Novel Topical Drug Delivery Systems in Ophthalmic Applications

Abstract

The eye is the utmost attention-grabbing organ owed to its drug disposition characteristics. Generally, topical application (90% are eye drops) is the method of choice because of its patient compliance and safety. Transcorneal penetration is the major route for ophthalmic drug absorption. However, corneal absorption has been observed to be slower process as compared to elimination. Therefore, conventional dosage forms are associated with rapid precorneal drug loss. Thus, to improve ocular drug bioavailability, there is a substantial effort directed toward the development of novel topical drug delivery systems for ophthalmic administration. These novel delivery systems (Contact lenses, In situ gels, Microemulsions, Niosomes, Liposomes, Implants, Microspheres, and Micelles) provide the controlled release behaviour for treating the chronic ailments, and help patients and doctors to curtail the dosing frequency and invasive method of treatment. Hence, the current chapter discusses the progress of novel topical ocular drug delivery systems in the pharmaceutical industry.

1. Introduction

Eye is the utmost attention-grabbing organ owed by its drug disposition characteristics. Drug delivery to the eye is hampered by the physiological barricades such as blinking & wash out by tears, nasolacrimal drainage, nonproductive losses, and impermeability of the cornea [1, 2]. Although its easy to administer the drug to eyes but there are various barriers to drug delivery, viz. tear mechanisms, membranes, and blood–aqueous and blood–retinal barriers [3]. The three main routes for administering ophthalmic medication are topical, systemic, and intraocular; each has its own set of benefits and drawbacks.

Topical application (90 percent of which are eye drops) is the preferred method due to patient compliance and safety. The most common route for ophthalmic drug absorption is through transcorneal penetration. Corneal absorption, on the other hand, is a much slower process than elimination. Despite the benefits of ocular formulations (ease of formulation, storage limitations, and drug instillation), they have several drawbacks, including limited drug accumulation for lipophilic agents, precorneal losses, and the cornea’s barrier [4]. As a result, traditional ocular dosage forms have been linked to rapid precorneal drug loss. Effective systemic delivery, can be achieved if high drug concentration circulates in the blood plasma. Furthermore, sustained release of oral drugs may be appropriate for glaucoma patients, allowing for continuous and effective treatment; butin this method the entire body is exposed to the drug, so, side effects can be observed [5]. Moreover, intravitreal drug delivery is an invasive procedure that carries some risk, such as retinal haemorrhage or detachment, especially if the technique is repeated multiple times for treating chronic disorders.

Traditional eye drops are convenient and easy method, but they are ineffective, and only a small portion of the dose is delivered to the target area; the majority is lost owing toclearance mechanisms. As a result, there are significant strategies aimed at developing novel topical drug delivery systems for ophthalmic administration in order to improve ocular drug bioavailability. Solubility enhancers are primarily used to increase the drug concentrations within the formulation; medication in the dosage form enhances the bioavailability. This strategy may allow for the application of a smaller droplet, and loss due to the reflex tearing and blinking can be prevented to larger extent [5]. Second, the formulation can be designed to withstand clearance; these dosage forms are retained for longer periods of time, giving them more time to remain accumulated within the ocular tissue. Finally, drug penetration enhancers can be added to the formulation to help the drug get through the cornea [6]. All of these approaches are novel drug delivery technologies that allow drugs to reach the posterior chamber. These delivery systems viz. contact lenses, in situ gels, microemulsions, niosomes, liposomes, implants, microspheres, and micelles provide controlled release for the treatment of chronic eye disorders, reducing dose frequency and invasive treatment.

