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WO2016074115A1 - 核/壳结构载药纳米防粘连膜及其制备方法 - Google Patents

核/壳结构载药纳米防粘连膜及其制备方法 Download PDF

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WO2016074115A1
WO2016074115A1 PCT/CN2014/001166 CN2014001166W WO2016074115A1 WO 2016074115 A1 WO2016074115 A1 WO 2016074115A1 CN 2014001166 W CN2014001166 W CN 2014001166W WO 2016074115 A1 WO2016074115 A1 WO 2016074115A1
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core
shell structure
drug
polylactic acid
glycolic acid
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PCT/CN2014/001166
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English (en)
French (fr)
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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
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上海工程技术大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/04—Macromolecular materials
    • A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D1/00—Treatment of filament-forming or like material
    • D01D1/02—Preparation of spinning solutions

Definitions

  • the invention relates to an anti-blocking film and a preparation method thereof.
  • 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.
  • 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.
  • 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.
  • biodegradable absorbent materials anti-adhesion gel, anti-adhesion liquid, anti-adhesion film, etc., which have certain effects on preventing postoperative adhesion.
  • 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.
  • 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.
  • 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 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.
  • 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;
  • the core comprises a therapeutically effective amount of an active ingredient and polyvinylpyrrolidone (PVP);
  • PVP polyvinylpyrrolidone
  • 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 ;
  • PLGA polylactic acid-glycolic acid
  • 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;
  • 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%;
  • the fiber has a fineness of 0.13 to 0.2;
  • 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:
  • 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;
  • the weight content of polyvinylpyrrolidone is 4 to 8%;
  • 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.
  • 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.
  • 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:
  • 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).
  • 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.
  • 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.
  • 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;
  • 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;
  • 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
  • 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.
  • 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;
  • the weight content of polyvinylpyrrolidone is 4%;
  • 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.
  • 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 1 (1) 60 ⁇ m thick, 100 ⁇ m thick, 160 ⁇ m thick, 220 ⁇ m 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.
  • 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;
  • 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;
  • 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.
  • M the total weight of the drug-loaded nanofiber membrane, mg
  • 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.
  • the amount of porogen should not be too much.
  • 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.

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Abstract

一种核/壳结构载药纳米防粘连膜及其制备方法，所述核/壳结构载药纳米防粘连膜，由内核和外壳结构的纤维并联构成；其中：所述的内核包括治疗有效量的活性成分和聚乙烯吡咯烷酮(PVP)；所述的外壳为聚乳酸-羟基乙酸(PLGA)，所述的外壳上设有微孔。该核/壳结构载药纳米防粘连膜，制备方法简单高效，价格低廉，制备的膜材料具有很好的可控比表面积性、可控孔隙大小、力学性能、透血液性能和可控生物降解性能，在防粘连时对人体无超敏反应，同时与人体内的血液及周边组织具有亲和力，具有生物粘合性表面且无排异现象。

