Interactive mixture as a rapid drug delivery system

The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.     

快速响应水凝胶在给药系统中的应用进展

传统智能水凝胶作为药物载体可控制药物的定点、定时、定量释放,具有提高药效、靶向,减少给药频率,增加安全性等优点。但由于存在响应速率慢的缺点而大大限制其应用。因此,近年来围绕提高智能水凝胶给药的响应速率的研究非常活跃,展示了广阔的应用前景。文中综述了快速响应水凝胶的类型、制备原理与给药系统中的应用进展,并指出其缺点及发展方向。     

内源性外泌体作为药物递释系统的研究进展

外泌体是一种活细胞分泌的直径为40~100nm的囊状小泡,是细胞间信息传递、物质交换的重要媒介。作为天然内源性的物质转运载体,采用外泌体负载药物具有毒性低、无免疫原性、渗透性好等优势,目前,外泌体已成功负载小分子化学药物、基因药物用于治疗肿瘤及阿尔茨海默症等疾病。文章将基于外泌体的发展情况就外泌体在药物递送系统中的应用进行详细的介绍分析。     

Preparation and Evaluation of Self-Microemulsifying Drug Delivery System Containing Vinpocetine

The main purpose of current investigation is to prepare a self-microemulsifying drug delivery system (SMEDDS) to enhance the oral bioavailability of vinpocetine, a poorly water-soluble drug. Suitable vehicles were screened by determining the solubility of vinpocetine in them. Certain surfactants were selected according to their emulsifying ability with different oils. Ternary phase diagrams were used to identify the efficient self-microemulsifying region and to screen the effect of surfactant/cosurfactant ratio (K_m). The optimized formulation for in vitro dissolution and bioavailability assessment was oil (ethyl oleate, 15%), surfactant (Solutol HS 15, 50%), and cosurfactant (Transcutol^® P, 35%). The release rate of vinpocetine from SMEDDS was significantly higher than that of the commercial tablet. Pharmacokinetics and bioavailability of SMEDDS were evaluated. It was found that the oral bioavailability of vinpocetine of SMEDDS was 1.72-fold higher as compared with that of the commercial tablet. These results obtained demonstrated that vinpocetine absorption was enhanced significantly by employing SMEDDS. Therefore, SMEDDS might provide an efficient way of improving oral bioavailability of poorly water-soluble drugs.     

Microemulsions as a Surrogate Carrier for Dermal Drug Delivery

Microemulsions are isotropic, thermodynamically stable transparent (or translucent) systems of oil, water, and surfactant, frequently in combination with a cosurfactant with a droplet size usually in the range of 20–200 nm. Since their discovery, they have attained increasing significance both in basic research and in industry. Due to their distinct advantages such as enhanced drug solubility, thermodynamic stability, facile preparation, and low cost, uses and applications of microemulsions have been numerous. Recently, there is a surge in the exploration of microemulsion for transdermal drug delivery for their ability to incorporate both hydrophilic (5-fluorouracil, apomorphine hydrochloride, diphenhydramine hydrochloride, tetracaine hydrochloride, and methotrexate) and lipophilic drugs (estradiol, finasteride, ketoprofen, meloxicam, felodipine, and triptolide) and enhance their permeation. Very low surface tension in conjunction with enormous increase in the interfacial area due to nanosized droplets of the microemulsion influences the drug permeation across the skin. A large number of oils and surfactants are available, which can be used as components of microemulsion systems for transdermal delivery but their toxicity, irritation potential, and unclear mechanism of action limit their use. Besides surfactants, oils can also act as penetration enhancers (oleic acid, linoleic acid, isopropyl myristate, isopropyl palmitate, etc.). The transdermal drug delivery potential of microemulsions is dependent not only on the applied constituents of the vehicle but also drastically on the composition/internal structure of the phases which may promote or hamper the drug distribution in the vehicles. This article explores microemulsion as transdermal drug delivery vehicles with emphasis on components selection for enhanced drug permeation and skin tolerability of these systems and further future directions.     

