CN100381183C - Preparation method of drug-loaded sustained-release micro/nanosphere digestive tract stent - Google Patents

Abstract

The invention discloses a preparation method of drug-loaded slow-release micro/nano ball digestive tract bracket, which belongs to the technical field of medicine and medical equipment. The present invention comprises the following steps: (1) The preparation of drug-loaded microspheres can be prepared by the following four methods respectively: 1. heat curing method, 2. adding crosslinking agent curing method, 3. volatile solvent aggregation method, 4. irradiation polymerization method . (2) The preparation of drug-loaded nanospheres can be prepared by the following four methods: ① emulsion polymerization method, ② natural polymer coacervation method, ③ drying method in liquid, and ④ automatic emulsification method. (3) Preparation of micro-nanosphere storage layer; (4) Preparation of backing layer; (5) Preparation of protective film layer. The stent prepared by the invention is used to treat benign and malignant stenosis of the esophagus and other digestive tracts. It not only has a mechanical expansion effect, but also has a local therapeutic effect. The micro/nano ball reservoir layer will directly release the drug to the tumor tissue or other diseased tissue, Treat the benign and malignant strictures of the digestive tract, and permanently solve the obstruction caused by benign and malignant strictures of the digestive tract.

Description

Preparation method of drug-loaded sustained-release micro/nanosphere digestive tract stent

technical field

The invention relates to a preparation method in the technical field of medicine and medical equipment, in particular to a preparation method of drug-loaded slow-release micro/nano ball digestive tract stent.

Background technique

Gastrointestinal benign and malignant strictures are clinically common diseases. Among them, malignant stenosis of the digestive tract is a high-incidence disease in patients with digestive tract cancer. In addition to surgical resection, radiotherapy and chemotherapy, commonly used interventional methods mainly include balloon dilatation (mainly for benign strictures) and stent placement. For patients with advanced digestive tract cancer, stent implantation is a very important palliative treatment method, which can effectively improve the quality of life and prolong the survival time of patients with advanced digestive tract cancer. However, traditional metal stents and covered stents still have at least the following two shortcomings: ① they do not have a real local therapeutic effect, they only play a palliative role of mechanical support and short-term relief, and they are powerless to prevent restenosis caused by tumor growth ; Although the covered stent can prevent tumor growth to a certain extent, it still cannot prevent tumor longitudinal overgrowth and compressive restenosis. ② After metal stent implantation, it is still necessary to cooperate with systemic drug treatment, but the blood concentration of cancer tissue after systemic drug administration is low, and it is difficult to achieve an effective therapeutic concentration; However, most anticancer drugs have very high toxicity and side effects, which is not advisable for most advanced cancer patients who have already developed organ lesions or are extremely weak. In order to solve this problem, by loading the drug on the stent in various ways, local drug delivery can be achieved and the purpose of reducing toxic and side effects can be achieved.

After searching the literature of the prior art, it is found that the Chinese patent publication number CN1159071C, the publication date is July 28, 2004, the patent name: the preparation method of biodegradable drug composite polymer scaffold material, and the patent reads as: "the Dissolve polymer polylactic acid, polycaprolactone and anti-restenosis drugs in a solvent; pour the prepared solution into a container, form a film, and make filaments; the filaments are made of L-lactic acid and glycolide copolymer , solvent and anti-restenosis drugs, soaked in a mixed solution prepared by drying, or freeze-dried; then soaked in an anti-coagulant solution, and dried; the filaments were wound on the mold and thermoset to form a polymer scaffold Material. The solvent is chloroform, 1,4 dioxane and dimethyl sulfoxide. The anti-restenosis drug is paclitaxel, paclitaxel, ethyl tretinoin, probucol, dexamethasone, Sirolimus. The anticoagulant solution is prepared by carboxylated sulfated chitosan aqueous solution or heparin sodium aqueous solution and acetone miscibility." If this patent is used to prepare digestive tract lumen stents, it mainly has the following deficiencies: 1. It is the lack of mechanical properties of degradable polymer materials, and the strength and elasticity cannot meet the requirements of digestive tract stents. In particular, the lumen of the digestive tract has contractile and peristaltic properties. The second is that the drug stent obtained by the preparation method has no protective layer, and the limited physical and mechanical properties of degradable polymer materials make it difficult for the stent to be completely delivered to the lesion.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art, and provide a preparation method of drug-loaded slow-release micro/nano ball digestive tract stent. The drug-loaded slow-release micro/nanosphere digestive tract stent prepared by it is used to treat benign and malignant strictures of the esophagus and other digestive tracts. It not only has a mechanical expansion effect, but also has a local therapeutic effect. Release drugs to tumor tissue or other diseased tissues to treat benign and malignant stenosis of digestive tract, and permanently solve the obstruction caused by benign and malignant stenosis.

