INTRODUCTION:

One of the most interesting and difficult endeavours for pharmaceutical scientists is ophthalmic therapeutic delivery. The eye's structure, physiology, and biochemistry make it extraordinarily resistant to external chemicals. Drug distribution to the eye can be divided into two categories: anterior and posterior.

For eye diseases such as infections, inflammation, dry eye syndrome, glaucoma, and retinopathies, ocular medication delivery is the recommended method of administration. Nanocarrier-based drug delivery systems have received much interest because they can overcome a lot of the biological barriers in the eye, resulting in better ocular therapeutic bioavailability. Nanocrystals have recently acquired interest as an ocular formulation strategy for weakly water-soluble drugs, leading to the rapid clinical development.¹Topical ophthalmic medicines do not reach the eye's posterior region. The posterior segment (retina, vitreous, and choroid) can be treated with an intravenous high-dosage medication regimen, intravitreal administration or implants, or periocular injections. The distribution of drugs to the posterior portion of the eye is now a fast developing topic of study in ophthalmic drug delivery. A appropriate ocular formulation allows the medication to get through the eye's protective barriers without generating chronic tissue damage. Topical installation and subconjunctival injection are popular means of administration for anterior-segment drugs, whereas systemic dosage, periocular and intravitreal injections, and topical dosing are common routes for posterior-segment drugs. Topical ocular medicinal delivery has two purposes: treating surface eye disorders like infections (e.g., conjunctivitis, blepharitis, keratitis sicca) and providing intraocular therapy for illnesses like glaucoma or uveitis via the cornea.²

Eye Anatomy: The eye is divided into two parts,

Posterior portions.

Anterior Portion anatomy of eye: The cornea and the lens are located in the smaller anterior portion of the eye. These structures transport light onto the retina's photoreceptor cells in the posterior segment. Topical administration is often recommended over systemic administration for eye diseases because any drug molecule delivered via the ocular route must first penetrate the precorneal barriers before contacting the anatomical barrier of the cornea. The tear film and the conjunctiva are the initial barriers that prevent an active substance from penetrating into the eye. Furthermore, repeated eye drop instillations are required to maintain a therapeutic medication level in the tear film or at the site of action. However, the use of highly concentrated alternatives on a frequent basis might result in dangerous side effects and cellular damage at the ocular surface.³

Posterior Portion anatomy of eye: The sclera, choroid, and retina constitute the posterior segment, which surrounds the vitreous cavity, which is filled through the vitreous body. The sclera is a thick outer layer of connective tissue that protects the eyes. It has a protective property and maintains the shape of the eyeball by resisting intraocular pressure. The choroid is a vascular layer that provides the blood supply for the retinal cells in combination with a separate retinal blood grant. The sensitive inner coat of the posterior segment of the eye is the retina, which is separated from the choroid by Bruch's membrane.⁴

Barriers to Ocular Drug Delivery: The presence of multiple barriers makes it difficult to achieve relevant therapeutic doses within the eye. There are two types of barrier which as follows:⁵

1. Anatomical barrier

2. Physiological barriers

1. Anatomical Barrier: There are two methods for a dosing form to penetrate: through the cornea or through the noncorneal pathway.

Corneal route: epithelial and endothelial barriers.The corneal epithelial barrier selectively restricts the trans-corneal absorption of ocular medicines (especially hydrophilic molecules), whereas the stroma and endothelium have less impact.⁶

Non-corneal route: conjunctiva and sclera: The non-corneal pathway, also known as the conjunctival/scleral pathway, is a competing and parallel absorption route. It is a moderate absorption path compared to the corneal route, but it contributes significantly to the absorption of a few molecules. The non-corneal pathway avoids the cornea by passing via the conjunctiva and sclera.

