CN102423294A - Thermo sensitive in situ gel loaded with drug by chemical bonds, and preparation method thereof - Google Patents
Thermo sensitive in situ gel loaded with drug by chemical bonds, and preparation method thereof Download PDFInfo
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- CN102423294A CN102423294A CN2011104371168A CN201110437116A CN102423294A CN 102423294 A CN102423294 A CN 102423294A CN 2011104371168 A CN2011104371168 A CN 2011104371168A CN 201110437116 A CN201110437116 A CN 201110437116A CN 102423294 A CN102423294 A CN 102423294A
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Abstract
The present invention discloses a thermo sensitive in situ gel loaded with a drug by chemical bonds, and a preparation method thereof. The gel is formed by dispersing a drug-bonded polyethylene glycol-polyester block copolymer in a water system, wherein the block copolymer is a C/B-A-B/C copolymer, an A-B/C copolymer, a C/A-B copolymer or a C/A-B/C copolymer, and is formed by a hydrophilic polyethylene glycol block A, a polyester block B, and a drug C. The preparation process comprises that: under a catalytic effect of tin octoate, the polyethylene glycol is adopted as an initiator to carry out a ring-opening polymerization reaction to obtain polyethylene glycol-polyester; a terminal group modification treatment is performed for the polyethylene glycol-polyester; the drug C is bonded to the polyethylene glycol-polyester by the chemical bonds; the drug-bonded polyethylene glycol-polyester copolymer is prepared into lyophilized powder; the lyophilized powder is dispersed in a water media, and the dispersion is transformed into the stagnant in situ gel when the mass concentration of the dispersion is 10-50% and the temperature is 25-60 DEG C. The preparation process of the gel of the present invention is simple, and the prepared drug-loaded thermo sensitive in situ gel has a plurality of application prospects of prodrugs.
Description
Technical field
The present invention relates to a kind of temperature sensing in situ gel rubber and preparation, belong to the high-molecular gel technical field that contains medicine by the chemical bond carrying medicament.
Background technology
The advantage that the nanoparticle that forms based on Polyethylene Glycol (PEG)-polyester-block copolymer drug self assembly has: can connect several drug molecules on (1) each polymer chain, improve drug loading.(2) amphipathic nature polyalcohol can self assembly form nanoparticle, is absorbed by tumor cell with the mode of engulfing usually.(3) anticarcinogen is connected through covalent bond with polymer, thereby prolongs blood circulation time and the release that reduces blood circulation process Chinese medicine.(4) medicine is connected with polymer through the responsive key of pH, thereby could discharge the availability that improves medicine at specific pH.Through the mPEG-PCL/PTX of ester bond link, mPEG-PLA-PTX, the existing report of PEO-(PCL/DOX) nanoparticle of amido link and the link of hydrazone key, and all demonstrate good anticancer effect in the test in vivo and in vitro.(Zhang，X.F.；Li，Y.X.；Chen，X.S.；Wang，X.H.；Xu，X.Y.；Liang，Q.Z.；Hu，J.L.；Jing，X.B.Biomaterials?2005，26，2121-2128.Xu，X.Y.；Zhang，X.F.；Wang，X.H.；Li，Y.X.；Jing，X.B.Polym.Adv.Technol.2009，20，843-848.Mikhail，A.；Allen，C.Biomacromolecules?2010，11，1273-1280.Tong，R.；Yala，L.；Fan?c，T.M.；Cheng，J.J.Biomaterials?2010，31，3043-3053.Shahin，M.；Lavasanifar，A.Int.J.Pharm.2010，389，213-222.Lee，Y.H.；Lee，K.；Park，T.G.Bioconjugate.Chem.2008，19，1319-1325.)。But also there is shortcoming in these polymer nanoparticles, as targeting property, along with blood circulation be excluded very soon external, the drug utilization degree is low etc.
The amphipathic nature polyalcohol Injectable in-situ gel need not surgical operation and promptly may be injected in the human body, and body temperature sol-gel transition takes place and original position formation situ-gel down, avoids the use of organic solvent and cross-linking agent, and in-vivo procedures is simple and safe.But the mode through physical blending is sneaked into gel with medicine, causes the prominent of hydrophilic medicament to release and the hydrophobic drug crystallization easily, influence the therapeutic effect of medicine, and drug loading is lower.The existing report of thermo-responsive hydro gel (Chun, the C.J. of the polyphosphazene-Polyethylene Glycol-cancer therapy drug that connects through chemical bond; Lee, S.M.; Kim, S.Y.; Yang, H.K.; Song, S.C.Biomaterials 2009,30,2349-2360.) and in the mice body have good anti-tumor effect.The difference of drug kinds, the difference of application demand; And the limitation of polyphosphazene structural behaviour; Make the situ-gel system of single a kind of polyphosphazene-PEG bonding medicine can't satisfy the demand of multiple medicine prodrug; And polyphosphazene costs an arm and a leg, the preparation condition requirement harsh, and production cost is too high, is difficult to industrialization.
Summary of the invention
The object of the present invention is to provide a kind of temperature sensing in situ gel rubber and preparation by the chemical bond carrying medicament, the temperature sensing in situ gel rubber of this carrying medicament has the application prospect of multiple prodrug.Its preparation method process is simple.