Osmotically Controlled Oral Drug Delivery*

It is advantageous to deliver some drugs with short half-life, and which are to be given frequently for chronic ailments, in the form of controlled-release (CR) formulations. The orally administered drugs, in the form of conventional matrix or reservoir type formulations, pose problems of bioavailability fluctuations due to gastric pH variations. Moreover, the release of drug(s) from these systems is affected by the hydrodynamic conditions of the body. Osmotically controlled drug delivery systems utilize the principles of osmotic pressure for the controlled delivery of active agent(s). The release rate of drug(s) from these systems is independent of the physiological factors of the gastrointestinal (GI) tract to a large extent. In the present review, theory underlying the delivery of drugs from osmotic systems is presented. Different types of oral osmotic systems, their advantages over conventional matrix and reservoir types of systems, and their applications are also discussed. Finally, some of the limitations, adverse effects, and patent and market status of these systems are reviewed. These systems form a major segment of drug delivery products. Because of their advantages and strong market potential, it appears that the future of osmotic systems in rate-controlled oral drug delivery is promising.     

Bubble-Based Microrobots with Rapid Circular Motions for Epithelial Pinning and Drug Delivery

Remotely powered microrobots are proposed as next-generation vehicles for drug delivery. However, most microrobots swim with linear trajectories and lack the capacity to robustly adhere to soft tissues. This limits their ability to navigate complex biological environments and sustainably release drugs at target sites. In this work, bubble-based microrobots with complex geometries are shown to efficiently swim with non-linear trajectories in a mouse bladder, robustly pin to the epithelium, and slowly release therapeutic drugs. The asymmetric fins on the exterior bodies of the microrobots induce a rapid rotational component to their swimming motions of up to ≈150 body lengths per second. Due to their fast speeds and sharp fins, the microrobots can mechanically pin themselves to the bladder epithelium and endure shear stresses commensurate with urination. Dexamethasone, a small molecule drug used for inflammatory diseases, is encapsulated within the polymeric bodies of the microrobots. The sustained release of the drug is shown to temper inflammation in a manner that surpasses the performance of free drug controls. This system provides a potential strategy to use microrobots to efficiently navigate large volumes, pin at soft tissue boundaries, and release drugs over several days for a range of diseases.     

药用高分子材料在脉冲释药系统中的应用

传统药用高分子材料如纤维素醚类衍生物、丙烯酸树脂类及聚乙烯吡咯烷酮类等具有良好的膨胀性、溶蚀性和渗透性等。当其受到外界信号刺激时,高分子材料的结构和性质随之发生变化,从而控制药物的脉冲释放。概述了传统药用高分子材料在脉冲式药系统中的应用研究,探讨了新型高分子材料的发展方向。     

Formulation of Rosuvastatin-Loaded Self-Nanoemulsifying Drug Delivery System Using Box-Behnken Design

The objectives of present study were to understand the effect of formulation variables of self-nanoemulsifying drug delivery system (SNEDDS) of rosuvastatin (RSV). Box-Behnken design in conjunction with desirability function was used to evaluate the main effect, interaction effect and quadratic effect of independent formulation variables that included amounts of Acconon 200 E6, Cremophor RH40, and Lipoxol 300. For a better understanding of the selected variables for the optimal performance of RSV SNEDDS, the models were presented as three-dimensional response surface graphs. A fresh batch of optimized formulations and were prepared with optimized levels of the independent variables to yield dependent variables (Y1–Y6) values that were remarkably close to the predicted values. Drug excipient compatibility studies using the Fourier transform infrared spectroscopy, differential scanning calorimeter and x-ray diffraction indicated the absence of any incompatibility between RSV and selected excipients. The transmission electron microscopy of selected optimized SNEDDS of RSV showed the spherical shape of globules with no signs of coalescence and precipitation of RSV. The study demonstrates the use of Box-Behnken design for the preparation of RSV SNEDDS. The desirable goals can be obtained by systematic formulation approach in minimum possible time.     

Development and Characterization of Self-Microemulsifying Drug Delivery System of Tacrolimus for Intravenous Administration

Tacrolimus (FK 506), a poorly soluble immunosuppressant is currently formulated in nonaqueous vehicle containing hydrogenated castor oil derivative for intravenous administration. Hydrogenated castor oil derivatives are associated with acute anaphylactic reactions. This proposes to overcome the problems of poor aqueous solubility of the drug and the toxicity associated with currently used excipients by the development of a new parenterally acceptable formulation using self-microemulsifying drug delivery system (SMEDDS). Solubility of FK 506 in various oils, surfactants, and cosurfactants was determined to identify SMEDDS components. Phase diagrams were constructed at different ratios of surfactants: cosurfactant (K_m) to determine microemulsion existence area. Influence of oily phase content, K_m, aqueous phase composition, dilution, and incorporation of drug on mean globule size of microemulsions was studied. SMEDDSs were developed using ethyl oleate as oily phase and Solutol HS 15 as surfactant. Glycofurol was used successfully as a cosurfactant. Developed SMEDDS could solubilize 0.8% (wt/wt) FK 506 and on addition to aqueous phase could form spontaneous microemulsion with mean globule size < 30 nm. The resulting microemulsion was iso-osmotic, did not show any phase separation or drug precipitation even after 24 h, and exhibited negligible hemolytic potential to red blood cells.     

