Ocular Drug Delivery Flashcards
- Describe the main regions of the eye.
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Front of eye:
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Cornea
- 5 basic layers of alternating lipid & water barriers
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Nasolacrimal duct
- Drains away the liquid in the eye via the nasolacrimal duct to the GI tract
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Conjuctiva
- Direct absorption into eye due to its large SA and vasculature (thus rapid removal from cornea)
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Cornea
- Back of eye:
- Vitreous
- Clear gel that fils the space betweent the lens and the retina. Thus, slow diffusion.
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Retina
- Retinal blood vessels has a Blood-Retina Barrier (tight junctions, pgp, cyp3A4)
- Vitreous
Describe the structure of the cornea and why the structure is difficult for most drug delivery into/across.
- Cornea structure consists of 5 basic layers
- Epithelium
- Bowman’s Layer
- Stroma
- Descemet’s Layer
- Endothelium
- This alternating lipid & water barrier makes it difficult for drugs to penetrate, as they will need:
- Specific set of properties to penetrate
- Time at the surface
What is the ultimate aim of topical treatment for the front of the eye?
Maintain contact while avoiding increased tear production.
Describe one consideration when delivering a topical treatment to the front of the eye.
- The eye does not have enough volume capacity to hold the volume of an administered dose, and is thus lost to overflow.
- Normal volume of tears in eye: 7 uL
- Maximum volume in eye (no blinking): 30 uL
- Volume of 2 drops of standard dropper: 100 uL
- Thus 70% of administered dose is lost
Describe THREE factors that affect transcorneal absorption. Which of these compete for route of drug clearance?
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Drainage via Nasolacrimal system
- Drained to throat, stomach, intestine.
- Stimulted by an INCREASE in volume in eye (>7uL)
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Absorption into Conjunctiva
- Large SA & very vascular. Therefore, rapid removal of drug.
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Ionisation
- ionised drug won’t partition into cornea
- Thus, there is only an absorbable fraction
Describe FOUR factors affecting nasolacrial drainage.
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Irritation due to change in surface tension
- Tear film is stabilised by the outermost lipid
- Addition of components (i.e. surfactants) can decrease surface tension by disrupting the lipid film to get a dry eye for better absorption.
- increase irritation = increase drainage = decrease residence time = decrease ocular absorption
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Irritation due to osmolarity
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Hyper- and hypo- tonic solutions are irritant
- Increase iritation = increase drainage = decrease residence time = decrease ocular absorption
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Hyper- and hypo- tonic solutions are irritant
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Particulates
- Increase irritacy = increase tears = increase clearance
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pH
- pH of tears = 6.9 - 7.5 (poor buffer capacity)
- instillation of solutions outside this range will cause
- irritation = increase tear throughput (replace tears) = increase drainage = decrease residence time = decrease ocular absorption
“Surfactants in eye formulation components is possibly counter-productive” Discuss.
- Surfactants are used to decrease the surface tension by disrupting the outermost lipid film of the eye.
- This helps to increase absorption across the surface of the eye.
- And causes a dry eye, which is also good for absorption because less tears are there for clearance.
- However, a dry eye will increase irritation, thus increasing tear production = stimulates nasolacrimal drainage = decreases the resisdence time for the drug on the eye = decreases transcorneal absorption.
What can be a limitation for using a suspension to administer poorly water soluble drugs, such as prednisolone (Prednefrin Forte)?
What is the formulation consideration for developing these suspensions?
- Suspension are essentially solid drug particles suspended in a liquid.
- Particulates in the eye can affect the rate of clearance because it causes irritancy which increases tear production from lacrimal glands, which then stimulate nasolacrimal drainage, thus increasing clearance of the drug.
- Therefore, dissolution rate must be greater than rate of clearance from cul-de-sac for the suspension to be absorped.
What is a formulation consideration of the pH of a topical eye drug? Why?
- The pH of the ocular solution can’t be too different from the pH of the tears (6.9 - 7.5) due to its poor buffer capacity. Otherwise, it will lead to irritation and increase in tear production from lacrimal glands, which stimulate nasolacrimal drainage, thus reducing residence time for the drug, and its ocular absorption.
Given that the pH of the eye is between 6.9 - 7.5 (poor buffer capacity), why is Pilocarpine buffered to a pH of 5, despite increased absorption occurs at higher pH?
- Pilocarpine has maximum stability at pH of 5.
- Pilocarpine is a base with pKa = 7.3
- Therefore, if the pH is increased to pH 9, it will become 99% un-ionised = better absorption into the lipid membrane of the cornea
- But, Pilocarpine also contains a lactone ring
- which undergoes hydrolysis, thus causing the pH of max stability around 5.
- = increases shelf-life
- Pilocarpine is a base with pKa = 7.3
- Therefore, most commercial formulations are buffered to a pH to 5 as a trade off to optimise shelf-life by sacrificing absorption.
Describe THREE methods of reducing clearance of drug in the eye.
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Viscous solutions (or gels)
- Increase viscosity; increases retention; increases bioavailability
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In-situ gelling agents
- Gel is rapidly formed from solution in response to temperature, ionic strength, or pH
- increases viscosity
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Ocular inserts
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A drug reservoir inbetween two polymer membranes that provides drug release for around a week
- increases exposure of the drug
- A flux enhancer can also be added to the reservoir to increase rate of delivery
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A drug reservoir inbetween two polymer membranes that provides drug release for around a week
How can you increase the rate of delivery in an ocular insert?
Add a flux enhancer to the reservoir.
List some advantages and disadvantages of ocular inserts.
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Advantages:
- Good science
- Good kinetics
- Reduced side effects
- Increased exposure of drug
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Disadvantages:
- Cost
- Requires good manual dexterity
- Invasive
“Drug delivery to the vitreous for internal treatment via systemic circulation is more significant than via the transcorneal route due the high blood flow of the retinal blood vessels.” True or False. Discuss.
- False.
- Despite retinal blood vessels having very high blood flow.
- The penetration from the systemic circulation is even more limited than transcorneal route.
- This is due to the Blood-Retina barrier.
- Has Tight junctions, P-gp, cyp3A4, etc.
What are the limitation of using intraviteral injections for Aged Related Macular Degeneration?
- Need to have injections for life due to its chronic condition
- Duration of action is poor, therefore injections are repeated around every 4 weeks
- Each injection = risk of infection
