CN101422615A - Oridonin polymer micelle administration preparation and preparation method thereof - Google Patents
Oridonin polymer micelle administration preparation and preparation method thereof Download PDFInfo
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- CN101422615A CN101422615A CNA2008102294729A CN200810229472A CN101422615A CN 101422615 A CN101422615 A CN 101422615A CN A2008102294729 A CNA2008102294729 A CN A2008102294729A CN 200810229472 A CN200810229472 A CN 200810229472A CN 101422615 A CN101422615 A CN 101422615A
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Abstract
The invention belongs to the medicine technology field, which provides an oridonin A polymer micelle drug delivery preparation and a preparation method thereof. The polymer is diblock copolymer, and the hydrophilic section is polyethylene glycol monomethyl ether while the hydrophobic section can be chosen from biodegradable poly (D, L-lactic acid), poly (L-lactic acid), poly (lactide-glycolide), caprolactone, PHDCA or the mixture thereof. The polymer medicament micelle traditional Chinese medicine is enveloped in one or two polymers by a physics form or prepared to be the micelle after being covalent bonded with the polymer by a chemical reaction. The prepared micelle exists in the state of aqueous dispersion or freeze-dried powder. The particle size distribution range of the oridonin A polymer micelle is 5 to 500nm while the drug loading is 0.01 to 40 percent. The oridonin A polymer micelle prolongs the circulation time of the medicament in bodies, and AUC0-infinite value is 2.19 times of that of common injections, thus leading the medicament to enrich in tumor parts easier, improving the efficacy and reducing the toxicity.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of Oridonin polymer micelle administration preparation and preparation method thereof, specifically the rubescensine A direct physical is encapsulated in the synthetic amphipathic nature block polymer, or rubescensine A and synthetic amphipathic nature block polymer further carried out the synthetic amphipathic nature block polymer of covalent bond-rubescensine A bonding medicine, and then be prepared into micelle.
Background technology
Rubescensine A (oridonin) is isolated a kind of kaurene Diterpenes (ent-kau-rene-diterpenoid) natural organic-compound from Labiatae (Labtea) Rabdosia (Rabdosia) plant, this composition has stronger anti-tumor activity, effective to multiple transplanted tumor, be mainly used in the treatment of hepatocarcinoma, the esophageal carcinoma, cancer of pancreas etc. clinically.The rubescensine A water solublity is bad, does not satisfy directly to be made into the demand that aqueous solution is used to inject, and need add surfactants such as tween 80 in order to be made into aqueous solution, but this constituents intravenous injection is easy to generate haemolysis, forbids in developed country.In order to address this problem, the someone is made into preparations such as cyclodextrin clathrate, Emulsion and liposome, has solved certain problem, but also exists a lot of not enough.The present invention is prepared into biodegradable polymer micellar aqueous solution or lyophilized powder with it, has improved his water solublity and drug loading greatly, and to the human body nonirritant, no haemolysis produces, and have good targeting, improved curative effect of medication, reduced toxicity.
Polymer micelle means the micelle that a class is made up of amphipathic nature block polymer, this amphipathic copolymer is made up of hydrophobic fragment and hydrophilic segment, and the hydrophilic segment volume is generally greater than hydrophobic fragment, can be in water spontaneously be arranged in hud typed structure, hydrophobic fragment forms the micelle kernel, and hydrophilic segment forms the micelle shell.The low-molecular-weight surfactant that pharmaceutics is used for the solubilising insoluble medicine is not that solubilizing effect is undesirable, has big toxicity exactly.The polyoxyethylene castor oil EL that for example is used for solubilising paclitaxel and Ciclosporin A can cause side reactions such as anaphylactic reaction, hyperlipemia, neurotoxicity and the reverse of P-glycoprotein.As a kind of novel carrier, polymer micelle has overcome above shortcoming substantially, and the medicine carrying scope is wide, Stability Analysis of Structures, have good tissue permeability, in the body holdup time long, can make medicine arrive target spot effectively.And it has lower CMC, and is comparatively stable in the body circulation.Based on above advantage, several years polymer micelle has in the past obtained extensive studies.Wherein but the biodegradable polymers micelle excretes owing to having degradation in vivo, does not produce the advantage of cumulative action in vivo, becomes the focus of research in recent years, and its application in the middle of the hydrophobicity anticarcinogen obtains broad research especially.With biodegradable amphipathic nature block polymer physical package medicine carrying thing is the method that a kind of physics mode prepares polymer micelle, and nearest another kind of polymer micelle dosage form-micellar preparation of polymer-bound medicine and research receive everybody very big concern." polymer-bound medicine micelle " promptly be with medicine by being covalently bound on the amphipathic nature block polymer polymer macromolecule, be prepared into micelle then.After being injected in the body, medicine disintegrates down from high molecular polymer under physiological condition, the effect of performance treatment or diagnosis.Improved the hydrophilic of medicine behind medicine and the high molecular polymer bonding, medicine can be avoided enzyme and immune attack in the physiological environment under the high molecular polymer protection, reaches slow release and long lasting purpose.Adopt amphipathic nature block polymer bonding medicine to be self-assembled into polymer micelle, medicine is in micellar kernel since with the copolymer covalent bond, therefore more stable, the micelle that carries of physical package relatively, medicine are difficult for from the micelle kernel diffusion and overflow.Therefore this micelle had both had the conventional physical bag and had carried micellar advantage, avoided prominent the releasing of causing because of the instability on the kinetics again, thereby the curative effect that has improved medicine had reduced toxicity.What the research of polymer micelle bonding medicine had had a report has amycin, paclitaxel, a Docetaxel etc.
