measurement of particle diameter and distribution, scanning electron microscope.Experimental result shows that curcumin dicaprate nano suspension has the long-acting slow-release effect, stores physical and chemical stability preferably in the environment of lucifuge, low temperature, drying.Experimental program and result are as follows:
The preparation of embodiment 1 curcumin dicaprate nano suspension
It is solvent that water for injection is adopted in planetary ball mill instrument wet grinding of the present invention, take CurDD 1.00g during grinding, add ball 25g, add the aqueous solution 1ml that contains the 50mg Pluronic L121, grinding 1h with rotating speed 650rpm grinds in flat planetary type ball-milling instrument, complete Hou Jiashui, move on to several times in clean cillin bottle, put-80 ℃ of freezing preservation 24h with the masking foil sealing and put into again the lyophilization of freezer dryer Program: pre-freeze-45 ℃ operation 6h; Dry-30 ℃ of operation 18h of one-level ,-20 ℃ of operation 5h, 0 ℃ of operation 4h; 20 ℃ of operation 4h of secondary drying namely get lyophilized powder and get lyophilized powder.The obtained freeze-drying powder is yellow powder shape solid, and the outward appearance excellent surface is without subsiding, and not shrinkage has individually micro-fractures.Precision takes lyophilizing nanometer suspension particle 500mg, is scattered in to be made into 100mg/g oil suspensoid injectio in 4.5g Oleum Arachidis hypogaeae semen.
The curcumin dicaprate suspensoid (also being curcumin dicaprate nano suspension) that following examples are used is the suspensoid of embodiment 1 preparation gained.
Embodiment 2 curcumin dicaprate nanoparticle particle size distribution
At first carry out light path and proofread and correct (to light, the instrument detection cell is water) before experiment, background is disturbed, detection laser intensity (greater than 70) without larger assorted peak.Ball milling instrument abrasive grains is dispersed in dispersant, disperses each other through ultrasonic making between microgranule, is added dropwise in the particles distribution instrument of preparing to measure, until obscurity reaches 5～10.After mixing stirs a period of time, press the Start key and begin instrument Instrument measuring particle size distribution.Its measuring principle is that microgranule passes through laser beam with certain flow velocity.Particle size is different, and angle of diffraction is also different.Diffraction light is collected by detector, and converts the signal that receives to particle size distribution.Size and the distribution of the curcumin dicaprate nanoparticle in experiments of measuring example 1, replication is averaged for three times, and result is D (0.5): 0.506 μ m.
The curcumin dicaprate nano freeze-dried powder that makes in experimental example 1 is carried out particle shape and particle size distribution observation with scanning electron microscope.Be fixed on the metal sample dish microgranule and metal spraying (3nm).As shown in Figure 2, the lyophilized powder nanoparticle is spherical in shape, and particle size range is concentrated between 300～700nm, and is consistent with particle size distribution particle diameter result.
Embodiment 4 differential scanning calorimeters (DSC) measurement result
Curcumin dicaprate nano freeze-dried powder, crude drug and the P401 that makes in experimental example 1 done the DSC test.Lyophilized powder and crude drug fusing point are identical as a result, fusing point and the enthalpy change of 55.5 ℃ of P401 do not occur, may be because curcumin dicaprate nano suspension in only contain the trace P401 absworption peak signal a little less than.
Measure the changes of contents of curcumin dicaprate lyophilized powder Chinese medicine under strong illumination, high temperature, super-humid conditions.Result is table 1.As shown in Table 1, lyophilized powder is under high light, high temperature, super-humid conditions, and content reduces all obvious over reducing more than 5%, should put under lucifuge, low temperature, drying condition and preserve.
Table 1 curcumin dicaprate nanosuspension frozen powder is at the different condition stability inferior
Lyophilized powder is dispersed in Oleum Arachidis hypogaeae semen, and the suspensoid after dispersion is placed in the 5ml test tube and seals, and writes down original height (H0) standing.Measure at regular intervals the precipitum height, until do not change, record precipitum height (H) at this moment, calculated settlement volume ratio V=H/H.The settling volume of nano suspension is 0.9 than after measured as a result.Settling volume is than the easier redispersion of larger medicine.
