Ocular drug delivery systems

Question 1

Structure of the eye

Answer 1

*

Question 2

Barriers to drug delivery

Answer 2

• Tear film is a barrier to drug delivery- wash out drugs
• Must consider
  
  • LogP- solubility
  • Charge
  • MW

Question 3

Barrier 1- Cornea

Answer 3

• 70% of the refractive power of the eye
• Transparent- 570um thick in the centre
• No blood supply
  
  • Nutrition from the aqueous humour
  • Oxygen from lachrymal secretions
• Cleared by eyelids which blink- 15 min-1
• The Main pathway for drug delivery
• Tight junctions
  
  • Limit transport of hydrophilic compounds to those less than 60-100 Da
    
    • E.g. glucose, Mr 180Da does not cross cornea

Question 4

Barrier 1 cornea

drug factors

Answer 4

• Lipophillic drugs
  
  • Pass epithelial barrier
  • Restrained by the hydrophilic stroma
• Typically, a parabolic relationship
  
  • Between partition co-efficient and flux will be observed
• Optimum partition co-efficient 10-100
  
  • LogP= 1-2
• The high concentration of esterases in epithelia
  
  • Used to activate lipophilic prodrugs of hydrophilic molecules

Question 5

Barrier 2- tear fluid

Answer 5

• Essential for good vision that surface moisture is maintained
  
  • Spread by blinking which forces fluid in inner margins
• Usually, the drug is washed away within 5 minutes
• Average volume in 7uL
  
  • Maximum ithe n corneal sac is 20uL
  • Up to 30uL may be present prior to blinking
• Fluid passes into the nasopharyngeal system

Question 6

Barrier 3- Vitreous humour

Answer 6

• A hydrogel in the cavity between retina and lens
  
  • 98-99.7% of water
  • Gel-like with collagen fibrils and hyaluronic acid
• Usually liquefies with age
  
  • Collects cellular bedris- floaters
  • Inflammation enhances delivery

Question 7

Drug delivery to the eye

Answer 7

• Systemic
  
  • Needs high dose of the drug in body circulation
  • Causes toxicity effect because of the inner and outer-blood retinal barriers with the isolation from the circulation
• Topical
  
  • Cornea readily accessible
    
    • Treatment of superficial infections/inflammation/anaesthesia
  • Significant barriers to delivery
    
    • For the treatment of glaucoma (to reduce IOP) or deeper infection and inflammation
• Direct injection/eye implants

Question 8

The fate of drug after administration

Answer 8

• Loss of drug if it enters the tear fluid

Question 9

Strategy 1- prodrug latanoprost

Answer 9

• Xalatan- F2a analogue- reduces intraocular pressure by increasing outflow of aqueous humour through enhanced uvosclearal outflow
• NaCl, needed for isotonicity (tears)
• Phosphate acts as a buffer
• Benzalkonium chloride- preservatives
• Isopropyl ester- prodrug

Question 10

Loteprednol Etabonate (a soft drug)

Answer 10

Question 11

Soft drug

Loteprednol Etabonate

Answer 11

• Used in post-operative inflammation
  
  • Ophthalmic suspension (0.5%)
• Modified prednisolone
  
  • C20 ester group rather than keto group
  • Claimed to have less danger of causing cataracts
• Active at site of action only
  
  • Metabolised by esterases to an inactive metabolite
  • No detectable serum levels of drug or metabolite found

Question 12

Strategy 2- ocular drug delivery systems

Answer 12

• Drug delivery systems to the anterior segment of the eye
  
  • Eye drop
  • Eye suspension
  • Eye ointment
  • Eye insert
  • These all target anterior of the eye

Question 13

Eye drops

Answer 13

• Variable dosage
  
  • Drop size varies
• Limited duration of action
  
  • Rapid elimination
• Systemic absorption
  
  • 80% drains into nasolachrymal duct
• Preservatives necessary: Benzalkonium chloride- adverse reaction

Question 14

Eye drops

Cyclodextrin

Benefits

Answer 14

• Improved aqueous solubility
• Improve the stability and bioavailability of poorly soluble drugs
• Reduce the irritation of drugs to eye
• Glucose rings shaped like a cup
• Hydrophilic outer and hydrophobic inner (drug) to increase solubility

Question 15

Eye drops- polymer

Answer 15

• Use of polymers to improve viscosity and retention time
  
  • Hydroxypropylmethyl cellulose, hydroxyethylcellulose
  • Sodium hyaluronate
    
    • Residence time t1/2 is
    • 50s in slaine (low)
    • 11.1 min at 0.2% polymer (significantly increased)
    • 23.5min at 0.3% polymer
      
      • Improved outcomes for patients

Question 16

Drugs for use in the anterior segment of the eye

Answer 16

• Memorise a couple for addition

Question 17

Eye suspensions

Answer 17

• Poorly soluble drugs
• Larger particles give longer dissolution times but are likely to increase irritation
  
  • Maximum particle sizes of 30-50um are recommended
• Care with polymorphic forms
  
  • may undergo transformation and crystal growth
  • Cause problems of both solubility and irritation

Question 18

Eye ointments

Answer 18

• Less popular than drops as visions are often blurred
  
  • Often for overnight use
  • Residence half-life may be <1h
• Tetracycline ointment effective delivery to the anterior chamber
  
  • Aqueous drops ineffective for intraocular infections
• Very lipophilic drugs (e.g. steroids) may not release well
  
  • W/S inserts may be better
• Useful for paediatric use
  
  • Children wash out drops rapidly when crying

Question 19

Formulations to treat dry eye

Answer 19

Question 20

Eye ocusert

Answer 20

• 1974, AlzaCorporation -the first controlled-released ocular insert Ocusert®Pilo-20 and Pilo-40 systems
  
  • Pilocarpinedelivered for one week
  • for glaucoma patients
    
    • 20% of patients lose device without knowing
  • Ocusert® system consists of an internal drug reservoir of pilocarpine with alginate gel, sandwiched between two outer membranes of ethylene-vinyl acetate copolymer (EVA)
• In 1982, Aton PharmInc. -an erodible ocular insert Lacrisert®
  
  • for the treatment of moderate to severe dry eye syndrome.
  • Rod-shaped cul-de-sac insert (~ 1.27 mm diameter and ~ 3.5 mm length)
  • 5 mg hydroxypropyl cellulose without preservatives and other excipients

Question 21

Eye ocusert

Answer 21

+ Don’t have to put things in your eye (drops)= patient compilance

+ Natural biodegradable polymer= dont have to take out

Question 22

Strategy 3- drug delivery systems to the posterior segment of the eye intravitreal injection

Answer 22

• Volume 0.1-0.2mL
• Elimination
  
  • Anterior by diffusion to the posterior chamber
    
    • And drainage with aqueous humour
    • t1/2 5-10h
• Still too short for many treatments
  
  • Depot devices are being developed- fewer injections needed= compliance
• Patient acceptability is poor (needle in your eye)

Question 23

Eye implants- vitrasert

Answer 23

• CMV retinitis in AIDS patients
  
  • Damage to retina leading to blindness
• Vitrasert
  
  • Ganciclovir (6mg)
  • Polymer coat with a range of permeabilities
  • Release of the drug at 1ugh-1 for four months
• Implanted in vitreous
  
  • Takes about 1h as an out-patient
  • Slows but does not cure conditions
    
    • 221 days to progression compared to 71d for IV
• Removed after5-8
• Inserts are placed on the eye, Implants are placed into the eye

Question 24

Drugs for use in the posterior segment of the eye

Answer 24

• Ozurdex- Made of PLGA