阅读说明：本技术 改善治疗剂的溶解度和生物利用度的方法 (Method for improving solubility and bioavailability of therapeutic agents ) 是由 A.K.杰哈 于 2018-04-06 设计创作，主要内容包括：本发明涉及制备纳米治疗化合物和包含纳米治疗化合物的组合物的方法。根据本文提供的方法制备的纳米治疗化合物可用于在需要它的受试者中治疗疾病,例如癌症。(The present invention relates to methods of preparing nanotherapeutic compounds and compositions comprising nanotherapeutic compounds. The nanotherapeutic compounds prepared according to the methods provided herein are useful for treating a disease, such as cancer, in a subject in need thereof.)

1. A method, comprising:

i) milling a pharmaceutical composition or a therapeutic agent in a ball milling apparatus to produce a milled nanoparticle form or a milled microparticle form of the pharmaceutical composition or therapeutic agent; and

ii) coating the pharmaceutical composition or therapeutic agent in a milled nanoparticle form or a milled microparticle form with one or more polymers;

wherein the pharmaceutical composition comprises a therapeutic agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

2. The method of claim 1, wherein the nanoparticle form of the pharmaceutical composition comprises a nanoparticle form of the therapeutic agent.

3. The method of claim 1 or 2, wherein the nanoparticle form of the pharmaceutical composition comprises a nanoparticle form of one or more pharmaceutically acceptable excipients.

4. The method of claim 1 or 2, wherein the microparticle form of the pharmaceutical composition comprises a microparticle form of the therapeutic agent.

5. The method of claim 1 or 2, wherein the microparticle form of the pharmaceutical composition comprises a microparticle form of one or more pharmaceutically acceptable excipients.

6. The method of claim 1 or 2, wherein the pharmaceutical composition comprises a solid mixture of the therapeutic agent and one or more pharmaceutically acceptable excipients.

7. The method of any one of claims 1-6, wherein the milling of step i) comprises physically blending the pharmaceutical composition or therapeutic agent.

8. The process of any one of claims 1 to 7, wherein the milling of step i) is carried out in the absence of a solvent component.

9. The process of any one of claims 1 to 8, wherein the median particle size of the pharmaceutical composition or therapeutic agent prior to the grinding of step i) is from about 1 to about 1000 μm.

10. The process of any one of claims 1 to 8, wherein the median particle size of the pharmaceutical composition prior to the grinding of step i) is from about 1 to about 100 μm.

11. The process of any one of claims 1 to 8, wherein the median particle size of the pharmaceutical composition prior to the grinding of step i) is from about 1 to about 75 μm.

12. The process of any one of claims 1 to 8, wherein the median particle size of the pharmaceutical composition prior to the grinding of step i) is from about 1 to about 50 μm.

13. The method of any one of claims 1-12, wherein the median particle size of the pharmaceutical composition is determined by laser diffraction, dynamic light scattering, or a combination thereof.

14. The method of any one of claims 1-13, wherein the surface area of the nanoparticle form of the pharmaceutical composition or therapeutic agent is from about 2 to about 400 times the surface area of the nanoparticle form of the pharmaceutical composition.

15. The method of any one of claims 1-14, wherein the surface area of the nanoparticle form of the pharmaceutical composition or therapeutic agent is from about 10 to about 300 times the surface area of the pharmaceutical composition.

16. The method of any one of claims 1-14, wherein the surface area of the nanoparticle form of the pharmaceutical composition or therapeutic agent is from about 20 to about 200 times the surface area of the pharmaceutical composition.

17. The method of any one of claims 1-16, wherein the surface area of the nanoparticle form of the pharmaceutical composition or therapeutic agent is determined by laser diffraction.

18. The method of any one of claims 1-17, wherein the bioavailability of the nanoparticulate form of the therapeutic agent, or pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 20-fold.

19. The method of any one of claims 1-18, wherein the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 50-fold compared to the therapeutic agent.

20. The method of any one of claims 1-18, wherein the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 20-fold compared to the therapeutic agent.

21. The method of any one of claims 1-18, wherein the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 10-fold compared to the therapeutic agent.

22. The method of any one of claims 1-21, wherein the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 100.

23. The method of any one of claims 1-21, wherein the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 50.

24. The method of any one of claims 1-21, wherein the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 10.

25. The method of any one of claims 1-24, wherein the pharmaceutical composition comprises about 1 to about 20 pharmaceutically acceptable excipients.

26. The method of any one of claims 1-24, wherein the pharmaceutical composition comprises from about 1 to about 10 pharmaceutically acceptable excipients.

27. The method of any one of claims 1-24, wherein the pharmaceutical composition comprises about 1 to about 5 pharmaceutically acceptable excipients.

28. The process of any of claims 1-27, wherein the coating of step ii) is performed using a melt extrusion process, a melt blowing process, a spunbonding process, or a high temperature grinding process.

29. The method of any one of claims 1-28, wherein each of the one or more polymers is independently selected from the group consisting of carboxylic acid functionalized polymers, neutral non-cellulosic polymers, and cellulosic polymers.

30. The method of any one of claims 1-29, wherein the polymer is copovidone.

31. The process of any one of claims 1 to 30, wherein the coating of step ii) further comprises one or more of the following steps: (a) mixing and melting and/or softening the nanoparticle or microparticle form of the pharmaceutical composition or therapeutic agent; (b) extruding a nanoparticle or microparticle form of the pharmaceutical composition or therapeutic agent; and (c) cooling and/or shaping the pharmaceutical composition or therapeutic agent.

32. The method of any one of claims 1-31, wherein the coating of step ii) results in an immediate release composition, a controlled release composition, a sustained release composition, a fast melting composition, a pulsed release composition, a mixed immediate release profile, and/or any combination of release profiles.

33. The method of any one of claims 1-32, wherein the one or more polymers of step ii) are applied to the pharmaceutical composition or therapeutic agent as a coating having a thickness of about 400 nm or less.

34. The method of any one of claims 1-33, wherein the one or more polymers of step ii) are applied to the pharmaceutical composition or therapeutic agent as a coating having a thickness of about 400 nm or greater.

35. The method of any one of claims 1-34, wherein the therapeutic agent is selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents, steroids, antibacterial agents, antiparasitic agents, antiviral agents, antimicrobial agents, and antifungal agents.

36. The method of any one of claims 1-35, wherein the therapeutic agent is a chemotherapeutic agent.

37. The method of any one of claims 1-35, wherein the therapeutic agent is an anti-inflammatory agent.

38. The method of any one of claims 1-35, wherein the therapeutic agent is an immunosuppressive agent.

39. The method of any one of claims 1-35, wherein the therapeutic agent is a steroid.

40. The method of any one of claims 1-35, wherein the therapeutic agent is an antibacterial agent.

41. The method of any one of claims 1-35, wherein the therapeutic agent is an antiparasitic agent.

42. The method of any one of claims 1-35, wherein the therapeutic agent is an antiviral agent.

43. The method of any one of claims 1-35, wherein the therapeutic agent is an antimicrobial agent.

44. The method of any one of claims 1-35, wherein the therapeutic agent is an antifungal agent.

45. The method of any one of claims 1-35, wherein the nanoparticle form of the therapeutic agent or pharmaceutically acceptable salt thereof is crystalline, amorphous, or a combination thereof.

46. The method of any one of claims 1-45, wherein the ball milling device is an attritor device.

47. A compound that is (1) in the form of nanoparticles of a therapeutic agent or a pharmaceutically acceptable salt thereof, or (2) in the form of microparticles of a therapeutic agent or a pharmaceutically acceptable salt thereof, wherein the nanoparticle form or microparticle form is prepared according to the method of any one of claims 1-46.

48. The compound of claim 47, wherein the compound is in the form of nanoparticles of a therapeutic agent or a pharmaceutically acceptable salt thereof.

