IOSR Journal Of Pharmacy
(e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219
Volume 10, Issue 11 Series. I (November 2020), PP. 01-11
www.iosrphr.org
Ocular Drug Delivery System:- A review
Corresponding Author: XXXXX
Received 05 November 2020; Accepted 18 November 2020
Abstract:Eye diseases are commonly encountered in day to day life, which are cured or prevented through the
conventionally used dosage forms like eye drops, ointments. Delivery to the internal parts of the eye still
remains troublesome due to the anatomical and protective structure of the eye. To overcome these problems
various types of dosage forms such as nanoparticles, liposomes and micro emulsions have been developed.
Ocular drug delivery is one of the most challenging tasks faced by Pharmaceutical researchers. Major barriers in
ocular medication are the ability to maintain a therapeutic level of the drug at the site of action for a prolonged
duration. The anatomy, physiology, and biochemistry of the eye is such that it is impervious to foreign
substances, therefore, it is a challenge for the formulator to pass through the protective barriers of the eye
without causing any permanent tissue damage. The introduction of new sensitive diagnostic techniques and
therapeutic agents necessitates the development of a successful and advanced ocular drug delivery system.
Current momentum in the invention of new drug delivery systems hold a promise toward much improved
therapies for the treatment of vision, threatening disorders.
I. INTRODUCTION:Topical application of drugs to the eye is the well established route of administration for the treatment
of various eye diseases like dryness, conjunctiva, eye flu etc. For illness of the eye, topical administration is
usually ideal over systemic administration, before reaching the anatomical barrier of the cornea, any drug
molecule administered by the ocular route firstly crosses the precorneal barriers. These are the first barriers that
slow the penetration of drug into the eye and consist of the tear film and the conjunctiva. The protective
mechanisms of the eye such as Blinking, baseline and reflex lacrimation, and drainage decrease the
bioavailability of drug and also help to remove rapidly foreign substances like the dust particles bacteria,
including drugs, from the surface of the eye. There are most commonly available ophthalmic preparations such
as drops and ointments about 70% of the eye dosage formulations in market. But these preparations when
instilled into eye they are rapidly drained away from the ocular surface due to blinking tear flow and lachrymal
nasal drainage of the eye1. With conventional ophthalmic solution normal dropper used which delivers about
50-75μl per drop and portion of these drops rapidly drain until the eye is back to normal resident volume of 7μl.
Due to this drug loss in front of the eye, very small drug is available to enter the cornea and inner tissue of the
eye. Actual corneal permeability of the drug is relatively low and very small corneal contact time (about 1-2
min) in humans for instilled solution usually less than 10%. Therefore only small amount of drug actually
penetrates the cornea and reaches intraocular tissue. Due to these limitations, newer pharmaceutical ophthalmic
formulation such as in-situ gel, nanoparticle, liposome, nanosuspension, microemulsion, iontophoresis and
ocular inserts have been developed in last three decades increase the bioavailability of the drug as a sustained
and controlled manner. An ideal ophthalmic drug delivery must be able to release the drug in sustained manner
and to remain in the area of front of the eye for prolong period of time. As a result it is necessary to optimize
ophthalmic drug delivery; the best way towards do so is by adding of polymers of various grades, development
of colloidal suspension or using erodible or non erodible insert, development of viscous gel to prolong the
precorneal drug retention Micro particle suspension or polymeric solution can be bio adhesive systems
ANATOMY & PHYSIOLOGY OF EYE:The eye consists of transparent cornea, lens, and vitreous body without blood vessels. The oxygen and
nutrients are transported to this non-vascular tissue by aqueous humor which is having high oxygen and same
osmotic pressure as blood. The aqueous humor in human is having volume of 300 μl that fills the anterior
chamber of the eye which is in front of lens. The cornea is covered by a thin epithelial layer continuous with the
conjunctiva at the cornea-sclerotic junction. The main bulk of cornea is formed of crisscrossing layers of
collagen and is bounded by elastic lamina on both front and back. Its posterior surface is covered by a layer of
endothelium. The cornea is richly supplied with free nerve endings. The transparent cornea is continued
posteriorly into the opaque white sclera which consists of tough fibrous tissue. Both cornea and sclera withstand
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Ocular Drug Delivery System:- A review
the intra ocular tension constantly maintained in the eye. The eye is constantly cleansed and lubricated by the
lacrimal apparatus which consists of four structures.
1. lacrimal glands
2. lacrimal canals
3. lacrimal sac
4. nasolacrimal duct.
