IN SITU GEL-FORMING SYSTEMS FOR SUSTAINED OCULAR DRUG DELIVERY

By Mahesh N Mali and Ashok A Hajare

Figure 1. Cross-section of eye.

n the development of ophthalmic products, drug delivery is one of the most challenging and difficult fields for investigators. The conventional formulations such as solutions, suspensions, ointments, etc. shows some constraints such as increased precorneal elimination, high variability in efficiency and blurred vision, respectively, which reduce their bioavailability. In situ activated gelforming systems are liquid upon instillation and undergo phase transition in the ocular cul-de-sac to form a viscoelastic gel in response to environmental changes such as change in temperature, pH and osmolarity. In the past few years, an impressive number of novel temperature, pH, and ion induced in situ gel-forming systems have been reported for sustain ophthalmic drug delivery. This review includes investigation of various temperature, pH and ion induced in situ-forming polymeric systems used to achieve prolonged contact time of drugs with the cornea and increase their bioavailability.

requirements of the eye.2 In spite of active and continued research and the frequent introduction of novel ophthalmic drugs, delivery systems do not seem to progress at the rapid pace typical of oral, transdermal or transmucosal delivery. The vast majority of existing ocular delivery systems are still fairly primitive and inefficient.3 Whenever any ophthalmic formulation is applied topically to the anterior segment of the eye, only a small amount (~5%) of drug penetrates through the cornea and reaches the internal anterior portion of the eye to have any effect. The most commonly used ophthalmic dosage forms are simple, usually water-soluble drugs delivered topically in an aqueous solution4 and waterinsoluble drugs administered topically as an ointment or aqueous suspension.
Anatomy and physiology of eye

Introduction

ASHOK A HAJARE is Head of the Department of Pharmaceutics, Bharati Vidyapeeth College of Pharmacy and Research Centre, Kolhapur, MS, India Email:aahajare@ rediffmail.com MAHESH N MALI is a research student at the same college

To improve ocular drug bioavailability, significant efforts are being directed towards new drug delivery systems for ophthalmic administration. The anatomy, physiology and biochemistry of the eye render it exquisitely impervious to foreign substances. Most ocular treatments call for topical administration of ophthalmically active drugs to the affected tissues. The basic ophthalmic solutions, suspensions and ointment dosage forms are clearly no longer sufficient to combat some presentday virulent diseases, especially in developing nations1. The development of new products for the treatment of ophthalmic diseases is facing a double challenge viz pharmacological and formulation factors. In addition, other problems are tolerability and comfort

An anatomical cross-section of the human eye (Figure 1) identifies the several ocular tissues for a better understanding of their functions and their involvement in selected ophthalmic disease, as well as to locate specific site of drug administration and action.5,6
Conventional dosage forms7

Medication is applied to the surface of the eye to treat infections such as conjunctivitis, blepharitis, keratitis sicca, etc. or to provide intraocular treatment through the cornea for diseases such as glaucoma. Conventional ophthalmic dosage forms with their benefits and constraints are listed in Table 1.
Constraints to ocular drug delivery

The poor ophthalmic bioavailability is the result of ocular anatomical and

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Table 1: Conventional ophthalmic dosage forms Dosage forms Benefits
Solutions Convenient

Constraints
Rapid precorneal elimination. Loss of drug by drainage. Non-sustained action. Drug properties decide performance. Loss of both solution & suspended solid. Blurred vision. Patients non-compliance. Possible oil entrapment. Sticking of eyelids. Blurred vision. Poor patient compliance. Drug choice limited by partition coefficient. Matted eyelids after use. No rate control on diffusion.

of the formulations prepared by these techniques require the experts and some are not comfortable to the patients. Hence no one technique is superior.
In situ gel systems

Suspensions

Patient compliance. Best for drug with slow dissolution.

Emulsions

Prolonged release of drug from vehicle.

Ointments

Flexibility in drug choice. Improved drug stability. Inhibition of dilution by tears. Resistance to nasolacrimal drainage.

