CN103690512A - Deoxidized podophyllotoxin polymer micelle freeze-drying preparation - Google Patents
Deoxidized podophyllotoxin polymer micelle freeze-drying preparation Download PDFInfo
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Abstract
The invention provides a deoxidized podophyllotoxin polymer micelle freeze-drying preparation. Polymer micelle consists of an amphiphilic block polymer, and a polyethylene glycol monomethyl ether-poly (D,L) lactide block copolymer is optimal. A preparation method of the preparation comprises the steps that deoxidized podophyllotoxin and the block polymer are dissolved in an organic solvent; the solvent is flooded to be gel; the gel is hydrated; the micelle is obtained; and the freeze-drying preparation is prepared further. The freeze-drying preparation can be used for treating a tumor; a medicine carrying encapsulation rate is above 90%; the particle size of the redissolved micelle is 40-70nm; and a redissolved micelle solution can be stabilized for 4-24h at 25 DEG C.
Description
Technical field
The present invention relates to a kind of freeze-drying medicinal composition and preparation method thereof, particularly a kind of compositions, preparation method and lyophilized formulations thereof that is loaded with deoxypodophyllotoxin micelle.
Background technology
Deoxypodophyllotoxin is from lignin plant, to extract the compound that purification obtains, and structural formula is as follows:
Existing experimental results show that of the nineties in last century: deoxypodophyllotoxin has In-vitro Inhibitory Effect to the cell strain of P-388 leukemia, people's lung cancer A-549 and colon cancer HT-29.Because deoxypodophyllotoxin is water insoluble, cannot, for the preparation of intravenous preparation, limit it in preparation industry and application clinically.In order to improve its water solublity, available technology adopting several different methods.
The clathrate of a kind of deoxypodophyllotoxin and beta-schardinger dextrin-is disclosed in Chinese patent CN101693112A; The improvement preparation method of a kind of deoxypodophyllotoxin and hydroxypropyl-beta-cyclodextrin inclusion is disclosed in Chinese patent CN102380104A.Above patent has solved the water solublity problem of deoxypodophyllotoxin, but the nephrotoxicity of beta-schardinger dextrin-compounds and cause that the hidden danger of pancreas tumor is confirmed by animal experiment.Find solubilising material outstanding, that toxic and side effects is less highly significant.
Polymer micelle is comprised of a plurality of amphipathic copolymers, spontaneous formation micelle in water, and its hydrophobic side is inside, and water-wet side is outside, is typical nucleocapsid structure.Its hydrophobic cores energy solubilising hydrophobic drug (as paclitaxel, amycin etc.).Block polymer has larger soft and moist property, and is easy to determine because polymer forms, therefore, better than randomcopolymer micelle repeatability while forming polymer micelle.Biodegradable high molecular, as the block copolymer of lactide and poly glycol monomethyl ether has good biocompatibility, medicine permeability and biological degradability, has obtained the attention of researcher.It is bi-block copolymer that the amphipathic nature block polymer for medicine controlled releasing system of current most study has a class.What form amphipathic nature block polymer hydrophilic block is mainly poly glycol monomethyl ether, has good hydrophilic, and the interfacial free energy contacting with water is low, has extended configuration in water, thereby has very high chain mobility, and certain spatial stability effect can be provided.The high-hydrophilic on pharmaceutical carrier surface can reduce the seepage of medicine, also can reduce the phagocytosis of blood vessel endothelium reticular system to medicine, has both improved the safety of medication, has extended again the blood circulation time of medicine.Hydrophobic block is used polyester, polyoxypropylene, polystyrene or polyamino acid conventionally, and they and poly glycol monomethyl ether form amphipathic copolymer, can form various micelles.
The object of polymer micelle is for injection, answers special preparation, meets injection requirement.Inventor finds poly glycol monomethyl ether-poly-(D, L) lactide block copolymer (mPEG-PDLLA) is suitable for injection, after special preparation, obtain, and paclitaxel based on mPEG-PDLLA and the patent of docetaxel are disclosed, refer to ZL03105348.3, ZL200610145383.7,201010001047.1,201010114289.1.
