CN1299775C - Injectable pharmaceutical slow-release carrier and preparation method thereof - Google Patents
Injectable pharmaceutical slow-release carrier and preparation method thereof Download PDFInfo
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- CN1299775C CN1299775C CNB2004100133404A CN200410013340A CN1299775C CN 1299775 C CN1299775 C CN 1299775C CN B2004100133404 A CNB2004100133404 A CN B2004100133404A CN 200410013340 A CN200410013340 A CN 200410013340A CN 1299775 C CN1299775 C CN 1299775C
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Abstract
The present invention relates to liquid unsaturated polyester resin which can be injected directly, is solidified in vivo and is used as medicinal slow-release material. The existing medicinal slow-release material has the defects that the medicinal slow-release material is solid at normal temperature, and operations are needed to implant solid slow-release medicinal pills into afflicted parts. In the present invention, a high vacuum melting polymerization method is adopted, diatomic fatty acid, unsaturated diacid or diacid anhydride and diatomic alcohol are copolymerized so as to synthesize an unsaturated polyester oligomer and prepare the unsaturated polyester resin which has the advantages of certain fluidity or rapid solidification at body temperature, good slow-release performance for hydrophilic medicine, degradability and absorbability in vivo and good biocompatibility. The liquid unsaturated polyester resin has the characteristics of direct injection, rapid solidification at body temperature and high mechanical strength. The liquid unsaturated polyester resin also has the characteristic of no need of operations on the partial administration of tumor chemotherapy by implanting a slow-release preparation containing chemotherapeutic medicine.
Description
Technical field
The present invention relates to and adopt binary fatty acid, unsaturated dibasic acid or dibasic acid anhydride and dihydroxylic alcohols copolymerization, but preparation is used for the interior solidified liquid unsaturated polyester resin of direct injection, body and the chemical synthesis process thereof of slow releasing carrier of medication.
Technical background
Be divided into two big classes as the biodegradable substrate of slow releasing carrier of medication, a class is natural macromolecular material such as albumin, gelatin, modification of polysaccharides etc.Another kind of is the macromolecular material of chemosynthesis, as polyester, comprises polylactic acid (PLA), Vicryl Rapide (PLGA) etc.; Poly-anhydride (LangerR:Biomaterials in drug delivery and tissue engineering:one laboratory ' sexperience. Acc Chem Res, 2000,33 (2): 94-101), as two pairs of carboxyl phenoxypropanes and decanedioic acid copolymer (PCPP-SA), fatty acid and decanedioic acid copolymer (PFAD-SA); Poe etc.These material good biocompatibilities can be degraded and absorbed in the body.Be used for by FDA approval at present that the Biodegradable material of biomedical sector is most to be polyesters, as
PLA (Coombers.G.A.; Major.; Wood.M; Biom, 1998,19,1073-1079) PLGA (Schakenraad, J.M.Nierwenhui, P.:J.Biomed Mat.Res, 1989,23,1271-1278) etc.The inventor herein had once applied for patent of invention: " the poly-anhydride and the synthetic method thereof that are used for slow releasing carrier of medication ", application number is: 200310111439.3.Fine vacuum melt-polycondensation is adopted in this invention, and the important intermediate dimeric dibasic acid that obtains with the Vegetable oil lipoprotein deep processing (Dimer Acid, DA) and C
11-16Fat diacid is a monomer, has synthesized the poly-anhydride material of serial different monomers proportioning with the fine vacuum melt-polycondensation.Yet above-described medicament slow release material is high molecular polymer (weight average molecular weight 1-4 ten thousand), be solid under the room temperature, common shortcoming is after surgery solid slow release pill to be implanted lesions position, have any problem for some diseases that are easy to recur such as cerebral glioma, osteomyelitis secondary drug treatment, its application is restricted.The injectable medicament slow release material of several class I liquid Is has appearred recently, as slow release Emulsion (A.T.Florence, D.Whitehill, Int.J.Pharm.11 (1982) 277-308). liposome (A.Sharma, U.S.Sharma, Int.J.Pharm.154 (1997) 123-140). degradable microsphere (A.Shendrova, T.G.Burke, S.P.Schwendeman, Stabilization, Pharm.Res.14 (10) (1997) 1406-1414), micelle (X.Zhang, J.K.Jackson, H.M.Bert, Int.J.Pharm.132 (1996) 195-206.) and hydrogel (J.A.Hubbell, J.Control.Release 39 (1996) 305-313) yet. these pharmaceutical carriers or discharge because of being difficult to fixed point, or because of slow release effect poor, or because of toxicity big, or environment for use required harsh and its application is restricted.
