CN104856950A - Paclitaxel micelle drug load system and preparation method thereof - Google Patents
Paclitaxel micelle drug load system and preparation method thereof Download PDFInfo
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- CN104856950A CN104856950A CN201510073940.8A CN201510073940A CN104856950A CN 104856950 A CN104856950 A CN 104856950A CN 201510073940 A CN201510073940 A CN 201510073940A CN 104856950 A CN104856950 A CN 104856950A
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- paclitaxel
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- micelle
- chain segment
- hydrophobic
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- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000000637 radiosensitizating effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 230000001954 sterilising effect Effects 0.000 description 1
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- 239000004094 surface-active agent Substances 0.000 description 1
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- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- KSBAEPSJVUENNK-UHFFFAOYSA-L tin(ii) 2-ethylhexanoate Chemical compound [Sn+2].CCCCC(CC)C([O-])=O.CCCCC(CC)C([O-])=O KSBAEPSJVUENNK-UHFFFAOYSA-L 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
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- 210000003462 vein Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a novel micelle drug load system formed by an amphiphilic segmented copolymer and paclitaxel. The amphiphilic segmented copolymer comprises a hydrophilic chain segment and a hydrophobic chain segment, the hydrophilic chain segment is polyethylene glycol monomethyl ether, the hydrophobic chain segment is polycaprolactone, and the end group of the hydrophobic chain segment is terminated by a hydrophobic group. The hydrophobic group is tertbutyloxycarbonyl phenylalanine, so the compatibility of a drug molecule with the hydrophobic chain segment in the segmented copolymer is improved, the interaction between the drug molecule and the segmented copolymer is increased, a large space is provided for accommodating the drug molecule, and a prepared micelle can effectively restrict the drug molecule in the core of the micelle, thereby a drug loaded micelle with high stability is obtained.
Description
Technical field
The present invention relates to drug-loading system of a kind of amphipathic nature block polymer and paclitaxel formation and preparation method thereof, belong to nano-drug preparation field.
Background technology
Tumor is the disease of a class serious threat human life safety, and research safety, effective antitumour medicine are significant for the life quality improving the mankind.
Paclitaxel (Paclitaxel, PTX) be a kind of very effectively and the antitumor drug of wide spectrum, its mechanism of action is mainly polymerized and stable microtubule, the tumor cell of fast division can be caused to be fixed on mitotic stages, cancerous cell to be copied blocked and dead.
Experiment in vitro proves: paclitaxel has significant radiosensitizing effect, and tumor cell can be made to terminate in G2 and M phase to radiotherapy sensitivity.But because it is water-soluble hardly, oral absorption is poor, at present can only drug administration by injection, listing preparation (trade name taxol) be by add polyoxyethylene castor oil (
eL) drug solubility is increased.Test proves, taxol exists shortcomings: (1) is owing to employing
eL easily causes anaphylaxis, therefore needs before patient medication to carry out antianaphylactic treatment; (2) medicine stability is poor, injection availability is not high: above-mentioned preparation is the easy Precipitation of medicine after dilution, need through special defecator when administration, and injection dilution need slowly be carried out, the degree varies often causing medicine to separate out because of the difference of operator causes, thus cause the dose that enters in body inaccurate, then produce Different therapeutical effect; (3) haematics toxicity is higher:
eL can cause haematics toxicity, becomes the principal element that limit treatment dosage improves.Therefore, research and develop development trend [the Charity D that new medicine-releasing system is taxanes cell toxicity medicament with the toxicity avoiding adjuvant to bring, William DF, Alex S.Therapeutics and Clinical Risk Management 2005,1 (2): 107-114.].
The kind of external listing has injection paclitaxel (albumin bound type) (Celgene company of the U.S.) and injection paclitaxel micelle (Samyang company of Korea S) at present, the former toxic and side effects and curative effect are all better than female medicine paclitaxel (Taxol), 2007 annual sales amounts reach 300,000,000 dollars, within 2008, American Pharmaceutical Partners (APP) company is with 4,000,000,000 U.S. dollar purchase Abraxis Bio Science, and sell at more than 30, whole world national registration, rear APP company is again by Celgene corporate buyout; The latter is in Korea S and India's listing, and do III clinical trial phase in the U.S., sales volume rises year by year.The novel formulation of domestic listing has injection Paclitaxel liposome (greenery pharmacy), and within 2003, obtain SFDA approval, Nanjing Cisco of greenery pharmacy related companies produces, and has become the key product of group company.
