1. The document discusses recent challenges and advances in ophthalmic drug delivery. It outlines barriers to drug transport in the eye like the tear film, conjunctiva, cornea, sclera, and blood-retinal barrier. 2. Conventional delivery systems like eye drops have poor bioavailability due to short residence time. Novel nanotechnology approaches like nanoparticles and nanomicelles can enhance permeability, control release, and target delivery to improve drug absorption. 3. The review examines approaches to overcome challenges through bioavailability enhancement and controlled release. Various conventional and modern ocular systems are analyzed along with their advantages for anterior and posterior segment delivery.

1. 8/12/20201
DEPARTMENT OF PHARMACEUTICS & SOCIAL PHARMACY, SCHOOL OF PHARMACY
MSc Program in Pharmaceutics
Review on Recent challenges and advances in ophthalmic drug
delivery
seminar I
BY; Gamachu Diba. (GSR/6811/12)
ADVISOR: Dr. Anteneh B.
BY GAMACHU(AAU)

2. Outline
 Introduction
 Anatomy & Physiology
 Body of review
 Barriers to restrict intraocular drug transport
 Ophthalmic drug delivery system
 Challenges in ophthalmic drug delivery system
 Approaches to improve challenges of ophthalmic drug delivery
system
 Types of ocular drug delivery system
 Conventional ocular drug delivery system
 Novel ocular drug delivery systems
 Physical device for ophthalmic drug delivery system
 Summery
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3. INTRODUCTION
Anatomy & Physiology
 The eye is complicated organs which is restricted by physiology
and defense mechanism
 Due to its barrier to drug delivery, the pharmaceutical scientists
challenged in designing a formulation and delivering it to the targeted
sites in sufficient concentrations.
mythili et al 2019, al kinani et al 2012
 To provide an effective treatment for a disease affecting both anterior
and posterior ocular tissue a close examination of ocular anatomy,
physiology and barriers is great importance.
Cholkar et al, 2013
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5. Bodyof review
Barriers to restrict intraocular drug transport
 Tear: Tear dilute drugs by mechanisms of
 Accelerated clearance,
 binding of the drug molecule to tear protein, and
 Tear turnover (approximately 1microliter/min).
Conjuctiva
 helps in formation and maintenance of the tear film and has a rich
supply of capillaries and lymphatics.
 Administrated drugs through this barrier may be cleared through blood
and lymph(10%: first hour in rat eyes. Lee et al, 2010
Cornea : composed of three layers; epithelium, stroma, and endothelium.
I. The epithelium - lipophilic nature- restrict paracellular drug permeation from the
tear film.
II. The stroma -collagen fibrils -barrier to the permeation of lipophilic drug
III. The endothelium-separating barrier between the stroma and aqueous humor.
Bourne and W.M, 2003, Nishida et al 2010
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Nayak et al, 2016,
Kuno et al, 2011

6. …
 Scleral: Scleral permeability depends on the :-molecular radius,
hydrophobicity, Charge of the drug molecule.
molecular radius scleral permeability.
lipophilicity the permeability of drug
compounds poor permeability binding to the negatively charged
proteoglycan matrix.
Dawson et al 2011, Dunlevy et al 2004
 Choroid/Bruch’s membrane: Thickness of this barrier affect drug
permeability from subconjunctival or episcleral space into the retina and
the vitreous [Kuno et al 2011, Nickla et al 2010].
 Retina : the thickest part eye (0.5mm) and it have Internal limiting
membrane(ILM) barriers restrict the penetration of drug from vitreous
to retina[kolbo and H,2011. Kuno et al 2011]
 Blood-retinal barrier: is particularly tight , restrictive and is a physiologic
barrier that regulates ion, protein, and water flux into and out of the
retina. [Cunha-Vaz et al, 2011] 8/12/2020BY GAMACHU(AAU)6