A more desirable dosage form would be one that can deliver drug in a solution form, create little to no problem of vision and need be dosed no more frequently than once or twice daily. In situ activated gelforming systems are those which are when exposed to physiological conditions will shift to a gel phase. This new concept of producing a gel in situ was suggested for the first time in the early 1980s. Gelation occurs via the cross-linking of polymer chains that can be achieved by covalent bond formation (chemical cross-linking) or non-covalent bond formation (physical cross-linking).14 The progress that has been made in gel technology is in the development of a droppable gel. In situ gel-forming systems can be described as low viscosity solutions that undergo phase transition in the conjunctival cul-de-sac to form viscoelastic gels due to conformational changes of polymers in response to the physiological environment.7, 15 The rate of in situ gel formation is important because between instillation in the eye and before a strong gel is formed, the solution or weak gel is produced by the fluid mechanism of the eye.16
Importance of in situ gel systems

Gels

Comfortable. Less blurred vision.

physiological constraints. Ocular tissues are protected from various mechanisms: continuous tear secretion, an impermeable surface epithelium and a transport system actively clearing the retina. Physiological barriers to the diffusion and active absorption of topically applied ophthalmic drugs exist in the precorneal and corneal spaces.8 Precorneal constraints include solution drainage, lacrimation, tear dilution, tear turnover and conjuctival absorption. For appropriate bioavailability, a proper duration of contact with the cornea should be maintained.9 An instilled dose leaves the corneal area within 5 minutes of instillation in humans.10 The natural capacity of the conjunctival cul-de-sac is 7-10l whereas an ophthalmic dropper delivers about 30l.11 Lacrimation can be induced by many factors: drug entity, pH and tonicity of the dosage form.12 Formulation adjuvants can also stimulate tear secretion.13 Tear turnover acts to remove drug solution from the conjuctival cul-de-sac.

Clearly, the physiological barriers to topical corneal absorption are formidable. The result is that the clinician is forced to recommend frequent high doses of drugs to achieve the desired therapeutic effect. This regimen not only results in extreme fluctuations in ocular drug concentration but may cause many local and/or systemic side effects. To solve these constraints and to improve bioavailability, various novel techniques have been developed such as the use of viscosity imparting agents, ocular penetration enhancers, corneal collagen shields, the design of drug delivery systems targeting the noncorneal route, ophthalmic inserts, ocular iontophoresis, using mucoadhesive polymers, aqueous gels, particulate systems viz microspheres and nanoparticles, vesicular systems viz liposomes, niosomes, pharmacosomes and discomes and last but not the least, in situ gel systems. All these techniques improve the bioavailability of ophthalmic formulations but some

The major importance is the possibility of administrating accurate and reproducible quantities compared to already formed gel. It is conveniently dropped as a solution into the conjunctival sac, enhancing patient compliance and minimizing interference with blinking. It increases the contact time of drug

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with the mucus at the site of absorption and has better bioavailability.17
Mechanism of in situ hydrogels in sustained ophthalmic drug delivery7

Many mechanisms have been employed to cause reversible sol-gel phase transition, ie. in situ gel forming system by different environmental conditions. The stimuli that induces various responses to form hydrogels includes: physical stimuli such as change in temperature, electric fields, light, pressure, sound and magnetic fields; chemical stimuli such as change in pH and ion activation from biological fluids; and biological or biochemical stimuli such as change in glucose level. Out of these different environmental conditions only pH, ion activated and temperature stimuli are used for ophthalmic drug delivery.
Temperature induced in situ gel systems

