CN100423780C - 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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- CN100423780C CN100423780C CNB2004100133391A CN200410013339A CN100423780C CN 100423780 C CN100423780 C CN 100423780C CN B2004100133391 A CNB2004100133391 A CN B2004100133391A CN 200410013339 A CN200410013339 A CN 200410013339A CN 100423780 C CN100423780 C CN 100423780C
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Abstract
The present invention relates to a liquid polyacid anhydride-unsaturated polyester block polymer which can be directly injected, is solidified in vivo and is used for 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, and diatomic alcohol, maleic diacid anhydride or fumaric diacid and C<10-16> diacid anhydride are used as raw materials so as to prepare a polyacid anhydride-unsaturated polyester block polymer oligomer. The liquid polyacid anhydride-unsaturated polyester block polymer has the characteristics of direct injection, rapid solidification at body temperature and high mechanical strength. The liquid polyacid anhydride-unsaturated polyester block polymer 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 and dihydroxylic alcohols copolymerization, preparation is used to do the injectable of slow releasing carrier of medication, the poly-anhydride of solidified liquid-unsaturated polyester (UP) block polymer and chemical synthesis process in the body.
Technical background
Be divided into two big classes as the biodegradable substrate of medicament slow release material, a class is natural macromolecular material such as albumin, gelatin, modification of polysaccharides etc.Another kind of is the macromolecular material of chemosynthesis, as poly-anhydride, polyester etc.Poly-anhydride is Langer of Massachusetts Institute Technology etc. early 1980s (Rosen HB) etc.: Bioerodible polyanhydrides for controlled drugdelivery.Biomaterials, 1983,4:131-133) the novel synthesising biological degradable high polymer material of a class of Fa Xianing, because it has excellent biological compatibility, unique surface erosion (surface erosion) degradability, degradation speed is adjustable and excellent properties such as workability, be applied very soon in fields, medical science forward position such as medicine sustained release.Particularly wherein one birds of the same feather flock together that [P (CPP-SA)] copolymer is as the novel matrix type medicine of class sustained release material for anhydride poly-[1, two (to the carboxyl phenoxy group) propane-decanedioic acid of 3-], the systematic study of recent two decades is gone through in front and back, its matrix type controlled release tablet Gliadel
TMObtained postoperative adjuvant chemotherapy (Langer R:Biomaterials in drug delivery and tissue engineering:one laboratory ' the s experience.Acc Chem Res that the FDA approval is applied to recur glioblastoma multiforme in 1996,2000,33 (2): 94-101).And the cylindrical controlled release medicine rod Septacin that poly-(erucic acid dimer-decanedioic acid) [P (EAD-SA)] copolymer of another anhydride of birdsing of the same feather flock together and gentamycin are formed
TMBe used for the treatment of osteomyelitis (the Stephens D etc.: Investigation of the in vitro release of gentamicin froma polyanhydride matrix.J Control Release, 2000:63 (3): 305-317) that entered the clinical experiment stage.。These material good biocompatibilities can be degraded and absorbed in the body.The Biodegradable material that is used for biomedical sector by FDA approval also has polyesters at present, as PLA (Coombers A.G.A.; Major D.; WoodJ.M.; Biom, 1998,19,1073-1079).The inventor herein had once applied for: " the poly-anhydride and the synthetic method thereof that are used for slow releasing carrier of medication ", number of patent application 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 the high molecular polymer of 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 adopts the method for melt polycondensation, with dihydroxylic alcohols, maleic anhydride (or fumaric acid) is that raw material has synthesized the slow releasing carrier of medication that a class is suitable for injecting: the poly-anhydride of thick liquid nano-unsaturated polyester (UP) block polymer under the room temperature, molecular weight is 4000-10000.
