ocular barriers and methods to overcome barriers

ocular drug delivery system
Ocular formulations
Ocuserts

1. Barriers and methods to overcome barriers of ocular drug delivery system By G.Tarun Kumar 10201S0301 1 st year M.Pharmacy [pharmaceutics ] Bapatla college of pharmacy

2. Contents Barriers of ocular drug delivery Methods to overcome intraocular barriers Approaches to improve ocular bioavailability Ophthalmic formulations

3. Barriers of Drug permeation 1.Ocular surface barriers 2.Ocular wall barriers 3.Retinal barriers 4.Viterous body 5.The lachrymal fluid 6.Solubility of the drug 7.lipophilisity of the drug 8.Mol.wt and size of the drug

4. 1.Occular surface barriers: The corneal and conjuctival superficial layers form the ocular surface i.e.,in contact with the tear film These create a defence barrier against permeation from undesired molecules Corneal surface 5%, C onjuntival surface 95% Out of corneal five layers only the outermost squamous epithelial layer forms a barrier

5. 2.Ocular wall barriers : Sclera&Choroid Sclera I t contain stroma made of bundles of collagen and fibroblasts covered by vascular episclera -occupies 80%of eye globe thickness is 0.3 to 1.0mm Choroid beneath sclera – highly vascular tissue thickness is 0.25mm

6. 3.Retinal barriers

7. 4.Vitreous body It occupies a vol about 4.5 ml and is the largest single structure in the eye Drugs are rapidly eliminated from the vitreous by first order kinetics 5.The lachrymal fluid It is an aqueous fluid which maintain I sotonicity and contain proteins[ lysozyme ]and lipids After topical application increase in lachrymal flow dilution of dose dimnished drug absorption Lowers drug concentration Rapid clearence of precorneal area by lacremation and nasolachrymal drainage and spillage decrease in Bioavailability

8. 5. Solubility of the drug Solubility is dependent on the pKa of the drug and pH of the solution -Usually unionised drugs permeate rapidly than ionised drug As the corneal epithelium bears negetive charge cationic species penetrate fast 6.Lipophilisity of the drug Outermost corneal epethlium is tend to permeate lipophilic drugs where as inner stromal layer of cornea permeate hydrophobic drugs Partition coefficient value ranging from 2-4 is found to be optimum 7.Molecular weight and size of Drug M.wt less than 500 daltons can permeate readily in corneal epithilium Conjunctva has larger paracellular pore diameter thus allow permeation of larger molecules such as small and medium size peptides[5000-10000d] Permeation through sclera is by aquous pores Sclera permeability is half of conjunctiva but much higher than cornea

9. Methods to overcome I ntraocular B arriers Microneedle drug delivery Ultrasound mediated Drug Delivery Iontophorosis Periocuar route DDS Intravitreal injection

10. 1.Microneedle It is an non invasive method to deliver drugs to intraocular regions Researchers have developed drug coated microneedles with a length of 500-750 μ m Drug to be delivered can be coated on a solid metal On administration coated molecules dissolve rapidly and subsequently microneedles are removed from the tissue Similarly intrascleral hollow microneedles have also developed . This delivery system is able to deliver microparticles,nanoparticles and drugs in a solution with minimal invasion

11. 2.Ultrasound mediated Drug delivery It includes application of ultrasound waves across cornea to enhance drug permeability Delivery of hydrophilic molecules – sod.flourosceine at an ultrasound frequency of 880KHz with 5 min duration reported 10 fold enhancement in corneal permeation with minor changes in epithelium Delivery of beta blockers such as Atenelol,timolol and beraxalol was attempted

12. 3.Iontophoresis Ocular iontophoresis is an non invasive method to deliver drugs to both anterior and posterior segments It is a method of transferring ionised drugs through membrane with low electric current Ocular iontophoresis is classified into transcorneal and corneoscleral or trans- scleral iontophoresis Drugs moved across the membrane by 2 mechanisms include migration and electro-osmosis Trans scleral delivery allows drug transfer to posterior segment Disadvantages No sustained half life Requires repeated administration Mild pain in some cases Low patient compliance becuause of frequent administration that may needed

13. 4.Periocular route It has been considered as most promising and efficient route for administering drugs to posterior eye segment Periocular refers to region surrounding the eye Drug solution placed in close proximity to sclera, which results in high retinal and vitreal concentration It has an advantage like improved drug absorption over systemically and topically and more safety towards posterior segment of eye

14. 5.Intravitreal injection Short term complications include :retinal detachment,endophthalmitis Intravitreal hemorrage Disadvantages : Injection display first order kinetics Short half life Pain caused due to repeated injections Increased intraocular pressure &intraocular bleeding Increased chances of infection This involves injection of drug solution into vitreous by using 30G needle which improve drug absorption Offers high drug concentrations in vitreous and retina

