RESEARCH PAPER
`
`Received 21 October 1993
`
`Indian J. Pharm. Sci., 1995, 57(3) pp. 109-112
`
`NEN
`Ophthalmic Irritation Potential of Propylene Glycol
`
`a A
`
`RUN SHIRWAIKAR®* AND P. GUNDU RAO.
`
`College of Pharm. Sciences, Manipal - 576119 Karnataka.
`
`Propylene glycol, anew vehicle for ophthalmic use tested here, has proved to be non-toxic to the rabbit
`eye. There was noseriousvision - 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 “MariginalIrritant” scope of 65.
`
`Write for injection has been used asa ve-
`
`is not
`it
`hicle for ophthalmic solutions but
`suitable as a solventfor a wide 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
`a variety of drugs. Propylene glycol was considered
`as a possible candidate for this purpose.
`
`Before any liquid can be used as a vehicle for
`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
`modelthat enables extrapolation of the data to man.
`The rabbit is the animal of choice’ at the present
`time for ocular irriation evaluations. It closely resem-
`bles the humanexternal eye. Howeverextrapolation
`must be done with the knowledge that manydiffer-
`ences do exist. The rabbit has in fact been shown
`to be more sensitive to many materials than the
`humaneye. With this backgroundin mind, the rabbit
`eye was chosenfor this study.
`
`*For Correspondence.
`
`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/mI at 20° C of 1.0350 to 1.0370
`g and boiling range of 186 - 188° was used in the
`present study. New Zealand white albino rabbits of
`either sex, weighing about 2 kg were employedin
`this investigation.
`
`Evaluation of irritation potential of propylene
`flycol
`
`For evauation of the irritation potential of pro-
`pylene glycol the following methodology was
`adopted’. Batches of New Zealandwhite 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 drog of propylene glycol wasinstilled
`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 togetherfor a
`second. The contralateral eye served as a control.
`The eyes were examined and graded after 24, 48
`and 72 hours and on day7 after instillation. Each
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`May—June 1995
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`Indian Journal of Pharmaceutical Sciences
`
`109
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`MYLANINST. EXHIBIT 1084 PAGE1
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`

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`examination included a study with fluorescein 2%
`topical drops (excess was washedwithsterile water).
`Fundus examination with direct opthalmoscope was
`perfomed everyday. Slit
`lamp observations were
`scored as follows:
`
`Absent
`
`tris total =
`
`2
`11
`
`Lids and Conjuctival Damage
`
`Hyperemea, Chemosis, Ulceration, Scarring (Each)
`
`Corneal damage
`
`Corneal damage (Edemathickeness), Flurescein
`(punctate staining and confluent staining) and Corneal
`Vascularization Scaring of pugment migration. (Each)
`
`Scorig
`
`0 < Area < 1/4
`
`1/4 < Area < 1/2
`
`1/2 < Area < 3/4
`3/4 <Area <1
`
`Intensity
`
`|
`
`Epithelial edema plusslight stromal edema
`
`One and a half times normal thickness
`
`Two times normal thickness
`
`Cornea entirely opaque
`
`Corneal Perforation
`
`1
`
`2
`
`3
`4
`
`—_
`
`-PPBWwWND
`
`Corneal total=
`
`20
`
`Anterior chamber
`
`Cells
`
`A few
`
`Moderate number
`
`Many
`
`Flare and Hyperemia ofIris (Each)
`Slight
`
`Moderate
`
`marked
`
`Pupillary light reflex
`Sluggish
`
`1
`
`3
`
`4
`
`2
`
`3
`
`1
`
`Slight
`
`Moderate
`
`Marked
`
`Staining
`Slight (1/3)
`Moderate (1/3-2/3)
`
`1
`
`2
`
`3
`
`1
`
`Extensive (2/3-3/3)
`,
`Lid and Conjuctival Total =
`
`15
`
`Bayard and Hehir (Gilman, 1982) considered cor-
`nea andiris injury to be morew relevant to the over
`allirritation potential and proposed weighing the daily
`scores by using amultiplier of 15 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
`Moderateirritant : 66 - 200
`Marginalirritant : 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 wasinstilled 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
`
`110 ‘
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`Indian Journal of Pharmaceutical Sciences
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`May—June 1995
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`MYLANINST. EXHIBIT 1084 PAGE 2
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`MYLAN INST. EXHIBIT 1084 PAGE 2
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`Table - 1: Scores recored when examined on days1,2,3 and 7 after 2 drop of propylene glycol wasin-
`stilled into the left eye of all six rabbits.
`
`i R
`
`Total Score
` Day7
`~
`DAY 3
`DAY 2
`DAY 1
`ABBIT NO.