The present invention is realized through the following technical solutions, and the present invention comprises the following steps:

(1) Preparation of drug-loaded microspheres:

Drug-loaded microspheres can be prepared by the following four methods:

①Heating curing method: microspheres are prepared by using the property of protein denaturation when exposed to heat.

The heat-curing method is specifically as follows: take bovine serum albumin and 5-fluorouracil in a mass ratio of 10:1, mix with 100ml cottonseed oil containing 10% Span, stir for 10min at a speed of 2500rpm, and ultrasonically emulsify. Take another 100ml of cottonseed oil and heat it to 180°C, gradually add the above emulsion at the same stirring speed, keep warm at 180°C for 10min, continue stirring to room temperature, add 200ml of ether or petroleum ether to degrease, centrifuge at 3000rpm, discard The oil phase was washed with ether and ethanol in turn to obtain 5-fluorouracil microspheres.

② Adding cross-linking agent curing method:

This method can be further divided into two methods.

Method 1: Disperse the drug in the solution of the carrier material, add a cross-linking agent (catalyst) to solidify into a gel, and then disperse into a particle dispersion system.

The method one in the method of adding a cross-linking agent solidification method, the specific steps are as follows: prepare mitomycin C microspheres, take mitomycin C and alginate in a mass ratio of 1:100, first put the alginate in distilled water Dissolve into a uniform viscous liquid at 80°C with a concentration of 6%, then add mitomycin C and 0.1 calcium chloride solution in an appropriate amount and mix well. A cross-linked network structure is formed to generate a gel, which is then processed and shredded into microspheres with an average particle size of 600um.

Method 2: Disperse the drug in the carrier material solution, emulsify it into a W/O emulsion (water-in-oil emulsion), and add a cross-linking agent (catalyst) to cross-link the oil-water interface of the droplets into solid particles , wash and serve.

The method two in the described cross-linking agent curing method, the specific steps are as follows: Methotrexate/PVA is dispersed in 10ml aqueous solution with a mass ratio of 1:5, and added to the oil containing 2.5% emulsifier under stirring at a rotating speed of 900rpm. In the solution, where water: oil = 1:3, continue to stir and emulsify to obtain a W/O emulsion, add a cross-linking agent to cross-link and solidify the oil-water interface of the emulsion, separate, and wash to obtain microspheres.

③ Volatile solvent polymerization method: disperse the drug and the matrix in an organic solvent, and add dropwise to the aqueous solution of the polymer while stirring to obtain an O/W emulsion (oil-in-water emulsion), evaporate the organic solvent, washed and dried to obtain microspheres.

Described volatile solvent aggregation method, its method is specifically as follows: cisplatin is dispersed in the dichloromethane solution of poly-L-propionate, the mass ratio of cisplatin and poly-L-propionate is 2: 7, and containing Mix 0.05% methyl cellulose and 4% polyvinyl alcohol mixed aqueous solution, sonicate and homogenize into an O/W type emulsion, distill off dichloromethane to obtain it.

④ Irradiation polymerization method: The monomer solution of the polymer is irradiated with r-rays or ultraviolet rays to induce polymerization reaction, and dispersed to obtain a particle dispersion system. Dissolve methyl methacrylate in 5-fluorouracil suspension, and then use Cor-rays to Irradiate to obtain the microspheres of methyl methacrylate polymer embedding drug.

The irradiation polymerization method is specifically as follows: methyl methacrylate is dissolved in 5-fluorouracil suspension, and the mass ratio of methyl methacrylate to 5-fluorouracil in the suspension is 6:1. Then it was irradiated with 5×10 ^-5 Gy of Cor r-rays.

(2) Preparation of drug-loaded nanospheres

Drug-loaded nanospheres can be prepared by the following four methods:

① Emulsion polymerization method: Weigh 5-fluorouracil and 0.1mol/l hydrochloric acid solution in a ratio of 1:15 [W(mg)/V(ml)] and dissolve it, add pluonicF68 solution and stabilizer, adjust the pH value, and stir Add dropwise the organic solvent containing isobutyl cyanoacrylate monomer, stir for 3 hours, add anhydrous sodium sulfate, continue stirring for 1 hour, and filter with a vertical fusing glass funnel to obtain the product.

The stabilizer is a surfactant, such as Tween 80.

②Natural polymer coacervation method: Weigh doxorubicin and gelatin at a ratio of 10:1 (W/W), emulsify in 3ml sesame oil, cool the formed emulsion in an ice bath, dilute it with acetone, and filter it with a pore size of 50nm Filter through a filter membrane, discard the large microspheres, wash off the oil on the nanospheres with acetone, add 10% formaldehyde in acetone solution 30ml, make the nanospheres solidify for 10 minutes, wash with acetone, and air-dry to obtain final product.

