Ocular drug delivery limitations

If the medical drug is applied topically to the eye, another important factor for ocular drug delivery and penetration has to be taken in account that is, the precorneal clearance which rapidly reduces the drug amount available for penetration. Thus, it is a major factor to take into consideration while evaluating (transcorneal) absorption. So far, due to experimental limitations, not much thought has been given to precorneal clearance in cell-based in vitro models. 

The synchronized movement of the eyelids spreads the precorneal tearfilm across the cornea and pushes it toward the nasolacrimal duct. Precorneal drainage is quite efficient. An aqueous instilled dose leaves the precorneal area within 5 min of instillation in humans. Most of the drug absorbed by transcorneal penetration, without retention modification, is spread across the cornea by the eyelids in the first minutes postdosing. In the precorneal space transcorneal penetration is limited by solution drainage, lacrimation and tear dilution, tear turnover, conjunctival absorption, and the corneal epithelium. Slowing down tear film turnover has well-established benefits to topical ocular drug delivery. 

Liposomes can be easily prepared from non-toxic materials, which are non-irritant and do not obscure vision. Unfortunately, routine use of liposomes in topical ocular drug delivery is presently limited by short shelf life of the formulation, limited drag loading capacity and obstacles in sterilizing the preparation. 

Liposomes are potentially valuable as ocular drug delivery systems due to their simplicity of preparation and versatility in physical characteristics. However, their use is limited by instability (due to hydrolysis of the phospholipids), limited drugloading capacity, technical difficulties in obtaining sterile preparations, and blurred vision due to their size and opacity [42],... 

Given all of these limitations, ocular drug delivery becomes a formidable challenge and the estimated bioavailability of most approved drugs falls within the range of 1—7% [17]. Hence, novel delivery methods are being explored to attain better ocular bioavailability and sustained action of ocular dmgs [18]. Some of the newer, successful ocular delivery systems include the use of bioresorbable polymer—based systems. 

During the past four decades, iimiunerous polymers have been used in the development of ocular drug delivery systems (ODDS). These systems allow overcoming some of the limitations associated with topical administration of drugs and combine features like controlled drug release over a long period of time, decreased dmg losses and adverse effects, and increased residence time of the dmg in the tear film [5]. 

The conventional concentration of benzalkonium chloride in eyedrops is 0.01%, with a range of 0.004-0.02% [111]. While uptake of benzalkonium chloride itself into ocular tissues is limited [113], even lower concentrations of benzalkonium chloride have been reported to enhance corneal penetration of other compounds including therapeutic agents [93,112,114]. The differential effect of this preservative on the cornea compared to the conjunctiva can be exploited to target a drug for corneal absorption and delivery to the posterior segment of the eye [115]. Its use has been proposed as a means of delivering systemic doses by an ocular route of administration [116]. 

The most common drug delivery method for treating ocular disorders is topical administration, due to its convenience and safety. However, the anterior segment of the eye also has various protective mechanisms for maintaining visual functions. After instillation of an ophthalmic drug, most of it is rapidly eliminated from the precorneal area due to drainage by the nasolacrimal duct and dilution by the tear turnover (approximately 1 pL/min) [17,18]. In addition, there is a finite limit to the size of the dose that can be applied and tolerated by... 

The ototopical antimicrobial preparations stated earlier suffice for most cases of otitis externa and selected cases of chronic suppurative otitis. However, these compounds have a limited effect in certain patients with resistant strains of bacteria, drug-induced allergies, or a tympanic membrane perforation that requires administration into the middle ear space. In the last case, ototopical preparations may cause pain because of the acidic pH or the presence of alcohol. Ototoxicity of neomycin, polymyxin B, and colistin is also of concern, and many otolaryngologists prefer topical ophthalmic preparations.f Ophthalmic preparations are discussed in the article Ocular Drug Formulation and Delivery in this volume. 

Most ocular diseases like dryness, conjunctiva, and eye flu are treated by topical drug application in the form of solutions, suspensions, and ointment. In the earlier period, drug delivery to the eye has been limited to topical application, redistribution into the eye following systemic administration, or direct intraocular/periocular injections. However, one of the major barriers of ocular medication is to obtain and maintain a therapeutic level at the site of action for a prolonged period of time. 

Drug delivery by injectable liposomes is well known in the pharmaceutical industry. Liposome suspensions of various compositions have been developed to enhance a sustained release of medications in the anterior segment of the eye, but one of the major problems in such ocular applications is limited drug uptake, because liposome suspensions are quickly washed away by tearing action. 

Ophthalmic diseases are most commonly treated by topical instillation of eye drops. These formulations evidence limitations like poor stability and efficacy, reduced cor-neal/scleral permeability, systemic toxicity and lack of compUance [2]. In this sense, the development of effective therapies for visual disorders is of high priority [1], which makes the field of ocular delivery one of the most interesting and challenging areas for pharmaceutical scientists [3]. There has been significant research directed towards the development of new systems for controlled drug delivery in ophthalmology such... 

Drug delivery to the eye is not an easy assignment, due to its unique anatomy and physiology, since the ocular tissue barriers limit the access of drugs to their targets, especially to the posterior segment [5,6]. 

---