Phar 323 Ophthalmic Drug Delivery

Front 1

most common ophtalmic drug delivery system

Back 1

eye drops

Front 2

drug absorption from drops can be increased by:

Back 2

-waiting 5-10min between drops

-compressing lacrimal sac

-keeping lids closed for 5 min after instillation

Front 3

eye drops must be:

Back 3

sterile, buffered, isotonic

Front 4

advantages of ophthlamic solutions

Back 4

-no or little interference with vision

-drug can be rapidly taken up by tissues

Front 5

disadvantages of ophthalmic solutions

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-brief contact time between medication and absorbing surfaces

contact time may be increased by adding a viscosity enhancing agent (eg methylcellulose)

-viscosity between 15-25cP is ideal for retention and comfort

-water is 1cP, veg oil is 50cP, antifreeze 15cP

Front 6

ocular ointment bases

Back 6

-typical bases consist of mixtures of petrolatum and liquid petrolatum (mineral oil)

-want an ointment that "liquifies" at body temp

Front 7

advantages of ocular ointments

Back 7

increase contact time of ocular medication

-more drug uptake, better effect

Front 8

disadvantages of ocular ointments

Back 8

blurred vision for the first few minutes

Front 9

ocular ointments are effective for what type of drugs?

Back 9

highly lipophilic drugs with some water solubility

sometimes a water miscible agents such as lanolin is added to allow water soluble drugs to be incorporated

(lanolin is amphiphilic compound - surfactant - get w/o emulsion)

Front 10

ocular bioavailability

Back 10

a combination of overflow losses, nasolacrimal drainage and dilution results in very inefficient ocular absorption and typical bioavailabilities in the range o f1-10%

-most drugs are in lower end of this range

Front 11

drainage of intraocular fluid

Back 11

10-20% through uveoscleral pathway

(uvea = cornea, ciliary body, iris)

80-90% through trabecular meshwork and Schlemm's canal

2-3uL/mL to episcleral vein (to systemic circulation

Front 12

transcornial diffusion

Back 12

corneal abs represents major mechanism of abs for most drugs

-abs of drugs is rate limited by cornea

-cornea composed of 3 major diffusion barriers: epithelium, stroma, endothelium

-epithelium is rate-limiting barrier for abs of hydrophilic drugs because it contains high lipid content (100x more than stroma)

-stroma (mostly hydrated collagen is rate-limiting barrier for very lipophilic drugs

-endothelium is lipoidal in nature, but does not offer a significant barrier to transcorneal diffusion of most drugs

Front 13

layers of cornea

Back 13

1200um:

epithelium (hydrophobic)

bowman's membrane

stroma (hydrophilic)

descemet's membrane

endothelium (hydrophobic)

Front 14

losses of drug during disposition in the eye

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precorneal area:

-conjunctival-scleral binding

-tear protein binding

-nasal lacrimal drainage

cornea:

drug-protein binding

-enzyme degradation

anterior chamber:

-drug-protein binding

-enzyme degradation

-trabecular network drainage

Front 15

ophthalmic suspension

Back 15

dispersion of finely divided solid drug particles in an aqueous vehicle containing suspending and dispersing agents

-surrounding soln is saturated w drug

-drug is absorbed from soln which is replenished from solid particles

Front 16

advantages of ophthalmic suspensions

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contact time and duration of action exceeds that of soln

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disadvantages of ophthalmic suspensions

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cosmetically not the most attractive

solid drug particles may irritate the eye, leading to excessive tearing and removal of the dose

-particles should be less than 10um

-careful of temp changes and Ostwald ripening (crystal growth)

Front 18

ocular diagnostic drugs

Back 18

Fluorescein dye

-available as drops or strips

uses:

-stain corneal abrasions

-applanation tonometry

-detecting wound leaks

-nasolacrimal duct (NLD) obstruction

-fluorescein angiography

caution:

-stains soft contact lenses

-fluorescein dropscan be contaminated by Pseudomonas sp

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principles of formulation of ophthalmic delivery systems

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1. Tonicity

2. Sterility

3. pH and buffers

4. Viscosity

5. Surfactants: wetting agents

Front 20

Tonicity (ophthalmic formulations)

