Effects of Sodium Salts of Fatty Acids and Their Derivatives on Skin Permeation of Cromolyn Sodium.

Atopic dermatitis is a chronic inflammatory disorder with rising prevalence. The safety concerns over usually used steroids are driving the need for developing an effective atopic dermatitis treatment. The use of therapeutic agents such as cromolyn sodium (CS) is suggested. However, due to its physicochemical properties, CS permeation across the skin is a challenge. The aim of this study was to investigate the effect of sodium salts of fatty acids or their derivatives with varied carbon chain lengths as potential enhancers on the skin permeation of CS. These included sodium caprylate, salcaprozate sodium, sodium decanoate, sodium palmitate, and sodium oleate dissolved in propylene glycol along with CS (4% w/w). In vitro permeation of the formulations across the dermatomed porcine ear skin was investigated over 24 h using Franz Diffusion cells. The amount of CS permeation from propylene glycol was 5.54 ± 1.06 µg/cm2 after 24 h. Initial screening of enhancers (enhancer: drug::1:1) showed enhancement in permeation of CS using sodium oleate and sodium caprylate, which were then investigated in higher ratio of drug: enhancer (1:2). Among all the formulations tested, sodium oleate (enhancer: drug::1:2) was observed to significantly (p < 0.05) enhance the permeation of CS with the highest total delivery of 359.79 ± 78.92 µg/cm2 across skin in 24 h and higher drug retention in the skin layers (153.0 ± 24.93 µg/cm2) as well. Overall, sodium oleate was found to be the most effective enhancer followed by sodium caprylate for improving the topical delivery of CS.

Penetration Enhancement Strategies for Intradermal Delivery of Cromolyn Sodium.

This study aimed to explore the use of chemical and physical enhancement strategies for the intradermal delivery of cromolyn sodium (CS) for treatment of atopic dermatitis. CS gels were formulated to individually contain 2.5 and 9% salcaprozate sodium (SNAC) as a potential chemical enhancer. The effect of microneedles, alone and in combination with SNAC, was investigated via in vitro permeation studies. Skin impedance and FTIR evaluation of SNAC-treated stratum corneum (SC) was done and compared to the control. The amount of drug delivered in the dermis after 24 h by the 2.5% and 9% SNAC gels was 23.29 ± 1.89 µg/cm2 and 35.87 ± 2.23 µg/cm2, respectively, which were significantly higher than the control (p < 0.05) but were not remarkably different from each other (p > 0.05). Microneedles enhanced permeation in both the control and 2.5% SNAC groups (p < 0.05); however, no synergistic enhancement was observed when microneedle and SNAC treatments were combined (p > 0.05). Over 24 h of treating the SC with 2.5% SNAC, FTIR evaluation showed stretches on the CH2 asymmetric and symmetric stretching vibrations observed at 2920.23 cm-1 and 2850.79 cm-1 respectively in untreated SC, which shifted to higher wavenumbers and indicated some lipid fluidizing effect. However, no significant drop in skin impedance was seen with SNAC as compared to the control (p > 0.05). SNAC was concluded to have skin permeation enhancement effect on CS, while microneedles effectively enhanced CS permeation even in the absence of SNAC.

Development and Validation of a Liquid Chromatography-Mass Spectrometry Assay for Determination of Cromolyn Sodium in Skin Permeation Studies.

Cromolyn sodium (CS) is a mast cell stabilizer administered to treat allergic diseases. A topical system would sustain its delivery and may be designed for treatment of atopic dermatitis. Established HPLC protocols for detection of CS are time consuming and intensive, indicating the need for a more streamlined method. This study aimed at developing and validating a sensitive and selective LC-MS method for quantifying CS in skin permeation studies that was less time and resource demanding. The optimized method involved an isocratic mobile phase (10 mM NH4HCO3, pH 8.0, 90% and ACN, 10%) at a flow rate of 0.25 mL/min. Detection involved direct MS/MS channels with m/z 467.0255 (precursor) and m/z 379.0517 (fragment) using argon as the collision gas. CS calibrants were prepared in PBS, pH 7.4, and methanol for validation (0.1-2.5 µg/mL). To ensure no skin interference, dermatomed porcine skin was mounted on Franz diffusion cells that were analyzed after 24 h. The skin layers were also separated, extracted in methanol, and analyzed using the developed method. Retention time was 1.9 min and 4.1 min in methanol and buffer, respectively. No interfering peaks were observed from the receptor and skin extracts, and linearity was established between 0.1 and 2.5 µg/mL. Interday and intraday accuracy and precision were within the acceptable limit of ±20% at the LLOQ and ±15% at other concentrations. Overall, the simplified, validated method showed sensitivity in detecting CS in skin without interference and was applied to demonstrate quantification of drug in skin following 4% cromolyn sodium gel exposure.

