INTRODUCTION:

The one of the most challenging task for pharmaceutical scientists is preparation of new Ocular drug delivery system. The required site of action of the drug molecule is limited due to the unique structure of eye. Eye can be classified into two parts first one is anterior segment and second one is posterior segment¹.The anterior part of the eye occupies one-third, while the rest portion is occupied by the posterior part. Anterior part of the eye composed of Tissues such as cornea, conjunctiva, aqueous humor, iris, ciliary body and lens and posterior part of the eye comprise sclera, choroid, retinal pigment epithelium, neural retina, optic nerve and vitreous humor^2,3. Most of the ophthalmic preparation present on the market are eye drops. These preparations (eye drops, ointment, and suspension) are mainly for ocular diseases in the anterior part of the eye⁴. For the treatment of vision threatening eye diseases, linear systems such as eye drops, suspension and ointment cannot be considered optimal¹.

The drugs applied topically to the eyes are cleared from the eye through various mechanisms (lacrimation, tear fluid and tear turnover) resulting in low ocular bioavailability of the drugs².

From over a decade there are various dramatic changes have been observed in the field of ocular drug delivery. In the eye there are various types of receptor/membrane present, which opened a new window for the preparation of new type of marketed formulation. The non-polar drug molecules permeate via receptor/transport membrane, and especially polar drug molecule, which cannot cross the receptor/transport membrane, can be delivered via targeted drug delivery system⁵. In case of ocular diseases topical eye drops are the preferable method of treatment. The only drawback associated with eye drops is that these preparations are less bioavailable. As the eye-drops are drained quickly from the ocular surface the absorption time is very low. The duration of absorption and bioavailability can be increased by utilizing sustained action dosage forms but these are not widely acceptable^6,⁷. Treatment of the Posterior segment of the eye (retina, vitreous, choroid) high drug doses given by intravenously or intra-vitreal administration⁸.

In eye there are various types of barriers present and they limit the entry of drug molecule via different routes to the eye. These barriers include epithelial layer, aqueous- vitreous barriers, blood retinal barrier etc⁹. For improving ocular bioavailabilty, many novel drug delivery systems have been developed. These systems can overcome the ocular barrier also. The example are nanoparticles, nano- micelles, liposomes, dendrimers, aqueous gels, nano emulsions and suspensions, in- situ gels etc¹⁰.

Nano-suspension:

Formulation of lipophilic compounds or drugs that are poorly soluble in water has always been a major challenges faced by the pharmaceutical scientists. Also, we know that more than 40% of drugs that are newly discovered belong to the poorly water soluble class. For all the drugs that belongs to BCS classes II and IV, nanoformulations are good choice to increase the solubility and bioavailability¹¹^-1⁵. A new field was developed for biomedical purpose by nanomaterials, nanoparticle, and Nano-composite which is called Nano-medicine, which indicate the medical application of nanotechnology and related research salient to the designing, testing and improving of the pharmaceutical formulations. It is the science of small particle having unique properties¹⁶.

(Nano-suspensions are different from nanoparticles. Nanoparticles are generally colloidal carriers of polymers. In Nano-suspension technology, the crystalline state was maintained by the reducing the particle size of drug. The decreased particle size of the drug increases the surface area, which increase the dissolution rate. The increased dissolution finally enhanced the bioavailability. The solution velocity and saturation solubility of nanoparticles incre ases with vapour pressure¹⁷.

Nano-drug formulations have been developed for poor aqueous solubility drug and to improve the dissolution and bioavailability of drugs¹⁸. The formulations of drug nanosuspensions is effective and hopeful¹⁹^–2¹. Drug Nano-suspensions are composed of submicron amorphous or crystalline nature drug particles suspended in a dispersion medium (mostly water) and stabilized by polymer or surfactant²². Nanosuspension are prepared by using these two methos (1) the top-down method (breaking of large drug particles during grinding and homogenization) (2)the bottom-up method (building nanoparticles from drug molecules by precipitation)²³.

Definition:

Pharmaceutical Nano-suspension can be defined as a very finely colloid, biphasic, dispersed system consisting of pure drug particles dispersed in an aqueous vehicle. Colloidal dispersions of nano-sized drug particles of nano-suspension stabilized with a surfactants. The diameter of the suspended particle is less than 1μm in size. The Nanosuspensions can also be lyophilized or spray dried²⁴^-²⁹.

