Indian Patents. 272638:PHARMACEUTICAL COMPOSITIONS COMPRISING IBOPAMINE MALEATE AND PROCESS FOR PREPARING THE SAME

Title of Invention	PHARMACEUTICAL COMPOSITIONS COMPRISING IBOPAMINE MALEATE AND PROCESS FOR PREPARING THE SAME
Abstract	Abstract Ibopamine maleate salt (1: 1), method for preparing it and pharmaceutical composition containing it.

Full Text	"Ibopamine maleate, method for preparing it and pharmaceutical compositions containing it" ********************* The present invention relates to the salt ibopamine maieate (1:1), to a method for preparing it and to a pharmaceutical composition for Ophthalmic use containing it. US 4 218 470 describes ibopamine (epinine 3,4-O-diisobutyrate) as a drug that is usefui in the systemic treatment of cardiovascular complaints. EP-A-0 205 606 describes the use of ibopamine and pharmaceutically acceptable acid-addition salts thereof as mydriatics. The pharmaceutically acceptable acid-addition salt specifically illustrated and tested in the said document is the hydrochloride. EP-A- 0 442 958 describes an aqueous pharmaceutical Solution for Ophthalmic use comprising a pharmaceutically acceptable acid-addition saft of ibopamine, in which the said Solution is buffered to pH 4.5 and comprises from 0.1 to 0.5 parts by weight of hydroxypropylmethyl-cellulose per one part by weight of the said ibopamine salt. In this case alsot the pharmaceutically acceptable acid-addition salt specifically illustrated and tested is the hydrochloride. It has now been found that the.maieate shows better local tolerability than the hydrochloride. In a first aspect, the present invention thus relates to ibopamine maieate (1:1). The salt ibopamine maieate (1:1) is readily prepared via known techniques, for instance the addition of maleic acid, dissolved in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a 1:1 molar ratio. The said addition is preferably performed under an atmosphere of an inert gas and at room temperature. The salt thus formed (ibopamine maleate 1:1) is then isolated via known techniques including the precipitation and filtration of the salt or removal of the solvents by evaporation. In one preferred embodiment, the abovementioned organic solvent is acetone,and the salt is precipitated from the acetone Solution via addition of ethyl ether. In a second aspect, the present invention thus relates to a method for preparing ibopamine maleate (1:1), characterized in that it includes the addition of maleic acid, dissolved in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a 1:1 molar ratio. By virtue of its better local tolerability, ibopamine maleate is found to be particularly useful for Ophthalmic use for diagnostic and therapeutic purposes. In a third aspect, the present invention thus relates to a pharmaceutical composition for Ophthalmic use, characterized in that it includes ibopamine maleate (1:1) together with at least one pharmaceutically acceptable vehicle, A typical example of a pathological condition that may find benefit from treatment with a pharmaceutical composition according to the present invention is ocular hypotonia. For diagnostic purposes, the pharmaceutical composition according to the present invention is advantageously used as a mydriatic. Preferably, the pharmaceutical composition according to the present invention will be in the form of an ointment or eyedrops and may also comprise other vehicies that are suitable for Ophthalmie use, for instance ethylene glycol, PEG, carboxymethylcellulose, mannitol, sorbitol, poloxamers, methyleeliulose, hydroxyethylcellulose, hydroxypropylcellulose and the like. This composition may also comprise other conventional ingredients, for instance: preserving agents, stabilizers, Surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, and the like. If required by particular diagnostic or therapeutic uses, the pharmaceuticai composition according to the present invention may comprise other pharmacologically active ingredients whose simultaneous administration is useful, for instance hyaluronic acid. The amount of ibopamine maleate in the pharmaceuticai composition of the present invention may vary within a wide ränge depending on known factors, for