tropicamide liposomes (63). Both polymer coatings of tropicamide-contain- ing liposomes failed to significantly increase the bioavailability of the entrapped drug relative to uncoated vesicles (63). However, in contrast to previous work (53), size and zeta potential measurements of uncoated tro- picamide liposomes and liposomes coated in both polymer solutions demon- strated an association between the Carbopols and the vesicles at both pH 7.4 and pH 5, as evidenced by an increase in size and a decrease in the corre- sponding zeta potential. It was suggested that the prolongation in precor- neal residence for Carbopol 1342–coated tropicamide liposomes was due to the formation of a three-dimensional microgel structure, which interacted with the phospholipid vesicles and subsequently increased their retention via a mechanism of adhesion to the mucin network (63). Microsphere formulations have been evaluated for their capacity to retain 111 In as indium chloride in the preocular (precorneal) area of the rabbit eye (64). Clearance of the radiolabeled compound was monitored using gamma scintigraphy, and the influence of pH and prehydration of the microspheres on precorneal retention was assessed. These authors pre- pared microspheres of poly(acrylic acid) (Carbopol 907) cross-linked with maltose by a water-in-oil (w/o) emulsification process. Precorneal clearance of the microspheres at pH 5 and 7.4 were compared to an 111 In aqueous suspension (64). Clearance of the microspheres demonstrated a biphasic ( ¼ rapid initial phase and ¼ slower phase) profile, and microspheres buffered at pH 5 exhibited a significantly slower phase than micr ospheres buffered at pH 7.4. Presumably, the neutralized Carbopol formulation (pH 7.4) did not possess the same degree of mucoadhesive strength as the micro- sphere preparation formulated at pH 5. In vitro tests of mucoadhesive strength verified that the force of detachment of the microspheres formu- lated at pH 5 from mucus glycoprotein was significantly greater than the corresponding value for microspheres buffered at pH 7.4 (64). A significant increase in the retention of prehydrated microspheres in the preocular area was observed compared to microsphere formulations that were not hydrated prior to instillation (64). Albasini and Ludwig (65) evaluated a series of polysaccharides for their potential inclusion in ocular dosage forms. The polysaccharides eval- uated were carrageenan, locust bean gum, guar gum, xanthan gum, and scleroglucan. Measurements of the dynamic surface tension, pH, refractive index, and a visual clarity check comprised the physical measurements and determination of viscosity, viscoelasticity, effect of ionic strength on the resulting viscosity, and mucoadhesive strength (as assessed by an increase in the viscosity of a solution of the polysaccharide and mucin) comprised the rheological analysis of all the polysaccharides evaluated (65). All ocular preparations were made by adding the required amount of each polysac- 426 Johnston et al. Copyright © 2003 Marcel Dekker, Inc. charide to an aqueous iso-osmotic vehicle at 90 C and stirring the mixture mechanically until the polysaccharide was completely dissolved (65). Only scleroglucan and xanthan gum were found to demonstrate desirable viscoe- lastic and mucoadhesive properties suitable for instillation into the eye. The two preparations were evaluated in human volunteers and found to possess no ocular irritancy (65). Polysaccharides have also been shown to have potential for drug delivery by other routes of administration. Using a high molecular weight polysaccharide gum, Hakea gibbosa, isolated from a tree, Alur et al. have shown that the gum possessed both the ability to sustain the release of low molecular weight, organic-based drug substances as well as therapeutic polypeptides (salmon calcitonin) both in vitro and in vivo following application to the buccal mucosa of rabbits (74–76). This polysaccharide may hold promise for sustained delivery to the eye of both conventional drugs and newer therapeutic polypeptides requiring retention of biological activity. The biomaterials for ocular use have been mainly synthetic polymers. Some natural biopolymers, such as collagen and hyaluronic acid, have also been examined. Of these, hyaluronic acid offers attractive possibilities (77– 80). Some of the materials indicated as ‘‘ocular mucoadhesives’’ are men- tioned below. A. Naturally Occurring Mucoadhesives Collagen and fibrin have been used as erodible insets for the long-term delivery of pilocarpine to the eye (81,82). The utility of these macromole- cules in ophthalmic drug delivery depends largely upon their attachment capability to the drug molecules and their interaction with the glycocalyx domain of the corneal surface for maximum mucoadhesion. Among these, lectins and fibronectin are most promising. The role of lectins as cellular-recognition mediators has been explored