Posterior Drug delivery - PowerPoint Presentation

Slide1

Posterior Drug delivery

Posterior

drug

delivery

Dr

Athmar

Dhahir

Habeeb

PhD in Industrial Pharmacy and pharmaceutical formulations

Slide2

Delivery of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains

of the

eye. There is an increasing need for managing rapidly progressing posterior eye diseases, such as age related macular degeneration, diabetic retinopathy, uveitis, macular oedema and retinitis pigmentosa. Drug delivery to the posterior segment of the eye is therefore compounded by the increasing number of new therapeutic entities (e.g. oligonucleotides, aptamers and antibodies) and the need for chronic therapy.

Anatomy of the posterior segment

Slide3

Barriers to posterior drug delivery

Slide4

The inner limiting membrane (ILM) and the BRB are the

main biological

barriers to drug transport from the vitreous to the retina. The ILM forms a border between the vitreous humour and the retina

and is the primary barrier to drug diffusion to the retina

The

BRB, which is composed of the endothelial cells of

retinal blood

vessels and the retinal pigmented epithelium (RPE),

forms the

secondary barrier to the transport of

lipophilic drugs

to

the inner

retinal cells.

Studies

have shown rapid clearance of

lipophilic molecules

administered into the vitreous by passive diffusion

via the

BRB.

Furthermore

, the efflux transporters in the

endothelium lead

to rapid elimination of molecules that are substrates for

this innate

active transport mechanism

Slide5

Topical, systemic, intravitreal

and

periocular routes can be used to deliver pharmaceuticals to the posterior segment of the eye. The topical route is inefficient in delivering therapeutic concentrations of a drug to the posterior segment, owing to rapid drainage through the nasolacrimal ducts, low permeability of the corneal epithelium, systemic absorption and the blood–aqueous barrier.

Routes of drug delivery to the posterior eye

Slide6

Conversely

the blood–retinal barrier (BRB) hinders the diffusion of systemically administered drugs to the posterior segment of the eye. Frequent systemic administration of high doses is also likely to exacerbate drug-related toxicities owing to nonspecific absorption.

Consequently, the ideal routes of drug delivery to the posterior segment are the intravitreal and the periocular routes

Slide7

Slide8

Intravitreal injection

provides

increased drug concentrations at the retina and minimizes systemic side effects. Drug molecules injected into the vitreous in the clinic are divided into two categories; high molecular weight proteins and small molecular weight molecules such as anti-inflammatory drugsThe two main routes by which a drug is eliminated from the vitreous humour are either via the anterior chamber or across the retinal surface

. The elimination and distribution kinetics are affected by the rate of drug diffusion through the vitreous and the geometry of the eye.

Intravitreal route

Slide9

Larger molecules

are retained

in the vitreous for long periods (weeks); but molecules that are <500 Da and are in the form of a solution need frequent administration, owing to a limited retention half life of approximately 3 days. Drugs with large molecular weight and high water solubility, such as proteins, are eliminated by permeation through blood aqueous barriers to the anterior chamber followed by elimination through aqueous turnover and uveal blood flow. Hydrophobic drug molecules and small molecular weight drugs

are eliminated through posterior route by permeation through blood retinal barriers

Slide10

schematic illustration of the main parts of the anterior and posterior segments, barriers to ophthalmic drug delivery and routes of drug elimination from the vitreous.

The location of

ophthalmic barriers

(encircled in red) are; I) the cornea and tear film; II) blood-retinal barriers; III) blood-aqueous barriers.

Routes

of elimination from the vitreous (encircled in blue) are; 1) venous blood flow after diffusing across the iris surface; 2) aqueous humour outflow; 3) diffusion into the anterior chamber (1, 2 and 3 are referred to diffusion through the blood-aqueous barriers); 4) diffusion through the blood–retinal

barrier

Slide11

Intravitreal injection

can provide adequate drug concentrations in the posterior segment. Owing to the invasive nature of the injection, it is important to design drug formulations to maintain the therapeutic drug concentration over prolonged periods and minimize the number of injections

Frequent administration of drugs via this route can lead to retinal detachment, retinal haemorrhage, endophthalmitis and increased intraocular pressureNovel drug-delivery systems have been developed in the form of biodegradable or non-biodegradable implants, which can be placed long term in the vitreous

Slide12

Biodegradable

and non-biodegradable Ocular implants provide a platform for the sustained release of molecules from either biodegradable or non-biodegradable polymeric matrices over several months to years. These implants are either injected into the vitreous or sutured onto the sclera for intravitreal or transscleral drug delivery.

