Preparation of further diagnostic agents

• US 6,348,186 B1
• Filed: 06/05/1995
• Issued: 02/19/2002
• Est. Priority Date: 10/10/1992
• Status: Expired due to Fees

• Current Assignee: Quadrant Drug Delivery Limited (Vectura Group Ltd.)
• Original Assignee: Quadrant Healthcare (UK) Limited (Vectura Group Ltd.)
• Inventors: Sutton, Andrew Derek, Johnson, Richard Alan
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/465,236
• Time in Patent Office: 2,451 Days
• Field of Search: 424/9.52, 424/9.51, 424/9.5, 424/489, 424/499, 128/662.02, 600/458, 516/11, 516/77, 428/213.3, 428/401, 264/12
• US Class Current: 424/9.52
• CPC Class Codes: A61K 47/42 Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein oligopeptides having up to five amino acids A61K47/183; polyamino acids A61K47/34
• CPC Class Codes: A61K 49/22 Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5052 Proteins, e.g. albumin

Abstract

Microspheres are prepared by a process comprising the steps of (i) spray-drying a solution or dispersion of a wall-forming material in order to obtain intermediate microspheres and (ii) reducing the water-solubility of at least the outside of the intermediate microspheres. Suitable wall-forming materials include proteins such as albumin and gelatin. The microsphere have walls of 40-500 nm thick and are useful in ultrasonic imaging. The control of median size, size distribution and degree of insolubilisation and cross-linking of the wall-forming material allows novel microsphere preparations to be produced. In particular, the microspheres may be 15-20 μm, targeted to selected areas of the body or of prolonged life in the circulation.

Claims

1. Microcapsules, suitable for intra-arterial administration, being hollow and enclosing a gas- or vapor-filled space essentially without solid material therein and being capable of being dried to form a powder of such microcapsules, in which more than 30% of the microcapsules have a diameter within a 2 μ

m range and at least 90% have a diameter within the range 12.0-25.0 μ

m.

37. Microcapsules according to claim 1 in which at least 10% of the microcapsules, when suspended in water, are capable of surviving a 0.25 s application of a pressure of 2.66×

10⁴ Pa without bursting, collapsing or filling with water.

2. Microcapsules, suitable for intra-arterial administration, being hollow and enclosing a gas- or vapor-filled space essentially without solid material therein and being capable of being dried to form a powder of such microcapsules, in which the interquartile range of diameters is 2 μ

m or less and the median diameter is between 12.0 μ

m and 25.0 μ

m inclusive.

38. Microcapsules according to claim 2 in which at least 10% of the microcapsules, when suspended in water, are capable of surviving a 0.25 s application of a pressure of 2.66×

10⁴ Pa without bursting, collapsing or filling with water.

3. A pharmaceutical composition suitable for intra-arterial administration, comprising hollow microcapsules of which at least 90% have a diameter of 12.0 to 25.0 μ

m, and at least 30% have a diameter within a 2 μ

m range essentially without solid material therein and being capable of being dried to form a powder of such microcapsules.

39. A composition according to claim 3 in which at least 10% of the microcapsules, when suspended in water, are capable of surviving a 0.25 s application of a pressure of 2.66×

10⁴ Pa without bursting, collapsing or filling with water.

4. A process comprising the step of atomizing a solution or dispersion of a wall-forming material in a liquid carrier into a gas in order to obtain hollow microcapsules by evaporation of the liquid carrier, wherein said microcapsules are suitable for intra-arterial administration, at least 90% of the microcapsules are 12.0-25.0 μ

m in diameter, and at least 30% have a diameter within a 2 μ

m range.

5. A process according to claim 4 wherein the product obtained thereby is subjected to the further step of reducing the water-solubility of at least the outside of the microcapsules.

