PRESERVED ETHERIFIED CYCLODEXTRIN DERIVATIVES CONTAINING LIQUID AQUEOUS PHARMACEUTICAL COMPOSITION

• US 20150025082A1
• Filed: 07/18/2014
• Published: 01/22/2015
• Est. Priority Date: 07/19/2013
• Status: Active Grant

• Current Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Original Assignee: Boehringer Ingelheim Vetmedica GmbH (C.H. Boehringer Sohn AG & Co. KG)
• Inventors: AVEN, Michael, LUKAS, Tim
• Granted Patent: US 10,071,162 B2
• Time in Patent Office: Days
• US Class Current: 514/252.06
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 47/6951 using cyclodextrin cyclodextrins used as simple excipients A61K47/40
• CPC Class Codes: A61K 9/0095 Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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.

Claims

1. A preserved liquid aqueous pharmaceutical composition comprising:

a. one or more etherified cyclodextrin derivatives;

b. 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;

more 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;

or combinations thereof; and

c. at least one pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble, wherein preferably the solubility of the at least one pharmaceutically active compound in water in the range of 15 to 25°

C. is defined as follows;

i. the at least one pharmaceutically active compound is poorly water-soluble if more than 100 mL of water per gram compound have to be used;

it is very poorly water-soluble if more than 1,000 mL of water per gram compound have to be used; and

it is water-insoluble if more than 10,000 mL water per gram compound has to be used to solubilize the compound, and

ii. preferably with the proviso that corticosteroids, in particular prednisolone and its prodrug prednisolone acetate, and fluoroquinolones, in particular ciprofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, lomefloxacin, grepafloxacin, gemifloxacin, norfloxacin, ofloxacin, levofloxacin and trovafloxacin, are independently from each other excluded as pharmaceutically active compound which is poorly water-soluble, very poorly water-soluble or water-insoluble.

2. The liquid pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one water-soluble antioxidant, which is preferably selected from the group consisting of ascorbic acid or pharmaceutically acceptable salts thereof, particularly sodium ascorbate;

citric acid (anhydrous and/or monohydrate) or pharmaceutically acceptable salts thereof, more preferably sodium citrate;

erythorbic acid;

fumaric acid;

malic acid;

monothioglycerol;

phosphoric acid;

sodium metabisulfite;

potassium metabisulfite;

propionic acid;

sodium bisulfite;

sodium sulfite;

resveratrol, butylhydroxyanisol, gallate derivatives, particularly propylgallate, or combinations thereof, most preferably ascorbic acid or pharmaceutically acceptable salts thereof, citric acid (anhydrous and/or monohydrate) or pharmaceutically acceptable salts thereof, sodium metabisulfite, or potassium metabisulfite.

3. The liquid pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one water-soluble polymer, preferably at least one water-soluble polymer and at least one water-soluble antioxidant.

4. The liquid pharmaceutical composition according to claim 1, wherein the one or more etherified cyclodextrin derivatives are selected from the group consisting of:

alpha-, beta-, and gamma-cyclodextrin ethers, preferably etherified β

-cyclodextrin having the chemical formula I

5. The liquid pharmaceutical composition according to claim 1, wherein the one or more etherified cyclodextrin derivative is hydroxyethyl-β

-cyclodextrin, hydroxypropyl-β

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, sulphobutyl ether-β

-cyclodextrin, preferably hydroxypropyl-β

-cyclodextrin.

6. The liquid pharmaceutical composition according to claim 3, 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 as well as combinations or copolymers thereof, preferably hydroxypropyl methylcellulose (hypromellose).

7. The liquid pharmaceutical composition according to claim 1, wherein the at least one pharmaceutically active compound is selected from:

a. benzimidazole derivatives, preferably substituted benzimidazole derivatives, more preferably thiabendazol, fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol, flubendazol, albendazol, oxfendazol, nocodazol, astemisol and pimobendan, pharmaceutically acceptable salts, derivatives, metabolites or pro-drugs thereof, most preferably pimobendan and pharmaceutically acceptable salts thereof;

or

b. oxicam derivatives, preferably substituted oxicam derivatives, more preferably ampiroxicam, droxicam, lornoxicam, piroxicam, tenoxicam and meloxicam, pharmaceutically acceptable salts, derivatives, metabolites or pro-drugs thereof, most preferably meloxicam and pharmaceutically acceptable salts thereof;

or

c. imidazolinone derivatives, preferably substituted imidazolinone derivatives, more preferably 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one (imepitoin), pharmaceutically acceptable salts, derivatives, metabolites or pro-drugs thereof, most preferably 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one (imepitoin) and pharmaceutically acceptable salts thereof;

or

d. glucopyranosyl-substituted benzene derivatives, preferably substituted glucopyranosyl-substituted benzene derivatives, more preferably 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β

-D-glucopyranos-1-yl)-benzene, or any pharmaceutically acceptable form and/or salt thereof, wherein the pharmaceutically acceptable form preferably is a crystalline complex between 1-cyano-2-(4-cyclopropyl-benzyl)-4-(3-D-glucopyranos-1-yl)-benzene and one or more amino acids, preferably wherein the one or more amino acids is proline, more preferably L-proline.

8. The liquid pharmaceutical composition according to claim 1, wherein the composition contains the one or more water-soluble preservatives in the range of from 0.05 g/100 mL to 3.0 g/100 mL, more preferably from 0.10 g/100 mL to 1.0 g/100 mL, most preferably from 0.20 g/100 mL to 0.40 g/100 mL.

9. The liquid pharmaceutical composition according to claim 2, wherein the ratio of water-soluble preservative and antioxidant is from 0.1 to 10, in particular from 0.1 to 1.5, most preferably from 0.2 to 0.8.

