Occular Drug Delivery

Question 1

Why is Absorption of topically applied agents is usually limited to the anterior ocular tissues?

Answer 1

due to ocular static and dynamic barriers

Question 2

What do tear liquids contain?

Answer 2

Secreted mucins and surface associated mucins

Form a hydrophobic blanket that moves over the ocular surface to clear debris and pathogens

Question 3

What size are polymeric nanoparticles for drug delivery to anterior segment of the eye?

Answer 3

1–1,000 nm

Question 4

Information: Polymeric Nanoparticles - Aqueous or aqueous

Answer 4

¥ Aqueous or non-aqueous suspension of drug-loaded nanoparticles can be administered to the eye
Ð Sustained drug delivery
Ð Reduce drug administration – improve retention time on eye
¥ The active drug is slowly released by either:
Ð Diffusion
Ð Dissolution
Ð Mechanical disintegration and/or erosion of the polymer matrix (could get diffusion out of the NP or if you use a biodegradable NP) Can drug release controlled by particle degrading. Can get degradation controlled release.

Question 5

Give an example of polymeric nanoparticle to be delivered to the anterior segment of the eye

Answer 5

PLGA nanoparticles blended with a cationic polymer (Eudragit®RL), or coated with anionic polymer (Carbopol®) would improve interactions with mucins

• Increased retention time due to muco-adhesion
• The nanoparticles provide sustained release of the drug
• Carbopol®-coated PLGA nanoparticles with negative surface charge showed higher tear film concentrations in comparison to non-coated PLGA nanoparticles
• Positively charged Eudragit®RL-PLGA nanoparticles further increased the tear film concentration
• Negatively-charged mucins on the preocular surface interact with these positively-charged formulations, to increase the residence time and enhance the cellular uptake of nanoparticles

Other polymers could be used to increase co-valent binding and form disulphide bonds

Question 6

Why are nanomicelles more pleasing to patients?

Answer 6

The most frequently utilized approach to formulate therapeutic agents in to a clear aqueous solution

Question 7

What polymers are nanomicelles made from?

Answer 7

• N-isopropylacrylamide,
• Vinyl pyrrolidone
• Acrylic acid

Question 8

What surfactants are nanomicelles made from?

Answer 8

• Pluronic F127
• Vitamin E TPGS
• octoxynol-40

Question 9

Describe how a NORMAL nanomicelle is formed?

Answer 9

When amphiphilic molecules are exposed to a suitable solvent they self-assemble .
- Normal: Hydrophilic portion orients towards the polar solvent
Hydrophobic section of the molecule orients away from the solvent
The hydrophilic portions are allied towards the outer surface to maximize contact with water

• Normal nano-micelles can be utilized to encapsulate, solubilize and deliver hydrophobic drugs (soluble drugs which has good absorption)

Question 10

Describe how REVERSE nanomicelles are formed?

Answer 10

Reverse:
Hydrophobic region towards outside
Hydrophilic portion towards inside

• Reverse nano-micelles can be utilized to encapsulate and act as better candidates for delivery of hydrophilic drugs. Hydrophilic core.

Question 11

What are the advantages of nanomicelles?

Answer 11

• Nanoscale size – improve solubility and absorption of particle itself
• Aqueous clear/transparent drug formulation
• Encapsulate and solubilize hydrophobic drugs
• Enable high permeation through ocular epithelia with minimal or no irritation

Question 12

Give an example of a nanomicelle.

Answer 12

Dexamethasone-loaded pluronic nanomicelles containing chitosan demonstrated 2.4 fold increase in concertation compared to dexamethasone suspension.

• Mixed nanomicellar system prepared from vitamin E TPGS and octoxynol-40.
• Able to encapsulate voclosporin, dexamethasone, and rapamycin
• Were clear and transparent
• Carried a high drug payload
• Enhanced drug bioavailability to the anterior segment of ocular tissues
• No sign of ocular irritation or toxicity
• Improved pharmacokinetic profile

Question 13

What are nano-suspensions?

Answer 13

Nano-suspensions are a colloidal dispersion of nano-sized particles stabilized by polymers or surfactants
- Used for the delivery of hydrophobic drugs

Question 14

What are the advantages of nano-suspensions?

Answer 14

• Sterilization
• Ease of eye drop formulation (can filter them through micron filter to take out bacteria).
• Less irritation – compared to a standard normal eye drops or suspension.
• Increase in precorneal residence time – nanoparticle absorbed into the tissue more than a large particle so less likely to be washed out
• Enhancement in ocular bioavailability of those drugs which are insoluble in tear fluid

Question 15

What is the current therapy for nano-suspensions?