The present invention realizes through following technical scheme; A kind of temperature sensing in situ gel rubber by the chemical bond carrying medicament; It is characterized in that; This gel is to be 10～50% to be scattered in the aqueous systems by the polyethylene glycol-ester block copolymer of bonding medicine with the quality percentage composition; 25 ℃～60 ℃ following formation; The polyethylene glycol-ester block copolymer of described bonding medicine is to be 600 to 10000 hydrophilic polyglycol block A by the number average relative molecular mass, with the number average relative molecular mass be 500 to 20000 hydrophobicity polyester block B, and with the medicine C with hydroxyl, carboxyl, amino or carbonyl functional group; And connect and compose the type copolymer of C/B-A-B/C type, A-B/C type, C/A-B type or C/A-B/C through ester bond, amido link or hydrazone key and Polyethylene Glycol block A or with the end group of polyester block B; Wherein, the quality that comprises the hydrophobic block B that contains the hydrophobic drug quality is (1～4) with the mass ratio that comprises the hydrophilic block A that contains the hydrophilic medicament quality: 1, medicine C and block A or with the end group mol ratio of B block be (0.1～2.0): 1.
Above-mentioned Polyethylene Glycol is selected from two hydroxyl Polyethylene Glycol, monohydroxy Polyethylene Glycol, polyoxyethylene and polyoxypropylene block copolymers and contains pure wherein a kind of in polymer diatomic alcohol or the unit of Polyethylene Glycol block.
Above-mentioned polyester is the homopolymer of caprolactone, lactic acid or lactide, hydroxyacetic acid or Acetic acid, hydroxy-, bimol. cyclic ester, hydroxybutyric acid or their copolymer.
It is wherein a kind of that above-mentioned medicine C is selected from paclitaxel, Docetaxel, amycin, dexamethasone, hydroxy camptothecin, insulin, cisplatin, 5-fluorouracil, reserpine and curcumin.
When the block copolymer in the above-mentioned gel is the C/B-A-B/C type; The number average relative molecular mass of B block is 500～10000; The medicine C of bonded blocks B end group and the mol ratio of B block are (0.1～1): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.0～3.0): 1.
When the block copolymer in the above-mentioned gel is A-B/C; Block A is single end capped Polyethylene Glycol; The number average relative molecular mass of B block is 2000～20000; The medicine C of bonded blocks B end group and the mol ratio of B block are (0.1～1): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.5～4.0): 1.
Block copolymer in the above-mentioned gel is C/A-B; The number average relative molecular mass of B block is 2000～20000; The medicine C of bonded blocks A end group and the mol ratio of B block are (0.1～1): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.5～4.0): 1.
When the block copolymer in the above-mentioned gel is C/A-B/C; The number average relative molecular mass of B block is 2000～20000; The medicine C of the medicine C of bonded blocks A end group and bonded blocks B end group and the mol ratio of B block are (0.2～2): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.5～4.0): 1.
The method for preparing of above-mentioned temperature sensing in situ gel rubber by the chemical bond carrying medicament; It is characterized in that comprising following process: 1) homopolymer or their copolymer with caprolactone, lactic acid or lactide, hydroxyacetic acid or Acetic acid, hydroxy-, bimol. cyclic ester, hydroxybutyric acid is monomer; Stannous octoate with monomer molar amount 1% is a catalyst; With molecular weight is that 2000～20000 Polyethylene Glycol is an initiator, 140 ℃ down reaction carried out ring-opening polymerisation in 6 hours and obtain; 2) succinic anhydrides of polyethylene glycol-ester and 1.1 times of polyethylene glycol-ester terminal hydroxy groups reacts down at 140 ℃ and held carboxylated in 5 hours; Or the N of polyethylene glycol-ester and 1.1 times of polyethylene glycol-ester terminal hydroxy groups, amination is held in N-carbonyl dimidazoles and hydrazine hydrate reaction; 3) be (0.1～2.0) with medicine C and block A or with the end group mol ratio of B block: 1 mixes; Pass through dicyclohexylcarbodiimide; 4-dimethylamino naphthyridine catalysis room temperature reaction obtained the polymer that ester bond connects in 24 hours; Or through 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide catalysis room temperature reaction obtained the polymer that the amido link key connects in 24 hours, or direct reaction got the polymer that the hydrazone key connects in 24 hours; 4) the polyethylene glycol-ester copolymer of keyed jointing medicine is processed lyophilized powder, its lyophilized powder is distributed in the aqueous medium again, and forming mass fraction is the dispersion liquid of 10%-50%, in 25-60 ℃ of environment of this dispersion liquid or change immobilising situ-gel in the organism into; Or the polyethylene glycol-ester copolymer of keyed jointing medicine is dissolved in acetone or the oxolane, and redispersion stirs and volatilizes solvent in aqueous medium, processes mass concentration and be 10%～50% dispersion liquid; 5) in 25-60 ℃ of environment of this dispersion liquid or change immobilising situ-gel in the organism into.
Above-mentioned aqueous medium comprises: pure water, the aqueous solution of various Organic substances or inorganic matter, aqueous emulsion or aqueous dispersions, tissue fluid, blood, normal saline, water for injection, distilled water for injection and glucose injection.
