Chapter 20
Cross-Linked Polyacid Matrices for Oral Drug Delivery 1,3
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Robert Z. Greenley , Hossein Zia , Joel and Robert L . Rodgers
Garbow ,
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Downloaded by PRINCETON UNIV on July 2, 2013 | http://pubs.acs.org Publication Date: August 15, 1991 | doi: 10.1021/bk-1991-0469.ch020
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Chemical Sciences, N M R Consortium, Monsanto Corporate Research, Monsanto Company, St. Louis, M O 63167 Department of Pharmacology and Toxicology, College of Pharmacy, University of Rhode Island, Kingston, R I 02881 5
Concentrated solutions of many therapeutic agents can be imbibed into a crosslinked polyacid powder. After removal of the solvent, the drug-polymer matrix may be administered orally. The polyacid swells minimally under gastric conditions - retaining the drug - and then is highly swollen by the basic intestinal medium, allowing the drug to be dissolved away from the matrix. These matrices, with insulin as a model agent, have been characterized by, in vitro release curves, drug-polymer interaction studies and in vivo animal studies. C REDOR NMR experiments were also run to define the dispersion of the agents in the polyacid resin. 13
The promise of the isolation and production of therapeutic polypeptides and proteins demands that for treatment of a chronic disease state an oral delivery system be developed which w i l l protect these valuable agents from the hostile gastric environment. Subsequently, the drugs will have to be completely released in the intestine, preferably in a state that will enhance their rapid dissolution and transport across the gut wall minimizing interaction with intestinal proteases. The design of a proper delivery system requires a knowledge of the G.I.tract (7). The nature of the gastric acidic and enzymatic medium has been elucidated. More recently Davis (2) and Harris (3) have studied the rate of emptying of the stomach. Dressman (4) has clinically followed pH variations in both the empty stomach and after a meal finding that sinusoidal p H reductions occur during mastication of solid food, whereas the duodenum maintains a relatively constant pH during introduction of the chyme. In 1987 Saffran and Neckers (5) disclosed a coating for a capsule containing the drug that appears to satisfy a need for oral insulin delivery when tested in animals. In this case, a solution of "crosslinked" polymer is coated onto the capsule. 0097-6156/91/0469-0213$07.00/0 © 1991 American Chemical Society
In Polymeric Drugs and Drug Delivery Systems; Dunn, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
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POLYMERIC DRUGS AND DRUG DELIVERY SYSTEMS
When the capsule reaches the ileo-cecal junction, the native bacteria cause rupture of the azo crosslink, allowing dissolution of the polymer and capsule material, releasing the insulin. Our approach to a delivery system is also based on a crosslinked system but the polymer crosslinks are maintained, rendering the nontherapeutic portion of the formulation insoluble and thus it cannot be absorbed by any portion of the G.I. tract. A polyacid, such as poly(acrylic acid), dissolves in water. When it is neutralized with a base, it is more readily dissolved. If the polyacid is crosslinked by running the polymerization in the presence of five to ten mol percent of a diacrylate, then it is no longer water soluble and is only slightly swollen by water. When the crosslinked polyacid is neutralized by base, a polyanion is formed. In this case, the polymer swells significandy in water to relieve the repulsions of the adjacent anions. If a drug is contained within the polymer matrix powder, it will be protected (except for any that is on the surface of the polymer particles) from the gastric environment and available for dissolution by the intestinal medium after neutralization of the acid functions by duodenal bicarbonate. If other polyacids, such as poly(methacrylic acid) or their copolymers are used, the swelling characteristics of the resins will be changed according to the hydrophobicity of the polymer backbones (Figure 1). Methods and Materials P o l y m e r Synthesis. A solution of 30 m L of (meth)acrylic acid, 5 m o l % triethyleneglycol di(meth)acrylate and 0.3 g K S 0 in 300 mL deionized water was stirred and heated at 95°C under N for two hours. The gelatinous mass was vacuum dried at 50°C for 48 hours. The polymer was then ground in a Micro-Mill. The portion passing through a 40 mesh screen (
