聚合物阵列微针及其在透皮给药系统的应用

阵列微针作为一种新型透皮给药方式,能够避免皮肤角质层的屏障作用,实现亲水性药物和生物大分子药物的高效透皮吸收,具有无痛、微创、高效等优点。聚合物阵列微针的制备材料和制备方法多种多样,其不仅具有其他阵列微针的优点,还具有生物相容性好、安全性高、载药量精确可控及制备成本低廉等优势,是目前研究最为广泛且最具应用前景的一类阵列微针。系统地综述了目前聚合物阵列微针的主要制备方法及其在透皮给药系统中的最新研究进展。     

Optimization of square microneedle arrays for increasing drug permeability in skin

Microneedles array is a new transdermal drug delivery technique designed to create holes in the epidermis and penetrate the stratum corneum, thus avoiding the high resistance of this barrier. Microneedles have been shown to increase the skin permeability of drugs with no or little pain. However, the skin permeability of epidermis while using microneedle arrays has yet to be fully studied. In some cases, microneedle and microneedle array designs which were developed based on certain criteria (e.g., material of the microneedles) have to be related to other criteria (e.g., drug permeability in skin, skin thickness, etc.). Therefore, in order to determine the optimum design of the microneedle arrays, the effect of different factors (e.g., number of the microneedle, surface area of the patch, etc.) along with skin permeability by using microneedles should be determined accurately. In this work, an optimization framework for transdermal delivery of high molecular weight drug from microneedle is presented. The outputs of this framework have allowed us to identify the optimum design of various microneedles. Data from this optimization algorithm is then used to predict skin permeability of high molecular weight injected into the skin from a microneedle system. The effect of the optimized microneedles on blood drug concentration has been determined. The outcome of this study is useful to propose an optimum design based on different measurement (e.g., variation of skin thickness) for transdermal delivery of drugs.     

A review on microfabrication of thermoplastic polymer‐based microneedle arrays

This article will provide an overview of recent developments for microneedles made using injection molding and hot embossing techniques for active transdermal drug delivery. Microneedle arrays are developed for pain‐free and efficient drug delivery without using a cold chain. The focus of this article will be on the use of engineering thermoplastics and microneedle manufacturing techniques including patterning. Recent developments demonstrate that commercialization of polymer‐based microneedle systems is feasible. POLYM. ENG. SCI., 59:877–890, 2019. © 2019 Society of Plastics Engineers     

Two Photon Polymerization of Polymer–Ceramic Hybrid Materials for Transdermal Drug Delivery

Three-dimensional microneedle devices were created by femtosecond laser two photon polymerization (2PP) of organically modified ceramic (Ormocer®) hybrid materials. Arrays of in-plane and out-of-plane hollow microneedles (microneedle length=800 μm, microneedle base diameter=150–300 μm) with various aspect ratios were fabricated. The fracture and penetration properties of the microneedle arrays were examined using compression load testing. In these studies, the microneedle arrays penetrated cadaveric porcine adipose tissue without fracture. Human epidermal keratinocyte viability on the Ormocer® surfaces polymerized using 2PP was similar to that on control surfaces. These results suggest that 2PP is able to create microneedle structures for transdermal drug delivery with a larger range of geometries than conventional microfabrication techniques.     

The effects of geometry on skin penetration and failure of polymer microneedles

Microneedles are small-scale devices that may be used for drug delivery and biosensing. In this study, the forces required for mechanical failure, the modes of mechanical failure, as well as the mechanisms for microneedle penetration into porcine skin were examined. Microneedles produced from the acrylate-based polymer e-Shell 200 using an indirect rapid prototyping approach involving two-photon polymerization and poly(dimethylsiloxane) micromolding were found to possess sufficient strength for penetration of porcine skin. The failure forces were an order of magnitude greater than the forces necessary for full insertion into the skin. Bending was the most common form of failure; an increasing aspect ratio and a decreasing tip diameter were associated with lower failure forces. Video captured during skin penetration revealed that microneedle penetration into the skin occurred by means of a series of insertions and not by means of a single insertion event. Images obtained during and after skin penetration confirmed microneedle penetration of skin as well as transdermal delivery of lucifer yellow dye. These findings shed insight into the mechanisms of microneedle penetration and failure, facilitating design improvements for polymer microneedles.     