The domestic and international taxone novel formulation grinding comprises micelle, Emulsion and microemulsion, prodrug, cyclodextrin clathrate, liposome etc. at present, and wherein polymer micelle is a kind of Novel Drug Delivery Systems that development in recent years is got up.Polymer micelle is usually aligned by a large amount of amphipathic nature block polymer strand and forms, its hydrophobic segment by and drug molecule between weak interaction pharmaceutical pack is wrapped in core, hydrophilic chain outwards stablizes micelle, presents typical nucleocapsid structure.Polymer micelle can not only increase the dissolubility of medicine, improves therapeutic dose, and medicine parcel wherein, can avoid inactivation of degrading, and reduces toxicity.Micelle particle diameter is usually at below l00nm, and periphery is hydrophilic PEG chain segment, therefore engulfing of reticuloendothelial system (RES) can be hidden, extension body circulation time, the effect to tumor passive target is reached by EPR effect (high-permeability and retention effect, enhanced permeability and retentioneffect).In addition, because polymer micelle molecular weight is large, therefore also can prevent kidney from removing.Compare with Small molecular surfactant, the CMC value (critical micelle concentration) of polymer micelle is very low, when carrier micelle dilutes, also can keep the stable of micellar structure, polymeric material has biodegradability and good biocompatibility simultaneously.Following table provides some important antitumor micelles carry out clinical research situation in the U.S..
Although polymer micelle is considered to a kind of Novel Drug Delivery Systems of great potential, particularly for the antitumor drug of some slightly solubilities, its stability is in vivo the most critical issue that this Novel Drug Delivery Systems of impact transforms to clinical research always.The injection paclitaxel micelle (trade name Genexol PM) gone on the market to take the lead in Korea S, its solution is no more than 24h[Lee SW et al.Ionically fixed polymeric nanoparticles as a novel drug carrier.Pharmaceutical Research 2007,24:1508-1516. stabilization time at ambient temperature].
How to improve micellar preparation in vivo stability be taxane micelle administration system research key, Chinese patent CN01809632.8 is by introducing the end-blocking of acetoxyl group or benzoyloxy at hydrophobic block, thus improve high polymer adjuvant to the affinity of medicine or absorbing power, improve the ability that medicine caught by adjuvant, improve medicine stability in vivo and in vitro, though its acetoxyl group selected or benzoyloxy can improve the vitro stability of micelle, but under simulated body fluid environment, to improving the limited in one's ability of medicine stability, related preparations does not still reach the standard of patent medicine.Therefore, find and a kind ofly become the urgent needs of paclitaxel new preparation developing significantly improving paclitaxel stability in vivo.
Summary of the invention
The object of the present invention is to provide a kind of amphipathic nature block polymer, to solve the above-mentioned problems in the prior art.Amphipathic nature block polymer of the present invention is material based on the poly glycol monomethyl ether-polyester block copolymer with generally recognized as safe, and the terminal hydroxy group hydrophobic group of polyester segment is carried out modification, introduce tertbutyloxycarbonyl phenylalanine structure and there is larger space structure, not only improve the compatibility of hydrophobic chain segment in drug molecule and block copolymer, increase the active force that it is mutual, and the hydrophobic group introduced has larger space structure, the core entering micelle for drug molecule provides larger space, thus make its more not easily stripping, thus acquisition has in height body, the carrier micelle of vitro stability.The most important significance of this invention is the stability at solution state improving micelle, the stability especially in body, thus the EPR effect playing micelle, reach higher bioavailability and better therapeutic effect.
Technical scheme provided by the invention is as follows:
A kind of micelle medicine carrying system, it is characterized in that this micelle medicine carrying system comprises amphipathic nature block polymer, the paclitaxel for the treatment of effective dose and pharmaceutically acceptable pharmaceutic adjuvant, described amphipathic nature block polymer comprises hydrophilic segment and hydrophobic chain segment, its hydrophilic segment is the Polyethylene Glycol of number-average molecular weight between 400 ~ 20000 or poly glycol monomethyl ether, its hydrophobic chain segment is selected from the polylactide of number-average molecular weight between 500 ~ 100000 adopting hydrophobic group end-blocking, and described hydrophobic group is tertbutyloxycarbonyl phenylalanine.
In the embodiment of recommending, the number-average molecular weight of described hydrophobic chain segment is between 1000 ~ 50000; The number-average molecular weight of described hydrophilic segment is between 750 ~ 5000.
