CN1754535B - Paclitaxel analog microsphere for topical injection, its preparation method and uses - Google Patents
Paclitaxel analog microsphere for topical injection, its preparation method and uses Download PDFInfo
- Publication number
- CN1754535B CN1754535B CN 200410085185 CN200410085185A CN1754535B CN 1754535 B CN1754535 B CN 1754535B CN 200410085185 CN200410085185 CN 200410085185 CN 200410085185 A CN200410085185 A CN 200410085185A CN 1754535 B CN1754535 B CN 1754535B
- Authority
- CN
- China
- Prior art keywords
- spheres
- sustained
- release micro
- microsphere
- glycolide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a category of Paclitaxel-containing slow release micro-balloons for local injection, which can be used for the local treatment of tumor tissues and focus positions. The micro-balloons comprise Paclitaxel 0.2-40wt% of the micro-balloon and biocompatible medicinal macromolecular adjuvant 50-99.8 wt% of micro-balloons having a molecular weight of 5000-70000 daltons. The actuation duration of the medicament can be extended.
Description
Technical field
The present invention relates to the slow releasing preparation of taxanes substance, specifically, the present invention relates to mean diameter between 1.0-50 μ m, can stablize release more than 7 days or more than 15 days or more than 30 days, and even more than 60 days, preferred more than 7 days, more preferably more than 15 days or the release injectable microsphere of the taxanes substance more than 30 days, its preparation method and application.
Background technology
Taxanes substance has become the focus of current cancer therapy drug research as a kind of natural drug with unique active anticancer.The antitumaous effect effect of taxanes substance is remarkable, has now become the common drug of treatment ovarian cancer and breast carcinoma.There is Drug resistance intractable ovarian cancer also effective to medicines such as platinum classes.The kaposi's sarcoma that melanoma colon cancer and HIV are caused also has curative effect preferably.Also be suitable for the treatment of entity tumor and eye proliferative vitreoretinopathy (PVR).Its possible mechanism of action is mainly: the first, and microtubule dynamic stabilization mechanism.It has been generally acknowledged that needs the kytoplasm microtubule depolymerization to form spindle microtubule in the mitosis process.And chromosome moves to the two poles of the earth under the effect of spindle fiber.Taxanes substance can be that β subunit N holds the 31st aminoacid in the direct combination of intracellular microtubule net site.Suppressed the depolymerization of cytotubule like this, thereby suppressed the formation of tumor cell spindle, made tumor cell stop at G
2Phase (prophase of cell division) and M phase (division stage) are until death.The second, immunologic mechanism.Taxanes substance and lipopolysaccharide (PLS) all can be killed tumor cell for activating macrophage signal is provided.And immunoregulatory factor As101 and taxanes substance share, and can promote macrophage to kill mastocyte.Therefore, taxanes substance also has the effect that activating macrophage is killed tumor.In addition, when it and IFN-are share, activating macrophage dissolving tumor there is potentiation.The 3rd, the generation of induced tumor necrosin TFN-α.TFN-α is mainly produced by the active component lipopolysaccharide activated mononuclear phagocyte of gram negative bacteria, and other cells then produce TFN-γ.TFN-α has Graft Versus Tumor and TFN-γ can increase the biological effect of TFN-α.The taxanes substance result of study is shown it can increase TFN-γ and induce the synthetic and secretion of NO and induce TFN-α gene expression.The 4th, taxanes substance also suppresses tumor cell migration.The mouse fibroblast cell of handling with taxanes substance can only produce flat shape of tail projection and [, can not move.
Carried out big quantity research with regard to taxanes substance, gone on the market at present or the medicine of taxanes substance to be gone on the market comprises paclitaxel, Docetaxel, PEG paclitaxel, lactose amide paclitaxel, agmatine paclitaxel or the like.And other paclitaxel derivant.This class material has become the focus of current cancer therapy drug research as a kind of medicine with unique active anticancer.
The taxanes medicine is as chemotherapeutics, because its structures etc. are not suitable for adopting oral formulations, generally all adopt injection type, but now be used for the oil preparation mostly clinical formulation for paclitaxel is to use Cremopher EL (polyoxy ethyl Oleum Ricini+ethanol, each is 50% years old) to make.This pharmaceutical carrier can cause some side effect, comprising severe anaphylactic reaction.Therefore, selecting a kind of drug-supplying system of non-toxic efficient is the key of development paclitaxel clinical practice.
