Stabilized assembled nanostructures for delivery of encapsulated agents

• US 9,962,339 B2
• Filed: 10/07/2016
• Issued: 05/08/2018
• 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:
  US15/288,816
• Publication Number:
  US 20170100342A1
• Time in Patent Office: 578 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 aggregation decreasing agents selected from the group consisting of sterols, phospholipids, and a combination thereof,

wherein the gelators and the aggregation decreasing agents co-assemble into hydrogel or organo-gel comprising nanostructures,

wherein the aggregation decreasing agent is at least 15 mole % of the composition.

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 aggregation decreasing 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 aggregation decreasing agent is at least 20, 25, or 30 mole % of the composition.

7. The composition of claim 1, wherein the aggregation decreasing agent is cholesterol.

8. The composition of claim 1, wherein the aggregation decreasing agent is a phospholipid.

9. The composition of claim 1, wherein the aggregation decreasing agent is dipalmitoyl phosphatidyl glycerol.

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

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

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

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

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

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

16. The kit of claim 15, wherein the dosage unit comprises one or more containers for dry components and one or more containers for liquid components, which mixed together form the self-assembled composition.

17. 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 aggregation decreasing agents as defined by claim 1, and optionally a therapeutic, prophylactic, or diagnostic agents to form an organo or hydrogel comprising nanostructures.

18. The method of claim 17 wherein the nanostructures are formed from the gelator and incorporate the aggregation decreasing agent.

19. The method of claim 17 wherein the nanostructures are formed and then the aggregation decreasing agent is added to the nanostructures.

20. The method of claim 17 comprising adding to the organo or hydrogel a therapeutic, prophylactic or diagnostic agent.

21. The method of claim 17 further comprising physically separating the organo or hydrogel into particles.

22. The method of claim 17 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.

23. A method of isolating particles with or without aggregation decreasing agents from the organo or hydrogel of claim 1, comprising:

adding water or a solvent or a solution to the organo or hydro gel,

mixing rapidly,

centrifuging, and

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

24. The method of claim 23 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.

25. A method of delivering a therapeutic, prophylactic, or diagnostic agent to a subject, comprising administering the composition of claim 13.

26. The method of claim 25, wherein the composition is administered intravenously.

27. The method of claim 25, wherein the composition accumulates in tumors compared to an agent delivered in its free form or in a self-assembled hydrogel or organo-gel without a aggregation decreasing agent.

28. The composition of claim 1, wherein the composition lacking the one or more aggregation decreasing agents aggregates to at least about twice the size the composition lacking the stabilizing agents 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.

29. The composition of claim 28, wherein the gelator is a triglycerol monoalkanoate.

30. The composition of claim 28, wherein the gelator is triglycerol mono-stearate.