Preparation of diagnostic agents

• US 5,518,709 A
• Filed: 03/15/1993
• Issued: 05/21/1996
• Est. Priority Date: 04/10/1991
• Status: Expired due to Term

• Current Assignee: Quadrant Drug Delivery Limited (Vectura Group Ltd.)
• Original Assignee: Andaris Limited
• Inventors: Johnson, Richard A., Heath, David, Sutton, Andrew D., Senior, Peter J.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US07/956,875
• Time in Patent Office: 1,163 Days
• Field of Search: 264/4.3, 264/4.6, 428/402.2, 424/9, 424/9.52, 128/660.01, 128/660.02, 128/660.05, 128/661.04, 128/662.02, 106/124, 106/125
• US Class Current: 424/9.52
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/225 Microparticles, microcapsules gas-filled to be classified in A61K49/223
• CPC Class Codes: A61K 9/1688 resulting in pure drug agglomerate optionally containing up to 5% of excipient
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: B01J 13/04 by physical processes, e.g. drying, spraying
• CPC Class Codes: B01J 13/043 Drying and spraying
• CPC Class Codes: B01J 13/14 Polymerisation; cross-linking
• CPC Class Codes: Y10S 516/928 Mixing combined with non-mixing operation or step, successively or simultaneously, e.g. heating, cooling, ph change, ageing, milling

Abstract

Microcapsules 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 microcapsules and (ii) reducing the water-solubility of at least the outside of the intermediate microcapsules.

Suitable wall-forming materials include proteins such as albumin and gelatin.

The microcapsules have walls of 40-500 nm thick and are useful in ultrasonic imaging. The control of median size, size distribution and degree of insolubilization and cross-linking of the wall-forming material allows novel microsphere preparations to be produced.

Claims

1. A process of forming a stable, sterile powder comprising hollow microcapsules which are suspendable in a medium suitable for parenteral administration to form a suspension suitable for ultrasound imaging when administered parenterally, said process comprising:

a) providing a solution of a protein selected from the group consisting of collagen, gelatin and serum albumin in a liquid;

b) atomizing said solution through an orifice into a heated gas such that said liquid evaporates thereby forming hollow microcapsules of said protein having a diameter of from 0.05 to 20 μ

m;

c) heating said microcapsules to reduce the water-solubility of said protein thereby obtaining said microcapsules as a stable powder; and

d) rendering said powder sterile.

2. A process according to claim 1, wherein said protein is human albumin prepared from serum or by recombinant DNA techniques.

3. A process according to claim 1 wherein the protein solution contains 10.0-30.0% protein.

4. A process according to claim 1 wherein the hollow microcapsules produced in step b) are 96-98% monomeric protein.

5. A process according to claim 1 wherein the hollow microcapsules produced in step c) contain no more than 5% monomeric protein.

6. A process according to claim 1 wherein said protein solution is atomized under conditions such that steps b) and c) are carried out substantially simultaneously.