Preparation of further diagnostic agents

Abstract

Microspheres are prepared by a process comprising (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 microspheres have walls of 40-500 nm thick and are useful in ultrasonic imaging. The control of 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.

1 . Hollow microspheres in which more than 30% of the microspheres have a diameter within a 2 μm range and at least 90% have a diameter within the range 10.1 to 19.9 μm.  
   
   
       2 . Hollow microspheres in which the interquartile range of diameters is 2 μm or less and the median diameter is between 10.1 μm and 19.9 μm inclusive.  
   
   
       3 . Hollow microspheres with proteinaceous walls in which at least 90% of the microspheres have a diameter in the range 1.0-8.0 μm; at least 90% of the microspheres have a wall thickness of 40-500 nm; at least 50% of the protein in the walls of the microspheres is so cross-linked as to be resistant to extraction in 1% HCl for 2 mins; and the microspheres either have an in vivo t½, of at least 5 minutes or are adapted for selective targeting to an area of the human or animal body.  
   
   
       4 . Hollow microspheres according to  claim 3  wherein at least 95% of the protein is cross-linked as said.  
   
   
       5 . Hollow microspheres predominantly of 1.0-10.0 μm in diameter, at least 10% of the microspheres, when suspended in water, being capable of surviving a 0.25 s application of a pressure of 2.66×10 4  Pa without bursting, collapsing or filling with water, wherein the microspheres either have an in vivo t½ of at least 5 minutes or are adapted for selective targeting to an area of the human or animal body.  
   
   
       6 . Hollow microspheres in which more than 30% of the microspheres have a diameter within a 2 μm range and at least 90% have a diameter within the range 1.0-8.0 μm, and the microspheres either have an in vivo t½ of at least 5 minutes or are adapted for selective targeting to an area of the human or animal body.  
   
   
       7 . Hollow microspheres in which the interquartile range of diameters is 2 μm or less, the median diameter is between 2.0 μm and 8.0 μm inclusive and the microspheres either have an in vivo t½ of at least 5 minutes or are adapted for selective targeting to an area of the human or animal body.  
   
   
       8 . A method of generating an image for subsequent inspection, comprising (a) injecting into the body of a mammal microspheres according to  claim 1 , (b) subjecting the mammal or part thereof to suitable ultrasonic radiation and (c) detecting ultrasonic radiation reflected, transmitted, resonated or frequency modulated by the said microspheres.  
   
   
       9 . A pharmaceutical composition suitable for intra-arterial administration, comprising hollow microspheres predominantly of diameter 10.1 to 19.9 μm.  
   
   
       10 . A method of generating an image for subsequent inspection, comprising (a) injecting into the body of a mammal microspheres predominantly of diameter 10.1-19.9 μm, (b) subjecting the mammal or part thereof to suitable ultrasonic radiation and (c) detecting ultrasonic radiation reflected, transmitted, resonated or frequency modulated by the said microspheres.  
   
   
       11 . A process comprising the step of atomising a solution or dispersion of a wall-forming material in a liquid carrier into a gas in order to obtain hollow microspheres by evaporation of the liquid carrier, wherein the microspheres are of 10.1-19.9 μm diameter, or have a human circulation of at least 5 minutes, or are adapted for selective targeting to an area of the human or animal body.  
   
   
       12 . A process according to  claim 11  wherein the product obtained thereby is subjected to the further step of reducing the water-solubility of at least the outside of the microspheres.  
   
   
       13 . A process according to  claim 11  or  12  wherein the wall-forming material is a protein.  
   
   
       14 . A process according to  claim 13  wherein the protein is collagen, gelatin or serum albumin.  
   
   
       15 . A process according to  claim 14  wherein the protein is human serum albumin, or an analogue or fragment thereof, derived from serum or prepared by recombinant DNA techniques.  
   
   
       16 . A process according to  claim 13  wherein the protein solution or dispersion comprises 10.0-30.0% protein.  
   
   
       17 . A process according to  claim 13  wherein the product of the process of  claim 11  comprises 96-98% monomeric protein.  
   
   
       18 . A process according to  claim 13  wherein the product of the step of  claim 12  comprises no more than 5% monomeric protein.  
   
   
       19 . A process according to  claim 12  wherein the conditions of the step of  claim 11  are such as to achieve the step of  claim 12  substantially simultaneously.  
   
   
       20 . Microspheres obtained by a process according to  claim 11 .  
   
   
       21 . Microspheres obtainable by a process according to  claim 11.