CN101234201A - High molecule impregnation implantation sustained-release drug delivering system and preparation thereof - Google Patents
High molecule impregnation implantation sustained-release drug delivering system and preparation thereof Download PDFInfo
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- CN101234201A CN101234201A CNA2008100330114A CN200810033011A CN101234201A CN 101234201 A CN101234201 A CN 101234201A CN A2008100330114 A CNA2008100330114 A CN A2008100330114A CN 200810033011 A CN200810033011 A CN 200810033011A CN 101234201 A CN101234201 A CN 101234201A
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Abstract
The invention discloses a sustained-release implant drug delivery system with macromolecule infusion and a preparation method thereof, which belongs to a field of medicine technology. The system comprises a medicine, a degradable polymer material, a degradable fiber or porous material, wherein the degradable polymer material is used as a drug carrier, the degradable fiber or porous material is used as a holder of the degradable polymer material. In general, the medicine content is 0.05-40 percent of the total weight of the medicine and the degradable polymer material (weight proportion), while the content of the degradable polymer material is about 60-99.5 percent of the total weight of the medicine and the degradable polymer material (weight proportion). The system is prepared by coating the macromolecule solution on the fiber or porous medical implant material that is used as a holder or a bracket, then obtaining the system after drying to remove the solvent. The chemical hydrophilicity of the bracket material in the invention can lead the degradable macromolecule to degrade the body, which is helpful to acquire the linear release of the holder with a simple method.
Description
Technical field
The present invention relates to Atrigel of a kind of technical field of pharmaceuticals and preparation method thereof, specifically is implantation sustained-release drug delivering system of a kind of high molecule impregnation and preparation method thereof.
Background technology
Though degradable or Biodegradable high-molecular are widely used in preparing the controlled release system of medicine and other medicine, a lot of technical matters, simplification such as release dynamics, macromolecule toxicity and the metabolism and the production technology of the envelop rate of release dynamics, medicine stability, medicine, medicine waits to solve better.Owing to there are these problems, this just provides the space of developing on a large scale very much for further improving technology.The present invention relates to the macromolecule is the simple and easy preparation technology of implantation sustained-release drug delivering system of carrier.Usually the microsphere of these underwent operative administrations implantation or diaphragm (Wafer) need to adopt complicated encapsulating process just can be prepared from.Along with increasing medicine maybe will be prepared to controlled release preparation, simplify production technology and become a major issue, and very big necessity is arranged developing this class controlled release system.
The use of macromolecule implantation sustained-release drug delivering system can be reviewed very many years ago.In 1996, the approval Ka Mositing (BCNU) of FDA-poly-anhydride was implanted diaphragm (Gliadel
) listing, it is the product that is approved for the treatment cerebral tumor in nearly 20 years first.The macromolecule implantation sustained-release drug delivering system is compared with oral administration having showed very big advantage aspect the topical therapeutic cerebroma, the bioavailability height of therapentic part, and the patient avoids suffering serious adverse.Therefore, conduct drugs to the macromolecule and the pharmaceutical combination of targeting moiety, be proved to be a kind of preferable carrier of suitable exploitation medicine-feeding technology.
