WO2020142420A1

WO2020142420A1 - Novel surfactant-lipid alloy drug substance, methods of making the same, and pharmaceutical compositions comprising the same

Info

Publication number: WO2020142420A1
Application number: PCT/US2019/068921
Authority: WO
Inventors: Catherine Crisp TURKEL; Jag SHUR
Original assignee: Novus Therapeutics, Inc.
Priority date: 2018-12-31
Filing date: 2019-12-30
Publication date: 2020-07-09

Abstract

The present disclosure relates to a novel surfactant-lipid alloy drug substance and methods of making a surfactant-lipid alloy drug substance. The present disclosure also relates to pharmaceutical compositions comprising the novel surfactant-lipid alloy drug substance and improvement of surface tension lowering effects of pharmaceutical compositions comprising surfactant-lipid alloy drug substances.

Description

NOVEL SURFACTANT-LIPID ALLOY DRUG SUBSTANCE, METHODS OF MAKING THE SAME, AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME

FIELD OF THE DISCLOSURE

[0001] This application claims the benefit of U.S. Provisional Application No. 62/786,778, filed on December 31 , 2018, the contents of which are incorporated by reference in their entirety.

[0002] Aspects of the present disclosure pertain to a novel surfactant-lipid alloy drug substance and methods of making the drug substance. Further aspects of the disclosure pertain to a pharmaceutical composition containing the novel surfactant-lipid alloy drug substance and surface tension effects of the pharmaceutical composition.

BACKGROUND OF THE DISCLOSURE

[0003] Certain surfactants and lipids are endogenous components present in the human nasal passages and its liquid surfaces, in the Eustachian tube (ET) and the ET mucosal lining, and throughout the human respiratory system. Without wishing to be bound by theory, it is believed that certain surfactants and lipids may be miscible with the mucosal air-liquid interface and capable of reducing the interfacial surface tension of the ET, thereby reducing the passive opening pressure required to open the ET and helping restore and/or enhance the physiological functions of the ET.

[0004] U.S. Patent No. 5,306,483 and references cited therein discuss the human surfactant system and certain components thereof. Non-limiting examples of surfactants present in the human surfactant system include dipalmitoylphosphatidylcholine (DPPC). Certain lipids present in the human surfactant system are believed to act as spreading agents, promoting the formation of films of DPPC on the air/liquid surfaces of the lungs. Non-limiting examples of lipids that, in some embodiments, may act as spreading agents, include cholesteryl esters (e.g., cholesteryl palmitate (CP)), phospholipids (e.g., diacylphosphatidylglycerols (PG), diacylphosphatidylethanolamines (PE), diacylphosphatidylserines (PS), diacylphosphatidylinositols (PI), sphingomyelin (Sph), cardiolipin (Card)), lysophospholipids, plasmalogens, dialkylphospholipids, phosphonolipids, carbohydrates and proteins (e.g., albumin and pulmonary surfactant proteins A, B, C, or D).

[0005] Compositions comprising surfactants and lipids have been investigated in, among other things, the treatment of ET dysfunction and the treatment of conditions that are associated with ET dysfunction, such as otitis media (OM). For example, U.S. Patent No.6,676,930 discusses the administration of a composition comprising a surfactant, a lipid, and a therapeutic agent to the mammalian ET and middle ear tissues to increase and enhance ET lumen patency and pressure equalization performance. WO 97/29738 discusses the delivery of surfactants by inhalation to the ET to reduce its passive opening pressure. The present inventors discovered that the simple mixtures disclosed in these documents exhibited poor stability, solubility, and experimental reproducibility. Thus, a need exists for improved compositions comprising surfactants and lipids.

SUMMARY OF THE DISCLOSURE

[0006] Aspects of the present disclosure address certain problems associated with previous pharmaceutical compositions comprising non-alloyed mixtures of a surfactant and a lipid, such as those discussed in the prior art. In some aspects, the present disclosure relates to the following embodiments:

1. A drug substance comprising a novel surfactant-lipid alloy, wherein the surfactant is dipalmitoylphosphatidylcholine and the lipid is cholesteryl palmitate.

2. The drug substance according to embodiment 1, wherein said novel surfactant- lipid alloy constitutes at least 70% of the drug substance by volume, at least 75% of the drug substance by volume, at least 80% of the drug substance by volume, at least 85% of the drug substance by volume, at least 90% of the drug substance by volume, at least 95% of the drug substance by volume, at least 97% of the drug substance by volume, or at least 99% of the drug substance by volume.

3. The drug substance according to embodiment 1 or embodiment 2, wherein the ratio of dipalmitoylphosphatidylcholine to cholesteryl palmitate in the surfactant-lipid alloy is selected from 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 30:1, 29:1, 28:1, 27:1,26:1,25:1,24:1,23:1,22:1,21:1,20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, and 10:1.

4. The alloy drug substance according to any one of embodiments 1 to 3, wherein the alloy drug substance has a particle size distribution X90 from 0.1 mm to 15 mm.

5. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has a particle size distribution X90 from 0.1 mm to 10 mm. 6. The alloy drug substance according to any one of embodiments 1 to 5, wherein the alloy drug substance has a particle size distribution X90 from 0.1 mm to 5 mm.

7. The alloy drug substance according to any one of embodiments 1 to 6, wherein the alloy drug substance has a particle size distribution X10 from 0.6 mm to 1.2 mm, X50 from 1.3 mm to 2.4 mm, and X90 from 2.9 mm to 4.4 mm.

8. The alloy drug substance according to any one of embodiments 1 to 7, wherein the alloy drug substance has a particle size distribution X10 from 0.6 mm to 1.2 mm, X50 from 1.5 mm to 2.4 mm, and X90 from 3.2 mm to 4.3 mm.

9. The alloy drug substance according to any one of embodiments 1 to 5, wherein the alloy drug substance has a particle size distribution X10 from 0.7 mm to 1.9 mm, X50 from 2.3 mm to 4.3 mm, and X90 from 4.4 mm to 9.3 mm.

10. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has a particle size distribution X10 from 1.4 mm to 1.7 mm, X50 from 3.7 mm to 4.4 mm, and X90 from 8.0 mm to 11.0 mm.

11. The alloy drug substance according to any one of embodiments 1 to 5, wherein the alloy drug substance has a particle size distribution X10 from 0.5 mm to 1.6 mm, X50 from 2.1 mm to 3.6 mm, and X90 from 3.8 mm to 7.2 mm.

12. The alloy drug substance according to any one of embodiments 1 to 5, wherein the alloy drug substance has a particle size distribution X10 from 0.5 mm to 1.2 mm, X50 from 2.1 mm to 3.2 mm, and X90 from 3.8 mm to 6.4 mm.

13. The alloy drug substance according to any one of embodiments 4 to 12, wherein the particle size distribution is measured by laser diffraction.

14. The alloy drug substance according to any one of embodiments 1 to 13, wherein the alloy drug substance has volume mean diameter from 1 mm to 8 mm.

15. The alloy drug substance according to claim any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 1 mm to 3 mm.

16. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 3 mm to 4 mm. 17. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 1 mm to 2 mm.

18. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 2 mm to 3 mm.

19. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 3 mm to 4 mm.

20. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 4 mm to 5 mm.

21. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 5 mm to 6 mm.

22. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 6 mm to 7 mm.

23. The alloy drug substance according to any one of embodiments 1 to 14, wherein the alloy drug substance has volume mean diameter from 7 mm to 8 mm.

24. The alloy drug substance according to any one of embodiments 14 to 23, wherein the volume mean diameter is measured by laser diffraction.

25. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has a Dv (10) of about 0.903 mm, a Dv (50) of about 2.53 mm, and a Dv (90) of about 6.25 mm, a Dv (10) of about 1.10 mm, Dv (50) of about 3.59 mm, and Dv (90) of about 13.0 mm, a Dv (10) of about 1.01 mm, a Dv (50) of about 2.79 mm, and a Dv (90) of about 6.78 mm, a Dv (10) of about 1.10 mm, a Dv (50) of about 3.59 mm, and a Dv (90) of about 13.0 mm, a Dv (10) of about 1.37 mm, a Dv (50) of about 3.65 mm, and a Dv (90) of about 8.01 mm, a Dv (10) of about 1.46 mm, a Dv (50) of about 4.00 mm, and a Dv (90) of about 10.5 mm, or a Dv (10) of about 1.30 mm, a Dv (50) of about 3.30 mm, and a Dv (90) of about 6.43 mm, or a Dv (10) of about 1.34 mm, a Dv (50) of about 3.40 mm, and a Dv (90) of about 7.03 mm, or a Dv (10) of about 1.08 mm, a Dv (50) of about 2.93 mm, and a Dv (90) of about 8.67 mm. 26. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has a D [4,3] of 7.60 mm, about 3.14 mm, about 3.32 mm, about 3.51 mm, about 6.10 mm, about 7.45 mm, about 3.60 mm, about 3.84 mm, or about 7.12 mm.

27. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has an SMD from 1 mm to 2 mm.

28. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has an SMD from 2 mm to 3 mm, from about 1.50 mm to about 2.40 mm, from about 1.60 mm to about 2.30 mm, from about 1.64 mm to about 2.25 mm,.

29. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has an SMD of 2.21 mm, 1.85 mm, 2.01 mm, 1.70 mm, 1.91 mm, 1.64 mm, 1.75 mm, or 2.13 mm.

30. The alloy drug substance according to any one of embodiments 1 to 4, wherein the alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 100.0% < 5.0 mm.

31. The alloy drug substance according to any one of embodiments 1 to 30, wherein the alloy drug substance exhibits a percent mass change due to absorption of water of less than 2.9% at 10% to 30% relative humidity.

32. The alloy drug substance according to any one of embodiments 1 to 30, wherein the alloy drug substance exhibits a percent mass change due to desorption of water of less than 4.5% at 0% to 10% relative humidity.

33. The alloy drug substance according to embodiments 31 or embodiments 32, wherein the percent mass change is measured by dynamic vapor sorption.

34. A homogeneous solution comprising dipalmitoylphosphatidylcholine, cholesteryl palmitate, and at least two miscible solvents.

35. The homogeneous solution according to embodiment 34, wherein the at least two miscible solvents are ethanol and dichloromethane. 36. The homogeneous solution according to embodiment 34, wherein the at least two miscible solvents are ethanol and ethyl acetate.

37. The homogeneous solution according to embodiment 34, comprising exactly two miscible solvents.

38. The homogeneous solution according to embodiment 34, wherein the exactly two miscible solvents are ethanol and dichloromethane.

39. The homogeneous solution according to embodiment 34, wherein the exactly two miscible solvents are ethanol and ethyl acetate.

40. The homogeneous solution according to embodiment 35 or embodiment 38, wherein the ethanol and dichloromethane are present in a ratio of 56:44 ethanol:dichloromethane.

41. The homogeneous solution according to embodiment 36 or embodiment 39, wherein the ethanol and ethyl acetate are present in a ratio selected from 50:50 ethanol:ethyl acetate and 30:70 ethanol:ethyl acetate.

42. A method of preparing the alloy drug substance according to any one of embodiments 1 to 33, comprising: providing the homogeneous solution of any one of embodiments 34 to 41 ; and spray-drying said homogeneous solution to provide said alloy drug substance as a powder.

43. A pharmaceutical composition comprising the alloy drug substance of any one of embodiments 1 to 33 and one or more propellants.

44. A pharmaceutical composition comprising the alloy drug substance of any one of embodiments 1 to 3 and one or more propellants.

45. The pharmaceutical composition of embodiment 43, wherein 1 , 1 ,1 ,2- tetrafluoroethane is used as a propellant.

46. The pharmaceutical composition of embodiment 44, wherein 1 , 1 ,1 ,2- tetrafluoroethane is used as a propellant. 47. The pharmaceutical composition according to any one of embodiments 43 to 46, wherein the alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of dipalmitoylphosphatidylcholine and cholesteryl palmitate in the same propellant.

48. The pharmaceutical composition according to any one of embodiments 43 to 47, wherein the alloy drug substance migrates to the surface of the propellant at a rate of less than 800 mm per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour.

49. The pharmaceutical composition according to any one of embodiments 43 to 48, wherein the alloy drug substance migrates to the surface of propellant at a rate of less than 800 millimeters per hour.

50. The pharmaceutical composition according to any one of embodiments 43 to 49, wherein the alloy drug substance migrates to the surface of the propellant at a rate of less than 500 millimeters per hour.

51 . The pharmaceutical composition according to any one of embodiments 43 to 50, wherein a layer of alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes.

52. The pharmaceutical composition according to any one of embodiments 43 to 51 , wherein a layer of alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes.

53. The pharmaceutical composition according to embodiment 45, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising a non-alloyed mixture of dipalmitoylphosphatidylcholine, cholesteryl palmitate, and 1 , 1 , 1 ,2- tetrafluoroethane.

54. The pharmaceutical composition according to embodiment 46, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising a non-alloyed mixture of dipalmitoylphosphatidylcholine, cholesteryl palmitate, and 1 , 1 , 1 ,2- tetrafluoroethane.

55. The pharmaceutical composition according to embodiment 53, wherein the greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium.

56. The pharmaceutical composition according to embodiment 54, wherein the greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium.

