(135g) Dynamics of NOVEL Multifunctional, Intelligent Mucoadhesive Copolymers for Oral Protein Delivery

Since the discovery that insulin can be used for treatment of diabetic patients in 1922, there have been copious amounts of research with little headway in administration options for insulin. To this day, the main course of administering insulin to diabetic patients is through injection. This is a painful and tedious experience that patients must endure. The shots that are administered into the peripheral circulation of the blood stream through subcutaneous methods result in problems mimicking insulin released into portal circulation that is seen in normal, healthy individuals. These problems can severely limit patient compliance which can ultimately cause severe medical problems such as blindness and kidney failure due to the lack of insulin. Even with compliance other problems can arise with a loss of the direct effect on hepatic metabolic processes due to the bypassing of the portal vein.

The lack of compliance with insulin is an area of great concern due to the large amount of people affected. There are 14.6 million people diagnosed with diabetes and an estimated 6.2 million that are yet to be diagnosed in the United States alone. These numbers increase every year due to increased obesity problems. With these numbers growing annually, there is an obvious need for a change in administration methods in order to increase patient compliance. With this and the problems mentioned previously the development of a novel oral delivery system could be the solution.

Graft copolymer networks of poly (methacrylic acid) (PMAA) containing well characterized tethers of high molecular weight poly (ethylene glycol) (PEG) containing different adhesive moieties with tetraethylene glycol dimethacrylate (TEGDMA) being used as a crosslinking agent were prepared using free radical solution UV-polymerization. These new tethers will be characterized to determine the interactions between the mucus layer and the polymer, and to better understand the interactions between the functional groups on the PEG tethers and the cell ligands along the epithelial cell layer of the small intestine. The copolymers were prepared in different ratios of PEG and PEG with adhesive moieties. The high molecular weight PEG was incorporated as an adhesion promoter to improve the already mucoadhesive PMAA through interpenetration into the mucous layer that covers the epithelial cells of the small intestine. Accomplishing this, should result in an improved residence time of the carrier and higher absorption at the drug delivery site.

The copolymers were characterized through dynamic swelling and adhesion testing. Swelling studies were carried out using dimethylglutaric acid (DMGA) buffer. Ten buffers were made each with a different pH ranging from 3.2 to 7.6. The initial or dry weight was recorded initially and then again after swelling to get the swollen weight. These two weights were used to calculate the weight swelling ratio of the polymer disks and plotted against pH to determine any pH sensitivity. Adhesion testing was carried out through the use of an Instron tensile testing machine. A polymer disk was placed on the upper clamp of the Instron through the application of cyanoacrylate medical adhesive. Porcine mucin was mixed with DI water in several concentrations and placed on the bottom clamp. These two clamps were brought into contact and then gradually pulled apart until there was no longer any contact between the mucin solution and the polymer disk. Data was gathered and plotted to gain a detachment force (N) versus displacement (m) curve, of which the area underneath was calculated and found to be the work of adhesion (?ÝJ). This procedure was also done for polymer-polymer adhesion where another polymer disk was substituted for the mucin solution on the lower clamp.

The swelling results indicate that there is definite pH sensitivity within all ratios.

Initial adhesion results suggest that the addition of the high molecular weight PEG tethers with adhesive moieties causes an increase in the adhesion to the mucus layer.

Further characterization will be done on these adhesive moieties some of which are present in several small intestines attacking.