characteristics of the delivery systems containing pluronic and by using a smaller dose volume. Carbopol (0.3%) and pluronic (14%) in combination shows a better retention of drugs than either alone. Miotic response of pilocarpine from xyloglucon and pluronic in situ was observed to be the same. Formulations containing 3% methyl cellulose and a low concentration of pluronic provided a potential delivery system with improved ocular bioavailability. The Gelrite gellan gum formulation is therapeutically efficacious and provides sustained release of drug over 8 hours. The gelation temperature of chondroitin 6sulfate-graft-poloxamer was dependent on the concentration and content of chondroitin 6-sulfate and found to be suitable for ciprofloxacin. Release rate of vitamin B12 is dependent on gel dissolution of pluronic-g-poly(acrylic acid). The system shows significant prolongation in the drug resident time and improved bioavailability.
pH induced in situ gel systems

concentration dependence and no significant difference in AUC between the different grades of Carbopol when used for pilocarpine nitrate. Carbopol has a greater release rate for ketorolac tromethamine and tropicamide than any other polymer. A Carbopol formulation has been shown to be therapeutically efficacious, stable, non irritant and provide sustained release of drug over 8 hours. When used for indomethacin it enhances the action and therapeutic efficacy over 8 hours. Hydroxy ethyl cellulose was found to increase viscosity and prolong diclofenac sodium release. This system is used as an in situ gelling vehicle to enhance the ocular bioavailability of pefloxacin mesylate.
Osmotically induced in situ gel systems:

Gelling of the solution is triggered by change in temperature, thus sustaining the drug release. This can be achieved by using a polymer that is a solution at room temperature (<25C) and a gel at body temperature.18 Thermosetting polymer poloxamer has been used for pilocarpine with significant increase of meiosis and can be used up to 20-30%. An increase in concentration of poloxamer increases contact time, increases elasticity of the gel and decreases the sol-gel transition temperature. Poloxomer has mucomimetic properties and optical clarity therefore it can be successfully used as a tear substitute. It can be used in combination with hyaluronic acid and Carbopol showing the highest meiotic response in man. Ocular bioavailability of pilocarpine can be increased more readily by altering both the rheological

Gelling of the solution is triggered by a change in pH. At pH 4.4 the formulation is a free-running solution which undergoes coagulation when the pH is raised by the tear fluid to pH 7.4. The pH change of about 2.8 units after instillation of the formulation (pH 4.4) into the tear film leads to an almost instantaneous transformation of the highly fluid latex into a viscous gel.19 Cellulose acetate phthalate latex, cross-linked polyacrylic and derivatives of carbomers are used. Preliminary investigations of the pH sensitive latex system for ophthalmic administration began in the early 1980s. Ocular drug delivery system containing pilocarpine with pH sensitive polymer cellulose acetate phthalate latex showed significantly prolonged meiosis in rabbit. There is no

Gelling of the solution can also be triggered by a change in ionic strength. It is assumed that the rate of gelation depend on the osmotic gradient across the surface of the gel. It is therefore likely that the osmolality of the solution might have an influence on the rate of the solgel transition occurring in the eye. The aqueous polymer solution forms a clear gel in the presence of the mono or divalent cations typically found in the tear fluids. The electrolyte of the tear fluid and especially Na, Ca and Mg cations are particularly suited to initiate gelation of the polymer when instilled as a liquid solution in the conjunctival cul-de-sac.20 The osmotically induced polymer Gelrite showed improvement in the ocular absorption of timolol in the albino rabbit. Favourable results of Gelrite for timolol maleate were obtained in terms of peak and duration of activity in 45 patients. When used for fluorescein, the gel produced a two-fold increase of penetration. Using hypotonic solutions of Gelrite, the gel can remain in the human eye for 20 hours.

