**4.5 Cyclodextrin nanoparticles**

Cyclodextrins (CDs) are a family of natural cyclic oligosaccharides which are usually composed of no more than 20 a-D-glucopyranoside units via the covalent conjugation of α-1,4-glycosidic linkages. CDs are cyclic structures whose hydrophilic outer surface is enclosed by the lipophilic internal cavity of low polarity. The features of their special structure predetermined their ease to form inclusion complexes for poorly water-soluble chemicals through non-covalent conjugations (electrostatic interactions, van der Waals contributions, hydrogen bonding, and charge-transfer interaction) [115]. CDs are not toxic for human beings [116], and they can improve the aqueous solubility, stability, activity, and dispersion of ophthalmic drugs [117].

Different types of oligomeric CD molecules are currently being used to produce cyclodextrin-based eye drops. These molecules are the β-CD [7], the γ-CD [8], its CD derivatives (hydroxypropyl-beta-cyclodextrin (HP-β-CD)), and the randomly methylated beta-cyclodextrin (RM-β-CD) [118]. Econazole nitrate (EC) and CD/ HP-β-CD were complexed to form different EC-CD inclusion complexes through coprecipitation in order to improve ocular bioavailability [119].

In the study of Loftsson et al. [120], inclusion complexes of dexamethasone and γ-CD were topically administered to rabbits. After 2 h of application, DEX reached its highest concentration in the vitreous and the retina. The same group performed a clinical trial to prove the efficiency of topical 1.5% dexamethasone γ-cyclodextrin nanoparticle eye drops (DexNP) compared to posteriorly the subtenon injection of triamcinolone acetonide in diabetic macular edema (DME) patients. Topical DexNP significantly improved visual acuity and decreased the macular thickness of patients with DME. The effect was similar to that of subtenon triamcinolone. However, a modest increase in intraocular pressure (IOP) was noted with DexNP, but IOP normalized after the discontinuation of the eye drops [21].

#### **4.6 Liposomes**

Liposomes were described for the first time by Alec Bangham in the 1960s at the Babraham Institute, University of Cambridge, and they consist of single or multiple concentric lipid bilayers encapsulating an aqueous compartment.

Liposomes as carriers for advanced drug delivery have been of much interest lately. They are biocompatible vesicles composed of a phospholipid bilayer with structural resemblance to the cell membrane that form small spheroids that are able to carry both hydrophilic and lipophilic drugs (**Figure 2**). Phospholipids combined with water immediately form a sphere as one end is water soluble, while the opposite end is water insoluble. Water-soluble medications added to water are

**35**

*4.6.1 Types of liposomes*

**Figure 2.**

*Spherical formation of liposomes.*

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

trapped inside the aggregation of hydrophobic ends and fat-soluble medications and incorporated into the phospholipid layer. Another significant characteristic of liposomes is their drug release rate, which depends on the liposomal composition,

chains, like that of egg phosphatidylethanolamine, or pure components like dioleoylphosphatidylethanolamine (DOPE). The lipid bilayer can fuse with other bilayers (e.g., the cell membrane), thus delivering the liposomal contents. By including liposomes in solutions with DNA or drugs (which would normally be unable to diffuse through the membrane), they can be delivered past the lipid bilayer. The use of liposomes for the transformation or transfection of DNA into a host cell is known as lipofection. Liposomes can be created by sonicating phospholipids in water. Low shear rates create multilamellar liposomes, which have many layers, like an onion. Continued high-shear sonication tends to form smaller unilamellar liposomes.

Liposomes can be composed of naturally derived phospholipids with mixed lipid

Depending upon their structure, there are two types of liposomes, unilamellar liposomes or unilamellar vesicles, which have a single phospholipid bilayer sphere enclosing an aqueous solution (**Figure 3**), or multilayer liposomes, which are multilamellar structures (**Figure 4**). In multilayer liposomes, several unilamellar vesicles will form one inside the other in diminished sizes, creating a multilamellar structure of concentric phospholipid spheres (like a Matryoshka doll) separated by

• Phospholipids such as phosphatidylcholine, phosphatidylglycerol, phosphati-

dylinositol, etc. For stable liposomes, saturated fatty acids are used.

• Sterols, such as cholesterol, with the potential to decrease the fluidity or microviscosity of the bilayer. It can reduce the permeability of the membrane to water-soluble molecules and stabilize the membrane in the presence of

layers of water. The structural components of liposomes could be:

• Sphingolipids like sphingomyelin.

biological fluids such as plasma.

the nature of the drug, and the method of encapsulation.

