Comparison of the Local Tolerability to 5 Long-acting Drug Nanosuspensions with Different Stabilizing Excipients, Following a Single Intramuscular Administration in the Rat

Abstract

To investigate the effects of common nanosuspension-stabilizing excipients on the nature and temporal evolution of histopathological changes at intramuscular (i.m.) administration sites, 5 groups of 39 male rats per group received a single injection of 1 of the 5 analogous crystalline drug nanosuspensions containing 200 mg/ml of an antiviral compound with particle sizes of ±200 nm and identical vehicle compositions, except for the type of nanosuspension stabilizer. The investigated stabilizers were poloxamer 338, poloxamer 407, d-α-tocopherol polyethylene glycol 1,000-succinate (TPGS), polysorbate 80, and polysorbate 80 combined with egg phosphatidylglycerol. Histopathology and immunohistochemistry revealed progressive inflammatory changes at the i.m. administration sites and the draining lymph nodes that differed according to the time point of sacrifice and the type of stabilizer. Although the overall time course of inflammatory changes was similar across the groups, differences in the nature, severity, and timing of the inflammatory response were observed between animals injected with poloxamer- or TPGS-containing nanosuspensions and those injected with formulations containing polysorbate 80. A more severe and prolonged active inflammatory phase, the presence of multinucleate giant cells, prolonged macrophage infiltration of the formulation depot, and more persistent histiocytic infiltrates in the lymph nodes were observed in the polysorbate 80-containing nanosuspension groups. Such vehicle-mediated effects could influence the overall tolerability profile of long-acting nanosuspensions.

Impact of Excipients and Seeding on the Solid-State Form Transformation of Indomethacin during Liquid Antisolvent Precipitation

“…More recently, the popularity of LAIs consisting of aqueous suspensions of solid drug particles, where the low solubility and slow dissolution rate of the solid itself control the rate of release, has re-emerged. , Crystalline aqueous solid drug suspensions are a well-established drug delivery platform, with several drug products already approved for marketing and even more under development for different therapeutic areas. In these formulations, a particle size distribution between 5 and 10 μm is usually applied . Although research in this field has increased in recent years, methods to manipulate the particle size (micro-/nanoparticles) and morphology require further development, as these are critical product quality attributes for the systems.…”

Design of Montelukast Nanocrystalline Suspension for Parenteral Prolonged Delivery

“…21,24 Moreover, the local inflammatory reaction at the injection site, including macrophage infiltration, phagocytosis of the injected dose, fibrosis, and angiogenesis, affects drug dissolution patterns at the injection site, modulating the pharmacokinetic profile following the drug suspension's SC injection. 25,26 In the drug suspension-based LA system design, the crystalline state of the drug particles is one of the factors dictating the crystalline suspension's physicochemical stability and pharmacokinetic behavior. The amorphous or thermodynamically unstable forms provide supersaturated solubility profile, showing faster release rates than the stable crystalline form.…”

“… 21 , 24 Moreover, the local inflammatory reaction at the injection site, including macrophage infiltration, phagocytosis of the injected dose, fibrosis, and angiogenesis, affects drug dissolution patterns at the injection site, modulating the pharmacokinetic profile following the drug suspension’s SC injection. 25 , 26 …”

Interpreting In Vitro Release Performance from Long-Acting Parenteral Nanosuspensions Using USP-4 Dissolution and Spectroscopic Techniques

“…1,2 These long-acting parenteral (LAP) products are highly desirable for patients that need life-long therapies and strict dosing regiments; however, the formulation of a variety of dosage forms (multiparticulate, in situ gel-forming depot, and implantable formulations) has proven to be laborious. Insufficient understanding of interactions in multimolecular systems 3,4 has generated particle stability issues, especially in products with high-drug loading for sustained release applications.…”

“…Enabling formulations for this space has dominated early development projects, with a heavy focus on depot-forming injections that can extend therapeutic drug concentrations over a long treatment period and reduce administration frequency. , These long-acting parenteral (LAP) products are highly desirable for patients that need life-long therapies and strict dosing regiments; however, the formulation of a variety of dosage forms (multiparticulate, in situ gel-forming depot, and implantable formulations) has proven to be laborious. Insufficient understanding of interactions in multimolecular systems , has generated particle stability issues, especially in products with high-drug loading for sustained release applications.…”