The lacrimal fluid secreted by lacrimal glands is emptied on the surface of the conjunctiva of the upper
eye lid at a turnover rate of 16% per min. It washes over the eye ball and is swept up by the blinking action of
eye lids. Muscles associated with the blinking reflux compress the lacrimal sac, when these muscles relax; the
sac expands, pulling the lacrimal fluid from the edges of the eye lids along the lacrimal canals, into the lacrimal
sacs. The lacrimal fluid volume in humans is 7 μl and is an isotonic aqueous solution of bicarbonate and sodium
chloride of pH 7.4. It serves to dilute irritants or to wash the foreign bodies out of the conjuctival sac. It
contains lysozyme, whose bactericidal activity reduces the bacterial count in the conjuctival sac. The
physiological barriers to diffusion and productive absorption of topically applied drug exist in the precorneal
and corneal spaces. The precorneal constraints that are responsible for poor bioavailability of conventional
ophthalmic dosage forms are solution drainage, lacrimation, tear dilution, tear turn over and conjuctival
absorption.
Barriers to Restrict Intraocular Drug Transport:Tear- One of the precorneal barriers is tear film which reduces the effective concentration of the
administrated drugs due to dilution by the tear turnover (approximately 1 μL/min), accelerated clearance, and
binding of the drug molecule to the tear proteins.In addition the dosing volume of instillation is usually 20–50
μL whereas the size of cul-de-sac is only 7–10 μL. The excess volume may spill out on the cheek or exit through
the nasolacrimal duct.[6] Cornea - The cornea consists of three layers; epithelium, stroma and endothelium, and
a mechanical barrier to inhibit transport of exogenous substances into the eye. Each layer possesses a different
polarity and a rate-limiting structure for drug permeation. The corneal epithelium is of a lipophilic nature, and
tight junctions among cells are formed to restrict paracellular drug permeation from the tear film. The stroma is
composed of an extracellular matrix of a lamellar arrangement of collagen fibrils. The highly hydrated structure
of the stroma acts as a barrier to permeation of lipophilic drug molecules. Corneal endothelium is the innermost
monolayer of hexagonal-shaped cells, and acts as a separating barrier between the stroma and aqueous humor.
The endothelial junctions are leaky and facilitate the passage of macromolecules between the aqueous humor
and stroma
Conjunctiva- of the eyelids and globe is a thin and transparent membrane, which is involved in the formation
and maintenance of the tear film. In addition, conjunctiva or episclera has a rich supply of capillaries and
lymphatics therefore, administrated drugs in the conjunctival or episcleral space may be cleared through blood
and lymph. The conjunctival blood vessels do not form a tight junction barrier, which means drug molecules
can enter into the blood circulation by pinocytosis and/or convective transport through paracellular pores in the
vascular endothelial layer. The conjunctival lymphatics act as an efflux system for the efficient elimination from
the conjunctival space. Recently, it has been reported that at least 10% of a small molecular weight hydrophilic
model compound (sodium fluorescein), administered in the subconjunctival space, and is eliminated via the
lymphatics within the first hour in rat eyes. Therefore, drugs transported by lymphatics in conjunction with the
elimination by blood circulation can contribute to systemic exposure, since the interstitial fluid is returned to the
systemic circulation after filtration through lymph nodes.
Sclera - The sclera mainly consists of collagen fibers and proteoglycans embedded in an extracellular matrix.
Scleral permeability has been shown to have a strong dependence on the molecular radius; Scleral permeability
decreases roughly exponentially with molecular radius additionally, the posterior sclera is composed of a looser
weave of collagen fibers than the anterior sclera and the human sclera is relatively thick near the limbus (0.53 ±
0.14 mm), thin at the equator (0.39 ± 0.17 mm).[7Choroid/Bruch‟s Membrane - Choroid is one of the most
highly vascularised tissues he body to supply the blood to the retina. Its blood flow per unit tissue weight is tenfold higher than in the brain. In addition the choroidal capillary endothelial cells are fenestrated and, in humans,
are relatively large in diameter (20–40 μm). Retina -The drugs in the vitreous are eliminated by two main routes
from anterior and posterior segments. All drugs are able to eliminate via the anterior route. This means drugs
can diffuse across the vitreous to the posterior chamber and, thereafter, eliminate via aqueous turnover and veal
blood flow. Elimination via the posterior route takes place by permeation across the retina. One of the barriers
restricting drug penetration from the vitreous to the retina is the internal limiting membrane (ILM). The ILM
separates the retina and the vitreous, and is composed of 10 distinct extracellular matrix proteins. Although a
previous study using primates has suggested that molecules exceeding 100 kDa cannot cross the retinal layers
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Ocular Drug Delivery System:- A review
into the subretinal space,[14] it has been confirmed by immunohistochemical analysis, a full-length, humanized,
anti- vascular endothelial growth factor (VEGF) monoclonal antibody, composed of 214 amino acids with a
molecular weight of 149 kDa, injected into the vitreous cavity, can penetrate through the sensory retina into
retinal pigment epitheliums (RPE), subretinal and choroidal space, in monkey and rabbit. In addition,
nanometer-sized particles whose mean diameter is below 200 nm can penetrate across the sensory retina into
RPE after intravitreal injection in rabbit. In intact retina, theoretically, the drugs in the subretinal fluid could
either be absorbed by the sensory retinal blood vessels or transported across the RPE, where it may be absorbed
into the choroidal vessels or pass through the sclera. Drug transport across the RPE takes place both by
transcellular and paracellular routes. The driving forces of outward transport of molecules from the subretinal
spaces are hydrostatic and osmotic, and small molecules might transport through the paracellular inter- RPE
cellular clefts and by active transport through.
