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Ocular drug delivery system

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ocular drug delivery system

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Ocular drug delivery system

  1. 1. By- Dr. Neeraj Agarwal
  2. 2. INTRODUCTION  Ocular administration of drug is primarily associated with the need to treat ophthalmic diseases. Eye is the most easily accessible site for topical administration of a medication. Ideal ophthalmic drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the eye for prolong period of time.
  3. 3. FACTORS AFFECTING INTRAOCULAR BIOAVAILABILITY:  1. Inflow & outflow of lacrimal fluids.  2. Efficient naso-lacrimal drainage.  3. Interaction of drug with lacrimal fluid.  4. dilution with tears.  5. Corneal barriers.  6. Active ion transport at cornea.
  4. 4. OCULAR ABSORPPTION PATHWAY 4
  5. 5. BARRIERS IN OCULAR ABSORPTIONPrecorneal Constraints It include – • Solution drainage • Lacrimation • Tear dilution • Tear turnover • Conjunctival absorption Corneal constraints • Cornea as rate limiting barrier • Anatomy of cornea 1.Outer- Epithelium(lipophilic), 2.Middle- Stroma(hydrophilic), 3.Inner- Endothelium(lipophilic) 5
  6. 6. Cornea  Epithelium- only non ionized drug penetrate  Stroma- only ionized drug can pass so drug must have capacity to exist in both ionized and nonionized form for a better penetration Eg- homatropine (proposed by KINSEY) Eg- Fluorescein is a negative charged ion so can not penetrate the intact epithelium and this property forms the basis of fluorescein dye test
  7. 7. SURFACE ACTIVE AGENT  Agents that reduce surface tenson, increase corneal wetting and therefore present more drug for absorption.  Eg.- Benzalkonium Chloride used as preservative also act as wetting agent.
  8. 8. PRO DRUG FORM  Prodrug is more Lipophilic so more absorbed by epithelium and afterthat converted into another form.  Eg.- Dipivefrine(alpha adrenergic agonist antiglaucoma drug) is lipophilic prodrug which hydrolysed by esterases into adrenaline
  9. 9. OCULAR DELIVERY SYSTEMS CONVENTIONAL VESICULAR CONTROL RELEASE PARTICULATE IMPLANTS INSERTS DENDRIMERS IONTOPORESIS COLLAGEN SHIELD POLYMERIC SOLUTIONS CONTACT LENSES MICROONEEDLE MICROSUSPENSION NANOSUSPENSION ADVANCED SCLERAL PLUGS GENE DELIVERY Si RNA STEM CELL ECT MICROPARTICLE S NANOPARTICLES LIPOSOMES NIOSOMES DISCOMES PHARMACOSOME S
  10. 10. CONVENTIONAL TYPES  1- SOLUTIONS  2- SUSPENSIONS  3- EMULSIONS  4- OINTMENT  5- GELS
  11. 11. ADVANTAGE  They are easily administered by the nurse  They are easily administered by the patient himself.  They have the quick absorption and effect.  less visual and systemic side effects.  better patient compliance.
  12. 12. DISADVANTAGE  The very short time the solution stays at the eye surface.  Its poor bioavailability.  The instability of the dissolved drug. The necessity of using preservative.
  13. 13. IDEAL CHARACTERISTICS Sterility Isotonicity Buffer/pH adjustment Less drainage tendency Minimum protein binding
  14. 14. Dosage Form Advantages Disadvantages solutions convenience Rapid precorneal elimination, non sustained action suspension Patient compliance, best for drug with slow dissolution Drug properties decide performance loss of both solutions and suspended particles emulsion Prolonged release of drug from vehicle Blurred vision, patient non compliance ointment Flexibility in drug choice, improved drug stability Sticking of eyes lids, blurred vision, poor patient compliance
  15. 15. CONVENTIONAL Eye Drops:  Drugs which are active at eye or eye surface are widely administered in the form of Solutions, Emulsion and Suspension.  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 % 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.
  16. 16. SOLUTIONS ADVANTAGE-  Ease of bulk scale manufacturing  High pt. Aceptibility  Drug product efficacy  Stability  Cost effectiveness
  17. 17. EMULSION  A Fine dispersion of minute droplets of one liquid into another liquid in which it is generally not soluble or misceble.