Following that, the chapter looks at how novel topical ocular drug delivery systems are progressing in the pharmaceutical industry. Future research is likely to lead to the discovery of polymers that outperform those currently in use, such as smart drug delivery systems that release their payload in response to a specific stimulus. Furthermore, a reassess of recent advances in ophthalmic drug delivery necessitates and aids drug delivery scientists in modulating their thought processes and developing novel and safe drug delivery techniques. Its goal is to sumup the existing traditional ocular delivery formulations and their advancements, as well as current developments. In addition, recent advancements in novel ocular drug delivery strategies, such as contact lenses, in situ gels, microemulsions, niosomes, liposomes, implants, microspheres, and micelles have been thoroughly discussed.

2. Dosage forms for topical ophthalmic drug delivery systems

2.1 Conventional therapy

2.1.1 Topical

Topical ocular administration is one of the most often used traditional ways for treating problems of the eye’s anterior structures, such as the pre-ocular, cornea, anterior, and posterior chambers. It has four major advantages over other delivery methods: (i) effects of drugs are localised, and very less drug enters the systemic circulation; (ii) it enhances the drug absorption into the eye, which is otherwise difficult to accomplish with systemic administration of drugs; (iii) it bypasses hepatic first-pass metabolism; and (iv) it is a relatively convenient, and painless way of administration. Despite its numerous advantages, topical drug delivery have limited bioavailability due to the numerous biological processes that exist to protect the eye and, as a result, limit the entry of ocular medications [7].

2.1.2 Eye ointments

Ointments are typically made from a combination of semisolid and solid hydrocarbons (paraffin), having a melting or softening point near body temperature and donot cause irritation to the eyes. Simple bases, in which the ointment forms a single continuous phase, or compounded bases, in which a two-phased system (e.g., an emulsion) is used, are the two types of ointments. The medicinal substance is either introduced as a solution or as a finely micronised powder to the base. Ointments break down into little droplets after being injected into the eye, and they stay in the cul-de-sac for a long time as a drug depot. As a result, ointments are useful for increasing bioavailability and sustaining release of drug. Ointments, despite being safe and well tolerated by the eye, have low patient compliance due to blurred vision and occasional discomfort [8].

2.1.3 Gel

Gel formation is a uniquecase of viscosity enhancement using viscosity enhancers, which leads to longer pre-corneal residence period. It provides benefits such as lower systemic exposure. Despite its extremely high viscosity, gel only improves bioavailability to a limited extent, and dose frequency can be reduced to once a day at most. The excessive viscosity, on the other hand, causes hazy vision and matted eyelashes, which significantly reduces patient acceptance. Polymers including polyacrylamide, poloxamer, carbomer, poly methylvinylethermaleic anhydride, and hydroxypropyl ethylcellulose are commonly used in aqueous gels. Controlled drug delivery systems are made up of swellable water insoluble polymers, known as hydrogels, or polymers with unusual swelling properties in aqueous medium. Most ofently swellings are observed when drugs are released through these systems via transport of solvent into the polymer matrix. Diffusion of the solute through the inflated polymer leads to erosion/dissolution in the final stage. In humans, a poly (acrylic acid) hydrogel has been shown to considerably increase tropicamide ocular bioavailability when compared to a paraffin ointment and viscous solution [9]. Pilopine HS® gel, introduced by Alcon in 1986, and more recently Merck’s Timoptic-XE®.

2.1.4 Intravitreal injection

Many debilitating and sight-threatening disorders are caused by posterior segment diseases, and the only method to cure them is through invasive treatments such as “intravitreal injection” In most cases, this is still true, although advances have resulted in a broad variety of viable implantable drug-delivery systems for diseases of posterior segment, and the several possibilities will now be explored. Injection into the vitreous humour of eye is the most popular method of placing drugs in the posterior chamber; this gives a high concentration of drug where it is needed while minimising systemic effects. Xu et al., found that the diffusion of polystyrene nanoparticles of different sizes and surface chemistries in fresh bovine vitreous humour and found that depending on the nanoparticle’s intended features, they were able to achieve adequate drug transport within the posterior chamber [10]. However, many disorders, such as cataracts, retinal detachment, haemorrhage, endophthalmitis, and ocular hypertension, necessitate frequent treatment, which can lead to intraocular complications.

