药物缓释用生物降解性高分子载体材料的研究

生物降解性聚合物安全、可靠,有良好的生物相容性,可通过生理途径代谢排出体外,成为了药物载体的首选材料。本文简要综述了主要常用天然和合成生物降解性聚合物,如壳聚糖、环糊精、胶原、聚乳酸、聚酸酐、氨基酸类聚合物的制备方法,在药物缓释体系的作用和效果,并对其发展趋势进行了展望。     

Core–shell biopolymer microspheres for sustained drug release

In this work, a core–shell biopolymer microsphere comprising a carvedilol‐loaded yeast cell wall polysaccharides core surrounded by a silk fibroin shell layer is developed to eliminate the risks of using synthetic polymers for drug encapsulation on human health and to avoid burst release and to prolong the release time. Transmission electron microscopy, Fourier‐transform infrared, confocal laser scanning microscope, and phase contrast microscopy analysis indicate that yeast treated with Tris–HCl containing cetyltrimethylammonium bromide, EDTA, and NaCl could provide much larger space for host drug as compared to plasmolyzed cells because the former can help maintain the original shape of yeast cells. In addition, its permeability barrier is significantly altered and nucleus becomes pyknotic. In contrast, plasmolyzed cells can hardly maintain the rigidity and integrity of their cell walls and will finally end up with cell fragments. SEM observation reveals that the carvedilol‐loaded cells maintain very similar shape and size before and after coating with 0.1% silk fibroin. In vitro release studies show that a drug delivery system using the carvedilol‐loaded cells can achieve a sustained drug release up to 20 days probably due to the electrostatic interaction between the positively charged carvedilol and the negatively charged yeast cells at the pH 7.4 and to the stability of the yeast cell helped by silk fibroin that provides an effective diffusion barrier. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41782.     

Electrospun core–shell nanofibers for drug encapsulation and sustained release

Fabrication of core–shell nanofibers by coaxial electrospinning system suited for drug delivery applications was investigated based on tetracycline hydrochloride (TCH) as the core and poly(lactide‐co‐glycolide) as the shell materials. Comparison of drug release from monolithic fibers (blend electrospinning) and core–shell structures was performed to evaluate the efficacy of the core–shell morphology. The nanofibrous webs are potentially interesting for wound healing purposes since they can be maintained for an adequate length of time to gradually disinfect a local area without the need of bandage renewal. Further, our studies showed the potential of core–shell nanostructures for sustained drug release, which also suppressed the burst release effect from 62 to 44% in the first 3 hours by adding only 1 wt% TCH to the polymeric shell. POLYM. ENG. SCI., 2013. © 2013 Society of Plastics Engineers     

Porous polyurethane film fabricated via the breath figure approach for sustained drug release

The breath figure (BF) method is an effective process for fabricating porous polymeric films. In this study, we fabricated porous polymer films from thermoplastic polyurethane (PU) through static BF with CHCl₃ as a solvent under 55–80% relative humidity. The porous PU films were prepared within various pore structures and sizes, which were adjustable, depending on the fabrication conditions. The humidity and exposure time were examined as variable parameters affecting the surface morphology, wettability, and cytotoxicity. Atorvastatin calcium, a hyperlipidemic agent, was loaded into the porous films during the casting process, and the drug-loading and drug-releasing behaviors of the porous PU membranes were evaluated. Approximately 60–80% of the drug was released in 14 days. The films exhibited sustained drug-release performances because of the hydrophobicity and nonbiodegradable nature of PU for perivascular drug administration. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 47658.     

