Diphosphonate-derivatized macromolecules

Claim 2

Diphosphonate-derivatized macromolecules of the formula wherein P is a macromolecule selected from the group consisting of proteins, polypeptides, polysaccharides, poly(acrylate), poly(acrylamide), poly(methacrylate), poly(ethacrylate), poly(hydroxyalkylmethacrylate), poly(vinyl alcohol), poly(maleic anhydride), poly(maleate), poly(amide), poly(ethylene amine), poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) and poly(vinyl benzyl chloride); and further contains one or more reactive end groups selected from the group consisting of -NH 2 , -COOH, -SH, CHO, -S-S, -OH, phenol, guanidino, imidazole or indole, and mixtures thereof; L is a linking moiety selected from the group consisting of Q is a spacing group selected from the group consisting of substituted aryl, unsubstituted aryl or C 1 to C 12 alkyl, where n is 0 or 1; and X is selected from the group consisting of H, OH, NH 2 , substituted or unsubstituted amino, halogen or C 1 -C 4 alkyl; and the pharmaceutically-acceptable salts of these derivatized macromolecules.

Claim 3

The diphosphonate derivatized macromolecules according to Claim 1 wherein P is a protein.

Claim 4

The diphosphonate-derivatized macromolecules according to Claim 2 wherein said protein is an antibody or antibody fragment.

Claim 5

The diphosphonate-derivatized macnomolecules according to Claim 2 wherein said linking moiety is selected from the group consisting of

Claim 8

The diphosphonate-derivatized macromolecules according to Claim 4 wherein said spacing group is an unsubstituted aryl.

Claim 9

The diphosphonate-derivatized macromolecules according to Claim 5 wherein X is selected from the group consisting of H, OH or N H 2 .

Claim 10

The diphosphonate-derviatized macromolecules according to Claim 1 selected from the group consisting of wherein n is an integer from 0 to about 12; and X is selected from the group consisting of H, OH and NH 2 .

Claim 11

A radiolabeled chelate wherein the diphosphonate-dervatized macromolecule according to Claim I is complexed with technetium 99-m.

Claim 12

A radiolabeled chelate wherein the diphosphonate-dervatized macromolecule according to Claim 6 is complexed with technetium 99-m.

Claim 13

A radiolabeled chelate wherein the diphosphonate-derivatized macromolecules according to Claim 7 are complexed with technetium 99-m.

Claim 14

A pharmaceutical composition for scintigraphic imaging in humans or animals which comprises a) a safe and effective amount of a diphosphonate derivatized macromolecule having the formula: wherein P is a macromolecule selected from the group consisting of proteins, polypeptides, polysaccharides, poly(acrylate), poly(acrylamide), poly(methacrylate), poly(ethacrylate), poly(hydroxyalkylmethacrylate) , poly(vinyl alcohol), poly(maleic anhydride), poly(maleate) poly(amide), poly(ethylene amine), poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) and poly(vinyl benzyl chloride); and further contains one or more reactive end groups selected from the group consisting of -NH 2 , -COOH, -SH, CHO, -S-S, -OH, phenol, guanidino, imidazole or indole, and mixtures thereof; L is a linking moiety selected from the group consisting of -N=CH-, -NH-CH 2 -, -CH 2 -S-CH 2 , -S-S, Q is a spacing group selected from the group consisting of substituted aryl, unsubstituted aryl or C 1 to C 12 alkyl, where n is 0 or 1; and X is selected from the group consisting of H, OH, NH 2 , substituted or unsubstituted amino, halogen or C1-C4 alkyl; and the pharmaceutically-acceptable salts of these derivatized macromolecules. b) a perchnetate reducing agent; c) a stabilizer compound; d) a pharmaceutically-acceptable carrier.