The present invention has synthesized the new slow releasing carrier of medication of a class: unsaturated polyester material, this material is oligomer (weight average molecular weight 1～5,000) when uncrosslinked for general medicament slow release material, after adding cross-linking agent certain flowability is arranged, character with unsaturated polyester (UP): can be under body temperature, rapid crosslinking curing becomes crosslinked high polymer solid in 5～30min, also has medicament slow release performance, biocompatibility and degradation property preferably.
The poly-anhydride material of mentioning in the patent of invention of this unsaturated polyester resin with respect to the above-mentioned said application once of inventor herein, poly-anhydride contains anhydride group, and molecular weight is big (weight average molecular weight 10000-40000), is solid under the room temperature, and unparalleled key can not be crosslinked.And unsaturated polyester (UP) of the present invention belongs to polyesters, contains ester group, weight average molecular weight 1000-5000, and relative molecular weight is less, is can flowing liquid, and main chain contains two keys and can be used for crosslinkedly, becomes solid after crosslinked; Therefore unsaturated polyester resin has essential distinction with respect to poly-anhydride material on structure and performance.This research related content has not yet to see report, has great practical value.
Summary of the invention
At being solid under the existing slow releasing carrier of medication room temperature, need operation solid slow release pill to be implanted the defective of lesions position.
A kind of with in dihydroxylic alcohols and the following binary acid of the present invention: decanedioic acid (Sebacic acid, SA), dodecanedioic acid (Laurel diacid, Dodecanedioic Acid, DDDA), tridecandioic acid (brassylic acid, Brassylic Acid, BA), tetracosandioic acid (Tetradecandioic Acid, TA), pentacosandioic acid (Pentadecandioic Acid, PA), hexadecandioic acid (hexadecane diacid) (HexadecanedioicAcid, HA) anhydride), fumaric acid (fumaric acid) or maleic anhydride (maleic anhydride) are monomer, adopt the synthetic unsaturated polyester ester oligomer of fine vacuum melt phase polycondensation, with dimeric dibasic acid, oleic acid, the N-vinyl pyrrolidone, isodecyl acrylate, one or more materials in the oleic acid glyceryl linoleate are cross-linking agent, and being intended to prepare has certain flowability, or it is quick-setting under the body temperature, hydrophilic medicament had good sustained release performance, degradable unsaturated polyester resin that absorb and good biocompatibility in vivo.
The structural formula of this unsaturated polyester (UP) is as follows:
X=8 in the formula～14, y=2～4, m is the molal quantity of poly-maleic anhydride-binary alcohol esters or fumaric acid-binary alcohol esters chain link, n is the molal quantity of the chain link of saturated dicarboxylic acids-binary alcohol esters, m/n=1/5～5/1.
