[Show abstract][Hide abstract] ABSTRACT: Recent reports have indicated that psoriasis may be caused by malfunctioning dermal immune cells, and psoralen ultraviolet A (PUVA) is an effective treatment for this chronic disease. However, conventional topical formulations achieve poor drug delivery across patches of psoriasis to their target sites. The present study describes the development of a novel psoralen transdermal delivery system employing ethosomes, flexible vesicles that can penetrate the stratum corneum and target deep skin layers. An in vitro skin permeation study showed that the permeability of psoralen-loaded ethosomes was superior to that of liposomes. Using ethosomes, psoralen transdermal flux and skin deposition were 38.89±0.32μg/cm(2)/h and 3.87±1.74μg/cm(2), respectively, 3.50 and 2.15 times those achieved using liposomes, respectively. The ethosomes and liposomes were found to be safe following daily application to rat skin in vivo, for 7 days. The ethosomes showed better biocompatibility with human embryonic skin fibroblasts than did an equivalent ethanol solution, indicating that the phosphatidylcholine present in ethosome vesicles improved their biocompatibility. These findings indicated that ethosomes could potentially improve the transdermal delivery of psoralen and possibly of other drugs requiring deep skin delivery.
Full-text · Article · Jun 2014 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: This study aimed to improve skin permeation and deposition of psoralen by using ethosomes and to investigate real-time drug release in the deep skin in rats. We used a uniform design method to evaluate the effects of different ethosome formulations on entrapment efficiency and drug skin deposition. Using in vitro and in vivo methods, we investigated skin penetration and release from psoralen-loaded ethosomes in comparison with an ethanol tincture. In in vitro studies, the use of ethosomes was associated with a 6.56-fold greater skin deposition of psoralen than that achieved with the use of the tincture. In vivo skin microdialysis showed that the peak concentration and area under the curve of psoralen from ethosomes were approximately 3.37 and 2.34 times higher, respectively, than those of psoralen from the tincture. Moreover, it revealed that the percutaneous permeability of ethosomes was greater when applied to the abdomen than when applied to the chest or scapulas. Enhanced permeation and skin deposition of psoralen delivered by ethosomes may help reduce toxicity and improve the efficacy of long-term psoralen treatment.
Full-text · Article · Jan 2014 · International Journal of Nanomedicine
[Show abstract][Hide abstract] ABSTRACT: In this study, we prepared solid lipid nanoparticles (TV-SLNs) loaded with toad venom extract and investigated their anti-tumor effects in vitro in HeLa and SKOV-3 cells. TV-SLNs were prepared using a cold homogenization technique, and the formulation was optimized by central composite design and response surface methods. The anti-tumor activities of TV-SLNs were evaluated by analyzing cell division and cell cycle distribution by using the MTT assay and flow cytometry. After incubation with TV-SLNs, the growth of both HeLa and SKOV-3 cells was inhibited significantly. The percentage of HeLa cells in G0/G1 phase decreased, whereas that in the S and G2/M phases increased. Thus, the S and G2/M phases were blocked after the incubation of HeLa cells with TV-SLNs for 24 h. In contrast, the percentage of SKOV-3 cells in G0/G1 phase increased and then decreased in S and G2/M phases, with the G0/G1 phase being blocked after incubation with TV-SLNs for 24 h. Our results demonstrate that TV-SLNs inhibited the fissiparism of HeLa and SKOV-3 cells in a time-and dose-dependent manner. TV-SLNs may be effective as a novel TV vaginal delivery system for the treatment of cervical and ovarian cancers.