This approach includes injecting a medication solution into the vitreous through the pars plana using a 30G needle, which improves drug absorption over systemically and topically administered drugs. It results in drug distribution to the eye’s target areas. Drug delivery to the posterior segment of the eye is much safer as compared to systemic mode of drug administration. Intravitreal injection, as opposed to other methods, gives larger medication concentrations in vitreous and retina. Following intravitreal delivery, a drug’s molecular weight determines how quickly it is eliminated [11]. Despite the fact that intravitreal delivery provides high drug concentrations in the retina, it is linked to a number of short-term problems, including retinal detachment, endophthalmitis, and intravitreal haemorrhages [12]. Patients must also be closely watched during intravitreal injections. It has disadvantages like first-order kinetics (this rapid rise may cause toxicity, and drug efficacy can diminish as the drug concentration falls below the targeted range), injections have a short half-life (a few hours), and they must be given repeatedly, and side effects like pain from repeated injections, discomfort, increased IOP, intraocular bleeding, increased infection risks, and the risk of retinal detachment.

2.1.5 Emulsions

A vast range of lipophilic medicines have been employed to treat eye problems in recent years. Oil-in-water emulsions have improved significantly bioavailability to ophthalmic region. Yamaguchi et al., combined a 0.05 percent w/v difluprednate (DFBA) ocular lipid emulsion with 5.0 percent castor oil and 4.0 percent polysorbate 80 to make a 0.05 percent w/v DFBA ophthalmic lipid emulsion [13]. At 1 hour after instillation, the lipid emulsion had a 5.7-fold greater concentration of DFB, an active metabolite of DFBA, in the aqueous humour than the DFBA ophthalmic suspension. The first time this product was sold in the United States was in 2008. Shen et al. created an ocular emulsion of flurbiprofenaxetil (FBA), a well-known NSAID, and discovered that the mean retention time (MRT) of flurbiprofen in aqueous humour increased as the oil content increased. Flurbiprofen’s area under the curve (AUC0–10 h) was 6.7 times higher in the FBA emulsion group than in the FBA oil solution group. A promising NSAID ophthalmic emulsion with minimal irritancy and increased anti-inflammatory action was found in the nanoparticle with a raised FBA concentration of 0.1 percent [14].

Cationic emulsion changes have been reported to improve spreading capabilities, decrease contact angle, and increase ocular surface residence time. Oleyamine, stearylamine, chitosan, arginine octadecylamine, and 1,2-dioleoyl-3-trimethylammonium-propane are examples of cationic materials (DOTAP). The tear fluid drug levels in the CE were 3.6 and 3.8 times greater than those in the non-coated emulsion (NE) after topical administration of indomethacin-chitosan-coated emulsion (CE) at 0.5 and 0.75 hours, respectively. CE’s residence time is 1.5 times longer than NE’s [15]. Klang et al., studied indomethacin corneal penetration in anionicsubmicron emulsions, cationic emulsions, and commercially available ocular solutions [16]. Cationic emulsions have four times the spreading coefficients of anionic emulsions. Other emulsions had substantially lower drug levels in aqueous humour and sclera-retina than this new therapy.

2.2 Novel therapies

2.2.1 Contact lenses

Contact lenses are polymeric devices with hydrophilic or hydrophobic charactersitics that are designed toplace directly onto the cornea to correct refractive errors of eye. In comparison to its anhydrous state, hydrogel contact lenses are practical materials for use as ocular medication delivery systems because they can ingest a considerable volume of aqueous solution. If the contact lens hydrating solution has enough pharmaceutically active material, it will be able to diffuse from the polymer matrix into the tear film bathing the eye and interact with the ocular tissue. However, there is still a requirement to keep the medicine in the devices long enough to ensure proper release of drugs.

