International Journal of Pharmaceutical Progress & Health...

International Journal of Pharmaceutical Progress & Health Sciences (IJPPHS) Vol 1 Issue 1

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The Implication Of Nanoformulations In Ocular Drug Delivery

Lalita,*, Dharam Pal Pathakb, Satish Manchandac

aDepartment of Quality Assurance, Delhi Institute of Pharmaceutical Science and Research, New

Delhi-17

bDepartment of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Science and

Research, New Delhi-17

cDepartment of Pharmaceutics, Delhi Institute of Pharmaceutical Science and Research, New

Delhi-17

Address for correspomdence: [email protected]

Abstract

The bioavailability of conventional ophthalmic formulations is only about 5% or even less than

this, which is because of the numerous barriers present in the eye and considerable drug loss. There

are three main barriers present in the human eye affecting drug absorption and bioavailability

namely (i) anatomical barrier (Cornea), (ii) physiological barrier (Lachrymal fluid), and (iii) blood-

ocular barrier (Blood aqueous and Blood-retinal barrier). The drug loss mainly occurs as a

consequence of drug overflow, normal tear turn-over, nasolacrimal drainage, drug metabolism,

and absorption via conjunctiva or sclera. Since the majority of ophthalmic disorders are clinically

managed using topical drug administration via suspensions, ointments, and solutions, therefore,

keeping in mind the diminished bioavailability and patient compliance, nanoformulations are

formulated in an attempt to enhance the bioavailability, reduce the frequency of dosage

administration, and at the same time lessen the frequency of adverse events. Numerous nano-based

formulations such as nanoemulsions, cyclodextrins, dendrimers, niosomes, liposomes, etc. have

been discussed here in the article.

Keywords: Nanoformulations, Ocular, Drug, Delivery

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1. Introduction

Nanotechnology is appeared to connect the

hindrance of natural and actual sciences by

applying nanostructures and nanophases at

different fields of science(1); extraordinarily

in nanomedicine and nano-based medication

conveyance frameworks, where such

particles are of significant interest(2).

Nanomaterials can be very much

characterized as a material with sizes ran

somewhere in the range of 1 and 100 nm,

which impacts the boondocks of

nanomedicine beginning from biosensors,

microfluidics, drug conveyance, and

microarray tests to tissue designing(3,4).

Nanotechnology utilizes corrective

specialists at the nanoscale level to create

nanomedicines. The field of biomedicine

including nanobiotechnology, drug

conveyance, biosensors, and tissue designing

has been controlled by nanoparticles(5). As

nanoparticles involve materials planned at

the atomic or molecular level, they are

normally little-sized nanospheres(6).

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Nanoscale-sized particles display exceptional

structural, chemical, mechanical, magnetic,

electrical, and biological properties.

Nanomedicines have gotten all-around

appreciated lately because of the way that

nanostructures could be used as conveyance

specialists by embodying drugs or connecting

remedial medications and convey them to

target tissues all the more exactly with a

controlled delivery(7,8). Nanomedicine is an

arising field carrying out the utilization of

information and strategies of nanoscience in

clinical science and sickness counteraction

and remediation. It embroils the usage of

nano-dimensional materials including

nanorobots, nano-sensors for analysis,

conveyance, and tactile purposes, and incite

materials in live cells. For instance, a

nanoparticle-based strategy has been created

which consolidated both the therapy and

imaging modalities of cancer conclusion(9).

The absolute original of nanoparticle-based

treatment included lipid frameworks like

liposomes and micelles, which are currently

FDA-affirmed(10). Polymeric nanoparticles

can be sorted into nanospheres and nano-

capsules the two of which are phenomenal

medication conveyance frameworks. In like

manner, conservative lipid nanostructures

and phospholipids including liposomes and

micelles are exceptionally valuable in

focused medication conveyance. The

utilization of the ideal nano-drug conveyance

framework is chosen principally dependent

on the biophysical and biochemical

properties of the focused drugs being chosen

for the treatment(11).

Nonetheless, issues, for example,

harmfulness showed by nanoparticles can't

be overlooked while considering the

utilization of nanomedicine. The green

science course of planning nanoparticles

stacked with drugs is broadly supported as it

limits the perilous constituents in the

biosynthetic interaction. Accordingly,

utilizing green nanoparticles for drug

delivery can diminish the results of the

prescriptions(8). Being nanosized, these

constructions enter in the tissue framework,

encourage simple take-up of the drug by

cells, license a productive drug delivery, and

guarantee activity at the focused on the spot.

