Ocular drug delivery Flashcards
Which conditions utilise ocular drug delivery for their treatments?
To the front of the eye:
Hayfever
Dry eye syndrome
Cataracts
Infections
To the back of the eye:
Glaucoma
Retinopathy
Age related macular degeneration (more difficult to treat)
How effective is eye drop absorption?
Not very effective, less than 5% of an eyedrop is actually bioavailable this is due to the high tear film rate being produced at 1 microlitre per minute which washes away the eye drops and the blinking reflex causing the eye drops to be washed off.
Outline the main barriers of permeation for topical ocular drug delivery.
Cornea
Conjunctiva
Sclera
Iris
Ciliary body
Outline the main barriers of permeation for systemic ocular drug delivery.
Blood-aqueous barrier
Blood-retinal barrier
Describe the precorneal barriers which limit drug delivery to the eye.
Precorneal barriers which limit ocular drug delivery absorption include:
Solution drainage, blinking, tear film, tear turnover and induced lacrimation.
Ultimately all of these factors result in low contact time between the drug with the absorptive membrane.
How does mucin limit drug delivery to the eye?
Mucin present in the tear film plays a protective role by forming a hydrophilic layer that moves over the glycocalyx of the ocular surface and
clears debris and pathogens.
Which anatomical layers of the eye prevent drug permeation?
Layers of the cornea
Conjunctiva
Sclera
All limit permeation
Which cells are responsible for lining the inner and outer blood-retinal barrier?
Retinal capillary endothelial cells and retinal pigment epithelium cells (RPE) which forms the the inner and outer blood–retinal barrier, respectively.
Need a drug delivery system either oral or IV which will transport molecules through the choroid into deeper layers of the retina however oral administration is limited due to inaccessibility of targeted ocular tissues.
Explain how Visudyne works.
It is licensed for age related macular degeneration. It is given by IV administration and exploits the leaky vessels at the back of the eye for drug delivery.
What are the four considerations for ocular drug delivery (eye drops)?
Osmolality
pH
Surface tension
Viscosity
What is osmolality?
Essential the same as osmotic pressure:
Concentration of a solution expressed as the total number of solute particles per kilogram of solvent (mOsmol/kg or mmol/kg)
What is osmolality determined by?
Determined by the concentration of salts in lacrimal fluids (Na+, K+, Ca2+, Cl- HCO3-)
What is the usual osmolality within the eye?
Healthy eyes ~ 302mmol/kg
Hypotonic solution will increase the epithelium permeability causing oedema or hypertonic solutions which will dehydrate the cornea epithelium.
There 0.9-1.0% of sodium will mimic the same osmotic pressure within the eye.
What is the usual pH of the eye?
pH range of tears 6.9-7.5 which is usually controlled by CO2, HCO3-, lysozyme (-), prealbumin (+) however the eye can tolerate a pH between 3.5-9.
Ideally want to the pH to be as close to the tears pH as possible.
What is the importance of the pH?
Important in controlling ionisation and corneal permeability
What is the surface tension of the tear fluid?
Between 43.6 to 46.6 mN/m
If there is an adequate amount of lipids/surfactants etc. and the surface tension is lowered- what happens?
The tear film will potentially become destabilised
Disperse lipid into droplets
Solubilised by drug/surfactants in formulation
Why is the viscosity of eye drops important?
Increased viscosity of eyedrops results in:
Prolonged drug retention-
Enhanced absorption
Reduced drainage
Increase thickness of precorneal tear film* Osmolality
As if the eyedrops are too runny this may cause increased wash off.
What viscosity do you want eyedrops to be?
Ideally between 0.2-0.8N, anything above 0.9N may be painful as you may be unable to blink.
State some examples of viscosity enhancing polymers.
PVP, PVA, MC, HPMC
What are some of the techniques for maintaining stability of ocular preparations?
Preservatives, broad spectrum – benzalkonium chloride however this can result in the development of tolerance over time
Single dose unit preparations
Antibacterial packaging
What are the major disadvantages of topical ocular drug delivery?
- Difficult to instill
- Variable dosing
- Dilution and washout
- Require high drug concentrations
- Ocular and systemic side effects
- Major compliance and execution issues
What are the advantages of solution preparations for eye drop formulation?
- Easy to manufacture
- Lowest cost of production
- Relatively easy to administer
- Rapid onset of action (no dissolution)
- Good dose uniformity
What are the disadvantages of solution preparations for eye drop formulations?
- Rapidly drained from the eye
- Rate of drainage proportional
to the size of the drop - Volume administered can be 25-56ul
- Shape of dropper
- Physicochemical properties of solution
- Manual usage of bottle
When are suspensions used as eye drops?
Poorly soluble drugs are suspended in solution such as steroids. However the size of the drug particles are limited due to the potential to cause irritation.
Must be shaken before administration to ensure the drug is readily dispersed.
What are some of the disadvantages associated with suspension eye drop use?
Can undergo polymorphic changes with storage – change solubility
Ostwald ripening, caking can be a problem
What do gels consist of?
They consist of a semi-solid system comprising of a water soluble base and they use polymers (PVA, HPMC, carbopol, carbomer) dispersed in a liquid
What is an advantage of using gels?
Increase the retention time
What is the appropriate methods of drug delivery for posterior ocular delivery?
To transport a drug to the back of the eye it is not possible to use topical methods of drug delivery and instead either systemic (PO/IV) or minor surgery is required for direct delivery through Intravitreal injections or Intraocular implants.
What are the different types of intraocular injections?
Either Intracameral injection (Anterior chambers) or Intravitreal injection where there is an injection into the vitreous humour.
Describe the drug distribution within the vitreous humour.
There is non-uniform drug delivery within the vitreous humour. Low molecular weights drug diffuse and distribute rapidly, this is not the same for high molecular weight drugs.
However is also to do with the structure of the drug. This is the most efficient way to get the drug to the back of the eye but is associated with poor patient compliance.
What are some examples of periocular injections?
- Subconjunctival injection
- Subtenon injection
- Retrobulbar injection
- Peribulbar injection
Describe the concept of the punctual plugs.
Screw like devices which can be pushed into the tear ducts where they stay for two to three months and slowly release the drugs to reduce the intraocular pressure used in the management of glaucoma.
Good for non-adherence.
What are the punctual plugs made of?
Silicone
Hydrogel
Polyprolactone
Give examples of injectable implants.
ILUVIEN® intravitreal implant 0.19mg:
is designed to release the corticosteroid fluocinolone acetonide over 3 years after being implanted in the back of the eye for
treating diabetic macular edema (DME).
It is a non-bioerodible implant made of polyimide
Durasert latanoprost implant:
Biodegradable drug delivery system for latanoprost that is injected into
subconjunctival space
Implant is bioerodible and is expected to deliver an appropriate dosage of
latanoprost for about three months
What is the concept of ocular iontophoresis?
The basic electrical principle that oppositely charged ions attract and same
charged ions repel is the central tenet of iontophoresis. The ionized substances are driven into the tissue by electrorepulsion at either the anode (for positive drug) or the cathode (for negatively charged drug)
What are some of the other methods of ocular drug delivery?
Drug eluting contact lenses
Topical ophthalmic drug delivery device which is a soft flexible device which floats on the surface of the sclera (so underneath the eye) provides 3-90 days of drug delivery.
What is Triggerfish?
Triggerfish is a contact lens sensor which is a minimally invasive medical device designed to provide continuous 24-hour recording of ocular dimensional changes (changes in the shape of the eye), related to intraocular pressure fluctuations.
