Craig McKelvey

Multifunctional protein-encapsulated polycaprolactone scaffolds: Fabrication and in vitro assessment for tissue engineering

Here we demonstrate the use of a twin screw extrusion/spiral winding (TSESW) process to generate protein-encapsulated tissue engineering scaffolds. Bovine serum albumin (BSA) was distributed into PCL matrix using both wet and hot melt extrusion methods. The encapsulation efficiency and the time-dependent release rate, as well as the tertiary structure of BSA (via circular dichroism), were investigated as a function of processing method and conditions. Within the relatively narrow processing window of this demonstration study it was determined that the wet extrusion method gave rise to greater stability of the BSA on the basis of circular dichroism data. The rate of proliferation of human fetal osteoblast (hFOB) cells and the rate of mineral deposition were found to be greater for wet extruded scaffolds, presumably due to the important differences in surface topographies (smoother scaffold surfaces upon wet extrusion). Overall, these findings suggest that the twin screw extrusion/spiral winding (TSESW) process offers significant advantages and flexibility in generating a wide variety of non-cytotoxic tissue engineering scaffolds with controllable distributions of porosity, physical and chemical properties and protein concentrations that can be tailored for the specific requirements of each tissue engineering application.

Development of amorphous solid dispersion formulations of a poorly water-soluble drug, MK-0364.

The goal of this study was to demonstrate that MK-0364 solid dispersions can be developed as a means to increase the solubility and bioavailability of a poorly water-soluble drug, MK-0364. The potential solid dispersions would enable an oral solid dosage form as a monotherapy or combination product of MK-0364. Preliminary screening included sample preparation via a solvent casting method, physical characterization, and in vitro dissolution testing. Lead formulations were subsequently manufactured using hot melt extrusion (HME) and spray-drying (SD). All HME (without polyvinyl pyrrolidone) and SD formulations exhibit characteristics of a single phase glass including an amorphous halo when analyzed with X-ray powder diffraction (XRPD), a single glass transition temperature (Tg) measured with differential scanning calorimetry (DSC), and supersaturation when dissolved in dissolution media. The oral absorption of MK-0364 from selected HME and SD formulations in monkeys results in marginally greater exposure with a consistently longer Tmax relative to a liquid filled capsule reference. Based on the processability, physical characterization, in vitro dissolution, and animal pharmacokinetic results, copovidone- and hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based solid dispersion formulations are viable product concepts. The physical stability of both the solid dispersion formulations was also evaluated for 54 weeks under different conditions. The copovidone-based solid dispersion requires protection from moisture.

Size Selectivity of Intestinal Mucus to Diffusing Particulates is Dependent on Surface Chemistry and Exposure to Lipids

Abstract Intestinal mucus provides a significant barrier to transport of orally delivered drug carriers, as well as other particulates (e.g. food, microbes). The relative significance of particle size, surface chemistry, and dosing medium to mucus barrier properties is not well characterized, but important in designing delivery systems targeted to the intestinal mucosa. In this study, multiple particle tracking (MPT) was used to study diffusion of 20–500 nm diameter carboxylate- and polyethylene glycol-(PEG-)functionalized polystyrene model carriers through intestinal mucus. The impact of exposure to mucus in buffer versus a partially digested triglyceride mixture was explored. Effective diffusivity of particles in intestinal mucus decreased with an increasing particle size less than and more than theoretically (Stokes–Einstein) expected in a homogenous medium when dosed in buffer and model-fed state intestinal contents, respectively. For example, effective diffusivity decreased 2.9- versus 20-fold with increase in the particle size from 100 to 500 nm when dosed to mucus in buffer versus lipid-containing medium. Functionalization with PEG dramatically decreased sensitivity to lipids in a dosing medium. The results indicate that reduction of particle size may increase particle transport through intestinal mucus barriers, but these effects are strongly dependent on intestinal contents and particle surface chemistry.

Hot-Melt Extrusion for Solid Dispersions: Composition and Design Considerations

Melt extrusion is a robust and efficient manufacturing platform that can be utilized for the production of amorphous dispersions. The development of these systems requires careful design of both formulation and process under a structured approach to ensure critical quality attributes are achieved and maintained. This chapter discusses specific aspects for selecting the manufacturing platform, developing and characterizing dispersions that are applicable to the compositional definition.

HME for Solid Dispersions: Scale-Up and Late-Stage Development

The advantages provided by melt extrusion over other amorphous dispersion manufacturing technologies make it uniquely suited for commercial applications. The proven scalability of the technology combined with the modular nature provides unmatched versatility. Extrusion has been utilized for dispersion manufacturing of commercial products across a range of scales and integrating with in-line monitoring technologies, it fully enables the benefits of continuous manufacturing. Novel applications, such as devolatilization and development using quality by design, allow for the technology to support both drug substance and drug product manufacturing.

Hot-Melt Extrusion: The Process-Product-Performance Interplay

Hot-melt extrusion is commonly used to manufacture amorphous solid dispersions. This chapter focuses on the process-formulation-performance interplay of a hot-melt-extruded product within the framework of a hypothetical phase diagram. Special attention is paid to the liquidous curve and melt mixing, the mixed-phase glass transition temperature, and hypothetical lower and upper critical solution temperatures. With a complete understanding of the liquidous curve, rheological properties, and the thermal liabilities, a workable processing temperature range for hot-melt extrusion can be defined. Strategies and processing solutions are given to minimize or avoid thermal degradation. Finally, the heat, mass, and momentum balances are outlined and can be leveraged to model the extrusion process when appropriate material properties are understood. The fundamental concepts provided herein will facilitate successful manufacture and scale-up of the extrusion process.