TYPES OF OCULAR DRUG DELIVERY SYSTEAM
Type-I are divided into different types
1.
Drug Delivery Systems to Anterior Segment of the Eye – e.g.
Eye-Drops
Contact Lens
Cul-de sac Inserts
Punctal Plugs
2.
Drug Delivery Systems to Posterior Segment of the Eye
Intravitreal Implants ( e.g.-Duraser Technology System, Novadu Technology, I-ratio TA, NT-501 )
Injectable Particulate Systems (RETAAC, Cortiject, Visudyne) Eye-Drops
3.
Physical Devices
Iontophoresis
Micro-Electromechanical Intraocular Drug Delivery Device
Type-II are divided into different type
1.Conventional delivery systems
Eye Drops
Ointment and Gels
Ocuserts and Lacrisert
2.
Vesicular system
Liposomes
Niosomes and Discomes
Pharmacosomes
3.
Control delivery systems
Implants
Iontophoresis
Dendrimer
Cyclodextrin
Contact lenses
Collagen Shield
Microemulsion
Nanosuspensions
Microneedle
Prodrugs
Penetration Enhancers
Mucoadhesive Polymers
Phase Transition Systems/Insitu gel system
4.
5.
Particulates (nanoparticles and microparticles)
Advanced delivery system
Cell Encapsulation
Gene Therapy
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Ocular Drug Delivery System:- A review
Stem cell Therapy
Protein and Peptide therapy
Scleral Plug therapy
siRNA therapy
Oligonucliotide therapy
Aptamer
Different ocular drug delivery system.
Eye Drops: Drugs which are active at eye or eye surface are widely administered in the form of Solutions,
Emulsion and Suspension. Generally eye drops are used only for anterior segment disorders as adequate drug
concentrations are not reached in the posterior tissues using this drugdelivery method. Various properties of eye
drops like hydrogen ion concentration, osmolality, viscosity and instilled volume can influence retention of a
solution in the eye. Less than 5 Percent of the dose is absorbed after topical administration into the eye. The
dose is mostly absorbed to the systemic blood circulation via the conjunctival and nasal blood vessels. Ocular
absorption is limited by the corneal epithelium, and it is only moderately increased by prolonged ocular contact.
The reported maximal attainable ocular absorption is only about 10 Percent of the dose. When eye drops is
administered in the inferior fornix of the conjunctiva, very small amount of the dose reaches to the intraocular
tissues and major fraction of the administered drug get washed away with the lachrymal fluid or absorbed
systemically in the nasolacrimal duct and pharyngeal sites.
Ointment and Gels:Prolongation of drug contact time with the external ocular surface can be achieved using ophthalmic
ointment vehicle but, the major drawback of this dosage form like, blurring of vision and matting of eyelids can
limits its use. Pilopine HS gel containing pilocarpine was used to provide sustain action over a period of 24
hours. A number of workers reported that ointments and gels vehicles can prolong the corneal contact time of
many drugs administered by topical ocular route, thus prolonging duration of action and enhancing ocular
bioavailability of drugs.
Ocuserts and Lacrisert: Ocular insert (Ocusert) are sterile preparation that prolong residence time of drug with a controlled
release manner and negligible or less affected by nasolacrimal damage.9 Inserts are available in different
varieties depending upon their composition and applications. Lacrisert is a sterile rod shaped device for the
treatment of dry eye syndrome and keratitis sicca and was introduced by Merck, Sharp and Dohme in 1981.
They act by imbibing water from the cornea and conjunctiva and form a hydrophilic film which lubricates the
cornea.
