INTRODUCTION:

Eye is the most easily reachable site for the administration of a drugocularly^[1,2,3]. The anatomy, physiology and biochemistry of eye shows that the eye ball has a specific and robust structure which is highly impermeable foreign substances. Its composition involves three layers: connective, vascular and neural tissues. The connective tissue composed of transparent cornea connected to white sclera through the limbus. The vascular tissue is composed of the choroid as well as two ciliary bodies in the middle connected by the iris in front of the globe. The retina formed by neural tissue, has the function of transmitting the electrical impulse to the brain through the optic nerve^[4,5].

The eye is divided into anterior (occupying one-third) and posterior (occupying two-third) segments by iris^[6]. The anterior segment consists of the cornea, iris, ciliary body, crystalline, aqueous humor, and conjunctive. The posterior segment contains theoptic nerve,sclera, choroid, retina and vitreous humor (fig. 1)^[7].

Figure 1: Anatomy of eye

Eye diseases:

Due to direct exposure to external environment the anterior segment tissues are susceptible to different diseases^[8]. These common diseases are: dry eye, pain, redness,discharge, allergic conjunctivitis (bacterial, viral, and fungal infections), blepharitis (inflammation of the eyelid)^[9]. On the other hand,the main diseases that affect the posterior segment are: retinoblastoma, choroidal neovascularization (CNV, growth of the choroidal capillaries below the retinal epithelium),and degenerative retinal diseases (formation of new blood capillaries in the retina), such as: diabetic retinopathy, diabetic macular edema and age-related macular degeneration^[10]. The inflammation of uvea is called as anterior or posterior uveitis, depending on if inflammation affects iris-ciliary body or choroid, respectively. Glaucoma is also a disease that affects both segments, is characterized by ocular tension of anterior segment tissues and/or elevated intraocular pressure after degeneration of retinal ganglion cells.

The main routes of drug administration in the eye:

i. Topical: Mostly in the form of eye drops, is employed to treat anterior segment disease. However, due to the precorneal factors and corneal barriers less than 5% of the administered drug is absorbed by the tissues, being necessary several administrations to maintain the therapeutic levels ^[11].

ii. Oral/Systemic: Drugs administered systemicallyreach the chorioretinal tissue through the bloodstream. However, their entry is greatly limited by the blood-aqueous and the blood-retinal barriers.To maintain therapeutic concentrations, a large amount of drug is required, that may lead to side effects^[12].

iii. Periocular: Thisrouteincludes subconjuntival, subtenon, retrobulbar and peribulbaradministration. It is safer than intravitreal route, but less effective in providing drugs to retinal tissues, due to choroidal and conjuntival blood circulation^[13].

iv. Intravitreal/intracameral/subtenon: Intravitreal injectionoffers distinct advantages as the moleculesare directly inserted into de vitreous. However, multiple injections may be required, as a result of the limited half-life of many compounds in the vitreous,that can promotes the risk of cataracts, retinal detachment, hemorrhage and endophthalmitis ^[14].

Figure 2: Drug administration routes to eye

Barriers of eye:

All the biological membranes are selectively permeable which serve as ocular factors influencing the efficacy of drug dose in terms of bioavailability. There can be static barriers (e.g. blood-aqueous barriers includes different layers of the cornea, sclera, iris/ciliary body and blood-retinal barriers) dynamic barriers (e.g., precorneal factors, choroidal and conjunctival blood flow and lymphatic clearance), and out flux pumps such as multi-drug resistance, known as P-glycoprotein (P-gp) and multi-drug resistance proteins^[15]. Precorneal factors, which are natural and mechanic barriers, are responsible for this lowbioavailability, and these are: drainage of solution, blinking, tear film, tear turn over and inducedlacrimation^[16]. Tear film, whose composition and amount are determinants of a healthyocular surface, offers the first resistance against installed topical pharmaceuticals, due to itshigh rate of turnover. The tear films plays a protective role by the presence of mucin which forms ahydrophilic layer that moves over the glycocalyx of the ocular surface and clears pathogens anddebris^[17]. The anatomic volume of cul-de-sac (~30μL) and the human tear volume (~7μL), in association with the rapid restoration time (~ 2-3 min), contribute to theelimination of applied eye drops in the ocular mucosa.In order to make the drug stay there nanoformulations (SNEEDS) are the best alternative ^[18].

