Category: Formulation and Quality
Purpose: Lipid-based formulations (LBFs) and amorphous solid dispersions, such as spray dried dispersions (SDD), are commonly used formulation platforms to enhance oral absorption. Drugs with solvation-limited absorption (i.e., “grease balls”) are considered good LBF candidates while drugs with solid-state limited absorption (i.e., “brick dust”) are considered as good SDD candidates. There are however limited published studies directly comparing drug absorption from LBFs or SDDs. Here, we compare head-to-head the oral absorption of abiraterone acetate (ABA) when formulated as a SDD or LBF, and evaluate the respective ability to deliver a Target Product Profile that addresses current challenges related to ABA products; (i) a 4-fold reduction in ABA dose from 1 g to 250 mg via improved absorption from the fasted state, (ii) eliminated food-effect and (iii) no increase in pill burden.
Methods: SDD formulations containing ABA and HPMCAS-L in a 1:3 weight ratio were prepared using a Lonza spray dryer. The SDD polymer was selected based on in vitro performance tests to identify formulations that offered greatest ABA solubilization and sustained supersaturation. Immediate-release SDD tablets were made at 125 mg dose strengths and generated using an F-Press. LBFs containing ABA dissolved in a blend of oil, cosurfactant and surfactant were designed and developed following a solubility screen and in vitro dispersion and digestion performance tests (1, 2). The ABA loading in the LBF was either 10% w/w or 6% w/w for T6 and T12 lead concepts, respectively, and LBFs were filled into size 00el hard gelatin capsules (Licaps®). In vivo studies were conducted in six male beagle dogs (8–12 kg). In dog study #1 (a sequential study), dogs received 250 mg ABA via either 1 x Zytiga® tablet, 2 x SDD tablets or 3 x LBF liquid-filled hard capsules (T6). All treatments were dosed in the fasted state, while the Zytiga® treatment was also dosed in fed dogs. In dog study #2 (a parallel study), dogs received 1 x Zytiga® 250 mg tablet and 1 x LBF 50 mg liquid-filled hard capsule (T12) in the fasted and fed state. Plasma ABA concentrations were measured using LC-MS.
Results: Dog study #1 (see Fig 1): ABA exposure (AUC0-24h) from Zytiga® in the fasted state was 475 ± 518 h·ng/ml while the coefficient of variability (CV) was 64%. Dosing Zytiga® in the fed state gave a 14-fold increase in exposure (6780 ± 1479 h·ng/ml) and reduced variability (CV = 22%). The SDD tablet gave a 2.3-fold increase in fasted state exposure (1104 ± 778 h·ng/ml) while the LBF (T6) capsule gave a 9.6-fold increase in exposure (4302 ± 2738 h·ng/ml). Variability in exposure was unchanged.
Low Dose LBF Formulation Optimization: ABA loading in the LBF was decreased from 10% to 6% w/w based on the significant improvement in ABA fasted state absorption observed in dog study 1 using the LBF capsule (vs. Zytiga®), which in turn unlocked a greater number of excipient options. An LBF formulation optimization study based on stressed digestion testing subsequently returned a new lead formulation (T12).
Dog Study #2 (see Fig 2): Exposure from the 50 mg LBF (T12) capsule in the fasted and fed state were similar (806 ± 199 and 757 ± 184 h·ng/ml, respectively) while variability was also low (CV = 28%). The fasted state exposure was also slightly greater than that of Zytiga® at 5 times the dose (652 ± 661 h·ng/ml).
Conclusion: In vivo results have once more confirmed that LBFs can out-perform SDDs when matched with the right API, specifically grease ball-type molecules such as abiraterone acetate. Furthermore, an optimized LBF (T12) exceeded the Target Product Profile, achieving (i) a 5-fold reduction in dose, (ii) eliminated food-effect and (iii) no increase in pill burden. Studies in humans are now needed to confirm these promising in vivo results.