The successful development of newer mucoadhesive dosage forms for ocular delivery still poses numerable challenges. Particularly important among these are the determination of the exact nature of the interactions occurring at the tissue mucoadhesive interface and the development of an ideal, nontoxic, nonimmunogenic mucoadhesive for clinical application. Moreover, a better understanding of the exact physical structure of mucin molecules by computational chemistry may aid in the calculation of the mucoadhesive strength.
The pioneering work of Hui and Robinson (55) illustrated the utilization of bioadhesive polymers in the enhancement of ocular bioavailability of progesterone (Fig. 5). Subsequently, several natural and synthetic polymers have been screened for their ability to adhere to mucin epithelial surfaces; however, little attention has been paid to their use in ophthalmic drug delivery.
Saettone et al. (56) undertook a study evaluating the efficacy of a series of bioadhesive dosage forms for ocular delivery of pilocarpine and tropica-
mide. From this study, hyaluronic acid emerged as the most promising mucoadhesive agent. The biological analysis data, however, revealed that the physicochemical properties of the drug itself had an impact on the efficacy of the delivery system.
To retard rapid drug loss from the precorneal area, various devices have been tested. Some of the potential candidates have been:
1. Erodible inserts of polyvinyl alcohol film or silicone rubber for the ocular delivery of pilocarpine and oxytetracycline, respectively (57,58)
2. Poly(vinyl methyl ether-maleic anhydride) matrices containing timolol (59)
3. Polycyanoacrylate nanoparticles to improve the corneal penetration of hydrophilic drugs (60)
4. An aqueous dispersion with limited water solubility (61)
5. In situ forming gel preparation (62)
6. Sustained-release liposomes coated with a mucoadhesive polymer (63)
7. Microsphere preparations (64)
8. Mucoadhesive polysaccharides (65)
Ocular inserts (cylindrical rods) fabricated from medical grade silicone rubber have also been evaluated for sustained delivery of oxytetracycline (OXT) when placed in the upper or lower conjunctival fornix (58). Cylindrical rods (diameter 0.9 mm, length 6-12 mm, weight 3-8 mg) all containing OXT were prepared from mixtures of silicone elastomer, OXT, and sodium chloride as a release modifier. A stable polyacrylic acid (PAA) or polymethacrylic acid (PMA) interpenetrating polymer network (IPN; 30% or 46% w/w) was grafted onto the insert's surface by treatment with a mixture of acrylic (or methacrylic) acid and ethylene glycol dimethacrylate in xylene at 100° C. This grafting procedure was employed since the hydro-phobic silicone rubber would not be mucoadhesive to the hydrophilic pal-pebral and scleral mucosae. The thickness of the IPN layer was positively correlated with the strength of mucoadhesion in vitro with the PMA IPN grafting causing a lower rate of release of OXT than the IPN graft comprised of PAA (58). Release of OXT in vitro was zero-order and spanned nearly a week for some of the PMA IPN grafted silicone rods. When tested in rabbits, some of the IPN grafted inserts maintained in the lacrimal fluid an OXT concentration of 20-30 ^g/mL for several days; an OXT concentration sufficient for killing microorganisms responsible for common ocular infections (58).
The use of poly(vinyl methyl ether-maleic anhydride) (PVMMA) ocular inserts containing timolol was shown to have both advantages and limitations. Timolol, a nonselective ^-adrenergic antagonist widely used to treat open-angle glaucoma, can produce unwanted respiratory and cardiovascular side effects when systematically absorbed following ocular instillation. Using pigmented rabbits, Lee et al. (66) demonstrated that timolol/ PVMMA inserts released the drug relatively slowly (ffi 50% of the loading dose in 6 h) in vitro but increased the extent of systemic timolol absorption (AUC). The timolol/PVMMA inserts reduced the peak timolol concentration in plasma (Cmax) and significantly delayed the time at which the timolol Cmax was attained, raising the possibility that delayed timolol absorption occurred until the timolol/PVMMA inserts were discharged into the nasal cavity (66).