Liposomes: Liposomes are biocompatible and biodegradable lipid vesicles made up of natural lipids and about 25–
10 000 nm in diameter. They are having an intimate contact with the corneal and conjunctival surfaces which is
desirable for drugs that are poorly absorbed, the drugs with low partition coefficient, poor solubility or those
with medium to high molecular weights and thus increases the probability of ocular drug absorption. The
corneal epithelium is thinly coated with negatively charged mucin to which the positive charged surface of the
liposomes may bind.
Niosomes and Discomes: The major limitations of liposomes are chemical instability, oxidative degradation of phospholipids,
cost and purity of natural phospholipids. To avoid this niosomes are developed as they are chemically stable as
compared to liposomes and can entrap both hydrophobic and hydrophilic drugs. They are non toxic and do not
require special handling techniques. Niosomes are nonionic surfactant vesicles that have potential applications
in the delivery of hydrophobic or amphiphilic drugs. Vyas and co workers reported that there was about 2.49
times increase in the ocular bioavailability of timolol maleate encapsulated in niosome as compared to timolol
maleate solution. Non-ionic surface active agents based discoidal vesicles known as (discomes) loaded with
timolol maleate were formulated and characterized for their in vivo parameters. In vivo studies showed that
discomes released the contents in a biphasic profile if the drug was loaded using a pH gradient technique.
Discomes may act as potential drug delivery carriers as they released drug in a sustained manner at the ocular
site.harmacosomes: This term is used for pure drug vesicles formed by the amphiphilic drugs. Any drug possessing a free
carboxyl group or an active hydrogen atom can be esterified (with or without a spacer group) to the hydroxyl
group of a lipid molecule, thus generating an amphiphilic prodrug. The amphiphilic prodrug is converted to
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Ocular Drug Delivery System:- A review
pharmacosomes on dilution with water. The pharmacosomes show greater shelf stability, facilitated transport
across the cornea, and a controlled release profile.
Implants: For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implants are effective drug delivery
system. Earlier non biodegradable polymers were used but they needed surgical procedures for insertion and
removal. Presently biodegradable polymers such as Poly Lactic Acid (PLA) are safe and effective to deliver
drugs in the vitreous cavity and show no toxic signs. Intravitreal implants of fluocinolone acetonide were
developed for the treatment of posterior segment and reported to control the ocular inflammation of retina.
Methods of Preparation of Nanoparticles:• Polymerization in a Continuous Aqueous Phase
In this process monomers are dissolved in the aqueous phase and within emulsifier micelles. Additional
monomers may be present as monomer droplets stabilized by emulsifier molecules. Initiation of polymerization
takes place in the aqueous phase when the dissolved monomer molecules are hit by a starter molecule or by
high-energy radiation. Polymerization and chain growth is maintained by further monomer molecules, which
originate from the aqueous phase, the emulsifier micelles, or the monomer droplets. The monomer droplets and
the emulsifier micelles therefore act mainly as reservoirs for the monomers or for the emulsifier, which later
stabilize the polymer particles after phase separation and prevent coagulation. Also, to prevent excessively rapid
polymerization and promote the formation of nanoparticles, emulsion polymerization is carried out at an acidic
pH (pH is 1–2). The drugs may be added before, during, or after polymerization and formation of particles.
• Interfacial Polymerization
Interfacial polymerization of the polyalkylcyanoacrylate polymers allows the formation of nanocapsules with a
shell-like wall65. This carrier type can encapsulate drugs with lipophilic character, and the rate of encapsulation
is generally related to the solubility of the drug in the oily compartment. The technique involves dissolving the
polyalkylcyanoacrylate (PACA) monomers and lipophilic drug in an ethanolic solution or oil and slowly
injecting this mixture into a well- stirred solution of 0.5% poloxamer 338 in water at pH 6 (may contain
nonionic surfactant). At the oil/water interface, nanoparticles with a shell-like wall are formed spontaneously by
hydroxyl ion–induced polymerization, and the polymeric colloidal suspension occurs immediately.
•
Polymerization by Denaturation or Desolvation of Natural Proteins
Macromol:-ecules such as albumin or gelatin can form nanoparticles through the desolvation and
denaturation processes. Desolvation of macromolecules in aqueous solution can be induced by changes in pH,
charge, or the addition of desolvating agents such as ethanol. The desolvation process induces the swollen
molecules to coil tightly. At this point, the tightly coiled macromolecules can be fixed and hardened by
crosslinking with glutaraldehyde to form nanoparticles rather than nanocapsules. Nanoparticles are then purified
by gel filtration. The denaturation process involves preparing an emulsion from an aqueous phase containing the
drug, magnetite particles, and the macromolecule and cottonseed oil. Polymerization is carried out by heat
denaturation at temperatures above 120 C or by chemical crosslinking. Nanoparticles are precipitated out and
washed with ether (or in the case of gelatin, acetone) and stored in the dry form.
