Drug delivery to the eye

Question 1

What are examples of conditions that occur and we treat in the front and in the back of the eye?

Answer 1

Front:
- Hayfever
- Dry eye syndrome
- Cataracts
- Infections
Back: These are harder to treat!
- Diabetic retinopathy
- Glaucoma
- Age-related macular degeneration

Question 2

What are the different chambers of the eye?

Answer 2

• Anterior and posterior = these have the aqueous humour- Colourless, watery fluid containing electrolytes, solutes, growth factors, proteins
• Vitreous cavity- contains vitreous humor- Hydrogel made of 98% water
  and 2% collagen fibres and hyaluronic acid, proteins, salts, glucose. Has a pH of 7.5 and is 2-4 times more viscous than water

Question 3

What parts of the eye can topical drugs target?

Answer 3

Cornea
Conjunctiva
Sclera
Iris
Cilliary body

Question 4

What parts of the eye do systemic drugs target?

Answer 4

These drugs are often given via IV to try and reach the back of the eye.

Question 5

What are the 2 barriers of systemic drugs getting to the back of the eye?

Answer 5

• Blood-aqueous barrier
• Blood-retinal barrier

Question 6

What are the barriers to topical drug delivery?

Answer 6

• Pre-cornial factors- solution drainage, blinking, tear film, tear turnover induced lacrimation (crying) = these all lead to low contact time of the drug with the absorptive membranes in the eye
• Mucin in tear film which acts as a protective hydrophilic layer over the glycocalyx of the ocular surface- this clears debris and pathogens
• Anatomical barriers- layers of cornea, conductive, sclera - all have an important role in limiting drug permeation

Question 7

What are the barriers for systemic ocular delivery?

Answer 7

Following systemic administration, the blood–aqueous barrier and blood–retinal barrier are the major barriers for anterior segment and posterior segment ocular drug delivery, respectively
- retinal capillary endothelial cells and retinal pigment epithelium cells (RPE) known as the inner and outer blood–retinal barrier, respectively
- specific oral or intravenous targeting systems are needed to transport molecules through the choroid into deeper layers of the retina
- limited accessibility to many of the targeted ocular tissues limits the utility of oral administration which necessitates high dosage to observe significant therapeutic efficacy

Examples: Visudyne- is given IV to target leaky vessels at the back of the eye in wet age-related macular degeneration

Question 8

What factors must be considered when developing ophthalmic formulations?

Answer 8

Osmolality
pH
Surface tension
Viscosity

OSMOLALITY:
- This is the concentration of solute expressed as a total number of solute particles per Kg of solvent
This is determined by the conc of salts in the lacrimal fluid- Na+, K+, Ca2+, HCO3-
- In healthy eyes, the osmolality is ~ 302 mmol/Kg
If solution becomes hypotonic: Increased epithelium permeability which leads to oedema
If solution becomes hypertonic: It will dehydrate the corneal epithelium
- Normal tear osmotic pressure – 0.9-1.0% sodium chloride
* Eye can tolerate 0.6-1.3% sodium chloride

pH:
- The pH of tears is 6.9-7.5
- This is controlled by CO2,HCO3-, lysozyme(-), prealbumin(+)
- But the eye can tolerate pH 3.5-9
- Try and formulate a drug as close to physiological pH as possible though

SURFACE TENSION:
- A healthy tear fluid is 43.6-46.6mN/m
- If eye drops decrease the surface tension:
Destabilises the tear film
Disperse lipid into droplets
Solubilised by drug/surfactants in formulation

VISCOSITY:
If prolong drug retention in tear film:
- Enhances drug absorption
- Reduce drainage rate
- Increase thickness of precorneal tearfilm
- Osmolality
Examples of Viscosity enhancing polymers: PVP, PVA, MC, HPMC
- We often use a more gel-like formulation now as liquids are quickly washed away.

• Blinking force required limits the viscosity:
  Normally is 0.2N-0.8N
  Above 0.9N may be painful- hard to blink

ALSO, STERILITY:
Drug formulation and process of manufacture needs to be sterile

Maintaining sterility during manufacture:
* Terminal sterilisation adopted where possible (or filtered)
* Raw materials should be sterile
* Manufacture should be sterile
* Labelled with duration once opened

Maintaining sterility during use
* Preservatives, broad spectrum – benzalkonium chloride
* Single dose unit preparations
* Antibacterial packaging

Question 9

What is the normal osmotic pressure of tears, and what pressure can the eye tolerate?