6. A process according to claim 4 wherein the wall-forming material is a protein.

7. A process according to claim 5 wherein the wall-forming material is a protein.

8. A process according to claim 6 wherein the protein is collagen, gelatin or serum albumin.

9. A process according to claim 8 wherein the protein is human serum albumin, or an analogue or fragment thereof, derived from serum or prepared by recombinant DNA techniques.

10. A process according to claim 7 wherein the protein is collagen, gelatin or serum albumin.

11. A process according to claim 10 wherein the protein is human serum albumin, or an analogue or fragment thereof derived from serum or prepared by recombinant DNA techniques.

12. A process according to any one of claims 6-9 or 10-11 wherein the protein solution or dispersion comprises 10.0-30.0% protein.

13. A process according to any one of claims 6-9 or 10-11 wherein said microcapsules obtained by a process comprising the step of atomizing a solution or dispersion of a wall-forming material in a liquid carrier into a gas in order to obtain hollow microcapsules by evaporation of the liquid carrier, wherein at least 90% of said microcapsules are 12.0-25.0 μ

m in diameter, and at least 30% have a diameter within a 2 μ

m range, comprise 96-98% monomeric protein.

14. A process according to claim 12 wherein said microcapsules obtained by a process comprising the step of atomizing a solution or dispersion of a wall-forming material in a liquid carrier into a gas in order to obtain hollow microcapsules by evaporation of the liquid carrier, wherein at least 90% of said microcapsules are 12.0-25.0 μ

m in diameter, and at least 30% have a diameter within a 2 μ

m range, comprise 96-98% monomeric protein.

15. A process according to any one of claims 7 or 10-11 the microcapsules subjected to the further step of reducing the water-solubility of at least the outside of the microcapsules comprise no more than 5% monomeric protein.

16. A process according to claim 12 wherein the microcapsules subjected to the further step of reducing the water-solubility of at least the outside of the microcapsules comprise no more than 5% monomeric protein.

17. A process according to claim 13 wherein the microcapsules subjected to the further step of reducing the water-solubility of at least the outside of the microcapsules comprise no more than 5% monomeric protein.

18. A process according to claim 14 wherein the microcapsules subjected to the further step of reducing the water-solubility of at least the outside of the microcapsules comprise no more than 5% monomeric protein.

19. A process according to any one of claims 6-9 or 10-11 wherein at least 90% of the microcapsules have a wall thickness of 40-500 nm.

20. A process according to claim 12 wherein at least at 90% of the microcapsules have a wall thickness of 40-500 nm.

21. A process according to claim 13 wherein at least at 90% of the microcapsules have a wall thickness of 40-500 nm.

22. A process according to claim 14 wherein at least 90% of the microcapsules have a wall thickness of 40-500 nm.

23. A process according to claim 15 wherein at least at 90% of the microcapsules have a wall thickness of 40-500 nm.

24. A process according to claim 16 wherein at least at 90% of the microcapsules have a wall thickness of 40-500 nm.

25. A process according to claim 17 wherein at least at 90% of the microcapsules have a wall thickness of 40-500 nm.

26. A process according to claim 18 wherein at least at 90% of the microcapsules have a wall thickness of 40-500 nm.

27. A process according to any one of claims 5-7 or 10-11 wherein the conditions of the atomizing step are such as to achieve the step of reducing the water-solubility of at least the outside of the microcapsules substantially simultaneously with the atomizing.

28. A process according to claim 12 wherein the conditions of the atomizing step are such as to achieve the step of reducing the water-solubility of at least the outside of the microcapsules substantially simultaneously with the atomizing.

29. Microcapsules obtained by a process according to any one of claims 4-9 or 10-11.

30. Microcapsules obtained by a process according to claim 12.

31. Microcapsules obtained by a process according to claim 13.

32. Microcapsules obtained by a process according to claim 14.

33. Microcapsules obtained by a process according to claim 15.

34. Microcapsules obtained by a process according to claim 16.

35. Microcapsules obtained by a process according to claim 17.

36. Microcapsules obtained by a process according to claim 18.