Dry mix formulation for bisphosphonic acids

• US 5,681,590 A
• Filed: 07/26/1995
• Issued: 10/28/1997
• Est. Priority Date: 12/02/1992
• Status: Expired due to Fees

• Current Assignee: Merck & Co., Inc.
• Original Assignee: Merck & Co., Inc.
• Inventors: Katdare, Ashok V., Kramer, Kenneth A., Bechard, Simon R.
• Primary Examiner(s): Hulina, Amy
• Application Number:
  US08/454,100
• Time in Patent Office: 825 Days
• Field of Search: 424/464, 424/465
• US Class Current: 424/464
• 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 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/04 for urolithiasis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• 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 9/00 Drugs for disorders of the cardiovascular system

Abstract

Pharmaceutical compositions of bisphosphonic acids, and salts thereof, are prepared by direct compression/dry mix tablet formulation. These pharmaceutical compositions are useful in the treatment of disturbances involving calcium or phosphate metabolism, in particular, the treatment and prevention of diseases involving bone resorption, especially osteoporosis, Paget'"'"'s disease, malignant hypercalcemia, and metastatic bone disease.

Claims

1. A process for the preparation of a tablet containing an active ingredient selected from:

4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

N-methyl-4-amino-1-hydroxybutylidene-1,1-bis-phosphonic acid;

4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;

1-hydroxy-2- 3-pyridyl!ethylidene-1,1-bisphosphonic acid;

4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine;

or a pharmaceutically acceptable salts thereof;

which process comprises;

forming a mixture by mixing the active ingredient with;

a diluent, selected from;

anhydrous lactose and hydrous fast

flow lactose,

a dry binder,

a disintegrant,

and optionally one or more additional ingredients selected

from the group consisting of;

compression aids, flavors,

flavor enhancers, sweeteners and preservatives;

lubricating the mixture with a lubricant; and

compressing the resultant lubricated mixture into a desired

tablet form.

2. The process of claim 1 wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

3. The process of claim 1 wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.

4. The process of claim 1 wherein the dry binder is microcrystalline cellulose.

5. The process of claim 1 wherein the disintegrant is selected from the group consisting of modified starch, modified cellulose polymer, and croscarmallose sodium, and a combination thereof.

6. The process of claim 1 wherein the disintegrant is croscarmallose sodium.

7. The process of claim 1 wherein the lubricant is magnesium stearate.

8. A solid dosage form containing an active ingredient selected from the group consisting of:

4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;

1-hydroxy-2- 3-pyridyl!ethylidene-1,1-bisphosphonic acid; and

4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine;

or a pharmaceutically acceptable salt thereof;

wherein the dosage form is prepared by the process of claim 1.

17. A solid dosage form containing as active ingredient a basic nitrogen containing bisphosphonate wherein the dosage form is prepared by the process of claim 1.

9. A pharmaceutical composition comprising by weight, about 0.5 to 40% by weight of an active ingredient selected from the group consisting of:

4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bis-phosphonic acid;

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;

1-hydroxy-2- 3-pyridyl!ethylidene-1,1-bisphosphonic acid; and

4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine;

or a pharmaceutically acceptable salt thereof;

and from about 60 to 99.5% by weight of excipients consisting essentially of;

hydrous fast flow lactose;

microcrystalline cellulose;

croscarmallose sodium; and

magnesium stearate.

10. A pharmaceutical composition comprising by weight, about 0.5 to 40% by weight of an active ingredient selected from the group consisting of:

4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

N-methyl-4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid;

4-(N,N-dimethylamino)-1-hydroxybutylidene-1,1-bisphosphonic acid;

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid;

3-(N,N-dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid;

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid;

1-hydroxy-2- 3-pyridyl!ethylidene-1,1-bisphosphonic acid; and

4-(hydroxymethylene-1,1-bisphosphonic acid)piperidine;

or a pharmaceutically acceptable salt thereof;

about 10 to 80% by weight of hydrous fast flow lactose;

about 5 to 50% by weight of microcrystalline cellulose;

about 0.5 to 10% by weight of croscarmallose sodium; and

about 0.1 to 5% by weight of magnesium stearate.

11. The pharmaceutical composition of claim 10 comprising about 0.5 to 25% by weight of the active ingredient, about 30% to 70% by weight of hydrous fast flow lactose;

about 30 to 50% by weight of microcrystalline cellulose;

about 0.5 to 5% by weight of croscarmallose sodium; and

about 0.1 to 2% by weight of magnesium stearate.

12. The pharmaceutical composition of claim 10 wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

13. The pharmaceutical composition of claim 10 wherein the active ingredient is 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium salt trihydrate.

14. A tablet prepared from the pharmaceutical composition of claim 13.

15. A tablet prepared from the pharmaceutical composition of claim 10.

16. A process for the preparation of a table containing as active ingredient a basic nitrogen containing bisphosphonate:

which process comprises;

forming a mixture by mixing the active ingredient with;

a diluent, selected from;

anhydrous lactose or hydrous fast flow lactose,

a dry binder,

a disintegrant,

and optionally one or more additional ingredients selected

from the group consisting of;

compression aids, flavors,

flavor enhancers, sweeteners and preservatives;

lubricating the mixture with a lubricant; and

compressing the resultant lubricated mixture into a desired tablet form.