Claims for Patent: 5,306,482

Summary for Patent: 5,306,482

Title:	Radiopharmaceutical bacteriostats
Abstract:	Benzalkonium chloride and benzethorium chloride are each useful in radiopharmaceutical preparations (optionally in the presence of a polymyxin or a polymyxin derivative) as bacteriostatic agents which are compatible with anti-oxidants.
Inventor(s):	Tartaglia; Daniel (Anjou, CA), Flanagan; Richard J. (St. Lazare, CA)
Assignee:	Merck Frosst Canada, Inc. (Montreal, CA)
Application Number:	07/841,281
Patent Claims:	1. A radiopharmaceutical composition comprising: (a) a .sup.99m Tc-based radiopharmaceutical; (b) a water-soluble pertechnetate reducing agent; (c) a radical-scavenging antioxidant; and (d) a first bacteriostat selected from: (i) benzalkonium chloride, and (ii) benzethonium chloride; (e) a second bacteriostat selected from: (i) a polymyxin selected from the group consisting of: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof; and (ii) an N-methanesulfonate derivative of a polymyxin wherein the polymyxin is selected from the group consisting of: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof. 2. The radiopharmaceutical composition of claim 1 wherein the first bacteriostat (d) is benzalkonium chloride. 3. The radiopharmaceutical composition of claim 1 wherein the first bacteriostat (d) is benzethonium chloride. 4. The radiopharmaceutical composition according to claim 1, wherein the first bacteriostat (d) is present in a concentration from about 0.00001% to about 0.01% (w/v) and the second bacteriostat (e) is present in a concentration from about 0.00001% to about 0.01% (w/v). 5. The radiopharmaceutical composition according to claim 4, wherein the first bacteriostat (d) is present in a concentration from about 0.00005% to about 0.001% (w/v) and the second bacteriostat (e) is present in a concentration from about 0.00005% to about 0.001% (w/v). 6. The radiopharmaceutical composition according to claim 5, wherein the first bacteriostat (d) is present in a concentration from about 0.0001% to about 0.0005% (w/v) and the second bacteriostat (e) is present in a concentration from about 0.0001% to about 0.0005% (w/v). 7. The radiopharmaceutical composition of claim 2 wherein the water-soluble pertechnetate reducing agent is stannous chloride. 8. The radiopharmaceutical composition of claim 1 wherein the radical-scavenging antioxidant is selected from the group consisting of: para-aminobenzoic acid; gentisic acid; and ascorbic acid. 9. The radiopharmaceutical composition of claim 7 wherein the radical-scavenging antioxidant is para-aminobenzoic acid. 10. The radiopharmaceutical compostion of claim 1 wherein the .sup.99m Tc-based radiopharmaceutical is selected from the group consisting of: .sup.99m Tc-methylene-disphosphonic acid; .sup.99m Tc-hydroxymethylene-diphosphonic acid; .sup.99m Tc-ethane-1-hydroxy-1,1-diphosphonic acid; .sup.99m Tc-1-hydroxypropane-1,1-diphosphonic acid; .sup.99m Tc-2,3-dicarboxypropane-1,1-diphosphonic acid; .sup.99m Tc-pyrophosphate; .sup.99m Tc-trimetaphosphate; .sup.99m Tc-diethylenetriaminepentaacetic acid; .sup.99m Tc-2,3-dimercaptosuccinic acid; .sup.99m Tc-glycero-glucoheptanoic acid; [N-[N-[N-(mercaptoacetyl)glycyl]glycyl]glycinato(5-)-N,N',N",S]-oxo-[.sup.9 9m Tc]technetate(V); .sup.99m Tc-macroaggregated albumin; .sup.99m Tc-albumin colloid; .sup.99m