Another object of the present invention is the preparation method providing a kind of micelle medicine carrying system, comprises the following steps:
1) hydrophilic segment of average molecular weight between 400 ~ 20000 of peeking joins in polymerization bottle, is heated to 100 DEG C ~ 130 DEG C vacuum dehydration 2h ~ 4h.The tetrahydrofuran solution that metallic potassium is dissolved in naphthalene forms naphthalene potassium, then naphthalene potassium solution is joined in the methoxy poly (ethylene glycol) of dehydration and react, then add lactide monomer polymerized at room temperature polymer after ethyl alcohol recrystallization, obtain methoxy poly (ethylene glycol)-polyester block copolymer, described hydrophilic segment is Polyethylene Glycol or poly glycol monomethyl ether;
2) block copolymer of hydrophilic segment and hydrophobic chain segment composition is got, dissolve with ethyl acetate, oxolane, dichloromethane, ethyl acetate or distilled water, then add tertbutyloxycarbonyl phenylalanine-neopentanoic acid acid anhydride to react, terminal hydroxy group is reacted and forms hydrophobic group, filter after removing insoluble matter and add enough ether sedimentation polymer, after filtering vacuum drying, obtain subject copolymers.
3) lyophilizing is carried out after copolymer, paclitaxel and suitable pharmaceutic adjuvant being made micellar solution.
In the embodiment of recommending, described pharmaceutic adjuvant is lyophilizing excipient.
In the present invention, described lyophilizing excipient is selected from least one in lactose, mannitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
In the embodiment of recommending, before described step of freeze drying, there is aseptic treatment step.
Another object of the present invention is the purposes of open micelle medicine carrying system in preparation tumor.
Another object of the present invention be open micelle medicine carrying system for the preparation of with the purposes in chemotherapeutic agent therapeutic alliance tumour medicine, described chemotherapeutic agent is SN38,10-hydroxycamptothecine, irinotecan, topotecan, vinorelbine, gemcitabine, cytosine arabinoside, ftorafur, methotrexate, doxorubicin, epirubicin, pirarubicin, idarubicin, mitomycin, Epothilones and derivant, mitoxantrone, ifosfamide, dacarbazine, cisplatin, oxaliplatin etc.
Micelle medicine carrying system of the present invention by injection administration, and is made generally in freeze-dried powder preparation, and in addition, those skilled in the art can refer to the dosage determination dosage of existing antitumor drug, and adjust up and down according to the difference of individual instances.
Compared with prior art, the present invention has following feature:
1) the present invention is according to the hydrophobicity on most of anti-tumor medicament structure and larger space structure, the terminal hydroxy group hydrophobic group of polyester segment is carried out modification, by improving the compatibility of hydrophobic chain segment in drug molecule and block copolymer, increase the active force that it is mutual, increase the space that can hold drug molecule in micelle core simultaneously, drug molecule is limited in the core of micelle and makes its not easily stripping, thus obtain a series of carrier micelle all in vivo and in vitro with high stability, this carrier micelle can be made into lyophilized formulations, convenient storage and transport;
2) with the ether sedimentation method purified high-molecular polymer that uses in prior art, the present invention adopts ethyl alcohol recrystallization method purified high-molecular polymer, and the macromolecule purity obtained is higher, and molecular weight distribution index can reach less than 1.1;
3) experiment results proved: can disperse rapidly to form yellow settled solution after the lyophilized formulations the made redissolution of the antitumor drug carrier micelle that amphipathic nature block polymer of the present invention prepares, this solution under room temperature environment still at least Absorbable organic halogens within more than 24 hours, separate out without obvious drug precipitation, after injection, can effectively play EPR effect in vivo, there is good commercial application prospect.
Accompanying drawing explanation
Accompanying drawing 1 high polymer adjuvant gel permeation chromatography figure.
Accompanying drawing 2 paclitaxel micelle freeze-drying powder and rear solution appearance of redissolving;
Solution grain size distribution (right side) is redissolved after solution grain size distribution (left side) and lyophilizing before accompanying drawing 3 lyophilizing;
The paclitaxel micelle rat plasma drug level rheological parameters' change with time curve chart of accompanying drawing 4 different end group end-blocking;
The mPEG-PLA/ paclitaxel micelle of the different end-blocking of accompanying drawing 5 is to the growth inhibited action diagram of carcinoma of prostate PC-3A nude mouse xenograft tumor;
The mPEG-PLA/ paclitaxel micelle of the different end-blocking of accompanying drawing 6 is to the growth inhibited action diagram of multiple myeloma RPMI8226 nude mouse xenograft tumor.
