OPTHALIMIC BIOPHARMACEUTICS

Question 1

cornea

Answer 1

does most of the light bending

it has its nutrients delivered in a different way compared to the rest of the eye

Question 2

lens

Answer 2

minor adjustments for sight ie)distance & close-work

light through the lens is focused on the FOVEA and surrounding tissue called the macula

the anterior structures are bathed in a solution of AQ salt

Question 3

the Canal of Schlemm

Answer 3

interfaces with blood vessels creating an exchange

Question 4

Vitreous Humour

Answer 4

all held together by a multilayered tissue containing :

Outer Sclera: conjunctiva covers the outer sclera and contains blood vessels (conjunctiva ends when the cornea starts)

Black Choroid: contains melanin to keep light out

Light Sensitive Retina : makes vision possible - sends electric messages through the optic nerve

membrane keeping the vitreous humour contained is called THE THYLOID

Question 5

the blindspot

Answer 5

the optic nerve found at the back of the eye

Question 6

trabecular mesh

Answer 6

liquid made in the eye by the cilary body structure floats under the iris and around the cornea, through the trabecular mesh and into the cornea

THE CILARY BODY HOLDS THE SENSORY LIGAMENTS WHICH MAKES THE LENSES CHANGE THEIR SHAPE

Question 7

layers of the cornea :

Answer 7

5 layers :
Epithelium 
Bowman's membrane 
stroma 
Decemet's membrane 
Endothelium

Question 8

epithelium cells

Answer 8

epithelial layer secretes gylcocalayse and mucus
regular structure creates transparency

glycocalyx frame work molecules
- exuded from the microvilli on the corneal epithelial surface
holds co-secreted mucus in place at the base of the tear film

Question 9

tear film

Answer 9

tears are mainly saline and bicarbonate (buffer) with dissolved proteins and mucins (mucus)

Question 10

tear film and the effect on viscosity

Answer 10

Proteins and mucins rase the the viscosity because of the tangled network
they give a yield value - it gelates when not stressed and doesn’t move until this stress is exceeded by the blink

Question 11

tear film and plastic behaviour

Answer 11

polymer alignment : “shear thinning” with an imposed shear sliding force - this shear thinning allows lubrication during blinking whilst debris

AQ layer of tears secreted by the tear glands(lie under the top lid of each eye and contains):
Proteins, sodium, potassium chloride , bicarbonate carbonic acid , proteins and mucins -this combination helps to clear away mucus and debris(viscosity)

outer layer contains secreted lipid produced by the MILBONIAM GLANDS which lie underneath the root of each eyelash
- stabilises tears - without it eyes tend to drip (dry eyes)
dry eyes are gritty and sore and feel like they are not lubricated

Question 12

treating intraocular conditions

Answer 12

surface conditions : fairly easy to treat
dry eyes , conjunctivitis , blepharitis , trachoma

Anterior conditions - more difficult to treat
cataract , anterior uveitis , causes of glaucoma (front of the eye)

Posterior conditions: requires continuous therapy but more difficult to asses and quickly cleared
macular and retinal degradation ,posterior uveitis , effects of glaucoma (back of the eye)

Question 13

Topical Drug Delivery : to surface and anterior inner structures

Answer 13

eye drops are cheap and easy to administer - BUT : overspills

nasolacrimal drainage : blinking occurs - pumps some of the drug down the duct
effective drug concentration gone from the cul-de-sac within 2 mins via the duct
PATIENTS SHPULD PRESS TO REDUCE THE EFFECT
with drops very little persists for more than a few mins (5%)

Question 14

considerations when formulating eye drops

Answer 14

sterility : must contain a bactericide so bacteria doesn’t grow when they are open for use (alternative they can be single does so sterile but no bactericide needed)

pH range of tears: normal range = 7.4,
low on waking - rises on loss of trapped CO2(carbonic acid),
contact lenses : gas permeable lenses = 7.3 due to build up of CO2
Comparatively high in some diseases such as dry eye (7.9)

comfort : produces by pH 7.4 - no excess tears
weak natural buffer capacity in tear film keeps the pH close to 7.4

stability during heat sterilisation : adjusting pH

Solubility : when pH=PKA the drug is always 50% ionsised & maintains solubility

damage : can be caused by extremes of pH and will precipitate structural proteins or create a soap form

surface tension : eye drops with surfactants can solublise natural lipid and thus produce dry eye artificially

toxicity : an isotonic solution has the same number of molecules/ ions per unit volume as plasma or tears - was (eg) if drug conc is low and the resulting in solution being hypotonic soduim chloride can be added)
BUT - very hypertonic solutions can cause temporary corneal swelling- hypertonic solution may cause some shedding of squamous cells but natural balance is quickly restored