Embodiment 7 curcumin dicaprate nano suspension syringeabilities are investigated
Lyophilized powder and crude drug are dispersed in respectively make suspensoid in Oleum Arachidis hypogaeae semen, investigate respectively the syringeability of two kinds of suspensoids with the different model syringe needle.Curcumin dicaprate nano suspension can be 0.45 syringe needle and curcumin dicaprate micron suspensoid only can be by 0.6 syringe needle by model.The syringeability of curcumin dicaprate nano suspension obviously is better than curcumin dicaprate micron suspensoid.
Embodiment 8 releases of curcumin dicaprate nano suspension in muscular tissue
Press dosage 100mg/kg, then the mode administration of every Mus intramuscular injection 300 μ l put to death the dislocation of rat cervical vertebra respectively at 1,2,3,4,7,15 day, rapidly-80 ℃ of freezing preservations was put in the muscle taking-up of injection site.
Freezing muscle samples is thawed, and weighing shreds, and adds normal saline by 1: 3, and homogenate is taken out 50 μ l (parallel get 3 parts) and is placed in rapidly-80 ℃ of freezing preservations from homogenate.The homogenate of above-mentioned taking-up is thawed, the SDS solution that adds 50 μ l 10%, the ethyl acetate that adds again 2ml, mixing 60s, 12000r, 5min are centrifugal, get supernatant, put the acetonitrile that adds 750 μ l 80% after drying up on Nitrogen evaporator, mixing 60s, 12000r, 5min are centrifugal, get supernatant, 5 μ l sample introductions.
Chromatographic column: phenomenex-C18 (4.6mm * 250mm, 5 μ m); Mobile phase: water (containing 0.5% formic acid): acetonitrile: oxolane=10: 50: 40; Flow velocity: 1ml/min; Column temperature: 30 ℃; Detect wavelength: 420nm; Sample size: 5 μ l.
Result as shown in Figure 3, result shows, curcumin dicaprate nano suspension continues 15 days at least in the release of injection site, has the effect of obvious long-acting slow-release after the intramuscular injection of curcumin dicaprate nano suspension.
The mensuration of embodiment 9 curcumin dicaprate nano suspensions content in brain tissue sample
Curcumin dicaprate nanoparticle and common microgranule 100mg are dispersed in respectively in the Oleum Arachidis hypogaeae semen of 1ml, and mixing is made curcumin dicaprate nanometer and the common peanut oil suspension of 100mg/ml.Dosage is according to equivalent curcumin 50mg/kg, the mode of 1ml/kg is carried out administration, after administered intramuscular, respectively at 8h, 1,4,7,11 and 15d rat cervical vertebra dislocation is put to death, broken end is got brain, peel off blood capillary on the ice face, wash away blood with normal saline, put rapidly-80 ℃ of freezing preservations.Freezing brain tissue sample is thawed, weigh, add normal saline according to 1: 3, homogenate in refiner, homogenate is placed in rapidly-80 ℃ of freezing preservations.Adopt Winnolin pharmacokinetic data available process software to carry out non-compartment model match to blood drug level-time data, calculate pharmacokinetic parameters.When medicine is dense, curve as shown in Figure 4.
Chromatographic column: phenomenex-C18 (2.0mm * 150mm, 5um); Mobile phase: 0.5% aqueous formic acid: acetonitrile: oxolane (THF)=30: 30: 40; Flow velocity: 0.3mL/min; Column temperature: 30 ℃; Sample size: 10 μ l; Auto injection actuator temperature: 4 ℃.