For improving the one-tenth property of medicine of deoxypodophyllotoxin, we attempt studying other ways of solubilising deoxypodophyllotoxin, yet by adding cosolvent as ethanol, isopropyl alcohol and glycerol, can not solve the dissolubility of deoxypodophyllotoxin; Further has studied and adopted respectively other block polymers if poloxamer or surfactant are as the way of Tween 80 solubilising, attempted by Micellar Solubilization, yet all unsuccessful, some at all cannot solubilising, in some cases solubilising but separate out precipitation at once.
In further research, we are surprised to find, and deoxypodophyllotoxin intrafascicularly has larger dissolubility at the polymer latex of mPEG-PDLLA, stability is better, and other drug-loading system cannot reach same object.
Summary of the invention
In order to improve the dissolubility of deoxypodophyllotoxin in water, be convenient to make the preparation of intravenously administrable, avoid the side effect of using cyclodextrin to bring simultaneously, we use mPEG-PDLLA as pharmaceutical carrier, are prepared into the micelle that is loaded with deoxypodophyllotoxin, and this micelle compared with prior art, there is envelop rate high, good stability, carrier consumption is little, is easy to make the advantage of lyophilized formulations.
The invention provides a kind of deoxypodophyllotoxin polymer micelle lyophilized formulations pharmaceutical composition, described compositions contains active constituents of medicine deoxypodophyllotoxin and drug carrier material poly glycol monomethyl ether-polyester block copolymer; Wherein the mass ratio of deoxypodophyllotoxin and poly glycol monomethyl ether-polyester block copolymer is 1:3～1:10.
Wherein said poly glycol monomethyl ether-polyester block copolymer, is amphipathic copolymer, and its hydrophobic parts is polyester, is selected from: PGA, polylactide, glycolide-lactide copolymer, its hydrophilic parts is poly glycol monomethyl ether.Preferred copolymer is: poly glycol monomethyl ether-poly-(D, L) lactide block copolymer.
In poly glycol monomethyl ether of the present invention-poly-(D, L) lactide block copolymer, the molecular weight of poly glycol monomethyl ether is 2000, and poly glycol monomethyl ether is 3:7～9:1 with the mass ratio of poly-(D, L) lactide, preferably 3:7-6:4.
Poly glycol monomethyl ether of the present invention-poly-(D, L) lactide block copolymer is also referred to as mPEG-PDLLA, this block copolymer can be according to document (Zhang, X., Jackson, J.K., Burt, H.M., the method for report preparation 1996.Development of amphiphilic diblock copolymers as micellar carriers of taxol.Int.J.Pharm.132,195-206.).
As required, in polymer micelle composition of the present invention, also can add the acceptable pharmaceutic adjuvant of medicine, as cosolvent, PH regulator, freeze drying protectant or there is the lyophilizing proppant of support effect.
For this reason, the present invention preferably fills a prescription composed as follows:
Deoxypodophyllotoxin 1-2 weight portion
MPEG-PDLLA20004/6 3-7 weight portion
Pharmaceutic adjuvant 5-10 weight portion.
The present invention also provides the preparation method of polymer micelle composition of the present invention, and step is as follows:
(1) mPEG-PDLLA and deoxypodophyllotoxin are dissolved in to organic solvent;
(2) organic solvent is concentrated, is driven most gel;
(3) to the aqueous solution that adds water or pharmaceutic adjuvant in the gel after concentrated, be heated to if desired uniform temperature aquation, obtain being loaded with the micellar solution of deoxypodophyllotoxin;
(4) above-mentioned micellar solution obtains lyophilized powder through lyophilizing.
