Electrospun nanofibers in drug delivery: recent developments and perspectives.

In this review article, some key challenges in drug delivery are first introduced and methods that have been applied in attempts to solve them enumerated. Particularly intractable problems are highlighted: these include issues of solubility, targeting and drug degradation. The technique of electrospinning is subsequently introduced, and the influence of processing parameters on the fibers produced discussed. The potential of electrospun nanofibers in drug delivery is then explored, with examples given from the recent literature to illustrate how fibers can be used to overcome hurdles in drug solubility, degradation and targeting. Future perspectives and challenges are also considered.

Antitumor activity of Dioscorea bulbifera L. rhizome in vivo.

Antitumor activities of water extract (fraction A), ethanol extract (fraction B), ethyl acetate extract (fraction C), non-ethyl acetate extract (fraction D) and compound diosbulbin B isolated from Dioscorea bulbifera L. (DB) were investigated in vivo in this present study. The results showed that fractions B and C both decreased tumor weight in S180 and H22 tumor cells bearing mice, while fractions A and D had no such effect. Furthermore, fraction C altered the weight of spleen and thymus, and the amounts of total leukocytes, lymphocytes and neutrophils in tumor-bearing mice. Further results showed that compound diosbulbin B demonstrated anti-tumor effects in the dose-dependent manner at the dosage of 2 to 16 mg/kg without significant toxicity in vivo. Furthermore, on the basis of chemical analysis of the above extracts by high-performance liquid chromatography (HPLC) with a diode array detector (DAD), diosbulbin B was found to be the major antitumor bioactive component of DB. These results suggest that DB has potential anti-tumor effects which may be related to influencing the immune system for the first time, and the compound diosbulbin B is the major antitumor component of DB.

Urinary (1)H-NMR metabonomics study on intervention effects of soya milk in Africans.

Metabonomics is an important tool in understanding the toxicological or therapeutic effects of interventions by analysing metabolic profiles and interpreting complex multi-dimensional spectroscopic/spectrometric data using multivariate data analysis. The objectives of this study were to evaluate the metabolic changes following a short-term 5 day soya milk intervention, and to investigate factors that influence soy-phytoestrogen metabolism focused on Africans based in either UK or Nigeria. (1)H-NMR metabonomics was applied to analyse urine samples collected at four phases I-IV (pre, days 3 and 5, and post) of the soy-intervention from African volunteers (n = 40 in total). Individual proton NMR spectra were visually and statistically assessed using multivariate analyses (MVA): principal component analysis (PCA) and (orthogonal-) partial-least square-discriminant analysis ((O-) PLS-DA). In addition, 22 endogenous metabolites were quantified using a Chenomx NMR suite. The results showed the levels of analysed endogenous metabolites (creatinine adjusted) present ranged from 4 µM to 12 mM with large inter-subject variances in acetate, acetone, lactate and trimethylamine. The MVA results showed high inter-individuality and sampling variances based on PCA score plots, and demonstrated soy metabolism to be significantly influenced by location and gender by both PLS-DA and O-PLS-DA.

Preparation of core-shell PAN nanofibers encapsulated α-tocopherol acetate and ascorbic acid 2-phosphate for photoprotection.

Magnesium l-ascorbic acid 2-phosphate (MAAP) and α-tocopherol acetate (α-TAc), as the stable vitamin C and vitamin E derivative, respectively, are often applied to skin care products for reducing UV damage. The encapsulation of MAAP (0.5%, g/mL) and α-TAc (5%, g/mL) together within the polyacrylonitrile (PAN) nanofibers was demonstrated using a coaxial electrospinning technique. The structure and morphology characterizations of the core-shell fibers MAAP/α-TAc-PAN were investigated by SEM, FTIR and XRD. As a negative control, the blend nanofibers MAAP/α-TAc/PAN were prepared from a normal electrospinning method. The results from SEM indicated that the morphology and diameter of the nanofibers were influenced by concentration of spinning solution, the polymer component of the shell, the carrying agent of the core and the fabricating methods, and the core-shell nanofibers obtained at the concentration of 8% had finer and uniform structure with the average diameters of 200 ± 15nm. From in vitro release studies it could be seen that both different fiber specimens showed a gradual increase in the amount of α-TAc or MAAP released from the nanofibers. Furthermore, α-TAc and MAAP released from the blend nanofibers showed the burst release at the maximum release of ∼15% and ∼40% during the first 6h, respectively, but their release amount from the core-shell nanofibers was only 10-12% during the initial part of the process. These results showed that core-shell nanofibers alleviated the initial burst release and gave better sustainability compared to that of the blend nanofibers. The present study would provide a basis for further optimization of processing conditions to obtain desired structured core-shell nanofibers and release kinetics for practical applications in dermal tissue.

