Advances in Ophthalmic Drug Delivery Systems : Part I

Precorneal contraints to ocular drug delivery include solution drainage, lacrimation and tear dilution, tear turnover, and conjunctival absorption. Drug solution drainage from the precorneal area has been shown to be the most significant factor in reducing the ocular contact time and bioavailability of solution dosage forms. The instilled dose leaves within 5 minutes of instillation in humans. The natural tendency of the cul-de-sac is to reduce its volume to 7- 10 microlitres. The typical ophthalmic dropper delivers 30 microlitres, most of which is rapidly lost through naslacrimal drainage. The drainage may then allow the drug to be systemically absorbed across the nasal mucosa or the gastrointestinal tract. The drug, the pH, and the tonicity of the dosage forms can induce lacrimation. Normal human tear turnover is 16 % per minute and it also contributes to remove drug solution from the conjunctival cul-de-sac (2).

The physiological barriers to topical corneal absorption are very significant. As a result, the clinician is forced to recommend frequent doses of drugs at extremely high concentration. This pulsed type of dosing not only results in extreme fluctuations in ocular drug concentrations but may also cause many untoward side effects.

Methods to prolong ocular drug residence

There are many approaches to prolong the ocular residence of the medication which include formulation factors, instilled volume and the administration technique (3). Formulation factors An ophthalmic formulation is composed of drug (s) and the adjuvants like antimicrobial preservatives, surfactants, viscolyzers etc. It has been observed that the high concentrations of drugs are irritant to the eye and low concentrations are less irritant and are slowly eliminated from the eye.  Accordingly, it is advised that the formulation must contain the lowest concentration of drug because these solutions have the lowest systemic resorption and the least adverse reaction. 

Most pharmacopoeia require that aqueous preparations supplied in multidose containers contain antimicrobial preservatives at appropriate concentrations, except when the preparation itself has adequate antimicrobial properties. At high concentrations, preservatives are irritant and elicit reflex lacrimation which leads to rapid removal of formulation from the eye. 

Surfactants are often used in ophthalmic solutions to improve the dispersion of suspended drugs and to increase the resorption of the drugs. Substances such as benzalkonium chloride, sodium lauryl sulphate, and the nonionic surfactants are irritant and elicit reflex lacrimation. The irritation power depends on the concentration in the solution.

Viscolyzers are used to increase the retention of ophthalmic solutions at the eye surface and to increase the bioavailability of the drug. Viscous solutions with low surface tensions are irritant and will be elimiated rapidly from the eye surface. For formulation, viscolyzers with high surface tension are chosen.

Instilled volume

The instilled volume of the ophthalmic solution must be limited so that it can remain on the eye surface. The maximum volume of a soluion that can be added into the lower eyelid sack is 30 microlitres.

Administration of solution

 To maximise the ocular contact time and presumably the drug penetration, and to maximise the rapid flow through the canaliculi and a systemic adsorption, administration technique that would increase bioavailability should be used.

CLASSIFICATION OF OCULAR DRUG DELIVERY SYSTEMS

A multitude of ocular dosage forms are available for delivery of drugs to the eye. These can be classified on the basis of their physical forms as follows:

1. Liquids : Solutions, Suspensions, Sol to gel systems, Sprays

2. Solids : Ocular inserts, Contact lenses, Corneal shield, Artificial tear inserts, Filter paper strips

3. Semi-solids : Ointments, Gels

4. Miscellaneous : Ocular iontophoresis, Vesicular systems, Mucoadhesive dosage forms, Particulates, Ocular penetration enhancers

    Use of Hyaluronic acid, Use of Hydroxy Beta Cyclodextrin.

Liquids

            Liquids are the most popular and desirable state of dosage forms for the eye. This is because the drug absorption is fastest from this state. The slow release of the drug from the suspended solids provides a sustained effect for a short duration of time.

