New In Vitro Methods to Understand and Mitigate Clinical Variability Associated with Injectable Suspensions

Injectable Suspensions for Improving Patient Compliance

The majority of FDA-approved injectable suspensions offer sustained drug release characteristics, which enhance drug product convenience (i.e., reduced dosing frequency) and therapeutic effectiveness (i.e., controlled drug release and reduced side effects). For example, a single injection of triamcinolone acetonide suspension can extend the therapeutic benefit for patients from hours to days or weeks. In addition, injectable suspensions are also very helpful for effective long-term management of chronic diseases, such as the 1- and 3-month paliperidone palmitate injections for maintenance treatment of schizophrenia. However, the prolonged duration of drug release, coupled with the relatively high amount of drug contained in one dose of an injectable suspension, may under some conditions entail higher risk, relative to an immediate release injectable. It is thus important to fully understand the formulation design and quality of injectable suspensions.

Formulation Design and Challenges With In Vitro or In Vivo Methods

Suspensions of crystalline drug particles, in the nanometer to micron size range, are often used for sustained-release injectable formulation, especially in the case of poorly water-soluble drug substances. The release and subsequent in vivo absorption of the drug is thereby dictated predominantly by particle size and size distribution as well as particle dissolution rate. Therefore, understanding the size and related dissolution behavior of the relevant particles is paramount to assess the product’s therapeutic performance. Both in vitro and in vivo methods have been used to understand dissolution characteristics of injectable suspension products. In general, in vitro methods are readily performed in the laboratory, can provide high reproducibility and sensitivity, and are relatively cost- and time-effective; however, clinical investigations are crucial for assessment of physiologically relevant characteristics and meaningful predictability of treatment outcomes.

To address information gaps between in vitro and clinical data, CDER researchers have investigated triamcinolone acetonide injectable suspensions as a model to develop improved methodologies to assess injectable suspension performance.1 Triamcinolone acetonide injectable suspensions exhibit significant clinical variability; for example, measurements of time to maximum concentration in vivo (Tmax) can vary from 1 to 216 hours.2-4 It is important to note that such high variability is not observed for other triamcinolone acetonide dosage forms (intravenous, intranasal, oral, topical);5 rather, the high clinical variability appears to be related to the flocculation state of the suspension particles.

Suspensions are often designed to flocculate, or form weakly bound agglomerates, to increase product stability. Flocculation is a complex phenomenon, governed by particle-particle interactions, and is reversible, so that the shaking of a vial (e.g., per labeling instructions to “shake before use”) can readily cause loose aggregates (i.e., “secondary” particles) to transition into smaller “primary” particles. In the case of triamcinolone acetonide injectable suspensions, flocculation can be rapidly reversed, with the breakup of flocculates (tens of microns) into primary particles (1 to 2 microns) occurring through the application of shear stress.1 CDER researchers have further determined that commonly encountered shear stress, which occurs upon stirring, pumping, sonication, or even needle injection, can affect the state of flocculation and likely also the rate of drug dissolution.

Development of New Methods to Measure Drug Dissolution

CDER researchers developed new methods to understand the impact of flocculation state on drug dissolution. Commonly used in vitro dissolution testing methods for suspension products are generally performed at high dilution (i.e., sink conditions) in high-shear environments (e.g., fast stirring); however, high dilution and high shear may not reflect dissolution conditions associated with intramuscular injection. In fact, intramuscular injection results in highly non-sink (i.e., concentrated) conditions for dissolution to occur, as perfusion of body fluid at the site of injection is very limited. Accordingly, CDER researchers developed an in vitro dissolution method that minimizes shear while maintaining suspension particles in a non-sink condition that more closely approximates the clinically relevant scenario.

CDER scientists tested the hypothesis that the high variability of dissolution observed for suspension injectable formulations (but not for other formulations) may be related to the flocculation state. As shown in Figure 2, syringe-induced shear during the introduction of suspensions greatly affected drug dissolution. Furthermore, the non-sink dissolution method was utilized in a novel testing setup that combined in-situ fiber optic (IFO) ultraviolet-visible (UV-Vis) spectroscopy with laser diffraction (LD) to simultaneously monitor particle dissolution as well as particle size distribution, thereby offering insight into dissolution mechanisms (Figure 1). Specifically, the IFO UV-Vis-LD method provided evidence that the flocculated and deflocculated particles followed different dissolution pathways.

Results and Understanding of Dissolution Characteristics

These recent investigations by CDER demonstrate that appropriately designed in vitro experiments can provide insight into product performance under clinically relevant conditions. The researchers found that there is a strong correlation between flocculation/deflocculation behavior and particle size distribution on the one hand and drug dissolution rate on the other, and this correlation has important ramifications for understanding the physical stability of suspensions as well as possible variations in clinical outcomes. Moreover, variations in the administration method or the injection procedure (e.g., the speed of injection and the size of needle) for triamcinolone acetonide injectable suspensions can affect the flocculation state of drug particles and subsequently the rate of drug dissolution (Figure 2). Therefore, appropriate control over the administration procedure (and thus over shear stress) of triamcinolone acetonide injectable suspensions may be critical for mitigating clinical variability in outcomes.

References

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[5] Derendorf H, Hochhaus G, Rohatagi S, Möllmann H, Barth J, Sourgens H, Erdmann M. Pharmacokinetics of triamcinolone acetonide after intravenous, oral, and inhaled administration. J Clin Pharmacol. 1995 Mar;35(3):302-5. doi: 10.1002/j.1552-4604.1995.tb04064.x. PMID: 7608322.