Michael Lowinger

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.

Practical Considerations for Spray Dried Formulation and Process Development

Amorphous solid dispersion formulations provide a way to improve the bioperformance of poorly water soluble compounds by converting the crystalline drug to a high energy polymer stabilized amorphous state. Spray drying is a mature process with demonstrated production capability from lab to commercial scale for manufacturing amorphous solid dispersions. However, the impact of the drying process on the performance, manufacture, and stability of the drug product is often complex and can impact the chemical and physical stability of the drug, as well as the in vivo performance of the drug product. Physical and chemical properties of the components in the spray dried formulation can be linked to process risks. Analytical technology can build the connection between the process and the components of the formulation by measuring both the process dependent parameters and the product itself. Models can also be used to obtain a fundamental understanding of the system and be predictive of changes across process spaces. The properties of spray dried powder are amenable to multiple drug delivery routes such as oral suspensions and solid oral dosage forms. However, the process and environmental stresses put on the spray dried amorphous solid dispersions bring forth specific technical challenges. This chapter seeks to review the opportunities and failure modes associated with the spray drying process and the downstream fate of amorphous solid dispersions in several drug delivery routes while linking failure modes to the physical and chemical properties of the drug and formulation.

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.

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

Bile salts are endogenous surfactants present in the human gastrointestinal tract in the form of mixed micelles that also contain phospholipids. Due to the inevitable encounter of oral drug formulations with bile salts, it is important to understand the impact of bile salts on the crystallization tendency of poorly soluble compounds that form supersaturated solutions in vivo in order to maximize oral drug absorption. Although there has been an increasing number of studies focusing on the role of individual bile salts on drug crystallization, the effects of mixed micelles and biorelevant media composition on crystallization kinetics have only been studied to a limited extent. In this study, we evaluated the ability of binary and ternary bile salt combinations to maintain supersaturated aqueous solutions of telaprevir. Crystallization kinetics were also compared in more complex media that also contained the phospholipid, lecithin. These included fasted state simulated intestinal fluid (FaSSIF) (a widely used medium for formulation testing which contains a single bile salt, sodium taurocholate), and media that contained several endogenous bile salts. Finally, the combined effects of a polymer, hydroxypropyl methyl cellulose acetate succinate, and the testing media on crystallization kinetics were evaluated to provide insights into supersaturation formulation design. Solution bile salt composition was found to significantly influence crystallization kinetics. However, the presence of the polymer increased induction times sufficiently that differences between media were minimized. This study suggests that when evaluating the crystallization kinetics of systems with a propensity to undergo supersaturation in vivo, attention should be paid to selecting biorelevant media.

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.