Solutions and Suspensions

Solutions are the pharmaceutical forms most widely used to administer drugs that must be active on the eye surface or in the eye after passage through the cornea or the conjunctiva. The drug in the solution is in the solved state and may be immediately active. This form also have disadvantages; the very short time the solution stays at the eye surface, its poor bioavailability (a major portion i.e. 75% is lost via nasolacrimal drainage), the instability of the dissolved drug, and the necessity of using preservatives. A considerable disadvantage of using eye drops is the rapid elimination of the solution and their poor bioavailability. This rapid elimination is due to solution state of the preparation and may be influenced by the composition of the solution. The retention of a solution in the eye is influenced by viscosity, hydrogen ion concentration, the osmolality and the instilled volume.

Extensive work has been done to prolong ocular retention of drugs in the solution state by enhancing the viscosity or altering the pH of the solution (4-13).

Sol to gel Systems

The new concept of producing a gel in situ ( eg., in the cul-de-sac of the eye ) was suggested for the first time in the early 1980s. It is widely accepted that increasing the viscosity of a drug formulation in the precorneal region will leads to an increased bioavailability, due to slower drainage from the cornea. Several concepts for the in situ gelling systems have been investigated. These systems can be triggered by pH, temperature or by ion activation. An anionic polymeric dispersion shows a low visosity upto pH 5. 0, and will coacervate in contact with tear fluid due to presence of a carbonic buffer system which regulates the pH of tears. In situ gelling by a temperature change is produced when the temperature of polymeric dispersion is raised from 25 to 37°C. Ion activation of polymeric dispersion occurred due to the presence of cations in the tear fluid.

 Vadnere et al studied a number of pluronic polyols with the aim of determining factors which influence the transition temperature of the hydrogels. All of the pluronic polyols studied showed endothermic enthalpy change for the sol-gel process. The presence of sodium chloride, potassium chloride and sodium sulphate decreased the transition temperature whereas the opposite effect was observed with urea, alcohol and sodium dodecylsulfate. The enthalpy of gel formation was significantly changed by the added substances suggesting that entropy plays the major role in the gelation process (14). Rozier et al formulated 0.6% w/v GelriteÒ solution and compared its effect with equiviscous hydroxy ethyl cellulose ( HEC ) solution on timolol bioavailability. An  enhanced drug bioavailability and longer retention time was obtained in case of GelriteÒ solution as compared to HEC solution in the rabbit's eye (15). Middleton and Robinson  prepared sol to gel system with mucoadhesive property  to deliver the steroid fluorometholone to the eye. The formulation gave better release of drug over a long period of time in the rabbit's eye, as compared to conventional eye drops (16). Lindell  and Engstrom studied in-vitro release of timolol maleate from in-situ gelling polymer system. It was found that in-vitro release rate was retarded with in-situ gelling polymer gelriteÒ compared to non-gelling ethyl hydroxy ethyl cellulose system (17). Kumar  et al developed in-situ forming gel for ophthalmic drug delivery which increased residence time of drug in the eye. A solution containing 1.5% methyl cellulose and 0.3% carbopol at pH 4.0 and 25°C was found to be an easily flowing liquid capable of administration as a drop and showed an increase in viscosity and conversion to a gel on changing pH to 7.4 by addition of 0.5 M NaOH (18). Kumar and Himmelstein investigated that in-situ gelling behaviour of carbopol solution can be modified by addition of hydroxy propyl methyl cellulose. They found that hydroxy propyl methyl cellulose-polyacrlic acid could be formulated as an eye drop and upon instillation into the cul-de-sac of the eye can undergo in-situ transition to form gels capable of sustained drug release (19).

Wei et al.  developed a thermosetting gel with a suitable phase transition temperature by combining Pluronic analogs and examined the influence of incorporating mucoadhesive polysaccharide, sodium hyaluronate (HA-Na), on the ocular retention of the gel by dynamic rheological method and single photon emission computing tomography (SPECT) technique (20).