Summary of the invention
The purpose of this invention is to provide a kind of Oridonin polymer micelle administration preparation and preparation method, and this polymer micelle comprises two kinds of forms, a kind of is that rubescensine A is encapsulated in physical form and is prepared into micelle in the polymer, another kind is that rubescensine A forms amphipathic nature block polymer-rubescensine A bonding medicine by being covalently bound in the high molecular polymer, and refabrication becomes micelle.
Polymer of the present invention is meant amphipathic nature block polymer, wherein hydrophilic section is poly glycol monomethyl ether (mPEG), hydrophobic section be selected from biodegradable hexadecanoic acid, poly-(D, L-lactic acid) (PDLLA), poly-(L-lactic acid) (PLLA), poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester) (PLGA), poly-epsilon-caprolactone (PCL), poly-(lactide, 6-caprolactone) (PCLA), poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone) (PCLGA) or their mixture.Wherein said hydrophobic block is the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, and the mass percent of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 99:1～1:99; Described hydrophobic block is the copolymer of lactide and 6-caprolactone, and the mass percent of lactide and 6-caprolactone is 99:1～1:99; Described hydrophobic block is the terpolymer of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone, and the mass percent of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone is 98～50:1～49:1～49.Wherein rubescensine A accounts for the 0.01-40% of medicine and total polymer weight; The molecular weight of described amphipathic nature block polymer is 500-100000, and wherein hydrophilic block number-average molecular weight is 200-50000, and hydrophobicity block number-average molecular weight is 50-50000; The hydrophilic block total amount accounts for the 10-98% of copolymer gross weight;
The Oridonin polymer micelle of preparation, wherein amphipathic nature block polymer is selected from biodegradable poly glycol monomethyl ether-hexadecanoic acid, poly glycol monomethyl ether-poly-(D, L-lactic acid) (mPEG-PDLLA), poly glycol monomethyl ether-poly-(L-lactic acid) (mPEG-PLLA), poly glycol monomethyl ether-poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester) (mPEG-PLGA), poly glycol monomethyl ether-pla-pcl (mPEG-PCL), poly glycol monomethyl ether-poly-(lactide, 6-caprolactone) (mPEG-PCLA) and poly glycol monomethyl ether-poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone) one or more in (mPEG-PCLGA).Wherein preferred mPEG-PDLLA, mPEG-PLLA and mPEG-PLGA.Wherein poly glycol monomethyl ether (mPEG) molecular weight distribution is 200-30000, preferred 1000-5000, and preferred especially 2000 and 5000.
The invention provides two kinds of amphipathic nature block polymers-micellar preparation method of rubescensine A bonding medicine, its step and condition are as follows:
Method 1:
Step (1): the block copolymer of preparation poly glycol monomethyl ether and various aliphatic cyclic esters
In the presence of poly glycol monomethyl ether, catalyst, carry out ring-opening polymerization with the aliphatic cyclic ester monomer.The aliphatic cyclic ester monomer is meant the ternary mixture of mixture, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone of mixture, lactide and the 6-caprolactone of lactide, 6-caprolactone, lactide and Acetic acid, hydroxy-, bimol. cyclic ester.In the monomer mixture of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, the mass percent of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 99:1～1:99; In the mixture of lactide and ε-caprolactone, the mass percent of lactide and 6-caprolactone is 99:1～1:99; In the ternary mixture of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and ε-caprolactone, the mass percent of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone is 98～50:1～49:1～49.Catalyst is a stannous octoate, and consumption is the 0.01-1% of polymerization single polymerization monomer quality, and 110～180 ℃ of polymerization temperatures, polymerization time are 3-24 hour;
Step (2): change the terminal hydroxy group of poly glycol monomethyl ether and aliphatic poly ester block copolymer into the end carboxyl
With the synthetic block copolymer of step (1) at catalyst pyridine, triethylamine or 4-N, the N-dimethylamino naphthyridine exists down, in anhydrous methylene chloride or 1,4-dioxane solution, under 0～25 ℃, carry out esterification with anhydride, catalyst amount is 0.05～2 times of block copolymer terminal hydroxy group molal weight, the anhydride consumption is 1～3 times of block copolymer terminal hydroxy group molal weight, and response time 24～48h changes the terminal hydroxy group of block copolymer into the end carboxyl.
Step (3): with the end carboxyl and the rubescensine A hydroxyl reaction of poly glycol monomethyl ether and aliphatic poly ester block copolymer, preparation amphipathic nature block polymer-rubescensine A bonding medicine
At catalyst 4-N, N-dimethylamino naphthyridine and condensing agent dicyclohexylcarbodiimide exist down, at dichloromethane, react in dimethyl sulfoxide or the dimethyl formamide solution, 0～25 ℃ of reaction temperature, response time 12-48h, wherein, 4-N, the mole dosage of N-dimethylamino naphthyridine is 0.05～2 times of block copolymer end carboxyl, the mole dosage of dicyclohexylcarbodiimide is 1～3 times of block copolymer end carboxyl, the mole dosage of rubescensine A is 1～2 times of block copolymer end carboxyl, and reaction obtains amphipathic nature block polymer-rubescensine A bonding medicine.
