Opthalmic Flashcards
What are 4 different eye formulations?
- Eye drops/Solutions
- Eye ointments
- Eye Lotions
- Sub-conjunctival injection
What 2 drug classes are administered through sub-conjunctival injections?
- anti-infective drugs
- corticosteroids
What comprises the outer layer of the eye?
2 spheres: the cornea and sclera
How much of the outer layer does the cornea cover?
the transparent forward 1/6th
How much of the outer layer does the sclera cover?
the back 5/6th of the globe
What is the sclera made of?
tough fibrous (dense connective) tissue, forming the ‘white’ of the eye
What are the 2 functions of the slcera?
- Protects the eye from the internal and external forces
- Maintain its shape + intraocular pressure
The tough, fibrous nature of the sclera also protects the eye from serious damage such as rupture from external trauma
What structure is in front of the iris and pupil?
the cornea
What nerves densely innervate the cornea
sensory nerves
What are the 2 functions of the cornea?
- refracts + transmits light to lens + retina
- protection of eye against infection and structural damage to deeper parts
What is the conjunctiva and where is it found?
- thin, transparent mucous membrane
- Covers the visible part of the sclera
- Extends to the inside of the eyelids
Where does the optic nerve emerge from?
the sclera
What covers the cornea and conjunctiva surfaces?
a film of tears produced by lacrimal gland
lubricates the eye surface and protects it from chemicals, microbes, airborne solid particles
What are the 3 layers of the film of tears?
- Mucous layer
- Aqueous layer:
- Superficial lipid layer
What does the mucous layer of the film of tears do?
- interact with cornea’s epithelial cells
- each eye blink allows the spread of the tear film over the eye surface
What composes the aqueous layer of the film of tears? (6)
electrolytes, proteins, glycoproteins, biopolymers, glucose, urea
What composes the superficial lipid layer of the film of tears?
sterol esters, wax esters and fatty acids
Why is it said that there’s a dynamic equilibrium in the pre-corneal tear film?
because there’s a continuous cycle of production, evaporation, drainage
What are the three chambers of the eye?
Anterior , posterior and vitreous cavity
What fills the anterior & posterior chambers of the eye?
aqueous humour
What does aqueous humour look like? What’s it made of? What does it do?
- Clear, colourless, watery fluid
- Electrolytes, organic solutes, growth factors, other proteins
- feeds non-vascularised tissue of the anterior chamber
Through which chamber does aqueous humour leave?
the anterior chamber through conventional and unconventional pathways
How does glaucoma arise? (hint: aqueous humour exit)
- exit in anterior chamber is blocked (aq humour cant leave)
- fluid accumulates
- increased pressure
- glaucoma + damage to optic nerve
What percentage volume of the eye does vitreous cavity make up and what does it look like?
- 80%
- transparent, colourless, gelatinous
What does the vitreous cavity do and contain?
- Fills the space between the lens of the eye and the retina lining the back of the eye
- Hydrogel containing 98% water
- The other 2% : collagen fibrils, hyaluronic acid (viscosity), protein, inorganic salts , glucose, ascorbic acid
The space between your cornea and iris is called..
the anterior chamber
The space between your lens and iris is called..
the posterior chamber
The chamber at the back of your eye is called…
the vitreous chamber
What are the 3 routes of ocular delivery?
roman numerals:
I. cornea
II. blood retinal barrier
III. intravitreal delivery route
What do drugs reach when delivered through the cornea?
the aqueous humour
main route of which ocular topically administered drugs reach aqueous humour
Cornea
What are the outer and inner barriers of the blood retinal barrier (BRB)?
roles?
outer: retinal pigment epithelium: regulates movement of solutes + nutrients from choroid to sub-retinal space
inner: retinal capillary endothelium: has tight junctions between cells mediate highly selective diffusion of molecules from the blood to retina
importance of inner barrier: retinal capillary endothelium of the BRB? (2)
has tight junctions between cells mediate highly selective diffusion of molecules from the blood to retina
- Essential in maintaining retinal homeostasis
- Restricts entry of drugs from systemic circulation into posterior segment of the eye
Where do drugs reach using the intravitreal route?
directly the back of the eye (vitreous chamber)
Which of the outer (RPE) and inner (RCE) layers of the blood retinal barrier is essential in maintaining retinal homeostasis?