This synthetic method is not the big high polymer of first synthetic molecular weight for general medicament slow release material, but the little oligomer of first synthetic molecular weight, oligomer is a liquid with small viscosity after adding diluent, is suitable for injection.Should gather anhydride-unsaturated polyester (UP) block polymer for the poly-anhydride material of mentioning in the patent of invention of the above-mentioned said application once of inventor herein, poly-anhydride-unsaturated polyester (UP) block polymer belongs to poly-anhydride modified polyesters, both contained anhydride group, contain ester group again, molecular weight less (weight average molecular weight 4000-10000), be can flowing liquid, main chain contains two keys and can be used for crosslinkedly, becomes solid after crosslinked; Can be under body temperature, rapid crosslinking curing becomes crosslinked high polymer solid in 5～30min.And poly-anhydride material only 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.On synthetic method; though all be the fine vacuum melt-polycondensation of usefulness; but condition is also inequality therebetween: poly-anhydride-when the unsaturated polyester (UP) block polymer is synthetic; earlier synthetic unsaturated polyester (UP) and poly-anhydride oligomer; mixture with unsaturated polyester (UP) and poly-anhydride oligomer is warming up to 170 ℃ of vacuum fusion polymerizations 1.0 hours again, during nitrogen protection.Polymerization finishes, and is cooled to 80 ℃, adds the cross-linking agent of mass ratio 30%, and cooling obtains the poly-anhydride-unsaturated polyester (UP) block polymer of certain viscosity.And poly-anhydride does not use oligomer when synthetic, but with monomer mixture at 170 ℃ of-200 ℃ of vacuum decompressions to 30-50Pa reaction 1.5 hours, during nitrogen protection.Polymerization finishes, and is cooled to room temperature, obtains macromolecule product.This research related content has not yet to see report, has great practical value.
Summary of the invention
At being solid under the existing medicament slow release material room temperature, need operation solid slow release pill to be implanted the defective of lesions position.
The present invention adopts the method for melt polycondensation, is the synthetic unsaturated polyester ester oligomer of raw material with dihydroxylic alcohols, maleic anhydride (or fumaric acid), with C
10-16Dicarboxylic anhydride is the synthetic poly-anhydride oligomer of raw material, again with unsaturated polyester ester oligomer and poly-anhydride oligomer melt polycondensation, obtains poly-anhydride-unsaturated polyester (UP) block polymer oligomer.As the diluent and the cross-linking agent that gather anhydride-unsaturated polyester (UP) block polymer oligomer, be intended to prepare the poly-anhydride-unsaturated polyester (UP) block polymer material that is used for slow releasing carrier of medication with dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone.
The present invention has synthesized the slow releasing carrier of medication that a class is suitable for injecting: the poly-anhydride of thick liquid nano-unsaturated polyester (UP) block polymer under the room temperature, molecular weight is 4000-10000.
The structural formula that should gather anhydride-unsaturated polyester (UP) block polymer is as follows:
X=2 in the formula～4, y=8～14, m is the molal quantity of poly-maleic acid-binary alcohol esters acid anhydride chain link or fumaric acid-binary alcohol esters chain link, n is the molal quantity of the chain link of saturated dicarboxylic acids, m/n=1/5～5/1.
Concrete technology of preparing of the present invention is as follows:
1. dibasic acid anhydride is synthetic
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), hexadecandioic acid (hexadecane diacid) (Hexadecanedioic Acid, HA) in molar ratio 1: 2-5 is respectively charged in the container of nitrogen protection; 140-200 ℃ back flow reaction 15-100 minute, be cooled to 60-100 ℃, acetic acid that pressure reducing and steaming does not react completely and acetic anhydride, product dissolves with dichloromethane, petroleum ether or cyclohexane extraction precipitation, sand core funnel filters, absolute ether or ethyl methyl ether or oxolane washing, vacuum drying obtains seven kinds of dibasic acid anhydrides.
