The Procter Gamble Company

Norwich Eaton Pharmaceuticals, Inc.

Intermedics Orthopedics/denver, Inc.

Other

Mallinckrodt, Inc.

Procter & Gample Pharmaceuticals, Inc.

James J Benedict

James W Poser

Richard J Sunberg

Karen Y Johnson

Frank Hallock Ebetino

Charles Raymond Degenhardt

Christopher Mark Perkins

Rodney D Bush

Joseph E Bugaj

Mahdi B Fawzi

Barry F Van Duzee

Christopher J Damien

Pharmaceutical compositions, useful for treating abnormal calcium and phosphate metabolism, which contain geminal-diphosphonic acid compounds; and a method of treating diseases characterized by abnormal calcium and phosphate metabolism utilizing these pharmaceutical compositions.

Pharmaceutical compositions containing geminal diphosphonates

Disclosed is a product which includes calcium carbonate and bone growth factor useful for the promotion of bone formation when implanted in the body. The calcium carbonate is preferably in the form of aragonite which can be recovered from naturally occurring coral. A preferred bone growth factor of the present invention is a protein mixture purified from bone. Also disclosed is a process for the induction of bone formation which includes implanting the product in a body. The product and process of the present invention are particularly useful in hip replacement operations, knee replacement operations, spinal fusion operations, repair of periodontal defects, treatment of osteoporosis, repair of bone tumor defects and repair of bone fractures.

Osteogenic product and process

The present invention relates to novel heterocycle-substituted diphosphonic acids, and the pharmaceutically-acceptable salts and esters thereof, in which the diphosphonate-substituted carbon atom moiety is attached to a carbon atom in a nitrogen-containing six membered ring heterocycle, preferably a piperidine ring. The heterocycle-substituted diphosphonic acid compounds have the general structure: ##STR1## wherein Z is a nitrogen-containing six membered ring heterocycle moiety selected from piperidinyl, diazinyl and triazinyl; m, n and m+n are from 0 to 10; Q is a covalent bond or a moiety selected from oxygen, sulfur or nitrogen; and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are substituent groups. The present invention further relates to pharmaceutical compositions containing these novel compounds. Finally this invention relates to methods for treating or preventing diseases characterized by abnormal calcium and phosphate metabolism by utilizing a compound or pharmaceutical composition of the present invention.

Heterocycle-substituted diphosphonate compounds, pharmaceutical

A method for purifying bone-derived osteoinductive factors including an ultrafiltration process, an anion exchange process, a cation exchange process, and a reverse phase HPLC process. The ultrafiltration process preferably includes a first ultrafiltration step using a membrane having a nominal molecular weight cutoff of approximately 100 kilodaltons (kD) and a second ultrafiltration step employing a membrane having a nominal molecular weight cutoff of approximately 10 kD. For the anion exchange process, a strongly cationic resin is used, preferably having quaternary amine functional groups. Typically, the eluant for the anion exchange process has a conductivity from about 10,260 micromhos (.mu.mhos) (1.026.times.10.sup.-2 siemens (S)) to about 11,200 .mu.mhos (1.120.times.10.sup.31 2 S). For the cation exchange process, a strongly anionic resin is used, preferably having sulfonic acid functional groups. The eluant for the cation exchange process typically has a conductivity from about 39,100 .mu.mhos (3.91.times.10.sup.-2 S) to about 82,700 .mu.mhos (8.27.times.10.sup.-2 S) or more. The HPLC process typically utilizes a column containing hydrocarbon-modified silica packing material. The osteoinductive proteins can be eluted from the HPLC column with an acetonitrile solution in combination with aqueous trifluoracetic acid. The purification processes yield osteoinductively active protein mixtures.

Osteoinductive protein mixtures and purification processes

A method for purifying bone-derived osteoinductive factors including an ultrafiltration process, an anion exchange process, a cation exchange process, and a reverse phase HPLC process. The ultrafiltration process preferably includes a first ultrafiltration step using a membrane having a nominal molecular weight cutoff of approximately 100 kilodaltons (kD) and a second ultrafiltration step employing a membrane having a nominal molecular weight cutoff of approximately 10 kD. For the anion exchange process, a strongly cationic resin is used, preferably having quaternary amine functional groups. Typically, the eluant for the anion exchange process has a conductivity from about 10,260 micromhos (.mu.mhos) (1.026.times.10.sup.-2 siemens (S)) to about 11,200 .mu.mhos (1.120.times.10.sup.-2 S). For the cation exchange process, a strongly anionic resin is used, preferably having sulfonic acid functional groups. The eluant for the cation exchange process typically has a conductivity from about 39,100 .mu.mhos (3.91.times.10.sup.-2 S) to about 82,700 .mu.mhos (8.27.times.10.sup.-2 S) or more. The HPLC process typically utilizes a column containing hydrocarbon-modified silica packing material. The osteoinductive proteins can be eluted from the HPLC column with an acetonitrile solution in combination with aqueous trifluoracetic acid. The purification processes yield osteoinductively active protein mixtures.

