Patent EA-001336-B1 (EA)
Title: Contrast media
Inventor: GUNTER WOLFGANG
IPC: A61K49/00
Filed: 1997-01-09
Abstract: 1. A process for producing composite magnetic particles, said process comprising:  (i) forming magnetic particles within carbohydrate, containing aqueous medium; and  (ii) cleaving said carbohydrate whereby to release said composite particles wherein said composite particles have the magnetic saturation moment above 50 EMU/g / r FeOx, r1, which is relaxation time T1, greater than 15 mM<-1>c<-1> (measured at 0.47 Tesla and 40 degree C), and a mean overall particle size is generally in the range 1 to 300 nm. 2. A process as claimed in claim 1 wherein said medium is a gel, wherein said gel contains anionic sites. 3. A process as claimed in claim 1 wherein said magnetic particles are iron oxide particles. 4. A process as claimed in claim 1 wherein said magnetic particles are superparamagnetic. 5. A process as claimed in claim 1 wherein said carbohydrate is a starch. 6. A process as claimed in claim 1 wherein said carbohydrate is oxidatively cleaved. 7. A process as claimed in claim 1 wherein cleavage of said carbohydrate is effected by treatment of particles which comprise a plurality of said magnetic particles within a matrix of said carbohydrate. 8. A process as claimed in claim 1 wherein said composite particles are further treated to attach thereto a coating of a hydrophilic blood-residence-prolonging polymer, wherein said hydrophilic blood-residence-prolonging polymer is present in said medium before step (ii), wherein more preferably said blood-residence-prolonging polymer is a functionalized polyalkyleneoxide. 9. A process as claimed in claim 1 wherein said aqueous medium further contains a linear polymer. 10. A process as claimed in claim 1 wherein said carbohydrate is cleaved following formation of magnetic particle-polymer composite particles. 11. A process as claimed in claim 1 which comprises the following sequential steps:  (i) combining in a heated aqueous solution a starch, ferrous and ferric salts, and a base; (ii) optionally, cooling said solution to below 15 degree C to allow a gel to set; (iii) reducing the pH to within the range 6.0 to 8.5, this step optionally being performed before step (ii); (iv) treating with an oxidant to cleave the starch and release said particles; (v) washing and filtering the released particles;  (vi) optionally, reacting the released particles with a functionalized polyalkyleneoxide derivative to bind said derivative to said particles; and  (vii) optionally, autoclave sterilizing the released particles. 12. A process as claimed in claim 11 wherein the step (iii) is performed by removing an excess water and the base at a reduced pressure prior to performing the step (ii). 13. A process as claimed in claim 12 wherein said base is ammonium hydroxide. 14. A process as claimed in claim 11 wherein the step (iii) is performed by adding an acid to regulate the base excess prior to performing the step (iv). 15. A process as claimed in claim 14 wherein said acid is HCl. 16. A process as claimed in claim 1 wherein the majority of composite particles so released contain a single magnetic particle. 17. A process as claimed in claim 1 wherein the cleavage of step (ii) is performed in two steps with the second cleavage step being so effected as to remove substantially all of said carbohydrate from the magnetic particles, said second cleavage step being effected in the presence of or following the addition of a stabilizing agent which binds to the magnetic particles.  18. A process as claimed in claim 1 wherein process steps (i) and (ii) are effected in the same reaction vessel. 19. A process as claimed in claim 1 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 100, and r2 is a relaxation time T2. 20. A process as claimed in claim 1 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 100. 21. A process as claimed in claim 1 wherein the ratio r2/r1 in said composite particles is less than 3. 22. A process as claimed in claim 1 wherein the ratio r2/r1 in said composite particles is in the range from 1,2 to 3. 23. Composite particles having a mean overall particle size of 4 to 30 nm, the magnetic saturation moment above 50 EMU/g / r FeOx, the value r1 greater than 15 mM<-1>c<-1> (measured at 0.47 Tesla and 40 degree C) and comprising superparamagnetic inorganic core particles with a cleaved carbohydrate coating material, wherein said coating material is preferably a cleaved starch. 24. The particles as claimed in claim 23 further comprising a coating of a hydrophilic blood-residence-prolonging polymer. 25. The particles as claimed in claim 23 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 100. 