Answer 9

• Normal tear osmotic pressure – 0.9-1.0% sodium chloride
• Eye can tolerate 0.6-1.3% sodium chloride

Question 10

What is the normal pH of tears and what can the eye tolerate?

Answer 10

pH of tears is 6.9-7.5 but the eye can tolerate a pH of 3.5-9.

Question 11

What are the disadvantages of topical drug delivery?

Answer 11

• Difficult to instill
• Variable dosing- depending on drop size used
• Dilution and washout- by tears etc- rapidly drained
• Require high drug concentrations
• Ocular and systemic side effects
• Major compliance and execution issues

Question 12

What are the advantages and disadvantages of using eye solutions?

Answer 12

+ easy to manufacture
+ Lower cost to make and buy
+ Relatively easy to administer
+ Rapid onset of action
+ Good dose uniformity

• Rapidly drained from the eye- Rate of drainage proportional to the size of the drop
  Volume administered can be 25-56ul depending on:
• Shape of dropper
• Physicochemical properties
  of solution
• Manual usage of bottle

Question 13

When are suspensions used?

Answer 13

Administration of sparingly soluble aqueous drugs (e.g. steroids)

To prolong drug release
* Particles are retained in the eye between the lid and eyeball
* Size limitations due to irritation
* Readily dispersible on shaking
* Homogeneity should be maintained
* Polymorphic changes with storage – change solubility
* Ostwald ripening, caking can be a problem
* Increase viscosity to avoid

Question 14

What are gels?

Answer 14

Semi-solid system comprising of a water soluble base
- They Use polymers e.g. (PVA,HPMC,carbopol,carbomer) dispersed in a liquid
e.g.
PilocarpinePilogel®
- Single gel instillation vs qds solution * Solution dose 8mg/day
* Gel dose 2mg/day

Gels can be activated to undergo phase transition in the eye e.g. from Liquid to Solid due to pH, temperature, ions

Question 15

Hoe do you achieve posterior ocular drug delivery?

Answer 15

This requires use of systemic delivery e.g. oral or IV
Or directly to the area e.g. Intravitreal injections or intraocular implants

Question 16

What are the different types of intraocular injections?

Answer 16

There are 2 types of intraocular injections: intracameral- injection into the anterior chamber and intravitreal- injection into the vitreous cavity

Question 17

What causes non-uniform distribution of drugs in the vitreous cavity?

Answer 17

drug distribution in the vitreous is non-uniform.
This is dependent on MW- Small molecules can rapidly distribute through the vitreous, whereas the diffusion of larger molecules is restricted and slower.

Question 18

What is the most efficient method of drug delivery to the back of they eye?

Answer 18

Intravitreal administration- Injection of drug into the vitreous cavity in the back of they eye.

Question 19

What is the major barrier to intravitreal administration?

Answer 19

Poor patient compliance

Question 20

What are examples of drugs that can be given via intravitreal administration and what does frequency of dosing depend on?

Answer 20

Drug retention in the vitreous space determines the frequency of administration
e.g.
* Pengaptanib sodium (Macugen®)
* Ranibizumab (Lucentis®) *Dexametasone
* Triamcinolone acetate

Question 21

What are the different routes by which periocular injections can be administered?

Answer 21

• Subconjunctival injection
• Subtenon injection
• Retrobulbar injection
• Peribulbar injection

Question 22

What are the options for drug delivery in glaucoma?

