Compositions and methods using microspheres and non-ionic contrast agents

• US 20060251582A1
• Filed: 05/09/2006
• Published: 11/09/2006
• 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
• Granted Patent: US 8,226,926 B2
• Time in Patent Office: Days
• US Class Current: 424/9.410
• 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 suitable for active embolization and/or drug delivery comprising:

(a) a non-ionic contrast agent,

(b) at least one drug, and

(c) a biocompatible polymeric material comprising a polyvinylalcohol polymer or copolymer, an acrylic acid polymer or copolymer, an acrylamide polymer or copolymer, an acrylamide polymer or copolymer, or an acrylic acid ester polymer or 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 microsphere of claim 1, wherein the polymeric material is superabsorbent.

3. The microsphere of claim 1, wherein the polymeric material further comprises a polyacrylate, polyacetal, polyamide, polycarbonate, polyester, polyimide, polyolefin, polyurethane, polystyrene, polysaccharide or a mixture thereof.

4. The microsphere of claim 1, wherein the polymeric material comprises a polyvinylalcohol-polyacrylate copolymer.

5. The microsphere of claim 4, wherein the polyacrylate is selected from the group consisting of sodium acrylate, potassium acrylate, ammonium acrylate, and mixtures thereof.

6. The microsphere of claim 1, wherein the biocompatible polymeric material is a polyvinylalcohol and sodium acrylate copolymer.

7. The microsphere of claim 1, wherein the polyvinylalcohol is not cross-linked.

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

9. The microsphere of claim 1, wherein the drug is selected from the group consisting of anti-neoplastic drugs, anti-angiogenesis drugs, anti-fungal drugs, anti-viral drugs, anti-inflammatory drugs, anti-bacterial drugs, anti-histamine drugs, pain-relieving drugs, and mixtures thereof.

10. The microsphere of claim 1, wherein the drug is an anti-neoplastic drug selected from the group consisting of actinomycin D, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, amifostine, aminoglutehimide, amphotercin B, amsacrine, anastrozole, ansamitocin, arabinosyl adenine, arsenic trioxide, asparaginase, aspariginase Erwinia, BCG Live, benzamide, bevacizumab, bexarotene, bleomycin, 3-bromopyruvate, busulfan, calusterone, capecitabine, carboplatin, carzelesin, carmustine, celecoxib, chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, dacarbazine, dactinomycin, Darbepoetin alfa, daunorubicin, daunomycin, denileukin diftitox, dexrazoxane, dexamethosone, docetaxel, doxorubicin, dromostanolone, epirubicin, Epoetin alfa, estramustine, estramustine, etoposide, VP-16, exemestane, filgrastim, floxuridine, fludarabine, fluorouracil (5-FU), flutamide, fulvestrant, demcitabine, gemcitabine, gemtuzumab, goserelin acetate, hydroxyurea, ibritumomab, idarubicin, ifosfamide, imatinib, interferon (e.g., interferon α

-2a, interferon α

-2b), imiotecan, letrozole, leucovorin, leuprolide, lomustine, meciorthamine, megestrol, melphalan, mercaptopurine, mercaptopolylysine, mesna, mesylate, methotrexate, methoxsalen, mithramycin, mitomycin, mitotane, mitoxantrone, nandrolone phenpropionate, nolvadex, oprelvekin, oxaliplatin, paclitaxel, pamidronate sodium, pegademase, pegaspargase, pegfilgrastim, pentostatin, pipobroman, plicamycin, porfimer sodium, procarbazine, quinacrine, raltitrexed, rasburicase, riboside, rituximab, sargramostim, spiroplatin, streptozocin, tamoxifen, tegafur-uracil, temozolomide, teniposide, testolactone, tioguanine, thiotepa, tissue plasminogen activator, topotecan, toremifene, tositumomab, trastuzumab, treosulfan, tretinoin, trilostane valrubicin, vinblastine, vincristine, vindesine, vinorelbine, zoledronate, salts thereof, or mixtures thereof.

11. The microsphere of claim 1, wherein the drug is cisplatin, mitomycin, paclitaxel, tamoxifen, doxorubicin, tamoxifen, or mixtures thereof.

12. The microsphere of claim 9, wherein the drug is a pain-relieving drug selected from the group consisting of ibuprofen, ketoprofen, dexketoprofen, phenyltoloxamine, chlorpheniramine, hurbiprofen, vioxx, celibrex, bexxstan, narbumetone, asperine, codeine, codeine phosphate, acetaminophen, hurbiprofen, paracetamol, xylocalne, salts and combinations thereof.

13. The microsphere of claim 1, wherein the non-ionic contrast agent contains iodine.

14. The microsphere of claim 1, wherein the contrast agent is metrizamide, iodixanol, iohexol, ioversol, iopromide, iobitridol, iomeprol, iopentol, ioxilan, iotrolan, gadodiamide, gadoteridol, or mixtures thereof.

15. The microsphere 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 the at least one drug, wherein the percent indicates the percent maximum saturation of the microsphere.

16. The microsphere of claim 1, wherein the diameter of the microsphere before swelling is from about 40 μ

m to about 1000 μ

m, from about 40 μ

m to about 400 μ

m, from about 50 μ

m to about 300 μ

m, from about 50 μ

m to about 200 μ

m, from about 70 μ

m to about 120 mm, from about 10 μ

m to about 400 μ

m, from about 10 μ

m to about 200 μ

m, from about 10 μ

m to about 120 μ

m, from about 10 μ

m to about 50 μ

m, from about 50 μ

m to about 100 μ

m, from about 53 μ

m to about 106 μ

m, from about 100 μ

m to about 150 μ

m, from about 106 μ

m to about 150 μ

m, from about 150 μ

m to about 200 μ

m, from about 150 μ

m to about 212 μ

m, from about 200 μ

m to about 250 μ

m, about 212 μ

m to about 250 μ

m, from about 250 μ

m to about 300 μ

m, from about 300 μ

m to about 350 μ

m, from about 350 μ

m to about 400 μ

m, from about 400 μ

m to about 450 μ

m, or from about 450 μ

m to about 500 μ

m.

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

m to about 2000 μ

m, from about 10 μ

m to about 1500 μ

m, from about 10 μ

m to about 1000 μ

m, from about 10 μ

m to about 500 μ

m, from about 10 μ

m to about 250 μ

m, from about 10 μ

m to about 150 μ

m, from about 750 μ

m to about 880 μ

m, or from about 1050 μ

m to about 1230 μ

m.

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

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

20. An injectable composition comprising the microsphere of claim 1 and a biocompatible carrier.

21. A method for active embolization in a mammal, comprising administering to the mammal in need of treatment thereof a substantially spherical microsphere comprising:

(a) a non-ionic contrast agent,

(b) at least one drug, and

(c) a biocompatible polymeric material comprising polyvinylalcohol, an acrylic acid polymer or copolymer, an acrylamide polymer or copolymer, an acrylamide polymer or copolymer, or an acrylic acid ester polymer or 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.

22. A method for drug delivery in a mammal, comprising administering to the mammal in need of treatment thereof a substantially spherical microsphere comprising:

(a) a non-ionic contrast agent,

(b) at least one drug, and

(c) a biocompatible polymeric material comprising polyvinylalcohol, an acrylic acid polymer or copolymer, an acrylamide polymer or copolymer, an acrylamide polymer or copolymer, or an acrylic acid ester polymer or 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.