Engineering a drug eluting ocular patch for delivery and sustained release of anti-inflammatory therapeutics

Ocular inflammation is commonly associated with eye disease or injury. Effective and sustained ocular delivery of therapeutics remains a challenge due to the eye physiology and structural barriers. Herein, we engineered a photocrosslinkable adhesive patch (GelPatch) incorporated with micelles (MCs) loaded with loteprednol etabonate (LE) for delivery and sustained release of drug. The engineered drug loaded adhesive hydrogel, with controlled physical properties, provided a matrix with high adhesion to the ocular surfaces. The incorporation of MCs within the GelPatch enabled solubilization of LE and its sustained release within 15 days. In vitro studies showed that MC loaded GelPatch supported cell viability and growth. In addition, subcutaneous implantation of the MC loaded GelPatch in rats confirmed its in vivo biocompatibility and stability within 28 days. This non-invasive, adhesive, and biocompatible drug eluting patch can be used as a matrix for the delivery and sustained release of hydrophobic drugs.     

Zein-based microcapsule for vanillin sustained release

Currently, microcapsules are attracting great attention and becoming more and more widely used in sustained release system. In this research, zein-based microcapsules were prepared by anti-solvent precipitation technology and spray drying. The properties of as-prepared microcapsules were optimized by adjusting the reaction conditions and parameters such as the mass ratio of zein to vanillin, the drying temperature and whether polyethylene glycol was added or not. Meanwhile, the morphologies, chemical structures, and application performances of microcapsules were characterized and determined by SEM, FT-IR, TG, and so on. The results showed that the morphology of as-obtained microcapsules was a regular spherical shape with no cracks when the mass ratio of zein to vanillin was 1:1, the inlet temperature was 120 C and the polyethylene glycol was introduced. Meanwhile, it was also proved that the polyethylene glycol has a positive effect on the encapsulation efficiency in microcapsules. Moreover, zein microcapsules can effectively improve the thermal stability and release behavior of vanillin, meanwhile the exist of polyethylene glycol can further improve the properties of zein microcapsules. This research provided guidelines for the study of microcapsules.     

低CMC纳米载体PEGMA-b-PLLA-b-PCL的制备及其药物缓释性能

以ε-己内酯（ε-CL）为疏水原料，聚乙二醇甲醚甲基丙烯酸酯（PEGMA）为亲水原料，通过引入亲疏水性过渡原料L-丙交酯（LLA），利用可逆加成-断裂链转移法（RAFT）制备了超低临界胶束浓度（CMC）的聚乙二醇甲醚甲基丙烯酸酯-聚丙交酯-聚己内酯（PEGMA-b-PLLA-b-PCL）。通过FTIR、1HNMR、GPC、DLS和SEM对聚合物的结构、相对分子质量（简称分子量）及粒径进行测定，用界面张力法测得PEGMA-b-PLLA-b-PCL 胶束溶液的CMC，用溶剂挥发法负载姜黄素（CUR）制备载药胶束溶液，并计算其载药量和包封率，进一步考察载药胶束溶液在不同环境下的释药能力。结果表明，聚合物相对分子质量（简称分子量）为1220~8782，粒径为28~180 nm，且最低CMC为0.62 μg/mL（pH=7.4）。载药胶束的载药量和包封率最高可达12.6%和78 .0% (pH=7.4)，且药物释放可在15 d内完成，在pH=5环境下释放量最高可达45.53%。     

Poly(ethoxytriethyleneglycol acrylate) cryogels as novel sustained drug release systems for oral application

Novel temperature sensitive cryogels of poly(ethoxytriethyleneglycol acrylate) (PETEGA), with in situ entrapped active substance, are synthesized employing the UV irradiation technique and tested as matrix for controlled release of the hydrophilic drug verapamil hydrochloride. PETEGA cryogels are non-toxic materials and, due to the macroporous structure, exhibit a reversible, ultra-rapid volume phase transition at temperature ca. 31 °C. Carriers based on PETEGA cryogels possess sustained release of verapamil hydrochloride over a period of more than 8 h, which is attributed to the hydrophobic state of the polymer network at physiological temperature and the method of drug immobilization. Drug release characteristics of PETEGA cryogels are compared with another cryogel systems, based on polyacrylamide (PAAm), poly(N-isopropylacrylamide) (PNIPAAm) and poly(2-hydroxyethyl methacrylate) (PHEMA), obtained via the same method.     

