CN101402736A - Biodegradable unsaturated polyphosphate, preparation and use method thereof - Google Patents
Biodegradable unsaturated polyphosphate, preparation and use method thereof Download PDFInfo
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Abstract
The invention relates to a biodegradable unsaturated polyphosphate ester containing phosphate ester and fumarate ester bonds and discloses a preparation method of the polyphosphate ester and a method for the application of the polyphosphate ester as a medical sustained release preparation for injecting into a treated part and as a hard tissue repair and filling material. The mixture composed of the polyphosphate ester, a cross-linking vinyl monomer, a free radical thermal initiator or photo initiator being capable of initiating or assist in initiating covalent cross-linking reaction and biologically active drugs has excellent medical sustained release effect and no toxic side effects. As a material for repairing the defects of osseous tissue, the biodegradable unsaturated polyphosphate ester can stimulate the formation of new bones; and the material can also be degraded gradually and finally be substituted by a new bone completely. The biodegradable unsaturated polyphosphate ester has outstanding biocompatibility and no obvious inflammation reactions and teratogenesis.
Description
Technical field
The present invention relates to a kind of biodegradable unsaturated polyphosphate and preparation and application method, in particular contain unsaturated polyester acid esters and the preparation and the application method of phosphoric acid ester and fumaric acid ester bond in the polymer backbone simultaneously.
Technical background
The biological medical polymer material that is used for damaged treatment of bone and drug delivery system, the most important condition are to have excellent biological compatibility, all tackle the nontoxic no teratogenesis of body comprising polymkeric substance itself and degraded product.The degradable biological medical polymer is used for implantable medical device and drug delivery system, can be after device be finished set function, resolve into small molecules and fragment by hydrolysis or enzymolysis, finally absorbed or excrete, exempted needing second operation to take out the misery of being brought by body.
Therefore poly phosphate has excellent biological compatibility owing to be similar to teichoic acid on its structure, and phosphoric acid ester bond hydrolyzable and the enzymolysis in the molecular structure simultaneously makes this base polymer degradable under physiological condition.Relatively and other Biodegradable high-moleculars, another key property of poly phosphate is the modifiability of its sense side group, drug molecule and bioactive molecules can be chemically bonded on the polymer by side group, and these medicines can discharge by hydrolysis again under physiological condition.The change of side group can also cause the change of the physical properties such as solvability, second-order transition temperature of polymkeric substance in addition, to adapt to different application needs.Poly phosphate mainly comprises tissue engineering material, drug release material, genophore etc. in the application of biomedical sector.This base polymer is generally phosphoric acid ester and other monomeric multipolymers, for example: (patent CN1256700A) synthetic terephthalate-phosphoric acid ester multipolymers such as hair Haiquan; Zhuo Renxi etc. (Chinese science B collects, and 2002,32 (6): 486) synthetic phosphoric acid ester-carbonate copolymer; Leong etc. (U.S. Pat 5176907) synthetic carbamate-phosphoric acid ester multipolymer; The aliphatic group of Dang Wenbing etc. (patent CN1337878A) preparation or the phosphoric acid ester multipolymer of terephthalic acid ester group; The lactic acid of Zhao medium (CN101125916A) preparation or the phosphoric acid ester multipolymer of oxyacetic acid.When these poly phosphates are applied to medicament slow release system and bone renovating material, be implanted in the body by operation again after need being prepared into definite shape in advance, bring very big misery to the patient, during in particular as bone renovating material, the filling particularly inconvenience damaged to erose bone brings difficulty for clinical use.
The present invention designs synthetic a kind of novel unsaturated polyphosphate, is to have the injectable performance under the bone renovating material of major ingredient and the medicament slow release system room temperature with it, can it be implanted in the body by Minimally Invasive Surgery.This unsaturated polyphosphate reaches and does not appear in the newspapers as yet based on its injectable bone repair materials and medicament slow release system.
Summary of the invention
The objective of the invention is to overcome existing poly phosphate material need be by the shortcoming of external moulding in advance, solve the current material filling reparation difficult defective damaged simultaneously, a kind of biodegradable unsaturated polyphosphate and preparation and application method are provided the out-of-shape bone.
Biodegradable unsaturated polyphosphate of the present invention, its general structure is as follows:
Wherein R is one of H or following groups: alkoxyl group, aliphatic secondary amino group, phenoxy group or phenylamino;
M
1Be ethylidene or propylidene;
M
2Be one of following groups: ethylidene, propylidene, isopropylidene, 1,2-dimethyl ethylidene, 2-methyl-propylidene, the inferior tertiary butyl, pentylidene, hexylidene, inferior heptyl, 2,2-dimethyl propylidene, octylene, phenylene, benzylidene, naphthylidene and phenanthrylene, inferior pyrryl, furylidene, inferior thiophene phenyl, pyridylidene, inferior pyrimidyl, polyoxyethylene groups, polyoxypropylene base;
X 〉=1, y 〉=0; N is generally between 1～5000.
The said alkoxyl group of above-mentioned R is: methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy or tert.-butoxy;
Aliphatic secondary amino group is: methylamino-, ethylamino, third amino, isopropylamino, n-butyl amine base or uncle's fourth amino.
The preparation method of biodegradable unsaturated polyphosphate of the present invention is as follows:
(1) preparation of reactant II
Reactant II structural formula is as follows, wherein M
1Be ethylidene or propylidene;
Fumaric acid and propylene oxide or oxyethane are joined in the pressure reaction still simultaneously with mol ratio 1.0: 1.0～1.0: 1.5 and catalyzer, and catalyzer is one of following compounds: pyridine, pyrroles, triethylamine, trolamine, Tetrabutyl amonium bromide, Dodecyl trimethyl ammonium chloride, Trimethyllaurylammonium bromide, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, octadecyl trimethyl ammonium chloride; The molar percentage of catalyst consumption and fumaric acid consumption is: 0.1%～5%; 40 ℃～80 ℃ stirring reactions of temperature control when treating that the still internal pressure drops to 0.1MPa～0.25MPa gradually, continue to be warming up to 80 ℃～110 ℃, keep this thermotonus 0.5～2 hour; After reaction was finished, unreacted propylene oxide or oxyethane were removed in air distillation, promptly get reactant II;
(2) preparation of unsaturated polyphosphate
At first reactant II and diol compound are joined in the reactor after being dissolved in inert solvent x/y=1/0～1000 in molar ratio, start agitator and add acid binding agent, the acid binding agent consumption is (x+y)～10 (x+y) moles; The dichloro-phosphoric acid ester of x+y mole is dissolved in the inert solvent, slowly is added drop-wise in the above-mentioned reaction mixture of refrigerative, reacted under low temperature or the room temperature 0.01～2 hour, temperature rising reflux is 0.5～36 hour again; Reaction is cooled to room temperature after finishing, and removes by filter the salt that generates in the reaction.Underpressure distillation removes desolvates, and product is dissolved in non-aqueous solvent such as ether, methylene dichloride, trichloromethane, the tetrachloromethane etc., and the alkalescence washing is washed to neutrality again; After the organic layer drying, splash under stirring fast in non-solvent such as sherwood oil, hexanaphthene, the whiteruss, be settled out polymkeric substance, precipitation process can repeat repeatedly.Last vacuum-drying is removed organic solvent and is obtained the unsaturated polyphosphate that structural formula is I.