Stimulus-Responsive Drug Delivery Nanoplatforms for Osteoarthritis Therapy

Osteoarthritis (OA) is one of the most prevalent age-related degenerative diseases. With an increasingly aging global population, greater numbers of OA patients are providing clear economic and societal burdens. Surgical and pharmacological treatments are the most common and conventional therapeutic strategies for OA, but often fall considerably short of desired or optimal outcomes. With the development of stimulus-responsive nanoplatforms has come the potential for improved therapeutic strategies for OA. Enhanced control, longer retention time, higher loading rates, and increased sensitivity are among the potential benefits. This review summarizes the advanced application of stimulus-responsive drug delivery nanoplatforms for OA, categorized by either those that depend on endogenous stimulus (reactive oxygen species, pH, enzyme, and temperature), or those that depend on exogenous stimulus (near-infrared ray, ultrasound, magnetic fields). The opportunities, restrictions, and limitations related to these various drug delivery systems, or their combinations, are discussed in areas such as multi-functionality, image guidance, and multi-stimulus response. The remaining constraints and potential solutions that are represented by the clinical application of stimulus-responsive drug delivery nanoplatforms are finally summarized.     

多孔碳纳米材料构建抗肿瘤药物靶向传递系统的研究进展

抗肿瘤药物靶向传递系统是提高传统化疗药物疗效,并降低其毒副作用的重要手段。以多孔碳纳米材料为药物载体,根据肿瘤组织微环境特点,构建抗肿瘤药物靶向传递系统是实现靶向治疗方案的有效方式。本文围绕基于多孔碳纳米材料的抗肿瘤药物靶向传递系统的构建及应用进行综述,描述了多孔碳纳米材料适宜载药的设计、合成及功能化修饰;通过理论与实例相结合的方式,介绍了提高多孔碳纳米材料载药量和实现联合给药的有效策略;从内源和外源性敏感刺激的角度,重点分析了多孔碳纳米材料基于肿瘤微环境构建的靶向传递系统的机制和应用;阐述了多孔碳纳米材料作为抗肿瘤药物载体面临的生物相容性和生物降解性的问题,并分析了可能的解决途径;展望了多孔碳纳米材料在构建肿瘤药物靶向传递系统应用中的前景及发展方向,为研发靶向、可控的抗肿瘤药物传递系统提供了理论依据和例证支持。     

Gold Nanoparticle–Protein Agglomerates as Versatile Nanocarriers for Drug Delivery

The fabrication of a versatile nanocarrier based on agglomerated structures of gold nanoparticle (Au NP)–lysozyme (Lyz) in aqueous medium is reported. The carriers exhibit efficient loading capacities for both hydrophilic (doxorubicin) and hydrophobic (pyrene) molecules. The nanocarriers are finally coated with an albumin layer to render them stable and also facilitate their uptake by cancer cells. The interaction between agglomerated structures and the payloads is non‐covalent. Cell viability assay in vitro showed that the nanocarriers by themselves are non‐cytotoxic, whereas the doxorubicin‐loaded ones are cytotoxic, with efficiencies higher than that of the free drug. Transmission electron microscopy and fluorescence microscopy along with flow cytometry analysis confirm the uptake of the drug‐loaded nanocarriers by a human cervical cancer HeLa cell line. Field‐emission scanning electron microscopy reveals the formation of apoptotic bodies leading to cell death, confirming the release of the payloads from the nanocarriers into the cell. Overall, the findings suggest the fabrication of novel Au NP–protein agglomerate‐based nanocarriers with efficient drug‐loading and ‐releasing capabilities, enabling them to act as multimodal drug‐delivery vehicles.     