Purpose of the present invention just provides a kind of local injection preparation of taxanes substance, this preparation can prolong drug action time, reduce the medication number of times, improve the bioavailability of taxanes substance, reduce the toxic and side effects of medicine.
Summary of the invention
Above-mentioned purpose of the present invention can realize by the local injection sustained-release micro-spheres of following taxanes substance.That is to say, discoveries such as the inventor, by preparing a kind of microball preparation that contains taxanes substance, the microsphere that particularly has the specified particle diameter scope, can realize the slow release and the controlled release of medicine, reducing the bioavailability of administration number of times, raising taxanes substance, reduce the toxic and side effects of medicine, is significant for treatment lung, liver, the entity tumor of spleen and the PVR of eye.The sustained-release micro-spheres of paclitaxel of the present invention there is no open in the past.
Because this microsphere can stop the long period in the part, thereby reaches the action time of prolong drug, reduce administration number of times and improve bioavailability of medicament, reduce the toxic and side effects of medicine.
Specifically, the topical sustained-release micro-spheres of taxanes substance of the present invention is mainly to be made up of the taxanes substance of the 0.2-40% that accounts for the microsphere gross weight (w/w) and biodegradation type medical high-molecular additive and other pharmaceutically acceptable adjuvants of molecular weight between 5000-70000 dalton that account for microsphere gross weight 50-99% (w/w).
Preferably, the topical of taxanes substance of the present invention with the particle size range of sustained-release micro-spheres is: 1.0-50 μ m.Wherein said biodegradable medical high-molecular additive is selected from a kind of in polylactide-co-glycolide, Polyethylene Glycol/polybutylene terephthalate (PBT), polylactic acid, polyglycolic acid, poly--the 3-butyric ester, poly-adjacent ester, polylactone, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, polylactic acid-polyglycol, the polyglycolic acid-Polyethylene Glycol; Preferred polylactide-co-glycolide, Polyethylene Glycol/polybutylene terephthalate (PBT), polylactic acid, poly butyric ester-hydroxyl pentanoate copolymer, more preferably, molecular weight is that daltonian polylactide-co-glycolide of 5000-70000 or molecular weight are 5,000-50,000 daltonian Polyethylene Glycol/polybutylene terephthalate (PBT).When being polylactide-co-glycolide, the ratio of lactide-Acetic acid, hydroxy-, bimol. cyclic ester is preferably 20: 80-80: 20.
Taxanes substance of the present invention in addition comprises known and the unknown various paclitaxels with taxanes mother nucleus structure, paclitaxel derivant, taxoid, prodrugs of paclitaxel and the classes of compounds of modifying based on the paclitaxel structure, as paclitaxel, Docetaxel, PEG paclitaxel, lactose amide paclitaxel, agmatine paclitaxel, Ramulus et folium taxi cuspidatae terpene or taxane etc., but be not limited thereto.
Above-mentioned other acceptable accessories comprises the pharmaceutical excipient that the common preparation of cosolvent, antiseptic, stabilizing agent is essential etc.To this, the present invention not work done in the manner of a certain author goes out restriction.
The sustained-release micro-spheres of taxanes substance of the present invention does not influence blood circulation after keeping certain timeliness, biological degradability and being injected in the body, particle diameter should be between the 1.0-50 μ m.Particle diameter is too small, is difficult to keep long drug effect, might pass through blood capillary simultaneously, is difficult to realize the purpose of local sustained release; Particle diameter is excessive, and the initial stage discharges too slow, does not reach the treatment effective blood drug concentration.
In the sustained-release micro-spheres of the present invention, as long as can realize the purpose of slow release, the content of taxanes substance is not particularly limited, but collateral security is the slow release effect and the balance angle that guarantees slow release effect of long effective blood drug concentration enough, preferred taxanes substance accounts for 0.2～50 weight % of microsphere, preferably is not less than 5 weight % again; Biodegradable medicinal high polymer adjuvant accounts for 50～99 weight %, preferably is not less than 60 weight %.If taxanes substance content is less than 0.2 weight %, can not guarantee sufficiently high blood drug level; Otherwise, if be higher than 50 weight %, might be able to not guarantee that then medicine steadily discharges, may cause the generation of side effect, taxanes substance is difficult to dissolving simultaneously, and is also difficult in the preparation.