The structural formula of above-mentioned said diol compound is as follows, wherein M
2Identical with the Compound I definition.
HO-M
2-OH
M
2Be one of following groups: ethylidene, propylidene, isopropylidene, 1,2-dimethyl ethylidene, 2-methyl-propylidene, the inferior tertiary butyl, pentylidene, hexylidene, inferior heptyl, 2,2-dimethyl propylidene, octylene, phenylene, benzylidene, naphthylidene and phenanthrylene, inferior pyrryl, furylidene, inferior thiophene phenyl, pyridylidene, inferior pyrimidyl, polyoxyethylene groups, polyoxypropylene base;
Above-mentioned said dichloro-phosphate ester structure formula is as follows:
Wherein R is identical with the Compound I definition.
R is one of H or following groups: alkoxyl group, aliphatic secondary amino group, phenoxy group or phenylamino; Alkoxyl group is: methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy or tert.-butoxy; Aliphatic secondary amino group is: methylamino-, ethylamino, third amino, isopropylamino, n-butyl amine base or uncle's fourth amino.
Above-mentioned said acid binding agent for absorbing the compound of byproduct hydrogen chloride is: triethylamine, Trimethylamine 99, aniline, pyridine, aminopyridine, 4-Dimethylamino pyridine.
Above-mentioned said inert solvent is: methylene dichloride, trichloromethane, tetracol phenixin, 1,2-ethylene dichloride.
Biodegradable unsaturated polyphosphate of the present invention directly is injected into the application method of therapentic part as medicament slow release preparation:
With following each component: the 1. unsaturated polyphosphate of structure shown in the formula I; 2. can with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure, account for 5～95% of medicament slow release system total mass; 3. can cause or auxiliary free radical thermal initiator or the light trigger that causes the covalent cross-linking reaction, account for 0.05～5% of medicament slow release system total mass; 4. biologically active drug accounts for 0.1～95% of delivery systme total mass, is mixed into the uniform fluid composition, is injected into therapentic part with the direct filling of this fluid composition or with syringe.Utilize the crosslinked of body temperature initiated polymerization thing, in-situ solidifying forms the medicament slow release system; Or utilize light directly to see through tissue such as integumentary musculature or light is incorporated into the photo-crosslinking curing of therapentic part initiated polymerization thing via optical fiber.
Above-mentioned 2. component is said can be with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure: N-vinyl pyrrolidone, vinylbenzene, Vinylstyrene; Esters of acrylic acid: methyl acrylate, ethyl propenoate, vinylformic acid 2-hydroxyl ethyl ester, methyl methacrylate, Jia Jibingxisuanyizhi, methacrylic acid 2-hydroxyl ethyl ester; Fumaric acid esters: monomethyl fumarate, monomethyl ester, dimethyl fumarate, DEF, fumaric acid two (2-hydroxypropyl) ester; The maleic acid ester class comprises monomethyl maleate, ethyl maleate, dimethyl maleate, ethyl maleate, toxilic acid two (2-hydroxypropyl) ester; Itaconic ester class: dimethyl itaconate, diethyl itaconate, methylene-succinic acid dipropyl; Acrylic amide: acrylamide, N hydroxymethyl acrylamide, Methacrylamide, N,N methylene bis acrylamide; Macrogol ester class: polyalkylene glycol acrylate ester; The methacrylic acid macrogol ester.
The said free radical thermal initiator that can cause or assist the initiation covalent cross-linking to react of above-mentioned 3. component is: azo-initiator: Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile); Organic peroxy class: benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid, peroxide tert pivalate ester, di-isopropyl peroxydicarbonate, di-cyclohexylperoxy dicarbonate; Inorganic peroxy class initiator: Potassium Persulphate, ammonium persulphate; Oxidation-reduction class initiator: oxygenant is hydrogen peroxide, persulphate, benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid, peroxide tert pivalate ester, and reductive agent is Fe
2+, Cu
+, NaHSO
3, Na
2S
2O
3, trolamine, N, accelerine, N, N-dimethyl-p-toluidine, oxalic acid, glucose, cobalt naphthenate.
The said free radical photo-initiation that can cause or assist the initiation covalent cross-linking to react of above-mentioned 3. component is: Diisopropyl azodicarboxylate, methyl vinyl ketone, st-yrax, benzophenone, fluorescein, eosin, Benzoin ethyl ether, 2,2-diethoxy acetophenone, camphorquinone, Alpha-hydroxy isopropyl benzene ketone, Alpha-hydroxy phenylcyclohexane ketone, 2-methyl-4 '-methylthio group-2-morpholinyl Propiophenone, 2,4-diethyl thiazolone.
