Nanoparticle Mediated P-Glycoprotein Silencing for Improved Drug Delivery across the Blood-Brain Barrier: A siRNA-Chitosan Approach

The blood-brain barrier (BBB), composed of tightly organized endothelial cells, limits the availability of drugs to therapeutic targets in the central nervous system. The barrier is maintained by membrane bound efflux pumps efficiently transporting specific xenobiotics back into the blood. The efflux pump P-glycoprotein (P-gp), expressed at high levels in brain endothelial cells, has several drug substrates. Consequently, siRNA mediated silencing of the P-gp gene is one possible strategy how to improve the delivery of drugs to the brain. Herein, we investigated the potential of siRNA-chitosan nanoparticles in silencing P-gp in a BBB model. We show that the transfection of rat brain endothelial cells mediated effective knockdown of P-gp with subsequent decrease in P-gp substrate efflux. This resulted in increased cellular delivery and efficacy of the model drug doxorubicin.     

Characterization of Polymeric Microneedle Arrays for Transdermal Drug Delivery

Microfabrication of dissolvable, swellable, and biodegradable polymeric microneedle arrays (MNs) were extensively investigated based in a nano sensitive fabrication style known as micromilling that is then combined with conventional micromolding technique. The aim of this study was to describe the polymer selection, and optimize formulation compounding parameters for various polymeric MNs. Inverse replication of micromilled master MNs reproduced with polydimethylsiloxane (PDMS), where solid out of plane polymeric MNs were subsequently assembled, and physicochemically characterized. Dissolvable, swellable, and biodegradable MNs were constructed to depth of less than 1 mm with an aspect ratio of 3.6, and 1/2 mm of both inter needle tip and base spacing. Micromolding step also enabled to replicate the MNs very precisely and accurate. Polymeric microneedles (MN) precision was ranging from ±0.18 to ±1.82% for microneedle height, ±0.45 to ±1.42% for base diameter, and ±0.22 to ±0.95% for interbase spacing. Although dissolvable sodium alginate MN showed less physical robustness than biodegradable polylactic-co-glycolic acid MN, their thermogravimetric analysis is of promise for constructing these polymeric types of matrix devices.     

Nanocarrier for the Transdermal Delivery of an Antiparkinsonian Drug

The purpose of the present study was to investigate the potential of nanoemulsions as nanodrug carrier systems for the percutaneous delivery of ropinirole. Nanoemulsions comprised Capryol 90 as the oil phase, Tween 20 as the surfactant, Carbitol as the cosurfactant, and water as an external phase. The effects of composition of nanoemulsion, including the ratio of surfactant and cosurfactant (S _mix) and their concentration on skin permeation, were evaluated. All the prepared nanoemulsions showed a significant increase in permeation parameters such as steady state flux (J _ss) and permeability coefficient (K _p) when compared to the control (p < 0.01). Nanoemulsion composition (NEL3) comprising ropinirole (0.5% w/w), Capryol 90 (5% w/w), S _mix 2:1 (35% w/w), and water (59.5% w/w) showed the highest flux (51.81 ± 5.03 μg/cm²/h) and was selected for formulation into nanoemulsion gel. The gel was further optimized with respect to oil concentration (Capryol 90), polymer concentration (Carbopol), and drug content by employing the Box–Behnken design, which statistically evaluated the effects of these components on ropinirole permeation. Oil and polymer concentrations were found to have a negative influence on permeation, while the drug content had a positive effect. Nanoemulsion gel showed a 7.5-fold increase in skin permeation rate when compared to the conventional hydrogel. In conclusion, the results of the present investigation suggested a promising role of nanoemulsions in enhancing the transdermal permeation of ropinirole.     

Fabrication of Tip-Dissolving Microneedles for Transdermal Drug Delivery of Meloxicam

Dissolving microneedles (MNs) offered a simple, minimally invasive method for meloxicam (MX) delivery to the skin. However, the fabrication of dissolving MNs still faced some challenges, such as significant time consumption, loss of drug activity, and difficulty in regulating MN drug loading. To address these issues, we developed the tip-dissolving (TD) MNs. Several kinds of drugs were encapsulated successfully, and the quantity of MX ranged from 37.23?±?8.40 to 332.53?±?13.37 μg was precisely controlled. The effects of fabrication process on biomacromolecules stability were studied, and it was found that tyrosinase kept 90.4% activity during the fabrication process. The whole process for the fabrication of MNs only takes approximately 1 h. In order to further evaluate the potential of the TD MNs, MX TD MNs were prepared for in vitro release experiments, in vivo release experiments, safety evaluation, pharmacokinetic studies, and pharmacodynamic studies. The results demonstrated that MX TD MNs offered several advantages, including rapid release of the encapsulated drug (91.72% within 30 min), efficient drug delivery to skin (79.18%), no obvious skin irritation, decent relative bioavailability (122.3%), and strong anti-inflammatory and analgesic effects. Based on these results, we envisage that the TD MNs have promising potential for transdermal drug delivery of MX.     

