CN101234201A - Implantable sustained-release drug delivery system impregnated with polymer and preparation method thereof - Google Patents

Abstract

The invention discloses a polymer-impregnated implanted sustained-release drug delivery system in the field of pharmaceutical technology and a preparation method thereof. The system includes drugs, degradable polymer materials, degradable fibers or porous materials, wherein the degradable polymer The material is used as a drug carrier, and the degradable fiber or porous material is used as a support for a degradable polymer material. Usually, the content of the drug is 0.05-40% (weight ratio) of the total weight of the drug and the degradable polymer material. The degradable polymer material It is about 60-99.5% (weight ratio) of the total weight of the medicine and the degradable polymer material. It is prepared by coating the polymer solution on the fiber or porous medical implant material as a support or scaffold, and then drying to remove the solvent. The chemical hydrophilicity of the stent material of the invention makes the degradable macromolecule bulk degraded, helps obtain the linear release of the load, and has a simple preparation method.

Description

Implantable sustained-release drug delivery system impregnated with polymer and preparation method thereof

technical field

The invention relates to a sustained-release drug delivery system in the field of pharmaceutical technology and a preparation method thereof, in particular to a polymer-impregnated implanted sustained-release drug delivery system and a preparation method thereof.

Background technique

Although degradable or biodegradable polymers are widely used in the preparation of sustained and controlled release systems for therapeutic drugs and other drugs, many technical issues, such as release kinetics, drug stability, drug encapsulation efficiency, drug release kinetics, The toxicity and metabolism of polymers, as well as the simplification of the production process, have yet to be better resolved. Because of these problems, this provides a lot of room for further improvement of the technology. The invention relates to a simple preparation process of an implanted sustained-release drug delivery system using polymer as a carrier. Usually, these microspheres or wafers (Wafer) implanted by surgical administration need complex encapsulation processes to be prepared. As more and more therapeutic drugs have been or will be prepared into controlled-release preparations, simplifying the production process has become an important issue, and there is a great necessity to develop such controlled-release systems.

The use of polymer-implanted sustained-release drug delivery systems dates back many years. In 1996, the US Food and Drug Administration approved carmustine (BCNU)-polyanhydride implantable film (Gliadel( ^R )), which was the first product approved for the treatment of brain tumors in nearly 20 years. The polymer implanted sustained-release drug delivery system has shown great advantages in the local treatment of brain tumors. Compared with oral administration, the bioavailability at the treatment site is high, and patients are free from severe side effects. Therefore, the combined form of polymers and drugs that deliver drugs to targeted sites has been proven to be a better carrier for the development of drug delivery technology.

Found through literature search to prior art, " BCNU-loadedpoly(D, L-lactide -co-glycolide)wafer and antitumor activity against XF-498human CNS tumor cells in vitro"("Carmustine loaded on polylactic acid/glycolic acid (PLGA) copolymer material discs and anti-XF-498 human CNS tumor cells in vitro The activity of tumor cells"), the article proposes to use a biodegradable and biocompatible polymer material polylactic acid/glycolic acid (PLGA) to prepare carmustine (BCNU) implanted film sheets, reducing the risk of burst release The method, the method is: mix carmustine and polylactic acid/glycolic acid (PLGA) thoroughly, and press it into a film sheet with a machine. Its shortcoming lies in: serious sudden release of carmustine drug, the depth of drug diffusion and how to make the implant contact with the target site closer and cover the treatment area as large as possible. Burst interpretation has attracted the interest of many researchers, but remains unsolved. Although some other drugs do not have the problem of diffusion distance, they show certain curative effect. However, biomacromolecules, such as protein drugs, vaccines, antibodies, or genes, still face technical obstacles in the preparation process. Other dosage forms also have other problems during treatment that may include burst release, poor stability, inactivation, and low drug loading efficiency. It was also found in the search that Lyons et al. applied for US Patent 6,331,317 in 2004, which proposed a method for preparing microparticles from polymer materials. Its shortcoming is: industrial batch production, its technicality is too strong, and technique is too complicated. Rosenthal et al. filed US Patent 5,466,462 in 1995 - "Shaped Sponge Containing Drugs", which proposes some surgical implants impregnated with drugs, which can reduce the formation of scars. Its shortcoming is that can not reach the effect of prolonged sustained release.

During surgery, doctors usually use hemostatic materials, such as Surgicel and gelatin sponge, to help patients recover from post-operative wounds. These surgical materials have been proven to be safe, non-toxic, biocompatible and bioabsorbable. Utilizing these existing surgical materials as scaffolds for the development of long-acting drug therapy formulations for postoperative therapy may provide a convenient and very simple approach to address the aforementioned issues.