Method 2:
Step (1): the block copolymer of preparation poly glycol monomethyl ether and various aliphatic cyclic esters
In the presence of poly glycol monomethyl ether, catalyst, carry out ring-opening polymerization with the aliphatic cyclic ester monomer.The aliphatic cyclic ester monomer is meant the ternary mixture of mixture, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone of mixture, lactide and the 6-caprolactone of lactide, ε-caprolactone, lactide and Acetic acid, hydroxy-, bimol. cyclic ester.In the monomer mixture of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, the mass percent of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 99:1～1:99; In the mixture of lactide and 6-caprolactone, the mass percent of lactide and 6-caprolactone is 99:1～1:99; In the ternary mixture of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone, the mass percent of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and ε-caprolactone is 98～50:1～49:1～49.Catalyst is a stannous octoate, and consumption is the 0.01-1% of polymerization single polymerization monomer quality, and 110～180 ℃ of polymerization temperatures, polymerization time are 3-24 hour;
Step (2): rubescensine A contains the preparation of carboxy derivatives
With rubescensine A at catalyst pyridine, triethylamine or 4-N, the N-dimethylamino naphthyridine exists down, in anhydrous chloroform or 1,4-dioxane solution, under 0～25 ℃, carry out esterification with anhydride, catalyst amount is 0.05-2 a times of rubescensine A molal weight, the anhydride consumption is 1～2 times of block copolymer terminal hydroxy group molal weight, and response time 24～48h obtains carboxylic Oridonin derivative.
Step (3): synthetic amphipathic nature block polymer of step (1) and carboxylic Oridonin derivative are carried out covalent bonding, preparation amphipathic nature block polymer-rubescensine A bonding medicine
At catalyst 4-N, N-dimethylamino naphthyridine and condensing agent dicyclohexylcarbodiimide exist down, at dichloromethane, react in dimethyl sulfoxide or the dimethyl formamide solution, 0～25 ℃ of reaction temperature, response time 12-48h, wherein, 4-N, the mole dosage of N-dimethylamino naphthyridine is 0.05～2 times of carboxylic Oridonin derivative, the mole dosage of dicyclohexylcarbodiimide is 1～3 times of carboxylic Oridonin derivative, the mole dosage of block copolymer is 0.5～1 times of carboxylic Oridonin derivative, and reaction obtains amphipathic nature block polymer-rubescensine A bonding medicine.
The preparation of Oridonin polymer micelle preparation of the present invention, its step is as follows:
Method 1: cosolvent volatility process
(1), preparation polymer micelle aqueous solution, at first with organic solvent-acetone, oxolane, dimethyl formamide, dimethyl sulfoxide or their mixture dissolving amphipathic nature block polymer and rubescensine A or amphipathic nature block polymer-rubescensine A bonding medicine, stir then and slowly join aqueous phase down, the uncovered stirring of room temperature volatilizes or the room temperature decompression volatilizes organic solvent, gets micellar aqueous solution.
(2) with micellar aqueous solution through 5000-20000r/min centrifugalize 5-30 minute, remove big aggregate particles, clear liquid filters promptly.
(3) centrifugal after-filtration clear liquid also can directly be made lyophilized powder through lyophilization, or adds in certain freeze drying protectant such as sucrose, glucose, mannitol, lactose, trehalose, dextran etc. one or more and make lyophilized powder through lyophilization again.The freeze drying protectant consumption is the 5-30% of preparation total amount.
Method 2: dialysis
(1) preparation polymer micelle aqueous solution, at first with organic solvent-acetone, oxolane, dimethyl formamide, dimethyl sulfoxide or their mixture dissolving amphipathic nature block polymer and rubescensine A or amphipathic nature block polymer-rubescensine A bonding medicine, stir then and slowly join aqueous phase down, get the micelle dispersion liquid, this dispersion liquid is put into the semipermeable membrane bag filter of certain molecular cut off, the bag filter outside adds a large amount of water, dialysis 24-48h removes organic solvent and micromolecule free drug, gets dialysis solution.
(2) will dialyse the back micellar aqueous solution through 5000-20000r/min centrifugalize 5-30 minute, remove big aggregate particles, and get clear liquid and filter promptly.
(3) centrifugal after-filtration clear liquid also can directly be made lyophilized powder through lyophilization, or adds in certain freeze drying protectant such as sucrose, glucose, mannitol, lactose, trehalose, dextran etc. one or more and make lyophilized powder through lyophilization again.The freeze drying protectant consumption is the 5-30% of preparation total amount.
The Oridonin polymer micelle of the present invention's preparation has prolonged the medicine body-internal-circulation time, makes the easier tumor locus that is enriched in of medicine, has improved curative effect, has reduced toxicity.
