Silk fibroin biomaterials for controlled release drug delivery

INTRODUCTION: Given the benefits of polymer drug delivery implants over traditional periodic systemic administration, the development of biomaterial systems with the necessary properties (biocompatibility, degradation, stabilization, controllability) is paramount. Silk fibroin represents a promising, naturally derived polymer for local, controlled, sustained drug release from fully degrading implants and the polymer can be processed into a broad array of material formats. AREAS COVERED: This review provides an overview of silk biomaterials for drug delivery, especially those that can function as long-term depots. Fundamentals of structure and assembly, processing options, control points and specific examples of implantable silk drug delivery systems (sponges, films) and injectable systems (microspheres, hydrogels) from the 1990s and onwards are reviewed. EXPERT OPINION: Owing to its unique material properties, stabilization effects and tight controllability, silk fibroin is a promising biomaterial for implantable and injectable drug delivery applications. Many promising control points have been identified, and characterization of the relationships between silk processing and/or material properties and the resulting drug loading and release kinetics will ultimately enhance the overall utility of this unique biomaterial. The ever-expanding biomaterial 'tool kit' that silk provides will eventually allow the simultaneous optimization of implant structure, material properties and drug release behavior that is needed to maximize the cost-efficiency, convenience, efficacy and safety of many new and existing therapeutics, especially those that cannot be delivered by means of traditional administration approaches.     

Silk fibroin as a novel coating material for controlled release of theophylline

The aim of this study was to explore potential use of the silk fibroin (SF) as an aqueous coating material for theophylline tablets. We have examined the film forming and coating properties of heat-treated fibroin, SF solution having different amounts of polyethylene glycol (PEG) and 1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC) cross-linked SF. Heat-treated SF material possessed a brittle structure, which resulted in poor film forming and coating properties. The optimum PEG amount in SF solution was determined as 17% (by weight) for an acceptable film forming and zero order release profile. EDC cross-linked SF has shown a very good film forming and coating property with a potential for sustaining the drug release from coated theophylline tablets. Dissolution data for coated theophylline tablets were analyzed using Ritger and Peppas equation to describe the mechanism of drug release. Drug release from the EDC coated tablets followed zero-order kinetics. Release rate constants were found to be 0.26, 0.19, 0.16% min⁻¹ for single-coated, double coated, and triple coated tablets, respectively. These results clearly demonstrated that silk fibroin has high utility as a novel aqueous coating material for controlled release products.     

温敏水凝胶在药物缓控释技术中的应用

温敏水凝胶是近几年来发展比较快的一种高分子材料,属于智能水凝胶的一种。虽然迄今为止多数仍停留在实验研究阶段,但可以预见该类水凝胶在医学、农学、生物学等研究领域都有着广阔的应用前景。目前在药物控制释放、组织工程以及生物免疫等多个领域备受关注。本文结合近年来国内外对温敏水凝胶的研究报道,主要介绍了温敏水凝胶的性质及其在药物缓控释中的应用,包括其在药物缓控释制剂中应用的优点、适用的药物类型以及存在的问题等。     

Design of diffusion‐controlled drug delivery devices for controlled release of Paclitaxel

Controlled drug delivery devices were predicted in a reverse engineering framework for the controlled release of Paclitaxel, an anti‐cancer drug, widely used in the treatment of solid tumors. Using quantitative structure–property relationship models for mutual diffusion coefficients of the drug in biocompatible and biodegradable polymers and partition coefficients of the drug between polymers and blood, a framework was developed to predict optimal drug delivery devices for desired dosage regimens. The validation of the predicted mutual diffusion and partition coefficients using experimental data was reported in previous studies. Optimal design parameters along with selection of most appropriate polymers suitable for different dosage regimens, selected based on current clinical practice, were predicted for maximum bioavailability of the drug while maintaining the released drug concentration in blood within the therapeutic range. Reservoir and monolithic type of diffusion‐controlled drug delivery devices of different shapes and sizes were predicted with different initial drug loadings and bioavailability for different dosage regimens. The effects of the released Paclitaxel from these devices on the tumor growth were also modeled using a previously reported mathematical pharmacokinetic–pharmacodynamic model. The proposed approach can easily be used to design other diffusion‐controlled drug delivery devices.     

How controlled release technology can aid gene delivery

Introduction: Many types of gene delivery systems have been developed to enhance the level of gene expression. Controlled release technology is a feasible gene delivery system which enables genes to extend the expression duration by maintaining and releasing them at the injection site in a controlled manner. This technology can reduce the adverse effects by the bolus dose administration and avoid the repeated administration. Biodegradable biomaterials are useful as materials for the controlled release-based gene delivery technology and various biodegradable biomaterials have been developed.