Concrete technology of preparing of the present invention is as follows:
Synthesizing of dibasic acid anhydride
With acetic anhydride respectively with following seven kinds of binary acid in a kind of: decanedioic acid (Sebacic acid, SA), heneicosanedioic acid (Undecanedioic Acid, UA), dodecanedioic acid (Laurel diacid, Dodecanedioic acid, DDDA), tridecandioic acid (brassylic acid, Brassylic Acid, BA), tetracosandioic acid (Tetradecanedioic Acid, TA), pentacosandioic acid (Pentadecanedioic Acid, PA), (Hexadecanedioic Acid HA) 1: 2 in molar ratio～5 is respectively charged in the container of nitrogen protection hexadecandioic acid (hexadecane diacid); 140～200 ℃ of back flow reaction 15～100 minutes are cooled to 60～100 ℃; Acetic anhydride that pressure reducing and steaming does not react completely and by-product acetic acid, product dissolves with dichloromethane, petroleum ether or cyclohexane extraction precipitation, sand core funnel filters, and uses a kind of washing of absolute ether, ethyl methyl ether, oxolane, and vacuum drying obtains dibasic acid anhydride;
Synthesizing of unsaturated polyester resin
The proportioning of a kind of m/n=1/5-5/1 in molar ratio in maleic anhydride or fumaric acid and the reactions steps 1. synthetic dicarboxylic anhydrides is mixed, be respectively charged in the polymerization pipe with 1.1 * (m+n) moles dihydroxylic alcohols again, place silicone oil bath, electromagnetic agitation; Be warming up to 170 ℃～200 ℃ reactions 1.5 hours, be cooled to 80 ℃, vacuum decompression to 30～50Pa is taken moisture away; 0.5 be warming up to 170 ℃ of melt polymerizations after hour 1.0 hours; Logical nitrogen was 10～20 seconds every 5～20 minutes, and evacuation again obtains the liquid unsaturated polyester resin of certain viscosity; The synthetic reaction formula of unsaturated polyester resin is as follows:
X=x=8 in the formula～14, y=2～4, m is fumaric molal quantity, n is the molal quantity of saturated dicarboxylic acid anhydride, m/n=1/5～5/1, fumaric acid can replace with maleic anhydride;
3. be one of following firming agent of 0.3%～1.0% with liquid unsaturated polyester (UP) and mass percent: methyl ethyl ketone peroxide, benzoyl peroxide; Mass percent is one of following curing accelerator of 0.1%～0.4%: cobalt naphthenate or triethanolamine; Mass percent is one of following cross-linking agent of 5%～30%: dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate, oleic acid glyceryl linoleate, 2-EHA and the medicine that will sneak into mix in container, be filled into syringe, can inject focus.
Characterize:
All synthetic unsaturated polyester resins all characterize with FT-IR, GPC, and with determination of ubbelohde viscometer viscosity (chloroform is a solvent, measure temperature 23 ℃).Experimental result shows the structure and theoretical expect consistent of all synthetic polymers.All synthetic polymers have certain viscosity and flowability, are suitable for injection, can solidify (10-20min) at normal temperatures rapidly after adding an amount of crosslinking and curing agent.The FT-IR spectrogram of all synthetic unsaturated polyester resins is presented at 1713-1735cm
-1Strong unsaturated polyester (UP) C=O stretching vibration characteristic absorption peak is arranged, at 1643cm
-1Unsaturated polyester (UP) C=C stretching vibration characteristic absorption peak is arranged, at 2926cm
-1And 2854cm
-1C-H stretching vibration absworption peak is arranged and at 1043cm
-1C-O stretching vibration absworption peak is arranged.At 3510cm
-1About weak-COOH absworption peak show residual in the polymer-COOH seldom.The GPC test result shows that the weight average molecular weight of synthetic unsaturated polyester resin is 1000～5000.
Performance:
1. it is curing system that normal temperature cure performance is selected methyl ethyl ketone peroxide (or cyclohexanone peroxide)-cobalt naphthenate system or benzoyl peroxide-triethanolamine system, a kind of in dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate and the oleic acid glyceryl linoleate is cross-linking agent, gathers the cure test of anhydride modified unsaturated polyester resin under the room temperature.The unsaturated polyester resin (70%-95%) of a certain amount of firming agent (0.3%～1.0%) and cross-linking agent (5%～30%) and modification is mixed on surface plate, leave standstill.(5～30min) resin crosslinks gelations, and hardening gradually become strong and tough material after a period of time.
