Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements

Solymosi, Tamás; Ötvös, Zsolt; Angi, Réka; Ordasi, Betti; Jordán, Tamás; Semsey, Sándor; Molnár, László; Ránky, Soma; Filipcsei, Genovéva; Heltovics, Gábor; Glavinas, Hristos

doi:10.1016/j.ijpharm.2017.09.031

Cited by 27 publications

(13 citation statements)

References 16 publications

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“…The drug concentration of the generic abiraterone acetate tablets in FaSSIF media was 25.74 µg/mL on average, which is similar to the abiraterone acetate FaSSIF solubility value of 64.6 ± 5.2 µM (i.e.,~25.29 µg/mL) reported in the literature [2]. Interestingly, in another study, the FaSSIF solubility of abiraterone acetate from Zytiga was reported to be only 18 µg/mL [15]. We observed that the average solubility of abiraterone API in FaSSIF was 11.33 µg/mL, which conflicts with the value of 12.7 ± 4.2 µM (i.e.,~4.43 µg/mL) reported previously [2].…”

Section: Dissolution Of Binary Ksdscontrasting

confidence: 84%

“…Yonsa showed only a modest improvement, by doubling the bioavailability of abiraterone [14]. Other reported attempts to improve the bioavailability of abiraterone include the development of nanoamorphous formulations, lipid-based formulations, nanoparticles, and self-microemulsifying formulations [15][16][17][18][19][20]. Unfortunately, none of these attempts could yield the maximum therapeutic potential of abiraterone.…”

Section: Introductionmentioning

confidence: 99%

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Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

Gala

Miller²,

Williams

2020

Pharmaceutics

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Abiraterone is a poorly water-soluble drug. It has a high melting point and limited solubility in organic solvents, making it difficult to formulate as an amorphous solid dispersion (ASD) with conventional technologies. KinetiSol® is a high-energy, fusion-based, solvent-free technology that can produce ASDs. The aim of this study was to evaluate the application of KinetiSol to make abiraterone ASDs. We developed binary KinetiSol ASDs (KSDs) using both polymers and oligomers. For the first time, we reported that KinetiSol can process hydroxypropyl-β-cyclodextrin (HPBCD), a low molecular-weight oligomer. Upon X-ray diffractometry and modulated differential scanning calorimetry analysis, we found the KSDs to be amorphous. In vitro dissolution analysis revealed that maximum abiraterone dissolution enhancement was achieved using a HPBCD binary KSD. However, the KSD showed significant abiraterone precipitation in fasted state simulated intestinal fluid (FaSSIF) media. Hence, hypromellose acetate succinate (HPMCAS126G) was selected as an abiraterone precipitation inhibitor and an optimized ternary KSD was developed. A pharmacokinetic study revealed that HPBCD based binary and ternary KSDs enhanced abiraterone bioavailability by 12.4-fold and 13.8-fold, respectively, compared to a generic abiraterone acetate tablet. Thus, this study is the first to demonstrate the successful production of an abiraterone ASD that exhibited enhanced dissolution and bioavailability.

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Section: Dissolution Of Binary Ksdscontrasting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

Gala

Miller²,

Williams

2020

Pharmaceutics

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“…Finally, the low-fat food effect of abiraterone in the target population appears minimal at best and is close to moot as a novel formulation of abiraterone without significant food effect in clinical trials. 10 We can only hope that the new formulation of abiraterone will be priced more reasonably.…”

mentioning

confidence: 99%

Low-Fat Abiraterone Food Effect Is of Little Consequence

Kolesar

Liu

2018

JCO

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“…Administration of the crystalline drug in the form of nanoparticles allowed dose reduction to 500 mg (7,8). Solymosi et al reported a negligible food effect for a novel formulation based on continuous flow precipitation with Soluplus (9,10). Finally, we have shown in a recent study that amorphous solid dispersion (ASD) formulation based on precipitation inhibitor allowed 2.5-fold bioavailability enhancement in fasted rats (11).…”

Section: Electronic Supplementary Materialsmentioning

confidence: 85%

Bioavailability Enhancement and Food Effect Elimination of Abiraterone Acetate by Encapsulation in Surfactant-Enriched Oil Marbles

Boleslavská

Rychecký

Krov

et al. 2020

AAPS J

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Abiraterone acetate has limited bioavailability in the fasted state and exhibits a strong positive food effect. We present a novel formulation concept based on the so-called oil marbles (OMs) and show by in vitro and in vivo experiments that the food effect can be suppressed. OMs are spherical particles with a core-shell structure, formed by coating oilbased droplets that contain the dissolved drug by a layer of powder that prevents the cores from sticking and coalescence. OMs prepared in this work contained abiraterone acetate in the amorphous form and showed enhanced dissolution properties during in vitro experiments when compared with originally marketed formulation of abiraterone acetate (Zytiga ® ). Based on in vitro comparison of OMs containing different oil/surfactant combinations, the most promising formulation was chosen for in vivo studies. To ensure relevance, it was verified that the food effect previously reported for Zytiga ® in humans was translated into the rat animal model. The bioavailability of abiraterone acetate formulated in OMs in the fasted state was then found to be enhanced by a factor of 2.7 in terms of AUC and by a factor of 4.0 in terms of C max . Crucially, the food effect reported in the literature for other abiraterone acetate formulations was successfully eliminated and OMs showed comparable extent of bioavailability in a fed-fasted study. Oil marbles therefore seem to be a promising formulation concept not only for abiraterone acetate but potentially also for other poorly soluble drugs that reveal a positive food effect.

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Development of an abiraterone acetate formulation with improved oral bioavailability guided by absorption modeling based on in vitro dissolution and permeability measurements

Cited by 27 publications

References 16 publications

Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

Improved Dissolution and Pharmacokinetics of Abiraterone through KinetiSol® Enabled Amorphous Solid Dispersions

Low-Fat Abiraterone Food Effect Is of Little Consequence

Bioavailability Enhancement and Food Effect Elimination of Abiraterone Acetate by Encapsulation in Surfactant-Enriched Oil Marbles

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