Question 15

DRUG ABSORPTION FROM EYE DROPS:

topically through the cornea

Answer 15

lipophilic and hydrophilic drugs pass across the cornea by trans and paracellular routes respectively

• the cell membrane in the cornea are lipiodial and some lipophilic molecules can travel through the membranes if they are small enough

some exceptions : CICLOSPORIN is a large molecule that can cross these membranes
other more hydrophilic molecules have to travel between them if they are small enough

most fat soluble drugs can transfer across the cornea and small molecules travel between them, it difficult to maintain a useful conc inside the eye
- the eye has flow membranes to eliminate drugs to the plasma

forgein substances like drugs are quickly eliminated from the eye interior

active transport - very few drugs cross it so it is not likely in the cornea

Question 16

DRUG ABSORPTION FROM EYE DROPS:
topically NOT through the cornea

1st diffusion through conjunctiva , sclera, choriod and retina:

Answer 16

Conjunctiva and sclera (form the white of the eye)
they are looses gels with fibers - blood vessels but drugs diffused around these
choriod and retina are cellular but not near the front
THIS IS NOT THE SAME AS PARACELLULAR SEEPAGE BETWEEN CELLS BECAUSE IN THESE LAYERS THERES IS VERY LITTLE CELL STRUCTURE

this route may be important for large hydrophillic drugs such as Timolol, Qentamicin - these molecules are too big to go by the paracellular route

Question 17

DRUG ABSORPTION FROM EYE DROPS:
topically NOT through the cornea

2nd diffusion through blood supply from the surface or other administration sites to the inner eye via the cilary body

Answer 17

these particular vessels dont deliver large hydrophillic molecules as the paracellular gaps are too small

application of drops may lead to some entering the blood supply into the cilary body so that the drug has a route to the inner eye

the blood vessels are highly constricted that large molecules cannot pass into the eye from them-n small lipophilic drugs can however be removed by elimination routes

PROBLEMS: all drugs delivered to the inner eye are also removed particularly by - aqueous blood: vascular and trabecular removes corneal and non corneal delivery.
in general corneal and non corneal diffusion can treat surface and anterior but will not reach the retina

Question 18

elinination routes

Answer 18

1. blood aqueous barrier and it removes corneal and non corneal delivered drug that has found its way to the aqueous barrier
2. aqueous humor is produced by the cilary body and flows out through the pupil and into the canal of schelmn, carrying drug molecules with it into the plasm which lies on the other side of the canal of schlemn

Question 19

TOPICAL DRUG DELIVERY :

Answer 19

prodrugs have an inert solubility and motility
drugs are usually inert at this stage - used to gain tissue access then discarded to activate

other ophthalmic prodrugs already used or in development - esters, oxides, phosphates, carbonates
eprinephrine oxazoilate (in oil)
glancilovoir valerate
carnabinoides

Question 20

prodrugs

Answer 20

one change in chemistry normally of a hydrophilic drug to attach to an inert lipophilic section (moiety)- its the main drug structure to do 2 things :

1. usually temporarily inactivates the drug
2. makes it more lipophilic and capable of crossing liposdial membranes
   allows it to travel across the epithelial and microstructures undetected - inside the tissue enzymes may cleave the moiety off and release the active drug

a back to front version is also used in ophthalmics
- the bonding of a hydrophilic moiety to a lipophilic drug that otherwise will not dissolve well in water

Question 21

formulation to sustain release and /or effect retention:

SINGLE PHASE

Answer 21

a solution without any solid or oily particles
increase the viscosity (thicken)or gel the system from the front of the eyeball to spill over the lid OR be pumped down the nasolacrimal pump into the throat

this means the drop has longer to deliver the medication and less is wasted or miss-delivered to the nose and throat

certain polymers will gel with a single change in pH, temperature change OR constant with particular ions that are present in tears

Question 22

formulation to sustain release and /or effect retention:

MULTIPHASE SYSTEMS

Answer 22

1. use of fine solids dispersed in a liquid (suspension)-micronised so that the solids are to small to cause irritation
   if the suspension stays on the surface of the eye it may slowly release the drug
2. Emulsions- droplets of one phase dispersed in another : water in oil / oil in water
   the interfacial tension is high and needs to be lowered to give the emulsion some stability so a surfactant would be used
   EYE DROPS WOULD BE EXPECTED TO BE OIL IN WATER EMULSIONS
3. liposomes - contain no central oil drop
   they can deliver drugs from the AQ centre and channels to the vesicles
   the surfactant is biocompatible (lecithins) and in a bilayer

