(T1330-04-25) The Impact of Surface Area per Volume Ratio on Drug Transport from Supersaturated Solutions of Ketoconazole

Purpose: Supersaturating drug delivery systems (SDDSs) have been developed to improve water solubility and low systemic exposure of poorly water-soluble drugs over the past decades [1]. Because supersaturation is a thermodynamically unstable state and leads to rapid drug precipitation when the dissolved concentration reaches the critical nucleation concentration, polymers such as hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, and hydroxypropyl methylcellulose acetate succinate have been used to maintain the supersaturation, which is known as the parachute effect [2]. The parachute effect plays a key role in enhancing drug dissolution. However, the impact of the parachute effect on improving drug absorption would strongly depend on two factors: drug permeability and the surface area per volume ratio (SA/V). When either drug permeability or SA/V is high, the contribution of the parachute effect would be small. In this study, vertical Franz diffusion cells (SA/V: 1.7 and 17 cm^-1) and rats were selected as in vitro and in vivo experimental models, respectively, to investigate the impact of the SA/V ratio on drug transport. In vitro dissolution, permeation, and in vivo absorption profiles from the supersaturated solutions (SSs) with or without HPMC were observed.

Methods: Ketoconazole (KTZ) was used as a model drug. The SS was prepared by the solvent-shift method. The stock solution for KTZ was prepared in DMSO at 37 mg/mL. Then, 0.1 mL of stock solution was diluted with 9.9 mL of fasted-state simulated intestinal fluid (FaSSIF, pH 6.5) in the absence and presence of 0.5w/v% HPMC. The final DMSO concentration was set at 1v/v%. The dissolved concentration of KTZ was observed through 2 h. The area under the dissolved concentration-time curve (AUC_dissolved) was calculated using the trapezoidal method. To observe the difference in the SA/V ratio on drug transport across the membrane for the SSs, 0.1 mL or 1 mL of each SS after preparation was immediately applied to the donor side of the Franz diffusion cell (SA = 1.7 cm²). Samples were collected from the receiver side filled with 4.5% BSA-HBSSg. Furthermore, 1 mL of SS with or without HPMC was intra-intestinally administered to the anesthetized rat, and the area under the plasma concentration-time curve (AUC_plasma), T_max, and C_max were calculated.

Results: For the SS without HPMC, KTZ concentration remained at approximately 300 μg/mL, with 80% dissolved, for 5 min and decreased between 5 and 30 min. This two-step precipitation process was also observed in our previous reports and would be attributed to the formation of LLPS [3,4]. For the SS with HPMC, KTZ concentration, with 80% dissolved, was maintained for more than 30 min, resulting in a 4.03-fold higher AUC_dissolved than the SS without HPMC. When the SA/V ratio was 1.7 cm^-1, the ratio of the permeated amount at 2 h (SS with HPMC/SS without HPMC) was 3.24, indicating that the HPMC-mediated parachute effect enhanced membrane permeation in vitro. In contrast, when the SA/V ratio increased to 17 cm^-1, the ratio of the permeated amount at 2 h decreased from 3.24 to 1.83, resulting in no significant difference between the two SSs. In vivo, all PK parameters (T_max, C_max, AUC_plasma) were also not statistically different between the two SSs. The HPMC-mediated parachute effect on enhancing drug transport disappeared with a high SA/V ratio in vivo. This result was consistent with the ratio of permeated at a SA/V ratio of 17 cm^-1 in vitro. In addition, the current data from the in vivo study showed that the dissolved drug was rapidly absorbed before precipitation regardless of the presence of HPMC. This indicates that a much longer duration of supersaturation would not be necessary to enhance in vivo absorption for highly permeable drugs. After all, the HPMC-mediated parachute effect (the ratio of SS with HPMC to SS without HPMC) gradually became small as the SA/V ratio increased through in vitro and in vivo studies. The performance of supersaturating formulations would be overestimated by in vitro studies with small SA/V ratios.

Conclusion: The addition of HPMC significantly prolonged the in vitro duration of the supersaturation of ketoconazole. However, the effect of HPMC on drug transport decreased as the SA/V ratio increased through in vitro and in vivo experiments. The absorption rate profiles revealed that ketoconazole was rapidly absorbed before precipitation irrespective of the absence/presence of HPMC. These findings indicate that the performance of SDDSs is greatly affected by the SA/V ratio and will help in the design of promising SDDSs.

References: [1] J Pharm Sci. 98 (2009) 2549-2572.
[2] Pharmaceutics. 10 (2018) 164.
[3] J Pharm Sci. 108 (2019) 2580-2587.
[4] Mol Pharm. 11 (2014) 746-754.