Challenges in Ocular Delivery

 Ophthalmic drug delivery is one of the interesting and challenging endeavors facing the pharmaceutical scientist today. The anatomy, physiology, and biochemistry of the eye render this organ highly impervious to foreign substances. A significant challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. Conventional eye drops, suspension, and ointment dosage forms no longer constitute optimal therapy for these indications. Research and development efforts to design better therapeutic systems particularly targeted to posterior segment are the primary focus of this text. The goal of pharmacotherapeutics is to treat a disease in a consistent and predictable fashion, assuming that a correlation exists between the concentration of a drug at its intended site of action and the resulting pharmacological effect. The specific aim of designing a therapeutic system is to achieve an optimal concentration of a drug at the active site for the appropriate duration of action. Ocular disposition and elimination of a therapeutic agent is dependent upon its physicochemical properties and relevant ocular anatomy and physiology . A successful design of drug delivery system, therefore, requires an integrated knowledge of the drug molecule and the constraints offered by the ocular route of administration. A host of different tissues are involved, each of which may pose its own challenge to the formulator of ophthalmic delivery systems. Hence, the drug entities need to be targeted to many sites within the globe. The focus of the research was delivery of drugs to the anterior to the anterior segment tissues. Recently, research has been directed to deliver the drug to the tissues of the posterior globe (the uveal tract, vitreous, choroid, and retina).

Anatomy and physiology of the eye

The human eye has a spherical shape with a diameter of 23 mm. The structural components of the eyeball are divided into three layers the outermost coat comprises the clear, transparent cornea and the white, opaque sclera; the middle layer comprises the iris anteriorly, the choroid posteriorly, and the ciliary body; and the inner layer is the retina, which is an extension of the central nervous system. The cornea is often the tissue through which drugs in ophthalmic preparations reach the inside of the eye, because the structure of the cornea consists of epithelium–stroma–epithelium, which is equivalent to a fat–water–fat structure. The penetration of nonpolar compounds through the cornea depends on their oil/water partition coefficients. The fluid systems in the eye — the aqueous humor and the vitreous humor also play an important role in ocular pharmacokinetics.. Drug disposition in the eye following topical application is a complex phenomenon resulting from both drug-dependent and independent parameters. Pharmacokinetics of ocular drugs, depends on the distribution and disposition of drugs in three regions of the eye: the precorneal area, cornea and the interior of the eye. The events that take place in the precorneal area of the eye are critical factors in determining how much of the instilled or applied dose is available for exerting pharmacologic effect. These precorneal factors include the effects of tear production and instilled fluid drainage, protein binding, metabolism, tear evaporation, and nonproductive absorption/ adsorption. The cornea is critical to an overall understanding of ocular drug disposition after topical dosing. There are three main factors contributing to the efficiency of corneal penetration of topically applied ophthalmic drugs: the corneal structure and its integrity, the physical–chemical properties of the applied drug, and the formulation in which the drug is prepared. There are several other factors that must be considered in the ultimate pharmacokinetic description of drug’s fate: the corneal volume or spaces (tissues) into which the drug distributes; binding of drug in both aqueous humor and tissues; partitioning behavior of drug between aqueous humor and the various ocular tissues, such as iris, lens, and vitreous humor; possible differences in equilibration time between aqueous humor and the various ocular tissues; drug metabolism in eye fluid or tissues if any ; and effect of drug in either stimulating or inhibiting aqueous humor production and turnover.

  

Schematic representation of structure of human eye and layers of cornea .

Pharmacokinetic considerations

Topical delivery into the cul-de-sac is the most common route of ocular drug delivery. Adsorption from this site may be corneal or non-corneal. The non-corneal route of absorption involves penetration across the sclera and conjunctiva into the intraocular tissues. This mechanism of absorption is usually non-productive, as drug penetrating the surface of the eye beyond the corneal-scleral limbus is taken up by the local capillary beds and removed to the general circulation. Recent studies, suggest that non-corneal route of absorption may be significant for drug molecules with poor corneal permeability. Drugs like inulin , timolol maleate , gentamicin , and prostaglandin PGF2α  gain intraocular access by diffusion across the conjunctiva and sclera. Penetration of these agents into the intraocular tissues appears to occur via diffusion across the conjunctiva and sclera and gain access to the iris–ciliary body without entry into the anterior chamber. Corneal absorption represents the major mechanism of absorption for most therapeutic entities. Topical absorption of these agents is then considered to be rate limited by the cornea. The cornea can be viewed as a trilaminate structure consisting of three diffusional barriers; epithelium, stroma, and endothelium.

Substantia propia (endothelium), composed mainly of hydrated collagen. Depending on the physiochemical properties of the drug entity, the diffusional resistance offered by these tissues varies greatly. Corneal surface and epithelial intracellular pore size has been estimated to be about 60 A˚. Small ionic and hydrophilic molecules appear to gain access to the anterior chamber through these pores. Fig 1.3 shows the schematic representation of ocular absorption and Table 1.1 gives the ocular pharmacokinetic factors of Rabbit and Human eye.

Schematic diagram of ocular absorption

Ocular pharmacokinetic factors of Rabbit and Human eye.