Cho et al studied in situ gel formation to enhance ocular bioavailability and duration of the drug activity. They reported grafting of poloxamer onto the hyaluronic acid for application of tissue engineering oriented ophthalmic drug delivery system. Graft copolymers were prepared by coupling mono amine-terminated poloxamer (MATP) with hyaluronic acid (HA) backbone using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC) and N-hydroxylsuccinimide (NHS) as coupling agents. The coupling of MATP with HA was clarified by 1H NMR and FT-IR spectroscopy. The gelation temperature of graft copolymers was dependent on the content of HA and the concentration of poloxamer. From drug release studies in vitro, ciprofloxacin was sustainedly released from the poloxamer-g-hyaluronic acid hydrogel due to the in situ gel formation of the copolymer and viscous properties of HA (21). Lin and Sung contributed to the field of  ophthalmic in situ gelling systems by the development  and characterization of a  series of carbopol- and pluronic-based solutions by studying their rheological behavior (22). Gunning et al. found that the ion activated in situ gelling systems of Gelrite for sezolamide and dorzolamide performed better then conventional deliveries (23).

Sprays

           Although not commonly used, some practitioners use mydriatics or cycloplegics alone or in combination in the form of eye spray. These sprays are used in the eye for dilating the pupil or for cycloplegic examination.

Solids

           The concept of using solids for the eye is based on providing sustained release characteristics.

Ocular inserts

Ocular inserts are solid dosage form and can overcome the disadvantage reported with traditional ophthalmic systems like aqueous solutions, suspensions and ointments. The typical pulse entry type drug release behavior observed with ocular aqueous solutions (eye drops), suspensions and ointments is replaced by more controlled, sustained and continuous drug delivery using a controlled release ocular drug delivery system. The eye drops provided pulse entry pattern of drug administration in the eye which is characterized by transient overdose, relatively short period of acceptable dosing, followed by prolonged periods of underdosing. The ocular inserts maintain an effective drug concentration in the target tissues and yet minimize the number of applications consonant with the function of controlled release systems. Limited popularity of ocular inserts has been attributed to psychological factors, such as reluctance of patients to abandon the traditional liquid and semisolid medications, and to occasional therapeutic failures ( e.g. unnoticed expulsion from the eye, membrane rupture etc. ). A number of ocular inserts were prepared utilizing different techniques to make soluble, erodible, nonerodible, and hydrogel inserts (24-46).

Contact lenses ( 14 )

            Contact lenses can absorb water soluble drugs when soaked in drug solutions. These drug saturatedcontact lenses are placed in the eye for releasing the drug for long period of time. The hydrophilic contact lenses can be used to prolong the ocular residence time of the drugs. In humans, the Bionite lens which was made from hydrophilic polymer (2-hydroxy ethyl methacrylate ) has been shown to produce a greater penetration of fluorescein.

  Corneal shield

A non cross-linked homogenized, porcine scleral collagen slice is developed by a company (Bio-cor (Bausch and Lomb pharmaceuticals). Topically applied antibiotics have been used in conjunction with the shield to promote healing of corneal ulcers. Collagen shields are fabricated with foetal calf skin tissue and originally developed as a corneal bandage. These devices, once softened by the tear fluid, form a thin pliable film that confirms exactly to the corneal surface, and undergoes dissolution up to 10, 24 or 72 hours. Collagen film proved as a promising carrier for ophthalmic drug delivery system because of its biological inertness, structural stability and good biocompatibility. Gussler et al investigated the delivery of trifluoro thymidine (TFT) in collagen shields and in topical drops in the cornea of normal rabbits and corneas with experimental epithelial defects. It was found that highest drug concentrations were found in the eyes treated with shields as compared to eye drops (47).

 Artificial tear inserts (48).

 A rod shaped pellet of hydroxypropyl cellulose without preservative is commercially available (Lacrisert). This device is designed as a sustained release artificial tear for the treatment of dry eye disorders. It was developed by Merck, Sharp and Dohme in 1981

Filter paper strips

Sodium fluorescein and rose Bengal dyes are commercially available as drug impregnated filter paper strips. These dyes are used diagnostically to disclose corneal injuries and infections such as herpes simplex, and dry eye disorders.