Poly(alkylcyanoacrylate) nanoparticles, specifically those formulated with poly(isobutylcyanoacrylate), have been systematically evaluated in vitro by Das et al. (67). Several formulation variables were assessed in a factorial design, including the use of dextran T40 or T70 and PluronicTM F-68 or TweenTM 20 acting as stabilizer and surfactant, respectively, and three pH levels (2, 4, and 7). Significant effects of pH, surfactant, and stabilizer were noted on the molecular weight and size distribution of the timolol-containing nanoparticles (67). As an example, the greatest percent yield of formulated timolol nanoparticles was the PluronicTM F-68 at pH 2. These authors concluded that formulation variables are extremely important for optimal in vivo performance of all poly(alkylcyanoacrylate)-based nanopar-ticles.
The aqueous dispersion upon instillation into the eye generated an apparent opaque mass, which adhered to and stayed in the lower fornix for extended periods of time. The slow dissolution of the polymer itself and diffusion of pilocarpine out of the polymeric matrix probably controls the availability of the drug for ocular absorption (68).
Similar results of pilocarpine ocular availability enhancement due to precorneal retention through mucoadhesion has been reported by Saettone et al. (69). This group investigated the use of a series of bioadhesive polymers, including hyaluronic acid, polygalacturonic acid, mesoglycan, and carboxymethylchitin.
In situ activated gel-forming systems can be described as viscous liquids, which undergo a transition to the gel phase upon exposure to certain physiological conditions like a pH change or temperature change. The systems utilize polymers that demonstrate transition from a sol to a gel phase when the dosage form is applied to the corneal surface. The phase transition occurs either due to a change in the pH (e.g., from 4.5 to 7.4) or due to a change in the temperature (from a lower temperature to the temperature of the corneal surface). Josh et al. were the first to report the use of a combination of polymers in such systems (70). They reported that a combination of polymers elicit the desired characteristics when subjected to changes in the physicochemical environment. Another factor that may affect this transition is the change in electrolyte composition. Several polymers such as carbopol, methylcellulose, pluronics, tetronics, and cellulose acetophthalate (CAP) have been used for this purpose. In order to reduce polymer content, Kumar and Himmelstein (71) developed a combination of polymers, which included polyacrylic acid (PAA) and hydroxypropylmethylcellulose (HPMC) for the release of timolol maleate. Various studies involving several different polymers have shown to increase ocular bioavailability. Rozier et al. found an improvement in the ocular absorption of timolol in the albino rabbit when administered in Gelrite, when compared with an equiviscous solution of hydroxyethylcellulose (72). Sanzigiri et al. compared various systems of methylprednisolone (MP): ester of Gelrite eyedrops, gellan-MP film, and gellan film with dispersed MP. The authors showed that the gellan eyedrops provided significant MP precorneal levels over a period of 6 hours (73).
Davies et al., using rabbits demonstrated that liposomes containing the mydriatic tropicamide and coated with either Carbopol 934P or Carbopol 1342 (a hydrophobic modified Carbopol resin) displayed a significant increase in precorneal retention at pH 5 compared to noncoated 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 demonstrated 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 corresponding 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 111In 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 prepared 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 mIn aqueous suspension (64). Clearance of the microspheres demonstrated a biphasic (a = rapid initial phase and p = slower phase) profile, and microspheres buffered at pH 5 exhibited a significantly slower p phase than microspheres 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 formulated 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 evaluated 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-
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 (7780). Some of the materials indicated as "ocular mucoadhesives" are mentioned below.
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 specifically 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.
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 vehicles have shown comparable corneal adhesion to that of mucin. The study concluded that ocular therapeutic agents would be well absorbed from topical formulations containing such polymers. Since only marginal improvements (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 interpenetration and subsequent physical entanglement. These kinds of networks may be formed by:
1. Physical intertwining of the polymers
2. Bridging of the polymer chains
Thus, cross-linked polyacrylic acid has been shown to have an excellent 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 formulations 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 formulations 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 underlying bulbar conjunctiva (88). A partially esterified acrylic acid polymer was successful in prolonging the therapeutic effect of topically applied pilocar-
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 vitreous 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.
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