Areas covered: Controlled release-based gene delivery plays a critical role in a conventional gene therapy and genetic engineering. In the gene therapy, the therapeutic gene is released from biodegradable biomaterial matrices around the tissue to be treated. On the other hand, the intracellular controlled release of gene from the sub-micro-sized matrices is required for genetic engineering. Genetic engineering is feasible for cell transplantation as well as research of stem cells biology and medicine.

Expert opinion: DNA hydrogel containing a sequence of therapeutic gene and the exosome including the individual specific nucleic acids may become candidates for controlled release carriers. Technologies to deliver genes to cell aggregates will play an important role in the promotion of regenerative research and therapy.     

注射用缓控释给药系统的研究进展

注射用缓控释给药系统因可延长药物的作用时间、减少注射次数、改善患者的顺应性而成为当前药剂研究的一大热点。现根据给药途径的不同，介绍了近年来注射用缓控释给药系统在静脉、肌内、皮下、鞘内及靶部位给药方面的研究状况，涉及微球、脂质体、纳米粒及原位凝胶等剂型，评价了该类制剂开发中存在的问题和潜在的医疗风险。     

Drug release kinetics and transport mechanisms of non-degradable and degradable polymeric delivery systems

Importance of the field: The advancement in material design and engineering has led to the rapid development of new materials with increasing complexity and functions. Both non-degradable and degradable polymers have found wide applications in the controlled delivery field. Studies on drug release kinetics provide important information into the function of material systems. To elucidate the detailed transport mechanism and the structure-function relationship of a material system, it is critical to bridge the gap between the macroscopic data and the transport behavior at the molecular level.

Areas covered in this review: The structure and function information of selected non-degradable and degradable polymers have been collected and summarized from literature published after the 1990s. The release kinetics of selected drug compounds from various material systems is discussed in case studies. Recent progress in the mathematical models based on different transport mechanisms is highlighted.

What the reader will gain: This article aims to provide an overview of structure-function relationships of selected non-degradable and degradable polymers as drug delivery matrices.

Take home message: Understanding the structure-function relationship of the material system is key to the successful design of a delivery system for a particular application. Moreover, developing complex polymeric matrices requires more robust mathematical models to elucidate the solute transport mechanisms.     

Hydrophobic weak acid polymers as controlled release carriers

Poly(carboxyalkyl methacrylates) were studied as a cationic-drug delivery system, at pH 6.8 and 8.0. Different polymer/drug complexes were used to prepare compressed tablets. By kinetics experiments, we have found that drug release is dependent on both the hydrophobicity of the whole complex and the pH of the environment. Furthermore, a mechanism of dissociation/erosion clearly describes the drug release from a complex formed by a polymer soluble at target pH; otherwise, a mechanism of dissolution/diffusion is depicted. Additionally, we have observed that hydrophilic fillers increase the drug release rate. Since our results using different polymer/drug complexes exhibit pH-sensitive drug release, we propose that the poly(carboxyalkyl methacrylates) have potential as a colon-specific drug-delivery system.     

Silk fibroin nanoparticles for enhanced bio-macromolecule delivery to the retina

The aim of this study was to investigate intravitreal injection of silk fibroin nanoparticles (SFNs) encapsulating bio-macromolecules, achieving enhanced drug bioavailability, and extended retention in retina. SFNs were prepared with regenerated silk fibroin using desolvation method with fluorescein isothiocyanate labeled bovine serum albumin (FITC-BSA) as bio-macromolecular model drug encapsulated. In vitro physicochemical properties and in vitro drug release of FITC-BSA loaded SFNs (FITC-BSA-SFNs) were evaluated. Cytotoxicity, cellular uptake, and retention of FITC-BSA-SFNs were determined in human retinal pigment epithelial cell line (ARPE-19). In addition, in vivo distribution and safety of intravitreally administered FITC-BSA-SFNs were investigated in New Zealand white rabbits. The particle size of FITC-BSA-SFNs was 179.1?±?3.7?nm with polydispersity index of 0.102?±?0.033 and the zeta potential was greater than ?25?mV. FITC-BSA-SFNs exhibited excellent biocompatibility with no cytotoxicity observed within 24 and 48?h in AREP-19 cells. Compared to FITC-BSA solution, FITC-BSA-SFNs showed enhanced cellular uptake and prolonged retention. Furthermore, FITC-BSA-SFNs achieved accumulated distribution and extended retention in retina in vivo following intravitreal injection compared to a single administration of free drug solution. Therefore, this bio-macromolecule delivery platform based on SFNs could have great potential in the treatment of posterior segment disorders.     