Evaluation of Meloxicam-Loaded Cationic Transfersomes as Transdermal Drug Delivery Carriers

The aim of this study is to develop meloxicam (MX)-loaded cationic transfersomes as skin delivery carriers and to investigate the influence of formulation factors such as cholesterol and cationic surfactants on the physicochemical properties of transfersomes (i.e., particle size, size distribution, droplet surface charge and morphology), entrapment efficiency, stability of formulations and in vitro skin permeation of MX. The transfersomes displayed a spherical structure. Their size, charge, and entrapment efficiency depended on the composition of cholesterol and cationic surfactants in the formulation. Transfersomes provided greater MX skin permeation than conventional liposomes and MX suspensions. The penetration-enhancing mechanism of skin permeation by the vesicles prepared in this study may be due to the vesicle adsorption to and/or fusion with the stratum corneum. Our results suggest that cationic transfersomes may be promising dermal delivery carriers of MX.     

Liquid Crystalline Systems for Transdermal Delivery of Celecoxib: In Vitro Drug Release and Skin Permeation Studies

Liquid crystalline systems of monoolein/water could be a promising approach for the delivery of celecoxib (CXB) to the skin because these systems can sustain drug release, improve drug penetration into the skin layers and minimize side effects. This study evaluated the potential of these systems for the delivery of CXB into the skin based on in vitro drug release and skin permeation studies. The amount of CXB that permeated into and/or was retained in the skin was assayed using an HPLC method. Polarizing light microscopy studies showed that liquid crystalline systems of monoolein/water were formed in the presence of CXB, without any changes in the mesophases. The liquid crystalline systems decreased drug release when compared to control solution. Drug release was independent of the initial water content of the systems and CXB was released from cubic phase systems, irrespective of the initial water content. The systems released the CXB following zero-order release kinetics. In vitro drug permeation studies showed that cubic phase systems allowed drug permeation and retention in the skin layers. Cubic phase systems of monoolein/water may be promising vehicles for the delivery of CXB in/through the skin because it improved CXB skin permeation compared with the control solution.KEY WORDS: celecoxib, drug delivery systems, liquid crystalline system, monoolein, skin permeation     

综述——纳米材料与药物输递：经皮给药中纳米制剂与皮肤的质构效关系

皮肤是人体最大的器官,也为药物的递送提供了重要途径。经皮给药是药物以皮肤为媒介,透过皮肤吸收的途径。因此,皮肤角质层是经皮给药的最大限速障碍。纳米经皮给药系统,具有提高透皮效率、缓释性、避免药物肝首过效应、减少副作用等优点,是通过纳米制剂与皮肤组织之间的相互作用实现的。其中,纳米制剂的结构和组分与其发挥皮肤促渗效用密切相关。对纳米制剂与皮肤质构效关系深入透彻的了解,有助于新型透皮纳米制剂的设计,并利用综合手段构建安全、高效、实用的经皮给药系统。     

经皮给药系统产业化开发的关键问题探讨

以经皮给药系统的开发及产业化为主体思路,在对经皮给药系统发展现状认识的基础上,重点对经皮给药产品研发中的吸收模型 及体内外相关性评价研究、产业化设备、国内外研发模式等进行初步探讨,分析经皮给药系统开发中存在的问题和挑战并提出相应的解 决方案,以期为今后国内经皮给药制剂的发展提供思路。     

Effect of Adhesive Layer Thickness and Drug Loading on Estradiol Crystallization in a Transdermal Drug Delivery System