instance the particular diagnostic use or the particular type of disease to be treated, the seriousness of the disease and the number of daily administrations. However, a person skilled in the art may easily and routinely determine the Optimum amount. Typically, the amount of ibopamine in the pharmaceuticai composition of the present invention is between 0.01% and 6% by weight and e.ven more preferably between 0.1% and 5% by weight. The dosage forms of the pharmaceuticai composition of the present invention may be prepared according to techniques that are well known to pharmaceuticai chemists, including mixing, dissolution, sterilization and the like. The examples that follow are given to illustrate the present invention without, however, iimiting it. Example 1 Preparation of Ibopamine Maleate Step a) Saturated sodium carbonate Solution was added to a Solution of ibopamine hydrochloride (4 g) in water (10 ml) until no further precipitate was formed. The precipitate was extracted with ethyl ether (50 ml). The organic phase was separated out, dried over sodium sulphate and rapidly filtered through a Büchner funnel. Finally, the ether was removed by evaporation at room temperature and under reduced pressure. The solid residue thus obtained consisted of ibopamine base (3 g). Step b) A Solution of maleic acid (674 mg; 0.005 mol) in acetone (5 ml) was added, under an inert atmosphere and without heating, at room temperature, to a Solution of ibopamine base (1.78 g; 0.005 mol) in acetone (10 ml). The Solution was left under stirring at room temperature (20 minutes). Ethyl ether was then added dropwise to the formation of opalescence, and stirring was continued until precipitation was complete (30 minutes from the Start of the opalescence). The solid was collected by filtration and washed with ethyl ether. The desired product (1 g) was thus obtained. m.p. = 107-108°C Elemental Analysis ForC21H29N1O8 C H N Calculated 59.56 6.90 3.31 Found 59.53 6.92 3.27 Test1 Ocular Tolerability Two aqueous soiutions were used. The first contained 2% by weight of ibopamine hydrochloride (corresponding to 1.79% by weight of ibopamine) buffered to pH 7.0. The second contained 2.46% by weight of ibopamine maleate (corresponding to 1.79% by weight of ibopamine) buffered to pH 7.0. 12 male rabbits (New Zealand White) with an average weight of 2 kg and an average age of ten months were used, divided into two groups of six rabbits each. The first group was treated with 0.1 ml of the first test Solution three times a day for fifteen days. The second group was treated with 0.1 ml of the second test Solution three times a day for fifteen days. The tolerability was evaluated according to J. Draize et a/., Pharmacol Exp. Ther., 83, 377-390 (1944). The results are shown in Table 1 below. CLAIMS 1. Ibopamine maleate salt (1:1). 2. Pharmaceutical composition for Ophthalmic use, characterized in that it comprises ibopamine maleate (1:1) together with at least one pharmaceutically acceptable vehicle. 3. Pharmaceutical composition according to Claim 2, characterized in that it is in the form of an ointment or eyedrops. 4. Pharmaceutical composition aecording to Claim 2 or 3, characterized in that the amount of ibopamine is between 0.01% and 6% by weight 5. Pharmaceutical composition aecording to Claim 2 or 3, characterized in that the amount of ibopamine is between 0.1% and 5% by weight. 6. Process for preparing the ibopamine maleate salt (1:1), characterized in that it includes the addition of maleic aeid, dissoived in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a 1:1 molar ratio. 7. Process aecording to Claim 6, characterized in that the abovementioned addition is performed under an atmosphere of an inert gas. 8. Process aecording to Claim 6 or 7, characterized in that the abovementioned addition is performed at room temperature. 9. Process aecording to any one of the preceding Claims 6 to 8, characterized in that the salt formed is isolated via preeipitation and filtration. 10. Process aecording to any one of the preceding Claims 6 to 9, characterized in that the abovementioned organic solvent is acetone. 1i. Process aecording to Claim 10, characterized in that the salt is