Description

核/壳结构载药纳米防粘连膜及其制备方法 技术领域
本发明涉及一种防粘连膜及其制备方法。
背景技术
手术后粘连是国内外外科手术领域至今尚未解决的重要医学难题之一。粘连不仅会引起严重的并发症，而且不良粘连也是再次手术时并发症明显增高的主要原因之一。导致粘连形成的原因是多方面的，大量试验结果表明，手术过程中出血及组织损伤是粘连形成的主要原因，另外，手术过程中异物的引入，如纱布纤维、线头、滑石粉，都能引发炎症反应，而炎症会造成大量的组织渗出，渗出物中的纤维蛋白就会助长和形成粘连。还有试验表明，把动物长时间暴露在空气中，使其浆膜层出现干燥性裂纹，当组织放回到腹腔后即出现粘连，说明干燥因子也是粘连形成的一个原因。其机理是干燥可以使腹膜间皮细胞死亡，形成血栓，从而导致粘连的形成。
生物可吸收降解高分子材料是目前较理想的医用高分子材料之一。静电纺丝是一种简便高效制备纳米纤维的技术。通过向聚合物溶液或熔体施加高电场产生喷射流，射流被拉伸的同时溶剂挥发形成直径在2-3000nm的纤维。可生物降解吸收材料已有很多产品，防粘连凝胶、防粘连液体、防粘连膜等，对防止术后粘连起到了一定的效果。但防粘连液体流动性强，不能很好地起到物理屏障作用，体内可随体位及引流而使创面部位浓度下降，减弱了防粘连的效果。而防粘连膜的隔离作用更好。理想的防粘连材料应具有低致敏性、适宜的组织粘附性，能完全覆盖创伤表面并且具有足够的体内存留时间，能降解吸收而不需二次手术将其取出，促进创面愈合，同时具有一定的机械强度而便于实施操作等。
目前已有的防粘连材料有以下几种：聚乳酸、改性壳聚糖、羧甲基纤维素、透明质酸。
聚乳酸因其具有较高的分子量和粘度从而可用作防粘剂，其作用可能是它能影响凝集反应的发生以达到防止体内膜粘连的效果。童晓春进行了聚乳酸凝胶预防腹腔粘连试验。聚乳酸临床应用中也发现存在某些问题：(1)临床应用中，发现有的患者会出现非特异性无菌性炎症，反应率为8％，考虑其原因可能为聚乳酸降解过程中，酸性降解产 物引起局部pH值下降。临床上可引起患者腹痛、发热等症状；(2)聚乳酸不易贴附在组织上，易于滑离创面，需缝合固定。
改性壳聚糖是比较常见的防粘连材料，具有优良的生物屏障性能和组织相容性，涂于组织创面，防止术后组织粘连。壳聚糖由于具有生物相容性和组织可降解性等特点，从理论上讲制成膜后可作为理想的手术后防粘连剂。但目前在临床上使用的壳聚糖存在纯度不够高，对很多防粘连效果差，降解速度难于认为调控，壳聚糖的降解还受到人体内溶菌酶水平高低的影响，吸收效果不可预知。
聚乳酸-羟基乙酸(PLGA)是典型的可合成可生物降解的聚合物，具有良好的生物相容性、无毒、良好的成囊和成膜的性能，被广泛应用于制药、医用工程材料和现代化工业领域。在美国PLGA通过FDA认证，被正式作为药用辅料收录进美国药典。PLGA的降解产物是乳酸和羟基乙酸，同时也是人代谢途径的副产物，所当它应用在医药和生物材料中时不会有毒副作用。通过调整单体比，进而改变PLGA的降解时间，这种方法已广泛应用于生物医学领域中，如：皮肤移植，伤口缝合，体内植入，微纳米粒等。目前，纯粹通过控制PLGA合成单体摩尔比来控制PLGA可控降解周期，还不能完全做到，主要是PLGA在降解过程中产生的低分子量的聚合物碎片比较复杂，难以准确对其降解行为进行定量分析。
发明内容
本发明的目的是提供一种核/壳结构载药纳米防粘连膜及其制备方法，以克服现有技术存在的缺陷。
所述的核/壳结构载药纳米防粘连膜，由内核和外壳结构的纤维并联构成；
其中：
所述的内核包括治疗有效量的活性成分和聚乙烯吡咯烷酮(PVP)；
所述的外壳为聚乳酸-羟基乙酸(PLGA)，所述的外壳上设有微孔，孔径为10～100纳米，每平方厘米的外壳上，微孔的数量为3×107～5×107个；
所述的聚乳酸-羟基乙酸的重均分子量为80000～100000；聚乙烯吡咯烷酮重均分子量为40000～55000；
优选的，所述的活性成分为氟比洛芬酯、布洛芬、酮洛芬、吲哚美辛或双氯芬酸；优选的，以活性成分和聚乙烯吡咯烷酮的总重量计，氟比洛芬酯的重量含量为0.1～0.4％；
优选的，所述的纤维的纤度为0.13～0.2；
优选的，所述聚乙烯吡咯烷酮与聚乳酸-羟基乙酸的重量比为2:1～10:1；
本发明所述的核/壳结构载药纳米防粘连膜的制备方法，包括如下步骤：
(1)将聚乳酸-羟基乙酸溶解于二氯甲烷(DCM)和N,N-二甲基甲酰胺(DMF)混合溶剂中，再加入纳米干冰粒子，混合分散，作为壳层纺丝溶液；