Tc-aggregated human albumin; .sup.99m Tc-recombinant human albumin/human serum albumin in microspherical form; .sup.99m Tc-imminodiphosphonic acid; .sup.99m Tc-[(acac).sub.2 en]; .sup.99m Tc-hydrophosphonic acid; .sup.99m Tc-monoclonal antibody to fibrin; .sup.99m Tc-monoclonal antibody to myosin; .sup.99m Tc-tissue plasminogen activator; hexakis(1-isocyano-2-methoxy-2-methylpropane)-[.sup.99m Tc]technetium(I); bis[(1,2-cyclohexanedionedioximato)-(1-)-0]-[(1,2-cyclohexanedionedioximato )-(2-)-0]-methylborato-(2-)-N,N',N",N"',N"",N""'-chloro[.sup.99m Tc]technetium (III); [bis(2,3-butanedione-dioximato)(1-)-0]-[(2,3-butanedione-dioximato)(2-)-0]- (2-methylpropyl)borato-(2-)-N,N',N",N"',N"",N""'-chloro[.sup.99m Tc]technetium; .sup.99m Tc-ethyl cystinate dimer; .sup.99m Tc-3,3'-[(2,2-dimethyltrimethylene)diimino]di-2-butanone-dioxime; bis[N-[2-[(3-bromo-2,4,6-trimethylphenyl)amino]-2-oxoethyl]-N-(carboxymethy l)-glycyl]-[.sup.99m Tc]technetium; bis[N-[2-[[2,6-bis(1-methylethyl)phenyl]amino]-2-oxoethyl]-N-(carboxymethyl )-glycyl]-[.sup.99m TC]technetium; bis[-N-(carboxymethyl)-N-[2-[2,6-dimethylphenyl)-amino]-2-oxoethyl)-glycyl] -[.sup.99m Tc]technetium; and .sup.99m Tc-polyisohexylcyanoacrylate nanoparticles; or a pharmaceutically acceptable salt thereof. 11. The radiopharmaceutical composition of claim 10 wherein the .sup.99m Tc-based radiopharmaceutical is selected from: .sup.99m Tc-methylene-disphosphonic acid; .sup.99m Tc-hydroxymethylene-diphosphonic acid; .sup.99m Tc-ethane-1-hydroxy-1,1-diphosphonic acid; .sup.99m Tc-1-hydroxypropane-1,1-diphosphonic acid; .sup.99m Tc-2,3-dicarboxypropane-1,1-diphosphonic acid; .sup.99m Tc-pyrophosphate; and .sup.99m Tc-trimetaphosphate; or a pharmaceutically acceptable salt thereof. 12. The radiopharmaceutical composition of claim 9 wherein the .sup.99m Tc-based radiopharmaceutical is .sup.99m Tc-methylene-disphosphonic acid or a pharmaceutically acceptable salt thereof. 13. The radiopharmaceutical composition of claim 10 wherein the .sup.99m Tc-based radiopharmaceutical is selected from: .sup.99m Tc-diethylenetriaminepentaacetic acid; .sup.99m Tc-2,3-dimercaptosuccinic acid; .sup.99m Tc-glycero-glucoheptanoic acid; and [N-[N-[N-(mercaptoacetyl)glycyl]glycyl]-glycinato(5-)-N,N',N",S]-oxo-[.sup. 99m Tc]technetate(V); or a pharmaceutically acceptable salt thereof. 14. The radiopharmaceutical composition of claim 10 wherein the .sup.99m Tc-based radiopharmaceutical is selected from: .sup.99m Tc-macroaggregated albumin; .sup.99m Tc-albumin colloid; .sup.99m Tc-aggregated human albumin; and .sup.99m Tc-recombinant human albumin/human serum albumin in microspherical form. 15. The radiopharmaceutical composition of claim 10 wherein the .sup.99m Tc-based radiopharmaceutical is selected from: .sup.99m Tc-imminodiphosphonic acid; .sup.99m Tc-[(acac).sub.2 en]; .sup.99m Tc-hydrophosphonic acid; .sup.99m Tc-monoclonal antibody to fibrin; .sup.99m Tc-monoclonal antibody to myosin; .sup.99m Tc-tissue plasminogen activator; hexakis(1-isocyano-2-methoxy-2-methylpropane)-[.sup.99m Tc]technetium(I); bis[(1,2-cyclohexanedionedioximato)-(1-)-0]-[(1,2-cyclohexanedionedioximato )-(2-)-0]-methylborato-(2-)-N,N',N",N"',N"",N""'-chloro[.sup.99m Tc]technetium (III); and .sup.99m Tc-glycero-glucoheptanoic acid; or a pharmaceutically acceptable salt thereof. 