Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Patent
1996-07-19
1998-04-21
Kight, John
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
424489, 424491, 252314, 2523635, A61K 4904, A61K 914, B01F 300
Patent
active
057414785
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the preparation of hollow proteinaceous microcapsules. One use for these microcapsules is to enhance ultrasound imaging.
The fact that air bubbles in the body can be used for echocardiography has been known for some time.
WO 92/18164 discloses the spray-drying of a solution of a wall-forming material, preferably a protein such as albumin, to form microcapsules. In WO 94/08627, the pressure at which the solution is sprayed into the heated chamber is reduced, to form larger microcapsules, or the half-life of the microcapsules in the bloodstream is increased, for example by including a surfactant in the solution which is sprayed, or the microcapsules are targeted to a selected part of the body, for example by suspending them in a solution of an electrically charged compound.
U.S. Pat. No. 4,420,442 (Sands; PQ Corpn) discloses adding organic solvents to dispersions of film-forming solids, before the suspensions are spray-dried to form hollow microspheres, but the solvents (for example cellosolve or diglyme) were less volatile than water.
We have now found that, by including a volatile compound in the aqueous solution which is spray-dried, microcapsules with improved properties can be formed, in higher yield, with narrower size distribution and thinner shells.
One aspect of the invention provides a process for forming microcapsules comprising (i) providing a solution of an aqueously-soluble material in an aqueous solvent and (ii) spraying the said solution into a gas such that the aqueous solvent evaporates, thereby forming hollow microcapsules, characterised in that the aqueous solution contains a liquid of greater volatility than water.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partly cut away perspective view from the front and one side of a suitable spray-drying apparatus.
Suitable volatile liquids include ethanol (the preferred volatile liquid) (boiling point 78.3.degree. C.), methanol (b.p. 64.5.degree. C.), and acetone (b.p. 56.degree. C.). The volatile liquid needs to act as a solvent for the wall-forming material and be miscible with water at the ratios used.
The proportion of the aqueous solution which is the volatile liquid will vary according to the identity of the volatile compound, the concentration and identity of the wall-forming material, the temperature and pressures at which the solution is to be sprayed, and the microcapsule product desired. Typically, between 0.1% and 80% v/v, preferably 1-50% v/v and most preferably 5-30% v/v, for example about 20% v/v, of the solution is the volatile liquid. Mixtures of volatile liquids may be used, in which case these percentages refer to the total content of volatile liquid.
The spray-drying may be a one step process such as to provide the desired microcapsule product immediately. Alternatively, the immediate product may be subjected to further process steps, for example heating to further cross-link and insolubilise the protein shell of the microcapsules. This constitutes a two step process.
For a product which is to be injected into the human bloodstream, for example as an echogenic contrast agent in ultrasound diagnostic procedures (which is one intended use of the product), the total process is preferably carried out under sterile conditions. Thus, the protein solution is sterile and nonpyrogenic, the gas in the chamber is first passed through a 0.2 .mu.m filter, the spray-drier is initially autoclaved and so on. Alternatively, or as well, the final product may be sterilised, for example by exposure to ionising radiation.
The wall-forming material is a water-soluble material, preferably a protein (the term being used to include non-naturally occurring polypeptides and polyamino acids). For example, it may be collagen, gelatin or (serum) albumin, in each case (if the microcapsules are to be administered to humans) preferably of human origin (ie derived from humans or corresponding in structure to the human protein) or polylysine or polyglutamate. It may be human serum albumin (HA) derived from blood donations o
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Johnson Richard Alan
Osborne Nicholas
Sutton Andrew Derek
Andaris Limited
Hartley Michael G.
Kight John
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