二氯甲烷与N,N-二甲基甲酰胺的重量比为2:1～5:1；
以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，聚乳酸-羟基乙酸的重量含量为8～12％；
以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，纳米干冰粒子的重量百分比为0.1％～5％，优选的为0.1％～0.5％；
(2)将聚乙烯吡咯烷酮和活性药物溶解在乙醇和N,N-二甲基甲酰胺混合溶剂中，20～25℃下搅拌，分散，无水乙醇与N,N-二甲基甲酰胺的重量比为1:1～3:1，获得核层纺丝溶液；
无水乙醇和N,N-二甲基甲酰胺混合溶剂中，聚乙烯吡咯烷酮的重量含量为4～8％；
(3)在壳层纺丝溶液制备后的3～10分钟内，25～30℃下，将壳层纺丝溶液和核层纺丝溶液，采用同轴静电纺丝方法，获得复合载药纤维膜材料；所述的同轴静电纺丝方法为本领域公知的方法，如香港大学王敏等A new nanofiber fabrication technique based on coaxial electrospinning[J].Materials Letters,2012,66:257-260.文献报道的方法。
(4)将获得的复合载药纤维膜材料冷冻干燥，放入加有活性炭的真空冷冻干燥器中，通过冷冻-吸附-升华法，-45～-55℃冷冻干燥20～24小时去除二氯甲烷、N,N-二甲基甲酰胺溶剂和水分，得到所述的积核/壳结构载药纳米防粘连膜；优选的，还包括灭菌步骤：真空灭菌4～8小时，然后顺着纤维取向，将纤维膜剪成30mm×50mm的长方形样品，压片成型。
本发明获得的核/壳结构载药纳米防粘连膜，可用于外科手术后伤口愈合期组织间防粘连，应用方法如下：
所有手术按常规进行后，于手术结束前，完成并彻底止血和清创后，将该防粘连膜均匀平摊于需要防止粘连的创面或组织间，(用量视创面大小由术者判定，建议较小创面用10mm×20mm；较大创面用30mm×50mm)，待粘附固化后(遇组织液1-2分钟固化)即可关闭手术通路。
药理试验证明，健康受试者使用氟比洛芬酯纳米纤维镇痛膜20mm×20mm(药物含 量50mg)后5～10min，血药浓度即达峰值。给药量在10～80mg之间时，血药浓度呈线性。药物消除半衰期为5.8h。用药后48h，尿中药物累积排泄量约为给剂量的85％。连续给药5次，每次间隔12h，最后一次用药后48h尿中药物累积排泄率达到近100％，未发现药物在体内蓄积。
本发明以纳米干冰粒子为成孔剂，采用同轴静电纺丝方法，获得了一种可控超高比表面积核/壳结构载药纳米防粘连膜，制备方法简单高效，价格低廉，制备的膜材料具有很好的可控比表面积性、可控孔隙大小、力学性能、透血液性能和可控生物降解性能，在防粘连时对人体无超敏反应，同时与人体内的血液及周边组织具有亲和力，具有生物粘合性表面且无排异现象。
附图说明
图1核/壳结构载药纳米纤维直径分布统计图；
图2核/壳结构载药纳米纤维表面相貌及核/壳结构扫描电镜图；
图3为NIH3T3细胞毒性检测结果；
图4为IEC-6细胞毒性检测结果；
图5为NIH3T3细胞在不同膜上的粘附率；
图6为IEC-6细胞在不同膜上的粘附率；
图7为药物累积释放量与成孔剂用量之间的关系图。
具体实施方式
下面结合附图对本发明进一步说明。
实施例1
(1)将聚乳酸-羟基乙酸溶解在二氯甲烷和N,N-二甲基甲酰胺混合溶剂中，25℃下电动搅拌10个小时(转速550r/min)后，加入粒径为500纳米的干冰粒子电动搅拌2小时，最后超声振荡20分钟，制得聚乳酸-羟基乙酸重量百分比含量为10％的纺丝液，作为壳层溶液；
二氯甲烷与N,N-二甲基甲酰胺的重量比为3:1；
以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，聚乳酸-羟基乙酸的重量含量为10％；
以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，纳米干冰粒子的重量百分比为0.1％；
(2)将聚乙烯吡咯烷酮、氟比洛芬酯溶解在无水乙醇和N,N-二甲基甲酰胺混合溶剂中，25℃下搅拌，分散，乙醇与N,N-二甲基甲酰胺的重量比为2:1，获得核层纺丝溶液；
无水乙醇和N,N-二甲基甲酰胺混合溶剂中，聚乙烯吡咯烷酮的重量含量为8％；