Figure 3: Factors attributing to poor bioavailability of ophthalmic formulations

Self-nano emulsifying drug delivery system:

To bridge the gap between the dose and bioavailability of a drug and to overcome the barrier, nano formulations are formulated. Ideal ocular drug delivery must be remain in the vicinity of front of the eye for prolong period of time and able to sustain the drug release. Self-nanoemulsifying drug delivery systems (SNEDDS) are homogenous anhydrous liquid mixtures consisting of oil, surfactant, drug and coemulsifier or solubilizer, which spontaneously form oil-in-water nanoemulsion of size approximately 200nm or less (preferably below 100 nm) on dilution with water under mild stirring^[19,20,21]. Self-Nano emulsifying Drug Delivery System (SNEDDS)is used to improve the aqueous solubility of poorly water-soluble drugs^[22]. Infact nanoemulsion, miniemulsion, ultrafine emulsion, submicron emulsionare SNEEDS where a drug undergoes dissolution rate limiting absorption to increase the rate as well as drug absorption andshows reproducibility of plasma profile of drug concentration^[23,23]. Thus SNEDD can be considered as one of the stable nano emulsion which provides a large interfacial area for partitioning of drug between oil and aqueous phase to have better drug dissolution rate and to increases bioavailability of drug formulation^[25,26].

FORMULATION ASPECTS

Generally there are following components of SNEEDS ^[27].

i. Oil/Lipid

ii. Surfactant/Co-surfactant

iii. Additives

i) Oil:

For the preparation of NEs, The commonly used oils in NEs preparation are IPM (Isopropyl Myristrate), Triacetin (Glyceryl triacetate), Sefsol 218 (Propylene glycol mono ethyl ether) etc. NEs prepared for eye, the viscosity must be between 2-3 centipose (keeping less than 5%).

ii) Surfactant:

The most frequently used surfactants in NEs formulation are phospholipids (generally from egg yolk sources), copolymers of polyoxyethylene-polyoxypropylene (poloxamer) and to a limited extent acetylated monoglycerides is also used. Other emulsifiers such as fatty acid esters of sorbitans (various types of Spans; ICI Americas) and polyoxyethylenesorbitans (various types of Tweens; ICI UK), are already approved by various pharmacopeias for parenteral administration and therefore, can be considered for emulsion formulation design. Non-ionic surfactants are preferred over ionic surfactant due to lower toxicity^[28].

iii) Additives:

For the the adjustment of pH and tonicity in NEs, additives are used in case of ocular and parentral administration. Usually glycerol is used as an isotonic agent in almost every parenteral emulsion while pH is adjusted with solution of NaOH or HCl with water and generally adjusted to 7-8 for physiological compatibility and sustaining physical composition of nanoemulsion by minimizing fatty acid ester hydrolysis. To prevent oxidation, antioxidants or reducing agents such as tocopherols, feroxaminemesylate and ascorbic acid are used. Stabilizing agent like oleic acidsor their sodium salts, are added to avoid phase separation^[29]. Cholic acid, deoxycholic acid and their respective salts are used to enhance NE solubility^[30].

Methods of preparation of nanoemulsions:

The preparations of Nanoemulsion (SNEDDS) are difficult to prepare because of requirement of high pressure homogenizer as well as ultrasonic equipment which is expensive. The Stability of Self Nanoemulsifying drug delivery system is also affected by Temperature and pH^[,31,32]. The methods are:

i. High energy methods: it includes High Pressure Homogenization, High-Shear Stirring, Ultrasonic Emulsification, Microfluidization^[33-37].

ii. Low energy methods: it inludes spontaneous nanoemulsification, Phase inversion methods and its components like Phase inversion temperature, Phase inversion composition^[38-48].

