Ophthalmic Drug Considerations

1. Ophthalmic DrugConsiderations Chapter 2 & 3 Clinical Ocular Pharmacology Bartlett & Jaanus

2. Movement of Drugs Within the Eye • The eye can be viewed as a series of compartments (Tear/Cornea/Aqueous/…) • Movement of medications in the eye depends on barrier resistance & passive diffusion.

3. Tear Film Considerations The Lipid Layer • Outermost. • Primarily from Meibomian glands. • Limits evaporation. • Readily washed away by saline or meds. • A change in Meibum causes a decreases tear film stability.

4. Tear Film Considerations Aqueous Layer • Thickest layer (7µm). • Unstable – Begins to thin after blink. • Healthy patient breakup time (BUT) averages 25 to 30 seconds. • Review the TBUT

5. Tear Film Considerations Mucin Layer • Composed of glycoproteins • Secreted by goblet cells. • Aids in cleansing the eye of particulate debris.

6. Tear Film Considerations • pH = 7.4 • Normal tear volume = 8 to 10 µl. • Maximum tear volume = 30µl. • Normal tear flow = 0.5 to 2.2 µl/min. • Decreases with age. • Increased by ocular irritation.

7. Effect of Drop Size in Drug Formulation Usual drop size is 50 µl (0.05 ml) • excess drains onto lid or into nasolacrimal duct. • systemic load increases linearly with drop size. • reducing bore size can achieve drops as small as 2 to 5 µl.

8. Effect of Tear Flow inDrug Formulations The amount of drug available to penetrate the cornea is inversely proportional to tear flow. • Punctal occlusion – reduces tear flow & increase drug concentration. • Age – reduced tear volume, decreased tear flow and epithelial cell damage leads to irritation of the eye? • Irritating drugs – increases tear flow & decreases drug concentration.

9. Cornea Considerations in Drug Formulation The Epithelia: • Basically a continuous plasma membrane barrier, resisting hydrophilic drugs. • Readily penetrated by lipophilic drugs.

10. Cornea Considerations in Drug Formulation The Corneal Stroma • 90% of the corneal thickness. • Close collagen bundles & proteoglycans. • A depot for hydrophilic drugs.

11. Cornea Considerations in Drug Formulation • Topically applied drugs must be lipophilic to penetrate the epithelia AND hydrophilic to penetrate the stroma. • Partition coefficient – will predict the drugs ability to penetrate the cornea.

12. The Partition Coefficient • Too low – the drug does not penetrate the epithelial barrier. • Too high – the drug tends to stay in the epithelia and only slowly enters the anterior chamber.

13. Cornea Considerations in Drug Formulation The Corneal Endothelium: • A Monolayer about 3 µm thick. • Loose intercellular junctions allowing water & solutes to leak into the stroma. • Actively pumped out (Na-K pump). • Injected fluorescein can accumulate in the stroma via the aqueous.

14. Other Ocular Structures and their Influence on Drugs Iris: • Pigment absorbs lipophilic drugs & can release them slowly over time. Ciliary Body: • Systemic medications enter the Anterior Chamber via the ciliary body vasculature and diffusing into the iris. • Contains drug metabolizing enzymes.

15. Other Ocular Structures and their Influence on Drugs The Crystalline Lens: • Primarily a barrier for drugs going from the aqueous to the vitreous. • High molecular weight hydrophilic drugs cannot be absorbed because of the lens epithelia. • The capsule prevents entry of large proteins. • Lipophilic drugs can enter but very slowly.

16. Other Ocular Structures and their Influence on Drugs The Vitreous: • Primarily acts as a depot for slow drug administration. • Injected drugs only because of the blood-retina barrier. • Injected hydrophilic drugs can have a half-life of 24 hours or more.

17. Other Ocular Structures and their Influence on Drugs The Retina: • Blood-Retina barrier protects against toxins and other hydrophilic drugs. • Lipophilic drugs cross the barrier easily in either direction.

18. Retinal Vessels: Removes drugs from Retina and Vitreous by Active transport. Uveal Vessels: Removes drugs from the iris and ciliary body by Bulk transport. Blood Supply & Drug Removal from the Eye • Direct Anterior Outflow: • Aqueous through TM, Canal of Schlemm and into episcleral vessels.

19. Prodrugs • The original drug becomes metabolized and the metabolite is the active drug. • A method to bypass the natural barriers of the eye. Example: Dipivalyl epinephrine

20. Considerations in Ophthalmic Drug Formulation Shelf Life/Stability: • At least 90% of the concentration on the bottle is present in the active form after storage at room temperature for the shelf life requested. • Once a sealed bottle is open the drug is subject to more rapid degradation.

21. Considerations in Ophthalmic Drug Formulation Stability: • Acidic formulations are generally more stable. • Sudden changes in pH can cause irritation. • What effect can this have on a drugs effectiveness?

