OPHTHALMIC DRUG DELIVERY 1. Key concept on ophthalmic drug delivery a. Route of absorption - ONLY through anterior segment tissue (cornea to lense) b. Amount of absorption - < 1% of instilled dose = poor bioavailability → 99% get into systemic circulation → high enough concentration → systemic side effects 2. Disease of the eye a. Anterior segment ocular disorder i. Dry eye – could be due to many different disorder (autoimmune, etc) ii. Infection – found in other countries & babies due to lack of immune system in eye iii. Glaucoma – increase in ocular pressure → optic nerve damage → diagnosis by measuring optic pressure iv. Cataracts – lens disorder, no drug available → surgery b. Posterior segment ocular disorder → must inject drug into the back of eye to treat i. Degeneration – age related macular degeneration (ARMD), retinitis pigmentosa ii. Vascular – diabetic retinopathy, retinal vein/artery occlusion, retinopathy of prematurity iii. Inflammation – uveitis iv. Infection – endophthalmitis v. Other – glaucoma, optic neuritis 3. Anatomy of eye a. Schlemm’s canal – drain aqueous humor from eye → no build up of pressure → no optic nerve damage b. Vitreous chamber – filled with gello-like hydroacid fluid c. Ciliary body – secrete NaCl into anterior chamber → water follow into anterior chamber i. Glaucoma drug - ↓ inflow & ↑ outflow → ↓ pressure d. Iris – had pigment produced by melanocyte → non- covalently bind to drug → keep drug around longer → good/bad depending what kind of drug & what drug is for e. Conjunctiva – highly vascularized, transparent layer that coat 80% of eye surface, sitting on top of sclera layer, continuous with cornea → major route for drug to enter systemic circulation i. Has globet cell → produce major component of tear (mucin, glycoprotein & antioxidant) → may interfere with drug delivery ii. Mechanism of transport – Paracellular – for hydrophilic solute (ions & water) → allow molecules up to 20kDa through (equivalent to pore wit radius of 5.5nm) >< < 5kDa for cornea 1. Active transporter on conjunctiva – L-NAME, neutral & cationic aa, nucleoside analog iii. Has microvilli cell – directional transport substance in 1 direction f. Aqueous humor i. Composition – 0.02% protein, with 1%/min turn-over rate ii. Location 1. Anterior chamber – region from lens to cornea, contain aqueous humor where [drug] is measured, has volume of 300μL = small volume → drug is concentrated → effect 2. Posterior chamber – 57μL iii. Function 1. Provide nutrition for lens & cornea 2. Generate pressure → maintain intraocular psi shape of cornea a. Normal condition – 15-18mmHg above Patm, > tissue (2-3mmHg) & CSF (7mmHg) b. Glaucoma – 20-40mmHg → asymptomatic until vision is lost 3. Distribute drug → where [drug] is sampled g. Cornea – avascularized, thin, transparent elastic layer covering 1/6 eye surface → 1o tissue preventing drug from getting into eye = direct route into anterior chamber i. Avascularized → receive nutrient & antibody through diffusion from aqueous humor ii. Lack immune system → may develop herpes → lesion to cornea → Tx – cornea transplant iii. Tight junction – cell joint by tight junction → only allow lipophilic molecule < 5kDa to get in iv. Has 5 layers – corneal epithelium, Bowman’s MB, stroma, descemete’s MB, & endothelium 4. Bioavailability of topical ocular drug a. Precorneal factors influences ocular drug bioavailability/ uptake i. Mixing – due to reflex blinking, viscosity, miscibility, surface tension ii. Tear –0.7% protein (<< blood 7%)low buffereing capacity → allow drug to be buffered at any pH 1. Dilution – tear resident volume is 7.5μL → ↑ total volume of solution without ↑ in total drug amt → ↓ [drug] → ↓ concentration gradient J = -D dC/dx a. EX - drug droplet is 30μL, tear is 7.5uL → total volume is 37.5μL b. Calculation EX – instill 30μL of 0.5% Timoptic → total volume – 30 + 10 = 40 μL → [drug] = (0.5% * 30μL) / 40μL = 0.375% → remained drug absorbed into systemic circulation 2. Drainage – into nasolacrimal duct → drug can be delivered into systemic circulation through rich vasculature of nasal cavity >< low volume = small drug amount → must be a very potent drug a. Eye tend to maintain tear volume constant at a turn-over rate of 16%/min (1μl/min) which ↓ as age ↑ & during sleep or local/ general anesthesia b. Drug application/ ↑ pH or tonicity → disturb homeostatis → eye ↑ tear production = ↑ total volume → ↑ rate of drainage c. The smaller the instilled volume, the lower turn-over rate, the longer drug remained in eye >< too small volume = not enough drug is delivered or drug is not soluble enough → most instilled volume = 25μL 3. pH = 7 on average >< varies from 7.30 to 7.5 throughout the day → influence drug absorption depending when drug is applied iii. Osmolarity – 270 to 300 mOsm/L → drug at this osmolarity doesn’t not hurt 1. Hypotonic drug – give soothing effect >< cell swell → drug cant be absorbed well 2. Hypertonic drug – not comfortable → tearing → lost of drug due to drainage >< stabilize cell → drug can be absorbed easily 3. Must choose a tonicity that is balanced between drug absorption & comfort iv. Protein binding – Drug + Protein → Drug-Protein = inactive drug – the more protein, the less drug available for effect v. Metabolism – not well studied, may convert pro-drug into active drug. EX – xalatan must be metabolized into active drug vi. Conjunctival loss – conjunctiva cover 80% eye surface with present of blood & lymphatic vessels → drug can get into systemic circulation through large surface area b. Experiment i. 3 conditions – drug (A) exposed to cornea & conjunctiva, (B) only exposed to conjunctiva, (C) only