2. the unsaturated polyester ester oligomer is synthetic
With in maleic anhydride or fumaric acid and the polymerization pipe of packing into after dihydroxylic alcohols mixed in 1: 1.1 in molar ratio, place silicone oil bath, electromagnetic agitation; Be warming up to 170 ℃～00 ℃ reaction 1.5 hours, be cooled to 80 ℃, vacuum decompression to 30～50Pa is taken moisture away, is warming up to 170 ℃ of melt polymerizations after 0.5 hour 1.0 hours; Logical nitrogen was 10～20 seconds every 5～20 minutes, again evacuation; Polymerization finishes, and cooling obtains the unsaturated polyester ester oligomer of certain viscosity.
The synthetic route of unsaturated polyester ester oligomer is shown below:
M is fumaric molal quantity in the formula, and the also available maleic anhydride of fumaric acid replaces.
3. poly-anhydride oligomer is synthetic
Synthetic poly-anhydride oligomer: with in seven kinds of dibasic acid anhydrides of step 1. preparation any by the purgation homopolymerization: a certain amount of dibasic acid anhydride is packed in the polymerization pipe, places silicone oil bath, electromagnetic agitation; Reaction is warming up to 160～200 ℃, vacuum decompression to 30～70Pa, melt polymerization 20～50 minutes; Logical nitrogen was 10～20 seconds every 5～10 minutes, again evacuation; After 30 minutes, stop polymerization, cool off the faint yellow solid product, dissolve with dichloromethane, the G4 sand core funnel filters, petroleum ether or cyclohexane extraction precipitation, sedimentation and filtration, a kind of washing after drying of use absolute ether, ethyl methyl ether, oxolane, obtain the flaxen seven anhydride homopolymer oligomer of birdsing of the same feather flock together, or with two kinds of dibasic acid anhydrides in molar ratio the proportioning of m/n=1/5-5/1 pack in the polymerization pipe, by the reaction condition copolymerization identical, obtain corresponding polyanhydride copolymer oligomer with homopolymer.Above poly-anhydride homopolymer or molecular weight of copolymer 2000-5000.
4. synthetic poly-anhydride-unsaturated polyester (UP) block polymer
Synthetic poly-anhydride and unsaturated polyester ester oligomer are mixed in the polymerization pipe of packing into by mass ratio 1/5-5/1, place silicone oil bath, electromagnetic agitation; Reaction is warming up to 170 ℃～200 ℃ reactions 1.5 hours, logical nitrogen 10-20 second every 5 minutes, evacuation again; After 30 minutes, stop polymerization, be cooled to 80 ℃, adding mass ratio is one of following dilution cross-linking agent of 5%～30%: dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate and 2-EHA, cooling obtains the liquid poly-anhydride of corresponding thickness-unsaturated polyester (UP) block polymer, molecular weight 4000-10000.Its structural formula is:
5. the using method of poly-anhydride-unsaturated polyester (UP) block polymer
With the poly-anhydride of liquid state-unsaturated polyester (UP) block polymer and mass percent is one of following firming agent of 0.3%～1.0%: 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, mix in container with the medicine that will sneak into, be filled into syringe, can inject focus.
Characterize
All synthetic poly-anhydride-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 poly-anhydride-unsaturated polyester resins is presented at 1713-1735cm
-1Strong unsaturated polyester (UP) C=O stretching vibration characteristic absorption peak is arranged, 1802cm
-1And 1720cm
-1The place has anhydride bond C=O stretching vibration characteristic absorption bimodal, 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 4000-10000.
Performance
1, normal temperature cure performance
Selecting methyl ethyl ketone peroxide (or cyclohexanone peroxide)-cobalt naphthenate system or benzoyl peroxide-triethanolamine system is curing system, a kind of in dimeric dibasic acid, the oleic acid is diluent and cross-linking agent, gathers the cure test of anhydride-unsaturated polyester resin under the room temperature.A certain amount of firming agent and diluent (0.3%-1.0%) and cross-linking agent (5%-30%) are mixed on surface plate with poly-anhydride-unsaturated polyester resin (70%-95%), 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 diluent 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 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 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%) and diluent 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 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.
