Ocular Bioavailability

1. Ocular Bioavailability
Prepared By
Sneha Arun Chavan
Department Of Pharmaceutics
M Pharmacy 1st year IInd semester
1

2. Factor Affecting
Bioavailability
Physicochemical
Factor
Physiological
Factor
2

3. PHYSICOCHEMICAL
FACTOR
 Particle size
 Molecular weight
 Concentration
 Solubility
 Lipophilicity
 Partition coefficient
 Ionization constant
 pH
 Tonicity
 Viscosity
3

4. Molecular weight
 Compound with MW > 500 Da offer poor corneal
penetration, because passive diffusion does not occur.
 Compound with MW < 500 Da generally diffuse through
membrane.
 Transcorneal permeability of hydrophobic drug are not
govern by their molecular weight but by their lipid
solubility.
 While hydrophilic substance govern by their MW
4

5. Particle size
 Drug particle deposited in eye surface are moved by
eyelid at each blink, which cause an abrasion of outer
epithelial layer.
 Also cause irritation of sensory nerve in epithelium.
 Irritation elicit reflex blink and reflex lacrimation.
 Concentration, shape, particle size together interact to
determine irritation potential of suspended drug particle.
 Commercial suspension are formulated to contain
nearly spherical particle less than 10 µm in size.
5

6. Concentration and Osmolality
 Tears are slightly hypertonic at about 330 mOsm.
 Hypertonic solutions above 400 mOsm can produce
discomfort and lacrimation, increasing loss of drug.
 Hypotonic solutions as low as 100 mOsm are still
comfortable in the eye and may improve bioavailability
of water-soluble drugs through the solvent-drag effect.
6

7. Partition coefficient
 Measure corneal penetration efficiency of drug
 For hydrophilic drug (log partition coefficient < 0), the
epithelium provide large % of the resistance to corneal
penetration.
 For lipophilic drug, with log partition coefficient between
1.6-2.5, stroma contribute significant % of resistance.
 Drug with log partition coefficient between 0 – 1.6 the
sum of stromal and endothelial resistance equal the
epithelial resistance.
 Optimal HLB in the molecular structure of penetrant
must be achieve to affect rapid penetration through the
lipophilic and hydrophilic barrier of the cornea.
7

8. Ionization constant
 Degree of ionization influence the extent of diffusion
across a membrane.
 The ionized form of drug is minimally lipid soluble and if
this molecule is too large, the rate of corneal
penetration may not be sufficient to produce therapeutic
level of drug in the eye.
 These Henderson Hasselbalch equation, determine
amount of unionized drug available for transcorneal
movement.
 Greater fraction of drug available in unionized form, the
greater extent of passive diffusion.
8

9. Lipophilicity and Solubility
 Altering the lipophilicity and solubility of a compound can
also enhance its ability to reach the target tissue.
 E.g., moxifloxacin,
 highly lipophilic, highly soluble in water.
 Elevated lipophilicity compared to other fluoroquinolones
allows moxifloxacin to pass more easily through the
corneal tissues,
 while the enhanced aqueous solubility increases
absorption by creating a strong concentration gradient
between the tear film and corneal epithelium.
 If drug is poorly soluble, its concentration in precorneal
tear film may be limited and therefore its rate of
absorption may not be high enough to achieve adequate
concentration for therapeutic activity and reverse is true.
9

10. pH
 The average pH of tears is 7.2 and eyes can tolerate pH
of 6.5-8.0 without much discomfort
 0.3% w/v concentration of Ofloxacin at pH 7.2 yields a
slightly turbid solution
 which becomes clear when pH is reduced to 6.4.
 Increasing the pH of the formulation to physiological pH
will reduce its irritation potential.
 So, in order to enhance the solubility of ofloxacin at pH
7.2, hydroxypropyl-β-cyclodextrin was employed.
 Cornea has an isoelectric point (pI) of 3.2, and above
this pH, cornea is negatively charged, and thus becomes
selectively permeable to cations.
10

11. Cont…
 Ofloxacin pKa1 of 5.5 (for the carboxyl group),
pKa2 of 8.0 (for the piperazinyl group) and
pI of 6.75.
 Thus, increasing the pH of ofloxacin solution from 6.4 to
7.2 will increase the unionized fraction of ofloxacin,
which should increase its corneal permeation.
 But the unionized drug concentration exceeds the
solubility of drug in water at pH 7.2; as a result it gives a
cloudy solution. Inclusion of cyclodextrin improved the
solubility of drug at pH 7.2.
 Cyclodextrins have earlier been reported to enhance
the corneal permeation of drugs.
11