[Show abstract][Hide abstract] ABSTRACT: Abstract In this study, cinnamic acid-loaded transfersomes were prepared and dermal microdialysis sampling was used in Sprague-Dawley rats to compare the amount of drug released into the skin using transfersomes as transdermal carriers with that released on using conventional liposomes. The formulation of cinnamic acid-loaded transfersomes was optimized by a uniform design through in vitro transdermal permeation studies. Hydration time was confirmed as a significant factor influencing the entrapment efficiency of transfersomes, further affecting their transdermal flux in vitro. The fluxes of cinnamic acid from transfersomes were all higher than those from conventional liposomes, and the flux from the optimal transfersome formulation was 3.01-fold higher than that from the conventional liposomes (p < 0.05). An in vivo microdialysis sampling method revealed that the dermal drug concentrations from transfersomes applied on various skin regions were much lower than those required with conventional liposomes. After the administration of drug-containing transfersomes and liposomes on abdominal skin regions of rats for a period of 10 h, the C(max) of cinnamic acid from the compared liposomes was 3.21 ± 0.25 μg/mL and that from the transfersomes was merely 0.59 ± 0.02 μg/mL. The results suggest that transfersomes can be used as carriers to enhance the transdermal delivery of cinnamic acid, and that these vehicles may penetrate the skin in the complete form, given their significant deformability.
Full-text · Article · Jan 2013 · Drug Development and Industrial Pharmacy
[Show abstract][Hide abstract] ABSTRACT: To investigate the cellular uptake of evodiamine and rutaecarpine in a microemulsion in comparison with aqueous suspensions and tinctures.
A microemulsion was prepared using the dropwise addition method. Mouse skin fibroblasts were cultured in vitro to investigate the optimal conditions for evodiamine and rutaecarpine uptake with different drug concentrations and administration times. Under optimal conditions, the cellular uptake of microemulsified drugs was assayed and compared to tinctures and aqueous suspensions. Rhodamine B labeling and laser scanning confocal microscopy (LSCM) were used to explore the distribution of fluorochrome transferred with the microemulsion in fibroblasts. Cellular morphology was also investigated, using optical microscopy to evaluate microemulsion-induced cellular toxicity.
The maximum cellular drug uptake amounts were obtained with a 20% concentration (v/v) of microemulsion and an 8 hour administration time. Drug uptake by mouse skin fibroblasts was lowest when the drugs were loaded in microemulsion. After incubation with rhodamine B-labeled microemulsion for 8 hours, the highest fluorescence intensity was achieved, and the fluorochrome was primarily distributed in the cytochylema. No obvious cellular morphologic changes were observed with the administration of either the microemulsion or the aqueous suspension; for the tincture group, however, massive cellular necrocytosis was observed.
The lower cellular uptake with microemulsion may be due to the fact that most of the drug loaded in the microemulsion vehicle was transported via the intercellular space, while a small quantity of free drug (released from the vehicle) was ingested through transmembrane transport. Mouse skin fibroblasts rarely endocytosed evodiamine and rutaecarpine with a microemulsion as the vehicle. The microemulsion had no obvious effect on cellular morphology, suggesting there is little or no cellular toxicity associated with the administration of microemulsion on mouse skin fibroblasts.
Full-text · Article · May 2012 · International Journal of Nanomedicine
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to prepare solid lipid nanoparticles (SLNs) for the oral delivery of frankincense and myrrh essential oils (FMO). Aqueous dispersions of SLNs were successfully prepared by a high-pressure homogenization method using Compritol 888 ATO as the solid lipid and soybean lecithin and Tween 80 as the surfactants. The properties of the SLNs such as particle size, zeta potential (ZP), and drug encapsulation efficiency (EE) were investigated. The morphology of SLNs was observed by transmission electron microscopy (TEM). The crystallinity of the formulation was analyzed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). In addition, drug evaporation release and antitumor activity were also studied. Round SLNs with a mean size of 113.3 ± 3.6 nm, a ZP of -16.8 ± 0.4 mV, and an EE of 80.60% ± 1.11% were obtained. DSC and XRD measurements revealed that less ordered structures were formed in the inner cores of the SLN particles. Evaporation loss of the active components in FMO could be reduced in the SLNs. Furthermore, the SLN formulation increased the antitumor efficacy of FMO in H22-bearing Kunming mice. Hence, the presented SLNs can be used as drug carriers for hydrophobic oil drugs extracted from traditional Chinese medicines.
Full-text · Article · Apr 2012 · International Journal of Nanomedicine
[Show abstract][Hide abstract] ABSTRACT: Indirubin, isolated from the leaves of the Chinese herb Isatis tinctoria L, is a protein kinase inhibitor and promising antitumor agent. However, the poor water solubility of indirubin has limited its application. In this study, a supersaturatable self-microemulsifying drug delivery system (S-SMEDDS) was developed to improve the oral bioavailability of indirubin.
