Polylysine-Containing Hydrogel Formulation of Fuzapladib, Inhibitor of Leukocyte-Function Associated Antigen-1 (LFA-1) Activation, for Sustained Release.

The aim of the present study was to develop an injectable hydrogel (HG) formulation of fuzapladib sodium (FZP), an animal drug for acute pancreatitis (AP), with the use of polyethyleneoxide (PEO) and polylysine (pLys), a cationic polymer. A mixture of pLys and FZP was added to PEO to prepare an HG formulation, and the formulation was optimized by release test and viscosity measurements. Circular dichroism (CD) and infrared absorption (IR) spectral analyses were applied to clarify the intermolecular interactions between FZP and pLys. The pharmacokinetic behavior of FZP was evaluated after a subcutaneous administration of FZP samples (2.0 mg-FZP/kg) to rats. Although the immediate release of FZP was observed for the HG formulation, the addition of pLys at a 20-fold amount of FZP or higher led to the sustained release of FZP. Considering release behavior, the concentration of pLys was optimized as 100-fold that of FZP in the HG formulation. CD and IR spectroscopic analyses of FZP and/or pLys demonstrated an intermolecular interaction between FZP and pLys, as evidenced by the slight spectral transition. After a subcutaneous administration of HG formulation containing pLys to rats, compared with FZP alone, significant differences were observed in the pharmacokinetic behavior with a decrease of Cmax from 2.3 to 0.9 mg/mL and slower elimination kinetics. HG formulation using pLys might be a viable dosage option for FZP for the treatment of AP in animals.

Nanocrystal solid dispersion of fuzapladib free acid with improved oral bioavailability.

This study aimed to develop an oral nanocrystal solid dispersion (nCSD) of fuzapladib (FZP) with enhanced absorbability for the treatment of acute pancreatitis (AP). The hydration properties of crystalline FZP free acid (crystalline FZP) and FZP sodium salt (FZP/Na) were assessed to select a stable crystal form. The nCSD of FZP free acid (nCSD/FZP) was prepared using a multi-inlet vortex mixer and evaluated in terms of physicochemical and pharmacokinetic properties. The results of X-ray powder diffraction analysis indicated that crystalline FZP was stable as an anhydrate, while FZP/Na was converted to its monohydrate at water activity of above 0.2. The nanocrystals in nCSD/FZP were dispersed in hydroxy propyl cellulose-SSL, and their mean particle size were 160 nm with uniform spherical shape. In dissolution testing, nCSD/FZP exhibited rapid dissolution compared with crystalline FZP and reached a saturated concentration of FZP within initial 30 min. After oral administration (2 mg-FZP/kg) to rats, the maximum plasma concentration and bioavailability were 7.3- and 5.2-fold higher for nCSD/FZP than crystalline FZP, respectively, due to improved dissolution by nanosization. In conclusion, nCSD/FZP may be a novel oral dosage form with enhanced absorbability facilitating potent therapeutic effects of FZP for the treatment of AP in animals.

Development of stabilized fuzapladib solution for injection: forced degradation study and pharmacokinetic evaluation.

The aim of the present study was to develop and evaluate stabilized injection solutions of fuzapladib sodium hydrate using antioxidants as the stabilizers. To estimate the possible degradation factors and pathways of fuzapladib, forced degradation studies were conducted under thermal, acid, base, oxidative, and light conditions. To select an optimal excipient to stabilize fuzapladib under a solution state, a screening study of antioxidants was carried out to evaluate their effects to inhibit the degradation. The influence of the selected stabilizers on its pharmacokinetic behavior was evaluated in rats after intravenous administration. On the basis of data from the forced degradation study, thermal and oxidative stresses were significant factors accelerating the degradation of fuzapladib. Among eight tested antioxidants, vitamin C (VC) was the most effective stabilizer to suppress the accelerated degradation by heating, as evidenced by 45% inhibition of the degradation. The stabilization effect was enhanced depending on the concentration of VC. After the intravenous administration of fuzapladib (0.5 mg/kg) with or without VC (2.1 mg/kg), there were no significant differences between the pharmacokinetic behaviors of each group. From these findings, VC might be a promising excipient to stabilize the injection solution of fuzapladib without significant influence on its pharmacokinetic behavior.

Fuzapladib in a randomized controlled multicenter masked study in dogs with presumptive acute onset pancreatitis.