12. PHYSIOLOGICAL FACTOR
 Instilled Solution Drainage
 Instilled Volume
 Dilution of drug by tear turnover
 Protein Binding
 Enzymatic metabolism
 Non productive drug absorption
 Membrane Factor
 Blood retinal barrier
 Blood aqueous layer
 Cornea
 Tear Film
 Active ion Transport
12

13. 1. Instilled Solution Drainage
 Normal volume of tear 7µl. (under normal condition)
 If blinking doesn’t occur the human eye can
accommodate 30 µl without spillage from palpebral
fissure.
 With an estimated drop volume of 50 µl
 Due to overflow 70% of administered dose is expelled.
 If blinking occur, then the residual volume left is 10 µl.
( 90% OF DOSE IS EXPELLED )
 Excess instilled either spill or rapidly drain into
nasolacrimal duct with subsequent absorption into
systemic circulation.
 Rate of drainage depend on volume of drug solution
instilled and increases with increase in volume.
 Drainage rate 100 times faster than rate of corneal 13

14. Cont…
 Lee and Robinson gave following
equation to predict drainage
14

15. 2. Instilled Volume
 More instilled volume of drug, more loss due to spillage or
overflow thus less absorption, less bioavailability.
 To overcome this,
 Reduction in dose volume and simultaneous increase in
instilled drug concentration, less drug loss thus increase
in bioavailability.
 Multiple dosing is more efficient when sufficient time
allowed to elapsed between instillation.
3. Dilution of drug by tear turnover
 Normal human Tear turnover is approx. 16% per minute
except during period of sleep and during anesthesia.
 Which is stimulated by factor drug entity, pH, tonicity of
dosage form.
15

16. Cont…
4. Protein Binding
 Tears contain about 0.7% of protein.
 Its level increases during inflammation and infection.
 Unlike the blood, where the drug protein complex is
continued to circulate, tears are replaced quickly thus
removing both free and bound form of the drug.
 Miotic response to topically applied pilocarpine was
reduced about 2 times as albumin concentration in
precorneal fluid was increased from 0 – 3%.
16

17. 5. Enzymatic metabolism
 Occur in Precorneal space or in the cornea
 Reduced bioavaibility of instilled dose
 To overcome this, frequent dose of drug at high conc.
are recommended.
6. Non productive drug absorption
 Upon instillation drug is absorbed into cornea and
conjunctiva.
 Surface area of conjunctiva is about 17 times that of the
cornea with 2 – 30 times greater permeability of many
drug.
 Drug absorption in tissue other than cornea is non
productive loss (systemic drug absorption).
 Loss can be minimized by two way : varying drug
lipophilicity or changing the drug formulation.
17

18. 7. Membrane Factor
 Area available for absorption, thickness, porosity and
tortuosity of the cornea and hydrophilic lipophilic
balance.
 Cornea consist of three layer: Epithelial, stroma and
endothelium
 Epithelial is lipophilic, low in porosity and high in
tortuosity and thickness, a rapidly penetrating drug
must possess log partition coefficient is greater than
1in order to achieve sufficient penetration rate.
 Stroma is acellular, hydrophilic in nature, high in
porosity, low in tortuosity and it represent 90% of
thickness of cornea.
 Endothelium and epithelium are lipophilic but,
endothelium is 2.7 times more permeable than the
epithelium. 18

19. Cont…
 Low corneal permeability (act as lipid barrier)
 Lipophilic agents of low molecular weight follow transcorneal
transport by passive diffusion and obey Fick's first law of
diffusion:
 J = - D . d Cm / dx
J = The flux rate across the membrane
D = diffusion coefficient
 The diffusion coefficient increases, as the molecular size of the
drug decreases.
 Cm = concentration gradient
 As the drug solubility increases, the gradient increases, the
driving force for drug entry into the aqueous humor increases.
 the drug should have dual solubility (oil and water soluble) to
traverse the corneal epithelium (lipid barrier) then the aqueous
humor.
19

