Biopharmaceutics - Ocular Drug Delivery System

1. BIOPHARMACEUTICAL ASPECTS IN
OCULAR DRUG DELIVERY SYSTEM
Rikesh Lal Shrestha
M.Pharm (2015), Industrial
Kathmandu University

2. OCULAR DRUG DELIVERY
Introduction
Challenges in Ocular Drug Delivery
 Anatomical and Physiological Considerations
 Pharmacokinetic Considerations
 Formulation Considerations
Formulation Approaches to Improve Ocular Bioavailability
 Conventional Dosage Forms
 Polymeric Delivery Systems
 Colloidal Delivery Systems
 Other Delivery Approaches
Conclusion
References

3. INTRODUCTION
• Due to the accessibility of the eye surface, topical administration of ophthalmic
medications is the most common method for treating conditions affecting the
exterior eye surface.
• The unique anatomy and physiology of the eye renders it difficult to achieve an
effective drug concentration at the target site. So, efficient delivery of a drug
through the protective ocular barriers with minimization of its systemic side effects
remains a major challenge.
• Ocular delivery systems, such a ointments, suspensions, micro - and nanocarriers,
and liposomes, have been investigated during the past two decades focusing two
main strategies:
– to increase the corneal permeability and
– to prolong the contact time on the ocular surface .

4. Challenges in
Ocular Drug Delivery
 Anatomical and Physiological
Considerations
Pharmacokinetic Considerations
Formulation Considerations

5. Anatomical and Physiological Considerations :
a) Spillage of drug by overflow:
• Eye can accommodate 30L without blinking.
• Eye dropper deliver volume of 50L, 70% of administered dose is expelled by over
flow.
• Upon Blinking 10L residual volume is left (i.e 90% of the dose expelled)
b) Dilution of drug by tears turn over:
Normal human tear turnover is approximately 16% per minute. Factors like drug entity,
pH, and tonicity of dosage form cause tears turn over.
c) Enzymatic metabolism
Precorneal and corneal enzymatic metabolism results in the loss of drugs entities
possessing labile bonds.
d) Conjunctival absorption:
The absorption of drug into pulpebral and bulbelar conjunctiva (highly vascular) with
concomitant removal from the ocular tissues by peripheral blood stream.

6. Anatomical and Physiological Considerations (Contd..) :
e) Nasolacrimal Drainage System
• Causes systemic side effect.
• The drainage rate is much faster than the ocular absorption rate. So, ocular
bioavailability of a drug still remains challenge.
Lacrimal gland
secrete
tear fluid in cornea
blinking
creates a suction mechanism, Fluid from the
lacrimal sac into nasolacrimal duct
the inferior nasal passage (highly vascular)
systemic drug absorption

7. Pharmacokinetic Consideration:
• Corneal absorption is considered to be the major penetration
pathway for topically applied drugs.
• There are two mechanisms for absorption across the corneal
epithelium are :
• Transcellular diffusion
• Paracellular diffusion
• Lipophilic drugs prefer the transcellular route.
• Hydrophilic drugs penetrate prefer paracellular route.
•Transport along the transcellular route includes :
 Simple diffusion/ Facilitated diffusion / Active transport
/ Endocytosis.
Figure: Cornea structures

8. Pharmacokinetic Consideration (Contd…….) :
•Transport along the paracellular route includes :
 Passive diffusion/ Limited by the pore size / Charge of the intracellular spaces.
• Relatively small molecules can permeate through the pores.
•Negatively charged molecules permeate at a slower rate than positively charged and
neutral ones.
•In addition, a positive charge may also decrease the permeation due to the possible
ionic interaction with the negatively charged carboxylic acid residues of the tight
junction proteins.
• Choice of the molecule in ascending order on basis of corneal permeation :
Neutral > positively charged molecules > Negatively charged molecules

9. Challenges in Ocular Drug Delivery
Formulation Consideration:
a) Physicochemical Drug Properties
b) Buffer Capacity and p H
c) Anti-oxidants
d) Instillation Volume
e) Tonicity adjustment
f) Surfactants
g) Preservatives
Note : General safety considerations such as sterility, ocular toxicity and irritation
need to be taken into account when formulating an ocular dosage form.

10. Formulation Consideration:
Physicochemical Drug Properties : It includes the factors that affcect the corneal
permeability of the drug.
• Lipophilicity of the drug as reflected by its n - octanol – water partition coefficient
• Molecular size and shape .
Buffer Capacity and p H: Normal Tear fluid pH 7.4 ,posses some buffering capacity.
• pH should be chosen to optimize drug stability.
• When pH deviates from 7.4 it is important to be aware of buffer capacity to minimize
lacrimation and irritation.
Instillation Volume : The cul - de - sac normally holds 7 – 9 L , & accommodate 30 L
without blinking.
• Upon application of Eye droppers (50 L volume), the excess volume removed by
Spillage (conjunctival sac ) & Nasolacrimal drainage system.
• Formulation target is to , keeping the applied dose constant while decreasing the
instilled volume.

