ABSTRACT
Myristyl nicotinate is an ester prodrug under development for delivery of nicotinic acid to skin for treatment and prevention of conditions that involve skin barrier impairment such as chronic photodamage and atopic dermatitis or for mitigating skin barrier impairment that results from therapy such as retinoids or steroids. The formulation stability of myristyl nicotinate is crucial because even small amounts of free nicotinic acid cause skin flushing, an effect that is not harmful but would severely limit tolerability. We report here reversed-phase HPLC methods for the rapid analysis of myristyl nicotinate and nicotinic acid in dermatological preparations. Because of the large differences in polarity, myristyl nicotinate and nicotinic acid were analyzed by different chromatographic conditions, but they can be rapidly extracted from cream formulations using HPLC mobile phase as a solvent followed by HPLC analysis in less than 10 min. The methods were validated in terms of linearity, precision and accuracy and mean recovery of myristyl nicotinate from topical creams ranged from 97.0-101.2%. Nicotinic acid at levels of 0.01% in the formulations could be quantified. Stability studies show that myristyl nicotinate formulations are stable at room temperature for 3 years with less than 0.05% conversion to nicotinic acid. These methods will be effective for routine analysis of myristyl nicotinate stability in dermatological formulations.
Subject(s)
Dermatologic Agents/analysis , Niacin/analogs & derivatives , Calibration , Chemistry, Pharmaceutical , Chromatography, High Pressure Liquid , Drug Stability , Indicators and Reagents , Linear Models , Niacin/analysis , Ointments , Reference Standards , Spectrophotometry, UltravioletABSTRACT
This study was designed to examine the kinetics of decomposition of paclitaxel 2'-N-methylpyridinium mesylate (PNMM), a derivative of paclitaxel. Further, the potential for PNMM to act as a prodrug of paclitaxel was assessed in vitro. Stability studies of PNMM were conducted over a pH range of 4.0 to 8.0 at 25 degrees C. The critical micelle concentration (CMC) of PNMM was determined by pulsating bubble surfactometry. Studies of the conversion of PNMM to paclitaxel were conducted in vitro in human plasma. Decomposition of PNMM followed apparent zero-order kinetics. The pH-rate profile exhibited no evidence of acid catalysis down to pH 4.0, while the rate was accelerated under base conditions. Surface tension studies suggested that PNMM formed micelles with a CMC of approximately 34 micro g/mL. Conversion studies in phosphate buffer showed that no more than 5% of PNMM converted to paclitaxel, while in human plasma the conversion was about 25%. The degradation of PNMM was via apparent zero-order kinetics and was dependent upon pH. The observed apparent zero-order kinetics of decomposition of PNMM was consistent with the formation of micelles in phosphate buffer. In buffered aqueous media alone or in human plasma, PNMM did not convert quantitatively to paclitaxel. Thus, the limiting factor in the application of PNMM as a prodrug would appear to be the poor potential to convert to paclitaxel.
Subject(s)
Antineoplastic Agents/metabolism , Paclitaxel/pharmacokinetics , Prodrugs/metabolism , Antineoplastic Agents/chemistry , Chemistry, Pharmaceutical , Drug Stability , Kinetics , Mesylates/chemistry , Paclitaxel/chemistry , Prodrugs/chemistry , SolubilityABSTRACT
Tissue deterioration and aging have long been associated with the accumulation of chemically induced protein and DNA damage. Reactive oxygen species (ROS) and reactive carbonyl species (RCS), especially alpha-dicarbonyl compounds, are key mediators of damage caused by oxidative stress, glycation, and UV-irradiation. The toxic effects of ROS are counteracted in vivo by antioxidants and antioxidant enzymes, and the deleterious effects of one RCS, methylglyoxal, are counteracted by a ubiquitous glyoxalase system. Carbonyl stress as a result of toxic effects of various mono-dicarbonyls (e.g. 4-hydroxynonenal) and alpha-dicarbonyls (e.g. glyoxal and deoxyosones) cannot be directly antagonized by antioxidants, and only a small number of biological carbonyl scavengers like glutathione (GSH) have been identified to date. We have developed a new screening method for the identification of carbonyl scavengers using a rapid glycation system that proceeds independent of oxygen and therefore, excludes identification of inhibitory compounds acting as antioxidants. Using this screening assay adapted to 96-well microtiter plates, we have identified the cysteine derivative 3,3-dimethyl-D-cysteine as a potent inhibitor of non-oxidative advanced glycation. Comparative kinetic analyses demonstrated the superior alpha-oxoaldehyde-scavenging activity of D-penicillamine over that of aminoguanidine. D-Penicillamine traps alpha-oxoaldehydes by forming a 2-acylthiazolidine derivative as shown by structure elucidation of reaction products between D-penicillamine and methylglyoxal or phenylglyoxal. We demonstrated that upon co-incubation, D-penicillamine protects human skin keratinocytes and fibroblasts (CF3 cells) against glyoxal- and methylglyoxal-induced carbonyl toxicity. Our research qualifies alpha-amino-beta-mercapto-beta,beta-dimethyl-ethane as a promising pharmacophore for the development of related alpha-dicarbonyl scavengers as therapeutic agents to protect cells against carbonyl stress.