Above-mentioned said 4. biologically active substance is: anti-infective: amoxycilline Trihydrate bp, ceftriaxone, cefuroxime axetil, cilastatin, ceftazime, mupirocin, paraxin, clindamycin, tsiklomitsin, gentamicin, Ciprofloxacin, levofloxacin, clotrimazole, fluconazole, Terbinafine, itraconazole, stavudine, KETOKONAZOL, azithromycin, clarithromycin, erythromycin, aztreonam, imipenum, the vazadrine, Rifampin, chloroquine, Pyrimethamine hcl, dapsone, Atovaquone, acyclovir, Indinavir, lamivudine, viracept see nelfinaivr, valacyclovir, Cymevan; Antineoplastic agent: carboplatin, cis-platinum, carmustine, methotrexate, 5 FU 5 fluorouracil, gemcitabine, Coserelin, Leuprolide, tamoxifen, rIL-2, taxol, interleukin-2, interferon alpha, tretinoin, bleomycin, dactinomycin, daunorubicin, Zorubicin, mitomycin, vinealeucoblastine(VLB) or vincristine(VCR); Treatment diabetes medicament: metformin, insulin human, troglitazone, acarbose, Glipizide, glimepiride, voglibose, Insulin lispro, Glyburide, rosiglitazone etc.; Biotechnological formulation: transforming growth factor-beta (TGF-β), fibroblast growth factor (FGF), nerve growth factor (NGF), tumor necrosis factor-alpha and β, somatotropin releasing factor, pHGF (HGF), insulin-like growth factor (IGF), bone morphogenetic protein 1～7 (BMP1～7), thyrocalcitonin.
Biodegradable unsaturated polyphosphate of the present invention is as the application method of hard tissue repair packing material:
With following each component: the unsaturated polyphosphate that 1. structure shown in the formula I is arranged; 2. can with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure, account for 5～95% of bone defect repair packing material system total mass; 3. can cause or auxiliary free radical thermal initiator or the light trigger that causes the covalent cross-linking reaction, account for 0.05～5% of bone defect repair packing material system total mass; 4. inorganic component accounts for 0～95% of bone defect repair packing material system total mass.5. pore-creating agent, the pore-creating agent consumption accounts for 0～90% of gross weight, is mixed into the uniform fluid composition, this fluid composition is directly filled or is injected into therapentic part with syringe.Utilize the crosslinked of body temperature initiated polymerization thing, it is damaged that in-situ solidifying is filled sclerous tissues; Or utilize light directly to see through tissue such as integumentary musculature or light is incorporated into the photo-crosslinking curing of filling position initiated polymerization thing via optical fiber.
Above-mentioned 2. component is said can be with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure: N-vinyl pyrrolidone, vinylbenzene, Vinylstyrene; Esters of acrylic acid: methyl acrylate, ethyl propenoate, vinylformic acid 2-hydroxyl ethyl ester, methyl methacrylate, Jia Jibingxisuanyizhi, methacrylic acid 2-hydroxyl ethyl ester; Fumaric acid esters: monomethyl fumarate, monomethyl ester, dimethyl fumarate, DEF, fumaric acid two (2-hydroxypropyl) ester; The maleic acid ester class comprises monomethyl maleate, ethyl maleate, dimethyl maleate, ethyl maleate, toxilic acid two (2-hydroxypropyl) ester; Itaconic ester class: dimethyl itaconate, diethyl itaconate, methylene-succinic acid dipropyl; Acrylic amide: acrylamide, N hydroxymethyl acrylamide, Methacrylamide, N,N methylene bis acrylamide; Macrogol ester class: polyalkylene glycol acrylate ester; The methacrylic acid macrogol ester.
The said free radical thermal initiator that can cause or assist the initiation covalent cross-linking to react of above-mentioned 3. component is: azo-initiator: Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile); Organic peroxy class: benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid, peroxide tert pivalate ester, di-isopropyl peroxydicarbonate, di-cyclohexylperoxy dicarbonate; Inorganic peroxy class initiator: Potassium Persulphate, ammonium persulphate; Oxidation-reduction class initiator: oxygenant is hydrogen peroxide, persulphate, benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid, peroxide tert pivalate ester, and reductive agent is Fe
2+, Cu
+, NaHSO
3, Na
2S
2O
3, trolamine, N, accelerine, N, N-dimethyl-p-toluidine, oxalic acid, glucose, cobalt naphthenate;
The said free radical photo-initiation that can cause or assist the initiation covalent cross-linking to react of above-mentioned 3. component is: Diisopropyl azodicarboxylate, methyl vinyl ketone, st-yrax, benzophenone, fluorescein, eosin, Benzoin ethyl ether, 2,2-diethoxy acetophenone, camphorquinone, Alpha-hydroxy isopropyl benzene ketone, Alpha-hydroxy phenylcyclohexane ketone, 2-methyl-4 '-methylthio group-2-morpholinyl Propiophenone, 2,4-diethyl thiazolone.
The said inorganic component of described 4. component is: calcium salt: hydroxyapatite, calcium deficiency type hydroxyapatite, alpha-calcium phosphate, beta-calcium phosphate, tetracalcium phosphate, secondary calcium phosphate, dicalcium phosphate dihydrate, octocalcium phosphate, five water octocalcium phosphate, monocalcium phosphate, calcium hydroxide, lime carbonate, Calcium hydrogen carbonate, calcium chloride, calcium lactate, calglucon, calcium stearate, citric acid tricalcium, the lactic acid calglucon, caoxalate, anhydrous calciumsulphate, calcium sulphate hemihydrate, terra alba or Calucium Silicate powder; Phosphoric acid salt: above-mentioned calcium phosphate salt, sodium phosphate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, potassiumphosphate, dipotassium hydrogen phosphate, potassium primary phosphate, ammonium phosphate, Secondary ammonium phosphate or primary ammonium phosphate;
The said pore-creating agent of described 5. component has water miscible following material: sodium-chlor, glucose, seminose, Xylitol, sucrose, Repone K, polyoxyethylene glycol, glycol ether, calcium chloride or yellow soda ash for having certain particle diameter.
The bonding aforesaid method of taking that is used for sclerous tissues such as bone, tooth will have mobile composition and be expelled to inside, crack, cause in-situ cross-linked reaction after, play adhesive effect.Also can adopt conventional operation method, need the adherent surface treatment after, be coated with the composition of poly phosphate, cross-linking and curing reaction takes place under the room temperature, play adhesive effect.
When the present composition uses as the hard tissue repair packing material, also can be in external moulding in advance, be prepared into the implant of desired shape and size, after the method for moulding much for example can be mixed composition, be poured in the mould, utilize heat or light-initiated its polymerization crosslinking to form the goods of solid shape; Also can after being cross-linked to form definite shape in advance, cut the goods that obtain desired shape again.Can form the almost implantation system of Any shape and size, for example implantable post, sheet, rod and microballoon etc. by these methods.