49. The compound of claim 47, wherein the compound is in the form of microparticles of the therapeutic agent or a pharmaceutically acceptable salt thereof.

50. The compound of claim 47 or 48 in the form of nanoparticles of a therapeutic agent selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents, steroids, antibacterial agents, antiparasitic agents, antiviral agents, antimicrobial agents, and antifungal agents, or a pharmaceutically acceptable salt thereof.

51. The compound of claim 47 or 48 in the form of nanoparticles of a chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

52. The compound of claim 47 or 48, wherein the compound is in the form of nanoparticles of a compound selected from the group consisting of raloxifene, dasatinib, abiraterone, sunitinib, axitinib, vandetanib, or cabozantinib, or a pharmaceutically acceptable salt thereof.

53. The compound of any one of claims 47, 48, and 51, wherein the compound is in the form of nanoparticles of raloxifene or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 47, 48, 51 and 52 wherein said compound is in the form of nanoparticles of raloxifene hydrochloride.

55. The compound of claim 54, wherein the nanoparticulate form of raloxifene hydrochloride is characterized by a DSC thermogram with an endothermic peak at about 267 ℃.

56. The compound of claim 54 or 55, wherein the nanoparticulate form of raloxifene hydrochloride has a DSC thermogram substantially as shown in figure 2.

57. The compound of any one of claims 54-56, wherein the nanoparticulate form of raloxifene hydrochloride has, in terms of 2 Θ, at least 5 XRD peaks selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

58. The compound of any one of claims 54-56, wherein the nanoparticulate form of raloxifene hydrochloride has, in terms of 2 Θ, at least 4 XRD peaks selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

59. The compound of any one of claims 54-56, wherein the nanoparticulate form of raloxifene hydrochloride has, in terms of 2 Θ, at least 3 XRD peaks selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

60. The compound of any one of claims 54-56, wherein the nanoparticulate form of raloxifene hydrochloride has, in terms of 2 Θ, at least 2 XRD peaks selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

61. The compound of any one of claims 54-56, wherein the nanoparticulate form of raloxifene hydrochloride has, in terms of 2 Θ, at least 1 XRD peak selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

62. The compound of any one of claims 54-61, wherein the nanoparticulate form of raloxifene hydrochloride has an XRD spectrum substantially as shown in figure 5.

63. The compound of any one of claims 54-62, wherein the nanoparticulate form of raloxifene hydrochloride has an FTIR spectrum substantially as shown in figure 3.

64. The compound of claim 47 or 48 in the form of nanoparticles of an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

65. The compound of claim 47 or 48 in the form of nanoparticles of an immunosuppressant or a pharmaceutically acceptable salt thereof.

66. The compound of claim 47 or 48, in the form of nanoparticles of a steroid or a pharmaceutically acceptable salt thereof.

67. The compound of claim 47 or 48 in the form of nanoparticles of an antibacterial agent or a pharmaceutically acceptable salt thereof.

68. The compound of claim 47 or 48 in the form of nanoparticles of an antiparasitic agent or a pharmaceutically acceptable salt thereof.

69. The compound of claim 47 or 48, in the form of nanoparticles of an antiviral agent or a pharmaceutically acceptable salt thereof.

70. The compound of claim 47 or 48 in the form of nanoparticles of an antimicrobial agent or a pharmaceutically acceptable salt thereof.

71. The compound of claim 47 or 48 in the form of nanoparticles of an antifungal agent or a pharmaceutically acceptable salt thereof.

72. The compound of claim 47 or 48, wherein the nanoparticle form of the therapeutic agent or a pharmaceutically acceptable salt thereof is crystalline.

73. A pharmaceutical composition comprising a compound of any one of claims 47-63, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

74. The pharmaceutical composition of claim 73, in the form of nanoparticles or microparticles of said pharmaceutical composition.

75. The pharmaceutical composition of claim 73, in the form of microparticles of said pharmaceutical composition.

76. A nanoparticulate form of the pharmaceutical composition prepared according to the process of any one of claims 1-46.

77. A pharmaceutical composition in the form of nanoparticles comprising raloxifene, or a pharmaceutically acceptable salt thereof, prepared according to the method of any one of claims 1-37.

78. A pharmaceutical composition in the form of nanoparticles comprising raloxifene hydrochloride prepared according to the method of any one of claims 1-46.

79. A pharmaceutical composition comprising raloxifene, or a pharmaceutically acceptable salt thereof, in the form of microparticles prepared according to the method of any one of claims 1-46.

80. A pharmaceutical composition comprising raloxifene hydrochloride in the form of microparticles prepared according to the method of any one of claims 1-46.

Technical Field

The present invention relates to methods of preparing nanotherapeutic compounds and compositions comprising nanotherapeutic compounds for treating diseases. The technology may have additional applications, for example in veterinary and agrochemical applications (such as herbicides and/or pesticides).

Background

Improving the bioavailability of a drug can lead to the benefit of treatment of various diseases in patients. Factors that affect the bioavailability of an active agent can include, for example, dosage form, mode of administration, and/or solubility of the active agent.

SUMMARY

The present application provides, among other things, a method comprising:

i) milling the pharmaceutical composition in a ball milling apparatus to produce a nanoparticulate form of the pharmaceutical composition; and

ii) coating the nanoparticulate form of the pharmaceutical composition with one or more polymers;

wherein the pharmaceutical composition comprises a therapeutic agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In some embodiments, the nanoparticle form of the pharmaceutical composition comprises a nanoparticle form of the therapeutic agent. In some embodiments, the pharmaceutical composition comprises a solid mixture of the therapeutic agent and one or more pharmaceutically acceptable excipients.

In some embodiments, the milling of step i) comprises physically blending the pharmaceutical composition. In some embodiments, the milling of step i) is performed in the absence of a solvent component.

In some embodiments, the median particle size of the pharmaceutical composition prior to grinding in step i) is from about 1 to about 100 μm. It is to be understood that if the median particle size of the pharmaceutical composition is greater than about 100 μm, additional particle size reduction techniques may be used to reduce the median particle size prior to performing the milling process provided herein. In some embodiments, the methods provided herein further comprise grinding the pharmaceutical composition having a median particle size of greater than about 100 μm using a grinding technique to form a pharmaceutical composition having a median particle size of from about 1 to about 100 μm.

In some embodiments, the median particle size of the pharmaceutical composition prior to grinding in step i) is from about 1 to about 75 μm. In some embodiments, the median particle size of the pharmaceutical composition prior to grinding in step i) is from about 1 to about 50 μm.

In some embodiments, the median particle size of the pharmaceutical composition is determined by laser diffraction, dynamic light scattering, or a combination thereof.

In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is from about 2 to about 400 times the surface area of the nanoparticle form of the pharmaceutical composition. In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is from about 10 to about 300 times the surface area of the pharmaceutical composition. In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is from about 20 to about 200 times the surface area of the pharmaceutical composition.

In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is determined by laser diffraction.

In some embodiments, the bioavailability of the nanoparticle form of the therapeutic agent or pharmaceutically acceptable salt thereof is increased from about 2-fold to about 20-fold.

In some embodiments, the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 50-fold compared to the therapeutic agent.

In some embodiments, the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 20-fold compared to the therapeutic agent. In some embodiments, the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 10-fold compared to the therapeutic agent.

In some embodiments, the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 100. In some embodiments, the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 50. In some embodiments, the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 10.

In some embodiments, the pharmaceutical composition comprises from about 1 to about 20 pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises from about 1 to about 10 pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises from about 1 to about 5 pharmaceutically acceptable excipients.

In some embodiments, the coating of step ii) is performed using a melt extrusion process, a melt blowing process, a spunbonding process, or a milling process (e.g., a high temperature milling process).

In some embodiments, each of the one or more polymers is independently selected from the group consisting of carboxylic acid functionalized polymers, neutral non-cellulosic polymers, and cellulosic polymers. In some embodiments, the polymer is copovidone.

