INTRODUCTION Ocular administration of drug isprimarily associated with the need totreat ophthalmic diseases.Eye is the most easily accessible site fortopical administration of a medication.Ideal ophthalmic drug delivery mustbe able to sustain the drug release andto remain in the vicinity of front of theeye for prolong period of time.
COMPOSITION OF EYE: Water - 98%, Solid -1.8%,Organic element – Protein - 0.67%, sugar - 0.65%, NaCl - 0.66% Other mineral element sodium,potassium and ammonia - 0.79%.
MECHANISM OF OCULAR ABSORPTIONNon- corneal absorption:Penetration across sclera & conjunctiva into intraocular tissues.Non productive: because penetrated drug isabsorbed by general circulation.Corneal absorption:Outer epithelium: rate limiting barrier, with poresize 60a, only access to small ionic and lipophilicmolecules.Trans cellular transport: transport betweencorneal epithelium and stroma.
FACTORS AFFECTINGINTRAOCULAR BIOAVAILABILITY:1. Inflow & outflow of lacrimal fluids.2. Efficient naso-lacrimal drainage.3. Interaction of drug with proteins oflacrimal fluid.4. dilution with tears.5. Corneal barriers.6. Active ion transport at cornea.
BARRIERS AVOIDING DRUG DELIVERY Drug in tear fluid Ocular absorptionCorneal route Conjunctival and scleral route Systemic absorption 50-100% of dose Major route- conjunctiva of eye, nose Minor route- lacrimal drainage system, pharynx, GIT, aqueous humorAqueous humor Ocular tissue ELIMINATION
OPHTHALMIC DOSAGE FORMOphthalmic preparations are sterileproducts essentially free from foreignparticles, suitably compounded andpackaged for instillation in to the eye. The following dosage forms have beendeveloped to ophthalmic drugs. Some are in common use, some aremerely experimental, and others are nolonger used.
5. Paper strips6. Ocuserts7. Hydro gel contact lenses8. Collagen shields9. Ophthalmic rods
ADVANTAGES: They are easily administered by the nurse They are easily administered by thepatient himself. They have the quick absorption andeffect. less visual and systemic side effects. increased shelf life. better patient compliance.
DISADVANTAGES: The very short time the solutionstays at the eye surface. Its poor bioavailability. The instability of the dissolveddrug.The necessity of using preservative.
IDEAL CHARACTERISTICS OF OCDDS:SterilityIsotonicity-e.g.:1.9% boric acid, 0.9% NaClBuffer/pH adjustmentLess drainage tendencyMinimum protein binding
FORMULATION OF OCULAR DRUG DELIVERY SYSTEM:Dosage Advantages DisadvantagesFormsolutions convenience Rapid precorneal elimination, non sustained actionsuspension Patient compliance, best for Drug properties decide drug with slow dissolution performance loss of both solutions and suspended particlesemulsion Prolonged release of drug Blurred vision, patient non from vehicle complianceointment Flexibility in drug choice, Sticking of eyes lids, blurred improved drug stability vision, poor patient compliance
RECENT FORMULATION TRENDS IN OCDDS:1. CONVENTIONAL DELIVERY SYSTEMS:Eye Drops:Drugs which are active at eye or eye surface are widely administered inthe form of Solutions, Emulsion and Suspension.Various properties of eye drops like hydrogen ion concentration,osmolality, viscosity and instilled volume can influence retention of asolution in the eye. Less than 5 % of the dose is absorbed after topical administration intothe eye.The dose is mostly absorbed to the systemic blood circulation via theconjunctival and nasal blood vessels.
Ointment and Gels: Prolongation of drug contact timewith the external ocular surface canbe achieved using ophthalmicointment vehicle but, the majordrawback of this dosage form like,blurring of vision & matting of eyelidscan limit its use.
Ocuserts and Lacrisert: Ocular insert (Ocusert) are sterile preparation thatprolong residence time of drug with a controlled releasemanner and negligible or less affected by nasolacrimaldamage. Inserts are available in different varieties dependingupon their composition and applications. Lacrisert is a sterile rod shaped device for thetreatment of dry eye syndrome and keratitis sicca.They act by imbibing water from the cornea andconjunctiva and form a hydrophilic film which lubricatesthe cornea.
2) VESICULAR SYSTEM: 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.
Niosomes and Discomes:The major limitations of liposomes are chemical instability, oxidativedegradation of phospholipids, cost and purity of natural phospholipids. To avoid this niosomes are developed as they are chemically stable ascompared to liposomes and can entrap both hydrophobic and hydrophilicdrugs.They are non toxic and do not require special handling techniques. Niosomes are nonionic surfactant vesicles that have potential applications inthe delivery of hydrophobic or amphiphilic drugs. Discomes may act as potential drug delivery carriers as they released drug ina sustained manner at the ocular site.Discosomes are giant niosomes (about 20 um size) containing poly-24- oxyethylene cholesteryl ether or otherwise known as Solulan 24. Pharmacosomes: This term is used for pure drug vesicles formed by theamphiphilic drugs.The amphiphilic prodrug is converted to pharmacosomes on dilution with water.
NIOSOME Vs LIPOSOME Non ionic surface active agent phospholipid Hydrophilic drugs in aqueous region encapsulated Lipophilic drugs located in the hydrophobic lamellaNiosomes are microscopic lamellar structures, which are formed on theadmixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol etherclass and cholesterol with subsequent hydration in aqueous media.Structurally, niosomes are similar to liposomes, in that they are also madeup of a bilayer. However, the bilayer in the case of niosomes is made up ofnon-ionic surface active agents rather than phospholipids as seen in the caseof liposomes.
3) CONTROL DELIVERY1. Implants: SYSTEMS:For chronic ocular diseases like cytomegalovirus (CMV) retinitis, implantsare effective drug delivery system. Earlier non biodegradable polymerswere used but they needed surgical procedures for insertion and removal. Presently biodegradable polymers such as Poly Lactic Acid (PLA) aresafe and effective to deliver drugs in the vitreous cavity and show no toxicsigns.2. Iontophoresis:In Iontophoresis direct current drives ions into cells or tissues. Foriontophoresis the ions of importance should be charged molecules of thedrug.Positively charged of drug are driven into the tissues at the anode andvice versa. Ocular iontophoresis delivery is not only fast, painless and safe but itcan also deliver high concentration of the drug to a specific site.3. Dendrimer: Dendrimers can successfully used for different routes of drugadministration and have better water-solubility, bioavailability andbiocompatibility.
4. Microemulsion: Microemulsion is dispersion of water and oil stabilized usingsurfactant and co- surfactant to reduce interfacial tension andusually characterized by small droplet size (100 nm), higherthermodynamic stability and clear appearance. Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are critical parameters which can affectstability of the system.5. Nanosuspensions: Nanosuspensions have emerged as a promising strategy for theefficient delivery of hydrophobic drugs because they enhancednot only the rate and extent of ophthalmic drug absorption butalso the intensity of drug action with significant extendedduration of drug effect. For commercial preparation of nanosuspensions, techniqueslike media milling and high-pressure homogenization have beenused.
6. Microneedle: Microneedle had shown prominent in vitro penetrationinto sclera and rapid dissolution of coating solution afterinsertion while in vivo drug level was found to besignificantly higher than the level observed following topicaldrug administration like pilocarpine.7. Mucoadhesive Polymers: They are basically macromolecular hydrocolloids withplentiful hydrophilic functional groups, such as hydroxyl,carboxyl, amide and sulphate having capability forestablishing electrostatic interactions A mucoadhesive drug formulation for the treatment ofglaucoma was developed using a highly potent beta blockerdrug, levobetaxolol (LB) hydrochloride and partiallyneutralized poly acrylic acid (PAA).
4) PARTICULATES (NANOPARTICLES AND MICROPARTICLES):The maximum size limit for microparticlesfor ophthalmic administration is about5-10 mm above which a scratching feeling inthe eye can result upon ocular instillation. That is why microspheres and nanoparticlesare promising drug carriers for ophthalmicapplication. Nanoparticles are prepared usingbioadhesive polymers to provide sustainedeffect to the entrapped drugs.
1) NON ERODIBLEOCUSERT: INSERTS The Ocusert therapeutic system is a flat, flexible, elliptical devicedesigned to be placed in the inferior cul-de-sac between the scleraand the eyelid and to release Pilocarpine continuously at a steadyrate for 7 days. The device consists of 3 layers…..1. Outer layer - ethylene vinyl acetate copolymer layer.2. Inner Core - Pilocarpine gelled with alginate main polymer.3. A retaining ring - of EVA impregnated with titanium di oxide (diagram) The ocuserts available in two forms.Pilo - 20 :- 20 microgram/hourPilo – 40 :-40 micrograms/hour
ADVANTAGES:Reduced local side effects andtoxicity.Around the clock control of IOP.Improved compliance.DISADVANTAGES:Retention in the eye for the full 7days.Periodical check of unit.Replacement of contaminated unitExpensive.