Detailed description of the invention
For the ease of understanding the present invention, spy enumerates embodiment, to annotate the present invention further, instead of the restriction to any mode of the present invention.
The synthesis of embodiment 1mPEG-PLA-Phe (Boc)
5g molecular weight is the methoxy poly (ethylene glycol) of 2000,6g lactide, 6mg stannous octoate, and 10ml toluene joins in polymerization bottle, and the moisture in 50 DEG C of vacuum removal toluene removing systems, vacuum tightness polymerization bottle is in 100
odEG C polymerization 24h, use dichloromethane lysate, after ether sedimentation methoxy poly (ethylene glycol)-polylactide block copolymer (MPEG-PLA).
6.65gBoc phenylalanine is dissolved in 50ml anhydrous ethyl acetate, adds 3.5ml triethylamine, adds 3.05ml pivalyl chloride after solution is cooled to-10 DEG C, and reactant at room temperature continues reaction 2h after being warming up to 0 DEG C of reaction 2h.Filter and remove insoluble matter, it is Boc phenylpropyl alcohol ammonia-neopentanoic acid acid anhydride that rotary evaporation obtains white solid after removing ethyl acetate.
50g MPEG-PCL is dissolved in 50ml anhydrous methylene chloride, and add 3.5ml triethylamine and 0.375g pyrollidinopyridine, solution is cooled to 0 DEG C.Above-mentioned reaction gained Boc phenylpropyl alcohol ammonia-neopentanoic acid acid anhydride is joined after being dissolved in 25ml anhydrous methylene chloride in MPEG-PLA solution, after reacting 1h at 0 DEG C, under room temperature, continues reaction 36h.Product is used 100ml dissolve with ethanol after removing solvent by rotary evaporation, solution freezing and crystallizing after filtering.Product 100ml ethyl alcohol recrystallization twice final vacuum is dry obtains target product MPEG-PLA-Phe (Boc).
Test proves: prepare the target product obtained and have very narrow molecular weight distribution index, purity is very high, and its gel permeation chromatography figure is shown in accompanying drawing 1.
The preparation of embodiment 2MPEG-PLA-Phe (Boc)/paclitaxel micelle
20mg paclitaxel, 100mg MPEG-PLA-Phe (Boc) is dissolved in 5ml ethanol, adds 5ml ultra-pure water and dissolve medicine film after 55 DEG C of rotary evaporations remove solvent, and the lyophilizing after 0.22 μm of sterilization film is filtered of gained micellar solution obtains paclitaxel micelle freeze-drying powder.Its solubility is good, and before and after redissolving, particle size distribution change is less, and detailed results is shown in accompanying drawing 2 and accompanying drawing 3.
Test example 3 pharmacokinetic trial
A, laboratory animal:
Male SD rat, body weight 240 ± 20g, is divided into four groups at random, and often group is 6, for subsequent use.
B, experimental preparation:
Preparation I: for supplying examination paclitaxel micelle freeze-drying powder preparation, prepare by embodiment 2, lot number 20131018, every bottle containing paclitaxel 10mg;
Preparation II: be reference paclitaxel micellar preparation, using MPEG-PLA disclosed in Chinese patent CN201110231519.7 as high polymer adjuvant, lot number 20131020, every bottle containing paclitaxel 10mg;
Formulation III: be reference paclitaxel micellar preparation, prepares paclitaxel micelle as high polymer adjuvant, lot number 20131022 using acetoxyl group end-blocking MPEG-PLA disclosed in Chinese patent CN01809632.8, and every bottle containing paclitaxel 10mg;
Preparation IV: be reference paclitaxel micellar preparation, prepares paclitaxel micelle as high polymer adjuvant, lot number 20131025 using benzoyl end-blocking MPEG-PLA disclosed in Chinese patent CN01809632.8, and every bottle containing paclitaxel 10mg.
C, administration and sample collection:
Experimental preparation I, II, III, IV to suitable concn, do not give two groups of rats in 25mg/kg dosage (all with paclitaxel) through tail vein injection in dissolved dilution before use.Respectively at after administration not in the same time through rat orbital venous plexus blood sample collection in anticoagulant heparin centrifuge tube, centrifugal separation plasma, puts-80 DEG C of ultra cold storage freezers frozen, to be measured.
