Liquid pharmaceutical compositions comprising SGLT-2 inhibitors

Patent metadata

Field	Value
Publication number	US-10220017-B2
Application number	US-201615245448-A
Country	US
Kind code	B2
Filing date	Aug 24, 2016
Priority date	Aug 27, 2015
Publication date	Mar 5, 2019
Grant date	Mar 5, 2019

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

wherein the two or more polar organic solvents are provided in amounts such that the liquid pharmaceutical composition as a whole is characterized by a LogP-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 additionally comprises water or an aqueous buffer.

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

5. 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.

6. The liquid pharmaceutical composition according to claim 5 , 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, propylenglycol derivatives and mixtures thereof.

7. The liquid pharmaceutical composition according to claim 6 , 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.

8. The liquid pharmaceutical composition according to claim 5 , 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.

9. The liquid pharmaceutical composition according to claim 8 , 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.

10. The liquid pharmaceutical composition according to claim 5 , 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.

11. 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.

12. The liquid pharmaceutical composition according to claim 1 , wherein the 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).

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

14. The liquid pharmaceutical composition according to claim 13 , wherein the mammal is a horse, cat or dog.

15. The liquid pharmaceutical composition according to claim 13 , wherein said liquid pharmaceutical composition is sterile.

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

17. The liquid pharmaceutical composition according to claim 16 , wherein said solution, an emulsion or a suspension has an NTU value of equal to or less than 10.0.

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

19. The liquid pharmaceutical composition according to claim 1 , wherein the composition further comprises:
(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.

20. A liquid pharmaceutical composition selected from the group consisting of the following compositions 1 to 7:

Composition 1
Composition 2
Composition 3
Composition 4
Composition 5
Composition 6
Composition 7

Ingredient
[% (w/w)]
[% (w/w)]
[% (w/w)]
[% (w/w)]
[% (w/w)]
[% (w/w)]
[% (w/w)]

1-cyano-
1.5
1.5
1.5
1.5
1.5
1.5
1.0

2-(4-

cyclopropyl-

benzyl)-4-

(β-D-

glucopyranos-

1-yl)

Assignees

• Boehringer Ingelheim Vetmedica Gmbh

Inventors

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

Classifications

• A61P9/12

  Antihypertensives · 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

• A61P5/48

  of the pancreatic hormones · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P29/00

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