The take-up of nanostructures by cells is a lot

higher than that of huge particles with the size

running somewhere in the range of 1 and 10

μm(5,12). Consequently, they

straightforwardly connect to treat the infected

cells with improved proficiency and

diminished adverse events.

2. Role of Nanotechnology in Drug

Conveyance

The advancement of compelling drug

delivery frameworks that can move and

convey a drug exactly and securely to its site

of activity is turning into a profoundly

significant examination territory for drug

researchers. Surely, an incredible number of

new delivery innovations surface every year,

and practically all aspects of the body have

been concentrated as an expected course for

administrating both traditional also, novel

prescriptions. Subsequently, encouraging

methods of conveying ineffectively

dissolvable drugs, peptides and proteins have

been formulated. In expansion, appealing

drug conveyance advances, like transdermal

patches, nanodevices, bio-adhesive systems,

implants, microfabricated systems, cell

encapsulation devices, and novel nasal drug

conveyance systems are presently under

concentrated investigation(13–15). Although

there are numerous likely upgrades to be

made in the fields of drug delivery and



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diagnostics, nanotechnology offers benefits

that permit more focus on drug delivery and

controllable arrival of the remedial

compound(13,16). The point of focused drug

delivery and controlled delivery is to oversee

better drug pharmacokinetics,

pharmacodynamics, vague poisonousness,

immunogenicity, and biorecognition of

frameworks in the journey for improved

adequacy.

3. Nanotechnology in Ophthalmic

Formulations

Ocular drug delivery is quite possibly the

most fascinating and testing attempt looked

at by the drug researcher, in light of the basic

and pharmacokinetically explicit climate that

exists in the eye(17–19). The anatomy,

physiology, and biochemistry of the eye

render this organ wonderfully impenetrable

to unfamiliar substances(20). In the eye, the

inward and external blood-retinal boundaries

separate the retina and the vitreous from the

systemic circulation and the vitreous body

and diminish the convection of particles since

it has no cell segments(21).

Thinking about these focuses, the

advancement of a drug delivery system

(DDS) is getting progressively significant in

the treatment of vitreoretinal illnesses, not

exclusively to encourage drug viability, yet

likewise to weaken unfavorable impacts(22).

In ophthalmic ailments, where angiogenesis

is an element, for example, choroidal

neovascularization (CNV), diabetic

retinopathy, central retinal vein occlusion

and intraocular solid tumors, drug focusing

on can be an effective mode of treatment.

Since the retina has a particular climate with

no lymph framework, retinal

neovascularization and CNV are assumed to

have a climate like solid tumors, having

improved penetrability and maintenance

(EPR) impacts, and are appropriate for drug

focusing on(21).

Ophthalmic drugs targeting has three

significant objectives:

Improving medication pervasion (for

example iontophoresis and transscleral

drug delivery system);

To control the arrival of medications (for

example miniature circles, liposomes,

and intraocular inserts);

To target drugs (for example prodrugs

with high atomic weight and

immunoconjugates).

4. The implication of Nano based

formulations in Ophthalmology

Although the different medication

conveyance frameworks referenced

previously offer various benefits over

customary medication treatment, in any case,

they are not without entanglements,

including

Poor patient consistency and trouble in

the insertion of ocular embeds.

Tissue aggravation and harm brought

about by permeation enhancers also,

collagen safeguards.

A significant part of the distributed

information proposes that on account of

ophthalmic drug conveyance, suitable

molecule size and a limited size range,

guaranteeing low irritation, sufficient

bioavailability, and similarity with ocular

tissues, ought to be looked for each

suspended drug(23). Other detailing factors,

that is the utilization of right wetting,

suspending, and buffering agents, protective

colloids, preservatives, and so on, ought to



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likewise be deliberately thought of.

Subsequently, an ideal visual medication

conveyance framework ought to be one that

can be conveyed as eye drops, causing no

obscured vision or touchiness and would

require close to one to two administration

each day(24). Different models that should be

thought of, while choosing the plan

boundaries for building up an appropriate

ophthalmic medication conveyance

framework are appeared in (Table 1). Even

though the conveyance of medications to the

anterior segment of the eye is accomplished

fundamentally through effective conveyance,

almost no of the topically applied medication

arrives at the posterior segment of the eye.

This requires administering certain

medications, for example, antiglaucoma

medications, corticosteroids, and certain anti-

infection agents by the systemic course.

Nonetheless, a little part of the portion comes

to the ocular tissues, following systemic

organization. The portions needed to give a

therapeutic impact employing this course, in

any case, can lead to extensive results.