Inner (RCE)
What does the blood retinal barrier (BRB) do?
restrict entry of drugs from systemic circulation into the posterior segment of the eye
Whereabouts in the eye does drug elimination occur (barriers to ocular delivery)? (4)
1 - aqueous humour into systemic uveoscleral circulation
2 - trabecular meshwork + Schlemm’s canal
3 - vitreous humour: diffn into ant chamber
4 - posterior route across BRB
what is Schlemm’s canal?
Circular channel in eye that collects aqueous humour from anterior chamber and delivers it into the bloodstream via the anterior ciliary veins
(a barrier to ocular drug elim)
What 6 parameters need to be adjusted when formulating opthalmic preparations?
- osmolality
- pH
- viscosity
- sterility
- surface tension
- surfactants
What determines the osmolality of the eye?
concentration of salt in lacrimal fluids
What are the predominant inorganic ions in tears? What do they control?
- Sodium, potassium, calcium, chloride and bicarbonate
- Control the osmotic pressure of the intra/extracellular fluids (cornea and conjunctiva)
What is the osmolality of healthy non-dry eyes?
~302mmol/kg @ daytime
What is dry eye syndrome caused by?
the tear film being hyperosmotic (hence drawing fluid out away from eye)
Why would hypotonic ophthalmic solutions be harmful?
- makes the corneal epithelium more permeable, irritating to the eye and increased production of tears
- water flows into the cornea
- oedema
Which solution has the normal tear osmotic pressure?
sodium chloride 0.9%
What are the 3 methods used to adjust tonicity?
- freezing-point depression method
- sodium chloride equivalent method
- isotonic solution V-value method
What is freezing point depression?
the phenomenon that when solute is added to a solution, its freezing point decreases
What is the freezing point depression of a solution isotonic with human blood/lacrimal fluid?
(-)0.52°C
How to adjust tonicity using freezing-point depression or sodium chloride equivalent method
- identify a reference soln and associated tonicity parameter
- determine contribution of drug(s) and additive(s) to total tonicity
- determine amount NaCl needed by SUBTRACTING contribution of actual soln from reference soln
- indicate whether hyper/hypo/isotonic
1% NaCl has a freezing point depression of 0.576°C. Find the concentration required to make a saline solution isotonic with lacrimal fluid.
- remember isotonic fluid has fdp 0.52°C
- if 1% = 0.576°C, simply use proportions to find your concentration
- 1/0.576 x 0.52 = 0.90
= 0.9% NaCl solution as you know is the isotonic reference solution
What special value does the freezing point depression method make use of?
the D value i.e. the depression value - given in reference books
What are the units of a D value?
degrees centigrade / (x % drug)
What are the D values for dexamethasone? How do they compare to the concentration?
- 0.05°C/0.5%, 0.180°C/0.2%, 0.52°C/6.75%
- almost proportional
worked example
How would you make an isotonic solution of dexamethasone sodium phosphate 0.1% and purified water qs 30ml? (i.e. how much NaCl do you need to add to make it isotonic? - D value is 0.05°C/0.5%)
1) identify reference solution and associated tonicity parameter: 0.9% NaCl w tonicity parameter fdp 0.52°C
2) determine the contribution of drug/additives using D value: dexamethasone has D value 0.05°C per 0.5% of drug, therefore 0.1% contributes 0.1°C to fdp
3) determine the amt of NaCl needed by subtracting drug/additives’ contribution from NaCl’s fdp: 0.52°C-0.1°C = 0.51°C
4) convert units so you’re finding how much NaCl you need to add in grams: 0.52°C/0.9% = 0.51°C/x, x = 0.883% = 0.883g in 100ml, so in 30ml (purified water qs remember) 0.265g NaCl is required to be added.
If a solution contributes less than the reference does to tonicity (the fdp), is it hypo or hypertonic? How do we adjust it?
