ocular drug delivery system ppt

BIOPHARMACEUTICAL ASPECTS IN OCULAR DRUG DELIVERY SYSTEM

Rikesh Lal ShresthaM.Pharm (2015), Industrial

Kathmandu University

OCULAR DRUG DELIVERY

IntroductionChallenges 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

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 .

Challenges in

Ocular Drug Delivery Anatomical and Physiological

Considerations

Pharmacokinetic Considerations

Formulation Considerations

Anatomical and Physiological Considerations :

a) Spillage of drug by overflow:• Eye can accommodate 30L without blinking. • Eye dropper deliver volume of 50L, 70% of administered dose is expelled by over flow. • Upon Blinking 10L 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.

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 secretetear 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

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

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

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 irritationneed to be taken into account when formulating an ocular dosage form.

Formulation Consideration:

Physicochemical Drug Properties : It includes the factors that affcect the cornealpermeability 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.

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.

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

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 .

FORMULATION APPROACHES TO

IMPROVE OCULAR BIOAVAILABILITY



Colloidal Delivery Systems

Other Delivery Approaches

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


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.

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.


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.


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.


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.


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.


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.


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.

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.

Other Delivery ApproachesProdrugs :

• 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.

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.


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.


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 .

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 .

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 .

• 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 .

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ocular drug delivery system ppt

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