Transdermal therapy for attention-deficit hyperactivity disorder with the methylphenidate patch (MTS).

Transdermal technology is currently approved in the US for the administration of more than 20 medications. This current review describes the clinical research pertaining to the use of a methylphenidate patch in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. PubMed searches were conducted using the search term 'methylphenidate transdermal system', and were limited to clinical trials. No limits were set for dates of publication. A total of 21 citations were identified. Studies evaluating the safety and efficacy of the methylphenidate transdermal system (MTS) in children and adolescents were included in this review. Additional studies were identified from bibliographies and the 'Related Citations' section of PubMed searches. The MTS delivers a range of methylphenidate doses using a drug-in-adhesive matrix patch. According to current labeling, the patch should be applied to the hip once daily for a maximum of 9 h. Serum methylphenidate levels increase over wear time, with mean time to maximum concentration (t max) reached between 8 and 10 h for a 9-h wear time, and the elimination half-life for methylphenidate is 3-4 h after patch removal. In clinical trials, ADHD symptoms were measured using the ADHD Rating Scale, Version IV, and several parent-, teacher-, and patient-rated scales. Treatment effects show statistically significant differences from baseline symptom scores starting at the first evaluation, 2 h after the patch is applied, with significant benefit lasting up to 12 h with a 9-h wear time. Adverse events with the MTS are similar to those seen with other formulations of methylphenidate, with the exception of skin-related reactions at the site of application, which were generally mild to moderate in severity. The incidence of contact allergic dermatitis with MTS is <1%. Statistically significant improvements in health-related quality of life and medication satisfaction were also observed with the MTS compared with placebo, and after switching from oral extended-release (ER) methylphenidate. Transdermal drug delivery is an effective and safe means of administering methylphenidate for patients with ADHD.

Use of a pH-sensitive fluorescent probe for measuring intracellular pH of Caco-2 cells.

This paper describes the application of a pH-sensitive fluorescent probe [2',7'-bis(2-carboxylethyl)-5(6)-carboxyfluorescein or BCECF] to measure intracellular pH (pH(i)) changes in Caco-2 cells. As a function of BCECF's ionization, the fluorescence was monitored at lambda(ex)=440 and 503nm, and lambda(em)=535nm. Time course studies were conducted with the addition of two weak acid delivery agents, one weak base delivery agent, oleic acid, or tetradecylamine. When applicable, 10microM bovine serum albumin or 10mM ammonium chloride was added into the cell suspension to hinder the pH gradient effect. Adding a weak acid at 2, 10, or 50mM to the cell suspension, the pH(i) dropped substantially from 7.4 to 7.1, 6.9, or 6.7, respectively. The pH(i) then increased gradually over a 10-min period but did not return to its initial value. Conversely, the pH(i) increased instantaneously after the addition of a weak base. When Caco-2 cells were placed in solutions with different bulk pH (7.0, 7.5, and 8.0), the lower the pH in which the cells were exposed, the larger the pH(i) drop occurred with the addition of an acid. The results suggest that these weak acids or bases are transported transcellularly across Caco-2 cells.

Approaches to oral drug delivery for challenging molecules.

Advances in biotechnology, high throughput screening and computational chemistry have led to a considerable increase in the number of protein and peptide therapeutics and other macromolecular drugs. Working with macromolecules, however, poses a number of challenges that must be overcome to successfully develop these compounds into safe and effective therapeutics. Significant efforts in pharmaceutical and academic laboratories have been expended in finding ways to deliver macromolecular drug molecules by the oral route, which can significantly improve patient compliance, convenience, and efficacy. Nevertheless, for a drug molecule to be orally bioavailable, it has to overcome the natural physiological processes of breaking down molecules in the gastrointestinal tract, and to traverse a relatively impermeable epithelial layer of cells that line the gastrointestinal tract. This article provides a summary of the challenges that researchers need to surmount in the development of orally absorbable peptide and protein drugs, and gives an overview of the novel approaches currently in progress in the field of oral delivery.

Drug delivery global summit--evaluating emerging technologies.

Two day-long sessions at the Drug delivery global summit, organised by SMi Group Ltd, were devoted to discussion on critical aspects of drug delivery, including advances in drug delivery systems and their applications to new products, with a primary focus on oral systems, but also highlighting recent progress in inhalation, parenteral and transdermal delivery. The event included case studies from big pharma, biotech and drug delivery companies to illustrate emerging delivery technologies and how they can be applied to develop innovative products. The conference created a platform for discussion on a range of topics from scientific issues and challenges to ways of establishing mutually beneficial relationships between technology and pharma companies.