Construction and evaluation of the hydroxypropyl methyl cellulose-sodium alginate composite hydrogel system for sustained drug release

We prepared a hydroxypropyl methyl cellulose-sodium alginate (HPMC-SA) composite hydrogel with a membrane covering the semi-interpenetrating network based on a semi-synthetic polymer hydroxypropyl methyl cellulose (HPMC) and a natural polymer sodium alginate (SA) by Ca²⁺ crosslinking and polyelectrolyte complexation with chitosan (CS) covering the hydrogel surface. The physiochemical properties of HPMC-SA hydrogels were evaluated by scanning electron microscopy, infrared spectrum, X-ray diffraction, and thermogravimetric analysis. The swelling ratio of the HPMC-SA composite hydrogel in simulated gastrointestinal fluid was measured. The drug release behavior of the HPMC-SA composite hydrogel for macro-molecular and small-molecule drugs was evaluated by using bovine serum albumin, metformin hydrochloride, and indomethacin as model drugs. The results showed that the HPMC-SA hydrogel had good water absorption and degradability, an increased swelling ratio of 55, and a prolonged time for maximum swelling degree of 50 h. Moreover, the hydrogel exhibited higher drug-loading capacity and improvements in the sustained release of bio-macromolecules, demonstrating its potential as a drug carrier for biomedical applications.     

Fabrication of polymer/drug‐loaded hydroxyapatite particle composite fibers for drug sustained release

The aim of this study is to fabricate polymer/hydroxyapatite (HA) particle composite fibers for drug encapsulation and sustained release. Firstly, drug‐loaded hydroxyapatite particles are synthesized in one step, then by electrospinning of the blends of drug‐loaded hydroxyapatite particles and polymer solution the drug‐loaded polymer/hydroxyapatite particle composite fibers are successfully prepared. Effect of loading ratio of drug‐loaded hydroxyapatite particles in the fibers and pH value of the release medium on the drug release kinetics are both investigated, and the results demonstrate that, as compared with the polymer/drug electrospun fibers, the drug in the polymer/drug‐loaded hydroxyapatite particle composite fibers shows a sustained release manner, and the drug release rate can be regulated by both the loading ratio of drug‐loaded hydroxyapatite particles in the composite fibers and pH value of the buffer solution. The results indicate that the developed drug‐loaded polymer/hydroxyapatite particle composite fibers show great potential in bone regeneration and other related biomedical fields. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42871.     

In situ gelation and sustained release of an antitumor drug by graphene oxide nanosheets

Graphene oxide nanosheets were used to induce the in situ gelation of doxorubicin hydrochloride as an antitumor drug. When a very small amount of the graphene oxide was introduced into an aqueous solution of doxorubicin hydrochloride at room temperature, a strong and thixotropic gel was rapidly formed without any polymers or chemical additives. The gelation mechanism was investigated by fluorescence spectroscopy, X-ray diffraction and scanning electron microscopy. The encapsulated doxorubicin hydrochloride was found to show sustained release and antitumor efficacy.     

抗紫外聚多巴胺香料纳米胶囊缓释体系的研究

利用多巴胺(DA)在碱性溶液中的自氧化和聚合,在香料乳液液滴表面涂覆聚多巴胺(PDA)层制备香料PDA纳米胶囊,比较了PDA对不同香料的包覆性能和缓释效果。结果发现苯乙醛和香茅醛因与多巴胺(DA)发生Maillard反应而不能被包覆,苯乙醇、香茅醇、乙酸苯乙酯和乙酸香茅酯则能被包覆在纳米胶囊内部,扫描电子显微镜(SEM)和动态激光光散射(DLS)结果显示:香料纳米胶囊基本呈球形,分布较均匀,香料种类对粒径影响大,可由88 nm(乙酸香茅酯)变化到556 nm(苯乙醇)。对香茅醇的包埋率最高,可达到19. 8%,在常温下保存50 d后香料保留率可保持69. 39%以上,具有良好的缓释性能,同时由于PDA对紫外及可见光有一定的吸收,因此可以为光敏性或光毒性香料的应用提供进一步的光屏蔽作用。     