2. Physiological Barriers: The tear film is the eye's first line of protection. Precorneal variables such solution drainage, tear dilution, tear turnover, and enhanced lacrimation lower the bioavailability of topically applied medications even further.The typical tear volume is 7-9μL, with a 16% per minute turnover rate. To avoid considerable precorneal loss, medications given as eye drops must be isotonic and non-irritating.⁶

Novel approach:

Nanotechnology:

One of the key priorities of pharmaceutical scientists is creating acceptable drug delivery methods for ocular disorders, which is an interesting task.

Hydrogels, microparticles, nanoparticles, liposomes, collagen shields, ocular inserts/discs, dendrimers, and trans corneal iontophoresis are among the innovative ophthalmic drug delivery technologies under development.

Nanotechnology is described as the science and engineering that takes place on a scale of10⁻⁹m. Techniques such as Bottom-Up Technology and Top-Down Technology are used to transfer drug microparticles/micronized drug powder to drug nanoparticles.⁷

Nanosuspensions are colloidal dispersions containing nanosized drug particles stabilised by surfactants that are submicron in size. Nanosuspensions are comprised of a weakly water-soluble medicament suspended in a dispersion without any matrix material. It is made up of ultramicroscopic medicament particles and causes little eye discomfort. It can increase the bioavailability of hydrophobic compounds by extending their retention period in precorneal tissues. As a result, it has a great prospect for transporting hydrophobic compounds. (8) Commercial ophthalmic suspension formulations have a number of issues, including non-homogeneity of dosage form, cake formation, particle settling, and suspended particle aggregation. To address these issues, researchers have attempted to create nanosuspensions for effective medication delivery. Nanosuspensions can also be employed in ocular inserts to produce continuous medication release by integrating or combining with an appropriate hydrogel or mucoadhesive basis.⁸

Nanosuspensions are made with poorly water soluble compounds suspended in a dispersion without any matrix component. These can be used to improve the solubility of medications that are insoluble in both water and lipid environments. It also enhances the stability and bioavailability of medications that are poorly soluble. The lowering of drug particles into the sub-micron range leads to an increase in dissolving rate.

Ionic strength, pH, monomer concentration, particle size, and molecular weight, as well as surfacecharge, are all significant physicochemical characteristics for drug delivery. Nanosuspensionsdemonstrated a faster onset of action and better dose proportionality than traditional suspensions. Nanosuspensions also change pharmacokinetic characteristics, enhancing drug safety and efficacy.⁹

Advantages of nanosuspension in ophthalmology:⁹

Nanosuspension enhance the bioavailability and solubility of drugs

Nanosuspension suitable for hydrophilic drugs and Dose reduction is possible

Higher drug loading can be achieved in nanosuspension and also provides a passive drug targeting

Nanosuspension enhance the physical and chemical stability of drugs.

Reduced administration quantities, which are necessary for intramuscular, subcutaneous, and ophthalmic administration.

Resistance to hydrolysis and oxidation has improved, as has physical stability in the face of settling.

The excipients in nanosuspension have a low rate of adverse affects

Formulation Consideration: Ingredients Used in the Formulation of Nanosuspension are following¹⁰

· Stabilizer;

· Organic solvents;

· Cosurfactants;

· Other additives

1. Stabilizer: In the preparation of nanosuspensions, the stabiliser is essential. A stabilizer's core roles areto fully hydrate the drug particles and to minimize The type and amount of stabiliser has a significant impact on nanosuspensions' physical stability and invivobehaviour. Cellulosics, poloxamers, polysorbates, lecithins, and povidones are some of thestabilisers that have been investigated so far. If you want to make a parenterally acceptable andautoclavable nanosuspension, lecithin is the stabiliser to use.¹⁰

2. Organic Solvents: If nanosuspensions are to be made utilising an emulsion or microemulsion as atemplate, organic solvents may be necessary in the formulation. Because these procedures are still intheir infancy, there isn't much information on formulation considerations.¹⁰