Contents of the invention

The purpose of the present invention is to address the deficiencies in the prior art, to provide a polymer-impregnated implanted sustained-release drug delivery system and a preparation method thereof, which skillfully combines surgical hemostatic gauze with a polymer-based drug sustained-release system. In combination, a novel drug sustained-release implantation system is constructed, which is simple and easy to implement, and is applicable to various drugs at the same time.

The present invention is achieved through the following technical solutions:

The polymer-impregnated implant sustained-release drug delivery system involved in the present invention includes drugs, degradable polymer materials, degradable fibers or porous materials. The degradable polymer material is used as a drug carrier (also called: controlled release material), and the degradable fiber or porous material is used as a degradable polymer material support (also called: a skeleton). Usually the content of the drug is 0.05-40% (weight ratio) of the total weight of the coating composed of the drug and the degradable polymer material, and the degradable polymer material is about 60-40% of the total weight of the drug and the degradable polymer material. 99.5% (by weight). Usually the weight of the drug and the degradable polymer material is about 5-80% of the weight of the entire implanted sustained-release drug delivery system.

The degradable polymer materials and drugs in the present invention can be natural or artificial, and/or materials that have been proven to originate in the human body. The degradable polymer material can be selected from widely used polylactic acid/glycolic acid (PLGA), polycaprolactone (PCL) or polylactic acid (PLA), and their derivatives, or other non-medical polymer materials.

The drugs are various therapeutic substances, which may be composed of anti-tumor chemical small molecule drugs, antibiotics, and biomacromolecules for local treatment.

The biological macromolecules include one or more mixed drugs of protein drugs, vaccines, antibody drugs or genes, or analogs and fragments and combinations thereof. The selected protein drug, vaccine, antibody drug or gene and polysaccharide form vitreous particles and then disperse in the polymer coating.

The protein drugs include erythropoietin (EPO), recombinant human granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), vaccines, 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 growth factor (VEGF) ), platelet growth factor (PDGF), endothelial growth factor (ECGF), nerve growth factor (NGF), bone-derived growth factor (BDGF), bone morphogenic protein (BMP), tissue polypeptide antigen (TPA), antibody (antibody) , coagulation factor VIII (VIII) and IX genetic factors. The sustained-release implant can be loaded with one or more of the above-mentioned protein or polypeptide drugs.

The tumor chemotherapeutic drug described in the present invention is selected from: adriamycin, cyclophosphamide, dactinomycin, bleomycin, daunorubicin, adriamycin, epirubicin, mitomycin, methotrexate Glycine, fluorouracil, carboplatin, carmustine (BCNU), semustine, cisplatin, etoposide, interferon, camptothecin and its derivatives, phenerine cholesterol, paclitaxel and its derivatives, multi Paclitaxel and its derivatives, vinblastine, vincristine, tamoxifen, etoposide, piposulfan, cyclophosphamide, or flutamide and its derivatives. The slow-release implant can be loaded with one or more of the above tumor chemotherapy drugs.

When the sustained-release system of the present invention is used for antibiotics, the antibiotics are selected from cyclosporine, levofloxacin, ofloxacin, or epinastine hydrochloride. The slow-release implant can be loaded with one or more of the above-mentioned antibiotics.

Described degradable macromolecule material is selected from: polylactic acid (PLA), polyacetic acid (PGA), polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL) and polylactic acid-glycolic acid copolymer Derivatives, and other biodegradable polymer materials. The polymer coating of the slow-release implant can be composed of one or a mixture of the above-mentioned polymer materials. The degradation rate of these polymers, and the corresponding drug release rate, can be maintained from several days to several months by changing the composition and molecular weight of the polymer material. PLGA is one of the preferred biodegradable polymer materials.

The degradable fiber or porous scaffold material can be selected from one or a combination of degradable surgical hemostatic materials made of absorbable gelatin sponge, absorbable oxidized cellulose, collagen, or the like.

The preparation method of the polymer-impregnated implanted slow-release drug delivery system involved in the present invention can adopt any one of the following methods:

Method 1 (includes the following steps):

a) dissolving the degradable polymer material in an organic solvent;

b) dissolving or uniformly suspending the drug in the polymer solution by stirring;

c) Coating the drug solution or suspension prepared in b) on the biodegradable fiber or porous material by means of spraying, brushing or dipping.

