ocular drug delivery system

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OCULAR DRUG DELIVERY:

OCULAR DRUG DELIVERY K.SANTHOSH REDDY M.Pharmacy (II sem ) DEPARTMENT OF PHARMACEUTICS SRR COLLEGE OF PHARMACEUTICAL SCIENCES VALBHAPUR

General considerations of opthalmic drug delivery:

General considerations of opthalmic drug delivery 1.Transcorneal permeation from the lachrymal fluid into the anterior chamber, 2.Noncorneal drug permeation across the conjunctiva and sclera into the anterior uvea , 3.Drug distribution from the blood stream through 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.

Slide 4:

Barriers to intraocular delivery. Copyright © by Society of Toxicologic Pathology

Slide 5:

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

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 )

Principles and practices of various drug delivery systems to eye:

Principles and practices of various drug delivery systems to eye H1 receptor antagonists Anti glaucoma drugs Anti fibrotic drugs Anti inflammatory drugs Anti viral drugs Anti fungal agents Immuno modulators Anti biotics

Requisites of controlled ocular delivery systems:

Requisites of controlled ocular delivery systems Polymeric solutions eg:MC , PVA, HPC& PVP Phase transition systems eg : Lutrol FC-127& Polaxomer 407 viscosity increases when its temperature raised to 37oC CAP pH sensitive Mucoadhesive / Bioadhesive dosage forms eg : Polycarbophil (acrylic acid based polymer) Collagen shields,Collasomes eg : antibiotic impregnated soft contact lenses Polymeric colloidal dispersions (o/w type emulsion) Ocular penetration enhancers Ocular Iontophoresis

Slide 9:

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 CONVENTIONAL DOSAGE FORMS

CONVENTIONAL DOSAGE FORMS:

CONVENTIONAL DOSAGE FORMS Formulation factors Physical considerations dosage cul-de-sac capacity Corneal absorption Non-corneal absorption Transcorneal penetration Enzyme metabolism Corneal barriers Selection criteria Duration of action Drug target site Reduced frequent dosing Patient compliance Cost effectiveness Safety Physician requirement Solutions, Gels, Ointments, suspensions, Emulsions, Inserts Intracameral injections Iontophoresis Subconjectival injection Retrobulber injection Mode of administration

Slide 11:

Disadvantages and complications associated with ocular drug delivery. Short B G Toxicol Pathol 2008;36:49-62

Advantages and disadvantages of various delivery systems to eye:

Advantages and disadvantages of various delivery systems to eye s.no Delivery/ dosage form Advantages Disadvantages 1 Drops -easy to apply -good patient acceptance -Poor ocular bioavailability -short duration of action 2 Systemic administration -more effective to treat diseases of the posterior segment of the eye than drops -do not bypass blood ocular barriers -side effects: systemic toxicity 3 Intravitreal , periocular subconjuctival injections -improve drug absorption -no systemic toxicity -deliver to target site of the eye - inj.Display 1 st order kinetics -short half life -poor acceptance by patients 4 Implants -The biodegradable implants donot need to be removed -stabilization of the drug -side effects increased risk -uncontrollable release of drug to eye 5 Micro particles , Nanoparticles liposomes -increase half life - decrese peak conc. -localized drug delivery -side effects -risk associated drug delivery 6 Cell encapsulation -patient compliance -limitations of toxicity -side effects -risk of operation 7 Iontophoresis -non invasive easy method -may use in combination -more patient compliace -No sustained half-life -risk of side effects -frequent administration reqired

Ocular inserts :

Ocular inserts Opthalmic inserts Soluble Bioerodable Insoluble natural polymer collagen shields reservoir systems Eg:SODI Eg:Lacrisert , PVAI minidisc Diffusion based( ocusert ) Osmatic based Soft (presoaked) contact lenses Def: S terile preparations with a thin, multilayered , drug impregnated solid or semi solid consistency devices placed into cul-de-sac (or) conjunctival sac

Advantages of ocular inserts:

Advantages of ocular inserts Increased ocular residence Releasing drugs at a slow,constant rate Acurate dosing Reduction of systemic absorption Better patient compliance Disadvantages of ocular inserts A capital disadvantage of ocular inserts resides In their solidity The occasional inadvertent loss during sleep or while Their interference with vision Difficult placement of the ocular inserts

OCULAR DRUG DELIVERY DEVICES:

OCULAR DRUG DELIVERY DEVICES MATRIX-TYPE DRUG DELIVERY SYSTEMS Hydrophilic soft contact lenses Soluble ocular inserts Scleral buckling material s CAPSULAR TYPE DRUG DELIVERY SYSTEMS Ocusert Implantable silicone rubber device IMPLANTABLE DRUG DELIVERY PUMPS Osmatic mini pump and implantable infusion system OTHER DELIVERY DEVICES Ocufit and Lacrisert Minidisk ocular therapeutic systems

Contact lens:

Contact lens 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

Slide 17:

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

Soluble ocular inserts:

Soluble ocular inserts Poly vinyl alcohol inserts(PVAI) Thin,elastic & oval plates Impregnated with antibiotics,sulfonamides , pilocarpine , atropine etc Limitations : poor patient compliance & difficulty of self insertion 2 ) Soluble opthalmic drug inserts(SODI) Thin,elastic & oval plates Composition: polymers and copolymers of polyacryl amide, Vinyl pyrolidone , ethyl acrylate . Weight 15-16mg In 10-15 sec softens In 10-15 min turns in viscous liquids After 30-90 min becomes polymeric solution Advantage: Single SODI application: replaces 4-12 eye drops Ones a day treatment of Glaucoma & Trachoma

Scleral buckling material:

Scleral buckling material Two types 1) Gelatin film 2) Solid Silicone rubber Antibiotic preparations are chloramphenicol & lincomycin Immersing the devices into aqueous antibiotic solution and then dried. They found sustained release of the antibiotic from these devices Use: To prevent postoperative infections after retinal detachment surgery

Ocusert::

Ocusert : 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

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

Lacrisert:

Lacrisert Sterile , rod shaped device Composition: HPC without preservative The devices have long retention(2 weeks or more) and sustained release features Weight: 5 mg Dimension:diameter 12.7mm, length 3.5mm Use:- dry eye treatment, keratitis

Minidisk :

Minidisk It shaped like contact lens,with convex front & concave back surface in contact with eye ball 4-5mm in diameter Composition: silicon based polymer Hydrophilic or hydrophobic Drug release from 170hr

Retrometabolic delivery system:

Retrometabolic delivery system 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

Slide 26:

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

Nanoparticle:

Nanoparticle The drug absoption in the eye is enhanced significantly in comparision to eye drop solutions Poly alkyl cyano acrylate (PACA) nanoparticles and nanocapsules improve corneal penetration of hydrophilic and lipophilic drugs Limitation: disruption of corneal epithelium cell membrane Poly- ԑ- caprolactone (PECL) nanocapsules increase ocular penetration of lipophilic drugs such as metipranolol,betaxolol . PECL taken up by the corneal epithelium cells without damaging the cell membrane Colloidal nature of the carrier is the main factor responsible for favourable corneal transport of drugs PARTICULATE SYSTEM FOR OCULAR DRUG DELIVERY

Liposomes:

Liposomes non-toxic, non irritant Biodegradable in nature Ability to incorporate almost any type of the drug regardless of the solubility Intimate contact with cornea and conjunctival surfaces Protect the drug from metabolic enzymes Phospholipids used are: phosphotidylcholine , phosphotidic acid, sphingomyline , phosphotydyleserine , cardiolipine 4 fold increase in passage of pencillin G across rabit cornea & 10 fold enhancement of indoxole passage across rat cornea were observed when the formulations compared with solutions VESICULAR SYSTEM FOR OCULAR DRUG DELIVERY

Slide 29:

Niosomes are non-ionic surfactant based multilamellar (>0.05µm),small unilamellar (0.025-0.05µm) or large unilamellar vesicles(>0.1µm) in which an aqueous solution of solute(s) is entirely enclosed by a membrane resulted from organization of surfactant macromolecules as bilayers STRUCTURAL COMPONENTS USED • Surfactants ( dialkyl polyoxy ethylene ether non ionic surfactant) • Cholesterol CHOLESTROL: 1. Cannot form bilayers , but bring changes in fluidity and permeability to bilayers . 2. Can be used in high molar concentrations. 3. Stabilize and prevent leak from vesicles. ADVANTAGES : The vesicle suspension being water based offers greater patient compliance over oil based systems Since the structure of the niosome offers place to accommodate hydrophilic, lipophilic as well as ampiphilic drug moieties, they can be used for a variety of drugs. The characteristics such as size, lamellarity etc. of the vesicle can be varied depending on the requirement. The vesicles can act as a depot to release the drug slowly and offer a controlled release. They are osmotically active and stable. They increase the stability of the entrapped drug Improves therapeutic performance of the drug by protecting it from the biological environment and restricting effects to target cells, thereby reducing the clearance of the drug. DISADVANTAGES Physical instability, Aggregation, Leaking of entrapped drug, Fusion, Neosomes

PHARMACOSOMES:

PHARMACOSOMES The vesicle formation takesplace not only just by association of phospholipids but also by amphiphilic molecular association Since many drugs are also amphiphiles , they can form the vesicles Advantages: Drug metabolism can be decreased Controled release profile can be achieved DISCOMES Solube surface active agents when added in critical amount to vesicular dispersion leads to solubilization or breakdown of vesicles & translates them into mixed micellar systems e.g : Egg yolk phosphatidyl choline liposomes by the addition of non ionic surfactants of poly oxy ethylene cetyl ether till the lamellar and mixed lamellar coexist Advantages: Minimal opacity imposes no hinderance to vision Increased patient compliance Zero order release can be easily attained

Advantages of vesicular systems :

Advantages of vesicular systems No difficulty of insertion as in the case of ocular inserts No tissue irritation and damage as caused by penetration enhancers Provide patient compliance as there is no difficulty of insertion as observed in the case of inserts The vesicular carriers are biocompatable and have minimum side effects Degradation products formed after the release of drugs are biocompatable They prevent the metabolism of drugs from the enzymes present at tear/corneal epithelium interface Provide a prolong and sustained release of drug

conclusion:

conclusion Quality , Efficacy and Safety should be the optimal parameters for drug delivery to eye in this context, more clinical studies are necessary to provide further information and insight in to new opthalmic drug delivery system.

References:

References Ophthalmic drug delivery system: Challenges and approaches PB Patel, DH Shastri , PK Shelat , AK Shukla Ocular Transporters in Ophthalmic Diseases and Drug Delivery; Edited by Joyce Tombran-Tink , Colin J. Barnstable. Targetted & Controlled Drug Delivery Novel Carrier Systems by S.P.Vyas,R.K.Khar Anatomy and physiology Tora Tora Ophthalmic drug delivery systems --recent advances C Le Bourlais , L Acar , H Zia, PA Sado … - Progress in retinal and …, 1998 – Elsevier Web searched: http://www.google/images/eye/anatomy&physiology http://pharmaxchange.info

Slide 34:

THE EYES ARE THE MIRROR OF THE SOUL TAKE CARE OF YOUR EYES WITH GENTLENESS….