Ophthalmic Preparations Flashcards
Drug penetration into the eye- pre-corneal problems
Residence time in conjunctival sac- increasing volume or irritation decreases time spent at barrier
Increasing viscosity increases time at barrier
Binding to tear proteins
Conjunctival drug absorption (large SA)
Systemic drug absorption
Drug penetration into the eye- corneal barrier problems
External epithelium- lipid rich, problem for hydrophilic
Stroma- aqueous, problem for lipophilic
Internal endothelium- lipid rich, problem for hydrophilic
Ophthalmic preparations definition
Sterile liquid, semi-solid or solid preparations intended for administration upon the eyeball and/or to the conjunctiva or for insertion in the conjunctival sac
Types of formulation
Liquids- surface of the eye
Semi-solids- margin of eyelid/conjunctival sac
Solids- modified release to surface of eye
Surgical implants- modified release within eye
Injections- e.g. intra-corneal
Irrigations- during surgery
Containers for eye preparations
Historically- liquids in glass containers with glass droppers, rubber teats, semi-solids in collapsible tin tubes
Now- flexible plastic (polyethylene or polypropylene) containers with built in droppers
Advantages and disadvantages of plastic eye drop bottles
Advantages: cheap, lightweight, non-fragile, easier to use, less contamination
Disadvantages: cannot be autoclaved, sorption, permeability
NB silicon teats for benzalkonium
Pharmacopoeial requirements for eye preparations
Containers comply with requirement of materials used for the manufacture and containers
Antimicrobial preservation demonstrated by a test described in efficacy of antimicrobial preservation
Efficacy of antimicrobial preservation
If preparation is not itself antimicrobial, add preservative to prevent proliferation or limit microbial contamination
Test by challenging the preparation with suitable micro-organisms
Storage in a sterile, airtight, tamper-proof container unless otherwise prescribed
Label states name of any added preservative
Drop size
Imprecise dosing due to variable drop size and number of drops added- blinking returns tear volume to normal
Increase residence time (bioavailability) by: using smaller drops, increasing concentration, increasing viscosity
Viscosity
Many eye drops formulated to 15 to 25 cP to increase residence time and bioavailability
Viscosity enhancing agents: dextran, macrogol, polyvinyl alcohol, povidone, methyl-cellulose derivatives
Increasing viscosity does not necessarily increase drug penetration (less drug diffusion) and can decrease tolerability
Solubility- solutions
Dosage uniformity, stable
Weak bases from hydrochloride, sulphate, nitrate, acetate, phosphate, hydrobromide salts
Weak acids form sodium salts e.g. diclofenac sodium, flurbiprofen sodium
Non-soluble drugs must be formulated as oily or aqueous suspensions
Solubility- suspensions
Solid particles must be very finely divided and comply with particle size test
Stability issue
Wetting agents- non-ionic surfactants e.g. polysorbate 80 are less toxic than cationic or anionic surfactants
Stability- oxidation
E.g. phenylephrine HCl
Add anti-oxidant e.g. sodium metabisulphate, sodium sulphite, ascorbic acid, acetylcysteine
And/or a chelating agent e.g. disodium edetate
Stability- pH
pH of tears is 7.2
Tolerated pH is 3.5-10.5
Buffers- borates e.g. chloramphenicol, atropine; phosphates e.g. timolol; citrates e.g. neomycin, hydrocortisone
Stability- tonicity
Ophthalmic solutions should be isotonic with lachrymal secretions i.e. ideally equivalent to 0.9% NaCl
Acceptable range 0.7-1.5% NaCl
Hypotonic solutions adjusted with NaCl, KCl, glucose, glycerol and buffers
Hypertonic solutions sometimes unavoidable
Preservation
Poor blood supply inside eyeball
Eye preparations for multi-use should contain a suitable antimicrobial preservative
NB cornea is sensitive to chemicals
Benzalkonium chloride
Present in over 70% of all eye drops
Well tolerated in the eye at concentrations up to 0.02%
Non-volatile and stable to autoclaving
Bactericidal against a wide range of gram +ve and -ve bacteria
Some people can be hypersensitive
Chlorhexidine
Effective at 0.01% against most bacteria, esp gram +ve
Activity decreased by metal ions and anionics and incompatible with sulphates
Activity increased with disodium edetate
Not as stable to autoclaving as BZC
Organic mercurials
Contain mercury
e.g. phenylmercuric acetate, phenylmercuric nitrate, thiomersal
Effective against most bacteria and fungi
Activity decreased by disodium edetate
Non-irritant/ no tear film disruption
Mercury deposition/ allergy/ hypersensitivity to thiomersal therefore prolonged use not recommended
Chlorbutol
Effective at 0.5% against most bacteria and fungi
Well tolerated
Compatible with most drugs but not fluroscein
Volatile/ only stable in acidic solution/ does not withstand autoclaving
Semi solid eye preparations definition
Sterile ointments, creams or gels intended for application to the conjunctiva or eyeballs
Eye ointments
Usually paraffin base with melting point close to body temperature, drugs incorporated into oily phase, aqueous phase or as fine powder
Additional excipients may be required to allow: dispersion in aqueous phase, stability in aqueous phase, antimicrobial preservation
Preservation can be difficult
Semi-solid eye preparations overview
Specified proportions of yellow soft paraffin, liquid paraffin and hard paraffin may be varied in hot climates but the active ingredients must remain the same
Comply with the monograph on topical semi-solid preparations and are non-irritant to conjunctiva
Must also pass particle size test
Eye lotions
Sterile aqueous solutions intended for use in rinsing or bathing the eye or for impregnating eye dressing
Used to remove foreign materials or relieve irritation
Used in large volumes therefore pH and tonicity important
Antimicrobial preservative required in multi-dose preparations
Ocular inserts
Sterile solid or semi-solid preparations of suitable size and shape, designed to be inserted in the conjunctival sac, to produce an ocular effect
Used to achieve prolonged release of drugs into the eye e.g. glaucoma
Elliptically shaped units with a core reservoir of drug surrounded by a diffusional membrane- diffuses drug into tear fluid
Ophthalmic inserts
Individually distributed into sterile containers
Means must be taken to ensure a suitable dissolution behaviour
Must comply with test for uniformity of dosage units/ uniformity of content
Label states, where applicable, the total quantity of active per insert and the dose released per unit time
