The use of mucoadhesive polymers in ocular drug delivery☆
Introduction
Topical application of drugs to the eye is the most popular and well-accepted route of administration for the treatment of various eye disorders. The bioavailability of ophthalmic drugs is, however, very poor due to efficient protective mechanisms of the eye. Blinking, baseline and reflex lachrymation, and drainage remove rapidly foreign substances, including drugs, from the surface of the eye. Moreover, the anatomy, physiology and barrier function of the cornea compromise the rapid absorption of drugs [1].
Frequent instillations of eye drops are necessary to maintain a therapeutic drug level in the tear film or at the site of action. But the frequent use of highly concentrated solutions may induce toxic side effects and cellular damage at the ocular surface [2], [3], [4].
To enhance the amount of active substance reaching the target tissue or exerting a local effect in the cul-de-sac, the residence time of the drug in the tear film should be lengthened. Moreover, once-a-day formulations should improve patient compliance.
Numerous strategies were developed to increase the bioavailability of ophthalmic drugs by prolonging the contact time between the preparation, and therefore the drug, and the corneal/conjunctival epithelium. The use of a water-soluble polymer to enhance the contact time and possibly also the penetration of the drug was first proposed by Swan [5]. Where very promising results and improved bioavailability were observed in animal studies, only a small increase in precorneal residence time was obtained in humans [6]. There is no reliable correlation between the performance of ophthalmic vehicles in rabbits and in humans, mainly due to differences in blinking frequency [7], [8], [9], [10], [11].
Viscous semi-solid preparations, such as gels and ointments, provide a sustained contact with the eye, but they cause a sticky sensation, blurred vision and induce reflex blinking due to discomfort or even irritation [12], [13].
An alternative approach has been the application of in situ gelling systems or phase transition systems, which are instilled in a liquid form and shift to a gel or solid phase in the cul-de-sac. The phase transition is triggered by the pH of the tears, the temperature at the eye surface or the electrolytes present in the tear film [14], [15], [16], [17].
A further approach to optimize the ocular dosage form was the implementation of the mucoadhesive concept, which was successful in buccal and oral applications [18], [19]. Interactions of suitable natural and synthetic polymers with mucins were evaluated. Due to interactions with the mucus layer or the eye tissues, an increase in the precorneal residence time of the preparation was observed. Some mucoadhesive polymers showed not only good potential to increase the bioavailability of the drug applied, but also protective and healing properties to epithelial cells [10], [17], [18], [20], [21], [22].
As excellent reviews on mucoadhesion in ocular drug delivery have been published previously [1], [10], [20], [21], [23], [24], [25], [26], [27], the present article will focus on the latest research and novel concepts.
Section snippets
Anatomy and physiology
Only a brief discussion of the structures of the eye, which come in contact with drug delivery systems administered topically, is given.
Tear film
The exposed part of the eye is covered by a thin fluid layer, the so-called precorneal tear film. The film thickness is reported to be about 3–10 μm depending on the measurement method used. The resident volume amounts to about 10 μl [10], [11], [50], [51]. According to the «three layers theory» the precorneal tear film consists of a superficial lipid layer, a central aqueous layer and an inner mucus layer (see Fig. 2) [10], [11].
The superficial lipid layer (a 100-nm-thick multimolecular film)
Conclusions
Considerable advances have been made in understanding the biochemistry of mucins. The implications to dry eye syndromes are now better understood. However, the exploitation of specific structural or chemical features for the development of drug delivery platforms has only started. A good balance between excellent adherence, prolonged residence time, controlled drug release and low irritation potential, tolerability and acceptance by the patients must be achieved.
In liquid dosage forms, such as
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Mucoadhesive Polymers: Strategies, Achievements and Future Challenges”, Vol. 57/11, 2005.