Preserved etherified cyclodextrin derivatives containing liquid aqueous pharmaceutical composition

Patent metadata

Field	Value
Publication number	US-10071162-B2
Application number	US-201414335080-A
Country	US
Kind code	B2
Filing date	Jul 18, 2014
Priority date	Jul 19, 2013
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present invention is directed to a preserved liquid aqueous pharmaceutical composition comprising one or more etherified cyclodextrin derivatives; one or more water-soluble preservatives; preferably selected from the group consisting of sorbic acid or salts thereof, preferably sodium sorbate, potassium sorbate, calcium sorbate; benzoic acid or salts thereof, preferably sodium benzoate; benzalkonium chloride; benzethonium chloride; cetylpyridinium chloride; sodium metabisulfite; sodium acetate; parabenes and salts thereof, preferably methylparabene, ethylparabene, propylparabene, butylparabene, butylparabene sodium; or combinations thereof; and at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble. The liquid aqueous pharmaceutical composition provides an acceptable solubility of the pharmaceutically active compound, such as pimobendan, in aqueous solution whereby the water-soluble preservatives retain their effectiveness in the presence of the etherified cyclodextrin derivatives allowing the use in an oral administration form.

First claim

What is claimed is:

1. A preserved liquid aqueous pharmaceutical composition comprising:
one or more etherified cyclodextrin derivatives in an amount of 5 g/ml to 40 g/ml;
one or more water-soluble preservatives in an amount of 0.1 g/ml to 1.0 g/ml, wherein the one or more water-soluble preservatives is sorbic acid or a salt thereof or sorbic acid or a salt thereof in combination with one or more selected from the group consisting of benzoic acid or a salt thereof, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium metabisulfite, sodium acetate, and a parabene or a salt thereof;
at least one water-soluble antioxidant in an amount of 0.05 g/ml to 1.0 g/ml, the at least one water-soluble antioxidant being ascorbic acid or a pharmaceutically acceptable salt thereof or ascorbic acid or a pharmaceutically acceptable salt thereof in combination with one or more selected from the group consisting of citric acid (anhydrous and/or monohydrate) or a pharmaceutically acceptable salt thereof, erythorbic acid, fumaric acid, malic acid, monothioglycerol, phosphoric acid, sodium metabisulfite, potassium metabisulfite, propionic acid, sodium bisulfate, sodium sulfite, resveratrol, butylhydroxyanisol, and a gallate derivative;
at least one water soluble-polymer in an amount of 0.01 g/ml to 0.75 g/ml; and
at least one pharmaceutically active compound in an amount of 0.01 g/ml to 1.0 g/ml, the at least one pharmaceutically active compound selected from:
a benzimidazole derivative; or
an oxicam derivative; or
an imidazolinone derivative; or, or
a glucopyranosyl-substituted benzene derivative.

2. The liquid pharmaceutical composition according to claim 1 , wherein the at least one water-soluble antioxidant is selected from the group consisting of sodium ascorbate, sodium citrate, propylgallate, and any one or more combinations thereof.

3. The liquid pharmaceutical composition according to claim 1 , wherein the one or more etherified cyclodextrin derivatives comprise etherified β-cyclodextrin having the chemical formula I

in which the residues R are independently from each other hydroxyalkyl groups.

4. The liquid pharmaceutical composition according to claim 1 , wherein the one or more etherified cyclodextrin derivatives comprise hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cycldextrin, dihydroxypropyl-β-cyclodextrin, or sulphobutyl ether-β-cyclodextrin.

5. The liquid pharmaceutical composition according to claim 1 , wherein the at least one water-soluble polymer is selected from hydroxypropyl methylcellulose (hypromellose, HPMC), hydroxypropyl cellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, ethylcellulose, methylcellulose, polyvinylpyrrolidone, polyvinylacetate and combinations or copolymers thereof.

6. The liquid pharmaceutical composition according to claim 1 , wherein the composition contains the one or more water-soluble preservatives in the range from 0.20 g/100 mL to 0.40 g/100 mL.

7. The liquid pharmaceutical composition according to claim 2 , wherein the ratio of water-soluble preservative and antioxidant is from 0.1 to 1.5.

