| 1

Ocular drug delivery

Dr. Herman J. Woerdenbag

Department of Pharmaceu1cal Technology and Biopharmacy
University of Groningen
The Netherlands
h.j.woerdenbag@rug.nl

2016 H.J.Woerdenbag

 | 2

The eye
Anatomy
Drug delivery sites
 | 3

The eye
Cornea lacks blood vessels
We can see
Infec1on less easily combated by the body

Intact eye seldom infected

Cornea is barrier
Lacrimal uid has an1bacterial ac1vity

Eye vulnerable organ

Composi1on eye prepara1ons is delicate
 | 4

Protec=on cornea
Blinking with eye lids
Closure of eyelids
Lacrima1on
Lysozyme (in lacrimal uid)
Low pain threshold

Irrita1on causes lacrima1on

Medica1on rinse out

 | 5

Lacrimal uid (tears)

To keep the cornea moist
To wash out dust and debris
Bactericide (lysozyme)
Preven1on of bacterial colonisa1on of the eye
Produc1on about 1.2 L/min
Normal tear volume 5-9 L
pH 6.9-7.5
Isotonic
Buered (bicarbonate, phosphate, amphoteric proteins)
 | 6

Tear lm three layers

Outer, oily lipid layer
To prevent evapora1on and to increase lubrica1on
Middle, watery, lacrimal component
Inner, consis1ng of mucous or mucin
To anchor the tears to the ocular surface
 | 7

Ocular diseases
Glaucoma
The red eye
Infec1on
Allergy
Trauma
Dry eye syndrome
Cataract
Macula degenera1on
 | 8

Glaucoma
Damage to and deteriora1on of the op1c nerve due to
enhanced intraocular pressure (>20 mm Hg)
Leads to progressive (irreversible) loss of vision (visual eld loss, blind
spots) and eventually blindness
Usually starts acer age of 40 (gradually progressing)
40-plus: about 1%
80-plus: 2-6%
Primary glaucoma
Open angle, chronic
Closed angle, acute
 | 9

Clinical picture of glaucoma

 | 10

Impaired vision by glaucoma

 | 11

Open angle and closed angle glaucoma

Fluid produced in posterior chamber

Drainage in anterior chamber via trabecular meshwork and Schlemm's canal
Open angle glaucoma: disturbed uid drainage yields increased intraocular pressure
Closed angle glaucoma: block in circula1on at level of pupil; iris closes o angle
 | 12

Treatment of glaucoma
Irreversible damage to the op1c nerve is untreatable
Target of treatment: reduc1on of ocular pressure
Slow down or stop progress of disease
Open angle (chronic)
Medica1on
Laser treatment
Surgery (trabeculectomy)
Closed angle (acute)
Laser or surgically, usually preceded by drug therapy
 | 13

Drugs used to treat glaucoma

Beta blockers
Prostaglandin analogues
Carbonic anhydrase inhibitors
Parasympathicomime1cs
Sympa1comime1cs

Mechanism of ac1on
Inhibi1on forma1on uid
Enhancement drainage
 | 14

The red eye

Infec1on
Allergy
Trauma
 | 15

Treatment red eye

Decongestants
Sympathicomime1cs (phenylephrine), zinc sulphate

An1bio1cs, an1virals
Fusidinic acid, tetracycline

An1histamines (azelas1ne), cromones

Cor1costeroids (prednisolone, dexamethasone)

 | 16

Dry eye syndrome

Chronic lack of sucient lubrica1on and moisture on the
surface of the eye
Constant irrita1on, inamma1on
Insucient tear produc1on
Ageing process
Medica1on
Eye drops with ar1cial tears
Insert lled with a lubrica1ng ingredient
Hydroxypropyl cellulose
 | 17

Cataract
Clouding of lens inside the eye
Decrease in vision
Blindness
Treatment
Surgery: lens replacement
Postopera1ve medica1on
Preven1on and treatment of pain
Preven1on of macula oedema
Prostaglandinsynthase inhibitors
- Indomethacine, diclofenac
 | 18

Macula degenera=on
Age related
> 50 years
Macula aected
Most sensi1ve part re1na
Loss of central vision
Dry
Degenera1on of light-sensi1ve cells
Wet
New blood vessels grow underneath macula and leak
Macula raises o the back of the eye
Intraocular injec1ons an1-VEGF
 | 19

Typical drugs for the eye

Decongestants
Adstringents
Mydria1cs
An1glaucoma
An1bio1cs
Cor1costeroids
An1histamins
Local anaesthe1cs
 | 20

Eye prepara=ons
OPTHALMICA (Ph. Eur.)

