A brief presentation on challenges of ocular drug delivery and advances using nanotechnology.

1. APPLICATION OF NANOTECHNOLOGY IN OCULAR DRUG DELIVERY:
RECENT
ADVANCEMENTS AND FUTURE PARADIGM
Prepared by : RISHI THAKKAR
Department : Pharmaceutics and Drug delivery.
Institute : University of Mississippi

2. Content…
■ Nanotechnology and drug delivery systems
■ Disorders related to eyesight
■ Introduction to ocular route
■ Current ocular delivery systems
■ Advancements in ocular delivery system
■ Introduction to Nanomicelles
■ conclusion

3. Nanotechnology and drug delivery
• Nanoparticles (gold particles attached with TNF;
Auroshells)
• Graphene strip linked drug
• Targeted chemotherapy[6]
Cancer therapy
• HDL imitating nanoparticles
• Plaque targeted nanomedicine
• Gold nanoparticles with collagen[6]
Heart diseases
• Nano diamonds for glaucoma treatment
• Nanoparticles controlling insulin release
• Nanoparticles to reach and penetrate lung
mucosa[2]
Other areas

4. Disorders related to eyesight
■ Glaucoma
■ Myasthenia gravis
■ Optic neuritis
■ Conjunctivitis
■ Sarcoidosis
■ Hyphema
■ Corneal ulcer
■ Different retinopathies (Diabetic, hypertensive)
■ Blepharitis
■ Cataract
■ Myopia; hypermetropia; astigmatism and many more…..

5. The ocular route
• Penetration across sclera
and conjunctiva into intra
ocular tissue.[1]
Non-
corneal
absorption:
•Outer epithelium rate limiting
barrier with pore size 60 Å
access only to small ionic or
lipophilic molecules.
•Trans cellular transport
between cornea and stroma.[1]
Corneal
absorption:
Routes of administration [8]

6. Factors
affecting
drug
absorption
Blinking;
reflex &
lacrimation
Low corneal
permeability
Enzymatic
biotransfor
mation
(Lysozyme)
Drainage
(Blood flow;
Nasolacrimal)
lacrimation
Blinking
Loss of
drug
/formulati
on
Formulation
drop
lacrimation

7. Ocular delivery systems
• Solution, Suspension, Emulsion, Ointment, Gels,
• insertsConventional
• Implants, Hydrogels, Collagen shield, Polymeric
• solutions, Contact lenses, Micro needle, Micro
• suspension and emulsion
Controlled
release
• Liposomes, Niosomes, Discomes,
PharmacosomesVesicular
• Microparticle, NanoparticlesParticulate

8. Nanomicelles
■ Polymeric micelles are spontaneously formed in aqueous media via the self-
assembly of amphiphilic block copolymers into Nano-sized particles at or above
the critical micelle concentration (CMC), range between 10-100nm.[4]
■ During the micellization process, the hydrophobic blocks associate to form the core
region, whereas the hydrophilic segments form hydrophilic shell of micelles.
■ Amphiphilic block copolymers can be tailored to have unique properties with
respect to delivery requirements such as:
• Prolong the stability of micelles in the eye fluids.
• Enhance residence time at the absorption membrane.
• Modify the drug release profiles. [7]

9. ■ The shell is responsible for micelle stabilization and in particular circumstances
interactions with absorption membranes.
■ The most commonly used shell-forming polymer is poly(ethylene oxide) (PEO) or
poly(ethylene glycol) (PEG).
■ PEO has unique solution properties, including minimal interfacial free energy with
water, high aqueous solubility, high mobility, and large exclusion volume.
■ PEO stabilizes the interface between the bulk aqueous phase and the hydrophobic
core of micelles by steric repulsive inter-particle forces, other polyesters include
poly(lactic acid) (PLA), poly(ε-caprolactone) (PCL), and poly(glycolic acid) (PGA) are
most commonly used polymers to encapsulate small lipophilic drugs.
■ Yet, the poly ion-complex (PIC) micelles are formed by electrostatic interaction of
charged polymer blocks, such as poly(ethyleneimine) (PEI), poly(aspartic acid) and
poly(L-lysine) (PLL), and nucleic acid-based therapeutics (e.g., plasmid DNA, siRNA)
or oppositely charged protein drugs.[5]

10. Micelle formation and characterization
■ Micelles are prepared by a combination of chemical, physical and electrostatic
principles, such as…[3]
• direct dissolution
• Dialysis
• oil-in-water emulsion
• various modifications of film-methods
• complexation.
■ Characterization & Evaluation
• FT-IR , H-NMR, X-ray diffraction studies
• Size Distribution (DLS, TEM)
• Surface characteristics (Zeta potential, CMC)
• Entrapment efficiency (%E)
• In vitro release behaviour in buffer solution
• In vitro trans corneal permeation study
• In vivo studies can also be conducted in animal models

