INTRODUCTION:

The eye is organ of sight. It is divided into two main parts anterior segment and posterior segment. Eye is a complex organ with special anatomy and physiology (Chen et al., 2018). It becomes indispensable to develop a formulation that is effective, safe and acceptable to patients (Chen et al., 2018). Bearing in mind about complex structures and barriers of eye, it is crucial to construct appropriate ophthalmic formulations for the treatment of ocular diseases.

Ocular drug delivery has been a major challenge due to its unique structure. The important objective of ocular formulation is to deliver drug, as well as maintain adequate concentration of drug at target site (Li Tseng et al., 2013). There are two types of barriers that cause rapid drainage of drug from the ocular surface.

First is static barriers which include different layers of cornea, sclera and retina including blood aqueous and blood-retinal barriers (Gaudana et al., 2010). Second is dynamic barriers, this included choroidal and cobnjunctival blood flow, lymphatic clearance and tear dilution. Other barriers that causes rapid drainage of drug is efflux pumps in conjunction pose. Conjunction pose is also a significant challenge for drug delivery of drug alone or in a dosage form, especially to

posterior segment (Gaudana et al., 2010). Specificity of barriers depends upon the route of administration i.e. topical, systemic and injectable. Along with barriers, various preformulation and physiological barriers are also considered for the preparation of ocular formulation.

Ophthalmic preparations are sterile liquid, semisolid or solid preparations that may contain one or more active pharmaceutical ingredients. Ophthalmic products are intended for application to the conjunctiva, the conjunctival sac or the eyelids. These products may be administered topically in the form of solutions, suspensions, emulsions, lotions, creams, ointments and gels or by subconjunctival or intraocular formulations (Karmer and Behrens-Baumann 2002). It is estimated that only one tenth of a dose penetrates into the eye (Hecht, 1995).

COVID-19 is a highly variable disease. It belongs to large family of viruses known to cause illness ranging from asymptomatic infection to severe organ and death (Vadim et al., 2021).The global pandemic alert arises in the middle of March 2020 and spread to more than 150 countries and territories leading to thousands of cases within a couple of months. COID-19 was first reported in Wuhan, China and subsequently spreaded worldwide. Coronaviridae is a family of viruses that causes respiratory diseases or infections in the form of common cold or pneumonia in human. COVID-19 also infect animals (Raghuvir et al., 2020). In 2003, SARS (Severe acute respiratory syndrome) was emerged and outbreak caused by SARS-CoV while after 10 years MERS (Middle east respiratory syndrome) outbreak in 2012 by MERS-CoV (Raghuvir et al., 2020). Both SARA and MERS are originated from bats and also have zoonotic origin. CoV-19 use angiotensin converting enzyme-2 (ACE-2) receptor or dipeptidyl peptidase-4 (DPP-4) protein to penetrate the cells for replication (). One of major risk of n-CoV is asymptomatic carriers, as these carriers appears for being super infectors of these disease. The droplets generated during coughing, talking or sneezing are direct mode of transmission of viruses. This are indirectly transmitted when effected person touches any object and that object touched by healthy individuals who may then touch their noses, mouth and eyes (Ge et al (2013) and Wang et al., (2013)). SARS CoV-2 also transmitted via faecal oral route (Raghuvir et al., 2020).

The International committee on taxonomy of virus has assigned official name to this deadliest disease (coronavirus) as severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) on the basis of phylogenetic analysis. The main goal of this study was to summarize the evidence regarding corticosteroids such as dexamethasone for the treatment of COVID-19.

Figure 1. Shows absorption of drug from the ocular surface

In ophthalmic formulations the suspension is the better option for incorporating poorly soluble active pharmaceutical ingredients (Anh Vo et al., 2020). As suspension improvise ophthalmic drug delivery by increasing ocular residence time of the drug (Anh Vo et al., 2020). Ophthalmic suspension enhanced the bioavailability of the drug by increasing retention time in cul de sac of eye (Anh Vo et al., 2020). Suspension gradually solubilise active pharmaceutical ingredient for prolonging its effect over longer period of time (Anh Vo et al., 2020).