*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*

**Figure 2.** *Spherical formation of liposomes.*

*Role of Novel Drug Delivery Vehicles in Nanobiomedicine*

**4.5 Cyclodextrin nanoparticles**

ophthalmic use [110]. Due to their enhanced aqueous solubility, a large variety of surface groups, and their nontoxic nature, polyamidoamine (PAMAM) dendrimers

Yavuz et al. [113] generated various anionic dexamethasone (DEX)-PAMAM complexes and evaluated the delivery of DEX to the posterior segment following topical administration in rats. The ocular tissue distribution study in rabbit eyes showed that anionic DEX-PANAM dendrimers reach the highest concentration of DEX in the vitreous body, the retina-choroid, and the sclera compared to topical DEX suspension. In addition, in vitro studies demonstrated that dendrimers with peripheral carboxyl or hydroxyl functional groups rarely showed cytotoxicity. Transport study results showed that dendrimer complexation increases DEX transport across both corneal and scleral tissues. Additionally, dendrimers have proven their efficiency to release genetic material when topically administered [114].

Cyclodextrins (CDs) are a family of natural cyclic oligosaccharides which are usually composed of no more than 20 a-D-glucopyranoside units via the covalent conjugation of α-1,4-glycosidic linkages. CDs are cyclic structures whose hydrophilic outer surface is enclosed by the lipophilic internal cavity of low polarity. The features of their special structure predetermined their ease to form inclusion complexes for poorly water-soluble chemicals through non-covalent conjugations (electrostatic interactions, van der Waals contributions, hydrogen bonding, and charge-transfer interaction) [115]. CDs are not toxic for human beings [116], and they can improve the aqueous solubility, stability, activity, and dispersion of ophthalmic drugs [117]. Different types of oligomeric CD molecules are currently being used to produce cyclodextrin-based eye drops. These molecules are the β-CD [7], the γ-CD [8], its CD derivatives (hydroxypropyl-beta-cyclodextrin (HP-β-CD)), and the randomly methylated beta-cyclodextrin (RM-β-CD) [118]. Econazole nitrate (EC) and CD/ HP-β-CD were complexed to form different EC-CD inclusion complexes through

In the study of Loftsson et al. [120], inclusion complexes of dexamethasone and γ-CD were topically administered to rabbits. After 2 h of application, DEX reached its highest concentration in the vitreous and the retina. The same group performed a clinical trial to prove the efficiency of topical 1.5% dexamethasone γ-cyclodextrin nanoparticle eye drops (DexNP) compared to posteriorly the subtenon injection of triamcinolone acetonide in diabetic macular edema (DME) patients. Topical DexNP significantly improved visual acuity and decreased the macular thickness of patients with DME. The effect was similar to that of subtenon triamcinolone. However, a modest increase in intraocular pressure (IOP) was noted with DexNP,

Liposomes were described for the first time by Alec Bangham in the 1960s at the Babraham Institute, University of Cambridge, and they consist of single or multiple

Liposomes as carriers for advanced drug delivery have been of much interest lately. They are biocompatible vesicles composed of a phospholipid bilayer with structural resemblance to the cell membrane that form small spheroids that are able to carry both hydrophilic and lipophilic drugs (**Figure 2**). Phospholipids combined with water immediately form a sphere as one end is water soluble, while the opposite end is water insoluble. Water-soluble medications added to water are

coprecipitation in order to improve ocular bioavailability [119].

but IOP normalized after the discontinuation of the eye drops [21].

concentric lipid bilayers encapsulating an aqueous compartment.

have been investigated the most in regard to ocular drug delivery [111, 112].

**34**

**4.6 Liposomes**

trapped inside the aggregation of hydrophobic ends and fat-soluble medications and incorporated into the phospholipid layer. Another significant characteristic of liposomes is their drug release rate, which depends on the liposomal composition, the nature of the drug, and the method of encapsulation.

Liposomes can be composed of naturally derived phospholipids with mixed lipid chains, like that of egg phosphatidylethanolamine, or pure components like dioleoylphosphatidylethanolamine (DOPE). The lipid bilayer can fuse with other bilayers (e.g., the cell membrane), thus delivering the liposomal contents. By including liposomes in solutions with DNA or drugs (which would normally be unable to diffuse through the membrane), they can be delivered past the lipid bilayer. The use of liposomes for the transformation or transfection of DNA into a host cell is known as lipofection. Liposomes can be created by sonicating phospholipids in water. Low shear rates create multilamellar liposomes, which have many layers, like an onion. Continued high-shear sonication tends to form smaller unilamellar liposomes.
