Hot Melt Extrusion: Development of an Amorphous Solid Dispersion for an Insoluble Drug from Mini-scale to Clinical Scale
Journal Title: AAPS PharmSciTech - Year 2016, Vol 17, Issue 1
Abstract
The objective of the study was to develop an amorphous solid dispersion (ASD) for an insoluble compound X by hot melt extrusion (HME) process. The focus was to identify material-sparing approaches to develop bioavailable and stable ASD including scale up of HME process using minimal drug. Mixtures of compound X and polymers with and without surfactants or pH modifiers were evaluated by hot stage microscopy (HSM), polarized light microscopy (PLM), and modulated differential scanning calorimetry (mDSC), which enabled systematic selection of ASD components. Formulation blends of compound X with PVP K12 and PVP VA64 polymers were extruded through a 9-mm twin screw mini-extruder. Physical characterization of extrudates by PLM, XRPD, and mDSC indicated formation of single-phase ASD’s. Accelerated stability testing was performed that allowed rapid selection of stable ASD’s and suitable packaging configurations. Dissolution testing by a discriminating two-step non-sink dissolution method showed 70–80% drug release from prototype ASD’s, which was around twofold higher compared to crystalline tablet formulations. The in vivo pharmacokinetic study in dogs showed that bioavailability from ASD of compound X with PVP VA64 was four times higher compared to crystalline tablet formulations. The HME process was scaled up from lab scale to clinical scale using volumetric scale up approach and scale-independent-specific energy parameter. The present study demonstrated systematic development of ASD dosage form and scale up of HME process to clinical scale using minimal drug (∼500 g), which allowed successful clinical batch manufacture of enabled formulation within 7 months.
Authors and Affiliations
Anjali M. Agrawal, Mayur S. Dudhedia, Ewa Zimny
Keywords
Related Articles
- EP ID EP682148
- DOI 10.1208/s12249-015-0425-7
- Views 91
- Downloads 0
How Do You Use AAPS PharmSciTech?
This editorial was also published in the January 2015 AAPS Newsmagazine.
Advances in Metered Dose Inhaler Technology: Hardware Development
Pressurized metered dose inhalers (MDIs) were first introduced in the 1950s and they are currently widely prescribed as portable systems to treat pulmonary conditions. MDIs consist of a formulation containing dissolved o...
Spontaneous Emulsification of Nifedipine-Loaded Self-Nanoemulsifying Drug Delivery System
Self-nanoemulsifying drug delivery system (SNEDDS) can be used to improve dissolution of poorly water-soluble drugs. The objective of this study was to prepare SNEDDS by using ternary phase diagram and investigate their...
Tolerability of High-Volume Subcutaneous Injections of a Viscous Placebo Buffer: A Randomized, Crossover Study in Healthy Subjects
Monoclonal antibody biotherapeutics are often administered by subcutaneous (SC) injection. Due to dose requirements and formulation limitations, SC injections >1 mL are often required. We used a viscous p...
Injectable Supramolecular Hydrogel from Insulin-Loaded Triblock PCL-PEG-PCL Copolymer and γ-Cyclodextrin with Sustained-Release Property
Supramolecular hydrogels formed by cyclodextrins and polymers have been widely investigated as a biocompatible, biodegradable and controllable drug delivery system. In this study, a supramolecular hydrogel based on biode...