- if it contributes less, then it’s hypotonic
- it’s adjusted by adding the right amt of NaCl
If a solution contributes more than the reference does to tonicity (the fdp), is it hypo or hypertonic? How do we adjust it?
- if it contributes more, then it’s hypertonic
- it can only be adjusted by solution
If we wanted to make the dexamethasone solution isotonic but using dextrose instead of NaCl, how would we do this?
1) we know the reference value is still 0.52°C (blood/lacrimal fluid), and the drug still contributes so the new fdp is 0.51°C
2) the d value for dextrose is 0.091°C/1% - we need to find conc of dextrose that will give us 0.51°C so we use proportions: 1%/0.091 = x/0.51, x = 5.6% dextrose needed
3) convert this into grams needed to add to 30ml: 5.6g in 100ml = 1.68g
What special value is used when calculating the sodium chloride equivalent method? What are its units?
the E (equivalent) value, representing the amount of NaCl that has the same osmotic effect as 1g of drug hence the units are g NaCl/g of drug at x% drug concentration
Is the E value proportional to the drug concentration and why?
no, due to the interionic attraction differing at diff concentrations of drug
worked example:
How would you make an isotonic solution of dexamethasone sodium phosphate 0.1% and purified water qs 30ml? (i.e. how much NaCl do you need to add to make it isotonic? - E value is 0.18g NaCl/g drug)
1) identify the reference solution: 0.9% NaCl and its associated tonicity parameter: so how much NaCl is in 30ml of liquid: 0.9g = 100ml, x = 30ml, x = 0.270g
2) Determine the contribution of drug: find how much is in 30ml - 0.1% = 0.1g in 100ml = 0.03g in 30ml; if 0.18g NaCl/1g, then 0.0054g NaCl/g of drug; 0.27 - 0.0054 = 0.2646g = 0.265g (same answer as that with fdp method)
How would you make an isotonic solution of dexamethasone sodium phosphate 0.1% and purified water qs 30ml? (i.e. how much dextrose do you need to add to make it isotonic? - E value is 0.18g NaCl/g drug, E value is 0.16g NaCl/g glucose)
1) we know that you would need 0.265g NaCl to make it isotonic, but we need to convert this to dextrose; if 0.16g NaCl is for 1g, then x is for 0.265g
2) therefore x = 1.66g dextrose
What special value does the isotonic solution V-value method use?
the V value
- the volume of water to be added to a specific mass of drug (0.3g or 1.0g)
- this is because 30ml is a commonly prescribed volume
What is the basic principle of the V-value method?
- prepare isotonic solution
- then dilute to final volume w suitable isotonic vehicle
worked example:
How would you make an isotonic solution of dexamethasone sodium phosphate 0.1% and purified water qs 30ml using the isotonic V value method? (i.e. how much drug do you need to dissolve what volume, and what should you do next? E value = 0.18g NaCl/g drug)
1) use the E value to calculate the V value: we know V value is how much volume to be added to 0.3g; 0.18g NaCl = 1g of drug, xg NaCl = 0.3g; x = 0.054g NaCl per 0.3g of drug; want a volume so use 0.9% - 0.9g in 100ml, the volume occupied by 0.054g will be 6ml so V value is 0.3g needs 6ml of water
2) find the amount of drug needed for the solution, and use the V value to find amount volume to dissolve it in: 0.1g in 100ml = 0.03g in 30ml; if 0.3g needs 6ml, then 0.03g needs 0.6ml; therefore dissolve 0.03g in 6ml of water, and make up to 30ml using suitable isotonic vehicle (e.g. 0.9% NaCl, 5.51% glucose)
What equation can you use to use the V value to find the amount of drug and volume to dissolve it in to make a solution isotonic?
V= Ω x E x 111.1
Ω = weight of drug in grams
E = E value
Is the pH of tears acidic, neutral or basic?
What controls its pH?
- pH of tears ~ neutral
- Controlled by: carbon dioxide, bicarbonate and proteins (e.g. lysozymes), acidic tear prealbumin
What is the buffer capacity of tear fluid (high or low)? What is responsible for its buffer capacity?