Microsphere of the present invention can adopt the conventional preparation method of microsphere to make, as adopting single-emulsion-liquid drying method, spray drying method etc.
When adopting single-emulsion-liquid drying method to prepare microsphere of the present invention, can be in the following ways: the higher fatty acids or the ester that take by weighing taxanes substance, Biodegradable high-molecular pharmaceutic adjuvant and isopropyl myristate (IPM) and so on according to certain ratio respectively, be dissolved in and form oil phase in the organic solvent, under high speed machine stirs, this solution is injected the continuous water of a small amount of high concentration, afterwards with the continuous aqueous phase solution dilution of a certain amount of low concentration, continue to stir certain hour with solvent flashing, wash afterwards, frozen centrifugation, obtain microsphere after the lyophilization.
The organic solvent that wherein forms oil phase is the low boiling point organic solvent with enough volatility, low-residual, for example can be selected from a kind of in dichloromethane, chloroform, dimethyl formamide, dimethyl sulfoxide, ethyl acetate, dioxane, ether, acetone, oxolane, the ethanol or two or more mixture wherein.The concentration of pharmaceutic adjuvant in organic solvent is preferably 10-1000mg/ml, and the concentration of taxanes substance is for reaching 10-500mg/ml.
Water adopts the aqueous solution of polyvinyl alcohol, polyvinylpyrrolidone, sodium polymethacrylate, sodium polyacrylate, poly-sodium carboxymethyl cellulose etc. continuously, and concentration is 0.5-25% (w/v).
In order to form emulsion, aqueous phase also should have emulsifying agent, is preferably non-ionic surface active agent.Its content is the 0.1-12% (w/v) of water.
The concentration ratio of getting in touch between water of high concentration and low concentration is 5-50 times.
When adopting spray drying method, with organic solvent biodegradable adjuvant and taxanes substance are dissolved, wherein said organic solvent is selected from wherein a kind of of dichloromethane, chloroform, dimethyl formamide, dimethyl sulfoxide, ethyl acetate, dioxane, ether, acetone, oxolane, ethanol or two or more mixture wherein, wherein the concentration of pharmaceutic adjuvant in organic solvent is 10-1000mg/ml, the concentration of taxanes substance is 10-500mg/ml, during preparation, adopt spray drying method to make microsphere.Control the particle diameter of microsphere by the nozzle size of control spray gun, the speed of spraying.Nozzle is more little, and spray rate is big more, and the microspherulite diameter that makes is more little.
In the said method, from control microsphere size, adjustment releasing effect, preferred single-emulsion-liquid drying method.
The microsphere administration of taxanes substance of the present invention is that the microsphere sterilized powder that will prepare is suspended in the solvent that contains CMC-Na, Tween 80 and mannitol, carries out the local injection administration.Degradation rate according to the preparation microsphere is set administration frequency, promptly discharges the microsphere in 2 weeks, and per 2 weeks are administered once; Discharge 1 month microsphere, be administered once in every month.
Description of drawings
Fig. 1 represents the particle size distribution of the taxol slow release microballoons of embodiment 1.
Fig. 2 represents the particle size distribution of the taxol slow release microballoons of embodiment 2.
Fig. 3 is the taxol slow release microballoons release in vitro curve of embodiment 1.
Fig. 4 is taxol slow release microballoons release profiles in the rabbit body of embodiment 1.
Fig. 5 is the interior release profiles of the taxol slow release microballoons beasle dog body of embodiment 1.
The specific embodiment
Further specify preparation method, particle diameter control, the prominent situation and the slow release effect released of the local injection sustained-release micro-spheres of taxanes substance of the present invention by the following examples.
Method of testing:
The mensuration of microspherulite diameter, drug loading and envelop rate:
The mensuration of the microspherulite diameter among the embodiment 1,2
Experimental technique: take by weighing suitable laboratory sample, use BT-9300H type laser granulometry to measure.