Claim 15

A pharmaceutical composition for scintigraphic imaging in humans or animals which comprises a) a safe and effective amount of a diphosphonate derivatized macromolecule having the formula: wherein P is a macromolecule selected from the group consisting of proteins, polypeptides, polysaccharides, poly(acrylate), poly(acrylamide), poly(methacrylate), poly(ethacrylate), poly(hydroxyalkylmethacrylate) , poly(vinyl alcohol), poly(maleic anhydride), poly(maleate) poly(amide), poly(ethylene amine), poly(ethylene glycol), poly(propylene glycol), poly(vinyl acetate) and poly(vinyl benzyl chloride); and further contains one or more reactive end groups selected from the group consisting of -NH 2 , -COOH, -SH, CHO, -S-S, -OH, phenol, guanidino, imidazole or indole, and mixtures thereof; L is a linking moiety selected from the group consisting of -N=CH-, -NH-CH 2 -, -CH 2 -S-CH 2 , -S-S, Q is a spacing group selected from the group consisting of substituted aryl, unsubstituted aryl or C 1 to C 12 alkyl, where n is 0 or 1; and X is selected from the group consisting of H, OH, NH 2 , substituted or unsubstituted amino, halogen or C1-C4 alkyl; and the pharmaceutically-acceptable salts of these derivatized macromolecules. b) a perchnetate reducing agent; c) a stabilizer compound; d) a pharmaceutically-acceptable carrier.

Claim 16

A pharmaceutical composition according to Claim 11 in liquid form comprising from about 1% to about 20% of the diphosphonate derivatized macromolecule, from .0001% to about 10% of a perchnetate reducing agent, from about .001% to about 20% of a stabilizer and from about 50% to about 98% of a pharmaceutically-acceptable carrier.

Claim 17

A pharmaceutical composition according to Claim 11 wherein P is a protein.

Claim 18

A pharmaceutical composition according to Claim 13 in liquid form comprising from about 0.01% to about 20% of the diphosphonate-derivatized protein, from about I X 10 -6 % to about 10% of a perchnetate reducing agent, from about 1 X 10 -5 % to about 20% of a stabilizer compound and from about 50% to about 99.9% of a pharmaceutically accepted carrier.

Claim 19

A pharmaceutical composition according to Claim 11 in lyophilized form.

Claim 20

A lyophilized pharmaceutical composition according to Claim 15 comprising from about 5% to about 99% of the diphosphonate-derivatized macromolecule, from about 0.0005% to about 10% of a pertechnetate reducing agent, from about 0.005% to about 20% of a stabilizer and from about 0.01% to about 60% of a pharmaceutically acceptable carrier.

Claim 21

A lyophilized pharmaceutical composition according to Claim 15 wherein P is a protein.

Claim 22

A lyophilized pharmaceutical composition according to Claim 17 comprsing from 1% to about 50% of the diphosphonate-derivatized protein, from about 0.0001% to about 10% of a pertechnetate reducing agent, from about 0.001% to about 20% of a stabilizer and from about 20% to about 98% of a pharmaceutically acceptable carrier.

Claim 23

A method for scintigraphic imaging of tissues in humans or animals which comprises mixing the pharmaceutical composition of Claim 12 with a pertechnetate-99m solution, administering from about 1 ml to about 150 ml of said mixture to said human or animal and subsequently imaging said human or animal with a scintigraphic device capable of detecting the radiation emitted from said mixture.

Claim 24

A method for scintigraphic imaging of tissues in humans or animals which comprises mixing the pharmaceutical composition of Claim 13 with a pertechnetate-99m solution, administering from 1 ml to about 150 ml of said mixture to said human or animal and subsequently imaging said human or animal with a scintigraphic device capable of detecting the radiation emitted from said mixture.

Claim 25

A method for scintigraphic imaging of tissues in humans or animals which comprises mixing the pharmaceutical composition of Claim 18 with a pertechnetate-99m solution, administering from about 1 ml to about 150 ml of said mixture to said human or animal and subsequently imaging said human or animal with a scintigraphic device capable of detecting the radiation emitted from said mixture.