Irrespective of the noninvasive route employed to deliver the peptide and protein drugs, some inherent delivery problems must be overcome. Table 3 lists some of the general methods that can be employed to negotiate such formulation difficulties.
Physical methods for increasing absorption such as iontophoresis and phonophoresis have been examined extensively (25-28). Such methods of enhancement are quite complex and may lead to chemical and physical instability of the permeating protein (29-31). Erratic results may also be obtained due to different degrees of surface absorption.
Prolongation of the biological half-life of proteins and enhancement of their systemic bioavailability are also necessary. An attempt has been made by coadministering proteins with known enzyme inhibitors (32). The cova-
Table 3 General Methods for Enhancing Protein Delivery
1. By increasing absorption through:
(a) Application of physical methods like iontophoresis or phonophoresis
(b) Coadministration with permeation enhancers
(c) Incorporation into liposomes or other carriers
(d) Chemical modification of primary structure and development of prodrugs
2. By minimizing metabolism through:
(a) Covalent attachment to a polymer
(b) Chemical modification of the primary structure
(c) Targeting to specific tissues
(d) Coadministration with an enzyme inhibitor
3. By prolonging blood levels through:
(a) Use of bioadhesives
(b) Protection using liposomes, polymers, or other carrier lent attachment of polymers has also been shown to protect a number of proteins from enzymatic hydrolysis (33-37). Thus, azopolymers may be used to deliver proteins orally whereby the system could bypass the digestive enzymes of the small intestine; however, in the flora of the colon the polymer will release the protein. In any event, the problem of low bioavailability still exists, and permeation enhancers may have to be used to overcome this obstacle.
The use of chemical permeation enhancers has been reviewed extensively relative to nasal, oral, and rectal absorption of proteins and peptides (38-41). Three major mechanisms of action are possible for these enhancers: perturbation of membrane integrity, expansion of the paracellular pathway, and increase in the thermodynamic activity of the permeating species.
The following section will briefly discuss the studies performed in other noninvasive routes of protein and peptide delivery, the findings of which may be useful in designing ocular peptide delivery systems.
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