Antitumor cystostatic and contrast agent

• US 6,479,033 B1
• Filed: 06/16/1997
• Issued: 11/12/2002
• Est. Priority Date: 12/02/1993
• Status: Expired due to Fees

• Current Assignee: Max Delbruck Zentrum Fur Molekulare Medizin
• Original Assignee: Max Delbruck Zentrum Fur Molekulare Medizin
• Inventors: Stiller, Detlef, Lippmann, Matthias, Pohlen, Uwe, Reszka, Regina, Berger, Gerd
• Primary Examiner(s): Hartley, Michael G.
• Application Number:
  US08/906,603
• Time in Patent Office: 1,975 Days
• Field of Search: 424/9.32, 424/9.3, 424/9.321, 424/9.322, 424/9.35, 424/9.36, 424/9.364, 424/9.365, 424/9.4, 424/9.43, 424/9.45, 424/450, 424/489, 424/492, 424/493, 424/498, 424/499, 424/649
• US Class Current: 424/9.32
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/28 Compounds containing heavy metals
• CPC Class Codes: A61K 33/24 Heavy metals; Compounds thereof
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 47/6913 the liposome being modified on its surface by an antibody
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 49/0476 Particles, beads, capsules, spheres
• CPC Class Codes: A61K 49/1818 particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

The invention concerns a composition for the treatment of tumors, of (i) at least one cytostatic drug component which is unencapsulated or is encapsulated in a PEG-, immuno-, or immuno/PEG liposome, (ii) at least one of lyophilized starch particles, degradable starch particles, and gelatine, in combination with (iii) a contrasting agent containing at least one of iodine, gadolinium, and magnetite.

Claims

1. A composition for the treatment of tumors, which comprises

(a) at least one cytostatic drug component in a PEG-, immuno-, or immuno/PEG liposome, together with

(b) an embolizing agent of at least one of

(i) starch particles or degradable starch particles lyophilized from a solution of starch, whereby the solution has a concentration of about 5 mg/ml to 70 mg/ml, wherein said particle range in size from 40 μ

m to 90 μ

m and are suspended in a physiological salt solution,

(ii) gelatine, or

(iii) nanoparticle, and

(c) a contrasting agent containing at least one of iodine, gadolinium, and magnetite.

2. The composition of claim 1, wherein the cytostatic drug is encapsulated in SUV-PEG, LUV-PEG, REV-PEG, MLV-PEG, anti-Ki-67 immuno PEG liposome, or anti-CEA PEG liposome.

3. The composition of claim 1 in which the component (a) comprises (a) a natural, semisynthetic, or synthetic amphiphilic compound, (b) a steroid, (c) a charged lipid component, (d) a water- or lipid-soluble cytostatic drug, and (e) a carrier optionally containing one or more additives.

4. The composition of claim 3, wherein the optional additive comprises nanoparticles.

5. The composition of claim 3, wherein said amphiphilic compound is a lipid, surfactant, emulsifier, polyethylene glycol, or lipid PEG.

6. The composition of claim 3, wherein said amphiphillic compound has the formula (I)

wherein R₁ and R₂ are independently of each other C_10-20 alkanoyl, alkenoyl, alkyl, and alkenyl.

7. The composition of claim 3, wherein said steroid has the formula (II)

wherein R=H (cholesterol) or CH₂—

CH₂—

O—

CH₂—

CH₂—

OH (diethoxycholesterol).

8. The composition of claim 3, wherein said charged lipid component is the anion of diacetyl phosphate, palmitic acid, stearic acid, the anion of a phospholipid, phosphatid acid, the anion of a sphingolipid, or polyethylene glycol.

9. The composition of claim 8, wherein said charged lipid component is phosphatidyl serine, sulfatid, or MPES-DSPE.

10. The composition of claim 1, wherein said cytostatic drug is carboplatin, 5-fluorouracyl, or 3-fluorouridine.

11. The composition of claim 3, wherein the components (a):

(b);

(c) are present in a molar ratio of from 0.1;

1;

1 to 1;

1;

0.5.

12. The composition of claim 4, wherein the molar ration of the component (c):

(d) is from 2;

1 to 10;

1.

13. The composition of claim 1, wherein the size of said starch particles is from 60 μ

m to 90 μ

m.

14. The composition of claim 1, wherein said gelatine is an absorbable gelatine powder.

15. The composition of claim 1, wherein said nanoparticle comprises Poloxamer.

16. The composition of claim 1, wherein said iodine containing contrasting agent comprises a mono- or polyiodated phenyl derivative.

17. The composition of claim 1, wherein said iodine containing contrasting agent comprises Iopromide, Ioxitalamate, Ioxaglate, Iopamidol, Iohexol, Iotralon, Metrizamide, or Ultravist.

18. The composition of claim 3, comprising said cytostatic drug being 5-fluorouracil encapsulated in SUV-PEG, Spherex starch particles, and gadolinium-DTPA contrasting agent.

19. The composition of claim 3, comprising said cytostatic drug being carboplatin encapsulated in SUV-PEG, Spherex or, gel foam starch particles, and Gadolinium-DTPA contrasting agent.

20. A method of treating a tumor, which comprises administering the composition of claim 1 to a patient in need therefor.

21. The method of claim 20, wherein said tumor is a metastasized liver tumor.

22. A method for preparing the composition of claim 1, when said component (b) comprises lyophilized or degradable starch particles, which comprises dissolving from 30 mg to 90 mg starch particles in from 3 ml to 6 ml contrasting agent, and adding thereto a therapeutically effective amount of said cytostatic drug component in said liposome.