Evaluation of a Simple Carrier Molecule to Enhance Drug Penetration of Dermal Layers by Utilizing Multivariate Methods, Structure Property Correlations, and Continuous System Modeling

摘要

Nicotinic acid is shown to be comparable to dihydropyridine in its capacity to facilitate penetration of an attached antibacterial drug through dermal layers. Antibacterial drugs examined with nicotinic acid or dihydropyridine carriers were β-lactam antibiotics: methicillin, oxacillin, benzylpenicillin, penicillin F, penicillin dihydro F, propicillin, carbenicillin, penicillin K, penicillin X, and ampicillin. An oxymethyl (-O-CH2-) group is inserted as the linker between the antibiotic and the carrier group. Structure Property Correlations and multivariate methods such as regression analysis, cluster analysis, principal component analysis, discriminate analysis, self-organizing tree algorithm, and factor analysis clearly showed that nicotinic acid performs as an effective carrier drug and is comparable to dihydropyridine. The skin penetration constant Kp was calculated for all 10 antibiotics having either dihydropyridine or nicotinic acid as carrier, and was found to have a mean of 5.13E-05 cm/hour and 1.83E-05 cm/hour, respectively. The standard deviation for each group showed the numerical values overlap as did the 90% confidence interval for each group. A hierarchical tree organization of skin shows the overlapped dermal layers as they exist in normal skin and for the model utilized in this work. A Deming-Regression analysis also shows the nicotinic acid and dihydropyridine structures to have similar and correlated water solubility. Plotting Kp of the dihydropyridine structures as independent variable versus Kp of the nicotinic acid structures show good correlation (Pearson correlation r = 0.6606) and no significant departure from linearity. Connected box plots showed the majority of Kp values for each group of modified antibiotics to exist in a tight cluster. Polar graph of the Log Kow values showed the two groups of modified antibiotics to be correlated and numerically adjacent in trend. ChemSketch property calculations and modeling demonstrates the affects of structural oxygens, nitrogens, carbonyl groups, amide groups, and aromatic rings that are important in understanding the pervasiveness through dermal layers. Continuous model analysis by acslXtreme is utilized and demonstrates three models of the dispersion of drugs through dermal layers based on diffusivity constant (D), Log Kp from Log Kow and formula weight, and Kp as a function of time.