Composition useful for in vivo delivery of biologics and methods employing same

• US 5,498,421 A
• Filed: 02/22/1994
• Issued: 03/12/1996
• Est. Priority Date: 02/22/1993
• Status: Expired due to Term

• Current Assignee: Abraxis Bioscience LLC (Bristol-Myers Squibb Company)
• Original Assignee: Vivorx Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Inventors: Soon-Shiong, Patrick, Wong, Michael, Desai, Neil P., Grinstaff, Mark W., Suslick, Kenneth S., Sandford, Paul A.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Benston, Jr., William E.
• Application Number:
  US08/200,235
• Time in Patent Office: 749 Days
• Field of Search: 424/451, 424/45, 424/450
• US Class Current: 424/450
• CPC Class Codes: A23L 33/40 Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 49/18 characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
• CPC Class Codes: A61K 49/1818 particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
• CPC Class Codes: A61K 49/1863 the organic macromolecular compound being a polysaccharide or derivative thereof, e.g. chitosan, chitin, cellulose, pectin, starch
• CPC Class Codes: A61K 49/222 characterised by a special physical form, e.g. emulsions, liposomes
• CPC Class Codes: A61K 49/223 Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
• CPC Class Codes: A61K 49/226 Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
• CPC Class Codes: A61K 9/0026 Blood substitute; Oxygen transporting formulations; Plasma extender
• CPC Class Codes: A61K 9/5052 Proteins, e.g. albumin
• CPC Class Codes: A61K 9/5138 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5146 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
• CPC Class Codes: A61K 9/5161 Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
• CPC Class Codes: A61K 9/5169 Proteins, e.g. albumin, gelatin
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

In accordance with the present invention, there are provided compositions useful for the in vivo delivery of a biologic, wherein the biologic is associated with a polymeric shell formulated from a biocompatible material. The biologic can be associated with the polymeric shell itself, and/or the biologic, optionally suspended/dispersed in a biocompatible dispersing agent, can be encased by the polymeric shell. In another aspect, the biologic associated with polymeric shell is administered to a subject, optionally dispersed in a suitable biocompatible liquid.

Claims

1. A composition for in vivo delivery of a biologic,

wherein said biologic is selected from:

a solid, optionally dispersed in a biocompatible dispersing agent, substantially completely contained within a polymeric shell,

a liquid, optionally dispersed in a biocompatible dispersing agent, substantially completely contained within a polymeric shell,

a gas, optionally dispersed in a biocompatible dispersing agent, substantially completely contained within a polymeric shell,

a gas associated with a polymeric shell, or combinations of any two or more thereof,

wherein the largest cross-sectional dimension of said shell is no greater than about 10 microns,

wherein said polymeric shell comprises a biocompatible material which is substantially crosslinked by way of disulfide bonds, and

wherein said polymeric shell is optionally modified by a suitable agent, wherein said agent is optionally associated with said polymeric shell through an optional covalent linkage.

2. A composition according to claim 1 wherein said polymeric shell, including the solid, liquid or gas associated therewith, is suitable for use as a blood substitute.

3. A composition according to claim 1 wherein said biologic is selected from a pharmaceutically active agent, a diagnostic agent, or an agent of nutritional value.

4. A composition according to claim 3 wherein said pharmaceutically active agent is selected from analgesic agents, anesthetic agents, anti-asthamatic agents, antibiotics, anti-depressant agents, anti-diabetic agents, anti-fungal agents, anti-hypertensive agents, anti-inflammatory agents, anti-neoplastic agents, anxiolytic agents, enzymatically active agents, nucleic acid constructs, immunostimulating agents, immunosuppressive agents, physiologically active gases or vaccines.

5. A composition according to claim 4 wherein said pharmaceutically active agent is a nucleic acid construct.

6. A composition according to claim 3 wherein said diagnostic agent is selected from ultrasound contrast agents, radiocontrast agents, or magnetic contrast agents.

7. A composition according to claim 6 wherein said magnetic contrast agent is a fluorine-containing magnetic resonance imaging agent.

8. A composition according to claim 7 wherein said fluorine-containing magnetic resonance imaging agent is selected from:

(a) C_x F_2x+y-z A_z, wherein;

x=1-30, preferably 5-15,

y=2;

or 0 or -2, when x≧

2;

or -4 when x ≧

4,

z=any whole number from 0 up to (2x+y-1), and

A is selected from H, halogens other than F, --CN, --OR, wherein R is H, alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl, fluoroalkynyl, aryl, fluoroaryl, alkanoyl, fluoroalkanoyl, alkenoyl, fluoroalkenoyl, alkynoyl, fluoroalkynoyl,

(b) [C_x F_2x+y'"'"'-z A_z ]_a JR_b-a, wherein;

x, z, A and R are as defined above,

y'"'"'=+1;

or -1 or -3, when x≧

2;

or -5 when x≧

4,

J=O, S, N, P, Al, or Si,

a=1, 2, 3, or 4, and

b=2 for a divalent J, or

3for a trivalent J,

4 for a tetravalent J,

(c) A'"'"'-[(CF₂)_x -O]_c -A", wherein;

x is as defined above,

A'"'"' is selected from H, halogens, --CN, --OR, wherein R is H, alkyl, fluoroalkyl, alkenyl, fluoroalkenyl, alkynyl, fluoroalkynyl, aryl, fluoroaryl, alkanoyl, fluoroalkanoyl, alkenoyl, fluoroalkenoyl, alkynoyl, fluoroalkynoyl,

A" is selected from H or R, wherein R is as defined above,

c=1-300, or ##STR3## wherein;

x is as defined above, and

c'"'"'=2-20,

as well as mixtures of any two or more thereof.

