**2.1 Static barriers**

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

drugs to the retinal tissue is not a completely solved subject.

topical administration of a drug is generally <5% [4, 5].

antibiotics, and anti-VEGF therapies [7–11].

different disabling illnesses, such as age-related macular degeneration, cystoid macular edema, diabetic retinopathy, and ocular vascular occlusion, which are the leading causes of nonreversible vision impairment [2, 3]. These retinal disorders could be pharmacologically addressed; however, the efficient and safe delivery of

Compared to drug delivery to other organs, ocular drug delivery faces significant challenges posed by various sophisticated ocular barriers. Many of these barriers are inherent and unique to ocular anatomy and physiology, making it a challenging task for drug delivery innovations. Corneal and conjunctival epithelium, bloodaqueous barriers (BAB), and blood-retinal barriers (BRBs) are the fundamental structures that restrict the passage of molecules and fluids to the retina and impede drug penetration; moreover, various elimination mechanisms, such as tear turnover, nasolacrimal drainage, protein binding, systemic absorption, and enzymatic degradation, limit the ocular bioavailability of drugs [4, 5]. Conventional drug administration systems such as eye drops, suspensions, and ointments are optimal in the treatment of the ocular surface (corneal and conjunctiva tissues) and anterior segment disorders. Nevertheless, due to the ocular barriers, drugs barely get into the posterior ocular segment [1]. It is well known that ocular bioavailability after the

Therefore, intravitreal (IVT) injections, which circumvent the ocular barriers, are the most frequent pathway to deliver drugs for the treatment of posterior ocular globe disorders. Today, the use of IVT injections has become the most common intraocular procedure worldwide [6] and the standard drug delivery method for the treatment of retinal diseases [2, 3]. Intravitreal injections are now routinely used for the intraocular administration of drugs such as corticosteroids, antimetabolites,

Although IVT injections are a well-described and feasible route for releasing drugs into the posterior pole of the eye, this procedure is associated with severe complications such as endophthalmitis, lens injury, and retinal detachment [12–14]. Moreover, it might be a burden for physicians, the health system, and patients with poor compliance in many cases [15]. Furthermore, the administration of IVT injections requires highly specialized human resources and special infrastructure, resulting in an expensive therapy option [16]. Research initiatives are continuously being proposed worldwide at fast pace by apex organizations and pharmaceutical companies in order

to find a safer and more effective ocular drug delivery method for ocular use.

permeability, and retention at the site of application [17].

Nanostructured carriers or nanocarriers (nanomaterials) have proven to be an effective and slightly invasive drug delivery system to keep drug concentrations in the posterior segment of the eyeball, preventing the use of IVT injections or reducing their frequency. The advantage of using nanocarriers is their ability to increase the biopharmaceutical properties of the incorporated drug: solubility, stability,

Nanocarriers are made of nanoparticles (NPs) (1–1000 nm), and they exemplify one of the multiple strategies of nanomedicine, which is interpreted as the application of NPs for medical purposes [18]. The most commonly used materials for NPs include lipids (liposomes), proteins (albumin NPs), cyclic oligosaccharides (cyclodextrins), synthetic polymers (polymeric micelles, dendrimers, hydrogel), and even inorganic compounds (cerium oxide NPs) [19]. Liposomes have been of much interest as carriers for advanced drug delivery in medicine and, especially, in ophthalmology for their potential to avoid the sophisticated ocular barriers, even when they are topically applied. In fact, liposomes and cyclodextrins are the only topically administered nanoparticles that have successfully proven to release corticosteroids in clinical assays [20, 21].

In the following sections, we will review the ocular barriers and routes for ocular drug delivery and discuss the different nanocarriers topically used in preclinical

**24**

The static barriers in the eye are physical barriers that prevent the diffusion of drug molecules into the posterior segment of the eye and the retina. The cornea is a mechanical barrier that comprises the anterior sixth of the eye. This transparent, ellipsoid barrier has different layers that play an important role in drug permeation: each layer offers a different polarity and a potential rate-limiting structure for drug permeation. The corneal epithelium is lipoidal in nature, and it contains 90% of cells in the cornea. These cells are joined by desmosomes and surrounded by ribbonlike tight junctional complexes. The presence of the *zonula occludens* delays paracellular drug permeation from the tear film into intracellular spaces of the epithelium, as well as into the inner layers of the cornea [22]. The epithelium has a significant resistance against the permeation of topical hydrophilic drugs. The highly hydrated stroma that comprises 90% of the corneal layer is made up by an extracellular matrix and a lamellar arrangement of collagen fibrils, and it is an important barrier against the permeation of lipophilic drug molecules. The hexagonal-shaped cells, or endothelium, represent the innermost layer of the cornea, and they have a selective

**Table 1.** *Types of barriers for ocular drug delivery.*

carrier-mediated transport and a secretory function. New drug delivery systems should have an amphipathic nature in order to permeate through the cornea [23].