智能水凝胶在脉冲控释制剂中的应用

智能水凝胶是一种新型功能高分子材料,在药物脉冲控释方面具有智能化、可自调式化和安全等优点,在药物脉冲控释方面有广泛应用前景。本文综述了温度、葡萄糖、pH值、磁场及电场敏感水凝胶的响应原理及在脉冲控释制剂中的最新应用。     

Triggered drug delivery from biomaterials

Importance of the field: Conventional dosing methods are frequently unable to deliver the clinical requirement of the patient. The ability to control the delivery of drugs from implanted materials is difficult to achieve, but offers promise in diverse areas such as infection-resistant medical devices and responsive implants for diabetics.

Areas covered in this review: This review gives a broad overview of recent progress in the use of triggers that can be used to achieve modulation of drug release rates from implantable biomaterials. In particular, these can be classified as being responsive to one or more of the following stimuli: a chemical species, light, heat, magnetism, ultrasound and mechanical force.

What the reader will gain: An overview of the potential for triggered drug delivery to give methods for tailoring the dose, location and time of release of a wide range of drugs where traditional dosing methods are not suitable. Particular emphasis is given to recently reported systems, and important historical reports are included.

Take home message: The use of externally or internally applied triggers of drug delivery to biomaterials has significant potential for improved delivery modalities and infection resistance.     

人工神经网络在药物控释系统研究中的应用

目的介绍人工神经网络在药物控释系统研究中的应用.方法查阅相关文献,总结、归纳国内外人工神经网络在药物控释系统中的应用.结果人工神经网络能优化处方组成和工艺过程,使其在控释片剂、控释微粒以及透皮吸收中得到应用.结论人工神经网络在设计和开发药物控释系统中具有广阔的前景.     

Pharmacokinetics and in vivo biodistribution of optimized PLGA nanoparticulate drug delivery system for controlled release of emtricitabine

Abstract

The objective of this study was to develop systematically optimized (OPT) nanoparticles (NPs) providing a controlled release using PLGA of emtricitabine (FTC) employing Formulation by Design (FbD), and evaluate their in vitro and in vivo performance. FTC generates severe adverse effects with risks of toxicity. Thus, NPs were prepared to reduce these drawbacks in this study. The NPs were prepared by water-in-oil-in-water (w/o/w) emulsion method, followed by high-pressure homogenization. The FTC NPs were systematically OPT using 3² central composite design and the OPT formulation located using overlay plot. The pharmacokinetics and in vivo biodistribution of OPT-FTC NPs were investigated in male Wistar rats via the oral administration. Transmission electron microscopy studies on OPT-FTC NPs demonstrated uniform shape and size of particles. In vitro release was sustained up to 15 days in PBS pH 7.4. Augmentation in the values of C_max (1.63 fold) and AUC_0-∞ (5.39 fold) indicated significant enhancement in the rate and extent of bioavailability by the OPT-FTC NPs compared to pure drug. OPT-FTC NPs showed 2.325 fold increase in the values of FTC concentrations in liver. The OPT-FTC NPs was found to be quite stable during 6 months of study period. Hence, the developed OPT-FTC NPs can be used as drug carrier for sustained/prolonged drug release and/or to reduce toxic effects.     

微凝胶的制备及其在药物缓控释系统中的应用

微凝胶是一种具有分子内交联网状结构,粒径在0.1~100 μm之间的功能性聚合物,具有粒径小、载药量高、环境响应性灵敏、生物相容性好等特点,在药物缓控释系统中的应用具有独特优势。笔者在查阅近年国内外文献的基础上综述了微凝胶的基本特性、制备方法、制备材料及在药物缓控释系统中的应用。     

Capped mesoporous silica nanoparticles as stimuli-responsive controlled release systems for intracellular drug/gene delivery

Importance of the field: The incorporation of stimuli-responsive properties into nanostructured systems has recently attracted significant attention in the research of intracellular drug/gene delivery. In particular, numerous surface-functionalized, end-capped mesoporous silica nanoparticle (MSN) materials have been designed as efficient stimuli-responsive controlled release systems with the advantageous ‘zero premature release’ property.

Areas covered in this review: Herein, the most recent research progress on the design of biocompatible, capped MSN materials for stimuli-responsive intracellular controlled release of therapeutics and genes is reviewed. A series of hard and soft caps for drug encapsulation and a variety of internal and external stimuli for controlled release of different cargoes are summarized. Recent investigations on the biocompatibility of MSN both in vitro and in vivo are also discussed.

What the reader will gain: The reader will gain an understanding of the challenges for the future exploration of biocompatible stimuli-responsive MSN devices.

Take home message: With a better understanding of the unique features of capped MSN and its behaviors in biological environment, these multifunctional materials will find a wide variety of applications in the field of drug/gene delivery.     

