Molecular aspects of muco- and bioadhesion:: Tethered structures and site-specific surfaces

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Abstract

Mucoadhesive controlled-release devices can improve the effectiveness of a drug by maintaining the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site. Acrylic-based hydrogels have been used extensively as mucoadhesive systems. They are well suited for bioadhesion due to their flexibility and nonabrasive characteristics in the partially swollen state, which reduce damage-causing attrition to the tissues in contact. Crosslinked polymeric devices may be rendered adhesive to the mucosa. For example, adhesive capabilities of these hydrogels can be improved by tethering of long flexible chains to their surfaces. Tethering of long poly(ethylene glycol) (PEG) chains on poly(acrylic acid) hydrogels and their copolymers can be achieved by grafting reactions, or by copolymerization in the presence of several PEG-containing acrylates. The ensuing hydrogels exhibit mucoadhesive properties due to enhanced anchoring of the chains with the mucosa. Theoretical calculations can lead to optimization of the tethered structure. Experimental results indicate that the chain interpenetration is a strong function of the PEG molecular weight, the polymer swelling ratio and the mucosa composition.

Introduction

Mucoadhesion involves the attachment of a natural or synthetic polymer to a biological substrate. It is a practical method of drug immobilization or localization and an important new aspect of controlled drug delivery. In recent years there has been an increased interest in mucoadhesive polymers for drug delivery [1], [2]. Therefore, molecular design of the alteration and optimization of the adhesive characteristics of candidate materials for such applications has been a major part of our work.

The motivation for controlled drug release is the necessity to maintain a constant effective drug concentration in the body for an extended time period. For optimal performance, drug concentrations in the body should be maintained above the effective level and below the toxic level. However, when a drug is administered to a patient, the initial concentration of the drug in the body will peak above a toxic level before gradually diminishing to an ineffective level due to excretion. A mucoadhesive controlled-release device can improve the effectiveness of a treatment by helping to maintain the drug concentration between the effective and toxic levels, inhibiting the dilution of the drug in the body fluids, and allowing targeting and localization of a drug at a specific site.

Mucoadhesion also increases the intimacy and duration of contact between a drug-containing polymer and a mucous surface. It is believed that the mucoadhesive nature of the device can increase the residence time of the drug in the body. The combined effects of the direct drug absorption and the decrease in excretion rate allow for an increased bioavailability of the drug with a smaller dosage and less frequent administration.

An advantage of using a mucoadhesive polymer carrier for drug delivery is the prevention of first-pass metabolism of certain protein drugs by the liver through the introduction of the drug via a route bypassing the digestive tract. Drugs that are absorbed through the mucosal lining of tissues can enter directly into the bloodstream and not be inactivated by enzymatic degradation in the gastrointestinal tract [3]. A polymeric device allows for slow, controlled, and predictable drug release over a period of time and hence reduces the overall amount of drug needed.

Several polymeric bioadhesive drug delivery systems have been fabricated and studied in the past 20 years, not always with success. Several such devices are currently used in clinical applications involving dental, orthopedic, ophthalmological, and surgical uses. Viable application sites include the mouth, intestine, nose, eye, and vagina. Acrylic-based hydrogels have been used extensively for bioadhesive devices. Acrylic-based hydrogels are well-suited for bioadhesion due to their flexibility and nonabrasive characteristics in the partially swollen state which reduce damage-causing attrition to the tissues in contact [4]. Furthermore, their high permeability in the swollen state allows unreacted monomer, uncrosslinked polymer chains, and the initiator to be washed out of the matrix after polymerization. Acrylic-based polymer devices exhibit very high adhesive bond strength [4], [5], [6].

Section snippets

Polymer–polymer interdiffusion and adhesion

The theories of polymer–polymer adhesion can be adapted to polymer–tissue adhesion or bioadhesion by recognizing that bioadhesion is different only because of the differing properties of the tissue as opposed to those of the polymer. Numerous theories have been developed to explain the phenomenon of bioadhesion. No individual theory has been universally accepted as the singular mechanism by which bioadhesion occurs, though a combination of theories may be used to describe the phenomenon. The

Molecular understanding of mucoadhesive promoters behavior

Theoretical and experimental evaluation of the diffusion theory of adhesion, especially for uncrosslinked polymer melts, has been the focus of substantial research. Interpenetration of polymer chains across the interface can result in adhesion. The intimate contact of the two substrates is essential for diffusion to occur; the driving force for the interdiffusion is the concentration gradient across the interface. The two phases must be compatible. These criteria are most likely fulfilled when

Tethered PEG chains and mucoadhesion

Tethered polymer chains are polymer chains with one of their ends attached on a d-dimensional surface [21], where d=1 denotes comb polymers, and d=2 denotes normal, flat surfaces. The polymer chain tethered structures have been extensively studied since the pioneering works of Alexander [22]. The behavior of tethered structures on solid surfaces is well understood. Thus, such systems have found numerous applications.

Though tethered structures attached to dry polymer systems have long been used

Site-specific and tethered structures

A key factor in promoting adhesion would be the ability of a matrix to have units that are specifically designed to adhere to a given surface. It is a commonly known fact that certain amino acid sequences have complementary parts on cell and mucosal surfaces. Thus amino acids sequences such as Arg–Gly–Asp and others, if attached to the matrix, could promote adhesion by binding with specific cell surface glycoproteins. Even more useful would be the ability to selectively adhere to diseased

Preparation of adhesion-promoted hydrogel systems

Adhesion promoting polymer chains can be introduced into a hydrogel system either by free loading or by chemical grafting. Hydrogel systems loaded with free polymer chains can be produced by addition of chemically inert polymer chains into the monomer mixtures before the polymerization process. For example, a useful system can be produced by photopolymerizing a mixture containing acrylic acid, crosslinking agent, photoinitiator, and PEG chains. The latter will not react with the acrylic acid in

Theoretical predictions

As polymer-tethered hydrogel surfaces approach the mucus surface, the tethered chains contact the mucus first. Their effect on the adhesion strength is determined by whether they diffuse into the mucus and how they behave in the interface region.

The diffusion process is thermodynamically controlled by the free energy change of the whole system when the hydrogel and mucus approach each other. The free energy change includes osmotic repulsion, entropy contribution from tethered polymers, and

Mucoadhesion measurement

The gels investigated here were grafted copolymers of PEG monomethacrylate with methacrylic acid (MAA) containing a 1:1 molar ratio of the two components. They were placed in a tensile tester (Instron) at 25°C and 90% relative humidity. The samples were adhered to the upper holder of the tester, whereas a sample of gelled bovine submaxillary mucin was placed on the lower jaws. The two jaws were brought together for 15 min and then separated at 1 mm/min. The detachment force was measured as a

Conclusions

In this paper, we analyzed the idea that polymer chains tethered on hydrogel surfaces may have important applications in drug delivery fields, such as mucoadhesion promotion and site-specific drug targeting. The advantage of tethered structures is the ability to modify the surface properties of hydrogel systems, which is important for bioadhesion and site-specific targeting, while its bulk properties remain unaffected which can be optimized separately for controlled release.

Theoretical

Acknowledgements

This work was supported by grants from the National Science Foundation (grant No. BES-97-06538) and the National Institutes of Health (grant No. GM-56231-01).

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