•
Solvent Evaporation Method
Gurny et al. were the first to use this process for the production of polylactic acid nanoparticles
containing testosterone. In this method, the polymer of interest is dissolved in an organic solvent, suspended in a
suitable water or oil medium, after which the solvent is extracted from the droplets. The particles obtained after
solvent evaporation are recovered by filtration, centrifugation, or lyophilization. In general, the diameter of the
particles depends on the size of the microdroplets that are formed in the emulsion before evaporation of the
solvent. Chiang et al. used the solvent evaporation technique with an oil-in-oil emulsion to prepare polylactideco- glycolide microspheres of 5-fluorouracil for ocular delivery. Microspheres containing cyclosporin A have
been prepared with a mixture of 50 : 50 polylactic and polyglycolic acid polymers using the solvent evaporation
process. The polymer and drug mixture was dissolved in a mixture of chloroform and acetone, emulsified in an
aqueous solution of polyvinyl alcohol, and stirred for 24 hours to evaporate the organic solvent and yield the
microparticle dispersion.
•
Ionic Gelation Technique
De Campos et al. developed chitosan nanoparticles using the ionic gelation technique. Nanoparticles
were obtained upon the addition of sodium tripolyphosphate aqueous solution to an aqueous polymer solution of
chitosan under magnetic stirring at room temperature. The formation of nanoparticles was a result of the
interaction between the negative groups of the tripolyphosphate and the positively charged amino groups of
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Ocular Drug Delivery System:- A review
chitosan. In this technique, drug in an acetonitrile-water mixture can be incorporated either into chitosan
solution or the tripolyphosphate solution.
•
Nano-precipitation
Fessi et al. developed nanoparticles using this method. In this technique a polymer and a specified
quantity of drug is dissolved in acetonitrile. The organic phase is then added dropwise to the aqueous phase and
stirred magnetically at room temperature until complete evaporation of the organic phase takes place. Drug-free
nanoparticles may be prepared using the same procedure by simply omitting the drug.
• Spray-Drying
In this technique, microparticles are prepared by dissolving the polymer of interest in an organic solvent. The
drug is added to this solution and spray-dried using a spray-dryer. The process parameters and spray nozzle size
are set up as required. The spray-dried product is collected by a cyclone separator.
•
Polymers used in the Preparation of Nanoparticles
A successful nanoparticulate system may be one that has a high loading capacity, thus reducing the
quantity of carrier required for administration. The drug can be either adsorbed onto the surface of performed
particles or incorporated into the nanospheres during the polymerization process. Concerning the loading
capacity of nanoparticles, it has been found that both the nature and quantities of the monomer used influences
the absorption capacity of the carrier. Generally, the longer the chain length, the higher is the affinity of the drug
to the polymer.
Several types of polymeric nanoparticles are used in ophthalmic drug Delivery Polymethylmethacrylate
(PMMA), acrylic copolymer Nanoparticles, polystyrene, polyvinyl pyridine, Cellulose acetate phthalate, PACA,
poly-e-caprolactone (PECL) nanocapsules, etc.[34]
•
Gene Therapy: - Along with tissue engineering, gene therapy approaches stand on the front line of
advanced biomedical research to treat blindness arising from corneal diseases, which are second only to cataract
as the leading cause of vision loss. Several kinds of viruses including adenovirus, retrovirus, adeno-associated
virus, and herpes simplex virus, have been manipulated for use in gene transfer and gene therapy applications.
Topical delivery to the eye is the most expedient way of ocular gene delivery. However, the challenge of
obtaining substantial gene expression following topical administration has led to the prevalence of invasive
ocular administration. Retroviral vectors have been widely used due to their high efficacy; however, they do not
have the ability to transduce nondividing cells, leads to restrict their clinical use. The advanced delivery systems
that prolong the contact time of the vector with the surface of the eye may enhance transgene expression,
thereby facilitate non-invasive administration.
•
Stem cell Therapy: Emerging cell therapies for the restoration of sight have focused on two areas of the eye that are
critical for visual function, the cornea and the retina. Current strategy for management of ocular conditions
consists of eliminating the injurious agent or attempting to minimize its effects. The most successful ocular
application has been the use of limbal stem cells, transplanted from a source other than the patient for the
renewal of corneal epithelium. The sources of limbal cells include donors, autografts, cadaver eyes, and
(recently) cells grown in culture. Stem-cell Therapy has demonstrated great success for certain maladies of the
anterior segment.
