Nanocrystals, compositions, and methods that aid particle transport in mucus

Patent metadata

Field	Value
Publication number	US-9056057-B2
Application number	US-201313886493-A
Country	US
Kind code	B2
Filing date	May 3, 2013
Priority date	May 3, 2012
Publication date	Jun 16, 2015
Grant date	Jun 16, 2015

Abstract

Nanocrystals, compositions, and methods that aid particle transport in mucus are provided. In some embodiments, the compositions and methods involve making mucus-penetrating particles (MPP) without any polymeric carriers, or with minimal use of polymeric carriers. The compositions and methods may include, in some embodiments, modifying the surface coatings of particles formed of pharmaceutical agents that have a low water solubility. Such methods and compositions can be used to achieve efficient transport of particles of pharmaceutical agents though mucus barriers in the body for a wide spectrum of applications, including drug delivery, imaging, and diagnostic applications. In certain embodiments, a pharmaceutical composition including such particles is well-suited for administration routes involving the particles passing through a mucosal barrier.

First claim

The invention claimed is:

1. A composition comprising a plurality of coated particles, wherein the coated particle comprises:
a core particle comprising a solid pharmaceutical agent or a salt thereof, wherein the agent or salt has an aqueous solubility of less than or equal to about 1 mg/mL at 25° C. at any point throughout the pH range,
wherein the pharmaceutical agent or salt thereof constitutes at least about 80 wt % of the core particle and a polymer constitutes less than about 20 wt % of each of the core particles; and

a coating comprising a surface-altering agent surrounding the core particle,
wherein the surface-altering agent comprises a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particle,
wherein the hydrophilic block is present at the surface of the coated particle and renders the coated particle hydrophilic, and
wherein the surface-altering agent is present on the surface of the core particle at a density of at least about 0.001 molecules per nanometer squared; and

wherein the coated particles have a relative velocity of greater than 0.5 in mucus.

2. A method, comprising:
delivering to a mucus membrane a composition comprising a plurality of coated particles, wherein the coated particle comprises:
a core particle comprising a solid pharmaceutical agent or a salt thereof, wherein the agent or salt has an aqueous solubility of less than or equal to about 1 mg/mL at 25° C. at any point throughout the pH range,
wherein the pharmaceutical agent or salt thereof constitutes at least about 80 wt % of the core particle and a polymer constitutes less than about 20 wt % of each of the core particles; and

a coating comprising a surface-altering agent surrounding the core particle,
wherein the surface-altering agent comprises a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particle,
wherein the hydrophilic block is present at the surface of the coated particle and renders the coated particle hydrophilic, and
wherein the surface-altering agent is present on the surface of the core particle at a density of at least about 0.001 molecules per nanometer squared; and

wherein the coated particles have a relative velocity of greater than 0.5 in mucus.

3. A method of forming coated particles, comprising:
combining core particles with a solution comprising a surface-altering agent,
wherein the core particles comprise a solid pharmaceutical agent or a salt thereof, wherein the agent or salt has a solubility of less than or equal to about 1 mg/mL in the solution at 25° C.,
wherein the pharmaceutical agent or salt thereof constitutes at least about 80 wt % of each of the core particles and a polymer constitutes less than about 20 wt % of each of the particles; and
coating the core particles with the surface-altering agent to form coated particles,
wherein the surface-altering agent comprises a triblock copolymer comprising a hydrophilic block-hydrophobic block-hydrophilic block configuration, wherein the hydrophobic block has a molecular weight of at least about 2 kDa, and the hydrophilic blocks constitute at least about 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particles,

wherein the hydrophilic block is present at the surface of the coated particles and renders the coated particles hydrophilic, and
wherein the coated particles have a relative velocity of greater than 0.5 in mucus.

4. The composition of claim 1 , wherein the surface-altering agent is covalently attached to the core particles.

5. The composition of claim 1 , wherein the surface-altering agent is non-covalently adsorbed to the core particles.

6. The composition of claim 1 , wherein the surface-altering agent is present on the surfaces of the coated particles at a density of at least about 0.01 molecules per nanometer squared.

7. The composition of claim 1 , wherein the hydrophilic blocks of the triblock copolymer constitute at least about 30 wt % of the triblock copolymer.

8. The composition of claim 7 , wherein the hydrophobic block portion of the triblock copolymer has a molecular weight of at least about 3 kDa.

9. The composition of claim 8 , wherein the triblock copolymer is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) or poly(ethylene glycol)-poly(propylene oxide)-poly(ethylene glycol).

10. The composition of claim 7 , wherein the hydrophilic block of the triblock copolymer comprises poly(ethylene oxide) or poly(ethylene glycol) or a derivative thereof.

11. The composition of claim 10 , wherein the poly(ethylene oxide) or poly(ethylene glycol) block has a molecular weight of at least about 2 kDa.

12. The composition of claim 1 , wherein the hydrophobic block of the triblock copolymer is poly(propylene oxide).

13. The composition of claim 12 , wherein the poly(propylene oxide) block has a molecular weight of, at least about 3 kDa.

14. The composition of claim 1 , wherein the surface-altering agent is present in a coating solution at a concentration of at least about 0.1% (w/v).

15. The composition of claim 1 , wherein the solid pharmaceutical agent is present in a crystalline form.

16. The composition of claim 1 , wherein the solid pharmaceutical agent is present in an amorphous form.

17. The composition of claim 1 , wherein the solid pharmaceutical agent is present in a salt form.

18. The composition of claim 1 , wherein the pharmaceutical agent is at least one of a therapeutic agent or a diagnostic agent.

19. The composition of claim 1 , wherein the pharmaceutical agent is at least one of a small molecule, a peptide, a peptidomimetic, a protein, a nucleic acid, or a lipid.

20. The composition of claim 1 , wherein the pharmaceutical agent or a salt thereof has an aqueous solubility of less than or equal to about 0.1 mg/mL at 25° C.

21. The composition of claim 1 , wherein the pharmaceutical agent constitutes at least about 85 wt % of the core particle.

22. The composition of claim 1 , wherein the core particle has an average size of at least about 20 nm and less than or equal to about 1 μm.

23. The composition of claim 1 , wherein the coated particles have an average size of at least about 20 nm and less than or equal to about 1 μm.

24. The composition of claim 1 , wherein the coated particles diffuse through human cervicovaginal mucus at a diffusivity that is greater than 1/500 the diffusivity that the particles diffuse through water on a time scale of 1 second.

25. The composition of claim 1 , wherein the coated particles have a relative velocity of greater than 0.8 in mucus.

26. The composition of claim 1 , wherein the mucus is human cervicovaginal mucus.

27. A pharmaceutical composition comprising the composition of claim 1 and one or more pharmaceutically acceptable carriers.

28. A pharmaceutical preparation

Assignees

• Kala Pharmaceuticals Inc
• Univ Johns Hopkins
• Univ Johns Hopkins

Inventors

• Popov Alexey
• Enlow Elizabeth M
• Bourassa James
• Gardner Colin R
• Chen Hongming
• Ensign Laura M
• Lai Samuel K
• Yu Tao
• Hanes Justin
• Yang Ming

Classifications

• A61K31/58

  containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048}) · CPC title

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K31/56

  Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids · CPC title

• A61K31/341

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title