Wherein, in step (1), organic solvent used is selected from acetonitrile, methanol, ethanol, isopropyl alcohol, oxolane, dioxane, dichloromethane, chloroform.The preferred 3:7-6:4 of mass ratio of poly glycol monomethyl ether and poly-(D, L) lactide in mPEG-PDLLA used, wherein the molecular weight of poly glycol monomethyl ether preferably 2000.Deoxypodophyllotoxin used and the mass ratio of mPEG-PDLLA are 1:3 to 1:10.The consumption of organic solvent is that every 150mg deoxypodophyllotoxin is used 1～25ml organic solvent.
In step (2), concentrated organic solvent can concentrate by normal pressure, also can concentrating under reduced pressure.When concentrated, temperature is that room temperature is to the boiling point of organic solvent used.
In step (3), the temperature of heating aquation is 20～60 ℃, and hydration time is 5～60 minutes.Micelle aquation can join water in the gel that upper step obtains, and jolting or stirring at suitable temperature, obtain the micelle after aquation; Also can carry out aquation with Rotary Evaporators.
Preferably, step (1) organic solvent used is methanol.
In step (2), the method for concentrated organic solvent adopts the method for concentrating under reduced pressure to carry out, and can or adopt similar technological means to concentrate with Rotary Evaporators.
In step (3), the temperature of heating aquation is 40 ℃.Pharmaceutic adjuvant comprises the adjuvant with frozen-dried protective and support effect, as mannitol, trehalose, sorbitol, glucose, sucrose, lactose, Macrogol 2000, Macrogol 4000, glycine, glucosan and mPEG-PDLLA, and preferred mPEG-PDLLA.The micelle that every 150mg deoxypodophyllotoxin is made can be used the adjuvant of 0.75g～3g.Preferred 1.5g.
The preferred preparation method of the present invention, step is as follows: by deoxypodophyllotoxin and mPEG-PDLLA20004/6 dissolve with methanol, being evaporated to methanol drives to the greatest extent, residue joins aquation in the aqueous solution of mPEG-PDLLA20004/6, with membrane filtration, filtrate subpackage, lyophilizing, obtains white loose bulk powder.
The present invention finds through screening, deoxypodophyllotoxin is combined with mPEG-PDLLA and is prepared into micelle and there is good water solublity, stability, solubility, can be prepared into freeze-dried pharmaceutical formulation for injection, particularly use mPEG-PDLLA as micelle copolymer, as lyophilizing proppant hydrotropy, greatly to improve drug quality again, simplified production technology.
Accompanying drawing explanation
Fig. 1 deoxypodophyllotoxin polymer micelle atomic force microscope figure
The specific embodiment
Below will by object lesson, the present invention will be further described, but it is pointed out that following examples can not form any limitation of the invention.
MPEG-PDLLA described in example is below by the different mPEG-PDLLA X Y/Z that are denoted as of the mass ratio of the molecular weight of mPEG and mPEG:PDLLA, wherein X represents the molecular weight of mPEG, Y/Z represents mPEG and PDLLA mass ratio, for example mPEG-PDLLA20004/6 represents that mPEG molecular weight is that 2000, mPEG and PDLLA mass ratio are 4/6.
Embodiment 1 be take the preparation of the deoxypodophyllotoxin solution that ethanol is cosolvent and composite
Deoxypodophyllotoxin 150mg and ethanol 10mL are placed in to eggplant-shape bottle, and heating makes to dissolve completely.It is in 0.9% sodium chloride solution that above-mentioned solution adds 500mL concentration, immediately visible crystallization.
Embodiment 2 be take preparation and the redissolution of the deoxypodophyllotoxin polymer micelle that polyoxyethylene sorbitan monoleate is solubilizing agent
Deoxypodophyllotoxin 150mg and polyoxyethylene sorbitan monoleate 1500mg are placed in to eggplant-shape bottle, add ethanol 20ml to make to dissolve completely, under decompression, remove ethanol.Obtain oily product.
Get this product 1000mg, adding 500mL concentration is in 0.9% sodium chloride solution, jolting, and visible mass crystallization is separated out, muddiness.