Method Two:

After the three steps of step a), b) and c) of method one, step d) is carried out:

d) Coating a layer of drug-free polymer coating on the drug-loaded polymer coating by means of spraying, brushing or dipping.

Method 3 (including the following steps):

Dissolving degradable polymer materials in organic solvents;

a) Suspending polysaccharide vitreous particles containing protein drugs, vaccines, antibody drugs or genes in the polymer solution;

b) Coating the suspension prepared in b) on the biodegradable fiber or porous material by spraying, brushing and dipping.

Method four:

All steps a), b), and c) are the same as method three, but added after c):

c) Coating a layer of drug-free polymer coating on the drug-loaded polymer coating by means of spraying, brushing or dipping.

The degradable fiber or porous material of the present invention adopts a clinical hemostatic material with a large surface area and rich in porous structure, which is used to be loaded on the degradable polymer material layer or structure, which facilitates the release of drugs therein. The hemostatic material not only serves as a support or scaffold, which simplifies the preparation process of the sustained release system, but also provides a unique drug release mechanism. As a support for biodegradable polymers, its high hydrophilicity and rapid degradability can effectively avoid the common incomplete release problems of drug slow-release species based on general polymer materials, and without prolonging the overall release period. Under these conditions, the drug-administered implants prepared with high molecular weight or high hydrophobic polymers can achieve linear release.

In the preparation process, since the complicated microencapsulation procedure is avoided, the drug-loaded degradable polymer material solution (forming a drug solution or suspension) can be easily coated on the hemostatic material, and at the same time, the microcapsules are avoided. The disadvantages of the chemical process are low encapsulation efficiency of drugs (40-60% per load), large amount of solvent used (because it needs to be used for washing and recovery of microspheres). These advantages make the present invention, compared with the previously reported implants, have better drug release linearity, convenient administration and simple and feasible production.

Description of drawings

Figure 1: Schematic diagram of a sustained-release drug delivery system for hemostatic (or fibrous) materials.

Figure 2: Schematic diagram of the preparation process of the sustained-release drug delivery system mentioned in the present invention.

Figure 3: The release profile of phenol red implanted into the sustained-release drug delivery system with different drug loadings and different molecular weights of PLGA.

Figure 4: The release profile of phenol red implanted into the sustained-release drug delivery system with different monomer ratios of PLGA (5% drug loading in the inner layer).

Figure 5: The release profile of phenol red implanted sustained-release drug delivery system containing different polymer coatings PLGA (50:50, 47K) (5% drug loading in the inner layer).

Figure 6: The release chart of the phenol red implanted sustained-release drug delivery system containing 10% PLGA (50:50, 47K) (inner layer drug loading 10%) with different polymer coatings.

Figure 7: The release graph of the phenol red implanted sustained-release drug delivery system containing 20% PLGA (50:50, 47K) (inner layer drug loading 20%) with different polymer coatings.

Figure 8: The release profile of carmustine implanted into the sustained-release drug delivery system with different drug loadings and different PLGA molecular weights.

Figure 9: The release curves of carmustine implanted into sustained-release drug delivery systems with different monomer ratios of PLGA (5% drug loading in the inner layer).

Figure 10: Comparison of the release of carmustine implanted in the sustained-release drug delivery system with and without coating of PLGA (65:35, 40K) (5% drug loading in the inner layer).

Figure 11: The release curves of the coated PLGA (65:35, 40K) carmustine with different drug loadings implanted into the sustained-release drug delivery system.

Detailed ways

The embodiments of the present invention are described in detail below in conjunction with the accompanying drawings: this embodiment is implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operating procedures are provided, but the protection scope of the present invention is not limited to the following the described embodiment.

The present invention specifically selects carmustine (BCNU) as an example to illustrate the drug delivery system of the present invention. Figures 9-11 show the drug release from the sustained release system prepared according to the method of the present invention. Compared with the dosage form without the non-drug-loaded surface layer, the burst release of carmustine was significantly reduced (from 40% to less than 10%) in the dosage form coated with a layer of non-drug-loaded PLGA layer on the surface. "Burst release" is defined herein to describe the percent release of drug within the first 24 hours. The most suitable polymer material used in the invention is PLGA with a molar ratio of LA and GA monomers from 100:0 to 50:50. Absorbable oxidized cellulose Surgicel (ETHICON) was used in the present invention to illustrate how surgical implants function in drug delivery systems. The most preferred polymer PLGA and Surgicel will be a better demonstration of the present invention. Fig. 1 is a schematic diagram of a sustained-release drug delivery system for hemostatic (or fibrous) materials.