The microsphere drug loading among the embodiment 1,2 and the mensuration of envelop rate
Experimental technique: precision takes by weighing the about 3mg of laboratory sample, places the 3ml dichloromethane, adds acetonitrile: the mixed solution of water (1: 1), and vortex, centrifugal back adopts high performance liquid chromatograph to measure content of medicines, and calculates the drug loading and the envelop rate of microsphere.Chromatographic condition: chromatograph model, Waters 2487Dual λ Absorbance Detector, Waters 1525 Binary HPLC Pump, USA; Chromatographic column, Symmetry C185 μ m4.6 * 150mm Column, USA; Mobile phase, acetonitrile: water (1: 1); Detect wavelength 227nm; Flow velocity 1ml/min.
Embodiment 1: mon-galacta method prepares taxol slow release microballoons
According to taking by weighing paclitaxel 40mg, PLGA respectively (75: 25,20000) 500mg and isopropyl myristate (IPM) 100mg, be dissolved in the 2ml dichloromethane, in the 2500rpm mechanical agitation, with No. 9 syringe needles this solution is injected 5% polyvinyl alcohol (PVA), with 20 times of amount 2%PVA solution dilutions, continue to stir more than 4 hours after 5 minutes.Wash afterwards, frozen centrifugation, obtain microsphere after the lyophilization, yield is 80%.The envelop rate of gained taxol slow release microballoons is 93.10%; The main particle size range of thus obtained microsphere: 5～10 μ m, the profile rounding is uniformly dispersed.Controlling may command microspherulite diameter after stir speed (S.S.), syringe needle charge velocity and the syringe needle size well.The gained result as shown in Figure 1.
Embodiment 2: mon-galacta method prepares taxol slow release microballoons
According to taking by weighing paclitaxel 30mg, PLGA respectively (75: 25,30000) 500mg and isopropyl myristate (IPM) 100mg, be dissolved in the 2ml dichloromethane, with No. 9 syringe needles this solution is injected 5% polyvinyl alcohol (PVA), simultaneously with the 10000rpm mechanical agitation, be 2% with the 5%PVA solution dilution after 5 minutes, continue to stir more than 4 hours.Wash afterwards, frozen centrifugation, obtain microsphere after the lyophilization.The envelop rate of taxol slow release microballoons be 91%; The main particle size range of thus obtained microsphere: 10～50 μ m, the profile rounding is uniformly dispersed.The gained result as shown in Figure 2.
Embodiment 3: paclitaxel microsphere extracorporeal releasing experiment
Will as the embodiment of the invention 1 prepared microballoon lyophilized powder 10 μ g of paclitaxel be dissolved in 10ml dissolution medium phosphate buffered solution (PBS, pH=7.4) in, 37 ℃ of horizontal joltings of constant temperature, timing sampling, HPLC measure to discharge the result.
Experimental technique: precision takes by weighing the about 10mg of laboratory sample, and the pH that places 10ml is 7.4 phosphate buffered solution, places constant temperature oscillator to keep uniform temperature and rotating speed, on time sampling.
Sampling method: the every time point of every batch sample is got sample respectively three times, takes out solution wherein, under the 3000rpm condition centrifugal 10 minutes, gets supernatant and carries out HPLC and measure.Sampling time point is respectively: 0 day, 1 day, 3 days, 5 days, 10 days, 15 days, 20 days, 25 days, 30 days.
The gained result as shown in Figure 3.Reaching in time of 30 days, taxol slow release microballoons of the present invention can be realized discharging reposefully.
Embodiment 4: release experiment in the paclitaxel microsphere
To go into the prepared microballoon lyophilized powder 100mg of paclitaxel of the embodiment of the invention 1, through Co
60Behind the radiation sterilization, be dissolved among the solvent 2ml that contains CMC-Na, Tween 80 and mannitol, carrying out injection under the rabbit, carry out auricular vein respectively at 1.5h, 3h, 6h, 10h, 1d, 2d, 7d, 14d, 21d, 28d, 35d and get blood, is that interior mark carries out HPLC mensuration with norethindrone.The gained result as shown in Figure 4.As seen from the figure, in the time that reached for 3 weeks, it is constant that blood drug level keeps substantially.