57. The pharmaceutical composition according to embodiment 55, wherein the ratio of dipalmitoylphosphatidylcholine to cholesteryl palmitate in the surfactant-lipid alloy is 10: 1 , 20: 1 , or 30: 1.

58. The pharmaceutical composition according to embodiment 56, wherein the ratio of dipalmitoylphosphatidylcholine to cholesteryl palmitate in the surfactant-lipid alloy is 10: 1 , 20: 1 , or 30: 1.

59. A pharmaceutical composition comprising the alloy drug substance of any one of embodiments 1 to 33, wherein the composition does not comprise a propellant.

60. The alloy drug substance according to any one of embodiments 1 to 33, wherein the alloy drug substance is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 22.

61 . The alloy drug substance according to any one of embodiments 1 to 33, wherein the alloy drug substance is characterized by a Raman spectrum substantially similar to that in FIG. 23. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0008] FIG. 1 A depicts the particle size distribution of a sample of a surfactant-lipid alloy drug substance comprising a surfactant-lipid alloy (batch 099#002).

[0009] FIG. 1 B depicts the particle size distribution of a sample of a surfactant-lipid alloy drug substance comprising a surfactant-lipid alloy (batch 099#003).

[0010] FIG. 1 C depicts the particle size distribution of a sample of a surfactant-lipid alloy drug substance comprising a surfactant-lipid alloy (batch 099#004).

[0011] FIG. 2 depicts DSC (differential scanning calorimetry) traces of dipalmitoylphosphatidylcholine (DPPC) and cholesteryl palmitate (CP).

[0012] FIG. 3A depicts first-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were spray-dried at 0.25 bar atomization pressure.

[0013] FIG. 3B depicts second-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were spray-dried at 0.25 bar atomization pressure.

[0014] FIG. 4A depicts first-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were prepared using DPPC and CP in a 20:1 ratio.

[0015] FIG. 4B depicts second-cycle DSC traces of samples of surfactant-lipid alloy drug substance that were prepared using DPPC and CP in a 20:1 ratio.

[0016] FIG. 5A depicts first-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were prepared using DPPC and CP in a 10:1 ratio.

[0017] FIG. 5B depicts second-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were prepared using DPPC and CP in a 10:1 ratio.

[0018] FIG. 6A depicts first-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were prepared using DPPC and CP in a 5:1 ratio.

[0019] FIG. 6B depicts second-cycle DSC traces of samples of surfactant-lipid alloy drug substances that were prepared using DPPC and CP in a 5:1 ratio.

[0020] FIG. 7A depicts first-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#018A).

[0021] FIG. 7B depicts second-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#018A).

[0022] FIG. 8A depicts first-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#018B). [0023] FIG. 8B depicts second-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#018B).

[0024] FIG. 9A depicts first-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#018C).

[0025] FIG. 9B depicts second-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid drug substance (batch 099#018C).

[0026] FIG. 10A depicts first-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#019A).

[0027] FIG. 10B depicts second-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#019A).

[0028] FIG. 11 A depicts first-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#019B).

[0029] FIG. 11 B depicts second-cycle DSC traces for DPPC, CP, and a sample of a surfactant-lipid alloy drug substance (batch 099#019B).

[0030] FIG. 12 depicts SEM (scanning electron microscopy) images of samples of spray-dried powders of surfactant-lipid alloy drug substances that were prepared using 20:1 DPPC:CP.

[0031] FIG. 13 depicts SEM images of samples of spray-dried powders of surfactant-lipid alloy drug substances that were prepared using 10:1 DPPC:CP.

[0032] FIG. 14 depicts SEM images of samples of spray-dried powders of surfactant-lipid alloy drug substances that were prepared using 5:1 DPPC:CP.

[0033] FIG. 15 depicts further SEM images of samples of spray-dried powders of surfactant-lipid alloy drug substances that were prepared using 20:1 , 10:1 , or 5:1 DPPC:CP.

[0034] FIG. 16 depicts SEM images of samples of spray-dried powders of a surfactant-lipid alloy drug substance that was prepared using 20: 1 DPPC:CP and 100% ethyl acetate.

[0035] FIG. 17 depicts the volume distribution of DPPC, CP, and alloyed DPPC and CP in six samples of surfactant-lipid alloy drug substances.

[0036] FIG. 18 depicts the peak thickness of a layer of drug substance formed, as a function of time, in certain compositions comprising surfactant-lipid alloy drug substances of the disclosure and a propellant, and the peak thickness of a layer of substance formed, as a function of time, in a comparative composition comprising a non- alloyed mixture of DPPC and CP and a propellant. [0037] FIG. 19A and 19B depict migration rates measured for surfactant-lipid alloy drug substances according to the disclosure in compositions comprising the drug substances and a propellant, with a comparison to a composition comprising a non- alloyed mixture of DPPC and CP and a propellant.

[0038] FIG. 20A depicts water sorption results from a DVS (dynamic vapor sorption) experiment conducted using CP.

[0039] FIG. 20B depicts a water sorption isotherm for CP.

[0040] FIG. 20C depicts water sorption results from a DVS experiment conducted using DPPC.

[0041] FIG. 20D depicts a water sorption isotherm for DPPC.

[0042] FIG. 20E depicts water sorption results from a DVS experiment conducted using a sample of a comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16:1 ratio.

[0043] FIG 20F depicts a water sorption isotherm for the comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16: 1 ratio.

[0044] FIG. 20G depicts water sorption results from a DVS experiment conducted using a sample of spray-dried powder of a surfactant-lipid alloy drug substance according to the disclosure (batch 099#023).

[0045] FIG. 20H depicts a water sorption isotherm for a sample of spray-dried powder of a surfactant-lipid alloy drug substance according to the disclosure (batch 099#023).

[0046] FIG. 20I depicts water sorption results from a DVS experiment conducted using a sample of spray-dried powder of a surfactant-lipid alloy drug substance according to the disclosure (batch 099#024).

[0047] FIG. 20J depicts a water sorption isotherm for a sample of spray-dried powder of a surfactant-lipid alloy drug substance according to the disclosure (batch 099#024).

[0048] FIG. 20K depicts water sorption results from a DVS experiment conducted using a sample of spray-dried powder of a surfactant-lipid alloy drug substance according to the disclosure (batch 099#025).

[0049] FIG. 20L depicts a water sorption isotherm for a sample of spray-dried powder of a surfactant-lipid alloy drug substance according to the disclosure (batch 099#025). [0050] FIG. 21 A depicts the configuration of the integrated dissolution and surface tension monitoring system.

[0051] FIG. 21 B depicts results of surface tension reduction experiments performed using CP only, DPPC only, a non-alloyed mixture of DPPC and CP, and surfactant-lipid alloy drug substances according to the disclosure.

[0052] FIG. 21 C depicts further results of surface tension reduction experiments performed using CP only, DPPC only, a non-alloyed mixture of DPPC and CP, and surfactant-lipid alloy drug substances according to the disclosure.

[0053] FIG. 21 D also depicts further results of surface tension reduction experiments performed using CP only, DPPC only, a non-alloyed mixture of DPPC and CP, and surfactant-lipid alloy drug substances according to the disclosure.

[0054] FIG. 22 depicts an X-ray powder diffractogram of a sample of DPPC-CP surfactant-lipid alloy according to the disclosure.

[0055] FIG. 23 depicts a Raman spectrum of a sample of DPPC-CP surfactant- lipid alloy according to the disclosure.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0056] Aspects of the present disclosure pertain to a novel surfactant-lipid alloy and to methods of making a surfactant-lipid alloy. In some embodiments, the surfactant is dipalmitoylphosphatidylcholine (DPPC) and the lipid is cholesteryl palmitate (CP).

[0057] Further aspects of the disclosure pertain to a drug substance comprising a novel surfactant-lipid alloy according to the disclosure (also referred to herein as a “surfactant-lipid alloy drug substance” or an“alloy drug substance”) and to methods of making the alloy drug substance. In some embodiments of the drug substance comprising a surfactant-lipid alloy, the surfactant is DPPC and the lipid is CP.

[0058] Additional aspects of the disclosure pertain to pharmaceutical compositions comprising a propellant and a surfactant-lipid alloy drug substance according to the disclosure and to methods of making the pharmaceutical composition. In some embodiments, 1 ,1 , 1 ,2-tetrafluoroethane is used as the propellant. Additional aspects of the disclosure pertain to pharmaceutical compositions comprising a surfactant-lipid alloy drug substance according to the disclosure and to methods of making the pharmaceutical composition, wherein the compositions do not comprise a propellant.

[0059] As used herein, the term“surfactant-lipid alloy” refers to a surfactant and lipid that have been intimately combined to form a single substance, wherein one or more properties of the intimate combination of the surfactant and the lipid (such as, as non limiting examples, its physical and/or chemical properties) differ from the corresponding property or properties of the surfactant alone and/or the lipid alone and/or from a non intimate (non-alloyed) mixture of the surfactant and the lipid.

[0060] As used herein, the term“drug substance” refers to a composition of matter comprising an active ingredient capable of exerting pharmacological activity or other effect in the diagnosis, cure, mitigation, treatment, and/or prevention of disease, and/or of affecting the structure and/or function of an organism (such as, as a non-limiting example, a human). In some embodiments, a drug substance comprises a surfactant- lipid alloy. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, a non-alloyed surfactant, and a non-alloyed lipid.

[0061] In some embodiments, a surfactant-lipid alloy constitutes at least 70% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 75% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 80% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 85% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 90% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 95% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 97% of a drug substance by volume. In some embodiments, a surfactant-lipid alloy constitutes at least 99% of a drug substance by volume.

[0062] In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 70% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 75% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 80% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant- lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 85% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 90% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 95% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant- lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 97% of the drug substance by volume. In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP, and said surfactant-lipid alloy constitutes at least 99% of the drug substance by volume.

[0063] Herein, ratios of surfactants to lipids refer to mass ratios. For example, a reference to a ratio of surfactant to lipid of 20:1 refers to a ratio of 20 parts surfactant by mass to 1 part lipid by mass. Accordingly, it is to be understood that, herein, ratios of DPPC to CP likewise refer to mass ratios. For example, a reference to a DPPC:CP ratio of 20:1 refers to a ratio of 20 parts DPPC by mass to 1 part CP by mass.

[0064] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the ratio of surfactant to lipid is 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1,31:1,30:1,29:1,28:1,27:1,26:1,25:1,24:1,23:1,22:1,21:1,20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, or 10:1.

[0065] In some embodiments, a drug substance comprises a surfactant-lipid alloy of the surfactant DPPC and the lipid CP and wherein the ratio of DPPC to CP is 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, or 10:1.

[0066] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the ratio of surfactant to lipid is 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1.

[0067] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and wherein the ratio of DPPC to CP is 30:1, 29:1, 28:1, 27:1, 26:1, 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1.

[0068] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the ratio of surfactant to lipid is 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 10:1, or 5:1. [0069] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and wherein the ratio of DPPC to CP is 21 : 1 , 20: 1 , 19:1 , 18: 1 , 17: 1 , 16: 1 , 15: 1 , 10: 1 , or 5: 1 .

[0070] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the ratio of surfactant to lipid is 21 : 1 , 20: 1 , 10: 1 , or 5: 1 .

[0071] In some embodiments, a drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and wherein the ratio of DPPC to CP is 21 : 1 , 20: 1 , 10: 1 , or 5: 1 .

[0072] In some embodiments, an alloy drug substance is in the form of a powder. In some embodiments, an alloy drug substance is in the form of a spray-dried powder.

[0073] In some embodiments, the mean particle size of a spray-dried powder of an alloy drug substance is expressed as the volume mean diameter (VMD). In some embodiments, particle sizes of spray-dried powders of alloy drug substances are expressed in terms of particle size distribution ( e.g . , X10, X16, X50, X84, X90, and/or X99 values).

[0074] As would be understood by a person having ordinary skill in the art, in the context of particle size distributions, X50 refers to the median diameter of the distribution, X10 refers to the diameter whereby 10% of the total volume population lies below this size, X16 refers to the diameter whereby 16% of the total volume population lies below this size, X84 refers to the diameter whereby 84% of the total volume population lies below this size, X90 refers to the diameter whereby 90% of the total volume population lies below this size, and X99 refers to the diameter whereby 99% of the total volume population lies below this size. As would also be understood by a person having ordinary skill in the art, when provided together with a particular value,“Q3” refers to the cumulative volume percentage of particles that have a diameter up to the value provided.

[0075] As would be understood by a person having ordinary skill in the art, particle sizes, volume mean diameters, and particle size distributions of powders can be measured using various techniques known in the art, such as laser diffraction. Thus, in some embodiments, the mean particle size of a drug substance is expressed as a volume mean diameter (VMD) as measured by laser diffraction. In some embodiments, particle size distributions of drug substances are expressed using values (e.g., X10, X16, X50, X84, X90, and/or X99 values) measured by laser diffraction.

[0076] In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 20 mm. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 15 mm. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 10 mm. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 5 mm.

[0077] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 20 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 15 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 10 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 5 mm.

