Claims for Patent: 4,396,597

Summary for Patent: 4,396,597

Title:	Process for the preparation of a sterile injectable physiologically acceptable solution of an X-ray contrast agent and solutions of the X-ray contrast agent and a buffer
Abstract:	Sterile, injectable, physiologically acceptable solutions of an X-ray contrast agent are prepared by autoclaving a solution of a m-carboxamido-o-iodo-N-(β-hydroxyalkyl)aniline X-ray contrast agent in the presence of a physiologically acceptable buffer system the pH of which decreases with increasing temperature.The presence of a temperature dependent buffer, preferably an amine, enables X-ray contrast agents to be sterilized by autoclaving without significant decomposition.Examples of the autoclaving processes are given and solutions for autoclaving containing a m-carboxamido-o-iodo-N-(β-hydroxyalkyl)aniline X-ray contrast agent and a physiologically acceptable buffer system the pH of which decreases with increasing temperature are described and claimed.
Inventor(s):	Fridtjov B. Rakli, Michael J. Kelly
Assignee:	GE Healthcare AS , Norgas AS
Application Number:	US06/233,137
Patent Claims:	1. A solution having a physiologically acceptable pH comprising a non-ionic m-carboxamido-o-iodo-N-(β-hydroxyalkyl)-aniline X-ray contrast agent in a concentration of from 100 to 450 mg I/ml of the solution and a physiologically acceptable buffer system containing an amine buffer of formula II NR.sup.1 R.sup.2 R.sup.3 (II) wherein R1, R2 and R3, which may be the same or different, each represents a hydrogen atom, a sugar residue, an alkyl group with 1 to 6 carbon atoms which may carry one or more hydroxy, mercapto, carboxyl, carboxamido, imidazolyl, indolyl or hydroxy substituted phenyl groups, alkylthio groups with 1 to 6 carbon atoms and/or groups of the formula: --NR4 R5 in which R4 and R5, which may be the same or different, each represents a hydrogen atom, a carboxamido or a ##STR6## group or an alkyl group with 1 to 6 carbon atoms; or any two of R1, R2 and R3 may, together with the intervening nitrogen atom, represent a pyrrolidine or piperidine ring which may carry hydroxy, carboxyl or carboxamido groups; the pH of which decreases with increasing temperature, the pKa of said buffer system at 15° C. being less than or equal to 9.5 and the concentration of said buffer in the solution being no greater than 50 m.molar. 2. A solution as claimed in claim 1 in which the amine buffer is the sole buffer present in the system. 3. A solution as claimed in claim 1 wherein the amine buffer is meglumine or tris(hydroxymethyl)methylamine. 4. A solution as claimed in claim 1 wherein the concentration of the buffer in the solution is no greater than 50 m.molar. 5. A solution as claimed in claim 4 wherein the concentration of the buffer in the solution is in the range 5 to 25 m.molar. 6. A solution as claimed in claim 1 wherein the m-carboxamido-o-iodo-N-(β-hydroxyalkyl)aniline X-ray contrast agent is of the formula ##STR7## wherein R1 represents either (a) the group ##STR8## in which R' and R", which may be the same or different, each represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms which may carry one or more --OH groups, or (b) a sugar residue having a β-OH group in β-position to the nitrogen atom to which the sugar residue is attached, said β-position being the 2-, 3- or 4-position within the sugar residue; R2 represents an alkylcarbonyl or alkylsulphonyl group containing 1 to 6 carbon atoms; R3 and R4, which may be the same or different, each represent hydrogen, C1 -C6 alkyl, C1 -C6 hydroxyalkyl or an acyloxy C1 -C6 alkyl group wherein the acyl group is an alkylcarbonyl or alkylsulphonyl group containing 1-6 carbon atoms or a sugar residue; and R5 represents a hydrogen atom or the group --CONR3 "R4 ", Ac'NR6 or --CH2 NAc' R6 in which R3 " and R4 ", which may the same or different, each represents hydrogen, C1 -C6 alkyl, C1 -C6 hydroxyalkyl or an acyloxy C1 -C6 alkyl group wherein the acyl group is an alkylcarbonyl or alkylsulphonyl group containing 1 to 6 carbon atoms or a sugar residue, Ac' is an alkylcarbonyl or alkylsulphonyl group containing 1 to 6 carbon atoms, and R6 represents hydrogen, C1 -C6 alkyl, C1 -C6 hydroxyalkyl, or an acyloxy C1 -C6 alkyl or acyl group wherein the acyl group is an alkylcarbonyl or alkylsulphonyl group containing 1-6 carbon atoms. 7. A solution as claimed in claim 6 wherein the m-carboxamido-o-iodo-N-(β-hydroxyalkyl)aniline X-ray contrast agent is 5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide. 8. A solution as claimed in claim 1 which is sterile and injectable. 9. A sterile injectable physiologically acceptable solution of a m-carboxamido-o-iodo-N-(β-hydroxyalkyl)-aniline X-ray contrast agent when prepared by a process which comprises autoclaving a solution of a m-carboxamido-o-iodo-N-(β-hydroxyalkyl)-aniline X-ray contrast agent in the presence of a physiologically acceptable buffer which is selected from the group consisting of ammonia and a water soluble amine having a pKa of ≦9.5 at 15° C. and which causes a decrease in the pH of the buffered solution with increasing temperature.