2. external degradation performance
Liquid resin and a certain amount of firming agent (0.3%-1.0%) and cross-linking agent (5%-30%) are mixed on surface plate, be filled into the 1ml disposable syringe, the 150mg resin injection is gone in the grass tube of diameter 4mm, after the curing grass tube is broken into pieces, taken out crosslinked resin bar.The unsaturated polyester resin bar is placed the 0.1mol/L pH7.4 phosphate buffered solution of 20mL, on 37 ℃ of constant temperature shaking tables, carry out degradation experiment (rotating speed 60rad/min).Take out sample at regular intervals,, put into P with distillation washing sample surfaces
2O
5Dry 24h weighs in the vacuum desiccator, by calculating degradation rate of poor quality before and after the sample degraded.Experimental result shows, the time of gained unsaturated polyester resin bar degraded 80%, and different with forming, do not wait from 20 days to 6 months.
3, medicine-releasing performance
With the ciprofloxacin is model drug, with liquid resin blend with it, add a certain amount of firming agent (0.3%-1.0%) again and cross-linking agent (20%-30%) mixes on surface plate, be filled into 1ml shot device, 150mg medicine carrying resin injection is gone in the grass tube of diameter 4mm, after the curing grass tube is broken into pieces, taken out slow release medicine rod.The medicine rod places the 0.1mol/L of 20mL respectively, in the phosphate buffered solution of pH=7.4, carries out degradation experiment (rotating speed 60rad/min) on 37 ℃ of constant temperature shaking tables.Exchange buffering solution at regular intervals, adopt the absorbance of UV spectroscopic assay release medium at wavelength 271nm place, according to the ciprofloxacin of measuring at 0.1mol/L, the regression equation A=0.27465 ρ-5.133 * 10 of the UV of 271nm place absorption in the phosphate buffered solution of pH=7.4
-4, in the formula: A is an absorbance; ρ is the ciprofloxacin mass concentration; Regression coefficient R=0.999 95; Measure the range of linearity 2.0～30.0 μ g, can calculate the drug level that is released in the buffer solution.
Experimental result shows that medicine does not have burst effect in dispose procedure.The drug release experimental result shows that this slow release medicine rod has good sustained release performance to ciprofloxacin, and the release of medicine is one-level release dynamics feature.Slow release medicine rod did not wait from 20 days to 6 months the release phase of 80% ciprofloxacin, was expected to be applied to as long-acting local implantation preparation the local chemotherapy of long-acting drug treatment of myelitic fixed point and solid tumor.
4, biocompatibility experiment
Preliminary study synthetic medicament slow release material in the subcutaneous histocompatibility of mice and in the subcutaneous degraded and absorbed of mice.The result shows that synthetic medicament slow release material has the favorable tissue compatibility and biodegradable absorption characteristic in vivo as subcutaneous novel embedded material.Fig. 2 has reflected that synthetic material has the favorable tissue compatibility in vivo.
The slow-releasing agent of such macromolecular material and medicine preparation can be implanted lesions position with the method for injection, under body temperature, solidify rapidly in the 5-30min, slow releasing pharmaceutical and final degraded are expected to realize solid tumor, myelitic non-operation or minor operation local sustained release administration chemotherapy then.Can solve must the have an operation problem of implantation, secondary drug treatment difficulty of solid medicament slow release material.The slow-releasing agent of the type macromolecular material and medicine preparation can be implanted lesions position with the method for injection, and body temperature solidifies rapidly down, is expected to realize solid tumor, myelitic non-operation or minor operation local sustained release administration chemotherapy.
