FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE COMPLETE SPECIFICATION
(See section 10)
1; PHARMACEUTICAL COMPOSITION FOR MYDRIASIS AND PROCESS FOR PRODUCING SAME.
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY,
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THIS INVENTION.

PHARMACEUTICAL COMPOSITION FOR MYDRIASIS AND PROCESS FOR PRODUCING SAME.
The present invention relates to pharmaceutical composition for mydriasis and process for producing same. The pharmaceutical composition as per present invention provides better mydriasis. The amount of mydriasis produced is more and inspite of being more the duration of action is smaller.
Ideal mydriatic is one, which produces prompt, maximal 'but transient mydriasis after a single instillation. The mydriasis should be maintained despite the intense light of indirect ophthalmoscopy. Of all currently available mydriatic agents, not a single one meets this requirement. Because of this reason combination of mydriatic agents are used.
There are two types of muscles whose action controls size of the pupil. They are known as dilator pupillae and sphincter pupillae: Mydriasis is achieved by contraction of dilator pupillae muscle or relaxation of sphincter pupillae. Contraction of dilator pupillae muscle is achieved by adrenergic mechanisms. The substances, which cause contraction of dilator pupillae muscle and there by work as a mydriatic include adrenaline, noradrenaline, phenylephrine, hydroxy amphetamine, ibopamine etc. The substances, which cause relaxation of sphincter pupillae and thereby work as a mydriatic, include tropicamide, cyclopentolale, homatropine, atropine etc.
Synergistic mydriatic compositions include drugs which contracts dilator pupillae muscle and relaxes sphincter pupillae muscle.
Two synergistic mydriatic compositions are in use currently in clinical practice. They include
1.. Tropicamide 0.8% + phenylephrine 5.0%
2. Hydroxy amphetamine 1% + Tropicamide 0.25%
Both of them are known to produce maximal Mydriasis after a single instillation. It takes around 6 to 8 hrs for pupil to become normal in size after use of these compositions. The combination of 0.8% tropicamide with 5% phenylephrine is the current synergistic mydriatic of choice. Lesser concentration of either drug (tropicamide 0.5% or phenylephrine: 2.5%) or use of only one or the other drug did not produce consistent and maintained mydriasis.
mere is a need to have a mydriatic wnose duration of action is lesser than abovementioned.compositions.
Other Synergistic mydriatic composition described in the literature includes:
1. 0.25% tropicamide + 1.25 % phenylephrine.
2. 0.125% tropicamide + 2% phenylephrine
Both of them are known 10 produce mydriasis, which is as good as 0.5% tropicamide and so do not offer any advantage over 0.5% tropicamide. This is the reason for their not being popular.

Other synergistic mydriatic composition described in literature include:
1. Cyclopentolate 0.5% with phenylephrine 2.5%.
2. Tropicamide 0.5% with phenylephrine 2:5%
3. Tropicamide 1% with phenylephrine-2.5%
All of these have longer duration of action and none of them are popular.
Mydriatic effect varies with pigmentation of iris. Mydriatic effect is maximum in light coloured iris and minimum in heavily pigmented iris. This makes it difficult to achieve good mydriatic effect in darkly pigmented iris than in lightly pigmented iris.
Of all mydriatic drugs Ibopamine a dopaminergic drug is found lo have shorter duration of action. All other mydriatic agents nave duration of action, which is longer than Ibopamine.
The problem with Ibopamine is inadequate mydriasis & shorter duration of peak mydriatic effect. The mydriasis achieved by Ibopamine is not as good as synergistic compositions described above.

References:
1. Havenar's Ocular pharmacology, Edition: Thomas F. Mauger and Elson L graig, Six edition 1994
2. Sinclair SH, Pelham V, Giovanoni R, Regan CD. Mydriatic solution for outpatient indirect ophthalmoscopy. Arch Ophthalmol. 1980 Sep;98a(9): 15724.
3. Paggiarino DA, Brancatoa LJ, Newton RE. The effects on pupil size and accommodation of sympathetic and parasympatholytic agents. Ann Opahthalmol 1993 Jul; 25(7): 244-9, 253.