Full Text

"Ibopamine maleate, method for preparing it and pharmaceutical
compositions containing it" *********************
The present invention relates to the salt ibopamine maieate (1:1), to a method for preparing it and to a pharmaceutical composition for Ophthalmic use containing it.
US 4 218 470 describes ibopamine (epinine 3,4-O-diisobutyrate) as a drug that is usefui in the systemic treatment of cardiovascular complaints.
EP-A-0 205 606 describes the use of ibopamine and pharmaceutically acceptable acid-addition salts thereof as mydriatics. The pharmaceutically acceptable acid-addition salt specifically illustrated and tested in the said document is the hydrochloride.
EP-A- 0 442 958 describes an aqueous pharmaceutical Solution for Ophthalmic use comprising a pharmaceutically acceptable acid-addition saft of ibopamine, in which the said Solution is buffered to pH 4.5 and comprises from 0.1 to 0.5 parts by weight of hydroxypropylmethyl-cellulose per one part by weight of the said ibopamine salt. In this case alsot the pharmaceutically acceptable acid-addition salt specifically illustrated and tested is the hydrochloride.
It has now been found that the.maieate shows better local tolerability than the hydrochloride.
In a first aspect, the present invention thus relates to ibopamine maieate (1:1).
The salt ibopamine maieate (1:1) is readily prepared via known techniques, for instance the addition of maleic acid, dissolved in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a 1:1 molar ratio.
The said addition is preferably performed under an atmosphere of an inert gas and at room temperature.

The salt thus formed (ibopamine maleate 1:1) is then isolated via known techniques including the precipitation and filtration of the salt or removal of the solvents by evaporation.
In one preferred embodiment, the abovementioned organic solvent is acetone,and the salt is precipitated from the acetone Solution via addition of ethyl ether.
In a second aspect, the present invention thus relates to a method for preparing ibopamine maleate (1:1), characterized in that it includes the addition of maleic acid, dissolved in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a 1:1 molar ratio.
By virtue of its better local tolerability, ibopamine maleate is found to be particularly useful for Ophthalmic use for diagnostic and therapeutic purposes.
In a third aspect, the present invention thus relates to a pharmaceutical composition for Ophthalmic use, characterized in that it includes ibopamine maleate (1:1) together with at least one pharmaceutically acceptable vehicle,
A typical example of a pathological condition that may find benefit from treatment with a pharmaceutical composition according to the present invention is ocular hypotonia.
For diagnostic purposes, the pharmaceutical composition according to the present invention is advantageously used as a mydriatic.
Preferably, the pharmaceutical composition according to the present invention will be in the form of an ointment or eyedrops and may also comprise other vehicies that are suitable for Ophthalmie use, for instance ethylene glycol, PEG, carboxymethylcellulose, mannitol, sorbitol, poloxamers, methyleeliulose, hydroxyethylcellulose, hydroxypropylcellulose and the like.

This composition may also comprise other conventional ingredients, for instance: preserving agents, stabilizers, Surfactants, buffers, salts for regulating osmotic pressure, emulsifiers, and the like.
If required by particular diagnostic or therapeutic uses, the pharmaceuticai composition according to the present invention may comprise other pharmacologically active ingredients whose simultaneous administration is useful, for instance hyaluronic acid.
The amount of ibopamine maleate in the pharmaceuticai composition of the present invention may vary within a wide ränge depending on known factors, for instance the particular diagnostic use or the particular type of disease to be treated, the seriousness of the disease and the number of daily administrations. However, a person skilled in the art may easily and routinely determine the Optimum amount.
Typically, the amount of ibopamine in the pharmaceuticai composition of the present invention is between 0.01% and 6% by weight and e.ven more preferably between 0.1% and 5% by weight.
The dosage forms of the pharmaceuticai composition of the present invention may be prepared according to techniques that are well known to pharmaceuticai chemists, including mixing, dissolution, sterilization and the like.
The examples that follow are given to illustrate the present invention without, however, iimiting it.
Example 1 Preparation of Ibopamine Maleate Step a)
Saturated sodium carbonate Solution was added to a Solution of ibopamine hydrochloride (4 g) in water (10 ml) until no further precipitate was formed.
The precipitate was extracted with ethyl ether (50 ml). The organic phase was separated out, dried over sodium sulphate and rapidly