[0078] In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.6 mm to 1 .2 mm, X50 from 1 .3 mm to 2.4 mm, and X90 from 2.9 mm to 4.4 mm. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.6 mm to 1 .2 mm, X50 from 1 .5 mm to 2.4 mm, and X90 from 3.2 mm to 4.3 mm. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.7 mm to 1 .9 mm, X50 from 2.3 mm to 4.3 mm, and X90 from 4.4 mm to 9.3 mm.

[0079] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.6 mm to 1.2 mm, X50 from 1.3 mm to 2.4 mm, and X90 from 2.9 mm to 4.4 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.6 mm to 1.2 mm, X50 from 1 .5 mm to 2.4 mm, and X90 from 3.2 mm to 4.3 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.7 mm to 1.9 mm, X50 from 2.3 mm to 4.3 mm, and X90 from 4.4 mm to 9.3 mm.

[0080] In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 1 .4 mm to 1 .7 mm, X50 from 3.7 mm to 4.4 mm, and X90 from 8.0 mm to 1 1 .0 mm. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.5 mm to 1 .6 mm, X50 from 2.1 mm to 3.6 mm, and X90 from 3.8 mGh to 7.2 mίti . In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.5 mm to 1 .2 mm, X50 from 2.1 mm to 3.2 mm, and X90 from 3.8 mm to 6.4 mm.

[0081] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 1.4 mm to 1.7 mm, X50 from 3.7 mm to 4.4 mm, and X90 from 8.0 mm to 1 1 .0 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.5 mm to 1.6 mm, X50 from 2.1 mm to 3.6 mm, and X90 from 3.8 mm to 7.2 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.5 mm to 1.2 mm, X50 from 2.1 mm to 3.2 mm, and X90 from 3.8 mm to 6.4 mm.

[0082] In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 20 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 15 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 10 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X90 from 0.1 mm to 5 mm as measured by laser diffraction.

[0083] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 20 mm as measured by laser diffraction. In some embodiments, a surfactant- lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 15 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 10 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X90 from 0.1 mm to 5 mm as measured by laser diffraction.

[0084] In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.6 mm to 1 .2 mm, X50 from 1 .3 mm to 2.4 mm, and X90 from 2.9 mm to 4.4 mm as measured by laser diffraction. In some embodiments, a surfactant- lipid alloy drug substance has a particle size distribution X10 from 0.6 mm to 1.2 mm, X50 from 1 .5 mm to 2.4 mm, and X90 from 3.2 mm to 4.3 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.7 mm to 1.9 mm, X50 from 2.3 mm to 4.3 mm, and X90 from 4.4 mm to 9.3 mm as measured by laser diffraction.

[0085] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.6 mm to 1.2 mm, X50 from 1 .3 mm to 2.4 mm, and X90 from 2.9 mm to 4.4 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.6 mm to 1 .2 mm, X50 from 1 .5 mm to 2.4 mm, and X90 from 3.2 mm to 4.3 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.7 mm to 1.9 mm, X50 from 2.3 mm to 4.3 mm, and X90 from 4.4 mm to 9.3 mm as measured by laser diffraction.

[0086] In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 1 .4 mm to 1 .7 mm, X50 from 3.7 mm to 4.4 mm, and X90 from 8.0 mm to 1 1.0 mm as measured by laser diffraction. In some embodiments, a surfactant- lipid alloy drug substance has a particle size distribution X10 from 0.5 mm to 1 .6 mm, X50 from 2.1 mm to 3.6 mm, and X90 from 3.8 mm to 7.2 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a particle size distribution X10 from 0.5 mm to 1.2 mm, X50 from 2.1 mm to 3.2 mm, and X90 from 3.8 mm to 6.4 mm as measured by laser diffraction.

[0087] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 1.4 mm to 1 .7 mm, X50 from 3.7 mm to 4.4 mm, and X90 from 8.0 mm to 1 1 .0 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.5 mm to 1.6 mm, X50 from 2.1 mm to 3.6 mm, and X90 from 3.8 mm to 7.2 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a particle size distribution X10 from 0.5 mm to 1 .2 mm, X50 from 2.1 mm to 3.2 mm, and X90 from 3.8 mm to 6.4 mm as measured by laser diffraction. [0088] In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 0.80 mm to about 1 .20 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 0.90 mm to about 1 .10 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 0.95 mm to about 1 .05 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 1.25 mm to about 1 .45 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 1 .35 mm to about 1 .55 mm. In some embodiments, a surfactant- lipid alloy drug substance has a Dv (10) from about 1 .20 mm to about 1 .40 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 1 .24 mm to about 1 .44 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from about 0.95 mm to about 1 .20 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) of about 0.903 mm, a Dv (50) of about 2.53 mm, and a Dv (90) of about 6.25 mm, or a Dv (10) of about 1 .01 mm, a Dv (50) of about 2.80 mm, and a Dv (90) of about 6.39 mm, or a Dv (10) of about 1 .01 mm, a Dv (50) of about 2.79 mm, and a Dv (90) of about 6.78 mm, or a Dv (10) of about 1 .10 mm, a Dv (50) of about 3.59 mm, and a Dv (90) of about 13.0 mm, or a Dv (10) of about 1.37 mm, a Dv (50) of about 3.65 mm, and a Dv (90) of about 8.01 mm, or a Dv (10) of about 1.46 mm, a Dv (50) of about 4.00 mm, and a Dv (90) of about 10.5 mm, or a Dv (10) of about 1 .30 mm, a Dv (50) of about 3.30 mm, and a Dv (90) of about 6.43 mm, or a Dv (10) of about 1 .34 mm, a Dv (50) of about 3.40 mm, and a Dv (90) of about 7.03 mm, or a Dv (10) of about 1 .08 mm, a Dv (50) of about 2.93 mm, and a Dv (90) of about 8.67 mm.

[0089] In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 0.80 mm to 1.20 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 0.90 mm to 1 .10 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 0.95 mm to 1 .05 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 1.25 mm to 1 .45 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 1 .35 mm to 1 .55 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 1.20 mm to 1 .40 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 1 .24 mm to 1.44 mm. In some embodiments, a surfactant-lipid alloy drug substance has a Dv (10) from 0.95 mm to 1 .20 mm. In some embodiments, a surfactant- lipid alloy drug substance has a Dv (10) of 0.903 mm, a Dv (50) of 2.53 mm, and a Dv (90) of 6.25 mm, or a Dv (10) of 1 .01 mm, a Dv (50) of 2.80 mίp, and a Dv (90) of 6.39 mm, or a Dv (10) of 1 .01 mm, a Dv (50) of 2.79 mίp, and a Dv (90) of 6.78 mm, or a Dv (10) of 1 .10 mm, a Dv (50) of 3.59 mίp, and a Dv (90) of 13.0 mm, or a Dv (10) of 1 .37 mm, a Dv (50) of 3.65 mm, and a Dv (90) of 8.01 mm, or a Dv (10) of 1.46 mm, a Dv (50) of 4.00 mm, and a Dv (90) of 10.5 mm, or a Dv (10) of 1 .30 mm, a Dv (50) of 3.30 mm, and a Dv (90) of 6.43 mm, or a Dv (10) of 1 .34 mm, a Dv (50) of 3.40 mm, and a Dv (90) of 7.03 mm, or a Dv (10) of 1 .08 mm, a Dv (50) of 2.93 mm, and a Dv (90) of 8.67 mm.

[0090] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a Dv (10) of about 0.903 mm, a Dv (50) of about 2.53 mm, and a Dv (90) of about 6.25 mm, or a Dv (10) of about 1 .01 mm, a Dv (50) of about 2.80 mm, and a Dv (90) of about 6.39 mm, or a Dv (10) of about 1 .01 mm, a Dv (50) of about 2.79 mm, and a Dv (90) of about 6.78 mm, or a Dv (10) of about 1 .10 mm, a Dv (50) of about 3.59 mm, and a Dv (90) of about 13.0 mm, or a Dv (10) of about 1.37 mm, a Dv (50) of about 3.65 mm, and a Dv (90) of about 8.01 mm, or a Dv (10) of about 1 .46 mm, a Dv (50) of about 4.00 mm, and a Dv (90) of about 10.5 mm, or a Dv (10) of about 1.30 mm, a Dv (50) of about 3.30 mm, and a Dv (90) of about 6.43 mm, or a Dv (10) of about 1.34 mm, a Dv (50) of about 3.40 mm, and a Dv (90) of about 7.03 mm, or a Dv (10) of about 1 .08 mm, a Dv (50) of about 2.93 mm, and a Dv (90) of about 8.67 mm.

[0091] In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 8 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 4 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 3 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 3 mm to 4 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter of 4 mm.

[0092] In some embodiments, a surfactant-lipid alloy drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and has a volume mean diameter from 1 mm to 8 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and has a volume mean diameter from 1 mm to 4 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and has a volume mean diameter from 1 mm to 3 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and has a volume mean diameter from 3 mm to 4 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises a surfactant-lipid alloy wherein the surfactant is DPPC and the lipid is CP and has a volume mean diameter of 4 mm.

[0093] In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 2 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 2 mm to 3 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 3 mm to 4 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 4 mm to 5 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 5 mm to 6 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 6 mm to 7 mm. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 7 mm to 8 mm.

[0094] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 1 mm to 2 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 2 mm to 3 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 3 mm to 4 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 4 mm to 5 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 5 mm to 6 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC and CP as the lipid and has a volume mean diameter from 6 mm to 7 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid.

[0095] In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 3.00 mm to about 3.70 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 3.05 mm to about 3.60 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 3.10 mm to about 3.50 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 7.00 mm to about 8.00 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 5.80 mm to about 6.40 mm. In some embodiments, a surfactant- lipid alloy drug substance has a D [4,3] from about 7.15 mm to about 7.95 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 3.20 mm to about 4.00 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 3.40 mm to about 4.30 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from about 6.80 mm to about 7.40 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] of about 7.60 mm, about 3.14 mm, about 3.32 mm, about 3.51 mm, about 6.10 mm, about 7.45 mm, about 3.60 mm, about 3.84 mm, or about 7.12 mm.

[0096] In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 3.00 mm to 3.70 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 3.05 mm to 3.60 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 3.10 mm to 3.50 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 7.00 mm to 8.00 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 5.80 mm to 6.40 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 7.15 mm to 7.95 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 3.20 mm to 4.00 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] from 3.40 mm to 4.30 mm. In some embodiments, a surfactant- lipid alloy drug substance has a D [4,3] from 6.80 mm to 7.40 mm. In some embodiments, a surfactant-lipid alloy drug substance has a D [4,3] of 7.60 mm, 3.14 mm, 3.32 mm, 3.51 mm, 6.10 mm, 7.45 mm, 3.60 mm, 3.84 mm, or 7.12 mm.

[0097] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a D [4,3] of about 7.60 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a D [4,3] of 7.60 mm.

[0098] In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 8 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 4 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 3 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 3 mm to 4 mm as measured by laser diffraction. [0099] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 1 mm to 8 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 1 mm to 4 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 1 mm to 3 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 3 mm to 4 mm as measured by laser diffraction.

[00100] In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 1 mm to 2 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 2 mm to 3 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 3 mm to 4 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 4 mm to 5 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 5 mm to 6 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 6 mm to 7 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance has a volume mean diameter from 7 mm to 8 mm as measured by laser diffraction.

[00101] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 1 mm to 2 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 2 mm to 3 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 3 mm to 4 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 4 mm to 5 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 5 mm to 6 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 6 mm to 7 mm as measured by laser diffraction. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a volume mean diameter from 7 mm to 8 mm as measured by laser diffraction.

[00102] In some embodiments, a surfactant-lipid alloy drug substance has an SMD (also referred to as D32 or D(3,2)) from 1 mm to 2 mm. In some embodiments, a surfactant- lipid alloy drug substance has an SMD from 2 mm to 3 mm. In some embodiments, a surfactant-lipid alloy drug substance has an SMD from about 1 .50 mm to about 2.40 mm. In some embodiments, a surfactant-lipid alloy drug substance has an SMD from about 1.60 mm to about 2.30 mm. In some embodiments, a surfactant-lipid alloy drug substance has an SMD from about 1.64 mm to about 2.25 mm. In some embodiments, a surfactant- lipid alloy drug substance has an SMD from 1 .50 mm to 2.40 mm. In some embodiments, a surfactant-lipid alloy drug substance has an SMD from 1 .60 mm to 2.30 mm. In some embodiments, a surfactant-lipid alloy drug substance has an SMD from 1 .64 mm to 2.25 mm. In some embodiments, a surfactant-lipid alloy drug substance has a SMD of about 2.21 mm, about 1 .85 mm, about 2.01 mm, about 1 .70 mm, about 1 .91 mm, about 1 .64 mm, about 1 .75 mm, or about 2.13 mm. In some embodiments, a surfactant-lipid alloy drug substance has an SMD of 2.21 mm, 1 .85 mm, 2.01 mm, 1.70 mm, 1 .91 mm, 1 .64 mm, 1 .75 mm, or 2.13 mm.

