CA1135619A - Solution of sodium iomorinate for use in peroral rapid cholecystography - Google Patents
Solution of sodium iomorinate for use in peroral rapid cholecystographyInfo
- Publication number
- CA1135619A CA1135619A CA000344763A CA344763A CA1135619A CA 1135619 A CA1135619 A CA 1135619A CA 000344763 A CA000344763 A CA 000344763A CA 344763 A CA344763 A CA 344763A CA 1135619 A CA1135619 A CA 1135619A
- Authority
- CA
- Canada
- Prior art keywords
- solution
- peroral
- rapid
- cholecystography
- volume
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0447—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
- A61K49/0495—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound intended for oral administration
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Aqueous solution, for use in peroral rapid cholecystography combined with cholangiography, which contains as the active ingredient the Na salt of N-?3 (1',3"-oxapentamethyleneamino-ethylideneamino)-2,44,6-triiodobenzoyl ?-.beta.-amino--.alpha.-methylpropionic acid. The solution makes possible visualisation of the cystic ducts within 60 - 90 minutes and of the gall bladder about 3 to 4 hours after administration.
O.Z.668 15.1.1980
Aqueous solution, for use in peroral rapid cholecystography combined with cholangiography, which contains as the active ingredient the Na salt of N-?3 (1',3"-oxapentamethyleneamino-ethylideneamino)-2,44,6-triiodobenzoyl ?-.beta.-amino--.alpha.-methylpropionic acid. The solution makes possible visualisation of the cystic ducts within 60 - 90 minutes and of the gall bladder about 3 to 4 hours after administration.
O.Z.668 15.1.1980
Description
- ~135619 Solution for use in peroral` rapid cholecystography The invention relates to an aqueous solution for use in peroral rapid cholecy-stography, with which flawless visualisation of the cystic ducts can be obtained in a significant number of cases.
In principle, two methods are available for the visualisation of the gall bladder in an X-ray picture, the visualisation after peroral administration, with which the contrast medium passes via resorption from the gastro-intestinal tract into the bile, and visualisation af ter intravenous administration, that is to say administration directly into the blood stream. Peroral cholecystrography, which in itself imposes less strain on the patient, is as a rule carried out by the patient taking the medium on the evening before the test. This procedure has the disadvantage that although the gall bladder is rendered visible, the cystic duct system is not rendered visible. Hitherto, intravenous cholecystography has been reserved for visualisation of the latter, but with this procedure the intra~enous administration into the vein of a substance with a high iodine content must be accepted.
In investigations made with the substance 13-/~-(dimethylamino-methylidene-amino)-2,4,6-triiodophenyl7-propionic acid (generic name Ipodate) and with a substance with the code name Sl~ 771 concerning the possibility of visualisa-tion of the bile ducts after oral application it was found, that bile ducts can also made visible, if contrast media are used which are considerably more rapidly resorbed and with which therefore higher concentrations in the bile can be obtained, than with the hitherto known products. See R.P.Schirmeisen, Ro.Bl.18, 12/65, page 606 ff. As prerequisite for the visualisation of the bile ducts with these compounds especially with SH 771, which has a significantly higher excretion concentration than Ipodate, there was found a rapid, undivi-ded passage of the total dose through the stomach. On the other hand, dissolution of the contrast medium in the stomach was regarded as being detrimental for this purpose, since in this case, passage through the stomach was delayed.
~135619 In this investigations the systematic visualisation of the bile ducts was permitted with SH 771, but this substance did not find any practical use.
Amongst the group of derivatives of 2,4,6-triiodo-3-aminobenzoic acid media have already been found, which, after peroral administration, were consi-derably more rapidly resorbed and excreted through the gall bladder than the hitherto known compounds, see US-patent specifications 3,484,481, 3,853,866, 3,925,412 and 3,890,318, so that administration and testing can be carried out whithin a few hours.
According to US-patent 3,890,318 of W.Obendorf et al. the compounds proposed for this purpose are specific triiodised aminobenzenecarboxylic acids which are substituted in the ~position by an amidino group, and specifically9 inter alia, the compound N-/~-(1',3"-oxapentamethyleneamino-ethylideneami-no)-2,4,6-triiodobenzoyl7-13 amino-C~-methylpropionic acid (iomorinic acid).