  18. 18. EMULSION  Emulsion are of 2 types-  1.Oil in Water- use in ophthal bcoz of less irritance nd better tolerance  2. Water in Oil  Eg.- Difluprednate 0.05%  Difluprednate 0.05% + Moxifloxacin 0.5%  E/d Cyclosporin is Emulsion
  19. 19.  Eg.- Fluribrophen axetil + Castor oil have better bioavailability and less irritation  Eg,- Chitosan coating and HPMC coating of indomethacin increase precorneal residence time
  20. 20. Advantage of emulsion  Improve residence time  Drug corneal permeation increase  Sustain drug release
  21. 21. SUSPENSION  Disperssion of finely divided insoluble API in an aqueous solvent consisting of suitable suspending and dispersing agent  Its activity is particle size dependent. So if size is optimum then optimal activity is achieved.  Suspension must be resuspended by shaking to provide accurate dosage.
  22. 22. SUSPENSION  Eg.- Tobramycin 0.3% + Dexa 0.1% (but have high viscosity)  Tobra 0.3% + Dexa 0.05% (TobraDex ST) have very low settling rate  Moxi 0.5% + Prednisolone 1%  Prednisolone 1%  Nepafenac 0.1% eye drop is suspension  Natamycin  Brinzolamode
  23. 23. OINTMENTS 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 & matting of eyelids can limit its use.
  24. 24. GELS  Eg.- pilocarpine 4% gel  Eg.- several artificial tear preparations are formulated as ophthalmic gels  Eg.- treatment with Timolol 0.5% gel once daily in the morning acheives intraocular pressure level equal to twice daily solution
  25. 25. OINTMENTS  Mixture of semisolid and solid hydrocarbons (parrfins) that have melting point at ocular temp. (34 c).  When applied to inferior conjuctival sac, ointments melt quickly and the excess spread out onto the lid margin, lashes, skin of lids.  It has a therapeutic effect for 6hr.  This method may be of practical value in paediatric and geriartic age group.
  26. 26.  Early formulations of ointment contained waxy grades of petroleum or unwashed lanolin which interfered with corneal wound healing.  Newer ointments not contain these but should be used cautiously in ulcer with impending perforation. And should not be used in any surgical wound in which there is a question of wound integrity, such as when difficulty is experienced maintaining the Ant. Chamber at surgery.
  27. 27. VESICULAR SYSTEM  Vesicular drug delivery system can be defined as highly ordered assemblies consisting of one or more concentric bilayers formed as a result of self-assembling of amphiphilic building blocks in presence of water.  Vesicular drug delivery systems are particularly important for targeted delivery of drugs because of their ability to localize the activity of drug at the site or organ of action thereby lowering its concentration at the other sites in body.
  28. 28. VESICULAR SYSTEM TYPES  1.- LIPOSOMES  2.- NIOSOMES  3.- DISCOSOMES  4.- PHARMACOSOMES
  29. 29. 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.
  30. 30. 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.
  31. 31. Niosomes are nonionic surfactant vesicles that have potential applications in the delivery of hydrophobic or amphiphilic drugs. Discomes may act as potential drug delivery carriers as they released drug in a sustained manner at the ocular site.  Discosomes are giant niosomes (about 20 um size) containing poly- 24- oxy ethylene cholesteryl ether or otherwise known as Solulan 24. Pharmacosomes: This term is used for pure drug vesicles formed by the amphiphilic drugs.  The amphiphilic prodrug is converted to pharmacosomes on dilution with water.
  32. 32. Non ionic surface active agent phospholipid Hydrophilic drugs in aqueous region encapsulated Lipophilic drugs located in the hydrophobic lamella NIOSOME Vs LIPOSOME
  33. 33. Niosomes are microscopic lamellar structures, which are formed on the admixture of non-ionic surfactant of the alkyl or dialkyl polyglycerol ether class and cholesterol with subsequent hydration in aqueous media. Structurally, niosomes are similar to liposomes, in that they are also made up of a bilayer. However, the bilayer in the case of niosomes is made up of non- ionic surface active agents rather than phospholipids as seen in the case of liposomes.
  34. 34. CONTROL RELEASE SYSTEM  1- IMPLANTS  2- IONTOPHORESIS  3- DENDRIMER  4- MICROEMULSION  5- NANOSUSPENSION  6- MICRONEEDLE  7- MUCOADHESIVE POLYMER  8- INSERTS
  35. 35. IMPLANTS  Implants help in circumventing multiple introcular injection and associated complications.  Implants use for drug delivery in posterior ocular tissue
  36. 36. 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
  37. 37. Eg. Of Implants-  NONBIODEGRADABLE-  VITRASERT- controlled release of ganciclovir for t/t of CMV retinitis.  RETISERT- release of Fluocinolone acetonide for t/t of chronic uveitis of post. Segment.  BIODEGRADABLE-  SURODEX- release Dexamethasone for controle of postop inflamation.  OZURDEX- for t/t of Macular Edema
  38. 38. IONTOPHORESIS In Iontophoresis direct current drives ions into cells or tissues. For iontophoresis the ions of importance should be charged molecules of the drug. Positively charged of drug are driven into the tissues at the anode and vice versa.  Ocular iontophoresis delivery is not only fast, painless and safe but it can also deliver high concentration of the drug to a specific site.
