Pharmaceutical development of an amorphous solid dispersion formulation of elacridar hydrochloride for proof-of-concept clinical studies. (3rd April 2017)

• Record Type: Journal Article
• Authors: Sawicki, E.; Schellens, J. H. M.; Beijnen, J. H.; Nuijen, B.
• Is Part Of: Drug development and industrial pharmacy. Volume 43:Number 4(2017)
• Page Start: 584
• Page End: 594
• Publication Date: 2017-04-03
• Subjects: Elacridar -- GF120918 -- GG918 -- solid dispersion -- dissolution -- spray drying -- freeze drying -- P-gp -- absorption -- brain penetration; Pharmaceutical chemistry -- Periodicals; Pharmaceutical industry -- Periodicals; Drug Industry -- Periodicals; Technology, Pharmaceutical -- Periodicals; 615.05
• DOI: 10.1080/03639045.2016.1274901
• Languages: English
• ISSNs: 0363-9045

Abstract

Abstract: Objective: A novel tablet formulation containing an amorphous solid dispersion (ASD) of elacridar hydrochloride was developed with the purpose to resolve the drug's low solubility in water and to conduct proof-of-concept clinical studies. Significance: Elacridar is highly demanded for proof-of-concept clinical trials that study the drug's suitability to boost brain penetration and bioavailability of numerous anticancer agents. Previously, clinical trials with elacridar were performed with a tablet containing elacridar hydrochloride. However, this tablet formulation resulted in poor and unpredictable absorption which was caused by the low aqueous solubility of elacridar hydrochloride. Methods: Twenty four different ASDs were produced and dissolution was compared to crystalline elacridar hydrochloride and a crystalline physical mixture. The formulation with highest dissolution was characterized for amorphicity. Subsequently, a tablet was developed and monitored for chemical/physical stability for 12 months at +15–25 °C, +2–8 °C and −20 °C. Results: The ASD powder was composed of freeze dried elacridar hydrochloride–povidone K30–sodium dodecyl sulfate (1:6:1, w/w/w), appeared fully amorphous and resulted in complete dissolution whereas crystalline elacridar hydrochloride resulted in only 1% dissolution. The ASD tablets contained 25 mg elacridar hydrochloride and were stable for at least 12 months at –20 °C. Conclusions: The ASD tablet was considered feasible for proof-of-concept clinical studies and is now used as such.