Find through literature search prior art, " BCNU-loadedpoly (D; L-lactide-co-glycolide) wafer and antitumor activity against XF-498human CNS tumor cells in vitro " that people such as Seong deliver on " International Journal ofPharmaceutics " (" international journal of Practical Pharmacy " 2003 the 251st phase 1-12 pages or leaves) (" Ka Mositing be supported on polylactic acid/hydroxy acetic acid (PLGA) copolymer material disk and in external anti-XF-498 people's cns tumor cell activity "), propose in this article to implant diaphragm with a kind of macromolecular material polylactic acid/hydroxy acetic acid (PLGA) preparation Ka Mositing (BCNU) biodegradable and biocompatibility, reduce the prominent method of releasing, method is: Ka Mositing and the abundant mixing of polylactic acid/hydroxy acetic acid (PLGA), become diaphragm with machine pressing.Its deficiency is: the Ka Mositing medicine is seriously prominent to be released, the drug diffusion degree of depth and how to make the more close contact of implant and target site, and covers treatment region as wide as possible.Release the interest that has attracted numerous researcheres and dash forward, but still unresolved.Though there is not the diffusion length problem in some other medicine, show certain curative effect.Yet, biomacromolecule, as protein drug, vaccine, antibody, or gene still are faced with technology barrier in preparation process.Other dosage forms also exist in therapeutic process and may comprise and other problems such as prominently release, poor stability, inactivation and medicine carrying efficient are low.Find also in the retrieval that people such as Lyons are at the United States Patent (USP) 6,331,317 of application in 2004, this patent proposes a kind of method for preparing microgranule with macromolecular material.Its deficiency is: industrial mass manufacture, and it is technical too strong, and technology is too complicated.The United States Patent (USP) 5,466 that people such as Rosenthal applied in nineteen ninety-five, 462-" the special-shaped sponge that contains medicine ", this patent proposes the operation implant of some pharmaceutical-impregnated, can reduce the formation of cicatrix.Its deficiency is to reach the effect that prolongs slow release.
In operation, the doctor adopts hemostatic material usually, is yarn (Surgicel) and gelfoam as speed, helps the sharp and post-operative wound rehabilitation of patient.These surgical materials all are proved to be safety non-toxic, and biocompatibility and Bioabsorbable are good.Utilize these existing surgical materials as support development aftertreatment depot drug product therapeutic dosage forms, can facilitate and very simple method solves the problems referred to above.
Summary of the invention
The objective of the invention is at the deficiencies in the prior art, implantation sustained-release drug delivering system of a kind of high molecule impregnation and preparation method thereof is provided, making it is that the medicament slow release system of substrate combines dexterously with surgical hemostasis gauze and macromolecule, construct novel medicament slow release implant system, simple and easy to do, all suitable to various kinds of drug simultaneously.
The present invention is achieved by the following technical solutions:
The implantation sustained-release drug delivering system of high molecule impregnation involved in the present invention comprises and contains medicine, degradable high polymer material, biodegradable fiber or porous material.Wherein (also claim: controlled-release material), biodegradable fiber or porous material (also claim: skeleton) as the degradable high polymer material holder degradable high polymer material as pharmaceutical carrier.Usually content of medicines is the 0.05-40% (weight ratio) of the gross weight of the coating that constitutes of medicine and degradable high polymer material, degradable high polymer material be medicine and degradable high polymer material gross weight be about 60-99.5% (weight ratio).Usually the weight of medicine and degradable high polymer material is the about 5-80% of whole implantation sustained-release drug delivering system weight.
Degradable high polymer material among the present invention and medicine can be nature or synthetical, and/or have confirmed to start from the material of implant into body.Degradable high polymer material can be selected from the polylactic acid/hydroxy acetic acid (PLGA) of extensive use, polycaprolactone (PCL) or polylactic acid (PLA), and derivant, or other non-therapeutic medical macromolecular material.
Described medicine is various therapeutic substances, can be made of the biomacromolecule of antitumor chemistry small-molecule drug, antibiotic and topical therapeutic etc.
Described biomacromolecule comprises one or more hybrid medicines of pharmaceutical grade protein, vaccine, antibody drug or gene or analog and fragment and combination kind thereof.The pharmaceutical grade protein of being selected, vaccine, antibody drug or gene and polysaccharide are scattered in this polymeric coating layer after forming the vitreous body granule.
Described pharmaceutical grade protein comprises erythropoietin (EPO), recombinant human granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimutaing factor (GM-CSF), vaccine, interferon (INF), growth hormone (GH), insulin (Insulin), epidermal growth factor (EGF), fibroblast growth factor (FGF), transforming growth factor (TGF-β), insulin like growth factor (IGF), vascular endothelial cell growth factor (VEGF), PDGF (PDGF), endothelial cell growth factor (ECGF) (ECGF), nerve growth factor (NGF), bone-derived growth factor (BDGF), bone morphogenetic protein(BMP) (BMP), tissue polypeptide antigen (TPA), antibody (antibody), blood coagulation factor VIII (VIII) and IX genetic factor.Sustained-release implant can be loaded with one or more in above-mentioned albumen or the polypeptide drugs.