③In-liquid drying method: Dissolve the drug and polymer in chloroform, and use ultrasonic emulsification for 45 minutes in a 0.5% gelatin aqueous solution at 15°C to obtain a W/O emulsion, then heat to 40°C, and continue to dry at 40°C. The solvent was evaporated under ultrasonic treatment, centrifuged, washed, and freeze-dried to obtain nanospheres with a particle size of 500 nm.

④Automatic emulsification method: suspend DL-lactide/glycolide copolymer and drug (10:1, W/W) in 1.5ml of water filtered by a 0.2um filter membrane, add a mixed solvent (acetone: dichloromethane) Methane=30:1), poured into 50ml of PVA aqueous solution (20g/L), acetone rapidly diffused into the water phase, forming nano-sized emulsion droplets (auto-emulsification). After 3-4 hours, dichloromethane volatilized from the solvent, and the emulsion droplets solidified in water to form nanospheres.

(3) Preparation of micro-nanosphere storage layer:

The prepared micro/nano balls are mixed with viscous polymer materials, and the thickness of the micro/nano ball storage layer is 10-1500um.

The viscous polymer material refers to one or more of the following: polyvinylpyrrolidone, polyvinyl alcohol, ethylene vinyl acetate copolymer, poloxamer, polyacrylic acid, sodium polyacrylate, carbomer , polyacrylic resin, starch, dextrin, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, gum arabic, gelatin, chitosan, sodium alginate, hyaluronic acid, Albumin, agar, polymaltotriose, xanthan gum, guar gum and pressure sensitive adhesive.

The pressure-sensitive adhesive composition includes: any one or more of rubber-type pressure-sensitive adhesives, thermoplastic elastomer pressure-sensitive adhesives, acrylate pressure-sensitive adhesives, and silicones.

(4) Prepare the backing layer:

The backing layer material can be directly formed into a film on the stent, or the existing film material can be used as a backing layer to be bonded to the stent. The backing layer can be single-layer or multi-layer, and the backing layer itself can be a biological phase. Capacitive pressure-sensitive adhesive, or containing biocompatible pressure-sensitive adhesive, the pressure-sensitive adhesive content is 0-100%, the prepared micro/nano ball reservoir layer can be prepared with the assistance of various polymer materials with bonding effect As for the backing layer, the micro/nano ball storage layer and the backing layer can be directly laminated by heat-sealing or pressing physical methods and chemical bonding methods, and the thickness of the backing layer is 2-1000um.

The polymer material with binding effect refers to any one or more of the following: polyvinylpyrrolidone, polyvinyl alcohol, ethylene vinyl acetate copolymer, poloxamer, polyacrylic acid, sodium polyacrylate , carbomer, polyacrylic acid resin, starch, dextrin, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, gum arabic, gelatin, chitosan, sodium alginate, Hyaluronic acid, albumin, agar, polymaltotriose, xanthan gum, guar gum and biocompatible pressure sensitive adhesives.

The pressure-sensitive adhesive component is any one or more of the following: rubber-type pressure-sensitive adhesive, thermoplastic elastomer pressure-sensitive adhesive, acrylate pressure-sensitive adhesive, organic silicon.

(5) Preparation of protective film layer:

After the micro/nanosphere reservoir layer is adhered to the backing layer, a protective layer is prepared thereon.

The preparation of the protective film layer is as follows: the prepared protective film is wrapped on the reservoir layer, or the protective film material is directly formed on the surface of the micro/nanosphere reservoir layer, the protective film layer The thickness is 1um-1000um. The protective film layer protects the micro/nanosphere drug film layer from being polluted, protects the micro/nanosphere storage layer from mechanical damage during transportation, and exposes the micro/nanosphere storage layer after dissolving in the body, directly contacting the tissue Contact for drug release.

The working principle of the present invention is: the backing layer is tightly covered on the stent, has biocompatibility and resistance to a certain pH value, prevents the drug solution from seeping out and does not allow the solid liquid in the digestive tract to immerse from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The drug will be released in a unique way after the body fluid soaks into the reservoir layer. The protective layer is located on the micro/nano ball storage layer, the layer has sufficient strength and toughness, can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. The protective layer is water-soluble, and can dissolve in mucus or tissue exudate by itself after being put into the body, so that the micro/nanosphere reservoir layer directly contacts with the diseased tissue and releases the drug, thus achieving local, targeted, and sustained release. The effect of drug administration. A slight loss or breakage of the protective film will not affect the release of the drug, because it does not act as a controlled-release film and does not affect the release of the drug. This is a general controlled-release film, an organic permeation-enhancing layer or the drug film itself. It cannot be achieved as a protective film.