PLGA based drug delivery systems (DDS) for the sustained release of insulin: insight into the protein/polyester interactions and the insulin release behavior

BACKGROUND: Drug delivery systems (DDS) were designed using insulin as model drug and poly (lactic–co‐glycolic) copolymers (PLGA) as polymeric matrix. The carriers were synthesized by direct self‐assembly of the insulin and the polyester under mild conditions. RESULTS: The kind and level of association between the protein and the polymer were studied using computational methods (combined MM2/PM3) and spectroscopic tools (Fourier transform infrared (FTIR), energy dispersive X‐ray (EDX) and X‐ray fluorescence spectroscopy (XFS)). The effect of the number average molecular weight (M_n) of the copolymer on the association efficiency (AE) drug–polymer as well as on the release profile has been explored. Mathematical models were used to predict the insulin release kinetic and mechanism. CONCLUSIONS: Satisfactory protein/PLGA association efficiencies (between 77 and 99%) were registered depending on the M_n of the PLGA. Hydrophobic and hydrophilic interactions were detected between the protein and the polymeric network by computational analysis. In vitro release studies demonstrated that copolyesters of about 8600 and 1500 Da were suitable for the gradual release of insulin while PLGA oligomers of average molecular weight between 700 and 800 Da were unsuitable as DDS. The insulin release kinetics fits well with the Korsmeyer model, following the anomalous transport mechanism. Copyright © 2010 Society of Chemical Industry     

A polypyrrole-based microchip for controlled drug release

A novel polypyrrole-based microchip has been developed by electrochemical deposition of drug-doped polypyrrole films on the Au microelectrode arrays. The drug release from the microchip is controlled by a potential application. Due to its unique configuration, the microchip exhibits some appealing characteristics, such as being able to supply single or multiple drugs with precise small doses, ability to achieve pulsatile release mode, small in size, and good biocompatibility, and thus has the potential for application as implantable device in the field of controlled drug release.     

药物控释用智能水凝胶研究进展

智能水凝胶在药物控释方面具有智能化、效率高和安全方便等优点.近年来,研究开发药物控释用智能水凝胶非常活跃,展示了广阔的应用前景.本文综述了药物控释用温度、pH值、葡萄糖、电场、磁场及光敏感水凝胶的最新研究进展.     

The application of a supercritical antisolvent process for sustained drug delivery

Supercritical processes for drug delivery system design have attracted considerable attention recently. This present work investigates the application of a supercritical antisolvent coating process for controlled drug release design. Hydrocortisone as the host drug particles and poly(lactide-co-glycolide) (PLGA) as the polymer carrier were selected as the model system for this purpose. In this research the drug particles were suspended in a polymer solution of dichloromethane. The suspension was then sprayed into supercritical CO₂ as an antisolvent. A parallel study of co-precipitation of the drug and polymer using the same supercritical antisolvent process at the same operating conditions was performed for comparison with the coating process. SEM images were used to characterize the drug particles before and after and the assay analysis was carried out using HPLC. The coated particles and co-precipitated particles were evaluated in terms of encapsulation efficiency and drug release profiles. The major advantage of this new approach is the ability to physically coat very fine (< 30 μm) particles without having to dissolve them in an organic solvent. It was found that higher polymer to drug ratios produced higher encapsulation efficiencies and the coated drug particles did show sustained release behavior. The co-precipitation of the drug and polymer (at the same operating conditions), however, did not exhibit any sustained release.     

