1. INTRODUCTION:

Topical application of drugs to the eye is the most accepted method for treatment in ocular diseases. The bioavailability of ophthalmic drugs is, very poor due to various barriers present on the eye such as blinking, baseline and reflex lachrymation, and drainage remove rapidly foreign substances, alongwith drugs, from the surface of the eye. Most of the drug administered in the eye is available in either drops or in gel, ointment form. But After instillation of an eye drop, typically less than 5% of an applied dose reaches the intraocular tissues. This is due to corneal barrier and rapid loss of the instilled solution through nasolachrymal drainage. Small amount is absorbed for its therapeutic effect which requires frequent dosing. ⁽¹⁾There is need to increase ocular bioavailability of the topical administered drug. The most commonly used methods are by increasing the corneal permeability and prolonging the contact time on the ocular surface^{. (2)}After the penetration of the drug through the cornea or sclera, transport is dependent on the by the diffusion characteristics of the drugs such as molecular weight or molecular volume, and binding characteristics of tissue binding sites, clearance of the fluid reservoirs. Therefore, after entry of the therapeutic agent into ophthalmic tissue, there is required the entry of component of the dosage in the tissue.

These afford can be effective when a non-toxic permeation enhancer used in preparation to increases the permeability of actives. This strategy is used in microemulsion to increase the permeability of the drug. The benefits of this formulation are diminished frequency of administration, low toxicity especially for internal ophthalmic administration, reduction of side effects, increased compatibility and stability for the drug.⁽^{3,4,5 )}

2.Routes of Ocular Drug delivery:

2.1.Topical route:

Topical administration of the drug into the eye is most common methods of drug administration because of drugs due to ease of access and patient compliance. But it has certain limitation that it shows low bioavailability due to the anatomical and physiological barriers such as tightness of the cornea1 barrier and rapid loss of the instilled solution from the precorneal area, systemic absorption, transient residence time in ocular surface, and the relative impermeability of the corneal epithelial membrane to the applied drug⁽⁶⁾. The sites of action for most ophthalmic drugs are located in the inner eye. After instillation of an eye drop, typically less than 10% of an applied dose reaches the intraocular tissues for action. There are various systems that have been designed to increase the ocular absorption of drugs. There are two main strategies for the increasing the bioavailability of the topically instilled drug, primarily by increasing the corneal permeability and prolonging the contact time on the ocular surface.Most of the formulator worked on increasing the absorption of the drug through prolongation of the drug residence time in the conjunctival sac. But increasing the residence time systemic absorption of ocularly applied drugs also increases. The conjunctival uptake of a topically applied drug from the tear fluids greater than corneal uptake. Because of systemic drug absorption following conjunctival uptake even though prolongations of the residence times of the vehicle in the conjunctival sac may not always result in significant improvements in ocular drug absorption.⁽⁷⁾

Fig no.1.Cross section of eye

2.2. Conjuctival route:

The drug delivery to the posterior segment of the eye occurs through the conjunctiva and sclera. The three major tissue barriers for drug penetration through the conjunctival sclera route for posterior drug delivery are the conjunctiva, sclera and the RPE-choroid. The conjunctiva, which is has tight epithelium, has major role in transport of ions, solutes, and water in the conjunctival surface and tear film. Drug transport occurs through epithelial barriers by occur by passive and active transport mechanisms^{(6, 7, 8)}.The transport of lipophilic drugs occurs through conjunctiva, by the transcellular route and , hydrophilic drugs through the paracellular route .Improving the conjunctival drug permeability is one of the major challenges in ocular drug delivery.The transcellular drug penetration can be enhanced by increasing drug lipophilicity through the use of prodrugs or analogs. The paracellular transport of the drug can be improved by using enhancers which opens tight junctions. The transcellular route significantly contributes toward the absorption of lipophilic drugs, but is less significant for hydrophilic species. ⁽⁹⁾

2.3. Intravitreal route:

Delivery of drugs to the posterior eye is difficult task. Recently, the intravitreal route is mostly used to deliver the therapeutic molecules to the retina. The advantage of the intravitereal administration technique is to circumvent the blood ocular barrier which keeps most drugs out of the eye in the case of systemic administration. ⁽¹⁰⁾ It should be observed that, delivery from the vitreous to the choroid is more complicated due to the hindrance by the RPE barrier. Small molecules are able to diffuse rapidly in the vitreous but themobility of large molecules, particularly positively charged, is restricted. After intravitreal injection the drug is eliminated by two main routes: anterior and posterior. All compounds are able to use the anterior route. This means drug diffusion across the vitreous to the posterior chamber and, thereafter, elimination via aqueous turnover and uveal blood flow. Posterior elimination takes place by permeation across the posterior blood eye barrier. This requires adequate passive permeability or active transport across these barriers. For these reasons, large molecular weight and water-solubility tend to prolong the half-life in the vitreous. ^{(11, 12, 13, 14, 15)}

2.4. Disadvantages of conventional ocular drug delivery:

· The anatomical and physiological constrains limited permeability of drug and hence affect bioavailability.