Such material than solid medicament slow release material except that general character with suitable drug release rate, degradable metabolism, good biocompatibility, injectable, body temperature curing rapidly down in addition, the characteristics that mechanical strength is high, for the cerebral glioma that is hidden in deeply in the cranial cavity, adopt injection to implant to contain the chemotherapeutics slow releasing preparation and carry out the topical chemotherapy, the tumor resection of need not having major operation, risk are low, the characteristics of the low repeat administration of medical expense but have.For being difficult to carcinoma in late period excision, that conventional treatments is difficult to cure, carry out the topical chemotherapy with injection at lesions position implantation slow release medicament and will become important treatment means.Degradation material solidified rapidly, that mechanical strength is high also is expected to organize backing material as the interim substitute of osseous tissue and other under injectable, the body temperature.The preparation of injectable slow-releasing agent is carried out at normal temperatures, and is most important to the drug effect that keeps thermo-labile medicine example hydrochloric acid amycin.
Description of drawings
Fig. 1 ciprofloxacin-modification cis is found the release rule of structure unsaturated polyester (UP) slow release medicine rod in the 0.1MpH7.4PBS buffer
Abscissa is pharmaceutical release time (natural law), and vertical coordinate is that drug accumulation discharges percentage rate
(a) mol is than cis-butenedioic anhydride: decanedioic acid: ethylene glycol=1: 1: 2.2;
(b) mol is than cis-butenedioic anhydride: decanedioic acid: ethylene glycol=1.5: 0.5: 2.2;
(c) mol is than cis-butenedioic anhydride: decanedioic acid: ethylene glycol=1.75: 0.25: 2.2.
Fig. 2 ciprofloxacin-release the rule of modification syndyotaxy unsaturated polyester (UP) slow release medicine rod in the 0.1MpH7.4PBS buffer
Abscissa is pharmaceutical release time (natural law), and vertical coordinate is that drug accumulation discharges percentage rate
(a) mol is than fumaric acid: decanedioic acid: ethylene glycol=1: 1: 2.2;
(b) mol is than fumaric acid: decanedioic acid: ethylene glycol=1.5: 0.5: 2.2;
(c) mol is than fumaric acid: decanedioic acid: ethylene glycol=1.75: 0.25: 2.2.
The synthetic modified unsaturated polyester material of Fig. 3 (cis-butenedioic anhydride: decanedioic acid: ethylene glycol mol is than=1: 1: 2.2) is implanted subcutaneous 10 days of mice (10 *)
The specific embodiment
Example 1: unsaturated polyester (UP) gathers the synthetic of (maleic anhydride-decanedioic acid-ethylene glycol) (P (MA-SA-GLY)) (cis-butenedioic anhydride: decanedioic acid: ethylene glycol mol is than=1: 1: 2.2) resin:
At φ 2cm, add maleic anhydride 1.96 grams (0.020mol), sebacic anhydride 5.64 grams (0.020mol) in the polymerization pipe of long 20cm, ethylene glycol 2.73 grams (0.044mol) place silicone oil bath with polymerization pipe, electromagnetic agitation.Be warming up to 170 ℃, melt polymerization 90 minutes, logical nitrogen was 15 seconds every 15 minutes.Be cooled to 80 ℃, vacuum decompression is taken moisture away to 30-50Pa, is warming up to 170 ℃ of melt polymerizations after 0.5 hour 1.0 hours; Logical nitrogen was 15 seconds every 15 minutes, again evacuation; Polymerization finishes, and is cooled to 80 ℃, and the adding mass ratio is 30% cross-linking agent isodecyl acrylate 4.43 grams, and cooling obtains the unsaturated polyester resin of certain viscosity.
Synthetic similar as stated above the carrying out of other different monomers quality proportionings.The FT-IR of the unsaturated polyester (UP) of 3 kinds of different proportionings (P (MA-SA-GLY)) and physicochemical property characterize (wherein P represents productive rate) as shown in Table 1.