In some embodiments, the therapeutic agent is selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents, steroids, antibacterial agents, antiparasitic agents, antiviral agents, antimicrobial agents, and antifungal agents. In some embodiments, the therapeutic agent is a chemotherapeutic agent. In some embodiments, the therapeutic agent is an anti-inflammatory agent. In some embodiments, the therapeutic agent is an immunosuppressive agent. In some embodiments, the therapeutic agent is a steroid. In some embodiments, the therapeutic agent is an antibacterial agent. In some embodiments, the therapeutic agent is an antiparasitic agent. In some embodiments, the therapeutic agent is an antiviral agent. In some embodiments, the therapeutic agent is an antimicrobial agent. In some embodiments, the therapeutic agent is an antifungal agent.

In some embodiments, the nanoparticle form of the therapeutic agent or a pharmaceutically acceptable salt thereof is crystalline, amorphous, or a combination thereof.

The present application further provides a compound that is a nanoparticle form of a therapeutic agent provided herein, or a pharmaceutically acceptable salt thereof, wherein the nanoparticle form is prepared according to one or more methods provided herein.

In some embodiments, the compound is in the form of nanoparticles of a therapeutic agent selected from a chemotherapeutic agent, an anti-inflammatory agent, an immunosuppressive agent, a steroid, an antibacterial agent, an antiparasitic agent, an antiviral agent, an antimicrobial agent, and an antifungal agent, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of the chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of a compound selected from raloxifene, dasatinib, abiraterone, sunitinib, axitinib, vandetanib, or cabozantinib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of raloxifene or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of raloxifene hydrochloride.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride is characterized by a DSC thermogram with an endothermic peak at about 267 ℃.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has a DSC thermogram substantially as shown in figure 2.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride is a crystalline form of raloxifene hydrochloride.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride is an amorphous form of raloxifene hydrochloride.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride is a combination of crystalline and amorphous forms of raloxifene hydrochloride.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 5 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 4 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 3 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 2 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 1 XRD peak (in terms of 2 Θ) selected from: about 12.5 °, 16.2 °, 19.5 °, 19.6 °, 19.0 °, 20.8 °, 21.0 °, 23.0 °, 25.5 °, and 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has an XRD spectrum substantially as shown in figure 5.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has an FTIR spectrum substantially as shown in figure 3.

In some embodiments, the compound is in the form of nanoparticles of an anti-inflammatory agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of an immunosuppressant or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of a steroid or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of an antibacterial agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of an antiparasitic agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of an antiviral agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of an antimicrobial agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of the antifungal agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the nanoparticle form of the therapeutic agent or a pharmaceutically acceptable salt thereof is crystalline.

The present application further provides a pharmaceutical composition comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

In some embodiments, the pharmaceutical composition is in the form of nanoparticles of the pharmaceutical composition.

The present application further provides nanoparticle forms of the pharmaceutical compositions prepared according to one or more methods provided herein.

The present application further provides a pharmaceutical composition in the form of nanoparticles comprising raloxifene, or a pharmaceutically acceptable salt thereof, prepared according to one or more methods provided herein.

The present application further provides pharmaceutical compositions in nanoparticle form comprising raloxifene hydrochloride prepared according to one or more methods provided herein.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The methods and materials used in the present invention are described herein, and other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Description of the drawings

Fig. 1 shows the particle size and distribution of representative nanoformulations prepared according to the milling methods provided herein.

Fig. 2 shows a comparison of Differential Scanning Calorimetry (DSC) thermograms of representative milled nano-formulations and unmilled formulations.

Figure 3 shows a comparison of Fourier Transform Infrared (FTIR) spectra of raloxifene hydrochloride from a nano-formulation prepared according to the milling process provided herein and an unmilled formulation.

Figure 4 shows a comparison of dissolution profiles of a nano-formulation of raloxifene hydrochloride salt prepared according to the milling process provided herein, with an unmilled formulation.

Figure 5 shows a comparison of XRD spectra of a nano-formulation of raloxifene hydrochloride prepared according to the milling process provided herein, and an unmilled formulation.

Figure 6 shows a comparison of raloxifene plasma concentrations in rats administered either a milled raloxifene nanoformulation (25 mg/kg) or an unmilled raloxifene formulation as provided herein.

Figures 7-8 show representative examples of particle size/particle size distribution of diclofenac nanoformulations. Data were acquired using a Mastersizer M3000 laser diffractometer.

Fig. 9 shows the particle size/particle size distribution of diclofenac nanopreparations using lactose monohydrate and mannitol as fillers. Data were acquired using a Mastersizer M3000 laser diffractometer.

Figure 10 shows the particle size/particle size distribution of diclofenac nanopreparations using different milling speeds. Data were acquired using a Mastersizer M3000 laser diffractometer.

Figure 11 shows the particle size/particle size distribution of diclofenac nanopreparations under various drug loading conditions. Data were acquired using a Mastersizer M3000 laser diffractometer.

Figure 12 shows the dissolution of diclofenac nanopreparations (15% drug loading) versus the commercial preparation. Unless otherwise specified, the data are for the 15% drug loaded formulation.

Figure 13 shows the dissolution of diclofenac nanoformulations versus commercial formulations under various drug loading conditions.

Figure 14 shows the dissolution of diclofenac nanoformulations versus commercially available formulations using lactose monohydrate or mannitol as filler.

Figure 15 shows the dissolution of diclofenac nanoformulations versus commercial formulations when milled at 250 rpm or 300 rpm.

Figure 16 shows FTIR data comparing diclofenac before milling, after milling and after extrusion.

FIG. 17 shows differential scanning calorimetry data comparing the melting peaks of diclofenac acid before milling, after milling, and after extrusion. Similar peaks with different amplitudes confirm that the melting point of the drug does not change during the nanoformulation and extrusion.

Fig. 18 shows X-ray diffraction spectra of diclofenac nanoformulations before milling, after milling, and after hot-melt extrusion.

Figure 19 shows a scanning electron microscopy micrograph of polymer coated diclofenac nanocrystals after hot melt extrusion.

Figure 20 shows particle size and distribution of abiraterone acetate nano-formulations. Data were acquired using a Mastersizer M3000 laser diffractometer.

Figure 21 shows differential scanning calorimetry data comparing the melting peaks of abiraterone acetate nanoformulations compared to unmilled commercial abiraterone acetate formulations.

Figure 22 shows Fourier Transform Infrared (FTIR) spectral data for abiraterone acetate nano-formulations compared to unmilled commercial abiraterone acetate formulations.

Figure 23 shows X-ray diffraction spectra of a nano-formulation of abiraterone acetate (milled) and a commercial formulation (milled).

Detailed description of the invention

Polishing method

The present application provides, among other things, a method comprising:

i) grinding the pharmaceutical composition or therapeutic agent in a ball milling apparatus; and

ii) coating the milled pharmaceutical composition or milled therapeutic agent with one or more polymers.

In some embodiments, the coating of step ii) stabilizes, increases the solubility of, enhances the bioavailability of, enhances the physicochemical properties of, enhances the biological performance of, modulates the release profile of, or any combination thereof, the pharmaceutical composition or therapeutic agent.

In some embodiments, the coating of step ii) improves the chemical stability of the milled pharmaceutical composition or therapeutic agent, increases the solubility of the milled pharmaceutical composition or therapeutic agent, increases the bioavailability of the milled pharmaceutical composition or therapeutic agent, improves the physicochemical properties of the milled pharmaceutical composition or therapeutic agent, improves the biological properties of the milled pharmaceutical composition or therapeutic agent, modulates the release profile of the milled pharmaceutical composition or therapeutic agent, or any combination or sub-combination thereof.