Answer 15

Current therapy with prednisolone, dexamethasone and hydrocortisone

However needs frequent administration at higher doses which can induce cataract formation, glaucoma, and damage optic nerve (need to look for ways to reduce frequency

Question 16

What are the advantages of nanoemulsions?

Answer 16

Ð High capacity to dissolve both hydrophilic and hydrophobic drugs
Ð Stability
Ð Improved bioavailability
Ð Good spreadability – emulsion will spread with blinking.
Ð Surfactants used in formulating emulsions can also act as penetration enhancers
Ð Improving drug permeability across the cornea
Ð Chitosan is a cationic polymer that has the ability to enhance corneal drug permeability by opening tight junctions
Ð It strongly interacts with negatively charged mucin and improves residence time on the precorneal surface

Question 17

What are liposomes?

Answer 17

Liposomes are drug carrier systems consisting of 2 compartments:

• Inner hydrophilic compartment
• Peripheral lipophilic compartment
• Has the ability to entrap both hydrophilic and lipophilic drugs
• Allows for surface modification with targeting agents (first, second generation of liposomes)

Question 18

Give an example of a liposome used for the anterior segment of the eye?

Answer 18

Dexamethasone-loaded sugar-chain surface-modified liposomes were investigated for the treatment of anterior chamber ocular inflammations

• Specific recognition and binding between lectin in the eye and sugar chain in the liposome
• Utilize sugar as a targeting moiety toward ocular inflammations

Question 19

Why is it a challenge to delivre drugs to the posterior segment of the eye?

Answer 19

The delivery of the drugs to the back of eye by systemic administration is greatly restricted by the blood-retinal barrier (to stop foreign bodies getting into the eye).

Question 20

What administration routes are available to put into the posterior segment of the eye?

Answer 20

Ð	Intravitreal injection
Ð	Subretinal injection
Ð	Transscleral administration
Ð	Subconjunctival injection
Topical instillation

All are invasive and can sometimes lead to post-administrative complications such as retinal toxicity, retinal detachment and intraocular infections (endophthalmitis). Want to reduce these.

Question 21

Where do larger nanoparticles remain?

Answer 21

Larger particles tend to remain in the vitreous cavity near the trabecular meshwork

Question 22

Where do smaller nanoparticles go?

Answer 22

Crosses the retinal barrier

Question 23

Information

Answer 23

¥ Positively-charged nanoparticles adhere to the anionic vitreous network components and aggregate within the vitreous (may slow down diffusion). However, less chance of being washed out.
¥ Anionic nanoparticles diffuse through the vitreous and penetrate the retinal layers (these are better). However, may diffuse out quicker.
- The inclusion of PEG on the surface of nanoparticles enabled them to diffuse through the vitreous and reach the retina

Question 24

What can subconjunctival administration do?

Answer 24

¥ Subconjunctival administration bypasses the lipid layers and places the drugs adjacent to the water-permeable sclera
-increasing the penetration of water-soluble drugs into the eye

Question 25

Where can intravitreal administration deliver to?

Answer 25

Intravitreal administration can directly deliver nanoparticles to the vitreous body, enabling further diffusion or penetration to the retina
Nanoparticle formulations can avoid the quick clearance and can improve retention in the vitreous and the retina for sustained delivery

Question 26

Information

Answer 26

Subretinal
- Subretinal injection of nanoparticles avoids the barrier effect of the vitreous and the limited penetration through the inner membrane
- Nanoparticle formulations can provide sustained delivery of drugs directly into the retina after subretinal injection
- Hydrophobic drugs will not want to diffuse into the aqueous sclera
o Increasing their diffusion into the retina

Question 27

What does the inner blood retinal barrier do?

Answer 27

• The inner BRB (iBRB) prevents the penetration of drugs after systemic administration reaching the ocular tissue
• it contains tight-junctions which form a selective barrier

Question 28

Information

Answer 28

PLGA nanoparticles surface-functionalized with transferrin were able to accumulate in the posterior segment of the eye which had Choroidal Neovascularization (CNV) after systemic administration

• The same particles did not accumulate in the posterior segment of a normal eye.
• CNV is the creation of new blood vessels in the choroid layer of the eye
• This and the transferrin enhance the accumulation of the nanoparticles

Question 29

Toxicity

Answer 29

The toxicity of nanoparticles in ocular tissues can be affected by:

• Their chemistry
• Size
• Dose
• Retention time (the longer they are there, the greater the toxicity)
• The biodistribution pattern of the particles in the eye
• Smaller particles will have an increased residence time (greater toxicity)
• Size and chemistry will also influence biodistribution