Macrocyclic Amphiphiles for Drug Delivery

Nanoparticles are the most crucial part of nanomedicine and various kinds of nanoparticles have been developed for drug delivery. As a new kind of nanoparticles, macrocyclic amphiphiles are gaining more and more attention in the field of nanomedicine due to their intrinsic features of molecular recognition and robust assembly. In this review, we summarized the reported works of drug delivery using macrocyclic amphiphiles, including cyclodextrin, calixarene, cucurbituril and pillararene species. These macrocyclic amphiphiles, serving as a new matrix of nanomedicine, can enhance drug solubility, improve drug stability, selectively deliver drugs to disease both in vitro and in vivo.     

Fluorescent Reporters for Drug Delivery Monitoring

Monitoring of drug delivery is an essential technique for innovative medical treatments, including cancer therapy. Fluorescence imaging has become an important tool in tracking drug delivery and thus improving treatment efficacy. Binding fluorescent reporters to therapeutic agents paves the way to real time monitoring of drug delivery and drug distribution in vitro and in vivo. This review discusses fluorescent reporters used in drug delivery monitoring and provides an overview of recent achievements in the development of fluorescence based drug delivery systems.     

(Trans) dermal insulin delivery based on polymeric systems

Abstract

Diabetes is one of the leading lethal diseases, which is often treated by hypodermic injection of insulin or by oral delivery. Oral drug delivery systems show limitations due to poor absorption and degradation that occurs in the GI tract and in the liver. Due to the patient discomfort that leads to poor patient compliance, alternative methods to administer insulin are of great interest. In recent years, much attention has been paid to transdermal delivery devices because of drug? delivery reliability to a target site with patient-friendly technologies. The major part of integumentary systems is skin, but skin drug delivery is challenging due to barrier properties exhibited by the outermost layer of skin stratum corneum. Transdermal drug delivery systems (TDDS) control the rate of release of the drug into the patient so that blood concentration maintains a steady state, and gastrointestinal absorption is avoidable. Controlled drug release causes minimum side effects and improves bioavailability of drugs, which showed poorly bioavailable drugs over other routes of delivery. The limiting factor in TDDS is stratum corneum, which is the outer layer of the skin and which acts as an effective barrier to the transport of biomolecules into the skin. For this reason, an effective method for drug delivery is hypodermic injection, which is a painful delivery. Besides, it needs a high level of expertise to administer the injection and the occasional risk of infections acquired through needle sticks. In recent year^’s microneedle (MN)-mediated drug delivery systems have been developed which can meet all the above goals.

?Microneedles are microscopic needles, which can deliver the drug to the target site by the degradation or dissolution of the polymer in the skin after insertion. This results in delivery of the encapsulated molecules, and no needles are left afterward. Microneedles are large and strong enough to insert into the skin and to deliver drugs into the skin, but they are short enough so that they do not reach the deeper layers of the skin to cause nerves stimulation. Microneedles offer an efficient and attractive method for delivering several classes of biomolecules and drugs to the skin in a self-administered manner. The overall goal of this research is TDDS and polymer micromodels system for insulin drug delivery, which can deliver an active biopharmaceutical in vivo for producing the desired physiological response.     

Biodegradable Porous Microneedles for an Electric Skin Patch

An array of porous microneedles (PMNs) made of biodegradable poly(lactic-co-glycolic acid) (PLGA) is fabricated by a combination of molding and freeze-drying methods. The optimized mixture of PLGA and 1,4-dioxane is poured into a mold of a microneedle array, followed by the freezing and sublimation of the frozen particles of 1,4-dioxane, a procedure that left an interconnecting porous structure in the PLGA with a porosity around 50%. The mechanical strength of the PMN made of PLGA (PLGA-PMN) is reinforced by modification with carboxymethylcellulose (CMC), resulting in sufficient strength enough for insertion into an excised porcine skin. The transdermal resistance is significantly decreased by the CMC-modified PLGA-PMN, which would improve the efficiency and safety of DC current-based transdermal techniques, including the electrical monitoring of the skin condition and iontophoresis for drug delivery and medical diagnosis.     