Development of SEDDS/nanoemuIsion formulations^[49]

For the development of SEDDS/nanoemulsion formulations, the selection of components is an important factor need to be considered.

Selection of Oil- The selection of oil for the development of SEDDS/nanoemulsion formulations is done on the basis of drug solubility studies. The oils which could solubilize maximum amount of drug are selected.

Selection of Surfactant:

The surfactants which showed maximum drug solubility are evaluated for their ability of emulsification.

Selection of Co-surfactant:

Similarly, the co-surfactants which gave maximum drug solubility is evaluated for their nanoemulsification ability. In order to measure the relative property of the co-surfactant to increase the nanoemulsification ability of the surfactant, turbidimetric method is generally used.

Solubility study and Partition coefficient are the basis to prepare of (SNEDDS)/Nanoemulsion. For above stated parameters, standard curve and calibration curve are to be plotted^[50].

i) Absorption maxima (λmax) determination^[51]

Preparation of artificial tear solution:

Dissolve 0.670g of sodium chloride, 0.200g of sodium bicarbonate, 0.008g of calcium chloride dihydrate in purified water and finally make up to 100ml volume with purified water^[52].

Preparation of stock solution:

10mg of drug intended is weighed accurately and transfer to 100ml volumetric flask. Dissolve the drug in 1% artificial tear solution and the volume is make up to 100 ml with respective solution to get the final concentration of 100μg/ml.

The absorbance of solution is to be measured (λmax) using spectrophotometer by putting reference standard of medium. The experiment is performed in triplicate and based on average absorbance; the equation for the best line is generated.

Figure 4: Graph for absorption maxima

ii) Calibration curve/Standard curve

Calibration curve in 1% v/v artificial tear solution The above stock solution (100μg/ml) prepared in 1% artificial tear solution is further diluted to get concentration in the range of 2-20μg/ml for 1% v/v artificial tear solution and in similar fashion calibration is drawn for other solvents too like in various oils, surfactants, co-surfactants. A set of standard dilutions of 2, 4, 6 up to20μg/ml is prepared by transferring 0.2, 0.4, 0.6 up to 2.0ml aliquots of stock solution (100μg/ml) to a series of 10.0ml volumetric flasks and volume is made up with artificial tear solution or solvents used. The absorbance of each dilution is measured in a UV spectrophotometer^[53].

Figure 5: standard curve for norfloxacin

iii) Solubility studies (quantitative and qualitative estimation of drug)^[54]

The quantitative analysis for solubility of drug intended to be as SNEEDS is done spectrophotometricaly using previously plotted calibration curves in different solvents (viz oils, surfactants and co-surfactants). The drug intended to be formulated as nanoemulsion (SEEDS) is dissolved into 5ml of solvents till saturation and then subjected to mechanical shaker for 72 hours. Supernatant is taken and concentrated is determined spectrophotometrically (eg Table no.1) with the help of calibration curves plotted previously.

Table1: Solubility (Qualitative)

Visual Inspection	Inference
Acetic acid	Freely Soluble Sparingly
Chloroform	soluble Slightly soluble
Acetone, Ethanol 95%	Very Slightly soluble
Water, Methanol, Ethyl, Acetone	Insoluble
Ether	Soluble
PBS (pH 7.4)	Soluble

Figure 6: Solubility analysis

iv) Partition coefficient determination^[55]

Shaking flask method is used to determine partition coefficient of drug in n-octanol: water system.10mg of drug is added into 50ml each of n-octanol and water. The mixture was shaken for 24 hours until equilibrium will be reached. Phases will be separated in a separating funnel and the aqueous phase is filtered through 0.2µ filter, suitably diluted and amount of drug in aqueous phase is determined by measuring the absorbance at λmax using UV spectrophotometer. The partition coefficient (P_o/w) of drugis calculated from the ratio between the concentration of drug in organic (C _oil) and aqueous phase (C_aq.) using following equation.