Description of drawings:
Fig. 1: rubescensine A structural formula
Fig. 2: mPEG-PDLLA
8000Oridonin polymer micelle release in vitro curve
Fig. 3: rubescensine A normal injection and polymer micelle solution rat body giving drugs into nose are for dynamics research ■---■ rubescensine A normal injection; ◆---◆ the rubescensine A block copolymer micelle
The specific embodiment
Embodiment 1: the preparation of amphipathic nature block polymer mPEG-PDLLA
(1) with 2.5g D, L-lactide and 4g poly glycol monomethyl ether (molecular weight 5000) join in the three-necked bottle that magnetic stir bar is housed, after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 8h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, with 200ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, get product mPEG-PDLLA, calculating PDLLA block molecule amount by the nuclear-magnetism spectrum is 3000.Molecular weight is 8000 mPEG-PDLLA
8000
(2) with 4.5g D, L-lactide and 4g poly glycol monomethyl ether (molecular weight 5000) join in the three-necked bottle that magnetic stir bar is housed, after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 10h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, with 200ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, get product mPEG-PDLLA, calculating PDLLA block molecule amount by the nuclear-magnetism spectrum is 5000.Molecular weight is 10000 mPEG-PDLLA
10000
(3) with 9g D, L-lactide and 4g poly glycol monomethyl ether (molecular weight 5000) join in the three-necked bottle that magnetic stir bar is housed, after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, be warming up to 160 ℃, continue reaction 10h, stopped reaction, cool to room temperature, product is with 15ml dichloromethane or chloroform dissolving, with 300ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, product mPEG-PDLLA, calculating PDLLA block molecule amount by nuclear-magnetism spectrum is 10000.Molecular weight is 15000 mPEG-PDLLA
15000
Embodiment 2: the preparation of amphipathic nature block polymer mPEG-PLLA
4.5g L-lactide and 4g poly glycol monomethyl ether (molecular weight 5000) are joined in the three-necked bottle that magnetic stir bar is housed, after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 10h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, precipitate with the 200ml cold diethyl ether, filter, 30 ℃ vacuum drying 24-48 hour, product mPEG-PLLA, calculating PLLA block molecule amount by nuclear-magnetism spectrum is 5000.Molecular weight is 10000 mPEG-PLLA
10000
Embodiment 3: the preparation of amphipathic nature block polymer mPEG-PLGA
(1) with 4.5g D, L-lactide and Acetic acid, hydroxy-, bimol. cyclic ester mixture (LA/GA=50/50) join in the three-necked bottle that magnetic stir bar is housed with 4g poly glycol monomethyl ether (molecular weight 5000), after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 10h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, with 200ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, get product mPEG-PLGA, calculating PLGA block molecule amount by the nuclear-magnetism spectrum is 5000.Molecular weight is 10000 mPEG-PLGA
10000 (50/50)
(2) with 4.5g D, L-lactide and Acetic acid, hydroxy-, bimol. cyclic ester mixture (LA/GA=75/25) join in the three-necked bottle that magnetic stir bar is housed with 4g poly glycol monomethyl ether (molecular weight 5000), after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 10h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, with 200ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, get product mPEG-PLGA, calculating PLGA block molecule amount by the nuclear-magnetism spectrum is 5000.Molecular weight is 10000 mPEG-PLGA
10000 (75/25)
Embodiment 4: the preparation of amphipathic nature block polymer mPEG-PDLLA
(1) with 2.5g D, L-lactide and 4g poly glycol monomethyl ether (molecular weight 2000) join in the three-necked bottle that magnetic stir bar is housed, after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 8h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, with 200ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, get product mPEG-PDLLA, calculating PDLLA block molecule amount by the nuclear-magnetism spectrum is 1250.Molecular weight is 3250 mPEG-PDLLA
3250
(2) with 4g D, L-lactide and 4g poly glycol monomethyl ether (molecular weight 2000) join in the three-necked bottle that magnetic stir bar is housed, after oil bath is heated to 140 ℃ of fusions (reduced vacuum), the adding mass percent is 0.05% stannous octoate catalyst, reaction 10h, stopped reaction, cool to room temperature, product dissolves with 10ml dichloromethane or chloroform, with 200ml cold diethyl ether precipitation, filter, 30 ℃ vacuum drying 24-48 hour, get product mPEG-PDLLA, calculating PDLLA block molecule amount by the nuclear-magnetism spectrum is 2000.Molecular weight is 4000 mPEG-PDLLA
4000
Embodiment 5
Weighing m PEG-PDLLA
8000100mg is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, the 10mg rubescensine A is dissolved in the polymer acetone soln, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add the dissolving of 0.2g trehalose, through 0.22 μ m filtering with microporous membrane, get the Oridonin polymer micelle lyophilized powder through lyophilization.The micelle mean diameter is 139nm.
Embodiment 6
Weighing m PEG-PDLLA
8000150mg is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, the 20mg rubescensine A is dissolved in the polymer acetone soln, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, and temperature is controlled at below 30 ℃, and the centrifugal 15min of gained suspension 10000r/min gets supernatant and promptly gets micellar solution.Add 0.1g mannose and 0.05g sucrose dissolved,, get the Oridonin polymer micelle lyophilized powder through lyophilization through 0.22 μ m filtering with microporous membrane.The micelle mean diameter is 144nm.