The sclera forms the firm, fibrous, outermost layer of the eye. It keeps the shape of the eye and provides an attachment for the insertion of the extraocular muscles. It is about 1 mm thick at the site where the optic nerve pierces it. The sclera is made of collagen and elastin chains that create a fiber matrix, where the pore diameter and intracellular spaces may determine the flow of drugs. Furthermore, the lateral orientation of fibers, the differences in the collagen architecture of the posterior sclera, and the differences in myopic eyes may affect drug transport with a lower or higher permeability depending on these changes. The permeability of the sclera for a number of molecules, such as dextrans, polyethylene glycol, anti-angiogenic molecules, antibiotics, oligonucleotides, and lipophilic compounds, has been measured [24–30]. There are different factors that may affect the scleral permeability of these molecules [2, 31–33]. Scleral permeability has a strong dependence on molecular weight, with smaller molecules having a better permeability. Similarly, since globular proteins are more permeable than linear dextrans of the same molecular weight, molecular radius is an important predictor of scleral permeability [32]. Finally, any surgical, pathological, or traumatic change in the anatomy of the sclera may lead to permeability changes [34].

Different studies on Bruch's membrane—the choroid and the retinal pigment epithelium (RPE)—show that permeability increases when lipophilicity does the same. Molecules that are passively transported across the RPE show similar permeability values in both outward (retina-choroid) and inward (choroid-retina) directions, while molecules that are actively transported show differences in permeability between the two of them [22]. The presence of RPE melanin may alter ocular drug disposition. Melanin binds to free radicals and drugs through electrostatic and van der Waals forces or through simple charge-transfer interactions with this pigment, which may alter the availability of the free drug at the targeted site [35]. All basic and lipophilic drugs bind to melanin; thereby, melanin binding may significantly lower pharmacological activity [36]. As a result of the presence of melanin, the binding of lipophilic compounds to the choroid-Bruch's membrane is higher; consequently, there is greater resistance to solute permeation across the choroid-Bruch's membrane than across the sclera, which is devoid of melanin [37–39].

Aging does not alter the permeability or ultrastructure of the sclera, but the permeability of Bruch's membrane and the choroid has shown to be significantly affected by age [2, 34]. Bruch's membrane may be a major resistance barrier against the movement of small solutes due to an increase in its thickness with aging (from 2 μm in the first decade of life to 4.7 μm in the tenth decade). Moreover, the accumulation of lipid-rich membranous debris and basal laminar deposits may have an important role in drug delivery [39].

#### **2.2 Dynamic barriers**

Dynamic barriers include the clearance through lymphatic and blood vessels, bulk fluid flow, and the active transport mechanisms of RPE transporter proteins. Precorneal barriers are highly effective and include solution drainage, blinking, tear film, tear turnover, and induced lacrimation.

Blinking is a normal reflex that protects the eye from dryness, bright light, and fingers or other objects coming toward it. Blinking also regulates tears, which nourish and cleanse the surface of the eye. The blinking rate in newborns is only two times per minute. This increases to 14–17 times per minute in adolescence and remains at this rate throughout the rest of the lifetime. Blinking may also increase in response to pain, bright light, changes in temperature and humidity, and conversations.

**27**

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

The tear film offers resistance, thanks to its high turnover rate. Mucin plays a protective role in tear film by forming a hydrophilic layer that moves over to the glycocalyx of the ocular surface and clears debris and pathogens [29, 40]. Human tear volume is estimated to be 7–10 μl, and the cul-de-sac can transiently contain around 30 μl of the administered eye drop. However, tear film displays a rapid restoration period of 2–3 min, and most of the topically administered solutions are washed away within just 15–30 s after instillation. Considering all of the precorneal factors, contact time with the absorptive membranes is lower, which is considered to be the primary reason for less than 5% of the applied dose reaching the intraocular tissues [41]. Precorneal fluid drainage is one of the main reasons for low ocular drug

After instillation, a big portion of an instilled volume (approximately from 80 to 90%) is drained into the nasolacrimal duct. Nasolacrimal drainage helps maintain the volume of precorneal fluid at about 7–10 μl at all times [46]. A natural protective physiological mechanism causes the loss of any excess fluid present: it is drained out through the nasolacrimal duct. Similarly, other factors such as the instilled volume, viscosity, pH, tonicity, and drug type may also alter the regular ocular physiological process. The higher the instilled volume, the higher the rate of solution drainage; increasing the drug's viscosity may extend contact time. Excessive tear production is associated with the instillation of acidic or alkaline solutions; hence the ideal ophthalmic formulation for topical delivery should be

