**3. Routes for drug delivery into the posterior segment of the eye**

Designing a drug delivery system to target a specific tissue inside the eye is a challenge due to the different ocular barriers. Different modes of administration for drugs are available for ophthalmologists, but many of them fail to reach a therapeutic dose of the drug to elicit clinical effects. The different routes of ocular drug administration (**Figure 1**) include topical, oral/systemic, subconjunctival, subtenon, retrobulbar, intracameral, and intravitreal injections.

#### **3.1 Topical administration**

Topical administration is the most common method for drug administration in ophthalmology, mostly in the form of eye drops due to the ease of administration and the low cost. Topical application is useful in the treatment of disorders affecting the anterior segment of the eye [60]. The site of contact is the cornea, the conjunctiva, and the sclera. A normal eyedropper delivers from 25 to 56 μL of topical formulation with an average volume of 39 μL. However, an eye can transiently hold up to 30 μL, and the rest is lost either through nasolacrimal drainage or reflex blinking (5–7 blinks/min), significantly decreasing the overall drug available for therapeutic action. Furthermore, after a drop is administered to the eye, a major fraction of the drug is lost through lacrimation, tear dilution, nasolacrimal drainage, and tear turnover following topical administration. Such precorneal losses result in very low ocular bioavailability. Typically, less than 5% of the total administered dose reaches the aqueous humor [22, 61]. Therefore, in order to maintain minimum inhibitory concentrations, the agents need to be frequently dosed, resulting in poor patient compliance or potential adverse events. Physical barriers such as the cornea and the sclera and dynamic barriers such as reflex blinking, tear turnover, nasolacrimal drainage, conjunctival clearance, episcleral clearance, choroidal clearance, and clearance through bulk fluid flow and uveoscleral outflow are some of the many sophisticated barriers that cause poor drug molecule concentrations in the target organ (retina). For these reasons, topical administration is regarded as a poor option for the treatment of posterior diseases such as macular edema, age-related macular degeneration, and diabetic retinopathy.

**29**

permeation.

**Figure 1.**

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery…*

*DOI: http://dx.doi.org/10.5772/intechopen.86601*

**3.2 Oral/systemic administration**

The oral and systemic administration of drugs is the most common drug delivery form in medicine (but this is not the case for eyes). Following oral/systemic administration, the blood-aqueous and blood-retinal barriers are major problems for drug delivery. The ciliary epithelium produces aqueous humor, which acts as an ultrafilter and restricts the entry of macromolecules such as antibiotics and plasma proteins [42]. Drug delivery to the posterior pole and the retina is very difficult due to the fact that blood-retinal barriers prevent the diffusion of drugs into the posterior pole of the eye. BRBs are composed of retinal capillary endothelial cells and RPE, which are known as the inner and outer blood-retinal barriers, respectively. RPE is a monolayer of highly specialized cells, and it aids in biochemical functions by selectively transporting molecules between photoreceptors and choriocapillaris [38]. However, the tight junctions of RPE efficiently restrict intercellular

*Barriers for ocular drug delivery and different routes of drug administration to the eye. (1) Topical;* 

*(2) subconjunctival/subtenon; (3) intravitreal; (4) peribulbar; and (5) retrobulbar.*

Drugs can easily enter the choroid, thanks to its high vasculature compared to that of retinal capillaries. The choriocapillaris are fenestrated, resulting in rapid equilibration of drug molecules in the bloodstream with the extravascular space of the choroid. However, RPE restricts further entry of drugs from the choroid to the retina. Because the blood-retinal barrier, which is selectively permeable to more lipophilic molecules, mainly governs the entry of drug molecules into the posterior segment of the eye, this results in the need for frequent administration of high

amounts of drugs, which leads to systemic side effects [62].

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery… DOI: http://dx.doi.org/10.5772/intechopen.86601*

#### **Figure 1.**

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

perature, and drug concentration [56].

**2.3 Metabolic barriers**

commercial drugs [59].