[00103] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has an SMD from 1 mm to 2 mm, from 2 mm to 3 mm, from 1.50 mm to 2.40 mm, from 1.60 mm to 2.30 mm, from 1 .64 mm to 2.25 mm, from 1 .50 mm to 2.40 mm, from 1 .60 mm to 2.30 mm, or from 1 .64 mm to 2.25 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has an SMD of about 2.21 mm, about 1 .85 mm, about 2.01 mm, about 1.70 mm, about 1 .91 mm, about 1 .64 mm, about 1 .75 mm, or about 2.13 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has an SMD of 2.21 mm, 1.85 mm, 2.01 mm, 1 .70 mm, 1 .91 mm, 1 .64 mm, 1 .75 mm, or 2.13 mm. [00104] In some embodiments, the SMD of a surfactant-lipid alloy drug substance is measured using a Malvern particle size analyzer. In some embodiments, the SMD of a surfactant-lipid alloy drug substance is measured using a Sympatec HELOS instrument.

[00105] In some embodiments, the SMD of a drug substance comprising a surfactant-lipid alloy of the surfactant DPPC and the lipid CP is measured using a Malvern particle size analyzer. In some embodiments, the SMD of a surfactant-lipid alloy drug substance is measured using a Sympatec HELOS instrument.

[00106] In some embodiments, a surfactant-lipid alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 100.0% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 99.05% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 99.0% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 98.5% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 98.46% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance has a cumulative particle size distribution Q3 from 60.0% to 98% < 5.0 mm.

[00107] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a cumulative particle size distribution Q3 from 60.0% to 100.0% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a cumulative particle size distribution Q3 from 60.0% to 99.05% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a cumulative particle size distribution Q3 from 60.0% to 99.0% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a cumulative particle size distribution Q3 from 60.0% to 98.5% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a cumulative particle size distribution Q3 from 60.0% to 98.46% < 5.0 mm. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and has a cumulative particle size distribution Q3 from 60.0% to 98% < 5.0 mm.

[00108] In some embodiments, a surfactant-lipid alloy drug substance exhibits a percent mass change due to absorption of water of less than 2.9% at 10% to 30% relative humidity. In some embodiments, a surfactant-lipid alloy drug substance exhibits a percent mass change due to desorption of water of less than 4.5% at 0% to 10% relative humidity. In some embodiments, the percent mass change(s) due to absorption or desorption of water are measured by dynamic vapor sorption.

[00109] In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and exhibits a percent mass change due to absorption of water of less than 2.9% at 10% to 30% relative humidity. In some embodiments, a surfactant-lipid alloy drug substance comprises DPPC as the surfactant and CP as the lipid and exhibits a percent mass change due to desorption of water of less than 4.5% at 0% to 10% relative humidity. In some embodiments, the percent mass change(s) due to absorption or desorption of water are measured by dynamic vapor sorption.

[00110] The present disclosure also pertains to homogeneous solutions comprising a surfactant, a lipid, and at least two miscible solvents.

[00111] As would be understood by the person having ordinary skill in the art, certain solvents may be classified as“Class 1 ,”“Class 2,” or“Class 3” (see, e.g., U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologies Evaluation and Research (CBER),“Q3C— Tables and List Guidance for Industry” (2017), retrieved from fda.gov on August 31 , 2018). It is to be understood that, as used herein, the terms“Class 2 solvent,”“Class 2 solvents,”“Class 3 solvent,” and“Class 3 solvents” include the solvent(s) described and classified in the aforementioned “Q3C — Tables and List Guidance for Industry” reference.

[00112] In some embodiments, homogeneous solutions comprise a surfactant, a lipid, and at least two miscible Class 2 solvents. In some embodiments, homogeneous solutions comprise a surfactant, a lipid, at least one Class 2 solvent, and at least one Class 3 solvent, wherein the at least one Class 2 solvent and the at least one Class 3 solvent are miscible.

[00113] In some embodiments, homogeneous solutions comprise DPPC, CP, and at least two miscible solvents. In some embodiments, homogeneous solutions comprise DPPC, CP, and at least two miscible Class 2 solvents. In some embodiments, homogeneous solutions comprise DPPC, CP, at least one Class 2 solvent, and at least one Class 3 solvent, wherein the at least one Class 2 solvent and the at least one Class 3 solvent are miscible. [00114] In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate.

[00115] In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 80:20. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 70:30. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 60:40. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 59:41. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 58:42. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 57:43. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 55:45. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 56:44. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 54:46. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 53:47. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 52:48. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 51 :49. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 50:40. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 45:55. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 40:60. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 30:70. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and dichloromethane, wherein the ratio of ethanol:dichloromethane is 20:80.

[00116] In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 80:20. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 75:25. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 70:30. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 65:35. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 60:40. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 55:45. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 50:50. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 45:55. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 40:60. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 35:65. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 30:70. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 25:75. In some embodiments, homogeneous solutions comprise DPPC, CP, ethanol, and ethyl acetate, wherein the ratio of ethanol:ethyl acetate is 20:80.

[00117] The present disclosure also pertains to homogeneous solutions comprising a surfactant, a lipid, and exactly two miscible solvents. In some embodiments, homogeneous solutions comprise a surfactant, a lipid, and exactly two miscible Class 2 solvents. In some embodiments, homogeneous solutions comprise a surfactant, a lipid, and exactly two miscible solvents, wherein one solvent is a Class 2 solvent and the other is a Class 3 solvent.

[00118] In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents. In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible Class 2 solvents. In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents, wherein one solvent is a Class 2 solvent and the other is a Class 3 solvent. In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents that are ethanol and dichloromethane. In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents that are ethanol and ethyl acetate.

[00119] In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents that are ethanol and dichloromethane and that are present in a 56:44 ratio of ethanol:dichloromethane. In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents that are ethanol and ethyl acetate and that are present in a ratio of 50:50 ethanol:ethyl acetate. In some embodiments, homogeneous solutions comprise DPPC, CP, and exactly two miscible solvents that are ethanol and ethyl acetate and that are present in a ratio of 30:70 ethanol:ethyl acetate.

[00120] The present disclosure also pertains to methods of preparing drug substances comprising surfactant-lipid alloys according to the disclosure. In some embodiments, a method of preparing a drug substance comprising a surfactant-lipid alloy comprises providing a homogeneous solution according to the disclosure and spray drying said homogeneous solution to provide a drug substance comprising a surfactant- lipid alloy according to the disclosure as a powder.

[00121] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising a surfactant, a lipid, and at least two miscible solvents and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising a surfactant, a lipid, and at least two miscible Class 2 solvents and spray-drying said homogeneous solution to provide a drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising a surfactant, a lipid, at least one Class 2 solvent, and at least one Class 3 solvent, wherein the at least one Class 2 solvent and the at least one Class 3 solvent are miscible, and spray-drying said homogeneous solution to provide a drug substance as a powder.

[00122] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and at least two miscible solvents and spray-drying said homogeneous solution to provide a drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and at least two miscible Class 2 solvents and spray-drying said homogeneous solution to provide a drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, at least one Class 2 solvent, and at least one Class 3 solvent, wherein the at least one Class 2 solvent and the at least one Class 3 solvent are miscible, and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00123] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, ethanol, and dichloromethane and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, ethanol, and ethyl acetate and spray-drying said homogeneous solution to provide a drug substance as a powder.

[00124] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, ethanol, and dichloromethane in a 56:44 ratio of ethanol:dichloromethane and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00125] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, ethanol, and ethyl acetate in a 50:50 ratio of ethanol:ethyl acetate and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00126] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, ethanol, and ethyl acetate in a 30:70 ratio of ethanol:ethyl acetate and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00127] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising a surfactant, a lipid, and exactly two miscible solvents and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising a surfactant, a lipid, and exactly two miscible Class 2 solvents and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising a surfactant, a lipid, and exactly two miscible solvents, wherein one solvent is a Class 2 solvent and the other is a Class 3 solvent, and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00128] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible Class 2 solvents and spray drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder. In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents, wherein one solvent is a Class 2 solvent and the other is a Class 3 solvent, and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00129] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents that are ethanol and dichloromethane and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00130] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents that are ethanol and ethyl acetate and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00131] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents that are ethanol and dichloromethane present in a 56:44 ratio of ethanol:dichloromethane and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00132] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents that are ethanol and dichloromethane present in a 50:50 ratio of ethanol:ethyl acetate and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00133] In some embodiments, a method of preparing a surfactant-lipid alloy drug substance comprises providing a homogeneous solution comprising DPPC, CP, and exactly two miscible solvents that are ethanol and dichloromethane present in a 30:70 ratio of ethanol:ethyl acetate and spray-drying said homogeneous solution to provide a surfactant-lipid alloy drug substance as a powder.

[00134] The present disclosure also pertains to pharmaceutical compositions comprising a surfactant-lipid alloy drug substance according to the disclosure. In some embodiments, a pharmaceutical composition according to the disclosure comprises a surfactant-lipid alloy drug substance, wherein the surfactant is DPPC and the lipid is CP.

[00135] In some embodiments, a pharmaceutical composition according to the disclosure may be in the form of a solution, an emulsion, a dispersion, or a suspension. In some embodiments, a pharmaceutical composition according to the disclosure may comprise one or more carriers, vehicles, excipients, thickeners, diluents, buffers, and/or preservatives. Suitable carriers, vehicles, excipients, thickeners, diluents, buffers, and/or preservatives are well-known to persons having ordinary skill in the art (see, as a non limiting example, Remington: The Science and Practice of Pharmacy, 22^nd Edition, Loyd V. Allen (Ed.), Pharmaceutical Press, Philadelphia, PA (2012), and any other editions, which are hereby incorporated by reference).

[00136] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance but do not comprise a propellant. In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the pharmaceutical composition is in the form of a heterogeneous suspension. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane (also known as“HFA-134a”).

[00137] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance, wherein the surfactant is DPPC and the lipid is CP, and a propellant. In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance, wherein the surfactant is DPPC and the lipid is CP, but do not comprise a propellant. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance, wherein the surfactant is DPPC and the lipid is CP, and a propellant, wherein the pharmaceutical composition is in the form of a heterogeneous suspension. In some embodiments, said propellant includes 1 , 1 , 1 ,2- tetrafluoroethane.

[00138] As would be understood by a person having ordinary skill in the art, “creaming” is a phenomenon associated with certain compositions comprising drug particles and a propellant, wherein particles gradually accumulate at a surface and form a“cream” layer, which is a concentrated layer of particles. See, e.g., E. Javaheri, et al., “Numerical Modeling of Flocculation and Creaming of Drug Particles inside the Canister of a Metered Dose Inhaler” (2012) 3 Respiratory Drug Delivery 2012 769. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant. In some embodiments, said propellant includes 1 , 1 , 1 ,2- tetrafluoroethane.

[00139] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00140] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00141] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour. In some embodiments, said propellant includes 1 ,1 ,1 ,2- tetrafluoroethane.

[00142] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour. In some embodiments, said propellant includes 1 , 1 ,1 ,2- tetrafluoroethane.

[00143] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour. In some embodiments, said propellant includes 1 ,1 ,1 ,2-tetrafluoroethane.

[00144] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour. In some embodiments, said propellant includes 1 ,1 ,1 ,2- tetrafluoroethane.

[00145] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant, and wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour. In some embodiments, said propellant includes 1 ,1 ,1 ,2-tetrafluoroethane.

[00146] In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, and wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour. In some embodiments, said propellant includes 1 ,1 ,1 ,2-tetrafluoroethane.

[00147] In some embodiments, pharmaceutical compositions comprise a drug substance comprising a surfactant-lipid alloy, wherein the surfactant is DPPC and the lipid is CP, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, and wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00148] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant, and wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00149] In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, and wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour. In some embodiments, said propellant includes 1 , 1 ,1 ,2-tetrafluoroethane.

[00150] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, and wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour. In some embodiments, said propellant includes 1 , 1 ,1 ,2- tetrafluoroethane.

[00151] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance and a propellant, wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane. [00152] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 ,1 ,2-tetrafluoroethane.

[00153] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00154] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 ,1 ,2-tetrafluoroethane.

[00155] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 ,1 ,1 ,2- tetrafluoroethane.

[00156] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2- tetrafluoroethane.

[00157] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00158] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour, at a rate of less than 750 millimeters per hour, at a rate of less than 700 millimeters per hour, at a rate of less than 650 millimeters per hour, at a rate of less than 600 millimeters per hour, at a rate of less than 550 millimeters per hour, at a rate of less than 500 millimeters per hour, at a rate of less than 450 millimeters per hour, at a rate of less than 400 millimeters per hour, at a rate of less than 350 millimeters per hour, at a rate of less than 300 millimeters per hour, at a rate of less than 250 millimeters per hour, at a rate of less than 200 millimeters per hour, at a rate of less than 150 millimeters per hour, or at a rate of less than 100 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00159] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00160] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of surfactant and lipid in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00161] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00162] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2- tetrafluoroethane.

[00163] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 4 mm or less over a period of 30 seconds, of 5 mm or less over a period of 120 seconds, or of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00164] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the surfactant-lipid alloy drug substance exhibits reduced creaming in the propellant relative to a non-alloyed mixture of DPPC and CP in the same propellant, wherein the surfactant-lipid alloy drug substance migrates to the surface of the propellant at a rate of less than 800 millimeters per hour or at a rate of less than 500 millimeters per hour, and wherein a layer of the surfactant-lipid alloy drug substance formed in the composition reaches a peak thickness of 7 mm or less over a period of 10 minutes. In some embodiments, said propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00165] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising a non-alloyed mixture of the surfactant and the lipid. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance and a propellant, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising the propellant and a non-alloyed mixture of the surfactant and the lipid. In some embodiments, said greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium. In some embodiments, said greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium and the ratio of dipalmitoylphosphatidylcholine to cholesteryl palmitate in the surfactant-lipid alloy is 10: 1 , 20: 1 , or 30: 1. In some embodiments, the propellant includes 1 , 1 , 1 ,2-tetrafluoroethane.