In some embodiments, the coating of step ii) improves the chemical stability of the milled pharmaceutical composition (e.g., compared to a milled pharmaceutical composition that has not been coated or a pharmaceutical composition that has not been milled according to step i)). In some embodiments, the coating of step ii) improves shelf-life stability of the milled pharmaceutical composition or therapeutic agent. In some embodiments, the coating of step ii) improves the chemical stability of the milled pharmaceutical composition or therapeutic agent in a low pH environment (e.g., in the stomach of a subject).

In some embodiments, the coating of step ii) increases the solubility of the milled pharmaceutical composition (e.g., as compared to a milled pharmaceutical composition that has not been coated or a pharmaceutical composition that has not been milled according to step i)).

In some embodiments, the coating of step ii) increases the bioavailability of the milled pharmaceutical composition (e.g., as compared to a milled pharmaceutical composition that has not been coated or a pharmaceutical composition that has not been milled according to step i)).

In some embodiments, the coating of step ii) improves the physicochemical properties (e.g., solubility, pH profile, solid state stability, solvent stability, etc.) of the milled pharmaceutical composition (e.g., as compared to a milled pharmaceutical composition that has not been coated or a pharmaceutical composition that has not been milled according to step i)).

In some embodiments, the coating of step ii) modulates a biological property (e.g., pharmacokinetic property) of the milled pharmaceutical composition (e.g., as compared to a milled pharmaceutical composition that has not been coated or a pharmaceutical composition that has not been milled according to step i)).

In some embodiments, the coating of step ii) modulates the release profile (e.g., controlled release, pulsatile release, sustained release, etc.) of the milled pharmaceutical composition (e.g., the release profile of the subject as compared to an uncoated milled pharmaceutical composition or a pharmaceutical composition that has not been milled according to step i)).

In some embodiments, the pharmaceutical composition comprises a therapeutic agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In some embodiments, the present application provides a method of preparing a nanoparticle form or a microparticle form of a pharmaceutical composition or a nanoparticle form or a microparticle form of a therapeutic agent, the method comprising milling the pharmaceutical composition or the therapeutic agent in a ball milling apparatus (e.g., an attritor mill milling apparatus) to form the nanoparticle form or the microparticle form of the pharmaceutical composition or the nanoparticle form or the microparticle form of the therapeutic agent.

In some embodiments, the present application provides methods of coating a pharmaceutical composition or a therapeutic agent (e.g., a nanoparticle form of a pharmaceutical composition or a nanoparticle form of a therapeutic agent) with one or more polymers.

In some embodiments, the method comprises:

i) milling the pharmaceutical composition in a ball milling apparatus (e.g., an attritor milling apparatus) to produce a nanoparticulate form of the pharmaceutical composition; and

ii) coating the nanoparticulate form of the pharmaceutical composition with one or more polymers;

wherein the pharmaceutical composition comprises a therapeutic agent or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In some embodiments, the coating of step ii) stabilizes, increases the solubility of, enhances the bioavailability of, enhances the physicochemical properties of, enhances the biological performance of, modulates the release profile of, or any combination thereof, the pharmaceutical composition or therapeutic agent.

The methods provided herein provide for nanoformulations that can contain larger drug loads (e.g., greater than 2% w/w) and methods that provide for better control of particle size in nanoparticle form, as compared to alternative methods available in the public domain. In some embodiments, the methods provided herein provide a nanoformulation having a drug loading of greater than about 2%, greater than about 10%, greater than about 25%, or greater than about 50% w/w. In some embodiments, the drug load of the nano-or micro-formulation is about 10% to about 20% w/w. In some embodiments, the drug load of the nano-or micro-formulation is about 10% to about 15% w/w. In some embodiments, the drug load of the nano-or micro-formulation is about 15% w/w to about 20% w/w. In some embodiments, the nano-or micro-formulation comprises a drug loading of about 10% w/w. In some embodiments, the nano-or micro-formulation comprises a drug loading of about 12% w/w. In some embodiments, the nano-or micro-formulation comprises a drug loading of about 15% w/w. In some embodiments, the nano-or micro-formulation comprises a drug loading of about 20% w/w. The methods provided herein also include significantly fewer steps to produce stable nanoparticles than alternative methods available in the public domain.

In some embodiments, the coating of step ii) is performed as a batch process. In some embodiments, the coating of step ii) is performed as a continuous process.

The coating of step ii) stabilizes the nanoparticles prepared in step i), thereby preventing or inhibiting aggregation, agglomeration, or a combination thereof of the nanoparticles. In some embodiments, the coating of step ii) inhibits aggregation of the nanoparticles prepared in step i). In some embodiments, the coating of step ii) inhibits agglomeration of the nanoparticles prepared in step i). In some embodiments, the coating of step ii) prevents aggregation of the nanoparticles prepared in step i). In some embodiments, the coating of step ii) prevents agglomeration of the nanoparticles prepared in step i).

The coating of step ii) further increases the permeability of the pharmaceutical composition or therapeutic agent. For example, the coating can increase the permeability of the pharmaceutical composition or therapeutic agent for use in techniques associated with therapeutic agents classified as BCS II, BCSIII, and/or BCS IV drugs in a Biopharmaceutical Classification System (BCS).

The coating of step ii) also reduces the likelihood of drug-drug interactions of a pharmaceutical composition comprising more than one Active Pharmaceutical Ingredient (API) and enables the preparation of more than one drug in a unit dose.

In some embodiments, the methods provided herein provide a coated pharmaceutical composition (e.g., in the form of a coated nanoparticle of a pharmaceutical composition) or a coated therapeutic agent, wherein the nanoparticle is a crystalline nanoparticle, an amorphous nanoparticle, or a combination thereof. In some embodiments, the nanoparticle is a crystalline nanoparticle. In some embodiments, the nanoparticle is an amorphous nanoparticle. In some embodiments, the nanoparticles comprise a mixture of crystalline and amorphous nanoparticles.

In some embodiments, the nanoparticle form of the pharmaceutical composition comprises a nanoparticle form of the therapeutic agent. In some embodiments, the pharmaceutical composition comprises a solid mixture of the therapeutic agent and one or more pharmaceutically acceptable excipients.

In some embodiments, the milling of step i) comprises physically blending the pharmaceutical composition. In some embodiments, the milling of step i) is performed in the absence of a solvent component.

In some embodiments, the milling is performed using steel balls, zirconia balls, glass beads, or any combination thereof. In some embodiments, the milling is performed using balls and/or beads having an average diameter of about 0.1 inch to about 0.5 inch, such as about 0.1 inch to about 0.5 inch, about 0.1 inch to about 0.4 inch, about 0.1 inch to about 0.3 inch, about 0.1 inch to about 0.25 inch, about 0.1 inch to about 0.2 inch, about 0.2 inch to about 0.5 inch, about 0.2 inch to about 0.4 inch, about 0.2 inch to about 0.3 inch, about 0.2 inch to about 0.25 inch, about 0.25 inch to about 0.5 inch, about 0.25 inch to about 0.4 inch, about 0.25 inch to about 0.3 inch, about 0.3 inch to about 0.5 inch, about 0.3 inch to about 0.4 inch, or about 0.4 inch to about 0.5 inch. In some embodiments, milling is performed using balls and/or beads having an average diameter of about 0.2 inches to about 0.4 inches. In some embodiments, milling is performed using balls and/or beads having an average diameter of about 0.25 inches to about 0.375 inches (i.e., 1/4 "-about 3/8"). In some embodiments, milling is performed using balls and/or beads having an average diameter of about 0.25 inches (i.e., 1/4 "). In some embodiments, milling is performed using balls and/or beads having an average diameter of about 0.375 inches (i.e., 3/8 "). In some embodiments, the ball milling device is an attritor.