The drug-loaded slow-release micro/nano ball digestive tract stent prepared by the invention is used for targeted treatment of digestive tract obstruction or stenosis caused by benign and malignant tumors and other lesions. The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. Micro/nanospheres can relatively increase the dissolution rate of drugs, improve the biomembrane permeability of drugs, and play a targeting role to improve the bioavailability of drugs. After the micro/nanospheres are attached to the digestive tract stent, they can be targeted, slow and long-term released at the tumor site and nearby mucosal sites, and can have a good therapeutic effect on patients with digestive tract cancer. The dissolution of the protective film layer, the reduction of the micro/nano ball reservoir layer, and the recovery of the diseased tissue will further expand the caliber of the stent and increase the patency of the lumen.

Detailed ways

Example 1

1. Preparation of drug-loaded microspheres by heating and curing method:

Dissolve 250 mg of bovine serum albumin in 1 mL of 1% 5-fluorouracil solution, mix it with 100 ml of cottonseed oil containing 10% Span, stir at 2500 rpm for 10 min, and then ultrasonic emulsify. Take another 100ml of cottonseed oil and heat it to 180°C, gradually add the above emulsion under stirring at 2500rpm, keep warm at 180°C for 10min, continue stirring to room temperature, add 200ml of ether or petroleum ether to degrease, centrifuge at 3000rpm, discard The oil phase was washed with ether and ethanol in turn to obtain 5-fluorouracil microspheres.

2. Preparation of microsphere storage layer:

The microspheres are mixed with the viscous substance PVP to prepare a microsphere reservoir layer and adhered on the backing layer, and the thickness of the reservoir layer is 200um.

3. Preparation of backing layer:

Take 10g of silicone rubber and dissolve it in 20ml of toluene. Then add 0.5g tetraethyl orthosilicate, 0.1g curing agent, stir for 10 minutes to make it uniform. Then immerse the cleaned stent in it and take it out after staying for 5 minutes. Install and rotate the bracket on a rotary evaporator, and heat and humidify for 2 hours to form a uniform film as a backing layer. The thickness is 1000um.

4. Preparation of protective film layer:

Weigh 500 mg of HPMC, add 100 ml of double distilled water to dissolve, and pour it into a self-made uniform spray device. Place the bracket on the evaporator rotating at a constant speed for quantitative spraying. Finally, an HPMC protective layer with a thickness of 50um is formed on the reservoir layer.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 2

1. Preparation of drug-loaded microspheres by adding cross-linking agent curing method:

To prepare mitomycin C microspheres, take 10 mg of mitomycin C and 1000 mg of alginate in a ratio of 1:100 (W/W). Firstly, 1 g of alginate was dissolved in distilled water at 80°C to form a uniform viscous liquid with a concentration of 6%, then 10 mg of mitomycin C and 0.5 ml of 0.1% calcium chloride solution were added in sequence, and mixed well. Under the action of acid, high-valent metal ions and other bifunctional cross-linking agents, the mixed solution forms a cross-linked network structure to form a gel, which is then processed and shredded into microspheres with an average particle diameter of 600um.

2. Preparation of microsphere storage layer:

The microspheres are mixed with the viscous substance PVP to prepare a microsphere reservoir layer and adhered on the backing layer, and the thickness of the reservoir layer is 1200um.

3. Preparation of backing layer:

The backing layer is two layers. Take 10g of ethylene/vinyl acetate copolymer and dissolve it in 80ml of toluene. Immerse the cleaned stent in it and take it out after staying for 5 minutes. Place in an oven at 90°C for 5 hours to evaporate the solvent to form a film, which is used as the inner backing layer with a thickness of 10um. Another acrylate pressure-sensitive adhesive film is used as the outer backing layer with a thickness of 20um.

4. Preparation of protective film layer:

Weigh 10 mg of low molecular weight PVA, add 100 ml of double distilled water to dissolve, and pour it into a self-made uniform spray device. Place the bracket on the evaporator rotating at a constant speed for quantitative spraying. Finally, a PVA protective layer with a thickness of 1000um is formed on the reservoir layer.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 3

1. Preparation of drug-loaded microspheres:

Disperse cisplatin 200 mg into 700 mg of poly-L-propionate in 50 ml of dichloromethane solution, mix it with a mixed aqueous solution containing 0.05% MC and 4% PVA, sonicate it into an O/W type emulsion, distill off di That is obtained after methyl chloride.

2. Preparation of micro-nanosphere storage layer:

The prepared microspheres were mixed with PLGA and added dextrin and bonded with the backing layer. The thickness of the reservoir layer is 200um.

3. Preparation of backing layer:

2g polyurethane was dissolved in 20ml DMF solution. Dissolve under stirring at 40°C for 6 hours and then pour it onto glass to form a film. The membrane was then glued to the scaffold with silicone glue. The thickness is 20um.