Wichterle and Lim proposed the notion of employing hydrogel contact lenses as drug-delivery devices in their 1965 patent, which suggested including medication following lens hydration to provide extended drug availability throughout usage [17]. The type of contact lens dictates how it is worn; daily, weekly, and monthly disposable versions are available [17]. The absorption of a drug-loaded solution during pre-wear soaking was used in early efforts to contact lens-assisted drug delivery. Drug distribution through standard contact lenses is inconsistent, with a brief initial “burst release” and then a quick fall. Drug-loaded coating or the insertion of a sandwich layer of drug-loaded polymer, the inclusion of drug-loaded nanoparticles, and cyclodextrin grafting are some of the other techniques. Molecular imprinting technology is a method of modifying polymer formulations to increase their affinity for drug molecules, hence enhancing drug loading potential and extending delivery time [18, 19, 20]. Hiratani et al., 2006 used this strategy to construct a system that used methacrylic acid, N, N-diethylacrylamide, and the medication timolol to generate sustained timolol release in vitro for over 48 hours. Alvarez-Lorenzo et al., used the same approach to make norfloxacin-loaded poly (hydroxyethyl methacrylate) (pHEMA) contact lenses, reporting a 300-fold increase in reservoir capacity over pHEMA lenses without molecular imprinting technology [21]. HEMA, mono-methacrylated-cyclodextrin, and trimethylolpropane trimethacrylate were used by Xu et al. [22] to make hydrogel films and contact lenses. Puerarin was used as a model medication by soaking the gel in a drug solution to hydrate it [22]. Loading and release rates were found to be dependent on -cyclodextrin content in in vitro tests. In vivo tests on rabbits revealed that the gels provided better medication release and performance than commercial puerarin eye drops. The researchers believe the material is suitable for drug delivery from reusable daily wear contact lenses because the devices have outstanding mechanical qualities.

2.2.2 Niosomes

Niosomes are nonionic structural vesicles with two layers that can encapsulate both lipophilic and hydrophilic substances. Niosomes boost ocular bioavailability by reducing systemic drainage and increasing residence duration. In nature, they are nonbiodegradable and nonbiocompatible. Niosomal formulation was developed as a new way to distribute cyclopentolate. The medication was released regardless of pH, leading in a considerable increase in ocular bioavailability. A niosomal formulation of coated (chitosan or carbopol) timolol maleate had a significant influence on decreasing IOP in rabbits compared to timolol solution [23].

2.2.3 Microemulsion

Microemulsions are stable water-oil dispersions aided by the use of a surfactant and co-surfactant combination to lower interfacial tension. The drug’s ocular bioavailability is improved, and the frequency of administration is reduced, thanks to microemulsion. Higher thermodynamic stability, tiny droplet size (100 nm), and a clean appearance are common characteristics of these systems [24]. An oil-in-water system containing pilocarpine, lecithin, propylene glycol, PEG 200 as a surfactant/co surfactant, and isopropyl myristate as the oil phase did not irritate the rabbit animal model. Such formulations frequently enable continuous medication release, reducing drug delivery frequency. Its stability is affected by the potential toxicity of greater surfactant/co-surfactant concentrations, surfactant/co-surfactant selection, and aqueous/organic phase.

2.2.4 Liposomes

Liposomes are tiny vesicles made up of one or more lipid bilayers separated by water or an aqueous buffer. Liposomes have the ability to make close contact with the corneal and conjunctival surfaces, improving the chances of ocular medication absorption. This capability is especially useful for drugs that are poorly absorbed, have a low partition coefficient, poor solubility, or have a molecular weight of medium to high. The surface charge of liposomes has been discovered to play a role in their behaviour as an ocular medication delivery system. In comparison to neutral or negatively charged liposomes, positively charged liposomes appear to be preferentially trapped at the corneal surface which has negative charged. It has the properties of being droppable, biocompatible, and biodegradable. It decreased the drug’s toxicity. It allows for long-term release and site-specific delivery. Liposomes are difficult to make in a sterile environment. It has drawbacks such as a low drug load and poor water stability. Schaeffer et al., found that liposome uptake by the cornea is greatest for positively charged liposomes and least for neutral liposomes when working with indole and penicillin G. This finding suggests that electrostatic adsorption is the initial interaction between the corneal surface and liposomes [25].