3. Co-surfactants: The bile salts and dipotassium glycerrhizinate are described in the literature as cosurfactants,other solubilizers, such as Transcutol, glycofurol, ethanol, and isopropanol, can be employedsafely as co-surfactants in the formation of microemulsions.¹⁰

4. Other-additives: Depending on the method of administration or the qualities of the drug moiety,nanosuspensions may contain additives such as buffers, salts, polyols, osmogent, and cryoprotectant.¹⁰

Method of Preparation: Nanosuspensions are often prepared using one of two methods: "Bottom-up technology" or "Top-down technology."¹¹

Bottom-up technology		Top-down technology
Crude drug powder		Crude drug powder
Surfactant and solvent		Nanocrystals or amorphous powder
Precipitation		Addition of surfactant and solvent
High pressure homogenization and milling

Bottom-up technology involves the disintegration of larger particles into nanoparticles, such as high-pressure homogenization and milling methods, and top-down technology involves the disintegration of larger particles into nanoparticles, such as precipitation, microemulsion, and melt emulsification methods.¹²

A. Top-down technology:¹³

I. Media milling (Nanocrystal): Liversidge et al. discovered this approach in 1992.

The high shear rate reduces the particle size here. Furthermore, the entire procedure is carried out at a constant temperature. If the shear rate is too high, heating will build up, degrading some of the components in the dosage form. High shear media milling, often known as pearl mills, is the name given to this type of technology.

a) The milling chamber,

b) Milling shaft, and

c) Recirculation chamber are the three principal columns in this mill.

Principle: "Impaction" is the key principle at work here in terms of size reduction. The microparticles are broken down into nanoparticles by this shear. We can reduce particle size to 200nm in 30–60 minutes using this method. This method is very easy, cost-effective, and scalable.

I. High pressure homogenization (HPH): This method is mostly utilised for molecules with a low solubility. This approach includes squeezing a course suspension containing drugs and stabilisers through a pressure-sensitive valve with a small hole. Suspension is used in this course across a limited region with high pressure up to 1500 bar, resulting in an increase in dynamic pressure with a simultaneous decrease in static pressure, lowering the boiling point of the water to normal (room) temperature.¹⁴

Types of Pressure Homogenization¹⁵

a) Homogenization in Non-Aqueous Media (Nanopure): It involves homogenization in water mixes or water-free media and is used to prepare thermolabile compounds. Nanopure is also known as deep freezing because drug suspensions are homogenised in non-aqueous medium at 0^oC temperature, i.e. drug suspensions in non-aqueous media are homogenised at 0°C or even below the freezing point, and hence are referred to as deep freeze homogenization.

b) Combined Precipitation and Homogenization (Nanoedge): Both precipitation and homogenization are done at the same time, as the name implies. Combined precipitation, also known as nanoedge, is a process in which a medication is combined with an organic solvent and subsequently precipitated with a miscible anti-solvent. In the case of water solvent mixtures and drug precipitates, solubility is low. High shear processing has also been used in conjunction with precipitation. Nanoedge works on the same principles as precipitation and homogenization. This approach reduces particle size to the nanoscale and improves stability in a short period of time.

c) HPH in Water (Dissocubes): Muller invented the Dissocubes technology in 1999. With a volume capacity of 40 ml, the instrument may function at pressures ranging from 100 to 1500 bars (2 800 - 21 300 psi) and up to 2 000 bars (for laboratory scale). This approach was used to make nanosuspensions of pharmaceuticals suchAmphotericin B, Ordinon, Thiomerasol, Fenofibrate, Melarsoprol, Buparvaquone, Prednisolone, Carbamazepine, and Dexamethasone.