Standards for the determination of ideal definition boundaries when designing up an

ophthalmic medication conveyance framework

Characteristic Feature

Drug Especially lipophilic. Non-ionizable lipophilic mixtures will gather into the

corneal epithelium, while ionizable lipophilic ones will segment ate into the

aqueous humor.

Vector size Relies upon an embodied molecule. Ought to facilitate high loading dose to

minimize the instilled volume.

Career size Least conceivable to encourage corneal take-up and passage.

Osmotic pressure Isotonic with physiological fluids to prevent displeasure and lacrimation.

pH Near physiological pH to maintain a strategic distance from aggravation and

lacrimation. A buffer of the lowest possible concentration (<0.1 M) should

be employed.

The utilization of nanotechnology-based

medication conveyance frameworks like

nanosuspensions, solid lipid nanoparticles,

and liposomes has driven the arrangement of

different solvency-related issues of

inadequately dissolvable medications,

similar to dexamethasone, budesonide,

gancyclovir, and so on(25). Medications can

likewise be focused on mononuclear

phagocyte frameworks to permit local

explicit conveyance and limit side impacts in

different organs(26). Nanotechnology-based

medication conveyance is additionally

productive in intersecting membrane

boundaries, like the blood-retinal hindrance

in the eye(27,28). The medication

conveyance frameworks based on

nanotechnology may end up being the best

medication conveyance model for some

chronic ophthalmic ailments, where incessant

medication organization is fundamental, for

instance in ophthalmic infections like chronic

cytomegalovirus retinitis (CMV). In this



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sickness, the effective conveyance of

medications like ganciclovir (GCV) is

forestalled and intravitreal conveyance is

favored. Even though the half-life of GCV,

following intravitreal organization, is 13 h,

regular infusions are important to keep up

therapeutic levels, since this medication

forestalls the replication of the viral

deoxyribonucleic acid (DNA), however,

doesn't eradicate the infection from the tissue.

Hence, long-term treatment is fundamental,

which may bring about cataract progression,

retinal detachment, and endophthalmitis(29).

5. Various Nano-Particulate Based Drug

Conveyance Frameworks

Fabrication of numerous nanoparticulate-

based formulations like Nanoemulsions,

Dendrimers, Cyclodextrins, Liposomes,

Niosomes, etc. can significantly result in

enhanced ocular bioavailability of the drug

(Figure 1).

Figure 1. A diagrammatic representation of various nanoparticulate-based ocular drug conveyance

models (a) Cyclodextrins, (b) Dendrimer, (c) Nanoemulsions, (d)Niosome, and (e) Liposome.

6.1. Microemulsions

MEs are thermodynamically steady stage

transition frameworks, which exhibits low

surface tension and little bead size (5–200

nm), which may bring about high medication

assimilation and saturation, and thus, possess

a higher chance of medication conveyance to

the posterior portion of the eye. The term ME

was first-authored by Hoar and Schulman in

1943(30). Miniature emulsions are an

intriguing option in contrast to effective

visual drug conveyance, in light of their



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inborn properties and explicit structures; they

can be effortlessly set up through

emulsification, can be effortlessly sterilized,

are stable, and have a high limit with regards

to dissolving drugs(31). The administration

of oil-in-water microemulsions could be

invaluable, because of the presence of

surfactant furthermore, the co-surfactant

enhances the membrane permeability,

accordingly expanding drug take-up. For this

situation, these frameworks perform as

permeation boosters to assist corneal drug

conveyance(32). The presence of surfactant

and co-surfactant will result in an agonistic

effect on the corneal permeation of the drug.

Additionally, microemulsions accomplish

sustained arrival of medication applied to the

cornea and higher penetration into the more

profound layers of the ocular structure and

the aqueous humor than the local drug. These

frameworks offer extra benefits including

low viscosity, a more noteworthy capacity as

medication conveyance vehicles, and

expanded properties as absorption enhancers.

Besides, the sustained release of medications

in microemulsions makes these vehicles

exceptionally appealing for ocular structures

and can significantly diminish the recurrence

of the utilization of eye drops(31). There are

numerous plans of microemulsions proposed

for ophthalmic use. Studies have additionally

shown that some pilocarpine-based

microemulsions defer the movement of the

medication so that twice every day

instillations of these frameworks were

comparable to four instillations of

conventional eye drops(33).