4. Gelmi C, Palazzuolo A, Lucchetti M, Trimarchi F. Pupillographic evaluation of the mydriatic effect of ibopamine solution. Int J Clin Pharmacol Ther Toxicol 1989 Jul;27(7): 346-51.
5. Larkin KM, Charap A, Cheetham JK, Frank J. Ideal concentration of tropicamide with hydroxyamphetamine 1% for routine papillary dilation. Ann Ophthalmol 1989 Sep;21(9): 340-4.
6. Apt L, Henrick A. Pupillary dilatation with single eye drop mydriatic combinations. Am .f Ophthalmol 1980 Apr;'89(4): 553-9.

SUMMARY OF INVENTION
According to present invention it is possible to use mydriatics working on sphincter pupillae muscle and combination with Ibopamine to provide a synergistic mydriatic composition.
According to present invention it is found that when parasympatholytic (anti cholinergic drugs) are used along with Ibopamine the synergistic action is achieved. However when they are used in therapeutic concentrations the resulting duration of action of composition is as good as parasympatholytic agent.
Surprisingly it is seen that when sub therapeutic dose of parasympatholytic agents are used, the synergistic mydriatic effect is maintained with reduction in duration of action or time taken for pupil to become normal in size.
The objective of present invention is to provide a synergistic mydriatic composition with a shorter duration of action.
The further objective of the present invention is to provide a synergistic mydriatic composition, which maintains peak pupillary dilatation for a longer time than Ibopamine.
The further, objective of present invention is to provide a synergistic mydriatic composition whose action can be reversed .by other pharmacological agents and thereby its duration of action can be further shortened,
The further objective of the present invention is to provide a synergistic mydriatic composition with minimal systemic effects.

DETAILED DESCRIPTION OF THE INVENTION

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.
Ibopamine is used as 2% solution for mydriasis. The effect is short lasting but inadequate. It does not have any systemic side effects. The effect of Tropicamide and any other mydnatric agent known so far is longer than Ibopamine. The combination of Ibopamine (1 to 2 %) with lropicamideiig',5% to 1% results in a synergistic mydriatic composition with a duration of action lasting 6-8 hours.
However, surprisingly according to present invention when Ibopamine is combined with subtherapeutic dosage of Tropicamid, it results in to a mydriatic composition whose duration of action is as good as that of Ibopamine, but effect is significantly more than that of Ibopamine. The subtherapeutic dosage of Tropicamide fails to provide mydriasis.
When amount of tropicamide (one of the parasympatholytics) is reduced from 0.5 to 0.2 % in combination of Ibopamine 2% the synergistic mydriatic action is maintained with reduction in duration of action of tropicaifiide. Surprisingly it was also found to increase duration of peak pupillary dilatations.
The parasymatholytic mydrial agents that can be used for the purpose of present invention along with tropicamide include tropicamide, cyclopentolate, honatropine, etc. In pigmented eyes the subtherapeutic dose 'is fail to elicit papillary dilatatian.
Followings are the example of describing preferred, embodiment of the invetion, however, scope of present invention is not be limited by them.
I Examples of pharmaceutical compositions
A.
Ibopamine Hydrochloride 100:00 mg
Benzylconium chloride 0:50 mg
Disodium hydrogen phosphate 18.50 mg
Citric Acid anhydrous 17.55-mg
Disodium edetate 0,375 mg
Tropicamide 10.00 mg
B
Water for Injection I.P. 5 ml
Ibopamine Hydrochloride 100.00 mg
Benzylconium chloride 0.50 mg
Disodium hydrogen phosphate 18!50 mg
Citric Acid anhydrous 17.55 mg
Disodium edetate 0.375 mg
Tropicamide 5.00 mg
Water for Injection I.P. 5 ml. .

