Ophthalmic Preparations

Question 1

Drug penetration into the eye- pre-corneal problems

Answer 1

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

Question 2

Drug penetration into the eye- corneal barrier problems

Answer 2

External epithelium- lipid rich, problem for hydrophilic
Stroma- aqueous, problem for lipophilic
Internal endothelium- lipid rich, problem for hydrophilic

Question 3

Ophthalmic preparations definition

Answer 3

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

Question 4

Types of formulation

Answer 4

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

Question 5

Containers for eye preparations

Answer 5

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

Question 6

Advantages and disadvantages of plastic eye drop bottles

Answer 6

Advantages: cheap, lightweight, non-fragile, easier to use, less contamination
Disadvantages: cannot be autoclaved, sorption, permeability
NB silicon teats for benzalkonium

Question 7

Pharmacopoeial requirements for eye preparations

Answer 7

Containers comply with requirement of materials used for the manufacture and containers
Antimicrobial preservation demonstrated by a test described in efficacy of antimicrobial preservation

Question 8

Efficacy of antimicrobial preservation

Answer 8

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

Question 9

Drop size

Answer 9

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

Question 10

Viscosity

Answer 10

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

Question 11

Solubility- solutions

Answer 11

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

Question 12

Solubility- suspensions

Answer 12

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

Question 13

Stability- oxidation

Answer 13

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

Question 14

Stability- pH

Answer 14

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

Question 15

Stability- tonicity

Answer 15

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

Question 16

Preservation

Answer 16

Poor blood supply inside eyeball
Eye preparations for multi-use should contain a suitable antimicrobial preservative
NB cornea is sensitive to chemicals

Question 17

Benzalkonium chloride

Answer 17

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

Question 18

Chlorhexidine

Answer 18

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

Question 19

Organic mercurials

Answer 19

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

Question 20

Chlorbutol

Answer 20

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

Question 21

Semi solid eye preparations definition

Answer 21

Sterile ointments, creams or gels intended for application to the conjunctiva or eyeballs

Question 22

Eye ointments

Answer 22

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

Question 23

Semi-solid eye preparations overview

Answer 23

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

Question 24

Eye lotions

Answer 24

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

Question 25

Ocular inserts

Answer 25

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

Question 26

Ophthalmic inserts

Answer 26

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