5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B totreat Cryptococcus neoformans meningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediaterelease product demonstrated 80% release at 0.28 h, as determined in vitro by the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P < 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitro dissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.Cryptococcus neoformans is an opportunistic fungal pathogen that is associated with significant morbidity and mortality. A 27% mortality rate has been associated with Cryptococcus neoformans meningoencephalitis (CNME) among AIDS patients in South Africa (15). An induction antifungal regimen of amphotericin B (AMB) and 5-fluorocytosine (5FC) for 2 weeks, followed by long-term fluconazole (FLZ) maintenance therapy, is considered the standard of care for AIDS patients with CNME (20). While it is effective, the use of induction therapy has been too complex for implementation in developing countries (11). The use of FLZ monotherapy in AIDS patients with CNME has been utilized but is associated with treatment failure and the emergence of resistance (3, 18). Hence, access to a simple, easy-to-administer combination oral antifungal regimen could improve CNME-related outcomes in countries without sufficient resources. The use of oral 5FC and FLZ combination regimens have demonstrated promising clinical results (4,8,10,14,16).However, currently recommended 5FC dosing regimens may not be optimal on the basis of pharmacokinetic (PK) and pharmacodynamic (PD) principles (7). For example, administration of 5FC at 25 mg/kg of body weight by mouth every 6 h yields steady-state maximum plasma concentrations (C max s) of 60 to 80 g/ml and minimum plasma concentrations (C min s) of 5 to 20 g/m...

The concentration of hypromellose (HPMC) is known to significantly impact the viscosity of coating solutions. The purpose of this study was to determine the viscosity of novel low-molecular-weight (LMW) HPMC products as a function of polymer concentration. The mechanical properties and water vapor permeability of free films prepared from these novel LMW HPMC polymers were also determined and the results were compared with films prepared with conventional HPMC. Solutions of LMW and conventional HPMC 2910 and 2906 containing up to 40% polyethylene glycol (PEG) 400 were prepared and the viscosities were measured using a Brookfield viscometer. Solutions were then cast onto glass plates and stored at 30?C and 50% relative humidity until films were formed. A Chatillon digital force gauge attached to a motorized test stand was used to quantify the mechanical properties of the films, whereas water vapor permeabilities were determined according to the ASTM E96 M-05 water method. As expected, the novel LMW polymer solutions exhibited significantly lower viscosities than the conventional comparators at equivalent polymer concentrations. Film strength of the LMW materials was lower than films prepared from the conventional HPMC solutions, although this effect was not as evident for the HPMC 2906 chemistry. Increasing concentrations of the plasticizer resulted in decreased tensile strength and Young?s modulus and increased elongation as well as increased water vapor permeability, irrespective of polymer type. No statistical difference was found between the tensile strength to Young?s modulus ratios of the F chemistry LMW and conventional HPMC polymer films.