Embodiment 3 be take preparation and the redissolution of the deoxypodophyllotoxin polymer micelle that PLURONICS F87 is solubilizing agent
Deoxypodophyllotoxin 150mg and PLURONICS F87 4000mg are placed in to eggplant-shape bottle, add ethanol 20ml to make to dissolve completely, under decompression, remove ethanol.Obtain white block product.
Get this product 2000mg, adding 500mL concentration is in 0.9% sodium chloride solution, jolting, and visible mass crystallization is separated out, muddiness.
More than be comparative example, cannot arrive object of the present invention.
The present invention adopts mPEG-PDLLA as carrier material, and specific embodiment is as follows:
Embodiment 4 does not contain the preparation of protectant injection deoxypodophyllotoxin polymer micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20004/6450mg are placed in to eggplant-shape bottle, add methanol 12ml to make to dissolve completely, at the bottom of 40 ℃ of heating in water bath reduction vaporization to transparent gel-forms invest bottle.Add water for injection 25ml, in 50 ℃ of heating in water bath, thin film rotation aquation 20 minutes, obtains tool opalescence micelle.With 0.22 μ m membrane filtration, filtrate is sub-packed in cillin bottle by every bottle of 5ml, and lyophilizing obtains white loose bulk powder.
Embodiment 5 be take preparation and the physical property of mPEG-PDLLA20004/6 as protectant injection deoxypodophyllotoxin polymer micelle
1, the preparation of deoxypodophyllotoxin micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20004/6450mg are placed in to eggplant-shape bottle, add methanol 12ml to make to dissolve completely, in 40 ℃ of heating in water bath reduction vaporization to methanol, drive to the greatest extent, at the bottom of being that thin transparent is membranaceous and investing bottle.Add 30mg/ml mPEG-PDLLA20004/6 aqueous solution 25ml, in 40 ℃ of heating in water bath, thin film rotation aquation 20 minutes, obtains tool opalescence micelle.With 0.22 μ m membrane filtration, filtrate is sub-packed in cillin bottle by every bottle of 5ml, and lyophilizing obtains white loose bulk powder.
2, carrier micelle morphologic observation
Get lyophilized formulations take water redissolve to the concentration of deoxypodophyllotoxin be 1mg/ml, and be diluted to 10 μ g/ml.Get 1 of this solution and under atomic force microscope, observe on coverslip, the results are shown in accompanying drawing 1.Visible, micelle is spherical in shape or class is spherical.And embodiment 4 does not add protectant deoxypodophyllotoxin polymer micelle redissolution difficulty, need heating, and unstable after redissolving.
3, content and entrapment efficiency determination
Get lyophilized formulations take normal saline redissolve to the concentration of deoxypodophyllotoxin be 6mg/ml.Get this redissolution liquid 0.1ml and be placed in 10ml measuring bottle, with methanol constant volume, with ultraviolet-uisible spectrophotometer, at wavelength 294nm, measure absorbance A
1.This wavelength place polymer is without absorption.It is appropriate that precision takes deoxypodophyllotoxin reference substance, with dissolve with methanol, is also quantitatively diluted to the contrast solution containing deoxypodophyllotoxin approximately 60 μ g/ml, in 294nm, measures absorbance A
0.By A
1, A
0try to achieve and redissolve the content of deoxypodophyllotoxin in liquid with the concentration of reference substance solution.
Separately get this redissolution liquid 2ml in centrifuge tube, with 10000rpm ultracentrifugation 5 minutes, get supernatant 0.1ml and be placed in 10ml measuring bottle, with methanol constant volume, with ultraviolet-uisible spectrophotometer, at wavelength 294nm, measure absorbance A
2, envelop rate computing formula is as follows: envelop rate %=A
2/ A
1* 100%.
The content that records deoxypodophyllotoxin is 5.86mg/ml, and envelop rate is 97.27%.
