CN103690512B - A kind of deoxypodophyllotoxin polymer micelle lyophilized formulations - Google Patents
A kind of deoxypodophyllotoxin polymer micelle lyophilized formulations Download PDFInfo
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Abstract
The invention provides a kind of deoxypodophyllotoxin polymer micelle lyophilized formulations, wherein polymer micelle is made up of Amphipathilic block polymer, preferred poly glycol monomethyl ether-poly-(D, L) lactide block copolymer, the preparation method of described preparation comprises dissolves deoxypodophyllotoxin and block polymer in organic solvent, solvent is driven most gel, after gel aquation, obtain micelle, make lyophilized formulations further; This lyophilized formulations may be used for treating tumor, and medicine carrying envelop rate is more than 90%, and after redissolving, micelle particle diameter is 40 ~ 70nm, the 25 DEG C of Absorbable organic halogens 4 ~ 24h of the micellar solution after redissolution.
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 being loaded with deoxypodophyllotoxin micelle.
Background technology
Deoxypodophyllotoxin is the compound that extraction purification obtains from lignin plant, and structural formula is as follows:
The existing experiment of the nineties in last century proves: the cell strain of deoxypodophyllotoxin to P-388 leukemia, people's lung cancer A-549 and colon cancer HT-29 has In-vitro Inhibitory Effect.Because deoxypodophyllotoxin is water insoluble, for the preparation of intravenous preparation, cannot be limited it in preparation industry and application clinically.In order to improve its water solublity, in prior art, have employed multiple method.
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 solves the water solubility problems of deoxypodophyllotoxin, but the nephrotoxicity of beta-schardinger dextrin-compounds and cause the hidden danger of pancreas tumor to be confirmed by animal experiment.Find outstanding, that toxic and side effects is less solubilising material highly significant.
Polymer micelle is made up of multiple amphipathic copolymer, spontaneous formation micelle in water, and its hydrophobic side is inside, and water-wet side is outside, in typical nucleocapsid structure.Its hydrophobic cores energy solubilisation of hydrophobic medicine (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 during composition polymer micelle.The block copolymer of Biodegradable high molecular as lactide and poly glycol monomethyl ether has excellent biocompatibility, agent permeates therethrough and biological degradability, obtains the attention of researcher.Current most study for there being a class to be bi-block copolymer in the amphipathic nature block polymer of controlled drug delivery systems.Form the mainly poly glycol monomethyl ether of amphipathic nature block polymer hydrophilic block, have good hydrophilic, the interfacial free energy contacted with water is low, in water, have extended configuration, thus has very high chain mobility, can provide certain spatial stability effect.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, both improve the safety of medication, extend again the blood circulation time of medicine.Hydrophobic block uses polyester, polyoxypropylene, polystyrene or polyamino acid usually, and they and poly glycol monomethyl ether form amphipathic copolymer, can form various micelle.
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, obtain after special preparation, and the patent of the paclitaxel disclosed based on mPEG-PDLLA and docetaxel, refer to ZL03105348.3, ZL200610145383.7,201010001047.1,201010114289.1.
For improving the druggability of deoxypodophyllotoxin, we attempt other ways studying solubilising deoxypodophyllotoxin, but by adding cosolvent as ethanol, isopropyl alcohol and glycerol, can not solve the dissolubility of deoxypodophyllotoxin; Further study and adopt other block polymers if poloxamer or surfactant are as the way of Tween 80 solubilising respectively, attempt by Micellar Solubilization, but all unsuccessful, some at all cannot solubilising, in some cases solubilising but at once separate out precipitation.
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 the preparation making intravenously administrable, avoid the side effect using cyclodextrin to bring simultaneously, we use mPEG-PDLLA as pharmaceutical carrier, are prepared into the micelle being loaded with deoxypodophyllotoxin, and this micelle compared with prior art, there is envelop rate high, good stability, carrier consumption is little, is easy to the advantage making 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, be amphipathic copolymer, its hydrophobic parts is polyester, is selected from: PGA, polylactide, glycolide-lactide copolymer, and its hydrophilic parts is poly glycol monomethyl ether.Preferred copolymer is: poly glycol monomethyl ether-poly-(D, L) lactide block copolymer.