7. Ophthalmic drug delivery system
 Major challenges for pharmaceutical and medicinal sciences.
 To treat the disease affect the anterior segment of eye topical
instillation is the most widely preferred. [Patel et al, 2013]
 The drug can be delivered to the posterior segment by different
modes, intravitreal injections(common route), periocular
injections(alternative), and systemic administration.
Patel et al, 2013, Gaudana et al,2009
 To overcome the ocular drug delivery barriers and improve ocular
bioavailability, various conventional and novel drug delivery
systems have been developed.
 This review will provide an overview of some challenges of ocular
delivery systems and various conventional and novel ophthalmic
drug delivery systems.
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8. Challenges in ophthalmic drug delivery system
 Major Challenges: achieving an optimal concentration of a drug{active
site with appropriate duration& high therapeutic efficacy}.
Suri et al, 2020, Al-Kinani et al 2012
 Suri et al, 2020 shows, the major challenges of anterior segment
drug delivery following topical administration are Poor bioavailability&
relative impermeability.
 Nayak et al, 2018 show that, the major challenges of posterior
segment drug delivery is the blood-retinal barrier (BRB)[more
lipophilic].
 The ideal characteristics include: Good corneal penetration,
prolonging contact time with the corneal tissue, Simplicity of instillation,
Reduced frequency of administration & Patient compliance, Lower
toxicity, and side effects, & etc
Patel et al, 2011
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9. Approaches to improve challenges of ophthalmic
drug delivery system
 Solanki et al 2018: There are two main approaches:-
 bioavailability improvement and controlled release drug delivery.
 Conventionally anterior segment  improve BA
 viscosity enhancers, gel, penetration enhancer, prodrug, [Rawat et
al 2020]
 modern approaches  anterior segment  improve BA & Sustained
release
 In situ gel, Nano-suspension, nanoparticles, liposomes, niosomes,
and implants
 The current approach  Deliver to posterior segment
 intravitreal injections, iontophoresis, subconjunctival injection, and
periocular route
 Solanki et al 2018
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10. Types of ocular drug delivery system
 Two most common : conventional and novel ODDS.
1. Conventional ocular drug delivery system
A. Topical liquid/solution eye drop(70%)
 Shows poor bioavailability’s(1–5% ), Relatively impermeable ,<5min
RT,[Patel et al, 2010, Pepić et al,2010 ]
 Precorneal residence time and bioavailability can be improve, by using
viscosity enhancers, permeation enhancers and complexation with
Cyclodextrins [Karakatsani et al, 2010 , Patel et al, 2013, Aldrich et al,
2013]
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11. Emulsion:
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 patel et al,2013 shows; improve precorneal residence time, drug
corneal penetration, providing sustained release of the drug, and
enhance drug bioavailability
 Tiwari et al,2018 ; Lipid-based emulsion (LE)increase the BA of
poorly soluble drugs & decrease side effects
 Liu Y et al,2009: Azithromycin emulsion reveal higher chemical
stability, precorneal residence time (slowed drug release), , and
bioavailability than the solution
Suspensions:
 in comparison with solution, suspension particle increase contact time,
duration of action, and retains in the precorneal pocket.[Kumar et al,
2016]
 Scoper et al 2008: combination of dexamethasone and tobramycin
suspension viscosity was higher than solution, very low settling over
24 h (3%) relative to solution(66%), better formulation characteristics,
pharmacokinetics, bactericidal characteristic, and patient compliance

12. …
Ointments
 Yellepeddi et al 2016: Ointments over solution
 reduced nasolacrimal drainage, increased contact time,
 minimization of tear dilution, and higher effective concentrations.
 Currently, the use of water-soluble bases called the gels has
increased
 Polymers with mucoadhesive property,  enhance the contact time,
ocular bioavailability(PEG200, PEG 400, etc.)
 Patel et al 2013 : ointment bases should have melting point or softening
point close to body temperature.
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13. Novel ocular drug delivery systems
Nanotechnology based ocular drug delivery
 The technology that highly important research area for
pharmaceutical researchers.
 In ocular drug delivery system, it is promising ways of delivering
poorly soluble drugs, peptides, and proteins).
 Recently, Nano-scaled drug-delivery systems have emerged
increase due to
It improved precorneal retention through mucoadhesive
characteristics,
Enhanced ocular permeation and bioavailability
Allows more targeted drug delivery and controllable release of the
therapeutic compound
Overcoming retinal barriers and very efficient in crossing
membrane barriers.
Lakhani et al, 2018
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14. …
 Sahoo et al, 2008: Main goal of novel ocular drug delivery systems
are three:-
 Enhancing drug permeation
 To control the release of drugs
 Target drugs delivery.
 Designed to ensure :- low irritation, adequate bioavailability, and
ocular tissue compatibility
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15. Nanomicellar
 Are self-assembling nanosized (100 nm) and prepare in clear
aqueous solution
 Made with amphiphilic (surfactant or polymeric).
 Recently, nanomicellar tremendous increased due to reasons of:-
 high drug encapsulation capability,
 simple to prepare,
 very small in size and water solublity
 enhance the bioavailability of the therapeutic drugs
 ability to deeply penetrate to the tissue to access target drug
delivery.
Patel et al 2013, Trivedi et al, 2010, Sahoo et al, 2008
 It is promising DDS for Rx of both anterior segment (dry eye
syndrome)and posterior segment [diabetic retinopathy, Age-related
macular degeneration, glaucoma, etc.]
 The industrial acceptance is highly increasing due to their simplicity
and cost-effectiveness preparation [Mandal et al, 2017].8/12/2020BY GAMACHU(AAU)15