Solid dispersions in the form of electrospun core-sheath nanofibers.

BACKGROUND: The objective of this investigation was to develop a new type of solid dispersion in the form of core-sheath nanofibers using coaxial electrospinning for poorly water-soluble drugs. Different functional ingredients can be placed in various parts of core-sheath nanofibers to improve synergistically the dissolution and permeation properties of encapsulated drugs and to enable drugs to exert their actions. METHODS: Using acyclovir as a model drug, polyvinylpyrrolidone as the hydrophilic filament-forming polymer matrix, sodium dodecyl sulfate as a transmembrane enhancer, and sucralose as a sweetener, core-sheath nanofibers were successfully prepared, with the sheath part consisting of polyvinylpyrrolidone, sodium dodecyl sulfate, and sucralose, and the core part composed of polyvinylpyrrolidone and acyclovir. RESULTS: The core-sheath nanofibers had an average diameter of 410 ± 94 nm with a uniform structure and smooth surface. Differential scanning calorimetry and x-ray diffraction results demonstrated that acyclovir, sodium dodecyl sulfate, and sucralose were well distributed in the polyvinylpyrrolidone matrix in an amorphous state due to favoring of second-order interactions. In vitro dissolution and permeation studies showed that the core-sheath nanofiber solid dispersions could rapidly release acyclovir within one minute, with an over six-fold increased permeation rate across the sublingual mucosa compared with that of crude acyclovir particles. CONCLUSION: The study reported here provides an example of the systematic design, preparation, characterization, and application of a novel type of solid dispersion consisting of multiple components and structural characteristics.

Treatment with Qing'E, a kidney-invigorating Chinese herbal formula, antagonizes the estrogen decline in ovariectomized mice.

A Chinese herbal preparation, Qing'E formula (QEF), has been used clinically for treating osteoporosis in postmenopausal women by virtue of its kidney-invigorating function; however, no evidence base links QEF to estrogen replacement therapy. In this study, we undertake a characterization of estrogenic activity of QEF using an in vivo model of ovariectomized (OVX) mice together with in vitro studies with the MCF-7 cells for further molecular characterization. OVX mice were treated intragastrically with QEF at doses of 0.85, 1.7, and 3.4 g/kg per day for 4 weeks. QEF treatments restored the estrus cycle and demonstrated significant estrogenic activity, as indicated by reversal of uterine atrophy (six-fold increase in uterine weight), reduction in rectal temperature, and increased expression (1.6-fold) of estrogen receptors (ERs) in the uterus. Notably, the largest changes in these three parameters were found at the lowest dose. At the highest dose of QEF, significant changes were found in adrenal gland weight (30% increase), serum estradiol (E(2)) (60% increase), and luteinizing hormone (LH) (17% decrease) compared with untreated OVX controls. The data suggest estrogenic responses induced by QEF show tissue variation that reflects different affinities of ERs for QEF components. QEF could significantly induce luciferase expression (2.7-fold compared with control) from an estrogen response element luciferase reporter and induced expression of ERalpha and ERbeta (1.2-fold and 1.7-fold respectively) in MCF-7 cells. Both activities were inhibited 80-90% by the estrogen antagonist ICI 182,780. This study demonstrates that QEF activity is mediated through estrogenic components and provides an evidence base for QEF treatment of postmenopausal symptoms.

Ester prodrug-loaded electrospun cellulose acetate fiber mats as transdermal drug delivery systems.