· The drug administered can be cleared by lacrimal draianage which gives unwanted systemic absorption.

· The rapid elimination of the drug through the blinking and tear flow results in a short residence time of drug which requires frequent administration of the drug.^(16,17)

3. Microemulsion for ocular delivery:

Typically topical ocular drug is formulated as a eye drops, but it has disadvantage of short contact time as well as lo bioavailability on the eye surface. The contact, and thereby duration of drug action, and bioavailability can be enhanced by formulation design. One such approach is formulation of microemulsion of drug for ophthalmic delivery. The presence of surfactant increases permeability of the drug to the eye as well presence of oil also increases contact time of the drug on the ocular surface. ^{(7.8,
12, 13, 14)}

4.Component of microemulsion as a drug carrier:

4.1. Surfactant and cosurfactant:

The role of surfactant in the formulation of microemulsion is to lower the interfacial tension which assists the dispersion during the preparation of microemulsion by providing a flexible film around the droplets. The surfactant should have appropriate lipophilic character to provide the correct curvature at the interfacial region. Generally, low HLB surfactants are suitable for w/o microemulsion, whereas high HLB (>12) are suitable for o/w microemulsion. ⁽¹⁸⁾

Wei-san Pan et al studied ocular irritation of cationic\anionic\nonionic surfactants using confocal laser scanning ophthalmoscopy in which corneal lesions subsequent to instillation of surfactants are specifically marked by fluorescein and assessed by digital image processing. Eight nonionic, cationic and anionic surfactants were applied onto the cornea of rabbits and mice, at various concentrations. The cornea was evaluated in vivo for ocular tolerance by confocal microscopy. In both rabbits and mice, the test shown irritation potency of surfactant in order of cationic, anionic, nonionic surfactants. Nonionic surfactants are the major type of surface active agents used in ophthalmic delivery systems since their advantages with respect to compatibility, stability, and toxicity. They are generally less toxic, hemolytic, and less irritating to the ocular surface, and tend to maintain near physiological pH values when in solution. Applications of other polyoxyethylated surfactants such as Cremophor EL, Brij, and alpha-Tocopherol TPGS have also been reported in the literature. ^{(19, 20)}

Co-surfactants are mainly used in microemulsion formulation for making interfacial film flexible to form microemulsion. Short to medium chain length alcohols (C3-C8) are used which reduce the interfacial tension and increase the fluidity of the interface. Surfactant having HLB greater than 20 often require the presence of cosurfactant to reduce their effective HLB to a value within the range required for microemulsion formulation. Generally used cosurfactant are, propylene glycol, propylene glycol monocaprylate, 2-(2-ethoxyethoxy) and ethanol. ^(21,
22)

4.2. Oil phase:

The oily phase comprises an oil which may be a vegetable oil, a mineral oil, a medium chain triglyceride oil, i.e. a triglyceride oil in which the carbohydrate chain has 8-12 carbons, or a combination of two or three of such oils, oily fatty acids, Isopropyl myristate, oily fatty alcohols, esters of sorbitol and fatty acids, oily sucrose esters can also be used as drug-solubilising systems. Examples of vegetable oils include soybean oil, cotton seed oil, olive oil, sesame oil and castor oil. Fatty acids and alcohols can be utilized in synergism with oily phase when the drug shows a very poor solubility in the selected oily phase. Oily fatty acids, such as oleic acid and linoleic acid, fatty alcohols, such as oleyl alcohol, and fatty esters, such as sorbitan monooleate and sucrose mono- di- or tri-palmitate, can also be used as the oil component, although these are not as preferred as the other oils mentioned above ^{(21, 22)}.Some example of which are developed for ophthalmic use are shown shown in Table no.1