(3)在壳层纺丝溶液制备后的10分钟内，25℃下，将壳层纺丝溶液和核层纺丝溶液，采用同轴静电纺丝方法，获得复合载药纤维膜材料；
温度25℃，相对湿度50％，壳层纺丝流速0.8mm/min，核层纺丝流速0.05mm/min，纺丝正高压18kV，负高压1.25kV，卷筒接收条件下进行同轴静电纺丝。
(4)将获得的复合载药纤维膜材料，放入加有活性炭的真空冷冻干燥器中，通过冷冻-吸附-升华法，-55℃冷冻干燥20小时去除二氯甲烷、N,N-二甲基甲酰胺溶剂和水分，得到所述的可控超高比表面积核/壳结构载药纳米防粘连膜；优选的，还包括灭菌步骤：真空灭菌4小时，然后顺着纤维取向，将纤维膜剪成30mm×50mm的长方形样品，压片成型。外壳上微孔的孔径为100纳米，每平方厘米的外壳上，微孔的数量为3×107个；
聚乳酸羟基乙酸的重均分子量为100000；聚乙烯吡咯烷酮重均分子量为55000；
以氟比洛芬酯和聚乙烯吡咯烷酮的总重量计，氟比洛芬酯的重量含量为0.4％；
纤维的纤度为0.2；
聚乙烯吡咯烷酮与聚乳酸-羟基乙酸的重量比为2:1；
外壳上微孔的孔径可采用C.J.Luo等A novel method ofselecting solvents for polymer electrospinning[J].Polymer,2010,51(7):1654-1662.文献报道的方法进行检测，或者采用Young You等Preparation of porous ultrafine PGA fibers via selective dissolution of electrospun PGA/PLA blend fibers[J].Materials Letters,2006,60:757-760.方法进行检测微孔的数量可采用Z.Huang等Electrospinning and mechanical characterization of gelatin nanofibers[J].Polymer,2004,45(15):5361-5368.文献报道的方法进行检测，或者采用BET方程进行测定；
图1为核/壳结构载药纳米纤维直径分布统计图；其中：
a图代表聚乳酸-羟基乙酸/氟比洛芬酯共混纳米纤维膜直径分布，b图代表聚乳酸-羟基乙酸/4％聚乙烯吡咯烷酮/氟比洛芬酯核/壳纳米纤维膜直径分布，c图代表聚乳酸-羟基乙酸/6％聚乙烯吡咯烷酮/氟比洛芬酯核/壳纳米纤维膜直径分布，d图代表聚乳酸-羟基乙酸/6％聚乳酸-羟基乙酸/氟比洛芬酯核/壳纳米纤维膜直径分布。
图2为核/壳结构载药纳米纤维表面相貌及核/壳结构SEM图。
实施例2
(1)将聚乳酸-羟基乙酸溶解在二氯甲烷和N,N-二甲基甲酰胺混合溶剂中，25℃下电动搅拌10个小时(转速550r/min)后，加入粒径为500纳米的干冰粒子电动搅拌2小时，最后超声振荡20分钟，制得聚乳酸-羟基乙酸重量百分比含量为10％的纺丝液，作为壳层溶液；
二氯甲烷与N,N-二甲基甲酰胺的重量比为5:1；
以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，聚乳酸-羟基乙酸的重量含量为12％；
以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，纳米干冰粒子的重量百分比为0.5％；
(2)将聚乙烯吡咯烷酮、氟比洛芬酯溶解在无水乙醇和N,N-二甲基甲酰胺混合溶剂中，25℃下搅拌，分散，无水乙醇与N,N-二甲基甲酰胺的重量比为1:1，获得核层纺丝溶液；
无水乙醇和N,N-二甲基甲酰胺混合溶剂中，聚乙烯吡咯烷酮的重量含量为4％；
(3)在壳层纺丝溶液制备后的25分钟内，30℃下，将壳层纺丝溶液和核层纺丝溶液，采用同轴静电纺丝方法，获得复合载药纤维膜材料；
温度25℃，相对湿度50％，壳层纺丝流速0.8mm/min，核层纺丝流速0.05mm/min，纺丝正高压18kV，负高压1.25kV，卷筒接收条件下进行同轴静电纺丝。
(5)将获得的复合载药纤维膜材料冷冻干燥，放入加有活性炭的真空冷冻干燥器中，-45℃冷冻干燥20小时，去除二氯甲烷/N,N-二甲基甲酰胺、无水乙醇/N,N-二甲基甲酰胺，再在室温下真空干燥20小时，去除残余的二氯甲烷/N,N-二甲基甲酰胺、无水乙醇/N,N-二甲基甲酰胺和水分，得到所述的可控超高比表面积核/壳结构载药纳米防粘连膜；真空干燥15小时，然后顺着纤维取向，将纤维膜剪成30mm×50mm的长方形样品，压片成型。