The invention has the advantages that the gel low in raw material cost is easy to get, preparation technology is simple and since medicine through chemical bond and polymer bonds with, both improved drug loading, increase stability of formulation and have slowly advantage lastingly of long, release of holdup time; And utilize temperature sensing in situ gel rubber character, and can navigate to specific part to medicine through injection system, realize location, long lasting drug release; Simultaneously hybrid medicine, protein, polypeptide, polysaccharide, water-soluble polymer, inorganic salt, organic solvent, enzyme, cell in this gel rubber system; Or mix with the polyethylene glycol-ester copolymer temperature-sensitive situ-gel system of other bonding medicine, be used for pharmaceutical preparation, cell culture and histoorgan reparation.
Description of drawings:
Fig. 1 is the nuclear magnetic spectrogram that bonding has the polyethylene glycol-ester copolymer of paclitaxel.Wherein a is the nuclear magnetic spectrogram of PCL-PEG-PCL; B is the nuclear magnetic spectrogram of COOH-PCL-PEG-PCL-COOH; C is the nuclear magnetic spectrogram of PTX, and d is the nuclear magnetic spectrogram of PTX/PCL-PEG-PCL/PTX (I-1), can prove that PTX can successfully be keyed on the COOH-PCL-PEG-PCL-COOH.
Be the flowable state photo under 23 ℃ of states of the aqueous dispersions of Fig. 2 PTX/PCL-PEG-PCL/PTX (I-1).
Be the gel state photo under 37 ℃ of the aqueous dispersions of Fig. 3 PTX/PCL-PEG-PCL/PTX (I-1).
Fig. 4 is the nuclear magnetic spectrogram that bonding has the polyethylene glycol-ester copolymer of amycin.Wherein a is the nuclear magnetic spectrogram of COOH-PCL-PEG-PCL-COOH, and b is the nuclear magnetic spectrogram of DOX, and C proves that for the nuclear magnetic spectrogram of the DOX/PCL-PEG-PCL/DOX (III-1) of amine key connection DOX (amycin) successfully is keyed on the COOH-PCL-PEG-PCL-COOH.
Fig. 5 is the infrared spectrum that bonding has the polyethylene glycol-ester copolymer of amycin.A is the infrared spectrum of PCL-PEG-PCL, and b proves that for the infrared spectrum of hydrazone key connection DOX/PCL-PEG-PCL/DOX (V-1) DOX is connected on the PCL-PEG-PCL through the hydrazone key.
Fig. 6 is the PTX release in vitro curve of temperature-sensitive situ-gel system under pH7.4,37 ℃ of the d (I-1) among Fig. 1, and visible, this temperature sensing in situ gel rubber can be good at sustained release PTX.
Fig. 7 is hydrazone key DOX/PCL-PEG-PCL/DOX (V-1) the nanoparticle release in vitro curve among Fig. 5, and is visible, and DOX discharges and influenced by pH.
Fig. 8 be PTX/PCL-PEG-PCL/PTX (I-1) among Fig. 1 to the vitro cytotoxicity of MCF-7 (human breast cancer cell), visible PTX can discharge from PTX/PCL-PEG-PCL/PTX (I-1), and has kept the antitumous effect of PTX.
The specific embodiment
With embodiment the present invention is further explained again below.
Embodiment 1:
Polymer is connected with the medicine ester bond:
In the dry reaction bottle, add 1.5g dihydroxy PEG (number-average molecular weight 1500Da), 2mL 6-caprolactone, 117 μ l stannous octoate (Sn (Oct)
2), evacuation, inflated with nitrogen.140 ℃ stop behind the reaction 6h down.With the dichloromethane dissolving, ether sedimentation, vacuum filtration obtain polycaprolactone (PCL)-PEG-PCL.3.5g PCL-PEG-PCL and 0.22g succinic anhydride are put into dry flask, and evacuation leads to nitrogen.Reactant reacts 5h down at 140 ℃, is cooled to room temperature then, the dichloromethane dissolving, and ether sedimentation, vacuum filtration obtains COOH-PCL-PEG-PCL-COOH.In the dry reaction pipe, add 0.35gCOOH-PCL-PEG-PCL-COOH then successively; 0.17g paclitaxel (PTX) and 82.52mg dicyclohexylcarbodiimide (DCC); Dimethyl formamide (DMF) dissolving adds 48.87mg 4-dimethylamino naphthyridine (DMAP) at last.Evacuation, inflated with nitrogen.At room temperature react 24h.The reactant liquor 24h that in DMF, dialyses; 24h then dialyses in distilled water; Afterwards with product lyophilization 24h, obtain the PEG-PCL lyophilized co-polymer powder PTX/PCL-PEG-PCL/PTX (being called for short I-1) of (C/B-A-B/C type) on the B end group that medicine PTX is bonded to B-A-B.The nuclear magnetic spectrogram of PCL-PEG-PCL, COOH-PCL-PEG-PCL-COOH, PTX and I-1 is as shown in Figure 1.0.1g PTX/PCL-PEG-PCL/PTX (I-1) nano-granule freeze-dried powder (method for preparing is seen embodiment 12) is distributed in 0.2mL～1mL aqueous medium, and processing concentration is 10%～50% aqueous dispersions system, and this system forms situ-gel under 25～60 ℃.
