Formulations and carrier systems including farnesylthiosalicylic moieties

Patent metadata

Field	Value
Publication number	US-10376591-B2
Application number	US-201715703110-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Feb 19, 2014
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

A formulation includes a carrier agent formed by conjugating at least one biologically active hydrophobic compound with at least one hydrophilic compound, the at least one biologically active hydrophobic compound selected from the group of farnesylthiosalicylic acid and a derivative of farnesylthiosalicylic acid which is biologically active as an RAS antagonist, wherein a plurality of the carrier agents are adapted to assemble into a structure and the at least one biologically active hydrophobic compound is conjugated with the at least one hydrophilic compound via a linkage which is labile in vivo, and a biologically active compound associated with the carrier agent.

First claim

What is claimed is:

1. A method of forming a formulation, comprising:
forming a carrier agent by conjugating at least one biologically active hydrophobic compound with at least one hydrophilic oligomer or at least one hydrophilic polymer, the at least one biologically active hydrophobic compound selected from the group of farnesylthiosalicylic acid and a derivative of farnesylthiosalicylic acid which is biologically active as an RAS antagonist, wherein a plurality of the carrier agents are adapted to assemble into a structure and the at least one biologically active hydrophobic compound is conjugated with the at least one hydrophilic oligomer or at least one hydrophilic polymer via a linkage which is labile in vivo, and
associating a biologically active compound with the carrier agent.

2. The method of claim 1 wherein the at least one hydrophilic oligomer or at least one hydrophilic polymer is a polyalkylene oxide.

3. The method of claim 2 wherein the at least one biologically active hydrophobic compound is farnesylthiosalicylic acid or a farnesylthiosalicylic acid amide.

4. The method of claim 1 wherein the at least one biologically active hydrophobic compound is selected from the group consisting of S-trans, trans-farnesylthiosalicylic acid, S-trans, trans-farnesylthiosalicylic acid amide (FTS-amide), S-trans, trans-farnesylthiosalicylic acid methylamide (FTS-MA) and S-trans, trans-farnesylthiosalicylic acid dimethylamide (FTS-DMA).

5. The method of claim 1 wherein the linkage comprises at least one of an ester linkage, a disulfide linkage, pH-sensitive linkage, ROS-sensitive linkage, or protease-sensitive linkage.

6. The method of claim 1 wherein the linkage comprises a disulfide linkage.

7. The method of claim 1 wherein the at least one biologically active hydrophobic compound is conjugated with at least one hydrophilic polymer.

8. The method of claim 1 wherein the hydrophilic oligomer or the hydrophilic polymer is selected from the group consisting of a polyalkylene oxide, a polyvinylalcohol, a polyacrylic acid, a polyacrylamide, a polyoxazoline, a polysaccharide and a polypeptide.

9. The method of claim 8 wherein the polyalkylene oxide is a polyethylene glycol.

10. The method of claim 9 wherein the polyethylene glycol has a molecular weight of at least 1 KDa.

11. The method of claim 1 wherein the carrier agent provides a loading capacity for the biologically active compound of at least 10%.

12. The method of claim 1 wherein the biologically active compound is paclitaxel, doxorubicin, curcumin, bicalutamide, etoposide, camptothecin, a camptothecin analog, pemetrexed, docetaxel, epirubicin, doxorubicin, vinblastine, vindesine, etoposide, hydroxycamptothecin, irinotecan, mitoxantrone, tamoxifen, imatinib, gefitinib, erlotinib, sorafenib, and bortezomib.

13. The method of claim 1 wherein the biologically active compound is an anticancer agent.

14. The method of claim 1 wherein the carrier agent is formed by conjugating the at least one biologically active hydrophobic compound with at least one compound interactive agent and the at least one hydrophilic oligomer or at least one hydrophilic polymer, the at least one compound interactive agent comprising at least one group that interacts with the biologically active compound.

15. The method of claim 14 wherein the at least one compound interactive agent comprises at least one of a fluorenylmethyloxycarbonyl group, a carbobenzyloxy group, an isobutoxycarbamate group, a naphthylacetyl group, a carbazole group, a quinolone group, an isoquinolone group, or a group which is a residue of a molecule selected from the group of the biologically active compound, a portion of the biologically active compound, (9H-fluoren-9-yl)methanamine, (9H-fluoren-9-yl)methanol, 9H-fluoren-9-amine, naphthalene, 1,1′-bi-2-naphthol (BINOL), camptothecin, a camptothecin analog, pemetrexed, docetaxel, paclitaxel, epirubicin, doxorubicin, vinblastine, vindesine, etoposide, hydroxycamptothecin, irinotecan, mitoxantrone, tamoxifen, tretinoin, curcumin, imatinib, gefitinib, erlotinib, sorafenib, and bortezomib, or a derivative thereof.

16. The method of claim 14 wherein the at least one compound interactive agent comprises at least one fluorenylmethyloxycarbonyl group or a derivative thereof.

17. The method of claim 1 wherein the plurality of the carrier agents are adapted to assemble into micelles.

18. The method of claim 17 wherein the average size of the micelles is less than 100 nm.

19. The method of claim 17 wherein the average size of the micelles is less than 40 nm.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Li Song
• Huang Yixian
• Zhang Xiaolan
• Gao Xiang

Classifications

• C08G65/33306

  acyclic · CPC title

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C08G65/3311

  containing a hydroxy group · CPC title

• C08G65/331

  containing oxygen {(cyclic ether compounds C08G65/26)} · CPC title

• A61K31/337 Primary

  having four-membered rings, e.g. taxol · CPC title