4. Preparation of protective film layer:

Weigh low molecular weight HPMC, add 100ml double distilled water to dissolve, and pour into a self-made uniform spray device. Place the bracket on the evaporator rotating at a constant speed for quantitative spraying. Finally, an HPMC protective layer with a thickness of 1um is formed on the reservoir layer. The thickness is 50um.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 4

1. Preparation of drug-loaded microspheres by irradiation polymerization:

Dissolve 600 mg of methyl methacrylate in 100 mg of 5-fluorouracil solution, and then irradiate with 5×10-5 Gy of Cor-rays to obtain drug-embedded microspheres polymerized by methyl methacrylate.

2. Preparation of microsphere storage layer:

The prepared microspheres are mixed with viscous substance PVP, and hot pressed on the backing layer.

3. Preparation of backing layer:

Lay the glass plate with the perimeter flat. Add 2-hydroxyethyl methacrylate and a crosslinking agent mixed solution (10:0.5). Then irradiate UV or visible light for a certain period of time to make it cross-linked. Repeatedly, the film-formed drug film is used as a substrate, and film formation is continued on it. As a backing layer, the thickness is 100um.

4. Preparation of protective layer:

On the drug storage layer, a macroporous silicon rubber that does not affect drug release is attached as a protective layer. The thickness is 100um.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 5

1. Preparation of drug-loaded nanospheres by emulsion polymerization:

Weigh 10mg of 5-fluorouracil, add 100ml 0.1mol/l hydrochloric acid solution to dissolve, add pluonicF68 solution and stabilizer, adjust the pH value, add dropwise the organic solvent containing isobutyl cyanoacrylate monomer under stirring, stir After 3 hours, add anhydrous sodium sulfate, continue to stir for 1 hour, and filter with a G3 vertical fusing glass funnel to obtain the obtained product.

2. Preparation of nanosphere storage layer:

The prepared drug-loaded nanospheres are mixed with the viscous substance PVP and adhered on the backing layer. The thickness of the nanosphere storage layer is 10um.

3. Preparation of backing layer:

Take 10g of silicone rubber and dissolve it in 20ml of toluene. Then add 0.5g tetraethyl orthosilicate, 0.1g curing agent, stir for 10 minutes to make it uniform. Then immerse the cleaned stent in it and take it out after staying for 5 minutes. Install and rotate the bracket on a rotary evaporator, and heat and humidify for 2 hours to form a uniform film as a backing layer. The thickness is 2um.

4. Preparation of protective layer:

Spray gelatin as a protective layer with a thickness of 50um.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 6

1. Preparation of drug-loaded nanospheres by natural polymer aggregation method:

Weigh 50 mg of doxorubicin, add 3 ml of gelatin, and emulsify in 3 ml of sesame oil. The formed emulsion was cooled in an ice bath, then diluted with acetone, filtered through a filter membrane with a pore size of 50 nm, and the large microspheres were discarded. Wash off the oil on the nanospheres with acetone, add 30 ml of acetone solution of 10% formaldehyde to solidify the nanospheres for 10 minutes, wash with acetone, and air-dry to obtain.

2. Preparation of microsphere storage layer:

The nanospheres are mixed with sticky starch and adhered on the backing layer, and the thickness of the drug storage layer is 1500um.

3. Preparation of backing layer:

The backing layer is a mixture of PVA and silicone rubber. Take 10g of silicone rubber and dissolve it in 20ml of toluene. Then add 0.5g tetraethyl orthosilicate, 0.1g curing agent, stir for 10 minutes to make it uniform. Then immerse the cleaned stent in it and take it out after staying for 5 minutes. Install and rotate the bracket on a rotary evaporator, and heat and humidify for 2 hours to form a uniform film. Dip the PVA solution on it again, evaporate it dry, and use it as a backing layer. The thickness is 20um.

4. Preparation of protective film layer:

Weigh 10 mg of low molecular weight HPMC, add 100 ml of double distilled water to dissolve, and pour it into a self-made uniform spray device. Place the bracket on the evaporator rotating at a constant speed for quantitative spraying. Finally, an HPMC protective layer with a thickness of 50um is formed on the reservoir layer.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 7

1. Preparation of drug-loaded nanospheres:

Liquid drying method. Dissolve paclitaxel 100mg and polycaprolactone 1g in chloroform, and use ultrasonic emulsification in 0.5% gelatin aqueous solution for 45 minutes at 15°C to prepare

.O/W type emulsion. Then heated to 40° C. and continued to evaporate the solvent under ultrasonic treatment, centrifuged, washed, and freeze-dried to obtain nanospheres with a particle size of 500 nm.

2. Preparation of nanosphere storage layer:

The nanospheres are mixed with sticky starch and adhered on the backing layer, and the thickness of the drug storage layer is 250um.

