Nanoparticulate and macroparticulate formulations

Patent metadata

Field	Value
Publication number	US-9598377-B2
Application number	US-201414772540-A
Country	US
Kind code	B2
Filing date	Mar 12, 2014
Priority date	Mar 12, 2013
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The present invention is directed to particles prepared via the polymerization of at least one surfactant and an isocyanate-containing compound. Pharmaceutical compositions prepared using these particles are also described.

First claim

What is claimed:

1. A method of preparing bendamustine free base-containing particles comprising:
forming an emulsion by mixing a continuous phase comprising an organic solvent, a dispersed phase comprising an aqueous solution of a pharmaceutically acceptable salt of bendamustine, and at least one polyhydric alcohol surfactant;
treating the emulsion with an amount of base sufficient to convert the pharmaceutically acceptable salt of bendamustine to bendamustine free base;
treating the emulsion with a compound comprising at least two isocyanate moieties;
allowing sufficient time for the isocyanate-containing compound to polymerize with the at least one polyhydric alcohol surfactant at the water-polyhydric alcohol interface to form the bendamustine-containing particles; and
optionally isolating the particles.

2. A method of preparing particles comprising:
forming an emulsion comprising a continuous phase comprising an organic solvent, a dispersed aqueous phase, and at least one polyhydric alcohol surfactant;
treating the emulsion with a compound comprising at least two isocyanate moieties;
allowing sufficient time for the compound comprising at least two isocyanate moieties to polymerize with the at least one polyhydric alcohol surfactant at the aqueous phase-polyhydric alcohol interface to form the particles; and
optionally isolating the particles.

3. The method of claim 2 , wherein the aqueous phase comprises water and a water soluble therapeutic agent.

4. The method of claim 3 , wherein the therapeutic agent is a peptide or protein.

5. The method of claim 3 , wherein the therapeutic agent is a polynucleotide.

6. The method of claim 3 , wherein the therapeutic agent is in the form of a pharmaceutically acceptable salt.

7. The method of claim 6 , further comprising treating the emulsion with an amount of base or an amount of acid sufficient to convert the pharmaceutically acceptable salt form of the therapeutic agent into the free acid or free base form of the therapeutic agent.

8. The method of claim 1 , wherein the base is ammonia or an alkyl amine.

9. The method of claim 1 wherein the emulsion is a nanoemulsion.

10. The method of claim 1 , wherein the particles are nanoparticles.

11. The method of claim 1 , wherein the particles are nanocapsules.

12. The method of claim 1 , wherein the particles have an average diameter of between about 50 nm and about 300 nm, about 60 nm to about 600 nm, about 20 nm to about 800 nm, or about 20 nm to about 600 nm.

13. The method of claim 1 , wherein the organic solvent is a C5-10alkane, acetone, ethyl acetate, acetonitrile, or a mixture thereof.

14. The method of claim 13 , wherein the C5-10alkane is pentane, hexane, heptane, octane, nonane, decane, or a mixture thereof.

15. The method of claim 14 , wherein the organic solvent is hexane.

16. The method of claim 1 wherein the polyhydric alcohol surfactant is a surfactant derived from polyethoxylated sorbitan and oleic acid, polyoxyethylene derivatives of sorbitan monolaurate, a surfactant that is a sorbitan ester, or a mixture thereof.

17. The method of claim 1 , wherein the compound comprising at least two isocyanate moieties further comprises at least one pH-sensitive moiety.

18. The method of claim 1 , wherein the compound comprising at least two isocyanate moieties further comprises at least one maleimide moiety.

19. The method of claim 18 , wherein the at least one maleimide moiety serves as a linker to connect the at least one pH-sensitive moiety.

20. The method of claim 17 , wherein the pH-sensitive moiety is a tetrahydropyran moiety.

21. The method of claim 1 , wherein the compound comprising at least two isocyanate moieties further comprises at least one water-solubilizing moiety.

22. The method of claim 18 , wherein the at least one maleimide moiety serves as a linker to connect the at least one water-solubilizing moiety.

23. The method of claim 21 , wherein the at least one water-solubilizing moiety is a PEG moiety, a functionalized PEG moiety, or a mixture thereof.

24. The method of claim 18 , further comprising the step of treating the particles with at least one water-solubilizing compound.

25. The method of claim 24 , wherein the at least one water-solubilizing compound is an SH-PEG-containing compound or an NH2-PEG-containing compound.

26. The method of claim 1 , wherein the compound comprising at least two isocyanate moieties has between four and ten isocyanate moieties.

27. The method of claim 1 , wherein the compound comprising at least two isocyanate moieties is a diisocyanate.

28. The method of claim 27 , wherein the compound comprising at least two isocyanate moieties is an alkyldiisocyanate.

29. The method according to claim 1 wherein the step of isolating the particles comprises the steps of:
a. optionally evaporating the organic solvent; and
b. dispersing the particles in an aqueous solution to form an aqueous dispersion of the particles.

30. The method according to claim 29 further comprising the step of lyophilizing the aqueous dispersion.

31. Particles prepared according to the method of claim 1 .

32. The particles of claim 31 , wherein said particles have an average diameter of between 50 nm and about 300 nm, about 60 nm to about 600 nm, about 20 nm to about 800 nm, or about 20 nm to about 600 nm.

33. A pharmaceutical composition comprising the particles of claim 31 and a pharmaceutically acceptable diluent or excipient.

34. The pharmaceutical composition according to claim 33 , wherein said pharmaceutically acceptable diluent is phosphate-buffered saline (PBS).

35. Nanocapsules comprising a polymeric shell and a core containing bendamustine free base.

36. The nanocapsules of claim 35 wherein the average diameter of said nanocapsules is between about 10 nm about about 1000 nm.

37. The nanocapsules of claim 36 , wherein the average diameter of said nanocapsules is between about 60 nm and about 600 nm.

38. The nanocapsules according to claim 35 , wherein the polymeric shell of said nanocapsules optionally comprises at least one pH-sensitive moiety.

39. The nanocapsules of claim 38 , wherein the pH-sensitive moiety is a tetrahydropyran moiety.

40. The nanocapsules according to claim 35 wherein the polymeric shell optionally comprises at least one targeting ligand.

41. The nanocapsules according to claim 35 , wherein said polymeric shell optionally comprises at least one PEG moiety.

42. A pharmaceutical composition comprising the nanocapsules according to claim 35 and a pharmaceutically acceptable diluent or excipient.

43. A method of treating cancer in a patient comprising administering the pharmaceutical composition according to claim 42 to a patient in need thereof.

44. The method according to claim 43 , wherein the cancer is chronic lymphocytic leukemia, Hodgkin's disease, indolent non-Hodgkin's lymphoma, aggressive non-Hodgkin's lymphoma, multiple myeloma, acute lymphocytic leukemia, breast cancer or lung cancer.

45. The method of claim 43 , wherein the cancer is sarcoma, bladder ca

Assignees

• Cephalon Inc

Inventors

• Brown Peter D
• Drager Anthony S

Classifications

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61K38/02

  Peptides of undefined number of amino acids; Derivatives thereof · CPC title

• A61K47/6935

  the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol · CPC title

• A61K47/60

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

• A61K9/5089

  Processes · CPC title