Complex Drug Delivery Systems: Controlling Transdermal Permeation Rates with Multiple Active Pharmaceutical Ingredients.

A transdermal drug delivery system (TDDS) is generally designed to deliver an active pharmaceutical ingredient (API) through the skin for systemic action. Permeation of an API through the skin is controlled by adjusting drug concentration, formulation composition, and patch design. A bilayer, drug-in-adhesive TDDS design may allow improved modulation of the drug release profile by facilitating varying layer thicknesses and drug spatial distribution across each layer. We hypothesized that the co-release of two fixed-dose APIs from a bilayer TDDS could be controlled by modifying spatial distribution and layer thickness while maintaining the same overall formulation composition. Franz cell diffusion studies demonstrated that three different bilayer patch designs, with different spatial distribution of drug and layer thicknesses, could modulate drug permeation and be compared with a reference single-layer monolith patch design. Compared with the monolith, decreased opioid antagonist permeation while maintaining fentanyl permeation could be achieved using a bilayer design. In addition, modulation of the drug spatial distribution and individual layer thicknesses, control of each drug's permeation could be independently achieved. Bilayer patch performance did not change over an 8-week period in accelerated stability storage conditions. In conclusion, modifying the patch design of a bilayer TDDS achieves an individualized permeation of each API while maintaining constant patch composition.

Development of low-cost, weight-adjustable clofazimine mini-tablets for treatment of tuberculosis in pediatrics.

Clofazimine (CFZ) is an important component of the World Health Organization's (WHO) recommended all-oral drug regimen for treatment of multi-drug resistant tuberculosis (MDR-TB). However, the lack of a dividable oral dosage form has limited the use of the drug in pediatric populations, who may require lowering of the dose to reduce the likelihood of adverse drug events. In this study, pediatric-friendly CFZ mini-tablets were prepared from micronized powder via direct compression. Rapid disintegration and maximized dissolution in GI fluids was achieved using an iterative formulation design process. Pharmacokinetic (PK) parameters of the optimized mini-tablets were obtained in Sprague-Dawley rats and compared against an oral suspension of micronized CFZ particles to examine the effect of processing and formulation on the oral absorption of the drug. Differences in maximum concentration and area under the curve between the two formulations were non-significant at the highest dosing level tested. Variability between rats prevented bioequivalence from being determined according to guidelines outlined by the Food and Drug Administration (FDA). These studies provide an important proof-of-concept for an alternative, low-cost formulation and processing approach for the oral delivery of CFZ in manner that is suitable for children as young as 6 months of age.

Strategies to facilitate or block nose-to-brain drug delivery.

Nose-to-brain delivery has gained significant interest over the past several decades. This has resulted in numerous strategies described to improve the delivery of drugs to the brain directly through the olfactory epithelium of the nasal cavity. In some cases, intranasal administration may be more effective than other routes of administration in treating central nervous system and related disorders. Here, we briefly review the strategies that have been used to facilitate nose-to-brain delivery as well as approaches to block the delivery of drugs from the nose to the brain. Even though numerous strategies have already been used to increase nose-to-brain delivery, the research for strategies inhibitory of nose-to-brain delivery seems to be scarce.

A human skin high-throughput formulation screening method using a model hydrophilic drug.

Franz cell (FC) experiments in topical and transdermal drug development represent the gold standard in vitro method but require a relatively high quantity of human skin, are low-throughput, and are time-consuming to perform. To address these issues, we studied a micro-well plate-based screening method for permeability and retention that could enable the direct screening of large numbers of formulations simultaneously across human skin. Using freshly excised dermatomed human skin modified to reflect poor barrier function and a model hydrophilic compound, Sulforhodamine B (SRB), FC permeation and retention quantification was compared to the 96-well high-throughput system (HTS). The skin was analyzed using 2-photon microscopy to determine the drug distribution within the skin. A screen of 15 different formulations in triplicate in a single piece of human skin, using full factorial design was then conducted. Permeability of SRB across the skin as well as the drug distribution profile of SRB retained in the skin were similar for the FC and HTS system. The influence of different excipients on drug retention was observed in the full factorial formulation screen. The HTS method is promising for the investigation of large numbers of formulations and the influence of formulations changes in skin retention of drug.

Pseudoparasitism by Calodium hepaticum (syn. Capillaria hepatica; Hepaticola hepatica) in the Negro River, Brazilian Amazon.

We report the finding of eggs of Calodium spp. (syn. Capillaria spp.; Hepaticola spp.) in a fecal sample from an old woman living in a riverine community in the Negro River Basin and describe the associated epidemiological investigation. The case probably does not represent true parasitism; the eggs, which were compatible with the species Calodium hepaticum, were most likely ingested upon consumption of infected tapir (Tapirus terrestris) liver, subsequently passing through the gut and being eliminated. The evolution of these eggs to infective stages in the environment, given the poor sanitation background, could provide the risk of occurrence of hepatic disease in humans.