20. 20

21. Ion transport
 Corneal epithelial contains ionic channel that selective for
cation over anion.
 active transport is saturable and it's possible that once it's at
full capacity, passive diffusion prevails.
 Also contain anion channel in apical membrane and
conductive for potassium channel in basal cell.
 Two types of transporters that have been found to move
drugs into and out of the cornea are
multidrug resistance proteins (MRPs) – Efflux Transporter
and protein-coupled oligopeptide
transporter (POT) superfamily.- Influx Transporter
 Unfortunately, corneal transporter-mediated uptake and
elimination can differ greatly between species, making it
more difficult to apply animal models of corneal absorption to
humans 21

22. Physiological condition
 The tear film is also highly variable between individuals
as there is up to a six fold difference in tear flow.
 For example, dry-eye patients, who by definition have a
deficiency in the quantity and/or quality of the tear film,
may experience enhanced drug absorption due to the
failure of this barrier function.
 Effect of a drug in normal subjects can be increased by
administration after tear-film breakup.
22

23. Approaches to Improve
Bioavailability
 Approaches to prolong the contact time of drug with
corneal surface
 Approaches to enhance corneal permeability either by
mild or transient structural alteration of corneal
epithelium or by modification of chemical structure of
the drug molecule
23

24. Viscosity enhancers
 Increased vehicle viscosity should correspond to a
slower elimination from the preocular area, which lead
to improved precorneal residence time and hence a
greater transcorneal penetration of the drug into the
anterior chamber.
 The polymers used include polyvinyl alcohol (PVA),
Polyvinylpyrrolidone (PVP), methylcellulose,
hydroxyethyl cellulose, hydroxypropyl methylcellulose
(HPMC), and hydroxypropyl cellulose.
 The retention of drug in the precorneal tear film is
related to the
a. viscosity of the vehicle,
b. the surface spreading characteristics of the vehicle
and
c. the ability of a polymer to drag water as the vehicle 24

25. Cont…
 E.g., Eye ointments, Gel, Polymeric Solution
 improving drug bioavailability and in sustaining drug
release.
 Prolonged residence time, reduced systemic
exposure.
 the dosing frequency can be decreased to once a day
at most.
 blurred vision and matted eyelids, which substantially
reduce patient acceptability.
25

26. Phase Transition System or In-
Situ Activated Gel Forming
Agent
26
 Polymer like Lutrol FC – 127 and poloxamer 407 whose
viscosity increases when its temperature raised to 37ºC
 Cellulose acetate phthalate (CAP) coagulate when its pH of
4.5 is raised by tear fluid to pH 7.4
 Low acetyl gellan gum which gel clearly in presence of
sodium ion in tear.
 Concentration of sodium ion in tear is 2.6g/L.
 That cause gelation of material when topically instilled into
the conjunctival sac.
Liquid
dosage form
When
instilled in
cul-de-sac
Gel or
solid
phase

27.  Xanthan gum has capacity to form gel with the
enzyme LYSOZYME which is present in the tear
fluid.
 Sodium alginate:-
 Alginate is the block copolymer of the ß – D –
mannuronic acid and alpha- d – glucoronic acid. But
only the glucoronic acid content is responsible for the
gelling capacity. it forms 3D gel in presence of
calcium ions.
 Calcium linked alginate gels have good mechanical
properties even if prepared from very less
27

28. Cont…
 Recent trends in sol-gel transition (graft copolymers):-
 Graft copolymers are the polymers which are made up by grafting
one polymer of desired characteristics. On the another one.
 For example, poloxamer is thermo gelling polymer which is 1st
converted in to monoamine terminated poloxamer and then its
amine terminated part is grafted with the hyaluronic acid. and the
generated polymer is called poloxamer-g-hyaluronic acid which
has dual properties means it has thermo gelling properties as well
as penetration enhancing properties.
 Another example is poloxamer-g-c6s (c6s = chondroitoin -6 –
sulphate).
28

29. Ocular Penetration Enhancers
 The use of substances facilitating drug penetration
through the corneal to improve ophthalmic
bioavailability.
 Penetration enhancer like actin filament inhibitor, bile
salts, chelator and organic compound also used to
increase bioavailability of topically applied peptides and
protein.
 Protein is poorly absorbed due to molecular size,
hydrophilicity, susceptible to degradation by an
peptidase enzyme.
29

