WO2016074115A1

WO2016074115A1 - Drug loaded nano anti-adhering membrane with core/shell structure and preparation method thereof

Info

Publication number: WO2016074115A1
Application number: PCT/CN2014/001166
Authority: WO
Inventors: 朱同贺; 陈思浩; 楼建中; 王继虎; 邢晨晨; 包一鸣; 杨春宇; 徐刚; 陈志昌; 马小彪; 周超; 张红梅
Original assignee: 上海工程技术大学
Priority date: 2014-11-14
Filing date: 2014-12-23
Publication date: 2016-05-19
Also published as: CN104491932A

Abstract

Disclosed is a drug loaded nano anti-adhering membrane with a core/shell structure and a preparation method thereof. The drug loaded nano anti-adhering membrane with a core/shell structure is formed by connecting fibers of a core and a shell structure in parallel, wherein the core comprises a therapeutically effective amount of an active ingredient and polyvinylpyrrolidone(PVP); the shell is of poly (lactic-co-glycolic acid) (PLGA), and micropores are provided on the shell. The drug loaded nano anti-adhering membrane with a core/shell structure has a preparation method which is easy, simple and efficient and the cost of which is low, wherein the membrane material prepared has a very good controllable specific surface area, a controllable pore size, mechanical properties, blood osmosis properties and a controllable biodegradability, and when preventing adhesion, causes no hypersensitivity to humans, while having affinities with blood and surrounding tissues in the human body, and having a bioadhesive surface and not rejecting.

Description

Core/shell structure drug-loaded nano anti-blocking film and preparation method thereof

Technical field

The invention relates to an anti-blocking film and a preparation method thereof.

Background technique

Adhesion after surgery is one of the important medical problems that have not yet been solved in the field of surgery at home and abroad. Adhesion not only causes serious complications, but also poor adhesion is one of the main reasons for the significant increase in complications during reoperation. The causes of adhesion formation are multifaceted. A large number of test results indicate that bleeding and tissue damage during surgery are the main causes of adhesion formation. In addition, the introduction of foreign matter, such as gauze fibers, thread ends, and talcum powder, can be triggered during surgery. Inflammation, and inflammation causes a large amount of tissue exudation, and fibrin in the exudate promotes and forms adhesions. It has also been shown that the animal is exposed to the air for a long time, causing dry cracks in the serosa layer. When the tissue is placed back into the abdominal cavity, adhesion occurs, indicating that the drying factor is also a cause of adhesion formation. The mechanism is that drying can cause the peritoneal mesothelial cells to die and form a thrombus, which leads to the formation of adhesions.

Bioabsorbable and degradable polymer materials are currently one of the ideal medical polymer materials. Electrospinning is a simple and efficient technique for preparing nanofibers. The jet is produced by applying a high electric field to the polymer solution or melt, and the jet is stretched while the solvent volatilizes to form fibers having a diameter of from 2 to 3000 nm. There are many products for biodegradable absorbent materials, anti-adhesion gel, anti-adhesion liquid, anti-adhesion film, etc., which have certain effects on preventing postoperative adhesion. However, the anti-adhesion liquid has strong fluidity and cannot function well as a physical barrier. The body can decrease the concentration of the wound site with body position and drainage, and the anti-adhesion effect is weakened. The anti-adhesion film has better isolation. The ideal anti-adhesion material should have low sensitization, suitable tissue adhesion, can completely cover the wound surface and have sufficient body retention time, can be degraded and absorbed without secondary surgery to remove it, and promote wound healing. It has a certain mechanical strength to facilitate the operation and the like.

At present, there are several anti-adhesion materials: polylactic acid, modified chitosan, carboxymethyl cellulose, and hyaluronic acid.