6.2. Nano Emulsions

Emulsions are splendid dispersions of tiny

droplets of two immiscible liquids. By

definition, Nanoemulsions have a dispersed

phase in which the particle size is on the scale

of submicron or nanometer. Nano-emulsions

for the most part include at least one

amphiphilic lipid(s) or surfactants(34).

Elevation of corneal residence time

significantly results in higher bioavailability

of the medications employed in ophthalmic

disorders. There should be a set consistency

on the ophthalmic drugs and an approach to

improve the consistency of such formulation

is to surge the portion of the oil phase

available in Nanoemulsions, which will

ultimately result in enhancement of the

corneal residence time of the drug.

Advantages:-

Water solubility and bioavailability of

lipophilic drugs can greatly be improved

by fabricating the drug in the form of

nanoemulsion(35).

Drugs aggravating gastric irritation can

be administered in the form of

nanoemulsions(36).

A highly effective dosage form for the

administration of drugs susceptible to the

first-pass metabolism(35).

Factors such as creaming, coalescence,

flocculation, and sedimentation leading

to destabilization of emulsions are hardly

observed in the case of

nanoemulsions(35).

Liposomes and vesicles can be replaced

with nanoemulsions(37).

Due to the smaller size of droplets in

nanoemulsion, it offers more noteworthy

absorption because of the more

prominent surface area(38).

Disadvantages:-

Ostwald’s ripening effect results in the

destabilization of the nanoemulsion(39).



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Fabrication cost is somewhat

uneconomic or higher(40).

pH and temperature greatly influence the

stabilization of the nanoemulsions(41).

Fabrication of nanoemulsions involves a

higher amount of surfactant for its

stabilization which may aggravate

toxicity(41).

5.3. Liposomes

Liposomes resemble Nanoparticles in respect

of their focused drug conveyance function.

They comprise one or a few concentric

circles which involve a lipid bilayer that is

isolated by fluid or water compartments that

are made out of phospholipids. They can

exemplify both hydrophobic just as

hydrophilic drug particles, this quality assists

liposomes with playing out an ophthalmic

drug conveyance framework since it shields

the drug particle from any debasement from

metabolic chemicals that are available on the

outside of the eye just as in the tear

liquid(42). Liposomes are small unnatural

vesicles that can be fabricated from

characteristic non-harmful phospholipids and

cholesterol. On account of their size,

amphiphilic properties, and biocompatibility,

liposomes are promising frameworks for

drug conveyance. Liposome properties shift

considerably with lipid arrangement, size,

surface charge, and the strategy for readiness.

The conduct of liposomes as an ophthalmic

drug conveyance framework has been

observed to be, partially, in contrast to their

surface charge. Emphatically charged

liposomes appear to be especially caught at

the contrarily charged corneal surface,

contrasted and impartial or adversely charged

liposomes. Cationic vehicles are relied upon

to back off drug disposal by lachrymal stream

by enhancing the consistency of the colloid

and by collaborating with the negative

charges of the mucus(43).

5.4. Niosomes

Niosomes, which have a bilayer architecture

and are formulated by the self-association of

nonionic surfactants and cholesterol in an

aqueous environment, are viable drug

carriers. Niosomes are nonimmunogenic,

biodegradable, and possess good

biocompatibility. They have a good shelf life,

are extremely stable, and allow for controlled

and/or sustained drug conveyance at the

desired site of action(44). Vesicular

frameworks are having the capacity to

convey the therapeutic effect in different

ophthalmic infections. The vesicular

framework gives high medication (s)

embodiment effectiveness and improved

ocular infiltration. A few vesicular

frameworks for effective (ophthalmic)

applications have been examined and are

currently being utilized as a promising

vehicle to improve the bioavailability of the

drug in the ocular tissue. Among these

frameworks, surfactant-based drug

conveyance frameworks i.e., niosomes are

considered a better choice to convey desired

therapeutic effect to the eyes(45–47). The

various procedures for the fabrication of

unilamellar and multilamellar niosomes are

like liposomal fabrication. On account of the

different benefits offered by the niosomes

over liposomes, for example, (I) better skin

pervasion potential, (ii)higher compound

strength, (iii) sustained delivery properties,

(iv) budget-oriented, (v) biocompatibility,

(vi)non-immunogenicity(45), and (vii)cost

compelling dealing with strategies like no

particular prerequisite for storage under low-



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temperature conditions and utilization of

nitrogen for the formulation, the niosomes

have been one of the area of interest for the

scientists(47).

