Preclinical Development of a Dry Powder Formulation of Loxapine for Intranasal Delivery

Acute agitation (AA) is a common symptom of psychiatric conditions such as bipolar disorder and schizophrenia, resulting in 1.7 million emergency room visits per year in the United States. Loxapine, administered by inhalation, is an approved treatment for such scenarios. A boxed warning for bronchospasm when administered via inhalation limits its use to inpatient settings, making effective treatment for AA in outpatient settings an unmet need. The objective of this study was to develop and identify a lead intranasal dry powder formulation for outpatient treatment of AA.

Seven spray-dried nasal powders (Formulations A-G) consisting of loxapine succinate (Medichem, ES) and various excipients were manufactured and filled in a Unidose Nasal Powder system (Aptar Pharma, FR). In this pharmacokinetic study with non-compartmental analysis, formulations were evaluated both in vitro and in vivo (n = 4 non-human primates [NHPs]). Formulations were characterized by yield, assay, water content, particle size distribution, emitted dose, and impactor-sized mass.

Formulation B, comprising mannitol and hypromellose with 30% loxapine by weight, was identified as the lead candidate. In the in vivo portion of the study, all formulations were well tolerated. The plasma versus time profile for the NHP study indicated that Formulation B achieved the greatest extent of absorption (203.9 ng/mL*h) compared to the intravenous (control) formulation (231.5 ng/mL*h), each administered as a 3 mg dose. The full pharmacokinetic results for all formulations showed similar rapid absorption following dosing, although the area under the concentration-time curve and maximum concentration were lower than those observed with Formulation B. All formulations had similar apparent terminal half-lives.

Formulation B showed clear advantages both in vitro and in vivo, supporting its suitability for further development as an outpatient treatment for AA in schizophrenia and bipolar disorder.