Claims for Patent: 10,864,219

Summary for Patent: 10,864,219

Title:	Compositions and methods for ophthalmic and/or other applications
Abstract:	Particles, compositions, and methods that aid particle transport in mucus are provided. The particles, compositions, and methods may be used, in some instances, for ophthalmic and/or other applications. In some embodiments, the compositions and methods may involve modifying the surface coatings of particles, such as particles of pharmaceutical agents that have a low aqueous solubility. Such compositions and methods 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 ophthalmic applications, and may be used for delivering pharmaceutical agents to the front of the eye and/or the back of the eye.
Inventor(s):	Popov; Alexey (Waltham, MA), Enlow; Elizabeth M. (Waltham, MA), Chen; Hongming (Belmont, MA), Bourassa; James (Somerville, MA)
Assignee:	The Johns Hopkins University (Baltimore, MD)
Application Number:	16/221,253
Patent Claims:	1. A method for treating ocular inflammation, comprising: administering to an eye of a subject in need of treatment for ocular inflammation an effective amount of a pharmaceutical composition comprising: (a) a plurality of coated nanoparticles, each coated nanoparticle comprising: (i) a core particle comprising loteprednol etabonate, wherein the loteprednol etabonate constitutes at least 80% of the core particle by weight; and (ii) a mucus penetration-enhancing coating comprising a (poly(ethylene oxide))-(poly(propylene oxide))-(poly(ethylene oxide)) triblock copolymer, wherein the poly(propylene oxide) block has a molecular weight of about 3600 Da and the poly(ethylene oxide) blocks constitute about 70 wt % of the triblock copolymer, and wherein the triblock copolymer is non-covalently adsorbed to the core particle; (b) about 0.5% w/v to about 3% w/v glycerin; and (c) about 0.1% w/v to about 1% w/v sodium chloride; wherein the topical pharmaceutical composition comprises loteprednol etabonate at about 1% w/v in total; wherein the pharmaceutical composition is a topical suspension; and wherein the ratio of the total weight of loteprednol etabonate to the total weight of triblock copolymer comprised in the pharmaceutical composition is about 2:1. 2. The method of claim 1, wherein the method treats post-surgical inflammation or post-surgical pain in the subject. 3. The method of claim 1, wherein the pharmaceutical composition is administered to the subject twice a day. 4. The method of claim 1, wherein the triblock copolymer is poloxamer 407. 5. The method of claim 1, wherein the loteprednol etabonate comprises at least 90 wt % of the core particle. 6. The method of claim 5, wherein the core particle is substantially free of a polymeric component. 7. The method of claim 6, wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm. 8. The method of claim 7, wherein the average size is measured by dynamic light scattering. 9. The method of claim 8, wherein the average size is as measured in Z-average diameter by dynamic light scattering. 10. The method of claim 7, wherein the polydispersity index of the pharmaceutical composition is less than or equal to about 0.5. 11. The method of claim 7, wherein the polydispersity index of the pharmaceutical composition is less than or equal to about 0.4. 12. The method of claim 11, wherein the polydispersity index is measured by dynamic light scattering. 13. The method of claim 5, wherein the coated nanoparticles have the triblock copolymer adsorbed to the core particle at an average density of at least 0.1 molecules/nm.sup.2 and less than 1 molecule/nm.sup.2. 14. The method of claim 5, wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus. 15. The method of claim 5, wherein the pharmaceutical composition further comprises less than or equal to 0.5 wt % 17.alpha.-[(ethoxycarbonyl)oxy]-11.beta.-hydroxy-3-oxoandrosta-4-ene-17-c- arboxylic acid chloromethyl ester relative to the weight of the loteprednol etabonate in the pharmaceutical composition. 16. The method of claim 15, wherein the pharmaceutical composition is made sterile by a sterilization proves comprising gamma irradiation, and wherein the 17.alpha.-[(ethoxycarbonyl)oxy]-11.beta.