**4.2 PLA: PCL: PEG: PCL: PLA copolymers**

Endophthalmitis, impaired vision, increased cataract formation, intraocular pressure, and an elevated vulnerability of retinal detachment are all side effects of numerous intravitreal corticosteroid injections, which are induced by maintaining sustained levels of corticosteroids in the case of maculae edoema. Copolymers can be used to lessen these undesirable effects. Recently, there has been a lot of interest in amphiphilic block copolymers based on biodegradable polyesters like poly-caprolactone (PCL) and polyethylene glycol (PEG) [46]. PEG is a typical component in block copolymers as the hydrophilic section. PEG is a promising medication delivery material because of its high water solubility and minimal cytotoxicity [47]. PCL is a thermoplastic polyester that is biocompatible, biodegradable, and nontoxic. Its segments may come together to form a hydrophobic core that serves as a storage space for drugs that are insoluble in water [46].

Perret and his colleagues were the first to develop a series of PEG and PCL block copolymers [48]. Since then, numerous experiments on PCL and PEG-based di and tri-block copolymers have been done. Gong and coworkers formulated honokiolloaded PEGPCL-PEG micelles using a direct dissolution method assisted by ultrasonication [49]. Lue *et al* created a thermosensitive PEG–PCL–PEG hydrogel and investigated its ability for diclofenac sodium ocular medication delivery (DIC) [50]. Peng and colleagues looked into the use of PEG-PCL-PEG hydroge in rabbits as an intracameral implant to prevent scarring after surgery. They discovered that the prolonged release of bevacizumab from the hydrogel reduced neovascularization and scar formation [51]. Furthermore, due to the high crystallinity of PCL blocks, triblock copolymers based on PCL appear to have limits in terms of biodegradability and drug release [49].

#### **4.3 PLGA**

The poly lactic-co-glycolic acid (PLGA) copolymer comprising poly lactic acid (PLA) and poly glycolic acid (PGA), which is employed in medical applications such surgical sutures, bone plates and screws, tissue engineering scaffolds, and drug carrier systems, has been successfully created [52]. The mechanical characteristics of poly lactic-co-glycolic acid (PLGA), a biocompatible, biodegradable, and tunable polymer, can be changed by varying the molecular weight and PLA/PGA ratio. When utilised for medicine delivery, PLGA is hydrolyzed in vivo to produce biodegradable metabolite monomers such lactic acid and glycolic acid, which have very low systemic toxicity [53].

The use of PLGA-based-NPs for ocular drug administration has several advantages, including protection of encapsulated pharmaceuticals against fast inactivation, delayed drug release owing to polymer breakdown (e.g. Ciprofloxacin-loaded PLGA), and surface modification to target specific regions or cells. For example Flurbiprofen was loaded in PLGA nanoparticles with Poloxamer 188, diclofenacloaded PLGA nanoparticles and flurbiprofen-loaded nanoparticles are used against ophthalmic anti-inflammatorydisorders and enhanced permeability of inflamed area [54]. Additionally, hydrophilic or hydrophobic medications as well as macromolecules, proteins, peptides, and nucleic acids can be efficiently encapsulated in PLGA nanoparticles [55].

#### **4.4 Vitamin E TPGS**

Chemically, vitamin E TPGS is polyethylene glycol-esterified vitamin E succinate (PEG-1000). The chemical composition of TPGS is classified as a surfactant with no charges on its surface; the hydrophilic head section is separated from the lipophilic

#### *Novel Topical Drug Delivery Systems in Ophthalmic Applications DOI: http://dx.doi.org/10.5772/intechopen.108915*

tail portion by an alkyl group. The well-known adjuvant TPGS has been employed in a variety of medicinal compositions. The word "TPGS" refers to an oil-soluble vitamin also known as tocopherols and tocotrienols. Tocopherol, a naturally occurring vitamin, is the one with the highest potency [56]. As an antioxidant, vitamin E TPGS works to reduce oxidative stress, which has been associated to a number of eye conditions, including glaucoma, age-related macular degeneration, uveitis, and cataracts. Age-related disorders are most frequently brought on by oxidative stress, despite the fact that the exact aetiology is uncertain. As a result, TPGS may be a great alternative to conventional drugs in treating these conditions, acting as a neuroprotectant in age-related diseases [57].

