A Novel Protocol Using Small-Scale Spray-Drying for the Efficient Screening of Solid Dispersions in Early Drug Development and Formulation, as a Straight Pathway from Screening to Manufacturing Stages.

Aymeric Ousset,Kalliopi Dodou,Pascal Somville,Florent Robin,Rosanna Chirico,Martin Schubert

doi:10.3390/ph11030081

Aymeric Ousset, Kalliopi Dodou + Show 4 more

Open Access

https://doi.org/10.3390/ph11030081

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Journal: Pharmaceuticals	Publication Date: Aug 27, 2018
Citations: 1	License type: CC BY 4.0

Affiliation: University of Sunderland, UCB Pharma (Belgium)

Abstract

This work describes a novel screening strategy that implements small-scale spray-drying in early development of binary amorphous solid dispersions (ASDs). The proposed methodology consists of a three-stage decision protocol in which small batches (20–100 mg) of spray-dried solid dispersions (SDSDs) are evaluated in terms of drug–polymer miscibility, physical stability and dissolution performance in bio-predictive conditions. The objectives are to select the adequate carrier and drug-loading (DL) for the manufacturing of robust SDSD; and the appropriate stabilizer dissolved in the liquid vehicle of SDSD suspensions, which constitutes the common dosage form used during non-clinical studies. This methodology was verified with CDP146, a poorly water soluble (<2 µg/mL) API combined with four enteric polymers and four stabilizers. CDP146/HPMCAS-LF 40:60 (w/w) and 10% (w/v) PVPVA were identified as the lead SDSD and the best performing stabilizer, respectively. Lead SDSD suspensions (1–50 mg/mL) were found to preserve complete amorphous state during 8 h and maintain supersaturation in simulated rat intestinal fluids during the absorption window. Therefore, the implementation of spray-drying as a small-scale screening approach allowed maximizing screening effectiveness with respect to very limited API amounts (735 mg) and time resources (9 days), while removing transfer steps between screening and manufacturing phases.

Highlights

Non-clinical testing is a mandatory step of drug development that aims to evaluate the pharmacodynamics, pharmacokinetics and toxicity profiles of new chemical entities (NCEs) so that safe initial dose level can be identified for the first human exposure [1]
The present paper describes a new step-wise strategy for the (i) the screening of binary spray-dried solid dispersions (SDSDs) in early drug and formulation, and (ii) the development of SDSD dosed as non-clinical suspension formulation for oral administration
The proposed screening approach implements for the first time spray-drying in a methodical small-scale approach for the development of amorphous solid dispersions (ASDs) during preclinical activities

Summary

Introduction

Non-clinical testing is a mandatory step of drug development that aims to evaluate the pharmacodynamics, pharmacokinetics and toxicity profiles of new chemical entities (NCEs) so that safe initial dose level can be identified for the first human exposure [1]. Suspension formulations consist of the dispersion of drug solid particles throughout an aqueous medium containing additional excipients, typically emulsifying, suspending or ionizing agents as well as surfactants and solvents [4] This standard non-clinical formulation is generally administrated to animals via oral gavage. As the number of NCEs with poorly water soluble properties is continuously increasing during drug discovery phase, the conduction of non-clinical studies becomes challenging [3,6] In this regard, the use of amorphous solid dispersions (ASD) has become a common strategy to tackle low solubility and improve absorption of the active pharmaceutical ingredient (API) in early drug development and formulation [7]. The key expectations regarding the development of a solid dispersion are the successful manufacturing of the amorphous form of the drug, its stability during the shelf life of the product and its capacity to maintain supersaturation during dissolution test [11]

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