There are three main routes commonly used for administering drugs to the eye:
1. Topical—drops or ointment
2. Systemic—oral or injection
3. Intra-ocular injection
The most common form of topical administration is the eye drop. It is apparently easy to use, relatively inexpensive and does not impair vision. The major problems with these types of formulation are their inability to sustain high local concentrations of drug and they only have a short contact time with the eye.
Most eye-drops consist of an aqueous medium, to which can be added buffers (phosphate, borate, acetate and glucuronate), organic and inorganic excipients, emulsifiers, and wetting agents in order to accommodate a wide range of drugs with varying degrees of polarity. Vehicles may include water, aqueous mixtures of lower alkanols, vegetable oils, polyalkylene glycols, or petrolatum based jelly. Other excipients include ethylcellulose, ethyl oleate, carboxymethylcellulose and polyvinylpyrrolidone.
Contact time between the vehicle and the eye can be increased by the addition of polymers such as polyvinyl alcohol and methylcellulose, although generally the effects on drug absorption are not dramatic. Drainage from the cul-de-sac may also be reduced by punctual occlusion or simple eyelid closure, which prolongs the contact time of the drug with the external eye. This serves two purposes- first it maximises the contact of drug with the periocular tissues increasing absorption through the cornea and second, the systemic absorption is reduced.
Continuous and constant perfusion of the eye with drug solutions can be achieved by the use of ambulatory motor driven syringes that deliver drug solutions through fine polyethylene tubing positioned in the conjunctival sac. The flow rate of the perfusate through a minipump can be adjusted to produce continuous irrigation of the eye surface (36 ml.min- 1) or slow delivery (0.2 ml.min-1) to avoid overflow. This system allows the use of a lower drug concentration than used in conventional eye-drops, yet will produce the same potency. Side effects are reduced and constant therapeutic action is maintained. This system is not used very often due to the inconvenience and the cost involved, but may find application for irritant drugs or for sight-threatening situations
Spray systems produce similar results to eye-drops in terms of duration of drug action and side effects. Sprays have several advantages over eye-drops:
2. precise instillation requiring less manual dexterity than for eye-drop administration and is particularly useful for treating patients with unsteady hand movements
3. contamination and eye injury due to eye-drop application are avoided
4. spray delivery causes less reflex lacrimation.
5. Can be used by patients who have difficulty bending their neck back to administer drops.
The only disadvantage is that sprays are more expensive to produce than eye-drops so they are not widely used; however, several manufacturers have advanced spray systems at a pre-production stage. Prototype devices that force small volumes through a valving system look promising as delivery devices of the future. Recently, it has been demonstrated that one sixth of the conventional dose of pilocarpine hydrochloride delivered in this manner produces an equivalent miosis to the standard dose12.
The viscosity of ophthalmic solutions is often increased to improve retention times of a drug on the corneal surface and hence bioavailability. Soluble polymers in aqueous solution are often used to extend the drug residence time in the cul-de-sac. The more commonly used viscolyzing agents include polyvinyl alcohol (PVA) and derivatives of cellulose. Cellulosic polymers, such as methylcellulose, hydroxyethylcellulose (HEC), hydroxypropyl-methylcellulose (HPMC) and hydroxypropylcellulose (HPC), are widely used as viscolyzers showing Newtonian properties. They have common properties: i). a wide range of viscosity (400 to 15000 cps); ii). compatibility with many topically applied drugs and iii). increased stability of the lacrimal film. There is a general relationship between increasing viscosity and improving bioavailability which would be expected since contact with the absorbing surface is prolonged; however, solutions that are so thick they require a force of more than 0.9 N to shear them markedly interfere with blinking.
Of the many naturally occurring polymers, sodium hyaluronate and chondroitin sulphate have been extensively investigated as potential ophthalmic drug delivery vehicles. Sodium hyaluronate is a high molecular weight polymer extracted by a patented process from sources including rooster coxcombs. The molecule consists of a linear, unbranched, non-sulphated, polyanionic glycosaminoglycan, composed of a repeating disaccharide unit (D-sodium glucuronate and N-acetyl-D-glucosamine). Sodium hyaluronate has an unusual rheological behaviour, undergoing a rapid transformation from a gel to a liquid on application of shear stress (pseudoplasticity). Hence, the viscosity is higher at the resting phase, so it provides a thickened tear film, with slow drainage and an improved distribution on the cornea during blinking. Furthermore, the carboxyl groups of hyaluronate form hydrogen bonds with hydroxyl groups of mucin in the eye, producing an intimate contact with the cornea. They demonstrate a considerably prolonged residence time when compared to saline (T 1/2=11.1 minutes at 0.2% concentration and 23.5 minutes at 0.3% compared to a T 1/2 of 50 seconds for the saline13).
Products based on hyaluronates are widely used in intraocular surgery as a substitute for vitreous humor and as an adjuvant to promote tissue repair. Hyaluronates protect the corneal endothelium and other delicate tissues from mechanical damage by providing a stabilised hydrogel. These unique properties give hyaluronates great potential in the ocular drug delivery.
Chondroitin sulphate is a glycosaminoglycan with a repeat unit containing
E-D-glucoronic acid and E-D-N-acetyl galactosamine. It is similar to hyaluronic acid except for modification of the position of a hydroxyl group and the addition of sulphate groups to the galactosamine residue. Chondroitin sulphate has a good affinity to the corneal surface, preventing premature break-up of the tear film between blinks14. Thus, formulations containing chondroitin have been used for the treatment of dry eye and they are superior to hyaluronic acid particularly in severe cases.
Carbomers (carbopols) are polyacrylic acid polymers widely used in pharmaceutical and cosmetic industries. They have several advantages, including high viscosities at low concentrations, strong adhesion to mucosa without irritation, thickening properties, compatibility with many active ingredients, good patient acceptability and low toxicity profiles. These properties have made carbomers very valuable in the field of ophthalmic formulations, particularly for the treatment of dry eye since they have long ocular residence times.
At high concentrations, carbomers form acidic, low viscosity, aqueous solutions that transform into stiff gels when the pH is raised. Although these materials gel in the conjunctival sac upon instillation, at this concentration they can cause irritation to the eye due to their high acidity which cannot always be neutralized by the buffering action of the tear fluid. At low concentrations, the carbopol gels show long retention increasing the contact time of solutes and suspended solids.
Gelling systems that make the transition from a liquid phase to a gel or solid phase in response to a specific trigger, such as pH, temperature or concentration of ions, have been used to deliver drugs to the eye. They have the advantage over viscous solutions in that the material can be dispensed from the bottle or tube easily, and only thickens on contact with the tear film gelling in situ, usually in the eye cul-de-sac. The polymers used are natural (such as gellan gum) or synthetic such as cellulose acetate phthalate or a pluronic.
Gellan gum is an anionic polysaccharide formulated in aqueous solution, which forms clear gels, the strength of which increases proportionally to the amount of either monovalent or divalent cations present. Gelation occurs in the eye due to the concentration of sodium present in human tears (~2.6 pg.pl-1). The reflex tearing, which usually leads to a dilution of ophthalmic solutions, in this case further enhances the viscosity of the gellan gum by providing cations needed for gelation. Gellan gum based formulations (0.6% w/v) do demonstrate prolonged ocular retention in man16 17.
Other gels that form in situ are characterised by a high polymer concentration, such as 25% pluronics and 30% cellulose acetophthalate (CAP) which were found to cause discomfort. To reduce the total polymer content in the system, polymers were combined to improve gelling properties. A system was explored which contained carbopol, which demonstrates pH-mediated phase transitions, and methylcellulose, which exhibits thermal gelation. Such system could be formulated as a liquid at a specific pH and room temperature but would gel on exposure to the physiological conditions of the surface of the eye i.e. pH 7.4 and 34°C18.
Ointments are not as popular as eye drops since vision is blurred by the oil base, making ointments impractical for daytime use. They are usually applied for overnight use or if the eye is to be bandaged. They are especially useful for paediatric use since small children often wash out drugs by crying. Ointments are generally non-toxic and safe to use on the exterior of the surface of the eye. However, ointment bases such as lanolin, petrolatum and vegetable oil are toxic to the interior of the eye, causing corneal oedema, vascularization, scarring and endothelial damage. Intraocular contamination with these vehicles should therefore be avoided. Formulations based on white petrolatum-mineral oil have a residence half-time of over an hour in man19.
Antibiotics such as tetracyclines are used in the form of an ointment, producing effective antibacterial concentrations in the anterior chamber for several hours, whereas an aqueous solution of tetracycline is ineffective for intraocular infections. A problem with extremely lipophilic drugs, including corticosteroids, is that the therapeutic agent may not be released as it partitions into the oil base. For these drugs, alternative systems such as water-soluble inserts may be preferable.
Poorly soluble drugs for ophthalmic administration are frequently formulated as micronised suspensions. Larger particles theoretically provide prolongation of effect due to the increased size of the reservoir; however, an increase in particle size is associated with irritation giving rise to an increased rate of removal, assisted by agglomeration of particles and ejection. The relationship between particle size and retention is poorly understood and size is probably not the only determining factor, with parameters such as zeta potential and surface chemistry also being important. Increasing the size of particles to 25 pm in diameter will increase retention time to around 12 hours in a rabbit, compared to 3 pm particles which disappear almost as fast as aqueous solutions20. However, increasing the particle size of 0.1% 3H-dexamethasone suspension, from 5.75, to 22 pm demonstrated that clearance of the larger particle size from the eye is faster than complete dissolution21. Similarly, increasing the concentration of fluorometholone solids in a suspension did not increase the aqueous humour drug concentration-time profile22. Hence, small particle sizes generally improve patient comfort and acceptability of suspension formulations.
Interestingly, submicron or nanosphere formulations demonstrate therapeutic advantages over aqueous solutions, although one would expect rapid clearance from the eye. For example, pilocarpine (2% w/v) adsorbed onto a biocompatible latex of average size 0.3 pm will maintain a constant miosis in the rabbit for up to 10 hours compared to 4 hours with pilocarpine eye drops23. Other nanoparticle systems have been investigated for the prolongation of contact time in order to increase the ocular absorption. Betaxolol-poly-e-caprolactone nanoparticles produce a significantly greater reduction in intra-ocular pressure compared to the commercial eyedrops24. Similar improvements were obtained with carteolol (a E-blocker) which caused a better penetration of the drug in the nanosphere formulation.
Although some particulate systems could be classified as sustained release devices, the term is applied here only to macroscopic devices such as inserts. Provision of a matrix to sustain drug release in the eye can be achieved in several ways. For example, a hydrophilic (soft) contact lens can serve as a drug reservoir. The drug is incorporated into the lens by either instilling drops on the lens when in the eye, or pre-soaking the lens in a solution of the drug. Other systems are not placed on the cornea, but are inserted under the eyelid, such as insoluble inserts of polyvinyl alcohol or soluble collagen which dissolve in lacrimal fluid or disintegrate while releasing the drug. Soluble inserts are made of such substances as gelatin, alginates, agar and hydroxypropylmethylcellulose. These systems have been developed as a method for delivering larger amounts of drugs to the eye over a long period.
Ocuserts® (Alza Corporation, U.S.A.) are insoluble inserts containing pilocarpine used in the treatment of glaucoma, and have a one-week duration of action. The major advantages of this system include longer duration of drug action, avoidance of
Figure 11.11 Combined photographic and scintigraphic image of the eye (left); illustration of contact area (right)
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