4, redissolution time and particle diameter study on the stability
Get 1 bottle of lyophilized formulations, add normal saline 5ml and redissolve, extremely the light blue required time of clarification micellar solution is about 1min to measure lyophilized powder redissolution.Adopt its particle diameter of dynamic light scattering determination, angle of scattering is 90 °, and data are with spherical model collection.Micellar solution after redissolving is put to 25 ℃ of water-baths and place, change of size in monitoring 24h, to investigate micelle dynamic stability.Record particle diameter 49.8nm, can stablize about 24h.
Embodiment 6 be take preparation and the physical property of lactose as protectant injection deoxypodophyllotoxin polymer micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20005/5750mg are placed in to eggplant-shape bottle, add 20ml methanol to make to dissolve completely, in 40 ℃ of heating in water bath reduction vaporization to methanol, drive to the greatest extent, at the bottom of being that thin transparent is membranaceous and investing bottle.Add 30mg/ml lactose aqueous solution 25ml, in 40 ℃ of heating in water bath, thin film rotation aquation 20 minutes, obtains tool opalescence micelle.With 0.22 μ m membrane filtration, by every bottle of 5ml, be sub-packed in cillin bottle, lyophilizing, obtains white loose bulk powder.Adding 5ml normal saline to redissolve, be tool opalescence micelle, is 5.32mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, about 3min of redissolution time, and envelop rate 90.93%, particle diameter 68.6nm, can stablize about 16h.
Embodiment 7 be take preparation and the physical property of Macrogol 2000 as protectant injection deoxypodophyllotoxin polymer micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20006/41000mg are placed in to eggplant-shape bottle, add ethanol 15ml to make to dissolve completely, in 40 ℃ of heating in water bath reduction vaporization to ethanol, drive to the greatest extent, at the bottom of being that thin transparent is membranaceous and investing bottle.Add 30mg/ml Macrogol 2000 aqueous solution 25ml, in 40 ℃ of heating in water bath, thin film rotation aquation 15 minutes, obtains tool opalescence micelle.With 0.22 μ m membrane filtration, by every bottle of 5ml, be sub-packed in cillin bottle, lyophilizing, obtains white loose bulk powder.Adding 5ml normal saline to redissolve, be tool opalescence micelle, is 5.57mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, about 4min of redissolution time, and envelop rate 93.93%, particle diameter 43.1nm, can stablize about 8h.
Embodiment 8 be take preparation and the physical property of glucosan D40 as protectant injection deoxypodophyllotoxin polymer micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20006/41350mg are placed in to eggplant-shape bottle, add isopropyl alcohol 20ml to make to dissolve completely, in 40 ℃ of heating in water bath reduction vaporizations to isopropyl alcohol flooding to the greatest extent, at the bottom of being that thin transparent is membranaceous and investing bottle.Add 50mg/ml glucosan D40 aqueous solution 25ml, in 40 ℃ of heating in water bath, thin film rotation aquation 35 minutes, obtains tool opalescence micelle.With 0.22 μ m membrane filtration, by every bottle of 5ml, be sub-packed in cillin bottle, lyophilizing, obtains white loose bulk powder.Adding 5ml normal saline to redissolve, be tool opalescence micelle, is 5.58mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, about 3min of redissolution time, and envelop rate 92.27%, particle diameter 40.8nm, can stablize about 4h.
Embodiment 9 be take preparation and the physical property of PLURONICS F87 as protectant injection deoxypodophyllotoxin polymer micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20005/5450mg are placed in to eggplant-shape bottle, add acetonitrile 12ml to make to dissolve completely, in 40 ℃ of heating in water bath reduction vaporization to acetonitriles, drive to the greatest extent, at the bottom of being that thin transparent is membranaceous and investing bottle.Add 30mg/ml PLURONICS F87 aqueous solution 25ml, in 40 ℃ of heating in water bath, thin film rotation aquation 30 minutes, obtains tool opalescence micelle.With 0.22 μ m membrane filtration, by every bottle of 5ml, be sub-packed in cillin bottle, lyophilizing, obtains white loose bulk powder.Adding the redissolution of shaking of 5ml normal saline, be tool opalescence micelle, is 5.86mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, about 2min of redissolution time, and envelop rate 97.27%, particle diameter 49.8nm, can stablize about 8h.