Semi-solids

A wide variety of semisolids vehicles are used for topical ocular delivery which falls into two general categories : simple and compound bases. Simple bases refer to a single continuous phase. These include white petrolatum, lanolin and viscous gels prepared from polymers such as PVA, carbopol etc. Compound bases are usually of a biphasic type forming either water in oil or oil in water emulsions. A drug in either a simple or compound base provide an increase in the duration of action due to reduction in dilution by tears, reduction in drainage by way of a sustained release effect, and prolonged corneal contact time. The most commonly used semisolid preparation are ointments consisting of dispersion of a solid drug in an appropriate vehicle base.

Semi-solids dosage forms are applied once or twice daily and provide sustained effects. The primary purpose of the ophthalmic ointment vehicle is to prolong drug contact time with the external ocular surface. But they present a disadvantage of causing blurring of vision and matting of eyelids. Ophthalmic gels are similar in viscosity and clinical usage to ophthalmic ointments. Pilopine HS is one of the ophthalmic preparation available in gel form and is intended to provide sustained action of pilocarpine over a period of 24 hours.  Semi-solids vehicles were found to prolong the ocular contact time of many drugs, which ultimately leads to an enhanced bioavailability (49-58).

Miscellaneous

Ocular iontophoresis (59).

Iontophoresis ( Greek iontos = ion; phoresis = to bear ) is the process in which direct current drives ions into cells or tissues. When iontophoresis is used for drug delivery, the ions of importance are charged molecules of drug. If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode.

Ocular iontophoresis offers a drug delivery system that is fast, painless, safe, and, in most cases, results in the delivery of a high concentration of the drug to a specific site. Increased incidence of bacterial keratitis, frequently resulting in corneal scarring, offers a clinical condition that may benefit from drug delivery by iontophoresis. Iontophoretic application of antibiotics may enhance their bactericidal activity and reduce the severity of disease; similar application of anti-inflammatory agents, could prevent or reduce vision threatening side effects ( 61-62). But the role of iontophoresis in clinical ophthalmology remains to be identified.            

Vesicular systems

            Vesicular systems have been developed to provide improvement in ocular contact time, providing sustained effect and reducing side effects of the drug(s) entrapped.

Liposomes

Liposomes are phospholipid-lipid vesicles for targeting the drugs to the specific sites in the body. Because of their structural versatility they can incorporate any kind of drug substance regardless of its solubility. They provide the controlled and selective drug delivery and improved bioavailability and their potential in ocular drug delivery appears greater for lipophilic than hydrophilic compounds. Liposomes are vesicles composed of a lipid membrane enclosing an aqueous volume. Liposomes offer the advantage of being completely biodegradable and relatively nontoxic but are less stable than particulate polymeric drug delivery systems. Liposomes were found to be potential delivery system for administration of a number of drugs to the eye (63-66).

Table 1 and 2 provides list of work done on various ocular drug delivery system and the U.S. patents obtained for ocular applications.

