Nanocrystals, compositions, and methods that aid particle transport in mucus
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.
1. A composition comprising a plurality of coated particles, wherein the coated particles comprise:
a core particle comprising a solid pharmaceutical agent or a salt thereof, wherein the pharmaceutical agent or salt thereof constitutes at least 80 wt % of the core particle; 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 2 kDa, and the hydrophilic blocks constitute at least 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particle and renders the coated particle hydrophilic,
wherein the coated particles have an average size of at least 5 nm and less than or equal to 1000 nm, and
wherein the coated particles are mucus-penetrating.
2. The composition of claim 1 , wherein the surface-altering agent is covalently attached to the core particles.
3. The composition of claim 1 , wherein the surface-altering agent is non-covalently adsorbed to the core particles.
4. 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 0.001 molecules per nanometer squared.
5. The composition of claim 1 , wherein the hydrophilic blocks of the triblock copolymer constitute at least 30 wt % of the triblock copolymer.
6. The composition of claim 1 , wherein the hydrophilic block of the triblock copolymer comprises poly(ethylene oxide) or poly(ethylene glycol) or a derivative thereof.
7. The composition of claim 1 , wherein the hydrophobic block of the triblock copolymer is poly(propylene oxide).
8. The composition of claim 1 , wherein the triblock copolymer is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) or poly(ethylene glycol)-poly(propylene oxide)-poly(ethylene glycol).
9. The composition of claim 6 , wherein the poly(ethylene oxide) or poly(ethylene glycol) block has a molecular weight of at least 2 kDa.
10. The composition of claim 7 , wherein the poly(propylene oxide) block has a molecular weight of at least 3 kDa.
11. The composition of claim 1 , wherein each of the core particles comprises a crystalline pharmaceutical agent or a salt thereof.
12. The composition of claim 1 , wherein each of the core particles comprises an amorphous pharmaceutical agent or a salt thereof.
13. The composition of claim 1 , wherein each of the core particles comprises a salt of the solid pharmaceutical agent.
14. The composition of claim 1 , wherein the pharmaceutical agent is at least one of a therapeutic agent or a diagnostic agent.
15. 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.
16. The composition of claim 1 , wherein the pharmaceutical agent or a salt thereof has an aqueous solubility of less than or equal to 0.1 mg/mL at 25° C.
17. The composition of claim 1 , wherein the coated particles have an average size of at least 50 nm and less than or equal to 500 nm.
18. The composition of claim 1 , wherein the coated particles have an average size of less than or equal to 400 nm.
19. 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.
20. The composition of claim 1 , wherein the coated particles have a relative velocity of greater than 0.5 in mucus.
21. A composition comprising a plurality of coated particles, wherein the coated particles comprise:
a core particle comprising a solid pharmaceutical agent or a salt thereof, wherein the pharmaceutical agent or salt thereof constitutes at least 80 wt % of the core particle; 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 2 kDa, and the hydrophilic blocks constitute at least 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particle and renders the coated particle hydrophilic,
wherein the coated particles have an average size of less than or equal to 400 nm, and
wherein the coated particles are mucus-penetrating.
22. The composition of claim 21 , wherein the surface-altering agent is covalently attached to the core particles.
23. The composition of claim 21 , wherein the surface-altering agent is non-covalently adsorbed to the core particles.
24. The composition of claim 21 , wherein the surface-altering agent is present on the surfaces of the coated particles at a density of at least 0.001 molecules per nanometer squared.
25. The composition of claim 21 , wherein the hydrophilic blocks of the triblock copolymer constitute at least 30 wt % of the triblock copolymer.
26. The composition of claim 21 , wherein the hydrophilic block of the triblock copolymer comprises poly(ethylene oxide) or poly(ethylene glycol) or a derivative thereof.
27. The composition of claim 21 , wherein the hydrophobic block of the triblock copolymer is poly(propylene oxide).
28. The composition of claim 21 , wherein the triblock copolymer is poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) or poly(ethylene glycol)-poly(propylene oxide)-poly(ethylene glycol).
29. The composition of claim 26 , wherein the poly(ethylene oxide) or poly(ethylene glycol) block has a molecular weight of at least 2 kDa.
30. The composition of claim 27 , wherein the poly(propylene oxide) block has a molecular weight of at least 3 kDa.
31. The composition of claim 21 , wherein each of the core particles comprises a crystalline pharmaceutical agent or a salt thereof.
32. The composition of claim 21 , wherein each of the core particles comprises an amorphous pharmaceutical agent or a salt thereof.
33. The composition of claim 21 , 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.
34. The composition of claim 21 , wherein the coated particles have a relative velocity of greater than 0.5 in mucus.
35. A pharmaceutical composition suitable for inhalation, injection, or topical administration to a mucus membrane, wherein the composition comprises a plurality of coated particles, wherein the coated particles comprise:
a core particle comprising a solid pharmaceutical agent or a salt thereof, wherein the pharmaceutical agent or salt thereof constitutes at least 80 wt % of the core particle; 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 2 kDa, and the hydrophilic blocks constitute at least 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particle and renders the coated particle hydrophilic,
wherein the coated particles have an average size of at least 50 nm and less than or equal to 500 nm, and
wherein the coated particles are mucus-penetrating.
36. A method of delivering a pharmaceutical agent across a mucosal barrier, the method comprising delivering to the mucosal barrier a composition comprising coated particles, wherein the coated particles comprise:
a core particle comprising a solid pharmaceutical agent or a salt thereof, wherein the pharmaceutical agent or salt thereof constitutes at least 80 wt % of the core particle; 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 2 kDa, and the hydrophilic blocks constitute at least 15 wt % of the triblock copolymer,
wherein the hydrophobic block associates with the surface of the core particle and renders the coated particle hydrophilic,
wherein the coated particles have an average size of at least 50 nm and less than or equal to 500 nm, and
wherein the coated particles are mucus-penetrating.
37. The method of claim 36 , wherein the mucosal barrier is mucus or a mucosal membrane.
38. The method of claim 36 , wherein the mucosal barrier is present in a mucosal tissue.
39. The method of claim 36 , wherein the coated particles have an average size of at least 5 nm and less than or equal to 1000 nm.
40. The method of claim 36 , wherein the coated particles have an average size of less than or equal to 400 nm.