8. The liquid pharmaceutical composition according to claim 1 , wherein:
the at least one pharmaceutically active compound is in the form of:
a substituted benzimidazole selected from the group consisting of thiabendazol, fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol, flubendazol, albendazol, oxfendazol, nocodazol, astemisol, pimobendan, and pharmaceutically acceptable salts thereof; or
a substituted oxicam selected from the group consisting of ampiroxicam, droxicam, lornoxicam, piroxicam, tenoxicam, meloxicam, and pharmaceutical acceptable salts thereof; or
a substituted glucopyranosyl-substituted benzene derivative selected from the group consisting of 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene or any pharmaceutically acceptable form and/or salt thereof, and a crystalline complex between 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene and one or more amino acids;

the one or more etherified cyclodextrin derivatives comprise an etherified β-cycldextrin selected from the group consisting of hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and dihydroxypropyl-β-cyclodextrin;
the composition further comprises sodium metabisulfite, potassium metabisulfite or resveratrol; and
the at least one water-soluble polymer has a molar mass of 5,000 to 500,000 g/mol.

9. The liquid pharmaceutical composition according to claim 1 , wherein the composition comprises:
0.1 g/100 mL to 0.25 g/100 mL pimobendan or a pharmaceutically acceptable salt thereof; or meloxicam or a pharmaceutically acceptable salt thereof; or 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one (imepitoin) or a pharmaceutically acceptable salt thereof; or 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene, or any pharmaceutically acceptable form and/or salt thereof;
20 g/100 mL to 35 g/100 mL of a hydroxypropyl-β-cyclodextrin;
0.05 g/100 mL to 0.30 g/100 mL of hydroxypropyl methylcellulose (hypromellose);
0.20 g/100 mL to 0.40 g/100 mL of the water-soluble preservative; and
0.3 g/100 mL to 1.0 g/100 mL of the antioxidant.

10. The liquid pharmaceutical composition according to claim 1 , wherein the pH of the composition is between 2 to 10.

11. The liquid pharmaceutical composition according to claim 1 , wherein the composition is for oral and/or parenteral administration.

12. A kit of parts comprising:
a preserved liquid aqueous pharmaceutical composition according claim 1 ; and
a package leaflet including the information that the pharmaceutical composition is to be used for the prevention and/or treatment of heart failure and/or hypertrophic cardiomyopathy, in a subject in need of such prevention or treatment.

13. The liquid pharmaceutical composition according to claim 1 , wherein each water-soluble preservative is selected from the group consisting of sodium sorbate, potassium sorbate, calcium sorbate, sodium benzoate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium metabisulfite, sodium acetate, methylparabene, ethylparabene, propylparabene, butylparabene, butylparabene sodium, and any one or more combinations thereof.

14. The liquid pharmaceutical composition according to claim 1 , wherein the ratio of water-soluble preservative to antioxidant is from 0.2 to 0.8.

15. The liquid pharmaceutical composition according to claim 14 , wherein the liquid pharmaceutical composition has a pH from 2.5 to 4.5.

16. A preserved liquid aqueous pharmaceutical composition comprising:
one or more etherified cyclodextrin derivatives in an amount of 5 g/ml to 40 g/ml;
one or more water-soluble preservatives in an amount of 0.1 g/ml to 1.0 g/ml, wherein the one or more water-soluble preservatives is sorbic acid or a salt thereof or sorbic acid or a salt thereof in combination with one or more selected from the group consisting of benzoic acid or a salt thereof, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium metabisulfite, sodium acetate, and a parabene or a salt thereof;
at least one water-soluble antioxidant in an amount of 0.05 g/ml to 1.0 g/ml, the at least one water-soluble antioxidant being ascorbic acid or a pharmaceutically acceptable salt thereof or ascorbic acid or a pharmaceutically acceptable salt thereof in combination with one or more selected from the group c

Assignees

• Aven Michael
• Lukas Tim
• Boehringer Ingelheim Vetmedica Gmbh

Inventors

• Aven Michael
• Lukas Tim

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P3/08

  for glucose homeostasis (pancreatic hormones A61P5/48) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title