Modelling critical parameters of the intramuscular injection site

Abstract

The intramuscular (IM) injection is a common parenteral procedure used for all manner of pharmaceuticals, form small molecule drugs to biopharmaceuticals, in rapid-release and long acting formats. IM administrations deposit material directly into densely vascularised skeletal muscle tissue. However, despite widespread use of IM-approved drugs in the clinic, there is a chronic lack of understanding regarding how drugs behave within the IM environment post injection (e.g., interactions with specific skeletal muscle structural elements, or aberrant precipitation of material). These can directly affect pharmacokinetic (PK) outcomes, e.g., the drug release rate, of an injectable. In vivo modelling regularly fails to accurately predict post injection events and PK outcomes. This is complicated by both inappropriate application of non-biorelevant in vitro tools, and the lack of biorelevant in vitro technologies specifically designed to study post-IM injection outcomes. Here, we describe the development of a novel, biorelevant in vitro tool, the Simulator of IntraMuscular Injections (SIMI).

A tractable hydrogel matrix was designed, based on the composition of skeletal muscle fascial layers, to act as an injection site for the SIMI. Human extracellular matrix elements were originally studied for the hydrogel design. However, these were replaced with bovine type-I collagen, and hyaluronic acid, after bioinformatic comparison of human and bovine-sourced extracellular matrix proteins. The hydrogels were studied in terms of viscoelastic rheology, amenability to bolus formation after injection of materials, and the potential for application of Raman spectroscopic technologies. To act as an infinite sink for material releasing from the hydrogel, we investigated IM interstitial fluid (ISF). Using published data and mathematics, we proposed the composition of an ISF-mimic buffer system for use in the SIMI.

We used the SIMI to examine the impact of individual drug, formulation, and injection site parameters on drug release from the hydrogel injection site into the infinite sink. Using green fluorescent protein as an investigative tool, we observed how drug charge, formulation excipient choices, and injection site composition resulted in individual, and combined, effects on drug release outcomes over a 24-hour period. These findings were corroborated by challenging the SIMI with a clinically approved, poorly water-soluble IM injectable (“drug X”) over a 7-day period. To model soluble protein of the ISF, addition of the bovine serum albumin (as a surrogate of human serum albumin) to the hydrogel and infinite sink environments increased the cumulative release of drug X from the SIMI hydrogel injection site over a 7-day period, indicating the impact of serum albumin on poorly water-soluble IM drug release in vivo.

Date of Award	26 Jul 2023
Original language	English
Awarding Institution	University of Bath
Supervisor	Randy Mrsny (Supervisor), Matthew Jones (Supervisor) & Paul De Bank (Supervisor)