Embodiment 2-embodiment 13:
Press embodiment 1 method, change the composition and the kind of Polyethylene Glycol, polyester, medicine, (I-2～I-13) and temperature sensing in situ gel rubber thereof, concrete parameter is as shown in table 1 to obtain the PEG-polyester of multiple different C/B-A-B/C type bonding medicines.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of the bonding medicine of table 1 C/B-A-B/C type (ester bond)
M
PEG: the number average relative molecular mass of PEG; M
PE: the number average relative molecular mass of polyester; N: medicine and polyester block mol ratio; W
ABC: the mass ratio of hydrophobic block/hydrophilic block (hydrophobic drug content contributes in the hydrophobic block quality, and hydrophilic medicament content contributes in the hydrophilic block quality); C
Gel: the PEG-amount of polyester of bonding medicine in the situ-gel system; T
Gel: the gelling temperature zone; PTX: paclitaxel; Docetaxel PCLA: the copolymer of caprolactone and lactide; PLGA: the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester; DOX: amycin, DEX: dexamethasone
* resulting I-11 or I-12 lyophilized powder directly are distributed in water or the PBS aqueous solution, stir, prepare gel rubber system.
Embodiment 14 (II-1)
In the dry reaction bottle, add 1.0g poly glycol monomethyl ether (mPEG) (number-average molecular weight 750Da), 3.2mL 6-caprolactone, 100 μ l stannous octoate (Sn (Oct)
2), evacuation, inflated with nitrogen.140 ℃ stop behind the reaction 6h down.With the dichloromethane dissolving, ether sedimentation, vacuum filtration obtains mPEG-PCL.3.15g mPEG-PCL and 0.11g succinic anhydride are put into dry flask, and evacuation leads to nitrogen.Reactant reacts 5h down at 140 ℃, is cooled to room temperature then, the dichloromethane dissolving, and ether sedimentation, vacuum filtration obtains mPEG-PCL-COOH.In the dry reaction pipe, add 0.32g mPEG-PCL-COOH then successively, 0.17g paclitaxel (PTX) and 82.52mg dicyclohexylcarbodiimide (DCC), dimethyl formamide (DMF) dissolving adds 48.87mg4-dimethylamino naphthyridine (DMAP) at last.Evacuation, inflated with nitrogen.At room temperature react 24h.The reactant liquor 24h that in DMF, dialyses; 24h then dialyses in distilled water; Afterwards with product lyophilization 24h; Obtaining (A-B/C type) on the B end group that medicine PTX is bonded to A-B is distributed to 0.1g mPEG-PCL/PTX (II-1) nano-granule freeze-dried powder (method for preparing is seen embodiment 103) in 0.2mL～1.0mL aqueous medium by the PEG-PCL copolymer mPEG-PCL/PTX (being called for short II-1) of chemical bond carrying medicament; Process variable concentrations aqueous dispersions temperature-sensitive situ-gel system, this system forms situ-gel under 25～60 ℃.
Press embodiment 14 methods; Adopting single end capped Polyethylene Glycol is initiator; Cause ring-opening polymerisation, change the composition and the kind of Polyethylene Glycol, polyester, medicine, can prepare the polyethylene glycol-ester copolymer (II-2～II-13) of the bonding medicine of a series of A-B/C types; Can obtain corresponding temperature-sensitive situ-gel system equally, as shown in table 2.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of the bonding medicine of table 2A-B/C type (ester bond)
M
PEG: the number average relative molecular mass of PEG; M
PE: the number average relative molecular mass of polyester; N: medicine and polyester block mol ratio; W
ABC: the mass ratio of hydrophobic block/hydrophilic block (hydrophobic drug content contributes in the hydrophobic block quality, and hydrophilic medicament content contributes in the hydrophilic block quality); C
Gel: the PEG-amount of polyester of bonding medicine in the situ-gel system; T
Gel: the gelling temperature zone; PTX: paclitaxel; DEX: dexamethasone; PCLA: the copolymer of caprolactone and lactide; PLGA: the copolymer of lactide and Acetic acid, hydroxy-, bimol. cyclic ester.
Embodiment 27 (III-1):
Polymer is connected with the medicine amido link:
In the dry reaction bottle, add 4g dihydroxy PEG (number-average molecular weight 4000Da), 3.98mL 6-caprolactone, 117 μ l stannous octoate (Sn (Oct)
2), evacuation, inflated with nitrogen, repeatable operation three times.140 ℃ stop behind the reaction 6h down.With the dichloromethane dissolving, ether sedimentation, vacuum filtration obtain polycaprolactone (PCL)-PEG-PCL.3.5g PCL-PEG-PCL and 0.22g succinic anhydride are put into dry flask, and evacuation leads to nitrogen.Reactant reacts 5h down at 140 ℃, is cooled to room temperature then, the dichloromethane dissolving, and ether sedimentation, vacuum filtration obtains COOH-PCL-PEG-PCL-COOH.In the dry reaction pipe, add 0.8gCOOH-PCL-PEG-PCL-COOH then successively; 0.116g amycin (DOXHCl); 20 μ L triethylamines; 60mg1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC) with 10mL DMSO dissolving, adds 50mg N-hydroxy-succinamide (NHS) at last.Evacuation, inflated with nitrogen repeats 3 times.At room temperature react 24h.Distilled water dialysis 24h, lyophilization gets DOX/PCL-PEG-PCL/DOX (being called for short III-1).0.1gDOX/PCL-PEG-PCL/DOX (III-1) nano-granule freeze-dried powder (method for preparing is seen embodiment 103) is distributed in 0.2mL～1.0mL aqueous medium; Process variable concentrations aqueous dispersions temperature-sensitive situ-gel system; This system forms situ-gel under 28～56 ℃.NMR spectrogram such as Fig. 4.