In some embodiments, prior to the grinding of step i), the median particle size of the pharmaceutical composition is from about 1 μm to about 100 μm, e.g., from about 1 μm to about 100 μm, from about 1 μm to about 90 μm, from about 1 μm to about 80 μm, from about 1 μm to about 70 μm, from about 1 μm to about 60 μm, from about 1 μm to about 50 μm, from about 1 μm to about 40 μm, from about 1 μm to about 30 μm, from about 1 μm to about 20 μm, from about 1 μm to about 10 μm, from about 10 μm to about 100 μm, from about 10 μm to about 90 μm, from about 10 μm to about 80 μm, from about 10 μm to about 70 μm, from about 10 μm to about 60 μm, from about 10 μm to about 50 μm, About 10 μm to about 40 μm, about 10 μm to about 30 μm, about 10 μm to about 20 μm, about 20 μm to about 100 μm, about 20 μm to about 90 μm, about 20 μm to about 80 μm, about 20 μm to about 70 μm, about 20 μm to about 60 μm, about 20 μm to about 50 μm, about 20 μm to about 40 μm, about 20 μm to about 30 μm, about 30 μm to about 100 μm, about 30 μm to about 90 μm, about 30 μm to about 80 μm, about 30 μm to about 70 μm, about 30 μm to about 60 μm, about 30 μm to about 50 μm, about 30 μm to about 40 μm, about 30 μm to about 100 μm to about 50 μm, about 30 μm to about 40 μm to about 100 μm, about 30 μm to about 50 μm to about 40 μm to about 100 μm, About 40 μm to about 90 μm, about 40 μm to about 80 μm, about 40 μm to about 70 μm, about 40 μm to about 60 μm, about 40 μm to about 50 μm, about 50 μm to about 100 μm, about 50 μm to about 90 μm, about 50 μm to about 80 μm, about 50 μm to about 70 μm, about 50 μm to about 60 μm, about 60 μm to about 100 μm, about 60 μm to about 90 μm, about 60 μm to about 80 μm, about 60 μm to about 70 μm, about 70 μm to about 100 μm, about 70 μm to about 90 μm, about 70 μm to about 80 μm, about 80 μm to about 100 μm, about 80 μm to about 90 μm, about 80 μm to about 100 μm, or about 80 μm to about 90 μm to about 100 μm. In some embodiments, the median particle size of the pharmaceutical composition prior to grinding in step i) is from about 1 to about 80 μm. In some embodiments, the median particle size of the pharmaceutical composition prior to grinding in step i) is from about 1 to about 75 μm. In some embodiments, the median particle size of the pharmaceutical composition prior to grinding in step i) is from about 1 to about 50 μm.

In some embodiments, the median particle size of the pharmaceutical composition can be determined by methods standard in the art and readily known to those of ordinary skill in the art (e.g., laser diffraction and/or dynamic light scattering). In some embodiments, the median particle size of the pharmaceutical composition is determined by laser diffraction, dynamic light scattering, or a combination thereof.

In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is from about 2 to about 400 times, e.g., from about 2 to about 400 times, from about 2 to about 300 times, from about 2 to about 200 times, from about 2 to about 100 times, from about 2 to about 50 times, from about 2 to about 10 times, from about 10 to about 400 times, from about 10 to about 300 times, from about 10 to about 200 times, from about 10 to about 100 times, from about 10 to about 50 times, from about 50 to about 400 times, from about 50 to about 300 times, from about 50 to about 200 times, from about 50 to about 100 times, from about 100 to about 400 times, from about 100 to about 300 times, from about 100 to about 200 times, from about 200 to about 400 times, from about 200 to about 300 times, or from about 300 to about 400 times the surface area of the nanoparticle form of the pharmaceutical composition. In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is from about 10 to about 300 times the surface area of the pharmaceutical composition. In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is from about 20 to about 200 times the surface area of the pharmaceutical composition.

In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition can be determined by methods standard in the art and readily known to those of ordinary skill in the art (e.g., laser diffraction). In some embodiments, the surface area of the nanoparticle form of the pharmaceutical composition is determined by laser diffraction.

In some embodiments, the bioavailability of the nanoparticulate form of the therapeutic agent, or pharmaceutically acceptable salt thereof, prepared according to the methods provided herein is increased as compared to the non-nanoparticulate form of the therapeutic agent, or pharmaceutically acceptable salt thereof (i.e., the therapeutic agent, or pharmaceutically acceptable salt thereof, prior to performing the methods described herein).

In some embodiments, the bioavailability of the nanoparticulate form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, prepared according to the methods provided herein is increased from about 2-fold to about 20-fold, e.g., from about 2-fold to about 20-fold, from about 2-fold to about 15-fold, from about 2-fold to about 10-fold, from about 2-fold to about 5-fold, from about 5-fold to about 20-fold, from about 5-fold to about 15-fold, from about 5-fold to about 10-fold, from about 10-fold to about 20-fold, from about 10-fold to about 15-fold, or from about 15-fold to about 20-fold, as compared to the non-nanoparticulate form of the therapeutic agent, or a pharmaceutically acceptable salt thereof.

In some embodiments, the solubility of the nanoparticle form of a therapeutic agent or a pharmaceutically acceptable salt thereof prepared according to the methods provided herein is increased as compared to the non-nanoparticle form of the therapeutic agent or a pharmaceutically acceptable salt thereof (i.e., the therapeutic agent or a pharmaceutically acceptable salt thereof prior to performing the methods described herein).

In some embodiments, the solubility of the nanoparticulate form of the therapeutic agent, or pharmaceutically acceptable salt thereof, prepared according to the methods provided herein is increased from about 2 fold to about 100 fold, e.g., from about 2 fold to about 100 fold, from about 2 fold to about 50 fold, from about 2 fold to about 20 fold, from about 2 fold to about 10 fold, from about 2 fold to about 5 fold, from about 5 fold to about 100 fold, from about 5 fold to about 50 fold, from about 5 fold to about 20 fold, from about 5 fold to about 10 fold, from about 10 fold to about 100 fold, from about 10 fold to about 50 fold, from about 10 fold to about 20 fold, from about 20 fold to about 100 fold, from about 20 fold to about 50 fold, or from about 50 fold to about 100 fold, as compared to the non-nanoparticulate form of the therapeutic agent, or pharmaceutically acceptable salt thereof. In some embodiments, the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 20-fold compared to the therapeutic agent. In some embodiments, the solubility of the nanoparticle form of the therapeutic agent, or a pharmaceutically acceptable salt thereof, is increased from about 2-fold to about 50-fold compared to the therapeutic agent.

In some embodiments, the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to one or more pharmaceutically acceptable excipients (i.e., therapeutic agent: one or more pharmaceutically acceptable excipients) of about 1:100, for example about 1:100, about 1:90, about 1:80, about 1:70, about 1:60, about 1:50, about 1:40, about 1:30, about 1:20, about 1:10, about 1:5, or about 1: 2. In some embodiments, the pharmaceutical composition comprises a therapeutic agent and one or more pharmaceutically acceptable excipients in about a 1:50 stoichiometric ratio. In some embodiments, the pharmaceutical composition comprises a stoichiometric ratio of the therapeutic agent to the one or more pharmaceutically acceptable excipients of about 1: 10.

In some embodiments, the pharmaceutical composition comprises from about 1 to about 20 pharmaceutically acceptable excipients, such as from about 1 to about 20, from about 1 to about 15, from about 1 to about 10, from about 1 to about 5, from about 1 to about 3, from about 1 to about 2, from about 2 to about 20, from about 2 to about 15, from about 2 to about 10, from about 2 to about 5, from about 2 to about 3, from about 3 to about 20, from about 3 to about 15, from 3 to about 10, from about 3 to about 5, from about 5 to about 20, from about 5 to about 15, from about 5 to about 10, from about 10 to about 20, from about 10 to about 15, or from about 15 to about 20. In some embodiments, the pharmaceutical composition comprises from about 1 to about 10 pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises from about 1 to about 5 pharmaceutically acceptable excipients.

