# US 9,040,022 B2 · Compositions and methods using microspheres and non-ionic contrast agents

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- Number: US 9,040,022 B2
- Document ID: US9040022B2
- Status: Granted
- Kind: B2
- Application number: 14/180,983
- Filed: 2014-02-14
- Published: 2014-10-23
- Granted: 2015-05-26
- Earliest claimed: 2005-05-09
- Assignees: Biosphere Medical, Inc.
- Applicants: Biosphere Medical, S.A.
- Inventors: Philippe Reb
- Web page: https://patentgrep.com/patent/US9040022B2

## CPC

- A61K 49/1818: {particles, e.g. uncoated or non-functionalised microparticles or nanoparticles}
- A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 33/243: Platinum; Compounds thereof
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 49/0438: {Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol}
- A61K 49/048: {Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer}
- A61K 49/0485: {Nanoparticles, nanobeads, nanospheres, nanocapsules, i.e. having a size or diameter smaller than 1 micrometer}
- A61K 49/10: Organic compounds
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## 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

### Claim 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 μm to about 1000 μm before swelling, and wherein the diameter of the microsphere is from about 40 μm to about 2000 μm after swelling.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

The method of claim 12, wherein the hepatocellular disease is at least one of the following: a liver cancer, a hepatocellular carcinoma, and hepatitis.

### Claim 14 (depends on 12)

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.

### Claim 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 μm to about 1000 μm before swelling, and wherein the diameter of the microsphere is from about 40 μm to about 2000 μm after swelling.

### Claim 16 (depends on 15)

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.

### Claim 17 (depends on 15)

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

### Claim 18 (depends on 15)

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

### Claim 19 (depends on 15)

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

### Claim 20 (depends on 15)

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

### Claim 21 (depends on 15)

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.

### Claim 22 (depends on 15)

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.