9. A composition according to claim 7 wherein said diagnostic agent is capable of undergoing a change in relaxation rate due to changes in the local oxygen concentration.

10. A composition according to claim 7 wherein said diagnostic agent is capable of undergoing a solid to liquid phase transition in the temperature range of about 22°

up to 55°

C.

11. A composition according to claim 3 wherein said agent of nutritional value is selected from amino acids, proteins, nucleic acids, sugars, carbohydrates, lipid-soluble vitamins, lipids, or combinations of any two or more thereof.

12. A composition according to claim 3 wherein said pharmacologically active agent within said shell is dissolved or suspended in a biocompatible dispersing agent.

13. A composition according to claim 12 wherein said biocompatible dispersing agent is selected from soybean oil, coconut oil, olive oil, safflower oil, cotton seed oil, aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms, aliphatic or aromatic alcohols having 2-30 carbon atoms, aliphatic or aromatic esters having 2-30 carbon atoms, alkyl, aryl, or cyclic ethers having 2-30 carbon atoms, alkyl or aryl halides having 1-30 carbon atoms, optionally having more than one halogen substutuent, ketones having 3-30 carbon atoms, polyalkylene glycol, or combinations of any two or more thereof.

14. A composition according to claim 3 wherein said pharmacologically active agent is contained within said shell neat.

15. A composition according to claim 1 wherein said crosslinked polymer is a naturally occurring polymer, a synthetic polymer, or a combination thereof,

wherein said polymer, prior to crosslinking, has covalently attached thereto sulfhydryl groups or disulfide linkages.

16. A composition according to claim 15 wherein said naturally occurring polymer is selected from proteins containing sulfhydryl groups and/or disulfide groups, polypeptides containing sulfhydryl groups and/or disulfide groups, lipids containing sulfhydryl groups and/or disulfide groups, polynucleic acids containing sulfhydryl groups and/or disulfide groups, or polysaccharides containing sulfhydryl groups and/or disulfide groups.

17. A composition according to claim 16 wherein said protein is selected from hemoglobin, myoglobin, albumin, insulin, lysozyme, immunoglobulins, α

-2-macroglobulin, fibronectin, vitronectin, fibrinogen, or combinations of any two or more thereof.

18. A composition according to claim 17 wherein said protein is albumin.

19. A composition according to claim 17 wherein said protein is hemoglobin.

20. A composition according to claim 17 wherein said protein is a combination of albumin and hemoglobin.

21. A composition according to claim 16 wherein said polysaccharides are selected from alginate, high M-content alginates, polymannuronic acid, polymannuronates, hyaluronic acid, hyaluronate, heparin, dextran, chitosan, chitin, cellulose, starch, glycogen, guar gum, locust bean gum, dextran, levan, inulin, cyclodextran, agarose, xanthan gum, carageenan, heparin, pectin, gellan gum, scleroglucan, or combinations of any two or more thereof.

22. A composition according to claim 15 wherein said synthetic polymer is selected from synthetic polyamino acids containing cysteine residues and/or disulfide groups, synthetic polypeptides containing sulfhydryl groups and/or disulfide groups, polyvinyl alcohol modified to contain free sulfhydryl groups and/or disulfide groups, polyhydroxyethyl methacrylate modified to contain free sulfhydryl groups and/or disulfide groups, polyacrylic acid modified to contain free sulfhydryl groups and/or disulfide groups, polyethyloxazoline modified to contain free sulfhydryl groups and/or disulfide groups, polyacrylamide modified to contain free sulfhydryl groups and/or disulfide groups, polyvinyl pyrrolidinone modified to contain free sulfhydryl groups and/or disulfide groups, polyalkylene glycols modified to contain free sulfhydryl groups and/or disulfide groups, as well as mixtures of any two or more thereof.

23. A composition according to claim 1 wherein said gas is selected from air, oxygen, argon, nitrogen, carbon monoxide, carbon dioxide, helium, xenon, nitrous oxide, nitric oxide, nitrogen dioxide, or combination of any two or more thereof.

24. A composition according to claim 1 wherein the disulfide bonds on the crosslinked polymer are formed by ultrasonic irradiation.

25. A composition according to claim 1 wherein said polymeric shell containing biologic is suspended in a biocompatible medium, and wherein said biocompatible medium is selected from water, buffered aqueous media, saline, buffered saline, solutions of amino acids, solutions of proteins, solutions of sugars, solutions of vitamins, solutions of carbohydrates, solutions of synthetic polymers, lipid-containing emulsions, or combinations of any two or more thereof.

26. A composition according to claim 1 wherein said polymeric shell is modified by a suitable agent, wherein said suitable agent is selected from a synthetic polymer, phospholipid, a protein, a polysaccharide, a surface active agent, a chemical modifying agent, or combination thereof, wherein said agent is associated with said polymeric shell through an optional covalent linkage.

27. A method for the delivery of biologics to a subject, said method comprising administering to said subject an effective amount of composition according to claim 1.

28. A method for the delivery of a blood substitute to a subject, said method comprising administering to said subject an effective amount of composition according to claim 2.

29. A method for the delivery of biologics to a subject, said method comprising administering to said subject an effective amount of composition according to claim 25.

30. A method to obtain in vivo magnetic resonance images by administering to a subject a composition as described in claim 8.