外壳上微孔的孔径为10纳米，每平方厘米的外壳上，微孔的数量为5×107个；
聚乳酸羟基乙酸的重均分子量为80000；聚乙烯吡咯烷酮重均分子量为40000；
以氟比洛芬酯和聚乙烯吡咯烷酮的总重量计，氟比洛芬酯的重量含量为0.1％；
纤维的纤度为0.13；
聚乙烯吡咯烷酮与聚乳酸-羟基乙酸的重量比为10:1。
实施例3
载药型聚乳酸-羟基乙酸静电纺丝膜的细胞毒性试验
(1)将对数生长期的细胞接种到96孔板中，确保孵育2天的细胞数目为6000个/孔，孵育4天和7天的细胞数目分别为4000个/孔和3000个/孔；
(2)把接种好的细胞在培养箱中贴壁6小时，然后将已准备好的与96孔大小相仿的不同规格的实施例1的载药静电纺丝膜放在培养基中，以浸泡在培养基中为准；
(3)分别孵育2、4、7天后，取出载药型聚乳酸-羟基乙酸静电纺丝膜，对细胞进行CCK-8测定；
(4)以没有放膜的孔作为对照孔，进行数据分析。
将氟比洛芬酯/聚乙烯吡咯烷酮/聚乳酸-羟基乙酸复合纳米纤维膜与IEC-6细胞、NIH3T3细胞分别进行共同培养，通过CCK-8试剂检测法进行检测，可知氟比洛芬酯/聚乙烯吡咯烷酮/聚乳酸-羟基乙酸复合纳米纤维膜没有毒性。
实施例4
细胞在载药型聚乳酸-羟基乙酸静电纺丝膜上的粘附性试验
(1)分别将60μm厚、100μm厚、160μm厚、220μm厚实施例1的载药型聚乳酸-羟基乙酸静电纺丝膜和商业膜剪成和盖玻片大小的方片，铺到6孔板中，每种膜做6个复孔，将6孔板盖揭开，分别对膜进行紫外照射30min；同时也对放在6孔板中的载玻片进行紫外照射30min，准备接种细胞；
(2)向每孔接种细胞，孵育不同时间段(2天、4天、7天)，确保孵育2天的细胞数目为400000个/孔，孵育4天、7天的细胞数目分别为40000个/孔和4000个/孔，孵育完毕后，轻轻吸出上清，然后将膜和盖玻片转到新的6孔板上，每孔加MTT溶液1.5mL(5mg/mL用PBS配制，使用前用培养基稀释10倍)，继续孵育4小时；
(3)小心吸弃孔内培养上清液，每孔加1mL二甲基亚砜，振荡10min，使结晶物充分融解；
(4)比色：选择490nm波长，在酶联免疫监测仪上测定各孔光吸收值，记录结果；
(5)以盖玻片吸光值为对照，计算粘附率；
(6)粘附率计算方法：粘附率＝(对照孔吸光值-试验孔吸光值)/对照孔吸光值×100％。
将IEC-6、NIH3T3两种细胞在不同厚度的氟比洛芬酯/聚乙烯吡咯烷酮/聚乳酸-羟基乙酸复合纳米纤维膜上进行培养，然后经过相关处理，利用MTT比色法进行检测，与对照组相比，结果显示细胞不易粘附在氟比洛芬酯/聚乙烯吡咯烷酮/聚乳酸-羟基乙酸复合纳米纤维膜上。
实施例5
药剂中药物累积释放效果实验
分别精确称取一定量的聚乳酸-羟基乙酸载药纳米纤维膜于100mL锥形瓶中，加入50mLPBS(pH＝7.4)缓冲溶液，密封后置于恒温摇床中，设置温度为37℃，摇床速度为100转每分钟。在设定的时间间隔量取10mL溶液待测，同时向原样中补充10mL新鲜PBS，保持原样体积不变。将取出的样品溶液在246.0nm波长，测定吸光度A，并通过标准曲线A＝3.95952C+0.02474计算出样品溶液中药的浓度C，进一步计算其累积释放率。
药物累积释放公式：
Figure PCTCN2014001166-appb-000001
C—氟比洛芬酯的浓度，μg/mL；
ΣW—取样累积消耗药量，μg；
m—载药纳米纤维膜的总重量，mg；
R—纤维膜中的载药量。
通过同轴静电纺丝技术制备的载药纳米纤维膜包封率都比较高，接近于100％，主要是由于氟比洛芬酯通过共混的方法溶解在聚乙烯吡咯烷酮溶液中，再通过同轴静电纺丝技术包载到聚乳酸-羟基乙酸基体中，整个制备过程中药物的损失量很小；聚乳酸-羟基乙酸基纳米纤维膜的载药量主要受到纤维表面孔隙率的影响较大，当纤维表面孔隙率增大时，对应的相同时间内药物累积释放率也会增大。致孔剂的在纤维基体中含量时影响载药纳米纤维表面孔隙率及纤维比表面积最重要的因素。致孔剂用量增加，单根纤维表面孔直径增大，孔隙率增加，纤维膜比表面积增大。但致孔剂用量不宜过多，当超过一定用量时，纤维内所在药物会暴露，纤维对药物不仅没有起到可控释放，反而会产生更加严重的突释现象；反之，致孔剂用量较小时，对于药效周期较短，血药浓度较高的镇痛类药物(如本专利所载药物)，虽然可以达到可控释放效果，但并不能起到很好的药效。

