The long-term goal of this research is to minimize morbidity due to non-adherence to outpatient antipsychotic-antimanic therapy with olanzapine. Olanzapine is currently a mainstay of treatment for psychotic disorders and mania. Its elimination half-life of (ca. 30 h in humans) is appropriate for once-daily oral dosing. Most psychotic and manic-depressive disorders require long-term, maintenance treatment, in which reliable and sustained adherence to therapy is a major clinical challenge and limitation to therapeutic effectiveness. Long-term adherence to antipsychotic treatment can be enhanced with long-acting, injectable preparations. The only such agents licensed in the US currently are long-chain fatty acid esters of the older neuroleptics fluphenazine and haloperidol, which carry a high risk of adverse extrapyramidal neurological effects, including tardive dyskinesia, and a sustained release formulation of risperidone incorporated into carbohydrate microspheres which has recently been approved for twice-monthly injection. Based on the clear clinical need and market opportunity, we have developed a formulation of olanzapine, currently one of the most widely clinically employed and versatile antipsychotic-antimanic agents. This preparation promises to support twice-monthly administration of olanzapine. We believe that the development of an injectable sustained release olanzapine is readily achievable and that it will become a useful tool in the outpatient treatment of patients with highly prevalent major mental disorders including schizophrenia and manic-depressive illness, which together affect several percent of the general population at any time. In Phase 1 of this work we have accomplished our stated specific aims. We have formulated an injectable subcutaneous sustained release delivery system using novel particle parameters and coating strategies. This formulation demonstrates release over approximately 2 weeks into buffer in vitro and achieves a significant increase in the plasma half-life in the rat compared to oral. We have demonstrated tissue compatibility for this formulation and have demonstrated a sustained pharmacodynamic effect in the standard rat model. In so doing we have demonstrated both the general feasibility of the approach and our ability as a team to carry out the proposed work.
Schizophrenia and manic depression affect millions of patients in United States. Psychotic episodes often necessitate hospitalization where treatment is instituted and results in diminution of symptoms sufficient to allow discharge. However, once discharged these patients often do not take their medicines which can then re-start the cycle: admission - control - discharge - nonadherence - admission....... Injectable treatment using sustained release formulations has long been a mainstay of therapy for these patients. However there exists only one sustained release formulation (Risperdal Consta(R)) for an atypical antipsychotic: the class of drugs is most effective. We have developed sustained release formulations for the atypical antipsychotic olanzapine. The successful development of products based on these formulations can potentially aid in the treatment of hundreds of thousands of patients. Other groups are working to achieve the same goal using different sustained release technologies. We believe our proprietary drug delivery platform has significant technological advantages which will allow us to succeed where others have failed. The principal investigator has been responsible for two existing release drug delivery products which have been approved through the NDA process by the FDA. This is impossible by licensing at the appropriate stage to corporate partners with resources necessary for such an undertaking. We plan to repeat this strategy in the development of these important treatments for schizophrenia and manic-depressive illness.