Poly glycol monomethyl ether of the present invention-poly-(D, L) in 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, preferred 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 according to document (Zhang, X., Jackson, J.K., Burt, H.M., 1996.Developmentofamphiphilicdiblockcopolymersasmicellar carriersoftaxol.Int.J.Pharm.132,195-206.) the middle method preparation reported.
As required, in polymer micelle composition of the present invention, the acceptable pharmaceutic adjuvant of medicine also can be added, as cosolvent, PH regulator, freeze drying protectant or there is the lyophilizing proppant of support effect.
For this reason, the preferred formula of the present invention is composed as follows:
Deoxypodophyllotoxin 1-2 weight portion
MPEG-PDLLA20004/63-7 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 organic solvent;
(2) organic solvent concentrated, drive most gel;
(3) in the gel after concentrated, add the aqueous solution of water or pharmaceutic adjuvant, be heated to uniform temperature aquation if desired, obtain the micellar solution being loaded with 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, the wherein 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 uses 1 ~ 25ml organic solvent.
In step (2), concentrated organic solvent can concentrate by normal pressure, also can concentrating under reduced pressure.Time concentrated, temperature is the boiling point of room temperature to organic solvent used.
In step (3), the temperature of heating aquation is 20 ~ 60 DEG C, and hydration time is 5 ~ 60 minutes.Water can join in the gel that upper step obtains by micelle aquation, and jolting or stirring at a proper temperature, obtains the micelle after aquation; Also Rotary Evaporators can be used to carry out aquation.
Preferably, the organic solvent that step (1) is 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 use Rotary Evaporators or adopt similar technological means to concentrate.
In step (3), the temperature of heating aquation is 40 DEG C.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 use 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 there is good water solublity, stability, solubility, freeze-dried pharmaceutical formulation can be prepared into for injection, not only particularly use mPEG-PDLLA to substantially increase drug quality as micelle copolymer but also as lyophilizing proppant hydrotropy, simplify production technology.
Accompanying drawing explanation
Fig. 1 deoxypodophyllotoxin polymer micelle atomic force microscope figure
Detailed description of the invention
Below will the present invention will be further described by object lesson, but it is pointed out that following examples can not form any limitation of the invention.
MPEG-PDLLA described in example is below denoted as mPEG-PDLLAXY/Z by the molecular weight of mPEG is different with the mass ratio of mPEG:PDLLA, wherein X represents the molecular weight of mPEG, Y/Z represents mPEG and PDLLA mass ratio, it be 2000, mPEG and PDLLA mass ratio is 4/6 that such as mPEG-PDLLA20004/6 represents mPEG molecular weight.
Embodiment 1 take ethanol as the preparation of the deoxypodophyllotoxin solution of cosolvent and composite
Deoxypodophyllotoxin 150mg and ethanol 10mL is placed in 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 take polyoxyethylene sorbitan monoleate as preparation and the redissolution of the deoxypodophyllotoxin polymer micelle of solubilizing agent
Deoxypodophyllotoxin 150mg and polyoxyethylene sorbitan monoleate 1500mg is placed in eggplant-shape bottle, adds ethanol 20ml and make to dissolve completely, under decompression, remove ethanol.Obtain oil 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 take PLURONICS F87 as preparation and the redissolution of the deoxypodophyllotoxin polymer micelle of solubilizing agent
Deoxypodophyllotoxin 150mg and PLURONICS F87 4000mg is placed in eggplant-shape bottle, adds ethanol 20ml and make to dissolve completely, under decompression, remove ethanol.Obtain white chunks 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, object of the present invention cannot be arrived.
The present invention adopts mPEG-PDLLA as carrier material, and specific embodiment is as follows:
Embodiment 4 is not containing the preparation of protectant injection deoxypodophyllotoxin polymer micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20004/6450mg is placed in eggplant-shape bottle, adds methanol 12ml and make to dissolve completely, at the bottom of 40 DEG C of heating in water bath reduction vaporization to transparent gel-forms invest bottle.Add water for injection 25ml, in 50 DEG C of heating in water bath, thin film rotates aquation 20 minutes, obtains tool opalescence micelle.With 0.22 μm of membrane filtration, filtrate is sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtains white loose bulk powder.
