(M0930-11-70) A Comparative Study of In Vitro Itraconazole Drug Release from Amorphous Solid Dispersions (ASDs): Sempera® and Tolsura® under Fed State Conditions

Purpose: Itraconazole (ITRA) is a Biopharmaceutics Classification System (BCS) class II weak base, with very poor solubility under small intestinal conditions, suggesting the need for solubility and dissolution enhancement to effect adequate oral bioavailability. Characterization of formulations of ITRA under biorelevant conditions is expected to contribute to the understanding of its absorption potential and hence bioavailability from different formulations. In this study, we compared the in vitro release and supersaturation of ITRA from two different commercially available formulations (Sempera® 100 mg and Tolsura® 65 mg) in a biorelevant dissolution set-up, reflecting fed state dissolution media.

Methods: Dissolution of the two ITRA formulations (n = 3) was tested in 500 mL FeSSIF-V2, FEDGAS mid and FEDGAS late and in 900 mL FEDGAS early media in USP Apparatus 2 at 75 rpm. All media were prepared according to the instructions provided by biorelevant.com [1]. The dissolution tests were carried out in accordance with the ICH M9 guideline [2] with the marketed capsule formulations (Sempera® 100 mg and Tolsura® 65 mg) after removing the content from the capsule shell to avoid shell-related artefacts. Samples were withdrawn at predefined time points and the sample volume was replaced with fresh medium. Samples were prefiltered (10 µm polyethylene filters), followed by filtration through 0.1 µm aluminum oxide filters (Sempera®) or 0.45 µm regenerated cellulose filters (Tolsura®) and dilution with mobile phase for analysis by HPLC-UV.

Results: Sempera® contains amorphous itraconazole spray-dried on sugar spheres with hypromellose serving as the fixing polymer, followed by polyethylene glycol as a sealing film, resulting in coated pellets that are then housed in a gelatin capsule. Since ITRA is dispersed in a pH-independent matrix, the pH-dependency of ITRA solubility is expected to be the main influence on the release behavior of the dispersion in this product. Indeed, dissolution in FEDGAS (Figure 1) showed pH-dependent release, with higher ITRA release at lower pH. More precisely, approximately 7% and 24% of the dose was released within 120 minutes in FEDGAS early (pH 6) and FEDGAS mid (pH 4.5), respectively. In FEDGAS late (pH 3), the release was even faster during the first 60 minutes, with maximum values of 22% released, but this was followed by precipitation. Tolsura® is manufactured with a novel, unique spray-drying technology (SUBA® process), delivering microencapsulated nanoparticles of amorphous ITRA dispersed in a retentive hypromellose phthalate matrix, which enables release at pH 5 or above [3]. The influence of the matrix was observed in the dissolution tests in FEDGAS, where about 45 % of the dose was released in FEDGAS early, whilst in FEDGAS mid and FEDGAS late a maximum of just 10% release was observed (Figure 1). In FeSSIF-V2, representing the small intestine after meal intake, Sempera® showed just 9% release of the dose (100 mg) within the first 30 min, followed by precipitation to an equilibrium concentration corresponding to approximately 1% released. By contrast, high release rates were observed, and complete dissolution of the dose (65 mg) was attained within 5 minutes when the Tolsura® product was tested. Rapid precipitation of ITRA commenced after 20 minutes resulting in 42% release at 40 minutes. Concentrations increased slightly to 48% release after 50 minutes, indicating partial redissolution. Thereafter, ITRA precipitated slowly to a value of 23% after 240 minutes (Figure 2). The precipitation observed in vitro may overestimate the in vivo precipitation due to the high intestinal permeability of ITRA.

Conclusion: Sempera® and Tolsura® release ITRA to different extents in fed state biorelevant media. The fed state dissolution results align well with clinical data for Tolsura® 65 mg capsules, where bioavailability of up to 90% was reported and shown to be nearly twice as high as for the Sempera® 100 mg formulation in the fed state [3]. The remarkably high initial intestinal release of the novel formulation Tolsura® may be especially important to the much higher bioavailability of ITRA from this formulation.

References: [1] Media preparation instructions by Biorelevant Ltd., QMB Innovation Centre, 42 New Road, London E1 2AX, United Kingdom
[2] European Medicines Agency, 2020. ICH M9 guideline on biopharmaceutics classification system-based biowaivers, EMA/CHMP/ICH/493213/2018.
[3] Official website of Tolsura itraconazole 65 mg, Mayne Pharma, 1240 Sugg Parkway, Greenville, NC 27834

Acknowledgements: This work was funded and kindly supported by the US Food and Drug Administration.

Figure 1: Mean release [%] of ITRA from (a) Sempera 100 mg pellets and (b) Tolsura 65 mg powder in FEDGAS with a paddle speed of 75 rpm.

Figure 2: Mean release [%] of ITRA from (a) Sempera 100 mg capsules (sinker) (black dots) or pellets (blue squared) and from (b) Tolsura 65 mg powder in FeSSIF-V2 with a paddle speed of 75 rpm.