in great detail in the field of cellular biology. Lectins belong to a class of proteins of nonimmune origin that bind carbohydrates specifically and non- covalently (83). The most commonly studied lectin is the one derived from tomatoes. This particular lectin has been found to be nontoxic, binds spe- cifically to the sialic acids (a major component of the mucus glycoproteins), and is transported into the cells by endocytosis (84). Such properties could be useful for the delivery of therapeutic agents into the ocular chambers. Fibronectin is a glycoprotein and a component of the extracellular matrix. The pentapeptide backbone of this substance has been identified as having a cell-attachment property (85). Purified fibronectin has been reported to lessen the healing time of corneal ulcers (86). It has also been used in conjunction with hyaluronic acid for decreasing the healing time. Mucoadhesive Polymers in Ophthalmic Drug Delivery 427 Copyright © 2003 Marcel Dekker, Inc. B. Synthetic Mucoadhesives As discussed earlier, the potential of a mucoadhesive agent is determined by a number of parameters; i.e., chain length, configuration, and molecular weight. The extent of corneal adhesion of some neutral polymers has been reported to be comparable to that of natural mucins. Lemp and Szymanski (87) measured the extent of corneal adsorption of water-soluble polymers onto the epithelial surface. Among the polymers, 1.4% polyvinyl alcohol, 0.5% hydroxypropyl methyl cellulose, and 2% hydroxyethyl cellulose vehi- cles have shown comparable corneal adhesion to that of mucin. The study concluded that ocular therapeutic agents would be well absorbed from topi- cal formulations containing such polymers. Since only marginal improve- ments (two- to threefold) in ocular bioavailability were seen with these agents, the adsorbed polymers were either unable to hold the drug or were being rapidly removed from the surface by the bathing tears. Other water-soluble polymers like polyacrylic acid also improved the ocular bio- availability of pilocarpine, albeit by a factor of two. A polymer most effective as a mucoadhesive will be the one that can form an extended and hydrated network to allow for greater interpenetra- tion and subsequent physical entanglement. These kinds of networks may be formed by: 1. Physical intertwining of the polymers 2. Bridging of the polymer chains 3. Cross-linking of the polymer chains Thus, cross-linked polyacrylic acid has been shown to have an excel- lent mucoadhesive property, causing significant enhancement in ocular bio- availability (55). Using pigmented rabbits, Lehr et al. (88) demonstrated a twofold increase in the uptake of gentamicin by the bulbar conjunctiva when the aminoglycoside was delivered as a mucoadhesive, polycarbophil [a poly(acrylic acid)–based polymer] formulation. Two gentamicin formula- tions of this polymer (neutralized vs. nonneutralized) were evaluated and compared to an aqueous control formulation. While both the neutralized (pH 7.5) and nonneutralized (pH 2.5) gentamicin/polycarbophil formula- tions increased the uptake of the aminoglycoside antibiotic by the bulbar conjunctiva, only the nonneutralized aminoglycoside formulation provided drug penetration into the aqueous humor. Penetration of gentamicin into the aqueous humor from the nonneutralized formulation was suggested to result from drug absorption via the conjunctival-scleral pathway facilitated by intensified contact between the mucoadhesive polymer and the under- lying bulbar conjunctiva (88). A partially esterified acrylic acid polymer was successful in prolonging the therapeutic effect of topically applied pilocar- 428 Johnston et al. Copyright © 2003 Marcel Dekker, Inc. pine (89). Urtti et al. (90) also indicated that the use of a polyacrylamide and a copolymer of acrylamide (N-vinyl pyrrolidone and ethyl acrylate) as a matrix, which resulted in a threefold increase in the ocular bioavailability of pilocarpine. Similarly, cyanoacrylates have been used in the field of opthalmology to seal corneal perforations and ulcers, to stop leakage of aqueous or vitr- eous humor, and to protect against external contamination (91,92). These agents have a potential as effective ocular mucoadhesive agents provided the monomer polymerization could be controlled. III. WHAT IS IN STORE FOR THE FUTURE? A multidisciplinary approach will be necessary to overcome the challenges associated with the development of ocular mucoadhesives. A nonbiodegrad- able adhesive is adequate for topical use to treat perforations and ulcera- tions. However, the use of a nontoxic biodegradable surgical adhesive is deemed necessary for long-term use in ocular drug delivery. Mucoadhesives can make an important contribution in this area. An ideal ocular mucoadhesive would be site specific, durable for the desired period of time, biodegradable, and above all nontoxic, nonimmunogenic, and nonir- ritant. It would be even better if the adhesive could serve as absorption enhancers (for therapeutic protein and peptide drugs) and/or as enzyme inhibitors. REFERENCES 1. Harris, D., and Robinson, J. R. (1990). 