D, plasma treatment and mensuration:
Plasma sample, to carry out LC-MS/MS analysis after extraction into ethyl acetate, measures wherein taxol drug concentration.
E, experimental result:
Draw blood plasma taxol drug concentration rheological parameters' change with time curve (accompanying drawing 4) of four kinds of preparations respectively, and calculate main blood plasma pharmacokinetic parameters.Result shows, paclitaxel polymer micelle prepared by the present invention and publication (CN201110231519.7) and CN01809632.8 micelle give rat through intravenous route under same dose, the former has significantly high plasma drug level and AUC, paclitaxel in vivo clearance rate significantly reduces, and eliminates Increased Plasma Half-life.The paclitaxel micellar phase that result reflects prepared by the present invention has superior stability and unique in vivo release characteristic than patent CN201110231519.7 and CN01809632.8.
Embodiment 4 pharmacodynamics test
4.1 injection paclitaxel micelles are to the growth inhibited effect of carcinoma of prostate PC-3A Adriamycin resistant cell nude mouse xenograft tumor
Male BALB/c nude mouse veutro subcutaneous vaccination 5 × 10
6individual PC-3A cell.After about one week, mice with tumor tumor average volume reaches 100mm
3time above, 30 tumor-bearing mices press the grouping of gross tumor volume random stratified, be respectively: solvent group, preparation I (20mg/kg, derive from embodiment 2), Formulation II, Formulation III, preparation IV prepares (20mg/kg) with reference to patent CN201110231519.7 and CN01809632.8, intravenously administrable, gave a medicine every 3 days, amount to 3 times.Experimental session, measures weekly animal tumor volume (computing formula ab
2/ 2, a, b are respectively the length of tumor and wide) and body weight.Result as shown in Figure 5; the experiment later stage; be significantly higher than other three kinds of paclitaxel micelles (P<0.05) Deng dosage injection tertbutyloxycarbonyl phenylalanine end-blocking mPEG-PLA/ paclitaxel micelle tumour inhibiting rate, and paclitaxel micelle tumor-inhibiting action prepared by mPEG-PLA, acetoxyl group end-blocking mPEG-PLA, benzoyl end-blocking mPEG-PLA is relatively weak.
4.2 injection paclitaxel micelles are to the growth inhibited effect of multiple myeloma RPMI8226 nude mouse xenograft tumor
Male BALB/c nude mouse veutro subcutaneous vaccination 5 × 10
6individual RPMI8226 cell.After about one week, mice with tumor tumor average volume reaches 100mm
3time above, 30 tumor-bearing mices press the grouping of gross tumor volume random stratified, be respectively: solvent group, preparation I (20mg/kg, derive from embodiment 2), Formulation II, Formulation III, preparation IV prepares (20mg/kg) with reference to patent CN201110231519.7 and CN01809632.8, intravenously administrable, gave a medicine every 3 days, amount to 3 times.Experimental session, measures weekly animal tumor volume (computing formula ab
2/ 2, a, b are respectively the length of tumor and wide) and body weight.Result as shown in Figure 6; the experiment later stage; be significantly higher than other three kinds of paclitaxel micelles (P<0.05) Deng dosage injection tertbutyloxycarbonyl phenylalanine end-blocking mPEG-PLA/ paclitaxel micelle tumour inhibiting rate, and paclitaxel micelle tumor-inhibiting action prepared by mPEG-PLA, acetoxyl group end-blocking mPEG-PLA, benzoyl end-blocking mPEG-PLA is relatively weak.
Claims (8)
1. a paclitaxel micelle medicine carrying system, it is characterized in that this micelle medicine carrying system comprises amphipathic nature block polymer, the paclitaxel for the treatment of effective dose and pharmaceutically acceptable pharmaceutic adjuvant, described amphipathic nature block polymer comprises hydrophilic segment and hydrophobic chain segment, its hydrophilic segment is the Polyethylene Glycol of number-average molecular weight between 400 ~ 20000 or poly glycol monomethyl ether, its hydrophobic chain segment is selected from the polylactide of number-average molecular weight between 500 ~ 100000 adopting hydrophobic group end-blocking, and described hydrophobic group is tertbutyloxycarbonyl phenylalanine.
