Development of Microparticles Created from Physically Modified Starch Granules for the Uptake and Release of Drugs

Abstract

Controlled release drug delivery systems are, depending on the desired effect, generally an improvement over conventional drug delivery. Through material design, drugs can be delivered with temporal and spatial control, ideally delivering a therapeutically relevant dose for a relevant duration. Hydrogels, a network of cross-linked water-soluble polymers, are a common choice of material for creating such a delivery system, due to their general similarity to biological tissue because of their high-water content. Hydrogels can be used in a variety of formats for drug delivery, with options on length scales from nanometers to centimeters, with microparticles being a common choice. When used biologically, it is important that the polymers used are biocompatible. One polymer option is starch, the polymer obtained from starch granules. The work presented in this thesis aims to use hydrogel-like microparticles created from native starch granules through a simple swelling process for a controlled release drug delivery system. In working towards this goal, the starch granule swelling process and swelled starch itself are characterized.

First, helium ion microscopy (HIM) was used to characterize the morphology of native corn starch. HIM is a relatively new method, which is similar to scanning electron microscopy, but instead of using an electron beam, a beam of He+ is used. HIM can create images that have high contrast, high depth-of-field, and can resolve features down to a few nanometers. The method has been particularly useful for nanomaterials research and has been used on a number of materials, such as nanoporous SiO2, cellulose nanofibrils, and mammalian cells. To the best of my knowledge, this is the first report of this method for imaging starch. The images I produced are capable of resolving features of starch not possible with scanning electron microscopy (SEM). With some areas of starch structure still not well understood, further characterization with HIM can assist with improving the understanding of starch’s structure. “Blocklets,” which are theorized substructures of starch were not observed using HIM. These structures are often referred to in the literature, but evidence for their existence is contentious.

Next, the process of making starch microcapsules (a term used in this thesis for swelled particles made from native normal corn starch granules) by manipulating physical conditions was studied. When heated in water, starch swells and undergoes partial gelatinization. The swelling process for normal corn starch was controlled with heating temperature and heating time. As a result of particle size and particle solubility being correlated with swelling extent, these properties were also controlled. The internal cavity present in native corn starch granules increased in size as the particles swelled. This size of the internal cavity was modulated through control of swelling extent. It was hypothesized that a microparticle with an internal cavity could allow for an improvement of controlled release compared to a similar microparticle without an internal cavity. The internal cavity of SMCs was characterized using SEM, HIM, brightfield microscopy, polarizing light microscopy, and confocal laser scanning microscopy. The swelling process and the resulting change in internal cavity size was mathematically modeled.

To evaluate the most appropriate SMCs for use in drug delivery, the starch swelling process, differences between SMCs created from different starch types, and a number of properties of SMCs were studied. The response of pea, potato, wheat, waxy corn, and normal corn starch to various heating temperatures were evaluated. The morphological changes of the SMCs were characterized using SEM and brightfield microscopy. The effect of swelling on particle size distributions was measured and the polydispersity increased as expected. Normal corn starch type appeared to be best suited for use in a drug delivery system. With swelling power being a key measurement for characterizing SMCs, the effect of centrifugal force was evaluated; higher force led to lower measurements of swelling power.

The digestibility of microparticles is a key factor for particles intended for oral drug delivery, and so the in vitro digestibility of SMCs was evaluated. Greater swelling led to higher digestibility. As a method of altering the rigidity of SMCs to potentially lock-in drugs, the outer shell of the SMCs was cross-linked. The cross-linking resulted in inhibited swelling when the SMCs were subjected to greater heating. Selective water uptake in SMCs was observed when SMCs were placed in a solution of bovine serum albumin (BSA), suggesting that SMCs are limited in the size of molecule they can carry.

Finally, preliminary investigations into the ability of SMCs to be loaded with a drug and to subsequently release it were conducted. A challenge with characterizing loading of microparticles is the interstitial and intraparticle volume of water amongst tightly packed microparticles, the sum of which I term “drug-accessible water.” Often the effect of this volume is ignored when determining loading capacity, but to properly characterize loading, this volume must be accounted for. Additionally, when characterizing adsorption, it is generally assumed that the hard sphere size exclusion is negligible. However, this assumption is not reasonable for large molecules. To improve loading characterization, these factors must be considered. SMCs were loaded with methylene blue (MB) and the drug-accessible-water volume was determined. The data was fit to a Langmuir adsorption isotherm, and adsorptions of 3.61, 2.14, and 2.06 mg/g for native normal corn starch, SMC65, and SMC70 were observed, respectively. Due to greater swelling and resulting greater drug-accessible-water volumes, the opposite trend was observed for loading capacities, where native normal corn starch, SMC65, and SMC70 had loading capacities of 3.81, 5.11, and 9.65 mg/g, respectively. The fraction of the drug-accessible water that is interstitial verses intraparticle was also estimated based on a comparison of experimental results with geometrically calculated theoretical swelling powers. An experimental method was used to directly calculate the interstitial volume. In addition, confocal laser scanning microscopy (CLSM) with the fluorescent dyes RITC-dextran and FITC-BSA as model drugs, was used to visualize drug loading and to determine where drugs were loaded spatially within the SMCs. Drug can be found in the internal cavity of SMCs.

In conclusion, swelled normal corn starch granules show promise for use in a drug delivery system. Modulation of heating temperatures and times allowed for control of the swelling extent and of the size of the internal cavity. The microcapsules are candidates for use in a controlled release drug delivery system. Further work to characterize the interaction between the microparticles and more model drugs should be conducted. In addition, in vitro testing in simulated intestinal and gastric fluids needs to be conducted to determine the drug release capabilities.