RESEARCH PAPER
`
`Received 21 October 1993
`
`Indian J. Pharm. Scl., 1995, 57(3) pp. 109-112
`
`________‘______________.__.___._____.________————
`
`Ophthalmic Irritation Potential of Propylene Glycol
`___________________________.___________
`
`ARUN SHIRWAlKAR" AND P. GUNDU RAO.
`
`College of Pharm. Sciences. Manipal - 576119 Karnataka.
`
`Propylene glycol, a new vehicle for ophthalmic use tested here, has proved to be non-toxic to the rabbit
`eye. There was no serious vision - threatening side effects or a microscopic structural damage to the
`eye. It was proved to be safe on frequent usage too. All irritation scores recorded being consistently
`below the "l'Jlariginal Irritant" scope of 65.
`
`WWATER for injection has been used as a ve-
`
`it
`
`is not
`
`hicle for ophthalmic solutions but
`
`MATERIALS AND METHODS
`
`Materials
`
`1. Propylene glycol obtained from Ranbaxy Lab-
`oratories Limited, having a refractive index of 1.4320
`to 1.4330, with a Wt/ml at 20° c of 1.0350 to 1.0370
`g and boiling range of 186 - 188° was used in the
`
`suitable as asolvent for awide variety of antibacterial
`
`and antifungal agents and their combinations which
`
`are insoluble in it. Moreover it is not viscous enough
`
`to retain the drug in the eye for adequate time.
`
`Though oils are viscous and have been tried they
`have not received acceptance. For an ophthalmic ’
`
`vehicle to be acceptable it should be viscous, non-
`irritant, water miscible and it should be a solvent for
`
`present study. New Zealand white albino rabbits of
`
`either sex, weighing about 2 kg were employed in
`
`a variety of drugs. Propylene glycol was considered
`
`this investigation.
`
`as a possible candidate for this purpose.
`
`Before any liquid can be used as a vehicle for
`
`flycol
`
`Evaluation of irritation potential of propylene
`
`opthalmic preparation, it has to be thoroughly inves-
`
`tigated for its irritation potential. Here a systematic
`
`toxicity study was undertaken on this vehicle the
`
`potential for permanent damage any vehicle may
`
`exhibit, accentuates the necessity for an animal
`
`model that enables extrapolation of the data to man.
`The rabbit is the animal of choice1 at the present
`time for ocular irriation evaluations. It closely resem-
`bles the human external eye. However extrapolation
`must be done with the knowledge that many differ-
`ences do exist. The rabbit has in fact been shown
`
`to be more sensitive to many materials than the
`human eye. With this background in mind, the rabbit
`eye was chosen for this study.
`
`
`
`*For Correspondence.
`
`For evauation of the irritation potential of pro—
`
`pylene glycol the following methodology was
`adoptedz. Batches of New Zealand white albino rab-
`
`bits were chosen. All eyes were found to be normal
`
`externally on slit lamp examination under cobalt blue
`illumination.
`
`Batches of six rabbits were used as a time for
`
`each study. One drop of propylene glycol was instilled
`
`into the conjuctival sac. The lower lid was gently
`pulled away to form a cup and propylene glycol was
`
`then instilled and the lids were held together for a
`second. The contralateral eye served as a control.
`The eyes were examined and graded after 24, 48
`
`and 72 hours and on day 7 after instillation. Each
`
`May-dune 1995
`
`Indian Journal of Pharmaceutical Sciences
`
`109
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`MYLAN INST. EXHIBIT 1084 PAGE 1
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`MYLAN INST. EXHIBIT 1084 PAGE 1
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`MYLAN INST. EXHIBIT 1084 PAGE 1
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`

