A relationship between bulk density, surface area, and onset of mass loss has also been reported by Mehta et al. [33]. Hence, a low bulk density is indicative of highly porous microspheres, since porosity correlates well with polymer hydration, and thereby, degradation; bulk density VX-770 in vivo values are an indicator of drug release rates [52, 53]. Table 1 summarizes the results of bulk density measurements. Values for all the formulations ranged from Inhibitors,research,lifescience,medical 0.65 to 0.76g/cc. The high

bulk density values were indicative of a low degree of internal porosity with similar pore volumes for Formulations A–D. Given that particle sizes for all four formulations are similar and bulk density is high, both parameters were expected to contribute equally to Inhibitors,research,lifescience,medical the initial burst release from the microspheres. 3.1.3. Drug Content Drug content is an important property of the microsphere dosage form as it provides information related to the amount of drug available for release from the dosage form. Results of drug content, as determined by HPLC, are presented in Table 1. For the purposes

of the current study, high drug loadings were targeted in part to mimic Inhibitors,research,lifescience,medical the loading level of 38.1% in the marketed Risperidone depot formulation [50]. Therefore, Formulations A–D were prepared at loadings between 25 and 34% (Table 1). These values suggest a high drug:polymer ratio for the four formulations, at a value higher than the drug solubility in the polymer. This situation favors the initial burst Inhibitors,research,lifescience,medical release phenomenon. Hence, a high value of initial burst was expected for all four formulations. Based on the morphology, particle size, and drug content data, the formulations were expected to behave in the following manner: (a) High initial burst was expected from all the formulations, and (b) Formulations Inhibitors,research,lifescience,medical A and B, manufactured using 50:50 PLGA, were expected to exhibit a shorter duration of action than Formulations C and D, where

the duration of action was expected to be prolonged. 3.2. In Vivo Results 3.2.1. Serum Levels of Risperidone and Its Metabolite for Formulations A, B, C, and D In vivo, Risperidone is extensively metabolized in the liver by CYP2D6 to form 9-hydroxyrisperidone, a pharmacologically active metabolite. Serum levels of Risperidone and its metabolite for each formulation, after administration of a single subcutaneous Chlormezanone dose, are shown in Figures 2(a)to 2(d), including the levels of “active moiety” which is the sum of Risperidone and metabolite levels. Figure 2 In vivo release of Risperidone and 9-hydroxyrisperidone from microsphere Formulations A, B, C, and D. Formulations A and B administered to a 20mg/kg dose in rats showed an initial burst around 100ng/mL of Risperidone followed by a trough in levels by day 1. The high initial burst was attributed to a combination of the small particle size and high loading levels for both formulations.