Nanostructured gels capable of controlled release of entrapped agents

• US 9,974,859 B2
• Filed: 06/06/2016
• Issued: 05/22/2018
• Est. Priority Date: 09/24/2010
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Original Assignee: Brigham and Women's Hospital Incorporated, Massachusetts Institute of Technology
• Inventors: Karp, Jeffrey M., Vemula, Praveen Kumar, Campbell, Nathaniel R., Syed, Abdullah M., Zhang, Sufeng, Farokhzad, Omid C., Langer, Robert S.
• Primary Examiner(s): Wax, Robert A
• Assistant Examiner(s): NIELSEN, THOR B
• Application Number:
  US15/174,267
• Publication Number:
  US 20170000888A1
• Time in Patent Office: 715 Days
• Field of Search: None
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/4188 condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/28 Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
• 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: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Self-assembled gel compositions including a gelator, e.g., an enzyme-cleavable gelator, e.g., having a molecular weight of 2500 or less, are described. The self-assembled gel compositions can encapsulate one or more agents. Methods of making the self-assembled gel compositions, and methods of drug delivery using the self-assembled gel compositions are also described.

Claims

1. A self-assembled gel composition controllably releasing an agent comprising

a gel composition prepared by self-assembly of a homogeneous solution of an enzyme cleavable amphiphilic gelator having a molecular weight of 2500 or less in a concentration of greater than 3 wt/vol % in one or more aqueous solvents containing an organic solvent in a concentration of between 0.5 and 75 vol/vol % of the total solvent volume, wherein the gelator meets the requirements of the FDA for Generally Recognized As Safe compounds;

and

one or more agents for delivery from the gel composition;

wherein the self-assembled gel composition comprises nanostructures comprising lamellar structures, fibers, sheet-like structures, tape-like structures, nanoparticles, or combinations thereof, each comprising the enzyme cleavable amphiphilic gelator;

wherein the one or more agents are at least partially encapsulated or entrapped by the nano structures, and

wherein the agent is released from the gel composition in the presence of enzyme, and

wherein the self-assembled gel is a viscous homogenous gel stable to inversion,

optionally wherein solvent is removed from the gel composition by centrifugation, washing, lyophilization, drying, or combinations thereof.

2. The self-assembled gel composition of claim 1 wherein the enzyme cleavable amphiphilic gelator is an ascorbyl alkanoate selected from the group consisting of ascorbyl palmitate, ascorbyl decanoate ascorbyl laurate, ascorbyl caprylate, ascorbyl myristate, ascorbyl oleate, and combinations thereof.

3. The self-assembled gel composition of claim 2, wherein the ascorbyl alkanoate is ascorbyl palmitate.

4. The self-assembled gel composition of claim 1, wherein the enzyme cleavable amphiphilic gelator is a sorbitan alkanoate selected from the group consisting of sorbitan monostearate, sorbitan decanoate, sorbitan laurate, sorbitan caprylate, sorbitan myristate, sorbitan oleate, and combinations thereof.

5. The self-assembled gel composition of claim 4, wherein the sorbitan alkanoate is sorbitan monostearate.

6. The self-assembled gel composition of claim 1, wherein the enzyme cleavable amphiphilic gelator is a triglycerol monoalkanoate selected from the group consisting of triglycerol monopalmitate, triglycerol monodecanoate, triglycerol monolaurate, triglycerol monocaprylate, triglycerol monomyristate, triglycerol monostearate, triglycerol monooleate, and combinations thereof.

7. The self-assembled gel composition of claim 6, wherein the triglycerol monoalkanoate is triglycerol monopalmitate.

8. The self-assembled gel composition of claim 1, wherein the enzyme cleavable amphiphilic gelator is a sucrose alkanoate selected from the group consisting of sucrose palmitate, sucrose decanoate, sucrose laurate, sucrose caprylate, sucrose myristate, sucrose oleate, and combinations thereof.

9. The self-assembled gel composition of claim 8, wherein the sucrose alkanoate is sucrose palmitate.

10. The self-assembled gel composition of claim 1, wherein the enzyme cleavable amphiphilic gelator is glycocholic acid.

12. The self-assembled gel composition of claim 1, wherein the solvent is removed completely and the self-assembled gel composition is in the form of a powder or powder formulation.

13. The self-assembled gel composition of claim 1, from which all of the solvent has been removed.

14. The self-assembled gel composition of claim 1, wherein the organic solvent is selected from the group consisting of benzene, toluene, carbon tetrachloride, acetonitrile, glycerol, 1,4-dioxane, dimethyl sulfoxide, ethylene glycol, methanol, chloroform, hexane, acetone, N, N′

-dimethyl formamide, ethanol, and combinations thereof.

15. The self-assembled gel composition of claim 1, wherein the one or more agents are selected from the group consisting of peptides, proteins, nucleic acids, polynucleotides, small molecule agents, and combinations thereof.