The use of variotherm systems for microinjection molding

Microinjection molding (μIM) is a fast‐developing technology which is used to produce polymeric microcomponents or components with micro/nanoscale features, such as are used in many fields including microfluidic diagnostics, microneedle drug delivery devices, microgears, and microswitches. The capabilities and performance of the microinjection molding process can be improved by incorporating a variotherm system. This leads to improved component quality, especially for high aspect ratio features. It can also help to increase the polymer flow path, improve feature replication, reduce residual stresses and molecular orientations, and also can eliminate weld lines. This article reviews the use of different variotherm systems in μIM, and describes how simulation of its use can provide insight when designing a mold cavity or a component with challenging microfeatures. The article highlights important problems, challenges and areas for further research. An increased understanding of these issues will provide opportunities to enhance further developments in the μIM process. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 42962.     

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.     

Drug Delivery Systems for Tuberculosis Treatment

Drug delivery systems based on polyurethane have been used for the controlled release of chemotherapeutic agents for the treatment of the chronic microbial disease tuberculosis. The drugs used in the investigation were isoniazid, ethionamide and florimicin. An in vitro technique was used to determine the release characteristics of the drugs into model biological media. It was shown that drug release occurs in accordance with first-order kinetics. The influence of drug loadings on release profiles was studied. The possibility of application of the drug delivery systems for tuberculosis treatment was shown by some medical and biological tests. © 1997 SCI     

微针技术应用研究现状

微针是通过微制造加工获得的一种针状体,单个针体尺寸为微米级,多个针体组成微针阵列,能够穿透皮肤角质层直达真皮层,在研发初期主要用于药物递送。与口服给药相比,微针能避开消化系统对药物的代谢作用;与注射针头相比,微针能够有效减小患者疼痛感,提高患者依从性。此外,微针技术因为其便捷的透皮作用方式,在疫苗接种、组织液提取、生物标志物检测、医疗美容等领域的应用也被广泛开发。微针的制作材料有硅、不锈钢及生物降解材料,如透明质酸、聚乳酸等;从给药方式上可分为固体、包被、溶解、空心以及水凝胶等多种微针类型。本综述结合近年来微针技术相关进展,简要概述微针的制造材料及作用形式,重点介绍微针在药物递送、疫苗接种及组织液提取和生物标志物检测等领域的应用,探讨微针的机械强度、生物安全性、无菌化处理及稳定性等对其在市场上推广应用的影响,并对其未来发展进行了展望。     

The Potential of Cucurbit[n]urils in Drug Delivery

In this paper we review cucurbit[n]urils (CB[n]), a relatively new family of macrocycles that has shown potential in improving drug delivery. Encapsulation of drugs within the homologues CB[6], CB[7], or CB[8] can impart enhanced chemical and physical stability, improve drug solubility, and control drug release. The formulation of CB[n] into a dosage form suitable for clinical use is a non-trivial task, because the free macrocycle and its host-drug complex generally exhibit pseudo-polymorphism in the solid state. Despite this, cucurbiturils have been included in tablets for oral delivery and inserts for nasal delivery. Here we examine the potential use of cucurbiturils in drug delivery in the context of getting a new drug into clinical trials and discuss what further research is needed in this area.     

