Pharmaceutics, Volume 6, Issue 4 (December 2014) – 8 articles , Pages 543-671

Purpose: The objective of this study was to investigate the use of iontophoresis, soluble microneedles and their combination for the transdermal delivery of glycopyrrolate. Methods: In vitro permeation was tested using full thickness porcine ear skin mounted onto Franz diffusion cells. Iontophoresis (0.5 mA/cm²) was done for 4 h using Ag/AgCl electrodes. For microneedles, three line array (27 needles/line) of maltose microneedles were used to microporate the skin prior to mounting. Pore uniformity was determined by taking fluorescent images of distribution of calcein into pores and processing the images using an image analysis tool, which measured the fluorescent intensity in and around each pore to provide a pore permeability index (PPI). The donor chamber contained 500 µL of a 1 mg/mL solution of glycopyrrolate, and the receptor chamber contained 5 mL of 50 mM NaCl in deionized water. Samples were collected at predetermined time points over a period of 24 h and analyzed by HPLC. Skin irritation testing was performed with a 3D cell culture kit of human skin. MTT assay determined cell viability; viability less than 50% was considered irritant. Results: A control experiment which investigated passive permeation of glycopyrrolate delivered an average cumulative amount of 24.92 ± 1.77 µg/cm² at 24 h, while microneedle pretreatment increased permeability to 46.54 ± 6.9 µg/cm². Both iontophoresis (158.53 ± 17.50 µg/cm²) and a combination of iontophoresis and microneedles (182.43 ± 20.06 µg/ cm²) significantly increased delivery compared to passive and microneedles alone. Glycopyrrolate solution was found to be nonirritant with cell viability of 70.4% ± 5.03%. Conclusion: Iontophoresis and a combination of iontophoresis with microneedle pretreatment can be effectively used to enhance the transdermal delivery of glycopyrrolate. Glycopyrrolate was found to be non-irritant to skin. Full article

Pharmaceutical drugs are available to astronauts to help them overcome the deleterious effects of weightlessness, sickness and injuries. Unfortunately, recent studies have shown that some of the drugs currently used may degrade more rapidly in space, losing their potency before their expiration dates. To complicate matters, the degradation products of some drugs can be toxic. Here, we present a preliminary investigation of the ability of Raman spectroscopy to quantify mixtures of four drugs; acetaminophen, azithromycin, epinephrine, and lidocaine, with their primary degradation products. The Raman spectra for the mixtures were replicated by adding the pure spectra of the drug and its degradant to determine the relative percent contributions using classical least squares. This multivariate approach allowed determining concentrations in ~10 min with a limit of detection of ~4% of the degradant. These results suggest that a Raman analyzer could be used to assess drug potency, nondestructively, at the time of use to ensure crewmember safety. Full article

Dovitinib (TKI-258) is under development for the treatment of diverse cancer entities. No published information on its pharmacokinetic drug interaction potential is available. Thus, we assessed its interaction with important drug metabolising enzymes and drug transporters and its efficacy in multidrug resistant cells in vitro. P-glycoprotein (P-gp, MDR1, ABCB1) inhibition was evaluated by calcein assay, inhibition of breast cancer resistance protein (BCRP, ABCG2) by pheophorbide A efflux, and inhibition of organic anion transporting polypeptides (OATPs) by 8-fluorescein-cAMP uptake. Inhibition of cytochrome P450 3A4, 2C19, and 2D6 was assessed by using commercial kits. Induction of transporters and enzymes was quantified by real-time RT-PCR. Possible aryl hydrocarbon receptor (AhR) activating properties were assessed by a reporter gene assay. Substrate characteristics were evaluated by growth inhibition assays in cells over-expressing P-gp or BCRP. Dovitinib weakly inhibited CYP2C19, CYP3A4, P-gp and OATPs. The strongest inhibition was observed for BCRP (IC₅₀ = 10.3 ± 4.5 μM). Among the genes investigated, dovitinib only induced mRNA expression of CYP1A1, CYP1A2, ABCC3 (coding for multidrug resistance-associated protein 3), and ABCG2 and suppressed mRNA expression of some transporters and drug metabolising enzymes. AhR reporter gene assay demonstrated that dovitinib is an activator of this nuclear receptor. Dovitinib retained its efficacy in cell lines over-expressing P-gp or BCRP. Our analysis indicates that dovitinib will most likely retain its efficacy in tumours over-expressing P-gp or BCRP and gives first evidence that dovitinib might act as a perpetrator drug in pharmacokinetic drug–drug interactions. Full article

