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Aspects of Anatomy Important to Drug Delivery:

Aspects of Anatomy Important to Drug Delivery Cornea Barrier to drug delivery: (i) can only pass through if very low molecular weight and (ii) cornea normally negatively charged. Not route to systemic circulation, i.e. only used as site for local drug delivery Retina Highly vascularised as acts as barrier between eye and circulation: site for systemic delivery Conjunctiva Large SA for absorption (18 cm 2 ) and 10-100x more permeable than cornea However helps produce and maintain tear film

- Acts to remove foreign bodies from eye 7 μL / pH 7.4 / turnover rate of 1 μL/min :

- Acts to remove foreign bodies from eye 7 μ L / pH 7.4 / turnover rate of 1 μ L/min Tear Film - Eye-drops upon instillation stimulates tear production - Increase spillage & dilution of drug - Binding of the drug to tear proteins Buffering system in the tear affects the extent of ionized/ unionized form of drug - Reflex blinking causing drug clearance via tears

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Conventional Eye-drops Must be sterile & isotonic (pH 7.4) Local administration Systemic uptake very low Absorption of drugs through the conjunctival sac or corneal membrane - cornea is permselective i.e. discriminates between molecules with different charges - at pH 7.4 cornea is negatively charged and selectively permeable to cations - anions repelled unless pH can be lowered (eye- irritation). However bioavailability low (1-5 %) - loss through tear dilution and drainage and blinking. Alternative systems sought.


CONTROLLED OCULAR DRUG DELIVERY Prolonged action by: A. Reducing drainage - viscosity-enhancing agents, suspensions, matrices. B. Enhancing corneal penetration - prodrugs, liposomes.

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A. Drainage Reduction Viscosity-enhancing agent s e.g. polymers such as methylcellulose, polyvinyl alcohol, hydroxypropylcellulose & polyvinylpyrrolidone. (optimal viscosity of 12-15 mPa.s increases contact time) (b) Soluble gels e.g. pilocarpine 4% in a high viscosity acrylic vehicle delivers a prolonged dose from a single night-time placement (Pilogel ® ) (c) In situ gels - liquid applied forms gel due to pH or temperature change

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A. Drainage Reduction (continued) Ointments - interfere with vision, therefore night-time ointment use combined with day-time eye-drop use. - higher bioavailability: no tear dilution, resistant to nasolacrimal drainage chloramphenicol for eye infections ( Chloromycetin ® ) Emulsions - anionic lipid emulsion ( Restasis ® ) approved for dry-eye disease contains 0.05% Cyclosporin A attached to Carbomer gel (aqueous phase washed- out of eye before oil -phase which has increased contact resulting in increased partitioning from oil to cell membrane in eye resulting in improved bioavailability.

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B. Enhanced Corneal Penetration (Facilitated transport) Ion-pairing - association between ions of opposite charge - charges are neutralised leading to reduced aqueous solubility which increases uptake e.g. sodium cromoglycate ( conjunctivitist ) quaternary ammmonium dianion Pro-drugs - diesterification of adrenalin - compound made more lipophilic - 10-fold increase in corneal absorption ( Dipivefrine - Propine ® ). After absorption, esterases within cornea act rapidly to regenerate the adrenalin.

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B. Enhanced Corneal Penetration (continued) (c) Penetration enhancers - increase permeability of cornea. - interact with tight junction proteins between cells resulting in change in cell morphology - gaps between cells appear (increased permeability) - traditional enhancers, e.g. calcium chelators (EDTA) and surfactants, tend to cause damage to cells therefore safer permeation enhancers are sought (amphiphillic polymers?)

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B. Enhanced Corneal Penetration (continued) (d) Nanoparticles - eliminated slowly due to small size - may be suspension of solid particles or colloidal dispersion - may contain bioadhesive polymer to increase the residence time - small size may allow for paracellular and transcellular transport of dosage form through cornea.

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OCUSERT ® (Alza Corporation) - first system contained pilocarpine for glaucoma (see diagram on next slide) - placed in the cul-de-sac of the eye, drug is released continuously for 4-7 days, - tear fluid penetrates membrane, dissolves pilocarpine and drug diffuses from insert to membrane, - thin disc of pilocarpine alginate sandwiched between two transparent sheets of microporous membrane made from ethylene vinyl acetate copolymer, - titanium dioxide ring used to maintain localisation in the eye. CONTROLLED RELEASE SYSTEMS

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Ocusert ® Titanium dioxide ethylene vinyl acetate copolymer

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- increases ocular residence time - able to release the drug at a slow constant rate - accurate dosing - reduction of systemic absorption, i.e. increased local absorption. Advantages of Ocusert ® Disadvantages of Ocusert ® - felt by patients as a ‘foreign body’ in the eye - movement of inserts around the eye - occasional accidental loss of the insert - interference of the insert with vision - difficulty with self-insertion.

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- soluble copolymers in form of sterile films or wafers of oval shape - conforms to eyeball shape, i.e. like contact lenses - would not have to be removed after drug is exhausted - degradation & dissolution occurs slowly - surface-only hydrolysis from contact with tears - results in solubilisation and erosion of only the outermost layer with release of contained drug, - continuous progress of the process, layer by layer, provides a non-pulsed, constant rate of release Soluble and Bioerodible Systems

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- very difficult as have to apply to interior of eye, which means injection into the eye...! - may cause damage to eye - repeated injection may be necessary - some work carried out to produce biodegradable implants to overcome need for repeated injection, but still have to be injected first - useful as can avoid first pass effect, but patient acceptability low. - other non-GI routes usually favoured . SYSTEMIC ABSORPTION

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Martin’s Physical Pharmacy and Pharmaceutical Sciences 5 th edition (2006), ‘Drug Delivery Systems’, Sinko (Ed), Ch.22, Section 5, pp. 646-649. Kaur IP and Kanwar M (2002), ‘Ocular preparations: the formulation approach.’, Drug Development and Industrial Pharmacy , 28 (5), 473-493. References http://informahealthcare.com/doi/pdf/10.1081/DDC-120003445

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