Ocular iontophoresis
Iontophoresis is the process in which direct current drives ions into cells or tissues. When iontophoresis is used for drug delivery, the ions of importance are charged molecules of the drug. [90] If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode. Ocular iontophoresis offers a drug delivery system that is fast, painless and safe; and in most cases, it results in the delivery of a high concentration of the drug to a specific site. Increased incidence of bacterial keratitis, frequently resulting in corneal scarring, offers a clinical condition that may benefit from drug delivery by iontophoresis. Iontophoretic application of antibiotics may enhance their bactericidal activity and reduce the severity of disease; similar application of anti-inflammatory agents could prevent or reduce vision threatening side effects. [91-92] But the role of iontophoresis in clinical ophthalmology remains to be identified.

Figure 15: Treatment via ocular ionotophoresis.

Liposomes are phospholipid-lipid vesicles for targeting drugs to the specific sites in the body. They provide controlled and selective drug delivery and improved bioavailability and their potential in ocular drug delivery appears greater for lipophilic than hydrophilic compounds. Liposomes offer the advantage of being completely biodegradable and relatively nontoxic but are less stable than particulate polymeric drug delivery systems. Liposomes were found to be a potential delivery system for administration of a number of drugs to the eye. [93-94]

In order to circumvent the limitations of liposomes, such as chemical instability, oxidative degradation of phospholipids, cost and purity of natural phospholipids, niosomes have been developed as they are chemically stable compared to liposomes and can entrap both hydrophilic and hydrophobic drugs. They are nontoxic and do not require special handling techniques.

Mucoadhesive dosage forms
The successful development of newer mucoadhesive dosage forms for ocular delivery still poses numerable challenges. [95] This approach relies on vehicles containing polymers which will attach, via noncovalent bonds, to conjunctival mucin. Mucoadhesive polymers are usually macromolecular hydrocolloids with numerous hydrophilic functional groups such as carboxyl-, hydroxyl-, amide and sulphate, capable of establishing electrostatic interactions. The bioadhesive dosage form showed more bioavailability of the drug as compared to conventional dosage forms. Thermes et al evaluated the effect of polyacrylic acid as a bioadhesive polymer on the ocular bioavailability of timolol. It was found that polyacrylic acid prolonged the effect of timolol. The pioneering work of Hui and Robinson illustrated the utilization of bioadhesive polymers in the enhancement of ocular bioavailability of progesterone. 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. [96]

Nanoparticles and microparticles
Particulate polymeric drug delivery systems include micro and nanoparticles. The upper size limit for microparticles for ophthalmic administration is about 5-10 mm.  Above this size, a scratching feeling in the eye can result after ocular application. Microspheres and nanoparticles represent promising drug carriers for ophthalmic application.The binding of the drug depends on the physicochemical properties of the drugs, as well as of the nano- or micro-particle polymer. After optimal drug binding to these particles, the drug absorption in the eye is enhanced significantly in comparison to eye drops. Particulates such as nanoparticles, nanocapsules, submicron emulsions, nanosuspensions improved the bioavailability of ocularly applied drugs. [97-99]

Ocular penetration enhancer
Typically classical penetration enhancers have a nonspecific action on biological membranes. They work by reversibly or permanently damaging membranes; therefore, their safety is questionable. Newer penetration enhancers that have been introduced in ocular drug delivery recently with the aim of solving these problems are cyclodextrins, 1-Dodecylazacycloheptan-2-one, Saponin, α-AminoAcid, Pz peptide, etc. Obviously, penetration enhancement has its limit. It is not possible to increase bioavailability indefinitely by use of penetration enhancement alone. Other approaches such as increased residence time and inhibition of metabolizing enzymes should be used in conjunction with penetration enhancement. [100]

Use of hyaluronic acid
The sodium salt of hyaluronic acid (SH) is a high molecular weight biological polymer, made of repeating disaccharide units of glucuronic acid and N-acetyl-b-glucosamine. In the eye, SH is present in the vitreous body and, in lower concentrations, the aqueous humor. SH have several uses in ophthalmic therapy, such as protecting corneal endothelial cells during intraocular surgery, replacing vitreous humor, acting as a tear substitute in the treatment of dry eye and increasing the precorneal residence time of various drugs.

The development of an ophthalmic drug delivery system based on cyclodextrins is relatively recent, occurring in the Patel GM, et al.: Advances and challenges in ocular drug delivery system early 1990s. Cyclodextrins were introduced in ocular drug formulations initially with the aim of increasing the solubility of lipophilic drugs in solution. The authors also observed a decreased toxicity of the drug cyclodextrin complex compared to the usual drug formulation or the prodrug solution (e.g., Pilocarpine Prodrug). Finally, most authors showed increased corneal permeability and increased bioavailability of the drug despite the assumption that the complexes did not penetrate across biological membranes. However, cyclodextrin derivatives possess their own toxicity and these observations vary depending on the studies. Kanai et al (1989) tested different combinations of ~-CD and a lipophilic immunosuppressive agent cyclosporin. They found that the complex of cyclosporin-~-CD resulted in lower corneal toxicity and penetrated into the cornea 5–10 times more than did the drug in a lipophilic vehicle.[101] Cheeks et al confirmed these results in their study on the corneal penetration of cyclosporin.[102] Sasamoto et al, when testing the same cyclosporin-~-cyclodextrin complex to increase drug solubility, recommended topical ~-cyclodextrin-cyclosporin for treating anterior uveitis in rats with the same efficacy as topical fluorometholone solution.[103]

Non-aqueous vehicle
A non-aqueous, comfortable vehicle is desired for topical ophthalmic drug delivery because of drug degradation triggered by water or the premature leakage of the drug from the delivery system in the presence of water. Typically, lipophilic vehicles (that is, mineral oils and vegetable oils) have been used, but they are poorly accepted by patients due to blurred vision and matted eyelids. Reconstitution with water prior to use is unacceptable because of cost and patient compliance issues. Perfluorocarbons or fluorinated silicone liquids have recently been suggested as good non-aqueous vehicles for topical ophthalmic drug delivery. [104] They are chemically and biologically inert and have low surface tension, excellent spreading characteristics and close-to-water refractive indices. Perfluorocarbons have been studied for years as a blood substitute; minimal systemic toxicity is expected via the topical route. [105]

Oxime and methoxime analogs of β-blockers (soft β-blockers for eye targeting)
Several oxime or methoxime analogs of known β-adrenergic blockers are of interest as potential antiglaucoma agents. [106,107] They represent an important class of potential drugs developed using general retro-metabolic drug design principles and can be considered as site-specific enzyme-activated chemical delivery systems (CDSs).[108] The oxime-type CDS approach proposed here provides site-specific or site-enhanced delivery through sequential, multi-step enzymatic and/or chemical transformations [Figure 7]. In the case of eye-targeting CDS, this is achieved through a targetor (T) moiety that is converted into a biologically active function by enzymatic reactions that take place primarily, exclusively or at higher activity at the site of action (i.e., Enz2) as a result of differential distribution of certain enzymes found at the site of action.



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