Log P = Conc. of drug in organic phase/Conc. of drug in aqueous phase

v) Aqueous Titration method (Psedoternary Phase Diagram)^[56,57]

Psedoternary phase diagram is important for determination of self nanoemulsifying drug delivery system (SNEDDS). It is diagrammatic representation of oil, surfactant and co-surfactant (Smix), water is known as Psedoternary phase diagram. Psedoternary phase diagram is constructed by Phase titration method and Phase inversion method.

The procedure consist of preparing solutions containing oil and the different ratio of surfactant to co-surfactant by weight such as 1:1, 2; 1, 3:1 etc, these solutions then vortex for 5 min to obtain isotropic mixture and observed for their appearance (turbid or clear). A coarse emulsion is said to be formed if it appears turbid, whereas a clear isotropic solution would indicate the formation of a nanoemulsion (SNEDDS). The percentage of oil, Smix and watervaluesis used to prepare Pseudo ternary phase diagram. This diagram corners represent 100% concentration of each phase. The diagram is crucialwhich gives information related to binary mixture of two components such as surfactant/cosurfactant, water/drug or oil/drug. The Psedoternary phase diagram is represent mixture of surfactant, co-surfactant, oiland water phase is shown in Figure No.7.

Figure 7: Pseudoternary diagram

CHARACTERIZATION^[58,59]

Droplet size distribution (PDI)^[60-64]

Droplet size was determined by photon correlation spectroscopy (PCS) it analyzes the fluctuations in light scattering due to Brownian motion of the droplets using a Zeta-sizer. Lower the value PDI, stable the formulation is.

Zeta potential^[65,66-68]

The surface charge is determined using a Zetasizer at 25 °C by measuring the surface charge of thenanoemulsion formulation. Suitable dilution of nanoemulsion formulation is done with distilled water. Higher the Negative charge more, will be the stability of the SNEEDS.

Figure 8: charge potential

Figure 9: Size distribution

Transmission Electron Microscopy (TEM)^[69-71]

To analyze the morphology and structure of the formed nanoemulsion droplets, TEM is performed. This enables point to point resolution. In this study, a drop of the nanoemulsion is deposited on the copper grid film and observed after drying.

Determination of pH^[72,73]

The pH of the formulation was determinate using digital pH meter. Formulation of drug nanoemulsion is taken in beaker containing 10 ml of water and pH is determined. Results should be taken in triplicate and the average is determined.

Ocular Irritatency Test^[64]

In vivo ocular irritation study is performed by Draize technique where single administration of 60μL instilled in the left eye of each rabbit while keeping the untreated eye as the control. The sterile SEEDS formulation is administered twice daily for a period of 21 days (1, 2, 3, 4, 7, 10, 15, 18 and 21 days). The rabbits are observed periodically for redness, swelling and watering of the eye.

Stability Study^{[74,75,76,77]}

Sterile nanoemulsion (5 mL) is stored in an amber colored container for a period of three months in the refrigerator (2–8°C). The stability of formulation sample is observed visually, initially on a daily and later on a weekly basis for pH, phase separation, flocculation or precipitation. Stability of nanoemulsion is also checked by centrifugation (Remi Centrifuge, Mumbai, India) by 12,000rpm for 30 min and then the clarity, phase separation and concentration of drug is to be investigated. Droplet size of the nanoemulsion upon storage is also determined to assess the stability in terms of drastic changes in the mean droplet diameter due to droplet coalescence or aggregation.

ACKNOWLEDGEMENT:

Authors are thankful to Vice Chancellor of Integral University, Lucknow Uttar Pradesh, India for valuable guidance (Manuscript Communication No.

IU/R and D/2019-MCN000650).

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Received on 07.11.2019 Modified on 19.01.2020

Research J. Pharm. and Tech. 2020; 13(11):5576-5582.

DOI: 10.5958/0974-360X.2020.00973.7