One of the crucial factor which influences physical stability of the dosage form and treatment efficiency of ophthalmic suspension is the particle size. Particle size of the ophthalmic suspensions typically does not exceed 25 micro meters in order to avoid eye irritation (Uddin, Mamum et al. 2017). One of main difficulty arises in the manufacturing of ophthalmic suspension is to keep particles in suspended form within formulation for long duration. Particles tend to form floccules. Floccules are loosely aggregated particles which can easily redisperse by applying small shear force.

Table 1. Shows critical characteristics of ophthalmic suspension

S. N.	Parameters	Scale	Reference
1	Particle size	<10µm	Saettone et al., 2000
2	pH	7.3-7.4	Lim et al., 2014
3	Viscosity	15–25 cp	Dale et al., 2013
4	Drop size	20–70 μL	Gokulakrishnan et al.,
5	Density of medium (for aqueous)	20–70 μL	Gokulakrishnan et al.,

During long term storage or improper manufacturing, floccules tend to forms cohesive cakes. These cohesive cakes are very difficult to redisperse. Differences in manufacturing or the formulation design leads to variation in particle sizes. Moreover these physicochemical properties affect the residence time, drug release as well as ocular bioavailability of the drug. Accuracy of dose is impaired by sedimentation, aggregation and crystal growth of particles. For effective therapy mean dose of potent drug should be adapted according to the patient need. This depends on various other factors which are discussed as following: anatomy and physiology of eye; charges on the ocular surfaces; formulation development method; key analytical parameters.

Figure 2. Mechanism of inflammation

Anatomy and Physiology of The Eye:

Eyes are photosensitive organs. Each eye is a hollow ball like spherical structure which is called eye ball. Each eye is located in the notch of lachrymal bone, called as “Eye –orbit”. Only 1/5th part is evident outside from the whole eye. Eyes are protected with two muscular eyelids and skeletal muscles responsible for rotation of eyeball within the eye. Eye ball is comprised of three layers - Fibrous tunic, vascular tunic and neurosensory tunic.

Fibrous tunic is outermost covering of eyeball. Cornea is outer evident part of fibrous tunic. It is the primary part of the eye which reflects the light coming from object. Sclera is interior portion of eyeball made up of white, hard, opaque thick fibrous connective tissue. Vascular tunic is middle layer of eyeball which is richly supplied with blood capillaries. Neurosensory tunic is interior portion of eyeball and divided into two parts: Pars indica and Pars optica, pars optica is also known as retina.

Pathophysiology of Covid-19

Single stranded RNA enters in the host cell after gaining entry from any of the mucous membrane. Once it cross mucous membrane then it uses transmembrane serine protease (TNPR ss2), ACE-2 receptor and entered in host cell. After entry this leads to fusion and endocytosis with the host cell (Fehr & Perlman, Chen et al., (2020) and Hoffmann et al., (2020)). The uncoated RNA in the host cell is then translated and synthesised viral proteins (Raghuvir et al., 2020). New RNA strand is produced with the help of RNA dependent RNA polymerase for the new virions. A cluster of new virions was released from cell lysis into patients body. The pathophysiological features of severe covid-19 include autopsy, diffuse alveolar damage, inflammatory infiltrates, microvascular thrombosis (Carsana et al., 2020), viral pneumonias such as highly pathogenic avian influenza (de Jong et al., 2006), SARS (Wong et al., 2004) and seasonal influenza (Baillie., 2013).