Natural and synthetic biomaterials for controlled drug delivery

A wide variety of delivery systems have been developed and many products based on the drug delivery technology are commercially available. The development of controlled-release technologies accelerated new dosage form design by altering pharmacokinetic and pharmacodynamics profiles of given drugs, resulting in improved efficacy and safety. Various natural or synthetic polymers have been applied to make matrix, reservoir or implant forms due to the characteristics of polymers, especially ease of control for modifications of biocompatibility, biodegradation, porosity, charge, mechanical strength and hydrophobicity/hydrophilicity. Hydrogel is a hydrophilic, polymeric network capable of imbibing large amount of water and biological fluids. This review article introduces various applications of natural and synthetic polymer-based hydrogels from pharmaceutical, biomedical and bioengineering points of view.     

单层芯渗透泵片用于水不溶性药物的控制释放单层芯渗透泵片用于水不溶性药物的控制释放

渗透泵片是一种理想的口服控释制剂。国外已将其商品化并依靠它取得了很好的经济效益 ,国内从 2 0世纪 80年代开始研究 ,但是 ,在过渡到工业化时遇到困难[1] 。高速、准确地辨识双层芯渗透泵片的药物层是确保正确打释药孔的必须而又困难的环节 ,也是大规模工业化生产的主要障碍。本文[2 ] 研制的夹芯渗透泵片免去了药物层辨识过程。单层芯渗透泵片既免去药物层辨识过程 ,又简化片芯制备 ,更容易实现工业化生产。本工作研究片芯处方变量对单层芯渗透泵片释药的影响规律。材料与方法药品与仪器、硝苯吡啶定量法和体外释放度测定法等参照文献 [2 ]。单层芯渗透泵片制备　片芯成分在研钵中研磨混匀过 80目筛后 ,直接压成直径 8mm的单层芯片。以 2 5 %醋酸纤维素 (辅以 35 %的聚乙二醇和 5 %的三醋酸甘油酯 )丙酮溶液作包衣液 ,将片芯置于包衣锅内 ,吹入热空气 ,包衣层至 170 μm厚。将包衣片在 6 0℃干燥 2 4h。然后 ,在包衣片两侧各制备一个直径 0 5mm的释药孔。结果与讨论1　聚氧乙烯分子量对释药的影响聚氧乙烯 (PEO)分子质量为 30 0 0 0 0时释药最快 ,10 0 0 0 0和 90...     

Development of controlled release oral drug delivery system by membrane-coating method-I

In order to develop a controlled-release oral drug delivery system (DDS) which sustains the plasma acetaminophen (AAP) concentration for a certain period of time, microporous membrane-coated tablets were prepared and evaluatedin vitro. Firstly, highly water-soluble core tablets of AAP were prepared with various formulations by wet granulation and compression technique. Then the core tablets were coated with polyvinylchloride (PVC) in which micronized sucrose particles were dispersed. Effect of formula compositions of core tablets and coating suspensions on the pharmaceutical characteristics such as drug release kinetics and membrane stability of the coated tablets was investigatedin vitro. AAP was released from the coated tablets at a zero-order rate in a pH-independent manner. This independency of AAP release to pH change from 1.2 to 7.2 is favorable for the controlled oral drug delivery, since it will produce a constant drug release in the stomach and intestine regardless of the pH change in the GI tract. Drug release could be extended upto 10 h according to the coating condition. The release rate could be controlled by changing the formula compositions of the core tablets and coating suspensions, coat weight per each tablet, and especially PVC/sucrose ratio and particle size of the sucrose in the coating suspension. The coated tablets prepared in this study had a fairly good pharmaceutical characteristicsin vitro, however, overall evaluation of the coated tablets should awaitin vivo absorption study in man.     

Moulded cross-linked chitosan matrix systems for controlled drug release

Matrix-type drug delivery systems were prepared by moulding and drying cross-linked chitosan gels in 24-well plates and they were evaluated in terms of their physical properties, drug content, surface morphology and swelling. Furthermore, the in vitro drug release profiles were subjected to kinetic modelling at two different pH values. In general, the moulded matrix systems showed statistically significantly slower drug release compared to immediate release tablets as measured by the mean dissolution time. Drug release from the moulded matrix systems prepared from chitosan cross-linked with tripolyphosphate was pH-dependent as can be seen from the release exponent value (n) of 0.75 at pH 5.8 (anomalous transport, erosion), while the n value was only 0.40 at pH 7.4 (Fickian diffusion). The matrix systems obtained from chitosan cross-linked with sodium lauryl sulphate showed higher swelling but mostly Fickian diffusional release (n?=?0.25 at pH 7.4, n?=?0.41 at pH 5.8).