Question 23

inserts

Answer 23

Ocusert- free pelocarpine base in alginate carriers behind rate controling (EVA) Ethyene Vinyl Acetate
membranes that resist osmotic flow - this delivery did not deminish with time

SOME LOSS THROUGH DUCTS BUT NO SPILLS - MUCH MORE EFFECTIVE DELIVERY
MUCH LESS DRUG EXPOSURE THROUGH NASAL DRAINAGE
Glaucoma therapy much improved in the uk with this prescribed

Question 24

eye ointments

Answer 24

ointments containing wool fat (which mixes with water)
when it does this the eye ointment base emulsifies the water so its almost insoluble and therefore can carry soluble drugs dispersed in fine emulsions through the oily paraffin centre
Ointments can also contain yellow paraffin and liquid paraffin (often used for lid treatment)
if paraffins alone were used the drug will not emulsify in the product

this is a cheap and simple formulation :
it can be heat sterilised and aseptically mixed with an AQ solution of a drug
OR mixed with a suspension
OR used to make only solutions of lipophilic drugs

Question 25

treatment by injection (PARENTERALS)

Answer 25

this is an injection into the eyeball itself aiming to target the retina
It reaches the target by breaking local tissue and injecting near the target
chronic diseases need repeated doses and its not a pleasant procedure - retinal toxicity can occur if the concentration is too high and THE CONC NEEDS TO BE HIGH BECAUSE THE INJECTED VOLUME CANT BE ABOVE 2ML

Question 26

intraocular (intravitreal) drug delivery :

Answer 26

once the drug is in the vitrous humour, distance to the retina is not great- diffusion rate to the target needs to be quite high

there is an elimination route via the retinal and underlying layers
the retinal barrier seems to operate mainly to prevent the drug form entering the eye and FROM SYSTEMICALLY DELIVERING THE DRUG FROM OTHER TYPES OF INJECTIONS
The AQ flow of the canal of shclem at the front of the eye does remove drug from these injections into the vitrous humour
Active removal processes via the retina/choroid is quite fast reducing resistance time
Passive diffusion and fluid flow away though the anterior route is now thought to be the faster removal mechanism

Question 27

intraocular (intravitreal) drug delivery :

sustained release

fine carrier suspensions

erodible devises and fine precipitated suspensions

infection free bots

external activation at time intervals

Answer 27

sustained release :
bioadhesive and insite gelling formulations
monolacromal antibodies (ranibizamab for macular degeneration)
fusion proteins (conbercept for neovascular glaucoma )

fine carrier suspensions :
antiviral (glacilovir)
cytotoxic (dainomycin)
gene therapy by multifunctional particles

erodible devises and fine precipitated suspensions:
extend delivery of the antiviral glacilovir (HIV retinal disease),the cytotoxic dianomycin and for gene therapy multifunctional particles that have been formulated to deliver appropriate genetic material such as DNA and RNA for cell nuclei

infection free bots :
externally pulsed activation at time intervals
using pH and laser responsive formulations

external activation at time intervals :
can be achieved using dye containig liposomes where a laser activated dye can be used by shining a laser right through the cornea which activates the dye to become a cytotoxic agent
THERE ARE DYES THAT CAN ACHIEVE THIS,BETWEEN ACTIVATION TIMES THE DYE STAYS SAFELY IN THE LIPOSOME although eventually everything is metabolised

Question 28

Plugs ,screws and devices

Answer 28

aim is to deliver zero order which implies a constant dose rate overtime - without any/small loss of dosage rate
the aim is to make invasion of the ye as less as we can so patients don’t have to go to a monthly clinic
some of the devises are made from matrix materials like POLY VINLY ACETATE (non erodible and may need retreval) POLYOULPHONE (erodible and with the possibility of being porous) POLYCAPROLACTONE (erodible )
they all carry the look of a conditions called retinal detachements where on pushing the devices through the eyeball wall the inner layer (retina) can tear blinding the patient

Question 29

matrices

Answer 29

Glancilovir (6mg) in PVA-EVA matrix construction is non erodible - release for 32 weeks at 1-ug/h (clinically accepted)
dexamethasone has a simila construction
daunomycin in non-errodible polysulphone capillary fibre containing 1% of drug tristearin (not yet clinically acceptable)
doxourbein 1% from erodible sedral plugs -erodible tubular reservoir made from polycaprolacotone made with sodium chloride

Question 30

matrices :

DISADVANTAGES / RISKS :

Answer 30

inflamation :
increases passive removal
decreases water removal

retinal detachment
removal if not erodible