Sirirat Pinsuwan

Review on the systemic delivery of insulin via the ocular route.

Systemic drug absorption from the ocular route is well known. Although there is some absorption from the conjunctival sac, the nasal meatus is the site where the majority of systemic absorption of instilled drug takes place. This article reviews the principles of systemic absorption of insulin applied topically to the eye. The physiological and pharmaceutical considerations for formulation development and the strategy of improving the systemic absorption and bioavailability of insulin are also discussed.

Characterization of mefenamic acid-guaiacol ester: stability and transport across Caco-2 cell monolayers.

AbstractPurpose. Prodrug of non-steroidal anti-inflammatory drugs (NSAIDs) or NSAIDs linked with guaiacol have been reported to suppress gastrointestinal (GI) toxicity or induce GI protective effect. In this study, mefenamic-guaiacol ester was synthesized and its physicochemical properties, stability, and transport across Caco-2 monolayers were investigated. Methods. Synthesis of the ester was carried out using mefenamic acid, guaiacol, N, N′-dimethylaminopyridine, and N, N′dicyclohexylcarbodiimide. The hydrolysis of the ester was investigated in aqueous buffer solutions pH 1-12 as well as in Caco-2 homogenate, human plasma, and porcine liver esterase. Caco-2 cell monolayers were utilized for transport studies. Due to the high lipophilicity of the ester with a calculated logP of 6.15, bovine serum albumin (BSA, 4%) was included in the receiver compartment to obtain a good in vitro-in vivo correlation. Permeation of the ester was assessed with or without the exposure of cells to PMSF, an inhibitor of esterase. Results. The ester was stable at a wide pH range from 1-10. However, it was hydrolyzed by enzymes from porcine liver esterase and Caco-2 homogenate. With the PMSF exposure on the apical (AP) side and in the presence of 4% BSA on the basolateral (BL) side, the transported amount of the ester from AP-to-BL direction was 14.63% after 3 hr with a lag time of 23 min. The Papp for the ester was 4.72 × 10-6 cm s-1. Conclusion. The results from hydrolysis studies indicate that this ester is a prodrug. The Papp value suggests the moderate absorption characteristic of the compound. The accumulation of this highly lipophilic ester in Caco-2 cells is reduced in the presence of BSA.

AQUAFAC 5 : AQUeous Functional group Activity Coefficients; application to alcohols and acids

AQUAFAC, a group contribution method developed by Myrdal et al.(1992) for estimating the aqueous coefficients, has been studied on a large set of organic compounds including hydrocarbons, halogenated hydrocarbons, non-hydrogen bonding oxygen containing compounds, and nitrogen containing compounds. This study presented new group contribution values for alcohols and acids. This brings the number of the individual solubility values in the AQUAFAC database to over 3,150 for over 1,290 different compounds.

Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions

The kinetics of degradation of the new anti-tumor drug, 4-dedimethylamino sancycline (col-3) in aqueous solution at 25oC were investigated by high-pressure liquid chromatography (HPLC) over the pH-range of 2-10. The influences of pH, buffer concentration, light, temperature, and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first order kinetics. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions and inhibited by EDTA and Sodium bisulfite.

Experimental and computational studies of epithelial transport of mefenamic acid ester prodrugs.

Purpose.A series of ester derivatives of mefenamic acid were synthesized with the aim of suppressing local gastrointestinal toxicity of mefenamic acid. A computational method was used to assist the design of the prodrug and to gain insights into the structure relationship of these compounds as P-glycoprotein (P-gp) substrates. The prodrugs were studied for their enzymatic stability, bidirectional permeability across Caco-2 monolayer, and their potential as transporter modulatorsMethods.Bidirectional transport studies were performed using Caco-2 cells. Compounds exhibiting an efflux ratio of ≥2 were further examined for their potential interaction with P-gp and multidrug resistance–associated protein (MRP) using verapamil and indomethacin. Calcein efflux inhibition studies were conducted to investigate the efflux mechanism of these compounds. Geometry optimization of the esters was performed, and the spatial separation of two electron donor groups of each prodrug was measured.Results.Morpholinoethyl ester (3) and pyrrolidinoethyl ester (4) of mefenamic acid showed evidence of efflux mechanism. Inhibition by verapamil had a pronounced effect on the transport of 3 and 4. Indomethacin, however, completely inhibited the apical efflux of 3 but enhanced the efflux ratio of 4. Both compounds increased the ratio of cellular calcein accumulation by 3- to 5-fold over control. Consistent with the experimental data, the computational results suggest the involvement of P-gp or its interaction in 3 and 4 transport.Conclusions.Apical efflux of 3 is associated with P-gp and MRP, but the efflux of 4 involves P-gp and/or MRP. The computational approach used in this study provided the basis for P-gp substrates of compounds 3 and 4 from their electron donor subunits spatial separation.

A comparison of AQUAFAC group q-values to their corresponding CLOGP f-values

Abstract Previous studies1,2 have shown that AQUAFAC is more accurate than the general solubility equation for the estimation of aqueous solubility. The relationship between AQUAFAC group q-values and their corresponding CLOGP f-values is investigated in this study. The q- and f-values are comparable in magnitude for hydrocarbon and halocarbou groups but not for hydrogen bonding groups.

Determination of melanotan II in rabbit urine using solid-phase extraction sample preparation followed by reversed-phase high-performance liquid chromatography

A solid-phase extraction (SPE) method has been developed for the isolation of melanotan II from rabbit urine. The proposed extraction method makes it possible to selectively isolate melanotan II without significant loss of the peptide. Standard curves obtained from high-performance liquid chromatographic (HPLC) analysis of spiked urine extracts are linear from 0.1 to 4.0 micrograms/ml. The analytical method is shown to be highly reproducible, giving a relative standard deviation of less than 5% for both between-day and same-day analyses. The accuracy of the method obtained from standard plots ranges from -3.3 to 3.1%.