Compositions and methods using microspheres and non-ionic contrast agents

• US 8,226,926 B2
• Filed: 05/09/2006
• Issued: 07/24/2012
• Est. Priority Date: 05/09/2005
• Status: Active Grant

• Current Assignee: BioSphere Medical, S.A. (Merit Medical Systems, Inc.)
• Original Assignee: BioSphere Medical, S.A. (Merit Medical Systems, Inc.)
• Inventors: Reb, Philippe
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): SAMALA, JAGADISHWAR RAO
• Application Number:
  US11/430,789
• Publication Number:
  US 20060251582A1
• Time in Patent Office: 2,268 Days
• Field of Search: 424422-423, 424/9.3, 424488-489, 424/78.31, 424/1.11, 424/9.36
• US Class Current: 424/1.11
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 33/243 Platinum; Compounds thereof
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 49/0438 Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
• CPC Class Codes: A61K 49/048 Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer
• CPC Class Codes: A61K 49/0485 Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer
• CPC Class Codes: A61K 49/10 Organic compounds
• CPC Class Codes: A61K 49/1818 particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
• CPC Class Codes: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

The present invention relates to compositions and methods for treating diseases and disorders including cancer and various other angiogenic-dependent diseases, vascular malfunctions, arteriovenous malformations (AVM), hemorrhagic processes and treatment of pain, in particular tumor-related pain by drug delivery and/or therapeutic embolization using microspheres. More particularly the invention relates to microspheres containing non-ionic contrast agents, to compositions comprising these microspheres, as well as methods for preparing and using such compositions for embolization therapy. The invention further relates to compositions and methods using detectable microspheres for targeted drug delivery, irrespective of whether embolization is also needed.

Claims

1. A method for managing or treating a hepatocellular disease in a patient, comprising administering to the patient a substantially spherical microsphere comprising:

(a) a non-ionic contrast agent, wherein the contrast agent is metrizamide, iodixanol, iohexyl, ioversol, iopromide, iobitridol, iomeprol, iopentol, ioxilan, iotrolan, or mixtures thereof, (b) doxorubicin, wherein microsphere comprising a biocompatible polymeric material comprising a sodium acrylate and vinyl alcohol copolymer, wherein the microsphere is swellable in a pharmaceutically acceptable solution and has a diameter of from about 10 μ

m to about 2000 μ

m before swelling.

2. The method of claim 1, wherein the polymeric material is high water absorbing or superabsorbant.

3. The method of claim 1, wherein the microsphere is about 10% to about 90% saturated with non-ionic contrast media and about 90% to about 10% saturated with doxorubicin, wherein the percent indicates the percent maximum saturation of the microsphere.

4. The method of claim 1, wherein the diameter of the microsphere after swelling is from about 10 μ

m to about 2000 μ

m.

5. The method of claim 1, wherein the microsphere swells prior to injection into a patient.

6. The method of claim 1, wherein the microsphere swells after injection into a patient.

7. The method of claim 1, wherein the microsphere has a water absorption rate of at least about 300, 400, 500, 600, 700, or 750 g/g dry weight.

8. The method of claim 1, wherein the composition is administered to the liver of the patient.

9. The method of claim 1, wherein the composition is administered to a hepatic artery of the patient.

10. The method of claim 1, wherein the hepatocellular disease is a liver cancer.

11. The method of claim 10, wherein the liver cancer is a benign hepatic tumor.

12. The method of claim 11, wherein the benign hepatic tumor is a hepatocellular adenoma, cavernous haemangioma, or focal nodular hyperplasia.

13. The method of claim 11, wherein the benign hepatic tumor is a bile duct adenoma, bile duct cystadenoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, or nodular regenerative hyperplasia.

14. The method of claim 10, wherein the liver cancer is a malignant hepatic tumor.

15. The method of claim 14, wherein the malignant hepatic tumor is a primary malignant hepatic tumor.

16. The method of claim 15, wherein the primary malignant hepatic tumor is hepatocellular carcinoma, cholangiocarcinoma, angiosarcoma, cystadenocarcinoma, squamous cell carcinoma, or hepatoblastoma.

17. The method of claim 14, wherein the malignant hepatic tumor is a secondary malignant hepatic tumor.

18. The method of claim 1, wherein the patient is a human.

19. The method of claim 18, wherein the human patient is 18-75 years of age.

20. The method of claim 18, wherein the human patient is less than 18 years of age.

21. The method of claim 18, wherein the human patient is older than 75 years of age.

22. The method of claim 1, wherein the non-ionic contrast agent is absorbed, adsorbed or otherwise contained within the microsphere.

23. The method of claim 1, wherein the non-ionic contrast agent is a carrier for the microsphere.

24. The method of claim 1, wherein between about 10% and about 100% of the doxorubicin is released from the microsphere within a period of between about 3 hours and about 10 weeks following the administration to the patient.

25. The method of claim 1, wherein between about 1% and 30% of the doxorubicin is released from the microsphere within a period of between about 72 hours to about four weeks following the administration to the patient.