C ibopamine Hydrochloride Benzylconium chloride

50.00 mg 0.50 mg

D
E
G

Disodium hydrogen phosphate 18.50 mg
Citric Acid anhydrous 17,55 mg
Disodium edetate 0.375 mg
Tropicamide 10:00 mg
Water for Injection I.P 5 ml.
Ibopamine Hydrochloride 100.00 mg
Benzylconium chloride 0.10 mg
Disodium hydrogen phosphate 25.00. mg
Citric Acid anhydrous 25.0:0 mg
Disodium edetate 0.37.5 mg
Tropicamide 10<66. mg
Water for Injection LP. 5 mi. '
Ibopamine Hydrochloride 50.00 mg
Benzylconium chloride 0.50 mg
Disodium hydrogen phosphate 18.50 mg
Citric Acid anhydrous 17.55 mg
Disodium edetate 0.375 mg
Tropicamide 5.00 mg
Water for Injection I.P. 5 ml.
Ibopamine Hydrochloride 100.00 mg
Benzylconium chloride 0.50 mg
Disodium hydrogen phosphate 18.50 mg
Citric Acid anhydrous. 17.55 mg
Disodium edetate 0375 mg
Cyclopentolate 10.00 mg
Water for Injection I.P! 5 ml.
Ibopamine Hydrochloride 50:00 mg
Benzylconium chloride 0.50 mg
Disodium' hydrogen phosphate 18^50 mg
Citric Acid anhydrous 17".55 mg
Disodium edetate 0.375 mg
Cyclopentolate 10.00 mg
Water for Injection I.P. 5 ml.

Process of preparing pharmaceutical composition as per present invention.
1 Take water for injection. Add disodium hydrogen phosphate, citric acid, disodium edetate to boiling water and dissolve it completely while stirring.
2 Take water for injection and heat it to 80°C add benzylconium chloride. Dissolve it completely while stirring. Add it to above solution.
3 Add Ibopamine to above solution and dissolve it completely.
4 Measure pH it should be between 3-5 to 4.5.
5 Prepare solution of prarasymahtolytic agent (tropicamide) in water for injection.
6 Add prarasymahtolytic agent (tropicamide) solution prepared in above step to solution of-Ibopomine prepared.
7 Filter solution using Nylon 66 membrane filter of 0.22 micron pore
size. Fill solution in an area where in humidity and temperature are
controlled (50 ± 5% and 23°C + 2°C)
1 Take water for injection. Add disodium hydrogen phosphate, citric acid, disodium edetate to boiling water and dissolve it completely while stirring.
2 Take water for injection and heat it to 80°C add benzylconium chloride. Dissolve it completely while stirring. Add it to above solution.
3 Add Ibopamine to above solution and dissolve it completely.
4 Measure pH it should be between 3-5 to 4..5r:
5 Prepare solution of prarasymahtolytic agent (tropicamide) in water for injection.
6 Add prarasymahtolytic agent (tropicamide) solution prepared in above step to solution of Ibopomine prepared.

7 Filter solution using Nylon 66 membrajne filter of 0.22 micron pore size. Fill solution in an area where in humidity and temperature are controlled (50 ± 5% and 23°C ± 2°C).
8 Lyophilisation to performed.
9 End point should be white to ivory white powder.
10 The powder is reconstituted before use by adding water for injection.
1 Take water for injection. Add excipients: and dissolve it completely while stirring.
2 Take water for injection and heat it to. 809C add preservative. Dissolve it completely while stirring. Add it to above solution.
3 Add Ibopamine to above solution and dissolve it completely,
4 Measure pH it should be between 3-5 to 4.5.
5 Prepare solution of prarasymahtolytic agent (tropicamide) in water for injection.
6 Filter both solutions using Nylon 66 membrane filter of 0.22 micron pore size. Fill solution in an area where in humidity and temperature are controlled (50 ± 5% and 23° C± 2° C).

7 Lyophilisation of solution containing Ibopamine is performed.
8 End point should be while to ivory white powder.
9 The powder is reconstituted before use by adding solution containing Tropicamide.