exposed to sclera (conjunctiva removed) ii. Measurement – in aqueous humor, cornea & ciliary body at different time iii. Conclusion – 1. Lipophilic drug – hydrocortisone → drug absorbed through cornea only 2. Hydrophilic drug – pilocarpine → some absorption into ciliary body → conjunctiva play some role in drug absorption >< cornea is still major route of absorption c. Factors improve bioavailability i. ↓ solution drainage ii. ↓ tear turn over iii. ↓ drug metabolism iv. ↓ conjunctival absorption v. ↓ protein binding vi. EX – valycyclovir – metabolized into avacyclovir (active form) by replacing NH2 group with OH (not ionized at tear pH) → more drug can be absorbed + valycyclovir are transported by protein transport into cornea vii. EX – xalatan (synthetic prostaglandin) must be metabolized into active form → must prevent metabolism before prodrug entering cornea to ↑ amount of drug absorbed 5. Other ocular dosage form & their bioavailability – all dosage form has same elimination rate once dissolved a. Suspension – reside on cornea longer = depot effect (stick to conjunctiva → get release after drug in other area has been washed away) → work better than solution i. Middle line in graph – suspension = drug remained in aqueous humor much longer after drug in solution has been completely eliminated b. Ointment – use absorption base i. Advantages 1. ↑ viscosity → longer contact time (longest among 3 different dosage form) 2. ↑ [oil-soluble drug] in oleaginous base→ ↑ concentration gradient. EX: fluorometholone 3. Water soluble drug (pilocarpine) → can be made with surfactant >< not as much drug get in ii. Disadvantages 1. Mixing problem – ointment cant be mixed easily with tear → dependent on mechanical mixing to ↑ surface area for absorption 2. Uncomfortable – drug must partition from ointment to tears → drug might not want to get out of ointment base 3. Rupture – ointment may soften cornea → ↑ rupture chance c. Inserts – contact lens form i. Controlling rate of release of drug → ↑ Pt compliance & ↓ systemic SE ii. Best for pilocarpine (has lots of side effect) iii. EX – ocusert for chronic open angle glaucoma – lens of flexible,, biocompatible ethylene/vinyl acetate copolymer MB = hydrophobic → reistant osmotic uptake of water, z dilution of drug + core of pilocarpine & alginic acid + annular ring d. Gel – bioadhesive system = solution that turn into gel when exposed to tear → adhesive bonding to mucin or epithelium → keep drug in place longer i. Type of gel 1. Form gel due to temperature stimulus – Poloxamer 407 (polysaccharide) → gel at body temperature 2. Form gel due to pH stimulus – cellulose acetate phthalate (carbohydrate polymer) → gel at higher pH → formulation must be made at pH 4.5 to prevent gelling → cant be used for eye due to low buffering capacity + high pH is painful to eye 3. Form gel due to ions presence – Gelrite (low acetyle gellan gum = linear chain of polysaccharide of glucose, rhamnose & glucuronic acid subunits) → gel in present of Na+, Ca2+, Mg2+ found in tear e. Subconjunctival route i. Iontophoresis – inject drug using electrodes (1 with drug on outside, 1 without inside) >< slow ii. Nano/microparticle matrix materials – implantation of polymer under conjunctiva → drug is released overtime → good for chronic glaucoma 6. Route of systemic entry for topical ophthalmic drug a. Through conjunctiva & lymphatic drainage b. Through vascular system in back of eye after absorption (1-5%) c. Through nasal cavity vascular system → block this drainage with pressure → ↓ systemic absorption d. Case study – timolol systemic absorption i. Gel form – bottom line, has lowest systemic absorption (very low k1) since amount drug release is mostly absorbed into eye → not as much drug get into nasal cavity ii. Suspension – middle line – almost as high systemic absorption as top line (solution) with longer duration in plasma relative to solution iii. Solution – square dot – highest systemic side effect, but drug is also eliminated faster 7. Review questions a. How does volume of solution instilled affect percent of dose absorbed into eye? Inverse relationship b. Based on what is known of precorneal solutions dynamics, i. What would be the ideal instilled dose volume? Why? 30μL , < 30μL = not enough drug, > 30μL = too high turn over rate ii. In multidrop therapy, would the order of drop instillation affect drug bioavailability? How far apart should the drops be spaced? What would be a solution to the problem? c. How do polymers reduce the rate of solution drainage? Gel or contact lens i. What polymers can be used? ii. Would the chemical nature of the polymer affect the rate of solution drainage? Yes on lipiphilic vs. hydrophilic drug d. How do solution pH and tonicity affect the percent of instilled dose of a weakly acidic drug that would be absorbed into the eye? e. Which of the five layers in the cornea is the rate-limiting barrier to the drug penetration? Epithelium f. How can the integrity of the corneal epithelium be disrupted? Oily substance can soften cornea g. How can corneal drug penetration be improved? h. How would the size of the particles in an ophthalmic suspension affect ocular drug bioavailability? i. Would the ocular pharmacokinetics of water-soluble drugs in an oleagenous ointment be the same as that of oil-soluble drugs? Please explain. j. Would the drug release rate from an Ocusert be dependent on the physicochemical properties of the drug? Please explain. k. Can precorneal drug residence be achieved using a soft-contact lens? Please explain. l. How can systemic drug absorption following topical ocular drug administration be reduced?