3. Preparation of backing layer:

10 g of polyurethane was dissolved in dimethyl sulfoxide to prepare a solution, and stirred at a speed of 100 rpm for 10 minutes to make it uniform. Then immerse the cleaned stent and stay for 10 minutes, then take it out and place it in a special rotary evaporator, heat and humidify for 2 hours, the temperature is 40-80°C, the humidity is 80-100%, and the back lining. The thickness is 80nm.

4. Preparation of protective film layer:

Weigh low-molecular-weight HPMC, add 100ml of double-distilled water to dissolve, and pour it into a self-made uniform spray device. Place the bracket on the evaporator rotating at a constant speed for quantitative spraying. Finally, an HPMC protective layer with a thickness of 50um is formed on the reservoir layer.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 8

1. Preparation of drug-loaded nanospheres by automatic emulsification method:

Mix 100 mg of DL-lactide/glycolide copolymer and 10 mg of 5-fluorouracil in 1.5 ml of water filtered through a 0.2um membrane filter, add a mixed solvent (15 ml of acetone, 0.5 ml of dichloromethane), and pour 50 ml of PVA aqueous solution ( 20 g/L), acetone rapidly diffuses into the water phase, forming nano-sized emulsion droplets (auto-emulsification). After 3-4 hours, dichloromethane volatilized from the solvent, and the emulsion droplets solidified in water to form nanospheres.

2. Preparation of nanosphere storage layer:

The nanospheres are mixed with sticky starch and hot-pressed on the backing layer, and the thickness of the drug storage layer is 250um.

3. Preparation of backing layer:

Rubber-type pressure-sensitive adhesive is used as the backing layer. The thickness is 40um.

4. Preparation of protective layer:

Spray gelatin as a protective layer with a thickness of 1um.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stenosis.

Example 9

1. Preparation of drug-loaded nanospheres:

Liquid drying method. Dissolve paclitaxel 200mg and polycaprolactone 2g in chloroform, and use ultrasonic emulsification in 0.5% gelatin aqueous solution at 15°C for 45 minutes to obtain an O/W type emulsion. Then heated to 40° C. and continued to evaporate the solvent under ultrasonic treatment, centrifuged, washed, and freeze-dried to obtain nanospheres with a particle size of 500 nm.

2. Preparation of nanosphere storage layer:

The nanospheres are mixed with sticky starch and hot-pressed on the backing layer, and the thickness of the drug storage layer is 250um.

3. Preparation of backing layer:

A thermoplastic elastomer pressure sensitive adhesive is used as the backing layer. The thickness is 1000um.

4. Preparation of protective film layer:

Weigh low-molecular-weight HPMC, add 100ml of double-distilled water to dissolve, and pour it into a self-made uniform spray device. Place the bracket on the evaporator rotating at a constant speed for quantitative spraying. Finally, an HPMC protective layer with a thickness of 50um is formed on the reservoir layer.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stricture.

Example 10

1. Preparation of drug-loaded nanospheres by automatic emulsification method:

Mix 200mg of DL-lactide/glycolide copolymer and 20mg of 5-fluorouracil in 3.0ml of water filtered through a 0.2um filter membrane, add a mixed solvent (30ml of acetone, 1ml of dichloromethane), and pour 100ml of PVA aqueous solution (20g /L), acetone rapidly diffuses into the aqueous phase, forming nano-sized emulsion droplets (auto-emulsification). After 3-4 hours, dichloromethane volatilized from the solvent, and the emulsion droplets solidified in water to form nanospheres.

2. Preparation of microsphere storage layer:

The nanospheres are mixed with sticky starch and hot-pressed on the backing layer, and the thickness of the drug storage layer is 250um.

3. Preparation of backing layer:

Rubber-type pressure-sensitive adhesive is used as the backing layer. The thickness is 5um.

4. Preparation of protective layer:

Spray gelatin as a protective layer with a thickness of 50um.

The prepared micro/nano spheres have good particle size and particle size distribution, high encapsulation efficiency and drug loading rate. The backing layer is tightly covered on the stent, so as to prevent the seepage of the drug solution and the infiltration of the solid liquid in the digestive tract from the backing layer. On the backing layer is a storage layer of micro-nanospheres, in which medicines are stored in the form of micro-nanospheres and protected from damage by acid-base liquid and enzymes in the digestive tract. The protective layer is located on the micro/nano ball storage layer, which can protect the drug film from contamination, and protect the drug-loaded slow-release micro/nano ball stent from being fully implanted in the human body. After the micro/nanosphere-loaded stent is implanted in the human body, it directly acts on the diseased tissue or its vicinity, so that local slow and long-term administration can be performed to achieve the purpose of treating digestive tract stricture.