PCL microsphere/PEG-based composite hydrogels for sustained release of methadone hydrochloride

Hydrogels have increasingly received considerable attention for local opioids delivery in order to sustained wound pain relief. However, burst release of drugs is a critical problem of hydrogels. To this aim, a local drug delivery system consisting of polycaprolactone (PCL) microspheres containing methadone hydrochloride/polyethylene glycol (PEG)-based hydrogels were developed to prolong drug release with potential utilization in pain treatment. Four different drug delivery systems, including methadone hydrochloride/PEG-(N₃)₄-based hydrogel, methadone hydrochloride/PEG-(N₃)₂-based hydrogel, methadone hydrochloride/PCL/PEG-(N₃)₄, and methadone hydrochloride/PCL/PEG-(N₃)₂ composite hydrogels, were fabricated to investigate drug release profiles of these systems. The results showed that drug released can be controlled by both the double-barrier matrix (hydrogel/microsphere), and the crosslinking density of hydrogels. Therefore, methadone hydrochloride/PCL/PEG-(N₃)₂ composite hydrogel with high crosslinking density has great potential application in sustained release systems for wound pain relief. © 2020 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020 , 137, 48967.     

MCM-41的制备及用于吡拉西坦缓释性能研究

以十六烷基三甲基溴化铵（CTAB）为模板剂,正硅酸乙酯（TEOS）为硅源,合成MCM-41分子筛.以其做载体,吡拉西坦为模型药物,研究了吡拉西坦在MCM-41分子筛的负载与释放性能.并通过扫描电子显微镜（SEM）、粉末X-射线衍射（XRD）和傅立叶变换红外光谱（FT-IR）等方法对MCM-41分子筛以及负载吡拉西坦后的样品进行表征.研究了吡拉西坦的负载量及释放性能,定时检测了制备药物在模拟体液中的释放过程,从而确定以MCM-41作为吡拉西坦缓释载体的可能性.     

Polymeric coating of fluidizing nano-curcumin via anti-solvent supercritical method for sustained release

Nano-curcumin was coated by poly(lactic-co-glycolic acid) (PLGA) using a novel fluidization assisted supercritical anti-solvent procedure. PLGA solution was sprayed into supercritical CO₂ media, in which nano-curcumin particles were fluidized by ultrasonic vibration. The influences of process parameters, such as solvent types, solution concentrations, CO₂ flow rates, the ratio of PLGA to curcumin, and ultrasonic power on the particles size and the curcumin loading were investigated. Scanning electron microscopy, laser particle size analyzer, and differential scanning calorimetry were used to characterize as-produced samples in terms of the structure, morphology and particle size distribution. The PLGA-curcumin nano-capsules were obtained with the average size of 63 nm and the loading of 38%, under the ultrasonic power of 210 W, and with the average size of 40 nm and 36% loading, at the ultrasonic power of 350 W. In vitro studies prove that proposed method is successful in preparing sustained release systems.     

pH-responsive PMAA-b-PEG-b-PMAA triblock copolymer micelles for prednisone drug release and release kinetics

pH-sensitive hydrophilic poly(methacrylic acid)-b-poly(ethylene glycol)-b-poly(methacrylic acid) (PMAA-b-PEG-b-PMAA) triblock copolymers were synthesized through atom transfer radical polymerization, and were characterized by FT-IR, ¹H NMR, and GPC. The as-synthesized polymers can self-assemble into stable and almost spherical nanomicelles in aqueous solution with an average size range from 18 to 89?nm, depending on the micellar concentrations, while they assumed well-defined spherical morphologies in PBS solutions. The micellization behavior in different media was investigated by a fluorescence spectroscopy technique, UV–Vis transmittance, and dynamic light scattering measurements. The critical micelle concentration and size of the micelles decrease with the increasing the length or molecular weights of PEG and PMAA chains. A pH-dependent phase transition behavior produces at a pH value of about 5.2, and the stable pH micellization behavior varied within a narrow pH range from ca. 4.8 to 7.4. These triblock copolymers are generally low cytotoxicity at a micellar concentration below 400?mg?L^?1, as revealed by the MTT assay. The prednisone release and release kinetics studies disclosed that these pH-sensitive polymeric micelles are good carriers for the drug delivery.