Embodiment 5 is preparation and the physical property of protectant injection deoxypodophyllotoxin polymer micelle with mPEG-PDLLA20004/6
1, the preparation of deoxypodophyllotoxin micelle
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20004/6450mg is placed in eggplant-shape bottle, adds methanol 12ml and make to dissolve completely, drive to the greatest extent in 40 DEG C of heating in water bath reduction vaporization to methanol, at the bottom of transparent film like invests bottle.Add 30mg/mlmPEG-PDLLA20004/6 aqueous solution 25ml, in 40 DEG C of heating in water bath, thin film rotates aquation 20 minutes, obtains tool opalescence micelle.With 0.22 μm of membrane filtration, filtrate is sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtains white loose bulk powder.
2, carrier micelle morphologic observation
Get lyophilized formulations to redissolve to the concentration of deoxypodophyllotoxin for 1mg/ml with water, and be diluted to 10 μ g/ml.Get this solution 1 on coverslip, observe under atomic force microscope, 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 instability after redissolving.
3, content and entrapment efficiency determination
Get lyophilized formulations to redissolve to the concentration of deoxypodophyllotoxin for 6mg/ml with normal saline.Get this redissolution liquid 0.1ml and be placed in 10ml measuring bottle, with methanol constant volume, measure absorbance A with ultraviolet-uisible spectrophotometer at wavelength 294nm
1.This wavelength place polymer is without absorption.It is appropriate that precision takes deoxypodophyllotoxin reference substance, is also quantitatively diluted to the contrast solution containing deoxypodophyllotoxin about 60 μ g/ml, measures absorbance A in 294nm with dissolve with methanol
0.By A
1, A
0the content of deoxypodophyllotoxin in redissolution liquid is tried to achieve 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, measure absorbance A with ultraviolet-uisible spectrophotometer at wavelength 294nm
2, envelop rate computing formula is as follows: envelop rate %=A
2/ A
1× 100%.
The content recording deoxypodophyllotoxin is 5.86mg/ml, and envelop rate is 97.27%.
4, redissolution time and grain size stability are investigated
Get lyophilized formulations 1 bottle, add normal saline 5ml and redissolve, measure lyophilized powder redissolution and be about 1min to the time needed for light blue clear micellar solution.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 25 DEG C of water-baths placements, and change of size in monitoring 24h, to investigate micellar kinetic stability.Record particle diameter 49.8nm, Absorbable organic halogens is about 24h.
Embodiment 6 is preparation and the physical property of protectant injection deoxypodophyllotoxin polymer micelle with lactose
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20005/5750mg is placed in eggplant-shape bottle, adds 20ml methanol and make to dissolve completely, drive to the greatest extent in 40 DEG C of heating in water bath reduction vaporization to methanol, at the bottom of transparent film like invests bottle.Add 30mg/ml lactose aqueous solution 25ml, in 40 DEG C of heating in water bath, thin film rotates aquation 20 minutes, obtains tool opalescence micelle.With 0.22 μm of membrane filtration, be sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtain white loose bulk powder.Add 5ml normal saline to redissolve, in tool opalescence micelle, be 5.32mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, the redissolution time is about 3min, envelop rate 90.93%, and particle diameter 68.6nm, Absorbable organic halogens is about 16h.
Embodiment 7 is preparation and the physical property of protectant injection deoxypodophyllotoxin polymer micelle with Macrogol 2000
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20006/41000mg is placed in eggplant-shape bottle, adds ethanol 15ml and make to dissolve completely, drive to the greatest extent in 40 DEG C of heating in water bath reduction vaporization to ethanol, at the bottom of transparent film like invests bottle.Add 30mg/ml Macrogol 2000 aqueous solution 25ml, in 40 DEG C of heating in water bath, thin film rotates aquation 15 minutes, obtains tool opalescence micelle.With 0.22 μm of membrane filtration, be sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtain white loose bulk powder.Add 5ml normal saline to redissolve, in tool opalescence micelle, be 5.57mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, the redissolution time is about 4min, envelop rate 93.93%, and particle diameter 43.1nm, Absorbable organic halogens is about 8h.