Table: 1 Microemulsion prepared for ophthalmic use

S.No.	Drug	Surfactant	Oils/Lipid	Reference
1	Levobunolol	Lecithin	Isopropyl myristate, octanoic acid	Gallarate et al., 1993⁽²³⁾
2	Pilocarpinenitrate	Macrogol-1500- Glyceroltriricinoleate and lecithin	Isopropyl myristate	Habe and Kiepert, 1997⁽²⁴⁾
3	Dexamethasone	Chremophore EL	Isopropyl myristate	Fialho and da Silva-Cunha, 2004 ⁽²⁵⁾
4	Lidocaine	Tween 80 and Panodan SDK, Brij 97	Canola oil, Hexadecane	Anuj Chauhan et al.2005⁽²⁶⁾
5	Chloramphenical	Span20/80 , Tween20/80	Isopropyl palmitate (IPP) and isopropyl myristate (IPM)	Li-Qiang Zheng et al ,2005⁽²⁷⁾
6	Chloramphenicol	Tween 20	Isopropyl myristate	Lv et al., 2006 ⁽²⁸⁾
7	Pilocarpine hydrochloride	Sorbitan laurate, polysorbate 80	Ethyl oleate	Alany et al., 2006⁽²⁹⁾
8	Pilocarpine hydrochloride	Polyoxyethylene sorbitan monooleate	Ethyl oleate	Chan et al., 2007⁽³⁰⁾
9	Cyclosporine A	Solutol HS 15	Castor oil	Yong Gan 2008⁽³¹⁾
10	Everolimus	Poloxamer 184		Baspinar et al., 2008⁽³²⁾
11	Prednisolone acetate	Tween 80, Pluronic F68	Soybean oil, ethyl oleate	Gehanne A.S. Awad et al,2009⁽³³⁾
12	Dexamethasone	Tween 80	Isopropyl myristate	Kesavan et al., 2013⁽³⁴⁾

CONCLUSION:

Eye drops represent 90% of all ophthalmic dosage forms, there is a significant effort directed towards new drug delivery systems for ophthalmic administration. It is the suggestion of most clinicians that the patient prefers a solution form of ocular drug delivery system provided that extended duration can be accomplished by these forms. Most of the formulation efforts aim at maximizing ocular drug absorption through prolongation of the drug residence time in the cornea and conjunctival sac as well as to slow drug release from the delivery system and minimize precorneal drug loss. The microemulsion fulfils all the requirements and in addition, it has the advantage of drug to be administered in the form of a drop, which increases patient compliance.

REFERENCE:

1 Tangri P., Khurana S. “Basics of Ocular Drug Delivery Systems, International Journal of Research in Pharmaceutical and Biomedical Sciences”, 2(4) 2011, 1541-1552.

2 Urttia Arto et al. “Ocular absorption following topical delivery”, Advanced Drug Delivery Reviews 16 (1995) 3-19.

3 Lang John C. “Ocular drug delivery conventional ocular formulations”, Advanced Drug Delivery Reviews 16 (1995) 39-43.

4 Wilson Clive G., “Topical drug delivery in the eye, Experimental Eye Research” 78 (2004) 737–743.

5 Kwang-Jin et al.”Roles of the conjunctiva in ocular drug delivery: a review of conjunctival transport mechanisms and their regulation” European Journal of Pharmaceutics and Biopharmaceutics 60 (2005) 227–240.

6 Jiao Jim, “Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery”, Advanced Drug Delivery Reviews 60 (2008) 1663–1673.

7 Suruse Pravin, and Bodhake Atul, “Ophthalmic Microemulsion: A Comprehensive Review” Int. J. Pharm Bio Sci 2012 July; 3(3): P 1 – 13.

8 Patrick M. Hughes et al.”Topical and systemic drug delivery to the posterior segments “Advanced Drug Delivery Reviews 57 (2005) 2010– 2032.

9 Kim Kwang-Jin et al.”Roles of the conjunctiva in ocular drug delivery: a review of conjunctival transport mechanisms and their regulation” European Journal of Pharmaceutics and Biopharmaceutics 60 (2005) 227–240.

10 Elias Fattal, “Liposomes for intravitreal drug delivery: A state of the art” Journal of Controlled Release, 161 (2012) 628–634.

11 A. Urtti et al. “Vitreous is a barrier in non-viral gene transfer by cationic lipids and polymers” Pharm. Res. 20 (2003) 576–583.

12 Kim Hyuncheol et al.” The pharmacokinetics of Rituximab following an intravitreal injection” Experimental Eye Research 82 (2006) 760–766.