Claims (10)

1. the preparation method of a carried medicine sustained-release micro-/ nano ball alimentary stent is characterized in that, may further comprise the steps:

(1) a kind of preparation medicine carrying microballoons in the following four kinds of methods of employing: the genealogy of law 1. is heating and curing; 2. add the cross-linking agent solidification method; 3. the solvent aggregation method volatilizees; 4. shine polymerization;

The described genealogy of law that is heating and curing, specific as follows: by mass ratio is to get bovine serum albumin and 5-fluorouracil at 10: 1, the Oleum Gossypii semen that contains 10%Span with 100ml mixes, speed with 2500rpm stirs 10min, ultrasonic emulsification, other gets Oleum Gossypii semen 100ml and is heated to 180 ℃, under same mixing speed, add above-mentioned emulsion gradually, 180 ℃ of insulation 10min continue to be stirred to room temperature, add diethyl ether or petroleum ether 200ml defat, speed with 3000rpm is centrifugal, discard oil phase, precipitation is used ether, ethanol rinsing successively, makes the 5-fluorouracil microsphere;

The described cross-linking agent solidification method that adds adopts in following two kinds of methods any one: method one: medicine is scattered in the solution of carrier material, adds cross-linking agent and be solidified into gel, be dispersed into microparticulate system; Perhaps method two: medicine is dispersed in the carrier material solution, is emulsified into w/o type emulsion, add cross-linking agent again and make the oil-water interfaces of microdroplet be cross-linked into solid particle, washing promptly;

Described volatilization solvent aggregation method, its method is: medicine and substrate are scattered in the organic solvent, in the time of stirring, dropwise are added in the aqueous solution of polymer, obtain 0/W type emulsion, fling to organic solvent, washing, the dry microsphere that gets.4. shine polymerization: the monomer solution of polymer is brought out polyreaction with r ray or ultraviolet radiation, disperse to such an extent that microparticulate is, methyl methacrylate is dissolved in the 5-fluorouracil suspension, and reuse Co r-roentgenization obtains the microsphere of methyl methacrylate polymerization embedding medicinal;

Described irradiation polymerization, its method is: the monomer solution of polymer is brought out polyreaction with r ray or ultraviolet radiation, disperse to such an extent that microparticulate is, methyl methacrylate is dissolved in the 5-fluorouracil suspension, reuse Co r-roentgenization obtains the microsphere of methyl methacrylate polymerization embedding medicinal;

(2) adopt a kind of preparation medicine-carried nanospheres in following four kinds of methods: 1. emulsion polymerization method; 2. natural polymer coacervation; 3. intra-liquid desiccation method; 4. automatic emulsified method;

Described emulsion polymerization method, its method is: after taking by weighing 5-fluorouracil and dissolve with hydrochloric acid solution, add pluonicF68 solution and stabilizing agent, after regulating pH value, under agitation drip the monomeric organic solvent of cyano-containing Isobutyl 2-propenoate, stir, add anhydrous sodium sulfate, continue again to stir, filter with sintered glass funnel, promptly;

Described natural polymer coacervation, its method is: take by weighing amycin and gelatin, emulsifying in Oleum sesami, the emulsion that forms is cooled off in ice bath, the reuse acetone diluted filters with filter membrane, discards big microsphere, with the oil on the acetone flush away nanosphere, the acetone soln that adds formaldehyde makes nanosphere solidify washing with acetone, air drying, promptly;

Described intra-liquid desiccation method, its method is: medicine and polymer is dissolved in chloroform, in aqueous gelatin solution, makes w/o type emulsion with ultrasonic emulsification, heating, and continue under supersound process, to make solvent evaporation, centrifugal, washing, lyophilizing gets nanosphere;

Described automatic emulsified method, its method is: DL-poly (lactide-co-glycolide) and medicine are suspended in the water of membrane filtration, add acetone and dichloromethane mixed solvent, pour in the PVA aqueous solution, acetone diffuses into water rapidly, forms the emulsion droplet of nano-scale, leaves standstill, dichloromethane volatilizees from solvent, and emulsion droplet solidify to form nanosphere in water;

(3) preparation of micro-nano ball storage layer: the micro-/ nano ball for preparing is mixed with the macromolecular material with viscosity;

(4) preparation backing layer: directly with the backing layer material filming on support, perhaps existing film material is bonded on the support as backing layer;

(5) preparation protective film: after adhering to micro-/ nano ball storage layer on the backing layer, on micro-/ nano ball storage layer, prepare layer protective layer.

2. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, the described method one that adds in the cross-linking agent solidification method, concrete steps are as follows: preparation ametycin microsphere, get ametycin and Algin by 1: 100 mass ratio, earlier Algin is dissolved into the homogeneous thick liquid with distilled water in 80 ℃, concentration is 6%, add ametycin and an amount of mixing of 0.1 calcium chloride solution more successively, this mixed liquor is in acid, high volence metal ion and other bi-functional cross-linking agent effect form cross-linked network structure down and generate gel, and reprocessing is shredded into the microsphere that mean diameter is 600um;

The described method two that adds in the cross-linking agent solidification method, concrete steps are as follows: methotrexate/PVA is distributed in the 10ml aqueous solution with mass ratio at 1: 5, be added under rotating speed 900rpm stirs and contain in the 2.5% emulsifying agent oil solution, water wherein: oil=1: 3, continue to stir, emulsifying gets w/o type emulsion, adds cross-linking agent and makes emulsion droplet oil-water interfaces crosslinking curing, separate, washing promptly gets microsphere.

3. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described volatilization solvent aggregation method, its method is specific as follows: cisplatin is distributed in the dichloromethane solution of poly-L-propionic ester, the mass ratio of cisplatin and poly-L-propionic ester is 2: 7, with contain 0.05% methylcellulose and 4% polyvinyl alcohol mixing water solution mixes, ultrasonic breast is spared into O/W type emulsion, behind the steaming vibrating dichloromethane promptly.

4. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described irradiation polymerization, specific as follows: that methyl methacrylate is dissolved in the 5-fluorouracil suspension, described suspension, the mass ratio of its methyl methacrylate and 5-fluorouracil is 6: 1, reuse 5 * 10 ^-5The Co r-roentgenization of Gy.

5. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described emulsion polymerization method, it is specific as follows: in proportion 1: after 15W (mg)/V (ml) takes by weighing 5-fluorouracil and 0.1mol/l dissolve with hydrochloric acid solution, add pluonicF68 solution and stabilizing agent, after regulating pH value, under agitation drip the monomeric organic solvent of cyano-containing Isobutyl 2-propenoate, stirred 3 hours, add anhydrous sodium sulfate, continue again to stir 1 hour, filter with sintered glass funnel, promptly.

6. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described natural polymer coacervation, specific as follows: by 10: 1W/W takes by weighing amycin and gelatin, emulsifying in the 3ml Oleum sesami, the emulsion that forms is cooled off in ice bath, the reuse acetone diluted, the filter membrane filtration with the 50nm aperture discards big microsphere, with the oil on the acetone flush away nanosphere, the acetone soln 30ml that adds 10% formaldehyde solidified nanosphere 10 minutes, and acetone is washed, air drying, promptly.

7. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described intra-liquid desiccation method, specific as follows: that medicine and polymer are dissolved in chloroform, in 15 ℃, 0.5% aqueous gelatin solution, can make w/o type emulsion in 45 minutes with ultrasonic emulsification, reheat to 40 ℃, and continue under supersound process, to make solvent evaporation, centrifugal, washing, lyophilizing, the nanosphere of particle diameter 500nm.

8. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described automatic emulsified method, specific as follows: with DL-poly (lactide-co-glycolide) and medicine with 10: 1W/W is suspended among the water 1.5ml of 0.2um membrane filtration, add mixed solvent acetone: dichloromethane=30: 1, pour among the 50mlPVA aqueous solution 20g/L, acetone diffuses into water rapidly, form the emulsion droplet of nano-scale, through 3-4 hour, dichloromethane volatilizees from solvent, and emulsion droplet solidify to form nanosphere in water.

9. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that described macromolecular material with viscosity is meant following one or more: polyvinyl pyrrolidone, polyvinyl alcohol, ethylene vinyl acetate copolymer, poloxamer, polyacrylic acid, sodium polyacrylate, carbomer, polyacrylic resin, starch, dextrin, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, arabic gum, gelatin, chitosan, sodium alginate, hyaluronic acid, albumin, agar, poly-maltotriose, xanthan gum, guar gum and pressure sensitive adhesive; Described pressure sensitive adhesive composition comprises: any one or a few in rubber type pressure-sensitive adhesive, thermoplastic elastomer pressure-sensitive adhesive, Acrylic Pressure Sensitive Adhesive, the organosilicon.

10. the preparation method of carried medicine sustained-release micro-/ nano ball alimentary stent according to claim 1, it is characterized in that, described backing layer is a single or multiple lift, backing layer itself is the biocompatibility pressure sensitive adhesive, perhaps for containing the material of biocompatibility pressure sensitive adhesive, perhaps for having the macromolecular material of cementation; Described macromolecular material with cementation is meant following any one or multiple: polyvinyl pyrrolidone, polyvinyl alcohol, ethylene vinyl acetate copolymer, poloxamer, polyacrylic acid, sodium polyacrylate, carbomer, polyacrylic resin, starch, dextrin, methylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hypromellose, arabic gum, gelatin, chitosan, sodium alginate, hyaluronic acid, albumin, agar, poly-maltotriose, xanthan gum, guar gum and biocompatibility pressure sensitive adhesive; Described pressure sensitive adhesive composition is following any one or multiple: rubber type pressure-sensitive adhesive, thermoplastic elastomer pressure-sensitive adhesive, Acrylic Pressure Sensitive Adhesive, organosilicon.