Cellulose acetate (CA) fibers loaded with the ester prodrugs of naproxen, including methyl ester, ethyl ester and isopropyl ester, were prepared through electrospinning using acetone/N,N-dimethylacetamide(DMAc)/ethanol (4:1:1, v/v/v) as solvent. The chemical and morphological characterizations of the medicated fibers were investigated by means of SEM, DSC, XRD and FTIR, as well as the studies of the drug release properties. The results indicated that the morphology and diameter of the fibers were influenced by the concentration of spinning solution, applied voltage, electrospun solvent and the surfactants. The average diameters of the fibers ranged between 100 and 500 nm for three prodrugs. There was good compatibility between CA and three prodrugs in the blended fibers, respectively. In vitro release indicated that constant drug release from the fiber was observed over 6 days. The prodrugs were successfully encapsulated into the fibers, and this system was stable in terms of effectiveness in release.

Arachidonic and docosahexaenoic acid deficits in preterm neonatal mononuclear cell membranes. Implications for the immune response at birth.

Preterm neonates are more susceptible to infection than term neonates. Arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3) are biologically active components of cell membrane phospholipids. Arachidonic acid is a substrate for the synthesis of eicosanoids, potent regulators of immune function. Preterm babies may have a deficiency of arachidonic acid and docosahexaenoic acid, but the impact of this deficit on maturation of the immune system is unknown. To address this we explored links between placental provision of fatty acids to cord blood mononuclear cell (CBMC) membranes using gas chromatography (GC), and maturation of the immune response with gestational age by analysing lymphocyte subsets by flow cytometry. This is the first study to examine the lipid profile of the phosphatidylcholine (PC) and phosphatidylethanolamine (PE) fractions of CBMC membranes from preterm neonates. The long chain polyunsaturated fatty acid (LCPUFA) composition of CBMC membranes was dominated by arachidonic acid in both PE (34%) and PC (15%) fractions in healthy term neonates (> or =37 weeks, n=9), whilst in healthy preterm neonates (<37 weeks, n=10) the level of arachidonic acid was significantly lower at 28.8% and 12.5% respectively (p<0.05). Preterm neonates (<37 weeks, n=23) also had significantly lower absolute numbers of CD4+ (p<0.05) leukocytes and CD4+ (p<0.01) and CD8+ (p<0.05) naïve T-cells than term (> or =37 weeks, n=24) neonates that correlated with gestational age (p<0.01-0.05).

Electrospun shikonin-loaded PCL/PTMC composite fiber mats with potential biomedical applications.

Novel electrospun poly(epsilon-caprolactone) (PCL)/poly(trimethylene carbonate) (PTMC) ultrafine composite fiber mats were prepared and used as drug-carrying materials to encapsulate the herbal medicine shikonin isolated from the plant Lithospermum erythrorhizon Sieb. et Zucc. The PCL/PTMC blended solutions in various ratios (9:1, 7:3, and 5:5, w/w) containing 1 and 5 wt.% shikonin were studied for electrospinning into nanoscale fiber mats. With good drug stability and high drug-loading efficacy, incorporation of shikonin in the polymer media did not appear to influence the morphology of the resulting fibers, as both the drug-free and the shikonin-loaded composite fibers remained unaltered, microscopically. The average diameter of the composite fibers decreased, and the morphology of the fibers became finer with the increasing content of PTMC. In vitro drug release studies demonstrated an initial rapid release of shikonin followed by a plateau after 11 h. It was found that the release behavior could be tailored by the PCL/PTMC blend ratio and drug-loading content. Moreover, the free radical scavenging activity and the antibacterial effects of the shikonin-loaded fiber mats indicated that it could act not only as a drug delivery system but also in the treatment of wound healing or dermal bacterial infections.

Polyacrylonitrile fibers efficiently loaded with tamoxifen citrate using wet-spinning from co-dissolving solution.