13 Lucero Ma Jesu´s et al.” Determination and pharmacokinetic profile of liposomal Foscarnet in rabbit ocular tissues after intravitreal administration” Experimental Eye Research 88 (2009) 528–534.

14 Kim Hyuncheol et al. “The movement of self-assembled amphiphilic polymeric nanoparticles in the vitreous and retina after intravitreal injection”, Biomaterials 33 (2012) 3485-3493.

15 Muchtar S. “Exvivo permeation study of Indomethacin from a submicron emulsion through albino rabbit cornea,” Journal of Controlled Release, 44(1) 55–64, 1997.

16 Contia B.et al.”Biodegradable microspheres for the intravitreal administration of Acyclovir: in vitro / in vivo evaluation “European Journal of Pharmaceutical Sciences, 5 (1997) 287–293.

17 Banker, G.S. and C.T. Rhodes, 2007. Modern Pharmaceutics. Marcel Dekker, pp: 415-443.

18 Yusuf, A. and K. Lehmussaari,”Industrial, Perspective in Ocular Drug Delivery” Advanced Drug, Delivery Reviews, 58(2006): 1258-1268.

19 Wei-san Pana et al. “A controlled-release ocular delivery system for Ibuprofen based on nanostructured lipid carriers” International Journal of Pharmaceutics 363 (2008) 177–182.

20 ha S.K1 et al.”Microemulsions- Potential Carrier for Improved Drug Delivery “Asian Journal of Biomedical and Pharmaceutical Sciences 1 (1) 2011, 5-9.

21 Submicron emulsions as ocular 0253472a1 1/1988 European pat. Off. Drug delivery vehicles United States patent.

22 Vandamme Th.F.” Microemulsions as ocular drug delivery systems: recent developments and future challenges” Progress in Retinal and Eye Research 21 (2002) 15–34.

23 Gasco M. R., M.et al. “Preparation and evaluation in vitro of solutions and o/w microemulsions containing Levobunolol as ion-pair,” International Journal of Pharmaceutics, 100, (1993), 219–225.

24 Haße A et al, “Development and characterization of microemulsions for ocular application,” European Journal of Pharmaceutics and Biopharmaceutics, 43, (1997), 179–183.

25 Fialho S. L. and Da Silva-Cunha A, “New vehicle based on a microemulsion for topical ocular administration of Dexamethasone,” Clinical and Experimental Ophthalmology, 32, 6, (2004) 626–632.

26 Chauhan Anuj and Gulsen Derya “Dispersion of microemulsion drops in HEMA hydrogel: a potential ophthalmic drug delivery vehicle” International Journal of Pharmaceutics 292 (2005) 95–117.

27 Li-Qiang Zheng et al. “Novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of lipophilic cyclosporine A: In vitro and in vivo results” International Journal of Pharmaceutics 365 (2009) 143–149.

28 Lv F. F et al., “Studies on the stability of the Chloramphenicol in the microemulsion free of alcohols,” European Journal of Pharmaceutics and Biopharmaceutics, 62, 3 (2006), 288–294.

29 Alany R. G., “W/O microemulsions for ocular delivery: evaluation of ocular irritation and precorneal retention,” Journal of Controlled Release, 111, (2006) 145–152.

30 Chan J., et al. “Phase transition water-in-oil microemulsions as ocular drug delivery systems: in vitro and in vivo evaluation,” International Journal of Pharmaceutics, vol. 328, no. 1, pp. 65–71, 2007.

31 Yong Ganb et al.” Novel microemulsion in situ electrolyte-triggered gelling system for ophthalmic delivery of lipophilic cyclosporine A: In vitro and in vivo results “International Journal of Pharmaceutics 365 (2009) 143–149.

32 Baspinar Y. et al. “Corneal permeation studies of everolimus microemulsion,” Journal of ocular Pharmacology and Therapeutics, 24, (2008), 399–402.

33 Awad Gehanne A.S.” Comparative effects of different cosurfactants on sterile Prednisolone acetate ocular submicron emulsions stability and release” Colloids and Surfaces B: Biointerfaces 69 (2009) 225–231.

34 Kesavan, S.Kant, Singh P.N., and Pandit J.K., “Mucoadhesive chitosan-coated cationic microemulsion of Dexamethasone for ocular delivery: in vitro and in vivo evaluation,” Current Eye Research, 38, 3, (2013) 342–352.

Received on 04.11.2013 Accepted on 14.01.2014

Asian J. Pharm. Tech. 2014; Vol. 4: Issue 3, Pg 147-150