Elsevier

Advanced Drug Delivery Reviews

Volume 57, Issue 11, 3 November 2005, Pages 1595-1639
Advanced Drug Delivery Reviews

The use of mucoadhesive polymers in ocular drug delivery

https://doi.org/10.1016/j.addr.2005.07.005Get rights and content

Abstract

In the present update on mucoadhesive ocular dosage forms, the tremendous advances in the biochemistry of mucins, the development of new polymers, the use of drug complexes and other technological advances are discussed. This review focusses on recent literature regarding mucoadhesive liquid (viscous solutions, particulate systems), semi-solid (hydrogel, in situ gelling system) and solid dosage forms, with special attention to in vivo studies. Gel-forming minitablets and inserts made of thiomers show an interesting potential for future applications in the treatment of ocular diseases.

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

References (341)

  • Y. Ban et al.

    Tight junction-related protein expression and distribution in human corneal epithelium

    Exp. Eye Res.

    (2003)
  • K. Järvinen et al.

    Ocular absorption following topical delivery

    Adv. Drug Deliv. Rev.

    (1995)
  • M.I. Roat et al.

    Conjunctival epithelial cell hypermitosis, goblet cell hyperplasia in atopic keratoconjunctivitis

    Am. J. Ophthalmol.

    (1993)
  • K. Tsubota

    Tear dynamics and dry eye

    Prog. Retin. Eye Res.

    (1998)
  • P.L. Lama

    Systemic adverse effects of beta-adrenergic blockers: an evidence-based assessment

    Am. J. Ophthalmol.

    (2002)
  • S.C.G. Tseng et al.

    Important concepts for treating ocular surface and tear disorders

    Am. J. Ophthalmol.

    (1997)
  • N.J. Van Haeringen

    Clinical biochemistry of tears

    Surv. Ophthalmol.

    (1981)
  • J.C. Pandit et al.

    Physical properties of stimulated and unstimulated tears

    Exp. Eye Res.

    (1999)
  • K. Khanvilkar et al.

    Drug transfer through mucus

    Adv. Drug Deliv. Rev.

    (2001)
  • T.J. McMaster et al.

    Atomic force microscopy of the submolecular architecture of hydrated ocular mucins

    Biophys. J.

    (1999)
  • P. Argüeso et al.

    Epithelial mucins of the ocular surface: structure, biosynthesis and function

    Exp. Eye Res.

    (2001)
  • I.K. Gipson et al.

    Mucin genes expressed by the ocular surface epithelium

    Prog. Retin. Eye Res.

    (1997)
  • C. Lange et al.

    Mucin gene expression is not regulated by estrogen and/or progesterone in the ocular surface epithelia of mice

    Exp. Eye Res.

    (2003)
  • H.B. Paz et al.

    The role of calcium in mucin packaging within goblet cells

    Exp. Eye Res.

    (2003)
  • L.P. Aristoteli et al.

    Isolation of conjunctival mucin and differential interaction with Pseudomonas aeruginosa strains of varied pathogenic potential

    Exp. Eye Res.

    (2003)
  • J.E. Jumblatt et al.

    Regulation of ocular mucin secretion by P2Y2 nucleotide receptors in rabbit and human conjunctiva

    Exp. Eye Res.

    (1998)
  • O.D. Schein et al.

    Relation between signs and symptoms of dry eye in the elderly. A population-based perspective

    Ophthalmology

    (1997)
  • C.A. McCarty et al.

    The epidemiology of dry eye in Melbourne, Australia

    Ophthalmology

    (1998)
  • A. Tomlinson et al.

    Effect of oral contraceptives on tear physiology

    Ophthalmic Physiol. Opt.

    (2001)
  • V.H.L. Lee et al.

    Review: topical ocular drug delivery: recent developments and future challenges

    J. Ocul. Pharmacol.

    (1986)
  • L. Salminen

    Review: systemic absorption of topically applied ocular drugs in humans

    J. Ocul. Pharmacol.

    (1990)
  • C. Baudouin

    Side effects of antiglaucomatous drugs on the ocular surface

    Curr. Opin. Ophthalmol.

    (1996)
  • A. Topalkara et al.

    Adverse effects of topical antiglaucoma drugs on the ocular surface

    Clin. Exp. Ophthalmol.

    (2000)
  • K.C. Swan

    The use of methyl cellulose in ophthalmology

    Arch. Ophthalmol.

    (1945)
  • A. Ludwig et al.

    Influence of viscolysers on the residence of ophthalmic solutions evaluated by slit lamp fluorophotometry

    S.T.P. Pharma Sci.

    (1992)
  • M.F. Saettone et al.

    Vehicle effects on ophthalmic bioavailability: the influence of different polymers on the activity of pilocarpine in rabbit and man

    J. Pharm. Pharmacol.

    (1982)
  • M.F. Saettone et al.

    The validity of rabbits for investigations on ophthalmic vehicles: a comparison of four different vehicles containing tropicamide in humans and rabbits

    Pharm. Acta Helv.

    (1982)
  • I. Zaki et al.

    A comparison of the effects of viscosity on the precorneal residence of solutions in rabbit and man

    J. Pharm. Pharmacol.

    (1986)
  • J.C. Robinson

    Ocular anatomy and physiology relevant to ocular drug delivery

  • O. Dudinski et al.

    Acceptability of thickened eye drops to human subjects

    Curr. Ther. Res.

    (1983)
  • M.B. Sintzel et al.

    Biomaterials in ophthalmic drug delivery

    Eur. J. Pharm. Biopharm.

    (1996)
  • J.R. Robinson

    Ocular drug delivery. Mechanism(s) of corneal transport and mucoadhesive delivery systems

    S.T.P. Pharma

    (1989)
  • C.A. Le Bourlais et al.

    New ophthalmic drug delivery systems

    Drug Dev. Ind. Pharm.

    (1995)
  • R. Krisnamoorthy et al.

    Mucoadhesive polymers in ocular drug delivery

  • M.F. Saettone et al.

    Ocular bioadhesive drug delivery systems

  • I.P. Kaur et al.

    Penetration enhancers and ocular bioadhesives: two new avenues for ophthalmic drug delivery

    Drug Dev. Ind. Pharm.

    (2002)
  • M.M. Van Ooteghem

    Factors influencing the retention of ophthalmic solutions on the eye surface

  • P. Versura et al.

    Scanning electron microscopy of normal corneal epithelium obtained by scraping-off in vivo

    Acta Ophthalmol. (Copenh.)

    (1985)
  • A.J.W. Huang et al.

    Paracellular permeability of corneal and conjunctival epithelia

    Invest. Ophthalmol. Visual Sci.

    (1989)
  • A.C.H. Yeo et al.

    Relationship between goblet cell density and tear function tests

    Ophthalmic Physiol. Opt.

    (2003)
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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.

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