Mass spectrum condition: adopt atmospheric pressure electric spray ion source (ESI), multiple reaction selects ion monitoring (MRM) to carry out the segmentation detection, adopt positive ion mode to detect curcumin at 0～2.2min, mark emodin in 2.2～5min adopts the negative ion mode detection.Collision gas (Collision gas, CAD): Low; Gas curtain gas (Curtain gas, CUR): 10psi; Ionspray voltage (Ion sprayvoltage, IS): 5500V; Dry gas temperature: 250 ℃; Ion source gas 1 (GAS1): 25psi; Ion source gas 2 (GAS2): 30psi.Positive ion mode, curcumin parent ion and daughter ion are m/z 369.4/177.0, and ion removes a bunch voltage (DP): 51V, entrance voltage (EP): 8V, impact energy (CE): 25V, collision cell outlet voltage (CXP): 10V, (CEP): 16V.Negative ion mode, emodin parent ion and daughter ion are m/z 269.0/225.0, and ion removes a bunch voltage (DP) :-65V, entrance voltage (EP) :-7V, impact energy (CE) :-36V, collision cell outlet voltage (CXP) :-1V, (CEP) :-18V.
The processing of cerebral tissue: get the 200 μ l of brain tissue sample and add 10) 0 μ l 10%SDS aqueous solution and 1ml ethyl acetate, mixing 60s, 12000r/min 5min is centrifugal, getting 950 μ l supernatant puts on Nitrogen evaporator and dries up, residue redissolves with the acetonitrile of 150 μ l 80%, 12000r/mi n 5min is centrifugal, and supernatant is analyzed.
Result as shown in Figure 4, the curcumin dicaprate concentration of curcumin dicaprate nanometer suspension injection oil preparation is significantly higher than the concentration of common suspendible injection oil preparation, and curcumin dicaprate nanometer suspension microgranule is described, more easily penetrates blood brain barrier, enters brain cell.More than the sustainable 15d of the content of curcumin dicaprate in brain, illustrate that curcumin dicaprate nano suspension has the long-acting slow-release effect.
Setting up chronic unpredictability stress depression model mice, presses dosage 128.8mg/kg, and the mode administration of intramuscular injection gave once in every 7 days.Omnidistance administration 3 times.Stress after 21 days, measure the impact of Depressive behavior index and neurotransmitter.Measurement result Spass, Dunnett ' s t-test statistical analysis.
Learn in test at the antidepressant behavior of research, by measuring the outstanding tail dead time, as shown in Figure 5, result shows that the administration group compared significant difference with model group, significantly reduces the dead time.NE content, DA content, 5-HT content in mouse brain, comparing the administration group with model group has significant difference.The administration group is similar to positive control imipramine group result, has improved neurotransmitter.As following table.
The impact of table 2 curcumin dicaprate on chronic stress Mouse Whole Brain monoamine neurotransmitter
(n＝10，mean±S.E.M.)
Compare with matched group
*P＜0.05,
*P＜0.01,
* *P＜0.001, CCD is curcumin dicaprate nano suspension
Above result shows that the mixed suspensoid of curcumin dicaprate nanometer in the model of chronic stress depression mice, has antidepressant effect.Take every mode that was administered once in 7 days, result shows that medicine has slow release effect.
Embodiment 11 curcumin dicaprate nano suspension antitumous effects
Set up the S180 bearing mouse model, S180 tumor liquid 3 * 107 is inoculated in the mice oxter.After meeting tumor 24h, after three disposable target administrations of dosage group of curcumin dicaprate nano suspension (CDD) 46mg/kg, 92mg/kg and 184mg/kg the 10th day, put to death, get tumor, weigh.The suspension of result various dose as shown in table 3 below is respectively 23.2%, 34.8% and 57.1% to the tumour inhibiting rate of tumor-bearing mice, compares with model group, and the heavy significance of tumor reduces.Curcumin and positive control administration every day continue to put to death and get tumor after 10 days.The impact that curcumin 20mg/kg group weighs tumor is compared with model group does not have significant difference; The tumour inhibiting rate of curcumin 50mg/kg group is 54.3%; The tumour inhibiting rate of 5-Fu group is 61.1%.Above result shows that curcumin dicaprate nano suspension has significant antitumor action.
The impact of table 3 capric acid curcumin on tumor weight and tumour inhibiting rate
(n＝10，mean±S.E.M.)
Industrial applicability
Curcumin dicaprate nano suspension of the present invention, had the long-acting slow-release improved effect bioavailability used of curcumin low, many restrictive factors such as absorption difference, and preparation is simple is easy to industrialization and has a wide range of applications.
