IJCRR - Vol 02 Issue 01, January, 2010
Date of Publication: 30-Nov--0001
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OCULAR INSERTS: A REVIEW
Author: N. K. Sahane, S. K. Banarjee, D. D. Gaikwad, S. L. Jadhav, R. M. Thorat
Abstract:Ophthalmic drug delivery is one of the most interesting and challenging endeavors facing the pharmaceutical scientist. The anatomy, physiology and biochemistry of the eye render this organ exquisitely impervious to foreign substances. The challenge to the formulator is to circumvent the protective barriers of the eye without causing permanent tissue damage. Newer delivery system is being explored to develop extended duration and controlled release strategy. Some of the newer, sensitive and successful ocular delivery system like
inserts, biodegradable polymeric system, and collagen shields are being developed in order to attain better ocular bioavailability and sustained action of ocular drugs.
Keywords: Diffusional inserts, Osmotic inserts, Contact lenses, Soluble inserts, Bioerodible inserts.
Eye, as a portal for drug delivery is generally used for the local therapy as against systemic therapy in order to avoid the risk of eye damage from high blood concentrations of drug which are not intended for eye.
Newer delivery systems are being explored to develop extended duration and controlled release strategy. Some of the newer, sensitive and successful ocular delivery systems like inserts, biodegradable polymeric systems, collagen shields are being developed in order to attain better ocular bioavailability and sustained action of ocular drugs.
The following recent trends are in vogue : a) Mucoadhesive dosage forms b) Ocular inserts c) Collagen shields d) Drug presoaked hydrogel type contact lens and pledgets. e) Ocular iontophoresis f) Phase transition systems g) Microspheres and nanoparticles h) Chemical delivery systems vesicular systems.
Utilization of the principle of controlled release as embodied by ocular inserts therefore offers an attractive alternative approach to the difficult problem of prolonging pre-corneal drug residence time14.
Recentaly, drug-presoaked hydrogel contact lenses and pledgets have gained some popularity in an attempt to bypass the need for repeatative drug dosing and to avoid the peak and valley activity time curve resulted from periodic application of eye drops and ointment. A micropump type delivery system have also been developed for the continuous administration of fluid to dry eyes or medication to infected eyes. These drug delivery system have successed in significantly reducing the frequency of dosing and also in remarkably improving the therapeutic efficacy of ophthalmic drug 5 .
Ocular disposition and elimination of a therapeutic agent is dependent upon its physicochemical properties as well as the relevant ocular anatomy and physiology 6 . The successful design of a drug delivery system, therefore, requires an integrated knowledge of the drug entity and the constraints to delivery offered by the ocular route of administration.
mechanism of ocular drug absorption
Topical delivery into the cul-de-sac is, by far, the most common route of ocular drug delivery. Absorption from this site may, i. Corneal ii. Non-cornea The non-corneal route of absorption involves penetration across the sclera and conjunctiva into the intraocular tissues. This mechanism of absorption is usually not productive, as drug penetrating the surface of the eye beyond the corneal-sclera limbs is picked up by local capillary beds and removed to the general circulation. This non-corneal absorption in general precludes entry into the aqueous humor.
The non-corneal route of administration may be significant for drug molecules with poor corneal permeability. Studies with Insulin, Timolol Maleate, Gentamycin suggest that these drugs gain intraocular access by diffusion across the conjunctiva and sclera 7 .
Corneal absorption Represents the major mechanism of absorption for most therapeutic entities. Topical absorption of these agents, then is, considered to be rate limited by the cornea. The anatomical structures of the cornea exert unique differential solubility requirements for drug candidates. Cornea can be viewed as a trilaminate structure consisting of these major diffusional barriers.
Out of three, the epithelium and endothelium contains on the order of 100 fold the most of lipid material than stroma. Depending on the physicochemical properties of the drug entity, the diffusional resistance offered by the tissues varies greatly .
The outermost layer, the epithelium, represents the rate limiting barrier for transcorneal diffusion of most hydrophilic drugs.
The flattened epithelial cells preclude paracellular transport of most ophthalmic drugs and limits lateral movement within the anterior epithelium. Corneal surface epithelial intracellular pore size has been estimated to be about 60 A0 . Hence small ionic and hydrophilic molecules appear theogain access to the anterior chamber through these pores. However, for most drugs, paracellular transport is precluded by the interjunctional complexes.
The stroma comprises 85-90% of the total corneal mass and is composed mainly of hydrated collagen. The stroma exerts a diffusional barrier to highly lipophilic drugs owing to its hydrophilic nature. There are no tight junction complexes in the stroma, and paracellular transport through this tissue is possible.