2.2.5 Implants

The intraocular implant’s purpose is to provide sustained activity with regulated medication release from the implant’s polymeric substance. The implants must constantly be administered intraocular, which necessitates minimal surgery. They are usually implanted intravitreal, at the pars plana of the eye (abruptly anterior to the retina and posterior to the lens) [26, 27]. Despite the fact that this is an invasive procedure, the implants have the advantages of (1) delivering consistent therapeutic doses of medication straight to the site of action by avoiding the blood-ocular barrier, (2) avoiding the negative effects linked to repeated intravitreal and systemic injections, and (3) requiring a smaller amount of drug during treatment. Ocular implants are divided into two categories: non-biodegradable and biodegradable. Non-biodegradable implants can enable more precise medication release control and longer release times than biodegradable polymers, but they require surgical implant removal, which comes with its own set of dangers.

The delivery rate of implants could be controlled by changing the polymer composition. Solid, semisolid, or particulate-based delivery systems can be used to deliver implants. There are typically three phases to the drug release from polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid: an initial burst, a middle diffusive phase, and a final burst of the drug. It’s a better option to repeated injections because it extends the drug’s half-life and may help to reduce peak plasma levels; it may also enhance patient acceptance and amenability. It has drawbacks, such as side effects: the insertion of these devices is invasive, and there are ocular complications that come with it (retinal detachment and intravitreal haemorrhage for intravitreal implant). Once the device has been depleted of the drug, it must be harvested through surgery (risk of ocular complications). The drug release profile of the biodegradable implants has an uncontrollable final burst [27].

2.2.6 In situ-forming gel

When the droppable gels are instilled, they become liquid and then transition to a viscoelastic gel in the ocular cul-de-sac, providing a response to environmental changes. It raises the level of patient acceptance. It extends the drug’s time in the eye and improves its ocular bioavailability. pH, temperature, and ionic strength are all variables that can affect and trigger the phase transition of droppable gels. Gelling is caused by a variety of factors, including a change in pH, which causes CAP latex cross-linked polyacrylic acid and its derivatives, carbomers and polycarbophil, a change in temperature, which causes poloxamers, methyl cellulose, and Smart HydrogelTM, and a change in ionic strength, which causes Gelrite and alginate [28, 29, 30, 31].

2.2.7 Microspheres

It has been described how erodible, non-erodible, and lipid microspheres can be used for ophthalmic delivery. The drug is uniformly dispersed (monolithic system) in the polymer matrix. Due to this, the drug may or may not be present in the liquid carrier medium in which the drug-loaded microparticles are suspended. Pilocarpine-loaded gelatin and albumin microspheres were released and pharmacokinetic data were presented by Leucatta et al., in 1989. Hardened proteinaceous microspheres with a diameter of about 30 pm produced biphasic release of pilocarpine over a period of two to five days. Drug recovery was reported to be around 20% in gelatin and 28% in albumin microspheres. The colloidal system outperformed the aqueous control in terms of significant pharmacokinetic parameters.

Furthermore, the lipid microspheres significantly increased intraocular steroid penetration when compared to non-detectable or no penetration with suspension. The release of proteins of various sizes, including lysosome, trypsin, heparinize, ovalbumin, albumin, and immunoglobin, from poly(anhydrides) microspheres (50–125 pm) and poly(anhydrides) copolymers has been reported [32]. Fatty acid dimer and sebacic acid were copolymerized in various ratios with various molecular weights to create microspheres. The particle size, cross linking density, and drug loading all influence the in vitro release of drugs from microspheres. For a week, these microspheres generated release rates that were nearly constant or zero. The liquid medium in which the microparticles are suspended should have a pH and osmolarity that are acceptable to the eye, and the dosage form should be soothing and non-irritating to the user. Additionally, neither the polymer nor its degradants should be harmful to the eyes [33].