Figure 3. Shows human eye anatomy

Figure 4. Shows accommodation of eye

1. Dexamethasone in COVID-19:

Dexamethasone became one of standard choice of drug for care of COVID-19 patient in 2019 (Barbara et al., 2021). Dexamethasone may modulate inflammation mediated lung injury and thereby reduce chances of respiratory failure as well as death (Dr. Herby et al., 2020). The effect of dexamethasone in hospitalized COVID-19 patients was nicely explained by Peter Herby and their colleagues designed trial method and examined hospitalized patient of COVID-19, to evaluate the effects of potential treatment in them. The recovery trial method was performed at 176 National Health Service organization in the United Kingdom and was supported by the National Institute for Health Research Clinical Research network. Clinically suspected or laboratory confirmed SARS-CoV-2 infected patients were eligible for the recovery trial patients.

National guidelines are followed to treat patients. Peter Herby and their colleagues collected data by using a Web-based case report. The Web-based data included information of demographic data, respiratory level report and major coexisting illness. According to Web-based case report patients are divided into eligible and consenting patients and assigned in a 2:1 ratio. As per assigned ratio patients receive either standard dose alone or usual standard care plus of oral or intravenous dexamethasone (6mg once daily for upto 10 days). They concluded that the patients who consumed dexamethasone for 10 days resulted lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization.

Figure 5. Mechanism of Dexamethasone

Figure 6. Dexamethasone as ophthalmic suspension for COVID-19

2. Charges on the Ocular Surfaces:

Charges on the cell surface plays important role in the transportation of different substances through the cell layer (Gusev et al., 1989). The cornea and conjunctiva portion of the eye possess negative charges on their surfaces. It is expected that cationic particles penetrate more efficiently than anionic particles through the negatively charged ocular tissues. Arrangement of negative charges on ocular surface is well explained by Gusev and his friends in their article. To determine arrangement of charges in the ocular surfaces, they used positively charged dense markers in combination with Transmission electron microscopy (TEM). The anionic charged present in ocular surface is in discrete form. There is no uniform arrangement of charges on ocular surfaces (Gusev et al., 1989). Stereoultrastructure of ocular surface, marking and position of negatively charged particles can be studied using scanning electron microscopy (SEM). Ching-Li Tseng and their co-workers also explained about charges on ocular surfaces and transportation of charges across ocular surfaces. They worked with cationic gelatine nanoparticles (GPs). They examined the transportation of GPs on the ocular surfaces. They prepared two different types of charged gelatine nanoparticles, GPs (+) having size of 180.6±45.7 while GPs (-) having size of 230.7±84.6 nm. They also determine their zeta potential (GPs (+) 33.4±10.9 and GPs (-) -44.2±7.2). In-vitro biocompatibility of GPs was evaluated using human corneal epithelium (HCE) cells (Tseng et al., 2013s). They performed experiment on rabbit eyes. They observed widely distribution of GP(+) carriers from anterior to posterior part of the cornea. GPs are efficiently adsorbed on the negatively charged cornea without irritating the eyes of the rabbits. They also found that retention time of cationic charges GPs are longer than anionic charged GPs.

Figure 7. Shows diffusion of charges from ocular surface

3. Pharmacokinetic of ophthalmic suspension:

Popularity of topical route of ophthalmic formulation over other route of ophthalmic formulation is due to its ease of administration and avoiding of non-invasive route. Once the ophthalmic suspension is instilled on the eye, than API of suspension finds several routes of absorption into the body. Drug absorbed via diffusion across cornea and various barriers of eyeball. The API which are in dissolved form only then can absorbed through the cornea and conjunctival portion of the eye. The nasolacrimal drainage cleared solid and solution phase of the ophthalmic suspension from the eye surface. The direct process of diffusion of drug to the ocular tissues is tear film. However drug can also diffuse from systemic circulation. Diffusion of drug and its absorption through systemic circulation pathway remains minor as compared to tear film. The increase in dose not affects the initial drug concentration in the solution phase.

