Cyclodextrins in ophthalmic drug delivery
Introduction
Drugs used in ophthalmology are either administered systematically (e.g. by oral route) or locally to the eye. Usually local drug administration is preferred, and then in the form of topically applied low viscosity aqueous eye drop solutions. Other topically applied drug formulations, such as suspensions, oily drops, gels, ointments and solid inserts, have also been used but most of these formulations give rise to unwanted side-effects (e.g. eye irritation and blurred vision) [1].
Cyclodextrins (CDs) are a group of cyclic oligosaccharides which have been shown to improve physicochemical properties of many drugs through formation of inclusion complexes. In drug development, CDs have mainly been used to increase the aqueous solubility and stability of poorly water-soluble drugs. CD complexation of lipophilic drugs has also been shown to increase drug bioavailability. Frequently, this has been attributed to the increased solubility or dissolution rate of the complexed material [2], but sometimes increased drug bioavailability has been associated with interactions of CDs with biological membranes. Most studies on CDs and their pharmaceutical applications have dealt with oral and parenteral drug delivery. Relatively little attention has been paid to the use of CDs in ophthalmic drug delivery. However, both advantages and disadvantages of CD incorporation into ophthalmic drug formulations have gained considerable interest. Ophthalmic applications of CDs have previously been reviewed 1, 2, 3, 4. Following is a review of application of CDs in topical drug delivery to the eye with emphasis on the mode of CD action in aqueous ophthalmic drug formulations.
Section snippets
Topical drug delivery to the eye
Topical delivery of eye drops, suspensions or ointments into the lower cul-de-sac is the most common method of drug treatment in ocular diseases and diagnostics. In general, the site of action of ophthalmic drugs is located inside the eye. Unfortunately, after instillation of an eye-drop, typically less than 5% of an applied dose reaches the intraocular tissues. The main reason of this low ocular drug availability is poor drug penetration across the cornea barrier and a rapid loss of the
Toxicological considerations
The safety profiles of the three most common natural CDs and some of their derivatives have recently been reviewed 37, 38. In general, the natural CDs and their hydrophilic derivatives are only able to permeate lipophilic biological membranes, such as the eye cornea, with considerable difficulty. Even the somewhat lipophilic randomly methylated β-cyclodextrin (RM-β-CD) does not readily permeate lipophilic membranes, although it interacts more readily with the membranes than the hydrophilic CD
Cyclodextrins and ocular drug delivery
In general, the ocular bioavailability of topically applied drugs is very low, frequently less than 5% 50, 51. The main ocular barrier to drug permeability into the eye consist of lipophilic membranes (i.e. cornea, conjunctiva and sclera) but the membrane exterior consist of aqueous tear fluid and a hydrophilic mucin layer at the membrane surface. The drug molecule must be somewhat hydrophilic (i.e. water-soluble) to be able to permeate through this aqueous exterior of the eye surface but, at
Cyclodextrins as anti-irritants
Eye drops are commonly dosed at high drug concentrations, directly on the corneal surface and thus, it is not surprising that ophthalmic irritation is a common drawback in ophthalmic drug development and in their clinical use. Ophthalmic irritation may decrease patient compliance or in the case of a strong irritation, may even be a reason for patients to stop their medication. In principal, CDs may decrease the irritation of ophthalmic drugs by formation of inclusion complexes, thereby masking
Cyclodextrin stabilisation of drugs in aqueous ophthalmic formulations
The most common dosage form for topical ocular administration is the aqueous eye drop solution, which is easy to use, relatively inexpensive and does not impair vision. However, in aqueous solution, most drugs are subject to chemical degradation. The consequence of drug degradation is a decrease of drug potency and the formation of degradation products which may be harmful. Drug stability in eye drop solutions has traditionally been increased by appropriate adjustment of pH and storage
The effects of polymers on cyclodextrin complexation and the availability of drugs in cyclodextrin complexes
For a variety of reasons, including toxicological considerations, isotonicity adjustments, drug bioavailability and production cost, it is important to include as little CD as possible in ophthalmic drug formulations. Even at optimum CD concentration the drug bioavailability can be inadequate resulting in less than optimal drug delivery. Addition of small amount of water-soluble polymer to aqueous drug formulations can result in significant enhancement of the drug/CD complexation. Thus, less CD
Limitations of cyclodextrin applications in ophthalmic drug delivery
Recent studies have shown that addition of CDs to ophthalmic drug formulations can offer many advantages. However, inclusion of CDs in ophthalmic formulations has revealed that there are some basic differences between the ophthalmic formulations and other CD containing drug formulations, and that these differences may induce some limitations in the ophthalmic applications of CDs. For purpose of general overview, the various advantages and drawbacks of including CDs in ophthalmic formulations
Formulation and clinical evaluation of aqueous eye drop solutions in humans
As mentioned before, it is very important to optimise CD containing drug formulation with regard to drug availability. Simple addition of undefined amount of CD to existing formulations really leads to the desired result. Following are two examples of formulation and testing of aqueous eye drop solutions. In both cases the drug availability was enhanced through addition of a water-soluble polymer and heating in an autoclave (120–140°C for 20–40 mm).
Conclusions
Until recently the functions of CDs in ophthalmic drug delivery were poorly understood. However, numerous studies have shown that CDs are useful additives in ophthalmic formulations for increasing the aqueous solubility, stability and bioavailability of ophthalmic drugs, and to decrease drug irritation. The CD complexation of water-soluble drugs (e.g., in order to increase their chemical stability or to decrease ophthalmic drug irritation) may decrease their ophthalmic bioavailability, but this
Acknowledgements
Tomi Järvinen was supported by the Academy of Finland. Thorsteinn Loftsson gratefully acknowledges financial support from the Nagai Foundation Tokyo, Japan.
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