opthalmic drug delivery

Anatomy of the eye: the cornea as the absorption barrier

~ 0.5 to 0.7 mm & is composed of five layers  

• Squamous stratified epithelium 

  • thickness of ~ 50-100 μm & a turnover of about one cell layer/day.

  • The tight junctions and hydrophobic domains in this layer make it the most important barrier to drug delivery. Lipophilic barrier to hydrophilic drugs

• Bowman's membrane 

  • an acellular homogenous sheet of ~ 8-14 μm. Not a barrier

• Stroma or substantia propia

  • ~ 90 % of the corneal thickness with 600 -1100 μm thick.

  • Contains ~ 85% water & is relatively open & will normally allow the diffusion of hydrophilic solutes. Hydrophilic barrier to lipophilic drugs.

• Descemet's membrane

  • ~ 6 μm in thickness and is a strong, resistant membrane. Not a barrier.

• Endothelium 

  • Maintains normal corneal hydration. 

  • Is in direct contact with the anterior chamber & has a  passive  influx  of  water  from  the aqueous  humor towards  the stroma.  

• Thus, a drug must have both hydrophilic and lipophilic properties for passive transcellular transport.

Absorption pathways into the eye

Passive transcellular diffusion via the 

• Cornea (local action)

  • Only 5% of administered dose reaches the aqueous humour

  • Works best with small, lipophilic drugs

  • Further drug loss can occur through melanin binding or metabolism

• perivascular spaces in the conjunctiva or sclera.  (systemic absorption/ loss pathway)

  • Large hydrophilic molecules are quickly absorbed into systemic circulation

Overall ocular bioavailability is very low compared to the dose administered.  

• Remember goal is local action

Loss due to systemic absorption

• Through conjunctival absorption &

• Nasolacrimal drainage

• ~ 90% of the administered dose

• Keep in mind the dose administered to the eye is so low that systemic side effects are minimal even if 100% of the dose is absorbed systemically.

Challenges anatomical and physiological

LO2: analyze the physiochemical characteristics needed for ophthalmic drug delivery. 

cornea is the primary barrier to topical delivery to the eye, only small molecules with the appropriate hydrophilic, lipophilic balance are appropriate candidates. 

• MW: ≤ 500 Da 

• Log Ko/w: between 1 to 3 

• Ester prodrugs: can be used, which rely on the metabolic properties of their eye to convert to the active drug.  

  • These prodrugs are usually more lipophilic and therefore have better penetration across the cornea.

LO3:analyze the formulation characteristics needed for ophthalmic drug delivery. 

Issues with formulating drugs for the eye 

• Eye is very sensitive 

  • Easily infected

  • Easily damaged 

  • Requires sterile and preserved products 

• Retention of product in the eye is difficult

  • Low volume of instillation (20-30 uL)

    • Ideal installation volume to decrease blinking reflex and decrease naso-lacrimal drainage: 7-10 uL

  • Removal by tears (naso-lacrimal drainage)

    • Isotonic solutions preferred to reduce loss due to naso-lacrimal drainage

    • Using viscosity enhancers & mucoadhesives can increase contact time with the eye eg. Cellulose derivatives & polyvinyl alcohol (PVA)

    • Use non-irritating drugs & excipients

    • If suspensions are used size of particles < 10 µm

    • Formulation pH should be between 7 – 7.7

LO3

Solutions

• Most common and inexpensive 

• Most convenient in terms of usage

• Available as multidose or unit dose 

  • Multidose MUST have preservative 

• Typical formulation 

  • Drug 

  • Viscosity enhancers to ↑ contact time

  • Tonicity agents to ↓ nasolacrimal drainage

  • Buffering agents to ↓ nasolacrimal drainage

  • Surfactants or co-solvents to enhance solubility

  • Preservative

  • Vehicle

Eg. Betimol

• Timalol maleate ophthalmic solution 

• Reduces intraocular pressure 

• Formulation 

  • Drug:Timalol maleate @ 0.25 % or 0.5 %

  • Buffer: Sodium Phosphate

  • Preservative: Benzalkonium chloride

  • pH = 7.0

  • 274 – 328 mOsm

Emulsions

• Limited products available due to stability issues

• Available as multidose or unit dose 

  • Multidose must have preservative 

• Typical formulation 

  • Drug 

  • Viscosity enhancers to ↑ contact time

  • Tonicity agents to ↓ nasolacrimal drainage

  • Buffering agents to ↓ nasolacrimal drainage

  • Surfactants to stabilize the interface

  • Oil

  • Water 

  • Preservative

  • Vehicle
    

Eg. Restasis

• Cyclosporine A 0.05% ophthalmic emulsion

• Increase tear production 

• Formulation 

  • Drug: Cyclosporine A 0.05% 

  • Oil phase: glycerin & castor oil

  • Surfactant: Polysorbate 80

  • Viscosity enhancer: Carbomer copolymer type A

  • Water phase: Purified water 

  • pH adjuster: NaOH

  • pH = 6.5 – 8.0

  • 230-320 mOsm

  • Appearance: white opaque to slightly translucent homogeneous emulsion

  • only FDA-approved, preservative-free medication in a bottle

Suspensions 

• More common than emulsions

• Particle size <10 um to reduce the feeling grittiness in the eye

• Longer contact time than solutions as the particle adhere to the conjunctiva 

• The rate of particle dissolution must be faster than the naso-lacrimal drainage to have ocular bioavailability 