Polylactic acid can be used as a release agent because of its high molecular weight and viscosity, and its action may be that it can affect the occurrence of agglutination reaction to prevent the adhesion of the film in the body. Tong Xiaochun conducted a polylactic acid gel to prevent abdominal adhesion test. Some problems have also been found in the clinical application of polylactic acid: (1) In clinical application, some patients are found to have non-specific aseptic inflammation, and the response rate is 8%. Considering the reason may be polylactic acid degradation process, acidity Degradation The substance causes a drop in local pH. Clinically, it can cause symptoms such as abdominal pain and fever in patients; (2) Polylactic acid is not easy to attach to tissues, and it is easy to slide off the wound surface and needs to be fixed by suture.

Modified chitosan is a relatively common anti-adhesion material with excellent bio-barrier properties and histocompatibility, applied to tissue wounds to prevent postoperative tissue adhesion. Chitosan has the characteristics of biocompatibility and tissue degradability, and theoretically it can be used as an anti-adhesion agent after surgery. However, the chitosan used in clinical practice is not high enough in purity, and the anti-adhesion effect is poor, and the degradation rate is difficult to be considered. The degradation of chitosan is also affected by the level of lysozyme in the human body, and the absorption effect is unpredictable.

Polylactic acid-glycolic acid (PLGA) is a typical biodegradable polymer with good biocompatibility, non-toxicity, good capsular and film-forming properties, and is widely used in pharmaceutical and medical engineering materials. And modern industrial fields. In the United States, PLGA passed the FDA certification and was officially included as a pharmaceutical excipient in the US Pharmacopoeia. The degradation products of PLGA are lactic acid and glycolic acid, and are also by-products of the human metabolic pathway, which does not have toxic side effects when applied to medicines and biological materials. By adjusting the monomer ratio and thus changing the degradation time of PLGA, this method has been widely used in the field of biomedicine, such as: skin transplantation, wound suturing, in vivo implantation, micro-nanoparticles, and the like. At present, the controllable degradation cycle of PLGA is controlled purely by controlling the molar ratio of PLGA synthesis monomer, which cannot be completely achieved. The low molecular weight polymer fragments produced by PLGA in the degradation process are complicated, and it is difficult to accurately degrade its degradation behavior. Quantitative analysis.

Summary of the invention

The object of the present invention is to provide a core/shell structure drug-loaded nano anti-adhesion film and a preparation method thereof to overcome the defects of the prior art.

The core/shell structure drug-loaded nano anti-adhesion film is composed of a core and a fiber of a shell structure in parallel;

among them:

The core comprises a therapeutically effective amount of an active ingredient and polyvinylpyrrolidone (PVP);

The outer casing is polylactic acid-glycolic acid (PLGA), and the outer casing is provided with micropores, the pore diameter is 10 to 100 nanometers, and the number of micropores per square centimeter of the outer shell is 3×10 ⁷ to 5×. 10 ⁷ ;

The polylactic acid-glycolic acid has a weight average molecular weight of 80,000 to 100,000; and the polyvinylpyrrolidone has a weight average molecular weight of 40,000 to 55,000;

Preferably, the active ingredient is flurbiprofen, ibuprofen, ketoprofen, indomethacin or diclofenac; preferably, flurbiprofen ester is based on the total weight of the active ingredient and polyvinylpyrrolidone The weight content is 0.1 to 0.4%;

Preferably, the fiber has a fineness of 0.13 to 0.2;

Preferably, the weight ratio of the polyvinylpyrrolidone to the polylactic acid-glycolic acid is from 2:1 to 10:1;

The method for preparing a core/shell structure drug-loaded nano anti-adhesion film according to the present invention comprises the following steps:

(1) dissolving polylactic acid-glycolic acid in a mixed solvent of dichloromethane (DCM) and N,N-dimethylformamide (DMF), adding nano dry ice particles, mixing and dispersing, as a shell spinning solution;

The weight ratio of dichloromethane to N,N-dimethylformamide is from 2:1 to 5:1;

The polylactic acid-glycolic acid is present in an amount of 8 to 12% by weight based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide, and nano dry ice particles;

