Making the Leap from Daily Oral Dosing to Long-Acting Injectables: Lessons from the Antipsychotics

Abstract

There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot.

Lipid–Drug Conjugate for Enhancing Drug Delivery

“…The physical chemical properties of LDCs will, in turn, affect drug release profiles. 85 Inspired by the applications of LDCs in long-acting injectable formulations for treating antipsychotics, several other studies have been performed to explore their applications in developing extended release formulations for other drugs. For example, a lipophilic prodrug approach was used to develop a one-month sustained release formulation of nalmefene, which is a drug used to reduce alcohol intake.…”

Modeling the Time Course of the Tissue Responses to Intramuscular Long-acting Paliperidone Palmitate Nano-/Microcrystals and Polystyrene Microspheres in the Rat

“…Long-acting intramuscular (IM) or subcutaneous (SC) injectable (LAI) drug nano-/microsuspensions constitute a relatively new class of formulations that enable prolonged and stable therapeutic drug exposure from 2 weeks to several months (Remenar 2014). They consist of pure drug nanocrystals and/or microcrystals (i.e., size range typically 100 nm-10 mm), which are dispersed in a buffered aqueous vehicle containing small amounts of stabilizing excipients (e.g., hydrophilic polymers and/or surfactants) to avoid particle agglomeration (Rabinow 2004).…”

“…The principles dictating the nano-/microsuspension formulation development and determining the drug dissolution rate have been extensively reviewed elsewhere (Shegokar and Müller 2010;Möschwitzer 2013). This attractive formulation strategy has so far resulted in the successful marketing of 3 once-monthly IM injectable nano-/microsuspensions, and several promising candidates are currently being tested in clinical trials (Samtani, Vermeulen, and Stuyckens 2009;Lindenmayer 2010;Gopalakrishna, Aggarwal, and Lauriello 2013;Spreen, Margolis, and Pottage 2013;Remenar 2014).…”

Aripiprazole Lauroxil

“…This approach was used to lower the solubility of aripiprazole to develop a dosage form that allows for controlled release after injection and extend exposure to the active molecule. 10 Once the aqueous suspension is injected into the gluteal or deltoid muscle, the conversion of aripiprazole lauroxil to aripiprazole is governed by the slow dissolution of aripiprazole lauroxil and subsequent enzyme-mediated cleavage by esterases, generating N -hydroxymethyl aripiprazole and lauric acid. Lauric acid, also called dodecanoic acid, is a fatty acid found in coconut oil, human breast milk, and cow's milk.…”