**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

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

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 [18–20]. 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, monomethacrylated-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.

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

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 [28–31].

#### *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. Pilocarpineloaded 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 nonirritating 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 [34–36].