Back 20

eyes can tolerate equivalents of 0.5-1.6% NaCl without great discomfort

-adjust ophthalmics to isotonicity wherever possible

Front 21

examples of tonicity agents

Back 21

NaCl

Dextrose

Glycerin

Front 22

examples of preservatives

Back 22

benzalkonium chloride

phenylethyl alcohol

chlrobutanol

phenylmercuric nitrate

parabens

EDTA often added to enhance effectiveness of preservatives

Front 23

pH and buffers (ophthalmic formulations)

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stability

-optimal stability for most weak base salts is low pH (2-4)

irritation

-pH of tears is 7.4

-irritation occurs at pH > 8 or <6

solubility

-for weak base salts, solubility is increased at lower pHs

optimizing pH: stability is most important consideration but may have to compromise if pH is too low

-tears have some buffering capacity and can raise pH of drug soln

Front 24

examples of buffers

Back 24

boric acid

phosphate

Front 25

viscosity (ophthalmic formulations)

Back 25

increase viscosity:

-increase contact time on cornea

-decrease nasolacrimal drainage rate

-increase abs and bioavailability

Front 26

examples of viscosity agents

Back 26

methylcellulose

hydroxymethylcellulose

polyvinyl alcohol

gellan gum

Front 27

examples of surfactants (wetting agents)

Back 27

nonionics only: polysorbates

Front 28

Pluronic PF127

Back 28

thermosensitive polymer

-viscous liquid at room temp, turns into semisolid transparent gel at body temp

driving force: water-polymer interaction, phase change at lower critical soln temp (LCST)

PEO-PPO-PEO triblock copolymer

Front 29

how gel dissolution relates to drug release

Back 29

the higher the drug dissolution, the more drug released

Front 30

Ocular DDS Reservoir Devices - rate controlling membrane

Back 30

-assume that the concentration in the reservoir is very high (assumed constant) and the concentration in the sink is very low (~0)

-after an initial unsteady period, we will reach steady state

-zero order release (constant rate of drug release from device)

Front 31

what type of drugs are good to use for intraocular inection therapy?

Back 31

if can't get drug in another way

(eg Pilocarpine goes in so well from patch or eye drops so don't need injection)

commonly used:

-hydrophilic antibiotics

-antibodies

Front 32

example of intracameral injection

Back 32

intracameral acetylcholine during cataract surgery

Front 33

examples of intravitreal (intraocular) injection

Back 33

-intravitreal antibiotics in cases of endophthalmitis

-intravitreal steroid in macular edema

Front 34

Peri-ocular injections

Back 34

-bypass the conjunctival and corneal epithelium

-good for drugs with low lipid solubility (eg penicillins)

Front 35

drawbacks of intraocular injections

Back 35

-poor pt acceptablity

-rapid drug elimination from vitreous humor (to systemic circulation)

-potential retinal toxicity

-hazards associated with repeated intravitreal injections (clouding of vitreous humor, retinal detachment, lens damage, endophtalmitis)

to minimize these, frequency of injection should be reduced with adequately designed controlled release systems (once or twice per year)

Front 36

components of retina

Back 36

some blood vessels

photoreceptors (rods/cones)

retinal pigment epithelial cells

Bruch's membrane

Choroidea (blood vessels)

Sclera

Front 37

Vitrasert

Back 37

-tablet-shaped implant containing 4.5mg ganiclovir and coated with polyvinyl alcohol and ethylene vinyl acetate

-release takes place over 5-8 mths by passive diffusion through a hole in the system (not degradation!)

-indicated for site-directed intravitreal therapy of CMV (cytomegalovirus) retinitis in pts w AIDS

Front 38

components of Vitrasert

Back 38

-impermeable polymer (ehtyl vinyl acetate)

-permeable polymer (polyvinyl alcohol) - regulates release of drug

-ganiclovir

-suture tag

Front 39

magnetic stem cell delivery

Back 39

stems cells that can take up nanoparticles

-put magnet under plate

-cells move to magnet and accumulate

-cells filled with magnet nanoparticles (magnitized stem cells)

-inject into pt

-magnet at back of eye

-attract particles close to retina