Compositions and methods using microspheres and non-ionic contrast agents

• US 9,040,022 B2
• Filed: 02/14/2014
• Issued: 05/26/2015
• 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:
  US14/180,983
• Publication Number:
  US 20140314678A1
• Time in Patent Office: 466 Days
• Field of Search: 424/9.37, 424/9.4, 424/9.45, 424/9.5, 424489-490, 424/501
• US Class Current: 424/9.37
• 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 substantially spherical microsphere comprising:

a biocompatible polymeric material comprising polyvinylalcohol,

doxorubicin in a concentration of about 10 mg to about 400 mg of doxorubicin per 100 mg of dry microspheres, and

a non-ionic contrast agent containing iodine, wherein the concentration of the non-ionic contrast agent is from about 100 mg to about 3200 mg iodine per 100 mg of dry microspheres,

wherein the microsphere is swellable in a pharmaceutically acceptable solution and has a diameter of from about 10 μ

m to about 1000 μ

m before swelling, and wherein the diameter of the microsphere is from about 40 μ

m to about 2000 μ

m after swelling.

2. The microsphere of claim 1, wherein the non-ionic contrast agent is selected from at least one of the following:

X-ray, CT, paramagnetic and superparamagnetic contrast agents.

3. The microsphere of claim 1, wherein the non-ionic contrast agent is selected from at least one of the following:

metrizamide, iopamidol, iodixanol, iohexol, ioversol, iopromide, iobitridol, iomeprol, iopentol, iopamiron, ioxilan, iotrolan, iotrol, and combinations thereof.

4. The microsphere of claim 1, wherein the microsphere comprises about 1% to about 95% by weight of polyvinylalcohol.

5. The microsphere of claim 1, wherein the polyvinylalcohol is cross-linked.

6. The microsphere of claim 1, wherein the polyvinylalcohol comprises a copolymer of polyvinylalcohol.

7. The microsphere of claim 1, wherein the polymeric material further comprises an ionic group.

8. The microsphere of claim 1, wherein the polymeric material can absorb at least 5% by weight of water.

9. The microsphere of claim 1, wherein the polymeric material has a water absorption rate between about 300 and about 750 gm/gm of dry weight.

10. The microsphere of claim 1, wherein the concentration of non-ionic contrast agent is from about 100 mg to about 1500 mg iodine per 100 mg of dry microspheres.

11. The microsphere of claim 1, wherein more than 1% but less than 20% of the loaded doxorubicin is configured to be released within a period of 72 hours.

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

13. The method of claim 12, wherein the hepatocellular disease is at least one of the following:

a liver cancer, a hepatocellular carcinoma, and hepatitis.

14. The method of claim 12, wherein between about 10% and about 100% of doxorubicin is released from the microsphere within a period of between about 3 hours and about 10 weeks following administration to the patient.

15. A substantially spherical microsphere comprising:

a biocompatible polymeric material comprising polyvinylalcohol,

a drug selected from at least one of the following;

daunorubicin, daunomycin, doxorubicin, irinotecan and topotecan, wherein the concentration of the drug is from about 10 mg to about 400 mg of drug per 100 mg of dry microspheres, and

a non-ionic contrast agent containing iodine, wherein the concentration of the non-ionic contrast agent is from about 100 mg to about 3200 mg iodine per 100 mg of dry microspheres,

wherein the microsphere is swellable in a pharmaceutically acceptable solution and has a diameter of from about 10 μ

m to about 1000 μ

m before swelling, and wherein the diameter of the microsphere is from about 40 μ

m to about 2000 μ

m after swelling.

16. The microsphere of claim 15, wherein the non-ionic contrast agent is selected from at least one of the following:

metrizamide, iopamidol, iodixanol, iohexol, ioversol, iopromide, iobitridol, iomeprol, iopentol, iopamiron, ioxilan, iotrolan, iotrol, and combinations thereof.

17. The microsphere of claim 15, wherein the microsphere comprises about 1% to about 95% by weight of polyvinylalcohol.

18. The microsphere of claim 15, wherein the polyvinylalcohol is cross-linked.

19. The microsphere of claim 15, wherein the polyvinylalcohol comprises a copolymer of polyvinylalcohol.

20. The microsphere of claim 15, wherein the polymeric material further comprises an ionic group.

21. The microsphere of claim 15, wherein the concentration of non-ionic contrast agent is from about 100 mg to about 1500 mg iodine per 100 mg of dry microspheres.

22. The microsphere of claim 15, wherein more than 1% but less than 20% of the loaded drug is configured to be released within a period of 72 hours.