The weight percentage of the nano dry ice particles is 0.1% to 5%, preferably 0.1% to 0.5%, based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide and the nano dry ice particles;

(2) Dissolving polyvinylpyrrolidone and active drug in a mixed solvent of ethanol and N,N-dimethylformamide, stirring at 20-25 ° C, dispersing, and ethanol and N,N-dimethylformamide The weight ratio is 1:1 to 3:1, and a nuclear layer spinning solution is obtained;

In a mixed solvent of anhydrous ethanol and N,N-dimethylformamide, the weight content of polyvinylpyrrolidone is 4 to 8%;

(3) In the 3 to 10 minutes after the preparation of the shell spinning solution, the shell spinning solution and the core layer spinning solution are subjected to coaxial electrospinning at 25 to 30 ° C to obtain a composite drug-loading fiber. Membrane material; the coaxial electrospinning method is a well-known method in the art, such as A new nanofiber fabrication technique based on coaxial electrospinning [J]. Materials Letters, 2012, 66: 257-260. The method of reporting.

(4) The obtained composite drug-loaded fiber membrane material is freeze-dried, placed in a vacuum freeze dryer equipped with activated carbon, and freeze-dried at -45 to -55 ° C for 20 to 24 hours to remove dichloride by freeze-adsorption-sublimation method. Methane, N,N-dimethylformamide solvent and water, to obtain the core/shell structure drug-loading nano anti-adhesion film; preferably, the sterilization step is further: vacuum sterilization for 4-8 hours, then With the fiber orientation, the fiber membrane was cut into a rectangular sample of 30 mm × 50 mm, and tableted.

The core/shell structure drug-loaded nano anti-adhesion film obtained by the invention can be used for anti-adhesion between tissues during wound healing after surgery, and the application method is as follows:

After all the operations were performed routinely, before the end of the operation, after complete and complete hemostasis and debridement, the anti-adhesion membrane was evenly spread between the wounds or tissues that need to prevent adhesion. (The amount of the wound depends on the size of the wound. The smaller wounds are 10mm×20mm; the larger wounds are 30mm×50mm), and the surgical pathway can be closed after the adhesion is cured (in the case of tissue fluid for 1-2 minutes).

Pharmacological tests have shown that healthy subjects use flurbiprofen avinate nanofiber analgesic membrane 20mm × 20mm (drug containing After 5 to 10 minutes after the amount of 50 mg), the blood drug concentration reached a peak. When the dose is between 10 and 80 mg, the blood concentration is linear. The drug elimination half-life was 5.8 h. At 48 hours after administration, the cumulative amount of urinary drug excretion was about 85% of the dose. The drug was administered continuously for 5 times at intervals of 12 hours. The cumulative drug excretion rate in the urine reached nearly 100% 48 hours after the last administration. No drug accumulation was found in the body.

The nano-dry ice particles are used as a pore-forming agent, and a nano-anti-adhesion film with a controllable ultra-high specific surface area core/shell structure is obtained by a coaxial electrospinning method, and the preparation method is simple and efficient, and the price is low. Membrane material has good controllable specific surface area, controllable pore size, mechanical properties, blood permeability and controllable biodegradability. It has no hypersensitivity to anti-adhesion, and it also has blood and surrounding tissues in human body. Affinity, bioadhesive surface and no rejection.

DRAWINGS

Figure 1 is a statistical diagram of the diameter distribution of the drug-loaded nanofibers in the core/shell structure;

Fig. 2 Scanning electron micrograph of the surface morphology and core/shell structure of the drug-loaded nanofibers in the core/shell structure;

Figure 3 shows the results of NIH3T3 cytotoxicity test;

Figure 4 shows the results of IEC-6 cytotoxicity test;

Figure 5 shows the adhesion rate of NIH3T3 cells on different membranes;

Figure 6 shows the adhesion rate of IEC-6 cells on different membranes;

Figure 7 is a graph showing the relationship between the cumulative amount of drug released and the amount of porogen.

detailed description

The invention will now be further described with reference to the accompanying drawings.

