Process for making doses formulation of contrast media from concentrate

• US 5,592,940 A
• Filed: 09/19/1995
• Issued: 01/14/1997
• Est. Priority Date: 04/22/1991
• Status: Expired due to Term

• Current Assignee: Medrad Incorporated (Bayer AG)
• Original Assignee: Schering Ag (Merck & Co., Inc.)
• Inventors: Kampfe, Michael, Better, Bernhard
• Primary Examiner(s): JAWORSKI, FRANCIS J
• Application Number:
  US08/529,972
• Time in Patent Office: 483 Days
• Field of Search: 424/9, 128/662.02, 128/653.1, 128/654, 141/83, 141/99, 141/234
• US Class Current: 600/431
• CPC Class Codes: A61K 49/0433 containing an organic halogenated X-ray contrast-enhancing agent
• CPC Class Codes: A61K 49/103 the complex-forming compound being acyclic, e.g. DTPA
• CPC Class Codes: A61K 49/106 the complex-forming compound being cyclic, e.g. DOTA
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1866 the nanoparticle having a (super)(para)magnetic core coated or functionalised with a peptide, e.g. protein, polyamino acid
• CPC Class Codes: A61K 49/1878 the nanoparticle having a magnetically inert core and a (super)(para)magnetic coating
• CPC Class Codes: A61M 31/005 for contrast media
• CPC Class Codes: A61M 5/16827 controlling delivery of multiple fluids, e.g. sequencing, mixing or via separate flow-paths infusion of multiple fluids without using a controller A61M5/1407
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The invention relates to a process for preparing pharmaceutically acceptable dosage forms of contrast medium from concentrated contrast medium using a fluid delivery system suitable for removing predetermined amounts of fluids from a plurality of vessels and mixing same together.

Claims

1. A process for the production of a diagnostic contrast medium comprising at least one contrast agent and an aqueous solution, said process comprising:

delivering, under sterile conditions, a predetermined amount of at least a first contrast medium concentrate containing 340-450 mg of I/ml of X-ray contrast agent, 0.5-4 mol of NMR contrast agent/liter, or an ultrasound contrast agent, from at least a first container by a first pipe to a mixing chamber;

delivering a predetermined amount of diluent from a second container by a second pipe to the mixing chamber, wherein said predetermined amounts are mixed to form a physiologically compatible preparation; and

delivering the resultant mixture to a discharge station.

2. A process according to claim 1, wherein said concentrate is in liquid, form.

3. A process according to claim 1, wherein said contrast agent is iotrolan, iopromide, iohexol, iosimide, metrizamide, a salt of amidoacetic acid, iotroxinic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodo-isopththalic;

acid-(2,3-dihydroxy-N-methylropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5-[N-(2-hydroxyethyl)-acetamido]-2,4,6-triiodobenzoic acid-[(1RS, 2SR)-2,3-dihydroxy-1-hydroxymethylpropyl]-amide, dispersions of iodipamide ethyl ester, gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10[1-hydroxymethyl-2,3-dihydroxy-propyl]-1,4,7-tris[(carboxymethyl)-1,4,7,10-tetraaza-cyclodecane], an iron porphyrin chelate, a manganese porphyrin chelate, a stable magnetite dispersion, an aqueous dispersion of galactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.

4. A process according to claim 3, wherein said contrast agent is a dispersion of cyanoacrylate and/or albumin microspheres of trapped air.

5. A process according to claim 1, wherein said diluent is water or an aqueous solution.

6. A process according to claim 1, wherein said diluent is an aqueous medium containing:

0-0.5 mol/l of NMR contrast agent, 0-350 mg of I/ml of X-ray contrast agent and/or

medicinally active substances, and/or

buffer substances, and/or

isotonically active additives, and/or

complexing agents.

7. A process according to claim 1, wherein said concentrate is in powdered form.

8. A process according to claim 1, wherein said first contrast medium concentrate and said diluent are conveyed to said mixing chamber by gravity.

9. A process according to claim 1, wherein said first contrast medium concentrate and said diluent are conveyed to said mixing chamber by pump.

10. A process according to claim 1, wherein said first pipe and said second pipe are joined together upstream of the mixing chamber at a junction point and a single pipe connects said junction point to said mixing chamber.