Also can add aforesaid biologically active substance in the present composition, in the process of growth of new bone, polymer materials is degraded gradually, and the biologically active substance of institute's load slowly releases, and reaches therapeutic action in repairing bone defect.
Polymkeric substance of the present invention also can be made structure shape medical apparatus, for example implant, biological Ventricular dissociation device, the degradable fabric is with layered product, biological degradability suture, dressing for skin, Antiadhesive film or be used for adventitia on other implanted devices etc.
The composition of poly phosphate of the present invention has sustained drug release effect preferably, has no side effect.Utilize the compositions, repairs osseous tissue of poly phosphate of the present invention damaged, can promote the formation of new bone, in the forming process of new bone, material is degraded gradually, is finally replaced by new bone fully.Material has excellent biological compatibility, does not have tangible inflammatory reaction and teratogenesis.
Description of drawings:
Fig. 1: the infrared spectrogram of unsaturated polyphosphate
X-coordinate is wave number (cm
-1), ordinate zou is a transmitance.
Fig. 2: unsaturated polyphosphate
1The H-NMR spectrogram
Fig. 3: unsaturated polyphosphate
13The C-NMR spectrogram
Fig. 4: unsaturated polyphosphate
31The P-NMR spectrogram
Fig. 5: the molecular weight of polymkeric substance and return time relation
X-coordinate be return time (hour), ordinate zou is polymericular weight (g/mol)
● expression weight-average molecular weight, ▲ expression number-average molecular weight.
Fig. 6: differential calorimetric scanning (DSC) curve of different molecular weight poly phosphate
X-coordinate be temperature (℃), ordinate zou is hot-fluid (mW)
●: molecular weight is 5960g/mol, Tg=-13.24 ℃;
▲: molecular weight is 4040g/mol, Tg=-32.86 ℃;
■: molecular weight is 3200g/mol, Tg=-33.52 ℃.
Fig. 7: the sustained release of Ciprofloxacin
X-coordinate be time of releasing (hour), ordinate zou is total release percentage (%)
▲: W Ciprofloxacin/P (BPGF-EDP)=0.05/1.0 (g/g);
●: W Ciprofloxacin/P (BPGF-EDP)=0.20/1.0 (g/g).
Fig. 8: the medicine sustained release of tsiklomitsin
X-coordinate be time of releasing (hour), ordinate zou is total release percentage (%)
■: W tsiklomitsin/P (BPGF-EDP)=0.085/1.0 (g/g);
▲: W tsiklomitsin/P (BPGF-EDP)=0.26/1.0 (g/g);
●: W tsiklomitsin/P (BPGF-EDP)=0.43/1.0 (g/g).
Fig. 9: the compressive strength of the damaged packing material of bone is with the variation relation of pore-creating agent consumption
X-coordinate is the consumption (g/g) of NaCl with respect to unsaturated polyphosphate, and ordinate zou is compressive strength (MPa)
Figure 10: the modulus of compression of the damaged packing material of bone is with the variation relation of pore-creating agent consumption
X-coordinate is the consumption (g/g) of NaCl with respect to unsaturated polyphosphate, and ordinate zou is modulus of compression (MPa)
Figure 11: the modulus of compression of the damaged packing material of bone is with the variation relation of mineral filler consumption
X-coordinate is the consumption (g/g) of β-TCP with respect to unsaturated polyphosphate, and ordinate zou is compressive strength (MPa)
Figure 12: the modulus of compression of the damaged packing material of bone is with the variation relation of mineral filler consumption
X-coordinate is the consumption (g/g) of β-TCP with respect to unsaturated polyphosphate, and ordinate zou is modulus of compression (MPa)
Embodiment
Embodiment 1: unsaturated polyphosphate---and P's (BPGF-EDP) is synthetic
In reactor, add fumaric acid 116.07 grams (1.0mol), propylene oxide 63.89 grams (1.1mol) and pyridine 0.79 gram (0.01mol), go out air in the still with nitrogen replacement, elevated temperature to 40 ℃ stirring reaction reacted about 8 hours with this understanding, and the pressure in the reactor is reduced to 0.12MPa, be warming up to 90 ℃, continue reaction and steam excessive propylene oxide after 1 hour, obtain faint yellow oily fumaric acid two (1, the 2-propylene glycol) ester.
92.9g (0.4mol) fumaric acid two (1, the 2-propylene glycol) ester (BPGF) is dissolved in the 1500ml dry methylene chloride, joins in the reaction flask, starts stirring, adds triethylamine 89.0g (0.88mol), nitrogen protection.Reaction flask is put in the ice-water bath, stirs fast down, slowly drips dichloro etherophosphoric acid (EDP) 65.2g (0.40mol) that is dissolved in the 200ml methylene dichloride, and about 1h of dropping time drips the back temperature rising reflux, and the backflow certain hour is used 2mol.L respectively after the cooling
-1Hydrochloric acid and dilute sodium chloride solution washing, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure, methylene dichloride-anhydrous diethyl ether reprecipitation three times, vacuum-drying gets the deep yellow sticky polymers, productive rate 83%
The structure of unsaturated polyphosphate by FTIR (Fig. 1) and
1H-NMR (Fig. 2),
13C-NMR (Fig. 3),
31P-NMR (Fig. 4) determines.
Molecular weight determines that with GPC under the reactant reaction with same mole, reflux time is when 1～18h, and the polymkeric substance number-average molecular weight is 630～5330, and weight-average molecular weight is 1180～5960.The molecular weight of polymkeric substance and return time relation are seen Fig. 5.
Embodiment 2: unsaturated polyphosphate---and P's (BEGF-EDP) is synthetic
In reactor, add fumaric acid 116.07 grams (1.0mol) and pyridine 0.79 gram (0.01mol), go out air in the still with nitrogen replacement, add oxyethane 48.4 grams (1.1mol), elevated temperature to 40 ℃ stirring reaction reacted about 8 hours with this understanding, and the pressure in the reactor is reduced to 0.28MPa, be warming up to 90 ℃, continue reaction and steam excessive oxyethane after 1 hour, obtain faint yellow oily fumaric acid two (1) ester.
