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1. WO1986003970 - COMPOSITIONS PHARMACEUTIQUES ET LEUR UTILISATION COMME AGENTS MYDRIATIQUES

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"Pharmaceutical compositions and their use as mydriatics"
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This invention relates to new pharmaceutical compositions and their use in ophthalmology.
More particularly this invention relates to new pharmaceutical compositions comprising ibopamine or a pharmaceutically acceptable addition salt thereof, and to their use as mydriatics.
Ibopamine (epinine 3,4-0-diisobutyrate) is a drug useful for systemic use in cardiovascular therapy (U. S. patent No. 4,218,470).
Now it has been found that ibopamine administered locally shows a considerable mydriatic effect and thus has different ophthal ological applications both in diagnosis, for examination of the fundus and refraction, and in ophthalmic surgery when it is desired to antagonize intraoperative myosis.
Although the use of sympathomimetic amines as mydriatics is conceptually a potentially beneficial alternative to the use of anticholinergic agents the only sympathomimetic agent finding limited use as a mydriatic is phenylephrine.
Phenylephrine has a moderate action and is not free of drawbacks because of systemic effects shown at the high concentrations (from 10 to 36%) which must be used to obtain the desired effect. Also the other available sympathomimetic drugs, particu-larly adrenaline are not free from drawbacks concerning local tolerability and the risk of systemic effects.
Surprisingly ibopamine has proven to be well suited as a mydriatic agent.
Ibopamine exhibits a strong mydriatic effect which is associated to an excellent pharmacodynamic profile characterized by rapid onset and subsequent rapid exhaustion of the effect with considerable benefit for the patient.
Along with this favourable profile of effectiveness it shows a very good local tolerability and absence of systemic side effects.
With respect to the atropine-like compounds which are the drugs most commonly used as mydriatics ibopamine has the advantage of producing a rapid onset of the effect which lasts just for a period of time consistent with the needs of the oph-thalmological examination and is more rapidly exhausted. This behaviour is very favourable in ophthalmic diagnosis allowing rapid recovery of normal visual functions of the patient.
The mydriatic effect of the compounds was evaluated on male New Zealand rabbits weighing 2.5-3 kg in accordance with the following method.
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The animals were placed in retention cages in a room lit with artificial light.
The diameter of the pupil was measured with a gauge (to 1/10 mm) and with the aid of a magnifying glass (1.5 diameters).
The compounds were dissolved in physiological solution and instilled in a 0.1 ml volume in the conjunctival sac of one eye while the contra-lateral eye was treated with an equal volume of physiological solution.
In the control animals physiological solution was instilled in both eyes.
The mydriatic effect of ibopamine was tested in comparison with adrenaline, adrenaline diisobutyrate and dipivalate, epinine and epinine dipivalate (U. S. Patent No. 4,218,470 mentioned above) (Table 1).
Local tolerability and systemic effects in the rabbit, more particularly pressor effects (Table 1) were also investigated. Table 1. Effect on the rabbit after conjuctival instillation.

Substance Concentration Tolerability Blood
(conjunctival pressure
irritation and vari at.i-on3
relative
concentration
[mM]2) ( mHg)

Epinine HCl 100 - (100) - 7

Epinine 3,4-0-diiso-butyrate hydrochloride 6.2 - (100) - 7 Epinine 3,4-0-dipivalate
hydrochloride 6.2 + (50) not tested dl-Adrenaline HCl 6.2 - (50) + 48 dl-Adrenaline 3,4-0-di-isobutyrate HCl 12.5 - (50) + 40 dl-Adrenaline 3,4-0-di-pivalate hydrochloride 3.1 (50) + 35

1 Concentrations causing an increase in pupil diameter of comparable degree (approximately 1mm). 2 + present; - absent. 3 Instillation of 0.1 ml of 0.5M solution.
The results shown in Table 1 prove that ibopamine is endowed with high mydriatic effect, with good local tolerability and absence of side effects.
Epinine proved to exhibit slight mydriatic effect while adrenaline proved to be effective experimentally but it is well-known that its clinical use is riskful because of systemic effects, which are evident also from the blood pressure increase which occured in the experimental animal.
Epinine dipivalate proved to be as effective as ibopamine but was irritating at nearly mydriatic concentrations.
Similarly, adrenaline dipivalate showed poor separation between the active dose and the dose which induce irritation and systemic effects while adrenaline diisobutyrate proved less active than adrenaline as a mydriatic agent although it showed significant systemic effects.
As a matter of fact, adrenaline dipivalate (dipivefrine) is used clinically only in low doses in the therapy of glaucoma. Ibopamine therefore possesses to a surprising degree charac-teristics of effectiveness, absence of undesired systemic effects, and excellent local tolerability, characteristics not possessed simultaneously by epinine and by other catecholamiπes or their derivatives.
Additional experiments to confirm the safety of ibopamine compared with (+)-adrenaline, (+)-adrenaline dipivalate and phenylephrine were performed by intravenous administration in the anesthetized rabbit. The three reference drugs induced hypertension in the following order of strength: (+)-adrenaline> phenylephrine>(+)adrenaline dipivalate. Ibopamine did not induce hypertension but a moderate reduction of blood pressure. The results are given in Table 2.
Table 2. Effect on blood pressure and on heart rate in rabbit.
Dose/kg iv Number of Variation in
animals mean blood
pressure

Compound μ mol m + E.S.