In order to increase drug translocation in the cornea, TPGS can be utilised in conjunction with transdermal medication delivery because low water solubility of medications restricts their pharmacological effects for eye illnesses and limits their penetration. Cholkar *et al.* used TPGS and octoxynol-40 to make dexamethasoneloaded micelles. When compared to TPGS (0.025 wt percent) and Oc-40, the combined polymers had a reduced CMC (0.012 wt %) (0.107 wt %). The cytotoxicity of the formulations on rabbit primary corneal epithelial cells demonstrated their safety [58]. Rapamycin-loaded micelles were also created using TPGS and Oc-40, and in vitro tests on human retinal pigment epithelium and rabbit primary corneal epithelial cells demonstrated that they were well tolerated and barely harmful. Additionally, the micelles demonstrated clinical viability, exhibiting modest drug partition into vitreous fluid but very high drug concentrations at the retina-choroid target region [59].

In recent years, TPGS has been studied for ocular disorders along with several drugs such as cyclosporine (a micellar system was produced using Poloxamer and vitamin E TPGS to enhance drug concentration during delivery);curcumin (formulated with Pluronic P123 (P123) and vitamin E TPGS to increase permeation across cornea); rapamycin (formulated using vitamin E TPGS and octoxynol-40 to enhance its water solubility); acyclovir (formulated with vitamin E TPGS and octoxynol-4 to slow the release of drug and site specific absorption); riboflavin (to improve riboflavin penetration across the cornea even without removing the epithelium); dexamethasone (formulated with polylactide-co-glycolide (PLGA) and vitamin E TPGS to decrease the limitations of the posterior segment drug delivery); dorzolamide (to overcome the problem of frequent instillation) and timolol (to enhance intraocular pressure reduction capability of contact lens even at lower dose) [57].

#### **4.5 Cyclodextrin**

Cyclodextrins are oligosaccharides with a hydrophilic outer surface and a lipophilic interior chamber that can form water-soluble complexes [60]. When applied topically, cyclodextrin nanoparticles promote mucoadhesion, I increase the concentration of dissolved medicine in the eye drop and subsequently in tear fluid, (ii) and (iii) allow drug molecules transit through the unstirred water layer immediately close to the eye surface [10, 61, 62]. Tanito et al. [61] examined the impact of nanoparticlecyclodextrin dexamethasone eye drops on diabetic macular oedema and discovered a notable decrease in retinal thickness and an improvement in visual acuity, with outcomes comparable to those attained with intravitreal therapy [63].

Cyclodextrins are cyclic oligosaccharides that form complexes with lipophilic medicines to boost their solubility. Cyclodextrin interactions with biological membranes have also been discovered to play a part in their efficacy in increasing solubility. The number of Cyclodextrins used for solubility improvement is quite important. Large quantities can reduce bioavailability by holding medicine in tears; ideally, 15% or less should be supplied [64, 65]. Some of the eyedrops that contain Cyclodextrins that are registered in Europe are chloramphenicol (Clorocil®: Edol), diclofenac (Voltaren Ophthalmic®: Novartis), and indomethacin (Indocid®: Merck Sharp & Dohme-Chibret).