Embodiment 5: pharmacodynamic experiment in the paclitaxel microsphere
To go into the prepared microballoon lyophilized powder 100mg of paclitaxel of the embodiment of the invention 1, through Co
60After shining the mattress that goes out, be dissolved among the solvent 2ml that contains CMC-Na, Tween 80 and mannitol, the Kunming mouse of setting up the entity tumor model is carried out subcutaneous injection.Got tumor on the 10th day after the administration and weigh, compare, utilize formula [the heavy suppression ratio %=(1-T/C) * 100% of tumor] to calculate tumour inhibiting rate in the paclitaxel microsphere with matched group Kunming mouse tumor.It is 50～85% that experimental result obtains tumour inhibiting rate.
| Group | Average tumor is heavy | Tumour inhibiting rate (all being contrast) % with the negative control group |
| Dosage group low dose group positive controls negative control group in the high dose group | 0.52 0.63 0.93 1.01 1.10 | 52.94 42.74 15.85 8.34 - |
Claims (6)
1. the sustained-release micro-spheres of a taxanes substance, it is characterized in that it mainly by the molecular weight ranges of the taxanes substance of microsphere weight 0.2-40% and microsphere weight 50-99.8% 5,000-70, biodegradable between 000 dalton and medicinal high polymer adjuvant and other pharmaceutically acceptable adjuvants with biocompatibility are formed; Wherein,
Described taxanes substance is Ramulus et folium taxi cuspidatae terpene, taxane or paclitaxel;
Described medicinal high polymer adjuvant is selected from polylactide-co-glycolide;
And the lactide of described polylactide-co-glycolide and the polymerization ratio of Acetic acid, hydroxy-, bimol. cyclic ester are 75: 25, and the molecular weight of described polylactide-co-glycolide is 20,000～30,000 dalton,
The particle diameter of described sustained-release micro-spheres is 1.0-50 μ m.
2. according to the described sustained-release micro-spheres of claim 1, described taxanes substance is a paclitaxel, and described medicinal high polymer adjuvant is a polylactide-co-glycolide.
3. according to the described sustained-release micro-spheres of claim 1, wherein said taxanes substance sustained-release micro-spheres is to be used for topical therapeutic ovarian cancer, breast carcinoma, pulmonary carcinoma, hepatocarcinoma, gastric cancer, intestinal cancer and other entity cancers and topical therapeutic proliferative vitreoretinopathy PVR.
4. according to the described sustained-release micro-spheres of claim 1, the molecular weight of described polylactide-co-glycolide is 20,000 dalton.
5. according to the described sustained-release micro-spheres of claim 1, the molecular weight of described polylactide-co-glycolide is 30,000 dalton.
6. the preparation method of the sustained-release micro-spheres of each described taxanes substance of claim 1～5, it is characterized in that with dichloromethane, chloroform, ethyl acetate, ethanol, methanol, acetone taxanes substance and biodegradable pharmaceutic adjuvant and isopropyl myristate dissolving, wherein the bulking value percent of pharmaceutic adjuvant in organic solvent is 3-35%, and isopropyl myristate or higher fatty acids similar with it or the ester bulking value percent in organic solvent is 0-30%; What prepare continuous water employing in addition is polyvinyl alcohol, polyvinylpyrrolidone, poly-sodium carboxymethyl cellulose, sodium polyacrylate, sodium polymethacrylate, wherein they are 0.1-10% in the percetage by weight of aqueous phase, the emulsifying agent of aqueous phase is the emulsifying agent of nonionic, and consumption is the 0.1-12% of water; At first decentralized photo slowly is injected in a small amount of high concentration continuous phase emulsifying by tubule; Second step, this emulsified solution dilute with 5-50 times of low concentration continuous phase, continue to stir solvent flashing, wash then, centrifugal, lyophilization promptly.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410085185 CN1754535B (en) | 2004-09-30 | 2004-09-30 | Paclitaxel analog microsphere for topical injection, its preparation method and uses |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410085185 CN1754535B (en) | 2004-09-30 | 2004-09-30 | Paclitaxel analog microsphere for topical injection, its preparation method and uses |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1754535A CN1754535A (en) | 2006-04-05 |