Pharmacokinetic Factor	Rabbit	Humans
Tear volume (µL)	5-10	7-30
Tear turnover rate (µL/min)	0.6 - 0.8	0.5 – 2.2
Spontaneous blinking rate	4 – 5 times/ hr	6- 15 times/min
Nictitating membrane	Present	Absent
Lacrimal punctum / puncta	1	2
pH of lacrimal fluids	7.3 – 7.7	7.3- 7.7
Milliosmolarity of tears	305	305
Corneal Thickness (mm)	0.40	0.52
Corneal Diameter (mm)	15	12
Corneal Surface area (cm2 )	1.5 – 2.0	1.04
Ratio of conjunctival surface and corneal surface	9	17
Aqueous Humor volume (mL)	0.25 - 0.3	0.1- 0.25
Aqueous Humor turnover rate (µL/min)	3 - 4.7	2-3

 

Formulation considerations

Irritation of the eye after using an ocular delivery system can be induced by a number of factors such as the instilled volume, pH and the osmolality of the formulation, and the drug itself. All these factors can induce reflex tearing and as a result increase lacrimal drainage, thereby reducing the ocular bioavailability of the drug. General safety considerations such as sterility, ocular toxicity and irritation, and the amount of preservative used, must be taken into account in ophthalmic formulations. Figure below explains the important factors that must be considered , for formulating a suitable ocular dosage form.

Formulation approaches to improve ocular bioavailability

The major problem encountered with topical administration is the rapid pre-corneal loss caused by nasolacrimal drainage and high tear fluid turnover which leads to only 10% drug concentrations available at the site of actions. Approaches to improve the ocular bioavailability aim at increasing the corneal permeability by using penetration enhancers or prodrugs, and prolonging the contact time with the ocular surface by using viscosity-enhancing or in-situ gelling polymers.Marketed ophthalmic delivery systems based on new formulation approaches are given in the below Table

Marketed ophthalmic delivery systems.

Formulation approach	Polymer/Base	Product	Company
suspensions/ micropaticulates	Carbomer ion exchange resin	Betoptic ® S	Alcon
Ointments	Wool fat, liquid paraffin, white soft paraffin,	Polyvisc ®	Alcon
Viscosity enhancers	PEG,PG.HP-guar, Dextran, HPMC, Na CMC,PVA,Hyaluronic acid	Systane ® Bion ® tears Refresh ® Hy-drops ®	Alcon Alcon Allergan Bausch & Lomb
Insitu gelling systems	Gellan gum Xanthan gum	Timoptic®XE Timoptic®GFS	Merck Alcon
Prodrugs	Dipivefrin HCl (epinephrine prodrug)	Propine®	Allergan
Ocular inserts	Alginic acid Hydroxypropyl cellulose Silicone elastomer Collagen shield	Ocusert® Lacrisert® Ocufit® SR MediLens®	Alza Corp. Merck. Escalon Medical Corp. Chiron.

  

Polymeric delivery systems

Polymers used for ocular drug delivery can be subdivided into three groups: viscosity enhancing polymers, which simply increase the formulation’s viscosity, resulting in decreased lacrimal drainage and enhanced bioavailability, mucoadhesive polymers which interact with the ocular mucin thereby increasing the contact time with the ocular tissues, and in-situ gelling polymers, which undergo sol-to-gel phase transition on exposure to the physiological conditions present in the eye. There are no defined boundaries between the different polymer groups and most of the polymers exhibit more than one of these properties.

Viscosity enhancing polymers

Various polymers have been   added to increase the viscosity of conventional eye drops, prolong pre-corneal contact time and subsequently improve ocular bioavailability of the drug. The hydrophilic polymers studied for ophthalmic use are polyvinyl alcohol and polyvinyl pyrrolidone, cellulose derivates such as methylcellulose and polyacrylic acids (carbopols).

Mucoadhesive polymers

Mucoadhesive polymers are usually hydrocolloids with numerous hydrophilic functional groups such as carboxyl, hydroxyl, amide and sulphate. These groups can establish electrostatic interactions, hydrophobic interactions, van der Waals intermolecular interactions and hydrogen bonding with mucus substrates. Hydrogen bonding appears to play a significant role in mucoadhesion, thus the presence of water seems to be a prerequisite for mucoadhesion. The following synthetic, semi-synthetic and naturally occurring polymers (hydroxypropylcellulose, polyacrylic acid, high-molecular-weight (>200,000) polyethylene glycols, dextrans, hyaluronic polygalacturonic acid, xyloglucan, etc.) have been evaluated for mucoadhesion.  These polymers increase the contact time of formulation with the tear film and simulate the continuous delivery of tears due to a high water restraining capacity. They also decrease the instillation frequency compared to eye drops and are therefore useful as artificial tear products²⁹. This approach relies on vehicles containing polymers that adhere via non-covalent bonds to conjunctival mucin, thus ensuring better contact of the medication with the pre-corneal tissues until mucin turnover causes elimination of the polymer. Research on mucoadhesive polymers as ingredients for ophthalmic vehicles, will hopefully lead to the development of more efficient ocular delivery systems^.

In-situ gelling systems

In-situ gelling systems are viscous polymer-based liquids that exhibit sol-to-gel phase transition on the ocular surface due to change in a specific physico-chemical parameter (ionic strength, temperature or pH). In situ gel forming systems can be classified as temperature dependent systems (e.g Pluronics, Tetronics and polymethacrylates), pH triggered systems (e.g Carbopols and cellulose acetate phthalate) and ion activated systems (e.g Gelrite and sodium alginate). The principal advantage of in-situ gelling systems is the easy, accurate and reproducible administration of a dose compared to the application of preformed gels. The concept of forming gels in-situ (e.g. in the cul-de-sac of the eye) was first suggested in the early 1980s, and since then various triggers of in-situ gelling have been further investigated. They have an advantage over preformed gels that they can be easily instilled in liquid form, and are capable of prolonging the residence time of the formulation on the surface of the eye due to gelling. Figure below explains the classification of in situ gels.