81.0g (0.4mol) fumaric acid two (1) ester (BPGF) is dissolved in the 1500ml dry methylene chloride, joins in the reaction flask, starts stirring, adds triethylamine 89.0g (0.88mol), nitrogen protection.Reaction flask is put in the ice-water bath, stirs fast down, slowly drips dichloro etherophosphoric acid (EDP) 65.2g (0.40mol) that is dissolved in the 200ml methylene dichloride, and about 1h of dropping time drips the back temperature rising reflux, and the backflow certain hour is used 2mol.L respectively after the cooling
-1Hydrochloric acid and dilute sodium chloride solution washing, anhydrous magnesium sulfate drying filters, concentrating under reduced pressure, methylene dichloride-anhydrous diethyl ether reprecipitation three times, vacuum-drying gets the deep yellow sticky polymers, productive rate 78%
Embodiment 3: fumaric acid two (1, the 2-propylene glycol) ester---dichloro-phenyl phosphate polymkeric substance synthetic
Except that replace dichloro etherophosphoric acid monomer with the dichloro-phenyl phosphate monomer, synthetic and separation processes produce fumaric acid two (1, the 2-propylene glycol) ester-dichloro-phenyl phosphate polymkeric substance that adopts embodiment 1 to describe.
Synthesizing of embodiment 4:P (EDP-BPGF/PEO400,1/1) multipolymer
In reactor, add fumaric acid 116.07 grams (1.0mol), propylene oxide 63.89 grams (1.1mol) and pyridine 0.79 gram (0.01mol), go out air in the still with nitrogen replacement, elevated temperature to 40 ℃ stirring reaction reacted about 8 hours with this understanding, and the pressure in the reactor is reduced to 0.12MPa, be warming up to 90 ℃, continue reaction and steam excessive propylene oxide after 1 hour, obtain faint yellow oily fumaric acid two (1, the 2-propylene glycol) ester.
46.45g (0.2mol) BPGF and 74.91g (0.2mol) polyoxyethylene glycol-400 is dissolved in the 1500ml dry methylene chloride, joins in the reaction flask, starts stirring, adds triethylamine 89.0g (0.88mol), nitrogen protection.Reaction flask is put in the ice-water bath, stir fast down, slowly drip dichloro etherophosphoric acid (EDP) 65.2g (0.40mol) that is dissolved in the 200ml methylene dichloride, about 1h of dropping time drips the back temperature rising reflux, refluxes for 18 times, leach the hydrochloride of triethylamine after the cooling, methylene dichloride-anhydrous diethyl ether reprecipitation three times, vacuum-drying gets the deep yellow sticky polymers, productive rate 87%.GPC measures polymkeric substance weight-average molecular weight 7760.
Synthesizing of embodiment 5:P (EDP-BPGF/PEO400,1/2) multipolymer
Be respectively 30.9g (0.133mol) and the 99.51g (0.133mol) except that changing BPGF and PEO charging capacity, synthetic and separation processes produce (EDP-BPGF/PEO400, the 1/2) multipolymer that adopts embodiment 4 to describe, GPC measures weight-average molecular weight 9650.
Synthesizing of embodiment 6:P (EDP-BPGF/PEO600,1/1) multipolymer
Except that the 74.91g poly(oxyethylene glycol) 400 is made into the 102.25g Polyethylene Glycol-600, adopt synthetic and separation processes produce (EDP-BPGF/PEO600, the 1/1) multipolymer of embodiment 4 descriptions, it is 8490 that GPC measures weight-average molecular weight.
Embodiment 7: the second-order transition temperature of different molecular weight crosslinkable poly phosphate homopolymer
The second-order transition temperature of crosslinkable poly phosphate of three kinds of molecular weight that utilized determine with dsc method, Fig. 6 is the DSC curve of three kinds of polymkeric substance.
Embodiment 8: the solvability of polymkeric substance
Measure the solvability of institute of the present invention synthetic polymkeric substance, the results are shown in following table:
Embodiment 9: cross-linking properties
The P (BPGF-EDP) that gets 1.0g mixes with N-vinyl pyrrolidone (NVP), adds initiator N, and N-dimethyl-p-toluidine (DMA) and benzoyl peroxide (BPO) mix.Measure set time (t) and the highest crosslinking temperature (T down at 37 ℃
MAX), the results are shown in following table:
Embodiment 10: contain Ciprofloxacin poly phosphate preparation of compositions and release in vitro
The P (BPGF-EDP) that gets 1.0g mixes with 0.7gN-vinyl pyrrolidone and Ciprofloxacin, with 0.003g benzoyl peroxide and 0.001g N, the N-dimethyl-p-toluidine causes crosslinking reaction, and 37 ℃ of following isothermal curings are measured the drug releasing rate in the phosphate buffered saline buffer.This system has sustained release performance preferably.Its release rate curve such as Fig. 7.
Embodiment 11: contain tsiklomitsin poly phosphate preparation of compositions and release in vitro
The P (BPGF-EDP) that gets 1.0g mixes with 0.7gN-vinyl pyrrolidone and tsiklomitsin, with 0.003g benzoyl peroxide and 0.001g N, the N-dimethyl-p-toluidine causes crosslinking reaction, and 37 ℃ of following isothermal curings are measured the drug releasing rate in the phosphate buffered saline buffer.This system has sustained release performance preferably, its release rate curve such as Fig. 8.
Embodiment 12: contain 5 FU 5 fluorouracil antitumor drug poly phosphate preparation of compositions and tumor-inhibiting action
The P (BPGF-EDP) that gets 0.1g mixes with 0.07g N-vinyl pyrrolidone and 0.05g 5 FU 5 fluorouracil, adds 0.001g benzoyl peroxide and 0.0005g N, and the N-dimethyl-p-toluidine mixes, and transfers to syringe.With the big white mouse is subjects, with 2 * 10
5Tumor cell of liver is injected in its hypochondrium, treats that tumor growth after three weeks, is injected into above-mentioned composition in the knurl, solidifies in about 15 minutes.Treat and observe the tumour size after 30 days, the result shows that said composition has the obvious suppression effect to the liver tumor growth of cancer cells.
Embodiment 13: contain taxal anti-tumor medicine poly phosphate preparation of compositions and tumor-inhibiting action
The P (BPGF-EDP) that gets 0.1g mixes with 0.07g N-vinyl pyrrolidone and 0.05g taxol, adds 0.001g benzoyl peroxide and 0.0005g N, and the N-dimethyl-p-toluidine mixes, and transfers to syringe.With the big white mouse is subjects, with 2 * 10
5Tumor cell of liver is injected in its hypochondrium, treats that tumor growth after three weeks, is injected into above-mentioned composition in the knurl, solidifies in about 15 minutes.Treat and observe the tumour size after 30 days, the result shows that said composition has the obvious suppression effect to the liver tumor growth of cancer cells.
