Polysaccharide gel microspheres for peptide and protein drug encapsulation
Abstract
Oral delivery of peptide and protein drugs has challenged various attempts at delivery development. The main reasons for the low oral bioavailability of biological drugs are pre-systemic enzymatic degradation and poor penetration of intestinal mucosa. The objective of the thesis study is to investigate the feasibility of encapsulation of protein drugs into polysaccharide gel microspheres for a potential oral administration. The model polysaccharide adopted in the study is alginate because of its unique property of gel-formation under mild process conditions, in the presence of divalent cations such as calcium, and its controllable biodegradation behavior though the adjustment of the acidity and/or the ionic strength of the medium. ^ In this thesis, calcium alginate (Ca-alginate) gel microspheres with and without the encapsulated protein were prepared by utilizing an electrodispersion technique with a precise control of particle size, size distribution and morphology. The electrodispersion was achieved by atomizing an aqueous solution of sodium alginate and CaCO3 nanoparticles with or without protein mixed, into a continuous electrically insulating organic liquid containing acetic acid. The gelation was triggered by the internal dissolution of the calcium source. The thesis work demonstrates Ca-alginate gel microspheres prepared by this method have a narrow size distribution with an average size distribution adjustable from 412 ± 90 μm to 10 ± 3 μm. A high drug loading efficiency was achieved and a fast and biphasic release profile of Ca-alginate particulate system was observed in a mimicked gastrointestinal tract environment. Therefore, the electrodispersion methodology was successfully extended for biopharmaceutical applications. Furthermore, a complete evaluation of the protein-polysaccharide interaction and the effect of formulation process parameters on the protein bioactivity were conducted. From the analysis, the mechanism responsible for protein-polysaccharide complexes formation was elucidated, showing that the protein is mainly bonded electrostatically to anionic alginate chains through the positively charged amino acids. The protein retained its structural integrity after the dissociation of the protein-alginate complexes. Finally, a population balance model was introduced to understand the fundamental polymerization kinetics for the Ca-alginate sol-gel transition. ^
Degree
Ph.D.
Advisors
Michael T. Harris, Purdue University.
Subject Area
Health Sciences, Pharmacology|Engineering, Chemical
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.