Process for making doses formulation of contrast media from concentrate

• US 5,450,847 A
• Filed: 10/24/1991
• Issued: 09/19/1995
• 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
• Application Number:
  US07/779,492
• Time in Patent Office: 1,426 Days
• Field of Search: 424/9, 128/653.1, 128/654, 128/662.02, 141/99, 141/234
• US Class Current: 600/420
• 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, in which at least one X-ray contrast medium compound or at least one NMR contrast medium compound is mixed with an aqueous solution, comprising:

delivering, under sterile conditions, a predetermined amount of at least a first contrast medium concentrate in an amount of 350-450 mg of I/ml of X-ray contrast medium compound or 0.5-4 mol/l of NMR contrast medium compound 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 by stirring 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, dispersion or powdered form.

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

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

contrast media in a concentration of 0-0.5 mol/l NMR contrast medium compound or 0-350 mg of I/ml of X-ray contrast medium compound and/or medicinally active substances, and/or

buffer substances, and/or

isotonically active additives, and/or

complexing agents.

5. A process according to claim 1, wherein said X-ray contrast medium compound is iotrolan, iopromide, iohexol, iosimide, metrizamide, a salt of amidoacetic acid, iotroxic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodo-isophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5-{N-(2-hydroxyethyl)-acetamide}-2,4,6-triiodobenzoic acid-{(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl}-amide, or a dispersion of iodipamide ethyl ester.

6. A process according to claim 1, wherein said NMR contrast medium compound is 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, or a stable magnetite dispersion.

7. A kit comprising:

a contrast medium concentrate in an amount of 350-450 mg of I/ml of X-ray contrast medium compound or 0.5-4 mol/l of NMR contrast medium compound in a first container with a content of 0.1-100 l; and

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

8. A kit according to claim 7, wherein said first contrast medium compound at a concentration of 350-450 mgI/ml and said second container contains 1-100 liters of said diluent.

9. A kit according to claim 7, wherein said first container contains 100 ml-100 l of NMR contrast medium compound at a concentration of 0.5-4 l mol/l.

10. A kit according to claim 7, wherein the agent of said concentrate contains as compound iotrolan, iopromide, iohexol, iosimide, metrizamide, a salt of amidoacetic acid, iotroxic acid, iopamidol, 5-hydroxy-acetamido-2,4,6-triiodoisophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxy-ethyl)-diamide, 3-carbamoyl-5-[N-(2-hydroxyethyl-acetamido]-2,4,6-triiodobenzoic acid-[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl]-amide, a dispersion of iodipamide ethyl ester, 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, or a stable magnetite dispersion.

11. 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; and

(e) delivering said amount of contrast medium and said amount of diluent to a mixing chamber wherein said contrast medium and diluent are mixed by stirring, thereby forming a contrast medium in a pharmaceutically acceptable dosage form.

12. A method according to claim 11, wherein said diagnostic contrast medium is an X-ray diagnostic contrast medium.

13. A method according to claim 11, wherein said diagnostic contrast medium is an NMR contrast medium.

14. A method according to claim 11, wherein said diagnostic contrast medium is an ultrasound diagnostic contrast medium.

15. 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 thereby form a contrast medium in a pharmaceutically acceptable dosage form.

16. 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 a means for detecting the concentration of contrast medium contained therein by sensing the density of the resultant mixture;

(viii) control means, in connection with said means for detecting 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.

17. A method according to claim 16, wherein said diagnostic contrast medium is an X-ray diagnostic contrast medium.

18. A method according to claim 16, wherein said diagnostic contrast medium is an NMR contrast medium.

19. A method according to claim 16, wherein said diagnostic contrast medium is an ultrasound contrast medium.

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

(a) preparing a dosage form of contrast medium according to the method of claim 16, and

(b) administering said contrast medium dosage form to a patient.

25. A method according to claim 24, further comprising providing means for placing said mixing chamber in fluid communication with a patient and wherein said contrast medium is administered to said patient by direct infusion.

26. A method according to claim 24, further comprising means for placing said mixing chamber in fluid communication with a sterile sealed container.

27. A method according to claim 24, further comprising providing means for placing said mixing chamber in fluid communication with an injector.

28. A method according to claim 24, further comprising providing means for placing said mixing chamber in fluid communication with an injection syringe.

29. A method according to claim 24, wherein said contrast medium is an NMR contrast medium.

30. A method according to claim 24, wherein said contrast medium is an NMR contract medium.

31. A method according to claim 24, wherein said contrast medium is an ultrasound contrast medium.

20. In a method comprising preparing a dosage form of diagnostic contrast medium, the improvement wherein

an amount of concentrated flowable contrast medium is removed from a first vessel and an amount of fluid is removed from a second vessel by a fluid delivery device for removing predetermined amounts of fluid from a plurality of vessels, and

said amounts of contrast medium and fluid are combined in a mixing chamber and mixed by stirring therein to form a pharmaceutically acceptable dosage form of contrast medium.

21. A method according to claim 20, wherein said diagnostic contrast medium is an iodinated X-ray contrast agent.

22. A method according to claim 20, wherein said diagnostic contrast medium is an NMR contrast medium.

23. A method according to claim 20, wherein said diagnostic contrast medium is an ultrasound contrast medium.

32. In a method comprising performing an X-ray diagnostic examination upon a patient, the improvement wherein an X-ray contrast agent is administered to the patient by:

(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 wherein they are mixed by stirring, thereby forming a contrast medium in a pharmaceutically acceptable dosage form; and

(f) administering said contrast medium dosage form to a patient.

33. In a method comprising performing NMR imaging of a patient, the improvement wherein an NMR contrast agent is administered to the patient by:

(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 wherein they are mixed by stirring, thereby forming a contrast medium in a pharmaceutically acceptable dosage form; and

(f) administering said contrast medium dosage form to a patient.

34. A process for the production of a diagnostic contrast medium in which at least one ultrasound contrast medium compound is mixed with an aqueous solution, comprising:

delivering, under sterile conditions, a predetermined amount of at least a first ultrasound contrast medium concentrate from at least a first container by a first pipe to a mixing chamber;

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

delivering the resultant mixture to a discharge station.

35. A process according to claim 34, wherein said ultrasound contrast agent is a dispersion of cyanoacrylate and/or albumin microspheres of trapped air.

36. A method according to claim 34, wherein said ultrasound contrast medium is an aqueous dispersion of galactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.