Tamoxifen citrate (TAM)-loaded polyacrylonitrile (PAN) fibers were prepared using an improved wet-spinning technique. TAM was used as a model drug to evaluate the potential application of the loaded fiber system for drug delivery. PAN was first homogeneously dissolved in the N,N-dimethylacetamide (DMAc) solution containing TAM and then the co-dissolving solution was solidified to prepare the fibers using a wet-spinning method. Chemical, morphological and mechanical property characterizations were carried out, as well as the studies of the drug release properties. TAM was successfully encapsulated into a monofilament fiber, and this system was stable in terms of high loading capacity and effectiveness in release. The diameter of drug-loaded fiber was in the range of 40-60 microm. The best values of the tensile strength at 2.968 cN/dtex and breaking elongation at 14.9% of drug-loaded fibers were obtained when the drug loading content was 23.1 wt.%. These characteristics were suitable for the weaving process. The in vitro release experiment indicated that constant drug release from the fiber was observed for a long duration of time. Kinetic studies demonstrated that the system followed the Higuchi kinetics. These findings demonstrate that controlled release of drugs from PAN fibers could be potentially useful in drug delivery systems.

Microencapsulation of tamoxifen: application to cotton fabric.

Tamoxifen microcapsules and drug loaded medicated fabrics were investigated. The microcapsules were prepared using a complex coacervation procedure involving gelatin B and acacia gum. The morphology, particle size, drug loading capacity and in vitro release characteristics of the drug microcapsules were optimized for coating tamoxifen microcapsules onto the cotton fabrics. Infrared (IR) spectra and SEM were used to characterize the medicated fabrics and air permeability and laundering testing were undertaken to determine the efficiency and effectiveness of the system. Results showed that optimum condition for the microcapsules was at drug/polymer ratio 1:4, polymer concentration 3%, and rate of stirring 1000 rpm. In vitro release assays demonstrated that the tamoxifen was liberated over 10h after an initial bust rate period. SEM images illustrated that the tamoxifen microcapsules were spherical in shape and were also tightly fixed on to the cotton fabrics fast. These observations demonstrate that we have designed and fabricated a medicated system that potentially could be applied within a transdermal drug delivery system and so act in a system for the treatment of breast cancer.

Three-dimensional printing in pharmaceutics: promises and problems.

Three-dimensional printing (3DP) is a rapid prototyping (RP) technology. Prototyping involves constructing specific layers that uses powder processing and liquid binding materials. Reports in the literature have highlighted the many advantages of the 3DP system over other processes in enhancing pharmaceutical applications, these include new methods in design, development, manufacture, and commercialization of various types of solid dosage forms. For example, 3DP technology is flexible in that it can be used in applications linked to linear drug delivery systems (DDS), colon-targeted DDS, oral fast disintegrating DDS, floating DDS, time controlled, and pulse release DDS as well as dosage form with multiphase release properties and implantable DDS. In addition 3DP can also provide solutions for resolving difficulties relating to the delivery of poorly water-soluble drugs, peptides and proteins, preparation of DDS for high toxic and potent drugs and controlled-release of multidrugs in a single dosage forms. Due to its flexible and highly reproducible manufacturing process, 3DP has some advantages over conventional compressing and other RP technologies in fabricating solid DDS. This enables 3DP to be further developed for use in pharmaceutics applications. However, there are some problems that limit the further applications of the system, such as the selections of suitable excipients and the pharmacotechnical properties of 3DP products. Further developments are therefore needed to overcome these issues where 3DP systems can be successfully combined with conventional pharmaceutics. Here we present an overview and the potential 3DP in the development of new drug delivery systems.

Quantitative analysis of total retronecine esters-type pyrrolizidine alkaloids in plant by high performance liquid chromatography.