[00166] In some embodiments, pharmaceutical compositions comprise a surfactant- lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising a non- alloyed mixture of DPPC and CP. In some embodiments, pharmaceutical compositions comprise a surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid, and a propellant, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising the propellant and a non-alloyed mixture of DPPC and CP. In some embodiments, said greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium. In some embodiments, said greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium and the ratio of DPPC to CP is 10: 1 , 20: 1 , or 30: 1 . In some embodiments, the propellant includes 1 , 1 , 1 ,2- tetrafluoroethane.

[00167] In some embodiments, a pharmaceutical composition is formulated as a non-aqueous pressurized metered dose spray for intranasal administration. In some embodiments, formulation ingredients comprise, consist essentially of, or consist of DPPC and CP in a target 20:1 weight/weight ratio and a compendial inactive ingredient, Norflurane Ph.Eur. (HFA-134a). In some embodiments, the formulation is filled into a canister/metered valve/actuator assembly. In some embodiments, the unit compositions are provided as follows:

[00168] As would be understood by a person having ordinary skill in the art, dynamic vapor sorption (DVS) is a gravimetric technique that can be used to measure the extent to which a sample of material absorbs and/or desorbs a solvent and the rate at which these absorption and/or desorption events occur. Aspects of the present disclosure pertain to the study of the absorption and/or desorption behaviors of drug substances according to the disclosure using DVS. In some embodiments, DVS analysis comprises measuring the percent mass change of a test sample as a function of the relative humidity (RH) to which the sample is exposed. In some embodiments, the test sample is a surfactant-lipid alloy drug substance according to the disclosure. In some embodiments, the test sample is a spray-dried powder of surfactant-lipid alloy drug substance according to the disclosure. In some embodiments, the test sample is a spray-dried powder of drug substance comprising a surfactant-lipid alloy, wherein the surfactant is DPPC and the lipid is CP.

[00169] In some embodiments, a surfactant-lipid alloy drug substance exhibits a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1.0%, or less than 0.5%.

[00170] In some embodiments, drug substances comprising a surfactant-lipid alloy of the surfactant DPPC and the lipid CP exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%.

[00171] In some embodiments, a surfactant-lipid alloy drug substance exhibits a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS). [00172] In some embodiments, surfactant-lipid alloy drug substances comprise DPPC as the surfactant and CP as the lipid and exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00173] In some embodiments, surfactant-lipid alloy drug substances exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%.

[00174] In some embodiments, surfactant-lipid alloy drug substances comprise DPPC as the surfactant and CP as the lipid and exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%.

[00175] In some embodiments, surfactant-lipid alloy drug substances exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00176] In some embodiments, surfactant-lipid alloy drug substances comprise DPPC as the surfactant and CP as the lipid and exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00177] In some embodiments, a surfactant-lipid alloy drug substance exhibits a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%.

[00178] In some embodiments, drug substances comprising a surfactant-lipid alloy of the surfactant DPPC and the lipid CP exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%.

[00179] In some embodiments, a surfactant-lipid alloy drug substance exhibits a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00180] In some embodiments, drug substances comprising a surfactant-lipid alloy of the surfactant DPPC and the lipid CP exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00181] In some embodiments, surfactant-lipid alloy drug substances exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%.

[00182] In some embodiments, surfactant-lipid alloy drug substances comprise DPPC as the surfactant and CP as the lipid and exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%.

[00183] In some embodiments, surfactant-lipid alloy drug substances exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00184] In some embodiments, surfactant-lipid alloy drug substances comprise DPPC as the surfactant and CP as the lipid and exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00185] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1 .0%, or less than 0.5%.

[00186] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%.

[00187] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00188] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00189] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%.

[00190] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%.

[00191] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00192] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to absorption of water between 10% RH and 30% RH that is less than 2.9% or that is less than 2.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00193] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1 .5%, less than 1 .0%, or less than 0.5%.

[00194] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1 .0%, or less than 0.5%. [00195] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1.0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00196] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 3.5%, less than 3.0%, less than 2.5%, less than 2.0%, less than 1.5%, less than 1 .0%, or less than 0.5%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00197] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%.

[00198] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%.

[00199] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00200] In some embodiments, spray-dried powders of surfactant-lipid alloy drug substance comprising DPPC as the surfactant and CP as the lipid exhibit a percent mass change due to desorption of water between 0% RH and 10% RH that is less than 4.5%, less than 4.0%, less than 2.5%, or less than 2.0%, wherein the percent mass change is measured by dynamic vapor sorption (DVS).

[00201] The following non-limiting examples and data illustrate various aspects and features of the surfactant-lipid alloy drug substance according to the disclosure, compositions comprising the surfactant-lipid alloy drug substance according to the disclosure, and methods of making the same. It is to be understood that the present disclosure is in no way limited to, or by, the following examples and/or data. [00202] Example 1 - Solubility Screening of DPPC and CP

[00203] DPPC and CP were combined in different solvents and solvent mixtures to identify solvents and/or solvent mixtures capable of dissolving both components. The experimental conditions and results are presented in Table 1.

Table 1 ^a

a Except where indicated otherwise, all solutions comprise 20:1 DPPC:CP at a solid content of 4% w/v. DMSO = dimethylsulfoxide; DCM = dichloromethane.

b Result observed for each of 20:1 , 10:1 , and 5:1 DPPC:CP ratios.

[00204] For each of 20: 1 , 10: 1 , and 5: 1 DPPC:CP ratios, a solvent mixture of 56:44 ethanol:dichloromethane provided a clear solution at a solid content of 4% w/v. These results correspond to an effective concentration of 60 mg/mL DPPC in ethanol and 15 mg/mL CP in dichloromethane. The solubility of DPPC in ethanol in the combined solution was thus greater than the solubility of only DPPC in ethanol (estimated at 30-40 mg/mL). The solubility of DPPC in pure dichloromethane was < 5 mg/mL. Without wishing to be bound by theory, these results suggest an interaction occurs between CP and DPPC that acts to increase solubility (for example, an interaction wherein CP acts to solubilize DPPC).

[00205] The solubility of CP alone in different pure solvents and at various concentrations was also examined. For each experiment, approximately 50 mg of CP was added to a vial. Solvent was added in 1 mL increments up to 5 mL. After each solvent addition, the sample was vortexed for ~ 30 seconds and then roller mixed for 5 minutes. If CP dissolved, no further solvent was added. Results from experiments performed using either dichloromethane or one of six different Class 3 solvents are presented in Table 2. Table 2^a

a Insol. = Insoluble, Partial = Partially Soluble, Sol. = Soluble.

[00206] Upon consideration of such factors as toxicity and solvent boiling point, ethyl acetate was selected for further investigation as a co-solvent to be used in conjunction with ethanol.

[00207] Mixtures of DPPC:CP (20: 1 ) in varying volume ratios of ethanol:ethyl acetate and with varying solid loadings (% w/v) were heated to 40-50°C, allowed to cool, and observed visually ( see Table 3). Upon heating to 40-50°C, DPPC and CP dissolved at all studied concentrations. In some instances, solids precipitated from the solution over time. However, a solution comprising 2.5% w/v solids in 50:50 ethanol:ethyl acetate was stable for > 18 hours after cooling ( see entry 3).

Table 3

[00208] From these experiments, 56:44 ethanol:dichloromethane and mixtures of ethanol: ethyl acetate ( e.g ., 50:50 ethanol:ethyl acetate) were identified as co-solvent systems that dissolved both DPPC and CP.

[00209] Example 2 - Spray Drying of Surfactant-Lipid Alloy Drug Substance and Particle Size Analysis by Laser Diffraction (EtOH:DCM)

[00210] Mixtures of DPPC and CP were spray-dried to produce powders of the surfactant-lipid alloy drug substance comprising a surfactant-lipid alloy according to the disclosure by following the methods and conditions described below, with reference to Table 4 and Table 5.

[00211] DPPC and CP were dissolved in a solution of ethanol:dichloromethane (56:44) to achieve 4% w/v solids of the indicated DPPC: CP ratio, except for batch 099#007, wherein a 6% w/v feed solution was used. The solution so-obtained was pumped using a Masterflex pump with Viton-14 tubing and spray-dried using a Buchi B290 lab scale spray dryer fitted with a two-fluid nozzle. The aspirator was set to 100% for all batches. A standard (S) or high performance (HP) cyclone was used.

[00212] DPPC, CP, and spray-dried surfactant-lipid alloy drug substance powders were analyzed by laser diffraction using a SympaTec HELOS particle size analyzer with a RODOS dry powder dispersion unit. Dispersal was achieved using compressed air with a gap height of 6 mm and a depression pressure of 75 mbar. Approximately 100 mg of spray-dried drug substance was introduced into the RODOS unit by a VIBRI feeder. Measurements were made in triplicate using an R3 lens.

[00213] During initial analyses of three batches of spray-dried surfactant-lipid alloy drug substance powders (batches 099#002, 099#003, and 099#004), the dispersion pressure was varied from 1 to 3 bar. These conditions and particle size results are presented in Table 4. Without wishing to be bound by theory, these results suggest that there was a negligible impact of dispersion pressure on particle size. During subsequent analyses, a dispersion pressure of 2.0 bar was used.

Table 4

[00214] Initial spray-drying experiments were performed using DPPC:CP ratios of 20: 1 , a flow rate of 2 g/min, a spray pressure of 2.5 bar, and outlet temperatures of 30°C, 40°C, or 50°C (batches 099#002, 099#003, and 099#004, respectively). As shown in Table 5, VMD for these batches ranged from between 2.3 and 3.6 micron. Powders obtained using an outlet temperature of 30°C (see, e.g., batch 099#002) were larger in size and a number of fine particles were not collected in the cyclone but instead progressed to the filter, causing a drop in filter pressure over time. Collection using a high- performance cyclone did not lead to a decrease in VMD (batch 099#005). Batches prepared using a DPPC:CP ratio of 10: 1 or 5: 1 were spray-dried at outlet temperatures of 30°C and 20°C and atomization pressures of 0.25 bar and 0.75 bar, respectively (batches 099#009 and 099#010). In each instance, incomplete drying was observed with large agglomeration or deposition in the drying chamber. Accordingly, 40°C was selected as the outlet temperature.

[00215] Spray-dried powders of surfactant-lipid alloy drug substance with a VMD of 2-4 micron were thus obtained using an atomization pressure of 2.5 bar. Decreasing atomization pressure from 2.5 bar to 0.25 bar resulted in an increase in VMD from 2.25 to 5.18 ( compare batches 099#003 and 099#006). Increasing the solid content from 4 to 6% (w/v) and the spray rate from 2 to 4 g/min resulted in a further increase in VMD to 10.18 micron (see batch 099#007). However, the tailing size distribution suggested aggregation of smaller particles rather than production of larger particles.

[00216] FIG. 1 A, FIG. 1 B, and FIG. 1 C depict particle sizes and distribution densities (q3*) for batches 099#002, 099#003, and 099#004, respectively.

Table 5

[00217] As shown in Table 6, four additional batches of spray-dried powders of alloy drug substance were prepared using DPPC:CP ratios of 5: 1 or 10: 1 (batches 099#01 1 to 099#014). Each batch of spray-dried powder was produced as a fine, white powder with no observed stickiness and/or tackiness. Upon spray-drying at 2.50 bar of atomization pressure, particles with VMD of 2.01 or 2.26 micron were obtained, and upon spray-drying at 0.25 bar of atomization pressure, particles with VMD of 4.48 or 5.67 micron were obtained.

Table 6

[00218] Example 3 - Spray Drying of Surfactant-Lipid Alloy Drug Substance and Particle Size Analysis by Laser Diffraction (Ethyl Acetate and EthanohEthyl Acetate)

[00219] Batches of spray-dried surfactant-lipid alloy drug substance powders were prepared according to the procedure described below, with reference to Table 7.

[00220] DPPC and CP were combined in the indicated ratio and in the indicated solvent system. The resulting mixture was heated to 40-50°C then either held at 45-48°C or allowed to cool to ambient temperature before spraying drying. Without wishing to be bound by theory, experimental results suggested that when the solids content was greater than 3% w/v, holding the solution at 45-48°C for spray-drying was beneficial to prevent precipitation of solids.

[00221] Feed solutions were spray-dried using a Buchi B290 lab scale spray dryer fitted with a two-fluid nozzle and a high-performance cyclone. The nozzle was heated using a recirculating hot water jacket (45-48°C). The aspirator was set to 100% for all batches. The liquid feed rate was 2 g/min, and the atomization pressure was 2.5 bar. The inlet temperature was 60°C, and the outlet temperature was 45°C. After spray drying, powders were collected into glass vials, para-filmed, and stored at -20°C.