A prototype S-SMEDDS was designed using solubility studies and phase diagram construction. Precipitation inhibitors were selected from hydrophilic polymers according to their crystallization-inhibiting capacity through in vitro precipitation tests. In vitro release of indirubin from S-SMEDDS was examined to investigate its likely release behavior in vivo. The in vivo bioavailability of indirubin from S-SMEDDS and from SMEDDS was compared in rats.
The prototype formulation of S-SMEDDS comprised Maisine™ 35-1:Cremophor(®) EL:Transcutol(®) P (15:40:45, w/w/w). Polyvinylpyrrolidone K17, a hydrophilic polymer, was used as a precipitation inhibitor based on its better crystallization-inhibiting capacity compared with polyethylene glycol 4000 and hydroxypropyl methylcellulose. In vitro release analysis showed more rapid drug release from S-SMEDDS than from SMEDDS. In vivo bioavailability analysis in rats indicated that improved oral absorption was achieved and that the relative bioavailability of S-SMEDDS was 129.5% compared with SMEDDS.
The novel S-SMEDDS developed in this study increased the dissolution rate and improved the oral bioavailability of indirubin in rats. The results suggest that S-SMEDDS is a superior means of oral delivery of indirubin.
Full-text · Article · Feb 2012 · International Journal of Nanomedicine
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to develop an active targeting strategy to improve the therapeutic antitumor efficacy of oridonin (ORI), the main active ingredient in the medicinal herb Rabdosia rubescens.
A modified spontaneous emulsification solvent diffusion method was used to prepare the ORI-loaded atactic poly(D,L-lactic acid) nanoparticles (ORI-PLA-NPs). Surface cross-linking with the peptide Arg-Gly-Asp (RGD) further modified the ORI-PLA-NPs, generating ORI-PLA-RGD-NPs. The NPs were characterized and release experiments were performed in vitro. The pharmacokinetics, tissue distribution, and antitumor activity of the NPs were studied in mice bearing hepatocarcinoma 22 (H22)-derived tumors.
The ORI-PLA-NPs and ORI-PLA-RGD-NPs were smooth, sphere-like, and relatively uniform in size. The RGD surface modification slightly increased the mean particle size (95.8 nm for ORI-PLA-NPs versus 105.2 nm for ORI-PLA-RGD-NPs) and considerably altered the surface electrical property (-10.19 mV for ORI-PLA-NPs versus -21.95 mV for ORI-PLA-RGD-NPs), but it had no obvious influence on ORI loading (8.23% ± 0.35% for ORI-PLA-NPs versus 8.02% ± 0.38% for ORI-PLA-RGD-NPs), entrapment efficiency (28.86% ± 0.93% for ORI-PLA-NPs versus 28.24% ± 0.81% for ORI-PLA-RGD-NPs), or the release of ORI. The pharmacokinetic properties of free ORI were improved by encapsulation in NPs, as shown by increased area under the concentration-time curve (11.89 ± 0.35 μg·mL(-1) · h for ORI solution versus 22.03 ± 0.01 μg · mL(-1) · h for ORI-PLA-RGD-NPs) and prolonged mean retention time (2.03 ± 0.09 hours for ORI solution versus 8.68 ± 0.66 hours for ORI-PLA-RGD-NPs). In the tissue distribution study, more ORI targeted tumor tissue in the mice treated with ORI-PLA-RGD-NPs than with ORI-PLA-NPs or ORI solution. Consistent with these observations, ORI-PLA-RGD-NPs showed greater antitumor efficacy than ORI-PLA-RGD-NPs or ORI solution, as reflected by the decreased tumor growth and the prolonged survival time of mice bearing H22 tumors.
The tumor-targeting efficiency and subsequent antitumor efficacy of ORI is increased by incorporation into ORI-PLA-RGD-NPs.
