Method of preparing particles suitable for tabletting into diagnostic reagents

• US 4,820,627 A
• Filed: 03/24/1986
• Issued: 04/11/1989
• Est. Priority Date: 03/24/1986
• Status: Expired due to Term

• Current Assignee: EMD Chemicals Incorporated (Merck & Co., Inc.)
• Original Assignee: EM Diagnostic Systems Incorporated
• Inventors: McGeehan, John K.
• Primary Examiner(s): Rosen, Sam
• Application Number:
  US06/842,968
• Time in Patent Office: 1,114 Days
• Field of Search: 424/464, 424/465, 435/4, 435/6, 435/7, 435/11, 435/14, 435/15, 435/17, 435/18, 435/21, 435/25, 435/28, 436/8, 436/174, 436/183
• US Class Current: 435/4
• CPC Class Codes: C12Q 1/00 Measuring or testing processes involving enzymes, nucleic acids or microorganisms measuring or testing apparatus with condition measuring or sensing means, e.g. colony counters, C12M1/34; Compositions therefor; Processes of preparing such compositions
• CPC Class Codes: G01N 33/531 Production of immunochemical test materials
• CPC Class Codes: G01N 33/548 Carbohydrates, e.g. dextran
• CPC Class Codes: Y10T 436/10 Composition for standardization, calibration, simulation, stabilization, preparation or preservation; processes of use in preparation for chemical testing
• CPC Class Codes: Y10T 436/25 including sample preparation

Abstract

A completely water-soluble, solid, labile biochemical-containing diagnostic reagent is prepared without the need of a lyophilization step, by spraying, preferably by a fluidized bed process, an aqueous solution of labile biochemical, e.g., an enzyme, onto small particles, e.g., lower than 20 mesh, of an inert, completely water-soluble solid bulking agent, e.g., mannitol; drying the resultant labile biochemical-coated bulking agent to the desired dryness; and then forming resultant dried labile biochemical-coated bulking agent into a tablet suitable for a diagnostic test reagent, said tablet having a predetermined rate of dissolution.

Claims

1. A process for the preparation of a completely water-soluble, solid, labile biochemical-containing diagnostic reagent, comprising the steps of:

(a) providing an aqueous solution of labile biochemical;

(b) providing particulate, inert, completely water-soluble solid bulking agent;

(c) atomizing and uniformly spraying said aqueous solution of labile biochemical in the form of fine droplets, in a small amount, over an extended time period, onto said particulate bulking agent, the latter undergoing continuous agitation while in contact with a surrounding gaseous medium, and continuously evaporating water from said aqueous solution of labile biochemical while incorporating said labile biochemical on said particulate bulking agent under conditions effective to provide uniform distribution of said labile biochemical on said particulate bulking agent and to prevent substantial agglomeration of said bulking agent or build-up of substantial wetness in said bulking agent;

(d) drying resultant labile biochemical-coated bulking agent to the desired dryness; and

(e) then forming resultant dried labile biochemical-coated bulking agent into a tablet suitable for a diagnostic test reagent, said tablet having a predetermined rate of dissolution.

2. A process according to claim 1, wherein said labile biochemical was never lyophilized.

3. A process according to claim 1, wherein said labile biochemical comprises an enzyme.

4. A process according to claim 1, wherein said labile biochemical comprises an antibody.

5. A process according to claim 1, wherein said labile biochemical comprises a coenzyme.

6. A process according to claim 1, wherein said labile biochemical comprises an nucleotide.

7. A process according to claim 1, wherein said solution of labile biochemical contains an enzyme and a stabilizer to prevent degradation of the enzyme during the process.

8. A process according to claim 1, wherein said particulate bulking agent is non-hygroscopic and substantially spherical in shape.