[00222] For batches 099#018A and 099#018B, the mixtures were clear within 15 minutes of heating to 40-50°C. Spray-drying of each batch produced a dry, free-flowing powder with no visible deposition in the spray chamber. For batch 099#18C, upon heating to 40-50°C, CP dissolved and DPPC was homogeneously dispersed. The mixture had a milky-white appearance. The mixture was aged for 15 minutes with mixing. DPPC settled in the container; therefore, the mixture was mixed by swirling throughout the run. A dry powder was collected from the cyclone and collection pot.

[00223] To incorporate different ratios of DPPC:CP in batches 099#019A and 099#019B, the solid content (% w/v) and ratio of ethanol:ethyl acetate were adjusted. For each batch, the mixture was solubilized at 40-50°C. Batch 099#019A exhibited solubility upon cooling for 15 minutes. Batch 099#019B exhibited solubility upon cooling for 22 minutes. While solution cooling occurs during pumping in the spray-drying process, these solubility conditions were deemed sufficient to permit spray-drying of the mixtures.

[00224] Spray-dried surfactant-lipid alloy drug substance powders were analyzed by laser diffraction using the conditions described in Example 2, except that: (1 ) approximately 50 to 100 mg of spray-dried surfactant-lipid alloy drug substance powder was introduced to the RODOS unit by the VIBRI feeder, and (2) dispersal was achieved using compressed air at a pressure of 2.0 bar.

[00225] As shown in Table 7, for batches 099#018A and 099#018B (prepared using 20:1 DPPC:CP and 50:50 ethanol:ethyl acetate), mean particle sizes (VMD) varied from 2.16 to 2.32 micron as the feed concentration increased from 2.5% to 4.0% w/v. In this regard, particle sizes were consistent with those obtained using 56:44 ethanol:dichloromethane ( compare , e.g., Table 5, batch 099#003). For batch 099#018C (prepared using 20:1 DPPC:CP and 100% ethyl acetate), the mean particle size (VMD) of 8.56 micron was larger than that obtained from other batches that were spray-dried under similar conditions (e.g., at an atomization pressure of 2.5 bar; compare batches 099#018A and 099#018B and Table 5, batch 099#003).

[00226] Batches 099#019A and 099#019B were prepared using DPPC:CP ratios of 10:1 and 5:1 , respectively. The mean particle size (VMD) of batch 099#019A (10:1 DPPC:CP) was consistent with that of other batches (e.g., batches 099#018A and 099#018B and Table 5, batch 099#003). The mean particle size (VMD) of batch 099#019B (5:1 DPPC:CP) was larger than that of certain other batches. In addition, for batch 099#019B, the powder was cohesive and the yield was greater than that of certain other batches, results that may suggest that the batch comprised a greater residual solvent content relative to certain other batches. Without wishing to be bound by theory, the larger VMD observed may have been the result of increased aggregation relative to certain other batches, and the possible increase in residual solvent content may have resulted from the change in the ratio of ethanol to ethyl acetate and the corresponding change in the evaporative capacity of these solvents in the mixed solvent system.

[00227] Spray-dried powders of surfactant-lipid alloy drug substance were thus obtained from mixtures prepared using 100% ethyl acetate or various ethanol:ethyl acetate solvent systems and using DPPC:CP ratios of 20:1 , 10:1 , or 5:1. The volume mean diameters (VMD) of certain batches (e.g., 099#018A, 099#018B, and 099#019A) ranged from 1.81 -2.32 micron and were consistent with the volume mean diameters of certain batches prepared using ethanol:dichloromethane ( compare , e.g., Table 5, batch 099#003). A comparatively larger VMD (3.53 micron) was observed from a batch preparing using 5:1 DPPC:CP in ethanol:ethyl acetate. Table 7

aDuring spraying, slight solvent condensation was observed in the collection pot, and the outlet temperature was increased from 40°C to 45°C. Upon this increase, no condensation was observed, and a dry powder was produced.

[00228] Additional batches of spray-dried powders of surfactant-lipid alloy drug substance, identified below as Samples IDs 1A to 29I, were prepared according to methods similar to those described elsewhere herein. Specifically, mixtures DPPC and CP were combined in ethanol: DCM and spray-dried to provide surfactant-lipid alloy drug substances according to the disclosure, wherein the surfactant is DPPC and the lipid is CP. Particle size data are presented in Table 8 and Table 9

Table 8

Table 9

[00229] Additional batches of spray-dried powders of surfactant-lipid alloy drug substance, identified below as Samples IDs 30 to 33, were prepared according to methods similar to those described elsewhere herein. Specifically, mixtures of DPPC and CP were combined in ethanol: DCM (Sample IDs 30 to 32) or ethanol:ethyl acetate (Sample ID 33) and spray-dried to provide surfactant-lipid alloy drug substances according to the disclosure, wherein the surfactant is DPPC and the lipid is CP. Further batches of spray-dried powders of surfactant-lipid alloy drug substance, identified below as Samples IDs 34 to 36, were also prepared according to methods similar to those described elsewhere herein. Particle size data are presented in Table 10.

Table 10

[00230] Additional batches of spray-dried powders of surfactant-lipid alloy drug substance, identified below as Samples IDs 37 to 41 , were prepared according to methods similar to those described elsewhere herein, with reference to Table 11. Specifically, mixtures DPPC and CP were combined in ethanol:ethyl acetate and spray- dried to provide surfactant-lipid alloy drug substances according to the disclosure, wherein the surfactant is DPPC and the lipid is CP. Particle size data are presented in Table 11.

Table 1 1

a Particle size measurement performed at the beginning of process. ^b Particle size measurement performed at the end of process

[00231] Example 4 - Spray Drying of Surfactant-Lipid Alloy Drug Substance and Particle Size Analysis by Laser Diffraction (ProCepT Spray Dryer, EthanohDCM)

[00232] Batches of spray-dried powders of surfactant-lipid alloy drug substance were prepared using a ProCepT 4M8-TriX Spray Dryer as described below and with reference to Tables 12 and 13. A mixture of DPPC and CP (25 g, 20:1 weight ratio) in 625 mL of ethanol:DCM (625 mL, 56:44 volume/volume ratio) was prepared. The solids dissolved within 45 minutes. The solution was divided into nine aliquots for spray drying (batches 099#022A to 099#022l). The solution was pumped using a ProCepT integrated pump with Viton 3-stop tubing connected to the nozzle with FEP tubing and was spray dried using the ProCepT spray dryer. The ProCepT was fitted with a bi-fluid nozzle tip (either 0.6 mm or 1.2 mm) and a medium cyclone. After spray drying, powders were collected into glass vials, sealed with plastic paraffin film, and stored at -20°C.

[00233] The particle sizes of these spray-dried powders of drug substance were analyzed using laser diffraction, using a SympaTec HELOS particle size analyzer with a RODOS dry powder dispersion unit. Dispersal was achieved using compressed air at a pressure of 2.0 bar, a gap height of 6 mm, and a depression pressure of 75 mbar. Approximately 100 mg of spray-dried product was introduced into the RODOS unit using a VIBRI feeder. Measurements were made in triplicate using the R3 lens, and mean data were recorded.

Table 12

[00234] Without wishing to be bound by theory, these experimental results suggest that a decrease in outlet temperature from 40°C to 30°C was associated with an increased yield in the collection pot and reduced deposition of material in the cyclone. Also without wishing to be bound by theory, these experimental results suggest that a change in atomization pressure from 2.50 bar to 0.25 bar was associated with an increase in VMD {compare batch 099#022E with batch 099#022F). Also without wishing to be bound by theory, these experimental results suggest that a change in atomization pressure from 1.0 bar to 2.50 bar, wherein the flow rate was 4 g/min, was associated with little change in particle size distribution ( compare batch 099#022D with batch 099#022E). Also without wishing to be bound by theory, these experimental results suggest that use of an atomization pressure of 0.75 bar was associated with higher yields (see, e.g., batch 099#022l).

[00235] Three additional batches of spray-dried surfactant-lipid alloy drug substance powders were prepared on 10 gram scale according to methods described above, again using a ProCepT 4M8-TriX Spray Dryer. The feed compositions comprised 20: 1 DPPC:CP or 10: 1 DPPC:CP at 4% (w/v) solid content in 56:44 ethanol:DCM. A standard cyclone was used, the outlet temperature was 30°C. In each experiment, the majority of the product was retrieved from the collection pot, and the spray-dried powders of surfactant-lipid alloy drug substance were obtained as fine, white powders. Additional conditions and results, including particle size measurements performed as described above in this Example, are presented in Table 13.

Table 13

[00236] Example 5 - DSC Analysis (EthanohDCM)

[00237] Samples of DPPC, CP, and surfactant-lipid alloy drug substances that were spray-dried from 56:44 ethanol:dichloromethane were analyzed using differential scanning calorimetry (DSC). DSC analysis was performed using a TA Instruments Q20 MDSC with an autosampler and refrigerated cooling accessory. Approximately 5 mg of sample was analyzed in a T Zero aluminum pan under N2 flow (50 mL/min). Pans were sealed using a T Zero pan press. The following cycle was performed:

1. Equilibrate at -20.00°C

2. Isothermal for 5.00 min

3. Ramp 10.00°C/min to 150.00°C

4. Isothermal for 5.00 min

5. Ramp 10.00°C/min to -20.00°C

6. Isothermal for 5.00 min

7. Ramp 10.00°C/min to 150.00°C

Data analysis was performed using TA Instrument Universal Analysis 2000 software (build 4.5.0.5).

[00238] As shown in FIG. 2, by DSC analysis, the melting points of the starting components DPPC and CP were 127.60°C and 79.62°C, respectively.

[00239] DSC analysis was performed on samples that were spray-dried at 2.5 bar and on samples that were spray-dried at 0.25 bar. The samples comprised different ratios of DPPC: CP. The analysis was performed using two heating cycles, wherein the first cycle shows the sample properties (including its thermal history) and the second cycle shows the material properties after eradication of the thermal history. In the first cycle, samples that were spray-dried at 2.5 bar showed two very weak glass transition temperatures (Tgs) at 2-13°C and 24-27°C followed by three melting events (results not depicted). Without wishing to be bound by theory, these three melting events may correspond to CP, a mixed phase, and DPPC, wherein the magnitude of the mixed phase melt may increase with CP content. In the second cycle, a single Tg was observed, the temperature and magnitude of which depended on the CP content, followed by multiple melting events.

[00240] As shown in FIG. 3A and FIG. 3B, samples that were spray-dried at 0.25 bar showed two very weak Tgs at 14-16°C & 27-29°C followed by three melting events in the first cycle. Without wishing to be bound by theory, these three melting events may correspond to CP, a mixed phase, and DPPC, wherein the magnitude of the mixed phase melt may increase with CP content. In the second cycle, a single Tg was observed, the temperature and magnitude of which depended on the CP content, followed by multiple melting events.

[00241] FIG. 4A, FIG. 4B, FIG. 5A, FIG. 5B, FIG. 6A, and FIG 6B depict first-cycle and second-cycle DSC traces for samples of surfactant-lipid alloy drug substance prepared using 20: 1 , 10: 1 , and 5: 1 DPPC:CP. For example, FIG. 5A overlays: (1 ) the first-cycle DSC trace of a sample from a batch that was prepared using 20: 1 DPPC:CP and wherein spray drying was performed at 2.50 bar (099#006), and (2) the first-cycle DSC trace of a sample from a batch that was prepared using 20: 1 DPPC:CP and wherein spray drying was performed at 0.25 bar (099#003). FIG. 4B overlays the corresponding second-cycle DSC traces of these samples. Without wishing to be bound by theory, certain differences between the first-cycle DSC traces of these two samples (FIG. 4A) suggest different temperature profiles resulting from the different particle sizes associated with each sample. Also without wishing to be bound by theory, the similarities between the second-cycle traces for these samples (FIG. 4B) suggest that the materials are intrinsically the same.

[00242] FIG. 5A overlays: (1 ) the first-cycle DSC trace of a sample from a batch that was prepared using 10: 1 DPPC:CP and wherein spray drying was performed at 2.50 bar (099#014), and (2) the first-cycle DSC trace of a sample from a batch that was prepared using 10: 1 DPPC:CP and wherein spray drying was performed at 0.25 bar (099#013). FIG. 5B overlays the corresponding second-cycle DSC traces of these samples. Likewise, FIG. 6A overlays: (1 ) the first-cycle DSC trace of a sample from a batch that was prepared using 5: 1 DPPC:CP and wherein spray drying was performed at 2.50 bar (099#012), and (2) the first-cycle DSC trace of a sample from a batch that was prepared using 5: 1 DPPC:CP and wherein spray drying was performed at 0.25 bar (099#01 1 ). FIG. 6B overlays the corresponding second-cycle DSC traces of these samples. For these samples, the first-cycle DSC behavior was generally similar to the second-cycle DSC behavior, although certain differences in the magnitudes of melting events were observed in the second-cycle traces ( compare , e.g., FIG. 5A to FIG. 5B or FIG. 6A to FIG. 6B). For material prepared from 20:1 DPPC:CP, a greater degree of difference between the first- cycle and second-cycle DSC behaviors was observed ( compare , e.g., FIG. 4A to FIG. 4B). Without wishing to be bound by theory, the foregoing results suggest that certain spray-dried materials prepared from 20: 1 DPPC:CP are somewhat less thermally stable relative to certain spray-dried materials prepared from 10: 1 or 5: 1 DPPC:CP. [00243] Without wishing to be bound by theory, the foregoing DSC results suggest that certain spray-dried batches of surfactant-lipid alloy drug substance comprise individual DPPC and CP phases and a mixed phase. Also without wishing to be bound by theory, the foregoing DSC results also suggest that the spray pressure used in preparing the surfactant-lipid alloy drug substance had minimal or no impact on the thermal properties of the powders.