`To
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Conjuctival scores
`Corneal scores
`Daytotal
`Conjuctival scores
`Corneal scores
`Daytotal
`Conjuctival scores
`Corneal scores
`Daytotal
`Conjuctival scores
`Corneal scores
`Daytotal
`
`Conjuctival scores
`Corneal scores |
`Daytotali2.
`Conjuctival scores
`Corneal scores
`Daytotal
`
`2x2=4
`1x15=15
`19
`1x2=2
`
`2
`1x2=2
`1x15=15
`17
`2x2=4
`
`4
`
`1x2=2
`
`1x2=2
`
`2
`1x2=2
`
`2
`
`1x2=2
`1x15=15
`17
`
`‘1x2=2
`
`2
`
`19
`
`2
`
`19
`
`6
`
`2
`
`19
`
`Note: Conjuctival scores wereall for hyperemia - slight or moderate. Corneal scores were all for punctate
`staining of corneainvolving less than one quarterare.
`Iritis was absentin all the eyes.
`Fundus was normalin 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
`a control).
`
`RESULTS AND DISCUSSIONS
`
`minimal supericial punctate staining involving far less
`than one quarter of the cornea. This too resolved
`‘in 24 hours. There were no otheranterior or posterior
`segmentfindings. The maximum score recorded was
`19 which is well below the “Marginal Irritant” score
`f 65.
`°
`
`Whenone drop of propylene glycol wasinstilled
`and the rabbit eyes examined thereafter on days
`1,2,3 and 7 (Table -1), the only consistentfinding
`was the slight to moderate conjuctival hyperemia
`seen on day 1 in all the rabbits this hyperemia quickly
`resovedin24 hours. There rabbits have shownevery
`
`The results were almost the same when 1 drop
`of propylene glycol wasinstilled every 24 hours for
`3 days and examined on days 1,2,3 and 7 (Table
`-2). The slight hyperemia had lasted in 2 rabbits
`upto day 3. One rabbit showed punctate superficial
`staining of less than one quarter of the cornea which
`
`May—June1995
`
`Indian Journalof Pharmaceutical Sciences
`
`ttt
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`MYLANINST. EXHIBIT 1084 PAGE 3
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`

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`Table - 2: Scores recorded after one drop of propylene glycol wasinstilled into the left eye of all the 6
`rabbits once every 24 hours for 3 consecutive days.
`nr
`
`DAY1 DAY 2 DAY 3 DAY 7RABBIT NO Total Scorenn
`
`
`
`
`
`
`
`
`
`
`
`1.
`
`2.
`
`3.
`
`4,
`
`5.
`
`6.
`
`Conjunctival scores
`Corneal scores
`Daytotal
`Conjunctival scores
`Corneal scores
`Day total
`
`Conjunctival scores
`Corneal scores
`Daytotal
`
`Cojunctival scores
`Corneal scores
`Daytotal
`
`Conjunctival scores
`Corneal scores
`Daytotal
`
`Conjunctival scores
`Corneal scores
`Daytotal
`
`1x2=2
`1x15=15
`17
`2x2=4
`1x15=15
`19
`
`2x2=4
`1x15=15
`19
`
`1x2=2
`1x15=15
`17
`
`2x2=4
`
`4
`
`1x2=2
`1x15=15
`17
`
`1x2=2
`
`2
`1x2=2
`1x15=15
`17
`
`1x2=2
`
`2
`
`1x2=2
`
`2
`
`1x2=2
`
`2
`
`,
`
`_
`
` 1x2=2
`
`2
`
`1x2=2
`
`2
`
`19
`
`38
`
`21
`
`17
`
`6
`
`21
`
`Note: Conjunctival scores wereall for hyperemia - slight or moderate Corneal scores wereall for punctate
`staining involving less than one quarter area of cornea.
`lritis was not presentin any eye.
`
`resolved on day 3. The maximum score recorded
`was 38 which is again below the “Marginal Irritant”
`score of 65.
`
`medicine and surgery, Kasturba Medical College,
`Manipalfor all the cooperation and facilities provided
`druring the work.
`
`The present study has opened portals for using
`propylene glycol, hither to unused as a vehicle in
`ophthalmic drops,
`for investigating different drug
`combinationsfor effective therapy in ophthalmology.
`
`ACKNOWLEDGEMENTS
`
`REFERENCES
`
`1, Aronoson S.B. and Mortan R. Mechanism of host re-
`sponse in the eye, Archives of ophthalmology 1971,
`85, 306.
`
`The authors thankthe Dean, Kasturba Medical
`College, Manipal for providing the facilities. The au-
`thors also thank the Department of Experimental
`
`2. Gilman, M.R. Skin and eye testing in animals.
`tn:
`Wallace A.H.(ed) Principles and methodsof toxicol-
`ogy, ist Edn., Raven Press, New York 1982, pp 216-
`220.
`
`112
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`Indian Journal of Pharmaceutical Sciences
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`May—June 1995
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