The effects of adhesive layer thickness and drug loading on estradiol crystallization were studied in a drug-in-adhesive patch. Patches containing different estradiol loadings (1.1% and 1.6% w/w) in different thicknesses (45, 60, and 90 μm) were prepared by coating of a homogenous mixture of adhesive solution and the drug on a siliconized release liner by a film applicator. After drying, the film was laminated on a Poly(ethylene terephthalate) backing layer and cut into appropriate size. Release tests were performed using thermostated Chien-type diffusion cells. Cross-section of the patches was observed by optical microscopy. Scanning electron microscopy was done for surface analysis of the patches after drug release test. Crystal formation was not expected in the adhesive layer based on the linear free-energy relationship formalisms however; crystalline regions were observed in different locations through the thickness of the patches. These regions were significantly more discontinuous in 45 μm samples which elucidated the effective role of adhesive layer thickness in drug crystallization. Extensive crystallization observed for thicker patches was attributed to the strong crosslinking capability of estradiol hemihydrate. Drug release study confirmed some of the crystallization results. No significant increase was observed in the burst release with increasing in thickness from 45 to 60 μm which can be attributed to the severe increase in the crystallization extent. Also, formation of a crystalline layer near the releasing surface and more discontinuous pattern of the crystals in some samples was confirmed by investigation of the drug release curves.     

A New Brain Drug Delivery Strategy: Focused Ultrasound-Enhanced Intranasal Drug Delivery

Central nervous system (CNS) diseases are difficult to treat because of the blood-brain barrier (BBB), which prevents most drugs from entering into the brain. Intranasal (IN) administration is a promising approach for drug delivery to the brain, bypassing the BBB; however, its application has been restricted to particularly potent substances and it does not offer localized delivery to specific brain sites. Focused ultrasound (FUS) in combination with microbubbles can deliver drugs to the brain at targeted locations. The present study proposed to combine these two different platform techniques (FUS+IN) for enhancing the delivery efficiency of intranasally administered drugs at a targeted location. After IN administration of 40 kDa fluorescently-labeled dextran as the model drug, FUS targeted at one region within the caudate putamen of mouse brains was applied in the presence of systemically administered microbubbles. To compare with the conventional FUS technique, in which intravenous (IV) drug injection is employed, FUS was also applied after IV injection of the same amount of dextran in another group of mice. Dextran delivery outcomes were evaluated using fluorescence imaging of brain slices. The results showed that FUS+IN enhanced drug delivery within the targeted region compared with that achieved by IN only. Despite the fact that the IN route has limited drug absorption across the nasal mucosa, the delivery efficiency of FUS+IN was not significantly different from that of FUS+IV. As a new drug delivery platform, the FUS+IN technique is potentially useful for treating CNS diseases.     

Chitosan-Modified PLGA Nanoparticles with Versatile Surface for Improved Drug Delivery

Shortage of functional groups on surface of poly(lactide-co-glycolide) (PLGA)-based drug delivery carriers always hampers its wide applications such as passive targeting and conjugation with targeting molecules. In this research, PLGA nanoparticles were modified with chitosan through physical adsorption and chemical binding methods. The surface charges were regulated by altering pH value in chitosan solutions. After the introduction of chitosan, zeta potential of the PLGA nanoparticle surface changed from negative charge to positive one, making the drug carriers more affinity to cancer cells. Functional groups were compared between PLGA nanoparticles and chitosan-modified PLGA nanoparticles. Amine groups were exhibited on PLGA nanoparticle surface after the chitosan modification as confirmed by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. The modified nanoparticles showed an initial burst release followed by a moderate and sustained release profile. Higher percentage of drugs from cumulative release can be achieved in the same prolonged time range. Therefore, PLGA nanoparticles modified by chitosan showed versatility of surface and a possible improvement in the efficacy of current PLGA-based drug delivery system.     

Orthopaedic Implant as Drug Delivery System: a Numerical Approach

Abstract

There is a current trend to propose cementless total joint arthroplasty (TJA) to younger patients. These patients have more demanding physical activity resulting in an increased failure rate of the implants. In particular for these type of patients, the desired service life of the implant should be extended. The actual implant used do not fulfil this requirement.

In this study, a new concept of orthopaedic implant is presented where the implant is not only a structural support but also a local drug delivery system. The delivered drug is meant to influence the bone remodeling in a way so as to compensate the effects of peri-implant osteolysis. To test this concept, we extended an existing bone remodeling model to include the effect of a drug. The results show that a more homogeneous bone density distribution can be obtained around the implant. Implants used as drug delivery systems could then be an alternative way to increase implant service life.     