Embodiment 7
Weighing m PEG-PDLLA
15000200mg is dissolved in the 2ml dimethyl formamide solution, places, treat that polymers swell fully after, the 40mg rubescensine A is dissolved in the polymer dimethyl formamide solution, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.It is in 10000 the bag filter that gained solution adds molecular cut off, bag filter external 2-4L distilled water dialysis 12h gets the interior solution of bag filter and promptly gets micellar solution, adds the dissolving of 0.2g mannose, through 0.22 μ m filtering with microporous membrane, get the Oridonin polymer micelle lyophilized powder through lyophilization.The micelle mean diameter is 187nm.
Embodiment 8
Weighing m PEG-PLLA
10000200mg is dissolved in the 2ml tetrahydrofuran solution, places, treat that polymer dissolution fully after, the 30mg rubescensine A is dissolved in the polymer tetrahydrofuran solution, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed oxolane, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add the dissolving of 0.3g glucose, through 0.22 μ m filtering with microporous membrane, get the Oridonin polymer micelle lyophilized powder through lyophilization.The micelle mean diameter is 167nm.
Embodiment 9
Weighing m PEG-PLLA
10000200mg and egg phosphatide 20mg are dissolved in the 3ml acetone soln, place, treat that polymer dissolution fully after, the 50mg rubescensine A is dissolved in the polymer acetone soln, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add the dissolving of 0.3g glucose, through 0.22 μ m filtering with microporous membrane, get the Oridonin polymer micelle lyophilized powder through lyophilization.The micelle mean diameter is 167nm.
Weighing m PEG-PLGA
10000 (75/25)200mg and soybean phospholipid 25mg are dissolved in the 3ml acetone soln, place, treat that polymer dissolution fully after, the 50mg rubescensine A is dissolved in the polymer acetone soln, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 50 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add 0.2g mannose and 0.1g sucrose dissolved, through 0.22 μ m filtering with microporous membrane, get the Oridonin polymer micelle lyophilized powder again through lyophilization.The micelle mean diameter is 154nm.
Embodiment 11
Weighing m PEG-PDLLA
4000100mg is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, the 10mg rubescensine A is dissolved in the polymer acetone soln, as oil phase.Under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, 0.1g mannose and 0.05g sucrose dissolved, through 0.22 μ m filtering with microporous membrane, get the Oridonin polymer micelle lyophilized powder through lyophilization.The micelle mean diameter is 118nm.
Embodiment 12: the amphipathic nature block polymer terminal hydroxy group is converted into the end carboxyl
(1) takes by weighing 1.6g mPEG-PDLLA
8000Be dissolved in that 20ml is anhydrous 1, in the 4-dioxane solution, add 0.04g succinic anhydride, 0.02gDMAP, 0.1mlTEA successively under 0 ℃.Stirring at room reaction 24h filters, and filtrate is filtered with the sedimentation of 300ml cold diethyl ether, precipitates 30 ℃ of vacuum drying 24h, gets mPEG-PDLLA
8000-COOH.
(2) take by weighing 0.65g mPEG-PDLLA
3250Be dissolved in that 20ml is anhydrous 1, in the 4-dioxane solution, add 0.04g succinic anhydride, 0.02gDMAP, 0.1mlTEA successively under 0 ℃.Stirring at room reaction 24h filters, and filtrate is filtered with the sedimentation of 200ml cold diethyl ether, precipitates 30 ℃ of vacuum drying 24h, gets mPEG-PDLLA
3250-COOH.
(3) take by weighing 0.8g mPEG-PDLLA
3250Be dissolved in that 20ml is anhydrous 1, in the 4-dioxane solution, add 0.04g succinic anhydride, 0.02gDMAP, 0.1mlTEA successively under 0 ℃.Stirring at room reaction 24h filters, and filtrate is filtered with the sedimentation of 200ml cold diethyl ether, precipitates 30 ℃ of vacuum drying 24h, gets mPEG-PDLLA
3250-COOH.
(4) take by weighing 2g mPEG-PLGA
10000 (75/25)Be dissolved in that 20ml is anhydrous 1, in the 4-dioxane solution, add 0.04g succinic anhydride, 0.02gDMAP, 0.1mlTEA successively under 0 ℃.Stirring at room reaction 24h filters, and filtrate is filtered with the sedimentation of 300ml cold diethyl ether, precipitates 30 ℃ of vacuum drying 24h, gets mPEG-PLGA
10000 (75/25)-COOH.
Embodiment 13: preparation amphipathic nature block polymer-rubescensine A bonding medicine
(1) weighing m PEG-PDLLA
8000-COOH1g is dissolved in the 20ml anhydrous methylene chloride, after the polymer dissolution, ice bath is cooled to 0 ℃, add 60mg rubescensine A, 25mgDCC, 15mgDMAP, 0 ℃ is reacted 24h, filters the precipitation of generation, filtrate is washed with the 0.1mol/l dilute hydrochloric acid solution, anhydrous sodium sulfate drying filters concentrated filtrate, a large amount of ether sedimentations, vacuum drying promptly gets the bonding medicine.Drug loading is 4.3%.