Table. I : Research work on ophthalmic drug delivery systems

S.No	Drug	Dosage form	Category of drug	Polymers / Bases	Reference No.
1	Pilocarpine	Ointment	Miotic agent	Petrolatum bases	50
2	Pilocarpine	Emulsion	Miotic agent	------	57
3	Pilocarpine	Sol to gel system	Miotic agent	Cellulose acetate phthalate	67
4	Pilocarpine	Matrices	Miotic agent	Hydroxyl propyl cellulose and Polyvinyl pyrrolidone	30
5	Pilocarpine	Hydrogel	Miotic agent	Polyacrylic acid and Polyacrylamide	68
6	Dexamethasone	Suspension	Anti-inflammatory	----	31
7	Dexamethasone	Ocular insert	Anti-inflammatory	Cellulose acetate phthalate, Eudragit RS. 100 and RL 100	31
8	Pilocarpine nitrate	Ocular insert	Miotic agent	Collagen	32
9	Pilocarpine nitrate	Ocular insert	Miotic agent	Mixtures of sodium salts of hyaluronic acid	69
10	Tropicamide	Ocular insert	Mydriatic agent	Mixtures of sodium salts of hyaluronic acid	69
11	Pilocarpine nitrate	Gel	Miotic agent	Polyacrylic acid	69
12	Timolol	Sol to gel system	Anti-glaucoma agent	GelriteÒ	15
13	Timolol Maleate	Ocular insert	Anti-glaucoma agent	Alkyl monoesters of poly vinyl methyl ether-maleic anhydride (PVM - MA)	33
14	Methyl Prednisolone	Films and Microspheres	Anti-inflammatory	Various esters of hyaluronic acid	34
15	Flurbiprofen	Gels	Anti-inflammatory	Pluronic F 127	56
16	Timolol maleate	Solutions	Anti-glaucoma agent	Polyacrylic acid	70
17	Penicillin G	Liposomes	Antibiotic	Phospholipids	71
18	Pilocarpine	Solution	Miotic agent	Hyaluronic acid sodium salt	72
19	Timolol maleate	In-situ forming gel	Anti-glaucoma agent	Hydroxy propyl methyl cellulose and Polyacrylic acid	19
20	Gentamicin, Tobramycin and Ciprofloxacin	Iontophoresis	Anti-infective agents	---	62
21	Gentamicin, Tobramycin and Ciprofloxacin	Corneal collagen shield	Anti-infective agents	Collagen	62
22	Sulphacetamide sodium and Trimethoprim	Solution	Anti-infective agents	---	73
23	Pilocarpine	Solution	Miotic agent		74
24	Piroxicam	Submicron emulsion	Anti-inflammatory	Poloxamer and Stearylamine as emulsifier	75
25	Indomethacin	Nanoparticles, Nanocapsules and Submicron emulsion	Anti-inflammatory	Poly-Î-caprolactone, Poloxamer	76
26	Hydrocortisone	Solution	Anti-inflammatory	Hydroxypropyl-b-cyclodextrin	77
27	Indomethacin	Nanocapsules	Anti-inflammatory	Chitosan and Poly-L-Lysine coated Poly-Î-caprolactone	78
28	Pilocarpine Hydrochloride	Gels	Miotic agent	Pluronic F127, Methyl cellulose, Hydroxypropyl methyl cellulose	79
29	Ciprofloxacin Hydrochloride	Ocular insert	Anti-infective agent	Hydroxy propyl methyl cellulose, Methyl cellulose, Ethyl cellulose and polyvinyl pyrrolidone	42
30	Insulin	Ocular devices	Anti diabetic	Absorbable gelatin sponge	80
31	Tropicamide	Liposomes dispersed in gel.	Mydriatic agent	Polycarbophil	63
32	Indomethacin	Solution	Anti-inflammatory	PluronicÔF68 and F127	81
33	Ketorolac Tromethamine	Ocular Inserts	Anti-inflammatory	Hydroxy propyl methyl cellulose, Polyvinyl Pyrrolidone, Methyl cellulose and Ethyl cellulose	82

{mospagebreak title=U.S. patents for ocular drug delivery devices}

Table 2 : U.S. patents obtained for ocular drug delivery devices/strategies

S.No.	Patent No.	Title	Reference No.
1	U.S.4,952,581	Use of a prostaglandin in combination with an adrenergic blocking agent for reduction of intraocular pressure	83
2	U.S.5,227,372	Method for retaining ophthalmological agents in ocular tissues	84
3	U.S.5,296,228	Compositions for controlled delivery of pharmaceutical compounds	85
4	U.S.5,480,914	Nonaqueous thixotropic drug delivery suspensions and methods of their use	86
5	U.S.5,578,638	Treatment of glaucoma and ocular hypertension with .beta..sub.3 -adrenergic agonists	87
6	U.S.5,705,194	Pharmaceutical compositions containing polyalkylene block copolymers which gel at physiological temperature	88
7	U.S.5,888,493	Ophthalmic aqueous gel formulation and related methods	89
8	U.S.6,242,442	Brinzolamide and brimonidine for treating ocular conditions	90
9	U.S.6,297,240	Method for treating ophthalmic disease through fast dispersing dosage forms	91
10	U.S.6,316,441	Brinzolamide and brimonidine for treating glaucoma	92
11	U.S.6,410,045	Drug delivery system for antiglaucomatous medication	93
12	U.S.6,416,740	Acoustically active drug delivery systems	94
13	U.S.20020071874	Compositions containing therapeutically active components having enhanced solubility	95
14	U.S.20020197300	Drug delivery system for anti-glaucomatous medication	96
15.	U.S.20030017199	Compositions having enhanced pharmacokinetic characteristics	97
16	U.S.5,837,226	Ocular microsphere delivery system	98
17	U.S.6,071,875	TGF.alpha. for the treatment of ocular hypertension and glaucoma	99
18.	U.S.6,154,671	Device for the intraocular transfer of active products by iontophoresis	100
19	U.S.6,217,896	Conjunctival inserts for topical delivery of medication or lubrication	101
20	U.S.6,319,240	Methods and apparatus for ocular iontophoresis	102
21	U.S.6,335,335	Prolonged-action eye drop	103
22	U.S.6,410,045	Drug delivery system for antiglaucomatous medication	104
23	U.S.6,539,251	Ocular iontophoretic apparatus	105
24	U.S.6,579,519	Sustained release and long residing ophthalmic formulation and the process of preparing the same	106
25	U.S.20020026176	Devices for intraocular drug delivery	107
26	U.S.20030147849	Topical formulations for delivery of interleukin-11	108
27	U.S.20020064513	Sustained release and long residing ophthalmic formulation and the process of preparing the same	109
28	U.S.20020114778.	Reversible gelling system for ocular drug delivery	110
29	U.S.20020119941	In-situ gel formation of pectin	111
30	U.S.20020197300	Drug delivery system for anti-glaucomatous medication	112
31	U.S.20030175324	Ocular therapeutic agent delivery devices and methods for making and using such devices	113
32	U.S.20030185892	Intraocular delivery compositions and methods	114
33	U.S.20030191426	Device for enhanced delivery of biologically active substances and compounds in an organism	115
34	U.S.20040037889	Stabilized, dry pharmaceutical compositions for drug delivery and methods of preparing same	116

Conclusion

In the past 2 decades, a considerable amount of research has been carried out on the development of ocular drug delivery systems. It is appreciated that the topical route is preferred for delivery of drugs to the eye.  The primary objective of all the ocular drug delivery systems developed till date is to increase ocular drug residence time which leads to improvement in ocular drug bioavailability, diminish side effects due to systemic absorption and diminishing the necessary amount of drug for a therapeutic response in the eye.

Bioadhesive properties of polymers illustrated in this review, seemed to be related to the precorneal retention of the drug more significantly in comparison with other iso-viscous and non-bioadhesive polymers. Encapsulation of drugs in liposomes and nanoparticles was correlated to an increase of the drug concentration in the ocular tissues. Solid ocular devices, inserts have been used to prolong drug action for an extended duration of time. Polymeric solutions, ointments, soluble and insoluble inserts and phase transition systems, iontophoresis, Hyaluronic acid etc. have been used to improve the bioavailability of topically applied drugs.

There is a need to develop an ocular drug delivery system in which drug could be entrapped to prolong corneal contact time and preserve visual acuity. Such systems should be more hydrophobic, minimize interference with blinking and exhibit pseudoplastic behaviour.

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About the authors

Yasmin Sultana, Rahul Jain, Rahul Rathod, Asgar Ali, M.Aqil^*

Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University, New Delhi 110062,  INDIA.

Dr. Mohd. Aqil received his doctorate in Pharmacy from Hamdard University, New Delhi (India). He has authored and/or coauthored over 25 publications. His research interests include Drug Delivery Systems, pharmacovigilance and drug utilization review. He is currently working as Lecturer at Faculty of Pharmacy, Hamdard University, New Delhi. His current job responsibilities include teaching UG/PG classes as well as supervising research. He is a Life Member of Indian Pharmaceutical Association, Society of Pharmacoviglilance (India) and Association of Pharmaceutical Teachers of India.

Contact Info:

Tel. # 91-11-26059688 Ext. 5632.
E-mail- aqilmalik@yahoo.com