Routes of administration are oral, topical, parenteral, ocular and pulmonary routes³⁰. The average particle size rangs from 200 - 600nm³¹. Nnanosuspensions increase drug safety and efficacy by solving solubility and bioavailability problems and altering drug pharmacokinetics. Drugs that are insoluble in water and inorganic media instead of using lipidic systems is used for nanosuspensions formulation approach. High melting point, and high dose, high log P value compounds are most suitable for Nano-suspension formulation approach. Nanosuspension helps to reduce dose of oral dosage form and it is reported to enhance absorption and bioavailability³⁰.

In this review article we are discussed some Nano-suspension formulations prepared by one or more scientist and application of formulation and its category, mechanism of action.

Preparation Methods of Nanosuspension:-

There are two main methods for preparing nanosuspension-

1. Bottom-up technology

2. Top-down technology

I. Media milling (Nanocrystals)

II. High-pressure homogenization in water (Dissocubes)

III. High pressure homogenization in nonaqueous media (Nanopure)

IV. Combination of precipitation and high-pressure homogenization (Nanoedge)³²

1. Bottom-up technology:

In this technique by increasing the size of particles frommolecular range to nano range the nano size is obtained³³. Conservative precipitation methods are called “bottom-up technology”³². Firstly an organic solvent is chosen to dissolve the drug and this solution is mixed with a miscible anti-solvent using a precipitation technique. In this technique the low cost and simple equipment is used and a poorly soluble drug, in both aqueous and non-aqueous media is not prepared by these technique.

2. Top down technology:

In this technique the reduction of large particle size into small particle size (range 1nm) to get nano sized particles³³.

I. Media milling (Nanocrystals):

This technology was developed by Liversidge et al. (1992). In this process, the nano-suspensions is prepared using a high-shear media mills or pearl mills. The important parts of media mill include a milling chamber, a milling shaft and a recirculation chamber. The milling process is done under the controlled temperature³⁴.

II. High-pressure homogenization in water (Dissocubes):

This instrument (dissocubes) was developed by Muller et al. in 1999³⁵. High pressure homogenization methods have been used to prepare nano-suspension of many poorly water soluble drugs. The process consists of forcing the suspension under pressure through a valve having a narrow orifice. The pressure of instrument were it can be operated at 100-1500 bars (2800- 21300 psi) and can operate up to 2000 bars³⁶.

III. High pressure homogenization in non-aqueous media (Nanopure):

Nano-pure is suspensions homogenized in water-free media or water mixtures. In "deep-freeze" homogenization the suspensions of active ingredient is homogenized in a non-aqueous medium at 0ºC or even below freezing point. This method is useful for temperature sensitive drug³³.

IV. Nano-edging (Precipitation combined with high-pressure homogenization):

The principle of Nano- edge is the combination of precipitation and homogenization techniques. The techniqueprovides smaller particle size and better stability in a shorter time. Also the problems the drawback comes out of precipitation technique, such as crystal growth and long-term stability and that can be resolved using the Nanoedge technology³⁶.

Characterization of Nano-Suspension:-

The characterstics of nanoparticle incorporate the major portion in the presupposition of nano drug delivery systems in vitro and in vivo. The size of particles, its distribution, zeta potential, crystalline state and particle morphology, collectively affects the In-vivo pharmacokinetic performance.

· Mean Particle Size and Particle Size Distribution:-

Using laser diffraction (LD), photon correlation spectroscopy, microscope, and coulter counter, the particle size distribution and its range named polydispersity index (PI) determined³⁷. Polydispersity Index provides the physical stability of the nanosuspensions, and should be as lower as possible to ensure the long-time stability of nanosuspensions. LD methods has been used to measure particles from 0.05 up to 2 000 μm³⁸.

· Crystalline State and Particle Morphology:

The degree of changes in the solid state and the amorphous portion of the drug particle were analyzes by X-ray diffraction⁴⁰ and supplemented with differential scanning calorimetry analysis. The polymorphic state and surface morphology can be easily detected by these methods^38,³⁹.

· Surface Charge (Zeta Potential):

The significance of surface charge is basically reflected in the stability of the nanosuspension.Electrostatically stablenanosuspensions requires a minimum zeta potential of ±30mV^41,⁴² and at least ±20mV for spatial stability⁴³. Electro acoustic technique is also used to determination of the zeta potential in the field of material sciences⁴⁴.