The FI-IR of table one unsaturated polyester (UP) P (MA-SA-GLY) and ester physicochemical property
| M MA∶M SA∶M GLY | Mw/10 3 | Mn/10 3 | [η] /dL.g -1 | ν IR/cm -1 | ||
| Cis C=C | C＝0 | C-0 | ||||
| 1.00∶1.00∶2.20 1.50∶0.50∶2.20 1.75∶0.25∶2.20 | 3.992 3.212 3.048 | 2.547 2.096 1.674 | 0.17 0.14 0.12 | 1431.49，701.13 1431.70，701.35 1432.51，701.68 | 1716.85 1720.43 1717.89 | 1043.19 1046.81 1046.37 |
Example 2: unsaturated polyester (UP) gathers the synthetic of (fumaric acid-decanedioic acid-ethylene glycol) (P (FA-SA-GLY)) (fumaric acid: decanedioic acid: ethylene glycol mol is than=1: 1: 2.2) resin
At φ 2cm, add fumaric acid (fumaric acid) 2.14 grams (0.020mol), sebacic anhydride 5.64 grams (0.020mol) in the polymerization pipe of long 20cm, ethylene glycol 2.73 grams (0.044mol) place silicone oil bath with polymerization pipe, electromagnetic agitation.Be warming up to 170 ℃, melt polymerization 4 hours, logical nitrogen was 15 seconds every 15 minutes.Be cooled to 80 ℃, vacuum decompression is taken moisture away to 30-50Pa, is warming up to 170 ℃ of melt polymerizations after 0.5 hour 1.0 hours; Logical nitrogen was 15 seconds every 15 minutes, again evacuation; Polymerization finishes, and is cooled to 80 ℃, adds cross-linking agent N-vinyl pyrrolidone 4.43 grams (mass ratio 30%), and cooling obtains the unsaturated polyester resin of certain viscosity.
Synthetic similar as stated above the carrying out of other different monomers quality proportionings.The FT-IR of the unsaturated polyester (UP) of 3 kinds of different proportionings (P (FA-SA-GLY)) and physicochemical property characterize (wherein P represents productive rate) as shown in Table 2.
FI-IR and the physicochemical property of table two unsaturated polyester (UP) P (FA-SA-GLY)
| M FA∶M SA∶M GLY | Mw/10 3 | Mn/10 3 | [η] /dL.g -1 | ν IR/cm -1 | ||
| Trans C=C | C＝0 | C-0 | ||||
| 1.00∶1.00∶2.20 1.50∶0.50∶2.20 1.75∶0.25∶2.20 | 4.791 3.732 3.563 | 3.348 2.472 2.054 | 0.22 0.16 0.14 | 1311.71，970.13 1312.60，971.35 1311.51，970.68 | 1716.85 1720.43 1717.89 | 1043.19 1046.81 1046.37 |
Example 3: unsaturated polyester (UP) gathers the sustained releasing character of ciprofloxacin in (maleic anhydride-decanedioic acid-ethylene glycol) (P (MA-SA-GLY)) resin-ciprofloxacin medicine rod
With the ciprofloxacin is model drug, with liquid resin blend with it, add a certain amount of firming agent (0.3%-1.0%) again and cross-linking agent (5%-30%) mixes on surface plate, be filled into 1ml shot device, 150mg medicine carrying resin injection is gone in the grass tube of diameter 4mm, after the curing grass tube is broken into pieces, taken out slow release medicine rod.The medicine rod places the 0.1mol/L of 20mL respectively, in the phosphate buffered solution of pH=7.4, carries out degradation experiment (rotating speed 60rad/min) on 37 ℃ of constant temperature shaking tables.Exchange buffering solution at regular intervals, adopt the absorbance of UV spectroscopic assay release medium at wavelength 271nm place, according to the ciprofloxacin of measuring at 0.1mol/L, the regression equation A=0.27465 ρ-5.133 * 10 of the UV of 271nm place absorption in the phosphate buffered solution of pH=7.4
-4, in the formula: A is an absorbance; ρ is the ciprofloxacin mass concentration; Regression coefficient R=0.999 95; Measure the range of linearity 2.0～30.0 μ g, can calculate the drug level that is released in the buffer solution.3 kinds of unsaturated polyester (UP)s that different proportionings are formed: the rate of releasing drug of poly-(maleic anhydride-decanedioic acid-ethylene glycol) (P (MA-SA-GLY)) resin is shown in figure one.