Answer 22

• decrease aqueous production (beta blockers (BB), alpha
  agonists (AA), and carbonic anhydrase inhibitors (CAIs))
• Improve aqueous outflow (cholinergics, PGAs).
• Topical BB and CAIs are associated with fewer systemic side-
  effects than their oral forms and are better tolerated by
  many patients
• PGAs have the advantage of effectiveness in lowering IOP
  with once daily dosing. However, some patients experience an irreversible change in iris colour and periorbital dermal darkening with PGAs

Question 23

Discuss devices that have been made to target treatment to the eye (go over more- this could be a q)

Answer 23

Punctal Plugs:
Plugs are inserted (1-2mm) into tear ducts where they stay for two to three months and slowly release drug overtime.
Plugs made of different polymers
* Silicone
* Hydrogel
* Polycaprolactone

Injectable implant:
E.g. Iluvien (Fluocinolone) intravitreal implant.
- is designed to release the corticosteroid, fluocinolone acetonide over 3 years after being implanted in the back of the eye.
- For treating diabetic macular edema (DME).
It is a non-bioerodible implant made of polyimide
Another examples is a Durasert (Lataboprost) implant that gives 3 months delivery to they eye. This is used in glaucoma.
- is inserted into the subconjunctival space with 25-gauge needle
- The implant is bioerodible and is expected to deliver an appropriate dosage of latanoprost for about three months

OCULAR IONTOPHORESIS- Is in research
Uses iontophoriesis to drive drug from the surface of the eye into the inside:
- The basic electrical principle that oppositely charged ions attract and same charged ions repel is the central tenet of iontophoresis. The ionized substances are driven into the tissue by electrorepulsion at either the anode (for positive drug) or the cathode (for negatively charged drug)
- For neutral molecules, Electroosmotic flow is the bulk fluid flow which occurs when a voltage difference is imposed across a charge membrane. Since the human membranes are negatively charged above pH 4, the electroosmotic flow occurs from anode to cathode, as the flow of the cationic counterions
- ocular iontophoresis is capable of delivering substantially higher ocular drug concentrations than traditional topical applications, leading to greater bioavailability and more sustained therapeutic effect and reducing the frequency of dosing

Drug-eluting contact lenses:
The lens is coated with a drug in the inner side providing steady drug release e.g. for steady maintenance of intraocilar pressure in glaucoma.
Reached the market in 2022

Topical Ophthalmic Drug Delivery Device (TODDD)
* A soft, flexible device that floats on the sclera completely concealed under the eyelid.
* Insert once for 30-90 days of continuous drug delivery via a reservoir
* Non-invasive
* In human clinical trial

Sensimed trigger fish
- Triggerfish is a contact lens device capable of continuous IOP measurements- (not for drug delivery). Is now recommended by NICE.
* It provides an automated recording of continuous ocular dimensional changes over 24 hours
* Contact lens sensor contains strain gauges that measure corneal curvature changes caused by intraocular pressure variations
* Microprocessor and an antenna integrated into the soft contact facilitate wireless powering and communication

Question 24

What are benefits over surgeries/injections as opposed to eye drops?

Answer 24

• Eye drops can be hard to use
• 1 surgery- better compliance than multiple daily eye drop doses- people don’t find injection of implant appealing but in glaucoma for example, eye drop adherence is less than 80%
• Lower risk of contamination- once eye drops are open they have a use-by date and should be stored in the fridge BUT, they are still exposed to the environment and there is risk of contamination

Question 25

Explain
why drug delivery methods such as eye drops and intracameral implants cannot deliver drug to the posterior chamber
of eye for diseases such as age-related macular degeneration

Answer 25

1.Barriers to Penetration:
1. Corneal Barrier:
The cornea acts as a protective barrier for the eye. Eye drops have difficulty penetrating the cornea
and reaching the posterior chamber due to its limited permeability.
2.Rapid Clearance and Dilution:
1. Tear Flow and Drainage:
Eye drops are often washed away by tear flow, limiting the time available for drug absorption.
2. Dilution in Aqueous Humor:
Intracameral implants may face dilution within the aqueous humor of the anterior chamber before
reaching the posterior segment.
3.Limited Retention Time:
1. Blink Reflex:
Frequent blinking and reflex tearing associated with eye drops can limit the retention time of the
drug on the ocular surface, reducing the chances of effective absorption.
1. Implant Displacement:
Intracameral implants may be subject to displacement or movement within the anterior chamber,
affecting their ability to reach the posterior segment.
4. Anatomical and Physiological Challenges:
1. Vitreous Humor:
The gel-like vitreous humor in the posterior segment can impede the distribution of drugs, making it difficult
for them to reach the macula in sufficient concentrations.