title: Microsphere delivery of Risperidone as an alternative to combination therapy.
abstract: The purpose of this study was to develop a parenteral delivery system of Risperidone that would provide initial and extended drug release and thereby avoid the need for co-administration of oral tablets. Key formulation parameters utilized to achieve desired therapeutic levels in vivo were particle size and drug loading. Three poly (D,L-lactide-co-glycolide) (PLGA) microsphere formulations (Formulations A, B, and C) that encapsulated Risperidone were prepared by varying particle size (19-49 μm) and drug loading parameters (31-37%) but with a uniform bulk density (0.66-0.69)g/cc and internal porosity, utilizing the solvent extraction/evaporation method. The microspheres were characterized for drug content by HPLC, particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM), and in vivo drug release. In vivo studies were performed in male Sprague-Dawley rats, and levels of the active moiety (Risperidone and its metabolite, 9-hydroxyrisperidone) were assessed. In vivo release profiles from the three microsphere formulations were dependent on particle size and drug loading. The smaller sized microspheres (Formulation A) exhibited a large initial burst and a shorter duration of action, while the larger particles exhibited a smaller initial burst (Formulations B and C) but released drug for a much longer period in vivo. Extended duration of drug release was ascribed to higher drug content in the microspheres. A biweekly simulation of multiple dosing revealed that Formulation C, the selected formulation, with a high load and large particle size would provide adequate initial and maintenance levels of the active moiety (Risperidone and its metabolite, 9-hydroxyrisperidone). A comparison of biweekly dosing in vivo of Formulation C with the marketed product showed that at steady state, though average concentrations for both preparations were similar, the time taken to achieve steady state was much faster for Formulation C. The delay in attaining steady state with Risperdal Consta® was attributed to the 3 week latency in drug release from the microspheres and was in accordance with previous studies indicating a good corroboration with clinical findings. Calculated cumulative AUC (area under the curve) levels for Formulation C were similar to the Risperdal Consta®, though there were marked differences in AUC levels at the early time points. Comparison of Risperidal Consta® and Formulation C by multiple dosing in vivo experiments revealed that the marketed preparation demonstrated a substantial delay in providing an initial loading dose, continuous circulating levels, and attainment of steady state; all of which were observed rapidly with Formulation C. Findings from the current study strongly suggest that a microsphere dosage form of Risperidone can be formulated with an optimum particle size and drug loading to provide an initial bolus followed by maintenance levels, thereby eliminating combination therapy and improving patient compliance.
authors.affiliation: University of Kentucky College of Pharmacy, Lexington, USA. Electronic address: dr_ssdsouza@yahoo.com.
authors.forename: Susan
authors.initials: S
authors.lastname: D'Souza
authors.forename: Jabar
authors.initials: J
authors.lastname: Faraj
authors.forename: Patrick
authors.initials: P
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems; D007555:Isoxazoles / Q000493:pharmacokinetics*; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008863:Microspheres; D000068882:Paliperidone Palmitate; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D016062:Porosity; D011743:Pyrimidines / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D007555:Isoxazoles; D011743:Pyrimidines; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: Combination therapy; Multiple dosing; PLGA microspheres; Patient compliance; Risperidone