The conjunctiva is another effective barrier against ocular drug delivery. It is well vascularized, and drug molecules present in the conjunctiva and episcleral tissues are cleared through blood and/or lymphatic vessels [47, 48]. Subconjunctively injected tracers have been detected in the cervical lymph nodes within 6 min [49, 50]. Furthermore, molecular size and molecular radius may affect the rate of clearance [2]. Future drug delivery systems will have to consider conjunctival/episcleral clearance mechanisms, given that they play a significant role in reducing intraocular

The choroid is a dark brown, highly vascularized layer located between the sclera and the retina. It extends from the *ora serrata* to the aperture of the optic nerve in the sclera. Drug molecules that are topically, systemically, and orally administered may be eliminated by the uptake of the rapid blood flow of the choroid. Drugs can be carried away by bulk fluid flows in ocular tissues and are ultimately mostly cleared through choroidal vasculature or conjunctival vascular and/or lymphatic vessels. Uveoscleral drainage has been reported within a range of 4–60% [51], and it generates an outward bulk flow fluid from the suprachoroidal space. Many drugs may be carried away by the convective current of aqueous humor and cleared by the conjunctival vascular and/or lymphatic vessels. The effect of aging on uveoscleral outflow must also be considered by future drug

The osmotic pressure of the choroid in rabbits is 12–14 mmHg, and the vitreous humor has an osmotic pressure of approximately 0–1 mmHg [52]. This difference in osmotic pressure between the choroid and the vitreous generates a fluid flow toward the choroid. The hydrostatic pressure difference between the suprachoroid and the episcleral tissue also contributes to the outward bulk fluid flow [53]. There is a hydrostatic pressure difference of about 12 mmHg between the suprachoroid and the episcleral tissue, which works as a driving force for the outward bulk fluid flow. Drug efflux pumps, such as P-glycoproteins (P-gp) and multidrug resistanceassociated proteins (MRPs), have been reported in RPE with an efflux effect directed toward the choroid [54, 55]. Finally, organic ion transporters may have an

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

absorption [42–45].

isotonic with tear secretions.

drug penetration.

delivery systems.

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

The tear film offers resistance, thanks to its high turnover rate. Mucin plays a protective role in tear film by forming a hydrophilic layer that moves over to the glycocalyx of the ocular surface and clears debris and pathogens [29, 40]. Human tear volume is estimated to be 7–10 μl, and the cul-de-sac can transiently contain around 30 μl of the administered eye drop. However, tear film displays a rapid restoration period of 2–3 min, and most of the topically administered solutions are washed away within just 15–30 s after instillation. Considering all of the precorneal factors, contact time with the absorptive membranes is lower, which is considered to be the primary reason for less than 5% of the applied dose reaching the intraocular tissues [41]. Precorneal fluid drainage is one of the main reasons for low ocular drug absorption [42–45].

After instillation, a big portion of an instilled volume (approximately from 80 to 90%) is drained into the nasolacrimal duct. Nasolacrimal drainage helps maintain the volume of precorneal fluid at about 7–10 μl at all times [46]. A natural protective physiological mechanism causes the loss of any excess fluid present: it is drained out through the nasolacrimal duct. Similarly, other factors such as the instilled volume, viscosity, pH, tonicity, and drug type may also alter the regular ocular physiological process. The higher the instilled volume, the higher the rate of solution drainage; increasing the drug's viscosity may extend contact time. Excessive tear production is associated with the instillation of acidic or alkaline solutions; hence the ideal ophthalmic formulation for topical delivery should be isotonic with tear secretions.

The conjunctiva is another effective barrier against ocular drug delivery. It is well vascularized, and drug molecules present in the conjunctiva and episcleral tissues are cleared through blood and/or lymphatic vessels [47, 48]. Subconjunctively injected tracers have been detected in the cervical lymph nodes within 6 min [49, 50]. Furthermore, molecular size and molecular radius may affect the rate of clearance [2]. Future drug delivery systems will have to consider conjunctival/episcleral clearance mechanisms, given that they play a significant role in reducing intraocular drug penetration.