•
Protein and Peptide therapy: Delivery of therapeutic proteins/ peptides has received a great attention over the last few years. The
intravitreous injection of ranibizumab is one such example. The designing of optimized methods for the
sustained delivery of proteins and to predict the clinical effects of new compounds to be administered in the eye,
the basic knowledge of Protein and Peptide is required. However; several limitations such as membrane
permeability, large size, metabolism and solubility restrict their efficient delivery. A number of approaches have
been used to overcome these limitations. Poor membrane permeability of hydrophilic peptides may be improved
by structurally modifying the compound, thus increasing their membrane permeability. Ocular route is not
preferred route for systemic delivery of such large molecules. Immunoglobulin G has been effectively delivered
to retina by trans Scleral route with insignificant systemic absorption.
•
Scleral Plug therapy: Scleral plug can be implanted using a simple procedure at the pars plane region of eye, made of
biodegradable polymers and drugs, and it gradually releases effective doses of drugs for several months upon
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Ocular Drug Delivery System:- A review
biodegradation. The release profiles vary with the kind of polymers used, their molecular weights, and the
amount of drug in the plug. The plugs are effective for treating vitreoretinal diseases such as proliferative
vitreoretinopathy, cytomegalovirus retinitis responds to repeated intravitreal injections and for vitreoretinal
disorders that require vasectomy.
SiRNA therapy: For various angiogenesis-related diseases, the use of siRNA is considered as a promising approach.
Feasibility of using siRNA for treatment of choroidal neovascularization has been demonstrated using siRNA
directed against vascular endothelial growth factor (VEGF) or VEGF receptor 1 (VEGFR1), and both of these
approaches are being tested in clinical trials. Topical delivery of siRNAs directed against VEGF or its receptors
has also been shown to suppress corneal neovascularisation. siRNA has become a valuable tool to explore the
potential role of various genes in ocular disease processes. It appears that siRNAs may be valuable in the
pathogenesis and development of new treatments for several ocular diseases, based on in vivo and in vitro
studies. However, its use in vivo remains problematic, largely due to unresolved difficulties in targeting delivery
of the siRNA to the tumor cells. Viral gene delivery is very efficient however it currently lacks adequate
selectivity for the target cell type. New encapsulated siRNA have been developed using liposomes, coupledantibodies or others polymer vesicles. Therapeutic approach using siRNA provides a major new class of drugs
that will shed light the gap in modern medicine.
•
Oligonucliotide therapy: Oligonucliotide (ON) therapy is based on the principle of blocking the synthesis of cellular proteins by
interfering with either the transcription of DNA to mRNA or the translation of mRNA to determine to contribute
to the efficacy of antisense ON. One primary consideration is the length of the ON species. Lengths of 17– 25
bases have been shown to be optimal, as longer ONs have the potential to partially hybridize with nontarget
RNA species Biological stability is the major barrier to consider when delivering both DNA and RNA
oligonucleotides to cells. Protection from nuclease action has been achieved by modification of phosphate
backbones, sugar moiety, and bases.
Aptamer: Aptamer are oligonucleotides legends that are used for high-affinity binding to molecular targets. They
are isolated from complex libraries of synthetic nucleic acid by an Iterative process of adsorption, recovery, and
reamplification. They bind with the target molecules at a very low level with high specificity. One of the earliest
aptamers studied structurally was the 15 mer DNA aptamer against thrombin, d (GGTTGGTGTGGTTGG).
Pegaptanib sodium is an RNA aptamer directed against VEGFb165, where VEGF isoform primarily responsible
for pathological ocular neovascularization and vascular permeability.
•
Ribozymes therapy: RNA enzymes or ribozymes are a relatively new class of single stranded RNA molecules capable of
assuming three dimensional conformations and exhibiting catalytic activity that induces site-specific cleavage,
ligation, and polymerization of nucleotides involving RNA or DNA. They function by binding to the target
RNA moiety through Watson-Crick base pairing and inactivate it by cleaving the phosphodiester backbone at a
specific cutting site. A disease named, Autosomal dominated retinitis pigmento sum (ADRP) is caused by
mutations in genes that produce mutated proteins, leading to the apoptotic death of photoreceptor cells.
CONVENTIONAL OCULAR FORMULATIONS ADVANTAGE AND DISADVANTAG
DOSAGE FORM ADVANTAGE DISADVANTAGE
Solution •
Convenience
•
Loss of drug drainage
•
Nonsustained action
Suspension
•
Patient compliance
•
Best for drug with slow dissolution •
Drug properties decide performance
Emulsion
•
Prolonged release of drug from vehicle
•
Patient non compliance
•
Blurred vision
•
Possible oil entrapment
Ointment
•
Flexibility of drug choice
•
Improved drug stability
•
Increased tissue contact time
•
Inhibition of dilution by tears.