[00244] Example 6 - DSC Analysis (Ethyl Acetate and EthanohEthyl Acetate)

[00245] Batches of surfactant-lipid alloy drug substance that were spray-dried from ethyl acetate or from mixtures of ethanol and ethyl acetate were analyzed using differential scanning calorimetry (DSC) according to the procedure described above in Example 5.

[00246] FIG. 7A and FIG. 7B depict first- and second-cycle DSC traces for DPPC, CP, and a sample from batch 099#018A. As described elsewhere herein, batch 099#018A was produced using 20: 1 DPPC: CP, 2.5% w/v solids, and 50:50 ethanol:ethyl acetate, wherein the mixture of DPPC and CP in the solvent system was cooled to 20°C before spray drying. As shown in FIG. 7A, the first-cycle trace showed a glass transition temperature at 39°C followed by a double melt at 77°C and 81 °C. No DPPC melt was observed. Without wishing to be bound by theory, the observed glass transition may result from amorphous DPPC, and the observed melt may result from CP and a mixed phase. Also without wishing to be bound by theory, the absence of a DPPC melt suggests good mixing of DPPC and CP. As shown in FIG. 7B, the second-cycle DSC trace showed some DPPC separating, with an additional melting peak appearing at 97°C.

[00247] FIG. 8A and FIG. 8B depict first- and second-cycle DSC traces for DPPC, CP, and a sample from batch 099#018B. As described elsewhere herein, batch 099#018B was produced using 20: 1 DPPC: CP, 4.0% w/v solids, and 50:50 ethanol:ethyl acetate, wherein the mixture of DPPC and CP in the solvent system was kept at 45-48 °C during spray drying. As shown in FIG. 8A, the first-cycle DSC trace showed a glass transition temperature at 33°C, followed by two melting peaks at 77°C and 84°C. No DPPC melt was observed. Without wishing to be bound by theory, the observed glass transition may result from amorphous DPPC, and the observed melt may result from CP and a mixed phase. Also without wishing to be bound by theory, the absence of a DPPC melt suggests good mixing of DPPC and CP. Without wishing to be bound by theory, a comparison of the relative size of the melting peaks in the DSC traces of batch 099#018B versus those of batch 099#018A ( compare FIG. 7 A with FIG. 7B and FIG. 8A with FIG. 8B) suggests that the mixed phase is less abundant in the former sample. As shown in FIG. 8B, the second-cycle DSC trace showed some DPPC separating, with an additional melting peak appearing at 100°C.

[00248] FIG. 9A and FIG. 9B depict first- and second-cycle DSC traces for DPPC, CP, and a sample from batch 099#018C. As described elsewhere herein, batch 099#018C was produced using 20: 1 DPPC:CP, 8.0% w/v solids, and 100% ethyl acetate. As shown in FIG. 9A, the first-cycle DSC trace showed a melting peak for CP at 76°C and a melting peak for DPPC at 125°C. Each of these melting peaks is slightly depressed compared to the melting points of the raw components ( compare , e.g., FIG. 2). Without wishing to be bound by theory, these results suggest that, while there is some interaction between phases, each phase is distinct and the two components have not mixed. As shown in FIG. 9B, the DSC behavior in the second cycle is influenced by DPPC but, without wishing to be bound by theory, suggests that a mixing of the phases occurred following the heating and cooling events.

[00249] FIG. 10A and FIG. 10B depict first- and second-cycle DSC traces for DPPC, CP, and a sample from batch 099#019A. As described elsewhere herein, batch 099#019A was produced using 10: 1 DPPC: CP, 4.0% w/v solids, and 50:50 ethanol:ethyl acetate. As shown in FIG. 10A, the first-cycle DSC trace depicts a glass transition at 33°C, followed by a melting peak from two components at 77°C and a further melting peak at 85°C. Without wishing to be bound by theory, the glass transition may result from amorphous DPPC, and the melting events may result from the presence of individual components (DPPC and CP) and a mixed phase. As shown in FIG. 10B, the second- cycle trace depicts behavior that is similar to the first trace but with differences in the relative peak heights of the three melting events. Without wishing to be bound by theory, these differences in relative peak heights may be the result of increased mixing occurring after heating.

[00250] FIG. HA and FIG. 1 1 B depict first- and second-cycle DSC traces for DPPC, CP, and a sample from batch 099#019B. As described elsewhere herein, batch 099#019B was produced using 5: 1 DPPC:CP, 3.0% w/v solids, and 30:70 ethanol:ethyl acetate. As shown in FIG. 1 1 A, the first-cycle trace depicts three melting peaks at 75°C, 77°C, and 87°C. Without wishing to be bound by theory, these three melting events may result from the presence of individual components (DPPC and CP) and a mixed phase. As shown in FIG. 1 1 B, the second-cycle trace depicts behavior that is similar to the first trace, with the addition of a glass transition at 35°C. [00251] Without wishing to be bound by theory, the foregoing DSC results suggest that certain samples of spray-dried powders of surfactant-lipid alloy drug substance prepared from ethanol:ethyl acetate mixtures comprise a combination of a mixed phase and individual DPPC and CP. Without wishing to be bound by theory, the differences observed between the first- and second-cycle DSC behaviors of certain samples of spray- dried powders of surfactant-lipid alloy drug substance suggest that certain powders of surfactant-lipid alloy drug substance are kinetically stable but not thermodynamically stable after spray-drying. Without wishing to be bound by theory, the DSC results for certain samples of spray-dried powders of drug substance prepared from 100% ethyl acetate suggest that a lesser degree of mixing between DPPC and CP occurred during the formation of these samples.

[00252] Example 7 - SEM Analysis (EthanohDCM)

[00253] The particle size and surface morphology of DPPC, CP, and samples of surfactant-lipid alloy drug substance that were spray-dried from 56:44 ethanol:dichloromethane were analyzed by scanning electron microscopy (SEM). Samples were sprinkled onto a sticky stub mounted onto an SEM specimen disc and coated for 200 seconds with gold using a Sputter Coater. Samples were analyzed using a JEOL 6490LV SEM, and images were taken at a range of magnifications (x1000 and x3000).

[00254] FIG. 12 depicts SEM images of samples of spray-dried powders of surfactant-lipid alloy drug substance that were prepared using 20: 1 DPPC: CP and an atomization pressure of 2.5 bar (top row) or 0.25 bar (bottom row). FIG. 13 depicts SEM images of samples of spray-dried powders that were prepared using 10: 1 DPPC:CP and an atomization pressure of 2.5 bar (top row) or 0.25 bar (bottom row). FIG. 14 depicts SEM images of samples of spray-dried powders that were prepared using 5: 1 DPPC:CP and an atomization pressure of 2.5 bar (top row) or 0.25 bar (bottom row). With regard to these samples, particle sizes appeared more similar among batches that were spray- dried using an atomization pressure of 2.5 bar versus those spray-dried using an atomization pressure of 0.25 bar. Without wishing to be bound by theory, these results suggest that a greater incidence of fluctuations occurred during a spray drying process that used an atomization pressure of 0.25 bar relative to a spray drying process that used an atomization pressure of 2.50 bar. For each of the aforementioned samples, the particles of spray-dried powder appeared irregularly spherical, and the observed particle sizes were consistent with the particle sizes measured via laser diffraction as described elsewhere herein. No obvious variations in appearance were observed with respect to spray-dried powders prepared using different DPPC:CP ratios.

[00255] Example 8 - SEM Analysis (Ethyl Acetate and EthanohEthyl Acetate)

[00256] The particle size and surface morphology of DPPC, CP, and samples of surfactant-lipid alloy drug substance that were spray-dried from ethyl acetate or from ethanol:ethyl acetate were analyzed by scanning electron microscopy (SEM). Samples were sprinkled onto a sticky carbon stub mounted onto an SEM specimen disc and coated for 240 seconds with gold using a Leica EM SCD005 Sputter Coater. Samples were analyzed using a JEOL/EO JSM-6060 SEM, and images were taken at a range of magnifications (x1000 & x3000).

[00257] FIG. 15 depicts SEM images of samples of spray-dried powders of surfactant-lipid alloy drug substance that were prepared using 20: 1 DPPC: CP (4% w/v solids, 50:50 ethanol:ethyl acetate), 10: 1 DPPC (4% w/v solids, 50:50 ethanol:ethyl acetate), or 5:1 DPPC:CP (3% w/v solids, 30:70 ethanol:ethyl acetate). Sample powders from batches prepared using 20: 1 or 10: 1 DPPC: CP appeared broadly spherical and of uniform size. Sample powders from a batch prepared using 5: 1 DPPC and 30:70 ethanol:ethyl acetate appeared more crystalline, with flat, irregularly-shaped particles.

[00258] FIG. 16 depicts SEM images of a sample of spray-dried powder of surfactant-lipid alloy drug substance that was prepared using 20: 1 DPPC:CP and 100% ethyl acetate. The sample appeared crystalline, with smaller spherical particles fused to the crystals. Without wishing to be bound by theory, these results suggest that the sample powder is formed of individual components of DPPC and CP. DPPC is not thought to be soluble in ethyl acetate. Thus, while not wishing to be bound by theory, these results suggest that the observed crystalline structure is DPPC in its native state and that spherical particles of CP are attached and/or adsorbed to the surface of this DPPC structure.

[00259] Example 9 - Volume Distribution Analysis of Surfactant-Lipid Drug Substance

[00260] FIG. 17 depicts the volume distribution of DPPC, CP, and surfactant-lipid alloy in six batches of embodiments of drug substance according to the disclosure (batches 099#012, 099#016, 099#01 1 , 099#014, 099#003, and 099#013) As shown therein, in terms of volume distribution, some embodiments of surfactant-lipid alloy drug substance comprised a greater amount of surfactant-lipid alloy relative to discrete DPPC and/or CP. For example, surfactant-lipid alloy drug substance from batch 099#012 comprised at least 75% surfactant-lipid alloy by volume, surfactant-lipid alloy drug substance from batch 099#013 comprised at least 80% surfactant-lipid alloy by volume, surfactant-lipid alloy drug substance from batch 099#016 comprised at least 80% surfactant-lipid alloy by volume, surfactant-lipid alloy drug substance from batch 099#014 comprised at least 85% surfactant-lipid alloy by volume, surfactant-lipid alloy drug substance from batch 099#01 1 comprised at least 90% surfactant-lipid alloy by volume, and surfactant-lipid alloy drug substance from batch 099#003 comprised at least 95% surfactant-lipid alloy by volume. Thus, in some embodiments, a surfactant-lipid alloy constitutes at least 75% of the surfactant-lipid alloy drug substance by volume, at least 80% of the surfactant-lipid alloy drug substance by volume, at least 85% of the surfactant- lipid alloy drug substance by volume, at least 90% of the surfactant-lipid alloy drug substance by volume, or at least 95% of the surfactant-lipid alloy drug substance by volume. In some embodiments of surfactant-lipid alloy drug substance, a surfactant-lipid alloy, wherein the surfactant is DPPC and the lipid is CP, constitutes at least 75% of the surfactant-lipid alloy drug substance by volume, at least 80% of the surfactant-lipid alloy drug substance by volume, at least 85% of the surfactant-lipid alloy drug substance by volume, at least 90% of the surfactant-lipid alloy drug substance by volume, or at least 95% of the surfactant-lipid alloy drug substance by volume.

[00261] Example 10 - Analysis of Compositions Comprising Surfactant-Lipid Alloy Drug Substance

[00262] In some embodiments, compositions according to the disclosure comprise the drug substance comprising a surfactant-lipid alloy according to the disclosure and a propellant, wherein the composition is in the form of a heterogeneous suspension. As would be understand by a person having ordinary skill in the art, one consideration regarding formulating a drug substance with a propellant is potential instability due to non ideal dispersion of the drug substance. See, e.g., P. B. Myrdal, et at., “Advances in Metered Dose Inhaler Technology: Formulation Develomment” (2014) 15:2 AAPS PharmSciTech 435. Without wishing to be bound by theory, such instability can occur due to phase separation, flocculation, agglomeration, interactions between certain drug particles and other drug materials, and/or the ingress of moisture. In some instances, depending on the relative densities of the suspended drug substance and the continuous phase, the drug substance may either cream or settle in the formulation. Without wishing to be bound by theory, in some instances such creaming or settling events can occur as drug particles associate to form large flocculates, with larger suspended particles tending to cream or settle faster than smaller particles.

