Abstract
PurposeSubcutaneously or intramuscularly administered biodegradable microsphere formulations have been successfully exploited in the management of chronic conditions for over two decades, yet mechanistic understanding of the impact of formulation attributes on in vivo absorption rate from such systems is still in its infancy.MethodsSuspension formulation physicochemical attributes may impact particulate deposition in subcutaneous (s.c.) tissue. Hence, the utility of synchrotron X-ray micro-computed tomography (μCT) for assessment of spatial distribution of suspension formulation components (PLG microspheres and vehicle) was evaluated in a porcine s.c. tissue model. Optical imaging of dyed vehicle and subsequent microscopic assessment of microsphere deposition was performed in parallel to compare the two approaches.ResultsOur findings demonstrate that synchrotron μCT can be applied to the assessment of microsphere and vehicle distribution in s.c. tissue, and that microspheres can also be visualised in the absence of contrast agent using this approach. The technique was deemed superior to optical imaging of macrotomy for the characterisation of microsphere deposition owing to its non-invasive nature and relatively rapid data acquisition time.ConclusionsThe method outlined in this study provides a proof of concept feasibility for μCT application to determining the vehicle and suspended PLG microspheres fate following s.c. injection. A potential application for our findings is understanding the impact of injection, device and formulation variables on initial and temporal depot geometry in pre-clinical or ex-vivo models that can inform product design.Graphical abstract
Highlights
IntroductionSelf-administration of long acting formulations via subcutaneous (s.c.) or intramuscular (i.m.) injection is an attractive treatment paradigm in a range of chronic conditions (e.g. type 2 diabetes, schizophrenia, acromegaly), contributing to improved patient adherence and tolerability through reduction of peak-to-trough plasma concentration ratios
Self-administration of long acting formulations via subcutaneous (s.c.) or intramuscular (i.m.) injection is an attractive treatment paradigm in a range of chronic conditions, contributing to improved patient adherence and tolerability through reduction of peak-to-trough plasma concentration ratios
The technique was deemed superior to optical imaging of macrotomy for the characterisation of microsphere deposition owing to its non-invasive nature and relatively rapid data acquisition time
Summary
Self-administration of long acting formulations via subcutaneous (s.c.) or intramuscular (i.m.) injection is an attractive treatment paradigm in a range of chronic conditions (e.g. type 2 diabetes, schizophrenia, acromegaly), contributing to improved patient adherence and tolerability through reduction of peak-to-trough plasma concentration ratios. Encapsulation of active pharmaceutical ingredients (APIs) within biodegradable polylactide-co-glycolide (PLG) microspheres has been exploited commercially as a drug delivery platform providing sustained release of therapeutic agents following subcutaneous or intramuscular injection. Factors governing the rate of appearance of API within the systemic circulation following subcutaneous injection of solutions have been extensively reviewed elsewhere [5,6,7,8]. The extent of spread and resultant interfacial surface area of the injected depot impacts i) the diffusional path length for the API ii) the interstitial pressure which influences convectional flow rate and iii) interaction with metabolic and immune processes within the subcutaneous tissue. Injection force, volume, viscosity, osmolality and interfacial tension have been cited as factors with the potential to affect rate (and extent) of API absorption [9]
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