11. Formulation Consideration(Contd…):
Tonicity Adjustment :
• Tonicity needs to be adjusted so that it exerts an osmotic pressure equal to that of
tear fluids (equivalent to 0.9% NaCl ideally) .
• Ophthalmic solutions are hypotonic to enhance absorption and provide concentration of
active ingredient sufficient to achieve efficacy.
• Common tonicity adjusting agents are NaCl , Cl, buffer salt, d-mannitol, propylene
glycol etc.
Anti-oxidants:
• They are commonly added to mitigate oxidation issues.
• Example : Sodium bisulfite or metabisulfite is used in concentrations up to 0.3% in
epinephrine hydrochloride and bitartrate solutions.

12. Formulation Consideration(Contd..):
Surfactants:
• Several nonionic surfactants are used in relatively low concentrations to achieve drug
solubility. Eg: Polysorbate, tyloxapol, polyoxyl 40 stearate etc.
• The order of surfactant toxicity is: Anionic > cationic > nonionic
• Nonionic surfactants preferred for ophthalmic use .
Preservatives :
• Help to prevent contamination of the bottle contents over the course of multiple uses.
• By preventing contamination, preservatives may help ensure product stability.
• Benzalkonium chloride is the most commonly used ophthalmic preservative and is used
in 72% of ophthalmic solutions

13. Formulation Consideration (Articles)
• Article: Kaur , I. P. , and Smitha , R. ( 2002 ), Penetration enhancers and ocular
bioadhesives: Two new avenues for ophthalmic drug delivery , Drug Dev. Ind. Pharm. ,
28 ( 4 ), 353 – 369 .
• Conclusion : According to Kaur and Smitha [36] , the optimum lipophilicity for corneal
absorption is found in drugs with an n - octanol – water partition coefficient between 10
and 100.
• Article: Huang , A. J. W. , Tseng , S. C. G, and Kenyon , K. R. ( 1989 ), Paracellular
permeability of corneal and conjunctival epithelia , Invest. Ophthalmol. Vis. Sci. , 30 ( 4
), 684 – 689 .
• Conclusion : The molecular size of the drug has an effect on the corneal absorption. The
cornea is impermeable to molecules larger than 5000 Da, whereas the conjunctival tissues
allow compounds of up to 20,000 Da to penetrate .
• Article : Chrai , S. S. , and Robinson , J. R. ( 1974 ), Ocular evaluation of methylcellulose
vehicle in albino rabbits , J. Pharm. Sci. , 63 ( 8 ), 1218 – 1223 .
• Conclusion : The drainage process followed first - order kinetics and found that the rate
of solution drainage from the conjunctival sac (as reflected by the elimination rate
constant) was directly proportional to the instilled volume .

14. FORMULATION
APPROACHES TO
IMPROVE OCULAR
BIOAVAILABILITY
 Conventional Dosage Forms
 Polymeric Delivery Systems
 Colloidal Delivery Systems
 Other Delivery Approaches

15. FORMULATION APPROACHES TO IMPROVE OCULAR
BIOAVAILABILITY
Approaches to improve the ocular bioavailability have been attempted in two
directions: To increase the corneal permeability
To prolong the contact time with the ocular surface
Conventional Dosage Forms Polymeric Delivery System
Solutions Viscosity - Enhancing Polymers
Suspensions Mucoadhesive Polymers
Ointments In Situ Gelling Systems
Colloidal Delivery Systems Other Delivery Approaches
Nanoparticles Prodrugs
Liposomes Penetration Enhancers
Niosomes Cyclodextrins
Microemulsions Ocular Inserts

16. Conventional Dosage Forms
Solutions:
• Addition of viscosity - enhancing agents such as cellulose derivates, which are believed to
increase the viscosity of the preparation .
• Reduce the drainage rate encountered installation
frequency.
Suspensions:
• Micronized drug ( < 10 μ m) in a suitable aqueous vehicle are formulated, where the active
compound is water insoluble.
• Particles greater than 10 μ m cause patient discomfort.
• Achieving a near - solution state with small particles that are easy to resuspend and show
minimal sedimentation.

