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Claims for Patent: 4,278,654

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Claims for Patent: 4,278,654

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 (Oslo, NO)
Application Number:06/054,440
Patent Claims: 1. A process for the preparation of a buffered sterile, injectable, physiologically acceptable solution of an X-ray contrast agent 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 of the pH of the buffered solution with increasing temperature.

2. A process as claimed in claim 1 wherein the m-carboxamido-o-iodo-N-(.beta.-hydroxyalkyl)aniline X-ray contrast agent is of the formula: ##STR6## wherein R.sub.1 represents either (a) the group ##STR7## 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 be 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.

3. A process as claimed in claim 1 wherein the concentration of X-ray contrast agent in the solution to be autoclaved is 100 to 450 mg I per ml.

4. A process as claimed in claim 1 wherein the concentration of the buffer in the solution is no greater than 50 m.molar.

5. A process 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 process as claimed in claim 1 wherein the buffer is a physiologically acceptable water soluble amine of the formula:

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 ##STR8## 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.

7. A process as claimed in claim 6 wherein the water soluble amine comprises tris-(hydroxymethyl)methylamine, meglumine or N,N-bis(2-hydroxyethyl)-tris(hydroxymethyl)-methylamine.

8. A process as claimed in claim 1 wherein the solution to be autoclaved contains a chelating agent.

9. A process as claimed in claim 8 wherein the chelating agent comprises ethylenediamine tetraacetate.

10. A process as claimed in claim 1 or claim 2 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.
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