The monomer ratio and molecular weight of the polymer are extremely important in changing the properties of the drug delivery system. Figure 3, Figure 5, Figure 8 and Figure 9 show the release conditions of drug delivery systems with different monomer ratios and molecular weights in the present invention, respectively. For the unsatisfactory burst release phenomenon, a better release curve can be obtained by coating the drug-free polymer layer on the original drug delivery system. The release conditions of different coating amounts are listed in Fig. 3, Fig. 4, Fig. 5, Fig. 10 and Fig. 11, respectively. These release results can achieve a satisfactory therapeutic effect.

The present invention also shows the release conditions of different drug loads in Fig. 3, Fig. 5, Fig. 7 and Fig. 9 . The above results prove that selecting the appropriate molecular weight and drug-free polymer coating amount will be a very important object of investigation. At the same time, the above-mentioned release characteristics show that this point is very significant. Comparing the legends, it can be seen that the distribution state of the drug in the drug delivery system also has a great influence. In the drug delivery system prepared by the process of the invention, the drug is distributed in the polymer material. Usually the content of the drug is 0.05-40% (weight ratio) of the total weight of the coating formed by the drug and the degradable polymer material. Usually the weight of the coating formed by the drug and the degradable polymer material is about 5%-80% (weight ratio) of the weight of the entire implanted sustained-release drug delivery system.

Fig. 2 is a schematic diagram of the preparation process of the sustained-release drug delivery system mentioned in the present invention. Both the sustained-release drug delivery system with coating and the sustained-release drug delivery system without coating are prepared according to the corresponding method in the figure. The sustained-release drug delivery system without coating can be prepared according to the following steps.

a) dissolving the degradable polymer material in an organic solvent;

b) dissolving or uniformly suspending the drug in the polymer solution by stirring;

c) Apply the drug solution or suspension prepared in b) evenly on the biodegradable fiber or porous material by spraying, brushing and dipping;

d) after the steps a), b) and c), and then dried under reduced pressure.

Similarly, the drug delivery system containing the PLGA coating can also be prepared in the above manner, that is, on the basis of the obtained sustained-release drug delivery system without coating, some polymer solution is additionally coated and dried.

Another typical example of the present invention is the preparation of a biomacromolecule drug delivery sustained release system. The preferred mode in Fig. 2 is also suitable for preparing the above-mentioned biomacromolecule drug delivery system, and the steps are as follows:

a) dissolving the degradable polymer material in an organic solvent;

b) Polysaccharide vitreous particles containing protein drugs, vaccines, antibody drugs or genes are dispersed in the polymer solution;

c) Apply the drug solution or suspension prepared in b) evenly on the biodegradable fiber or porous material by spraying, brushing and dipping;

d) after the steps a), b) and c), and then dried under reduced pressure.

Also according to Figure 2, the drug delivery system containing PLGA coating can also be prepared in the above manner, that is, it is formed by additionally coating some polymer solution on the basis of the obtained sustained-release drug delivery system without coating and drying.

Another example of the present invention is that some hydrophilic substances, lipophilic substances or other additives can be added to optimize the polymer-based sustained-release system to obtain more ideal performance or composition.

Example 1: Preparation of implanted sustained-release drug delivery system impregnated with polymers

Phenol red was selected as the model drug. Carmustine (BCNU) was chosen because the polyanhydride implantable film (Gliadel ^(R )) is an FDA-approved product.

Samples were prepared by the following method. First, PLGA was dissolved in ethyl acetate, and the drug was added into the PLGA ethyl acetate solution, and then it was dissolved or dispersed uniformly. Finally, the above 100ul PLGA solution and Surgicel (2.5cm*1cm) were coated, dried in vacuum for 24 hours, and the phenol red powder was dispersed in the drug delivery system according to Table 1. BCNU was dissolved in PLGA ethyl acetate solution according to Table 1. Statistically, the weight fluctuation rate is acceptable. Usually the content of the drug is 0.05-40% (weight ratio) of the total weight of the drug and the degradable polymer material, and the degradable polymer material is about 60-99.5% (weight ratio) of the total weight of the drug and the degradable polymer material. Compare). Usually the weight of the drug and the degradable polymer material is about 5% to 80% of the weight of the entire implanted sustained-release drug delivery system. The concentration of PLGA in the organic solution is preferably 1-40% (weight ratio), preferably 5-20% (weight ratio); the concentration of the drug is 0.01-20% (weight ratio), and 0.1-10% (weight ratio) better. The organic solvent is dichloromethane, ethyl acetate, acetonitrile, and dichloromethane and ethyl acetate mixed in any proportion as a solvent.