Tumor chemotherapeutic drug of the present invention is selected from: amycin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, amycin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine (BCNU), semustine, cisplatin, etoposide, interferon, camptothecine and derivant thereof, phenesterin, paclitaxel and derivant thereof, Docetaxel and derivant thereof, vinblastine, vincristine, zitazonium, etoposide, piposulfan, cyclophosphamide or flutamide and derivant thereof.Sustained-release implant can be loaded with one or more in the above-mentioned tumor chemotherapeutic drug.
When slow-released system of the present invention was used for antibiotic, antibiotic was selected from ciclosporin, levofloxacin, ofloxacin or epinastine hydrochloride.Sustained-release implant can be loaded with above-mentioned antibiotic one or more.
Described degradable high polymer material is selected from: derivant and other biodegradable polymer of polylactic acid (PLA), poly-acetic acid (PGA), polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA), polycaprolactone (PCL) and polylactic acid-glycolic guanidine-acetic acid copolymer.The polymeric coating layer of sustained-release implant can be made of one or more the mixture in the above-mentioned macromolecular material.These high molecular degradation rates, and relative medicine rate of release can maintain a couple of days to the several months, and its method is composition and the molecular weight that changes macromolecular material.PLGA is wherein preferable a kind of biodegradated polymer materal.
Described biodegradable fiber or porous support materials can be selected from a kind of or its combination in the degradable surgical hemostasis material that sponeostan, absorbability oxidized cellulose, collagen protein or analog etc. make.
The preparation method of the implantation sustained-release drug delivering system of high molecule impregnation involved in the present invention, can adopt in the following several method any one:
Method one (may further comprise the steps):
A) degradable high polymer material is dissolved in the organic solvent;
B) be suspended in this macromolecular solution with medicine dissolution or through stirring;
C) utilize spraying, brushing or impregnating method, with b) in the preparation drug solution or suspension coat on Biodegradable fiber or the porous material.
Method two:
At method one step a), b), c) three the step after, carry out step d):
D) utilize the same means coating one deck of spraying, brushing or impregnating method reuse on the medicine-carrying polymer coating not contain the polymeric coating layer of medicine.
Method three (may further comprise the steps):
Degradable high polymer material is dissolved in the organic solvent;
A) the polysaccharide vitreous granule that will contain pharmaceutical grade protein, vaccine, antibody drug or gene is suspended in this macromolecular solution;
B) utilize spraying, brushing and dipping method, with b) in the preparation suspension coat on Biodegradable fiber or the porous material.
Method four:
All a), b), c) three the step identical with method three, but at c) afterwards the adding:
C) utilize the same means coating one deck of spraying, brushing or impregnating method reuse on the medicine-carrying polymer coating not contain the polymeric coating layer of medicine.
Biodegradable fiber of the present invention or porous material have adopted surface area big and be rich in the clinical hemostatic material of loose structure, are used to support in degradable high polymer material layer or structure, are beneficial to the release of its Chinese medicine.This hemostatic material not only serves as holder or support, simplification slow-releasing system preparation process, unique mechanisms for drug release also is provided simultaneously.Holder as Biodegradable high molecular, its highly hydrophilic and quick degradability, having avoided general macromolecular material effectively is the common incomplete release problem of medicament slow release kind of substrate, and under the situation that does not prolong whole release period, utilize the administration implant of the macromolecule preparation that molecular weight is big or hydrophobicity is high to obtain linear release.
On preparation technology, owing to avoided numerous and diverse microencapsulation program, medicine carrying degradable high polymer material solution (forming drug solution or suspension) can be applied on the hemostatic material very simply, has also avoided encapsulation process entrapment efficiency low (removes 40-60%), the big weakness such as (being used for the washing and the recovery of microsphere because of need) of solvent use amount simultaneously.These advantages cause the present invention to compare with former report implant, and its drug release linear case is good, administration is convenient and produce simple and feasible.