9. A process according to claim 1, wherein said particulate bulking agent comprises mannitol.

10. A process according to claim 1, wherein said particulate bulking agent consists of mannitol.

11. A process according to claim 9, wherein said labile biochemical is α

-glucosidase, β

-glucosidase, glucose-6-phosphate dehydrogenase, hexokinase, glucose dehydrogenase, mutarotase, cholesterol oxidase, cholesterol esterase, glycerol phosphate oxidase, glycerol kinase or malate dehydrogenase.

12. A process according to claim 10, wherein said enzyme is α

-glucosidase, β

-glucosidase, glucose-6-phosphate dehydrogenase, hexokinase, glucose dehydrogenase or mutarotase.

13. A process according to claim 3, wherein said particulate bulking agent consists essentially of mannitol having a particle size of 40-60 mesh, and wherein said enzyme is glucose-6-phosphate dehydrogenase or hexokinase.

14. A process according to claim 3, wherein said particulate bulking agent consists essentially of mannitol having a particle size of about 40-60 mesh and wherein said enzyme is glucose dehydrogenase or mutarotase.

15. A process according to claim 4, wherein said antibody is a CK-M inhibiting antibody.

16. A process according to claim 5, wherein said coenzyme is pyridoxal 5'"'"' phosphate and the bulking agent comprises cogranules of mannitol and aspartic acid.

17. A process according to claim 6, wherein the nucleotide is nicotinamide adenine dinucleotide and the bulking agent comprises mannitol.

18. A process according to claim 1, further comprising providing a solution of polyethylene glycol 20,000 and intermediate steps (c) and (d) coating the resultant labile biochemical-coated particulate bulking agent with said solution.

19. A product as produced by the process of claim 1.

20. In a method of conducting a diagnostic test which comprises dissolving a diagnostic reagent in an analyte and ascertaining from the physical characteristics from the resultant solution, the assay of said analyte, the improvement which comprises employing as said diagnostic reagent, the product according to claim 19.

21. A process according to claim 1, wherein said labile biochemical is a substrate.

22. A process according to claim 21, wherein said substrate is p-nitrophenyl derivatized dextrans, α

-ketoglutarate, glucose-6-phosphate, phosphoenol pyruvate, glyceraldehyde-3-phosphate or fructose-6-phosphate.

23. A product as produced by the process of claim 2.

24. A product as produced by the process of claim 3.

25. A product as produced by the process of claim 4.

26. A product as produced by the process of claim 5.

27. A product as produced by the process of claim 6.

28. A product as produced by the process of claim 7.

29. A product as produced by the process of claim 8.

30. A product as produced by the process of claim 9.

31. A product as produced by the process of claim 10.

32. A product as produced by the process of claim 11.

33. A product as produced by the process of claim 12.

34. A product as produced by the process of claim 13.

35. A product as produced by the process of claim 14.

36. A product as produced by the process of claim 15.

37. A product as produced by the process of claim 16.

38. A product as produced by the process of claim 17.

39. A product as produced by the process of claim 18.

40. A product as produced by the process of claim 21.

41. A product as produced by the process of claim 22.

42. In the tabletting granulation of a diagnostic reagent comprising the steps of passing particulate material to a tabletting machine and then tabletting the particulate material, the improvement which comprises employing at least in part a product produced by a process comprising the steps of:

(a) providing an aqueous solution of labile biochemical;

(b) providing particulate, inert, non-hygroscopic, completely water-soluble solid bulking agent;

(C) atomizing and uniformly spraying said aqueous solution of labile biochemical in the form of fine droplets, in a small amount, over an extended time period, onto said particulate bulking agent, the latter undergoing continuous agitation while in contact with a surrounding gaseous medium, and continuously evaporating water from said aqueous solution of labile biochemical while incorporating said labile biochemical on said particulate bulking agent under conditions effective to provide uniform distribution of said labile biochemical on said particulate bulking agent and to prevent substantial agglomeration of said bulking agent or build-up of substantial wetness in said bulking agent; and

(d) drying resultant labile biochemical-coated bulking agent to the desired dryness.