`

`examination included a study with fluorescein 2%
`topical drops (excess was washed with sterile water).
`Fundus examination with direct opthalmoscope was
`
`pertomed everyday. Slit
`scored as follows:
`
`lamp observations were
`
`Absent
`
`lris total =
`
`2
`
`1 1
`
`Lids and Conjuctival Damage
`
`Hyper'emea, Chemosis, Ulceration, Scarring (Each)
`
`Corneal damage
`
`Corneal damage (Edema thickeness), Flurescein
`(punctate staining and confluent staining) and Corneal
`Vascularization Scaring of pugment migration. (Each)
`
`Scofig
`
`0 < Area < 1/4
`
`1/4<Area< 1/2
`
`1/2 < Area < 3/4
`
`3/4 < Area <1
`
`Intensity.
`
`Epithelial edema plus slight stromal edema
`
`One and a half times normal thickness
`
`Two times normal thickness
`
`Cornea entirely opaque
`
`Corneal Perforation
`
`1
`
`2
`
`3
`
`4
`
`1
`
`#AQN
`
`Corneal total =
`
`20
`
`Anterior chamber
`
`Cells
`
`A few
`
`Moderate number
`
`Many
`
`Flare and Hyperemia of Iris (Each)
`
`~
`
`.
`
`Slight
`
`Moderate
`
`marked
`
`Pupillary light reflex
`
`Sluggish
`
`110 ‘
`
`Slight
`
`Moderate
`Marked
`
`Staining
`
`Slight (1/3)
`
`Moderate (1/3-2/3)
`
`Extensive (2/3-3/3)
`
`.
`
`1
`
`2
`3
`
`1
`
`2
`
`3
`
`.
`
`Lid and Conjuctival Total :
`
`15
`
`Bayard and Hehir (Gilman, 1982) considered cor-
`nea and iris injury to be morew relevant to the over
`
`all irritation potential and proposed weighing the daily
`
`scores by using a multiplier of 1 5 for corneal damage
`score, and a multiplier of 5 for iris scores and a
`
`multiplier of 2 and lids and conjuctival damage
`scores.
`‘
`'
`
`The total score is further Weighed as shown
`below;
`
`Total score = Day 1 scores + Day 2 scores +
`
`Day 3 scores + Day 7 scores Final scores were
`
`evaluated using the following scale.
`
`Severe iritant : 326 - 550
`
`Strong irritant : 201 - 325
`Moderate irritant : 66 - 200
`
`Marginal irritant : 65
`
`Based on the above guidelines, evaluation of
`
`the irritation potential was carried out.
`
`In the first part of the study, 1 drop of propylene
`glycol was instilled into the left eye of all six rabbits
`
`(The right eye served as a control) and the eyes
`examined on days 1,2,3 and 7. In the second part
`of the study,
`1 drop of the propylene glycol was
`
`1
`
`2
`
`3
`
`1
`
`2
`
`‘3
`
`1
`
`Indian Journal of Pharmaceutical Sciences
`
`May—«lune 1995
`
`MYLAN INST. EXHIBIT 1084 PAGE 2
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`MYLAN INST. EXHIBIT 1084 PAGE 2
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`MYLAN INST. EXHIBIT 1084 PAGE 2
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`

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`Table -1: Scores recored when examined on days 1,2,3 and 7 after 2 drop of propylene glycol was in-
`stilled into the left eye of all six rabbits.
`
`W R
`
`Total Score
`Day 7
`DAY 3
`DAY 2
`DAY 1
`ABBIT NO.
`_________________________._____________._._____————————
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Conjuctivalscores
`Corneal scores
`
`Daytotal
`
`Conjuctivalscores
`Corneal scores
`
`Daytotal
`
`Conjuctivalscores
`Corneal scores
`
`Daytotal
`
`Conjuctivalscores
`Corneal scores
`
`2x2=4
`1x15:15
`
`19
`
`1x2=2
`
`2
`
`1x2=2
`1x15:15
`
`17
`
`2x2=4
`
`1x2=2
`
`2
`
`1x2=2
`
`Daytotal
`
`,
`
`4
`
`2
`
`Conjuctival scores
`Corneal scores '
`
`Daytotal12
`
`.
`
`Conjuctivalscores
`Corneal scores
`
`Daytotal
`
`1x2=2
`
`1x222
`1x15=15
`
`17
`
`‘1x2=2
`
`2
`
`19
`
`2
`
`19
`
`6
`
`2
`
`19
`
`Note: Conjuctival scores were all for hyperemia - slight or moderate. Corneal scores were‘all ior punctate
`
`staining of cornea involving less than one quarter are.
`
`lritis was absent in all the. eyes.
`Fundus was normal in all the eyes.
`
`instilled into the left eye of all the six rabbits once
`
`every 24 hours for 3 consecutive days and the eyes
`
`examined on days 1,2,3 and 7 (right eye served as
`
`minimalsupericialpunctate staininginvoivingfar less
`than one quarter of the cornea. This too resolved
`in 24 hours. There were no other anterior or posterior
`
`a control).
`
`RESULTS AND DISCUSSIONS
`
`segment findings. The maximum score recorded was
`
`19 which is well below the “Marginal irritant" score
`of 65.
`
`When one drop of propylene glycol was instilled
`
`and the rabbit eyes examined thereafter on days
`1,2,3 and 7 (Table -1), the only consistent finding
`
`The results were almost the same when 1 drop
`of propylene glycol was instilled every 24 hours for
`3 days and examined on days 1,2,3 and 7 (Table
`
`was the slight to moderate conjuctival hyperemia
`
`-2). The slight hyperemia had lasted in 2 rabbits
`
`seen on day 1 in all the rabbits this hyperemia quickly
`
`resoved in 24 hours. There rabbits have shown every
`
`upto day 3. One rabbit showed punctate superficial
`staining of less than one quarter of the cornea which
`
`May—June 1995
`
`lndian Journal of Pharmaceutical Sciences
`
`111
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`MYLAN INST. EXHIBIT 1084 PAGE 3
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`MYLAN INST. EXHIBIT 1084 PAGE 3
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`MYLAN INST. EXHIBIT 1084 PAGE 3
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`