16. The radiopharmaceutical composition of claim 10 wherein the .sup.99m Tc-based radiopharmaceutical is selected from: .sup.99m Tc-diethylenetriaminepentaacetic acid; bis(2,3-butanedione-dioximato)(1-)-0]-[(2,3-butanedione-dioximato)(2-)-0]-( 2-methylpropyl)borato-(2-)-N,N',N",N"',N"",N""'-chloro[.sup.99m Tc]technetium; .sup.99m Tc-ethyl cystinate dimer; and .sup.99m Tc-3,3'-[(2,2-dimethyltrimethylene)diimino]di-2-butanone-dioxime; or a pharmaceutically acceptable salt thereof. 17. The radiopharmaceutical composition of claim 10 wherein the .sup.99m Tc-based radiopharmaceutical is selected from: bis[N-[2-[(3-bromo-2,4,6-trimethylphenyl)-amino]-2-oxoethyl]-N-(carboxymeth yl)-glycyl]-.sup.99m Tc]technetium; bis[N-[2-[[2,6-bis(1-methylethyl)phenyl]-amino]-2-oxoethyl]-N-(carboxymethy l)-glycyl]-[.sup.99m Tc]technetium; bis[-N-(carboxymethyl)-N-[2-[2,6-dimethylphenyl)-amino]-2-oxoethyl]-glycyl] -[.sup.99m Tc]technetium; and .sup.99m Tc-polyisohexylcyanoacrylate nanoparticles; or a pharmaceutically acceptable salt thereof. 18. The radiopharmaceutical composition of claim 1 wherein the second bacteriostat (e) is polymyxin B. 19. The radiopharmaceutical composition of claim 1 wherein the second bacteriostat (e) is an N-methansulfonate derivative of polymyxin B. 20. An admixture for the preparation of a .sup.99m Tc-based radiopharmaceutical composition comprising: (a) a water-soluble pertechnetate reducing agent; (b) a radical-scavenging antioxidant; and (c) a first bacteriostat selected from: (i) benzalkonium chloride, and (ii) benzethonium chloride; (d) a second bacteriostat selected from: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof; and (ii) an N-methanesulfonate derivative of a polymyxin wherein the polymyxin is selected from the group consisting of: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof. 21. The admixture of claim 20 wherein the first bacteriostat (c) is benzalkonium chloride. 22. The admixture of claim 20 wherein (a), (b), (c) and (d) are present in a freeze-dried state. 23. The admixture of claim 20 which further comprises a ligand for .sup.99m Tc in the III, IV or V oxidation state. 24. A radiopharmaceutical composition comprising: (a) a radioactive iodine-based radiopharmaceutical; (b) an autoradiolytic decomposition-inhibiting antioxidant selected from: (i) ascorbic acid (ii) nicotinamide, (iii) nicotinic acid, and (iv) a mixture of acorbic acid and nicotinamide; (c) a first bacteriostat selected from: (i) benzalkonium chloride, and (ii) benzethonium chloride; (d) a second bacteriostat selected from: (A) polymyxin B, (B) polymyxin B.sub.1 (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof; and (ii) an N-methanesulfonate derivative of a polymyxin wherein the polymyxin is selected from the group consisting of: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof. 25. The radiopharmaceutical composition of claim 24 wherein the first bacteriostat (c) is benzalkonium chloride. 26. The radiopharmaceutical composition of claim 24 wherein the autoradiolytic decomposition-inhibiting antioxidant is nicotinamide. 