Description of drawings
Fig. 1: hemostasis (or fiber) material slow-release drug-supplying system sketch map.
Fig. 2: the Atrigel preparation process sketch map that the present invention addresses.
Fig. 3: different drug loading and the phenol red implantation sustained-release drug delivering system release graphics of different PLGA molecular weight.
Fig. 4: different monomers is than the phenol red implantation sustained-release drug delivering system release graphics of PLGA (internal layer drug loading 5%).
Fig. 5: contain different polymeric coating layer PLGA (50: 50,47K) (internal layer drug loading 5%) phenol red implantation sustained-release drug delivering system release graphics.
Fig. 6: contain different polymeric coating layer 10%PLGA (50: 50,47K) (internal layer drug loading 10%) phenol red implantation sustained-release drug delivering system release graphics.
Fig. 7: contain different polymeric coating layer 20%PLGA (50: 50,47K) (internal layer drug loading 20%) phenol red implantation sustained-release drug delivering system release graphics.
Fig. 8: different drug loading and different PLGA molecular weight Ka Mositing implantation sustained-release drug delivering system release graphics.
Fig. 9: different monomers is than PLGA (internal layer drug loading 5%) Ka Mositing implantation sustained-release drug delivering system release profiles.
Figure 10: (65: 35,40K) (internal layer drug loading 5%) Ka Mositing implantation sustained-release drug delivering system discharged comparison diagram to contain coating and uncoated PLGA.
Figure 11: different drug loading contain coating PLGA (65: 35,40K) Ka Mositing implantation sustained-release drug delivering system release profiles.
The specific embodiment
Below in conjunction with accompanying drawing embodiments of the invention are elaborated: present embodiment is being to implement under the prerequisite with the technical solution of the present invention, provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
The selected especially carmustine (BCNU) of the present invention is drug-supplying system of the present invention for example illustrates.Fig. 9-11 shows that medicine is from the release conditions by the slow-released system of method preparation of the present invention.The surface overbrushing one deck not the PLGA layer of medicine carrying dosage form with do not have not the dosage form on medicine carrying top layer compare, the prominent situation of releasing of Ka Mositing obviously reduces (dropping to below 10% from 40%)." prominent the releasing " of definition here is to be used to describe the percent of drug burst size that begins in 24 hours.The most suitable macromolecular material used of invention is LA and GA monomer mole ratio from 100: 0 to 50: 50 PLGA.Absorbed oxidized cellulose Surgicel among the present invention (speed is yarn) (ETHICON company) is used to illustrate how surgical implant acts in drug-supplying system.The most first-selected macromolecule PLGA and Surgicel will be preferable demonstrations of the present invention.Fig. 1 is hemostasis (or fiber) material slow-release drug-supplying system sketch map.
High molecular monomer ratio and molecular weight are of crucial importance to the character that changes drug-supplying system.The release conditions that changes the drug-supplying system of different monomers proportioning and molecular weight among the present invention is respectively Fig. 3, Fig. 5, Fig. 8 and Fig. 9.For the unsatisfactory prominent phenomenon of releasing, the pastille macromolecule layer is coated on original drug-supplying system by being coated with not, obtains better release profiles.The release conditions of different coating amount is listed in Fig. 3 respectively, Fig. 4, Fig. 5, Figure 10 and Figure 11.These discharge the result can reach satisfactory therapeutic effects.
The present invention is also at Fig. 3, and Fig. 5 has embodied the release conditions of different drug loading among Fig. 7 and Fig. 9.Above result prove select suitable molecular weight and not pastille polymeric coating layer amount will be very important investigation object.Simultaneously, to add bright this point meaning very great for above-mentioned release characteristics.Contrast each legend as can be known, medicine also has considerable influence in the distribution of drug-supplying system.The drug-supplying system of prepared of the present invention, wherein drug distribution is in macromolecular material.Usually content of medicines is the 0.05-40% (weight ratio) of the gross weight of medicine and the formed coating of degradable high polymer material.Usually the weight of medicine and the formed coating of degradable high polymer material is about 5%-80% (weight ratio) of whole implantation sustained-release drug delivering system weight.