Example 1

(1) Dissolving polylactic acid-glycolic acid in a mixed solvent of dichloromethane and N,N-dimethylformamide, and electrically stirring at 25 ° C for 10 hours (rotation speed 550 r / min), then adding a particle size of 500 nm The dry ice particles were electrically stirred for 2 hours, and finally ultrasonically shaken for 20 minutes to obtain a spinning solution having a polylactic acid-glycolic acid content of 10% by weight as a shell solution;

The weight ratio of dichloromethane to N,N-dimethylformamide is 3:1;

The polylactic acid-glycolic acid is 10% by weight based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide and nano dry ice particles;

The weight percentage of the nano dry ice particles is 0.1% based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide and the nano dry ice particles;

(2) Dissolving polyvinylpyrrolidone and flurbiprofen ester in a mixed solvent of absolute ethanol and N,N-dimethylformamide, stirring at 25 ° C, dispersing, ethanol and N,N-dimethylformamide a weight ratio of 2:1 to obtain a core layer spinning solution;

In a mixed solvent of anhydrous ethanol and N,N-dimethylformamide, the weight content of polyvinylpyrrolidone is 8%;

(3) In the 10 minutes after the preparation of the shell spinning solution, the shell spinning solution and the core layer spinning solution are subjected to coaxial electrospinning at 25 ° C to obtain a composite drug-loaded fiber membrane material;

Temperature 25 ° C, relative humidity 50%, shell spinning flow rate 0.8mm / min, core layer spinning flow rate 0.05mm / min, spinning positive high pressure 18kV, negative high pressure 1.25kV, coaxial electrospinning under reel receiving conditions wire.

(4) The obtained composite drug-loaded fiber membrane material was placed in a vacuum freeze dryer equipped with activated carbon, and subjected to freeze-adsorption-sublimation method, freeze-drying at -55 ° C for 20 hours to remove dichloromethane, N, N-di The methylformamide solvent and moisture are used to obtain the controlled ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film; preferably, the sterilization step is further: vacuum sterilization for 4 hours, and then following the fiber orientation, The fiber membrane was cut into a rectangular sample of 30 mm × 50 mm and molded into tablets. The pore size of the micropores on the outer shell is 100 nm, and the number of micropores per square centimeter of the outer shell is 3×10 ⁷ ;

The polylactic acid glycolic acid has a weight average molecular weight of 100,000; the polyvinylpyrrolidone has a weight average molecular weight of 55,000;

The weight content of flurbiprofen is 0.4% by weight based on the total weight of flurbiprofen and polyvinylpyrrolidone;

The fineness of the fiber is 0.2;

The weight ratio of polyvinylpyrrolidone to polylactic acid-glycolic acid is 2:1;

The pore size of the micropores on the outer shell can be detected by CJ Luo et al., A novel method of selecting solvents for polymer electrospinning [J]. Polymer, 2010, 51(7): 1654-1662. The method described in the literature, or by Young You et al. Porcelain ultrafine PGA fibers via selective dissolution of electrospun PGA/PLA blend fibers [J]. Materials Letters, 2006, 60: 757-760. Methods for detecting the number of micropores can be performed using Z. Huang et al. Electrospinning and mechanical characterization of gelatin nanofibers [ J]. Polymer, 2004, 45 (15): 5361-5368. The method reported in the literature is tested, or measured by the BET equation;

Figure 1 is a statistical diagram of the diameter distribution of drug-loaded nanofibers in a core/shell structure;

Figure a represents the diameter distribution of polylactic acid-glycolic acid/flurbiprofen ester blended nanofiber membrane, and b represents the diameter distribution of polylactic acid-glycolic acid/4% polyvinylpyrrolidone/flurbiprofen ester core/shell nanofiber membrane , Figure c represents polylactic acid-glycolic acid / 6% polyvinylpyrrolidone / flurbiprofen ester core / shell nanofiber membrane diameter distribution, d map represents polylactic acid - glycolic acid / 6% polylactic acid - glycolic acid / flurbi The distribution of fentanyl core/shell nanofiber membrane diameter.