Material of the present invention is oligomer (weight average molecular weight 2000-8000) when uncrosslinked for general medicament slow release material, after adding cross-linking agent certain flowability is arranged, character with unsaturated polyester (UP): can under body temperature, become cross-linked polymer (5-30min) by (37 ℃) rapid crosslinking curing, and biodegradable, have the character of poly-anhydride again: medicament slow release performance, biocompatibility and degradation property preferably.
The unsaturated polyester (UP) of liquid-poly-anhydride oligomer is injected in the animal body, is cross-linked into solid-state three-dimensional-structure macromole under the crosslinking and curing agent effect.Such material than solid medicament slow release material except that general character with suitable drug release rate, degradable metabolism, good biocompatibility, also have injectable, body temperature solidifies rapidly down, mechanical strength is high characteristics, can solve must the have an operation problem of implantation, secondary drug treatment difficulty of solid drugs slow-release material.The slow-releasing agent of such material and medicine preparation can be implanted lesions position with the method for injection, rapid crosslinking curing (5-30min) under the body temperature, slow releasing pharmaceutical and final degraded are expected to realize solid tumor, myelitic non-operation or minor operation local sustained release administration chemotherapy then.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
The release rule of the slow release medicine rod of the hydrochloric ciprofloxacin of Fig. 1 in 0.1M pH 7.4 PBS buffer
Abscissa is pharmaceutical release time (natural law), and vertical coordinate is that drug accumulation discharges percentage rate
Polyoxyethylene lauryl diacid-poly-(maleic anhydride-ethylene glycol) (mass ratio of PDDDA-P (MA-GLY) resin is formed:
(a) mass ratio PDDDA/P (MA-GLY)=5: 5;
(b) mass ratio PDDDA/P (MA-GLY)=4: 6;
(c) mass ratio PDDDA/P (MA-GLY)=3: 7.
The synthetic polyoxyethylene lauryl diacid of Fig. 2-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin material (mass ratio PDDDA/P (MA-GLY)=5: 5) is implanted subcutaneous 10 days of mice (10 *)
The specific embodiment
Example 1: polyoxyethylene lauryl diacid-gather synthesizing of (maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin
At φ 2cm, add maleic anhydride 3.92 grams (0.040mol), ethylene glycol 2.73 grams (0.044mol) in the polymerization pipe of long 20cm, polymerization pipe is placed silicone oil bath, 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, adds the polyoxyethylene lauryl diacid melt polymerization 1.0 hours of certain mass percent again, and logical nitrogen was 15 seconds every 15 minutes, again evacuation; Polymerization finishes, and is cooled to 80 ℃, adds the diluent and the cross-linking agent N-vinyl pyrrolidone of mass ratio 30%, and cooling obtains the poly-anhydride-unsaturated polyester resin (PDDDA-P (MA-GLY)) of certain viscosity.
FT-IR and the physicochemical property that should gather anhydride-unsaturated polyester (UP) (PDDDA-P (MA-GLY)) characterize as following table:
Table one gathers FI-IR and the physicochemical property of anhydride-unsaturated polyester (UP) (PDDDA-P (MA-GLY))
Example 2: the drug release characteristic of the polyoxyethylene lauryl diacid of hydrochloric ciprofloxacin-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin 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%) and diluent 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 range of linearity 2.0-30.0 μ g, can calculate the drug level that is released in the buffer solution.The rate of releasing drug of the polyoxyethylene lauryl diacid of 3 kinds of different proportionings compositions-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin medicine rod is shown in figure one.
Example 3: polyoxyethylene lauryl diacid-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin is 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, polyoxyethylene lauryl diacid-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin is estimated at the subcutaneous biocompatibility of mice.
Adopt injection, polyoxyethylene lauryl diacid-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) resin 150mg is added that firming agent aseptic injection implantation right side of mice forelimb oxter is subcutaneous, resin is solidified into lump (5-20 minute) 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 resin and surrounding tissue thereof are together downcut, and uses paraffin embedding, and microtome is thinly sliced, haematoxylin-Yihong (HE) dyeing, and 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 resin causes low weight (Fig. 3).Occur the infiltration of a small amount of neutrophilic granulocyte around the 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 polyoxyethylene lauryl diacid-poly-(maleic anhydride-ethylene glycol) (PDDDA-P (MA-GLY)) 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 poly-anhydride-unsaturated polyester (UP) block polymer 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, 2-EHA are formulated; The weight average molecular weight of poly-anhydride-unsaturated polyester (UP) block polymer is: 4000-10000, and its structural formula is as follows:
X=2 in the formula～4, y=8～14, m is the molal quantity of maleic acid-binary alcohol esters chain link or the molal quantity of fumaric acid-binary alcohol esters chain link, n is the molal quantity of the chain link of saturated dicarboxylic acid, 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) in molar ratio 1: 2-5 is respectively charged in the container of nitrogen protection; 140-200 ℃ of back flow reaction 15～100 minutes, be 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 are filtered, absolute ether or ethyl methyl ether or oxolane washing, vacuum drying obtains dibasic acid anhydride;
2. with in maleic acid or fumaric acid and the polymerization pipe of packing into after dihydroxylic alcohols mixed in 1: 1.1 in molar ratio, 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, is warming up to 170 ℃ of melt polymerizations after 0.5 hour 1.0 hours; Logical nitrogen 10-20 second every 5～20 minutes, evacuation again; Polymerization finishes, and cooling obtains the unsaturated polyester ester oligomer of certain viscosity, and its synthetic route is shown below:
In the formula x such as claim 1 definition;
3. any in the dibasic acid anhydride that 1. step is prepared is by the purgation homopolymerization: a certain amount of dibasic acid anhydride is packed in the polymerization pipe, place silicone oil bath, electromagnetic agitation; Reaction is warming up to 160～200 ℃, vacuum decompression to 30～70Pa, melt polymerization 20～50 minutes; Logical nitrogen was 10～20 seconds every 5～10 minutes, again evacuation; After 30 minutes, stop polymerization, cool off the faint yellow solid product, dissolve with dichloromethane, filter, petroleum ether or cyclohexane extraction precipitation, sedimentation and filtration, a kind of washing after drying of use absolute ether, ethyl methyl ether, oxolane, get flaxen poly-anhydride homopolymer oligomer, or with two kinds of dibasic acid anhydrides in molar ratio the proportioning of m/n=1/5-5/1 pack in the polymerization pipe, by the reaction condition copolymerization identical, obtain corresponding polyanhydride copolymer oligomer with homopolymer;
4. synthetic poly-anhydride and unsaturated polyester ester oligomer are mixed in the polymerization pipe of packing into by mass ratio 1/5～5/1, place silicone oil bath, electromagnetic agitation; Reaction is warming up to 170 ℃～200 ℃ reactions 1.5 hours, and logical nitrogen was 10～20 seconds every 5 minutes, again evacuation; After 30 minutes, stop polymerization, be cooled to 80 ℃, adding mass ratio is one of following dilution cross-linking agent of 5%～30%: dimeric dibasic acid, oleic acid, N-vinyl pyrrolidone, isodecyl acrylate and acrylic acid 2 one Octyl Nitrites, cooling obtains the poly-anhydride of corresponding thick liquid nano-unsaturated polyester (UP) block polymer, and its structural formula is:
X, y in the formula, m, n such as claim 1 definition;
5. be one of following firming agent of 0.3%～1.0% with liquid resin 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, 2-EHA, mix in container with the medicine that will sneak into, be filled into syringe, can inject focus.
3. but injectable slow releasing carrier of medication according to claim 1 is in preparation direct injection, the application in the body in the solidified medicament slow release material.
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| CNB2004100133391A Expired - Fee Related CN100423780C (en) | 2004-06-23 | 2004-06-23 | Injectable pharmaceutical slow-release carrier and preparation method thereof |
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| Country | Link |
|---|---|
| CN (1) | CN100423780C (en) |
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 |
-
2004
- 2004-06-23 CN CNB2004100133391A patent/CN100423780C/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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1593660A (en) | 2005-03-16 |
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