19. A kit according to claim 8, wherein the agent of said concentrate contains as compound iotrolan, iopromide, iohexol, iosimide, metrizamide, a salt of amidoacetic acid, iotroxinic acid, iopamidol, 5-hydroxy-acetamido-2,4,6-triiodo-isophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5[N-(2-hydroxyethyl)-acetamido]-2,4,6-triiodobenzoic acid[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl]-amide, dispersions of iodipamide ethyl gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10[1-hydroxymethyl-2,3-dihydroxypropyl]-1,4,7-tris[(carboxymethyl)-1,4,7,10-tetraazacyclodecane], an iron porphyrin chelate, a manganese porphyrin chelate, a stable magnetite dispersion, an aqueous dispersion of galactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.

11. A device for production of a contrast medium, comprising:

at least one concentrate container containing concentrated contrast media;

at least one diluent container containing a diluent suitable for use with contrast media;

a first feed pipe and a second feed pipe in connection with, respectively, said concentrate container and said diluent container, said feed pipes also being in fluid communication with a mixing chamber;

a delivery pipe in fluid communication with said feed pipes;

a mixing chamber provided between said feed pipes and said delivery pipe;

metering elements in said feed pipes which meter, respectively, predetermined amounts of said concentrated contrast media and said diluent;

means for determination of metered amounts of said concentrated contrast media and said diluent;

metering device in said delivery pipe, which discharges contrast medium from an end of said delivery pipe;

and a control unit which controls said metering elements.

12. A device according to claim 11, wherein the end of said delivery pipe is connected to a container or a syringe for receiving the resultant contrast medium.

13. A device according to claim 11, wherein said device further comprises shut-off elements in said first feed pipe, said second feed pipe and said delivery pipe, and wherein said control unit also controls said shut-off elements.

14. A device according to claim 13, wherein said means for determination is a weighing device connected to said mixing chamber and to said control unit.

15. A device according to claim 11, wherein said first feed pipe and said second feed pipe are provided with flow sensors.

16. A device according to claim 11, further comprising a density sensing means within said mixing chamber.

17. A device according to claim 11, further comprising at least one temperature control means for controlling fluid temperature.

18. A kit for production of a contrast medium, comprising:

a concentrate containing 530-450 mg of I/ml of X-ray contrast agent, 0.5-4 mol/liter of NMR contrast agent or a concentrated ultrasound contrast agent in a first container with a volume of 0.1-100 1; and

an aqueous diluent in a second container with a content of 1-100 liters.

20. A kit according to claim 18, wherein said first container contains 1-100 liters of concentrated X-ray contrast agent at a concentration of 350-450 mgI/ml and said second container contains 1-100 liters of said diluent.

21. A kit according to claim 18, wherein said NMR contrast agent is gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10[1-hydroxymethyl-2,3-dihydroxypropyl]1,4,7-tris[(carboxymethyl)-1,4,7,10-tetraazacyclododecane], or an iron porphyrin chelate, a manganese porphyrin chelate, or a stable magnetite dispersion.

22. A kit according to claim 18, wherein said ultrasound contrast agent is an aqueous dispersion of galactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.

23. A method of preparing a diagnostic contrast medium in dosage form, comprising:

(a) providing a first vessel containing a concentrated flowable contrast medium;

(b) providing a second vessel containing a pharmaceutically acceptable diluent fluid;

(c) removing a predetermined amount of said concentrated fluid contrast medium from said first vessel via a first conduit means;

(d) removing a predetermined amount of said pharmaceutically acceptable diluent via a second conduit means;

(e) delivering said amount of contrast medium and said amount of diluent to a mixing chamber and

(f) forming a contrast medium in a pharmaceutically acceptable dosage form within said mixing chamber.

24. A method according to claim 23, wherein said predetermined amount of concentrated fluid contrast medium and said predetermined amount of pharmaceutically acceptable diluent are simultaneously removed from said first vessel and said second vessel, respectively.

25. A method according to claim 23, wherein said predetermined amount of concentrated fluid contrast medium and said predetermined amount of pharmaceutically acceptable diluent are successively removed from said first vessel and said second vessel, respectively.

26. A method according to claim 23, wherein said concentrated fluid contrast medium and said pharmaceutically acceptable diluent are mixed within said mixing chamber to form a homogeneous contrast medium.