In some embodiments, the coating of step ii) is performed according to one or more of the methods described in U.S. patent No. 7491407, the disclosure of which is incorporated herein by reference in its entirety. For example, the coating of step ii) may comprise the steps of:

(1) a preparation step in which the ingredients of the pharmaceutical composition in the form of micron-sized particles (i.e., microparticles) or nanoparticles are mixed and melted or softened;

(2) an extrusion step, and optionally

(3) A cooling and/or shaping step.

An exemplary extrusion process that can be used for coating in step ii) is shown, for example, in figures 1-2 of U.S. patent No. 7491407.

In some embodiments, the coating of step ii) is performed using a melt extrusion process, a melt-blown process or a spunbond process or milling the polymer with other excipients and drugs at elevated temperature. In some embodiments, the coating of step ii) is performed using a melt extrusion process.

In some embodiments, the nanoparticulate form of the pharmaceutical composition prepared according to the methods provided herein is present in the form of one or more fibers having increased surface area to modulate and promote more rapid dissolution of the drug and other substances (e.g., polymer coatings).

In some embodiments, the coating of step ii) may be applied to achieve local drug delivery.

In some embodiments, the coating of step ii) may be applied to minimize and/or prevent adverse effects associated with the therapeutic agent or pharmaceutical composition, toxicity associated with the therapeutic agent or pharmaceutical composition, or any combination thereof.

In some embodiments, the coating of step ii) is applied to form an immediate release composition, a controlled release composition, a sustained release composition, a fast melting composition, a pulsed release composition, a mixed immediate release profile, and/or any combination of release profiles.

In some embodiments, the polymeric coating may be applied as a thin coating (e.g., <400 nm thick). In some embodiments, the polymeric coating may be applied as a thick coating (e.g., >400 nm).

In some embodiments, the coating of step ii) comprises coating the nanoparticle form of the pharmaceutical composition by mixing and/or blending one or more polymers in a suitable polymeric carrier, extruding the blended or mixed material by extrusion, thereby providing a method for delivering the polymer-coated nanoparticle composition. Examples of fibers that can be prepared according to the coating methods described herein are shown, for example, in figures 5-13 of U.S. patent No. 7491407. In some embodiments, the fibers are hollow. In some embodiments, the fiber comprises a sheath cross-section, a core cross-section, a solid cross-section, or a hollow cross-section. In some embodiments, the fibers are formed into a ribbon or stacked configuration. In some embodiments, the fibers have a side-by-side cross-section. In some embodiments, the fiber comprises an islands-in-the-sea cross-section. In some embodiments, the fibers comprise a segmented pie-shaped cross-section. In some embodiments, the polymer is a fibrous or non-fibrous polymer.

In some embodiments, each of the one or more polymers used for the coating of step ii) is independently selected from the group consisting of carboxylic acid functionalized polymers, neutral non-cellulosic polymers, and cellulosic polymers.

In some embodiments, the polymer used for the coating of step ii) comprises one or more neutral non-cellulosic polymers. Exemplary polymers include: vinyl polymers and copolymers having hydroxyl, alkyl, acyloxy, and cyclic amide substituents. These include polyvinyl alcohols (e.g., polyvinyl alcohol-polyvinyl acetate copolymers) having at least a portion of their repeating units in an unhydrolyzed (e.g., vinyl acetate) form; polyvinylpyrrolidone; polyethylene polyvinyl alcohol copolymers; polyvinyl alcohol, kollidon VA64, Plasdone S630, poloxamers, polyvinylpyrrolidone, and polyvinylpyrrolidone copolymers, such as polyvinylpyrrolidone-polyvinyl acetate copolymer and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. In some embodiments, the polymer comprises copovidone. In some embodiments, the polymer is copovidone.

In some embodiments, the polymer used for the coating of step ii) comprises one or more carboxylic acid functionalized polymers. Examples of carboxylic acid functionalized polymers include, but are not limited to, carboxylic acid functionalized polymers of: vinyl polymers, polymethacrylates, polyacrylates, amine-functionalized polyacrylates, proteins, and carboxylic acid-functionalized starches such as starch glycolate.

In some embodiments, the polymer used for the coating of step ii) comprises one or more cellulosic polymers. Exemplary cellulosic polymers include, but are not limited to, cellulosic polymers having at least one of the following celluloses with ester and/or ether linkages: cellulose ethyl benzoate, ethoxybenzoic acid substituents, cellulose phthalate; hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, cellulose acetate terephthalate and cellulose acetate isophthalate. In some embodiments, the cellulosic polymer is at least partially ionizable at physiologically relevant pH and comprises at least one ionizable substituent, which may be ether-linked or ester-linked.

In some embodiments, the polymer used for the coating of step ii) is copovidone.

It is to be understood that blends of polymers suitable for the compounds, compositions and methods provided herein, such blends of polymers may also be useful in the present invention. Thus, it should be understood that the term polymer is intended to include blends of polymers in addition to a single class of polymers. Additional polymers useful in the present invention also include one or more polymers disclosed in U.S. application publication No. 2015/0190402 (see, e.g., [0014] - [0036]), the disclosure of which is incorporated by reference herein in its entirety.

In some embodiments, the nanoparticle form of the therapeutic agent or a pharmaceutically acceptable salt thereof is crystalline.

In some embodiments, the therapeutic agent is selected from the group consisting of chemotherapeutic agents, anti-inflammatory agents, immunosuppressive agents, steroids, antibacterial agents, antiparasitic agents, antiviral agents, antimicrobial agents, and antifungal agents.

In some embodiments, the therapeutic agent is a chemotherapeutic agent. In some embodiments, the therapeutic agent is an anti-inflammatory agent. In some embodiments, the therapeutic agent is an immunosuppressive agent. In some embodiments, the therapeutic agent is a steroid. In some embodiments, the therapeutic agent is an antibacterial agent. In some embodiments, the therapeutic agent is an antiparasitic agent. In some embodiments, the therapeutic agent is an antiviral agent. In some embodiments, the therapeutic agent is an antimicrobial agent. In some embodiments, the therapeutic agent is an antifungal agent.

Exemplary therapeutic agents that may be used in the methods provided herein include, but are not limited to, raloxifene, cytostatics, proteasome inhibitors, cisplatin, doxorubicin, taxol, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, temozolomide, tipifarnib, gefitinib, erlotinib hydrochloride, EGFR antibodies, imatinib mesylate, gemcitabine, uracil mustard, mechlorethamine, ifosfamide, melphalan, pipobroman, triethylenemelamine, triethylthiophosphoramide, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, cytosine arabinoside, 6-mercaptopurine, fludarabine phosphate, oxaliplatin, folinic acid, pentostatin, vincristine, vindesine, ledin, dactinomycin, epirubicin, itraconazole, idoxuridine, amiloridine, doxycycline, dox.

In some embodiments, the therapeutic agent is selected from raloxifene, dasatinib, abiraterone, sunitinib, axitinib, vandetanib, or cabozantinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is raloxifene or a pharmaceutically acceptable salt thereof. In some embodiments, the therapeutic agent is raloxifene hydrochloride.

Nanoparticle compounds and pharmaceutical compositions

The present application further provides a compound that is a nanoparticle form of a therapeutic agent provided herein, or a pharmaceutically acceptable salt thereof, wherein the nanoparticle form is prepared according to one or more methods provided herein. In some embodiments, the nanoparticle form of the therapeutic agent or a pharmaceutically acceptable salt thereof is crystalline, amorphous, or a combination thereof.

The term "compound" as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the species in question. Unless otherwise specified, a compound identified herein by name or structure as one particular tautomeric form is intended to include other tautomeric forms.

All compounds and pharmaceutically acceptable salts thereof may be present (e.g. hydrates and solvates) with other substances such as water and solvents or may be isolated.

In some embodiments, preparation of the compounds may include addition of an acid or base to affect, for example, catalysis of the desired reaction or formation of salt forms such as acid addition salts.