The choroid is a dark brown, highly vascularized layer located between the sclera and the retina. It extends from the *ora serrata* to the aperture of the optic nerve in the sclera. Drug molecules that are topically, systemically, and orally administered may be eliminated by the uptake of the rapid blood flow of the choroid. Drugs can be carried away by bulk fluid flows in ocular tissues and are ultimately mostly cleared through choroidal vasculature or conjunctival vascular and/or lymphatic vessels. Uveoscleral drainage has been reported within a range of 4–60% [51], and it generates an outward bulk flow fluid from the suprachoroidal space. Many drugs may be carried away by the convective current of aqueous humor and cleared by the conjunctival vascular and/or lymphatic vessels. The effect of aging on uveoscleral outflow must also be considered by future drug delivery systems.

The osmotic pressure of the choroid in rabbits is 12–14 mmHg, and the vitreous humor has an osmotic pressure of approximately 0–1 mmHg [52]. This difference in osmotic pressure between the choroid and the vitreous generates a fluid flow toward the choroid. The hydrostatic pressure difference between the suprachoroid and the episcleral tissue also contributes to the outward bulk fluid flow [53]. There is a hydrostatic pressure difference of about 12 mmHg between the suprachoroid and the episcleral tissue, which works as a driving force for the outward bulk fluid flow. Drug efflux pumps, such as P-glycoproteins (P-gp) and multidrug resistanceassociated proteins (MRPs), have been reported in RPE with an efflux effect directed toward the choroid [54, 55]. Finally, organic ion transporters may have an

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

carrier-mediated transport and a secretory function. New drug delivery systems should have an amphipathic nature in order to permeate through the cornea [23]. The sclera forms the firm, fibrous, outermost layer of the eye. It keeps the shape of the eye and provides an attachment for the insertion of the extraocular muscles. It is about 1 mm thick at the site where the optic nerve pierces it. The sclera is made of collagen and elastin chains that create a fiber matrix, where the pore diameter and intracellular spaces may determine the flow of drugs. Furthermore, the lateral orientation of fibers, the differences in the collagen architecture of the posterior sclera, and the differences in myopic eyes may affect drug transport with a lower or higher permeability depending on these changes. The permeability of the sclera for a number of molecules, such as dextrans, polyethylene glycol, anti-angiogenic molecules, antibiotics, oligonucleotides, and lipophilic compounds, has been measured [24–30]. There are different factors that may affect the scleral permeability of these molecules [2, 31–33]. Scleral permeability has a strong dependence on molecular weight, with smaller molecules having a better permeability. Similarly, since globular proteins are more permeable than linear dextrans of the same molecular weight, molecular radius is an important predictor of scleral permeability [32]. Finally, any surgical, pathological, or traumatic change in the anatomy of the sclera may lead to permeability changes [34]. Different studies on Bruch's membrane—the choroid and the retinal pigment epithelium (RPE)—show that permeability increases when lipophilicity does the same. Molecules that are passively transported across the RPE show similar permeability values in both outward (retina-choroid) and inward (choroid-retina) directions, while molecules that are actively transported show differences in permeability between the two of them [22]. The presence of RPE melanin may alter ocular drug disposition. Melanin binds to free radicals and drugs through electrostatic and van der Waals forces or through simple charge-transfer interactions with this pigment, which may alter the availability of the free drug at the targeted site [35]. All basic and lipophilic drugs bind to melanin; thereby, melanin binding may significantly lower pharmacological activity [36]. As a result of the presence of melanin, the binding of lipophilic compounds to the choroid-Bruch's membrane is higher; consequently, there is greater resistance to solute permeation across the choroid-Bruch's membrane than across the sclera, which is devoid of melanin [37–39]. Aging does not alter the permeability or ultrastructure of the sclera, but the permeability of Bruch's membrane and the choroid has shown to be significantly affected by age [2, 34]. Bruch's membrane may be a major resistance barrier against the movement of small solutes due to an increase in its thickness with aging (from 2 μm in the first decade of life to 4.7 μm in the tenth decade). Moreover, the accumulation of lipid-rich membranous debris and basal laminar deposits may have an

Dynamic barriers include the clearance through lymphatic and blood vessels, bulk fluid flow, and the active transport mechanisms of RPE transporter proteins. Precorneal barriers are highly effective and include solution drainage, blinking, tear

Blinking is a normal reflex that protects the eye from dryness, bright light, and fingers or other objects coming toward it. Blinking also regulates tears, which nourish and cleanse the surface of the eye. The blinking rate in newborns is only two times per minute. This increases to 14–17 times per minute in adolescence and remains at this rate throughout the rest of the lifetime. Blinking may also increase in response to

pain, bright light, changes in temperature and humidity, and conversations.

**26**

important role in drug delivery [39].

film, tear turnover, and induced lacrimation.

**2.2 Dynamic barriers**

important role as active transport for drugs depending on extracellular pH, temperature, and drug concentration [56].