30. Cont…
 Actin cytoskeleton inhibitor (cytochalasin B)
 Act by disruption of actin microfilament at tight junction
of corneal epithelium resulting in increase permeability
at these junction.
 chelator
 EDTA bind to calcium ion present in tight junction of
epithelium result in decrease in calcium ion
concentration in these junction and thus decreasing the
transepithelial resistance to water soluble compound.
 Also cause corneal damage.
30

31.  Surfactant
 Breakdown in cohesion of epithelium by increasing the
width of intercellular space
 Also disruption of cell cytoplasm resulting in increased
permeability.
 The order of surfactant toxicity is:
 Anionic > cationic » nonionic
 Nonionic surfactants preferred for ophthalmic use
 Bile salt
 Sodium taurocholate (TC-Na), sodium
Taurodeoxycholate (TDC-Na) etc.
 Loosening of tight junction of corneal epithelial barrier
resulting in increased permeability
 TDC- Na and sodium ursodeoxycholate used as ocular
permeation enhancer for atenolol and timolol.
31

32.  Preservative
 Chlorobutanol reduces oxygen utilization in cornea result in loosened
epithelial adhesion.
 Organomercurial (phenyl mercuric acetate, phenyl mercuric nitrate) react
with membrane sulfhydryl group and alter membrane permeability and
transport system
 Benzalkonium chloride has a high affinity for membrane proteins and
can insert itself into the cellular membrane, possibly altering corneal ionic
resistance.
 Ion pairing salt
 Tetraphenylphosphonium chloride, tetraphenylarsonium chloride,
trimethylphenylammonium chloride etc.
 Association of an drug ion with counter ion give rise to an ion pair
 Ion pair posses no net charge and more lipid soluble than constituent ion
32

33. Prodrug
 chemically or enzymatically metabolized to the active parent
compound.
 Epinephrine Prodrugs
 Dipivefrine, a dipivalyl prodrug-ester of epinephrine, has
currently replaced epinephrine in the treatment of
glaucoma.
 Dipivalyl epinephrine (dipivefrine) is a dipivalic acid
diester of epinephrine which releases epinephrine after
cornea absorption.
 Dipivefrine penetrates the human cornea 17 times
better than epinephrine due to fact that dipivefrine is
600 times more lipophilic (at pH 7.2) than epinephrine.
 As compared to the conventional 2% epinephrine
hydrochloride eye drop, a 0.1% dipivefrine eye drop is
slightly less effective on IOP lowering effect, while side-
effects are greatly reduced. 33

34. Mucoadhesive / Bioadhesive
Dosage Form
 Cornea and conjunctival surface covers with mucin.
 If polymer adheres to mucin, the interaction referred as
mucoadhesion.
 Mucoadhesive system can either be polymeric solution
or microparticle suspension.
 They retained in cul-de-sac through adhesive bond with
mucin or epithelium thus increasing corneal contact
time.
 Water soluble polymer having short half life.
 Polycarbophil is an acrylic acid based polymer and able
to pickup water 100 times its weight at neutral pH
 Mucoadhesive polymer with numerous hydrophilic
functional group.
 Established electrostatic and hydrophobic interaction
and hydrogen bonding with underlying surface.
34

35. Pseudolatices
 New class of polymeric colloidal dispersion and film
forming agent, for sustaining drug activity in vivo.
 What is pseudolatices ?
 Organic solution of polymer is disperse in an aqueous
phase to form O/W emulsion subsequently using
appropriate means, i.e., by applying vacuum or by using
controlled temperature.
 Water is removed partially to an extent that residual
water is sufficient enough to keep polymeric phase
discrete and dispersed, such dispersion is called
pseudolatices.
 Which on application leave an intact non invasive
continuous polymeric film which reserve the drug.
 Drug from such system release slowly over prolonged
period of time.
 Ensuring better ocular bioavailability.
 Patient compliance by avoiding frequent instillation of
preparation. 35

36. Collagen shields
 Collagen (protein) that promote wound healing.
 Deliver variety of medicament to cornea and other
ocular tissue.
 Bloomfeild and coworker first suggest the use of
collagen insert as tear substitute and as delivery system
for gentamycin.
 Collagen corneal bandage in shape of contact lens as
an alternative to soft contact lens to protect the healing
of corneal epithelium after surgery.
 For drug delivery, the shield (package in sterile,
dehydrated form) are rehydrated in a water solution of
the drug, whereby the drug is absorbed by the protein
matrix and released once the shield dissolve in the eye.
36