Figure 2 is an SEM image of the surface morphology and core/shell structure of the drug/loaded nanofibers in the core/shell structure.

Example 2

The weight ratio of dichloromethane to N,N-dimethylformamide is 5:1;

The weight content of polylactic acid-glycolic acid is 12% by weight based on the total weight of polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide and nano dry ice particles;

The weight percentage of the nano dry ice particles is 0.5% based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide and the nano dry ice particles;

(2) Dissolving polyvinylpyrrolidone and flurbiprofen ester in a mixed solvent of absolute ethanol and N,N-dimethylformamide, stirring at 25 ° C, dispersing, anhydrous ethanol and N,N-dimethyl The weight ratio of formamide is 1:1, and a nuclear layer spinning solution is obtained;

In a mixed solvent of anhydrous ethanol and N,N-dimethylformamide, the weight content of polyvinylpyrrolidone is 4%;

(3) In the 25 minutes after the preparation of the shell spinning solution, the shell spinning solution and the core layer spinning solution are subjected to coaxial electrospinning at 30 ° C to obtain a composite drug-loaded fiber membrane material;

(5) The obtained composite drug-loaded fibrous membrane material was freeze-dried, placed in a vacuum freeze dryer equipped with activated carbon, and freeze-dried at -45 ° C for 20 hours to remove dichloromethane/N,N-dimethylformamide, Anhydrous ethanol / N, N-dimethylformamide, and then dried under vacuum at room temperature for 20 hours to remove residual dichloromethane / N, N-dimethylformamide, anhydrous ethanol / N, N-dimethyl The formamide and water were used to obtain the controlled ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film; vacuum drying for 15 hours, and then following the fiber orientation, the fiber membrane was cut into a rectangular sample of 30 mm×50 mm. Tablet molding.

The pore size of the micropores on the outer shell is 10 nanometers, and the number of micropores per square centimeter of the outer shell is 5×10 ⁷ ;

The polylactic acid glycolic acid has a weight average molecular weight of 80000; the polyvinylpyrrolidone weight average molecular weight is 40,000;

The weight content of flurbiprofen is 0.1% by weight based on the total weight of flurbiprofen and polyvinylpyrrolidone;

The fineness of the fiber is 0.13;

The weight ratio of polyvinylpyrrolidone to polylactic acid-glycolic acid was 10:1.

Example 3

Cytotoxicity test of drug-loaded polylactic acid-glycolic acid electrospinning membrane

(1) Inoculate cells in logarithmic growth phase into 96-well plates, ensuring that the number of cells incubated for 2 days is 6000/well, and the number of cells incubated for 4 days and 7 days is 4000/well and 3000/well, respectively. ;

(2) The inoculated cells were adhered to the incubator for 6 hours, and then the prepared drug-loaded electrospun membrane of Example 1 having a size similar to that of the 96-well was placed in the medium to be soaked. Subject to the medium;

(3) After incubating for 2, 4, and 7 days, respectively, the drug-loaded polylactic acid-glycolic acid electrospinning membrane was taken out, and the cells were subjected to CCK-8 measurement;

(4) Data analysis was performed using a well without a membrane as a control well.

The flurbiprofen ester/polyvinylpyrrolidone/polylactic acid-glycolic acid composite nanofiber membrane was co-cultured with IEC-6 cells and NIH3T3 cells, and detected by CCK-8 reagent detection method, it was found that flurbiprofen ester/ The polyvinylpyrrolidone/polylactic acid-glycolic acid composite nanofiber membrane is not toxic.