Claims (10)
1. a polymer micelle composition for deoxypodophyllotoxin, is characterized in that, described compositions contains active constituents of medicine deoxypodophyllotoxin and drug carrier material poly glycol monomethyl ether-polyester block copolymer; Wherein the mass ratio of deoxypodophyllotoxin and poly glycol monomethyl ether-polyester block copolymer is 1:3～1:10.
2. polymer micelle composition claimed in claim 1, it is characterized in that, wherein said poly glycol monomethyl ether-polyester block copolymer, for amphipathic copolymer, its hydrophobic parts is polyester, be selected from: PGA, polylactide, glycolide-lactide copolymer, its hydrophilic parts is poly glycol monomethyl ether.
3. polymer micelle composition claimed in claim 2, is characterized in that, wherein said poly glycol monomethyl ether-polyester block copolymer is poly glycol monomethyl ether-poly-(D, L) lactide block copolymer.
4. polymer micelle composition claimed in claim 3, it is characterized in that, in described poly glycol monomethyl ether-poly-(D, L) lactide block copolymer, the molecular weight of poly glycol monomethyl ether is 2000, poly glycol monomethyl ether is 3:7～9:1 with the mass ratio of poly-(D, L) lactide.
5. polymer micelle composition claimed in claim 4, is characterized in that, poly glycol monomethyl ether is 3:7-6:4 with the mass ratio of poly-(D, L) lactide.
6. polymer micelle composition claimed in claim 1, is characterized in that, fills a prescription as follows:
Deoxypodophyllotoxin 1-2 weight portion
MPEG-PDLLA20004/6 3-7 weight portion
Pharmaceutic adjuvant 5-10 weight portion
Described pharmaceutic adjuvant is selected from: mannitol, trehalose, sorbitol, glucose, sucrose, lactose, PLURONICS F87, Macrogol 2000, Macrogol 4000, glycine, glucosan and poly glycol monomethyl ether-poly-(D, L) lactide block copolymer.
7. the preparation method of polymer micelle composition claimed in claim 1, is characterized in that, step is as follows: (1) is dissolved in organic solvent by poly glycol monomethyl ether-poly-(D, L) lactide block copolymer and deoxypodophyllotoxin; (2) organic solvent concentrated, drive to the greatest extent to gel; (3) to the aqueous solution that adds water or pharmaceutic adjuvant in the gel after concentrated, be heated to if desired uniform temperature aquation, obtain being loaded with the micellar solution of deoxypodophyllotoxin; (4) lyophilizing of polymer micelle solution obtains lyophilized powder.
8. preparation method claimed in claim 7, is characterized in that, the organic solvent described in step (1) is selected from: acetonitrile, methanol, ethanol, isopropyl alcohol, oxolane, dioxane, dichloromethane; Pharmaceutic adjuvant described in step (3) is selected from: mannitol, trehalose, sorbitol, glucose, sucrose, lactose, PLURONICS F87, Macrogol 2000, Macrogol 4000, glycine, glucosan and poly glycol monomethyl ether-poly-(D, L) lactide block copolymer, described in step (3), be heated to uniform temperature aquation, hydration temperature is 20～60 ℃.
9. preparation method claimed in claim 8, it is characterized in that, step is as follows: by deoxypodophyllotoxin and mPEG-PDLLA20004/6 dissolve with methanol, being evaporated to methanol drives to the greatest extent, residue joins aquation in the aqueous solution of mPEG-PDLLA20004/6, with membrane filtration, and filtrate subpackage, lyophilizing, obtains white loose bulk powder.