Fig. 2 is the Atrigel preparation process sketch map that the present invention addresses.Containing coating sustained-released drug-supplying system and not containing coating sustained-released drug-supplying system all is to be prepared from by correlation method among the figure.Not containing coating sustained-released drug-supplying system can prepare according to the following steps.
A) degradable high polymer material is dissolved in the organic solvent;
B) be suspended in this macromolecular solution with medicine dissolution or through stirring;
C) utilize spraying, brushing and impregnating method, with b) in the preparation drug solution or suspension evenly coat on Biodegradable fiber or the porous material;
D) through a), b) and c) step, drying under reduced pressure is promptly again.
Equally, the drug-supplying system that contains the PLGA coating also can promptly be formed by extra some macromolecular solution dryings of coating on the basis that does not contain coating sustained-released drug-supplying system that has obtained by with the upper type preparation.
Another prominent example of the present invention is a preparation biomacromolecule macromolecule administration slow-released system.Preferred manner also is fit to the above-mentioned biomacromolecule drug-supplying system of preparation among Fig. 2, and step is as follows:
A) degradable high polymer material is dissolved in the organic solvent;
B) contain the polysaccharide vitreous Dispersion of Particles of pharmaceutical grade protein, vaccine, antibody drug or gene in this macromolecular solution;
C) utilize spraying, brushing and impregnating method, with b) in the preparation drug solution or suspension evenly coat on Biodegradable fiber or the porous material;
D) through a), b) and c) step, drying under reduced pressure is promptly again.
According to Fig. 2, the drug-supplying system that contains the PLGA coating also can promptly be formed by extra some macromolecular solution dryings of coating on the basis that does not contain coating sustained-released drug-supplying system that has obtained by with the upper type preparation equally.
Other example of the present invention is can add some hydroaropic substances, lipophilicity substance or other additives and be used to optimize polymer-based slow-released system, to obtain comparatively ideal performance or composition.
Example 1: the preparation of the implantation sustained-release drug delivering system of high molecule impregnation
The phenol red model drug that is chosen as.Selection card Mo Siting (BCNU) implants diaphragm (Gliadel because of poly-anhydride
) obtained the FDA approved products.
Sample is made through following method.At first, PLGA is dissolved in ethyl acetate, and adds medicine in the PLGA ethyl acetate solution, then with its dissolving or be uniformly dispersed.At last, be coated with above-mentioned 100ul PLGA solution and Surgicel and go up (2.5cm*1cm), vacuum drying 24 hours, phenol red powder is dispersed in drug-supplying system according to table 1.BCNU is dissolved in the PLGA ethyl acetate solution by table 1.By statistics, the weight stability bandwidth is acceptable.Usually content of medicines is the 0.05-40% (weight ratio) of the gross weight of medicine and degradable high polymer material, degradable high polymer material be medicine and degradable high polymer material gross weight be about 60-99.5% (weight ratio).Usually the weight of medicine and degradable high polymer material is whole implantation sustained-release drug delivering system weight about 5% to 80%.PLGA with 1-40% (weight ratio), is good with 5-20% (weight ratio) in the concentration of organic solution; Drug concentrations is good with 0.01-20% (weight ratio) with 0.1-10% (weight ratio).Organic solvent is that dichloromethane, ethyl acetate, acetonitrile and dichloromethane and ethyl acetate arbitrary proportion are mixed as solvent.
Table 1
| Drug loading | Medicine (mg) | PLGA(mg) | EtOAc(mg) |
| 5％ | 10 | 190 | 760 |
| 10％ | 20 | 180 | 720 |
| 20％ | 40 | 160 | 640 |
Example 2: contain the preparation of implantation sustained-release drug delivering system of the high molecule impregnation of coating
The carried medicine sustained-release drug-supplying system is according to example 1 described preparation.On this basis, be coated with above-mentioned 100ul again, 200ul and 400ul be pastille PLGA solution not, and be as shown in table 1, and vacuum drying 48 hours promptly.