According to Merdy and his co-workers administration of suspension shows a higher ocular Cmax and AUC as compared to a saturated solution. The particles suspended in a suspension serves as a reservoir for the drug in the solution phase. Moreover incorporation of suspended particles in the formulation leads to non-linear ocular pharmacokinetics. Viscosity of the drop plays important role in the residence time of thr drug. Viscosity can change the drug precorneal residence time, as well as it affects the precorneal drug absorption and clearance. Merdy and their co-workers also analysed that an increase in viscosity can extend the duration of precorneal residence time. Although increase in viscosity also increases ocular exposure upto 50-60% without affecting plasma exposure.

4. Formulation Development:

An ocular formulation could be in any form that is solution, emulsion, suspension or an ointment. A typical ophthalmic formulation should be sterile, isotonic, have some buffering capacity and wrapped into a suitable tamper-evident, multi dose dispensing system. According to physiological comfort and product stability, excipients and buffers are chosen with a proven track record with the FDA.

Active pharmaceutical ingredients (API) used in ophthalmic suspension should be sterilized prior to high pressure homogenization. API used in ocular preparations is selected from the group consisting of a carbonic anhydrase inhibitor, adrenergic agonist, non-steroidal anti-inflammatory, prostaglandin, antifungal agent, antibiotics, corticosteroids, beta blockers or their combinations (Cetina-Cizmek et al., 2013).

Aqueous vehicle used in ophthalmic suspension was usually comprises of water along with excipients like chelating agent which is selected from the group consisting of ethylenediaminetetraacetic acid, metal salts such as disodium edetate, trisodiumedetate, or their mixtures. Preferable amount of chelating agent added is in between 0.005 to 0.02 wt% based on weight of the total formulation (Cetina-Cizmek et al., 2013).

Preservatives used in ocular preparations is selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride, chlorhexidinegluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury acetate, thiomerosal, merthiolate, phenylmercuryborate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, butyl p-hydroxybenzoate or their mixtures. Preferable amount of preservative added is in between 0.008 to 0.015 wt% based on weight of the total formulation (Cetina-Cizmek et al 2013).

Buffers used in ophthalmic formulations are selected from the group consisting phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as citric acid or salts including sodium citrate) (Cetina-Cizmek et al., 2013).

5. OPHTHALMIC SUSPENSIONS:

Ophthalmic suspension is a formulation where insoluble particles are suspended in the vehicle to deliver active pharmaceutical ingredients to the targeted site with enhanced retention time, resulting in increased bioavailability of drug (Sieg, Robinson et al. 1975). One of major challenge during preparation of ophthalmic suspension is to easily redisperse settled particles before using or dispersing them as products. A desirable ophthalmic suspension should suspend particles for longer duration which will be enough to deliver accurate dose on each withdrawal, along with this a desirable suspension should have a suitable flow rate and do not form cake on standing the formulation for longer period of time. If desired uniformity dispersion is not obtained in pharmaceutical suspension then visible evident sediment is preferred with an instruction that shaking is required before applying the formulation into the eye (Barlette et al., 1995; Kass et al., 1982).

Key analytical consideration for preparation of ophthalmic suspension:

5.1 Particle size and viscosity-

Particle size play an key role in ophthalmic preparations as particle size impacts the rate and extent of dissolution as well as eye irritation in case of ophthalmic suspension formulations (Remington’s 21^st edition). Particle size whose diameter exceeds 30-40 µm is also responsible for corneal abrasions and irritation (Lippmann, 1957). According to Sieg and Robinson, particle size should be less than 10 µm to minimize irritation (Sieg, Robinson et al. 1975).

Figure 8. Shows effect of particle size on corneal surface

From Noyes Whitney law particle size reduction leads to increased surface area that result in rapid dissolution rate of a particle. Schoenwald and Stewart suggested as particle size increases, dissolution rate get decreases resulting particles removed before completion of dissolution from the conjunctival sac (Schoenwald, Stewart 1980). Although decreasing particle size to few micrometres may result in rapid elimination of suspended particles from conjuntival sac. There are 3 processes for reduction of particle size that are:

5.1.1 Probe sonication- In this method separate stock solution of active pharmaceutical ingredient and thickening agent is prepared. Stock solution is transferred to falcon tube and then centered inside an ice jacket. The parameters included in processing of this operations are time, amplitude, pulse on/off time and replenishment of ice (every hour). The formed suspension is mixed with compatible thickening agent solution to form final solution.

