Discovery and preclinical development of a novel prodrug conjugate of mesalamine with eicosapentaenoic acid and caprylic acid for the treatment of inflammatory bowel diseases.

Mesalamine (5-ASA) is one of the drugs indicated as first line therapy in ulcerative colitis for induction and maintenance of remission. Sulfasalazine and formulations of 5-ASA (pH-dependent and controlled release formulations) were developed to minimize the systemic absorption and maximize the delivery of the mesalamine to colon. Although, its efficacy and safety is well documented there are approximately 30% nonresponders to 5-ASA therapy. This necessitates the need for novel therapeutic options to improve the efficacy and safety of the currently available 5-ASA therapy. CLX-103 is a novel, patented prodrug molecular conjugate of mesalamine, eicosapentaenoic acid and caprylic acid designed to offer incremental benefits over the currently approved 5-ASA formulations. Results of in vitro and in vivo studies showed that CLX-103, was stable in simulated gastric fluid, but undergoes enzymatic hydrolysis in the small/large intestines to release the active moiety. Our data also showed that the active moiety is retained in the targeted intestinal tissues (ileum and colon) over a longer period of time in relation to sulfasalazine. The in vitro data supports the observed in vivo plasma kinetics of 5-ASA characterized by longer Tmax, low Cmax after the oral administration of CLX-103. Efficacy study of CLX-103 in acute dextran sodium sulfate (DSS) mouse colitis model showed improved potency measured as Disease Activity Index (DAI) and histological scores in the colon as compared to sulfasalazine. These findings indicate that CLX-103 could offer a differentiated drug product which is more efficacious and safer than the currently approved 5-ASA formulations in the treatment of inflammatory bowel diseases.

Two open-label, randomized, crossover studies assessing the bioequivalence of ofloxacin administered as immediate-and extended-release formulations in healthy subjects.

BACKGROUND: Ofloxacin is a fluoroquinolone agent available as an immediate-release (IR) tablet formulation administered twice daily. An extended-release (ER) formulation of ofloxacin has been developed for oncedaily administration. OBJECTIVES: The present studies compared the pharmacokinetic (PK) and safety profiles of the ER and IR formulations of ofloxacin. METHODS: Based on specific inclusion and exclusion criteria, healthy adult male and female volunteers were selected to receive single and multiple oral doses of ofloxacin ER 400 mg QD and ofloxacin IR 200 mg BID in 2 separate open-label, randomized, crossover studies. Multiple blood samples were collected, and plasma concentrations of ofloxacin were analyzed using a high-throughput liquid chromatography system. PK parameters were calculated using noncompartmental methods. Safety was assessed in the clinical pharmacology unit based on vital signs, electrocardiograms (ECGs), and reported adverse events. The relationship of an adverse event to study drugs (definitely, probably, possibly, remotely, or unrelated) was assessed by the principal investigator. RESULTS: Forty healthy subjects were included in each study. Thirty-seven subjects (28 men, 9 women; mean age, 37 years; mean weight, 71.2 kg) completed the single-dose study, and 38 subjects (33 men, 5 women; mean age, 36 years; mean weight, 72.2 kg) completed the multiple-dose study. With the exception of 3 black subjects in each study of African-American origin, all subjects in both studies were white. The mean AUC(0-24) values for the ER formulation in the single-and multiple-dose studies (18.6 and 21.4 mg . h/L, respectively) were similar to those for the IR formulation (17.7 and 22.8 mg x h/L), with the 90% CIs falling between 80.0 and 125.0. Mean C(max) values for the ER formulation in the single- and multiple-dose studies (2.02 and 2.12 mg/L) were also similar to those for the IR formulation (1.74 and 1.85 mg/L). Under steady-state conditions, median T(max) values for the ER formulation were significantly longer than those for the IR formulation (5.00 vs 2.00 hours, respectively; P < 0.05). All vital signs and ECGs were within normal ranges during the single- and multipledose studies. Adverse events probably related to study drugs (eg, nausea, loose stools, emesis) were similar in nature and frequency between the 2 formulations. No serious adverse events were reported during either study. CONCLUSION: In these 2 trials in a selected group of healthy adult male and female volunteers, the ER and IR formulations of ofloxacin displayed a similar rate and extent of bioavailability and comparable safety profiles.