5.5. Cyclodextrins

Cyclodextrins (CDs) are a gathering of cyclic

oligosaccharides which have been appeared

to improve physicochemical properties of

numerous medications through the

arrangement of incorporated complexes. In

drug advancement, CDs have mostly been

utilized to enhance the aqueous dissolvability

and steadiness of ineffectively water-

miscible drugs. Cyclodextrin complexation

of oleophilic drugs has likewise been

appeared to enhance drug bioavailability.

Habitually, this has been ascribed to the

improved dissolvability or disintegration

pace of the complexed material(48) however

this enhanced drug bioavailability has been

related to associations of CDs with biological

membranes. Most examinations on CDs and

their drug applications have managed oral

and parenteral drug conveyance. Moderately

little consideration has been paid to the

utilization of CDs in ophthalmic drug

conveyance. Notwithstanding, the benefits,

as well as detriments of CD consolidation

into ocular drug preparations, have acquired

a significant inquisitiveness. Using

cyclodextrin complexation it is feasible to

improve the aqueous dissolvability of some

lipophilic water-immiscible medications

without changing their sub-atomic

arrangement, that is without influencing their

inborn capacities to saturate biological

membranes. The cyclodextrin particles are

generally enormous (molecular weight

scaling from 1000-1500), with a hydrated

external surface, and under ordinary

conditions, cyclodextrin molecules will just

saturate biological layers with extensive

strain(49).

5.6. Dendrimers

A polymer formed of repeating, constantly

branching units is referred to as a dendrimer.

Many chemically unique dendrimer families

have also been synthesized, but hardly a few

have been thoroughly studied.

Polyamidoamine (PAMAM) dendrimers

have only been commercialized yet(50).

Initiation of PAMAM dendrimers fabrication

starts with focal center molecule and thereby

'generations' of branches are included as a

progression of consecutive reactions (Figure

2).

This course of action of reaction delivers

profoundly monodispersed and spherical

nanoparticles. With each progressive

generation, the radius of the molecule

elevates linearly, while the count of terminal

groups and sub-atomic weight develops

exponentially. This remarkable design

assigns dendrimers various useful properties

for drug conveyance not reflected by linear

polymers(51). Principally, their all-around

characterized center shell engineering and

limited polydispersity make bio-circulation

more unsurprising and simpler to control

through alterations to the terminal

groupings(52). Additionally, drugs and

different therapeutics can be stacked onto the

nanoparticle through various modalities, like

direct formation, ionic associations, or

trapping in the center of the molecule(53).

This flexibility makes dendrimers

exceptionally versatile stages that can be

intended to convey a wide scope of

therapeutics to a wide scope of targets(54). In

ocular drug conveyance researchers have



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Figure 2. Dendrimer Structure and its divergent and convergent synthesis.

adopted this tractability to develop

dendrimer-based methodologies

6. Conclusion

Nano-technology has made a significant

contribution to the development of the ocular

drug delivery system. Since the

bioavailability of most other ocular

formulations is about 5% or even less due to

the presence of various ocular hindrances,

nanoformulations prove to be one of the most

effective ocular drug conveyance models

which not only improve the bioavailability of

the medicament but at the same time lessen

the occurrence of adverse events.

Nanoformulations do meet patient

compliance by lessening the frequency of

dose administration in comparison with the

other conventional dosage forms available in

the market. Due to the above-stated benefits

of nano-based formulations over

conventional dosage forms, it had been the

area of major interest for researchers to focus

on.



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Table 1. Preclinical ophthalmic drug conveyance research using dendrimer vehicles.

Dendrimer Drug Indication

Topical Application

PAMAM (G1.5-4.0) Pilocarpine & Tropicarmide Midriasis & Cycloplegia(55).

PAMAM (G1.0-3.0) Acetazolamide Chronic simple (open-angle)

glaucoma(56).

PAMAM (divalent) Sulfonamide Dry eye syndrome(57).

PPI Acetazolamide Chronic simple (open-angle)

glaucoma(58).

PAMAM (G3.0 gel) Timolol & Brimonidine Open angle glaucoma(59).

Intravitreal Injection

PAMAM (G4.0-OH) Fluocinolone Acetonide Retinal

neuroinflammation(60).

PAMAM core micelle S I R agonist Retinal ganglion cell

degeneration(61).

PAMAM (G4.0-OH) Triamcinolone Acetonide Proliferative diabetic

neuropathy(62).

Subconjunctival Injection

PAMAM (G3.5) Carboplatin Murine retinoblastoma(63).

PAMAM (G3.5, 4.5) Dexamethasone Non-infectious posterior

uveitis(64).

PAMAM (G4.0-OH) Dexamethasone Corneal inflammation(65).

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