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PH4701- clinical pharmaceutics > Ocular drug delivery systems > Flashcards

Ocular drug delivery systems Flashcards

1
Q

Structure of the eye

A

*

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2
Q

Barriers to drug delivery

A
  • Tear film is a barrier to drug delivery- wash out drugs
  • Must consider
    • LogP- solubility
    • Charge
    • MW
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3
Q

Barrier 1- Cornea

A
  • 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
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4
Q

Barrier 1 cornea

drug factors

A
  • 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
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5
Q

Barrier 2- tear fluid

A
  • 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
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6
Q

Barrier 3- Vitreous humour

A
  • 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
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7
Q

Drug delivery to the eye

A
  • 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
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8
Q

The fate of drug after administration

A
  • Loss of drug if it enters the tear fluid
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9
Q

Strategy 1- prodrug latanoprost

A
  • 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
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10
Q

Loteprednol Etabonate (a soft drug)

A
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11
Q

Soft drug

Loteprednol Etabonate

A
  • 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
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12
Q

Strategy 2- ocular drug delivery systems

A
  • 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
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13
Q

Eye drops

A
  • Variable dosage
    • Drop size varies
  • Limited duration of action
    • Rapid elimination
  • Systemic absorption
    • 80% drains into nasolachrymal duct
  • Preservatives necessary: Benzalkonium chloride- adverse reaction
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14
Q

Eye drops

Cyclodextrin

Benefits

A
  • 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
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15
Q

Eye drops- polymer

A
  • 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
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16
Q

Drugs for use in the anterior segment of the eye

A
  • Memorise a couple for addition
17
Q

Eye suspensions

A
  • 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
18
Q

Eye ointments

A
  • 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
19
Q

Formulations to treat dry eye

A
20
Q

Eye ocusert

A
  • 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
21
Q

Eye ocusert

A

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

+ Natural biodegradable polymer= dont have to take out

22
Q

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

A
  • 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)
23
Q

Eye implants- vitrasert

A
  • 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
24
Q

Drugs for use in the posterior segment of the eye

A
  • Ozurdex- Made of PLGA

PH4701- clinical pharmaceutics (20 decks)

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