Embodiment 14: the preparation of hard tissue repair packing material
Get a certain amount of P (BPGF-EDP) unsaturated polyphosphate (Mw=5960g/mol,) be dissolved in the linking agent N-vinyl pyrrolidone, the adding beta-calcium phosphate (β-TCP), sodium-chlor (NaCl, particle diameter 100～200 μ m) mix after, add the BPO-DMA dissolving, fully stir evenly the back and inject tetrafluoroethylene mould (Φ 6mm * 12mm) rapidly, in 37 ℃ of isothermal curings 24 hours, each amounts of components saw the following form.
Measure the compressive strength of sample after the sample completely solidified on electronic universal tester, the sample mechanical property is with content such as Fig. 9 and Figure 10 of pore-creating agent, and the sample mechanical property is with variation such as Figure 11 and Figure 12 of the content of mineral filler β-TCP.The sample compressive strength is suitable as osseous tissue renovating material near the intensity of spongy bone.
Embodiment 15: the viscosity of sclerous tissues's tamanori
1.0g P (BPGF-EDP) is dissolved among the 0.7g NVP, add β-TCP and mix, be configured to slurry, with 25 ℃ of viscosity of measuring slurry down of cone-and-plate viscometer CAP2000+ (U.S. Brookfield company) room temperature, its viscosity all below 60Pa.s, is suitable for injection.The increase of the content of β-TCP causes slurry viscosity to rise, as Fig. 9.
Embodiment 16:
Get 1g P (BPGF-EDP) unsaturated polyphosphate (Mw=5960g/mol,), NVP mixes with the 0.7g linking agent, add the 0.8g beta-calcium phosphate, after 0.5g sodium-chlor (particle diameter 100～200 μ m) mixes, add 0.003g benzoyl peroxide and 0.001gN, the N-dimethyl-p-toluidine, join in the syringe after fully stirring evenly, composition is expelled to the damaged place of rabbit femoral, about 15 minutes curing moldings by syringe.Do not see suppuration after the implantation and ooze out good biocompatibility unusually.Postoperative alkaline phosphatase enzymatic reversion in 90 days normal level, material are implanted top layer, 2 week back and are degraded, the as seen new bone forming of material internal, and material degradation and new bone are alternative very obvious after 3 months, and material is degraded substantially fully and is also substituted by new bone after 12 months.
Embodiment 17:
Get 1g P (BPGF-EDP) unsaturated polyphosphate (Mw=1720g/mol,), NVP mixes with the 0.7g linking agent, add the 0.6g hydroxyapatite, after 0.7g sodium-chlor (particle diameter 100～200 μ m) mixes, add 0.003g benzoyl peroxide and 0.001g N, the N-dimethyl-p-toluidine, join in the syringe after fully stirring evenly, composition is expelled to the damaged place of rabbit femoral, about 15 minutes curing moldings by syringe.Do not see suppuration after the implantation and ooze out good biocompatibility unusually.Postoperative alkaline phosphatase enzymatic reversion in 90 days normal level, material are implanted top layer, 2 week back and are degraded, the as seen new bone forming of material internal, and material degradation and new bone are alternative very obvious after 3 months, and material is degraded substantially fully and is also substituted by new bone after 12 months.
Embodiment 18:
Get 1g P (EDP-BPGF/PEO400,1/1) unsaturated polyphosphate (Mw=5490g/mol,), NVP mixes with the 0.7g linking agent, adds the 0.8g beta-calcium phosphate, after 0.7g sodium-chlor (particle diameter 100～200 μ m) mixes, add 0.003g benzoyl peroxide and 0.001g N, the N-dimethyl-p-toluidine joins in the syringe after fully stirring evenly, by syringe composition is expelled to the damaged place of rabbit femoral, about 15 minutes curing moldings.Do not see suppuration after the implantation and ooze out good biocompatibility unusually.Postoperative alkaline phosphatase enzymatic reversion in 90 days normal level, material are implanted top layer, 2 week back and are degraded, the as seen new bone forming of material internal, and material degradation and new bone are alternative very obvious after 2 months, and material is degraded substantially fully and is also substituted by new bone after 8 months.
Claims (8)
1. biodegradable unsaturated polyphosphate, its general structure is as follows:
Wherein R is one of H or following groups: alkoxyl group, aliphatic secondary amino group, phenoxy group or phenylamino;
M
1Be ethylidene or propylidene;
M
2Be one of following groups: ethylidene, propylidene, isopropylidene, 1,2-dimethyl ethylidene, 2-methyl-propylidene, the inferior tertiary butyl, pentylidene, hexylidene, inferior heptyl, 2,2-dimethyl propylidene, octylene, phenylene, benzylidene, naphthylidene and phenanthrylene, inferior pyrryl, furylidene, inferior thiophene phenyl, pyridylidene, inferior pyrimidyl, polyoxyethylene groups, polyoxypropylene base;
X 〉=1, y 〉=0; N is 1～5000.
2. according to the biodegradable unsaturated polyphosphate of claim 1, the said alkoxyl group of R is: methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy or tert.-butoxy;
Said aliphatic secondary amino group is: methylamino-, ethylamino, third amino, isopropylamino, n-butyl amine base or uncle's fourth amino.