Claims (10)

  1. 核/壳结构载药纳米防粘连膜，其特征在于，由内核和外壳结构的纤维并联构成；其中：
    所述的内核包括治疗有效量的活性成分和聚乙烯吡咯烷酮(PVP)；
    所述的外壳为聚乳酸-羟基乙酸(PLGA)，所述的外壳上设有微孔。
  2. 根据权利要求1所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，所述的微孔孔径为10～100纳米，每平方厘米的外壳上，微孔的数量为3×107～5×107个。
  3. 根据权利要求1所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，所述的聚乳酸-羟基乙酸的重均分子量为80000～100000；聚乙烯吡咯烷酮重均分子量为40000～55000。
  4. 根据权利要求2所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，所述的聚乳酸-羟基乙酸的重均分子量为80000～100000；聚乙烯吡咯烷酮重均分子量为40000～55000。
  5. 根据权利要求1～4任一项所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，所述的活性成分为氟比洛芬酯、布洛芬、酮洛芬、吲哚美辛或双氯芬酸。
  6. 根据权利要求5所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，以活性成分和聚乙烯吡咯烷酮的总重量计，氟比洛芬酯的重量含量为0.1～0.4％；
  7. 根据权利要求1～4任一项所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，所述的纤维的纤度为0.13～0.2。
  8. 根据权利要求1～4任一项所述的可控超高比表面积核/壳结构载药纳米防粘连膜，其特征在于，所述聚乙烯吡咯烷酮与聚乳酸-羟基乙酸的重量比为2:1～10:1。
  9. 根据权利要求1～8任一项所述的可控超高比表面积核/壳结构载药纳米防粘连膜的制备方法，其特征在于，包括如下步骤：
    (1)将聚乳酸-羟基乙酸溶解于二氯甲烷(DCM)和N,N-二甲基甲酰胺(DMF)混合溶剂中，再加入纳米干冰粒子，混合分散，作为壳层纺丝溶液；
    (2)将聚乙烯吡咯烷酮和活性药物溶解在无水乙醇和N,N-二甲基甲酰胺混合溶剂 中，搅拌，分散，获得核层纺丝溶液；
    无水乙醇和N,N-二甲基甲酰胺混合溶剂中，聚乙烯吡咯烷酮的重量含量为4～8％；
    (3)在壳层纺丝溶液制备后的3～10分钟内，25～30℃下，将壳层纺丝溶液和核层纺丝溶液，采用同轴静电纺丝方法，获得复合载药纤维膜材料；
    (4)将获得的复合载药纤维膜材料放入加有活性炭的真空冷冻干燥器中，通过冷冻-吸附-升华法，-45～-55℃冷冻干燥20小时去除二氯甲烷、N,N-二甲基甲酰胺溶剂和水分，真空灭菌4～8小时，得到所述的可控超高比表面积核/壳结构载药纳米防粘连膜。
  10. 根据权利要求9所述的方法，其特征在于，步骤(1)中，二氯甲烷与N,N-二甲基甲酰胺的重量比为2:1～5:1；
    以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，聚乳酸-羟基乙酸的重量含量为8～12％；
    以聚乳酸-羟基乙酸、二氯甲烷、N,N-二甲基甲酰胺和纳米干冰粒子总重量计，纳米干冰粒子的重量百分比为0.1％～5％；
    步骤(2)中，无水乙醇与N,N-二甲基甲酰胺的重量比为1:1～3:1。
PCT/CN2014/001166 2014-11-14 2014-12-23 核/壳结构载药纳米防粘连膜及其制备方法 WO2016074115A1 (zh)

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