**3.1 Topical administration**

important role as active transport for drugs depending on extracellular pH, tem-

Transporters are membrane-bound proteins that play an important role in the active transport of nutrients or xenobiotics. These transporters play a significant role in humans in the processes of drug absorption, distribution, metabolism, and elimination. The presence of both efflux and influx transporters has been reported in various ocular tissues. The presence of efflux pumps in various ocular tissues has shown to regulate the intracellular drug concentration needed to achieve therapeutic activity. Drug-metabolizing enzymes are present in many ocular tissues such as the ciliary body and RPE [57, 58]. As a defense mechanism, the eye possesses several sophisticated metabolizing enzyme systems that degrade drug molecules, including those of the cytochrome P-450 (CYP) family, which are the most important drugmetabolizing enzymes. CYP3A isozyme, for example, metabolizes over 50% of

**3. Routes for drug delivery into the posterior segment of the eye**

subtenon, retrobulbar, intracameral, and intravitreal injections.

macular degeneration, and diabetic retinopathy.

Designing a drug delivery system to target a specific tissue inside the eye is a challenge due to the different ocular barriers. Different modes of administration for drugs are available for ophthalmologists, but many of them fail to reach a therapeutic dose of the drug to elicit clinical effects. The different routes of ocular drug administration (**Figure 1**) include topical, oral/systemic, subconjunctival,

Topical administration is the most common method for drug administration in ophthalmology, mostly in the form of eye drops due to the ease of administration and the low cost. Topical application is useful in the treatment of disorders affecting the anterior segment of the eye [60]. The site of contact is the cornea, the conjunctiva, and the sclera. A normal eyedropper delivers from 25 to 56 μL of topical formulation with an average volume of 39 μL. However, an eye can transiently hold up to 30 μL, and the rest is lost either through nasolacrimal drainage or reflex blinking (5–7 blinks/min), significantly decreasing the overall drug available for therapeutic action. Furthermore, after a drop is administered to the eye, a major fraction of the drug is lost through lacrimation, tear dilution, nasolacrimal drainage, and tear turnover following topical administration. Such precorneal losses result in very low ocular bioavailability. Typically, less than 5% of the total administered dose reaches the aqueous humor [22, 61]. Therefore, in order to maintain minimum inhibitory concentrations, the agents need to be frequently dosed, resulting in poor patient compliance or potential adverse events. Physical barriers such as the cornea and the sclera and dynamic barriers such as reflex blinking, tear turnover, nasolacrimal drainage, conjunctival clearance, episcleral clearance, choroidal clearance, and clearance through bulk fluid flow and uveoscleral outflow are some of the many sophisticated barriers that cause poor drug molecule concentrations in the target organ (retina). For these reasons, topical administration is regarded as a poor option for the treatment of posterior diseases such as macular edema, age-related

**28**

*Barriers for ocular drug delivery and different routes of drug administration to the eye. (1) Topical; (2) subconjunctival/subtenon; (3) intravitreal; (4) peribulbar; and (5) retrobulbar.*

#### **3.2 Oral/systemic administration**

The oral and systemic administration of drugs is the most common drug delivery form in medicine (but this is not the case for eyes). Following oral/systemic administration, the blood-aqueous and blood-retinal barriers are major problems for drug delivery. The ciliary epithelium produces aqueous humor, which acts as an ultrafilter and restricts the entry of macromolecules such as antibiotics and plasma proteins [42]. Drug delivery to the posterior pole and the retina is very difficult due to the fact that blood-retinal barriers prevent the diffusion of drugs into the posterior pole of the eye. BRBs are composed of retinal capillary endothelial cells and RPE, which are known as the inner and outer blood-retinal barriers, respectively. RPE is a monolayer of highly specialized cells, and it aids in biochemical functions by selectively transporting molecules between photoreceptors and choriocapillaris [38]. However, the tight junctions of RPE efficiently restrict intercellular permeation.

Drugs can easily enter the choroid, thanks to its high vasculature compared to that of retinal capillaries. The choriocapillaris are fenestrated, resulting in rapid equilibration of drug molecules in the bloodstream with the extravascular space of the choroid. However, RPE restricts further entry of drugs from the choroid to the retina. Because the blood-retinal barrier, which is selectively permeable to more lipophilic molecules, mainly governs the entry of drug molecules into the posterior segment of the eye, this results in the need for frequent administration of high amounts of drugs, which leads to systemic side effects [62].