22. Considerations in Ophthalmic Drug Formulation Osmolarity: • The tear film has a wide tolerance of osmolarity. • Hypertonic formulations will require dilution and the movement of water from the eye and lids will occur. (Muro 128) • Most ocular drugs are 290 mOsm.

23. Considerations in Ophthalmic Drug Formulation Preservatives: • Additives to assure sterility of the drugs. • Can irritate the eye and damage the ocular surface if the concentration is too high.

24. Preservatives Surfactants: • Ionically charged molecules that disrupt the plasma membrane -- Bactericidal. • Example is Benzalkonium Chloride (BAC) • toxic effects on corneal epithelia and tear film.

25. Preservatives Mercurials: • Works by disrupting internal cell respiration. • Example is Thimerosal • Caused contact sensitivity after weeks to months of use.

26. Considerations in Ophthalmic Drug Formulation Vehicles: • An agent other than the active drug or preservative that provides proper tonicity, buffering and viscosity to complement drug action -- Mullen et al, Surv Ophthal. 1973

27. Vehicles 1)Polyvinyl Alcohol (PVA) 1.4%: • used to increase residence time which helps with ocular absorption. 2) Hydroxypropyl Methylcellulose (HPMC) 0.5%: • has 2x the ocular retention time of PVA. • can increase the ability of some drugs to penetrate the cornea.

28. Vehicles Ointments: • Primarily a mixture of white petrolatum and liquid mineral oil. • Antibiotics are usually more stable in this vehicle. • Primary purpose is to increase the ocular contact time. • Advantages/Disadvantages

29. Drug Delivery

30. Topical Medications • Most common form of delivery in eye care. • Drugs that are toxic when delivered systemically can be used topically. • Primary source of drug loss is diffusion into the blood which results in decreased penetration into the eye.

31. Solutions & Suspensions • Advantages include ease of use, can be administered by patient, little disruption in vision. • Disadvantages include short contact time, possible injury & contamination of the tip. • Suspensions must be shaken before every dose. Example – Steroids

32. Pearls Concerning Eye Drops • Today’s eye drop delivery systems will administer 25 to 56 µl per drop. • One milliliter usually will deliver 15 - 20 drops. • Refrigeration will help the patient know that the drop was delivered correctly. • Expired eye drops increase the chance of drug toxicity and infection from contaminated product.

33. Eye Drop Instillation • Suggested to keep the tip at least 2 cm from the globe. • May instill onto the superior bulbar conjunctiva or inferior palpebral conjunctival sac. • Nasolacrimal occlusion for 2 to 3 minutes or eye closure for 1 to 2 minutes.

34. Unit-Dose Dispensers • Useful in patients requiring frequent long-term use of eye drops. • After the initial instillation the remaining solution should be discarded after 12 hours. • There are variants that have replaceable tips.

35. Ointments • Very good for medications that require longer contact time. • The longer contact time can result in contact dermatitis. • Can be applied in a number of ways. • Examples • When applied to the conjunctival sac they will cause blurred vision.

36. Lid Scrubs & Gels • Lid scrubs are useful in the treatment of seborrheic or staphylococcal blepharitis. • Home-made with baby shampoo or commercial preparations (Eye-Scrub by CIBA Vision, OcuClenz by Storz/Lederle, OCuSOFT by Cynacon/OCuSOFT). • Gels increase contact time like ointments but without the blur. (GenTeal Gel)

37. Solid Delivery Methods 1) Presoaked Soft Contact Lenses • Can provide aqueous levels as good as subconjunctival injections. 2) Collagen Shields • Rehydrated in the desired drug. Instilled after topical anesthetic. (Ex – B&L’s Bio-Cor)

38. Solid Delivery Methods 3) Filter Paper Strips • Primarily used in the diagnostic dyes fluorescein, lissamine green and rose bengal. 4) Cotton Pledgets • A 5 mm cotton segment soaked in drug. Good for dilating sluggish pupils or breaking posterior synechiae.

39. Solid Delivery Methods 5) Lacriserts • 1x4 mm pellet delivering 5 mg of hydroxypropylcellulose. • One pellet every 24 hours (Sometimes 2QD) • Blurry vision within 4-6 hours. 6) Ocuserts • A 2-membrane device delivering Pilocarpine at a constant rate. • More expensive and irritating to the patient.

40. Ocusert

41. Subconjunctival Injection • The delivery of drug between the conjunctiva and Tenon’s capsule. • Greatest benefit is in the treatment of severe corneal disease. • Delivers a greater concentration over a longer period of time. • Antibiotics and Steroids.

42. Intracameral & Intravitreral Intracameral - Injecting directly into the anterior chamber. • Commonly used with viscoelastic • Antibiotics can only be used in very small amounts. Intravitreal – injection directly into the vitreous. • Used to bypass the tight junctional complexes of the RPE & retinal capillaries of the blood-ocular barrier. • Endophthalmitis & Retinitis.

43. Intravitreal Injection

44. Have a Great Day!