- Buffer capacity of tear fluid is low but significant
- Balance of bicarbonate and carbon dioxide + proteins
Why are reflex tears generated in response to acidic/basic solutions instilled in the eye?
- tears can’t neutralise the solution
- reflex tears dilute drop to eliminate it
how is buffer capacity calculated?
either b = change in B (strong base) / change in pH
or Slykes eqn (SoM1)
What pH values of formulation can the eye tolerate?
3.5-7, however preferably close to physiological tear pH (6.9-7.5)
(awake hours)
What are the different types of tears ?
basal tear, emotional tear, and reflex tear
Why is it beneficial to formulate ophthalmic preparations to physiological pH?
- reduces discomfort + associated increased lacrimation
Why is lacrimation problematic with ophthalmic preparations?
The secretion of tears especially when abnormal or excessive…
drug is then from the eye
Apart from avoiding eye irritation, what else is the pH of ophthalmic preparations important for?
- drug ionisation
- product stability
How is pilocarpine (a natural alkaloid used to treat glaucoma) protected against degradation?
- it has pH dependent hydrolytic degradation
- the pH is maintained at 4-5 using a weak acidic buffer allowing lacrimal fluid to be restored to their normal pH
- also maintained for the sake of ionisation, solubility and being permeable across the corneal epithelium
What are common buffers used in these preparations?
- borate
- phosphate
to get solutions at a lower pH range:
- acetic acid/sodium acetate
- citric acid/sodium citrate
Strong buffers not to be used
how will drug ionation affect how effective it is in this route? (2)
Drug ionisation -> solubility -> permeability across the corneal epithelium
What is used to change the viscosity in these preparations?
viscosity enhancing polymers
What are the potential benefits of changing the viscosity of an ophthalmic preparations?
- prolongs drug retention in pre-corneal tear film
- enhances drug absorption
- reduces drainage rate
- increases thickness of pre-corneal tear film
- stabilises the aqueous layer as they spread over the corneal surface on blinking
- increased volume act as a reservoir of drug
What are 7 examples of viscosity enhancing polymers?
- Water soluble polymers
- Poly(vinyl) alcohol
- Poly(vinylpyrrolidone)
Cellulose derivatives:
- Methylcellulose
- Hydroxypropyl methycellulose
- Carboxymethyl cellulose (concentration 0.2-2.5%)
- Polyethylene glycol (concentration of 0.2-1%)
What is the surface tension value for healthy tear fluid physiological temperature?
43.6-46.6mN m⁻¹ (millinewtons per metre)
What would happen is a solution had lower surface tension than that of lacrimal fluid?
- it would destabilise the tear film
- it disperses lipid layer into droplets that are solubilised by the drug or surfactant in the formulation
- in a healthy eye, the oily film would reduce the rate of evaporation of the underlying aqueous layer
- hence once the oil film is lost, dry spots form that are painful and irritant
What excipient is included in these preparations? What do they do?
surfactants - solubilise or disperse drugs
Order these surfactants in their irritation power from highest to lowest: zwitterionic, non-ionic, anionic, cationic
cationic > anionic > zwitterionic > non-ionic.
therefore best to use are non-ionic
What are 2 examples of surfactants?
- polysorbate 20
- polyoxyl 40 stearate
What are the negative effects of non-ionic surfactants?
even though best to use?
- Remove the mucus layer
- Disrupt tight junctional complexes of the cornea
- Interact with polymeric substances ( viscosity enhancers ?) in the preparation
- Reduce the efficacy of preservatives
What do surfactants do at high concentrations?
foam with manufacturing and shaking
What can the concentration of surfactant affect?
- drug solubility
- patient safety and tolerance
At the time of filling and closing in a sealed container, what must ophthalmic preparations be?
sterile
What is the preferred method of sterilisation for ophthalmic preparations? If not, what is an alternative?
