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Liquid formulations of rupatadine fumarate

A liquid technology of rupatadine fumarate, which is applied in the direction of medical preparations containing non-active ingredients, medical preparations containing active ingredients, dispersion liquid delivery, etc. It can solve stability problems and is not suitable for use as drugs, etc. question

Inactive Publication Date: 2013-05-15
J·乌里亚奇·Y股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although aqueous liquid pharmaceutical compositions are disclosed in EP0577957 and ES2087818, the inventors have found that the solubility of rupatadine fumarate in water is 2.9 g / L (see Reference Example 1), so the prior art preparations have the Stability issues due to supersaturation of hepatadine free base or rupatadine fumarate and unsuitable for use as a drug

Method used

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  • Liquid formulations of rupatadine fumarate
  • Liquid formulations of rupatadine fumarate
  • Liquid formulations of rupatadine fumarate

Examples

Experimental program
Comparison scheme
Effect test

example 2

[0168] Reference Example 2: Formation Rate of Compound II in Rupatadine Fumarate Aqueous Solution

[0169] It has been found that rupatadine reacts with fumaric acid under acidic conditions to produce an adduct (compound II):

[0170]

[0171] Different aqueous solutions of different pH (3.41, 4.38 and 5.00) containing rupatadine fumarate at a concentration of 1 g (rupatadine fumarate) / L (the required amount of HCl (适量) or NaOH (适量) The solution was added to a solution containing only water and rupatadine fumarate) stored under different temperature conditions (room temperature and 40°C / 75%HR) for two months and at the beginning, one month and the end of the period , use method 2 analysis, as shown in the table below.

[0172]

[0173] These results show that the rate of formation of compound II is pH dependent. The lower the pH, the higher the rate of compound II formation.

example 3

[0174] Reference Example 3: Preparation of Compound II

[0175]

[0176] In a 1000 mL flask, 35 g (0.084 mol) of rupatadine (I) was dissolved in 260 mL of ethanol. To this solution was added 16.1 g (0.087 mol) of bromosuccinic acid, and the mixture was reacted at room temperature overnight. The mixture was concentrated to half volume and allowed to react at room temperature for 5 days.

[0177] The solvent was removed in vacuo and the solid was washed with ethanol and with a mixture of ethanol:water:ammonia. It was then purified by flash chromatography using a 9:1:1 ethanol:ammonia:water mixture.

[0178] Finally, 4.51 g (0.0085 mol, 9.7% yield) of the desired product (compound II) were obtained.

[0179] 1 H-NMR (300MHz, CD 3 OD): 8.71(broad peak signal, 2H), 8.31(m, 2H), 7.63(d, J=7.31Hz, 1H), 7.18(m, 4H), 5.48(dd, J=3.29Hz, J=11.70 Hz,1H),3.69(s,2H),3.41(m,3H),3.11(dd,J=11.7Hz,J=17.2Hz,1H),2.8(m,4H),2.54(s,3H), 2.45(m,2H),2.26(m,4H).

[0180] 13 C-NMR (75.43MH...

Embodiment 1

[0186] Embodiment 1: Preparation of nasal liquid formulation of rupatadine fumarate (1.00g (rupatadine) / L)

[0187] The quantitative composition of this formulation is disclosed in the table below.

[0188] Rupatadine fumarate was dissolved in polyethylene glycol 400. This is the "active solution".

[0189] Dissolve anhydrous citric acid and anhydrous disodium phosphate in pure water and stir until completely dissolved. This is the "carrier solution".

[0190] Mix and homogenize the "active solution" with the "carrier solution". Add preservatives to the final solution. Finally, pure water was added to the resulting mixture to the desired volume.

[0191]

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Abstract

The present invention provides cyclodextrin-free aqueous liquid formulations of rupatadine fumarate, useful for the treatment of allergic rhinitis and urticaria. Said formulations comprise rupatadine fumarate, one or more cosolvents and one or more pH regulating agents wherein the composition has a pH between 4 and 6.5.

Description

technical field [0001] The present invention relates to a cyclodextrin-free aqueous liquid preparation of rupatadine fumarate. Background technique [0002] Rupatadine (I) is an approved antihistamine and the IUPAC (International Union of Pure and Applied Chemistry) name for its free base is 8-chloro-6,11-dihydro-11-[1- [(5-Methyl-3-pyridyl)methyl]-4-hexahydropyridinyl]-5H-benzo[5,6]cyclohepta[1,2-b]pyridine, CAS (Chemical Abstracts of America Service Agency) number 158876-82-5 and has the following chemical formula: [0003] [0004] Rupatadine is currently marketed as 10 mg (rupatadine) tablets of rupatadine fumarate (CAS 182349-12-8 fumarate) for the treatment of allergic rhinitis and urticaria in adults and adolescents. measles. [0005] Rupatadine free base was first disclosed in EP0577957. [0006] Spanish patent application ES2087818 discloses monofumaric acid of rupatadine (ie, rupatadine fumarate) and an aqueous liquid pharmaceutical composition of rupatadine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4545A61K9/00A61K9/08A61K47/10G01N30/02A61P11/02A61P11/04A61P37/08
CPCA61K9/006A61K31/4545A61K9/0095A61P11/00A61P11/02A61P11/04A61P17/04A61P27/14A61P37/00A61P37/08
Inventor M·索雷欧·费勒S·莫尔里森·卡普德维拉
Owner J·乌里亚奇·Y股份有限公司
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