CONTACT LENSES: These are circular shaped structures. Dyes may be added during polymerization. Drug incorporation depends on whether their structure is hydrophilic or hydrophobic.Drug release depends upon : Amount of drug Soaking time. Drug concentration in soaking solution.ADVANTAGES: No preservation. Size and shapeDISADVANTAGES: Handling and cleaning Expensive
2) ERODIBLE INSERTS:The solid inserts absorb the aqueous tear fluidand gradually erode or disintegrate. The drug isslowly leached from the hydrophilic matrix.they quickly lose their solid integrity and aresqueezed out of the eye with eye movement andblinking.do not have to be removed at the end of theiruse.Three types :1. LACRISERTS2. SODI3. MINIDISC
LACRISERTS:Sterile rod shaped device made up of hydroxylpropyl cellulose without any preservative.For the treatment of dry eye syndromesIt weighs 5 mg and measures 1.27 mm indiameter with a length of 3.5 mm.It is inserted into the inferior fornix.SODI:Soluble ocular drug insertsSmall oval waferSterile thin film of oval shapeWeighs 15-16 mgUse – glaucomaAdvantage – Single application
MINIDISC:Countered disc with a convex front and aconcave back surfaceDiameter – 4 to 5 mmComposition:Silicone based prepolymer-alpha-w-dis(4-methacryloxy)-butyl poly di methylsiloxane. (M2DX)M-Methyl a cryloxy butyl functionalities.D – Di methyl siloxane functionalities.Pilocarpine, chloramphenicol
EVALUATION OF OCDDS:THICKNESS OF THE FILM:Measured by dial caliper at differentpoints and the mean value is calculated.DRUG CONTENT UNIFORMITY:The cast film cut at different places andtested for drug as per monograph.UNIFORMITY OF WEIGHT:Here, three patches are weighed.
PERCENTAGE MOISTURE ABSORPTION:Here ocular films are weighed and placed ina dessicator containing 100 ml of saturatedsolution of aluminium chloride and 79.5%humidity was maintained.After three days the ocular films arereweighed and the percentage moistureabsorbed is calculated using the formula =% moisture absorbed = Final weight –initial weight/ initial weight x 100
IN – VITRO EVALUATION METHODS: BOTTLE METHOD:In this, dosage forms are placed in the bottlecontaining dissolution medium maintained at specifiedtemperature and pH.The bottle is then shaken.A sample of medium is taken out at appropriateintervals and analyzed for the drug content.DIFFUSION METHOD:Drug solution is placed in the donor compartment andbuffer medium is placed in between donor and receptorcompartment.Drug diffused in receptor compartment is measured atvarious time intervals.
MODIFIED ROTATING BASKET METHOD:Dosage form is placed in a basket assembly connected to astirrer.The assembly is lowered into a jacketed beaker containingbuffer medium and temperature 37 degrees Centigrade.Samples are taken at appropriate time intervals andanalyzed for drug content.MODIFIED ROTATING PADDLE APPARATUS:Here, dosage form is placed into a diffusion cell which isplaced in the flask of rotating paddle apparatus.The buffer medium is placed in the flask and paddle isrotated at 50 rpm.The entire unit is maintained at 37 degree C.Aliquots of sample are removed at appropriate time intervalsand analyzed for drug content.
IN- VIVO STUDY:Here, the dosage form is applied to one eye ofanimals and the other eye serves as control.Then the dosage form is removed carefully atregular time interval and are analyzed for drugcontent.The drug remaining is subtracted from theinitial drug content, which will give the amountof the drug absorbed in the eye of animal atparticular time.After one week of washed period, theexperiment was repeated for two time as before.
ACCELERATED STABILITY STUDIES:These are carried out to predict thebreakdown that may occur over prolongedperiods of storage at normal shelf condition.Here, the dosage form is kept at elevatedtemperature or humidity or intensity of light,or oxygen.Then after regular intervals of time sampleis taken and analyzed for drug content.From these results, graphical datatreatment is plotted and shelf life and expirydate are determined.
CONCLUSION:All approaches improve ocular drugbioavailability by increasing ocular drugresidence time, diminish side effects due tosystemic absorption and diminishing thenecessary therapeutic amount of drug fortherapeutic response in anterior chamber.They improve patient compliance byreducing the frequency of dosing.They reduce the dose and thereby reducethe adverse effects of the drug.