11. Mechanism of Nano-micellar
absorption
Once the drug is released from the
polymeric micelles, drug molecule
size, charge, lipophilicity, solubility in
the eye fluid and metabolic stability
determine its in vivo fate in the eye
(e.g. trans-corneal, trans-
conjunctival/scleral absorption,
metabolic degradation, loss through
the tear drainage). [3]
Particle size of topically applied
colloidal carriers influences
absorption or permeation through the
ocular barrier, For example, the
nanoparticles of 100 nm are able to
permeate across the corneal
barrier.[3] Mechanism of ocular absorption [4]

12. Drug Formulation use
Dexamethasone
Vitamin E TPGS/octoxynol 40
mixed polymeric micelles or F
127/chitosan polymeric
micelles
After eye surgery or
inflammation in
eye.
Ciclosporine
MPEG-hexPLA polymeric
micelles or CS-modified CH
self-aggregated micelles
radiolabeled by 99mTc or
Polyoxyl 40 stearate polymeric
micelles
Treatment of dry
eyes, nummular
keratitis, adenoviral
conjunctivitis
Pilocarpine F 127 polymeric micelles
Glaucoma causes
miosis i.e
contraction of ciliary
muscles
Tropicamide
TY/CR/P 85 or CR/P 85 mixed
polymeric micelles
eye examination
and eye surgery
(mydriatic)
Indomethacin F 127 polymeric micelles
NSAID used in
retinopathy and
other inflammatory
conditions of eye
Vitamin E TPGS (D-alpha tocopheryl polyethylene
glycol 1000 succinate); F 127 (Pluronic F 127);
MPEG-hexPLA (methoxy poly(ethylene) glycol-
hexylsubstituted poly(lactides)); CS (Cholesterol); CH
(Chitosan); TY (Tyloxapol); CR (Cremophor EL); P 85
(Pluronic 85)
EXAMPLES OF NANOMICELLE
PREPERATIONS

13. conclusion
■ Polymeric micelles have the potential to target ocular tissues at high therapeutic
value offering several favourable biological properties, such as biodegradability,
biocompatibility and mucoadhesiveness, which fulfil the requirements for
ophthalmic application.
■ Physicochemical characteristics such as size, surface charge, morphology, physical
state of the encapsulated drug, drug release properties and stability of the Nano
systems are of particular importance for topical ocular application.
■ Adequate surface charge of polymeric micelles can be achieved to produce a
stable colloidal dispersion. Furthermore, surface charge of topically applied
polymeric micelles determines their performance at the absorbing surfaces, e.g.
their interactions with the cell membranes as well as the glycoproteins of the eye
tissue and/or fluids (e.g. cornea, conjunctiva, tears, vitreous humor) forming a
depot with prolonged release of the loaded drug.
■ Nano micelles can also be impregnated in contact lenses with digital imprinting
which will lead to controlled and continuous release of drug substance without
irritation, drug loss etc. which will increase patient compliance.

14. References
1. Wim H De Jong, Paul Borm, Drug delivery and nanoparticles: applications and hazards,
International journal of nanomedicines, 2008:3(2), 133-149.
2. Qingguo Xu, Siva P. Kambhampati, Rangaramanujam M. Kannan, Nanotechnology Approaches for
Ocular Drug Delivery, Symposium - Ocular Therapeutics of the Future, 10.4103/0974-
9233.106384.
3. I. Pepiæ, J. Lovriæ, and J. Filipoviæ-Grèiæ, Polymeric Micelles in Ocular Drug Delivery: Rationale,
Strategies and Challenges, Chem. Biochem. Eng. Q. 26 (4) 365–377 (2012)
4. Ajay Kumar Gupta, Sumit Madan, D.K. Majumdar , Amarnath Maitra, Ketorolac entrapped in
polymeric micelles: preparation, characterisation and ocular anti-inflammatory studies,
International journal of pharmaceutics 209 (2000) 1–14.
5. Adams, M.L., Lavasanifar, A., Kwon, G.S., J Pharm Sci 92 (2003) 1343.
6. www.understandingnano.com/nanotechnology-drugdelivery.html
7. http://www.sigmaaldrich.com/technical-documents/articles/chemistry/professor-and-product-
portal/lipshutz/faq.html
8. http://www.medeuronet.com/medeuronet/ocular-drug-delivery-in-search-of-the-holy-grail/

15. QUESTIONS?

16. THANK-YOU