2.2.8 Micelles

Amphiphilic surfactants or diblock polymers are used to make micelles. Recently, the efficacy of a polyion complex micelle system incorporating a dendritic phtalocyanine photosensitizer in photodynamic therapy of choroidal neovascularization was tested in rats. Absorption at 650 nm was observed in the micellar system, which is advantageous for the treating deep lesions. The formulation may be able to selectively accumulate in choroidal neovascularized lesions and extend bloodstream retention, but these possibilities will need to be further investigated [34, 35, 36].

3. Advantages of novel over conventional topical ophthalmic drug delivery systems

The delivery of ophthalmic drugs is one of the most difficult tasks confronting pharmaceutical researchers. Their target is to achieve and maintain a therapeutic level at the action site for a long time. To keep medication levels at the target site for an extended period of time, novel drug delivery methods should be created. In terms of distinct delivery methods or tools to be used before, during, or after administration, novel drug delivery systems are fresh on the market and variations on earlier ones. Existing remedies are becoming ineffective as a result of the development of new technology. By decreasing drug exposure to non-target cells and increasing the amount and durability of a drug around target cells, new drug delivery methods improve a drug’s therapeutic effects while minimising its harmful consequences [37]. One of the most difficult delivery methods for pharmaceutical researchers is ophthalmic medication delivery [38]. Traditional delivery methods like suspensions, solutions, emulsions, intravitreal injections, and ointments have poor ocular bioavailability, or less than 1%, as a result of various factors including fast yield, low absorption, short residence time in the cul-de-sac, and relatively impermeable drugs [39]. Within 5 minutes of administration, up to 80% of the administered dose may be lost due to tears and nasolachrymal drainage. Figure 1 illustrates the difference between conventional and novel drug delivery systems.

Figure 1.

Advantages of novel drug delivery systems over conventional systems in ophthalmic applications.

The use of viscosity enhancers, ophthalmic solutions in which the drug dissolves slowly, or ophthalmic inserts can all be used to extend the duration of therapy [37]. Because it prolongs drug release and allows for greater contact with the front of the eye, ophthalmic drug administration is optimal [38]. Novel ocular drug administration aims to prolong medicine retention duration in the eye or facilitate transcorneal drug penetration to boost drug bioavailability [40]. From eye drops to ophthalmic iontophoresis, in situ gels, dendrimers, ocular inserts mucoadhesive polymers, penetration enhancers, mucoadhesive polymers, hydrogels, and targeted drug delivery systems, topical ocular medication delivery has been enhanced [41]. Most frequently available ophthalmic preparations are eye drops and ointments. Nonetheless, due to tear flow and lachrymal nasal drainage, these preparations are rapidly drained away from the ocular cavity when instilled into the cul-de-sac. Because only a small amount is available for therapeutic effect, frequent dosing is required. Over the past three decades, newer pharmaceutical ophthalmic formulations have been created to address these problems. These formulations include in situ gel, nanoparticle, liposome, nano-suspension, microemulsion, iontophoresis, and ocular inserts [42].