3. the preparation method of the said biodegradable unsaturated polyphosphate of claim 1 is as follows:
(1) preparation of reactant II
Reactant II structural formula is as follows: M wherein
1Be ethylidene or propylidene;
Fumaric acid and propylene oxide or oxyethane are joined in the pressure reaction still simultaneously with mol ratio 1.0: 1.0～1.0: 1.5 and catalyzer, and catalyzer is one of following compounds: pyridine, pyrroles, triethylamine, trolamine, Tetrabutyl amonium bromide, Dodecyl trimethyl ammonium chloride, Trimethyllaurylammonium bromide, palmityl trimethyl ammonium chloride, cetyl trimethylammonium bromide, octadecyl trimethyl ammonium chloride; The molar percentage of catalyst consumption and fumaric acid consumption is: 0.1%～5%; 40 ℃～80 ℃ stirring reactions of temperature control when treating that the still internal pressure drops to 0.1MPa～0.25MPa gradually, continue to be warming up to 80 ℃～110 ℃, keep this thermotonus 0.5～2 hour; After reaction was finished, unreacted propylene oxide or oxyethane were removed in air distillation, promptly get reactant II;
(2) preparation of unsaturated polyphosphate
At first reactant II and diol compound are joined in the reactor after being dissolved in inert solvent x/y=1/0～1000 in molar ratio, start agitator and add acid binding agent, the acid binding agent consumption is (x+y)～10 (x+y) moles; The dichloro-phosphoric acid ester of x+y mole is dissolved in the inert solvent, slowly is added drop-wise in the above-mentioned reaction mixture of refrigerative, reacted under low temperature or the room temperature 0.01～2 hour, temperature rising reflux is 0.5～36 hour again; Reaction is cooled to room temperature after finishing, and removes by filter the salt that generates in the reaction.Underpressure distillation removes and desolvates, and product is dissolved in non-aqueous solvent: in ether, methylene dichloride, trichloromethane, the tetrachloromethane, the alkalescence washing is washed to neutrality again; After the organic layer drying, splash under stirring fast in non-solvent such as sherwood oil, hexanaphthene, the whiteruss, be settled out polymkeric substance, precipitation process can repeat repeatedly.Last vacuum-drying is removed organic solvent and is obtained the unsaturated polyphosphate that structural formula is I.
4. according to the preparation method of claim 3, the structural formula of the said diol compound of step (2) is as follows:
HO-M
2-OH
M
2Be one of following groups: ethylidene, propylidene, isopropylidene, 1,2-dimethyl ethylidene, 2-methyl-propylidene, the inferior tertiary butyl, pentylidene, hexylidene, inferior heptyl, 2,2-dimethyl propylidene, octylene, phenylene, benzylidene, naphthylidene and phenanthrylene, inferior pyrryl, furylidene, inferior thiophene phenyl, pyridylidene, inferior pyrimidyl, polyoxyethylene groups, polyoxypropylene base;
The said dichloro-phosphate ester structure of step (2) formula is as follows:
R is one of H or following groups: alkoxyl group, aliphatic secondary amino group, phenoxy group or phenylamino; Alkoxyl group is: methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy or tert.-butoxy; Aliphatic secondary amino group is: methylamino-, ethylamino, third amino, isopropylamino, n-butyl amine base or uncle's fourth amino;
The said acid binding agent of step (2) for the compound that can absorb byproduct hydrogen chloride is: triethylamine, Trimethylamine 99, aniline, pyridine, aminopyridine or 4-Dimethylamino pyridine;
The said inert solvent of step (2) is: methylene dichloride, trichloromethane, tetracol phenixin or 1,2-ethylene dichloride.
5. directly be injected into the application method of therapentic part as medicament slow release preparation according to the said biodegradable unsaturated polyphosphate of claim 1: with following each component: the 1. unsaturated polyphosphate of structure shown in the formula I; 2. can with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure, account for 5～95% of medicament slow release system total mass; 3. can cause or auxiliary free radical thermal initiator or the light trigger that causes the covalent cross-linking reaction, account for 0.05～5% of medicament slow release system total mass; 4. biologically active drug accounts for 0.1～95% of delivery systme total mass, is mixed into the uniform fluid composition, is injected into therapentic part with the direct filling of this fluid composition or with syringe.Utilize the crosslinked of body temperature initiated polymerization thing, in-situ solidifying forms the medicament slow release system; Or utilize light directly to see through tissue such as integumentary musculature or light is incorporated into the photo-crosslinking curing of therapentic part initiated polymerization thing via optical fiber.
6. according to the application method of claim 5, described 2. component is said can be with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure: N-vinyl pyrrolidone, vinylbenzene, Vinylstyrene; Esters of acrylic acid: methyl acrylate, ethyl propenoate, vinylformic acid 2-hydroxyl ethyl ester, methyl methacrylate, Jia Jibingxisuanyizhi or methacrylic acid 2-hydroxyl ethyl ester; Fumaric acid esters: monomethyl fumarate, monomethyl ester, dimethyl fumarate, DEF or fumaric acid two (2-hydroxypropyl) ester; Maleic acid ester class: monomethyl maleate, ethyl maleate, dimethyl maleate, ethyl maleate or toxilic acid two (2-hydroxypropyl) ester; Itaconic ester class: dimethyl itaconate, diethyl itaconate or methylene-succinic acid dipropyl; Acrylic amide: acrylamide, N hydroxymethyl acrylamide, Methacrylamide or N,N methylene bis acrylamide; Macrogol ester class: polyalkylene glycol acrylate ester or methacrylic acid macrogol ester;
The said free radical thermal initiator that can cause or assist the initiation covalent cross-linking to react of described 3. component is: azo-initiator: Diisopropyl azodicarboxylate or 2,2'-Azobis(2,4-dimethylvaleronitrile); Organic peroxy class: benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid, peroxide tert pivalate ester, di-isopropyl peroxydicarbonate or di-cyclohexylperoxy dicarbonate; Inorganic peroxy class initiator: Potassium Persulphate or ammonium persulphate; Oxidation-reduction class initiator: oxygenant is hydrogen peroxide, persulphate, benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid or peroxide tert pivalate ester, and reductive agent is Fe
2+, Cu
+, NaHSO
3, Na
2S
2O
3, trolamine, N, accelerine, N, N-dimethyl-p-toluidine, oxalic acid, glucose or cobalt naphthenate;
The said free radical photo-initiation that can cause or assist the initiation covalent cross-linking to react of described 3. component is: Diisopropyl azodicarboxylate, methyl vinyl ketone, st-yrax, benzophenone, fluorescein, eosin, Benzoin ethyl ether, 2,2-diethoxy acetophenone, camphorquinone, Alpha-hydroxy isopropyl benzene ketone, Alpha-hydroxy phenylcyclohexane ketone, 2-methyl-4 '-methylthio group-2-morpholinyl Propiophenone or 2,4-diethyl thiazolone;
Described said 4. biologically active substance is: anti-infective: amoxycilline Trihydrate bp, ceftriaxone, cefuroxime axetil, cilastatin, ceftazime, mupirocin, paraxin, clindamycin, tsiklomitsin, gentamicin, Ciprofloxacin, levofloxacin, clotrimazole, fluconazole, Terbinafine, itraconazole, stavudine, KETOKONAZOL, azithromycin, clarithromycin, erythromycin, aztreonam, imipenum, the vazadrine, Rifampin, chloroquine, Pyrimethamine hcl, dapsone, Atovaquone, acyclovir, Indinavir, lamivudine, viracept see nelfinaivr, valacyclovir or Cymevan; Antineoplastic agent: carboplatin, cis-platinum, carmustine, methotrexate, 5 FU 5 fluorouracil, gemcitabine, Coserelin, Leuprolide, tamoxifen, rIL-2, taxol, interleukin-2, interferon alpha, tretinoin, bleomycin, dactinomycin, daunorubicin, Zorubicin, mitomycin, vinealeucoblastine(VLB) or vincristine(VCR); Treatment diabetes medicament: metformin, insulin human, troglitazone, acarbose, Glipizide, glimepiride, voglibose, Insulin lispro, Glyburide or rosiglitazone etc.; Biotechnological formulation: transforming growth factor-beta, fibroblast growth factor, nerve growth factor, tumor necrosis factor-alpha and β, somatotropin releasing factor, pHGF, insulin-like growth factor, bone morphogenetic protein 1～7 or thyrocalcitonin.