Exemplary acids may be inorganic or organic acids and include, but are not limited to, strong and weak acids. Some exemplary acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, tartaric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, and capric acid.

Exemplary bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some exemplary strong bases include, but are not limited to, hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines, wherein alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; metal amides include sodium amide, potassium amide, and lithium amide; metal hydrides including sodium hydride, potassium hydride and lithium hydride; and metal dialkylamides including methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, trimethylsilyl, and cyclohexyl substituted lithium, sodium, and potassium amide salts.

In some embodiments, a compound provided herein or a salt thereof is substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation may include, for example, compositions enriched in the compounds provided herein. Substantially isolating can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound provided herein, or a salt thereof. Methods for isolating compounds and salts thereof are conventional in the art.

In some embodiments, the compound is in the form of nanoparticles of the chemotherapeutic agent or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of an anti-inflammatory agent or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of an immunosuppressant or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of a steroid or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of an antibacterial agent or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of an antiparasitic agent or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of an antiviral agent or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of an antimicrobial agent or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of the antifungal agent or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of a compound selected from raloxifene, dasatinib, abiraterone, sunitinib, axitinib, vandetanib, or cabozantinib, or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is in the form of nanoparticles of raloxifene or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of raloxifene hydrochloride. In some embodiments, the compound is in the form of nanoparticles of abiraterone. In some embodiments, the compound is in the form of nanoparticles of abiraterone acetate.

In some embodiments, the compound is in the form of nanoparticles of raloxifene, or a pharmaceutically acceptable salt thereof, which are crystalline. In some embodiments, the compound is in the form of nanoparticles of raloxifene hydrochloride, which are crystalline.

In some embodiments, the compound is in the form of nanoparticles of raloxifene, or a pharmaceutically acceptable salt thereof, which are amorphous. In some embodiments, the compound is in the form of nanoparticles of raloxifene hydrochloride, which are amorphous.

In some embodiments, the compound is in the form of nanoparticles of raloxifene, or a pharmaceutically acceptable salt thereof, which are crystalline, amorphous, or a combination thereof. In some embodiments, the compound is in the form of nanoparticles of raloxifene hydrochloride, which are crystalline, amorphous, or a combination thereof.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride is characterized by a DSC thermogram with an endothermic peak at about 267 ℃. In some embodiments, the nanoparticulate form of raloxifene hydrochloride has a DSC thermogram substantially as shown in figure 2.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 7 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 6 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 5 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 4 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 3 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 2 XRD peaks (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has at least 1 XRD peak (in terms of 2 Θ) selected from: about 12.5 °, about 16.2 °, about 19.5 °, about 19.6 °, about 19.0 °, about 20.8 °, about 21.0 °, about 23.0 °, about 25.5 °, and about 27.5 °.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has an XRD spectrum substantially as shown in figure 5.

In some embodiments, the nanoparticulate form of raloxifene hydrochloride has an FTIR spectrum substantially as shown in figure 3.

In some embodiments, the compound is in the form of nanoparticles of diclofenac (i.e., 2- (2, 6-dichloroanilino) phenylacetic acid; diclofenac), or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is a nanoparticulate form of diclofenac, or a pharmaceutically acceptable salt thereof, that is crystalline.

In some embodiments, the compound is a nanoparticulate form of diclofenac, or a pharmaceutically acceptable salt thereof, that is amorphous.

In some embodiments, the compound is a nanoparticulate form of diclofenac, or a pharmaceutically acceptable salt thereof, that is crystalline, amorphous, or a combination thereof.

In some embodiments, the nanoparticulate form of diclofenac has a DSC thermogram substantially as shown in figure 17.

In some embodiments, the nanoparticulate form of diclofenac has at least 7 XRD peaks (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has at least 6 XRD peaks (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has at least 5 XRD peaks (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has at least 4 XRD peaks (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has at least 3 XRD peaks (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has at least 2 XRD peaks (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has at least 1 XRD peak (in terms of 2 Θ) selected from: about 12.4 °, about 16.3 °, about 19.1 °, about 19.4 °, about 19.5 °, about 19.9 °, about 21.1 °, about 25.5 °, about 26.2 °, about 27.4 °, about 28.2 °, and about 28.5 °.

In some embodiments, the nanoparticulate form of diclofenac has an XRD spectrum substantially as shown in figure 18.

In some embodiments, the nanoparticulate form of diclofenac has an FTIR spectrum substantially as shown in figure 16.

In some embodiments, the compound is in the form of nanoparticles of abiraterone or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is in the form of nanoparticles of abiraterone acetate.

In some embodiments, the compound is in the form of nanoparticles of abiraterone, or a pharmaceutically acceptable salt thereof, which are crystalline. In some embodiments, the compound is in the form of nanoparticles of abiraterone acetate, which are crystalline.

In some embodiments, the compound is in the form of nanoparticles of abiraterone, or a pharmaceutically acceptable salt thereof, which are amorphous. In some embodiments, the compound is in the form of nanoparticles of abiraterone acetate, which are amorphous.

In some embodiments, the compound is in the form of nanoparticles of abiraterone or a pharmaceutically acceptable salt thereof, which are crystalline, amorphous, or a combination thereof. In some embodiments, the compound is in the form of nanoparticles of abiraterone acetate, which are crystalline, amorphous, or a combination thereof.

In some embodiments, the nanoparticulate form of abiraterone acetate has a DSC thermogram substantially as shown in figure 21.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 7 XRD peaks (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 6 XRD peaks (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 5 XRD peaks (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 4 XRD peaks (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 3 XRD peaks (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 2 XRD peaks (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has at least 1 XRD peak (in terms of 2 Θ) selected from: about 12 °, about 16 °, about 20 °, about 21 °, about 24 °, and about 27 °.

In some embodiments, the nanoparticulate form of abiraterone acetate has an XRD spectrum substantially as shown in figure 23.

In some embodiments, the nanoparticulate form of abiraterone acetate has an FTIR spectrum substantially as shown in figure 22.

The invention also includes pharmaceutically acceptable salts of the nanoparticle compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by conversion of an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (such as amines); alkali metal or organic salts of acidic residues (such as carboxylic acids); and so on. Pharmaceutically acceptable salts of the invention include non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally preferred are non-aqueous media like ether, ethyl acetate, alcohols (e.g. methanol, ethanol, isopropanol or butanol) or Acetonitrile (ACN). A list of suitable salts can be found inRemington's Pharmaceutical Sciences17th ed., Mack Publishing Company, Easton, Pa.,1985, p.1418 andJournal of Pharmaceutical Science66, 2 (1977), each of which is incorporated herein by reference in its entirety.

When used as a medicament, the nanoparticulate compounds and salts thereof provided herein can be administered in the form of a pharmaceutical composition; thus, the methods described herein can comprise administering a pharmaceutical composition provided herein. Accordingly, the present application further provides a pharmaceutical composition comprising a nanoparticulate form of a compound provided herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition is in the form of nanoparticles of the pharmaceutical composition (i.e., one or more components of the pharmaceutical composition is a nanoparticle component). In some embodiments, the nanoparticle form of the pharmaceutical composition is prepared according to one or more methods provided herein.

Nanoparticle compounds and compositions can be prepared in a manner well known in the pharmaceutical art and can be administered by a variety of routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be topical (including transdermal, epidermal, ocular, and to mucosal membranes, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral. Exemplary administration techniques include, but are not limited to, oral, pulmonary, rectal, colonic, parenteral, intracisternal, intravaginal, intraperitoneal, ocular, otic, topical, buccal, nasal, and topical administration. In some embodiments, the nanoparticle compounds and compositions provided herein can be formulated into a dosage form selected from the group consisting of: liquid dispersion, gel, aerosol, ointment, cream, lyophilized preparation, tablet, capsule; formulated into a dosage form selected from: controlled release formulations, fast melt formulations, delayed release formulations, extended release formulations, pulsed release formulations, mixed immediate release and controlled release formulations, or any combination thereof. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, or injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration may be in the form of a single bolus dose, or may be, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.