Example 4: unsaturated polyester (UP) gathers the sustained releasing character of ciprofloxacin in (fumaric acid-decanedioic acid-ethylene glycol) (P (FA-SA-GLY)) resin-ciprofloxacin medicine rod
With the ciprofloxacin is model drug, with liquid resin blend with it, add a certain amount of firming agent (0.3%-1.0%) again and cross-linking agent (5%-30%) mixes on surface plate, be filled into the 1ml disposable syringe, 150mg medicine carrying resin injection is gone in the grass tube of diameter 4mm, after the curing grass tube is broken into pieces, taken out slow release medicine rod.The medicine rod places the 0.1mol/L of 20mL respectively, in the phosphate buffered solution of pH=7.4, carries out degradation experiment (rotating speed 60rad/min) on 37 ℃ of constant temperature shaking tables.Exchange buffering solution at regular intervals, adopt the absorbance of UV spectroscopic assay release medium at wavelength 271nm place, according to the ciprofloxacin of measuring at 0.1mol/L, the regression equation A=0.27465 ρ-5.133 * 10 of the UV of 271nm place absorption in the phosphate buffered solution of pH=7.4
-4, in the formula: A is an absorbance; ρ is the ciprofloxacin mass concentration; Regression coefficient R=0.99995; Measure the range of linearity 2.0～30.0 μ g, can calculate the drug level that is released in the buffer solution.3 kinds of unsaturated polyester (UP)s that different proportionings are formed: the rate of releasing drug of poly-(fumaric acid-decanedioic acid-ethylene glycol) (P (FA-SA-GLY)) resin as shown in Figure 2.
Example 5: unsaturated polyester (UP) gathers (maleic anhydride-decanedioic acid-ethylene glycol) (P (MA-SA-GLY)) resin at the subcutaneous biocompatibility experiment of mice
According to " State Standard of the People's Republic of China's one medical apparatus and instruments biological assessment " (GB/T16886.1-1997) the 6th part, implant back local response test method, poly-(maleic anhydride-decanedioic acid-ethylene glycol) P (MA-SA-GLY) resin of unsaturated polyester (UP) is estimated at the subcutaneous biocompatibility of mice.
Adopt injection, poly-(maleic anhydride-decanedioic acid-ethylene glycol) (P (MA-SA-GLY)) the resin 150mg of unsaturated polyester (UP) is added that firming agent aseptic injection implantation right side of mice forelimb oxter is subcutaneous, resin is solidified into lump (5～20 minutes) very soon.Raise certain hour post-tensioning neck and put to death mice, take out material implant site tissue rapidly, formalin fixed with 10%.Sample is done crown section, and unsaturated polyester resin and surrounding tissue thereof are together downcut, and uses paraffin embedding, microtome is thinly sliced, haematoxylin-Yihong (HE) dyeing, microscopically is observed the inflammatory reaction of implantation region tissue, and the response feature of acute and chronic phase is described.Use the OlympusBH2 camera to take histology pictures, Kodak2000 colour film.At the 10th day of subacute stage, microscopically was observed, the inflammatory reaction that unsaturated polyester resin causes low weight (Fig. 3).Occur the infiltration of a small amount of neutrophilic granulocyte around the unsaturated polyester resin, accompany nuclear pyknosis simultaneously, downright bad feature such as cracked grade, hemorrhage and edema disappears gradually, only can see in a few regions.The above-mentioned reaction that the unsaturated polyester resin material causes is light than gelfoam.
