Stabilized assembled nanostructures for delivery of encapsulated agents

• US 10,300,023 B1
• Filed: 04/27/2018
• Issued: 05/28/2019
• Est. Priority Date: 10/08/2015
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Karp, Jeffrey M., Joshi, Nitin, Wiradharma, Nikken, Slaughter, Kai Vincent
• Primary Examiner(s): Young, Micah Paul
• Application Number:
  US15/965,499
• Time in Patent Office: 396 Days
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• 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 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• 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 49/0093 Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
• 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 9/1075 Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers A61K9/0026 takes precedence
• CPC Class Codes: A61K 9/1274 Non-vesicle bilayer structures, e.g. liquid crystals, tubules, cubic phases, cochleates; Sponge phases
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: A61P 35/00 Antineoplastic agents

Abstract

A non-covalently assembled hydrogel or organo-gel composition with serum stability is described. Low molecular weight (<2,500 Da), generally regarded as safe (GRAS), materials assemble in the presence of a stabilizing agent at an appropriate molar percentage, forming hydrogel or organo-gel with nanostructures that resist disassembly or destabilization in serum for an extended period of time. The composition is used to deliver one or more therapeutic, prophylactic, or diagnostic agents, allowing for controlled release in response to biological stimuli such as enzymes and a greatly improved dosing efficacy.

Claims

1. A self-assembled organo or hydrogel composition comprising

one or more low molecular weight amphiphilic gelators having a molecular weight of less than 2,500 Da and

one or more stabilizing agents,

wherein the gelators and the stabilizing agents co-assemble into hydrogel or organo-gel comprising nanostructures, or the gelators assemble into hydrogel or organo-gel comprising nanostructures that encapsulate the stabilizing agents,

wherein the composition maintains at least 50, 60, 70 or 80% of its size and does not aggregate to twice the size the composition was prior to exposure to serum proteins for at least 30 minutes in the presence of serum proteins in phosphate buffered saline at 37°

C.

2. The composition of claim 1 wherein the gelator is a compound meeting the requirements of the U.S. Food and Drug Administration as a generally recognized as safe (GRAS) compound.

3. The composition of claim 1, wherein the gelator is selected from the group consisting of ascorbyl alkanoate, sorbitan alkanoate, triglycerol monoalkanoate, sucrose alkanoate, glycocholic acid, and combinations thereof.

4. The composition of claim 3, wherein the gelator is ascorbyl palmitate.

5. The composition of claim 1 wherein the stabilizing agent imparts rigidity, increases the packing density, and/or enhances the strength of assembled structures, thus altering the phase transition process and transitioning temperature, and/or modulating the surface properties of bulk gel or particles thereof to reduce or prevent protein adhesion or accumulation.

6. The composition of claim 1, wherein the stabilizing agent is at least 5, 10, 15, 20, 25, or 30 mole % of the composition.

7. The composition of claim 1, wherein the stabilizing agent is selected from the group consisting of sterols, phospholipids, and low molecular weight therapeutic, prophylactic, or diagnostic agents.

8. The composition of claim 7, wherein the stabilizing agent is cholesterol.

9. The composition of claim 7, wherein the stabilizing agent is a phospholipid.

10. The composition of claim 7 wherein the stabilizing agent is dipalmitoyl phosphatidyl glycerol.

11. The composition of claim 7, wherein the stabilizing agent is docetaxel.

12. The composition of claim 1, wherein the nanostructures comprise fibers, lamellar structures, micellar structures, vesicular structures, sheets or tape-like structures.

13. The composition of claim 1, wherein the hydrogel or organo-gel are in the form of particles.

14. The composition of claim 1, wherein the nanostructures have a hydrodynamic diameter between 300 nm and 900 nm.

15. The composition of claim 1, further comprising one or more therapeutic, prophylactic, or diagnostic agents.

16. The composition of claim 1 further comprising one or more pharmaceutical excipients.

17. The composition of claim 1 comprising a kit comprising a dosage unit.

18. The kit of claim 17, wherein the dosage unit comprises one or more containers for dry components and one or more containers for liquid components, which can be mixed together to form the self-assembled composition.

19. A method of preparing a serum-stabilized, self-assembled hydro- or organo-gel composition comprising nanostructures, comprising:

combining one or more low molecular weight amphiphilic gelators of less than 2,500 Da, one or more stabilizing agents as defined by claim 1, and optionally a therapeutic, prophylactic, or diagnostic agents to form an organo or hydrogel comprising nanostructures.

20. The method of claim 19 wherein the nanostructures are formed from the gelator and incorporate the stabilizing agent.

21. The method of claim 19 wherein the nanostructures are formed and then the stabilizing agent is added to the nanostructures.

22. The method of claim 19 comprising adding to the organo or hydrogel a therapeutic, prophylactic or diagnostic agent.

23. The method of claim 19 further comprising physically separating the organo or hydrogel into particles.

24. The method of claim 19 comprising adding one or more gelators in a polar solvent by mixing or heating,

allowing the mixture to cool,

dissolving the mixture in water by mixing or heating, where gelation occurs,

and optionally removing un-assembled agents and un-encapsulated agents by centrifugation.

25. A method of isolating particles with or without stabilizing agents from the organo or hydrogel composition of claim 1, comprising:

adding water or a solvent or a solution to the organo or hydrogel,

mixing rapidly,

centrifuging, and

removing the supernatant to separate particles of the organo or hydrogel from the organo or hydrogel composition of claim 1.

26. The method of claim 25 comprising adding an aqueous solution or solvent to the centrifuged particles, and dispersing the particles in the aqueous solution by mixing with or without pulse sonication for 2 min.

27. A method of delivering a therapeutic, prophylactic, or diagnostic agent to a subject, comprising administering the composition of claim 15.

28. The method of claim 27, wherein the composition is administered intravenously.

29. The method of claim 27, wherein the composition accumulates in tumors compared to the agent delivered in its free form or in a self-assembled hydrogel or organo-gel without a stabilizing agent.

30. The composition of claim 3, wherein the gelator is triglycerol mono-stearate.