2. paclitaxel micelle medicine carrying system according to claim 1, is characterized in that the number-average molecular weight of described hydrophobic chain segment is between 1000 ~ 50000; The number-average molecular weight of described hydrophilic segment is between 750 ~ 5000.
3. the preparation method of paclitaxel micelle medicine carrying system described in claim 1 or 2, is characterized in that, comprise the following steps:
1) hydrophilic segment of average molecular weight between 400 ~ 20000 of peeking joins in polymerization bottle, be heated to 100 DEG C ~ 130 DEG C vacuum dehydration 2h ~ 4h, the tetrahydrofuran solution that metallic potassium is dissolved in naphthalene forms naphthalene potassium, then naphthalene potassium solution is joined in the methoxy poly (ethylene glycol) of dehydration and react, then add lactide monomer polymerized at room temperature polymer after ethyl alcohol recrystallization, obtain methoxy poly (ethylene glycol)-polyester block copolymer, described hydrophilic segment is Polyethylene Glycol or poly glycol monomethyl ether;
2) block copolymer of hydrophilic segment and hydrophobic chain segment composition is got, dissolve with ethyl acetate, oxolane, dichloromethane, ethyl acetate or distilled water, then add tertbutyloxycarbonyl phenylalanine-neopentanoic acid acid anhydride to react, terminal hydroxy group is reacted and forms hydrophobic group, filter after removing insoluble matter and add enough ether sedimentation polymer, after filtering vacuum drying, obtain subject copolymers;
3) lyophilizing is carried out after copolymer, paclitaxel and suitable pharmaceutic adjuvant being made micellar solution.
4. preparation method according to claim 3, is characterized in that described pharmaceutic adjuvant is lyophilizing excipient.
5. preparation method according to claim 4, is characterized in that described lyophilizing excipient is selected from least one in lactose, mannitol, sucrose, trehalose, fructose, glucose, sodium alginate or gelatin.
6. preparation method according to claim 3, has aseptic treatment step before it is characterized in that described step of freeze drying.
7. the purposes of paclitaxel micelle medicine carrying system described in claim 1 or 2 in preparation tumor.
8. paclitaxel micelle medicine carrying system described in claim 1 or 2 for the preparation of with the purposes in chemotherapeutic agent therapeutic alliance tumour medicine, described chemotherapeutic agent is SN38,10-hydroxycamptothecine, irinotecan, topotecan, vinorelbine, gemcitabine, cytosine arabinoside, ftorafur, methotrexate, doxorubicin, epirubicin, pirarubicin, idarubicin, mitomycin, Epothilones and derivant, mitoxantrone, ifosfamide, dacarbazine, cisplatin or oxaliplatin.
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| CN105287377A (en) * | 2015-10-16 | 2016-02-03 | 姚俊华 | Taxol polymer micelle drug-loading system and preparation method and application thereof |
| CN105367772A (en) * | 2015-10-16 | 2016-03-02 | 姚俊华 | Amphiphilic block copolymer and preparation method of micelle thereof and application |
| CN105367804A (en) * | 2015-10-16 | 2016-03-02 | 姚俊华 | Amphiphilic block polymer for carrying medicine and preparing method and application of amphiphilic block polymer |
| CN105399938A (en) * | 2015-10-16 | 2016-03-16 | 姚俊华 | Preparation method and application of amphiphilic block copolymer, and preparation method and application of micelle of copolymer |
| CN105399931A (en) * | 2015-10-16 | 2016-03-16 | 姚俊华 | Amphiphilic block copolymer, and preparation method and application thereof |
| CN105367772B (en) * | 2015-10-16 | 2019-04-12 | 江苏万高药业股份有限公司 | A kind of preparation method and application of Amphipathilic block polymer and its micella |
| CN105399931B (en) * | 2015-10-16 | 2019-05-03 | 江苏万高药业股份有限公司 | A kind of amphipathic nature block polymer and its preparation method and application |
| CN105399938B (en) * | 2015-10-16 | 2019-05-14 | 江苏万高药业股份有限公司 | A kind of preparation method and application of amphipathic nature block polymer and its micella |
| CN106361697A (en) * | 2016-08-26 | 2017-02-01 | 四川兴康脉通医疗器械有限公司 | Taxol-carrying micelle polymer containing ibuprofen, preparation, and preparation methods |
| CN106361697B (en) * | 2016-08-26 | 2019-06-07 | 四川兴康脉通医疗器械有限公司 | A kind of load taxol micellar copolymerization object, preparation and preparation method containing brufen |
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