10. The liquid pharmaceutical composition according to claim 3, comprising:

a. at least one pharmaceutically active compound in the form of a substituted benzimidazole or a pharmaceutically acceptable salt thereof, preferably thiabendazol, fuberidazol, oxibendazol, parbendazol, cambendazol, mebendazol, fenbendazol, flubendazol, albendazol, oxfendazol, nocodazol, astemisol or pimobendan, or pharmaceutically acceptable salts thereof, more preferably pimobendan or a pharmaceutically acceptable salt thereof;

or in the form of a substituted oxicam or a pharmaceutically acceptable salt thereof, preferably ampiroxicam, droxicam, lornoxicam, piroxicam, tenoxicam and meloxicam, or pharmaceutical acceptable salts thereof, more preferably meloxicam or a pharmaceutically acceptable salt thereof;

or in the form of a substituted imidazolinone or a pharmaceutically acceptable salt thereof, preferably 1-(4-chlorophenyl)-4-(4-morpholinyl)-2,5-dihydro-1H-imidazol-2-one (imepitoin) or a pharmaceutically acceptable salt thereof;

or in the form of a substituted glucopyranosyl-substituted benzene derivative or a pharmaceutically acceptable salt thereof, preferably 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β

-D-glucopyranos-1-yl)-benzene, or any pharmaceutically acceptable form and/or salt thereof, wherein the pharmaceutically acceptable form preferably is a crystalline complex between 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β

-D-glucopyranos-1-yl)-benzene and one or more amino acids, preferably wherein the one or more amino acids is proline, more preferably L-proline;

b. one or more etherified cyclodextrin derivative in the form of an etherified β

-cyclodextrin, preferably hydroxyethyl-β

-cyclodextrin, hydroxypropyl-β

-cyclodextrin, dihydroxypropyl-β

-cyclodextrin, more preferably hydroxypropyl-β

-cyclodextrin (HPβ

CD);

c. one or more water-soluble preservatives, preferably selected from the group consisting of sorbic acid or salts thereof, benzoic acid or salts thereof, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium metabisulfite, sodium acetate;

parabenes and salts thereof, preferably methylparabene, ethylparabene, propylparabene, butylparabene, butylparabene sodium;

or combinations thereof, more preferably selected from the group consisting of sorbic acid or salts thereof, benzoic acid or salts thereof, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, sodium metabisulfite, sodium acetate;

or combinations thereof, most preferably sorbic acid or salts thereof;

d. optionally at least one water-soluble antioxidant, preferably ascorbic acid or a pharmaceutically acceptable salt thereof;

citric acid (anhydrous and/or monohydrate) or a pharmaceutically acceptable salt thereof;

sodium metabisulfite, potassium metabisulfite or resveratrol; and

e. optionally at least one water-soluble polymer with a molar mass of 5,000 to 500,000 g/mol, preferably 10,000 to 300,000 g/mol, even more preferred 15,000 to 200,000 g/mol, even more preferred 20,000 to 200,000 g/mol, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, or methylcellulose, more preferably hydroxypropyl methylcellulose (hypromellose).

11. The liquid pharmaceutical composition according to claim 3, wherein the composition comprises:

a. 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, wherein the pharmaceutically acceptable form preferably is a crystalline complex between 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β

-D-glucopyranos-1-yl)-benzene and one or more amino acids, preferably wherein the one or more amino acids is proline, more preferably L-proline;

b. 20 g/100 mL to 35 g/100 mL of a hydroxypropyl-β

-cyclodextrin;

c. 0.05 g/100 mL to 0.30 g/100 mL of hydroxypropyl methylcellulose (hypromellose);

d. 0.20 g/100 mL to 0.40 g/100 mL of a water-soluble preservative, preferably sorbic acid or a salt thereof; and

e. 0.3 g/100 mL to 1.0 g/100 mL of an antioxidant, preferably ascorbic acid or a salt thereof.

12. The liquid pharmaceutical composition according to claim 1, wherein the pH of the composition is between 2 to 10, preferably 3 to 10, more preferably 3 to 8, more preferably 3 to 7, more preferably 2.5 to 5, even more preferably 3 to 5, even more preferably 3.4 to 5 and most preferably 3.4 to 4.

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

14. The liquid pharmaceutical composition according to claim 1, for use in a method for treating a subject in need of such treatment, preferably an animal, in particular a companion animal, even more preferred horse, dog or cat, guinea pig, hamster, cattle, goat, sheep, in particular cat or dog, selected from among the indications:

heart diseases, particularly a hypertrophic cardiomyopathy, more particularly heart failure (HF), congestive heart failure (CHF), acute CHF, decompensated endocardiosis (DCE), dilated cardiomyopathy (DCM), asymptomatic (occult) CHF, asymptomatic DCM, hypertrophic cardiomyopathy (HCM), restricted cardiomyopathy (RCM), and heart failure due to HCM, RCM, DCM and/or UCM.

15. A process for producing the pharmaceutical composition according to claim 1, comprising the steps:

a. adding at least one pharmaceutically active compound, one or more etherified cyclodextrin derivatives, one or more water-soluble preservatives, optionally one or more antioxidants and optionally at least one water-soluble polymer to water and mixing while stirring; and

b. adjusting the pH value using a pH adjustment agent;

wherein preferably the one or more water-soluble preservatives are added after the addition of the at least one pharmaceutically active compound.

16. A kit of parts comprising:

a. a preserved liquid aqueous pharmaceutical composition according claim 1; and

b. a package leaflet including the information that the pharmaceutical composition is to be used for the prevention and/or treatment of a heart disease, preferably heart failure and/or hypertrophic cardiomyopathy, in a subject in need of such prevention or treatment.