This invention relates to pyrindine-diphosphonic acid derivatives which are useful in treating or preventing diseases characterized by abnormal calcium and phosphate matabolism, in particular those which are characterized by abnormal bone metabolism. This invention further relates to pharmaceutical compositions which contain the novel compounds of the present invention, and to a method of treating or preventing diseases characterized by abnormal calcium and phosphate metabolism utilizing a compound of the present invention.

Certain bicycloalkane and azabicycloalkane-1,1-diphosphonic acid

Certain heterocyclic substituted diphosphonate compounds pharmaceutical

The present invention relates to oral compositions, such as dentifrices, toothpastes and mouthwashes, which provide an anticalculus benefit. These compositions comprise a safe and effective amount of an anticalculus agent which is a polyepoxysuccinic acid, or its pharmaceutically-acceptable salts, along with a pharmaceutically-acceptable carrier. The present invention also relates to a method for inhibiting or reducing the development of dental calculus by contacting the oral cavity with a safe and effective amount of an anticalculus agent which is a polyepoxysuccinic acid, or its pharmaceutically-acceptable salt.

Oral compositions and method for reducing dental calculus

Diphosphonate-derivatized macromolecules, such as proteins, suitable for use as technetium-99m-based scanning agents and as anticalcification agents are disclosed. The scanning agents are prepared by combining Tc-99m in a +3, +4 and/or +5 oxidation state with the diphosphonate-derivatized macromoleules. Also disclosed are pharmaceutical compositions containing these diphosphonate-derivatized macromolecules and methods for scintigraphic imaging using these diphosphonate-derivatized macromolecules labeled with Tc-99m.

Diphosphonate-derivatized macromolecules

Novel cyclic geminal-diphosphonic acid compounds, and pharmaceutical compositions containing these compounds, which are useful for treating diseases characterized by abnormal calcium and phosphate metabolism; and a method of treating diseases characterized by abnormal calcium and phosphate metabolism utilizing these novel cyclic diphosphonic acid compounds.

Certain cycloalkane-1,1-diphosphonic acids and derivatives thereof

Methods of treating non-inflammatory diseases characterized by abnormal calcium and phosphate metabolism comprising administering a pharmaceutical composition comprising a geminal diphosphonic acid compound in which the diphosphonic acid-containing carbon is linker via a sulfur atom or a sulfur-containing chain to a 6-membered aromatic ring containing one or more nitrogen atoms.

Methods of treating diseases with certain geminal diphosphonates

The present invention relates to oral compositions, such as dentrifices, toothpastes and mounthwashes, which provide an anticalculus benefit. These compositions comprise a safe and effective amount of an anticalculus agent which is a polyepoxysuccinic acid, or its pharmaceutically-acceptable salts, along with a pharmaceutically-acceptable carrier. The present invention also relates to a method for inhibiting or reducing the development of dental calculus by contacting the oral cavity with a safe and effective amount of an anticalculus agent which is a polyepoxysuccinic acid, or its pharmaceutically-acceptable salt.

Oral compositions and methods for reducing dental calculus

Diphosphonate-derivatized macromolecules, such as proteins, suitable for use as technetium-99m-based scanning agents and as anticalcification agents are disclosed. The scanning agents are prepared by combining Tc-99m in a +3, +4 and/or +5 oxidation state with the diphosphonate-derivatized macromolecules. Also disclosed are pharmaceutical compositions containing these diphosphonate-derivatized macromolecules and methods for scintigraphic imaging using these diphosphonate-derivatized macromolecules labeled with Tc-99m.

Novel cyclic geminal-diphosphonic acid compounds, and pharmaceutical compositions containing these compounds, which are useful for treating diseases characterized by abnormal calcium and phosphate metabolism; and a method of treating diseases characterized by abnormal calcium and phosphate metabolism utilizing these noval cyclic diphosphonic acid compounds.

Growing community of inventors

Golden, CO, United States of America

James J Benedict