Sterile liquid, semi-solid or solid prepara1ons intended for

administra1on upon the eyeball and/or to the conjunc1va, or
for inser1on in the conjunc1val sac

Eye drops
Eye solu1ons
Powders for eye drops and powders for eye solu1ons
Semi-solid eye prepara1ons
Ophthalmic inserts
 | 21

Requirements eye prepara=ons

Always sterilised (global requirement; all pharmacopoeias)
Mostly preserved
Not: hypersensi1vity, eye damage, soc contact lenses
More or less isohydric (pH 5.0-8.5)
More or less iso-osmo1c (0.6-2.0 % NaCl)
Limited buer capacity
Required more strictly for eye washes
Small par1cles, not sharp (suspensions)
Irrita1on and pain cause tear produc1on
Drug washed out
 | 22

Therapeu=c aspects
Site of ac1on
Absorp1on via cornea (route of entry)
On conjunc1va
Administra1on
In lower conjunc1val sac
Side eects
Via nasolacrimal duct absorp1on through nasal mucosa
Absorp1on through conjunc1va
Dilu1on and washing out by tears
Hygienic administra1on
 | 23

Biopharmacy eye prepara=ons

Lipophility and degree of ionisa1on of API
Membrane passage
Amount of API (determined by drop volume)
Local high concentra1ons of API are possible
pH
Buer capacity
Osmo1c value
Surface tension
Drainage and dilu1on by tear uid
Viscosity lacrimal lm
 | 24

Eye drops
Excipients
To adjust tonicity or viscosity
To adjust or stabilise pH
In increase solubility of ac1ve substance
To stabilise prepara1on
Preserva1ve, except for use in damaged eye or for surgical procedures
Mul1dose (10 mL) and single dose (1 mL) containers
Solu1ons
Suspensions
Controlled par1cle size and resuspendability
 | 25

Low bioavailability eye drops

Human tear lm 7 L / eye drop 30-50 L
Around 95% is lost
Excess pressed out upon eye closure
Canicular drainage
Spillage via conjunc1val epithelia
Absorp1on API
Self-administra1on can be dicult
Frequent administra1on
Jeopardise pa1ent compliance

Other dosage forms?

 | 26

Eye solu=ons
For rinsing or bathing the eye
First-aid, therapeu1c
For impregna1on of eye dressings

Mul1-dose containers contain at most 200 mL

Preserved
Single-dose containers for surgical procedures and rst-aid
treatment
Not preserved
 | 27

Semi-solid eye prepara=ons

Sterile ointments, creams or gels for applica1on to the eye lid
(conjunc1va) or to the eye
One or more ac1ve substances dissolved or dispersed
(demands for par1cle size) in a suitable basis
Small, sterilised collapsible tubes with sterilised cannula;
contain at most 10 g
Aqach beqer to the eye than eye drops
Slower washed out by tear produc1on
Longer ac1on (depot)
Disadvantage: impaired sight
Especially suitable for use at night
 | 28

Ophthalmic (ocular) inserts (1)

Sterile, solid or semi-solid prepara1ons of suitable size and
shape, to be inserted in the lower conjunc1val sac, to
produce an ocular eect
Reservoir of ac1ve substance embedded in matrix or
bounded by a rate-controlled membrane
Polymers (co-polymers): non-eroding, eroding

Ac1ve substance, more or less soluble in lacrimal uid, is

released over a determined period of 1me
Drug delivery on the basis of diusional mechanisms
Zero order release (near-constant, known rate)
 | 29

Ophthalmic (ocular) inserts (2)

Signicant frac1on of API will not be absorbed via cornea but
is absorbed via membrane conjunc1val sac
Manipula1ons may be dicult for (elderly) pa1ent
Inser1on (compare contact lens), removal

Alterna1ve ocular drug delivery form: drug loaded contact
lens
 | 30

Intra-ocular injec=ons
Intravitreal
100% bioavailability
Serious burden to the pa1ent
Formula1on related safety aspects of paramount importance
Elimina1on from site of injec1on slow
Only way to get suciently high concentra1on in the eye
An1bio1cs, monoclonal an1bodies
Slow clearance
Injected volume small
Rela1vely high concentra1on of API required
Clearance from the vitreous body is slow
 | 31

Dead space
Typical volume intra-ocular injec1on 50-100 L
Considerable dead space normal syringe
Adapted design
Cost reduc1on by less less spillage
Monoclonal an1bodies
| 32