17. Conventional Dosage Forms(Contd….)
Ointments:
•It remain in the cul - de - sac as a drug depot, reduce dilution of the drug via the tear film.
•Increased precorneal contact time .
•Blurred vision
•Matting of eyelids
Note : Ointments are used in combination with eye drops, which can be administered
during the day, while the ointment is applied at night, when clear vision is not required.

18. Polymeric Delivery Systems
Polymeric Delivery System
Viscosity - Enhancing Polymers:
•Simply increase the formulation viscosity.
•Decreased lacrimal drainage and enhanced bioavailability.
•Example : HPMC, PVA
Article : Trueblood , J. H. , Rossomondo , R. M. , Wilson , L. A. , and Carlton , W. H. (
1975 ), Corneal contact times of ophthalmic vehicles. Evaluation by
microscintigraphy , Arch. Ophthalmol, 93 ( 2 ), 127 – 130 .
Conclusion : Trueblood et al. [183] used lacrimal microscintigraphy to evaluate the
corneal contact time for saline, PVA, and hydroxpropyl methylcellulose (HPMC) and
observed the longest contact time for the formulation with HPMC as a viscosity -
enhancing agent.

19. Polymeric Delivery Systems
Polymeric Delivery System (Contd…)
Mucoadhesive Polymers :
•Mucoadhesive polymers, interact with the ocular mucin, increasing the contact
time with the ocular tissues.
•In order to spread onto the mucus polymers must show
the following features :
a) Strong hydrogen binding group,
b) Strong anionic charge
c) Sufficient chain flexibility
Article :Saettone , M. F. , Chetoni , P. , Tilde Torracca , M. , Burgalassi , S. , and
Giannaccini , B. ( 1989 ),Evaluation of muco - adhesive properties and in vivo activity
of ophthalmic vehicles based on hyaluronic acid , Int. J. Pharm. , 51 ( 3 ), 203 – 212 .
Conclusion :Saettone et al. evaluated a series of bioadhesive dosage forms for ocular
delivery of pilocarpine and tropicamide and found hyaluronic acid to be the most
promising mucoadhesive polymer.

20. Polymeric Delivery Systems
Polymeric Delivery System (Contd....)
In Situ Gelling Systems :
•Polymers undergo sol - to – gel phase transition upon exposure to the physiological
conditions present in the eye.
•Easy, accurate, and reproducible administration of a dose
Article :Shedden , A. H. , Laurence , J. , Barrish , A. , and Olah , T. V. ( 2001 ), Plasma
timolol concentrations of timolol maleate: Timolol gel - forming solution
(TIMOPTIC - XE) once daily versus timolol maleate ophthalmic solution twice daily
, Doc. Ophthalmol. , 103 ( 1 ),73 – 79 .
Conclusion :Shedden et al. [76] compared the plasma concentrations of timolol
following multiple applications of Timoptic - XE and a timolol maleate solution. They
found that a once - daily application of the in situ gelling formulation was
sufficient to reduce the intraocular pressure to levels comparable to a twice - daily
application of the solution, leading to better patient compliance as well as a
reduction in systemic side effects.

21. Polymeric Delivery Systems
Colloidal Delivery System
•Nanoparticles
•Polymeric ranging from 10 to 1000 nm in which the drug can be dissolved,
entrapped, encapsulated, or adsorbed.
•Nanoparticles retain in the cul - de - sac and the entrapped drug released from the
particles at a certain rate.
•Sustained drug release and a prolonged therapeutic activity.
Article : Ding , S. ( 1998 ), Recent developments in ophthalmic drug delivery ,
Pharm. Sci. Technol.Today , 1 ( 8 ), 328 – 335 .
Conclusion :
Betoptic S is obtained by binding of betaxolol to ion exchange resin particles.
Betoptic S 0.25% was found to be bioequivalent to the Betoptic 0.5% solution in
lowering the intraocular pressure.

22. Polymeric Delivery Systems
Colloidal Delivery System(Contd..)
Liposomes :
•Liposome’s are phospholipids-lipid vesicles that can entrap only Lipophilic drugs
.Improve in ocular contact time.
•Provide sustained effect
•Reduce side effects of the drug(s) entrapped.
Niosomes :
•Nisomes entrap both hydrophilic and lipophilic drugs.
•Here surfactants act as penetrations enhancer & remove the mucous layer from the
ocular surface.

23. Polymeric Delivery Systems
Colloidal Delivery System (Contd…)
Discomes :
•Modified version of niosomes (12 – 60 μm)
•Prevents drainage into the nasolacrimal drainage system.
•Disclike shape provides better fit in the cul - de - sac .
Article : Vyas , S . P. , Mysore , N. , Jaitely , V. , and Venkatesan , N. ( 1998 ),
Discoidal niosome based controlled ocular delivery of timolol maleate , Pharmazie ,
53 ( 7 ), 466 – 469 .
Conclusion: Vyas et al. demonstrated that discomes entrapped higher amounts of
timolol maleate than niosomes and that both niosomes and discomes significantly
increased the bioavailability of timolol maleate when compared to a conventional
timolol maleate solution.