· Entrapment Efficiency:

Entrapment efficiency can be determined by deep centrifugation method. The free drug concentration is determined in supernatant obtained. For the free drug measurement UV spectrophotometer or HPLC method can be used⁴⁵.

Application:

Cloricromene:

It is a platelets aggregation inhibitor. It is basically a coumarin derivative. It inhibits polymorphonuclear cells (PMN) neutrophil function and cause vasodialation⁴⁶. Pignatello et al.2006, produced cloricromene Eudragit nanosuspensions. They co-dispersed the drug into RS and RL polymers. By using this method they found particles in nano range with a positive surface charge. On storage the drug was found stable and showed a higher bioavailability⁴⁷.

Diclofenac:

It’s a class of non-steroidal anti-inflammatory drug used to treat pain, redness and swelling in patients who are recovering from cataract surgery⁴⁸. Ahuja M et al 2011, developed diclofenac eudragit nanosuspension. They followed nanoprecipitation method for preparing the same. The particle size of the prepared formulation was found 172 nm with stable zeta potential. The in- vitro and in-vivo drug release profile was found excellent⁴⁹. Agnihotri S M et al 2009, developed diclofenac nano-suspension. They used emulsion and solvent evaporation technique. In vitro release studies have demonstrated the long-term release profile of diclofenac from the nanoparticles. To ensure that there is no irritation to the structures of the eye, a modified Draize test was performed. The study suggested that these inert carriers were suitable for ophthalmic drug delivery⁵⁰.

Ibuprofen:

It is a class of NSAIDs drug used to treat pain and scleritis treatment⁵¹. Pignatello R et al 2002, prepared ibuprofen nanosuspension mean size was 100nm and a positive charge (zeta potential of 40/+60 mV) this make it to suitable for ophthalmic application. No significant changes occur when stored in refrigerator for 24 month but stored at room temperature for few months showed increasing the particle size that promote growth of microorganism. They found that there is no sign of irritation to rabbit eye on topical application of the nano-suspension⁵². Kocbek et al 2006, prepared nano-suspnsion using the melt emulsification process. Compared with solvent diffusion methods, these methods have the advantage of avoiding the use of organic solvents in the production process. They explained that as the bioavailability of ibuprofen is limited by the dissolution rate, so particle size reduction can greatly increase the effectiveness of the drug⁵³. BucoloC et al 2002, prepared ibuprofen RS nano-suspension for the treatment of mild conjunctival inflammation and hyperemia (0.5 hr) in rabbit eye and found great results⁵⁴. Tak D et al 2019, prepared Nano-suspension with benzalkonium chloride 0.002% and found average particle size 331nm. Nano-suspension of ibuprofen provides 2.1 fold higher ex vivo corneal permeation⁵⁵.

Sulfacetamide:

It belongs to a class of drugs known as sulfa antibiotics. It is used to treat bacterial eye infection (conjunctivitis). It works by blocking the growth of bacteria⁵⁶. Mandal B et al 2010, formulated nanosuspension with increased entrapment efficiency by changing the pH and adding polymethyl methacrylate to the formulation. The resulting nanosuspension showed good stability after storage at room temperature and at 40⁰C⁵⁷.

Sparfloxacin:

Sparfloxacin is a newer-generation hydrophobic fluoroquinolone used in treatment of bacterial conjunctivitis. It works by inhibiting the enzyme DNA gyrase and topoisomerase⁵⁸. Gupta H et al 2010, Prepared Sparfloxacin nanosuspension tested ocular tolerance using Hen Egg Test-Chorioallantoic Membrane (HET-CAM) method. It was found that the developed nanosuspension were more stable than the conventional marketed formulation with a good shelf life⁵⁹. Ambhore NP et al 2016, prepared Sparfloxacin ocular nanosuspension by the solvent diffusion method by optimizing the concentration of HPMC E5 and water soluble chitosan by using the probe sonication. The optimized formulation was found to be stable, isotonic, nontoxic with high antimicrobial activity in both the in vitro and in vivo conditions⁶⁰.

Olopatadine hydrochloride:

Olopatadine is a water soluble anti-allergic drug with a histamine H1 receptor antagonist that affects human mast cells in the conjunctiva⁶¹^-6³. Güvena U M et al 2019, Prepared olopatadine (olo)hydrochloride nanosuspension using kollidon SR polymer by spray-drying method. Characterization studies have shown that OLO is successfully loaded into the nanoparticles system and that the suspension formulation is suitable for ocular administration⁶⁴.

