betadex and Schizophrenia

Olanzapine (OLP), the most important atypical antipsychotic drug of the new generation, a high cost drug, has low aqueous solubility, affecting its dissolution and absorption. Its complexation with modified cyclodextrins (CDs) is designed to achieve novel vectorization systems with higher solubility, consequently higher bioavailability. From the CD selection, among β-CD, methyl-β-CD (MβCD) and hydroxypropyl-β-CD, it was obtained a phase solubility diagram suggesting a 1:1 (mol:mol) OLP-CD stoichiometry and complexation constants of 966.9, 149.4 and 91.1 L/mol, respectively. The MβCD was selected for the inclusion complexes (IC) attainment, a physical mixture (PM) and a rotatory evaporator product (ROE). The analysis showed differences in the structure, morphology and performance of OLP, MβCD, PM and ROE, revealing the occurrence of interactions between drug and CD. The ROE presented the higher dissolution efficiency and stability. The results suggest that the IC was formation, being a technological resource efficient and profitable for drug delivery.

Topics: Antipsychotic Agents; Benzodiazepines; beta-Cyclodextrins; Drug Carriers; Humans; Olanzapine; Schizophrenia

While clozapine is the acknowledged superior pharmacotherapeutic for the treatment of schizophrenia, the side effect profile, which includes potentially fatal complications, limits its usefulness. Central administration of clozapine directly into the brain could circumvent many of the side effect issues due to the dramatic reduction in dose and the limitation of the drug primarily to the CNS. The present study demonstrates that clozapine can be formulated as a stable solution at physiological pH, which does not have in vitro neurotoxic effects at concentrations which may be effective at treating symptoms. Acute central administration improved auditory gating deficits in a mouse model of schizophrenia-like deficits. Assessment of behavioral alterations in rats receiving chronic central infusions of clozapine via osmotic minipump was performed with the open field and elevated plus mazes. Neither paradigm revealed any detrimental effects of the infusion. While these data represent only an initial investigation, they none-the-less suggest that central administration of clozapine may be a viable alternate therapeutic approach for schizophrenia patients which may be effective in symptom reduction without causing behavioral or neurotoxic effects.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acoustic Stimulation; Animals; Antipsychotic Agents; Behavior, Animal; beta-Cyclodextrins; Cell Survival; Cells, Cultured; Chemistry, Pharmaceutical; Clozapine; Disease Models, Animal; Drug Design; Evoked Potentials, Auditory; Exploratory Behavior; Hippocampus; Humans; In Vitro Techniques; Injections, Intraventricular; Male; Maze Learning; Mice; Mice, Inbred DBA; Neurotoxicity Syndromes; Rats; Rats, Sprague-Dawley; Reflex, Startle; Schizophrenia; Schizophrenic Psychology