Vaginal tablets are being developed as an alternative to gels as an inexpensive, discreet dosage form for the administration of microbicides. This work describes the pharmacokinetic (PK) evaluation of rapidly disintegrating vaginal tablets containing tenofovir (TFV, 10 mg), emtricitabine (FTC, 10 mg), and the combination of TFV and FTC (10 mg each) under in vitro and in vivo conditions, and in direct comparison to the clinical TFV 1% gel, a microbicide product in Phase III clinical testing. The PK of TFV and FTC from tablets were also evaluated in female rabbits following intravaginal administration. Direct comparison of a single dose of TFV tablets (intact or predissolved at 10 mg/mL) and TFV 1% gel showed no differences in the vaginal PK of TFV between groups; however systemic bioavailability of TFV was significantly higher from the gel. When rabbits were dosed either once or daily for seven days with intact tablets of TFV, FTC, or the combination of TFV/FTC, vaginal and systemic concentrations of TFV and FTC were unaffected by co-formulation. Moreover, plasma PK parameters were similar following a single dose or seven once-daily doses. Tissue concentrations of TFV and FTC in the cranial vagina 4 h after administration ranged between 10⁴ and 10⁵ ng/g. Concentrations of TFV-diphospate (TFV-DP, the active metabolite) were also high (over 10³ ng/g or about 3000 to 6000 fmol/mg) in the cranial vagina 4 h after administration and similar to those measured following administration of TFV 1% gel. These data demonstrate that rapidly disintegrating vaginal tablets may be a suitable topical microbicide dosage form providing similar vaginal TFV PK to that of TFV 1% gel. The data also support co-administration of FTC with TFV in a single vaginal tablet to create a combination microbicide in a simple and inexpensive dosage form. Full article

The most bioactive soy isoflavones (SI), daidzein (DAI) and genistein (GEN) have poor water solubility, which reduces their bioavailability and health benefits and limits their use in industry. The goal of this study was to develop and characterize a new gelatin matrix to microencapsulate DAI and GEN from soy extract (SE) by spray drying, in order to obtain solid dispersions to overcome solubility problems and to allow controlled release. The influences of 1:2 (MP2) and 1:3 (MP3) SE/polymer ratios on the solid state, yield, morphology, encapsulation efficiency, particle size distribution, release kinetics and cumulative release were evaluated. Analyses showed integral microparticles and high drug content. MP3 and MP2 yield were 43.6% and 55.9%, respectively, with similar mean size (p > 0.05), respectively. X-ray diffraction revealed the amorphous solid state of SE. In vitro release tests showed that dissolution was drastically increased. The results indicated that SE microencapsulation might offer a good system to control SI release, as an alternative to improve bioavailability and industrial applications. Full article

The various classes of gene delivery vectors possess distinct advantages and disadvantages, each of which impacts on cargo loading, delivery and, ultimately, its function. With this in mind, herein we report on a small layered double hydroxide (sLDH)–liposome composite system, drawing upon the salient features of LDH and liposome classes of vectors, while avoiding their inherent shortfalls when used independently. sLDH–liposome composites were prepared by the hydration of freeze-dried matrix method. These composite systems, with a Z-average size of ≈200 nm, exhibited low cytotoxicity and demonstrated good suspension stability, both in water and cell culture medium after rehydration. Our studies demonstrate that short dsDNAs/ssDNAs were completely bound and protected in the composite system at an sLDH:DNA mass ratio of 20:1, regardless of the approach to DNA loading. This composite system delivered DNA to HCT-116 cells with ≈3-fold greater efficiency, when compared to sLDH alone. Our findings point towards the sLDH-liposome composite system being an effective and biocompatible gene delivery system. Full article

The blood–brain barrier acts as a physical barrier that prevents free entry of blood-derived substances, including those intended for therapeutic applications. The development of molecular Trojan horses is a promising drug targeting technology that allows for non-invasive delivery of therapeutics into the brain. This concept relies on the application of natural or genetically engineered proteins or small peptides, capable of specifically ferrying a drug-payload that is either directly coupled or encapsulated in an appropriate nanocarrier, across the blood–brain barrier via receptor-mediated transcytosis. Specifically, in this process the nanocarrier–drug system (“Trojan horse complex”) is transported transcellularly across the brain endothelium, from the blood to the brain interface, essentially trailed by a native receptor. Naturally, only certain properties would favor a receptor to serve as a transporter for nanocarriers, coated with appropriate ligands. Here we briefly discuss brain microvascular endothelial receptors that have been explored until now, highlighting molecular features that govern the efficiency of nanocarrier-mediated drug delivery into the brain. Full article

Therapeutic outcomes of vaginal products depend not only on their ability to deliver drugs to or through the vagina but also on acceptability and correct use. Women’s preferences, in turn, may vary according to age and cultural backgrounds. In this work, an anonymous online survey was completed by 2529 Portuguese women to assess their preferences for physical characteristics and mode of application of vaginal products, according to age. Additionally, intention to use and misconceptions about these issues were assessed. The majority of women of all age groups would use vaginal products to treat or prevent diseases, upon medical prescription. Women preferred vaginal products to be odorless and colorless gels, creams and ointments composed by natural origin drugs/excipients and applied by means of an applicator. Although the majority of women would prefer not to insert any product in the vagina, intention to use for self and recommendation to use for others was associated with previous experiences with vaginal products. General concerns and misconceptions related to use of vaginal products were rare. These data may contribute to the development of products that women are more prone to use. Full article