Example 4

Adhesion test of cells on drug-loaded polylactic acid-glycolic acid electrospinning membrane

(1) 60 μm thick, 100 μm thick, 160 μm thick, 220 μm thick of the drug-loaded polylactic acid-glycolic acid electrospinning film of Example 1 and a commercial film cut into a cover glass-sized square piece, and spread to 6 holes. In the plate, 6 holes were made for each membrane, and the 6-well plate was peeled off, and the film was irradiated with ultraviolet light for 30 minutes. The glass slides placed in the 6-well plate were also irradiated with ultraviolet light for 30 minutes to prepare cells for inoculation;

(2) Inoculate the cells into each well and incubate for different time periods (2 days, 4 days, 7 days), and ensure that the number of cells incubated for 2 days is 400,000/well, and the number of cells incubated for 4 days and 7 days is 40,000 respectively. /well and 4000/well, after incubation, gently aspirate the supernatant, then transfer the membrane and coverslip to a new 6-well plate, add 1.5 mL of MTT solution per well (5 mg/mL in PBS, use Pre-diluted 10 times with medium), continue to incubate for 4 hours;

(3) Carefully aspirate the culture supernatant in the well, add 1 mL of dimethyl sulfoxide per well, and shake for 10 min to fully melt the crystal;

(4) Colorimetric: select the wavelength of 490 nm, measure the light absorption value of each well on the enzyme-linked immunosorbent monitor, and record the result;

(5) Calculating the adhesion rate by comparing the absorbance of the coverslip;

(6) Calculation method of adhesion rate: adhesion rate = (control hole absorbance value - test hole absorbance value) / control hole absorbance value × 100%.

The IEC-6 and NIH3T3 cells were cultured on different thicknesses of flurbiprofen ester/polyvinylpyrrolidone/polylactic acid-glycolic acid composite nanofiber membrane, and then subjected to relevant treatment and detected by MTT colorimetry. Compared with the control group, the results showed that the cells were not easily adhered to the flurbiprofen ester/polyvinylpyrrolidone/polylactic acid-glycolic acid composite nanofiber membrane.

Example 5

Experiment on cumulative drug release in drugs

Accurately weigh a certain amount of polylactic acid-glycolic acid-loaded nanofiber membrane in a 100mL Erlenmeyer flask, add 50mL PBS (pH=7.4) buffer solution, seal and place in a constant temperature shaker, set the temperature to 37 °C, shake The bed speed is 100 rpm. A 10 mL solution was taken at a set time interval to be tested, and 10 mL of fresh PBS was added to the original sample to keep the original volume unchanged. The extracted sample solution was measured for absorbance A at a wavelength of 246.0 nm, and the concentration C of the sample solution was calculated by a standard curve A = 3.99552 C + 0.02474, and the cumulative release rate was further calculated.

Drug cumulative release formula:

C-flurbiprofen ester concentration, μg / mL;

ΣW—Sampling cumulative consumption, μg;

M—the total weight of the drug-loaded nanofiber membrane, mg;

R-loading amount in the fiber membrane.

The encapsulation efficiency of drug-loaded nanofiber membranes prepared by coaxial electrospinning technology is relatively high, close to 100%, mainly due to the dissolution of flurbiprofen ester in polyvinylpyrrolidone solution by blending, and then through the same The axis electrospinning technology is loaded into the polylactic acid-glycolic acid matrix, and the amount of drug lost during the whole preparation process is small; the drug loading of the polylactic acid-glycolic acid based nanofiber membrane is mainly affected by the porosity of the fiber surface. When the porosity of the fiber surface increases, the cumulative release rate of the drug in the corresponding same time will also increase. The porogen's content in the fiber matrix affects the surface porosity and fiber specific surface area of the drug-loaded nanofibers. The amount of porogen increased, the pore diameter of the single fiber surface increased, the porosity increased, and the specific surface area of the fiber membrane increased. However, the amount of porogen should not be too much. When the amount exceeds a certain amount, the drug in the fiber will be exposed, and the fiber will not release the drug in a controlled manner, but will produce a more serious burst release phenomenon; Hours, for an analgesic drug with a short drug-effect period and a high blood concentration (such as the drug contained in this patent), although it can achieve a controlled release effect, it does not have a good effect.