Claims (3)
1. an injectable slow releasing carrier of medication is characterized in that, is one of following firming agent of 0.3%～1.0% by unsaturated polyester (UP) and mass percent: methyl ethyl ketone peroxide, benzoyl peroxide; Mass percent is one of following curing accelerator of 0.1%～0.4%: cobalt naphthenate or triethanolamine; Mass percent is one of 5%～30% following cross-linking agent: dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate, oleic acid glyceryl linoleate are formulated; The structural formula of unsaturated polyester (UP) is as follows:
Weight average molecular weight is: 1～5,000, and x=8 in the formula～14, y=2～4, m is the molal quantity of maleic acid-binary alcohol esters or fumaric acid-binary alcohol esters chain link, n is the molal quantity of the chain link of saturated dicarboxylic acids-binary alcohol esters, m/n=1/5～5/1.
2. the preparation method of the described injectable slow releasing carrier of medication of claim 1 is characterized in that: concrete preparation process is as follows:
1. with acetic anhydride respectively with following seven kinds of binary acid in a kind of: decanedioic acid, heneicosanedioic acid, dodecanedioic acid, tridecandioic acid, tetracosandioic acid, pentacosandioic acid, hexadecandioic acid (hexadecane diacid) 1: 2 in molar ratio～5 is respectively charged in the container of nitrogen protection; 140～200 ℃ of back flow reaction 15～100 minutes are cooled to 60～100 ℃; Acetic anhydride that pressure reducing and steaming does not react completely and by-product acetic acid, product dissolves with dichloromethane, and petroleum ether or cyclohexane extraction precipitation are filtered, and use a kind of washing of absolute ether, ethyl methyl ether, oxolane, and vacuum drying obtains dibasic acid anhydride;
2. the proportioning of a kind of m/n=1/5 in molar ratio～5/1 in maleic acid or fumaric acid and the 1. synthetic dicarboxylic anhydride of reactions steps is mixed, be respectively charged in the polymerization pipe with 1.1 * (m+n) moles dihydroxylic alcohols again, place silicone oil bath, electromagnetic agitation; Be warming up to 170 ℃～200 ℃ reactions 1.5 hours, be cooled to 80 ℃, vacuum decompression to 30～50Pa is taken moisture away; 0.5 be warming up to 170 ℃ of melt polymerizations after hour 1.0 hours; Logical nitrogen was 10～20 seconds every 5～20 minutes, again evacuation; Obtain the liquid unsaturated polyester resin of certain viscosity; The synthetic reaction formula of unsaturated polyester resin is as follows:
X=8 in the formula～14, y=2～4, m is maleic acid or fumaric molal quantity, n is the molal quantity of saturated dicarboxylic acid anhydride, m/n=1/5～5/1;
3. be one of following firming agent of 0.3%～1.0% with liquid unsaturated polyester (UP) and mass percent: methyl ethyl ketone peroxide, benzoyl peroxide; Mass percent is one of following curing accelerator of 0.1%～0.4%: cobalt naphthenate or triethanolamine; Mass percent is one of 5%～30% following cross-linking agent: dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate, oleic acid glyceryl linoleate, 2-EHA and the medicine that will sneak into mix in container, cooling, be filled into syringe, can inject focus.
3. but the described injectable slow releasing carrier of medication of claim 1 application in the solidified slow releasing carrier of medication in preparation direct injection, body.
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| JPH07138182A (en) * | 1993-11-12 | 1995-05-30 | Toyobo Co Ltd | Sustained release type pharmaceutical preparation applicable to mucous membrane of oral cavity |
| WO2001078687A1 (en) * | 2000-04-18 | 2001-10-25 | Peptron Inc. | Injectable sustained release pharmaceutical composition and processes for preparing the same |
-
2004
- 2004-06-23 CN CNB2004100133404A patent/CN1299775C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH07138182A (en) * | 1993-11-12 | 1995-05-30 | Toyobo Co Ltd | Sustained release type pharmaceutical preparation applicable to mucous membrane of oral cavity |
| WO2001078687A1 (en) * | 2000-04-18 | 2001-10-25 | Peptron Inc. | Injectable sustained release pharmaceutical composition and processes for preparing the same |
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| Publication number | Publication date |
|---|---|
| CN1593661A (en) | 2005-03-16 |
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