The invention also includes pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, as the active ingredient in combination with one or more pharmaceutically acceptable carriers (excipients). In some embodiments, the composition is suitable for topical administration. In preparing the compositions of the present invention, the active ingredient is typically mixed with an excipient, diluted with an excipient or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments (containing, for example, up to 10% by weight of the active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

Some examples of suitable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally include, without limitation, lubricating agents (such as talc, magnesium stearate, and mineral oil), wetting agents, emulsifying and suspending agents, preserving agents (such as methyl and propyl hydroxybenzoate), sweetening agents, flavoring agents, or combinations thereof.

The active nanoparticle compounds can be effective over a wide dosage range and are typically administered in therapeutically effective amounts. It will be understood, however, that the amount of nanoparticle compound actually administered and the administration regimen will generally be determined by a physician in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual subject, the severity of the subject's symptoms, and the like.

The compositions may be formulated in unit dosage forms, each dose containing from about 5 to about 1000 mg (1 g), more usually from about 100 to about 500 mg, of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

In some embodiments, the compositions of the present invention may contain, for example, from about 5 to about 50 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compositions containing from about 5 to about 10, from about 10 to about 15, from about 15 to about 20, from about 20 to about 25, from about 25 to about 30, from about 30 to about 35, from about 35 to about 40, from about 40 to about 45, or from about 45 to about 50 mg of active ingredient.

In some embodiments, the compositions of the present invention may contain, for example, from about 0.1 to about 500 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compositions containing from about 0.1 to about 100, from about 0.5 to about 100, from about 1 to about 100, from about 10 to about 100, from about 25 to about 100, from about 50 to about 100, from about 100 to about 150, from about 150 to about 200, from about 200 to about 250, from about 250 to about 300, from about 350 to about 400, or from about 450 to about 500 mg of active ingredient.

In some embodiments, the compositions of the present invention may contain, for example, from about 500 to about 1000 mg of the active ingredient. One of ordinary skill in the art will appreciate that this embodies compositions containing from about 500 to about 550, from about 550 to about 600, from about 600 to about 650, from about 650 to about 700, from about 700 to about 750, from about 750 to about 800, from about 800 to about 850, from about 850 to about 900, from about 900 to about 950, or from about 950 to about 1000 mg of active ingredient.

Similar dosages of the nanoparticle compounds described herein may be used in the methods and uses of the invention.

The active compounds (e.g., nanoparticle compounds provided herein) can be effective over a wide dosage range and are typically administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will generally be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the compound actually administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

To prepare a solid composition, such as a tablet, the primary active ingredient (e.g., the nanoparticulate compound provided herein) is mixed with a pharmaceutically acceptable excipient to form a solid dosage composition comprising a homogeneous mixture of the compound of the invention. When these formulation compositions are referred to as homogeneous, the active ingredient is generally dispersed uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preparation is then subdivided into unit dosage forms of the type described above, containing, for example, from about 0.1 to about 1000 mg of the active ingredient of the invention.

The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, a tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of a coating on the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate.

Liquid forms which may be incorporated into the compounds and compositions of this invention for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions (in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof) and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal inhalation route to produce a local or systemic effect. The composition may be atomized by the use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure ventilator. Solution, suspension or powder compositions can be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

The topical formulations may contain one or more conventional carriers. In some embodiments, the ointment may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, and the like. The carrier composition of the cream may be based on a combination of water with glycerin and one or more other components (e.g., glyceryl monostearate, PEG-glyceryl monostearate, and cetearyl alcohol). Gels may be formulated using isopropanol and water, suitably in combination with other components such as glycerol, hydroxyethyl cellulose and the like. In some embodiments, the topical formulation contains at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2, or at least about 5 wt% of a compound of the present invention. The topical formulation may be suitably packaged in, for example, a 100 g tube, optionally together with instructions for treating a selected indication (e.g., psoriasis or other skin disorder).

The amount of the compound or composition administered to a patient will vary depending on the thing to be administered, the purpose of administration (such as prophylaxis or treatment), the state of the patient, the mode of administration, and the like. In therapeutic applications, the compositions may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the condition being treated and the judgment of the attending physician in light of factors such as the severity of the disease, the age, weight and general condition of the patient, etc.

The composition to be administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The aqueous solutions can be packaged for use as is or lyophilized, the lyophilized formulation being combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation is generally between 3 and 11, more preferably between 5 and 9 and most preferably between 7 and 8. It will be appreciated that the use of certain of the aforementioned excipients, carriers or stabilizers will result in the formation of pharmaceutically acceptable salts.

The therapeutic dosage of the compounds of the present invention may vary depending, for example, on the particular use being treated, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition may vary depending on a number of factors, including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the present invention may be provided in physiologically buffered aqueous solutions containing from about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dosage ranges are from about 1. mu.g/kg to about 1 g/kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight per day. The dosage may depend on variables such as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, the formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

Methods of use and combination therapy

The present application further provides a method of treating a disease in a subject in need thereof. The term "subject" as used herein refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the method comprises administering to a subject in need thereof a therapeutically effective amount of a nanoparticle compound or pharmaceutical composition provided herein, or a pharmaceutically acceptable salt thereof. In some embodiments, a nanoparticulate compound, salt thereof, or pharmaceutical composition is prepared according to one or more methods provided herein.

In some embodiments, the disease is selected from the group consisting of cancer, autoimmune diseases, cardiovascular diseases, central nervous system diseases (e.g., neurodegenerative diseases), and inflammatory diseases.

Exemplary cancers include, but are not limited to, lung cancer, melanoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, colon cancer, endometrial cancer, bladder cancer, skin cancer, uterine cancer, kidney cancer, stomach cancer, sarcoma, glioma, glioblastoma, or hematological cancers (e.g., leukemia or lymphoma). In some embodiments, the disease is breast cancer.

Exemplary central nervous system disorders include, but are not limited to, depression, schizophrenia, bipolar disorder, parkinson's disease, alzheimer's disease, and huntington's disease.

In some embodiments, the central nervous system disorder is selected from schizophrenia, bipolar disorder, alzheimer's disease, and huntington's disease.

Exemplary inflammatory and/or autoimmune diseases include, but are not limited to, alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes (type 1), juvenile idiopathic arthritis, glomerulonephritis, graves ' disease, guillain-barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, myocarditis, pemphigus/pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma/systemic sclerosis, sjogren's syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, and granulomatous polyangiitis (wegener's granulomatosis).

Exemplary cardiovascular diseases include, but are not limited to, coronary artery disease, hypertension, cardiac arrest, congestive heart failure, cardiac arrhythmias, peripheral artery disease, cardiomyopathy (e.g., dilated cardiomyopathy), ventricular fibrillation, tachycardia, myocardial infarction, long QT syndrome, Brugada syndrome, progressive cardiac conduction disease, sick sinus syndrome, atrial fibrillation, hypertension, myocarditis, and heart failure.

The phrase "pharmaceutically acceptable amount" or "therapeutically effective amount" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. For example, a "pharmaceutically acceptable amount" or "therapeutically effective amount" refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor, or other clinician.

The term "treating" or "treatment" as used herein refers to one or more of the following: (1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting a pathology or symptomatology of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptomatology); (2) ameliorating a disease, e.g., ameliorating a disease, condition or disorder (i.e., reversing pathology and/or symptomatology) in an individual who is experiencing or exhibiting pathology or symptomatology of a disease, condition or disorder, such as reducing the severity of a disease or reducing or alleviating one or more symptoms of a disease.

Examples

The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize that various non-critical parameters may be varied or modified to produce substantially the same results.