Formulations envisaged as the administration form for this compound for peroral rapid cholecystography are tablets, sugar-coated tablets, powders or granules which contain the acid or salts.
When peroral rapid cholecystography was carried out with these known media it was already seen, from pharmacological investigations on cats, that, in contrast to the oral cholecystography customary hitherto, cystic ducts were rendered visible in this case. However, when tests were carried out in practice on humans, for example using tablets based on the above mentioned Na iomorinate, it was found that the cases in which an adequate diagnosis of the cystic duct system was possible remained below 10 % and usually at about 5 %
of the total number of cases examined.
It has now been found that the percentage of cases in which there is a possibility of adequate diagnosis of the cystic ducts by means of oral rapid cholecystography can be increased decisively, that is to say to up to 50 % of the cases examined, when the Na iomorinate is administered perorally in the form of an aqueous solution thereof which has been adjusted to the physiologi-cal pH. This was surprising, since it was not to be expected that the substance administered in aqueous solution would pass sufficiently rapidly through the 11356~9 stomach, whilst hitherto rapid, undivided passage of the total dose through the stomach was regarded as a prerequisite for good visualisatin of the cystic ducts.
The present invention accordingly relates to a solution for use in peroral rapid cholecystography, combined with cholangiography, which solution consi-sting essentually of an aqueous solution of the sodium salt of N-/ 3-(1',3"-oxapentamethyleneamino-ethylidenamino)-2,4,6-triiodobenzoyl7-13-amino- o~ -methylpropionic acid (Na iomorinate), said solution having a pH-value within the range of 7 to 8 and containing the dosage for a single investigation of 3 to9 g of the sodium salt in a volume of 20 to 50 ml.
The solution according to the invention is prepared in a simple manner, by dissolving iomorinic acid in water in the presence of the stoichiometric amount of NaOH. The subsequent adjustment of the pH value to the physiolo-gical range of 7 to 8 and preferably about 7.4 is then effected by adding a small amount of dilute NaOH or a small amount of physiologically acceptable acids, such as hydrochloric acid or acetic acid, or of further iomorinic acid, after which the solution is diluted to the desired volume by adding water.
The addition of buff er substances is not necessary since, because of ~he amphoteric character of iomorinic acid, the solution is stable wihtout any additives.
The dosage with which a good diagnosis is obtained is from 3 to 9 g per patient and preferably about 4 to 6 g per patient. The concentration of the aqueous solution can be from about 10 to 30 % and it is possible to adapt the concentration within this range to the volume which is regarded as appropriate for a single administration, that is to say 20 to 50 ml. Thus, for example, 4.5 to 5.5 g of Na iomorinate can be processed to give a solution with a volume of 20 to 30 ml, an amount which can be taken by a patient in a single swallow.
Because of the liquid form, the administration according to the invention is particularly well tolerated and can be administered easily even to patients who have difficulty in swallowing solid forms, which is an advantage. It is then ~13S6~9 posslble to take the pictures of the cystic`duct system about 60 to 90 minutes after administration, whilst for ass~ssment of the gall bladder itself it is usually advisable also to take a second picture about 3 to 4 hours after administration. By this procedure it is thus possible for a considerable percentage of those patients for whom investigation of the cystic duct system is also required in addition to investigation of the gall bladder to be spared the procedure of intravenous administration with its possible allergic reactions.
However, the solution according to the invention also offers a particularly advantageous mode of administration. This is because if the solution accordin~
to the invention is not only administered in the dosage required for diagnostic purposes 60 to 120 minutes before the first X-ray picture is taken but, in addition, a dose Gf the same contrast medium or of another oral gall bladder contrast medium which suffices for diagnostic purposes is administered the evening before the investigation9 it is possible to render the gall bladder and the cystic ducts visible at the same time with a single X-ray picture. This mode of administration not only results in a considerably saving in work for the hospital personnel but also reduces to half the exposure of the patient to X-rays.