24. Colloidal Delivery System (Contd…)
Microemulsions :
• Microemulsions (MEs) are colloidal dispersions composed of an oil phase, an aqueous
phase, and one or more surfactants.
• Presence of surfactants is advantageous due to an increase in cellular membrane
permeability, which facilitates drug absorption and bioavailability.
• They are thermodynamically stable and transparent, possess low viscosity. Thus are
easy to instill, formulate, and sterilize.
• Example : poloxamers, polysorbates, and polyethylene glycol derivatives.
• Article: Gasco , M. R. , Gallarate , M. , Trotta , M. , Bauchiero , L. , Chiappero , O.
et al. ( 1989 ), Microemulsions as topical delivery vehicles: Ocular administration of
timolol , J. Pharm.Biomed. Anal. , 7 ( 4 ), 433 – 439 .
• Conclusion :The ocular bioavailability of the timolol ion pair incorporated into the
ME was compared to that of an ion pair solution as well as a simple timolol solution.
A prolonged absorption was achieved using the ME with detectable amounts of the
drug still present 120 min after instillation.

25. Other Delivery Approaches
Prodrugs :
• Of all enzymes participating in the activation of prodrugs, esterases are present in
all anterior segment tissues.
• So, majority of ophthalmic prodrugs developed from the esterification of the
hydroxyl or carboxylic acid groups present in the parent molecule.
• Article: Tirucherai , G. S. , Dias , C. , and Mitra , A. K. ( 2002 ), Corneal
permeation of ganciclovir: Mechanism of ganciclovir permeation enhancement
by acyl ester prodrug design ,J. Ocul. Pharmacol. Ther. , 18 ( 6 ), 535 – 548 .
• Conclusion : Tirucherai et al. [137] formulated an acylester prodrug of ganciclovir.
The increased permeability was associated with a linear increased
susceptibility of the ganciclovir esters to the esterases present in the cornea.

26. Other Delivery Approaches (Contd…)
Penetration Enhancers :
• It increases the permeability of the corneal cell membrane .
• It looses the tight junctions between the epithelial cells, which restrict the entry of
molecules via the paracellular pathway.
• Example : surfactants, bile salts, calcium chelators, fatty acids, some glycosides such a
saponin.
• Article : Grass , G. M. , Wood , R. W. , and Robinson , J. R. ( 1985 ), Effects of calcium
chelating agents on corneal permeability , Invest. Ophthalmol. Vis. Sci. , 26 ( 1 ), 110
– 113 .
• Conclusion : Grass et al. were among the first to emphasize the enhancing effects of
chelating agents for ocular drug delivery. They found that 0.5% EDTA doubled the
corneal absorption of topically applied glycerol and cromoclycin sodium.

27. Other Delivery Approaches (Contd…)
Cyclodextrins:
• They are a group of homologous cyclic oligosaccharides with a hydrophilic outer surface
and a lipophilic cavity in the center.
• Cyclodextrin complexation generally results in improved wettability, dissolution,
solubility, and stability in solution as well as reduced side effects.
• Article : Nijhawan , R. , and Agarwal , S. P. ( 2003 ), Development of an ophthalmic
formulation containing ciprofl oxacin - hydroxypropyl - β - cyclodextrin complex ,
Boll. Chim. Farm. ,142 ( 5 ), 214 – 219 .
• Conclusion : Nijhawan and Agarwal investigated inclusion complexes of ciprofloxacin
hydrochloride and hydroxy - propyl - β - cyclodextrin and found that the complexes
exhibited better stability, biological activity, and ocular tolerance than the
uncomplexed drug in solution.

28. Other Delivery Approaches (Contd…)
Ocular Inserts :
• It provide a sustained, and continuous drug delivery by maintaining an effective drug
concentration in the target tissues.
• However, this systems is less popular because
– Difficulty of insertion by the patient
– Foreign - body sensation by eye .

29. CONCLUSION :
An ophthalmic delivery system :
• Must be sterile and isotonic.
• Should have corneal permeability characteristic.
• Should have prolong contact time with the ocular surface.
• Should be easy to use for patient’s acceptance .