5.1.2 Micro fluidization- In this operation micro fluidizer is ejected twice with ethanol followed by purging with sterile filtered water. To cool down the sample cooling coil is immersed in ice. Departed sample from outlet was collected into sterilized bottle until the entire sample passed and the process is repeated for six times. After desired passes active drug suspension is mixed with thickening agent solution in order to get desired suspension.

5.1.3 Planetary centrifugal media milling- In this process milling operation split up into many loops, each and every loop is further composed of 10 milling operations along with 10min of pause for reduction in temperature of milling process.

Normally simple saline can be used as vehicle in ophthalmic formulations, but to enhance retention time in precorneal region slightly viscous solutions are prepared as viscosity helps to retain drug for longer period of time in conjunctival sac (Saettone, 2002). Generally 20-30 centipoises viscosity level is considered to be acceptable (Kompella et al. 2010). Viscosities above a certain level interfere with visual field or blocks puncti and canaliculi and hence, are not used.

Variation in particle size is due to differences introduced during manufacturing or the formulation design. This physicochemical properties may affect the residence time, drug release and ocular bioavailability.

5.2 Crystal growth- Crystal growth as well as polymorphic changes in suspension has always been worried subject to formulators (K.J. Frederick 1961). According to K.J. Frederick storage of ophthalmic suspension for longer period of time causes structural changes in crystals that is increase or decrease in crystals size which in turn results in enhancement or reduction in bioavailability of drug (Hecht 1995).

5.3 Ocular irritation studies- In order to maintain requisite ease level in patients, ocular irritation study should be established between active pharmaceuticals ingredient and excipients (Somaraju et al 2013).

5.4 Dose uniformity- Ocular preparations are arduous to prepare as drug particles tend to form loccules, that can easily broken up by applying shear stress, which are difficult to redisperse. In case of potent drug, precision or accuracy is required for the effective treatment to the patients but dose precision and accuracy can be lessen by sedimentation, aggregation and recrystallization of suspended particles during long term storage of ophthalmic suspension (M Diestelhorst et al. 1998). Uniformity or homogeneity of dosage in ophthalmic suspensions depends on the number of shaking, frequency of shaking as well as intensity of shaking the formulation (M Diestelhorst et al. 1998).

5.5 Stability- Apart from humidity conditions and some specific tests general exigency for ophthalmic pharmaceutical preparations (suspensions) are nearly same. Generally stability testing requirements are harmonized by (ICH), but despite of this few countries will still have their own particular requirements which should be concurred by companies (Brian R. Et al. 2000). The current ICH guidelines addresses about stability condition of ophthalmic aqueous products (eye suspensions or eye drops) in semi permeable containers as follows:

Containers containing ophthalmic suspensions should be designed in such a way that it provide permanent barrier to water loss (CPMP/ICH/380/95) (International Conference on Harmonisation 1994). ICH inscribed specific storage conditions for ophthalmic suspensions, according to ICH inscription same range of temperature should be applied in case of high relative humidity, while special consideration should be provided like appropriate testing in case of low relative humidity, as this conditions are unpropitious for packed ophthalmic suspensions in a small semi permeable containers (CPMP/ICH/380/95) (B.R. Mathews 1999).

Table 3 Shows stability criteria of the formulation

Storage Condition	Temperature	Humidity
Long term stability	25℃±2℃	40%±5%RHª
Intermediate accelerated condition (If 40℃fails)	3℃±2℃	40%±5%RH^b
Accelerated condition	40℃±2℃	15%±5%RH^c

Proposed stability storage conditions for ophthalmic liquid formulations in semi permeable containers.