26. The particles as claimed in claim 23 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 10. 27. The particles as claimed in claim 23 wherein the ratio r2/r1 in said composite particles is less than 3. 28. A process as claimed in claim 1 wherein the ratio r2/r1 in said composite particles is in the range from 1,2 to 3. 29. An aqueous suspension of superparamagnetic inorganic core particles having a mean overall particle size of 4 to 30 nm, the magnetic saturation moment above 50 EMU/g / r FeOx, the value r1 greater than 15 mM<-1>c<-1> (measured at 0.47 Tesla and 40 degree C) said particles being substantially freed of organic coating material and carrying a surface bound inorganic electrostatic stabilizing agent, wherein said agent is an oligo or polyphosphate. 30. Particles as claimed in claim 23 having a mean overall particle diameter of 4 to 30 nm comprising superparamagnetic inorganic core particles with bound to the core particle surface a biodistribution modifier, binding being via a plurality of iron ion binding groups or via an oligo- or polyphosphate group or a phosphonate group attached to said modifier, wherein said biodistribution modifier comprises a polyalkylene oxide moiety, further comprising, more preferably a cleaved carbohydrate coating material, wherein said coating material is preferably a cleaved starch. 31. Particles as claimed in any one of claims 23 to 28 and 30 having bound to the core particle surface a reporter moiety detectable in a diagnostic imaging modality, wherein said reporter moiety is an iodinated organophosphate. 32. An injectable composite particulate agent having a mean overall particle size of 4 to 30 nm, the magnetic saturation moment above 50 EMU/g / r FeOx, the value r1 greater than 15 mM<-1>c<-1> (measured at 0.47 Tesla and 40 degree C), wherein said agent comprising an inorganic particle core having chemically or physically bonded to the surface thereof a hydrophilic-blood-residence-prolonging polymer and provided with a binding site shielding hydrophilic organic polymer coating, wherein said coating material is preferably a cleaved starch, more preferably said hydrophilic-blood-residence-prolonging polymer, which is the functionalized polyalkyleneoxide. 33. The agent as claimed in claim 32 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 100. 34. The agent as claimed in claim 32 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 10. 35. The agent as claimed in claim 32 wherein the ratio r2/r1 in said composite particles is less than 3. 36. The agent as claimed in claim 32 wherein the ratio r2/r1 in said composite particles is in the range from 1,2 to 3. 37. A diagnostic composition comprising particles as claimed in any claim 1 to 28, 30 to 36 or produced according to any one of claims 1 to 28, 30 to 36 together with at least one physiologically acceptable carrier or excipient. 38. A contrast medium composition comprising a contrast effective amount of composite particles comprising superparamagnetic metal oxide core crystals and an organic coating, said core crystals having a mean diameter of 2 to 10 nm, the magnetic saturation moment above 50 EMU/g / r FeOx, the value r1 greater than 15 mM<-1>c<-1> (measured at 0.47 Tesla and 40 degree C), said coating comprising oxidatively cleaved starch, wherein said coating further comprises a functionalized polyalkylene oxide, wherein said core crystals have a mean diameter of from 4 to 8 nm and said particles have a mean diameter of up to 15 nm. 39. The composition as claimed in claim 38 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 100. 40. The composition as claimed in claim 38 wherein the ratio r2/r1 in said composite particles is in the range from 1 to 10. 41. The composition as claimed in claim 38 wherein the ratio r2/r1 in said composite particles is less than 3. 42. The agent as claimed in claim 38 wherein the ratio r2/r1 in said composite particles is in the range from 1,2 to 3. 43. A method of generating a contrast enhanced image of a human or non-human body, said method comprising administering to said body a composition according to any one of claims 37 to 42 and generating an image of a least part of said body into which said agent distributes. 44. A method of determining distribution of a contrast agent within a human or non-human, said method comprising administering to said body a composition according to any one of claims 37 to 42 and detecting a signal from said body emitted or modified by said particles.  45. The use of a composite magnetic particle of or produced according to any one of claims 1 to 36 for the manufacture of a diagnostic contrast agent composition for use in a method of diagnosis involving administration of said composition to a human or non-human animal body.