Embodiment 8 is preparation and the physical property of protectant injection deoxypodophyllotoxin polymer micelle with glucosan D40
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20006/41350mg is placed in eggplant-shape bottle, adds isopropyl alcohol 20ml and make to dissolve completely, in 40 DEG C of heating in water bath reduction vaporizations to isopropyl alcohol flooding to the greatest extent, at the bottom of transparent film like invests bottle.Add 50mg/ml glucosan D40 aqueous solution 25ml, in 40 DEG C of heating in water bath, thin film rotates aquation 35 minutes, obtains tool opalescence micelle.With 0.22 μm of membrane filtration, be sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtain white loose bulk powder.Add 5ml normal saline to redissolve, in tool opalescence micelle, be 5.58mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, the redissolution time is about 3min, envelop rate 92.27%, and particle diameter 40.8nm, Absorbable organic halogens is about 4h.
Embodiment 9 is preparation and the physical property of protectant injection deoxypodophyllotoxin polymer micelle with PLURONICS F87
Deoxypodophyllotoxin 150mg and mPEG-PDLLA20005/5450mg is placed in eggplant-shape bottle, adds acetonitrile 12ml and make to dissolve completely, drive to the greatest extent in 40 DEG C of heating in water bath reduction vaporization to acetonitriles, at the bottom of transparent film like invests bottle.Add 30mg/ml PLURONICS F87 aqueous solution 25ml, in 40 DEG C of heating in water bath, thin film rotates aquation 30 minutes, obtains tool opalescence micelle.With 0.22 μm of membrane filtration, be sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtain white loose bulk powder.Add 5ml normal saline to shake redissolution, in tool opalescence micelle, be 5.86mg/ml with the content of determined by ultraviolet spectrophotometry deoxypodophyllotoxin, the redissolution time is about 2min, envelop rate 97.27%, and particle diameter 49.8nm, Absorbable organic halogens is about 8h.
Claims (5)
1. a polymer micelle composition for deoxypodophyllotoxin, is characterized in that, formula is as follows:
Deoxypodophyllotoxin 1-2 weight portion
As the mPEG-PDLLA20004/63-7 weight portion of micelle copolymer
As the mPEG-PDLLA20004/65-10 weight portion of lyophilizing proppant
Wherein, in described mPEG-PDLLA20004/6, poly glycol monomethyl ether and the mass ratio 4:6 gathering (D, L) lactide, wherein the molecular weight of poly glycol monomethyl ether is 2000.
2. the preparation method of polymer micelle composition according to claim 1, is characterized in that, step is as follows: mPEG-PDLLA20004/6 and deoxypodophyllotoxin are dissolved in organic solvent by (1); (2) organic solvent concentrated, drive to the greatest extent to gel; (3) in the gel after concentrated, add the aqueous solution of the mPEG-PDLLA20004/6 as lyophilizing proppant, be heated to uniform temperature aquation, obtain the micellar solution being loaded with deoxypodophyllotoxin; (4) lyophilizing of polymer micelle solution obtains lyophilized powder.
3. preparation method according to claim 2, is characterized in that, the organic solvent described in step (1) is selected from: acetonitrile, methanol, ethanol, isopropyl alcohol, oxolane, dioxane, dichloromethane; Be heated to uniform temperature aquation described in step (3), hydration temperature is 20 ~ 60 DEG C.
4. preparation method according to claim 2, 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 as the mPEG-PDLLA20004/6 of lyophilizing proppant, with membrane filtration, and filtrate subpackage, lyophilizing, obtains white loose bulk powder.
5. preparation method according to claim 4, it is characterized in that, step is as follows: deoxypodophyllotoxin 150mg and mPEG-PDLLA20004/6450mg is placed in eggplant-shape bottle, add methanol 12ml to make to dissolve completely, drive to the greatest extent in 40 DEG C of heating in water bath reduction vaporization to methanol, at the bottom of transparent film like invests bottle, add the mPEG-PDLLA20004/6 aqueous solution 25ml of 30mg/ml as lyophilizing proppant, in 40 DEG C of heating in water bath, thin film rotates aquation 20 minutes, obtain tool opalescence micelle, with 0.22 μm of membrane filtration, filtrate is sub-packed in cillin bottle by every bottle of 5ml, lyophilizing, obtain white loose bulk powder.
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| 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 |
| 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 |
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| 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 |
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| 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 |
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