See Refs. 11 and 12

60% ± 5% RH; Ref. 11, 40% ± 5% RH, Ref. 12

Not more than 25% RH, Ref 11, 15% RH, Ref. 12

Table 4. Application of ophthalmic suspension

S. N.	Name of the drug	Class of drug	Site of disease	Application in the treatment of the diseases
1	Nepafenac	NSAID’S	Lens	In the treatment of cataract
2	Brinzolamide	Carbonic anhydrase inhibitors	Pressure build up in anterior portion of the eye	In the treatment of glaucoma
3	Prednisolone acetate	Corticosteroids	Posterior segment of the eye	In the treatment of floaters (Retinal detachment)
4	Prednisolone acetate Rebamipide	Corticosteroids	Clogging of meibomian glands	In the treatment of dry eyes
5	Loteprednol etabonate	Corticosteroids	Tiny blood vessels on the surface of the white of eyes	In the treatment of red eyes
6	Neomycin sulfate	Aminoglycosides	Middle layer of the eye	In the treatment of the uveitis
7	Besifloxacin	Fluro quinolones	Lined eyelid and covers white portion of eyeball	In the treatment of conjunctivitis
8	Rebamipide	Quinolones	Corneal portion of the ye	In the treatment of corneal diseases
9	Sulfacetamide sodium Dexamethasone	Sulfonamide	Anterior portion of the eye	It helps to reduce swelling, redness and itching of the eye. It has bacetriostatic activity

CONCLUSION:

In recent year’s ophthalmic suspension gained huge popularity among ophthalmic formulation. Preparation of any ophthalmic formulation has been a major challenge to pharmacologist and drug delivery scientist. It is due to complex structure as well various barriers of the eye. One of reason of gaining popularity dexamethasone in COVID-19 is its unique antiflammatory property that clinically lowers down mortality rate of COVID-19 patients. This review article includes significance of dexamethasone in COVID-19 as well as various factors for drug delivery as well as parameter for designing of ophthalmic suspension. Determining charges on ocular surfaces is considered as important factor for delivering drug through the eye. Apart from delivering of drug, designing of formulation is very important. Formulation designing includes proper selection of excipents. Example viscosity enhancer improvised ocular bioavailability of drug by enhancing retention time as well as some polymers serves controlled drug delivery. The approaches included in this review article lead us to conclude mortality rate of dexamethasone administered patients are 28 days lower than normal patients.

ACKNOWLEDGMENT:

I am thank full to Dr. Dheeraj Ahirwar, Principal of School of Pharmacy, Chouksey Engineering College, Bilaspur (Chhattisgarh) for their valuable support and guidance. Special thanks to Mr. Anish Chandy for their guidance and to share their tremendous knowledge for giving continuous and unlimited motivation. I would also like to thank my colleague Raju Sahu for helping me and supporting me to write this article.

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Received on 30.10.2021 Modified on 05.12.2021

Res. J. Pharmacology and Pharmacodynamics.2022;14(1):29-36.

DOI: 10.52711/2321-5836.2022.00005

S. N.	Polymers	Uses	Commercial preparations
1	Cellulosic derivatives: · Methyl cellulose (MC) · Hydroxyethylcellulose (HEC) · Hydroxypropylmethylcellulose (HPMC) · Sodium carboxymethylcellulose (CMCNa)	Viscosifiers	Adsorbotear Celluvisc Lacril
2	Poly(vinyl alcohol)	Increase drug bioavailability as well as pharmacological effects	HypoTearse Liquifilm
3	Sodium hyaluronate	Excellent biocompatibility, mucoadhesiveness, pseudoplastic and viscoelastic behaviour	Healon Viscoat
4	Carbomer: Poly acrylic acid	Enhance precorneal retention to the eye	Lacrigel Lacrinorm Iduviran Pilopine