32. A method of administering a contrast medium in dosage form comprising:

(a) preparing a diagnostic contrast medium in dosage form according to the method of claim 23, and

(b) administering a dose of said diagnostic contrast medium to a patient.

33. A method according to claim 32, further comprising:

providing means for placing said mixing chamber in fluid communication with a patient, and

administering said contrast medium to said patient by direct infusion.

34. A method according to claim 32, further comprising:

placing said mixing chamber in fluid communication with a sterile sealed container.

35. A method according to claim 32, further comprising:

placing said mixing chamber in fluid communication with a cartridge for an injector.

36. A method according to claim 32, further comprising:

placing said mixing chamber in fluid communication with a hypodermic syringe.

37. In a method of X-ray diagnostic examination comprising administering an X-ray contrast agent to a patient, the improvement wherein:

said X-ray contrast agent is administered to said patient in accordance with claim 32.

38. In a method of NMR imaging comprising administering an NMR contrast agent to a patient, the improvement wherein:

said NMR contrast agent is administered to said patient according to claim 32.

27. A method of preparing diagnostic contrast medium in dosage form, comprising:

(a) connecting a first vessel and a second vessel to a device for combining predetermined amounts of fluids from separate vessels, said first vessel containing concentrated flowable contrast medium and said second vessel containing a pharmaceutically acceptable diluent fluid;

(b) removing a predetermined amount of said concentrated contrast medium from said first vessel via a first conduit means;

(c) removing a predetermined amount of said pharmaceutically acceptable diluent via a second conduit means;

(d) delivering said amount of contrast medium and said amount of diluent to a mixing chamber; and

(e) forming a contrast medium in a pharmaceutically acceptable dosage form.

28. A method of preparing a diagnostic contrast medium in dosage form, comprising:

(a) providing a device for combining predetermined amounts of fluids from separate vessels, said device comprising;

(i) means for connecting a first vessel;

(ii) means for connecting a second vessel;

(iii) a first conduit means for removing flowable material from said first vessel;

(iv) a second conduit means for removing flowable material from said second vessel;

(v) a first fluid flow regulation means for controlling fluid flow in said first conduit means;

(vi) a second fluid flow regulation means for controlling fluid flow in said second conduit means;

(vii) a mixing chamber, in fluid communication with said first conduit means and second conduit means, for receiving amounts of flowable material from said first vessel and said second vessel, which is provided with means for mixing fluid from said first vessel and fluid from said second vessel to form a homogeneous mixture;

(viii) sensing means for sensing the amount of flowable material removed from said first vessel in said second vessel, the amount of flowable material delivered to said mixing chamber and/or the concentration of material in said mixing chamber;

(ix) control means, in connection with said sensing means and said fluid flow regulation means in said first and second conduit means, for regulating flow into said mixing chamber and determining the amounts of material removed from said first and second vessels and/or delivered to said mixing chamber and/or the concentration in said mixing chamber;

(b) connecting a first vessel containing concentrated flowable medium to said contact means for connecting a first vessel;

(c) connecting a second vessel containing a pharmaceutically acceptable fluid diluent to said means for connecting a second vessel;

(d) removing contrast medium and fluid diluent from said first and second vessels via said first and second conduit means and delivering said fluid contrast agent in fluid diluent to said mixing chamber,

whereby the resultant combination of said fluid contrast medium and said fluid diluent forms a pharmaceutically acceptable dosage form of said contrast medium.

29. A method according to claim 28, further comprising:

detecting the concentration of contrast medium contained in said mixing chamber by sensing the density of the resultant mixture in said mixing chamber.

30. In a method of preparing a dosage form of diagnostic contrast medium comprising combining a concentrated flowable contrast medium and a diluent, the improvement comprising:

employing a fluid delivery device suitable for removal of predetermined amounts of fluid from a plurality of vessels to remove an amount of said concentrated flowable contrast medium from a first vessel and an amount of said diluent from a second vessel; and

combining and mixing said amounts of concentrated contrast medium and diluent in a mixing chamber to form homogeneous contrast medium in a pharmaceutically acceptable dosage form.

31. A method according to claim 30, wherein said diagnostic contrast medium is an iodinated X-ray contrast agent.