Embodiment 28～embodiment 39:
Press embodiment 27 methods; Change the composition and the kind of Polyethylene Glycol, polyester, medicine; Can prepare a series of amido links and connect the C/B-A-B/C types by the polyethylene glycol-ester copolymer of chemical bond carrying medicament (III-2～III-13); Can obtain corresponding temperature-sensitive situ-gel system equally, as shown in table 3.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of table 3 C/B-A-B/C type (amido link) bonding medicine
PCGA: the copolymer of caprolactone and Acetic acid, hydroxy-, bimol. cyclic ester; PHA: poly butyric
* press embodiment 12 methods, the polymer of building with medicine of gained is prepared into nano-granule freeze-dried powder earlier, redispersion stirs in water or PBS aqueous solution, obtains gel rubber system.
Embodiment 40 (IV-1)
In the dry reaction bottle, add 1.0g poly glycol monomethyl ether (mPEG) (number-average molecular weight 750Da), 3.2mL 6-caprolactone, 100 μ l stannous octoate (Sn (Oct)
2), evacuation, inflated with nitrogen.140 ℃ stop behind the reaction 6h down.With the dichloromethane dissolving, ether sedimentation, vacuum filtration obtains mPEG-PCL.3.15g mPEG-PCL and 0.11g succinic anhydride are put into dry flask, and evacuation leads to nitrogen.Reactant reacts 5h down at 140 ℃, is cooled to room temperature then, the dichloromethane dissolving, and ether sedimentation, vacuum filtration obtains mPEG-PCL-COOH.In the dry reaction pipe, add 0.32g mPEG-PCL-COOH then successively, 0.10g DOX and 60mg EDC, dimethyl formamide (DMF) dissolving adds 50mg NHS at last.Evacuation, inflated with nitrogen.At room temperature react 24h.The reactant liquor 24h that in DMF, dialyses, the 24h that in distilled water, dialyses then afterwards with product lyophilization 24h, obtains the PEG-PCL copolymer mPEG-PCL/DOX (being called for short IV-1) of (A-B/C type) on the B end group that medicine DOX is bonded to A-B.0.1g mIV-1 nano-granule freeze-dried powder (method for preparing is seen embodiment 103) is distributed in 0.2mL～1.0mL aqueous medium, and processing concentration is 10～50% aqueous dispersions temperature-sensitive situ-gel systems, and this system forms situ-gel under 33～54 ℃.
Embodiment 41～embodiment 51:
Press embodiment 40 methods; Adopting single end capped Polyethylene Glycol is initiator; Cause ring-opening polymerisation, change the composition and the kind of Polyethylene Glycol, polyester, medicine, the polyethylene glycol-ester copolymer that can prepare a series of A-B/C type control drug release gets (IV-2～IV-12); Can obtain corresponding temperature-sensitive situ-gel system equally, as shown in table 4.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of (amido link) bonding medicine of table 4 A-B/C type
Embodiment 52:
Polymer is connected with medicine hydrazone key:
In the dry reaction bottle, add 4g dihydroxy PEG (number-average molecular weight 4000Da), 3.98mL 6-caprolactone, 117 μ L stannous octoate (Sn (Oct)
2), evacuation, inflated with nitrogen, repeatable operation three times.140 ℃ stop behind the reaction 6h down.With the dissolving of 6ml dichloromethane, precipitate in the ice ether, vacuum filtration obtains PCL-PEG-PCL.With 1.5g PCL-PEG-PCL, 0.35g N, N-carbonyl dimidazoles (CDI) are dissolved in the refining dichloromethane of 10mL.Evacuation leads to N
2, reacting 24h under the room temperature, ether sedimentation gets the activatory PCL-PEG-PCL of CDI.The activatory PCL-PEG-PCL of 1g CDI, 244 μ L hydrazine hydrates are dissolved in 10mL methanol, 70 ℃ of backflow 12h, the ice ether sedimentation must be held amido PCL-PEG-PCL.0.1g end amido PCL-PEG-PCL, 33mg doxorubicin hydrochloride, 20 μ L triethylamines; Be dissolved in 5mL DMF; Room temperature reaction 24h imports bag filter with reactant liquor and places the distilled water 24h that dialyses, and lyophilization gets the DOX/PCL-PEG-PCL/DOX nano-granule freeze-dried powder (being called for short V-1) that the hydrazone key connects.With 1gDOX-PCL-PEG-PCL/DOX (V-1) nano-granule freeze-dried powder redispersion in 2mL～10mL aqueous medium; Process concentration and be 10%～50% DOX-PCL-PEG-PCL/DOX (V-1) dispersion liquid temperature-sensitive situ-gel system; This system forms situ-gel under 28～56 ℃.Infrared spectrum such as Fig. 5, gelling properties is seen table 5.
Embodiment 53～embodiment 64:
Change the composition and the kind of Polyethylene Glycol, polyester, medicine, press embodiment 5 methods, can prepare a series of C/B-A-B/C types (hydrazone key) bonding medicine the PEG-polyester block copolymer (V-2～V-13), as shown in table 5.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of table 5 C/B-A-B/C type (hydrazone key) bonding medicine
PCGA: the copolymer of caprolactone and Acetic acid, hydroxy-, bimol. cyclic ester; PHA: poly butyric
Embodiment 65 (VI-1)
In the dry reaction bottle, add 1g mPEG (number-average molecular weight 750Da), 3.2mL 6-caprolactone, 100 μ L stannous octoate (Sn (Oct)
2), evacuation, inflated with nitrogen, repeatable operation three times.140 ℃ stop behind the reaction 6h down.With the dissolving of 6ml dichloromethane, precipitate in the ice ether, vacuum filtration obtains mPEG-PCL.With 3.15gmPEG-PCL, 0.35g N, N-carbonyl dimidazoles (CDI) are dissolved in the refining dichloromethane of 10mL.Evacuation leads to N
2, reacting 24h under the room temperature, ether sedimentation gets the activatory mPEG-PCL of CDI.The activatory mPEG-PCL of 1g CDI, 250 μ L hydrazine hydrates are dissolved in 10mL methanol, 70 ℃ of backflow 12h, the ice ether sedimentation must be held amido mPEG-PCL.0.1g end amido mPEG-PCL, the 30mg doxorubicin hydrochloride, 20 μ L triethylamines are dissolved in 5mLDMF, and room temperature reaction 24h imports bag filter with reactant liquor and places the distilled water 24h that dialyses, and lyophilization gets the mPEG-PCL/DOX (being called for short VI-1) that the hydrazone key connects.With 1g DOX-PCL-PEG-PCL/DOX (V-1) nano-granule freeze-dried powder redispersion in 2mL～10mL aqueous medium; Process concentration and be 10%～50% mPEG-PCL/DOX (VI-1) dispersion liquid temperature-sensitive situ-gel system; This system forms situ-gel under 34～52 ℃.
Embodiment 66～embodiment 77:
Change the composition and the kind of Polyethylene Glycol, polyester, medicine, press embodiment 65 methods, can prepare a series of A-B/C type bonding medicines the PEG-polyester block copolymer (VI-2～VI-12) and temperature sensing in situ gel rubber thereof, as shown in table 6.
The PEG-polyester temperature-sensitive situ-gel system of (hydrazone key) control drug release of table 6 A-B/C type
Embodiment 78 (VII-1)
Respectively with the single-ended amino PEG (NH of 2g
2-PEG number-average molecular weight 2000Da), 0.2g ibuprofen (IBU), 0.2g EDC; 0.15g NHS is dissolved in the water, evacuation leads to the nitrogen triplicate, under room temperature, reacts 24h; The 24h that in DMSO, dialyses then, in the distilled water dialysis 48 hours the PEG (IBU-PEG) that modifies of ibuprofen.Respectively at adding 2g IBU-PEG, 5ml caprolactone, 180ul Sn (Oct) in the reaction tube
2Evacuation leads to the nitrogen triplicate, reacts 8h, stopped reaction down in 140 ℃.Add the dissolving of 4ml dichloromethane, precipitate in the ice ether, medicine C is bonded to the PEG-polyester block copolymer (C/A-B) of the bonding medicine on the A end group of A-B, IBU/PEG-PCL (VII-1).1g VII-1 is dissolved in 3mL acetone or the oxolane, and redispersion stirs and to volatilize solvent in 2mL～10mL aqueous medium, processes concentration and be 10%～50% VII-1 dispersion liquid temperature-sensitive situ-gel system, and this system forms situ-gel under 34～53 ℃.
Embodiment 79～embodiment 89:
Change the composition and the kind of Polyethylene Glycol, polyester, medicine, press embodiment 78 methods, can obtain a series of C/A-B type bonding medicines the PEG-polyester copolymer (VII-2～VII-12), as shown in table 7.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of table 7 C/A-B type bonding medicine
Embodiment 90 (VIII-1)
On the basis of embodiment 78, can continue polymer chain is modified the PEG-polyester block copolymer that forms C/A-B/C type bonding medicine.With 0.6g VII-1,0.2g ibuprofen (IBU), 0.3g DCC, 0.2g DMAP are dissolved in the 10mLDMSO solution, and evacuation leads to nitrogen, reacts 24h under the room temperature.With the reactant liquor 24h that in DMSO, dialyses, the 48h that dialyses in the distilled water, lyophilization gets IBU-PEG-PCL-IBU (being called for short VIII-1).1g VIII-1 is dissolved in 3mL acetone or the oxolane, and redispersion is in aqueous medium, and redispersion is in 2mL～10mL aqueous medium; Stirring volatilizes solvent; Process concentration and be 10%～50% VIII-1 dispersion liquid temperature-sensitive situ-gel system, this system forms situ-gel under 30～57 ℃.
Embodiment 91～embodiment 100:
Change the composition and the kind of Polyethylene Glycol, polyester, medicine, can prepare the PEG-polyester block copolymer (VIII-2～VIII-12), see table 8 of a series of C/A-B/C type bonding medicines by embodiment 90 methods.
The PEG-polyester block copolymer and the temperature sensing in situ gel rubber thereof of table 8 C/A-B/C type bonding medicine
Embodiment 101:
1g I-1 joins in the test tube that contains the 5g distilled water, is uniformly dispersed under 20 ℃, in system, adds cisplatin 0.1g then, and mix homogeneously forms the temperature-sensitive situ-gel system of cisplatin/I-1.(A) test tube is put in 37 ℃ the waters, behind the 5min, takes out, gel formation, handstand test tube, gel do not flow.(B) temperature-sensitive situ-gel system with cisplatin/I-1 is drawn in the syringe, and it is subcutaneous to be expelled to mice, forms gel behind 5～10min in the injection site.