Example 3: the release in vitro situation of the implantation sustained-release drug delivering system of high molecule impregnation
The sample of all preparations is put in the 2ml PBS release medium (pH=7.4), and at 37 ℃, simulation discharges under the 150rpm condition.And regularly replace fresh release medium.Measure the burst size that contains phenol red PLGA slow-released system with ultraviolet spectrophotometer.Because Ka Mositing (BCNU) instability, it measures different.After all samples took out in the specific time, and lyophilization 24h.Sample is dissolved in the 1ml dichloromethane respectively then, adds 9 ml methanol precipitation PLGA again.Centrifugal 5 minutes, rotating speed was 12, and 000rpm gets 20ul supernatant carmustine content in the high effective liquid chromatography for measuring residual sample.In the different sampling periods, Ka Mositing discharges percentage ratio and calculates from system's total amount and system's residual quantity.Function with cumulative release percentage ratio and time shows release conditions.All test all triplicates.
Example 4: different drug loading and PLGA molecular weight are to the influence of the implantation sustained-release drug delivering system of high molecule impregnation
Sample only changes ((L/G=50/50,40K)) molecular weight and phenol red drug loading according to example 1 preparation.The result is as shown in Fig. 3 and Fig. 8: the slow release that reaches ten a couple of days to several weeks is able to not realize under the serious prominent situation of releasing and not exclusively discharging having.
Example 5: different PLGA monomer ratio are to the influence of the implantation sustained-release drug delivering system of high molecule impregnation
Sample only changes LA and GA monomer ratio according to the preparation of example 1 method.Experimental result is as shown in Fig. 4 and Fig. 9: the monomeric ratio of L/G is little to the drug release kinetics feature affects of carried medicine sustained-release drug-supplying system among the PLGA, the coating of different proportion does not all cause serious prominent releasing and not exclusively release, can satisfy the requirement of slow release treatment disease.
Example 6: pastille PLGA coating is not to the influence of the implantation sustained-release drug delivering system of phenol red high molecule impregnation
Sample prepares according to example 2 methods.Along with the change of PLGA coating and drug loading, the also corresponding change of release conditions Fig. 5, Fig. 6 and Fig. 7.Coating is thick more, and dashing forward, it is more little to release.Basically, to release contribution very not big to suppressing prominent in 24 hours for medicated layer, and make release conditions controlled.
Example 7: pastille PLGA coating and different drug loading be not to the influence of the implantation sustained-release drug delivering system of Ka Mositing high molecule impregnation
Sample is according to example 2 preparations, at surface coated 200ul PLGA ethyl acetate solution.Figure 11 display card Mo Siting discharges from system with controlled manner, and different drug loading are little to the influence of the Ka Mositing carried medicine sustained-release drug-supplying system of pastille PLGA coating not.This drug-supplying system can reach the effect of the treatment cerebral tumor.
Example 8: albumen, vaccine and DNA sample are made through following method.With epidermal growth factor (EGF) is example, at first, PLGA is dissolved in ethyl acetate, and the polysaccharide vitreous granule that adds EGF with its DL 5min, makes Dispersion of Particles even in the PLGA ethyl acetate solution then.At last, be coated with above-mentioned 100ul PLGA solution and Surgicel and go up (2.5cm*1cm), vacuum drying 24 hours, the polysaccharide vitreous granule of EGF is dispersed in drug-supplying system according to table 1.Usually the content of medicines scope is about 0.01-95% (weight ratio), with 0.1-40% (weight ratio) the best.Usually the weight of macromolecular material is that whole drug-supplying system is about 5-99.99% (weight ratio), with 60-99.9% (weight ratio) the best.PLGA with 1-40% (weight ratio), is good with 5-20% (weight ratio) in the concentration of organic solution; Drug concentrations is good with 0.01-20% (weight ratio) with 0.1-10% (weight ratio).This drug-supplying system can be treated the healing of skin injury such as skins such as burn, knife injury and operation.