(2) weighing m PEG-PDLLA
3250-COOH0.325g is dissolved in the 20ml anhydrous methylene chloride, after the polymer dissolution, ice bath is cooled to 0 ℃, add 45mg rubescensine A, 21mgDCC, 10mgDMAP, 0 ℃ is reacted 24h, filters the precipitation of generation, filtrate is washed with the 0.1mol/l dilute hydrochloric acid solution, anhydrous sodium sulfate drying filters concentrated filtrate, a large amount of ether sedimentations, vacuum drying promptly gets the bonding medicine.Drug loading is 10.5%.
(3) weighing m PEG-PDLLA
4000-COOH0.4g is dissolved in the 20ml anhydrous methylene chloride, after the polymer dissolution, ice bath is cooled to 0 ℃, add 45mg rubescensine A, 21mgDCC, 10mgDMAP, 0 ℃ is reacted 36h, filters the precipitation of generation, filtrate is washed with the 0.1mol/l dilute hydrochloric acid solution, anhydrous sodium sulfate drying filters concentrated filtrate, a large amount of ether sedimentations, vacuum drying promptly gets the bonding medicine.Drug loading is 8.3%.
(4) weighing m PEG-PLGA
10000-COOHlg is dissolved in the 20ml anhydrous methylene chloride, after the polymer dissolution, ice bath is cooled to 0 ℃, add 45mg rubescensine A, 21mgDCC, 10mgDMAP, 0 ℃ is reacted 24h, filters the precipitation of generation, filtrate is washed with the 0.1mol/l dilute hydrochloric acid solution, anhydrous sodium sulfate drying filters concentrated filtrate, a large amount of ether sedimentations, vacuum drying promptly gets the bonding medicine.Drug loading is 3.5%.
Embodiment 14: amphipathic nature block polymer-rubescensine A bonding medicine micelle freeze-drying powder, preparation method thereof one:
(1) gets 100mg mPEG-PDLLA
8000-rubescensine A bonding medicine is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, and temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add mannose 0.2g, through 0.22 μ m filtering with microporous membrane, the filtrate lyophilization gets the Oridonin polymer micelle lyophilized powder.Recording particle diameter is 156nm.
(2) get 100mg mPEG-PDLLA
3250-rubescensine A bonding medicine is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add mannose 0.1g and sucrose 0.1g, through 0.22 μ m filtering with microporous membrane, the filtrate lyophilization gets the Oridonin polymer micelle lyophilized powder.Recording particle diameter is 113nm.
(3) get 100mg mPEG-PDLLA
4000-rubescensine A bonding medicine is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add mannose 0.1g and sucrose 0.1g, through 0.22 μ m filtering with microporous membrane, the filtrate lyophilization gets the Oridonin polymer micelle lyophilized powder.Recording particle diameter is 126nm.
(4) get 100mg mPEG-PLGA
10000-rubescensine A bonding medicine is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, and temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add trehalose 0.2g, through 0.22 μ m filtering with microporous membrane, the filtrate lyophilization gets the Oridonin polymer micelle lyophilized powder.Recording particle diameter is 178nm.
Method two:
(1) gets rubescensine A 0.364g, be dissolved in that 20ml is anhydrous 1, in the 4-dioxane solution, after the polymer dissolution, ice bath is cooled to 0 ℃, adds succinic anhydride 0.2g, 0.1gDMAP successively, room temperature reaction 24h, filter the precipitation of generation, filtrate concentrates the back with the sedimentation of 200ml cold diethyl ether, filters, precipitate 40 ℃ of vacuum drying 24h, rubescensine A-COOH.
(2) get mPEG-PDLLA
40000.4g, be dissolved in the 20ml anhydrous methylene chloride, after the polymer dissolution, ice bath is cooled to 0 ℃, add 40mg rubescensine A-COOH, 25mgDCC, 15mgDMAP, 0 ℃ is reacted 24h, filters the precipitation of generation, filtrate is washed with the 0.1mol/l dilute hydrochloric acid solution, anhydrous sodium sulfate drying filters concentrated filtrate, a large amount of ether sedimentations, vacuum drying promptly gets the bonding medicine.
(3) get 100mg mPEG-PDLLA
4000-rubescensine A bonding medicine is dissolved in the 2ml acetone soln, places, treat that polymer dissolution fully after, under the magnetic agitation, slowly join the 10ml aqueous phase, continue to stir balance 2h.Gained solution decompression rotary evaporation is removed acetone, temperature is controlled at below 30 ℃, the centrifugal 15min of gained suspension 10000r/min, get supernatant and promptly get micellar solution, add mannose 0.1g and sucrose 0.1g, through 0.22 μ m filtering with microporous membrane, the filtrate lyophilization gets the Oridonin polymer micelle lyophilized powder.Recording particle diameter is 122nm.
Embodiment 15: get 10 healthy Wistar rats, be divided into 2 groups at random, 5 every group.At one night of fasting before the experiment, the tail vein gives the micellar solution that rubescensine A normal injection and embodiment 7 make respectively, and dosage is 20mg/kg.After the administration 0.0167,0.0833,0.167,0.333,0.5,1,2,4,8,12,24h gets blood 0.5ml in the dry centrifuge tube of the 1.5ml of 2% anticoagulant heparin from the rat eye socket, the centrifugal 5min of 5000r/min, get the 0.1ml plasma treatment and carry out HPLC mensuration drug level, use the 3P87 program and carry out date processing, calculate the moving parameter of medicine.The results are shown in Table 1,2.