B. Bottom-up technology:

This technique, as the name implies, begins at the molecular level andprogresses to molecular association for the formulation of small solid particles. This means it's an uniqueprecipitation approach in which the amount of solvent used is minimised.¹⁶

a. Precipitation (Hydrosol): The precipitation process work same as emulsification solvent evaporation does.The distinction is that the medication solvent and anti-solvent are completely miscible. High shear forces can overcome problems like ostwald ripening and crystal growth. It assures that the residual precipitate is smaller in size.¹⁷

C. Microemulsion as Template: Microemulsions are a thermodynamically stable and isotropically transparent dispersion of two immiscible liquids, such as oil and water, stabilised by an interfacial coating of surfactant and co-surfactant. To begin, the microemulsion was prepared. The produced emulsion was mixed with the retrieved solution, and the drug loading efficiency was measured.¹⁶

D. Emulsion as Template: This type of emulsion can also be used to make nanosuspensions. This procedure is used to make compounds that are insoluble in volatile organic solvents or only partially soluble in water.¹³

(i) Some Other Methods for Nanosuspension Preparation:^4,13

(ii) Laser fragmentation.

(iii) Nanojet technology.

(iv) Emulsion solvent diffusion method.

(v) Melt emulsification method.

(vi) Supercritical fluid method.

· Characterisation of Nanosuspension:The appearance, colour, odour, assay, associated impurities, particle size, zeta potential, crystalline state, dissolving investigations, and in vivo research of nanosuspensions are all studied. Among the topics covered were the most important characterisation techniques.

1. In Vitro Evaluation:

· Mean particle size and size distribution: The mean particle size and particle size distribution determine a number of factors in nanosuspensions, including saturation solubility, dissolving velocity, physical stability, and biological performance. ^{5, 19}

· Particle charge (Zeta Potential): The stability of the nanosuspension is determined by the zeta potential. The zeta potential of a nanosuspension is governed by both the stabiliser and the drugs. For electrostatically stabilised nanosuspension, a zeta potential of at least ±30 mV is required, while for electrostatic and steric stabilisation, a zeta potential of at least ±20 mV is required.¹⁹

· Crystalline state and particle morphology: It is essential to understand the drug's crystal shape in nanosuspension. The crystalline state and particle morphology can be used to predict polymorphic or morphological changes in drugs that occur during nanosizing.X-ray diffraction analysis is used to determine the amorphous condition of the drug generated during nanosuspension production. It provides information on drug particle physical state alterations as well as the extent of the amorphous fraction. For detecting the exact size and morphology of nanoparticles in suspension, techniques such as scanning electron microscopy (SEM), atomic force microscopy (AFM), or transmission electron microscopy (TEM) are preferred.^16,19

· Saturation solubility and dissolution velocity: Increased dissolving pressure and thus solubility arise from particle size reduction.The saturation solubility and dissolution velocity are determined using different physiological solutions at varying pH and temperatures, according to the techniques specified in the pharmacopoeia.¹⁰

· Stability: Nanosuspensions particle size of the suspended particles affects the stability. The surface energy of the particles increases as particle size decreases to the nano range, and the tendency of the particles to agglomerate increases.^{2, 13}

· pH: The pH of the nanosuspension can be easily measured by using pH meter.

· Osmolarity: Practically, Osmolarity of nanosuspension can be measured by using Osmometer.

· Drug content: The drug content of a nanosuspension formulation can be determined by extracting it in an appropriate solvent mixture, shaking it thoroughly, then centrifuging it.The absorbance can be measured at a suitablelambda max after the supernatants have been separated and diluted with the same solvent mixture. The calibration curve can then be used to calculate the drug content.

2. In Vivo Evaluation: The in vivo evaluation of nanosuspensions is required for each drug and method of delivery. In general, formulations are supplied by the prescribed route, and plasma drug concentrations are measured using HPLC-UV visible spectrophotometry.¹⁹

3. Surface Modified of Particles of evaluation:

· Surface Hydrophilicity:

· Adhesion properties

· Interaction with body proteins

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Received on 02.11.2022 Modified on 20.12.2022

Res. J. Pharma. Dosage Forms and Tech.2023; 15(1):45-50.

DOI: 10.52711/0975-4377.2023.00008