Gerard C. Mazzenga

The transdermal delivery of zwitterionic drugs I: the solubility of zwitterion salts

Abstract The use of selected salts of zwitterions of varying polarizability, size, hydrogen-bonding ability and lipophilicity as criteria to improve skin permeation of zwitterionic drugs is described. Prior to this study, it was not appreciated that salts of zwitterions have substantially reduced dipole moments compared to the free zwitterionic species. Consequently, it was demonstrated that typically for the salt form, the melting point decreased, the solubility in both polar and nonpolar media increased and the solubility in polyurethane membranes and in stratum comeum increased dramatically. To study this effect systematically, phenylalanine, baclofen and two diacid angiotensin converting enzyme inhibitors were selected as model zwitterionic compounds. Covalency was the key determinant in the counterion to optimize the increase in solubility of the salt. Rigidity of the zwitterion was related to the size of the enhancement.

The relationship of pKa and acute skin irritation in man.

The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15–88 µg/cm2/hr). Skin irritation and pKa are correlated for pKa ≤ 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa, erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa ≤ 4.

The Relationship between pKa and Skin Irritation for a Series of Basic Penetrants in Man

For a series of bases, which penetrate through human skin in vitro at similar rates (0.056-0.49 microM/cm2/hr), penetrant pKa is shown to correlate with erythema, edema, and color meter readings. As estimates of irritation, erythema, edema, and redness measurements are highly linearly correlated. For the selected series, irritation becomes significant for bases with a pKa greater than 8. The irritation potential of acids with pKa less than or equal to 4 has been previously reported; pKa appears highly predictive of acute skin irritation for acids and bases in man.

A transdermal nicotine system : feasibility studies

Abstract The permeation of nicotine through human epidermis in vitro, membranes, adhesives, an adhesive-membrane laminate, and the laminate with epidermis was measured. Skin irritation in rabbits was shown to depend on the driving force of nicotine in the donor phase. A transdermal nicotine system is described that provides substantial control of nicotine entry through skin by a rate-controlling membrane.

Relationship of PKA and Acute Skin Irritation in Humans

AbstractThe relationship between pKa and skin irritation in humans was studied for a homologous series of benzoic acid derivatives with predicted permeation through human skin at comparable rates (15-90 μg/cm2/hr). Skin irritation and pKa are strongly correlated, and, for pKa ≤4, skin irritation rapidly increases. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive variable.