Embodiment 102:
1g II-1 joins in the test tube that contains the 5g distilled water, is uniformly dispersed under 20 ℃, in system, adds cisplatin 0.1g then, and mix homogeneously forms the temperature-sensitive situ-gel system of cisplatin/prodrugs of paclitaxel I-1.(A) test tube is put in 37 ℃ the waters, behind the 5min, takes out, gel formation, handstand test tube, gel do not flow.(B) temperature-sensitive situ-gel system with cisplatin/prodrugs of paclitaxel I-1 is drawn in the syringe, and it is subcutaneous to be expelled to mice, forms gel behind 5～10min in the injection site.
Embodiment 103:
The preparation of I-1 nano-granule freeze-dried powder:
Concrete operations are following: take by weighing 1g I-1, be dissolved in the 10mL oxolane, in the 50mL beaker, put into magneton, add the 10mL distilled water, beaker is placed on the magnetic stirring apparatus stirs, dropwise add the tetrahydrofuran solution of polymer.Drip the back with the oxolane in the rotary evaporator evaporating liquid, oxolane evaporates behind the 0.5h, obtains nanoparticle solution, centrifugalize, and lyophilization gets nano-granule freeze-dried powder.
Accurately take by weighing three parts and be 0.1g I-1 nano-granule freeze-dried powder, add the 0.3ml distilled water respectively, place 37 ℃ of water-baths to stablize 12h in test tube after being uniformly dispersed.Test tube is taken out, in test tube, add 5mL PBS (pH7.4), place constant temperature oscillator (37 ℃ 70r/min) discharge.At regular intervals at interval, take out 5mL and discharge liquid, and the fresh PBS solution of additional 5mL.Detect release liquid with HPLC, utilize standard curve to calculate the drug level that receives in the liquid, by formula (2) calculating cumulative burst size.The concentration of paclitaxel is calculated by formula 1, and the cumulative release amount is calculated by formula 2.Result such as Fig. 3.
Y=B*X formula (1)
Linear fit draws: B=3.54432E-8 (R=0.99976).
In the formula: E is the cumulative release amount of PTX, μ g/mL; V
EBe the displaced volume of PBS, 5mL;
V
0For discharging liquid PBS volume, 5mL; C
iDischarge the concentration of liquid Chinese medicine when being the i time displacement sampling, μ g/mL;
N is the number of times of displacement PBS, m
0Be total dosage.
Embodiment 104:
Accurately take by weighing the 5mgV-1 nanoparticle, place in the bag filter, the PBS dispersing nanometer grain for preparing with 3mL.The bag filter of good seal is placed 22mL PBS, under 37 ℃ of constant temperature oscillators (70r/min), carry out extracorporeal releasing experiment.Get 20mL in per 1 hour and discharge liquid, and the fresh PBS of additional 20mL, promptly replacement amount is 20mL.Discharge liquid with ultraviolet detection, utilize standard curve to calculate and release the drug level of receiving in the liquid, by formula (2) calculating cumulative burst size.
The concentration of amycin is calculated by formula 3, and the cumulative release amount is calculated by formula 2.Result such as Fig. 4.
Y=B*X formula (3)
B＝58.70385(R＝0.99964)
Embodiment 105:
To contain 10% hyclone (FBS; Biochrom Ag, DMEM Germany) (Sigma-Aldrich USA) is basic culture solution, with cell (MCF-7, Tianjin Institute of Medicine Science) with 1 * 10
5Individual/mL cell concentration is inoculated in 96 orifice plates, places 37 ℃, 5%CO
2, cultivate under the saturated humidity condition.PCL-PEG-PCL (control), PTX and I-1DMSO solution with the DMEM dilution, obtain the solution of concentration at 10～100ng/ml behind ultraviolet radiation 1h.The above-mentioned solution of getting 100 each concentration of μ L is added to respectively and substitutes original fluid in the orifice plate of inoculating cell.The cell of cultivation in DMEM is as matched group.After cultivating a period of time respectively, take out culture plate, every hole adds the MTT liquid of 20 μ L; Behind every 4h; Add DMSO (100 μ L/ hole), room temperature 15～20min, the level dyeing of shaken cultivation plate after pouring out stock solution; Join detector with enzyme and detect absorbance value (OD), calculate cell by formula 4 and breed percentage rate RGR (Relative Growth Rate) relatively at the 492nm wavelength
Claims (10)
1. temperature sensing in situ gel rubber by the chemical bond carrying medicament; It is characterized in that; This gel is to be 10～50% to be scattered in the aqueous systems by the polyethylene glycol-ester block copolymer of bonding medicine with the quality percentage composition; 25 ℃～60 ℃ following formation; The polyethylene glycol-ester block copolymer of described bonding medicine is to be 600 to 10000 hydrophilic polyglycol block A by the number average relative molecular mass, with the number average relative molecular mass be 500 to 20000 hydrophobicity polyester block B, and with the medicine C with hydroxyl, carboxyl, amino or carbonyl functional group; And the copolymer of the C/B-A-B/C type, A-B/C type, C/A-B type or the C-A-B/C type that connect and compose through ester bond, amido link or hydrazone key and Polyethylene Glycol block A or with the end group of polyester block B; Wherein, comprise that the hydrophobic section quality that contains the hydrophobic drug quality is (1～4) with comprising the hydrophilic section mass ratio that contains the hydrophilic medicament quality: 1, medicine C and block A's or with the end group mol ratio of B block be (0.1～2.0): 1.