Claims

a core/shell structure drug-loaded nano anti-adhesion film characterized by being composed of a core and a shell structure of a fiber in parallel; wherein:

The core comprises a therapeutically effective amount of an active ingredient and polyvinylpyrrolidone (PVP);

The outer casing is polylactic acid-glycolic acid (PLGA), and the outer casing is provided with micropores.
The controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film according to claim 1, wherein the micropore pore size is 10 to 100 nm, and the pores per square centimeter are microporous. The number is 3 × 10 7 to 5 × 10 7 .
The controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-blocking film according to claim 1, wherein the polylactic acid-glycolic acid has a weight average molecular weight of 80,000 to 100,000; and the polyvinylpyrrolidone has a weight average The molecular weight is from 40,000 to 55,000.
The controllable ultrahigh specific surface area core/shell structure drug-loaded nano anti-adhesion film according to claim 2, wherein the polylactic acid-glycolic acid has a weight average molecular weight of 80000 to 100000; and the polyvinylpyrrolidone weight average The molecular weight is from 40,000 to 55,000.
The controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film according to any one of claims 1 to 4, wherein the active ingredient is flurbiprofen ester, ibuprofen, ketone Lofin, indomethacin or diclofenac.
The controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film according to claim 5, wherein the weight ratio of flurbiprofen ester is 0.1 based on the total weight of the active ingredient and polyvinylpyrrolidone. ~0.4%;
The controllable ultrahigh specific surface area core/shell structure drug-loaded nano anti-adhesion film according to any one of claims 1 to 4, wherein the fiber has a fineness of 0.13 to 0.2.
The controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film according to any one of claims 1 to 4, wherein the weight ratio of the polyvinylpyrrolidone to the polylactic acid-glycolic acid is 2: 1 to 10:1.
The method for preparing a controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film according to any one of claims 1 to 8, which comprises the following steps:

(1) dissolving polylactic acid-glycolic acid in a mixed solvent of dichloromethane (DCM) and N,N-dimethylformamide (DMF), adding nano dry ice particles, mixing and dispersing, as a shell spinning solution;

(2) Dissolving polyvinylpyrrolidone and active drug in a mixed solvent of absolute ethanol and N,N-dimethylformamide Medium, stirring, dispersing, obtaining a core layer spinning solution;

In a mixed solvent of anhydrous ethanol and N,N-dimethylformamide, the weight content of polyvinylpyrrolidone is 4 to 8%;

(3) In the 3 to 10 minutes after the preparation of the shell spinning solution, the shell spinning solution and the core layer spinning solution are subjected to coaxial electrospinning at 25 to 30 ° C to obtain a composite drug-loading fiber. Membrane material

(4) The obtained composite drug-loaded fiber membrane material was placed in a vacuum freeze dryer equipped with activated carbon, and freeze-dried by a freeze-adsorption-sublimation method at -45 to -55 ° C for 20 hours to remove dichloromethane, N, N. - dimethylformamide solvent and water, vacuum sterilization for 4-8 hours, to obtain the controllable ultra-high specific surface area core/shell structure drug-loaded nano anti-adhesion film.
The method according to claim 9, wherein the weight ratio of dichloromethane to N,N-dimethylformamide in step (1) is from 2:1 to 5:1;

The polylactic acid-glycolic acid is present in an amount of 8 to 12% by weight based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide, and nano dry ice particles;

The weight percentage of the nano dry ice particles is 0.1% to 5% based on the total weight of the polylactic acid-glycolic acid, dichloromethane, N,N-dimethylformamide and the nano dry ice particles;

In the step (2), the weight ratio of absolute ethanol to N,N-dimethylformamide is 1:1 to 3:1.