Implants

Slide13

Biodegradable implants do not require post-treatment removal, however

they

offer relatively less control over drug release compared to non-biodegradable implants it is very difficult to retrieve the implant when side effects start to show can cause more erratic drug-release profiles. Polymeric materials commonly used to fabricate biodegradable implants include poly(lactic-co-glycolic acid) (PLGA),

polycaprolactone

(PCL),

polyanhydride

and

poly(

ortho

ester) (POE).

Biodegradable implants

Slide14

Non-biodegradable implants require invasive surgical removal,

better

control over the release of the drug compared to biodegradable ones over prolonged period of time Polymers commonly used for the fabrication of non-biodegradable implants are silicone, polyvinyl alcohol (PVA) and ethylene vinyl acetate (EVA)Non-biodegradable implants

Slide15

Implants can be designed as either

a

reservoir or matrix system. Reservoir systems are noneroding devices that provide superior control of drug release by virtue of a specific physical rate control feature linked with the internal drug reservoir. This feature may be an opening in the device,

a porous

membrane or a coating through which

drug diffusion

is retarded.

It

is easier to achieve

zero-order drug

release kinetics using a reservoir system

as

there is only a single rate controlling variable

that may

impact drug delivery.

Slide16

In

a

matrix system, drug is comixed with the rate controlling polymer. A matrix device can be engineered to produce zero-order drug release kinetics, for example, if the polymer is noneroding and the release is then governed by polymeric chain relaxation and the dissolution rate of the drug. However, in such a device, the drug

concentration must

be high enough such that, when erosion

occurs from

the matrix, it produces sufficient

fenestrated channels

in the device for aqueous diffusion media

to reach

the internally located drug particles.

In a

noneroding

matrix system, the strength or

resilience of

the device could be compromised as diffused

drug produces

a series of interconnected voids through

the device.

Slide17

If the polymer in the matrix device is

bioerodible

then the device may exhibit more complex drug release kinetics due to the erosion factor of the polymer which may contribute independently to the drug dissolution or diffusion behaviourCurrently, two surgically implanted, non-biodegradable intravitreal implants (Vitrasert1 and Retisert1) are in clinical use. Vitrasert1 contains ganciclovir for the treatment of CMV retinitis for up to eight months and is the mainstay therapy for patients with CMV retinitisRetisert1, which contains fluocinolone

acetonide

, is used for the treatment of chronic non-infectious posterior uveitis. This reservoir system releases

fluocinolone

for up to 2.5 years

.

Iluvien

®

was developed to deliver a very low dose of

fluocinolone

acetonide

to the retina for up to 3 years as a treatment for diabetic macular

edema

Slide18

Slide19

Slide20

I-

vationTM

is a novel technology that incorporates a titanium helical coil to increase the surface area of drug release. The coil is coated with triamcinolone acetonide (TA) and non-biodegradable polymers and is expected to release TA for at least two years. Currently, I-vationTM is in Phase I clinical trials in patients with diabetic macular oedema

Slide21

Several new approaches for IVT implants have been investigated such as the use of refillable delivery systems and cell encapsulated technology (Chen 2015

).

Ciliary neurotrophic factor (CNTF) delivery through cell encapsulated technique has been investigated for the treatment of dry age related macular degeneration (AMD) and retinitis pigmentosa. The device is composed of sealed semipermeable membrane of polyethylene terephthalate surrounding human retinal pigment epitheliums cells (ARPE-19) genetically modified to secrete recombinant human CNTF. Microelectromechanical systems (MEMS) are intraocular DDS that can be refilled with drug solution for long term therapy. The device consists of refillable drug reservoir with flexible

canula

. The device would be implanted in the subconjunctival space and allow the

canula

to be directed into the vitreous or the anterior chamber

Slide22

Slide23

Biodegradable i

mplants

such as Ozurdex® (dexamethasone in poly(lactic-co-glycolic acid) PLGA) releases incorporated dexamethasone over four to six weeksNon-biodegradable, such as Vitrasert® (ganciclovir with polyvinyl alcohol (PVA) and ethylene vinyl acetate),