The innermost endothelium is lipoidal in nature; however, it does not offer a significant barrier to the transcorneal diffusion of most drugs. Studies have shown that endothelial permeability depends solely on molecular weight and not the charge or hydrophilic nature of the compound.
Transcellular transport across the corneal epithelium and stroma is the major mechanism of ocular absorption of topically applied ophthalmic pharmaceuticals. This type of Fickian diffusion is dependent upon many factors i.e., surface area, diffusivity, the concentration gradient established and the period over which the concentration gradient can be maintained.
The productive absorption of most ophthalmic drugs results from diffusional process across the corneal membrane. The efficiency of the absorption process is a function of the rate and extent at which the transport processes occur. The flux of any drug molecule across a biological membrane depends on the physicochemical properties of the permeating molecule and its interaction with the membrane. The absorption process is also a function of the physiological mechanism of pre-corneal fluid drainage or turnover 8 .
FACTORS AFFECTING CORNEAL TRANSPORT
The physicochemical properties of the drug substance like ionization constants, aqueous, oil/water partition coefficients.
1) The formulation in which the drug is prepared e.g. pH of the solution, types and concentrations of buffers, viscosity inducing agents and stabilizers. 2) The corneal structure and integrity 9 .
The topical application of ophthalmically active drugs to the eye is the most prescribed route of administration for the treatment of various ocular disorders. It is generally agreed that the intraocular bioavailability of topically applied drugs is extremely poor. Upon instillation of an ophthalmic solution, most of the instilled, volume is eliminated from the pre-corneal area1,10. This loss is mainly due to drainage of the excess fluid by the nasolacrimal duct and dilution and elimination of the solution by tear turnover and results in poor ocular bioavailability. Ocular bioavailability of drugs is an important parameter influencing efficacy of ophthalmic preparations. It has long been recognized that the vehicle or drug delivery system can affect bioavailability. This has been well established by invasive pharmacokinetic techniques11-13 Factors affecting intraocular bioavailability
i. The presence of lacrimal fluid in the cul-de-sac dilutes the drug solution instilled into the pre-corneal area of the eye, and the continual inflow and outflow of lacrimal fluid can also cause a significant loss of applied drug.
ii. Drug kinetics in the conjunctival culde-sac i.e. pre-corneal 9 .
iii. The efficient nasolacrimal drainage, acts as a conduct through which an instilled drug solution may be drained away from the pre-corneal area.
iv. The substances like protein present in the lacrimal fluid can interact with and/or degrade the drugs introduced into the ocular cavity.
v. The permeability of the cornea to drug species (Corneal).
vi. The rate at which drug is eliminated from the eye (post corneal) 9 .
vii. The productive and non-productive absorption to topically applied drugs into various ocular tissues, most notably the cornea and conjunctiva.
viii. The high corneal permeability corresponding to lipophilic compounds produces the highest bioavailability, and is relatively unaffected by drug volume14 .
ix. By making the dosage volume sufficiently small, a bioavailability factor of 4 can be obtained for drugs with low corneal permeability.
x. Ocular availability of the topically administered drug is dependent on the contact time that a drug has with the absorbing corneal surface 10 .
Ocular Pharmacokinetics and Pharmacodynamics
The study of pharmacokinetic processes called absorption, distribution and elimination, are fundamentals to determine the appropriate dosing regimen. These have also been indispensable in designing an improved therapeutic agent. When classic pharmacokinetic approaches have been applied to ophthalmic drugs, a number of limitations have been found to restrict the usefulness of pharmacokinetics in the practice of ophthalmology.l
Limitations to the practical use of classic modeling
The most significant reason for not conducting ocular pharmacokinetic studies in the human eye is the inability to sample tissues or fluids from the intact eye without risking pain and/or injury. Predicting human ocular pharmacokinetics from a rabbit data may not be precise for certain drugs. Moreover, samples, from eye tissues cannot be continuously sampled over time. Although a number of tissues can be removed quickly and precisely from the rabbit eye, one animal must be used to determine drug concentration at a single time point. Therefore, in order to construct a kinetic profile of drug concentration over time, a number of rabbits must be sacrificed at each time interval 15.
Ocular Pharmacokinetic Modeling
The classic pharmacokinetic approach of expressing the concentration-time curve into a sum of exponential has been applied to the eye,16 but much less extensively than other routes of administration. In the eye aqueous humor is most often assigned the central compartment, which is reversibly connected to one or more peripheral compartments and/or a reservoir compartments. Drugs instilled topically on the eye primarily reach the first third of the eye. These drugs do not reach the retina in significant concentrations.
The following is the scheme that is most commonly applied to ophthalmic drugs following topical application.l