Ketotifen Fumarate:

It is used to treat and prevent itching of the eye caused by allergies. It acts by blocking certain natural substance (histamin)⁶⁵. Soltani S et al 2016, prepared ketotifen fumarate (KF) nanosuspension using two polymers PLGA and Eudragit RL100, by two different methods that is nano-precipitation and evaporation of double emulsion solvent (W1/O/W2) at different drug and polymer ratio. They found better results with PLGA⁶⁶.

Amphotericin B:

Amphotericin B is a first-line drug used in the treatment of Candida spp.This cause keratitis and other related fungi. Jansook P et al 2020, designed nanosuspensions containing Amphotericin B and cyclodextrine. The nano-aggregates are within acceptable limits⁶⁷.

Glucocorticoid:

Glucocorticoidare widely used to treat inflammation of the conjunctiva and the front of the eye. Kassem MA et al 2007, prepared hydrocortisone, prednisolone or dexamethasone ophthalmic nanosuspension compared with solution and micro crystalline suspension, the nanosuspension enhance the rate and extent of absorption of ophthalmic drugs as well as the intensity of drug action and in some case nanosuspension extend the drug in of drug effect⁶⁸.

Indomethacin:

This NSAID is used to treat eye inflammation such as conjunctivitis, uveitis, and interior segment inflammation including post-operative pain after cataract surgery. It works by blocking the enzymesCOX-2, which is required for the bio-synthesis of prostaglandin⁶⁹. Bodmeier R et al 1990, prepared indomethacin nanosuspension by using micro-fluidization-solvent evaporation method⁷⁰.

Acyclovir:

Acyclovir is a class of antiviral drugs used to treat infections caused by some viruses. Ophthalmic acyclovir is used to treat eye infections caused by the herpes simplex virus(in the cornea)⁷¹. Dandagi P et al 2009, prepared acyclovir nanosuspension with average particle size range 100-200nm. In vivo studies showed that the concentrations in aqueous fluids were 82.83, 77.49 and 34.15mg/ml after 8 hour⁷².

Flurbiprofen:

It belongs to NSAIDs (Non-steroidal anti-inflammatory drug).It is used in eye surgery. It works by suppressing the release of certain natural substance that cause pain or swelling⁴⁸. Pignatello R. et al 2002, formulated nanosuspension by emulsion solvent diffusion technique. The mean particle size of the nano-suspension was 100 nm⁷³.

Natamycin:

It is used for the treatment of fungal eye infection. It works by blocking the growth of certain types of fungus⁶⁵. Joshi H P et al 2019, prepared natamycin nanosuspension using homogenization method. Increased amount of natamycin cause increasing the particle size of formulation. They told that when the formulation was stored at 40°C for 14 days of storage, the buff colored nanosuspension turned yellow. Proper storage conditions are required for the formulations⁷⁴.

Cyclosporine:

It is a class of immune-modulator drugs.It is used to increase tear production in patients having ocular dryness problems⁶⁵^,75. Nakarani M et al 2010, prepared nano-suspension of cyclosporine. The experiment showed that the particle size of cyclosporine has decreased and the saturation solubility has increased⁷⁵.

CONCLUSION:

On the basis of the review of literature done on the topic it can be concluded that the nanosuspension delivery system can be prepared by using different methods with improved efficiency. Nanosuspensions are exclusive and most practicable approach to resolve the poor solubility and bioavailability problems of hydrophobic dugs. Prominent features of nanosuspensions such as increased solubility and dissolution characteristics, versatile surface modification, feasible production processing etc made them preferable colloidal system in large scale productions. They are the system of choice in case of oral and parenteral routes. However their delivery through other routes like pulmonary, ocular, buccal and topical, are still under study and yet to be achieved.

CONFLICT OF INTEREST:

No conflict of interest

ACKNOWLEDGEMENT:

The author would like to thank the Principal, Prof. A. K. Jha, SSTC-Faculty of Pharmaceutical Sciences, Bhilai (C.G.) India, for his technical guidance and moral support in framing the article.

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Received on 22.11.2021 Modified on 10.03.2022

Research J. Pharm. and Tech 2023; 16(3):1533-1539.

DOI: 10.52711/0974-360X.2023.00251