16. The self-assembled gel composition of claim 1, wherein the one or more agents are selected from the group consisting of anti-inflammatory agents, chemotherapeutics, PARP-inhibitors, steroids, vitamins, anti-pain agents, anti-pyretic agents, anti-depression agents, vasodilators, vasoconstrictors, immune-suppressants, tissue regeneration promoters, combinations thereof.

17. The self-assembled gel composition of claim 1, wherein the one or more agents are selected from the group consisting of dexamethasone, temozolomide, triamcinolone acetonide, camptothecin, iodomethacin, paclitaxel, carmustine, curcumin, cisplatin, BMS-536924, ethambutol, insulin, 1,10-Dioctadecyl-3,3,30,30-tetramethylindodicarbocyanine 4-chlorobenzenesulfonate salt (DiD) dye, Cy3 dye, and small interfering RNA (siRNA).

18. The self-assembled gel composition of claim 16, wherein the PARP-inhibitors are selected from the group consisting of NU1025, BSI-201, AZD-2281, ABT-888, AGO-14699, 4-hydroxyquinazoline, 3-aminobenzamide, 1,5-isoquinolinediol, 4-amino-1,8-naphthalimide, and O⁶-benzylguanine.

19. The self-assembled gel composition of claim 1, wherein the agent is a chemotherapeutic agent.

20. The self-assembled gel composition of claim 19, wherein the chemotherapeutic agent is temozolomide, carmustine, camptothecin, or paclitaxel.

21. The self-assembled gel composition of claim 1, wherein the enzyme cleavable amphiphilic gelator having a molecular weight of 2500 or less is selected from the group consisting of ascorbyl alkanoate, sorbitan alkanoate, triglycerol monoalkanoate, sucrose alkanoate, glycocholic acid, and combinations thereof.

22. The self-assembled gel composition of claim 1, further comprising a non-independent gelator.

23. The self-assembled gel composition of claim 1, wherein the nanostructures are lamellar structures.

24. The self-assembled gel composition of claim 1 wherein the enzyme cleavable amphiphilic gelator and the one or more aqueous solvents are mixed with heating and the viscous homogeneous gel forms within 15 to 45 minutes of cooling.

25. The self-assembled gel composition of claim 1 comprising 4 wt/vol % or more of the enzyme cleavable amphiphilic gelator.

26. The self-assembled gel composition of claim 1 wherein in the absence of enzyme, the agent is released with a minimal burst of less than 20% of agent in the self-assembled gel composition measured at 37°

C. in phosphate buffered saline.

27. The self-assembled gel composition of claim 1 wherein the enzyme cleavable amphiphilic gelator is dissolved in a mixture of water and the organic solvent to form a stable gel in the absence of buffer.

28. The self-assembled gel composition of claim 1 in the form of an inhalable or intranasal dried powder.

29. The self-assembled gel composition of claim 1 in the form of dry powder incorporated into a lozenge or chewing gum.

32. The self-assembled gel composition of claim 1, wherein the organic solvent is in a concentration of between 0.5 and 30 vol/vol % of the solvent volume in the homogeneous solution.

11. A self-assembled gel composition controllably releasing an agent comprising

a gel composition prepared by self-assembly of a homogeneous solution containing at least 3 wt/vol % of an enzyme cleavable amphiphilic gelator having a molecular weight of 2500 or less, a non-independent gelator, in one or more aqueous solvents containing an organic solvent in a concentration of between 0.5 and 75 vol/vol % of the total solvent volume, wherein the gelator meets the requirements of the FDA for Generally Recognized As Safe compounds;

and

one or more agents for delivery from the gel composition after exposure to enzyme under physiological conditions;

wherein the enzyme cleavable amphiphilic gelator and the non-independent gelator in one or more aqueous solvents containing an organic solvent in a concentration of between 0.5 and 75 vol/vol % of the total solvent volume co-self-assemble into a viscous homogeneous gel,

wherein the gel composition is stable to inversion and comprises nanostructures comprising lamellar structures, fibers, sheet-like structures, tape-like structures, nanoparticles, or combinations thereof, each comprising the enzyme cleavable amphiphilic gelator and the non-independent gelator;

wherein the one or more agents are at least partially encapsulated or entrapped by the nano structures; and

wherein solvent is removed from the gel composition by centrifugation, washing, lyophilization, drying, or combinations thereof.

30. The self-assembled gel composition of claim 11, wherein the non-independent gelator is selected from the group consisting of alpha tocopherol acetate, retinyl acetate, and retinyl palmitate.

31. The self-assembled gel composition of claim 11 wherein, in the absence of enzyme, the agent is released with a minimal burst of less than 20% of the agent in the self-assembled gel composition measured at 37°

C. in phosphate buffered saline.

33. The self-assembled gel composition of claim 11, wherein the organic solvent is in a concentration of between 0.5 and 30 vol/vol % of the solvent volume in the homogeneous solution.