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 particle core comprising one or more solid pharmaceutical agents or salts thereof, and
a coating comprising a surface-altering agent surrounding the particle core;
wherein the one or more solid pharmaceutical agents or salts thereof constitutes at least 95% of the particle core by weight;
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;
wherein the hydrophilic block is present at the surface of the coated particle and renders the coated particle hydrophilic;
wherein the surface-altering agent is present on the surface of the core particle at a density of at least 0.001 molecules per nanometer squared; and,
wherein the coated particles have a relative velocity of greater than 0.5 in mucus.
2. The composition of claim 1 , wherein the one or more solid pharmaceutical agents or salts thereof constitutes at least 99% of the particle core by weight.
3. The composition of claim 1 wherein the coated particles consist essentially of:
a particle core consisting essentially of a solid pharmaceutical agent or a salt thereof, and
a coating comprising a surface-altering agent surrounding the particle core.
4. The composition of claim 1 wherein the coated particles consist of:
a particle core consisting of a solid pharmaceutical agent or a salt thereof, and
a coating comprising a surface-altering agent surrounding the particle core.
5. The composition of claim 1 , wherein the surface-altering agent is covalently attached to the particle core.
6. The composition of claim 1 , wherein the surface-altering agent is non-covalently adsorbed to the particle core.
7. 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 0.01 molecules per nanometer squared.
8. The composition of claim 1 , wherein the hydrophilic blocks of the triblock copolymer constitute at least 30 wt % of the triblock copolymer.
9. The composition of claim 8 , wherein the hydrophobic block portion of the triblock copolymer has a molecular weight of at least 3 kDa.
10. The composition of claim 9 , wherein the triblock copolymer is poly(ethylene oxide)-polypropylene oxide)-poly(ethylene oxide) or poly(ethylene glycol)-poly(propylene oxide)-poly(ethylene glycol).
11. The composition of claim 8 , wherein the hydrophilic block of the triblock copolymer comprises poly(ethylene oxide) or poly(ethylene glycol) or a derivative thereof.
12. The composition of claim 11 , wherein the poly(ethylene oxide) or poly(ethylene glycol) block has a molecular weight of at least 2 kDa.
13. The composition of claim 1 , wherein the hydrophobic block of the triblock copolymer is poly(propylene oxide).
14. The composition of claim 13 , wherein the poly(propylene oxide) block has a molecular weight of at least 3 kDa.
15. The composition of claim 1 , wherein the surface-altering agent is present in the solution at a concentration of at least 0.1% (w/v).
16. The composition of claim 1 , wherein each of the particle cores comprises a crystalline pharmaceutical agent or a salt thereof.
17. The composition of claim 1 , wherein each of the particle cores comprises an amorphous pharmaceutical agent or a salt thereof.
18. The composition of claim 1 , wherein each of the particle cores comprises a salt of the solid pharmaceutical agent.
19. The composition of claim 1 , wherein the pharmaceutical agent is at least one of a therapeutic agent or a diagnostic agent.
20. 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.
21. 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.
22. The composition of claim 1 , wherein the core particle has an average size of at least 20 nm and less than or equal to 1 μm.
23. The composition of claim 1 , wherein the coated particles have an average size of at least 20 nm and less than or equal to 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 suitable for inhalation, injection, or topical administration to a mucus membrane comprising the composition of claim 1 .