4. Harmonious additives and their role in novel topical ophthalmic drug delivery systems

4.1 Poloxamer

A thermoresponsive polymer called poloxamer begins as a liquid between 4 and 5°C and in a concentration range of 20 to 30% wt/wt before changing to a gel when the temperature of the medium increases. When used alone, higher concentrations of Poloxamer are necessary in a formulation; nevertheless, such amounts have been shown to irritate the eyes. In order to reduce the overall amount of Poloxamer utilised, enhance the gelling and mechanical properties of Poloxamer, and lower the risk of eye irritation, Poloxamer was combined with other polymers such methyl cellulose, chitosan, and others [43]. Poloxamers, also known as Pluronics, are tri-block copolymers made up of poly (ethylene oxide), poly (propylene oxide), and poly (ethylene oxide) (PEO-PPO-PEO). Kolliphor P188 (also known as Poloxamer 188 or Pluronic F-68) has roughly 27 PPO groups on one side and 80 PEO groups on the other. Kolliphor P188 has a molecular weight of about 8400 g mol1, which is higher than that of normal emulsifying surfactants [44]. Below 50°C, it exists as single molecules (unimers) and at higher temperatures polymolecular micelles starts to form. These can be used in a wide range of occular drug delivery applications due to the variety of microemulsion types created [45].

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 honokiol-loaded 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, tri-block 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, diclofenac-loaded 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 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 dexamethasone-loaded 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 nanoparticle-cyclodextrin 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].

5. Action plan and future prospective

As indicated by the literature from the pharmaceutical engineering, medical, and academic domains, an action plan to sustain future breakthroughs and clinical success is necessary to channel the increased interest in this topic. To continue these discussions and see the successful application of more drug delivery systems in ophthalmology, we propose: (i) increased collaboration at academic institutions between basic and applied scientific teams, where many novel drug delivery systems are discovered; (ii) collaboration between pharmaceutical corporations and researchers in basic and applied sciences to speed up technology transfer and enable the creation and sale of innovative prions; (iii) standardised procedures for collecting ocular tissue samples for pharmacokinetic comparisons. Samples of posterior ocular tissues like the choroid, retinal pigment epithelium, neuroretina (macula and peripheral retina), and sclera should be obtained consistently to improve data comparison; (iv) To help sponsors choose the best route to regulatory approval of innovative ocular drug delivery systems, there should be clear guidelines, including early and regular communication with regulatory bodies; (v) gatherings and organisations that foster conversation between fundamental, applied, and clinical researchers in order to support upcoming joint efforts in the creation of medical devices and drugs as well as in ophthalmology translational research; (vi) Rewards for participating persons and organisations; (vii) Journals that support and welcome translational research papers in subjects including the outcomes of preclinical testing, the creation of analytical techniques, plans for the advancement of investigational medications, and critical evaluation of trials that fall short of their objectives.

6. Conclusion

Drug distribution to ocular tissues has been a significant problem for ocular scientists for many years. The use of drug solutions as topical drops with conventional formulations had some drawbacks, prompting the development of new carrier systems for ocular delivery. Huge efforts are being made in ocular research to develop novel drug delivery strategies that are both safe and patient-friendly. Researchers are currently working hard to improve the in vivo performance of conventional formulations. On the other hand, ocular scientists are intrigued by the development of nanotechnology, innovative methods, gadgets, and their applications in drug delivery. Using invasive, non-invasive, or minimally invasive drug administration techniques, drug molecules are encapsulated in particulate or vesicular carrier systems or devices.

Contact lenses, in situ gels, microemulsions, niosomes, liposomes, implants, microspheres, and micelles are just a few of the nanotechnology-based carrier systems being developed and studied. A few of these are mass-produced commercially and used in clinical settings. The body of the patient gains from novel medication delivery methods by lowering drug-induced toxicity and visual loss. Additionally, these carriers or devices lengthen drug release, increase targeted moieties’ specificity, and help reduce dose frequency. However, after non-invasive medication administration, a carrier system that can reach targeted ocular tissue, including the tissues in the rear of the eye, is still required to be developed. A topical drop formulation that maintains a high precorneal residence time, prevents non-specific drug tissue buildup, and delivers therapeutic drug levels into targeted ocular tissue is anticipated at the current rate of ocular research and development (both anterior and posterior). Invasive drug delivery techniques like intravitreal and periocular injections may one day be replaced by this delivery technology.

Conflict of interest

Author(s) confirms that, there are no conflicts of interest.