Hejal Parekh's presentation on ocular drug delivery system

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OCULAR DRUG DELIVERY SYSTEM Presented by Hejal B. parekh M . Pharm II (2011-12), Roll.No.-18 NDDS-I Department of pharmaceutics C.U. Shah College Of Pharmacy & Research, Wadhwan 1

We shall discuss:: 

We shall discuss: Introduction Ocular disorders Anatomy of eye Mechanism of ocular absorption Barriers to intraocular drug delivery Routes of ocular drug delivery General safety consideration Evaluation Research article Classification Questions GTU Questions Refernces 2

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INTRODUCTION 1-7 : The ocular drug delivery systems is the specialized dosage forms designed to be instilled onto the topical, intraocular or periocular to the eye or used in conjunction with an ophthalmic device. Conventional topical therapeutic dosage form includes : Solutions, Suspensions, Ointments. Novel ocular drug delivery systems includes: Microemulsions, Nanoparticles, Liposomes, Niosomes, Nanosuspensions, Dendrimers, Implants and Hydrogels. The most commonly employed ophthalmic dosage forms are solutions, suspensions, and ointments. But these preparations when in­stilled into the eye are rapidly drained away from the ocular cavity due to tear flow and lacrimal drainage. To increase ocular bioavailability and retention time on the ocular surface, numerous ophthalmic vehicles such as viscous solutions, suspensions, emulsions, ointments, aqueous gels, and polymeric inserts, have been investigated. 3

Ideal ophthalmic delivery system8: : 

Ideal ophthalmic delivery system 8 : Following characteristics are required to optimize ocular drug delivery system: Good corneal penetration. Prolong contact time with corneal tissue. Simplicity of instillation for the patient. Non irritative and comfortable form. Appropriate rheological properties. 4

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ADVANTAGES OF OCULAR DRUG DELIVERY SYSTEM 9-11 Increased accurate dosing . To overcome the side effects of pulsed dosing produced by conventional systems. 2 . To provide sustained and controlled drug delivery. 3 . To increase the ocular bioavailability of drug by increasing the corneal contact time . This can be achieved by effective adherence to corneal surface. 4 . To provide targeting within the ocular globe so as to prevent the loss to other ocular tissues. 5 . To circumvent the protective barriers like drainage, lacrimation and conjunctival absorption. 6 . To provide comfort, better compliance to the patient and to improve therapeutic performance of drug. 5

Drugs used in the eye: 

Drugs used in the eye Miotics e.g. pilocarpine Hcl Mydriatics e.g. atropine Cycloplegics e.g. atropine Anti-inflammatories e.g. corticosteroids Anti-infectives (antibiotics, antivirals and antibacterials) Anti-glucoma drugs e.g. pilocarpine Hcl Surgical adjuncts e.g. irrigating solutions Diagnostic drugs e.g. sodiumfluorescein Anesthetics e.g. tetracaine

Common ocular disorders associated with various tissues of eye: 

Common ocular disorders associated with various tissues of eye Conjunctiva (conjunctivitis) Cornea (keratitis) Sclera (scleritis) miscellaneous Infective conjunctivitis, Allergic conjunctivitis Ulcerative keratitis, Non ulcerative keratitis Glaucoma, diabetic retiopathi, AMD Episcerates Scleritis(anterior,posterior) 7

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Disease Number of Patients Cataract 6–19% of patients older than 43 years Age-related macular degeneration 11–28% of patients older than 65 years Glaucoma 1–4% of patients older than 45 years Diabetic retinopathy 71–90% of diabetics older than 10 years Dry eye 50–60 million (10–15% of U.S. population) Ocular allergy ~25% of U.S. population Retinitis pigmentosa 1 in 3000–5000 TABLE —Leading causes of visual impairment and ocular discomfort. 12 8

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Diseases of the posterior segment: AMD 17 9

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10 Diabetic retinopathy 17

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Anatomy and Physiology of the Eye 18, 34, 39 : 11

Ocular pharmacokinetic19-22: 

Ocular pharmacokinetic 19-22 12 1) transcorneal permeation from the lacrimal fluid into the anterior chamber, 2) non-corneal drug permeation across the conjunctiva and sclera into the anterior uvea, 3) drug distribution from the blood stream via blood-aqueous barrier into the anterior chamber, 4) elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and Sclemm's canal, 5) drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier, 6) drug distribution from the blood into the posterior eye across the blood-retina barrier, 7) intravitreal drug administration, 8) drug elimination from the vitreous via posterior route across the blood-retina barrier, and 9) drug elimination from the vitreous via anterior route to the posterior chamber

Mechanism Of Ocular Absorption23: 

Mechanism Of Ocular Absorption 23 13

General Pathway For Ocular Absorption: 

General Pathway For Ocular Absorption 14

Corneal absorption:: 

Corneal absorption: 15

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TOPICALLY APPLIED OCULAR DOSAGE FORM Diffusion Dissolution Erosion Drug in tear film Lacrimal turnover Metabolism Irritation Also induces lacrimation Drainage Loss Absorption Corneal& Conjunctival Drug in inner ocular structures & aqueous humour Route of elimination ONLY 1-5 % OF ADMINISTERED DOSE

Absorption of drugs in the eye:: 

Absorption of drugs in the eye: Factors affecting drug availability: 1- Rapid solution drainage by gravity, induced lachrymation, blinking reflex, and normal tear turnover: The normal volume of tears = 7 ul , the blinking eye can accommodate a volume of up to 30 ul without spillage, the drop volume = 50 ul 17

Absorption of drugs in the eye:: 

Absorption of drugs in the eye: 2- Superficial absorption of drug into the conjunctiva and sclera and rapid removal by the peripheral blood flow: 3- Low corneal permeability (act as lipid barrier) In general: Transport of hydrophilic and macromolecular drugs occurs through scleral route Lipophilic agents of low molecular weight follow transcorneal transport by passive diffusion and obey Ficks ‘s first law of diffusion: J = - D . d C m / dx 18

Corneal absorption:: 

Corneal absorption: J = The flux rate across the membrane D = diffusion coefficient - The diffusion coeffecient , as the molecular size of the drug C m = concentration gradient As the drug solubility , the gradient , the driving force for drug entry into the aqueous humor N.B. the drug should have dual solubility (oil and water soluble) to traverse the corneal epithelium (lipid barrier) then the aqueous humour. 19

ENHANCEMENT OF BIOAVAILABILITY: 

ENHANCEMENT OF BIOAVAILABILITY Topical bioavailability can be improved by – Maximizing pre-corneal drug absorption Minimizing pre-corneal drug loss VISCOSITY IMPROVER : It Increases drug contact time. generally hydrophilic polymers- e. g cellulose, polyalcohols, polyacrylic acids, sodium carboxy methyl cellulose,carbomer is uses. 20

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PENETRATION ENHANCER : Act by increasing corneal uptake by modifying the integrity of the corneal epithelium PRODRUGS : modification of chemical structure - selective, site specific BIOADHESIVE POLYMERS : Adheres to the mucin coat covering the conjuctiva and corneal surface of the eye. Thus prolongs the residence time of drug in the conjuctival sac. 21

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Barriers to intraocular delivery 24-30 . 22

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23 1. Tear film

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24 2. Cornea

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25 3. Conjuctiva 4. Sclera 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 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.

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5.Blood-Ocular Barriers Two blood-ocular barrier systems control the movement of solutes and nutrients into inner ocular tissues; the blood- aqueous barrier (BAB) and blood-retinal barrier (BRB). The balancing of inflow and outflow of aqueous humor across these barriers controls intraocular pressure. Blood-ocular barriers can be overcome using intravitreal injection. 26

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27 BRB

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Influx and Efflux Transporters 30 28

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Route of Administration Advantages Limitations Topical Convenient to deliver drugs Inefficient delivery to the posterior segment, nasolacrimal drainage,short contact time of drug on the ocular surface Systemic Convenient to deliver large amounts as compared to eye drops Poor bioavailability of drug in the retina and systemic absorption Intravitreal Drug delivered directly to the vitreous and retina in the form of injections and implants Problems such as cataract, endophthalmitis, retinal detachment and hemorrhage Subconjunctival Both anterior and vitreous level of the drug can be achieved and act as common route of administration Difficult to deliver drugs to the retina due to the presence of retinal pigment epithelium Retrobulbar Provide medication to the posterior segments for the treatment of posterior diseases Effect provide by this route is very less as drug may enter the globe of the eye Intracameral Deliver drugs directly to the anterior and vitreous chamber Difficult to deliver the drugs to the posterior segment Subretinal Deliver drugs to the retina Retinal detachment occurs as a result of sub retinal delivery Ocular Routes for delivery of Bioactives 32 29

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Disadvantages and complications associated with ocular drug delivery 12 . 30

General safety considerations:: 

General safety considerations: 31 A. Sterility

B. Ocular toxicity and irritation:: 

B. Ocular toxicity and irritation: 32 C.Preservation and preservatives:

D. Manufacturing Environment: : 

D. Manufacturing Environment: 33

D. Manufacturing Environment: : 

D. Manufacturing Environment: 34

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OCULAR DRUG DELIVERY SYSTEMS ADVANCED DELIVERY SYSTEMS Scleral plugs Gene therapy Stem cell CONTROLLED DELIVERY SYSTEMS Implants Hydrogels Dendrimers Iontophorosis Polymeric solution Penetration enhancers Contact lenses Nano suspensions Micro emulsions Cyclodextrins Phase transition systems Mucoadhesive PARTICULATE SYSTEMS Nano particles Micro particles VESICULAR DELIVERY SYSTEMS Liposomes Neosomes Pharmacosomes discomes RETRO METABOLIC DELIVERY SYSTEMS Softdrug approach Chemical delivery systems SOLUTIONS GELS OINTMENTS SUSPENSIONS EYE DROPS CONVENTIOAL DOSAGE FORMS 35 Classification 33

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Dosage form Advantages Disadvantages Solutions Convenience Loss of drug by drainage Nonsustained action Suspensions Patient compliance Best for drugs with slow dissolution Drug properties decide performance Emulsions Prolonged release of drug from vehicle Patient non compliance Blurred vision Possible oil entrapment Ointment Flexibility in drug choice Improved drug stability Increased tissue contact time Inhibition of dilution by tears Resistance to nasolacrimal drainage. Sticking of eyelids Poor patient compliance Blurred vision No true sustained effect Drug choice limited by partition coefficient Gels Comfortable Less blurred vision than ointment No rate control on diffusion Matted eyelids after use 36 Conventional Ocular Formulation

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HOW CAN WE ENHANCE RESIDENCE TIME OF SOLUTION DOSAGE FORM IN EYE? 34, 35 TWO APPROACHES EARLY APPROACH:- ENHANCE THE VISCOSITY METHYL CELLULOSE POLY VINYL ALCOHOL HYDROXY PROPYL CELLULOSE POLY VINYL PYRROLIDINE RECENT APPROACH:- SOL TO GEL SYSTEMS {PHASE TRANSITION SYSTEMS}

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INITIALISATION OF GEL FORMATION

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MECHANISM OF SOL - GEL TRANSITION 1 . ION DEPENDENT GELLING:- KEY INGREDIENTS :- SODIUM ALGINATE & GELRITE ®

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GEL 2 GEL 1 HEAT ADD 3- DIMENTIONAL BI-HELICAL STRUCTURE OF GELLAN GUM.

2.pH DEPENDENT GELLING:-: 

2.pH DEPENDENT GELLING:- KEY INGEDIENTS :- CELLULOSE ACETATE PTHALATE CHITOSAN CARBOMERS

3.TEMPERATURE DEPENDENT GELLING:-: 

3.TEMPERATURE DEPENDENT GELLING:- KEY INGREDIENTS :- POLOXAMER 407 LUTROL FC - 127 4 .ENZYME DEPENDENT GELLING:- KEY INGREDIENT :- XANTHAN GUM :-

RECENT TRENDS IN PHASE TRANSITION SYSTEMS : 

RECENT TRENDS IN PHASE TRANSITION SYSTEMS GRAFT COPOLYMERS 1. MATP AND HA GRAFTING { Hyaluronic acid-g- poloxamer } 2. MATP AND C6S GRAFTING { C6S-g-Poloxamer } MATP : Mono Amine Terminated poloxamer HA : Hyaluronic acid C6S : Chondroitoin 6 - Sulphate (Ref:-Drug Development and Industrial Pharmacy,31:455–463, 2005)

Ocular Control Release System: Ophthalmic Inserts18, 32 : 

Ocular Control Release System : Ophthalmic Inserts 18, 32 Definition: S terile preparations with a thin, multilayered , drug impregnated solid or semi solid consistency devices placed into cul-de-sac (or) conjunctival sac Desired Criteria For Control Release Ocular Inserts. 45

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46

Types Of Ocular Control Release insert: 

Types Of Ocular Control Release insert 47

A) Erodible Inserts: 

A) Erodible Inserts 1.Lacrisert 32,33 : Sterile, Rod Shaped device. Composition: HPC without preservative. Weight:5mg, Dimension:Diameter:12.5mm, Length:3.5mm Use:-Dry eye treatment, Keratitis. 2.SODI 18 : Soluble Ocular Drug Insert. Small water soluble developed for Cosmonauts who could not use their eye drop in liquid condition. Composition : Acryl amide, Vinyl Pyrolidone, Ethylacrylate. Weight 15-16 mg. In 10-15 sec Softens; In 10-15 min. turns in Viscous Liquids; After 30-60min. Becomes Polymeric Solution. Advantage: Once a day treatment of Glaucoma & Trachoma. Single SODI application :replaces 4-12 eye drops Instillation, or 3-6 application of Ointments 48

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3. Minidisc: It is made up of counter disc with Convex front & Concave back surface in contact with eye ball. 4-5mm in diameter. Composition : Silicon based pre polymer. Hydrophilic or Hydrophobic. Drug release from 170 h r 49 4. PVAI Thin,elastic & oval plates Impregnated with antibiotics,sulfonamides, pilocarpine, atropine etc. Limitations : poor patient compliance & difficulty of self inser

5. Bioadhesive Ophthalmic Drug Inserts (BODI)18: 

5. Bioadhesive Ophthalmic Drug Inserts (BODI) 18 LIMIIATION OF CONVENTIOAL EYE INSERTS :- RISK OF EXPULSION FROM THE SITE. TO AVOID SUCH LIMITATION, BIOADHESIVE OPTHALMIC DRUG INSERTS ARE DEVELOPED. BIOADHESIVE polymers: sodium hyaluronate and carbomer

B) Non erodible insert Ocusert18, 33, 37:: 

B) Non erodible insert Ocusert 18, 33, 37 : Capsular-type drug delivery systems Developed by ALZA corporation Oval, flexible ocular insert Anular ring impregnated with Ti0 2 for flexibility Dimensions:major axis:13.4mm; minor axis:5.7mm, thickness:0.3mm Two types of ocusert are available, ocusert pilo-20& pilo-40 Part Material Drug reservoir Pilocarpine Carrier material Alginic acid Rate controller Ethylene vinyl acetate (EVA) copolymer membrane Energy source Conc. Of pilocarpine Flux enhancer Di(2-ethyl hexyl) phthalate

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52 Vitrasert ®12:- An ocular implant (Vitrasert) for delivering ganciclovir for the treatment of cytomegalovirus (CMV) has also been developed. This implant delivers the drug directly to the retina for over 5 months. It is useful for patients with AIDS-associated cytomegalovirus retinitis. The device was prepared by coating a ganciclovir pellet with PVA.

PROSERT®: 

PROSERT ® PROSERT® is an ophthalmic placebo insert which is insoluble, sterile and biocompatible. It is having a matrix able to contain one or several active components, surrounded by a dyalisantic membrane of a changeable thickness which allows the releasing controlled by the tears . tears tears tears tears Drug release through membrane

MYDRIASERT®: 

MYDRIASERT ® Mydriasert is an insoluble ophthalmic insert, gradually releasing two well-known active ingredients: Phenylephrine and Tropicamide. It is indicated in pre surgical mydriasis.

Contact lens18, 32, 33: 

Contact lens 18, 32, 33 Hydrophilic soft contact lenses Made up of hydrogels Marketed products are Bionite was developed by Griffin laboratory Soflens was developed by Bausch& lomb here the drug is fluorescein Other drugs: antiviral idoxuridine(IDU) polymyxin B, pilocarpine Ability of presoaked hydrophilic lens Contact lenses made from PHP(hefilcon-A) copolymer(80% 2-hydroxy ethyl methacrylate & 20% N-vinyl-2-pyrrolidone) diameter 16mm, thickness 0.3mm& their hydration was 40-45% Modern system classifies conract lens into three major types such as (i) soft (ii)semi soft (iii)hard contact lens

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Contact lens hydrogel containing molecular sites with drug affinity Liposomes on the surface of a contact lens hydrogel(left), liposomes with in a contact lens hydrogels(right) Drug polymer film coated by a contact lens hydrogel

Implantable silicone rubber devices: 

Implantable silicone rubber devices Drug delivery device for hydrophobic drugs e.g.:-BCNU(1,3-bis(2-chloro ethyl)-1-nitroso urea)---- an intraocular malignancy agent The device consists of two sheets of silicone rubber glued together only at the edges with silicone adhesive A tube of the same material extends from device The device released BCNU at a constant rate about 200-400mcg/hr

Implantable drug delivery pumps: 

Implantable drug delivery pumps Osmatic mini pump(ALZET) Constant drug delivery rate with a pumping duration of up to 2 weeks Implantable infusion system(Infusaid) Permitted long term infusion via refilling A drug pellet coated with polyvinyl alcohol and ethylene vinyl acetate A polysulfone capillary fiber

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INTRAOCULAR IMPLANTS 33 It employed to extend the release in ocular fluids and tissues particularly in the posterior segment. It may be biodegradable and non-biodegradable. With implants, the delivery rate could be modulated by varying polymer composition. Implants can be in the form of solid, semi-solid or particulate based delivery systems. These implants have been applied in the treatment of diseases affecting both anterior and posterior segments of the eye. Implant containing gancyclovir or, anti-neoplastic agents is release drug over a 5 to 8 months .

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60 Ocular iontophoresis 18, 32, 33 : Iontophoresis is the process in which direct current drives ions into cells or tissues. If the drug molecules carry a positive charge, they are driven into the tissues at the anode; if negatively charged, at the cathode. Ocular iontophoresis offers a drug delivery system that is fast , painless, safe, and results in the delivery of a high concentration of the drug to a specific site. iontophoresis is useful for the treatment of bacterial keratitis, Iontophoretic application of antibiotics may enhance their bactericidal activity and reduce the severity of disease

Iontophoresis38: 

Iontophoresis 38

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CYCLODEXTRINS 33, 34 : Cyclodextrins (CDs) forming inclusion complexes with many guest molecules. And aqueous solubility of hydrophobic drugs can be enhanced without changing their molecular structure and their intrinsic ability to permeate biological membranes. They increase corneal permeation of drugs and increase ocular bioavailability of poorly water soluble drugs. Applied in the form of eye drops. DENDRIMERS 33 : These are macromolecular compounds made up of a series of branches around a central core. Their nanosize, ease of preparation, functionalization and possibility to attach multiple surface groups provides suitable alternative vehicle for ophthalmic drug delivery. This system can entrap both hydrophilic and lipophilic drugs into their structure.

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MICROEMULSION They can be easily prepared through emulsification method, easily sterilized, and are more stable and have a high capacity for dissolving drugs. The presence of surfactants and co-surfactants in microemulsion increase the dug molecules permeability, thereby increasing bioavailability of drugs. they act as penetration enhancers to facilitate corneal drug delivery NANOSUSPENSIONS It is consist of pure, hydrophobic drugs (poorly water soluble), suspended in appropriate dispersion medium. The technology are utilised for drug components that form crystals with high energy content molecule, which renders them insoluble in either hydrophobic or hydrophilic media. It offer advantages such as more residence time and avoidance of the high tonicity created by water-soluble drugs, their performance depends on the intrinsic solubility of the drug in lachrymal fluids after administration. Thus, they controlled its release and increase ocular bioavailability.

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COLLAGEN SHIELDS 32 They are manufactured from porcine scleral tissue, which bears a collagen composition similar to that of hu­man cornea. They are hydrated before being placed on the eye and the drug is loaded with the collagen shield simply by soaking it in the drug solution. They provide a layer of collagen solution that lubricates the eye.

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65 Microneedle 33 : As an alternative to topical route Researchers have developed microneedle to deliver drug to posterior segment. The extent of lateral and transverse diffusion of sulforhodamine was reported to be similar across human cadaver sclera. Microneedle had shown prominent in vitro penetration into sclera and rapid dissolution of coating solution after insertion while in vivo drug level was found to be significantly higher than the level observed following topical drug administration like pilocarpine Mucoadhesive Polymer. mucoadhesive polymer, the tamarind seed polysaccharide, as a delivery system for the ocular administration of hydrophilic and hydrophobic antibiotics.

LIPOSOMES : 

LIPOSOMES LIPOSOMES HAVE POTENTIAL TO ACCOMMODATE HYDROPHILIC AND LIPOPHILIC DRUG IN A SINGLE VESICLE VESICULAR ODDS 32, 33, 34

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IN – VIVO CORNEAL PERMEABILITY FOR LIPOSOMES ++++ > ++++ > _ _ > _ _ > = POSITIVELY CHARGED LIPOSOMES HAS BETTER CORNEAL PERMEABILITY

LIPOSOME SEEMS TO BE IDEAL ONE BUT THIS IS NOT SO…: 

LIPOSOME SEEMS TO BE IDEAL ONE BUT THIS IS NOT SO… MAJOR DISADVANTAGES :- UNSTABILITY BECAUSE DECOMPOSITION OF PHOSPHOLIPIDS IN FORMULATION. LIMITED DRUG LOADING CAPACITY . TECHNICAL DIFFICULTIES IN OBTAINING STERILE LIPOSOMAL PREPARATION .

NEOSOMES: 

NEOSOMES THEY ARE DEVELOPED TO OVERCOME THE LIMITATION OF LIPOSOMES. ALSO KNOWN AS NON IONIC SURFACTANT VESICLES. MIXTURE OF CHOLESTEROL & SINGLE ALKYL CHAIN NON- INONIC SURFACTANT HYDRATION NEOSOMES

DISCOSOMES: 

DISCOSOMES A SPECIAL TYPE OF NEOSOMES . DISC SHAPE VESICLES AS THE NAME REVEALS. LARGER THAN NEOSOMES SO BETTER FIT IN TO CUL- DE - SAC AND THEREFORE NO LOSS DUE TO DRAINAGE. e.g. Timolol maleate

PHARMACOSOMES: 

PHARMACOSOMES PURE DRUG VESICLES. ( IF DRUG IS AMPHIPHILIC ) VESICLES WITH 100% DRUG LOADING. COOH OH NH2 A DRUG WITH COOH OR ACTIVE H + CONTAINING GROUP. ESTERIFICATION AMPHIPHILIC DRUG COOH PHARMACOSOMES GENERATED ON DILUTION WITH WATER

Particulate system- Nanoparticle12, 32:: 

Particulate system- Nanoparticle 12, 32 : 73

Retrometabolic delivery system12, 34: 

Retrometabolic delivery system 12, 34 Combination of SAR and SMR Retrometabolic drug design (RMDD) Metabolic activation of inactive delivery forms: chemical delivery systems CDS Drug inactive active Alkyl oxime datives oximes(enzymes located in iris-celiary body) Metabolic deactivation of specifically designed active species:soft drugs SD Mi Active inactive metabolites hydrocartisone spirothiazolidine RMDD represent novel, systemic approach to achieve these goles include two distinct methods aimed to increase the therapeutic index SOFT DRUG design CHEMICAL DELIVERY SYSTEM design

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The chemical delivery systems (CDSs)- chemical compounds – produced by synthetic chemical reaction(s) forming covalent bonds between the drug(D) and specifically designed ‘carrier ’ and other moieties. At least one chemical bond needs to be broken for active compound (D) to be released. The release of active compound from CDSs takes pace by enzymatic or hydrolytic cleavage. The basic principle of retrometabolic drug design approaches is that the drug metabolism considerations should actually be involved at a very early stage of the design process - not as an after thought inorder to explain some of the behaviours of the drug SAR+SMR=RETROMETABOLIC DRUG DELIVERY SYSTEM Drug targeting by CDS’s 1.enzymatic physical chemical based targeting 2.site specific-enzyme activated targeting 3.receptor based chemical targeting Drug targeting by soft drugs 1.soft drug analogs 2.activated soft coompounds 3.active metabolite type soft drugs 4.controlled release of endogenous soft compounds 5.Inactive metabolic approach

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76 ADVANCED DELIVERY SYSTEM 33 : Cell Encapsulation: -The entrapment of immunologically isolated cells with hollow fibres or microcapsules before their administration into the eye is called Encapsulated Cell Technology (ECT) which enables the controlled, continuous, and long-term delivery of therapeutic proteins directly to the posterior regions of the eye. -The polymer implant containing genetically modified human RPE cells secretes ciliary neurotrophic factor into the vitreous humour of the patients’ eyes. ECT can potentially serve as a delivery system for chronic ophthalmic diseases like neuroprotection in glaucoma, anti angiogenesis in choroidal neovascularization, anti-inflammatory factors for uveitis. 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 140 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.

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77 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 ofproteins and to predict the clinical effects of new compounds to be administered in the eye, the basic knowledge of Protein and Peptide is required. 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.

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78 Scleral Plug therapy: Scleral plug can be implanted using a simple procedure at the pars plana region of eye , made of biodegradable polymers and drugs, and it gradually releases effective doses of drugs for several months upon biodegradation. The release profiles vary with the kind of polymers used, their molecular weights, and the amount of drug in the plug. 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.

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79 Oligonucliotide therapy: Oligonucleotide (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 proteins. Among several mechanisms by which antisense molecules disrupt gene expression and inhibit protein synthesis, the ribonuclease H mechanisms is the most important. Aptamer: Aptamers are oligonucleotide ligands 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 (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against VEGFb165, where VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability.

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80 Ribozyme 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 pigmentosa (ADRP) is caused by mutations in genes that produce mutated proteins, leading to the apoptotic death of photoreceptor cells. Lewin and Hauswirth have worked on in the delivery of ribozymes in ADRP in rats shows promise for ribozyme therapy in many other autosomal dominant eye diseases, including glaucoma.

EVALUATION39, 40 : 

EVALUATION 39, 40 SOLUTIONS:- 1) pH 2) sterility 3) osmolarity SUSPENSIONS:- 1) particle size 2) adsorption on the inner wall of container PHASE – TRANSITION SYSTEMS:- 1) gelling efficiency 2) transparency of formed gel 3) release pattern 4) gelling temp. SEMISOLIDS:- 1) ease of application 2) particle size if drug is suspended.

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OCULAR INSERTS:- 1 ) Uniformity of Thickness 2) Uniformity of Weight 3) Drug Content Uniformity 4) Percentage Moisture 5) Percentage Moisture Loss 6) In vitro Drug Release Study 7) Draize Eye Irritancy Test 8) In vivo Drug Release Study 9) Swelling index 10) Folding endurance

Research paper: 

Research paper FORMULATION AND EVALUATION OF PH TRIGGERED IN SITU OPHTHALMIC GEL OF MOXIFLOXACIN HYDROCHLO RIDE. 83 IJPPS, vol 4, Issue 2, 2012

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84 Ingredients % w/v F1 F2 F3 F4 F5 F6 F7 Moxifloxacin Hcl 0.5 0.5 0.5 0.5 0.5 0.5 0.5 HPMC (K15 M) 0.1 0.2 0.3 0.3 0.3 0.3 0.3 Carbopol 934 0.1 0.2 0.3 0.4 0.5 0.6 0.7 Sodium chloride 0.9 0.9 0.9 0.9 0.9 0.9 0.9 Benzalkonium chloride 0.01 0.01 0.01 0.01 0.01 0.01 0.01 Distilled water (ml) 100 100 100 100 100 100 100