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[...]... favorable characteristic for a preferred pharmaceutical drug delivery system Copyright © 2003 Marcel Dekker, Inc Microparticles and Nanoparticles in Ocular Drug Delivery II PARTICULATE SYSTEMS IN OCULAR DRUG DELIVERY A 441 Topical Systems The isolation of the vitreous caused by the blood-retinal and blood-aqueous barriers creates difficulties for effective drug therapy in all eye diseases (23) Systemic administration... the polymer matrix (15) Microparticles for topical administration are of several types, including polymer -drug complex systems, erodible microspheres, responsive particulates, in situ gelling systems, ion-exchange systems, and nanoparticles (15) B Local Injectable Systems When the vitreous cavity is targeted for drug delivery, topical, systemic, or subconjunctival drug delivery prove unsatisfactory... shorter period of time V BIODEGRADATION AND DRUG RELEASE FROM PARTICULATE SYSTEMS In order to prolong the entrance of drugs into the intraocular structures, a long residence time of the particles in the cul-de-sac and a total desorption Copyright © 2003 Marcel Dekker, Inc Microparticles and Nanoparticles in Ocular Drug Delivery 4 47 of the drug from the particles during that time have to be attained... order to address the above-stated problems, micro- and nanotechnology involving drug- loaded polymer particles has been proposed as an ophthalmic drug delivery technique that may enhance dosage form acceptability while providing sustained release in the ocular milieu (14) Particulate drug delivery consists of systems described as microparticles, nanoparticles, microspheres, nanospheres, microcapsules,... that suggests that cya- Fig 3 Precorneal drainage profile of poly(isobutylcyanoacrylate) nanoparticles: M.W (*) 4, 275 ; (&) 13, 178 ; (~) 72 ,030; (þ) 128,865; (&) 6 07, 439 in g/mol (From Ref 77 .) Copyright © 2003 Marcel Dekker, Inc Microparticles and Nanoparticles in Ocular Drug Delivery 451 noacrylates may have an enhanced bioadhesiveness to inflamed tissues In addition, the ratio of nanoparticles between... polyisobutylcyanoacryate nanocapsules J Pharm Sci., 75 :361 17 Schulman, J A., and Peyman, G A (1993) Intracameral, intravitreal, and retinal drug delivery In: A K Mitra (ed.), Ophthalmic Drug Delivery Systems Marcel Dekker, New York, pp 383–425 18 Kreuter, J., Tauber, U., and Illi, V (1 979 ) Distribution and elimination of poly methyl- 2-1 4-( methacrylate) nanoparticle radioactivity after injection in rat and... rank Copyright © 2003 Marcel Dekker, Inc Microparticles and Nanoparticles in Ocular Drug Delivery 459 order for both the duration and intensity of miosis as II > III ) I, with all differences being significant IX CONCLUSIONS Particulate systems have the potential to become promising systems for ophthalmic drug delivery To date, only one microparticulate ophthalmic prescription product, Betoptic1 S, has... Marchal-Haussler, L., Fessi, H., Devissaguet, J P., Hoffman, M., and Maincent, P (1992) Colloidal drug delivery systems for the eye A comparison of the efficacy of three different polymers: polyisobutylcyanoacrylate, polylactic-coglycolic acid, poly-epsilon-caprolactone Pharm Sci., 2:98 67 Calvo, P., Vila-Jato, J L., and Alonso, M J (19 97) Evaluation of cationic polymer-coated nanocapsules as ocular drug. .. (1993) Liposomes and nanoparticles as ocular drug delivery systems In: Biopharmaceutics of Ocular Drug Delivery CRC Press, Inc., Boca Raton, pp 91–101 Harima, T., Kreuter, J., Speiser, P., Boye, T., Gurny, R., and Kubis, A (1986) Enhancement of miotic response of rabbits with pilocarpine-loaded polybutylcyanoacrylate nanoparticles Int J Pharm., 33:1 87 Kreuter, J (1 978 ) Nanoparticles and nanocapsules—new... time of the drug, enhance the corneal uptake of the drug in unionized form, and decrease the systemic side effects Moreover, the studies show that PECL nanocapsules demonstrate a better effect compared to the PECL nanoparticles for carteolol It was concluded that the drug entrapped in the oily core is more available for corneal absorption 3 H-Labeled hydrocortisone- 1 7- butyrate-21-propionate (3 H-HBP) loaded . above-stated problems, micro- and nanotech- nology involving drug- loaded polymer particles has been proposed as an ophthalmic drug delivery technique that may enhance dosage form accept- ability. of drug delivery to the eye is topical. Drug- loaded microparticulate systems are suspended in aqueous or nonaqueous medium and instilled typically in the cul-de-sac of the eye, wherefrom drug. with an oil-in-oil emulsion to prepare polylactide-co-glycolide Microparticles and Nanoparticles in Ocular Drug Delivery 443 Copyright © 2003 Marcel Dekker, Inc. microspheres of 5- uorouracil