Compositions for therapeutic percutaneous embolization and the use thereof

• US 4,795,741 A
• Filed: 05/06/1987
• Issued: 01/03/1989
• Est. Priority Date: 05/06/1987
• Status: Expired due to Term

• Current Assignee: Genzyme Biosurgery Corporation (Sanofi )
• Original Assignee: Biomatrix, Inc. (Sanofi )
• Inventors: Larsen, Nancy E., Hilal, Sadek K., Balazs, Endre A., Leshchiner, Adolf
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): Nutter, Nathan M.
• Application Number:
  US07/047,419
• Time in Patent Office: 608 Days
• Field of Search: 514/21, 514/781, 524/17, 524/29, 524/27, 536/4.1
• US Class Current: 424/94.64
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 49/04 X-ray contrast preparations
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61L 24/0073 with a macromolecular matrix
• CPC Class Codes: A61L 24/08 Polysaccharides A61L24/043 takes precedence
• 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: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

Percutaneous emboli are formed for therapeutic and/or corrective reasons by using a composition which includes crosslinked gells of hyaluronic acid (HA), hylan (HY) or mixed crosslinked gels of HA or HY with other materials, thrombin and cationic substances containing quaternary ammonium groups. Other optional materials include fillers and radio-opaque substances.

Claims

1. A composition for effecting embolization in blood vessels which comprises a physical mixture of

(a) a first component which is a cross-linked gel of hyaluronic acid, a cross-linked gel of hylan, or a mixed gel of hyaluronic acid or hylan co-cross-linked with at least one other hydrophilic polymer copolymerizable therewith;

(b) a cationic organic substance containing quaternary ammonium groups; and

(c) thrombin.

2. A composition according to claim 1 wherein said at least one other hydrophilic polymer is a natural or synthetic polysaccharide selected from the group consisting of hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, chondroitin sulfate and heparin, a protein selected from the group consisting of collagen, elastin, albumin, a globulin, keratin sulfate, a sulfated aminoglycosaminoglycan and a synthetic water soluble polymer.

3. A composition according to claim 1 wherein the cationic organic substance containing quaternary ammonium groups is a monomeric compound containing at least one cationic group selected from the group consisting of choline chloride, acetylcholine chloride and N,N,N,N'"'"',N'"'"',N'"'"'-hexamethyl - 1,6-diaminium bromide, hexadimethrine bromide or a soluble high molecular weight polymer containing quaternary ammonium groups.

4. A composition according to claim 1 wherein the thrombin is human thrombin.

5. A composition according to claim 1 wherein the first component has an apparent viscosity η

at a shear rate (γ

=0.01s^-1) of from 10 to several thousands Pa.s;

a dynamic storage modulus at 5 Hz of from 10 to 100 Pa;

a dynamic loss modulus at 5 Hz of from 5 to 20 Pa; and

a pseudoplasticity of from 10 to several thousands.

6. A composition according to claim 1 and further comprising a water insoluble filler.

7. A composition according to claim 6 wherein the water insoluble filler is a hydrophilic, hydrophobic, organic or inorganic material.

8. A composition according to claim 7 wherein the filler is an inorganic material.

9. A composition according to claim 8 wherein the inorganic material is a metal powder or an insoluble salt.

10. A composition according to claim 9 wherein the insoluble salt is barium sulfate.

11. A composition according to claim 7 wherein the filler is an organic material.

12. A composition according to claim 11 wherein the organic material is microcrystalline cellulose, polyethylene, polytetrafluoroethylene, cross-linked hyaluronic acid, agarose or an ion-exchange resin.

13. A composition according to claim 1 and further comprising a radio-opaque substance.

14. A composition according to claim 13 wherein the radio-opaque substance is an inorganic filler selected from the group consisting of powdered tantalum and barium sulfate.

15. A composition according to claim 13 wherein the radio-opaque substance is an iodinated organic substance.

16. A composition according to claim 15 wherein the iodinated organic substance is sodium iothalamate, sodium metrizoate or metrizamide.

17. A composition according to claim 1 wherein the cationic organic substance comprises from 0.1 to 20% by weight of the total weight and the composition contains from 0.5 to 1000 NIH units of thrombin per gram of the composition.

18. A composition according to claim 17 wherein the cationic organic substance comprises from 0.2 to 10% by weight.

19. A composition according to claim 18 wherein the cationic organic substance comprises from 1 to 5% by weight.

20. A composition according to claim 6 wherein the water insoluble filler comprises from 1 to 60% by weight of the total weight of the composition.

21. A composition according to claim 20 wherein the water insoluble filler comprises from 2 to 30% by weight.

22. A composition according to claim 21 wherein the water insoluble filler comprises from 5 to 25% by weight.

23. A composition according to claim 13 wherein the radio-opaque substance comprises from 2 to 30% by weight of the total weight of the composition.

24. A composition according to claim 23 wherein the radio-opaque substance comprises from 4 to 20% by weight.

25. A composition according to claim 24 wherein the radio-opaque substance comprises from 5 to 15% by weight.

26. A composition according to claim 1 and further comprising a fluorescent substance.

27. A method for producing a therapeutic embolus in vivo in an animal comprising intraarterially injecting into an animal an effective amount of a composition as claimed in claim 1.

28. A method for treating a tumor comprising producing an embolus in accordance with the method according to claim 26 at a point upstream of where an artery enters the tumor to be treated, thereby depriving the tumor of nutrients otherwise supplied thereto by said artery.

29. A drug delivery system comprising a composition according to claim 1 and an effective amount of a drug to be delivered from an embolus formed in vivo from the composition.