Example 1:
O.Z45 g of sodium hydroxide are dissolved in about 14 ml of water and the solution is warmed slightly. 4.365 g of N-/3-(1',3"-oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl 7-B-amino- ol` -methylpropionic acid are then introduced, with stirring, and the mixture is stirred until a clear solution is obtained. After fine adjustment of the pH value to 7.4, the solution is made up to a volume of 20 ml. The solution contains 4.5 g of the sodium salt of the above mentioned acid and corresponds to a normal dose for an investigation.
In the clinical test, for a total of 700 investigations, on average a picture ofthe gall bladder which was adequate for diagnosis was obtained in 67 % of the cases and a picture of the cystic ducts which was adequate for diagnosis was obtained in 39.1 % of the cases, after administration of this solution to patients on an empty stomach and taking pictures 60 minutes and 4 hours after the administration, that is to say, thus, that in 58 % of the cases in which the gall bladder was visible it was also possible to make a diagnosis of the cystic ducts.
Example 2:
4.5 g of sodium iomorinate are dissolved in a small amount of water and the pH of the solution, which has a slight alkaline reaction, is adjusted to 7.4 by the addition of a small amount of dilute hydrochloric acid. After diluting to a volume of 45 ml, the solution is ready for use.
In he same way, for example, it is also possible to prepare a solution containing 9.0 g of sodium iomorinate per 30 ml.
In principle, two methods are available for the visualisation of the gall bladder in an X-ray picture, the visualisation after peroral administration, with which the contrast medium passes via resorption from the gastro-intestinal tract into the bile, and visualisation af ter intravenous administration, that is to say administration directly into the blood stream. Peroral cholecystrography, which in itself imposes less strain on the patient, is as a rule carried out by the patient taking the medium on the evening before the test. This procedure has the disadvantage that although the gall bladder is rendered visible, the cystic duct system is not rendered visible. Hitherto, intravenous cholecystography has been reserved for visualisation of the latter, but with this procedure the intra~enous administration into the vein of a substance with a high iodine content must be accepted.
In investigations made with the substance 13-/~-(dimethylamino-methylidene-amino)-2,4,6-triiodophenyl7-propionic acid (generic name Ipodate) and with a substance with the code name Sl~ 771 concerning the possibility of visualisa-tion of the bile ducts after oral application it was found, that bile ducts can also made visible, if contrast media are used which are considerably more rapidly resorbed and with which therefore higher concentrations in the bile can be obtained, than with the hitherto known products. See R.P.Schirmeisen, Ro.Bl.18, 12/65, page 606 ff. As prerequisite for the visualisation of the bile ducts with these compounds especially with SH 771, which has a significantly higher excretion concentration than Ipodate, there was found a rapid, undivi-ded passage of the total dose through the stomach. On the other hand, dissolution of the contrast medium in the stomach was regarded as being detrimental for this purpose, since in this case, passage through the stomach was delayed.
~135619 In this investigations the systematic visualisation of the bile ducts was permitted with SH 771, but this substance did not find any practical use.
Amongst the group of derivatives of 2,4,6-triiodo-3-aminobenzoic acid media have already been found, which, after peroral administration, were consi-derably more rapidly resorbed and excreted through the gall bladder than the hitherto known compounds, see US-patent specifications 3,484,481, 3,853,866, 3,925,412 and 3,890,318, so that administration and testing can be carried out whithin a few hours.
According to US-patent 3,890,318 of W.Obendorf et al. the compounds proposed for this purpose are specific triiodised aminobenzenecarboxylic acids which are substituted in the ~position by an amidino group, and specifically9 inter alia, the compound N-/~-(1',3"-oxapentamethyleneamino-ethylideneami-no)-2,4,6-triiodobenzoyl7-13 amino-C~-methylpropionic acid (iomorinic acid).
Formulations envisaged as the administration form for this compound for peroral rapid cholecystography are tablets, sugar-coated tablets, powders or granules which contain the acid or salts.