15. Approaches to improve ocular bioavailability Viscosity enhancers viscosity increasing polymers are usually added to ophthalmicdrug solutions to increase vehicle viscosity This leads to improved precorneal residence time &grater trans-corneal penetration Polymers used: poly vinyl alcohol, poly vinyl pyrrolidone , Methyl cellulose , HPMC , HEC ,HPC Out of the polymers PVA is more effective due to its adhesive properties and its capability to increase thickness of precorneal tear film Prodrug Generally prodrugs are used for the drugs having low corneal permeability Prodrugs are used to increase corneal permeability by changing hydrophilicity / lipophilicity of the drug After corneal penetration the prodrug is chemically or enzymatically metobalised into its parent compound

16. Enzyme systems identified include:Esterases , ketone reductases and steroid 6-hydroxylase Prodrugs examples include anti viral medications : Genciclovir , Acyclovir Penetration enhancers The transportation across the cornea can be maximized by increasing the permeability of corneal epithelial membrane It can be maximized by modifying the integrity of corneal epithelium by permeation enhancers which leads to increased bioavailability Penetration enhancers include: cetylpyridinium chloride , lasalocid , benzalkonium chloride , parabens , tween 20 , bile acids , bile salts , azone Other drug formulations that can enhance drug bioavailability are: Eye ointments N anosuspension Lioposomes Microemulsions N iosomes Insitu forming gels Nanoparticles

17. Ophthalmic formulations Eye drops Ophthalmic solutions Microemulsions In situ gels Eye ointments Contact lenses coated with drugs Liposomes Niosomes and Discosomes Ocuserts

18. 1.Eye drops Eye drops are in the form of water and oil solitions,emulsions or suspensions of one or more active ingredients and may contain preservatives if stored in multidose packaging These are sterile and isotonic dosage forms The optimum pH for eye drops should be equal to pH of tear fluid which is about 7.4 If pH value gets outside the range , it is intolerated to the eye which leads to decrease in drug bioavalibility

19. 2.Ophthalmic solutions These are sterile , aqueous solutions used for cleansing and rinsing eyeballs They may contain excipitents for regulating osmotic pressure , pH and viscosity of preparations They may also contain preservatives if stored in multiuse packaging 3 .Microemulsions Microemulsion is stable dispersion of water and oil facilited by combination of surfactant and co-surfactant in a manner to reduce interfacial tension These are thermodynamically stable dosage forms having droplet size of [-100nm] and clear appearence These are inexpensive and easy to sterilize and stabilize, provides possibility to intorduce large amounts of active ingredient The mech of action involves the adsorption of nanodrops constituting a reservoir of drug and inner phase of microemulsion on corneal surface Active ingredients includes : Diflupendrate , cyclosporine A , Flubriprofen

20. 4.In situ gels [sol-to-gel systems] The droppable gels are liquid upon instillation and undergo a phase transition from sol-to-gel to form a viscoelastic gel in ocular region The change in the dosage form is triggered by factors like pH , temp and presence of electrolytes Polymers used are gellan gum , poloxamer and cellose acetate pthalate Active ingredients include Ciprofloxacin , Flucanazole , Pilocarpine 5.Eye ointments Ointments are semisolid dosage forms for external use , consisting solid or semisolid hrdrocarbon base having melting or softning point close to human temp After application it decomposes into small drops which stay for a longer period in conjunctival sac , thus increasing drug’s bioavailability These are safe and well tolerated with certain disadvantages of blurred vision and irritating effects . Thus these are preferred at night time.

21. In this type ,drug is coated on a contact lens and is released after applying the drug over the eyeball for a longer period of time Polymer used in the production of lenses is cross linked poly[2-hydroxy ethyl methacrylate ] with small amount of ethelene glycol dimethylacrylate Drugs include: Timolol , ciprofloxacin , dexamethasone , cyclosporine 7.Liposomes Liposomes are made of phospholipids which are microscopic vesicles containing one or more concentric lipid bilayers separated by water or aqueous buffer compartments These are biocompatable , biodegradable , amphiphilic and nontoxic in nature They have the ability to have intimate contact with corneal & conjunctival surfaces Desirable for drugs that are poorly absorbed , low partition Coefficient and poor solubility 6.Contact lenses coated with drugs

22. Positively charged liposomes are preferentially captured at negatively charged corneal surface Disadvantages Production is very expensive and very difficult technological preparation The effectiveness depends on many factors: encapsulation efficiency , size and charge of liposomes , stability of liposomes in conjunctival and corneal surfaces 8.Niosomes and Discosomes Niosomes are non ionic surfactants capable of encapsulating both hydrophilic and lipophilic compounds Biocompatable,biodegradable and non imunogenic carriers that extend time period Releases the drug which is independent of pH and temperature Discosomes are modified form of niosomes Larger in size , varies from 12-16 nm Discosomes differ from niosomes by using different non ionic surfactants Solulan C24 a derivative of lanolin Due to their size they cannot penetrate the general circulation Disc shape ensure better fitting into conjunctival sac Drugs include Genciclovir , cyclopentolate timolol