filtered through a Büchner funnel. Finally, the ether was removed by evaporation at room temperature and under reduced pressure.
The solid residue thus obtained consisted of ibopamine base (3 g). Step b)
A Solution of maleic acid (674 mg; 0.005 mol) in acetone (5 ml) was added, under an inert atmosphere and without heating, at room temperature, to a Solution of ibopamine base (1.78 g; 0.005 mol) in acetone (10 ml).
The Solution was left under stirring at room temperature (20 minutes). Ethyl ether was then added dropwise to the formation of opalescence, and stirring was continued until precipitation was complete (30 minutes from the Start of the opalescence).
The solid was collected by filtration and washed with ethyl ether. The
desired product (1 g) was thus obtained.
m.p. = 107-108°C
Elemental Analysis
ForC21H29N1O8 C H N
Calculated 59.56 6.90 3.31
Found 59.53 6.92 3.27
Test1
Ocular Tolerability Two aqueous soiutions were used.
The first contained 2% by weight of ibopamine hydrochloride (corresponding to 1.79% by weight of ibopamine) buffered to pH 7.0.
The second contained 2.46% by weight of ibopamine maleate (corresponding to 1.79% by weight of ibopamine) buffered to pH 7.0.
12 male rabbits (New Zealand White) with an average weight of 2 kg and an average age of ten months were used, divided into two groups of six rabbits each. The first group was treated with 0.1 ml of the first

test Solution three times a day for fifteen days. The second group was treated with 0.1 ml of the second test Solution three times a day for fifteen days.
The tolerability was evaluated according to J. Draize et a/., Pharmacol Exp. Ther., 83, 377-390 (1944). The results are shown in Table 1 below.

CLAIMS
1. Ibopamine maleate salt (1:1).
2. Pharmaceutical composition for Ophthalmic use, characterized in that it comprises ibopamine maleate (1:1) together with at least one pharmaceutically acceptable vehicle.
3. Pharmaceutical composition according to Claim 2, characterized in
that it is in the form of an ointment or eyedrops.
4. Pharmaceutical composition aecording to Claim 2 or 3,
characterized in that the amount of ibopamine is between 0.01%
and 6% by weight
5. Pharmaceutical composition aecording to Claim 2 or 3, characterized in that the amount of ibopamine is between 0.1% and 5% by weight.
6. Process for preparing the ibopamine maleate salt (1:1), characterized in that it includes the addition of maleic aeid, dissoived in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a 1:1 molar ratio.
7. Process aecording to Claim 6, characterized in that the
abovementioned addition is performed under an atmosphere of an
inert gas.
8. Process aecording to Claim 6 or 7, characterized in that the
abovementioned addition is performed at room temperature.
9. Process aecording to any one of the preceding Claims 6 to 8,
characterized in that the salt formed is isolated via preeipitation and
filtration.
10. Process aecording to any one of the preceding Claims 6 to 9,
characterized in that the abovementioned organic solvent is
acetone.
1i. Process aecording to Claim 10, characterized in that the salt is

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Patent Number

272638

Indian Patent Application Number

3140/CHENP/2006

PG Journal Number

17/2016

Publication Date

22-Apr-2016

Grant Date

13-Apr-2016

Date of Filing

30-Aug-2006

Name of Patentee

AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.P.A.

Applicant Address

Viale Amelia, 70, I-00181 Roma

Inventors:

#	Inventor's Name	Inventor's Address
1	PINZA, Mario	Via per Cesano Boscone, 24, I-20094 Corsico
2	MAUGERI, Caterina	Via Valseriana, 4, I-00141 Roma
3	CAZZOLLA, Nicola	Via Abetonia, 20/L, I-00041 Albano Laziale

PCT International Classification Number

C07C219/28,57/145,51/41,A61K31/222

PCT International Application Number

PCT/EP2005/000445

PCT International Filing date

2005-01-13

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	MI2004A000146	2004-01-30	Italy