Claims (10)
1, a kind of implantation sustained-release drug delivering system of high molecule impregnation, it is characterized in that, comprise medicine, have the degradable high polymer material of controlled-release function and as the biodegradable fiber or the porous material of support, wherein content of medicines is the percentage by weight 0.05-40% of the coating that medicine and degradable high polymer material constituted, and coating is the percentage by weight 5-80% of whole implant.
2, the implantation sustained-release drug delivering system of the described high molecule impregnation of claim 1 is characterized in that, content of medicines is that the percentage by weight of the coating that medicine and degradable high polymer material constituted is 1-20%; Coating is that the percentage by weight of whole implant is 20-60%.
3, the implantation sustained-release drug delivering system of the described high molecule impregnation of claim 1, it is characterized in that degradable high polymer material is selected from a kind of or any two kinds combination in polylactic acid (PLA), hydroxyacetic acid (PGA), polycaprolactone (PCL) or polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA) and the derivant thereof.
4, the implantation sustained-release drug delivering system of the described high molecule impregnation of claim 1 is characterized in that, medicine is one or more the combination in antitumor chemicals, antibiotic and the biopharmaceutical macromolecular drug.
5, the implantation sustained-release drug delivering system of the described high molecule impregnation of claim 4 is characterized in that, biopharmaceutical macromolecular drug is a kind of and several combination in pharmaceutical grade protein, vaccine, antibody drug or gene or analog and the fragment.
6, the described implantation sustained-release drug delivering system that supports in high molecule impregnation of claim 4 is characterized in that, biopharmaceutical macromolecular drug further is scattered in the degradable macromolecule coating with particulate form with the form that is dispersed in the polysaccharide microgranule.
7, the implantation sustained-release drug delivering system of the described high molecule impregnation of claim 4, it is characterized in that protein drug is an erythropoietin, recombinant human granulocyte colony stimulating factor, granulocyte-macrophage colony stimutaing factor, vaccine, interferon, growth hormone, insulin, epidermal growth factor, fibroblast growth factor, transforming growth factor, insulin like growth factor, vascular endothelial cell growth factor, PDGF, endothelial cell growth factor (ECGF), nerve growth factor, bone-derived growth factor, bone morphogenetic protein(BMP), tissue polypeptide antigen, antibody, blood coagulation factor VIII and IX genetic factor and protein that is used for the treatment of or the one or more combination in the polypeptide.
8, the implantation sustained-release drug delivering system of the described high molecule impregnation of claim 4 is characterized in that, the antitumor chemicals is an amycin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, amycin, epirubicin, mitomycin, methotrexate, fluorouracil, carboplatin, carmustine, semustine, cisplatin, etoposide, interferon, camptothecine and derivant thereof, phenesterin, paclitaxel and derivant thereof, Docetaxel and derivant thereof, vinblastine, vincristine, zitazonium, etoposide, piposulfan, cyclophosphamide, the one or more combination of flutamide and derivant thereof.
9, the preparation method of the implantation sustained-release drug delivering system of the described high molecule impregnation of a kind of claim 1 is characterized in that, may further comprise the steps:
A) degradable high polymer material is dissolved in the organic solvent;
B) be suspended in this macromolecular solution with medicine dissolution or through stirring, the polysaccharide vitreous granule that perhaps will contain pharmaceutical grade protein, vaccine, antibody drug or gene is suspended in this macromolecular solution;
C) utilize spraying, brushing or dipping method, with b) in the preparation drug solution or suspension coat on Biodegradable fiber or the porous material.
10, the preparation method of the implantation sustained-release drug delivering system of the described high molecule impregnation of a kind of claim 1 is characterized in that, may further comprise the steps:
A) degradable high polymer material is dissolved in the organic solvent;
B) be suspended in this macromolecular solution with medicine dissolution or through stirring, the polysaccharide vitreous granule that perhaps will contain pharmaceutical grade protein, vaccine, antibody drug or gene is suspended in this macromolecular solution;
C) utilize spraying, brushing and dipping method, with b) in the preparation suspension coat on Biodegradable fiber or the porous material;
D) utilize the same means coating one deck of spraying, brushing or dipping method reuse on the medicine-carrying polymer coating not contain the polymeric coating layer of medicine.
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