A Self-Disguised Nanospy for Improving Drug Delivery Efficiency via Decreasing Drug Protonation

Nanoscale drug carriers play a crucial role in reducing side effects of chemotherapy drugs. However, the mononuclear phagocyte system (MPS) and the drug protonation after nanoparticles (NPs) burst release still limit the drug delivery efficiency. In this work, a self-disguised Nanospy is designed to overcome this problem. The Nanospy is composed of: i) poly (lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG) loading doxorubicin is the core structure of the Nanospy. ii) CD47 mimic peptides (CD47p) is linked to NPs which conveyed the “don't eat me” signal. iii) 4-(2-aminoethyl) benzenesulfonamide (AEBS) as the inhibitor of Carbonic anhydrase IX (CAIX) linked to NPs. Briefly, when the Nanospy circulates in the bloodstream, CD47p binds to the regulatory protein α (SIRPα) on the surface of macrophages, which causes the Nanospy escapes from phagocytosis. Subsequently, the Nanospy enriches in tumor and the AEBS reverses the acidic microenvironment of tumor. Due to above characteristics, the Nanospy reduces liver macrophage phagocytosis by 25% and increases tumor in situ DOX concentration by 56% compared to PLGA@DOX treatment. In addition, the Nanospy effectively inhibits tumor growth with a 63% volume reduction. This work presents a unique design to evade the capture of MPS and overcomes the influence of acidic tumor microenvironment (TME) on weakly alkaline drugs.     

Advances in Biomaterials for Drug Delivery

Advances in biomaterials for drug delivery are enabling significant progress in biology and medicine. Multidisciplinary collaborations between physical scientists, engineers, biologists, and clinicians generate innovative strategies and materials to treat a range of diseases. Specifically, recent advances include major breakthroughs in materials for cancer immunotherapy, autoimmune diseases, and genome editing. Here, strategies for the design and implementation of biomaterials for drug delivery are reviewed. A brief history of the biomaterials field is first established, and then commentary on RNA delivery, responsive materials development, and immunomodulation are provided. Current challenges associated with these areas as well as opportunities to address long‐standing problems in biology and medicine are discussed throughout.     

明胶微球/磷酸镁基骨水泥复合药物缓释体系的构建

采用乳化交联法制备出粒径主要分布在100~300 μm的载药明胶微球, 分析了交联剂含量、药物含量和转速对载药率和包封率的影响及药物含量和转速对微球粒径的影响。对载药明胶微球与磷酸镁基骨水泥进行复合, 探讨微球降解过程中复合体系孔隙率的变化及其在体外药物释放的规律, 以期获得一种具有药物缓释性能的多孔磷酸镁基复合骨水泥。结果表明, 随着葡萄糖浓度增加, 载药率和包封率先上升再下降; 随着药物含量的增加, 载药率保持上升, 包封率先上升后下降; 随着转速增加, 载药率和包封率均下降。综合分析, 在转速为400 r/min、葡萄糖浓度为0.5 g/mL、药物与明胶质量比为1:2的条件下制备的载药明胶微球载药量较高, 且粒径合适。将复合不同比例该载药微球的磷酸镁基骨水泥浸泡在Tris-HCl缓冲溶液中进行体外药物释放研究, 结果表明: 在释放前期(0~10 h)药物释放速率较快, 之后药物释放明显减缓。7 d后, 微球几乎降解完全, 药物释放率达到60%~89%, 达到了一定的药物缓释效果。     

Remotely Triggerable Drug Delivery Systems

Triggerable drug delivery systems enable on‐demand controlled release profiles that may enhance therapeutic effectiveness and reduce systemic toxicity. Recently, a number of new materials have been developed that exhibit sensitivity to visible light, near‐infrared (NIR) light, ultrasound, or magnetic fields. This responsiveness can be triggered remotely to provide flexible control of dose magnitude and timing. Here we review triggerable materials that range in scale from nano to macro, and are activated by a range of stimuli.     

Neutrophil‐Based Drug Delivery Systems

White blood cells (WBCs) are a major component of immunity in response to pathogen invasion. Neutrophils are the most abundant WBCs in humans, playing a central role in acute inflammation induced by pathogens. Adhesion to vasculature and tissue infiltration of neutrophils are key processes in acute inflammation. Many inflammatory/autoimmune disorders and cancer therapies have been found to be involved in activation and tissue infiltration of neutrophils. A promising strategy to develop novel targeted drug delivery systems is the targeting and exploitation of activated neutrophils. Herein, a new drug delivery platform based on neutrophils is reviewed. There are two types of drug delivery systems: neutrophils as carriers and neutrophil‐membrane‐derived nanovesicles. It is discussed how nanoparticles hijack neutrophils in vivo to deliver therapeutics across blood vessel barriers and how neutrophil‐membrane‐derived nanovesicles target inflamed vasculature. Finally, the potential applications of neutrophil‐based drug delivery systems in treating inflammation and cancers are presented.