Pyrrolizidine alkaloids (PAs) are alkaloids which typically contain a necine (7-hydroxy-1-hydroxymethyl-6,7-dihydro-5H-pyrrolizidine) base unit, and they can be found in one third of the higher plants around the world. They are hepatotoxic, mutagenic and carcinogenic and pose a threat to human health and safety. A specific, quick and sensitive method is therefore needed to detect and quantify the PAs sometimes in trace amount in herbs, tea or food products. Based on high performance liquid chromatography with prior derivatization of the alkaloids using o-chloranil and Ehrlich's reagent, we report an improved method for quantitative analysis of the total amount of retronecine esters-type pyrrolizidine alkaloids (RET-PAs) in a plant extract. The total quantitation of RET-PAs is achieved because of a common colored retronecine marker, a 7-ethoxy-1-ethoxylmethyl retronecine derivative, is produced with all the different RET-PAs during the derivatization reaction. The chemical identity of the common retronecine marker was characterized on-line by positive mode electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy. The limit of detection using the improved method is 0.26 nmol mL(-1) and the limit of quantitation is 0.79 nmol mL(-1). The advantages of this method are much enhanced sensitivity in detection and quantitation, and, no restriction on the choice of RET-PA as a calibration standard. Application of the developed method to the quantitation of total RET esters-type PAs in Senecio scandens from different regions of China is also reported.

Pharmacokinetic behavior of gentiopicroside from decoction of Radix Gentianae, Gentiana macrophylla after oral administration in rats: a pharmacokinetic comaprison with gentiopicroside after oral and intravenous administration alone.

The pharmacokinetics in rats of gentiopicroside (GPS) from orally administered decoctions of Radix Gentianae (DRG) and Gentiana macrophlla (DGM) were compared with that of GPS alone administered at 150 mg/kg orally and 30 mg/kg intravenously. The metabolic profile of GPS after intravenous injection could be fitted to two-compartment model whereas oral administration decoctions DRG or DGM, or GPS alone, could all be fitted to a one-compartment model. After oral administration of GPS alone, GPS was absorbed quickly and reached a maximum plasma concentration (Cmax) value, 5.78 +/- 2.24 microg/mL within 0.75 +/- 0.62 h. The plasma level of GPS declined with a T1/2ke, 3.35 +/- 0.76 h. After oral administration of decoctions DRG and DGM, GPS was absorbed and reached significantly higher maximum concentrations of 10.53 +/- 3.20 microg/mL (p < 0.01) and 7.43 +/- 1.64 microg/mL (p < 0.05) at later time points 1.60 +/- 0.76 (p < 0.01) and 2.08 +/- 0.74 h (p < 0.05), for DRG and DGM respectively, compared with oral GPS alone. Significantly larger AUC values were found for decoctions of GPS (83.49 +/- 20.8 microgxh/mL for DRG and 59.43 +/- 12.9 microgxh/mL for DGM) compared with oral GPS alone (32.67 +/- 12.9 microgxh/mL). The results demonstrate that the bioavailability of GPS was markedly improved when administered as a decoction than as purified GPS. The decoction from Radix Gentianae provided 2.5 times better bioavailability and that from Gentiana macrophlla 1.8 times higher. The study confirms the importance of careful pharmacokinetic analysis in the characterization of herbal medicines when applied for future clinical applications.

Pharmacokinetics and bioavailability of gentiopicroside from decoctions of Gentianae and Longdan Xiegan Tang after oral administration in rats--comparison with gentiopicroside alone.

The pharmacokinetics and bioavailability of gentiopicroside (GPS), an active component of the Gentian plant species, from orally administered decoctions of Gentianae (DG), or in combination with other plants in the prescription of Longdan Xiegan Tang (LXT), was compared in rats with oral administration of GPS alone, using doses adjusted to deliver equivalent amounts of GPS (150 mg/kg). Changes in plasma levels of GPS following oral administration of GPS or DG could be fitted to a one compartment open model with elimination half times (T(1/2)Ke) of 3.35+/-0.76 h and 6.21+/-3.07 h, respectively. Kinetics of plasma GPS following oral administration of LXT could be fitted to a two compartments open model with an elimination half time (T((1/2)beta)) of 3.83+/-1.54 h. The bioavailability of GPS from DG was markedly better, and that from LXT markedly worse, compared with GPS alone, as judged by the area under concentration-time curve (AUC) values of 70.0+/-13.9 microgh/ml (DG), 32.7+/-12.9 microgh/ml (GPS) and 19.1+/-5.9 microgh/ml (LXT). The study demonstrates the marked variability in pharmacokinetics and bioavailability of an active component from different herbal preparations.