7. according to the application method of the said biodegradable unsaturated polyphosphate of claim 1: with following each component: the unsaturated polyphosphate that 1. structure shown in the formula I is arranged as the hard tissue repair packing material; 2. can with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure, account for 5～95% of bone defect repair packing material system total mass; 3. can cause or auxiliary free radical thermal initiator or the light trigger that causes the covalent cross-linking reaction, account for 0.05～5% of bone defect repair packing material system total mass; 4. inorganic component accounts for 0～95% of bone defect repair packing material system total mass; 5. pore-creating agent, the pore-creating agent consumption accounts for 0～90% of gross weight, is mixed into the uniform fluid composition, this fluid composition is directly filled or is injected into therapentic part with syringe; Utilize the crosslinked of body temperature initiated polymerization thing, it is damaged that in-situ solidifying is filled sclerous tissues; Or utilize light directly to see through tissue such as integumentary musculature or light is incorporated into the photo-crosslinking curing of filling position initiated polymerization thing via optical fiber.
8. according to the application method of claim 7, described 2. component is said can be with the vinyl monomer of the poly phosphate generation crosslinking copolymerization of formula I structure: N-vinyl pyrrolidone, vinylbenzene, Vinylstyrene; Esters of acrylic acid: methyl acrylate, ethyl propenoate, vinylformic acid 2-hydroxyl ethyl ester, methyl methacrylate, Jia Jibingxisuanyizhi, methacrylic acid 2-hydroxyl ethyl ester; Fumaric acid esters: monomethyl fumarate, monomethyl ester, dimethyl fumarate, DEF, fumaric acid two (2-hydroxypropyl) ester; Maleic acid ester class: monomethyl maleate, ethyl maleate, dimethyl maleate, ethyl maleate, toxilic acid two (2-hydroxypropyl) ester; Itaconic ester class: dimethyl itaconate, diethyl itaconate, methylene-succinic acid dipropyl; Acrylic amide: acrylamide, N hydroxymethyl acrylamide, Methacrylamide, N,N methylene bis acrylamide; Macrogol ester class: polyalkylene glycol acrylate ester; The methacrylic acid macrogol ester;
The said free radical thermal initiator that can cause or assist the initiation covalent cross-linking to react of described 3. component is: azo-initiator: Diisopropyl azodicarboxylate or 2,2'-Azobis(2,4-dimethylvaleronitrile); Organic peroxy class: benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid, peroxide tert pivalate ester, di-isopropyl peroxydicarbonate or di-cyclohexylperoxy dicarbonate; Inorganic peroxy class initiator: Potassium Persulphate, ammonium persulphate; Oxidation-reduction class initiator: oxygenant is hydrogen peroxide, persulphate, benzoyl peroxide, isopropyl benzene hydroperoxide, t-butyl hydrogen peroxide, dicumyl peroxide, di-tert-butyl peroxide, dilauroyl peroxide, the special butyl ester of peroxidation phenylformic acid or peroxide tert pivalate ester; Reductive agent is Fe
2+, Cu
+, NaHSO
3, Na
2S
2O
3, trolamine, N, accelerine, N, N-dimethyl-p-toluidine, oxalic acid, glucose or cobalt naphthenate;
The said free radical photo-initiation that can cause or assist the initiation covalent cross-linking to react of described 3. component is: Diisopropyl azodicarboxylate, methyl vinyl ketone, st-yrax, benzophenone, fluorescein, eosin, Benzoin ethyl ether, 2,2-diethoxy acetophenone, camphorquinone, Alpha-hydroxy isopropyl benzene ketone, Alpha-hydroxy phenylcyclohexane ketone, 2-methyl-4 '-methylthio group-2-morpholinyl Propiophenone or 2,4-diethyl thiazolone;
The said inorganic component of described 4. component is: calcium salt: hydroxyapatite, calcium deficiency type hydroxyapatite, alpha-calcium phosphate, beta-calcium phosphate, tetracalcium phosphate, secondary calcium phosphate, dicalcium phosphate dihydrate, octocalcium phosphate, five water octocalcium phosphate, monocalcium phosphate, calcium hydroxide, lime carbonate, Calcium hydrogen carbonate, calcium chloride, calcium lactate, calglucon, calcium stearate, citric acid tricalcium, the lactic acid calglucon, caoxalate, anhydrous calciumsulphate, calcium sulphate hemihydrate, terra alba or Calucium Silicate powder; Phosphoric acid salt: above-mentioned calcium phosphate salt, sodium phosphate, Sodium phosphate dibasic, SODIUM PHOSPHATE, MONOBASIC, potassiumphosphate, dipotassium hydrogen phosphate, potassium primary phosphate, ammonium phosphate, Secondary ammonium phosphate or primary ammonium phosphate;
The said pore-creating agent of described 5. component has water miscible following material: sodium-chlor, glucose, seminose, Xylitol, sucrose, Repone K, polyoxyethylene glycol, glycol ether, calcium chloride or yellow soda ash for having certain particle diameter.
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