Full-text · Article · Jan 2012 · International Journal of Nanomedicine
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to improve skin permeation of evodiamine and rutaecarpine for transdermal delivery with microemulsion as vehicle and investigate real-time cutaneous absorption of the drugs via in vivo microdialysis.
Pseudoternary phase diagrams were constructed to evaluate microemulsion regions with various surfactants and cosurfactants. Nine formulations of oil in water microemulsions were selected as vehicles for assessing skin permeation of evodiamine and rutaecarpine in ex vivo transdermal experiments. With a microdialysis hollow fiber membrane implanted in the skin beneath the site of topical drug administration, dialysis sampling was maintained for 10 hours and the samples were detected directly by high performance liquid chromatography. Real-time concentrations of the drugs in rat skin were investigated and compared with those of conventional formulations, such as ointment and tincture. Furthermore, the drugs were applied to various regions of the skin using microemulsion as vehicle.
In ex vivo transdermal experiments, cutaneous fluxes of evodiamine and rutaecarpine microemulsions were 2.55-fold to 11.36-fold and 1.17-fold to 6.33-fold higher, respectively, than those of aqueous suspensions. Different drug loadings, microemulsion water content, and transdermal enhancers markedly influenced the permeation of evodiamine and rutaecarpine. In microemulsion application with in vivo microdialysis, the maximum concentration of the drugs (evodiamine: 18.23 ± 1.54 ng/mL; rutaecarpine: 16.04 ± 0.69 ng/mL) were the highest, and the area under the curve(0-t) of evodiamine and rutaecarpine was 1.52-fold and 2.27-fold higher than ointment and 3.06-fold and 4.23-fold higher than tincture, respectively. A greater amount of drugs penetrated through and was absorbed by rat abdominal skin than shoulder and chest, and a reservoir in the skin was found to supply drugs even after the microemulsion was withdrawn.
Compared to conventional formulations, higher cutaneous fluxes of evodiamine and rutaecarpine were achieved with microemulsion. Based on this novel transdermal delivery, the transdermal route was effective for the administration of the two active alkaloids.
Full-text · Article · Oct 2011 · International Journal of Nanomedicine
[Show abstract][Hide abstract] ABSTRACT: To deliver 2,3,5,6-tetramethylpyrazine (TMP) in a relatively large dose through a transdermal route and facilitate the practical application of microemulison in transdermal drug delivery.
The pseudo-ternary phase diagram for microemulsion regions was constructed using isopropyl myristate as oil phase, Labrasol(®) as surfactant, and Plurol(®) Oleique CC 497 as cosurfactant. A uniform experimental design was applied for formulation optimization. In vitro skin permeation experiments of six formulations were undertaken with TMP transdermal patch (EUDRAGIT(®) E100 as matrix) and TMP saturated solution as controls. We prepared TMP-oil dispersed in water-ethylene vinyl acetate-transdermal therapeutic system (TMP-O/W-EVA-TTS) with microemulsion as reservoir and EVA membrane as release liner; pharmacokinetic and brain distribution studies in rats were conducted with TMP transdermal patches as control.
The skin fluxes of TMP from microemulsions were 8.2- to 26.7-fold and 0.9- to 4.7-fold higher than those of TMP transdermal patch and TMP saturated solution, respectively, and were strongly affected by the microemulsion composition. The improvement in TMP solubility as well as the skin permeation enhancement effect of microemulsion components contributed mainly to transdermal delivery facilitation. In the pharmacokinetic study, the relative bioavailability of TMP-O/W-EVA-TTS was 350.89% compared with the TMP transdermal patch. Higher and more stable TMP contents in rat plasma were obtained after administration of TMP-O/WEVA- TTS than after application of TMP transdermal patch. In the brain distribution study, higher rate and extent of TMP distribution to brain, and lower rate of TMP clearance from brain were observed after transdermal administration of TMP-O/W-EVA-TTS than after application of TMP transdermal patch.
The novel transdermal delivery system prepared in this study showed a remarkable skin permeation improvement of microemulsion and facilitated its practical application in transdermal drug delivery. With this system as a vehicle, a relatively large dose of TMP could enable successful drug delivery via the transdermal route.
Full-text · Article · Aug 2011 · International Journal of Nanomedicine