30. REFERENCES
• Chrai , S. S. , and Robinson , J. R. ( 1974 ), Ocular evaluation of methylcellulose vehicle in albino
rabbits , J. Pharm. Sci. , 63 ( 8 ), 1218 – 1223 .
• Ding , S. ( 1998 ), Recent developments in ophthalmic drug delivery , Pharm. Sci. Technol.Today ,
1 ( 8 ), 328 – 335 .
• Gasco , M. R. , Gallarate , M. , Trotta , M. , Bauchiero , L. , Chiappero , O. et al. ( 1989 ),
Microemulsions as topical delivery vehicles: Ocular administration of timolol , J. Pharm.Biomed.
Anal. , 7 ( 4 ), 433 – 439 .
• Grass , G. M. , Wood , R. W. , and Robinson , J. R. ( 1985 ), Effects of calcium chelating agents on
corneal permeability , Invest. Ophthalmol. Vis. Sci. , 26 ( 1 ), 110 – 113 .
• Greaves , J. L. , Wilson , C. G. , and Birmingham , A. T. ( 1993 ), Assessment of the precorneal
residence of an ophthalmic ointment in healthy subjects , Br. J. Clin. Pharmacol. , 35 ( 2 ), 188 –
192 .
• Huang , A. J. W. , Tseng , S. C. G, and Kenyon , K. R. ( 1989 ), Paracellular permeability of corneal
and conjunctival epithelia , Invest. Ophthalmol. Vis. Sci. , 30 ( 4 ), 684 – 689 .
• Jarvinen , K. , Jarvinen , T. , and Urtti , A. ( 1995 ), Ocular absorption following topical delivery,
Adv. Drug Deliv. Rev. , 16 ( 1 ), 3 – 19 .
• Kaur , I. P. , and Smitha , R. ( 2002 ), Penetration enhancers and ocular bioadhesives: Two new
avenues for ophthalmic drug delivery , Drug Dev. Ind. Pharm. , 28 ( 4 ), 353 – 369 .
• Nijhawan , R. , and Agarwal , S. P. ( 2003 ), Development of an ophthalmic formulation containing
ciprofl oxacin - hydroxypropyl - β - cyclodextrin complex , Boll. Chim. Farm. ,142 ( 5 ), 214 – 219
• Olejnik , O. ( 1993 ), Conventional systems in ophthalmic drug delivery , in Mitra , A . K. ,Ed.,
Ophthalmic Drug Delivery Systems , Marcel Dekker , New York , pp. 177 – 198 .

31. • Patton , T. F. , and R obinson , J. R. ( 1975 ), Ocular evaluation of polyvinyl alcohol vehicle in
rabbits , J. Pharm. Sci. , 64 ( 8 ), 1312 – 1316 .
• Priyanka Khokhar, Vikesh Shukla,Ocular Drug Delivery System-A Review Based on Ocuserts,
International Journal of Pharma Research & Review, August 2014; 3(8):29-41 ISSN: 2278-6074 .
• Saettone , M. F. , Chetoni , P. , Tilde Torracca , M. , Burgalassi , S. , and Giannaccini , B. ( 1989
),Evaluation of muco - adhesive properties and in vivo activity of ophthalmic vehicles based on
hyaluronic acid , Int. J. Pharm. , 51 ( 3 ), 203 – 212 .
• Shedden , A. H. , Laurence , J. , Barrish , A. , and Olah , T. V. ( 2001 ), Plasma timolol
concentrations of timolol maleate: Timolol gel - forming solution (TIMOPTIC - XE) once daily
versus timolol maleate ophthalmic solution twice daily , Doc. Ophthalmol. , 103 ( 1 ),73 – 79 .
• Sieg , J. W. , and Robinson , J. R. ( 1977 ), Vehicle effects on ocular drug bioavailability II:
Evaluation of pilocarpine , J. Pharm. Sci. , 66 ( 9 ), 1222 – 1228 .
• Tirucherai , G. S. , Dias , C. , and M itra , A. K. ( 2002 ), Corneal permeation of ganciclovir:
Mechanism of ganciclovir permeation enhancement by acyl ester prodrug design ,J. Ocul.
Pharmacol. Ther. , 18 ( 6 ), 535 – 548 .
• Trueblood , J. H. , Rossomondo , R. M. , Wilson , L. A. , and Carlton , W. H. ( 1975 ), Corneal
contact times of ophthalmic vehicles. Evaluation by microscintigraphy , Arch. Ophthalmol, 93 ( 2 ),
127 – 130 .
• Vyas , S . P. , Mysore , N. , Jaitely , V. , and Venkatesan , N. ( 1998 ), Discoidal niosome based
controlled ocular delivery of timolol maleate , Pharmazie , 53 ( 7 ), 466 – 469 .

32. THANK YOU