  39. 39. Types of iontophoresis- 1. transcorneal 2. transscleral
  40. 40. DENDRIMER  Dendrimer are nanosized, highly branched, star shaped polymerise system  Its highly branched structure allow incorporation of wide range of drugs (Hydrophobic and Hydrophilic )  Dendrimers can successfully used for different routes of drug administration and have better water-solubility, bioavailability and biocompatibility.
  41. 41. MICROEMULSION Microemulsion is dispersion of water and oil stabilized using surfactant and co- surfactant to reduce interfacial tension and usually characterized by small droplet size (100 nm), higher thermodynamic stability and clear appearance. Selection of aqueous phase, organic phase and surfactant/co-surfactant systems are critical parameters which can affect stability of the system
  42. 42. NANOSUSPENSION Nanosuspensions have emerged as a promising strategy for the efficient delivery of hydrophobic drugs because they enhanced not only the rate and extent of ophthalmic drug absorption but also the intensity of drug action with significant extended duration of drug effect. For commercial preparation of nanosuspensions, techniques like media milling and high-pressure homogenization have been used.
  43. 43. MICRONEEDLE 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
  44. 44. Microneedle is minimum invasive mode to deliver in posterior ocular tissue. Penetrate only 100 um of sclera so deposite drug into sclera or into suprachoroid space.
  45. 45. MUCOADHESIVE POLYMER  In this dosage form adhere to the precorneal mucus and residue in the eye until the polymer dissolve or mucin replace itself.  These are in early phase of research.  They are basically macromolecular hydrocolloids with plentiful hydrophilic functional groups, such as hydroxyl, carboxyl, amide and sulphate having capability for establishing electrostatic interactions.
  46. 46. Some mucoadhesives are- carboxymethycellulose. Carbopol, polymethymethacrylate, acrylic acid, polycarbophil, sodium alginate. A mucoadhesive drug formulation for the treatment of glaucoma was developed using a highly potent beta blocker drug, levobetaxolol (LB) hydrochloride and partially neutralized poly acrylic acid (PAA).
  47. 47. INSERTS  The ocular insert represents a significant advancement in the therapy of eye disease. Ocular inserts are defined as sterile, thin, multilayered, drug-impregnated, solid or semisolid consistency devices placed into the cul-de-sac or conjuctival sac, whose size and shape are especially designed for ophthalmic application.
  48. 48. 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-
  49. 49. ADVANTAGE  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.
  50. 50.  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.
  51. 51. Disadvantage  A major 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).
  52. 52. A) Insoluble inserts- e.g. Ocusert®:  20-40µg/hr for 7day  Annular ring : Impregnated with Ti02 : For Visibility 54 1. Diffusional Inserts : •Central reservoir of drug enclosed in Semi permeable or microporous membrane for diffusion of drug. •Diffusion is controlled by Lacrimal Fluid penetrating through it. •Release follows : Zero Order Kinetics.
  53. 53. 3) Contact Lens :  Presoaked Hydrophilic lens.  Drug Release : within 1st 30 Min.  Alternate approach : incorporate drug either as soln or suspension .e.g. Pilocarpine.  Release rate is up to : 180 hr. 55 2) Osmotic inserts • A central part surrounded by a peripheral part • Central part-single reservoir or two distinct compartments. • Peripheral part- an insoluble semi permeable polymer. •The tear fluid diffuse and induces dissolution. •Solubilized deposits generate a hydrostatic pressure. •Drug is then released through these apertures
  54. 54.  Use in treatment of Bullous keratopathy, Dry eye syndrome, corneal condition requiring protection such as traumatic corneal abrasion or erosions.
  55. 55. B) Soluble Inserts 1.SODI: Soluble Ocular Drug Insert. 57 • Small water soluble made of soluble synthetic polymers. • 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. •Single SODI application : replaces 4-12 eye drops Instillation, or 3-6 application of Ointments. •Once a day treatment of Glaucoma. Advantages of SODI :
  56. 56. 2.The corneal collagen shield  A disposable, short-term therapeutic bandage lens for the cornea.  It conforms to the shape of the eye, protects the corneal surface, and provides lubrication as it dissolves.  The shields are derived from bovine collagen and are 14.5 mm in diameter.  Sterilized by gamma irradiation. Disadvantages 1. It is not optically clear. 2. The collagen shield causes some discomfort. Clinical uses 1. Wound healing. 2. Treatment of dry eye. 58
  57. 57.  Shaped like contact lens  Thin membrane of porcine or bovine scleral collagen that conform to cornea when placed on the eye so multiple base curves are not necessary.  Typically the drug is loaded into collagen shield by soaking the shield into intended drug solution prior to application.  Hydrated shield form clear, thin film of 0.1mm thickness, with a diameter of 14.5 and base curve of 9mm.
  58. 58.  Packaged in dehydrated state and require rehydration before application.  Dissolution rate have 12hr, 24hr, 72hr depending on collagen cross linking.  Shield dissolve as a result of proteolytic degradation by the tear film.  Before insertion shields must be rehydrated for atleast 3 minutes in saline, lubricating solution, antibiotic or steroid.  Prior topical anesthetic may required.
  59. 59.  for water insoluble drug such as cyclosporin drug need to be incorporated into the shield at the time of manufacturing.  Collagen shield offers advantage of being entirely soluble so that it so that it does not need to be removed from its site of application.
  60. 60. C) Biodegradable inserts 1.Lacrisert: • Sterile, Rod Shaped device. • Composition: HPC. • Weight:5mg, • Dimension:Diameter:12.5mm, Length:3.5mm • Use:-Dry eye treatment. 2.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 polymer.  Drug release upto170 hr. 62
  61. 61. PARTICULATES (NANOPARTICLES AND MICROPARTICLES) Nanoparticle- <1 micrometre Microparticle- >1 micrometre The maximum size limit for microparticles for ophthalmic administration is about 5-10 micrometer above which a scratching feeling in the eye can result upon ocular instillation.  That is why micro and nanoparticles are promising drug carriers for ophthalmic application.
  62. 62.  Nanopaticles are produced by emulsion polymerisation.  Polyalkylcyanoacrylate are most commonly used ophthalmic nanoparicles.  Many antiglaucoma drugs loaded onto nanoparicles for testing efficacy.
  63. 63. CONCLUSION All approaches improve ocular drug bioavailability by increasing ocular drug residence time, diminish side effects due to systemic absorption and diminishing the necessary therapeutic amount of drug for therapeutic response in anterior chamber. They improve patient compliance by reducing the frequency of dosing. They reduce the dose and thereby reduce the adverse effects of the drug.
  64. 64. ROUTES OF ADMINSTRATION  Instillation into conjuctival sac  Subconjuctival injection  Sub tenon’s injection  Retrobulbar injection  Peribulbar injection  Intraocular injection  Systemic adminstration
  65. 65. SUBCONJUCTIVAL INJECTIONS Use for wider range of substances , as the sclera allows the free and indiscriminate transit of molecules of considerable size. It is usefull when higher intraocular concentration of antibiotic or steroids are required as in acute anterior segment infections and inflamtion.
  66. 66. SUB-TENON’S INJECTION 2types- 1. Anterior 2. Posterior Antrior injection offers no advantage over sub conjuctival injection. Infact it is associated with perforating the globe However anterior subtenon’s injection of corticostroids are occasionaly used in the treatment of severe uveitis.
  67. 67. Posterior subtenon’s injection- Used in t/t of chronic equatorial and mid zone posterior uveitis, including inflammation of the macular region.
  68. 68. RETROBULBAR INJECTION  This procedure was originally devloped to anesthetize the globe for cataract extraction and other intra ocular surgery.  However retrobulbar corticosteroids are used occasionally  Retrobulbar alcohol or phenol is rarely adminstrated for intractable ocular pain in blind eye.
  69. 69. PERIBULBAR INJECTIONS  Its also use the scleral route for acess into eye.  A short curved needle with its bevel towards the globe is passed through a conjuctival incision, and medication injected close to the inflamed tissue.  Use for t/t of intermediate and posterior inflamations.
  70. 70. INTRAOCULAR INJECTION  1- Intracameral- injected into anterior chamber  2- Intravitreal- into vitreous  Half life of many drugs in Aqueous is only a few hours, but in Vitreous it maybe 1-4 days.
  71. 71. SYSTEMIC ADMINSTRATION  Disease which involve posterior part of retina, optic nerve or orbit that can not be reached by local application require systemic adminstration.

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