2. by the described temperature sensing in situ gel rubber of claim 1 by the chemical bond carrying medicament; It is characterized in that Polyethylene Glycol is selected from two hydroxyl Polyethylene Glycol, monohydroxy Polyethylene Glycol, polyoxyethylene and polyoxypropylene block copolymers and contains pure wherein a kind of in polymer diatomic alcohol or the unit of Polyethylene Glycol block.
3. by the described temperature sensing in situ gel rubber of claim 1, it is characterized in that polyester is the homopolymer of caprolactone, lactic acid or lactide, hydroxyacetic acid or Acetic acid, hydroxy-, bimol. cyclic ester, hydroxybutyric acid or their copolymer by the chemical bond carrying medicament.
4. by the described temperature sensing in situ gel rubber of claim 1 by the chemical bond carrying medicament; It is characterized in that it is wherein a kind of that medicine is selected from paclitaxel, Docetaxel, amycin, dexamethasone, hydroxy camptothecin, insulin, cisplatin, 5-fluorouracil, reserpine and curcumin.
5. by the described temperature sensing in situ gel rubber of claim 1 by the chemical bond carrying medicament; It is characterized in that; When the block copolymer in the gel is the C/B-A-B/C type; The number average relative molecular mass of B block is 500～10000, and the medicine C of bonded blocks B end group and the mol ratio of B block are (0.1～1): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.0～3.0): 1.
6. by the described temperature sensing in situ gel rubber of claim 1 by the chemical bond carrying medicament; It is characterized in that; When the block copolymer in the gel was A-B/C, block A was single end capped Polyethylene Glycol, and the number average relative molecular mass of B block is 2000～20000; The medicine C of bonding B end group and the mol ratio of B block are (0.1～1): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.5～4.0): 1.
7. by the described temperature sensing in situ gel rubber of claim 1 by the chemical bond carrying medicament; It is characterized in that; When the block copolymer in the gel is C/A-B; The number average relative molecular mass of B block is 2000～20000, and the medicine C of bonded blocks A end group and the mol ratio of B block are (0.1～1): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.5～4.0): 1.
8. by the described temperature sensing in situ gel rubber of claim 1 by the chemical bond carrying medicament; It is characterized in that; When the block copolymer in the gel is C/A-B/C; The relative molecular mass of B block is 2000～20000, and the medicine C of the medicine C of bonded blocks A end group and bonded blocks B end group and the mol ratio of B are (0.2～2): 1, and comprise the hydrophobic section quality that contains the hydrophobic drug quality and comprise that the hydrophilic section mass ratio that contains the hydrophilic medicament quality is (1.5～4.0): 1.
9. method for preparing the described temperature sensing in situ gel rubber by the chemical bond carrying medicament of claim 1; It is characterized in that comprising following process: 1) homopolymer or their copolymer with caprolactone, lactic acid or lactide, hydroxyacetic acid or Acetic acid, hydroxy-, bimol. cyclic ester, hydroxybutyric acid is monomer; Stannous octoate with monomer molar amount 1% is a catalyst; With molecular weight is that 2000～20000 Polyethylene Glycol is an initiator, 140 ℃ down reaction carried out ring-opening polymerisation in 6 hours and obtain; 2) succinic anhydrides of polyethylene glycol-ester and 1.1 times of polyethylene glycol-ester terminal hydroxy groups reacts down at 140 ℃ and held carboxylated in 5 hours; Or the N of polyethylene glycol-ester and 1.1 times of polyethylene glycol-ester terminal hydroxy groups, amination is held in N-carbonyl dimidazoles and hydrazine hydrate reaction; 3) be (0.1～2.0) with medicine C and block A or with the end group mol ratio of B block: 1 mixes; Pass through dicyclohexylcarbodiimide; 4-dimethylamino naphthyridine catalysis room temperature reaction obtained the polymer that ester bond connects in 24 hours; Or through 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide catalysis room temperature reaction obtained the polymer that the amido link key connects in 24 hours, or direct reaction got the polymer that the hydrazone key connects in 24 hours; 4) the polyethylene glycol-ester copolymer of keyed jointing medicine is processed lyophilized powder, its lyophilized powder is distributed in the aqueous medium again, and forming mass fraction is the dispersion liquid of 10%-50%, in 25-60 ℃ of environment of this dispersion liquid or change immobilising situ-gel in the organism into; Or the polyethylene glycol-ester copolymer of keyed jointing medicine is dissolved in acetone or the oxolane, and redispersion stirs and volatilizes solvent in aqueous medium, processes mass concentration and be 10%～50% dispersion liquid; 5) in 25-60 ℃ of environment of this dispersion liquid or change immobilising situ-gel in the organism into.
10. by the method for the described preparation of claim 9 by the temperature sensing in situ gel rubber of chemical bond carrying medicament; It is characterized in that; Aqueous medium comprises: pure water, the aqueous solution of various Organic substances or inorganic matter, aqueous emulsion or aqueous dispersions, tissue fluid, blood, normal saline, water for injection, distilled water for injection and glucose injection.
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