Claims (20)
1. a curcumin dicaprate and/or its derivant suspensoid injectio, comprise that curcumin dicaprate and/or its derivant, surfactant and injection stage are with oily.Described derivant is nor-curcumin dicaprate or two nor-curcumin dicaprate.
2. suspensoid injectio claimed in claim 1, is characterized in that, the medicine in described injection comprises curcumin dicaprate and/or its derivant and surfactant.
3. suspensoid injectio as claimed in claim 1 or 2, is characterized in that, the medicine in described injection is micron or submicron particle.
4. suspensoid injectio as claimed in claim 3, is characterized in that, described particle by wet grinding, the high pressure breast is even or spray drying preparation.
5. suspensoid injectio as described in claim 3 or 4, the average geometric value that it is characterized in that particle diameter is 5 μ m or less.
6. suspensoid injectio as claimed in claim 5, is characterized in that at least 90% particle diameter is less than 5 μ m.
7. suspensoid injectio as claimed in claim 6, is characterized in that the average geometric particle size distribution is in 100nm～1000nm scope.
8. suspensoid injectio as described in any one in claim 4,6-7, is characterized in that, the surfactant that adds when particle prepares is the injection lipophilic surfactant.
9. suspensoid injectio as claimed in claim 8, is characterized in that, the amount of adding the injection lipophilic surfactant when particle prepares is the 5-80% of curcumin dicaprate and/or its derivant total amount.
10. suspensoid injectio as claimed in claim 9, is characterized in that, the amount of adding the injection lipophilic surfactant when particle prepares is the 5-20% of curcumin dicaprate amount and/or its derivant total amount.
11. suspensoid injectio as described in claim 9-10 is characterized in that, adding the injection lipophilic surfactant when particle prepares is poloxamer.
12. suspensoid injectio as claimed in claim 11 is characterized in that, adding the injection lipophilic surfactant when particle prepares is Pluronic L121.
13. suspensoid injectio as claimed in claim 3 is characterized in that, after described particle was dispersed in aqueous solution, lyophilization was prepared into the lyophilized powder dosage form.
14. suspensoid injectio as claimed in claim 13 is characterized in that, freeze dried powder can directly be dispersed in oil for injection.
15. suspensoid injectio as claimed in claim 1 is characterized in that for muscle or subcutaneous injection.
16. suspensoid injectio as claimed in claim 15 is characterized in that, described injection suspension is the long-acting release injectable preparation.
17. the described suspensoid injectio of claim 1-16 for the preparation of the treatment and the prevention of depression medicine in application.
18. suspensoid injectio for the preparation of the application in treatment and prevention of depression medicine, is characterized in that this suspensoid injectio is used for muscle or subcutaneous injection as claimed in claim 17.
19. the described suspensoid injectio of claim 1-16 for the preparation of the treatment and the prophylaxis of tumours medicine in application.
20. suspensoid injectio for the preparation of the application in treatment and prophylaxis of tumours medicine, is characterized in that this suspensoid injectio is used for muscle or subcutaneous injection as claimed in claim 19.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074374A (en) * | 2016-06-15 | 2016-11-09 | 南京林业大学 | A kind of mechanicals efforts prepares the method for curcumin nano granule transperent suspension liquid |
| WO2021058423A1 (en) * | 2019-09-23 | 2021-04-01 | CAPNOMED GmbH | Composition with drug micro-nano particles of an anti-cancer agent |
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2011
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106074374A (en) * | 2016-06-15 | 2016-11-09 | 南京林业大学 | A kind of mechanicals efforts prepares the method for curcumin nano granule transperent suspension liquid |
| CN106074374B (en) * | 2016-06-15 | 2019-02-22 | 南京林业大学 | A kind of method that mechanicals efforts prepare curcumin nano particle transperent suspension liquid |
| WO2021058423A1 (en) * | 2019-09-23 | 2021-04-01 | CAPNOMED GmbH | Composition with drug micro-nano particles of an anti-cancer agent |
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Application publication date: 20130529 |