BACKGROUND: Currently, no specific treatment is available for acute onset pancreatitis (AP), and management relies on symptomatic and supportive standard of care (SOC). Fuzapladib is a novel leukocyte function-associated antigen type-1 (LFA-1) activation inhibitor, blocking activation and subsequent adhesion and migration of neutrophils, potentially decreasing the risk of pancreatitis progression and systemic inflammation. OBJECTIVE: Evaluate the safety and clinical response of dogs with AP after 3 days of administration of fuzapladib. ANIMALS: Sixty-one client-owned dogs with presumptive AP. METHODS: Randomized, masked, and placebo controlled multicenter study. Sixty-one dogs with AP were included for safety assessment, whereas 35 evaluable cases (fuzapladib, n = 16; placebo, n = 19) were included for clinical evaluation. Clinical improvement was assessed based on the change in the modified clinical activity index (MCAI) score on Day 3 compared to Day 0. Secondary variables included canine acute pancreatitis clinical severity index (CAPCSI) scores and serum concentrations of canine pancreatic lipase immunoreactivity, cytokines, and C-reactive protein. RESULTS: Fuzapladib was well tolerated by all treated dogs. Mean change in MCAI scores was significantly higher in the fuzapladib-treated (-7.75) than the placebo group (-5.68; P = .02, 95% confidence interval [CI] for the difference, -4.33, -0.35), suggesting clinical improvement in fuzapladib-treated dogs. No significant difference was found in any of the secondary variables between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of fuzapladib to dogs was safe, and a favorable response was detected in 2 clinical activity scores. Effects of fuzapladib on survival and duration of hospitalization were not studied.

Suppressive effects of a new anti-inflammatory agent, IS-741, on dextran sulfate sodium-induced experimental colitis in rats.

A novel anti-inflammatory drug, IS-741, blocked the adhesion of inflammatory cells to microvascular endothelial cells in vivo and in vitro. We examined the efficacy of IS-741 in a dextran sulfate sodium (DSS)-induced colitis model. DSS colitis was induced by the oral administration of 3% DSS for 10 days in rats. The rats were then divided in two groups: a 1% DSS plus IS-741 group and a 1% DSS plus water group. IS-741 was dissolved in water and administered orally (10 mg/kg) once per day for 14 days. The rats treated with DSS plus IS-741 remained healthy, and their body weight increased. The wet weight of the colon was significantly lower and the total colon length was significantly longer in the IS-741-treated group. Histological examinations revealed a marked infiltration of inflammatory cells into both the mucosa and submucosa in the DSS plus water group, but these changes were attenuated in the IS-741-treated group. The mucosal damage score was significantly reduced by treatment with IS-741. IS-741 also significantly reduced the mucosal myeloperoxidase activity. FACS analysis revealed that IS-741 significantly reduced Mac-1 expression on blood neutrophils. In conclusion, IS-741 suppressed DSS-induced experimental colitis in rats. Some of the action of IS-741 may be associated with its inhibitory effects on the Mac-1 expression of neutrophils in association with the blockade of their adhesion to endothelial cells. The findings in this study suggest that IS-741 may be a useful new therapeutic agent for inflammatory bowel disease.

Inhibitory effects of the new anti-inflammatory agent, IS-741, on spontaneous colitis in HLA-B27/beta2-microglobulin transgenic rats.

BACKGROUND: A novel anti-inflammatory drug, IS-741, blocked the adhesion of inflammatory cells to microvascular endothelial cells both in vivo and in vitro. Transgenic rats expressing human leukocyte antigen (HLA)-B27 and human beta2-microglobulin (HLA-B27 rats) spontaneously develop chronic colitis, which resembles human inflammatory bowel disease. In the present study, the authors examined the efficacy of IS-741 against spontaneous colitis in HLA-B27 rats. METHODS: The HLA-B 27 rats were divided in two groups after the development of colitis. IS-741 was dissolved in water and administered orally (10 mg/kg) once per day for 14 days. RESULTS: The HLA-B27 rats treated with IS-741 remained healthy; the wet weight of the colon was significantly lower in the IS-741-treated group. Histological examinations revealed a marked infiltration of inflammatory cells into both the mucosa and the submucosa in the control HLA-B27 rats, but these changes were attenuated in the IS-741-treated group. The mucosal damage score was also significantly reduced by treatment with IS-741. IS-741 significantly reduced the mucosal myeloperoxidase activity and mucosal cytokine-induced neutrophil chemoattractant-1 levels. IS-741 also reduced CD3-positive T-cell infiltration. CONCLUSION: IS-741 suppressed the spontaneous colitis that developed in HLA-B27 rats. Some of the actions of IS-741 may be associated with its inhibitory effects on the adhesion of neutrophils to endothelial cells. The findings from the present study suggest that IS-741 may be a useful new therapeutic agent for inflammatory bowel disease.