Development and Validation of an Artificial Mechanical Skin Model for the Study of Interactions between Skin and Microneedles

Microneedles are small needle‐like structures that are almost invisible to the naked eye. They have an immense potential to serve as a valuable tool in many medical applications, such as painless vaccination. Microneedles work by breaking through the stratum corneum, the outermost barrier layer of the skin, and providing a direct path for drug delivery into the skin. A lot of research has been presented over the past two decades on the applications of microneedles, yet the fundamental mechanism of how they interact, pressure, and penetrate the skin in its native state is worth examining further. As such, a major difficulty with understanding the mechanism of microneedle–skin interaction is the lack of an artificial mechanical human skin model to use as a standardized substrate. In this research news, the development of an artificial mechanical skin model based on a thorough mechanical study of fresh human and porcine skin samples is presented. The artificial mechanical skin model can be used to study the mechanical interactions between microneedles and skin, but not diffusion of molecules across skin. This model can assist in improving the performance of microneedles by enhancing the reproducibility of microneedle depth insertions for optimal drug delivery and biosensing.

     

In situ incorporation of monodisperse drug nanoparticles into hydrogel scaffolds for hydrophobic drug release

The effective and locally sustained delivery of hydrophobic drug with hydrogels as carriers is still a challenge owing to the inherent incompatibility of hydrophilic hydrogel network and hydrophobic drug. One promising approach is to use porous hydrogels to encapsulate and deliver hydrophobic drug in the form of nanoparticles to the disease sites. However, this approach is currently limited by the inability to load concentrated hydrophobic drug nanoparticles into the hydrogels because of the severe nanoparticle aggregation during the loading process. In this article, we firstly designed and fabricated efficient drug nanoparticles embedded hydrogels for hydrophobic drug delivery by incorporating monodisperse silybin (hydrophobic drug for liver protection) nanoparticles into acrylated hyaluronic acid (HA‐AC) based hydrogels through in situ cross‐linking. The silybin nanoparticles embedded hydrogel scaffolds proved to be a good sustained release system with a long period of 36 h. The drug release from this hybrid hydrogels could be modulated by tuning HA‐AC concentration, cross‐linking ratio, chain length of cross‐linker and drug loading amount. The different kinetic models were applied, and it was observed that the release profile of silybin best followed the Hixson‐Crowell model for the release of drug from the hydrogels embedding silybin nanoparticles. It could be envisioned that this process would significantly advance the potential applications of hydrogel scaffolds mediated hydrophobic drug delivery in clinical therapies. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43111.     

Stimuli-accelerated polymeric drug delivery systems

The controlled delivery of active pharmaceutical ingredients to the site of disease represents a major challenge in drug therapy. Particularly when drugs have to be transported across biological barriers, suitable drug delivery systems are of importance. In recent years responsive delivery systems have been developed which enable a controlled drug release depending on internal or external stimuli such as changes in pH, redox environment or light and temperature. In some studies delivery systems with reactivity against two different stimuli were established either to enhance the response by synergies of the stimuli or to broaden the window of possible trigger events. In the present review numerous exciting developments of pH-, light- and redox-cleavable polymers suitable for the preparation of smart delivery systems are described. The review discusses the different stimuli that can be used for a controlled drug release of polymer-based delivery systems. It puts a focus on the different polymers described for the preparation of stimuli-sensitive systems, their preparation techniques as well as their stimuli-responsive degradation. © 2022 The Authors. Polymer International published by John Wiley & Sons Ltd on behalf of Society of Industrial Chemistry.     

PEGylated polylysine derived copolymers with reduction‐responsive side chains for anticancer drug delivery

