Methods of using microspheres for active embolization

• US 8,697,137 B2
• Filed: 03/23/2001
• Issued: 04/15/2014
• Est. Priority Date: 03/24/2000
• Status: Active Grant

• Current Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Original Assignee: Biosphere Medical Inc. (Merit Medical Systems, Inc.)
• Inventors: Vogel, Jean-Marie, Boschetti, Egisto
• Primary Examiner(s): KISHORE, GOLLAMUDI S
• Application Number:
  US10/220,982
• Publication Number:
  US 20030211165A1
• Time in Patent Office: 4,771 Days
• Field of Search: 424/422, 424/450, 424/489, 424/1.1, 424/401, 424/490, 424/501
• US Class Current: 424/501
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61L 2430/36 for embolization or occlusion, e.g. vaso-occlusive compositions or devices artificial blood vessels A61L27/507
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y10T 428/2982 Particulate matter [e.g., sphere, flake, etc.]

Abstract

The present invention relates to injectable compositions comprising biocompatible, swellable, substantially hydrophilic, non-toxic and substantially spherical polymeric material carriers which are capable of efficiently delivering bioactive therapeutic factor(s) for use in embolization drug therapy. The present invention further relates to methods of embolization gene therapy, particularly for the treatment of angiogenic and non-angiogenic-dependent diseases, using the injectable compositions.

Claims

1. A method for the treatment of a solid tumor by active embolization, comprising administering to a patient having the solid tumor a microsphere comprising a biocompatible sodium acrylate and vinyl alcohol copolymer, wherein the microsphere is associated with doxorubicin, and wherein the doxorubicin is released at the site of the tumor.

2. The method of claim 1, wherein said administration results in partial occlusion of blood flow to the tumor.

3. The method of claim 1, wherein said administration results in total occlusion of blood flow to the tumor.

4. The method of claim 1, wherein said administration is by injection into the vasculature of the patient.

5. The method of claim 1, wherein the doxorubicin is contained within the microsphere.

6. The method of claim 1, wherein the doxorubicin is associated with the copolymer by an ionic interaction.

7. The method of claim 1, wherein the composition further comprises a fluorescent marker derivative, chemical dye, contrast agent, magnetic resonance imaging agent, or a mixture thereof.

8. The method of claim 7, wherein the contrast agent is a paramagnetic or superparamagnetic contrast agent, or a mixture thereof.

9. The method of claim 7, wherein the contrast agent is a barium, magnetite or iodine salt, iron oxide, or a mixture thereof.

10. The method of claim 1, wherein the diameter of the microsphere ranges from about 10 μ

m to about 2000 μ

m.

11. The method of claim 10, wherein the diameter of the microsphere ranges from about 40 μ

m to about 1000 μ

m.

12. The method of claim 11, wherein the diameter of the microsphere ranges from about 40 μ

m to about 400 μ

m.

13. The method of claim 12, wherein the diameter of the microsphere ranges from about 50 μ

m to about 300 μ

m.

14. The method of claim 13, wherein the diameter of the microsphere ranges from about 50 μ

m to about 200 μ

m.

15. The method of claim 14, wherein the diameter of the microsphere ranges from about 70 μ

m to about 120 μ

m.

16. The method of claim 1, wherein the diameter of the microsphere ranges from about 10 μ

m to about 400 μ

m before swelling.

17. The method of claim 16, wherein the diameter of the microsphere ranges from about 10 μ

m to about 200 μ

m before swelling.

18. The method of claim 17, wherein the diameter of the microsphere ranges from about 10 μ

m to about 120 μ

m before swelling.

19. The method of claim 1, wherein the diameter of the microsphere ranges from about 10 μ

m to about 2000 μ

m after swelling.

20. The method of claim 1, wherein the microsphere swells prior to administration into the patient.

21. The method of claim 20, wherein the microsphere further swells after administration into the patient.

22. The method of claim 1, wherein the microsphere swells after administration into the patient.

23. The method of claim 1, wherein the microsphere swells up to about 15 times its original size.

24. The method of claim 1, wherein the microsphere is sterile.

25. The method of claim 1, wherein the doxorubicin-loaded microsphere is administered as a composition that further comprises a biocompatible carrier.

26. The method of claim 25, wherein the composition comprises the microspheres in an amount from about 10% to about 90% by weight and the biocompatible carrier in an amount from about 10% to about 90% by weight.

27. The method of claim composition of claim 25, wherein the composition comprises the microspheres in an amount from about 10% to about 50% by weight and the biocompatible carrier in an amount from about 50% to about 90% by weight.

28. The method of claim 25, wherein the composition is a suspension of said microspheres in said biocompatible carrier.

29. The method of claim 28, wherein the biocompatible carrier is an emulsion.

30. The method of claim 28, wherein the biocompatible carrier is a solution selected from the group consisting of aqueous-based, hydro-organic, and non-aqueous solutions, and mixtures thereof.

31. The method of claim 28, wherein the biocompatible carrier comprises a salt composed of cations selected from the group consisting of sodium, potassium, calcium, magnesium, iron, zinc, ammonium, and mixtures thereof, in an amount of from about 0.01 M to about 5 M.

32. The method of claim 31, wherein the salt is supplied in form of a contrast agent.

33. The method of claim 25, wherein the composition is injectable through a needle of about 18 gauge or smaller.

34. The method of claim 1, wherein the drug release is substantially prevented for a period of time.

35. The method of claim 34, wherein the drug is coated on the microsphere, and the drug is maintained on the surface of the microsphere in an amount selected from the group consisting of greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or about 100% until said release.

36. The method of claim 34, wherein the drug is contained within the microsphere in an amount selected from the group consisting of greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90%, or about 100% until said release.

37. The method of claim 34, wherein the period of time is one or more weeks.

38. The method of claim 34, wherein the period of time is one or more months.

39. The method of claim 1, wherein the solid tumor is a hepatic tumor.

40. The method of claim 39, wherein the hepatic tumor is a hepatocellular carcinoma.

41. The method of claim 39, wherein the hepatic tumor is a benign hepatic tumor.

42. The method of claim 41, wherein the benign hepatic tumor is a hepatocellular adenoma, cavernous haemangioma, or focal nodular hyperplasia.

43. The method of claim 41, wherein the benign hepatic tumor is a bile duct adenoma, bile duct cystadenoma, fibroma, lipoma, leiomyoma, mesothelioma, teratoma, myxoma, or nodular regenerative hyperplasia.

44. The method of claim 39, wherein the hepatic tumor is a malignant hepatic tumor.

45. The method of claim 44, wherein the malignant hepatic tumor is a primary malignant hepatic tumor.

46. The method of claim 45, wherein the primary malignant hepatic tumor is cholangiocarcinoma, angiosarcoma, cystadenocarcinoma, squamous cell carcinoma, or hepatoblastoma.