Table 1 rubescensine A injection pharmacokinetic parameter
Table 2 rubescensine A block copolymer micelle pharmacokinetic parameter
Contrasting as can be seen from table 1,2, the moving parameter of medicine of rubescensine A normal injection is t
1/2π=0.158h, t
1/2α=1.179h, t
1/2β=8.404h, AUC
0-∞=7.686 (mg/L) h, MRT
0-∞=9.261h.The moving parameter of the medicine of rubescensine A block copolymer micelle is t
1/2π=0.095h, t
1/2α=3.097h, t
1/2β=48.68h, AUC
0-∞=16.75 (mg/L) h, MRT
0-∞=17.37h.Analysis result explanation rubescensine A block copolymer micelle has obvious slowly releasing effect, the AUC of getting in its pharmacokinetics in rats behavior
0-∞Value is 2.19 times of injection, has improved the bioavailability of rubescensine A.
Claims (10)
1, a kind of Oridonin polymer micelle, it is characterized in that: this micelle be encapsulated in one or both polymer by rubescensine A with physical form or form amphipathic nature block polymer-rubescensine A bonding medicine by chemical reaction and polymer covalent bond after form, wherein rubescensine A accounts for the 0.01-40% of gross weight, described polymer be meant amphipathic nature block polymer or with the mixture of phospholipid.
2, Oridonin polymer micelle according to claim 1, it is characterized in that: wherein phospholipid is selected from soybean phospholipid, egg phosphatide, saturated soybean phospholipid, in the saturated egg phosphatide one or more, amphipathic nature block polymer are selected from biodegradable poly glycol monomethyl ether-hexadecanoic acid, poly glycol monomethyl ether-poly-(D, L-lactic acid), poly glycol monomethyl ether-poly-(L-lactic acid), poly glycol monomethyl ether-poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester), poly glycol monomethyl ether-pla-pcl, poly glycol monomethyl ether-poly-(lactide, 6-caprolactone) and poly glycol monomethyl ether-poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone) one or more in.
3, Oridonin polymer micelle according to claim 1, it is characterized in that: the hydrophilic section of described amphipathic nature block polymer is a poly glycol monomethyl ether, and hydrophobic section is selected from biodegradable poly-cetyl cyanoacrylate, poly-(D, L-lactic acid), poly-(L-lactic acid), poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester), poly-epsilon-caprolactone, poly-(lactide, 6-caprolactone), poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone) or their mixture; In wherein said poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester), the mass percent of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 99:1～1:99; The mass percent of lactide and 6-caprolactone is 99:1～1:99 in poly-(lactide, 6-caprolactone); In poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone), the mass percent of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone is 98～50:1～49:1～49; The molecular weight of described amphipathic nature block polymer is 500-100000, and wherein hydrophilic block number-average molecular weight is 200-50000, and hydrophobicity block number-average molecular weight is 50-50000; Wherein the hydrophilic block total amount accounts for the 10-98% of copolymer gross weight.
4, Oridonin polymer micelle according to claim 1, wherein the hydrophilic section of amphipathic nature block polymer is a poly glycol monomethyl ether, its molecular weight distribution is 200-30000.
5, a kind of preparation method of Oridonin polymer micelle as claimed in claim 1 is characterized in that, its step is as follows:
(1): the block copolymer of preparation poly glycol monomethyl ether and various aliphatic cyclic esters
In the presence of poly glycol monomethyl ether, catalyst, carry out ring-opening polymerization with the aliphatic cyclic ester monomer, catalyst is a stannous octoate, and consumption is the 0.01-1% of polymerization single polymerization monomer quality, and 110～180 ℃ of polymerization temperatures, polymerization time are 3-24 hour;
(2): change the terminal hydroxy group of poly glycol monomethyl ether and aliphatic poly ester block copolymer into the end carboxyl;
With (1) synthetic block copolymer at catalyst pyridine, triethylamine (TEA) or 4-N, N-dimethylamino naphthyridine (DMAP) exists down, in anhydrous methylene chloride or 1,4-dioxane solution, under 0～25 ℃, carry out esterification with anhydride, catalyst amount is 0.05～2 times of block copolymer terminal hydroxy group molal weight, the anhydride consumption is 1～3 times of block copolymer terminal hydroxy group molal weight, and response time 24～48h changes the terminal hydroxy group of block copolymer into the end carboxyl;
(3): with the end carboxyl and the rubescensine A hydroxyl reaction of poly glycol monomethyl ether and aliphatic poly ester block copolymer, preparation amphipathic nature block polymer-rubescensine A bonding medicine
At catalyst 4-N, N-dimethylamino naphthyridine and condensing agent dicyclohexylcarbodiimide (DCC) exist down, at dichloromethane, react in dimethyl sulfoxide or the dimethyl formamide solution, 0～25 ℃ of reaction temperature, response time 12-48h, wherein, 4-N, the mole dosage of N-dimethylamino naphthyridine is 0.05～2 times of block copolymer end carboxyl, the mole dosage of dicyclohexylcarbodiimide is 1～3 times of block copolymer end carboxyl, the mole dosage of rubescensine A is 1～2 times of block copolymer end carboxyl, and reaction obtains amphipathic nature block polymer-rubescensine A bonding medicine.
