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Claims for Patent: 4,396,597

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Claims 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-(.beta.-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-(.beta.-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): Rakli; Fridtjov B. (Oslo, NO), Kelly; Michael J. (Oslo, NO)
Assignee: Nyegaard & Co. A/S (NO)
Application Number:06/233,137
Patent Claims: 1. A solution having a physiologically acceptable pH comprising a non-ionic m-carboxamido-o-iodo-N-(.beta.-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

wherein R.sup.1, R.sup.2 and R.sup.3, 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: --NR.sup.4 R.sup.5 in which R.sup.4 and R.sup.5, 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 R.sup.1, R.sup.2 and R.sup.3 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.degree. 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-(.beta.-hydroxyalkyl)aniline X-ray contrast agent is of the formula ##STR7## wherein R.sub.1 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 .beta.-OH group in .beta.-position to the nitrogen atom to which the sugar residue is attached, said .beta.-position being the 2-, 3- or 4-position within the sugar residue; R.sub.2 represents an alkylcarbonyl or alkylsulphonyl group containing 1 to 6 carbon atoms; R.sub.3 and R.sub.4, which may be the same or different, each represent hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl or an acyloxy C.sub.1 -C.sub.6 alkyl group wherein the acyl group is an alkylcarbonyl or alkylsulphonyl group containing 1-6 carbon atoms or a sugar residue; and R.sub.5 represents a hydrogen atom or the group --CONR.sub.3 "R.sub.4 ", Ac'NR.sup.6 or --CH.sub.2 NAc' R.sup.6 in which R.sub.3 " and R.sub.4 ", which may the same or different, each represents hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl or an acyloxy C.sub.1 -C.sub.6 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 R.sup.6 represents hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 hydroxyalkyl, or an acyloxy C.sub.1 -C.sub.6 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-(.beta.-hydroxyalkyl)aniline X-ray contrast agent is 5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxy propyl)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-(.beta.-hydroxyalkyl)-aniline X-ray contrast agent when prepared by a process which comprises autoclaving a solution of a m-carboxamido-o-iodo-N-(.beta.-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 .ltoreq.9.5 at 15.degree. C. and which causes a decrease in the pH of the buffered solution with increasing temperature.
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