16. Nanoparticles
 Is colloidal carriers with 10 to 100nm.
 Composed of lipids, proteins, natural or synthetic polymer
 They are loaded in two ways, Nanocapsule, and Nanospheres.
 Nanocapsules  the drug is enclosed inside the polymeric shell
 Nanospheres  the drug is uniformly distributed throughout the polymeric
matrix.
 promising Nanocarriers due: low frequent administration from it is
sustained releases and small size which improve irritation.
Patel et al, 2013
 Mucoadhesive properties improve precorneal residence time,
sustained release drug for posterior segment, Low clearance by blood
and lymphatic circulations
 de Vries et al, 2018 loaded nanoparticles drug has
 Proven effective than bare antibiotics for prevention of bacterial growth
on porcine corneal tissue
 Exhibited an excellent safety profile
 Dramatically increase the adherence time of the drug8/12/2020BY GAMACHU(AAU)16

17. Nanosuspensions
 colloidal dispersion of submicron drug particles, which stabilized by
polymer(s) or surfactant(s).
 Consist of pure, poorly water-soluble drugs, suspended in an
appropriate dispersion medium.
 capable of prolonging drug release and enhancing bioavailability and do
not irritate cornea, iris, and conjunctiva.
 Sahoo et al 2008 : improve the efficacy and ocular bioavailability of the
glucocorticoids.
 Kassem et al 2007 : bioavailability of various glucocorticoids shows higher
/more
 extent of drug absorption and
 Intense drug effects than that for the respective drug solutions.
 High ability of ophthalmic drug delivery system for delivery of poorly
soluble drugs [Patel et al, 2013].
 Güven et al,2019 shows it exhibited prolonged release of the drug
over an extended period of time and reduced frequency administered,
thereby resulting in better patient compliance. 8/12/2020BY GAMACHU(AAU)17

