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Details for Patent: 5,560,933

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Details for Patent: 5,560,933

Title: Methods for in vivo delivery of substantially water insoluble pharmacologically active agents and compositions useful therefor
Abstract:In accordance with the present invention, there are provided compositions for the in vivo delivery of substantially water insoluble pharmacologically active agents (such as the anticancer drug taxol) in which the pharmacologically active agent is delivered in a soluble form or in the form of suspended particles. In particular, the soluble form may comprise a solution of pharmacologically active agent in a biocompatible dispersing agent contained within a protein walled shell. Alternatively, the protein walled shell may contain particles of taxol. In another aspect, the suspended form comprises particles of pharmacologically active agent in a biocompatible aqueous liquid.
Inventor(s): Soon-Shiong; Patrick (Los Angeles, CA), Desai; Neil P. (Los Angeles, CA), Grinstaff; Mark W. (Pasadena, CA), Sandford; Paul A. (Los Angeles, CA), Suslick; Kenneth S. (Champaign, IL)
Assignee: VivoRx Pharmaceuticals, Inc. (Santa Monica, CA)
Filing Date:Mar 29, 1995
Application Number:08/412,726
Claims:1. A method for the preparation of a substantially water insoluble pharmacologically active agent for in vivo delivery, said method comprising subjecting a mixture comprising:

a dispersing agent containing said pharmacologically active agent dispersed therein, and

aqueous medium containing a biocompatible polymer capable of being crosslinked by disulfide bonds to sonication conditions for a time sufficient to promote crosslinking of said biocompatible polymer by disulfide bonds to produce a polymeric shell containing the pharmacologically active agent therein.

2. A method for the preparation of substantially water insoluble pharmaceutical agents for in vivo delivery, said method comprising subjecting taxol and suitable medium to sonication conditions for a time sufficient to produce particles having a maximum cross-sectional dimension of no greater than about 10 microns.

3. The method according to claim 1 wherein said 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 substituent, ketones having 3-30 carbon atoms, polyalkylene glycol, or combinations of any two or more thereof.

4. The method according to claim 3 wherein said dispersing agent comprises a volatile dispersing agent.

5. The method according to claim 4 wherein the volatile dispersing agent is selected from benzene, toluene, hexane, ethyl ether, dichloromethane, or ethyl acetate.

6. The method according to claim 1 wherein said substantially water insoluble pharmacologically active agent is selected from a pharmaceutically active agent, a diagnostic agent, or an agent of nutritional value.

7. The method according to claim 6 wherein said pharmaceutically active agent is selected from taxol, taxotere, campothecin, aspirin, ibuprofen, piroxicam, cimetidine, substantially water insoluble steroids, phenesterine, duanorubicin, doxorubicin, mitotane, visadine, halonitrosoureas, anthrocylines, ellipticine, diazepam, methoxyfluorane, isofluorane, enfluorane, halothane, benzocaine, dantrolene, or barbiturates.

8. The method according to claim 6 where said pharmaceutically active agent is a substantially water insoluble immunosuppressive agent selected from cyclosporines, azathioprine, 17-ally-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl ]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1. 0.sup.4,9 ]octacos-18-ene-2,3,10,16-tetraone, or prednisone.

9. The method according to claim 6 wherein said diagnostic agent is selected from ultrasound contrast agents radiocontrast agents, or magnetic contrast agents.

10. The method according to claim 9 wherein said radiocontrast agent is selected from iodo-octanes, halocarbons, or renografin.

11. The method according to claim 9 wherein said magnetic contrast agent is a lipid soluble paramagnetic compound.

12. The method according to claim 6 wherein said agent of nutritional value is selected from amino acids, sugars, proteins, carbohydrates, fat-soluble vitamins, or fat, or combinations of any two or more thereof.

13. The method according to claim 12 wherein said pharmacologically active agent within said shell is dissolved in a biocompatible dispersing agent.

14. The method according to claim 1 wherein said pharmacologically active agent within said shell is suspended in a biocompatible dispersing agent.

15. The method according to claim 1 further comprising suspending the polymeric shells in a biocompatible aqueous liquid.

16. The method according to claim 15 wherein said biocompatible aqueous liquid is selected from water, saline, a solution containing appropriate buffers, or a solution containing nutritional agents.

17. The method according to claim 1 wherein said biocompatible 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.

18. The method according to claim 17 wherein said naturally occurring polymers are selected from proteins, lipids, polynucleic acids or polysaccharides.

19. The method according to claim 18 wherein said protein is selected from albumin, insulin, hemoglobin, lysozyme, immunoglobulins, alpha-2-macroglobulin, fibronectin, vitronectin, or fibrinogen.

20. The method according to claim 19 wherein said protein is albumin.

21. The method according to claim 18 wherein said polysaccharide is selected from starch, cellulose, dextrans, alginates, chitosan, pectin, or hyaluronic acid.

22. The method according to claim 17 wherein said synthetic polymers are selected from synthetic polyamino acids containing cysteine residues 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 pyrrolidone 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. The method according to claim 1 wherein the mixture is subjected to sonication conditions comprising acoustic power in the range of 1 up to 1000 watts/cm.sup.2.

24. The method according to claim 1 wherein the mixture is subjected to sonication conditions comprising acoustic power in the range of 50 up to 500 watts/cm.sup.2.

25. The method according to claim 1 wherein the mixture is subjected to sonication for less than 5 minutes.

26. The method according to claim 1 wherein the mixture is subjected to sonication for a time ranging from 15 to 60 seconds.

27. The method according to claim 1 further comprising removing the dispersing agent from the mixture.

28. The method according to claim 1 wherein the largest cross-sectional dimension of said shell is no greater than about 10 microns.
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