Reduction‐responsive drug delivery systems have recently gained intense attention in intracellular delivery of anticancer drugs. In this study, we developed a PEGylated polypeptide, poly(ethylene glycol)‐block‐poly(?‐propargyloxycarbonyl‐l ‐lysine) (PEG₁₁₃‐b‐PPAL), as a novel clickable substrate for conjugation of reduction‐responsive side chains for antineoplastic drug delivery. PEG₁₁₃‐b‐PPAL was synthesized through ring‐opening polymerization of alkyne‐containing N‐carboxyanhydride monomers. A designed disulfide‐containing side chain was introduced onto the PEGylated polypeptide by click reaction. The obtained copolymer PEG₁₁₃‐b‐P(Lys‐DSA) formed micelles by self‐assembly, which exhibited reduction‐responsive behavior under the stimulus of 10 mmol L^–1 glutathione (GSH) in water. A small molecule intermediate, compound 2 , was used as a model to investigate the thiol reduction mechanism of PEG₁₁₃‐b‐P(Lys‐DSA) copolymers. The anticancer drug doxorubicin (DOX) was then loaded into the micelles with a drug loading content of 6.73 wt% and a loading efficiency of 40.3%. Both the blank and the drug‐loaded micelles (DOX‐loaded polylysine derived polymeric micelles (LMs/DOX)) adopted a spherical morphology, with average diameters of 48.0 ± 13.1 and 63.8 ± 20.0 nm, respectively. The in vitro drug release results indicated that DOX could be released faster from the micelles by the trigger of GSH in phosphate buffered saline. Confocal laser scanning microscopy and flow cytometer analysis further proved the intracellular delivery of DOX by LMs/DOX and their GSH‐sensitive release behavior. A 3‐(4,5‐dimethyl‐thiazol‐2‐yl)‐2,5‐diphenyl tetrazolium bromide assay showed that the polymers exhibited negligible cytotoxicity towards normal L929 cells or cancer MCF‐7 cells with a treated concentration up to 1.0 mg mL^–1. In conclusion, our synthesized biocompatible and biodegradable PEGylated polypeptides hold great promise for intracellular antineoplastic drug delivery. © 2019 Society of Chemical Industry     

Charge-Conversional Binary Drug Delivery Polymeric Micelles for Combined Chemotherapy of Cervical Cancer

Candesartan-g-polyethyleneimine-cis-1,2-cyclohexanedicarboxylic anhydride (CD-g-PEI-HHPA, CPH) polymer-drug conjugates based on charge-conversional delivery, enhanced buffering capacity, amidase-triggered drug release, and combined cancer chemotherapy strategies were successfully synthesized for simultaneous and effective codelivery of CD and paclitaxel (PTX) to treat cervical cancer. The CPH polymer-drug conjugates could self-assemble into core-shell structure micelle of around 100 nm in diameter with negative surface charge and were employed to load PTX to formulate binary drug delivery system. The CPH polymeric micelles could mediate quick endosomal escape and amidase-responsive drug-release manners. In vitro cytotoxicity and in vivo investigations confirmed CPH binary drug delivery system exerted strong antitumor efficacy.     

Controlled co‐delivery of hydrophilic and hydrophobic drugs from thermosensitive and crystallizable copolymer nanoparticles

Functionalized amphiphilic block copolymers poly(N‐isopropyl acrylamide)‐b‐poly(stearyl methacrylate) (PNIPAM‐PSMA) are synthesized. Their self‐assembled core‐shell nanoparticles have the hydrophilic thermosensitive shell and hydrophobic crystallizable core. Nanoparticles exhibit volume phase transition at temperature of 38 °C and its poly(stearyl methacrylate) (PSMA) moiety could form nano size crystals to retain drugs, making them good carriers for drug co‐delivery system. Thermosensitivity and crystallinity of nanoparticles are characterized with dynamic light scattering (DLS), differential scanning calorimetry (DSC), small‐angle X‐ray scattering (SAXS), and atomic force microscopy (AFM). The interactions and relationship between chemical structures of copolymer nanoparticles and loading drugs are discussed. Different loading techniques and combined loading of hydrophobic/hydrophilic drugs are studied. Nanoparticles show a good and controllable drug loading capacity (DL) of hydrophilic/hydrophobic drugs. The drugs release kinetics is analyzed with Fick's law and Weibull model. A general method for analyzing drug release kinetics from nanoparticles is proposed. Weibull model is well fitted and the parameters with definite physical meaning are analyzed. PNIPAM‐PSMA nanoparticles show a quite different thermal response, temporal regulation, and sustained release effect of hydrophilic and hydrophobic drugs, suggesting a promising application in extended and controlled co‐delivery system of multi‐drug. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 44132.