Although topical and systemic routes are convenient, the lack of adequate bioavailability and the failure to deliver therapeutic amounts of drugs into the retina prompted vision scientists to search for alternative routes of administration. Hence, specific oral or intravenous targeting systems are needed to transport molecules through the choroid and into deeper layers of the retina [43]. An example of a systemic drug for the treatment of retinal diseases is Visudyne, which is used in photodynamic therapy for the treatment of wet age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC). However, owing to toxicity and delivery concerns, intravenous administration is not very common in treating ocular diseases.

### **3.3 Periocular administration**

Although not very patient compliant, these routes are partly used to overcome the inefficiency of topical and systemic dosing in order to deliver therapeutic drug concentrations to the posterior segment of the eye globe. Moreover, systemic administration may lead to side effects, making it a less desirable delivery route for geriatric patients. Periocular routes include subconjunctival, subtenon, retrobulbar, and peribulbar administrations, and they are comparatively less invasive than intravitreal routes. Drugs administered by periocular injections can reach the posterior segment through three different pathways: the transscleral pathway, systemic circulation through the choroid, and the anterior pathway through the tear film, cornea, aqueous humor, and vitreous humor [63]. The administration of a drug via subtenon injection resulted in the highest and more sustained vitreous concentration of drug molecules compared to other periocular injections [64]. However, anterior segment complications have been described in some patients following periocular injections. The complications include ocular hypertension, cataract, hyphema, strabismus, and corneal decompensation [65]. Additionally, the concentration of many drugs, such as that of anti-angiogenic drugs, is better if an intravitreal injection is used as a delivery pathway.

#### **3.4 Intravitreal injection**

Nowadays, intravitreal injection is the preferred route for ocular delivery for the treatment of diseases of the retina. It offers important advantages over periocular injections as drug molecules are directly inserted into the vitreous chamber. This method involves the injection of a drug solution directly into the vitreous, via the pars plana, using a 30-Ga needle. Unlike other routes, intravitreal injection offers higher drug concentrations in the vitreous and the retina. The advantage of IVT injection is the circumvention of the blood-retinal barrier, which keeps most drugs out of the eye in the case of oral and systemic administrations [43]. Therefore, IVT administration is able to maximize the intraocular level of drugs in the vitreous and the retina while avoiding toxicities associated with systemic treatment [66–69]. The benefits of intravitreal therapies in retinal diseases have been well documented, and the current standard of care is the injection of a bolus of anti-VEGF into the vitreous cavity on a frequent basis. Such a large bolus of a drug has been associated with some side effects [70]. In addition, this administration procedure creates a typical curve with a large peak of drug concentrations and a rapid decay. Literature supports the fact that the half-life of anti-VEGFs, such as ranibizumab, is indeed very short (halflife = 2.6–4.0 days) [71], making it necessary to use a higher initial dose in order to exceed therapeutic levels so as to allow a longer 28-day treatment interval. Moreover, mathematical modeling demonstrates that the binding activity of 0.5 mg of ranibizumab is fivefold higher if given every 14 days instead of every 28 days [72].

**31**

**the eyeball**

and liposomes.

**4.1 Polymeric nanoparticles**

and poly(lactic-co-glycolic acid) (PLGA) [57, 85].

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery…*

In this context, they also share many of the problems of IVT injections.