27. The radiopharmaceutical composition of claim 24 wherein the radioactive iodine-based radiopharmaceutical contains a radioisotope selcted from .sup.123 I, .sup.125 I or .sup.131 I. 28. The radiopharmaceutical composition of claim 24 wherein the radioactive iodine-based radiopharmaceutical is selected from the group consisting of: [.sup.123 I], [.sup.125 I] or [.sup.131 I]-N-[2-iodo-benzoyl]-glycine; [.sup.131 I]N,N,N'-trimethyl-N'-(2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine [.sup.123 I]1,3-dihydro-3-(4-iodobenzoylamino)-1-methyl-5-phenyl-2H-1,4-benzodiazepi n-2-one; [.sup.12 I]N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzoiazepin-3-yl)-N'-(3- iodophenyl)urea; [.sup.123 I]4-iodo-alpha-methyl-N-(1-methylethyl)benzeneethanamine; [.sup.131 I]-19-iodo-cholest-5-en-3.beta.-ol; [hu 123I] or [.sup.131 I]-6-iodo-cholest-5-en-3.beta.-ol; [.sup.123 I] or [.sup.131 I]-m-iodobenzylguanidine; [.sup.123 I] or [.sup.131 I]-p-iodo-N-isopropylamphetamine; [.sup.123 I] or [.sup.131 I]-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)-methyl]benzamide ; [.sup.123 I] or [.sup.131 I]-9-(3,3-diethyl-ureido)-4,6,6a,7,8,9-hexahydro-7-methyl-21-iodo-indolo[4 ,3-f,g]quinoline; [.sup.123 I] or [.sup.131 I]-N- (8-benzyl-1.alpha..alpha.,5.alpha.H-nortropan-3.beta.-yl)-2,3-dimethoxy-4- iodo-benzylamide; and [.sup.123 I] or [.sup.131 I]-N-(2-diethylaminoethyl)-4-iodobenzamide; or a pharmaceutically acceptable salt thereof. 29. A method of administering a radiopharmaceutical agent to a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 1 by intravenous, oral, or nebular administration. 30. A method for bone scintigraphy in a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 11 by intravenous administration. 31. A method for radioimaging of the kidney in a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 13 by intravenous administration. 32. A method for radioimaging of the lung in a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 14 by intravenous or nebular administration. 33. A method for radioimaging of blood pool and myocardial infarct in a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 15 by intravenous administration. 34. A method for brain/cerebral perfusion radioimaging in a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 16 by intravenous administration. 35. A method for radioimaging of the liver, gall bladder, and/or spleen in a subject, which comprises administering an effective amount of the radiopharmaceutical composition of claim 17 by intravenous administration. 36. A method of inhibiting bacterial growth in a .sup.99m Tc-based radiopharmaceutical composition, comprising codissolving a bacteriostatic amount of a first bacteriostat selected from: (i) benzalkonium chloride; and (ii) benzethonium chloride; and a second bacteriostat selected from: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof; and (ii) an N-methanesulfonate derivative of a polymyxin wherein the polymyxin is selected from the group consisting of: (A) polymyxin B, (B) polymyxin B.sub.1, (C) polymyxin B.sub.2, (D) polymyxin D.sub.1, (E) polymyxin D.sub.2, and (F) polymyxin E, or a pharmaceutically acceptable salt thereof with an aqueous solution of a .sup.99m Tc-based radiopharmaceutical and a radical-scavenging antioxidant.

Details for Patent 5,306,482

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Grifols Therapeutics Llc	ALBUKED, PLASBUMIN-20, PLASBUMIN-25, PLASBUMIN-5	albumin (human)	For Injection	101138	10/21/1942		2011-04-09
Baxalta Us Inc.	BUMINATE, FLEXBUMIN	albumin (human)	Injection	101452	03/03/1954		2011-04-09
Csl Behring Ag	ALBURX	albumin (human)	Injection	102366	07/23/1976		2011-04-09