-hydroxy-3-oxoandrosta-4-ene-17-c- arboxylic acid chloromethyl ester is at less than or equal to 0.5 wt % relative to the weight of the loteprednol etabonate in the pharmaceutical composition after the gamma irradiation. 17. A method for treating ocular inflammation, comprising: administering to an eye of a subject in need of treatment for ocular inflammation a pharmaceutical composition comprising: (a) a plurality of coated nanoparticles, each of the coated nanoparticles comprising: (i) a core particle comprising a single pharmaceutical agent, wherein the single pharmaceutical agent is loteprednol etabonate, and wherein the loteprednol etabonate comprises at least 90 wt % of the core particle; and (ii) a coating on the core particle, the coating comprising poloxamer 407 non-covalently adsorbed to the core particle; and (b) one or more ophthalmically acceptable carriers, additives, and/or diluents; wherein the pharmaceutical composition is a topical suspension; and wherein the pharmaceutical composition comprises about 1% w/v loteprednol etabonate in total and about 0.5% w/v poloxamer 407 in total. 18. The method of claim 17, wherein the method treats post-surgical inflammation in the subject. 19. The method of claim 17, wherein the pharmaceutical composition is administered to the subject twice a day. 20. The method of claim 17, wherein the core particle is substantially free of a polymeric component. 21. The method of claim 17, wherein the pharmaceutical composition comprises an ionic tonicity agent. 22. The method of claim 21, wherein the ionic tonicity agent is sodium chloride. 23. The method of claim 22, wherein the pharmaceutical composition comprises about 0.1 to about 1% w/v sodium chloride. 24. The method of claim 22, wherein the pharmaceutical composition further comprises about 0.5 to about 3% w/v glycerin. 25. The method of claim 17, wherein the coated nanoparticles have a relative velocity of greater than 0.5 and less than 6.0 in human cervicovaginal mucus. 26. The method of claim 17, wherein the coated nanoparticles have poloxamer 407 adsorbed to the core particle at an average density of at least 0.01 molecules/nm.sup.2 and less than 1 molecule/nm.sup.2. 27. The method of claim 26, wherein the average density is at least 0.1 molecules/nm.sup.2 and less than 1 molecule/nm.sup.2. 28. The method of claim 21, wherein the coated nanoparticles have an average size of about 50 nm to about 700 nm. 29. The method of claim 28, wherein the average size is measured by dynamic light scattering. 30. The method of claim 29, wherein the average size is as measured in Z-average diameter by dynamic light scattering. 31. The method of claim 28, wherein the polydispersity index of the pharmaceutical composition is less than or equal to 0.5. 32. The method of claim 28, wherein the polydispersity index of the pharmaceutical composition is less than or equal to 0.4. 33. The method of claim 32, wherein the polydispersity index is measured by dynamic light scattering. 34. The method of claim 24, wherein the pharmaceutical composition comprises less than or equal to 0.5 wt % 17.alpha.-[(ethoxycarbonyl)oxy]-11.beta.-hydroxy-3-oxoandrosta-4-ene-17-c- arboxylic acid chloromethyl ester relative to the weight of the loteprednol etabonate in the pharmaceutical composition. 35. The method of claim 34, wherein the pharmaceutical composition is made sterile by a sterilization process comprising gamma irradiation, and wherein the 17.alpha.-[(ethoxycarbonyl)oxy]-11.beta.-hydroxy-3-oxoandrosta-4-ene-17-c- arboxylic acid chloromethyl ester is at less than or equal to 0.5 wt % relative to the weight of the loteprednol etabonate in the pharmaceutical composition after the gamma irradiation. 36. The method of claim 1, wherein the loteprednol etabonate constitutes at least 95% of the core particle by weight. 37. The method of claim 36, wherein the loteprednol etabonate constitutes at least 99% of the core particle by weight. 38. The method of claim 17, wherein the loteprednol etabonate constitutes at least 95% of the core particle by weight. 39. The method of claim 38, wherein the loteprednol etabonate constitutes at least 99% of the core particle by weight.