Amino Acid Conjugation: An Approach to Enhance Aqueous Solubility and Permeability of Poorly Water Soluble Drug Ritonavir

Objective: The objective of present work is to improve physicochemical and pharmacokinetic profile of poorly water soluble HIV protease inhibitor, ritonavir (RT) by preparing its amino acid conjugates. Methods: Ester conjugates of ritonavir with various amino acids were synthesized by a simple esterification process using dicyclohexyl carbodiimide (DCC) as a coupling agent. The synthesized compounds were characterized by thin layer chromatography (TLC), fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR) and mass spectroscopy. All conjugates were evaluated by saturation solubility and hydrolytic stability studies. Cytotoxicity and permeability studies were conducted using Caco-2 cell line. Results: All amino acid conjugates showed a significantly higher aqueous solubility compared to the pure RT. With respect to hydrolysis, alkaline hydrolysis of conjugates was rapid relative to acidic hydrolysis. No cytotoxicity was shown by conjugates for concentration as high as 100μM, which indicates promising therapeutic potential. Transport studies across Caco-2 cells showed that prepared amino acid conjugates improved the permeation of RT compared to pure RT. Conclusion: In vitro studies demonstrated that amino acid conjugation of RT may be an effective strategy to improve its aqueous solubility as well as permeability and can be used to improve oral absorption and thereby oral bioavailability of protease inhibitors. Keywords: Ritonavir, amino acids, conjugates, solubility, HIV, hydrolysi

Synthesis and evaluation of analgesic, anti-asthmatic activity of (E)-1-(8-hydroxyquinolin-7-yl)-3-phenylprop-2-en-1 ones

Abstract Seventeen (E)-1-(8-hydroxyquinolin-7-yl)-3-phenylprop-2-en-1 one derivatives were synthesized via aldol condensation of substituted benzaldehydes with quinoline chalcones starting from 8-hydroxy quinoline. Molecular docking studies were performed on COX-2 protein for analgesic activity and PDE 4 enzyme for anti-asthmatic activity. Docking studies for analgesic activity reveal that the compounds 2 , 4 , 12 , 14 , and 15 showed significant interaction in terms of hydrogen bonding, hydrophobic attachment and van der Waal interaction with COX-2. The docking studies and pharmacological screening indicate that substitution of hydroxyl and conjugated ketone groups on the aldehyde ring and the quinoline ring accelerates analgesia with better binding to active site. Eddy's hot plate method was used to evaluate analgesic activity of the synthesized compounds. Compounds showed a substantial increase in reaction time when compared with standard pentazocin. Compounds 2 , 4 , 7 , 9 and 13 showed significant binding interactions with PDE 4 enzyme and hence were selected for evaluation of anti-asthmatic activity using the goat tracheal chain method. Studies reveal that substitution of the methoxy group at 4th & 5th positions for compounds 2 , 4 & 7 leads to significant percentage inhibition of histamine induced contraction. The synthesized compounds are thus found to be potent as analgesic and anti-asthmatic agents

Physicochemical characterization and solubility enhancement studies of allopurinol solid dispersions

Allopurinol is a commonly used drug in the treatment of chronic gout or hyperuricaemia associated with treatment of diuretic conditions. One of the major problems with the drug is that it is practically insoluble in water, which results in poor bioavailability after oral administration. In the present study, solid dispersions of allopurinol were prepared by solvent evaporation, kneading method, co-precipitation method, co-grinding method and closed melting methods to increase its water solubility. Hydrophilic carriers such as polyvinylpyrrolidone, polyethylene glycol 6000 were used in the ratio of 1:1, 1:2 and 1:4 (drug to carrier ratio). The aqueous solubility of allopurinol was favored by the presence of both polymers. These new formulations were characterized in the liquid state by phase solubility studies and in the solid state by differential scanning calorimetry, powder X-ray diffraction, UV and Fourier Transform Infrared spectroscopy. Solid state characterizations indicated that allopurinol was present as an amorphous material and entrapped in polymer matrix. In contrast to the very slow dissolution rate of pure allopurinol, the dispersion of the drug in the polymers considerably enhanced the dissolution rate. Solid dispersion prepared with polyvinylpyrrolidone showed highest improvement in wettability and dissolution rate of allopurinol. Mathematical modeling of in vitro dissolution data indicated the best fitting with Korsemeyer-Peppas model and the drug release kinetics primarily as Non-Fickian diffusion. Therefore, the present study showed that polyvinylpyrrolidone and polyethylene glycol 6000 have a significant solubilizing effect on allopurinol.<br>Alopurinol é fármaco comumente utilizado no tratamento de gota crônica ou hiperuricemia associada com o tratamento em condições diuréticas. Um dos maiores problemas com o fármaco é que este é praticamente insolúvel em água, o que resulta em baixa biodisponibilidade na administração oral. No presente estudo, dispersões sólidas de alopurinol foram preparadas pela evaporação do solvente, pelos métodos de amassamento, de coprecipitação, de comoagem e fusão fechada para aumentar sua solubilidade em água. Transportadores hidrofílicos, como polivinilpirrolidona, polietilenoglicol 6000 foram utilizados nas proporções de 1:1. 1:2 e 1:4 (fármaco: transportador). A solubilidade aquosa do alopurinol foi favorecida pela presença de ambos os polímeros. Estas novas formulações forma caracterizadas no estado líquido pelos estudos de solubilidade de fase e no estado sólido pela calorimetria diferencial de varredura, difração de Raio-X, espectroscopia de UV e de IV com transformada de Fourier. As caracterizações do estado sólido indicaram que o alopurinol estava presente como material amorfo e embebido em matriz polimérica. Ao contrário da velocidade de dissolução lenta do alopurinol puro, a dispersão do fármaco nos polímeros aumentou consideravelmente a taxa de dissolução. A dispersão sólida preparada com polivinilpirrolidona mostrou as maiores melhorias na molhabilidade e taxa de dissolução do alopurinol. A modelagem matemática dos dados da dissolução in vitro indicou o melhor ajuste ao modelo de Korsemeyer-Peppas e a cinética de liberação do fármaco primariamente como difusão não-Fickiana. Assim, o presente estudo mostrou que a polivinilpirrolidona e o polietilenoglicol 6000 têm efeito significativo na solubilização do alopurinol