Topical medication administration to the anterior and posterior segments based on cyclodextrin has been claimed to have the ability to overcome physio-anatomical limitations, as well as the inadequacies and side effects associated with ocular drug delivery [66]. The use of cyclodextrin inclusion complex to boost the drug molecule's water solubility has been widely questioned, leading in a rise in the number of formulations on the market that use cyclodextrin as an excipient. Cyclodextrins are cyclic oligosaccharides formed naturally when starch is digested by bacteria. Compared to linear dextrin, the structure of −1,4-glyosidic connections of -D glucopyranose units is cyclic, making it more resistant to non-enzymatic degradation. When compared to fungizon, cyclodextrin improved issolution and penetration when combined with dexamethasone or ilomastat, and its combination with amphotericin raised antifungal activity by 35 times [67].

#### **4.6 Carbopol**

Carbopol, carbomer, and acrylic acid polymers are polymers of acrylic acid with allyl sucrose or allyl ethers of pentaerythritol that are synthesised at high molecular weight [68]. Each can be used as a bioadhesive component, controlled release agent, emulsifying agent, emulsion stabiliser, rheology modifier, or stabilising agent in ophthalmic formulations [69]. The -blockers timolol, betaxolol, carteolol, and metipranolol were combined with carbopol to create a formulation that was demonstrated to be particularly successful in lowering intraocular pressure [70]. Each one may be utilised in ophthalmic formulations as a bioadhesive component, controlled release agent, emulsifying agent, emulsion stabiliser, rheology modifier, or stabilising agent.

Carbopol has also been utilised in Gel-Larmes-Thea formulations to treat dry eye syndrome [71]. When the pH exceeds its pKa, a sol-to-gel transition occurs in aqueous solution, and the reaction to shear strain is Newtonian time-dependent. The nonlinear synthetic nonlinear polymers that make up the carbopol resins (910, 934, 940, 941, and 962) mostly consist of acrylic acid and are cross-linked with a polyalkenyl polyether. Johnson et al. demonstrated the effectiveness of carbopol in extending corneal residence time in rabbits by injecting pilocarpine nitrate into their eyes [72]. The bioadhesive properties of carbopol are another advantage, as they can increase viscosity and, consequently, residence time. They can also form potent non-covalent bonds with the mucin that covers biological membranes and remain there for a similar amount of time.

#### **4.7 Polysorbate 80**

Tween 80 and Polysorbate 80 are both non-ionic polyethoxylated (PEO) sorbitan monooleates [45]. It is composed of a copolymer of sorbitol oleate ester and its anhydrides, in which 20 mol of PEG are added for every mole of sorbitol and its anhydrides [73]. A sorbitan ring is connected to four hydrophilic PEO head groups for a total of 20. In the hydrophobic area, an ester couples an oleyl, unsaturated tail to one PEO group [74]. The kink in Polysorbate 80's hydrophobic tail allows for flexibility, resulting in an ideal curvature and packing characteristic for microemulsion

production [75]. In rabbits, the oil in water emultion formulation of Difluprednate combined with Polysorbate 80 aids in the stabilisation of a greater dose in the aqueous humour than the suspension formulation [13].

#### **4.8 PEG-40 hydrogenated Castor oil**

Cremophors are polyethoxylated castor oils produced by reacting varying concentrations of hydrogenated castor oil with ethylene oxide. To create PEG-40 hydrogenated castor oil, 40 mol of ethylene oxide are combined with 1 mol of hydrogenated castor oil. Glycerol polyethylene ricinoleate is the hydrophobic portion of such surfactants, while polyethylene glycols and glycerol ethoxylates are the hydrophilic portion [76]. PEG-40 hydrogenated castor oil is predominantly made up of hydrophobic elements, the most prominent of which being glycerol polyethylene glycol 12 hydroxystearate [76]. The HLB value is still high (14–16), and its water solubility has increased, as a result of the many hydrophilic polyethylene oxide (PEO) groups. As a result, PEG-40 hydrogenated castor oil can function as an oil solubilizer as well as an o/w microemulsion emulsifier [45]. Cyclosporine is combined with hydrogenated castor oil to provide a topical ophthalmic medication with improved solubility [77].
