75 Formulation Properties of Long-acting Injectable Antipsychotics and the Impact on Administration: Focus on Aripiprazole Lauroxil
Authors: Farwick Sarah , Hickey Magali , Vandiver Jennifer , Weiden Peter J 
Published: March 2019

Clinicians using long-acting injectable (LAI) antipsychotics may assume that there is uniformity in the injection technique for all LAIs. However, because LAIs have significant differences in their formulation, each requires a specific administration procedure. Here, we focus on how the formulation properties of the atypical LAI aripiprazole lauroxil impact its administration.

The history of LAI formulations is presented as a background to recent advances in formulation technology. A shared challenge for new LAIs is to adapt the formulation of insoluble drugs to aqueous-based suspensions.

The early LAIs kept the drug product dissolved as oil-based solutions, which were stable and did not require mixing prior to injection. However, oil-based solutions tend to be viscous and cause injection-site reactions (ISRs).

New LAI formulations tend to be aqueous-based suspensions and need to be resuspended or reconstituted before injection. Beyond this common element, formulation properties lead to differences in administration for each of the available LAIs.

We reviewed the formulations of LAIs indicated for the treatment of schizophrenia and how they impact instructions for use, with a focus on aripiprazole lauroxil.

Aripiprazole monohydrate and olanzapine pamoate are lyophilized powders that require reconstitution before administration and should be injected slowly. Risperidone is formulated as microspheres in powder form that require reconstitution before injection, although the injection speed is not specified. Paliperidone palmitate is a ready-to-use aqueous suspension of crystalline particles and should be injected slowly. Aripiprazole lauroxil is an aqueous-based, ready-to-use suspension of crystalline particles. Unlike other LAIs, the formulation of aripiprazole lauroxil contains particles that are loosely associated to facilitate resuspension. Because loosely associated suspensions are shear-thinning, meaning the viscosity of the formulation decreases with higher injection force, the injection must be given rapidly. Vigorous shaking and rapid injection are key aspects of administration and have been accepted by patients and investigators in clinical trials. In a pivotal phase 3 study of aripiprazole lauroxil, the incidence of ISRs was low (3.9% and 5.8% for aripiprazole lauroxil 441mg and 882mg , respectively) and mostly associated with the first injection.

Advances in formulation technology have increased LAI options for patients with schizophrenia. The aripiprazole lauroxil formulation differs from other LAIs in that the particles are loosely associated to support use as a ready-to-use pre-filled syringe. Because the suspension is shear-thinning, aripiprazole lauroxil requires rapid injection, which is not required when using other LAIs. An understanding of the differences in formulation design and how they impact the specific techniques associated with an LAI is essential for successful administration.

Funding Acknowledgements: This study was funded by Alkermes, Inc.