When peroral rapid cholecystography was carried out with these known media it was already seen, from pharmacological investigations on cats, that, in contrast to the oral cholecystography customary hitherto, cystic ducts were rendered visible in this case. However, when tests were carried out in practice on humans, for example using tablets based on the above mentioned Na iomorinate, it was found that the cases in which an adequate diagnosis of the cystic duct system was possible remained below 10 % and usually at about 5 %
of the total number of cases examined.
It has now been found that the percentage of cases in which there is a possibility of adequate diagnosis of the cystic ducts by means of oral rapid cholecystography can be increased decisively, that is to say to up to 50 % of the cases examined, when the Na iomorinate is administered perorally in the form of an aqueous solution thereof which has been adjusted to the physiologi-cal pH. This was surprising, since it was not to be expected that the substance administered in aqueous solution would pass sufficiently rapidly through the 11356~9 stomach, whilst hitherto rapid, undivided passage of the total dose through the stomach was regarded as a prerequisite for good visualisatin of the cystic ducts.
The present invention accordingly relates to a solution for use in peroral rapid cholecystography, combined with cholangiography, which solution consi-sting essentually of an aqueous solution of the sodium salt of N-/ 3-(1',3"-oxapentamethyleneamino-ethylidenamino)-2,4,6-triiodobenzoyl7-13-amino- o~ -methylpropionic acid (Na iomorinate), said solution having a pH-value within the range of 7 to 8 and containing the dosage for a single investigation of 3 to9 g of the sodium salt in a volume of 20 to 50 ml.
The solution according to the invention is prepared in a simple manner, by dissolving iomorinic acid in water in the presence of the stoichiometric amount of NaOH. The subsequent adjustment of the pH value to the physiolo-gical range of 7 to 8 and preferably about 7.4 is then effected by adding a small amount of dilute NaOH or a small amount of physiologically acceptable acids, such as hydrochloric acid or acetic acid, or of further iomorinic acid, after which the solution is diluted to the desired volume by adding water.
The addition of buff er substances is not necessary since, because of ~he amphoteric character of iomorinic acid, the solution is stable wihtout any additives.
The dosage with which a good diagnosis is obtained is from 3 to 9 g per patient and preferably about 4 to 6 g per patient. The concentration of the aqueous solution can be from about 10 to 30 % and it is possible to adapt the concentration within this range to the volume which is regarded as appropriate for a single administration, that is to say 20 to 50 ml. Thus, for example, 4.5 to 5.5 g of Na iomorinate can be processed to give a solution with a volume of 20 to 30 ml, an amount which can be taken by a patient in a single swallow.
Because of the liquid form, the administration according to the invention is particularly well tolerated and can be administered easily even to patients who have difficulty in swallowing solid forms, which is an advantage. It is then ~13S6~9 posslble to take the pictures of the cystic`duct system about 60 to 90 minutes after administration, whilst for ass~ssment of the gall bladder itself it is usually advisable also to take a second picture about 3 to 4 hours after administration. By this procedure it is thus possible for a considerable percentage of those patients for whom investigation of the cystic duct system is also required in addition to investigation of the gall bladder to be spared the procedure of intravenous administration with its possible allergic reactions.
However, the solution according to the invention also offers a particularly advantageous mode of administration. This is because if the solution accordin~
to the invention is not only administered in the dosage required for diagnostic purposes 60 to 120 minutes before the first X-ray picture is taken but, in addition, a dose Gf the same contrast medium or of another oral gall bladder contrast medium which suffices for diagnostic purposes is administered the evening before the investigation9 it is possible to render the gall bladder and the cystic ducts visible at the same time with a single X-ray picture. This mode of administration not only results in a considerably saving in work for the hospital personnel but also reduces to half the exposure of the patient to X-rays.
Example 1:
O.Z45 g of sodium hydroxide are dissolved in about 14 ml of water and the solution is warmed slightly. 4.365 g of N-/3-(1',3"-oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl 7-B-amino- ol` -methylpropionic acid are then introduced, with stirring, and the mixture is stirred until a clear solution is obtained. After fine adjustment of the pH value to 7.4, the solution is made up to a volume of 20 ml. The solution contains 4.5 g of the sodium salt of the above mentioned acid and corresponds to a normal dose for an investigation.
