In vivo screening of subcutaneous tolerability for the development of novel excipients

To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be requ...

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Bibliographic Details
Published in:Journal of Toxicologic Pathology 2022, Vol.35(4), pp.355-360
Main Authors: Takai, Yuichi, Powlin, Stephanie, Awasaki, Yasuyuki, Yamauchi, Toshiaki, Sano, Tomoya, Takahashi, Haruyuki, Ranneh, Abdul-Hackam, Arai, Yuta
Format: Article
Language:English
Subjects:
Degeneration
Dosage
Evaluation
Excipients
Formulations
in vivo screening
Injection
Irritation
Lipids
Necrosis
novel excipient
Optimization
Pharmaceuticals
Physicochemical properties
Polymers
rat
Risk reduction
Safety
Screening
Technnical Report
ubcutaneous
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Summary:To develop safe subcutaneous formulations and minimize the risk of local irritation, it is essential to optimize the composition of active pharmaceutical ingredients and excipients. Depending on the physicochemical properties of the active pharmaceutical ingredient, additional excipients may be required to improve the stability and solubility of the active pharmaceutical ingredient. However, some of these excipients may not have been previously used in injectable drugs. Owing to the lack of safety data for such excipients, especially those used in subcutaneous dosing, it is important to evaluate their potential for local irritation during the early stages of formulation development. We evaluated the tolerability of 44 formulations with 24 candidate novel excipients, such as surfactants, polymers, and lipids, in a single subcutaneous dose in rats. Excipient formulations were administered as single bolus subcutaneous injections with an injection volume of 1 mL. The injection sites were observed for 2 days, and macroscopic and microscopic examinations were conducted. Local tolerability was evaluated on the basis of severity, incidence, and pathophysiology of each finding. Formulations that caused tissue degeneration or necrosis, which is indicative of tissue injury, were determined to be irritative and poorly tolerated. A single-dose subcutaneous screening study in rats was considered effective in ranking the safety of candidate excipients during the formulation optimization phase.
ISSN:0914-9198
1881-915X
1347-7404
DOI:10.1293/tox.2022-0035