•
Sticking of eyelids
•
Poor patient compliance
•
Blurr vision
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Ocular Drug Delivery System:- A review
•
No true sustained effect.
Gels
•
Comfortable
•
Less blurred vision than ointment •
No rate control on diffusion
•
Mattered eyelids after use
Erodible inserts •
Sophisticated and effective delivery system
•
Flexibility in drug type and dissolution rate
•
Need only be introduced into eye and not removed •
Patient discomfort
•
Requires patient insertion
•
Movement of system around eye can cause abrasion
Non-erodible insert
•
Controlled rate of release
•
Prolonged delivery
•
Flexibility for type of drug selected •
Patient discomfort
•
Irritation to eye
•
Patient placement and removal
•
Tissue fibrosis
OCULAR INSERTS AS AN OCULAR SUSTAINED RELEASE DRUG DELIVERY SYSTEM
• The main objective of the ophthalmic inserts is to increase the contact time between the preparation and the
conjunctival tissue, to ensure a sustained release suited for topical or systemic treatment.The advantages of
ocular inserts over the traditional ophthalmic preparation can be summarized as follows:
Increased ocular residence, hence, prolonged drug activity and higher bioavailability with respect to
standard vehicles.
• Release of drugs at a slow, constant rate.
• Accurate dosing (insert contains a precise dose, which is fully retained at the administration site).
• Reduction of systemic absorption.
• Better patient compliance, due to reduced frequency of administration and less incidence of visual and
systemic side-effects.
• Possibility of targeting internal ocular tissues through non-corneal (conjunctival scleral) routes.
• Increased shelf life with respect to aqueous solutions.
• Exclusion of preservatives, thus reducing the risk of sensitivity reactions.
• Incorporation of various novel chemical / technological approaches, such as pro-drugs, mucoadhesives,
permeation enhancers, micro particulates, salts acting as a buffer.
All of the benefits listed above cannot be present in a single, ideal device. Each type of insert is a compromise
between the desirable properties inherent to solid dosage forms and negative constraints possessed by the
structure and components of the insert, fabrication costs, and physical / physiological constraints of the
application site. It also bears some disadvantages, which are as follows:
•disadvantage of ocular inserts resides in their „solidity‟, that is, they are felt by the (often oversensitive) patients
as an extraneous body in the eye. This may constitute a difficult physical and psychological barrier to patient
compliance.
•
Their movement around the eye, in rare instances, the simple removal is made more difficult by
unwanted migration of the insert to the upper fornix.
•
The occasional unintentional loss during sleep or while rubbing the eyes.
•
Their interference with vision.
•
Difficulty in placement of the ocular inserts (and removal, for insoluble types).
CLASSIFICATION OF OCULAR INSERT
The foreign-body sensation leads to discomfort, which causes poor-patient compliance, excessive
lachrymation that accompanies irritation, dilutes the drug, and reduces its concentration.[1 properly designed
ocular insert will minimize the sensation caused by its insertion.
Classification of ocular inserts
• Ease of handling and insertion.
• Lack of expulsion while wearing it.
• Reproducibility of release kinetics (Zero-order drug delivery).
• Applicable to variety of drugs.
• No interference with vision and oxygen permeability.
• Sterility.
• Stability.
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Ocular Drug Delivery System:- A review
•
Ease of manufacturing.
Insoluble Ophthalmic Inserts Diffusion inserts
The diffusion systems are composed of a drug reservoir enclosed in a specially designed semipermeable or microporous membrane, which allows the drug to diffuse from the reservoir The drug release from
such a system is controlled by the lachrymal fluid, which permeates through the membrane. A sufficient internal
pressure is achieved to drive the drug out from the reservoir. The drug delivery rate is controlled by diffusion
through the membrane.
Osmotic inserts:The osmotic inserts are generally divided into two types, in the first case the central part of the insert is
surrounded by a peripheral part.[19] The centrapart.The composed of a single reservoir, which is composed of
the drug with or without an osmotic solute dispersed through a polymeric matrix, so that the drug is surrounded
by the polymer as discrete small deposits. IN the second, drug and the osmotic solutes are placed in two separate
compartments, the drug reservoir is surrounded by an elastic impermeable membrane and the osmotic solute
reservoir surrounded by a semi-permeable membrane. The peripheral part of these osmotic inserts are comprised
of a film covering made of an insoluble semi-permeable polymer.[21] The tear fluid dies into the peripheral
deposits through the semi-permeable polymeric membrane, wets them, and induces their dissolution. The
solubilized deposits create a hydrostatic pressure against the polymer matrix, and cause its rupture in the form of
apertures. Rge drug is then released through these apertures from the deposits near the surface of the device.[22]
The release of drug through the osmotic insert follows the zero-order drug release profile.