III. Experiment the evaluate efficacy of new formulation for its synergistic effect.
The efficacy was evaluated in healthy normal individuals by instilling the drop of different formulations made as per the present invention in one eye and the commercially available drops containing different mydriatric agents.
1. Ibopamine 2% + Tropicamide 0.2% was evaluated against tropicamide 1% for evaluation of synergistic effect. In one eye one drop of combination drug and die other eye one drop of tropicamide 1% was instilled. This was done in 10 healthy individuals with normal eyes. The mean difference in peak pupillary size between two eyes was 1.6 m.m. with tropicamide having smaller size of pupil.
2. Ibopamine 2% + Tropicamide 0.2% was evaluated against phenylephrine 10% for evaluation of synergistic effect. In one eye one drop of combination drug and the other eye. one drop of phenylephrine 1.0% was instilled. This was done in 10 healthy individuals with normal eyes. The difference between combination of Ibopamine and combination of Phenylephrine is 1.33 m.m. with Ibopamine combination achieving larger pupil.

3. Pupillary dilatation achieved after single drop of Ibopamine 2% plus tropicamide 0.2% was better than Ibopamine 2%. The difference in mean pupillary dilation between two was found to be 1.81 m.m. Duration of peak pupillary dilatation increased from about 30 minutes to about 60 minutes.
4. Ibopamine 2% + Tropicamide 0.2% 'was evaluated against tropicamide + phenylephrine containing commercial preparation (Tmide Plus) for evaluation of synergistic effect. The mean difference in papillary diameter achieved by both combination-was 1.33 mm. The effect. of Ibopamine 2% + Tropicamide 0.2% being better than Tmide Plus.
5. Ibopamine 2% + Tropicamide 0.2% was: evaluated against Ibopamine 1% + Tropicamide 0.2% for evaluation of mydiatric effect. The solution containing Ibopamine 2% was found to have significantly better mydriatric effect. The difference in mean papillary size was 1.81. mm.

6. Ibopamine 1% + Tropicamide 0.2% was evaluated against tropicamide + phenylephrine containing commercial, preparation'(Tmide Plus) for evaluation of synergistic effect. The effect on papillary diameter was identical by both combination.
7. Ibopamine 1%,+ Tropicamide 0.2%\yas-evaluated against Ibopamine 1% + Tropicamide 01% for evaluation of mydiatric effect. The solution containing Tropicamide. 0.2% was found to have significantly better mydriatric effect. The difference in mean papillary size was 1.50 mm.
Similarly solutions containing cyclopentolate in place of tropicamide were evaluated. They were also found to have synergestic mydriatric effect.
The addition of another mydiatric agent to ibopamme results in faster onset of papillary dilatation and faster achievement of peak pupillary diameter.
Reducing the concentration of tropicamide to 0.1% maintained synergistic mydriatic effect and achieved peak pupillary size comparable to previous composition having .0.2 % tropicamide. However there is a little increase in time taken to reach peak

pupillary diameter. The mean increase in time for peak pupillary diameter ranged from 3 to 5 minutes compared to combination having tropicamide 0.2% but always less than use of Ibopamine 2% alone by 10 to; 12 minutes. It also resulted in reduction in time taken to achieve normal size. This, time was found to be identical to Ibopamine alone. The onset of significant dilatation was observed within 15-20 minutes, which is significantly better than Ibopamine. Inspite of this mean duration of peak Pupillary dilatation was found to be 68 minutes.
Another synergistic combination of 0.1% tropicamide-1-1.0% Ibopamine was prepared and evaluated for its effect on pupil.
The peak pupillary diameter was found to be little less compared to previous two combinations evaluated but. was more than Ibopamine 2%. Time taken for onset of obvious pupillary dilatation was also more than previous combination and close to what is seen with Ibopamine 2%. However time taken to reach peak pupillary dilatation was close to previous combinations and significantly less than Ibopamine 2%. Duration of peak pupillary dilatation was reduced by about 10 minutes compared to previous combination but was significantly more than Ibopamine. Time taken for pupil to become normal in size was found to be identical to Ibopamine 2% alone or in combination with tropicamide 0.1%.
Thus according to present invention it is possible to provide synergistic mydriatic composition having sub therapeutic dose of parasympatholytic (anti cholinergic drugs) with Ibopamine.
Effect of mydriatric agents on various other parameter. (Time In Minutes)