Ibopamine HCl 3.4 0.01 3 -10 +7.5
6.8 0.02 3 - -14 +6.4
13.6 0.04 3 -13 +6.4
27.2 0.0 3 -18 +2.2 54.4 0.16 3 -12 +4.1
108.8 0.32 2 -17 +7.8

dl-Adrenaline HCl 1.8 0.01- 5 22 +3.8
3.6 0.02 5 32 +4.6
7.2 0.04 3 49 ±3.5
14.4 0.08 3 65 +9.3
28.8 0.16 2 100 +4.5

dl-Adrenaline 3,4-0- 3.8 0.01 2 0 dipivalate HCl 7.6 0.02 3 1 +4.8
15.2 0.04 3 7 +7.2
30.4 0.08 3 6 +2.4
60.8 0.16 2 30 +4.5

Phenylephrine HCl 2.3 0.01 1 5
4.6 0.02 2 14 +3.5
9.2 0.04 3 18 +3.0
18.4 0.08 3 23 +2.7
36.8 0.16 3 30 +3.1
73.6 0.32 3 48 +4.2

In case of ibopamine, the absence of side effects was confirmed by clinical tests in humans in which maximal mydriasis was observed by instilling 1-2 drops of 2% collyrium. Mydriasis begins in 15-30 minutes and recedes after approximately 1 hour.

Blood pressure and heart rate are unchanged.
In case of phenylephrine increases in blood pressure were observed in particular in children (Barromeo MacGrail et al, Ocular Therapeutics, 1980, 119).
Ibopamine and the pharmaceutically acceptable acid addition salts thereof, preferably hydrochloride, may be formulated in suitable pharmaceutical preparations.
Suitable pharmaceutical forms are those normally used in ophthalmology such as collyria and ointments.
Said preparations comprise an effective amount of ibopamine or a salt thereof together with pharmaceutically acceptable diluents, preservatives, buffers, stabilizing agent and the like.
The amount of ibopamine or of a salt thereof may range from 0.01 to 10% (w/v) and preferably from 0.1 to 5%.
The collyrium may be preformed or instantly prepared by dilution of a suitable solid or liquid pharmaceutical form.
In preparing these pharmaceutical forms the skilled in the art will pay due attention to those conditions of concentration, pH and ionic strength which ensure at the same time adequate stability and optimal tolerability and allow transcorneal absorption of the drug.
It has been found that these optimal requirements are met for example by a formulation of ibopamine hydrochloride in crystal-lized or lyophilized sterile powder, optionally in combination with suitable excipients such as maπnitol and poly-vinylpyrrolidone; the preparation is dissolved before use in water or in a sterile saline solution, for example of sodium chloride, or in a sterile buffer solution suitable to obtain a pH between 4 and 6. The amount of ibopamine hydrochloride and the concentration of the saline and buffer solutions are balanced in such a manner as to obtain solutions having ionic concentrations suitable for the purposes of stability and absorption; ibopamine hydrochloride concentration ranges between 0.5 and 5%. The solutions may contain a suitable preservative such as benzalkonium chloride, an antioxidant such as ascorbic acid or sodium metabisulphite or a sequestrating agent such as ethyleπdiaminetetracetic acid and its salts.
To better illustrate this invention the following examples a re given.
Example 1
A solution having the following composition (for 1ml) is formed at the time of use:-a) Crystallized ibopamine HCl
sterile powder 20.00mg
b) Sterile solution of:- citric acid moπohydrate 5.72mg
disodium phosphate . 12 H O 16.27mg
benzalkonium chloride 0.10mg
sodium chloride 1.00mg
in distilled water (q.s. to 1 ml)
The ingredients are filled into a suitable container of from 1 to 10 ml capacity fitted with a dropper.
Example 2
A solution having the following composition (for 1 ml) is formed at time of use:-a) Sterile lyophilized mixture of:- ibopa ine HCl 10.0mg
mannitol 20.0mg
b) Sterile solution of:
benzalkonium chloride 0.1mg
in distilled water (q.s. to 1 ml)
The ingredients are filled into a suitable container of from 1 to 10ml capacity fitted with a dropper.