Liquid pharmaceutical compositions comprising SGLT-2 inhibitors

Patent metadata

Field	Value
Publication number	US-10709683-B2
Application number	US-201916238346-A
Country	US
Kind code	B2
Filing date	Jan 2, 2019
Priority date	Aug 27, 2015
Publication date	Jul 14, 2020
Grant date	Jul 14, 2020

Abstract

The invention relates to novel liquid pharmaceutical compositions comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the at least one SGLT-2 inhibitor comprises 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene according to formula (I):

as well as corresponding processes of manufacturing such liquid pharmaceutical compositions and their medical uses.

First claim

The invention claimed is:

1. An aqueous liquid pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the one or more polar organic solvents is selected from the group consisting of ethanol, propane-1,2-diol (propylene glycol), propane-1,2,3-triol (glycerol), and mixtures thereof, and the at least one SGLT-2 inhibitor comprises 1-cyano-2-(4-cyclopropyl-benzyl)-4-(μ-D-glucopyranos-1-yl)-benzene according to formula (I):

wherein each of the one or more polar organic solvents is provided in an amount such that the liquid pharmaceutical composition as a whole is characterized by a Log P-Parameter of less than zero and equal to or greater than −2.0.

2. The liquid pharmaceutical composition according to claim 1 , wherein 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene is the only SGLT-2 inhibitor contained in such liquid pharmaceutical composition.

3. The liquid pharmaceutical composition according to claim 1 , wherein said liquid pharmaceutical composition is suitable for direct administration to a mammal.

4. The liquid pharmaceutical composition according to claim 3 , wherein the mammal is a horse, cat or dog.

5. The liquid pharmaceutical composition according to claim 3 , wherein said liquid pharmaceutical composition is sterile.

6. The liquid pharmaceutical composition according to claim 1 , wherein said liquid pharmaceutical composition is a solution, an emulsion or a suspension.

7. The liquid pharmaceutical composition according to claim 1 , wherein the one or more polar organic solvents are independently from each other characterized by a negative log 10 P value.

8. The liquid pharmaceutical composition according to claim 7 , wherein said polar organic solvents are independently of each other characterized by a negative decadic logarithmic partition coefficient (P) in an n-octanol/water system according to formula (II):
log 10 P n-octanol/water =concentration of unionized compound in n -octanol/concentration of unionized compound in water  (II).

9. The liquid pharmaceutical composition according to claim 1 , wherein said liquid pharmaceutical composition does not: (a) comprise ethanol as the one or more polar organic solvents; or (b) comprise only propane-1,2-diol (propylene glycol) as single polar organic solvent.

10. The liquid pharmaceutical composition according to claim 1 , wherein said liquid pharmaceutical composition additionally comprises an aqueous buffer.

11. The liquid pharmaceutical composition according to claim 10 , wherein said liquid pharmaceutical composition has a measured pH value of from 3 to 9.

12. The liquid pharmaceutical composition according to claim 1 , wherein said liquid pharmaceutical composition additionally comprises one or more solubilizing agents, one or more viscosity-enhancing agents, or one or more flavors or sweeteners.

13. The liquid pharmaceutical composition according to claim 12 , wherein said one or more solubilizing agents are selected from the group consisting of: surfactants, anionic surfactants, non-ionic surfactants, hydrogenated castor oils, polyoxyethylene-polyoxypropylene block copolymers, polyethylene glycols, propyleneglycol derivatives and mixtures thereof.

14. The liquid pharmaceutical composition according to claim 13 , wherein said one or more solubilizing agents are selected from the group consisting of: Sodium dodecyl sulphate (SDS), Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil, Macrogol glycerol hydroxystearate 40), polysorbate 20, Lutrol F 68 (Poloxamer 188), PEG 300, propylenglycol monolaurate and mixtures thereof.

15. The liquid pharmaceutical composition according to claim 12 , wherein said one or more viscosity-enhancing agents are selected from the group consisting of: inorganic gel forming agents, organic gel forming agents, cellulose derivatives, and mixtures thereof.

16. The liquid pharmaceutical composition according to claim 15 , wherein said one or more viscosity-enhancing agents are selected from the group consisting of: hydroxyl ethyl cellulose, hydroxyl propyl methyl cellulose, silicon dioxide, and mixtures thereof.

17. The liquid pharmaceutical composition according to claim 12 , wherein said one or more flavors or sweeteners are selected from the group consisting of: honey flavor, lime/salvia flavor, jasmine flavor, lavender flavor, peppermint flavor, raspberry flavor, lemon flavor, herbs flavor, saccharine, aspartame, and mixtures thereof.

18. The liquid pharmaceutical composition according to claim 1 , wherein said liquid pharmaceutical composition does not comprise any apolar organic solvents, which are independently from each other characterized by a log 10 P value of equal to or higher than 0.

19. The liquid pharmaceutical composition according to claim 1 , wherein such liquid pharmaceutical composition is for oral or parenteral administration.

20. The liquid pharmaceutical composition according to claim 1 , comprising:
(i) 0.5-5.0 g/100 mL (% w/w) 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene;
(ii) 10-60 g/100 mL (% w/w) propylene glycol;
(iii) 0-60 g/100 mL (% w/w) glycerol;
(iv) 0-20 g/100 mL (% w/w) ethanol;
(v) 0-1 g/100 mL (% w/w) flavor and/or sweetener;
(vi) 0-52 g/100 mL (% w/w) aqueous buffer;
(vii) 0-10 g/100 mL (% w/w) solubilizing agent; and
(viii) 0-5 g/100 mL (% w/w) viscosity-enhancing agent.

21. An aqueous liquid pharmaceutical composition comprising at least one SGLT-2 inhibitor and one or more polar organic solvents, wherein the one or more polar organic solvents is selected from the group consisting of ethanol, propane-1,2-diol (propylene glycol), propane-1,2,3-triol (glycerol), and mixtures thereof, and the at least one SGLT-2 inhibitor comprises 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene according to formula (I):

wherein each of the one or more polar organic solvents is provided in an amount such that the liquid pharmaceutical composition has a NTU (Nephelometric Turbidity Unit) value of equal to or less than 10.0.

22. The liquid pharmaceutical composition according to claim 21 , wherein the liquid pharmaceutical composition has a NTU (Nephelometric Turbidity Unit) value of less than 3.0.

23. A kit-of-parts comprising:
(a) a liquid pharmaceutical composition according to claim 1 ; and
(b) a package leaflet including the information that the liquid pharmaceutical composition is to be used for the prevention or treatment of one or more medicinal indications in a subject in need of such prevention or treatment, which are selected from among the medicinal indications:
(i) a metabolic disorder of an equine animal, wherein the metabolic disorder is selected from the group consisting of: insulin resistance, hyperinsulinemia, impaired glucose tolerance, dyslipidemia, dysadipokinemia, subclinical inflammation, systemic inflammation, low grade systemic inflammation, obesity, regional adiposity, and mixtures thereof;
(ii) a metabolic disorder of an equine animal, wherein the metabolic disorder is selected from the group consisting of: laminitis, vascular dysfunction, hypertension, hepatic lipidosis, atherosclerosis, hyperadrenocorticism, Pituitary Pars Intermedia Dysfunction, Equine Metabolic Syndrome and

Assignees

• Boehringer Ingelheim Vetmedica Gmbh

Inventors

• Weiler Claudius
• Duch Thomas
• HAASE Marbod
• Priddy Timothy Shane
• STETTLER Heike

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61K31/7034

  attached to a carbocyclic compound, e.g. phloridzin · CPC title

• A61K9/0095

  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 title

• A61K47/10

  Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers · CPC title