In the clinical test, for a total of 700 investigations, on average a picture ofthe gall bladder which was adequate for diagnosis was obtained in 67 % of the cases and a picture of the cystic ducts which was adequate for diagnosis was obtained in 39.1 % of the cases, after administration of this solution to patients on an empty stomach and taking pictures 60 minutes and 4 hours after the administration, that is to say, thus, that in 58 % of the cases in which the gall bladder was visible it was also possible to make a diagnosis of the cystic ducts.
Example 2:
4.5 g of sodium iomorinate are dissolved in a small amount of water and the pH of the solution, which has a slight alkaline reaction, is adjusted to 7.4 by the addition of a small amount of dilute hydrochloric acid. After diluting to a volume of 45 ml, the solution is ready for use.
In he same way, for example, it is also possible to prepare a solution containing 9.0 g of sodium iomorinate per 30 ml.
Claims (3)
1. A solution for use in peroral rapid cholcystography combined with cholangiography consisting essentially of an aqueous solution of the sodium salt of N-[3-(l',3"-oxapentamethyleneamino-ethylideneamino)-2,4,6-triiodobenzoyl]-.beta.-amino-.alpha.-methyl-propionic acid, said solution having a pH-value within the range of 7 to 8 and containing the dosage for a single investigation of 3 to 9 g of the sodium salt in a volume of 20 to 50 ml.
2. An aqueous solution according to claim 1, containing 4.5 to 5.5 g of the sodium salt in a volume of 20 to 30 ml.
3. Process for the preparation of the solution according to claim 1, comprising dissolving N-[3-(1',3"-oxapentamethylenea-mino-ethylidenamino)-2,4,6-triiodobenzoyl]-.beta.-amino-.alpha.-methylpropionic acid in water in the presence of the stoichiometric amount of NaOH, adjusting the pH value of the solution to the range of 7 to 8 by adding dilute sodium hydroxide or further acid and adjusting the volume to the desired end volume by adding water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2906246 | 1979-02-19 | ||
| DEP2906246.2 | 1979-02-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1135619A true CA1135619A (en) | 1982-11-16 |
Family
ID=6063261
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000344763A Expired CA1135619A (en) | 1979-02-19 | 1980-01-31 | Solution of sodium iomorinate for use in peroral rapid cholecystography |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0014821B1 (en) |
| JP (1) | JPS5810364B2 (en) |
| AU (1) | AU537817B2 (en) |
| CA (1) | CA1135619A (en) |
| DE (1) | DE3064989D1 (en) |
| NZ (1) | NZ192829A (en) |
| ZA (1) | ZA80615B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2235935C3 (en) * | 1972-07-21 | 1979-07-26 | Lentia Gmbh | New derivatives of triiodinated aminobenzenecarboxylic acids, a process for their preparation and X-ray contrast media containing these compounds |
| DE2505218A1 (en) * | 1975-02-05 | 1976-08-19 | Schering Ag | NEW ORAL X-RAY CONTRASTS AND PROCEDURES FOR THEIR PRODUCTION |
-
1980
- 1980-01-04 DE DE8080100037T patent/DE3064989D1/en not_active Expired
- 1980-01-04 EP EP80100037A patent/EP0014821B1/en not_active Expired
- 1980-01-31 CA CA000344763A patent/CA1135619A/en not_active Expired
- 1980-02-01 ZA ZA00800615A patent/ZA80615B/en unknown
- 1980-02-08 NZ NZ192829A patent/NZ192829A/en unknown
- 1980-02-13 AU AU55475/80A patent/AU537817B2/en not_active Ceased
- 1980-02-19 JP JP55018634A patent/JPS5810364B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ZA80615B (en) | 1981-02-25 |
| JPS55115828A (en) | 1980-09-06 |
| AU5547580A (en) | 1980-08-28 |
| JPS5810364B2 (en) | 1983-02-25 |
| EP0014821B1 (en) | 1983-09-28 |
| AU537817B2 (en) | 1984-07-12 |
| EP0014821A1 (en) | 1980-09-03 |
| DE3064989D1 (en) | 1983-11-03 |
| NZ192829A (en) | 1981-11-19 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |