MXPA06008531A - Ibopamine maleate, method for preparing it and pharmaceutical compositions containing it - Google Patents
Ibopamine maleate, method for preparing it and pharmaceutical compositions containing itInfo
- Publication number
- MXPA06008531A MXPA06008531A MXPA/A/2006/008531A MXPA06008531A MXPA06008531A MX PA06008531 A MXPA06008531 A MX PA06008531A MX PA06008531 A MXPA06008531 A MX PA06008531A MX PA06008531 A MXPA06008531 A MX PA06008531A
- Authority
- MX
- Mexico
- Prior art keywords
- ibopamine
- pharmaceutical composition
- maleate
- process according
- salt
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 16
- 229960004370 ibopamine Drugs 0.000 title claims description 28
- WDKXLLJDNUBYCY-UHFFFAOYSA-N Ibopamine Chemical compound CNCCC1=CC=C(OC(=O)C(C)C)C(OC(=O)C(C)C)=C1 WDKXLLJDNUBYCY-UHFFFAOYSA-N 0.000 title claims description 27
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 title claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000007792 addition Methods 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 5
- -1 Ibopamine maleate salt Chemical class 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000011976 maleic acid Substances 0.000 claims description 4
- 239000012298 atmosphere Substances 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- 229940012356 Eye Drops Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000003889 eye drop Substances 0.000 claims description 2
- 239000011261 inert gas Substances 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 description 4
- 231100000730 tolerability Toxicity 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 230000001105 regulatory Effects 0.000 description 3
- 229960001216 Ibopamine hydrochloride Drugs 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- ALIXRWKJZYLBJI-UHFFFAOYSA-N [4-[2-(methylamino)ethyl]-2-(2-methylpropanoyloxy)phenyl] 2-methylpropanoate;hydrochloride Chemical compound Cl.CNCCC1=CC=C(OC(=O)C(C)C)C(OC(=O)C(C)C)=C1 ALIXRWKJZYLBJI-UHFFFAOYSA-N 0.000 description 2
- 230000035492 administration Effects 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 230000002911 mydriatic Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 230000001225 therapeutic Effects 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000007379 Muscle Hypotonia Diseases 0.000 description 1
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002637 mydriatic agent Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 230000001575 pathological Effects 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- MAKUBRYLFHZREJ-JWBQXVCJSA-M sodium;(2S,3S,4R,5R,6R)-3-[(2S,3R,5S,6R)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylate Chemical compound [Na+].CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@H](O)[C@H]1O MAKUBRYLFHZREJ-JWBQXVCJSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
1), method for preparing it and pharmaceutical composition containing it.
Description
MALEATE OF IBOPAMINE, METHOD FOR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT
The present invention relates to salt ibopamine maleate (1: 1), to a method for its preparation and to the pharmaceutical composition for ophthalmic use containing it. EU 4 218 470 describes ibopamine (epinin 3,4-O-diisobutyrate) as a drug that is useful in the systemic treatment of cardiovascular affectations. EP-A-0 205 606 discloses the use of ibopamine and pharmaceutically acceptable acid addition salts thereof as mydriatics. The pharmaceutically acceptable acid addition salt specifically illustrated and examined in said document is the hydrochloride. EP-A-0 442 958 discloses an aqueous pharmaceutical solution for ophthalmic use comprising a pharmaceutically acceptable acid addition salt of ibopamine, wherein said solution is adjusted to pH 4.5 and comprises from 0.1 to 0.5 parts by weight of hydroxypropylmethyl. cellulose per part by weight of said ibopamine salt. Also in this case, the pharmaceutically acceptable acid addition salt, specifically illustrated and examined is the hydrochloride. It has now been found that the maleate shows a better local tolerability than the hydrochloride. In a first aspect, the present invention thus relates to ibopamine maleate (1: 1). The salt ibopamine maleate (1: 1) is easily prepared by known techniques, for example, the addition of maleic acid, dissolved in a suitable organic solvent, to ibopamine base, also dissolved in a suitable organic solvent, in a molar ratio of 1: 1. Said addition is preferably carried out under an atmosphere of an inert gas and at room temperature. The salt thus formed (ibopamine maleate 1: 1) is then isolated by known techniques including precipitation and filtration of the salt or removal of the solvents by evaporation. In a preferred embodiment, the above-mentioned organic solvent is acetone and the salt is precipitated from the acetone solution through the addition of ethyl ether. In a second aspect, the present invention thus relates to a method for the preparation of ibopamine maleate (1: 1), characterized in that it includes the addition of maleic acid, dissolved in a suitable organic solvent, based on ibopamine, also dissolved in a suitable organic solvent, in a molar ratio of 1: 1. 