Introduction
A successful ophthalmic therapy requires therapeutic concentrations of the active substance in the target tissue. Depending on the disease, the drug must be distributed on the corneal surface or reach intraocular tissues. In case of pathologies affecting the ocular surface, such as the dry eye syndrome, inflammation, allergy, or infection of the cornea and/or conjunctiva, ophthalmic formulations must remain onto the ocular surface as long as possible. Furthermore, topical ophthalmic products must be soft and well tolerated. Due to the poor bioavailability of the active substances after topical administration, if the drug has to reach the anterior segment, frequent instillations are needed. New topical ophthalmic formulations are directed to increase the ocular contact time of the drug on the ocular surface or enhance its penetration through the cornea.
Pathologies affecting the posterior segment of the eye are one of the major causes of blindness in developed countries. Generally, back of the eye diseases are chronic and degenerative and some of them are related with the elderly. A successful treatment for these pathologies requires effective concentrations of the active substance maintained over a long period of time in the target site. Static and dynamic barriers as well as efflux pumps effectively limit the access of the active substance to the posterior segment.1 Four routes of administration can be theoretically employed to deliver active substances in the vitreous cavity: topical, systemic, intraocular, and periocular.2 The poor bioavailability of topical administered drugs limits their access to intraocular tissues. In its turn, systemic administration requires high doses of the therapeutic molecule to achieve adequate therapeutic levels in the eye, with the inherent risk of systemic adverse effects. Local drug administration is an alternative to systemic administration and includes injections into the anterior chamber of the eye (intracameral), in the vitreous 2(intravitreal), or into the periocular tissues (subconjunctival, sub-Tenon, and retrobulbar). Administration in the suprachoroidal can also be performed. However, for a successful therapy repeated intraocular injections are required and they are associated to adverse effects such as cataracts, retinal detachment, and hemorrhages, among others. Moreover, the risk of the nondesired effects increases with the number of injections.3
Innovative formulations such as intraocular drug delivery systems have been developed to provide sustained drug concentrations of the active substance in the intraocular target site. Depending on the size, devices are classified into implants (>1 mm), microparticles (1–1000 μm), and nanoparticles (1–1000 nm). Among them, implants and microparticles are able to release the active substance for long periods of time, resulting especially useful for the treatment of chronic intraocular diseases.
Bioavailability of ophthalmic formulations and routes of administration
The bioavailability of topical ophthalmic formulations is generally low. It is estimated that only a small percentage of the administered dose (1–5%) is able to access the interior of the eye.4 If the drug has to reach the anterior segment, frequent instillations are needed. Active substances can enter into the eye through the cornea (transcorneal route) or through the conjunctiva and sclera (conjunctival/scleral route). Most of the drugs gain access into the eye through the cornea. The physiological factors and the physicochemical properties of the active substance and the ophthalmic formulation also influence the bioavailability of drugs administered by topical route.
The cornea is composed of three layers of different nature (epithelium, stroma, and endothelium) whose common characteristic is the lack of irrigation. Corneal thickness in humans is 0.5–0.6 mm in its central portion. The epithelium and endothelium are hydrophobic. By contrast, the stroma is hydrophilic. As a biphasic barrier, the passage of active substances through the cornea is conditioned by the nature of the layers and the properties of the therapeutic molecule (solubility, molecular size, and hydrophilic–lipophilic balance). Active substances can cross through the cornea via paracellular and transcellular routes (Figure 1.1). The passage through the corneal epithelium and endothelium is favored for lipophilic molecules, while the stroma has high permeability to aqueous soluble substances. Small size molecules (<500 g/mol) can cross through the cornea or conjunctiva to reach anterior segment tissues. However, the access of higher molecular weight molecules is restricted.5 Paracellular junctions present in the cornea hinder the passage of the active substances. Conjunctiva results more permeable to drugs as the number of pores are greater than the ones present in the cornea.
After instillation of an ophthalmic solution, the drop (40–60 μL) is rapidly diluted in the tear fluid. Under normal conditions, the maximum volume that can hold the conjunctival sac is between 20 and 30 μL.3
Figure 1.1: Corneal layers: epithelium, stroma, and endothelium. The epithelium and endothelium are lipophilic and the stroma is hydrophilic. The passage of substances through the cornea and conjunctiva can be performed via paracellular and transcellular routes. Example of a weak basic drug: nonionized drug (a lipid soluble form) can be passed through the epithelium and the ionized form (hydrophilic) the stroma
The excess of volume accesses the nasolacrimal duct, decreasing drug bioavailability. The drainage of the ophthalmic formulation by the nasolacrimal duct is known as a type of nonproductive absorption. However, the loss of this dose can be avoided by performing a nasolacrimal occlusion after the instillation. If two consecutive administrations are needed, it is recommended to space them at least 5 minutes.
As previously mentioned, eyedrops instillation can cause reflex tears able to dilute the drug and therefore to decrease its bioavailability. The osmolarity of the formulation can also affect drug bioavailability. Hypotonic formulations may produce corneal edema if hypotonicity is too low (osmolarity of tears is around 300 mOsm/L). The use of viscosizing and bioadhesive agents is useful to extend the contact time of the formulations with the corneal surface and additionally increase the bioavailability of drugs administered topically.
In the periocular administration, the formulation is injected in the subconjunctival, sub-Tenon's or retrobulbar sites. The sclera is a relatively avascular connective tissue. Effective barriers in the trans-scleral route are static and dynamic.6 Once administered, the drug must diffuse through the static barriers to reach the retina (sclera, Bruch's membrane, and retinal pigment epithelium). The thickness of the sclera changes from 1 to 0.3–0.4 mm at its thinnest point. The rate of drug diffusion through the sclera depends on the size and the lipophilicity of the molecule. Small size molecules diffuse rapidly and macromolecules such as polypeptides and proteins diffuse to a lesser degree. The main dynamic barriers to trans-scleral drug delivery are the conjunctival lymphatic/blood vessels and the choroids.4
The suprachoroidal space serves as a reservoir for the drug and prevents passage through the sclera. This route is of great interest if the site of action is the choroid or the retinal pigment epithelium.
Intraocular administration includes intracamerular and intravitreal injections. Intravitreal administration is most commonly used for local treatment of diseases affecting the posterior segment, as the access to this area is difficult to achieve by topical or systemic administration. Direct deposit of the formulation in the vitreous allows the drug to diffuse through the vitreous to reach the target site.
Ophthalmic topical formulations
Conventional Ophthalmic Formulations
Topical administration is the most common route of administration for ocular drugs. Dosage formulations for ophthalmic topical administration are drops (solutions, emulsions, and suspensions), ointments, gels, solid inserts, and therapeutic lenses.7 All of them are sterile preparations destined to topical administration on the ocular surface or to be inserted into the conjunctival cul-de-sac.
Eyedrops
Eyedrops are preparations, which are intended for instillation on the ocular mucosa for therapeutic or diagnostic purposes. They can contain one or more drugs. These ophthalmic formulations must satisfy several requirements, which include clarity (except suspensions), tonicity, sterility, and a pH compatible with the lacrimal fluid. Most requirements are achieved with the help of excipients. Adjuvants in eyedrops include isotonic agents, buffer substances, surfactants, solubilizing agents, viscosizing agents, and preservatives.
Sterility
All the ophthalmic formulations topically applied must fulfill the sterility criteria reported in the pharmacopoeias. Furthermore, the sterility must be maintained during the shelf life of the product.
pH/buffering
The pH of a topical ophthalmic preparation is recommended to be close to the physiological pH (7.4), although the eye can tolerate a wide range of pH (3.5–10) for a single drug administration. The pH of the ophthalmic solution may influence the bioavailability of weak acid and base drugs. Generally, the unionized form of an active substance penetrates through the lipophilic epithelium. If the pH promotes the nonionized form of the drug, its bioavailability will be augmented.5
Sodium and potassium salt solutions are employed as main components of buffer solutions (i.e. carbonate and citrate). Other compounds as acetic, boric, hydrochloric, and phosphoric are also used.
Isotonicity
Recommendations regarding the tonicity of formulations indicate that topical ophthalmic solutions must be isotonic with the tears (a solution of sodium chloride at a concentration of 0.9% is considered isotonic). An acceptable range of tonicity for topical ophthalmic formulations is between 0.7 and 2%. Salts or sugars can be employed to adjust tonicity in ophthalmic preparations. In addition, dextran (40 and 70), glycerin, propylene glycol, potassium chloride, and sodium chloride can also be used.
Wetting agents
These inactive ingredients promote the ability of the ophthalmic formulation to spread properly over the ocular surface. These excipients can also be employed to increase the solubility of poor soluble drugs and/or to stabilize suspensions.
Antioxidants
Antioxidants prevent or delay the degradation of products by oxygen. If the drug is labile to oxygen, certain additives can stabilize the product by minimizing oxidation. One example of antioxidant is sodium bisulfite.
Viscosity increasing agents
Viscosity-increasing agents produce a slow drainage of the product from the ocular surface. Viscous ophthalmic solutions are able to increase the residence contact time of the formulation with the corneal surface. The optimal viscosity of the ophthalmic formulations containing viscosity agents is between 25 and 55 cP, although it is recommended not increase the viscosity over 50 cP to prevent clogging of the lacrimal canal. The most commonly polymers used in eyedrops formulations are cellulose derivatives (methylcellulose, carboxymethylcellulose sodium salt, hydroxyethyl cellulose, hydroxypropyl methylcellulose) polyvinyl alcohol, hyaluronic acid, and derivatives of acrylic acids, such as carbopol, polysorbate 80, propylene glycol, polyethylene glycol, poloxamer 407, glycerin, gelatin, guar gum, and polyvinylpyrrolidone.8
If the viscosity of the formulation is high enough, its consistency increases and the preparations are named gels.
Preservatives
Ophthalmic topical solutions, which are presented in multidose containers, must include an suitable antimicrobial preservative in an appropriate concentration to avoid contamination of the preparation. Among the preservatives employed in topical ophthalmic formulations are the 6quaternary ammonium derivatives (benzalkonium chloride, benzethonium chloride, and cetylpyridinium chloride), mercurial compounds such as thimerosal and phenylmercuric derivatives (nitrate, acetate, and borate), sodium benzoate, sodium propionate, sorbic acid, polyquaternium, phenylethyl alcohol, and ethylenediaminetetraacetic acid.
Preservatives may cause changes in the ocular surface, especially when they are used in high concentrations or in chronic treatments. Ocular allergies and advances in the treatment of dry eye have led to the search of preservatives that have a better tolerance by the patient. Currently, there are less toxic preservatives such as the stabilized chlorine and oxygen complex (Purite), sodium perborate, and SofZia.7 In any case, one of the most relevant advances in the treatment of dry eye has been the development of artificial tears without preservatives in single containers or the use of multidose containers including a sterilizing filter.
Other Topical Ophthalmic Formulations: Aqueous Suspensions, Semisolid Preparations, and Artificial Tears
Ophthalmic suspensions are sterile liquid preparations containing dispersed solid particles in a vehicle in which the active substance is nonsoluble.
Semisolid preparations as ointments and gels extend the drug contact time with the ocular surface. As a disadvantage, they produce blurred vision, and this fact limits their use for night treatments. Ophthalmic inserts are sterile solid or semisolid preparations intended to be inserted into the conjunctival cul-de-sac. In this case, the active substance is dispersed in a matrix or surrounded by a membrane to control the release rate of the drug.
Artificial tears are aimed to the relief of dry eye symptoms. These preparations are used chronically so a high tolerance by patients is extremely important. The ophthalmic solutions destined to the dry eye management may be isotonic (values close to 300 mOsm/L) or slightly hypotonic (150–190 mOsm/L) since formulations with values lower than 150 mOsm/L might produce corneal alterations.
Inserts and implants
An example of an artificial tear insert is a translucent rod-shape device made from hydroxypropyl cellulose (1.27-mm diameter and 3.5-mm long). The rod is deposited into the inferior cul-de-sac of the eye, and it is used for the treatment of the dry eye. Other implants such as those made of collagen are also used for the relief of dry eyes and other surface ocular disorders. The polymer is slowly dissolved in the cornea and thus lubrication occurs, facilitating healing of the damaged cornea.
Intraocular formulations
Intraocular injections must fulfill the same criteria than parenteral formu-lations (osmolarity, sterility, etc.). Conventional ophthalmic formulations for 7intraocular administration include solutions, suspensions, and emulsions. Other ophthalmic preparations such as vitreous substitutes and depot systems are also injected in the vitreous. Depot systems contain poor soluble active substances that precipitate in the vitreous after their injection. Once injected, the drug is slowly dissolved in the vitreous. Examples of therapeutic substances with low dissolution rate are fluocinolone and triamcinolone. The main problem of these formulations is the formation of crystalline structures in the proximal areas to the retina.
Novel formulations of ocular administration
As mentioned previously the main disadvantages of conventional pharmaceutical formulations for topical ophthalmic administration are the poor drug penetration across the cornea and the short contact time of the formulation on the ocular surface. Several strategies are under evaluation to increase drug bioavailability by this route.8
On the other hand, the treatment of degenerative and chronic diseases that affect the back of the eye requires concentrations of the active substance in the target site for extended periods of time. To achieve therapeutic concentrations, frequent intraocular injections are needed. However, successive intravitreal administrations are associated with adverse effects. New intraocular drug delivery systems are under investigation to avoid the use of multiple injections.8 These novel formulations are able to deliver the active molecule in a controlled fashion during long periods of time. They are also able to achieve the same effect of multiple injections with a single administration (Figure 1.2).
Figure 1.2: Intraocular drug delivery systems: implants (>1 mm) (C and B), microparticles (1–1000 micrometers) (A). Depending on the biomaterial the devices remain (nonbiodegradable) or disappear (biodegradable) from the site of administration after delivering the drug
Novel Topical Ophthalmic Formulations
Among the strategies developed to increase bioavailability of the active compounds administered topically are the use of prodrugs, bioadhesive polymers, ‘in situ’ gelling systems, soft contact lenses, inserts, and colloidal systems.8
Prodrugs are used to improve the penetration of drugs through the cornea. They are usually obtained by esterification of the active substance. The ester of the active substance penetrates the cornea more easily. Finally, in a certain area, the ester hydrolysis occurs and then the drug is released (i.e. prostaglandin analogs with intraocular hypotensive activity).
Bioadhesive polymers are able to increase the contact time of the formulation with the ocular surface. Their functional groups are capable of interacting with the mucin present in the ocular surface (corneal and conjunctival epithelium). Among the bioadhesive polymers employed in topical ophthalmic formulations are the cationic and anionic compounds such as cellulose derivatives, polyacrylic acids, chitosan, and hyaluronic acid.
In situ gelling systems contain a polymer sensitive to an external stimuli (pH, temperature, or variations in electrolyte concentration). They are administered as a drop and form a gel upon instillation in response to any of the external stimuli. Absorption promoters are capable of favoring the passage of drugs through increased permeability of the corneal epithelium.
Soft contact lenses are impregnated with a drug which is gradually released over a period of time.
Liposomes, niosomes nanoparticles, dendrimers, and microemulsions are colloidal systems under research in ophthalmology. Liposomes are vesicles formed by one or more aqueous cores which are surrounded by an equal number of lipid bilayers. They may incorporate hydrophilic substances in the aqueous core and lipophilic molecules in the lipid bilayers. Positively charged liposomes are known to interact, with the ocular surface mucins with a greater extent than negative charged systems. If the vesicles are formed from synthetic lipids, they are named niosomes. The nanoparticles consist of natural or synthetic polymers. The active substance can be incorporated into or adsorbed on the particle surface. Under certain conditions, liposomes and nanoparticles may be able to direct the drug to a specific area of the body through a process known as vectorization. They are also able to introduce genetic material into the cell by transfection.
Microemulsions are formed from two immiscible liquid phases (oily and aqueous liquids). To be formed, an emulgent and a cosolvent are needed.
Dendrimers are under investigation to be used as nonviral transfection agents and also to increase the bioavailability of active substances after topical ophthalmic administration. The dendritic structure of these colloidal systems makes them very interesting for encapsulation of genetic material.9
Intraocular Drug Delivery Systems
In the last decades, the development of new systems for intraocular administration, able to release the drug over a long period of time, has gained a great attention. This type of preparations may lead to a prolonged duration of drug effect with a single administration because the active substance is released from the system in a controlled manner. Depending on the biomaterial employed, these systems can be biodegradable or nonbiodegradable. Depending on their size, systems are classified into implants (>1 mm), microparticles (1–1000 μm), and nanoparticles (1–1000 nm). If the active substance forms a core surrounded by a polymer layer, forming a reservoir structure which receives the name of microcapsules. By the contrary, if the drug is mixed with the polymer, as a matrix system receives the name of microspheres.
Implants destined to intraocular administration can be biodegradable or Nonbiodegradable, depending on the biopolymer used for their preparation. Nonbiodegradable implants remain in the site of implantation during the lifetime of the patient. If biodegradable implants are used they disappear from the site of action after delivering the drug. Vitrasert (ganciclovir) and Retisert (fluocinolone acetonide) are within the nonbiodegradable implants. Both require surgery for implantation. The Iluvien device containing fluocinolone is nonbioerodible and can be implanted through a 25 G needle.
Biodegradable systems are gaining a lot of interest in recent years, because the removal of the device is not necessary. Different biodegradable systems such as liposomes, implants, and nano- and microparticles for intraocular drug delivery are under evaluation.
Liposomes have been investigated for encapsulating oligonucleotides and for the administration of prodrugs. The main disadvantage of these vesicular systems is the possible interference with the vision that may occur after their administration, although they tend to disappear between 2 and 3 weeks later.
Biodegradable implants are very useful. There is already marketed an implant of dexamethasone (Ozurdex). The biodegradable polymer used in this implant is poly (lactic-co-glycolic) acid. Other biodegradable devices adopt different shapes such as rods, scleral nails, pellets, disks, and sheets9 to be deposited in different areas (anterior chamber, peribulbar or intrascleral space, scleral surface or vitreous cavity).
Suspensions of biodegradable nano- and microparticles have a high degree of innovation and are able to accommodate a large number of active substances.
Nanotechnology for intraocular drug delivery can incorporate poorly soluble drugs and protect the encapsulated molecules from hydrolysis. They are also used to increase transfection and in imaging techniques.
In the case of biodegradable microparticles, the poly (lactic-co-glycolic) acid polymer is the most popular. This biomaterial has been frequently 10employed as suture material and present good tolerance. In ophthalmology, microspheres (matrix structure) have been injected via intravitreal and periocular routes.10 Among the advantages of the microparticles is that they can be injected without the need of surgery. Moreover, particles suffer aggregation after administration behaving as an implant. Microspheres allow for a personalized medicine as the therapy may be adjusted by the administration of different amounts of particles.
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