Development of an extemporaneous preparation formulation using a simple and non-solubilizing matrix for first in human clinical study.

Autor: Chiang CW; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Tang S; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Boonstra JM; Early Clinical & Bioanalytical Services (Manufacturing Division), ICON plc. (formerly known as PRA Health Sciences), Van Swietenlaan 6, 9728 NZ Groningen, the Netherlands., van Tilburg LP; Early Clinical & Bioanalytical Services (Quality & Control Division), ICON plc. (formerly known as PRA Health Sciences), Amerikaweg 18, 9407 TK Assen, the Netherlands., Liu J; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Chiang PC; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Rich S; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Wu N; Small Molecule Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Nguyen HQ; Small Molecule Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Zhang W; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: zhang.wei@gene.com., Hou HH; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA., Leung DH; Small Molecule Pharmaceutical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Jazyk: angličtina
Zdroj: International journal of pharmaceutics [Int J Pharm] 2024 Mar 25; Vol. 653, pp. 123868. Date of Electronic Publication: 2024 Feb 02.
DOI: 10.1016/j.ijpharm.2024.123868
Abstrakt: Extemporaneous preparation (EP) formulation is an attractive strategy to accelerate the formulation development of new chemical entities for first entry into human study. In this work, an EP suspension formulation for a development drug candidate GDC-6599 was successfully developed. The formulation spanned a wide concentration range from 0.1 to 2.0 mg/mL. A non-solubilizing vehicle, 0.6 % (w/v) methylcellulose solution was used to suspend GDC-6599. An aversive agent denatonium benzoate at an extremely low level (6 ppm) was applied as a taste masking agent. This enabled a simple matrix for the analysis of related substances from GDC-6599 during all stability studies. Microcrystalline cellulose at 10 mg/mL concentration was added to the EP formulation to generate a suspension appearance, leading to the success of using a single placebo for matching active formulation at all concentrations. The developed formulation demonstrated excellent homogeneity, sufficient stability and passed microbiological enumeration test. Rinsing performance test demonstrated that greater than 99.8 % amount of drug was successfully recovered by rinsing with water twice, providing guidance for clinical dosing. Biopharmaceutical assessment was conducted by both in silico simulation and in vitro tests. Greater than 90 % bioaccessibility of the EP suspension formulation was obtained via an in vitro system mimicking the human gastrointestinal absorption, consistent with the result from the in silico modeling. The developed EP formulation was successfully used to support the early single ascending dose (SAD) cohorts of GDC-6599 Phase I clinical study. The formulation matrix and assessment workflow developed in this work are generalizable as a platform for EP formulation development of new chemical entities for early phase clinical studies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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