title: Repurposing and reformulation of active pharmaceutical ingredients for delivery through parenteral routes
Creators: name: Unsworth, Catherine
Publisher: name: University of Liverpool Repository
Year: 2025

description: Despite the existence of vaccines and potent active pharmaceutical ingredients (APIs), there
remain key barriers to reducing the global burden of disease. For existing therapeutic
regimens which require lengthy oral dosing, good adherence is often essential to ensuring
positive outcomes such as sustained viral suppression. Glecaprevir (GLE) is administered
orally, as a co-formulation with pibrentasvir (PIB) for the treatment of hepatitis C. Pill
burden from daily dosing is high and adherence to a full curative regimen is often
compromised. An administration form that could offer longer dosing intervals could
improve hepatitis C cure rates. Many therapeutic options are characterised by low
bioavailability, resulting from physicochemical properties of the API; this limits the potential
applications for many compounds which may be applied to a range of indications. For APIs
characterised by poor bioavailability after oral dosing such as niclosamide (NCL), parenteral
administration options which bypass clearance by the liver, kidneys and small intestine
could provide the systemic concentrations required for therapy which are challenging with
the current oral regimens. Reformulation and repurposing strategies can be used to develop
novel therapeutic options from existing APIs, addressing barriers to adherence and low
bioavailability, while also reducing developmental costs and timelines.
Nanomedicine formulation strategies such as solid drug nanoparticle (SDN) generation
methodologies can be a route to production of high-concentration particle dispersions of
APIs. If such SDN materials are generated with suitable material properties, they could be
used to develop parenterally administrable therapies such as long-acting injectables (LAIs),
or inhalable suspensions for respiratory indications. In this work “bottom-up” SDN
formulations strategies were used to generate GLE SDN and NCL SDN materials, and the key
parameters that could be used to manipulate dispersibility and particle size distribution
were compared. From this, generation methodologies for GLE SDN and NCL SDN
formulations were scaled, and the physical properties of generated materials were
characterised to assess their suitability for parenteral delivery options. For GLE SDNs a
high-concentration injectable formulation was developed and optimised to minimise
injection site discomfort upon administration. For NCL SDNs a similar LAI formulation was
developed, alongside a formulation suitable for dispersion in an ionic medium for delivery
via a vibrating mesh nebuliser. In vitro testing of developmental formulations assessed their
suitability for future preclinical study. For LAI formulations, sustained release into an
aqueous medium was demonstrated. For the inhalable NCL formulation, the effects of
nebulisation on dispersion characteristics, and likely region of NCL deposition in the
respiratory system were assessed. In vivo assessment of long-acting release of GLE, PIB and
NCL from dispersed SDN was carried out after intramuscular administration using a rat
model.
“Bottom-up” SDN generation methodologies provided sufficient formulation flexibility to
generate SDNs with a range of variable characteristics, including particle size distribution,
crystallinity, and powder morphology, which might be tailored to a range of applications.
Use of an appropriate process solvent was a key parameter in generation of stable SDN
dispersions. It was also demonstrated to be pivotal in modifying SDN powder characteristics
including maximum syringability: the highest mass that can be withdrawn and discharged
through a suitability sized syringe and needle. Other SDN characteristics such as particle size
distribution were not found to be reliable predictors of maximum syringability. Throughout
the formulation generation and optimisation process, attempts were made to develop an
SDN formulation and development methodology that might be applied in the future to any
candidate API. However, it was repeatedly found that candidate formulations required
case-by-case consideration, to generate SDN materials with properties suitable for specific
applications.