• Usually used to admin steroids

• Available as multidose or unit dose 

  • Multidose must have preservatives 

• Typical formulation 

  • Drug 

  • Viscosity enhancers to ↑ contact time

  • Tonicity agents to ↓ nasolacrimal drainage

  • Buffering agents to ↓ nasolacrimal drainage

  • Suspending agents

  • Preservative

  • Vehicle

Eg. Blephamide Ophthalmic Suspension

Ointments 

• Formulated only with oleogenous or absorption bases only as they are the least irritating 

• The drug is either dissolved or suspended in the base 

• Ointments have better ocular bioavailability than liquid products due to longer contact time with the eye & because they do not get diluted with tears.  

• Drawbacks include blurred vision & difficulty in dosing.

• Typical formulation

  • Drug 

  • Base

  • Preservative

  • Levigating agent / wetting agent

Eg. Blephamide Opthalmic ointment 

• Sulfacetamide sodium 10%, prednisolone acetate (microfine suspension) 0.2%

• For eye infections

• Formulation:

  • Drugs sulfacetamine sodium 10% & prednisolone acetate 0.2%

  • Preservative: Phenylmercuric acetate 0.0008%

  • Wetting agent: Mineral oil 

  • Base: Petrolatum, Lanolin alcohol & White petrolatum

Aqueous Gels

• more acceptable than ointments to patients because of ease of use and “feel” issues.  

• Two types of gels:

  • formulated like a gel and are used like ointments 

  • Formulated as sol-gels – solution in bottle, gel in the eye due to change in pH or other physiological 

• Like ointments, sol-gels also cause blurred vision, but unlike ointments can be dosed more accurately.  

• Like ointments, all gels have long retention times and therefore higher ocular bioavailability than liquid dosage forms

• Typical formulation

  • Drug 

  • Gelling agent

  • Tonicity agents to ↓ nasolacrimal drainage

  • Buffering agents to ↓ nasolacrimal drainage

  • Surfactants or co-solvents to enhance solubility

  • Preservative

  • Vehicle

Eg. Timoptic XE Ophthalmic gel formation solution 

• Timalol maleate @ 0.25 or 0.5 %

• For eye infections

• Formulation:

  • Drug: Timalol maleate @ 0.25 % or 0.5%

  • Preservative: benzododecinium bromide 0.012%.

  • Tonicity agent: Mannitol

  • pH: 7.0

  • Osmolarity: 260-330 mOsm

  • Vehicle: Water for injection

  • Tromethamine: alkalizing agent

  • GELRITE Gellan gum: The gel forming solution contains a purified anionic heteropolysaccharide derived from gellan gum. An aqueous solution of gellan gum, in the presence of a cation, has the ability to gel. Upon contact with the precorneal tear film, TIMOPTIC-XE forms a gel that is subsequently removed by the flow of tears.

Inserts 

• most accurate of all the topically administered dosage forms

• Least systemic side effects  

• Unaffected by tear flow or nasolacrimal drainage and have extended contact times.  

• The inserts are of 2 varieties

  • non-degradable

  • Soluble inserts are not as reproducible in dosing as drug release mechanisms are dependent on both drug diffusion and insert dissolution. 

Eg. Ocusert 

• Pilocarpine @ 20or 40 ug/hr

• For reducing intraocular pressure 

• Formulation: 

  • Drug: Pilocarpine released at 20 or 40 µg/hr

    • Continuously releases pilocarpine over 7 days

  • Insoluble ocular insert

    • Carrier material: Alginic acid

    • Rate controller: ethylene vinyl acetate copolymer

    • Annular ring contains titanium dioxide for visibility

  • First few hours (~ 5 hours) release rate is 3X labeled release rate (burst effect)

    • Labeled release rate achieved in ~ 6hr

  • Maximum ocular hypotensive effect in 1 – 2 hr

more on insert

Use of Ocusert 

• Lower conjunctival cul-de-sac

  • At bedtime to counteract Pilocarpine-induced myopia

• Manipulate from lower to upper cul-de-sac 

  • Before sleep for best retention

  • Gentle digital massage through lid

  • Or if retention problems during daytime

• Check for presence of OCUSERT®

  • Before retiring at night 

  • Upon arising

Comparison over 1 week of Pilocarpine 2% ophthalmic solution vs Ocusert® Pilo-40