Response of the lung to pulmonary insulin dosing in the rat model and effects of changes in formulation.

BACKGROUND: The hope that pulmonary insulin will provide increased patient compliance and quality of life has created great interest in patients with diabetes, the medical community, and the general public. A pulmonary insulin product is becoming a reality with clinical trials indicating comparable glycemic control with no change in pulmonary function. However, the longterm effects of pulmonary insulin dosing are not known, and as more pulmonary formulations for insulin and other proteins are rapidly being developed the need for further safety data continues to grow. METHODS: Using gene microarrays, we compared differences in the levels of mRNAs in the lung tissue of rats that were administered a subcutaneous injection or a pulmonary instillation of insulin, as well as rats receiving an pulmonary instillation of insulin and a drug delivery agent. RESULTS: While the insulin doses achieved comparable blood glucose depression and serum insulin concentrations, 30 mRNAs were differentially regulated in response to pulmonary dosing, including 10 mRNAs associated with an immune response and four associated with the lung's response to injury, as well as ion channels and transcription factors. When disodium 8-((N-salicyloyl-2-amino-4-chloro)phenoxy)octanoate, a drug delivery agent known to facilitate pulmonary absorption, was instilled in combination with the pulmonary insulin dose, an attenuation of this response was observed. CONCLUSIONS: These findings suggest that undesirable effects of pulmonary dosing may be avoided by changes in formulation and that further evaluation of the effects of chronic pulmonary administration of insulin is warranted.

Oral absorption enhancement of cromolyn sodium through noncovalent complexation.

PURPOSE: To determine the effect of Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate (SNAC) on the permeation of cromolyn across Caco-2 cell monolayers and explore the molecular basis for the enhanced absorption. METHODS: Transport studies of cromolyn across Caco-2 cell monolayers were conducted in the presence of various SNAC concentrations. Permeation of cellular transport markers and lactate dehydrogenase (LDH) release were measured to evaluate cell integrity. Molecular interactions betweent the two compounds were investigated using isothermal titration calorimetry (ITC), nuclear magnetic resonance (NMR), and Fourier-transfrom infrared (FTIR) spectroscopies and molecular dynamics simulations. RESULTS: The absorption of cromolyn across Caco-2 monolayers was enhanced markedly by SNAC. SNAC did not cause significant LDH leakage and changes in the permeation of transport markers. ITC, spectroscopies, and molecular dynamic simulations indicated the existence of intermolecular interactions between cromolyn and SNAC that involve the 2-hydroxybenzamide moiety on SNAC and weaken the hydrogen bonding between cromolyn and surrounding water molecules. CONCLUSIONS: SNAC increases the permeability of Caco-2 monolayers to cromolyn without measurable cell damage. SNAC interacts with cromolyn mainly via ring stacking. One major mode of interaction appears to involve the insertion of the aromatic ring of SNAC between cromolyn's rings. Such interaction appears to reduce the hydration of cromolyn and thus optimize its hydrophobicity for oral absorption.

Pathway of oral absorption of heparin with sodium N-[8-(2-hydroxybenzoyl)amino] caprylate.

PURPOSE: The oral bioavailability of heparin is negligible. Recent studies, however, have shown that sodium N-[8-(2-hydroxybenzoyl) amino]caprylate (SNAC) and other N-acylated amino acids enable oral heparin absorption. To investigate the mechanism by which heparin crosses the intestinal epithelium in the presence of SNAC, we have used fluorescence microscopy to follow the transport of heparin across Caco-2 cell monolayers. METHODS: The experiments were carried out on Caco-2 monolayers and Caco-2 cells grown to confluence on culture dishes, using different concentrations of SNAC. The localization of fluorescently labeled heparin was determined using epi-fluorescence and confocal microscopy. DNA dyes were used to determine the effect of SNAC on the plasma membrane integrity. F-actin was labeled with fluorescent phalloidin to investigate the stability of perijunctional actin rings in the presence of SNAC. RESULTS: Heparin was detected in the cytoplasm only after incubation of the cells with heparin and SNAC. No DNA staining was observed in cells incubated with a DNA dye in the presence of SNAC concentrations at which heparin transport occurred. In addition, no signs of actin redistribution or perijunctional ring disbandment were observed during the transport of heparin. CONCLUSIONS: The results indicate that SNAC enables heparin transport across Caco-2 monolayers via the transcellular pathway. Heparin transport in the presence of SNAC is selective and does not involve permeabilization of the plasma membrane or tight junction disruption.