Ocular drug delivery

Question 1

Which conditions utilise ocular drug delivery for their treatments?

Answer 1

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)

Question 2

How effective is eye drop absorption?

Answer 2

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.

Question 3

Outline the main barriers of permeation for topical ocular drug delivery.

Answer 3

Cornea
Conjunctiva
Sclera
Iris
Ciliary body

Question 4

Outline the main barriers of permeation for systemic ocular drug delivery.

Answer 4

Blood-aqueous barrier
Blood-retinal barrier

Question 5

Describe the precorneal barriers which limit drug delivery to the eye.

Answer 5

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.

Question 6

How does mucin limit drug delivery to the eye?

Answer 6

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.

Question 7

Which anatomical layers of the eye prevent drug permeation?

Answer 7

Layers of the cornea
Conjunctiva
Sclera
All limit permeation

Question 8

Which cells are responsible for lining the inner and outer blood-retinal barrier?

Answer 8

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.

Question 9

Explain how Visudyne works.

Answer 9

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.

Question 10

What are the four considerations for ocular drug delivery (eye drops)?

Answer 10

Osmolality
pH
Surface tension
Viscosity

Question 11

What is osmolality?

Answer 11

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)

Question 12

What is osmolality determined by?

Answer 12

Determined by the concentration of salts in lacrimal fluids (Na+, K+, Ca2+, Cl- HCO3-)

Question 13

What is the usual osmolality within the eye?

Answer 13

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.

Question 14

What is the usual pH of the eye?

Answer 14

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.

Question 15

What is the importance of the pH?

Answer 15

Important in controlling ionisation and corneal permeability

Question 16

What is the surface tension of the tear fluid?

Answer 16

Between 43.6 to 46.6 mN/m

Question 17

If there is an adequate amount of lipids/surfactants etc. and the surface tension is lowered- what happens?

Answer 17

The tear film will potentially become destabilised
Disperse lipid into droplets
Solubilised by drug/surfactants in formulation

Question 18

Why is the viscosity of eye drops important?

Answer 18

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.

Question 19

What viscosity do you want eyedrops to be?

Answer 19

Ideally between 0.2-0.8N, anything above 0.9N may be painful as you may be unable to blink.

Question 20

State some examples of viscosity enhancing polymers.

Answer 20

PVP, PVA, MC, HPMC

Question 21

What are some of the techniques for maintaining stability of ocular preparations?

Answer 21

Preservatives, broad spectrum – benzalkonium chloride however this can result in the development of tolerance over time
Single dose unit preparations
Antibacterial packaging

Question 22

What are the major disadvantages of topical ocular drug delivery?

Answer 22

• Difficult to instill
• Variable dosing
• Dilution and washout
• Require high drug concentrations
• Ocular and systemic side effects
• Major compliance and execution issues

Question 23

What are the advantages of solution preparations for eye drop formulation?

Answer 23

• Easy to manufacture
• Lowest cost of production
• Relatively easy to administer
• Rapid onset of action (no dissolution)
• Good dose uniformity

Question 24

What are the disadvantages of solution preparations for eye drop formulations?

Answer 24

• 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

Question 25

When are suspensions used as eye drops?

Answer 25

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.

Question 26

What are some of the disadvantages associated with suspension eye drop use?

Answer 26

Can undergo polymorphic changes with storage – change solubility
Ostwald ripening, caking can be a problem

Question 27

What do gels consist of?

Answer 27

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

Question 28

What is an advantage of using gels?

Answer 28

Increase the retention time

Question 29

What is the appropriate methods of drug delivery for posterior ocular delivery?

Answer 29

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.

Question 30

What are the different types of intraocular injections?

Answer 30

Either Intracameral injection (Anterior chambers) or Intravitreal injection where there is an injection into the vitreous humour.

Question 31

Describe the drug distribution within the vitreous humour.

Answer 31

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.

Question 32

What are some examples of periocular injections?

Answer 32

• Subconjunctival injection
• Subtenon injection
• Retrobulbar injection
• Peribulbar injection

Question 33

Describe the concept of the punctual plugs.

Answer 33

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.

Question 34

What are the punctual plugs made of?

Answer 34

Silicone
Hydrogel
Polyprolactone

Question 35

Give examples of injectable implants.

Answer 35

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

Question 36

What is the concept of ocular iontophoresis?

Answer 36

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)

Question 37

What are some of the other methods of ocular drug delivery?

Answer 37

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.

Question 38

What is Triggerfish?

Answer 38

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.