| CN1754535B true CN1754535B (en) | 2010-10-13 |
Family
ID=36688271
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410085185 Expired - Fee Related CN1754535B (en) | 2004-09-30 | 2004-09-30 | Paclitaxel analog microsphere for topical injection, its preparation method and uses |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1754535B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105616359A (en) * | 2016-03-16 | 2016-06-01 | 四川大学 | Multi-block polymer nanofiber drug carrying microsphere and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6447796B1 (en) * | 1994-05-16 | 2002-09-10 | The United States Of America As Represented By The Secretary Of The Army | Sustained release hydrophobic bioactive PLGA microspheres |
-
2004
- 2004-09-30 CN CN 200410085185 patent/CN1754535B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6447796B1 (en) * | 1994-05-16 | 2002-09-10 | The United States Of America As Represented By The Secretary Of The Army | Sustained release hydrophobic bioactive PLGA microspheres |
Non-Patent Citations (2)
| Title |
|---|
| 张爱英等.生物可降解聚乙二醇－b－聚对苯二甲酸丁二醇酯共聚物载药微球的制备.应用化学第20卷 第3期.2003,20(3),293. |
| 张爱英等.生物可降解聚乙二醇-b-聚对苯二甲酸丁二醇酯共聚物载药微球的制备.应用化学第20卷 第3期.2003,20(3),293. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1754535A (en) | 2006-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1234416C (en) | Compositions for sustained delivery of hydrophobic drugs and process for preparation thereof | |
| Liu et al. | A novel trans-lymphatic drug delivery system: implantable gelatin sponge impregnated with PLGA–paclitaxel microspheres | |
| Lee et al. | In vivo efficacy of paclitaxel-loaded injectable in situ-forming gel against subcutaneous tumor growth | |
| ES2385384T3 (en) | Small-molecule extended-release drug formulation | |
| CN101163464A (en) | Polymeric implants, preferably containing a mixture of PEG and PLG, for controlled release of a GnRH | |
| JP2007153896A (en) | Compound of nanoparticle and/or microparticle for treating vascular disease based on topical injection | |
| CN1969818A (en) | Anticancer sustained release injection containing epothilone derivatives | |
| CN101396340A (en) | Anti-cancer sustained-released injection containing epothilone derivate | |
| CN101396342A (en) | Anti-cancer sustained-released injection containing epothilone derivate | |
| CN1969816A (en) | Anticancer sustained release agent containing epothilone | |
| Naraharisetti et al. | In vivo performance of implantable biodegradable preparations delivering Paclitaxel and Etanidazole for the treatment of glioma | |
| CN101336899A (en) | Anticancer sustained-released injection containing taxane | |
| CN1676121A (en) | Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use | |
| EP2074988B1 (en) | Sustained release composition and manufacturing method thereof | |
| CN102133180B (en) | A kind of long-acting injection preparation of sterides 5 alpha-reductase inhibitor and preparation method thereof | |
| CN1754535B (en) | Paclitaxel analog microsphere for topical injection, its preparation method and uses | |
| CN100423719C (en) | Nano granules of Docetaxel and preparing method | |
| Zeng et al. | Poly (lactide-co-glycolide) nanoparticles as carriers for norcantharidin | |
| CN101380303A (en) | Anti-cancer medicine sustained-released injection loaded with platinum compound and synergist thereof | |
| CN101134012A (en) | Method for producing injectable drug administration preparations using mixed polyacid anhydride as the carrier for middle-size or small molecule medicament and application thereof | |
| US20140045895A1 (en) | Pharmaceutical depot for 5-fluoro-2-[[(1s)-1-(5-fluoro-2-pyridyl)ethyl]amino]-6-[(5-isopropoxy-1h-pyrazol-3-yl)amino]pyridine-3-carbonitrile | |
| CN1961863A (en) | An anticancer sustained releasing agent containing mesenchyme hydrolytic reagent and cytotoxic drug | |
| CN101081209A (en) | Anticancer composition containing tyrosine kinase restraining agent and taxane | |
| CN101254166A (en) | An anticancer sustained release injection carrying clorfarabine and its synergist | |
| CN101336900A (en) | Anticancer sustained-released injection containing taxane |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101013 Termination date: 20200930 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |