Ocular drug delivery

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Chapter: Pharmaceutical Drugs and Dosage: Organ-specific drug delivery

Antibiotics and steroids are the most common classes of drugs typically administered to the eye.

Ocular drug delivery

Antibiotics and steroids are the most common classes of drugs typically administered to the eye. These drugs are administered most commonly through the topical route by instilling or application to the surface (cornea) of the eye. Nevertheless, drug delivery is often required for different segments and anatomical regions of the eye that are difficult to access. Treatment of ocular disorders is challenging due to anatomical and physiological con-straints of the eye, including its vascular permeation and sequential presence of both lipophilic and hydrophilic barriers to drug penetration upon topical administration. In Section, we will discuss the structure of the eye, challenges to drug delivery to the eye, and the approaches that have been taken to overcome these challenges.

1. Structure of the eye

The eye is divided into two chambers—commonly known as the anterior chamber and the posterior chamber (Figure 15.2). The anterior chamber is mainly comprised of cornea, conjunctiva, iris, ciliary body, and lens. 

Figure 15.2 Drug delivery to the eye: Structure and schematic representation of various routes of drug delivery to the eye. (Reproduced from Mishra, G.P. et al., Recent advances in ocular drug delivery: Role of transporters, receptors, and nanocarriers, in Narang, A.S., and Mahato, R.I. (Eds.), Targeted Delivery of Small and Macromolecular Drugs , Boca Raton, FL: CRC Press, Taylor & Francis Group, pp. 421–453, 2010. With permission.)

The posterior chamber includes sclera, choroid, vitreous humor, and retina.3 Cornea is the outermost, avascular and transparent membrane of the eye. The conjunctiva is a clear mucous membrane that covers the inner part of the eyelid and the visible part of sclera (white part of the eye) and lubricates the eye by producing mucus and some tears. Aqueous humor lies between the lens and the cornea. It circulates from the posterior to the anterior chamber of the eye and through the canal of Schlemm. Impaired outflow of aqueous humor causes elevated intraocular pressure that leads to permanent damage of the optic nerve and consequential visual field loss that can progress to blindness. Retina is a light-sensitive tissue behind the aqueous humor. The vitreous humor is a hydrogel matrix composed of hyaluronic acid and collagen fibrils and is located between the retina and the lens.

2. Routes of drug administration into the eye

Depending on the targeted location of drug action within the various com-ponents and compartments of the eye, the selection of the site of adminis-tration can play a key role in drug targeting.

1.        Topical route of drug administration: Treatment of anterior segment diseases usually utilizes topical route of drug administration. This route presents challenges such as precorneal tear clearance, limited conjunctival drug absorption, metabolism by the iris-ciliary body, and elimination through the canal of Schlemm.

2.        Systemic drug administration: Systemic drug administration is usu-ally not preferred for drug delivery to the eye. However, in certain cases, such as the treatment of glaucoma, administration of drugs, such as acetazolamide, through the systemic route may be preferred to obviate the drug absorption limitation due to high intraocular pressure.

3.        Intravitreal administration: Intravitreal (IVT) injection is utilized for the treatment of posterior segment diseases, for example, diabetic retinopathy, and viral infections, for example, human cytomegalovi-rus (HCMV) retinitis and endophthalmitis. Direct administration to the vitreous humor overcomes the blood-retinal barrier (BRB). This route, however, requires injections in the eye and may cause retinal detachment, which could lead to vision loss. Thus, prolonged drug release strategies, including prodrugs, have been utilized to prolong drug residence time in the vitreous humor.

4.        Periocular administration: The periocular route of administra-tion provides direct access to the sclera, and can result in high drug concentration both in the anterior and posterior segments of the eye. The periocular drug injections could be retrobulbar, peribulbar, sub-tenon, and subconjunctival, depending on the site of injection.

5.        Retrobulbar injection: Direct injection into the retrobulbar space can be useful for drug delivery into the macular region (highly pig-mented yellow spot near the center of retina, rich in ganglion cells and responsible for central vision). This injection can, however, result in damage to the blood vessels.

6.        Peribulbar injection: The peribulbar injection can be circumocular, periocular, periconal, or apical depending on the exact site of injection. This route is generally utilized for the administration of analgesics.

7.        Subtenon injection: This site of drug injection can be utilized for drug delivery to the posterior segment of the eye. The drug is administered into the tenon space, which is formed by the void between the tenon’s capsule and the sclera.

8.        Subconjunctival injection: This periocular route of drug administra-tion can allow up to 500 μL of drug solution to be injected. This route is utilized for the treatment of both anterior and posterior segment diseases.

3. Challenges to ocular drug delivery

Topically administered drugs can be eliminated via precorneal tear clear-ance, blinking, and nasolacrimal drainage. This presents challenges to the entry of drug molecules to the anterior segment of the eye (Figure 15.2). Drug delivery to the posterior segment of the eye is challenged by barriers such as inner and outer BRBs and efflux pumps. In addition, the presence of efflux pumps, such as P-glycoprotein (P-gp), multidrug resistance associ-ated proteins (MRPs), and breast cancer resistant protein, also limits the ocular bioavailability of drugs.

For drugs administered through the topical route, the cornea is the main barrier to drug absorption. The cornea and the conjunctiva are covered with a thin film, the tear film, which protects the cornea from dehydration and infection. Following topical administration, a drug is eliminated from the eye by nasolacrimal drainage, tear turnover, productive corneal absorp-tion. and nonproductive conjunctival uptake. The cornea has three ana-tomical parts: (1) the epithelium, (2) the stroma, and (3) the endothelium. Both the endothelium and the epithelium have high lipid content, and thus are penetrated by drugs in their unionized lipid-soluble forms. The stroma lying between these two structures has high water content. To penetrate the cornea, drugs have to go through both the lipidic and aqueous anatomical components.

For drugs injected into the eye, there are two main barriers to ocular drug adsorption: (a) the blood-aqueous barrier and (b) the blood-retina barrier. The blood-aqueous barrier is composed of the ciliary epithelium, the epithelium of the posterior surface of the iris, and blood vessels within the iris. Drugs enter the aqueous humor at the ciliary epithelium and in the blood vessels. Many substances are transported out of the vitreous humor at the retinal surface.

4. Physicochemical characteristics of the drug for ocular absorption

Drug ionization impacts absorption through the ocular route not only by impacting drug permeability but also by affecting tear turnover. A pH 5 solution induces more tear flow than a pH 8 solution. Greater tear turnover can lead to reduction of concentration gradient in addition to drug loss on blinking. Transport of both ionized and unionized drugs is less at pH 5.

The duration of drug action in the eye can be extended by two approaches:

1. Reducing drainage with viscosity-enhancing agents, suspensions, emulsions, ointments, and polymeric matrices

2. Improving corneal drug penetration with ionophores and liposomes

5. Approaches for enhancing drug delivery to the eye

Drug delivery to the eye can utilize multiple mechanisms to overcome the barriers to drug absorption. These include the modification of physi-cochemical properties of the drug such as by making prodrugs, targeting natural transporters and receptors for uptake, inhibition of efflux trans-porters, prolonging the drug residence time at the site of absorption by using nanoparticles, microparticles, micelles, and liposomes; or using mucoadhe-sive ocular implants and hydrogel-based aqueous formulations to achieve relatively constant drug levels at the target site for a longer duration.

1. Prodrugs: Prodrugs are chemical entities that are pharmacologically inactive but can generate an active drug upon absorption through various chemical bond cleavage mechanisms, such as hydrolysis. Prodrugs can be utilized for changing the physiochemical properties of a drug, such as aqueous solubility and lipophilicity, or targeting specific transporters or receptors expressed on cell membranes. For example, lipophilic acyl ester prodrugs of acyclovir (ACV) were inves-tigated to allow high drug permeability through lipophilic membrane. Prodrug hydrolysis to the parent ACV after prodrug permeation and its transformation to ACV-triphosphate prevent diffusive back trans-port of the ACV. Amino acid and peptide prodrugs of quinidine and ganciclovir were investigated to bypass efflux pumps and to target peptide transporters for drug absorption.

2. Permeability and efflux pump modification: Formulation strategies for topically administered drugs that modify drug permeability and/or inhibit P-gp mediated efflux can be utilized to improve drug perme-ation into the eye. Several surfactants (such as d-alpha-tocopheryl polyethylene glycol 1000 succinate (Vitamin E-TPGS), Cremophor® EL, Polysorbate 80, and Pluronic® F85) and polymers (such as poly-(ethyleneoxide)/poly-(propyleneoxide) block copolymers, and amphiphilic diblock copolymers methoxypolyethylene glycol-block-polycaprolactone) inhibit P-gp efflux pump. Use of these ingredients in the formulation can help delivery of sensitive drugs to the eye.

3. Nanoparticles and liposomes: Nanosuspensions of drugs can be utilized to deliver poorly soluble drugs, such as flurbiprofen, meth-ylprednisolone acetate, and glucocorticoids (e.g., hydrocortisone, prednisolone, and dexamethasone) into the eye. The nanosuspensions can enable enhanced retention at the target site and sustained-release (SR) properties to the drug. The retention of nanoparticles in the periocular space versus clearance by blood and lymphatic circulation would depend on the size and surface properties of the nanoparticles. Liposomes, lipid vesicles containing an aqueous core, can protect a drug against enzymatic degradation, increase the capacity to cross the cell membrane, provide SR, and/or prevent drug efflux.

4. Intraocular implants: Implants can be utilized for drugs targeted to both the anterior and posterior segments of the eye for diseases such as proliferative vitreoretinopathy, CMV retinitis, and endophthalmitis. The implants can be made with biodegradable or nonbiodegrad-able polymers such as poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactide-co-glycolide (PLGA), poly(glycolide-co-lactide-co-caprolactone (PGLC) copolymer, poly(caprolactone) (PCL), polyanhydrides, and polyorthoesters (POE). Drugs that have been investigated for drug delivery by implantable DDS include dexameth-asone, cyclosporine, 5-fluorouridine (5-FU), triamcilone acetonide, and recombinant tissue plasminogen activator.

5. Hydrogels: Hydrogels are three-dimensional, hydrophilic, poly-meric networks capable of absorbing and holding a large amount of water. Thermosensitive hydrogels prepared by cross-linking poly(N-isopropylacrylamide) (PNIPAAm) with PEG have been investigated for drug delivery to the posterior segment of the eye. Drugs such as bevacizumab and ranibizumab have been tested for delivery in hydrogels.

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