10. preparation method claimed in claim 9, it is characterized in that, step is as follows: deoxypodophyllotoxin 150mg and mPEG-PDLLA20004/6450mg are placed in to eggplant-shape bottle, add methanol 12ml to make to dissolve completely, in 40 ℃ of heating in water bath reduction vaporization to methanol, drive to the greatest extent, at the bottom of being that thin transparent is membranaceous and investing bottle, add 30mg/ml mPEG-PDLLA20004/6 aqueous solution 25ml, in 40 ℃ of heating in water bath, thin film rotation aquation 20 minutes, obtain tool opalescence micelle, with 0.22 μ m membrane filtration, filtrate is sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtain white loose bulk powder.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104398504A (en) * | 2014-11-03 | 2015-03-11 | 浙江尖峰药业有限公司 | Deoxypodophyllotoxin medicine-containing pharmaceutical composition and preparation method and preparation thereof |
| CN105315444A (en) * | 2014-07-16 | 2016-02-10 | 西南药业股份有限公司 | Purification method of polyethylene glycol monomethyl ether-polylactic acid amphiphilic segmented copolymer for injection |
| CN105732651A (en) * | 2016-03-17 | 2016-07-06 | 重庆药友制药有限责任公司 | Micromolecular lung targeting medicine |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1416902A (en) * | 2002-12-02 | 2003-05-14 | 天津大学 | Combined polymer-medicine micelle and its prepn process |
| CN101972480A (en) * | 2010-01-19 | 2011-02-16 | 南京泛太化工医药研究所 | Docetaxel polymeric micelle medicine composition taking amino acid as stabilizing agent |
-
2013
- 2013-12-24 CN CN201310722262.4A patent/CN103690512B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1416902A (en) * | 2002-12-02 | 2003-05-14 | 天津大学 | Combined polymer-medicine micelle and its prepn process |
| CN101972480A (en) * | 2010-01-19 | 2011-02-16 | 南京泛太化工医药研究所 | Docetaxel polymeric micelle medicine composition taking amino acid as stabilizing agent |
Non-Patent Citations (3)
| Title |
|---|
| 姜同英等: "共聚物胶束对鬼臼毒素的增溶和保护作用", 《中国药剂学杂志》, vol. 7, no. 3, 31 May 2009 (2009-05-31), pages 115 - 120 * |
| 王莉莉等: "抗癌物质鬼臼毒素及其衍生物研究进展", 《国外医药·植物药分册》, vol. 21, no. 1, 31 December 2006 (2006-12-31), pages 6 - 9 * |
| 高鹏: "鬼臼毒素的聚乙二醇－聚己内酯胶束的制备", 《江西中医药》, vol. 41, no. 326, 28 February 2010 (2010-02-28), pages 57 - 59 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105315444A (en) * | 2014-07-16 | 2016-02-10 | 西南药业股份有限公司 | Purification method of polyethylene glycol monomethyl ether-polylactic acid amphiphilic segmented copolymer for injection |
| CN105315444B (en) * | 2014-07-16 | 2018-04-17 | 西南药业股份有限公司 | The purification process of injection poly glycol monomethyl ether polylactic acid amphiphilic block copolymer |
| CN104398504A (en) * | 2014-11-03 | 2015-03-11 | 浙江尖峰药业有限公司 | Deoxypodophyllotoxin medicine-containing pharmaceutical composition and preparation method and preparation thereof |
| CN104398504B (en) * | 2014-11-03 | 2017-07-25 | 浙江尖峰药业有限公司 | A kind of pharmaceutical composition of deoxypodophyllotoxin class medicine and preparation method thereof and preparation |
| CN105732651A (en) * | 2016-03-17 | 2016-07-06 | 重庆药友制药有限责任公司 | Micromolecular lung targeting medicine |
| CN105732651B (en) * | 2016-03-17 | 2018-07-20 | 重庆药友制药有限责任公司 | A kind of small molecule Lung targeting drug |
| US10639295B2 (en) | 2016-03-17 | 2020-05-05 | Yaopharma Co., Ltd. | Podophyllotoxin derivative with 4-position nitrogen substitution and preparation method and application thereof |
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| CN103690512B (en) | 2016-03-09 |
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