Sr.No. Parameters Ibopamine2% + Tropicamide0.2% Ibopamine1% + Tropicamide0.2% Tmideplus Tropicamide 1% (Tmide)
1 Onset of effect 19.00 28.00 16.66 16.87
-2 Onset of peak 37.60 51.25 38.33 26.875
3 Duration of Peak Effect 67.00 34.00 >180 >150
4 Time taken by pupil to be normal sized 217 172 >270 >270
5 Amount of Peak effect in mm 4.93 3.25 3.518 2.98
6 Time taken for pupil to be reacting to light 172.72 126.25 >245 >213.3
From above table it is very clear that pharmaceutical composition made as per present invention result in synergestic pharmaceutical composition with a faster onset of action, quicker and better peak papillary size compared to lbopomine but returns to the normal faster compared to other mydriatric .agents like Tmide and Tmide Plus. The reduced time taken to achieve of pupil reacting to light as well as normal size is of significant advantage. However, at' the same time they provide much better mydriasis for a longer period of time compared to Ibopamine.

We claim
1. Process for producing pharmaceutical composition for mydriasis having shorter duration of action and provide better mydriasis comprises steps of a. Dissolving Ibopamine in solvent till completely solubilized. b- .Dissolving physiologically acceptable excipients into solvent till completely solubilized.
c. Mixing solutions of step (a) & (b).
d. Preparing solution of tropicamide.
e. Adding tropicamide solution of d to solution of step (a) so that final
concentration of tropicamide is not more than 0.3% in final
formulation.
f. Optionally lyophilisation of the solution made in step (e).
g. Optionally lyophilisation of solution made in step ( c) & reconstituting
it before use by addition of tropicamide. Solutions made in step (d) so
that concentration of tropicamide does not exceed 0.3% in final
solution.
2. Process as claimed in claimed 1 wherein concentration is Ibopamine is less than 5% in final solution.
3. Process as claimed in claim 1 & 2 wherein concentration of Ibopamine is less than 3% in final solution.
4. Pharmaceutical composition for mydriasis wherein active ingredients are Ibopamine and Tropicamide in a ratio of 30:1 to 3:1 so as to provide synergistic effect on amount of mydriasis without increasing durations of mydriasis.
5. Pharmaceutical composition as claimed in claim 4 wherein Ibopamine and Tropicamide are in a ratio of 20:1 to 10:1.

6. Pharmaceutical composition as claimed in claim 1 to 5 contains physiologically acceptable preservative in appropriate amount.
7. Pharmaceutical composition as claimed above in claim 1 wherein solvent used is water.
8. Pharmaceutical compositions and method of preparation as described in the specification and exemplified by Example J. and II.
Dr. Bakulesh M Khamar Director - Research
Cadila Pharmaceuticals Limited Dated July 9, 2003

l Khamar


ABSTRACT
PHARMACEUTICAL COMPOSITION FOR MYDRIASIS AND PROCESS FOR PRODUCING SAME.
The present invention relates to pharmaceutical composition for mydriasis and process for producing same. The pharmaceutical composition as per present invention provides better mydriasis. The amount of mydtiasis produced is more and inspite of being more the duration.of action is smaller.
According to present invention Combining 'Jbopamine with other parasympatholytic agents like Tropicamide provide synergistic mydriatic composition. However when amount of tropicamide is reduced significantly than also synergistic effect is maintained in difficult .to dilate pigmented people iris like that of Indians. What is also observed is reducing the amount of tropicamide results in decreased duration of action of combination product.
The synergistic mydriatic effect with significantly decreased duration of action is seen ' with combination of-Ibopamine 1 or 2% and tropicamide 0.1% or 0.2%.