23. 9. Ocuserts Ocuserts [ocular inserts] are defined as sterile preparations , multilayered, solid or semisolid devices placed in cul-de-sac or conjunctival sac and whose size and shape are designed especially for ophthalmic application Deliveres at constant rate by diffusion mechanism Ocuserts increase corneal contact time , prolongs duration of action , improve bioavailability , reduces the frequency of administration and thus acheive patient compliance Ocusert ® , pilocarpine ocular therapeutic system is the firstproduct by Alza incorporationUSA from this catogary Generally all types of ocuserts consist of 3 components namely : 1.A central drug reservoir 2.Rate controlling membrane 3.An outer annular ring meant for easy handling

24. Classification of ocular inserts Insoluble ocular inserts : a. Diffusional inserts b. Osmotic inserts c. Hydrophilic contact lenses Soluble ocular inserts : a. Natural polymeric inserts b. Synthetic insert Bio erodable inserts : a. Soluble ocular drug inserts [SODI] b. Lacrisert c. Minidiscs d. Collagen shields

25. 1. Insoluble ocular inserts a. Diffusional inserts The release of drug from the inserts is based on diffusional release mechanism Drug release is controlled by the lachrymal fluid permeating through the membrane and when sufficient internal pressure was developed , then only drug comes out of the reservoir b. Osmotic inserts The osmotic inserts consist of a central part surrounded by a peripheral part and are of two types Type 1 Type 2 Central part is composed of single reservoir of drug with osmotic solute dispersed throughout a polymeric matrix The peripheral part comprise a covering film made of an insoluble semi permeable membrane The osmotic pressure against the polymer matrix causes its rupture form apertures from where drug releases Central part is composed of two distinct compartments , the drug and osmotic solute in two separate compartments Drug reservoir is surrounded by elastic impermeable membrane and osmotic layer is by semi permeable membrane Osmotic pressure that stretches the elastic membrane and contracts the compartments , so drug release from aperture

26. C. Hydrophilic contact lenses These are covalently cross linked hydrophilic or hydrophobic polymers that forms a 3 dimensional matrix capable of retaining water , aqueous solution or solid components Provide extended release of drugs into the eye There are two types of contact lenses : Hard contact lenses and Soft contact lences Soft lenses are used to aid corneal wound healing in patients with infections and corneal ulcers . They treat corneal erosions and epithelial defects after corneal transplantation 2 . Soluble ocular inserts Soluble inserts offer the advantage of being entirely soluble so that they need not to be removed from their site of application Simple design and easily processed by conventional methods Controlled by diffusion mechanism Natural polymeric inserts : collagen type Synthetic polymeric inserts : cellulose derivatives

27. 3. Bio erodible ocular inserts These are formed by bio erodible polymers Ex. Cross linked gelatin derivatives , polyester derivatives They can modulate their erosion rate by modifying the final structure during synthesis and by addition of anionic or cationic surfactants A. Soluble ophthalmic drug insert [SODI] It is a small oval wafer developed by soviet scientists for cosmonauts who could not use eye drops in weightless conditions It is a thin film made from acrylamide , N- vinylpyrrolidone and ethylacrylate B. Lacrisert Sterile rod shaped device made of HPC without any preservatives Weight is 5mg , diameter 12.7mm , length 3.5mm Used in treatment of keratitis , inserted into inferior fornix by a special applicator Imbibes water from cornea and conjunctiva , forms hydrophilic film which stabilizes the tear film and hydrates and lubricates the cornea .

28. C. Minidiscs Minidiscs are profiled , convex outside , concave from the side of contact with eye surface , d is 4-5 mm which are similar to contact lenses Main copolymers are ᾳ - ῳ - bis [4-methacryloxy]-butyl poly[ dimethylsiloxane ] and poly [ hydroxyethyl methacylate ] This dosage form is either hydrophilic or hydrophobic which enables extended time period of release of water soluble and poorly soluble drugs D. Collagen shield Collagen is the structural protein of bones , tendons , ligaments and skin and comprises more than 25% of total body protein in mammals Produces higher drug concentration in cornea and aqueous humour when compared with eye drops and contact lenses Collagen shields are fabricated with foetal calf skin tissue and originally developed as a corneal bandage

29. Adavntages Increased ocular residence, hence prolonged drug activity and higher bioavailability Releasing drugs at slow and constant rate Accurate dosing Reduction of systemic absorption Better patient compliance , targeting internal ocular tissues through conjunctival and scleral routes Disadvantages A capital disadvantage of ocular inserts is their solidity which results in inconvenience in patients Unwanted migration of inserts to upper fornix Interference with vision Difficult in placement of ocular inserts