Lecture 10: Ocular Drug Delivery I Flashcards
What is the conjunctiva?
Thin mucous membrane lining eyelids and sclera
What are the main components of the eye?
Conjunctiva Conjunctival cul de sac (fornix) Nasolacrimal duct Cornea Anterior chamber Posterior chamber
What is the role of the conjunctiva?
Secrets mucin, contains heavily glycosylated proteins
What is the conjunctiva cul de sac or fornix?
Loose arching foods connecting conjunctival membrane lining the inside of the eyelid.
It is the site of application for most opthalmic dosage forms and has a capacity of approx 10ul
What is the cornea?
A clear, transparent and multilayered component of the eye
The membranes of the cornea present a biphasic environment:
What is the biphasic environment of the cornea?
Lipophilic epithelial and endothelial membranes
Hydrophilic stroma in the middle
Drugs therefore must possess biphasic solubility characteristics to gain access to the anterior chamber of the eye
What is the anterior chamber?
Fluid filled chamber between iris and cornea
What is the posterior chamber?
Fluid filled chamber between lens and iris
What are the different types of anterior segment disease?
Blepharitis Dry eye Corneal infection Keatoconus Keratopathy and band keratopathy Conjunctivitis
What is blepharitis ?
Inflammation of the eyelids
Treated with antibiotic eye drops
What is dry eye?
When there is inadequate production of tears to lubricate the cornea
Treated with artificial tears (CMC, PEG, PVA)
What is corneal infection?
Infection of the cornea. Could be bacteria, fungal or viral
Treated with antibiotic eye drops?
What is keratoconus?
When the corneal collagen cross links with the riboflavin
Treated with…
What is keratopathy and band keratopathy ?
…
Treated with naltrexone and IGF
What is conjunctivitis?
Inflammation of the conjunctiva
Can be bacterial, viral or allergic
Treated with antihistamines, artificial tests, antibiotics
What is glaucoma?
Where there is intraocular pressure associated with optic neuropathy
Treated with prostaglandin analogues like Xalatan and beta adrenergic receptor antagonists like Timolol
What are the advantages of ocular drug delivery?
Can administer for local effect (glaucoma cannot be treated orally) as systemically available drugs will not reach the eye due to the blood-eye barrier
Allows targeted delivery
Ease of administration - depends on patient
Small dose required
Fast action
Ease of manufacturing
What are the disadvantages of ocular drug delivery?
Bioavailability of drugs is extremely poor: less than 5% of the administered drug reaches the target
Contamination - limits shelf life
Addition of preservatives may cause toxicity
Limited permeability
Tear removal leading to irritation
Can only administer Small volumes
Systemic absorption can cause side effects
Solubility
What are the barriers to ODD?
Drainage Lacrimation Metabolism Absorption Corneal permeability
What is the tear film?
The precoeneal tear film is a 6.5um thick layered structure which consists of:
- superficial oily layer
- middle fluid layer
- deep mucoid layer
The uptake of atmospheric oxygen through the tear film is necessary for normal corneal metabolism .
What is the first protective structure encountered by topically applied drugs?
The tear film
What is the volume of normal tear?
7-10uL
How much (volume) can the lower eyelid hold?
30uL
How much (volume) does an eyedrop usually deliver?
40-70uL
What is the washout effect?
Where the tear fluid turnover doubles after an eyedrop application as a result of reflex tearing due to irritation
What are the causes of eye irritation?
Incompatible pH, foreign body sensation
How should an eyedrop be administered?
Apply one drop into the lower lid pocket
Close eyes and place finger on the tear duct to obstruct it
Try not to blink for about 2 minutes
What happens if there is normal blinking after administering an eyedrop?
More than <10% of the drug remains after 5 minutes
What happens if there is no blinking for more than 2 minutes?
More than 50% of the drug remains after 5 minutes
What happens if there is no nasolacrimal obstruction?
More than 80% of the drug will LEAVE via the duct within 5 minutes
What is the effect of washout ?
At 30 seconds, 50% of the drug is washed out
At 120 seconds, 17% of the drug is washout out
At 5 minutes, 5% of the drug is washed out
What is the corneal barrier?
An important mechanical barrier and the main pathway for ocular penetration,
It is a sandwich like structure consisting of oil phase, water phase and another oil phase
What are the Physicochemical requirements of drugs to pass through the corneal barrier?
Drugs with MW<5kDa and logP of 10-100
How does corneal permeability relate to pH?
If PKA of drug is 9.7 aka homatropine,
At pH7: more than 99% of the drug is unionised and can then penetrate the lipophilic epithelium
At pH greater than 7: there is a higher proportion of ionised drug which can easily diffuse through the hydrophilic stroma
What is the difference between pulsatile and controlled release?
With pulsatile release, the drug is released at set intervals and may exceed the therapeutic range causing periods of sub therapeutic concentration and possible toxicity
With controlled release, there is a given concentration over a period of time which is within the therapeutic range.
What are the formulation considerations with eyedrops?
Physicochemical properties (concentration, lipophilicity, MW, charge, PKA, pl)
Buffer capacity and pH (drug best formulated between 7.0-7.7)
Viscosity (best around 15mPas)
Instillation volume (limited by cul de sac holding maximum of 30uL)
Osmotic pressure (ranges between 310-350mOsm/kg. can’t be less than 260 or more than 480)
What are the reasons that two drops of the same drug concentration not being bioequivalent?
Ph of the formulation resulting in different solubilities and permeabilised due to different pKa
Particle size (suspension) resulting in different drainage and irritations
Addition of preservatives which alters the permeability of the drug. They may increase absorption by 50% however they could cause toxicity
What is the general pharmacokinetic journey of an ocular delivered drug?
The dose in instilled into the precorneal area.
- there is drug protein binding, drug metabolism, normal tear turnover and nasolacrimal drainage challenges the drug must overcome
50-100% of the drug is systemically absorbed leading to elimination
<10% of the drug is ocularly absorbed and will go via the corneal route or conjunctival and sclera route
- corneal route leads into aqueous humour, leading into ocular tissues like iris, retina and ciliary bodies
- conjunctival and scleral route leads into ocular tissues without going through aqueous humour
Systemic absorption is still possible via the conjunctival and scleral route, the aqueous humour, and after the drug has reached the ocular tissues
How can ocular bioavailability be improved after topical application ?
Increase corneal penetration
Prolonged corneal resident time
How can corneal penetration be increased?
Changing the solubility
Decreasing particle size
Using penetration enhancers
Use of novel drug delivery systems
How does change of drug solubility increase corneal penetration?
Optimisation of drug solubility may mean a change in drug PKA, and corneal permeability due to differences in % of the unionised and ionised forms
How can reduction of particle size increase corneal permeability?
Can reduce particle sizes of drugs in suspension so that they are more likely to pass through the corneal barrier
How can novel drug delivery systems increase corneal penetration?
Can incorporate drugs into contact lenses which prolong resident time and therefore may increase corneal penetration
How is prolong corneal resident time achieved?
With viscosity enhancers and bioadhesives
How can a bioadhesive improve corneal resident time?
Allows the drug to stick to selected tissues causing nasolacrimal drainage and washout to have less effect
How can permeability enhancers help in ocular drug delivery ?
These can increase corneal permeability and thus drug bioavailability, but high concentrations may also result in ocular toxicity
What are the advantages of chitosan in ocular formulations?
Cationic
Bioadhesive
Permeation enhancer