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 carrier. 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 eye drops and may also comprise other vehicles which are suitable for ophthalmic use, for example, ethylene glycol, PEG, carboxymethylcellulose, mannitol, sorbitol, poloxamers, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like. This composition may also comprise other conventional ingredients, for example: preservation agents, stabilizers, surfactants, regulators, salts for regulating the osmotic pressure, emulsifiers and the like. If required by particular diagnostic or therapeutic uses, the pharmaceutical composition according to the present invention may comprise other pharmacologically active ingredients whose simultaneous administration is useful, for example, hyaluronic acid. The amount of ibopamine maleate in the pharmaceutical composition of the present invention can vary within a wide range, depending on known factors, for example, the particular diagnostic use or the type of disease to be treated in particular, the seriousness of the disease and the number of daily administrations. However, a person skilled in the art will easily and routinely determine the optimum amount. Typically, the amount of ibopamine in the pharmaceutical composition of the present invention is between 0.01% and 6% by weight and even more preferably between 0.1% and 5% by weight. The dosage forms of the pharmaceutical composition of the present invention can be prepared according to techniques that are well known to pharmaceutical chemists, including, mixing, dissolving, sterilizing and the like. The following examples give in order to illustrate the present invention, however, without limiting it.
Example 1 Preparation of Ibopamine Maleate Step a) The saturated sodium carbonate solution was added to a solution of ibopamine hydrochloride (4 g) in water (10 ml) until no more precipitate formed. The precipitate was extracted with ethyl ether (50 ml). The organic phase was separated, dried over sodium sulfate and filtered rapidly and filtered through a Büchner tunnel. 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). The ethyl ether was then added dropwise to the opalescence formation and stirring was continued until precipitation was complete (30 minutes from the onset of opalescence). The solid was collected by filtration and rinsed with ethyl ether. The desired product (1 g) was thus obtained. m.p. = 107-108 ° C Elemental Analysis for Czi HzgNiOß C H N Calculated 59.56 6.90 3.31 Found 59.53 6.92 3.27
Test 1 Ocular Tolerability Two aqueous solutions were used.
The first contained 2% by weight of ibopamine hydrochloride (corresponding to 1.79% by weight of ibopamine) regulated at pH 7.0. The second contained 2.46% by weight of ibopamine maleate (corresponding to 1.79% by weight of ibopamine) regulated at pH 7.0. We used 12 male rabbits (New Zealand White) with an average weight of 2 kg and an average age of ten months, were 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. Tolerability was evaluated according to J. Draize et al. , Pharmacol. Exp. Ther. , 83, 377-390 (1944). The results are shown in Table 1 below. Table 1
Claims (10)
- 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 carrier.
- 3. Pharmaceutical composition according to claim 2, characterized in that it is in the form of an ointment or eye drops.
- 4. Pharmaceutical composition according to claim 2 or 3, characterized in that the amount of ibopamine is between 0.01% and 6% by weight.
- 5. Pharmaceutical composition according to claim 2 or 3, characterized in that the amount of ibopamine is between 0.1% and 5% by weight.
- 6. Process for the preparation of the ibopamine maleate salt (1: 1), characterized in that it includes the addition of maleic acid, dissolved in a suitable organic solvent, based on ibopamine, also dissolved in a suitable organic solvent, in a molar ratio of 1 .1.
- Process according to claim 6, characterized in that the aforementioned addition is carried out under an atmosphere of an inert gas.
- Process according to claim 6 or 7, characterized in that the aforementioned addition is carried out at room temperature.
- 9. Process according to any of the preceding claims 6 to 8, characterized in that the formed salt is isolated through precipitation and filtration. Process according to any of the preceding claims 6 to 9, characterized in that the organic solvent mentioned above is acetone. eleven . Process according to claim 10, characterized in that the salt is precipitated from the acetone solution through the addition of ethyl ether.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MIMI2004A000146 | 2004-01-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06008531A true MXPA06008531A (en) | 2007-04-20 |
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