- terminal sterilisation of product in fianl container
- filtration under aseptic conditions w a pore size 0.22μm
What must the raw materials for ophthalmic preparations be?
sterile, or meet a low specified bioburden control limit
What label should be put on ophthalmic preparations referring to their use once opened?
duration of use once opened
In what types of ophthalmic preparations are preservatives included for? What for?
multidose, to destroy and inhibit microorganism growth
What are route of administration for ophthalmic preparations are preservatives not included in and why?
intraocular - can cause irritation
What properties must preservatives for ophthalmic preparations have?
- should be harmless to ocular tissue
- should be broad spectrum; effective against a range of microorganisms
- should be compatible w other ingredients in preparation and container
Being harmless to ocular tissue
What are 2 commonly used preservatives?
- benzalkonium chloride (0.004-0.02%)
- phenylmercuric nitrate
What is benzalkonium chloride, and what is its disadvantage?
- quaternary ammonium salt
- repeated use leads to epithelial toxicity
What is phenylmercuric nitrate and what are its effects?
- organomercury compound
- powerful antifungal and antiseptic effects
- used in low concentrations
What types of ophthalmic preparations have no preservatives?
single dose, however they can be expensive to manufacture and package
What is the maximum volume that can be in a ophthalmic preparation for hospital use?
10ml
What are the labelling requirements for hospital ophthalmic preparations?
- Volume of contents (must not exceed 10 ml in any one container)
- The official name of the preparation
- name and concentration of active ingredient (w/v%)
- name and concentration of antimicrobial agent (w/v%)
- “sterile until opened”
- “use w care to avoid contamination”
- “to be discarded … after first opening container”
- in hospital ward: to be used for 1 eye of 1 patient only (or if for named patient in which eye)
- direction for use if any
- storage requirement if stated on monograph
- name and address of supplier
- POM or P
- expiry date
- batch and product license number
- name of patient (hospital ward)
- date of issue
- “external use only”
- “keep out of reach of children”
What are the labelling requirements for home (domiciliary) ophthalmic preparations?
- The official name of the preparation unless requested not to label product ( N.B Then label it THE EYE DROPS)
- Concentration of active ingredient (usually as %w/v) when the monograph allows eye drops of variable concentration
- Directions for use
- “Sterile until opened”
- “Use with care to avoid contamination during use”
- “To be discarded one month after first opening the container”
- Storage requirement ( if stated in monograph)
- Name of patient
- Date of dispensing
- “Keep out of the reach of children”
- “For external use only”
- Name and address of supplier
What can eye drop containers be made of?
glass or plastic w suitable closures (to exculde microorganisms)
What are 2 types of glass used for eye drop containers?
- neutral
- soda
What are 2 key features of eye drop glass to indicate they are for external use?
- amber
- vertically ribbed
What type of closures can be supplied with eye drop glass bottle containers?
- phenolic plastic screw cap that incorporates a neutral glass dropper tube, fitted w a natural or synthetic rubber teat
- complete dropper closure that is sterilised and separately supplied with a suitable liner
What are rubber teats incompatible with?
benzalkonium chloride
What is an alternative to a rubber teat?
a silicone rubber teat
What is the limitation to silicone rubber teats? How is this overcome?
- limit duration of use to 3 months due to being permeable to water vapour, hence allowing progressive loss of water from preparation
- complete dropper assembly should be supplied as a separately wrapped sterilised unit, and before issue for use, the dropper assembly should be exchanged w a plain phenolic cap w silicone rubber liner (readily breakable seals)
ophthalmic solutions advantages?
or ocular delivery, it provides several advantages such as sterilization, ease of eye drop formulation, less irritation, increase precorneal residence time and enhancement in ocular bioavailability of drugs which are insoluble in tear fluid.
ophthalmic solutions advantages?
local effect, sterilization, ease of eye drop formulation, less irritation, flush out any residual contaminating or injurious particles. prevent further damage by keeping the eye lubricated.
ophthalmic solutions disadvantages?
limited drug concentration for lipophilic agents, precorneal losses and the barrier function of the cornea
poor bioavailability
Drug elimination can occur from what 3 pathways?
1) aqueous humour -> systemic uveoscleral circulation;
2) aqueous humour outflow through trabecular meshwork + Schlemm’s canal;
3) from vitreous humour
4) via posterior route across blood retinal barrier BRB