37. Cont…
 Drawback
 Application of shield require to anaesthetize the cornea and
produce some discomfort and interfere with vision.
 A new preparation referred to as COLLASOMES consist of
small pieces (1mm×2mm×0.1mm) of collagen suspended in
1% methylcellulose vehicle.
 It has same therapeutic advantage as that of shields.
 Shields disadvantage are circumvented.
 Marketed products:-
 1) Medi lens® ( Chiron, irvine, ca)
 2) Pro shield® (alcon, fortworth, tx)
37

38. Novel Drug Delivery System
 Liposome
 Niosome
 Microemulsion
 Nanosuspension
 Cyclodextrin
 Discomes
 Microneedle
38

39. DISCOMES
 Disc shaped niosomes are known as discomes.
 large size may prevent their drainage into the systemic
pool.
 Furthermore, their ‘‘disc’’ shape provides for a better fit
in the cul-de-sac of the eye.
USE OF CYCLODEXTRIN
 hydrophilic cyclodextrins act as true carriers by keeping
the lipophilic water-insoluble drug molecules in solution
and delivering them to the membrane surface where
they partition from the cyclodextrin cavity into the
lipophilic membrane.
39

40. 40

41. Microneedle
 Deliver the drug to back of eye tissue in minimally non
invasive manner.
 May reduce the risk and complication associated with IVT
injection such as retinal detachment, cataract, hemorrhage,
endophthalmitis.
 Circumvent BRB and provide efficient treatment strategy for
age related macular degeneration (AMD), diabetic
retinopathy and posterior uveitis.
 These are penetrate into the sclera or subarchoroidal
space (SCS), the region between sclera and choroid
 Also used for anterior segment of ocular drug delivery.
41

42. Cont…
 Sclera is static barrier to microneedle.
 After microneedle scleral penetration, surface coated
drug rapidly accumulated in the microneedle
penetration region, forming depot.
 This depot formation increase bioavailability.
 Carrier system if placed near the back of eye tissue
(i.e., in SCS) can deliver high drug concentration to the
retina choroid.
42

43. Micro Emulsions
 w/o Micro emulsions offer a promising alternative. They are
thermodynamically stable and optically isotropic colloidal
systems with excellent wetting and spreading properties
Moreover, they are comprised of aqueous and oily components
and therefore can accommodate both hydrophilic as well as
lipophilic drugs.
 w/o micro emulsions where administered in the eye; converted
into the LC state which releases the drug slowly and produce a
sustained release preparation for eye.
 Cationic emulsions:-
 They are developed by the Novagali pharmaceuticals for
ophthalmic applications.
 The topical administration of a cationic emulsion onto the eye
has shown to increase the residence time of the drug on the
cornea, with a lower contact angle and an increased spreading
coefficient in comparison with conventional eye drops and
anionic emulsions.
43

44. 44

45. 45

46. Matrix Type Of DDS
 Hydrophilic soft contact lens
 Made up of hydrogel that absorb aqueous solution
 Drug delivery to anterior segment of the eye. E.g.,
polymixin B, pilocarpine, antiviral idoxuridine
 Soluble ocular insert
 Such as polyvinyl alcohol insert (PVAI)
soluble opthalamic drug insert (SODI)
 Thin, elastic and oval shaped plates are impregnated with
drug (antibiotics, pilocarpine, atropine etc.)
 After insertion into conjunctival sac, absorb tear and
swells, dissolve in about 30 – 90 min
 Difficulty of self insertion, but free the patient from task of
removing the device.
 Controlled release, enhanced drug absorption, enhanced
BIOAVAILABILITY
46

47. Scleral Buckling Material
 Used in retinal detachment surgery.
 Cause pre and postoperative infection
 Common scleral buckling material, gelatine film and
solid silicone rubber impregnated with antibiotics, and
biological activity evaluated using agar plate method.
 Sustain release of drug help to cure infection.
Novel Metered Delivery System
 Another novel metered delivery system in development
is a small-volume nebulizer that delivers a mist to the
eye.
 In a clinical study, the nebulizer system produced a
significantly higher bioavailability of vitamin B12 than
standard topical delivery
47