**4. Topical nanocarriers for drug delivery into the posterior segment of** 

To date, different nanocarriers have proven to be capable technologies to circumvent most of the ocular barriers and effectively deliver drugs to the posterior segment of the eye. Their favorable physicochemical properties, such as the small size and adjustable surface, render them advantageous in targeting drugs to the retina. Although different administration routes have been analyzed, we consider that the topical route is the one of greatest interest because of its favorable characteristics such as its ease for the patient, a potentially better compliance, and lower incidence of serious complications than injected methods. The main topically proven nanocarriers are polymeric NPs, lipid nanoparticles, micelles, dendrimers,

Polymeric nanoparticles (PNPs) are colloidal particles (10–1000 nm) where the drug is uniformly distributed throughout the particle matrix (nanospheres) or encapsulated inside a polymer shell (nanocapsules) [82]. Synthetic and natural biocompatible polymers can be used to develop PNPs. The polymers used to generate PNPs for ocular applications have been made from poly(alkyl cyanoacrylates) [83, 84], polycaprolactone, chitosan (CS), hyaluronic acid (HA), Eudragit (RS100 and RL100), Carbopol, gelatin, poly(butyl cyanoacrylate), polylactic acid (PLA),

In regard to topical PNPs for posterior segment drug delivery, we would like to highlight the study performed by Tahara K et al., where submicron-sized poly(D,Llactide-co-glycolide) (PLGA) nanoparticles were used to improve the efficiency of drug delivery to the retina through topically administered drugs. Chitosan and glycol chitosan (GCS), which are mucoadhesive polymers, and polysorbate 80

Intravitreal injection can avoid ocular barriers for direct drug placement in the vitreous cavity, but drug distribution in the vitreous is not uniform. Small molecules can rapidly be distributed throughout the vitreous, whereas the diffusion of larger molecules is restricted. This distribution also depends on the presence of physiopathological conditions of the vitreous (vitrectomized patients present poor concentrations after 3 days) and the molecular weight of the administered drug [69]. In order to reach and maintain effective therapeutic concentrations, repeated injections are necessary. The frequent administration of drugs via this route can lead to endophthalmitis, damage to the lens, retinal detachment, and hemorrhage. Moreover, high acute intraocular drug concentrations may induce severe local toxicity and increase intraocular pressure. Additionally, it may be a burden for physicians, the health system, and patients with poor compliance in many cases [15]. Furthermore, IVT injections require highly specialized human resources and special infrastructure to apply them, and it is a costly option in developing countries [16]. Due to these limitations, new drug delivery systems are needed in order to find a safer and more effective ocular drug delivery method for the treatment of retinal diseases such as those from intraocular implants. Various drug delivery systems have been proposed using a group of biodegradable and nonbiodegradable platforms to passively deliver anti-angiogenic drugs [73–81]. However, one of the limitations of these drug delivery platforms is that, once implanted, they elute an unchangeable dosage of the drug and can only be stopped by explanting the device.

*DOI: http://dx.doi.org/10.5772/intechopen.86601*

*Breaking down the Barrier: Topical Liposomes as Nanocarriers for Drug Delivery… DOI: http://dx.doi.org/10.5772/intechopen.86601*

Intravitreal injection can avoid ocular barriers for direct drug placement in the vitreous cavity, but drug distribution in the vitreous is not uniform. Small molecules can rapidly be distributed throughout the vitreous, whereas the diffusion of larger molecules is restricted. This distribution also depends on the presence of physiopathological conditions of the vitreous (vitrectomized patients present poor concentrations after 3 days) and the molecular weight of the administered drug [69]. In order to reach and maintain effective therapeutic concentrations, repeated injections are necessary. The frequent administration of drugs via this route can lead to endophthalmitis, damage to the lens, retinal detachment, and hemorrhage. Moreover, high acute intraocular drug concentrations may induce severe local toxicity and increase intraocular pressure. Additionally, it may be a burden for physicians, the health system, and patients with poor compliance in many cases [15]. Furthermore, IVT injections require highly specialized human resources and special infrastructure to apply them, and it is a costly option in developing countries [16].

Due to these limitations, new drug delivery systems are needed in order to find a safer and more effective ocular drug delivery method for the treatment of retinal diseases such as those from intraocular implants. Various drug delivery systems have been proposed using a group of biodegradable and nonbiodegradable platforms to passively deliver anti-angiogenic drugs [73–81]. However, one of the limitations of these drug delivery platforms is that, once implanted, they elute an unchangeable dosage of the drug and can only be stopped by explanting the device. In this context, they also share many of the problems of IVT injections.
