Improved ziprasidone formulations with enhanced bioavailability in the fasted state and a reduced food effect.

PURPOSE: To develop and characterize new formulations of ziprasidone with a reduced food effect achieved by increasing exposure in the fasted state. METHODS: Formulations were developed utilizing the following solubilization technologies: inclusion complex of ziprasidone mesylate and cyclodextrin, ziprasidone free base nano-suspension, and semi-ordered ziprasidone HCl in polymer matrix. Pharmacokinetic studies were conducted with these formulations to examine the bioavailability of test formulations in fasted and fed state compared to commercial capsules (Geodon®) dosed in the fed state. RESULTS: All formulations containing solubilized ziprasidone showed either no food effect or a reduced food effect compared to commercial capsules. Two formulations when taken in the fasted or fed state were comparable to the commercial capsules dosed in the fed state with respect to total exposure. However, peak concentrations were ~30-40% higher. CONCLUSIONS: Pharmacokinetic studies indicated solubilization technologies can be employed to successfully increase the extent of ziprasidone absorption in the fasted state, thereby reducing the food effect. Such formulations could provide simple and convenient dosing while retaining the familiar safety and efficacy profile of currently marketed capsules.

Utility of hydroxypropylmethylcellulose acetate succinate (HPMCAS) for initiation and maintenance of drug supersaturation in the GI milieu.

PURPOSE: To identify materials and processes which effect supersaturation of the GI milieu for low solubility drugs in order to increase oral bioavailability. METHODS: A variety of small and polymeric molecules were screened for their ability to inhibit drug precipitation in supersaturated solutions. The best polymeric materials were utilized to create spray-dried dispersions (SDDs) of drug and polymer, and these were tested for drug form and homogeneity. Dispersions were tested in vitro for their ability to achieve and maintain drug supersaturation, for a variety of drug structures. RESULTS: Of the 41 materials tested, HPMCAS was the most effective at maintaining drug supersaturation. Drug/HPMCAS SDDs were consistently more effective at achieving and maintaining drug supersaturation in vitro than were SDDs prepared with other polymers. Drug/HPMCAS SDDs were effective in vitro for eight low solubility drugs of widely varying structure. Drug/HPMCAS SDDs were more effective at achieving and maintaining supersaturation than were rotoevaporated Drug/HPMCAS dispersions or physical mixtures of Drug and HPMCAS. The degree of achievable drug supersaturation increased with increasing polymer content in the SDD. The drug in Drug /HPMCAS SDDs was amorphous, and the dispersions were demonstrated to have a single glass transition and were thus homogeneous. CONCLUSION: HPMCAS has been identified as a uniquely effective polymer for use in SDDs of low solubility drugs, with broad applicability across a variety of drug structures and properties.

Formulation design and pharmaceutical development of a novel controlled release form of azithromycin for single-dose therapy.

BACKGROUND: Azithromycin's long serum half-life (approximately 68 hours) allows for a short 5-day, 3-day, and now 1-day course therapy with a large 2-g dose. Although the single-dose, 1-day therapy offers the advantage of 100% patient compliance, tolerance of such large dose becomes an issue. METHODS: The dosage form discussed in this article employed a melt-congealing process to produce matrix microspheres with a 3-hour, first-order release. The vehicle blend included alkalizing agents to minimize GI side effects, minimize loss of bioavailability, and mask the bitter taste of azithromycin. RESULTS: Azithromycin microspheres are small (approximately 200 microm) with a narrow particle size distribution. Drug release was optimized by controlling the amount of dissolution enhancer in the microspheres and by the addition of proper amount of alkalizing agents in the vehicle blend. The final formulation was selected based on a balance between bioavailability and tolerability. CONCLUSIONS: Drug release from the microspheres was shown to occur via diffusion through the larger pores formed by dissolution of azithromycin crystals and the smaller interconnected pores formed by dissolution of poloxamer. Several clinical studies have been conducted with the formulation to evaluate its pharmacokinetics and to demonstrate its safety and efficacy. The combined suspension formulation for a 2-g dose of azithromycin provided taste-masking and good tolerability.