Soft contact lenses:These structure are m:-adeup of a covalently cross-linked hydrophilic or hydrophobic polymer that
forms a three-dimensional matrix capable of retaining water, aqueous solution or solid components .When a
hydrophilic co.When is soaked in a drug solution, it absorbs the drug, but does not deliver the drug as precisely
as that provided by other non-soluble ophthalmic systems. The drug release from the system is generally very
rapid at the beginning and then declines exponentially with time. The release rate can be decreased by adding
the drug homogeneously during the manufacture or by adding a hydrophobic component.Contact lenses have
prospects as ocular drug delivery systems.
Soluble OphthalmicInserts:Soluble inserts correspond to the oldest class of ocular inserts, which offer the advantage of being wholly
soluble, so they need not be removed from the site of application, thus, limiting the interventions to insertion
only.They are further category:
Based on natural polymers, for example, collagen. Based on synthetic or semi-synthetic polymers.
The therapeutic agent is absorbed by soaking the insert in a solution containing the drug, and drying and
rehydrating it before use in the eye. The amount of drug contained will depend upon the capacity of the binding
agent, concentration of the drug solution into which the insert is soaked, and the duration of soaking The soluble
ophthalmic inserts are easily processed by
conventional methods – slow erating extrusion, compression or injection molding. The release of the drug takes
place when tears penetrate into the insert. This induces drug release by diffusion and forms a layer of gel around
the core of the insert. This gelification causes further release of the drug, but it is still controlled by diffusion.
The release rate, J, is derived f
rom Fick's law, which yields the following expression.
J= Adkcs/ L
A – do not Surface area of membrane k – Diffusion coefficient of the drug
L – Membrane thickness
CS – Drug solubility in water
d – Diffusion coefficient of the Ocuserts membrane
As all the terms on the right hand side of the above equation are constant, the release rate of the device is also
constant.
Bioerodible Ophthalmic Inserts
9
Ocular Drug Delivery System:- A review
The bioerodible inserts are composed of homogeneous dispersion of a drug which can be included in or not
included in the hydrophobic coat made of bioerodible polymers, which is impermeable to the drug.
MECHANISM OF DRUG RELEASE FROM OCULAR INSERT
Diffusion
In this mechanism, the drug is released continuously at a controlled rate through the membrane into the
tear fluid. If the insert is formed of a solid non-erodible body having pores and drug is in a dispersed form, the
drug release takes place via diffusion through the pores. Controlled release of the drug can be maintained by a
gradual dissolution of the solid dispersed drug in the matrix, as a result of the inward diffusion of aqueous
solutions. In a soluble device, true dissolution occurs mainly through polymer swelling. In swelling-controlled
devices, the active agent is homogeneously dispersed in a glassy polymer. As glassy polymers are essentially
drug- impermeable, no diffusion occurs through the dry matrix. When the insert is placed in the eye, water from
the tear fluid begins to penetrate the matrix, swelling occurs, and consequently polymer chain relaxation occurs
and drug diffusion takes place. The dissolution of the matrix, followed by the swelling process depends on the
polymer structure. A linear amorphous polymer dissolves at a faster rate than a cross-linked or partially
crystalline polymer.
Osmosis
In the Osmosis mechanism, the insert is made of a transverse impermeable elastic membrane, which
divides the interior of the insert into two compartments, first and second; the first compartment is surrounded by
a semi-permeable membrane and the impermeable elastic membrane, and the second compartment is surrounded
by an impermeable material and the elastic membrane. There is a drug release orifice in the impermeable
membrane of the insert. The first compartment contains a solute that cannot pass through the semi-permeable
membrane and the second compartment provides a reservoir for the drug, which is in liquid or gel form. When
the insert is placed in the aqueous environment of the eye, water diffuses in the first compartment, which
stretches the elastic membrane to expand the first compartment and contract the second compartment so that the
drug is forced to come out through the drug release orifices
Bioerosion:In the bioerosion mechanism, the insert is comprised of a matrix of bioerodible material in which the
drug is dispersed. Contact of the insert with the tear fluid results in controlled sustained release of the drug by
bioerosion of the matrix. The drug is dispersed uniformly throughout the matrix, but it is believed that a more
controlled release is obtained if the drug is superficially concentrated in the matrix. In truly erodible or E-type
devices, the drug release is controlled by a chemical or enzymatic hydrolytic reaction that leads to polymer
solubilization, or degrades to smaller, water-soluble molecules. These polymers may undergo bulk or surface
hydrolysis, which displays zero-order release kinetics; provided the devices maintain a constant surface
geometry and the drug is poorly water-soluble.
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