Table 1

Drug loading Drug (mg) PLGA(mg) EtOAc(mg) 5% 10 190 760 10% 20 180 720 20% 40 160 640

Example 2: Preparation of coated polymer-impregnated implantable sustained-release drug delivery system

The drug-loaded sustained-release drug delivery system was prepared as described in Example 1. On this basis, apply the above-mentioned 100ul, 200ul and 400ul drug-free PLGA solution, as shown in Table 1, and vacuum dry for 48 hours.

Example 3: In vitro release of polymer-impregnated implanted sustained-release drug delivery system

All prepared samples were placed in 2ml PBS release medium (pH=7.4) and simulated release at 37°C and 150rpm. And periodically replace with fresh release medium. The release amount of the phenol red-containing PLGA sustained-release system was measured with an ultraviolet spectrophotometer. Because carmustine (BCNU) is unstable, its measurement is different. All samples were taken out at specific times and freeze-dried for 24 hours. The samples were then dissolved in 1 ml of dichloromethane, and 9 ml of methanol was added to precipitate PLGA. Centrifuge for 5 minutes at a speed of 12,000 rpm, take 20ul of the supernatant and use high performance liquid chromatography to determine the content of carmustine in the residual sample. In different sampling periods, the release percentage of carmustine was calculated from the total amount of the system and the residual amount of the system. Release is shown as a function of percent cumulative release versus time. All experiments were repeated three times.

Example 4: Effects of different drug loadings and PLGA molecular weights on polymer-impregnated implantable sustained-release drug delivery systems

The sample was prepared according to Example 1, only changing ((L/G=50/50, 40K)) molecular weight and phenol red drug loading. The results are shown in Fig. 3 and Fig. 8: the sustained release lasting for several days to several weeks can be realized without serious sudden release and incomplete release.

Example 5: The effect of different PLGA monomer ratios on polymer-impregnated implanted sustained-release drug delivery system

The sample was prepared according to the method in Example 1, only the ratio of LA and GA monomers was changed. The experimental results are shown in Figure 4 and Figure 9: the ratio of L/G monomer in PLGA has little effect on the drug release kinetics characteristics of the drug-loaded sustained-release drug delivery system, and the coatings with different ratios do not cause severe burst release And incomplete release, can meet the requirements of sustained release treatment of diseases.

Example 6: Effect of drug-free PLGA coating on implanted sustained-release drug delivery system impregnated with phenol red polymer

Samples were prepared according to the method in Example 2. With the change of PLGA coating and drug loading, the release profiles in Figure 5, Figure 6 and Figure 7 also changed accordingly. The thicker the coating, the smaller the burst. Basically, the drug-free layer contributed a lot to inhibiting the burst release within 24 hours and made the release profile controllable.

Example 7: Effects of drug-free PLGA coating and different drug loadings on implanted sustained-release drug delivery system impregnated with carmustine polymer

The sample was prepared according to Example 2, and 200ul PLGA ethyl acetate solution was coated on the surface. Figure 11 shows that carmustine is released from the system in a controlled manner, and different drug loadings have little effect on the drug-free PLGA-coated carmustine-loaded sustained-release delivery system. This drug delivery system can achieve the effect of treating brain tumors.

Example 8: Protein, vaccine and DNA samples were prepared by the following method. Taking epidermal growth factor (EGF) as an example, first, dissolve PLGA in ethyl acetate, and add EGF polysaccharide vitreous particles to the PLGA ethyl acetate solution, and then vortex it for 5 minutes to disperse the particles evenly. Finally, apply the above-mentioned 100ul PLGA solution and Surgicel (2.5cm*1cm), and vacuum-dry for 24 hours, and the polysaccharide vitreous particles of EGF are dispersed in the drug delivery system according to Table 1. Usually the content of the drug is in the range of about 0.01-95% (weight ratio), preferably 0.1-40% (weight ratio). Usually the weight of the polymer material is about 5-99.99% (weight ratio) of the whole drug delivery system, preferably 60-99.9% (weight ratio). The concentration of PLGA in the organic solution is preferably 1-40% (weight ratio), preferably 5-20% (weight ratio); the concentration of the drug is 0.01-20% (weight ratio), and 0.1-10% (weight ratio) better. This drug delivery system can treat skin injuries such as burns, knife wounds and skin healing such as surgery.

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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