48. 48

49. The New Opthalamic Delivery
System (Nods)
 Drug-incorporated-water soluble polyvinyl alcohol film
 Each NODS consists of a drug loaded film or (flag) attached to a
handle by means of thin membrane
 On contact with the tear film in the lower conjunctival sac the
membrane-quickly dissolves-releases the flag into the tear film
 Flag-hydrates-disperses allowing diffusion and absorption of the
drug
 Handle provided with paper backing for strength
 Both soluble drugs such as pilocarpine and insoluble drugs such as
tropicamide can be formulated into the NODS
 NODS containing 40,80 and 170 μg pilocarpine nitrate showed eight
fold increase in bioavailability compared with a standard 2% eye 49

50. Intravitreal Injections/Implants
 Two antivirals have been approved for treatment of the
ocular sequelae of AIDS with direct emplacement in the
vitreous cavity so as to provide high localized ocular
therapeutic concentrations.
 A polymer-coated sterile tablet containing ganciclovir,
called a Vitrasert,47 is implanted by the surgeon in the
vitreous cavity, where it releases drug over a period of
several months and then is removed and replaced with a
new tablet.
 The tablet is formulated with magnesium stearate as the
drug carrier and coated with polymers that provide the
prolonged drug release.
 during handling, this polymer coating is not damaged and
the special sterile packaging not be compromised.
 A sterile solution of fomivirsen is also available for
intravitreal injection to treat cytomegalovirus retinitis.
 It is supplied in single-use vials and is injected intravitreal
without requiring surgery but must be repeated every 2 to 50

51. CHEMICAL APPROACHES FOR OCULAR DRUG
DELIVERY
A) CHEMICAL DRUG DELIVERY SYSTEM
 A chemical delivery system (CDS), is an inactive species
obtained by chemical modifications of the active agent
based on metabolic considerations.
 Conceptually, a CDS upon its administration will undergo
several predictable enzymatic transformations via
inactive intermediates and finally deliver the active
species to the target site.
B) SOFT DRUG APPROACH:-
 It Produce the desired pharmacological activity at
the site of application but at other sites do not show
any action even though the same receptor is
present.
51

52. 52

53. IONTOPHORESIS
 noninvasive nature of delivery to both anterior and posterior
segment.
 Transferring ionized drugs through membranes with low
electrical current.
 The drugs are moved across the membranes by two
mechanisms: migration and electro-osmosis.
 Ocular iontophoresis is classified into transcorneal,
corneoscleral, or trans-scleral iontophoresis,
 The sclera has larger surface area than the cornea (about 17
cm2 vs 1.3 cm2), high degree of hydration, low number of
cells, and it is permeable to large molecular weight
compounds.
 noninvasive method, easy to use, less risk of toxicity, a broad
applicability to deliver a broad range of drugs or genes to
treat several ophthalmic diseases in the posterior segment of53

54. Disadvantage
 no sustained half-life, requires repeated
administrations, side effects include mild pain in some
cases, but no risk of infections or ulcerations, risk of low
patient compliance because the frequent
administrations that may be needed.
 OcuPhor™ system has been designed with an
applicator, dispersive electrode, and a dose controller
for trans scleral iontophoresis (DDT).
 This device releases the active drug into retina-choroid
as well. A similar device has been designed called
Visulex™ to allow selective transport of ionized
molecules through sclera.
 Examples of antibiotics successfully employed are
gentamicin, tobramycin, ciprofloxacin and steroid.
54

55. REFERENCE
 Remington Essential of Pharmaceutics, edited by Linda
Felton, page no. 545 - 562
 Ophthalmic Drug Delivery System: Challenges and
Approaches Patel PB, Shastri DH, Shelat PK, Shukla
AK Systematic Reviews in Pharmacy | July-December
2010 | Vol 1 | Issue 2
 Progress and Problems in Ophthalmic Drug Delivery, a report
by Professor Marco Fabrizio Saettone
 Ocular drug delivery, Aswani Dutt Vadlapudi, Kishore Cholkar,
supriya Reddy Desari, and Ashim K. Mitra
 https://www.reviewofophthalmology.com/article/the-secret-
world-of-pharmacokinetics
 Indian Journal of experimental of biology Vol. 39, January
2001, pp 11-24 Review Article, Permeation through Cornea,
by Majusha Malhotra and D. K. Mujumdar
55