Retisert

®

(

fluocinolone

acetonide

with silicone and PVA),

Iluvien

®

(

fluocinolone

acetonide

with polyimide and PVA)

Slide24

Periocular routes

Slide25

The periocular route

of drug delivery enables the deposition

of molecules against the external surface of the sclera, thereby minimizing the risk of endophthalmitis and retinal damage associated with the intravitreal route of administration It is considered to be the least painful and the most efficient route of drug delivery to the posterior eyeBoth the subconjunctival and the

subtenon

routes are

widely used

in research into

transscleral

drug delivery

owing to

their proximity

to the sclera.

Slide26

With

subconjunctival injection

, the formulation is placed beneath the conjunctival membrane that covers the sclera. This enables the drugs to bypass the conjunctiva– cornea barrier, giving direct access to the transscleral route. Subtenon injection involves the placement of a formulation between the sclera and Tenon’s capsule, an avascular membrane. As such, the contact time between the administered drug and the sclera is prolonged. Consequently, the subtenon route is considered to be one of the most promising routes for targeting the posterior segment of the eyeNevertheless, only minute concentrations of a drug administered via the

transscleral

route end up in the

vitreous.

This low bioavailability can be attributed to the loss of the drug from the periocular space, BRB, choroidal circulation and the binding of drugs to tissue proteins as well as efflux transporters.

Slide27

Slide28

Various preclinical studies have demonstrated the efficacy

of micro-

and nanoparticles in delivering drugs to the posterior ocular tissue via the periocular routes and the intravitreal route of administrationThe present evidence suggests polymeric micro- and nanoparticles to be of value in targeted and controlled gene delivery for posterior eye diseases. However, a few barriers have to be overcome before micro- and nanoparticles can be tested in clinical trials for posterior eye diseases. These include improvement in encapsulation efficacy

, control of particle size and drug release rate,

stability of

molecules during manufacturing and large-scale

manufacturing of

sterile preparations

Micro- and nanoparticles

Slide29

Such systems use a delivery method to localize a

photosensitizing compound

in the target tissue followed by activation using a non-thermal laser light. Verteporfin (Visudyne1) is a clinically available light-activated drug used for the treatment of wet AMD. Verteporfin is activated 15 min after IV administration using a non-thermal red laser light. The activated drug causes the

occlusion of

neovascular

vessels;

Light-induced systems

Slide30

Iontophoresis has been shown to increase the

transscleral

permeability of many drugs, including fluorescein, steroids, antibiotics, antivirals and macromolecules. Transscleral iontophoresis delivers high concentrations of the applied drug to the choroid and the retina with minimal side effectsAdverse effects of iontophoresis include epithelial oedema, a decrease in endothelial cells, inflammatory infiltration and burns, the extent of which depends on the site of application, current density and duration.Recently, several iontophoresis devices have been developed with better tolerability and ease of use. These include Ocuphor1, EyeGate1 and Visulex1. Further assessment of these types of device is needed to determine the optimal protocol and conditions for safe and efficient application of ocular iontophoresis.

Iontophoresis

Slide31

Conclusion

Delivery

of drugs to the posterior eye is challenging, owing to anatomical and physiological constrains of the eye. Currently, the intravitreal route is widely used to deliver therapeutic entities to the retina. However, frequent administration of drugs via this route can lead to retinal detachment, endophthalmitis and increased intraocular pressure. Various controlled delivery systems, such as biodegradable and non-biodegradable implants

, liposomes and nanoparticles, have been developed to overcome such adverse effects, with

some success.

The periocular route is a promising alternative, owing to the large surface area and the

relatively high

permeability of the sclera. Yet, the blood–retinal barrier and efflux transporters hamper the

transport of

therapeutic entities to the retina.

As

such, the efficient delivery of drugs to the posterior eye remains

a major

challenge facing the pharmaceutical scientist.