Parenteral bisphosphonate composition with improved local tolerance

• US 20010011082A1
• Filed: 01/11/2001
• Published: 08/02/2001
• Est. Priority Date: 01/20/2000
• Status: Active Grant

• Current Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Diederich, Anke, Goldbach, Pierre, Pfister, Thomas
• Granted Patent: US 6,677,320 B2
• Time in Patent Office: Days
• US Class Current: 514/89
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents

Abstract

The present invention relates to a parenteral composition comprising a bisphosphonic acid or a pharmaceutically acceptable salt thereof (bisphosphonate) as active component and a pharmaceutically acceptable chelating agent, processes of the preparation of this composition, and methods of their use in the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget'"'"'s disease, hypercalcemia of malignancy, and metabolic bone disease. The compositions are especially useful for improving the local tolerance of the active component when administered parenterally.

Claims

1. A parenteral composition comprising a bisphosphonate and a pharmaceutically acceptable chelating agent.

2. The composition according to

claim 1

, wherein the bisphosphonate is a compound selected from the group consisting of

a) N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid,

b) 4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bis-phosphonic acid,

c) 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate),

d) 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid),

e) [3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate] (ibandronate),

f) 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisposphonic acid,

g) 1-hydroxy-2-[3-pyridinyl]ethylidene-1,1-bisphosphonic acid (risedronate),

h) 4-(hyroxymethylene-1,1-bisphosphonic acid)piperidine,

i) cycloheptylaminomethylene-1,1-bisposphonic acid (cimadronate),

j) 1,1-dichloromethylene-1,1-diphosphonic acid and the dissodium salt (clodronate),

k) 1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid (EB-1053),

l) 1-hydroxyethane-1,1-diphosphonic acid (etidronic acid),

m) 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate),

n) 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid (olpadronate),

o) [2-(2-pyridinyl) ethylidene]-1,1-bisphosphonic acid (piridronate),

p) (4-chlorophenyl)thiomethane-1,1-diphosponic acid (tiludronate), and/or

q) 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid (zolendronate).

r) [(cycloheptylamino)-methylene]-bisphosphonic acid (icadronate), and/or

s) [1-hydroxy-2imidazo-(1,2-a) pyridin-3-ylethylidene]-bisphosphonic acid

and pharmaceutically acceptable salts thereof.

3. The composition according to

claim 1

wherein the bisphosphonate is selected from the group consisting of cimadronate, clodronate, tiludronate, etidronate, ibandronate, risedronate, piridronate, pamidronate, zolendronate and pharmaceutically acceptable salts thereof.

4. The composition according to

claim 1

wherein the bisphosphonate is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid (ibandronic acid) or a pharmaceutically acceptable salt thereof.

5. The composition according to

claim 4

wherein the bisphosphonate is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate.

6. The composition according to

claim 1

wherein the pharmaceutically acceptable chelating agent or a pharmaceutically acceptable salt thereof is a compound, which forms via two or more of its functional groups ring-shaped complexes with metal cations.

7. The composition according to

claim 6

wherein the chelating agent is a pharmaceutically acceptable polyacetic acid or a pharmaceutically acceptable salt thereof.

8. The composition according to

claim 1

wherein the pharmaceutically chelating agent is selected from the group consisting of EDTA, DTPA, EGTA, HEDTA, NTA, triethanolamine, 8-hydroxyquinoline, citric acid, tartaric acid, phosphoric acid, gluconic acid, saccharic acid, thiodipropionic acid, acetonic dicarboxylic acid, lecithin, di(hydroxyethyl)glycine, phenylalanine, tryptophan, glycerin, sorbitol and pharmaceutically acceptable salts thereof.

9. The composition according to

claim 8

wherein the chelating agent is selected from the group consisting of EDTA, DTPA, citric acid, tartaric acid, phosphoric acid, gluconic acid or a pharmaceutically acceptable salt thereof.

10. The composition according to

claim 9

wherein the pharmaceutically chelating agent is EDTA and DTPA or a pharmaceutically acceptable salt thereof.

11. The composition according to

claim 1

wherein the molar ratio between the bisphosphonate and the pharmaceutically acceptable chelating agent is about 1:

0.01 to about 1;

500.

12. The composition according to

claim 11

wherein the molar ratio between the bisphosphonate and the pharmaceutically acceptable chelating agent is about 1:

0.1 to about 1;

50.

13. The composition according to

claim 12

wherein the molar ratio between the bisphosphonate and the pharmaceutically acceptable chelating agent is about 1:

10.

14. The composition according to

claim 1

wherein the composition further comprises one or more additional pharmaceutically acceptable chelating agent(s).

15. The composition according to

claim 1

, further comprising a pharmaceutically acceptable excipient.

16. The composition according to

claim 15

wherein the excipients are selected from diluents, solvents and/or preservatives.

17. The composition according to

claim 1

comprising a bisphosphonate or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable chelating agent, a tonicity agent, a pH adjusting agent, and a solvent.

18. The composition according to

claim 17

further comprising a local anaesthetic.

19. The composition according to

claim 17

wherein the pH is in the range of 2-10.

20. The composition according to

claim 19

wherein the pH is in the range of 4-9.

21. The composition according to

claim 20

wherein the pH is in the range of 6-8.

22. The composition according to

claim 21

wherein the pH is in the range of 7-8.

23. The composition according to

claim 22

wherein the pH is about 7.4.

24. The composition according to

claim 1

being a parenteral composition comprising

a) 0.1-10 mg 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate and

b) 0.5-50 mg EDTA, Na₂, 2H₂O.

25. The composition according to

claim 24

comprising

a) 0.1-10 mg 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate;

b) 0.5-50 mg EDTA, Na₂, 2H₂O;

c) about 9.0 mg sodium chloride,

d) sodium hydroxide q.s. to about pH 7.4 and

e) water for injection q.s. to 0.5 or 1.0 ml.

26. The composition according to

claim 25

comprising about 1.125 mg 0.1-10 mg 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate, about 10 mg EDTA, Na₂, 2H₂O, about 9.0 mg sodium chloride, sodium hydroxide q.s. to pH 7.4 and water for injection q.s. to 1.0 ml.

27. The composition according to

claim 24

comprising about 1.125 mg 0.1-10 mg 3-(N-methyl-N-pentyl) amino-1-hydroxypropane-1,1-bisphosphonic acid, monosodium salt, monohydrate, about 10 mg EDTA, Na₂, 2H₂O, about 5.78 mg lidocaine hydrochloride, about 9.0 mg sodium chloride, sodium hydroxide q.s. to pH 7.4 and water for injection q.s. to 1.0 ml.

28. A method for the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget'"'"'s disease, hypercalcemia of malignancy, and metabolic bone disease comprising the step of administering to a patient a composition as claimed in

claim 1

.