6, a kind of preparation method of Oridonin polymer micelle as claimed in claim 1, it is characterized in that: its preparation method is as follows:
(1): the block copolymer of preparation poly glycol monomethyl ether and various aliphatic cyclic esters
In the presence of poly glycol monomethyl ether, catalyst, carry out ring-opening polymerization with the aliphatic cyclic ester monomer, catalyst is a stannous octoate, and consumption is the 0.01-1% of polymerization single polymerization monomer quality, and 110～180 ℃ of polymerization temperatures, polymerization time are 3-24 hour;
(2): rubescensine A contains the preparation of carboxy derivatives
With rubescensine A at catalyst pyridine, triethylamine or 4-N, the N-dimethylamino naphthyridine exists down, in anhydrous chloroform or 1,4-dioxane solution, under 0～25 ℃, carry out esterification with anhydride, catalyst amount is 0.05-2 a times of rubescensine A molal weight, the anhydride consumption is 1～2 times of block copolymer terminal hydroxy group molal weight, and response time 24～48h obtains carboxylic Oridonin derivative;
(3): (1) synthetic amphipathic nature block polymer and carboxylic Oridonin derivative are carried out covalent bonding, preparation amphipathic nature block polymer-rubescensine A bonding medicine
At catalyst 4-N, N-dimethylamino naphthyridine and condensing agent dicyclohexylcarbodiimide exist down, at dichloromethane, react in dimethyl sulfoxide or the dimethyl formamide solution, 0～25 ℃ of reaction temperature, response time 12-48h, wherein, 4-N, the mole dosage of N-dimethylamino naphthyridine is 0.05～2 times of carboxylic Oridonin derivative, the mole dosage of dicyclohexylcarbodiimide is 1～3 times of carboxylic Oridonin derivative, the mole dosage of block copolymer is 0.5～1 times of carboxylic Oridonin derivative, and reaction obtains amphipathic nature block polymer-rubescensine A bonding medicine.
7, according to the preparation method of claim 5 or 6 described Oridonin polymer micelles, it is characterized in that: described aliphatic cyclic ester monomer is meant the ternary mixture of mixture, lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone of mixture, lactide and the 6-caprolactone of lactide, 6-caprolactone, lactide and Acetic acid, hydroxy-, bimol. cyclic ester; In the monomer mixture of lactide and Acetic acid, hydroxy-, bimol. cyclic ester, the mass percent of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 99:1～1:99; In the mixture of lactide and 6-caprolactone, the mass percent of lactide and 6-caprolactone is 99:1～1:99; In the ternary mixture of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone, the mass percent of lactide, Acetic acid, hydroxy-, bimol. cyclic ester and 6-caprolactone is 98～50:1～49:1～49; Be used for synthetic anhydride and be meant a kind of of acetic anhydride, succinic anhydride or maleic anhydride.
8, amphipathic nature block polymer according to claim 1-rubescensine A bonding medicine, comprise poly glycol monomethyl ether-poly-(D, L-lactic acid)-rubescensine A bonding medicine, poly glycol monomethyl ether-poly-(L-lactic acid)-rubescensine A bonding medicine, poly glycol monomethyl ether-poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester)-rubescensine A bonding medicine, poly glycol monomethyl ether-poly-(lactide, 6-caprolactone)-rubescensine A bonding medicine, poly glycol monomethyl ether-pla-pcl-rubescensine A bonding medicine, poly glycol monomethyl ether-poly-(lactide, Acetic acid, hydroxy-, bimol. cyclic ester, 6-caprolactone)-and rubescensine A bonding medicine, its bonding position is at 1 or 14 hydroxyls of rubescensine A.
9, the preparation method of Oridonin polymer micelle administration preparation, it is characterized in that: adopt cosolvent volatility process or dialysis, the cosolvent volatility process be with amphipathic nature block polymer and rubescensine A be dissolved in the miscible organic solvent of water in, stir and add aqueous phase down, room temperature is placed, the decompression rotary evaporation is removed organic solvent, promptly; Dialysis solvent evaporation method together is similar, just adopts bag filter to remove the method for organic solvent by outer water; The nano dispersion fluid of above method gained, through 0.22 μ m membrane filtration promptly, the Oridonin polymer micelle preparation exists micelle content in the aqueous dispersions below 40%, particle diameter is in the 5-500nm scope, also can get the Oridonin polymer micelle lyophilized powder through lyophilization, this lyophilized powder can be scattered in the water certainly, forms the polymer micelle aqueous dispersions of particle size distribution in the 5-500nm scope.
10, according to the preparation method of claim 9 Oridonin polymer micelle administration preparation, it is characterized in that: described organic solvent is meant chloroform, dichloromethane, acetone, dehydrated alcohol, dimethyl sulfoxide, dimethyl formamide, oxolane, the tert-butyl alcohol; Water can be distilled water or phosphate buffer; During the preparation lyophilized powder, can add frozen-dried supporting agent, can be one or more mixture in sucrose, mannitol, glucose, lactose, trehalose, the dextran, and additional proportion is 5～30% of a preparation total amount.
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