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85 FORMULATION: Preparation of In situ gelling system: The detailed procedure for preparing the in situ gel-forming system of Moxifloxacin Hcl is outlined above table. Required quantity of sodium chloride was dissolved in 50 ml of distilled water, HPMC K15M was added to the above solution and stirred slowly with Magnetic stirrer, Care was taken that no lumps of HPMC was formed during stirring. Carbopol 934 was sprinkled over this solution and allowed to hydrate overnight. The solution was again stirred with magnetic stirrer after 24 hrs. Moxifloxacin Hcl was dissolved in distilled water, benzalkonium chloride (BKC) was then added and the solution was filtered through 0.2-μm cellulose acetate membrane filter. The drug solution was added to the carbopol -HPMC solution under constant stirring until a uniform solution was obtained pH of the formulation was then set to 4.4 using 0.1 N NaOH. Distilled water was then added to make up the volume to 100 ml. The developed formulations were filled in 5 ml capacity amber glass vials, closed with gray butyl rubber closures and sealed with aluminium caps. The formulations in their final pack were subjected to terminal sterilization by autoclaving at 121 º C at 15 psi for 20 min.

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86 Formulations Appearance Clarity pH Gelling capacity Drug content F1 Light yellow Clear 4.41 - 94.2 % F2 Light yellow Clear 4.41 - 95.1 % F3 Light yellow Clear 4.44 + 91.6 % F4 Light yellow Clear 4.40 + 95.0 % F5 Light yellow Clear 4.40 ++ 98.8 % F6 Light yellow Clear 4.41 +++ 98.8 % F7 Light yellow Clear 4.43 +++ 85.6 % EVALUATION PARAMETRES AND RESULT:- - : No gellation + : Gels slowly and dissolves ++ : Gellation immediate and remains for hours +++: Gellation immediate and remains for extended period of time

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87 Viscosity study: Before gellation at Non Physiological After gellation at Physiological condition at pH 4.4 condition at pH 7.4

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88 IN VITRO STUDIES

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89 Eye part Cornea Iris Conjuctiva Total score 0 0 0 0 Ocular irritation studies-Draize Test:- Formulation F5 was used for this test. The formulation was found to be non irritating with no ocular damage or abnormal clinical signs to the cornea, iris or conjunctivae observed fig. Hence the formulation was suitable for the eye instillation. The scores are mentioned in table. Before instillation One week After instillation Table: Ocular irritation study as per the Draize test protocol

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90 CONCLUSION The present work was carried out to develop pH triggered in situ gel of Moxifloxacin Hydrochloride (0.5% w/v) using combination of HPMC K15M and carbopol 934. Attempts were made to design the formulation with low concentration of HPMC K15M (0.3%w/v). The formulations were in solution form at pH 4.4, which underwent sol gel transformation when instilled into eye ( pH 7.4) indicating increase in precorneal residence time of drug thus increasing ocular bioavailability, reducing the dosing frequency and improved patient compliance. The three formulations showed sustained release for a period of 8 hours. Because of higher viscosity of F6 and F7 the formulation F5 was optimized. Finally it can be concluded that in situ ophthalmic gel is an alternative for conventional eye drops and it will be boon to the patients in the future.

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91 QUESTIONS: Which factors affect bioavailability of ocular drug delivery and how can we increase the bioavailability? What are the barriers of ODDS & write advanced system of ODDS. GTU QUESTIONS: Describe formulation of controlled release ocular drug delivery system. (June/ July 2011) (Dec 2011) Explain hydrophilic soft contact lens. (July 2010) Write short note on erodible ousert. (July 2010)

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95 41. Shashank Nayak N*, BhAarani S Sogali, R S Thakur, Formulation and evaluation of PH triggered in situ ophthalmic gel of Moxifloxacin hydrochloride, International Journal of Pharmacy and Pharmaceutical Sciences, 2012, 4(2), pp. 452-459

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