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An in situ gelling alginate system is an excellent drug carrier for prolonged ophthalmic delivery of pilocarpine. Gatifloxacin has been formulated with sodium alginate and hydroxypropylmethyl cellulose as in situ gelling vehicle to enhance ocular bioavailability and patient compliance. The gatifloxacin and atenolol formulations with sodium alginate are therapeutically efficacious, stable, non irritant and provide sustained release of drug over 8 hours.
Conclusion

the last decades, an impressive number of novel stimuli sensitive in situ gel-forming solutions have been described in the literature. The choice of a particular system depends on its intrinsic properties and evidence of its therapeutic use.
References
1. Meqi SA, Deshpande SG. Ocular drug delivery. In: NK. Jain (Ed.), Controlled and novel drug delivery, CBS Publishers, New Delhi, 2002, p. 8284. 2. Wagh VD, Inamdar B, Samanta MK. Polymers used in ocular dosage form and drug delivery systems. Asian J Pharma. 2008; 1217. 3. Lee VH, Robinson JR. Topical ocular drug delivery: recent developments and future challenges. J Ocul Pharmacol. 1986; 2: 67108. 4. Lang JC. Ocular drug delivery conventional ocular formulations. Adv Drug Deliv Rev. 1995; 16: 3943. 5. Sreeraj M, Ashim KM. Overview of ocular drug delivery. In: AK. Mitra (Ed.) Ophthalmic drug delivery systems. 2nd edition, 2003, 111. 6. Gokulgandhi MR, Modi DM, Parikh JR. In situ gel systems for ocular drug delivery: a Review. Drug Del Tech. 2007; 7: 3037. 7. Bourlais CL, Acar L, Zia H, Sado PA, Needham T, Leverge R. Ophthalmic drug delivery systems Recent advances. Progress in retinal and eye research. 1998; 17: 3358. 8. Chrai SS, Makoid MC, Eriksen SP, Robinson JR. Drop size and initial dosing frequency problems of topically applied ophthalmic drugs. J Pharm Sci 1974; 63: 333338.

The complications in eye formulation are mainly due to specific anatomical and physiological features. The development of in situ stimuli activated gel-forming systems for ophthalmic drug delivery provides one of the simplest forms of in situ stimuli activated gel-forming systems. It is preferred over the other systems as it can be administered in drop form and create significantly fewer problems with vision as well as having sustained release properties. Over

9. Chrai SS, Patton TF, Mehta A, Robinson JR. Lachrymal and instilled fluid dynamics in rabbit eyes. J Pharm Sci. 1973; 62: 11121121. 10. Sieg JW, Robinson JR. Mechanistic studies on transcorneal permeation of pilocarpine. J Pharm Sci. 1976; 65: 18161822. 11. Mishima S, Gasset A, Klyce SD, Baum JL. Determination of tear volume and tear flow. Invest Ophthalmol. 1966; 5: 264276. 12. Conrad JM, Reay WA, Polcyn RE, Robinson JR. Influence of tonicity and pH on lacrimation and ocular drug bioavailability. J Parenter Drug Assoc. 1978; 32: 149161. 13. Mitra AK, Mikkelson TJ. Ophthalmic solution buffer systems I. The effect of buffer concentration on the ocular absorption of pilocarpine. Int J Pharm. 1982; 10: 219. 14. Kaur IP, Kanwar M. Ocular preparation: the formulation approach. Drug Devel Indust Pharm. 2002; 28: 373. 15. Joshi A, Ding S, Himmelstein KJ. Reversible gelation composition and method of use. US Patent No. 5,252,318, October 12, 1993. 16. Calfrs J, Edsman K, Peterson R, Jornving K. Rheological evaluation of Gelrite in situ gels for ophthalmic use. Eur J Pharm Sci. 1998; 6: 113119. 17. Calfrs J, Edsman K, Peterson R. Rheological evaluation of Poloxomer as an in situ gel for ophthalmic use. Eur J Pharm Sci. 1998; 6:105. 18. Wei G, Xu H, Ding PT, Li SM. Thermosetting gels with modulated gelation temperature for ophthalmic use: Rheological and gamma scintigraphic studies. J Contr Rel. 2002; 83: 65. 19. Ding S. Recent advances in ophthalmic drug delivery. Pharm Sci Technol Today. 1998; 1: 328335. 20. Bheskaran S, Lakshmi PK, Harish CG. Topical ocular drug delivery: a review. Ind J Pharm Sci. 2005; 64: 404408.

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