Formulation of Niosomal Gel for Enhanced Transdermal Lopinavir Delivery and Its Comparative Evaluation with Ethosomal Gel

The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC_0→∞, 72.87 h × μg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery.KEY WORDS: ethosomes, lopinavir, niosomes, transdermal     

Screening of Venlafaxine Hydrochloride for Transdermal Delivery: Passive Diffusion and Iontophoresis

The objective of the study was to investigate in vitro transdermal delivery of venlafaxine hydrochloride across the pigskin by passive diffusion and iontophoresis. For passive diffusion, experiments were carried out in Franz diffusion cell whereas for iontophoretic permeation, the diffusion cell was modified to contain both the donor and return electrode on the same side of skin. Anodal iontophoresis was carried out using a current density of 0.5 mA/cm². Donor concentrations used were 585.5 mg/ml (saturated solution) and 100 mg/ml. Experiments initially performed to determine the transport efficiency of venlafaxine ions showed promising results. Iontophoresis increased the permeation rate at both concentration levels over their passive counterparts (P < 0.01), but surprisingly higher steady-state flux was obtained from lower donor drug load (P < 0.01). The favorable pH of the unsaturated solutions is suggested to be the cause for this effect. Mild synergistic effect was observed when iontophoresis was carried out incorporating peppermint oil in the donor but the same was not found in passive diffusion. Highest steady-state flux obtained in the experiment was 3.279 μmol/cm²/h when peppermint oil (0.1%) was included in the donor. As the maintenance requirement of venlafaxine hydrochloride is approximately 9.956 μmol/h, the results suggested that the drug is a promising candidate for iontophoretic delivery.     

Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability

Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8 h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4°C for 6 months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil® tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1 M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability.     

Transfersomal Nanoparticles for Enhanced Transdermal Delivery of Clindamycin

The aim of this work was to study the potential of delivering clindamycin phosphate, as an efficient antibiotic drug, into a more absorbed, elastic ultradeformable form, transfersomes (TRSs). These vesicles showed an enhanced penetration through ex vivo permeation characters. TRSs were prepared using thin-film hydration method. Furthermore, they were evaluated for their entrapment efficiency, size, zeta potential, and morphology. Also, the prepared TRSs were converted into suitable gel formulation using carbopol 934 and were evaluated for their gel characteristics like pH, viscosity, spreadability, homogeneity, skin irritation, in vitro release, stability, and ex vivo permeation studies in rats. TRSs were efficiently formulated in a stable bilayer vesicle structure. Furthermore, clindamycin phosphate showed higher entrapment efficiency within the TRSs reaching about 93.3%?±?0.8 and has a uniform particle size. Moreover, the TRSs surface had a high negative charge which indicated the stability of the produced vesicles and resistance of aggregation. Clindamycin phosphate showed a significantly higher in vitro release (p?<?0.05; ANOVA/Tukey) compared with the control carbopol gel. Furthermore, the transfersomal gel showed a significantly higher (p?<?0.05; ANOVA/Tukey) cumulative amount of drug permeation and flux than both the transfersomal suspension and the control carbopol gel. In conclusion, the produced results suggest that TRS-loaded clindamycin are promising carriers for enhanced dermal delivery of clindamycin phosphate.     

新的药物传递系统:外泌体作为药物载体递送*

外泌体(exosomes)是细胞分泌的囊泡,在细胞与细胞之间通信中发挥重要作用。由于其固有的长距离通信能力和出色的生物相容性而具有很大的潜力作为药物递送载体,尤其适合递送蛋白质、核酸、基因治疗剂等治疗药物。许多研究表明外泌体可以有效地将许多不同种类的货物递送至靶细胞,因此,它们常被作为药物载体用于治疗。对外泌体作为药物递送系统中面临的外泌体分离,药物装载和靶向治疗应用的进展与挑战作一介绍,以期更好为外泌体药物递送系统开发提供新思路。     

新的药物传递系统:外泌体作为药物载体递送*

外泌体(exosomes)是细胞分泌的囊泡,在细胞与细胞之间通信中发挥重要作用。由于其固有的长距离通信能力和出色的生物相容性而具有很大的潜力作为药物递送载体,尤其适合递送蛋白质、核酸、基因治疗剂等治疗药物。许多研究表明外泌体可以有效地将许多不同种类的货物递送至靶细胞,因此,它们常被作为药物载体用于治疗。对外泌体作为药物递送系统中面临的外泌体分离,药物装载和靶向治疗应用的进展与挑战作一介绍,以期更好为外泌体药物递送系统开发提供新思路。