`

`Table - 2: Scores recorded after one drop of propylene glycol was instilled into the left eye of all the 6
`rabbits once every 24 hours for 3 consecutive days.
`
`W R
`
`
`
`
`
`DAY 1 DAY 2 DAY 3 DAY 7ABBlT NO Total ScoreW
`
`
`
`
`
`
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Conjunctivalscores
`Corneal scores
`
`Daytotal
`
`Conjunctivalscores
`Corneal scores
`
`Daytotal
`
`Conjunctivalscores
`Corneal scores
`
`Daytotal
`
`Cojunctivalscores
`Corneal scores
`
`Daytotal
`
`Conjunctivalscores
`Corneal scores
`
`Daytotal
`
`Conjunctivalscores
`Corneal scores
`
`Daytotal
`
`1x2:2
`1x15:15
`
`17
`
`1x2:2
`
`2
`
`'
`
`2x224
`1x15:15
`
`1x2:2
`1x15=15
`
`,
`
`1x2:2
`
`2
`
`17
`
`1x2:2
`
`2
`
`19
`
`2x2:4
`1x15:15
`
`19
`
`1x2:2
`1x15=15
`
`17
`
`2x2=4
`
`1x2:2
`
`4
`
`1x2:2
`1x15:15
`
`17
`
`2
`
`1x2:2
`
`2
`
`1x2:2
`
`2
`
`19
`
`‘
`
`38
`
`21
`
`17
`
`5
`
`21
`
`Note: Conjunctival scores were all for hyperemia - slight or moderate Corneal scores were all for punctate
`
`staining involving less than one quarter area of cornea.
`
`lritis was not present in any eye.
`
`resolved on day 3. The maximum score recorded
`
`medicine and surgery, Kasturba Medical College,
`
`was 38 which is again below the “Marginal Irritant"
`score of 65.
`
`Manipalforallthe cooperation andfacilities provided
`druring the work.
`
`The present study has opened portals for using
`
`propylene glycol, hither to unused as a vehicle in
`
`REFERENCES
`
`for investigating different drug
`ophthalmic drops,
`combinations for effective therapy in ophthalmology.
`
`ACKNOWLEDGEMENTS
`
`1. Aronoson SB. and Mortan R. Mechanism of host re—
`sponse in the eye, Archives of ophthalmology 1971,
`as: 306.
`
`The authors thank the Dean, KaSlurba Medical
`COllege, Manlpal for prOVldlng the faCllltleS. The aU"
`thors also thank the Department of Experimental
`
`In:
`2. Gilman, MR. Skin and eye testing in animals.
`Wallace A.H. (ed) Principles and methods of toxicol-
`ogy' 1st Edn" Raven Press, New York 1982' pp 216.
`220.
`
`112
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`lndian Journal of Pharmaceutical Sciences
`
`May—June 1995
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`MYLAN INST. EXHIBIT 1084 PAGE 4
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`MYLAN INST. EXHIBIT 1084 PAGE 4
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`MYLAN INST. EXHIBIT 1084 PAGE 4
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