18. Microemulsions
 Thermodynamically stable systems consisting of a dispersion
of water and oil.
 Improves permeation across the cornea and
 reduces the frequency of administration(extended release).
Shende et al 2016
 Bharti et al, 2017 show that the developed MEs showed
 acceptable physico-chemical behavior,
 good stability for 3 months, and
 exhibited sustained drug release.
 Microemulsion (ME) moxifloxacin is more effective ,sustained
release properties of microemulsion and
 better retaining (increase residence time, reduction in the
frequency of administration and thereby definitely improve
patient compliance)
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19. Liposome
 A most commonly used novel ophthalmic drug delivery systems, having
phospholipid bilayers
 The promising system (excellent biocompatibility and encapsulated
amphiphilicity)
 Sahoo et al, 2008 shows good effectiveness for both segments of
eyes
 Patel et al, 2013 enhance corneal penetration, precorneal RT
 Zhang et al, 2017 liposomal tacrolimus more effective in the
treatment of uveoretinitis and improve drug toxicity to inner retinal cell
than other.
 For posterior segment  improving half-life of the drug by reducing
clearance from vitreous humor, prevent labile molecule like oligonuclic
and peptides from degradation, and improve sustained drug release
 Santos et al, 2019enhance the amount of drug in the target
tissues, improve therapeutic index and therapeutic profiles, sustained
released , ability to penetrate cornealscleral tissue, are better patient
compliance and they are potentially affordable for patients
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20. Cubosome
 Is liquid crystalline phase nanoparticles with a cubic crystallographic
symmetric shape formed through self-assembly of amphiphilic or
surfactant molecules.
 Singh et al, 2018  dexamethasone cubosome  improve ocular
retention and ocular bioavailability and apparent in vitro
permeation coefficient 4.4-fold increase
 Huang et al, 2017 Timolol Maleate Cubosome
 more capable of improving corneal penetration by prolonging the
retention time of drugs and
 increasing the IOP-lowering of Timolol than conventional
 It shows biocompatible and no toxicity
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21. Dendrimers
 Is macromolecular compounds formulated from serious branches
around an inner core,
 It also characterized as nanosized, highly branched, star-shaped
polymeric systems.
 polymeric systems have a terminal end of Amine, carboxylic, and
hydroxyl functional group.
 Vandamme et al, 2005 aqueous poly (amidoamine) (PAMAM )
dendrimers are promising systems in the ocular route.
 show compatible physicochemical characteristics like PH,
Osmolality, and viscosity with ophthalmic drug delivery system
 Charge and molecular geometry of bioadhesive dendrimers also
influence ocular residence time.
 With carboxylate and hydroxyl surface groups  Greater
bioavailability
 Lin et al 2018 D-Dex  It improved efficacy and patient
compliance, reduced side effects, reduce frequency per day to every
1-2 month
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22. In situ hydrogel
 Is polymeric solution undergoes viscoelastic gel in response to
environmental stimuli from sol-gel transition.
 The thermosensitive gels
 improving ophthalmic bioavailability for both segments of eyes.
 viscous at room temperature and change to gel during it expose to
the physiological condition of the eye,
 increase residence time, via enhanced viscosity and
mucoadhesive properties
Patel et al, 2013, Geethalakshmi et al, 2013
 Wu et al 2019  prolong precorneal RT, sustained release,
improves bioavailability, enhances the therapeutic efficacy and
reduce systemic absorption & toxicity, decrease the frequency of
administration
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23. Contact lenses
 Are thin, and curved shape plastic disks, designed to cover the
cornea.
 Due to the surface tension, contact lens adheres to the film of tears
over the cornea.
 Β-blockers, antihistamines, and antimicrobials area common drug
loaded with a contact lens for ocular delivery.
 Usually, the drug is loaded into the contact lens by soaking them in
drug solutions
 Mahomed et al 2014 shows
 higher efficiency and have a longer residence time
 Hiratani H et al.2004 show that contact lenses has
 1.6 times higher timolol loading than the conventional method and
 provided sustained timolol delivery
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24. Implants
 Is designed to provide localized controlled drug release over an
extended period, specifically for posterior ocular tissues
 Lee SS et al, 2010  sustained drug release, local drug release to
diseased ocular tissues ,reduced side effects.
 Ocular implants are available as biodegradable and non-
biodegradable drug releasing devices
 non-biodegradable: Surgically implanted and removed after drug
depletion, which makes the treatment expensive and patient non-
compliance
 polyvinyl alcohol (PVA), ethylene-vinyl acetate (EVA), and
 polysulfone capillary fiber (PCF)
 Biodegradable: It is not required to be surgically removed
 Polylactic acid (PLA), polyglycolic acid (PGA), PLGA, and
polycaprolactones
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25. Microneedle
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 Is developed for delivery of the drug to posterior ocular tissues,
especially for
 a disease that threatening posterior ocular diseases such as
 age-related macular degeneration,
 diabetic retinopathy, and posterior uveitis.
 Reduce the risk and complications and circumvent the blood-
retinal barrier and deliver therapeutic drug levels to
retina/choroid[Donnelly et al, 2010]
 Jiang et al, 2009 shows nanoparticles suspensions and
microparticles were also delivered into sclera by microneedle.
 To deliver microparticles, there should be collagenase
spreading enzymes and hyaluronidase
 Patel et al 2011 shows, microneedle may provide a safe,
reliable, and targeted approach to chorioretinal tissues.

26. Physical device for ophthalmic drug delivery
system
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Iontophoresis: noninvasive technique
 avoids the complications of surgical implantation or frequent and high
dose of intravitreal injections for ocular drug delivery systems.
 Eljarrat et al, 2005 shows, iontophoresis of Dexamethasone phosphate
concentration of dexamethasone in the cornea after single transcorneal
iontophoresis for 1 min (1mA) where up to 30 fold higher compared to
those obtained after frequent eye drops instillation.
Sonophoresis
 Is a noninvasive technique used as ultrasound used as an effective tool
to enhance ocular drug delivery.
 Silverman et al, 2001 shows,
 The feasibility of using ultrasound for delivery of a clinically
relevant drug, dexamethasone sodium phosphate, in an in a Vivo
rabbit.
 Use of low frequency ultrasound (400 kHz to 1MHz) was more
effective to enhance the penetration of drugs to cornea

27. Summery
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 The eye is complicated organs and partially isolated in the human body.
 Have three segments of the precorneal area, the anterior segment, and
the posterior segment.
 Ocular drug delivery has been a major the challenge for scientists.
 challenges of anterior segment
 poor bioavailability of drugs from ocular dosage forms is mainly due to
the precorneal loss factors.
 challenges of posterior segment
 Due high efficiency of the blood-retinal barrier (BRB), and it is
 difficult to deliver the drug to posterior segment ocular tissues.
 To overcome such type of challenges,
 Develop various type of dosage form(+BA, Permeability, sustainably)
 Develop novel drug delivery system

28. Acknowledgment
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 We would like to thank my advisor Dr. Antenehe
Belete for giving me such advice in all direction.