[00263] As would be understood by a person having ordinary skill in the art, a Turbiscan instrument can be used to measure, for example, the instability of formulations of drug substances with propellants, their creaming phenomena, and the migration rates of drug substances in such formulations. As would also be understood by a person having ordinary skill in the art, instability detection using a Turbiscan instrument operates on the principle of multiple light scattering (MLS), wherein photons are scattered by particles or droplets of the subject dispersions before being detected by a backscattering detector. The intensity of the light that is backscattered by the sample is influenced by the diameter of the particles, their volume fraction, and the relative refractive index between the dispersed and continuous phases. The optical device of the Turbiscan instrument may thus detect changes resulting from a variation of particle size (e.g., flocculation and/or coalescence) or a local variation of the volume fraction (e.g., migration phenomena such as creaming and/or sedimentation). See, e.g., Formulaction,“Stability of Suspensions for Electronic Applications” (2009), retrieved from www.norlab.com on August 23, 2018; see also O. Mengual, et at.,“Characterisation of Instability of Concentrated Dispersions by a New Optical Analyser: The TURBISCAN MA 1000” (1999) 152 Colloids Surfaces A: Physicochem. Eng. Aspects 1 1 1 .

[00264] Turbiscan analysis was used to measure the migration rate of drug substances in compositions comprising samples of drug substance and a propellant.

[00265] FIG. 18 depicts the peak thickness of the layer of drug substance formed, as a function of time, in compositions comprising drug substance and a propellant. Six compositions were analyzed, each of which comprised a sample of spray-dried powder from one of batches 099#003, 099#006, 099#01 1 , 099#012, 099#014, or 099#013, and a propellant. FIG. 18 also depicts the peak thickness of a layer of substance formed, as a function of time, in a comparative composition comprising a mixture of DPPC and CP and a propellant (identified in FIG. 18 as“Original”). The mixture of DPPC and CP used in this comparative (“Original”) composition was not spray-dried and does not constitute a surfactant-lipid alloy drug substance according to the disclosure.

[00266] As FIG. 18 indicates, in the comparative composition comprising a mixture of DPPC and CP and a propellant (“Original”), a layer of substance over 7 mm thick formed within 30 seconds. At t = 120 seconds, this layer formed in the comparative composition was over 8 mm thick. In contrast, for each of the six compositions comprising surfactant-lipid alloy drug substance and a propellant, the layer of drug substance was less than 4 mm thick at t = 30 seconds and was less than 5 mm thick at t = 120 seconds. At t = 600 seconds (t = 10 minutes), the layer of drug substance in each of the six test compositions remained under 7 mm thick.

[00267] Turbiscan analysis was also used to measure the migration rate of drug substances in compositions comprising surfactant-lipid alloy drug substances and a propellant. FIG. 19A depicts migration rates measured for samples of six compositions, each of which comprised a sample of spray-dried powder of surfactant-lipid alloy drug substance from a batch identified above (one of 099#003, 099#006, 099#01 1 , 099#012, 099#013, or 099#014) and a propellant. For comparison purposes, Turbiscan analysis was also used to measure the migration rate of a substance in a composition comprising a non-alloyed mixture of DPPC, CP, and propellant. This measured migration rate for this comparative substance is also depicted in FIG. 19A (“Original”).

[00268] As shown in FIG. 19A, the substance in the comparative composition (“Original”) had a measured migration rate of between 900 mm/h and 1 ,000 mm/h. In contrast, migration rates were lower for drug substances according to the disclosure. For example, the migration rate of drug substance from batch 099#01 1 was less than 150 mm/h, the migration rate of drug substance from batch 099#006 was less than 200 mm/h, the migration rate of drug substance from batch 099#013 was less than 200 mm/h, the migration rate of drug substance from batch 099#014 was less than 250 mm/h, the migration rate of drug substance from batch 099#003 was less than 300 mm/h, and the migration rate of drug substance from batch 099#012 was less than 600 mm/h. As also shown in FIG. 19A, the migration rates of drug substances according to the disclosure for all six batches were all less than 800 mm/h.

[00269] FIG. 19B depicts migration rates measured for drug substances according to the disclosure for five additional compositions, each of which comprised a sample of spray-dried powder of drug substance from a batch identified above (one of 099#018C, 099#018B, 099#018A, 099#019B, or 099#019A) and a propellant. FIG. 19B also depicts the migration rate of a substance in a composition comprising a non-alloyed mixture of DPPC, CP, and propellant (“Original”).

[00270] As shown in FIG. 19B, the substance in the comparative composition (“Original”) exhibited a migration rate of between 900 mm/h and 1 ,000 mm/h. In contrast, migration rates were lower for drug substances according to the disclosure. For example, the migration rate of drug substance from batch 099#019B was less than 150 mm/h, the migration rate of drug substance from batch 099#019A was less than 150 mm/h, the migration rate of drug substance from batch 099#018B was less than 200 mm/h, the migration rate of drug substance from batch 099#018C was less than 350 mm/h, and the migration rate of drug substance from batch 099#018A was less than 400 mm/h. As also shown in FIG. 24B, the migration rates of drug substances according to the disclosure for all five batches were all less than 500 mm/h.

[00271] Example 11 - Dynamic Vapor Sorbption (DVS) Analysis

[00272] As a person having ordinary skill in the art would understand, DVS is a gravimetric technique used to measure the change in the mass of a sample as it is exposed to changes in temperature and/or humidity. To this end, DVS analysis is used to measure the extent to which a sample (e.g., as a non-limiting example, a dry powder) absorbs and/or desorbs a solvent (e.g. , as a non-limiting example, water vapor) and the rate at which these absorption and/or desorption events occur. In some instances, the vapor concentration (e.g. , humidity) around a sample is varied while the resulting change in mass is measured. For example, a test sample may be exposed to a series of step changes in relative humidity while the mass of the sample is measured and recorded. After each step change, the test sample is allowed to reach gravimetric equilibrium before moving to the next step in relative humidity. The obtained equilibrium mass values corresponding to each step of relative humidity can be used to generate an isotherm.

[00273] Samples of surfactant-lipid alloy drug substances according to the disclosure were subjected to dynamic vapor sorbption (DVS) analysis. In addition, samples of DPPC and CP were also subjected to DVS analysis, as was a comparative composition comprising a non-alloyed mixture of DPPC and CP.

[00274] FIG. 20A depicts water sorption results from a DVS experiment conducted using CP. As shown therein, when exposed to 0% relative humidity (RH), CP lost less than 0.05% (w/w) water. Upon exposure to 90% RH, the material took up 0.03% (w/w) water. Without wishing to be bound by theory, such a relatively low uptake of water may be due to the relatively large particle sizes (and, thus, relatively small surface areas) associated with CP.

[00275] FIG. 20B depicts a water sorption isotherm for CP. As shown therein, CP absorbed low levels of moisture in a relatively linear fashion from 0% RFI to approximately 60%. Following exposure to 70% RFI, the material began to absorb a greater amount of water. As also shown therein, the desorption kinetics for CP differed from its absorption kinetics, with the material desorbing water in a more gradual manner as a function of relative humidity. The relative mass changes observed were comparatively small. Without wishing to be bound by theory, this may have been due to the relatively large sizes of the CP particles as discussed above.

[00276] FIG. 20C depicts water sorption results from a DVS experiment conducted using DPPC. As shown therein, when exposed to 0% RH, DPPC lost approximately 1.00% (w/w) water. Upon exposure to 90% RH, the material took up approximately 9.00% (w/w) water. Between 10% RH and 60% RH, there was a relatively significant absorption of water. Between 10% RH and 40%, the material gradually absorbed water. Without wishing to be bound by theory, the water sorbption results suggest that, above 40% RH, the material is more likely to undergo swelling of a gel phase, that above 50% RH, the material undergoes a gel-liquid crystalline transition, and that above 70% RH, the material undergoes a swelling of the liquid crystalline phase.

[00277] FIG. 20D depicts a water sorption isotherm for DPPC. As shown therein, DPPC absorbed water gradually between 10% RH and 40% RH ( see marked area Ί”). As also shown therein, above 40% RH, the material experienced a more significant absorption of water that, without wishing to be bound by theory, suggests a swelling of a gel phase ( see marked area “2"). Also without wishing to be bound by theory, the absorption kinetics observed above 70% RH suggest that the material experienced a swelling of the liquid crystalline phase (see marked area“3”). With regard to desorption kinetics, the material exhibited slow but reversible desorption of water.

[00278] FIG. 20E depicts water sorption results from a DVS experiment conducted using a comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16: 1 ratio. As shown therein, upon exposure to 0% RH, this material lost approximately 5.0% (w/w) water. Upon exposure to 90% RH, the material took up approximately 8.0% (w/w) water. Between 10% RH and 40% RH, there was a relatively significant absorption of water. Between 40% RH and 70% RH, the material gradually absorbed water, with the material having absorbed more water above 70% RH.

[00279] FIG. 20F depicts a water sorption isotherm for the comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16: 1 ratio. As shown therein, between 10% and 40% RH, the material exhibited increased water uptake (see marked area“1”). Without wishing to be bound by theory, this result suggests a swelling of a gel phase. Above 40% RH, the material continued to absorb water (see marked area“2”). Without wishing to be bound by theory, this result also suggests a swelling of a gel phase. Above 70% RH, the material continued to absorb water (see marked area“3”). Without wishing to be bound by theory, this result suggests a swelling of a liquid crystalline phase. With regard to its desorption kinetics, the material exhibited slow but reversible desorption of water. A comparison between the water sorbption isotherm for DPPC ( see FIG. 20D) and the instant water sorption isotherm for the comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16:1 ratio suggests that the former and latter exhibited certain similarities in their sorbption profiles, but that the inclusion of CP in the latter composition resulted in certain shifts in its sorbption profile (e.g., a slightly more gradual uptake of water between 0% RH and 20% RH in the latter composition).

[00280] As depicted in FIG. 20F, this comparative composition exhibited a percent mass change due to absorption of water between 10% RFI and 30% RFI of approximately 3.1 %. Thus, this comparative composition exhibited a percent mass change due to absorption of water between 10% RFI and 30% RFI that was greater than 2.9%. As also depicted in FIG. 20F, this comparative composition exhibited a percent mass change due to desorption of water between 0% RFI and 10% RFI that was greater than 4.5%.

[00281] FIG. 20G depicts water sorption results from a DVS experiment conducted using a sample of spray-dried powder of drug substance from batch 099#023. As described elsewhere herein, batch 099#023 was prepared using a 20: 1 ratio of DPPC:CP. As shown in FIG. 20G, upon exposure to 0% RFI, this test material lost approximately 3.5% (w/w) water. Upon exposure to 90% RFI, this test material took up approximately 15.0% (w/w) water.

[00282] FIG. 20FI depicts a water sorption isotherm for a sample of spray-dried powder of drug substance from batch 099#023. The water sorption isotherm includes results from four separate runs, two of which measured absorption and two of which measured desorption. As shown therein, there existed substantial overlap with regard to the absorption and desorption behaviors of the spray-dried powder of drug substance. As described and depicted elsewhere herein, samples of DPPC, CP, and the comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16: 1 ratio did not exhibit such a marked degree of overlap with regard to their absorption and desorption behaviors. Without wishing to be bound by theory, this substantial overlap with regard to the absorption and desorption behaviors of the instant sample of surfactant-lipid alloy drug substance can be attributed to the presence of a surfactant-lipid alloy according to the disclosure in the instant sample.

[00283] As shown in FIG. 20H, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to absorption of water between 10% RH and 30% RH that was less than approximately 2.5%. Thus, this sample of spray-dried powder of drug substance exhibited a percent mass change due to absorption of water between 10% RH and 30% RH that was less than 2.9% ( compare FIG. 20F). As also shown in FIG. 20H, this sample of spray-dried powder of surfactant- lipid alloy drug substance exhibited a percent mass change due to desorption of water between 0% RH and 10% RH that was less than approximately 2.0%. Thus, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to desorption of water between 0% RH and 10% RH that was less than 4.5% {compare FIG. 20F). Without wishing to be bound by theory, these differences in the absorption and desorption kinetics between the instant sample of spray-dried powder of surfactant-lipid alloy drug substance and the comparative composition comprising a non- alloyed mixture of DPPC:CP in a 16: 1 ratio described above can be attributed to the presence of a surfactant-lipid alloy according to the disclosure in the instant sample.

[00284] FIG. 20I depicts water sorption results from a DVS experiment conducted using a sample of spray-dried powder of surfactant-lipid alloy drug substance from batch 099#024. As described elsewhere herein, batch 099#024 was prepared using a 10: 1 ratio of DPPC:CP. As shown in FIG. 20I, upon exposure to 0% RH, the test material lost approximately 3.0% (w/w) water. Upon exposure to 90% RH, the test material took up approximately 14.5% (w/w) water.

[00285] FIG. 20J depicts a water sorption isotherm for a sample of spray-dried powder of surfactant-lipid alloy drug substance from batch 099#024. The water sorption isotherm includes results from four separate runs, two of which measured absorption and two of which measured desorption. As shown therein, there existed substantial overlap with regard to the absorption and desorption behaviors of the spray-dried powder of surfactant-lipid alloy drug substance. As described and illustrated elsewhere herein, samples of DPPC, CP, and the comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16: 1 ratio did not exhibit such a marked degree of overlap with regard to their absorption and desorption behaviors. Without wishing to be bound by theory, this substantial overlap with regard to the absorption and desorption behaviors of the instant sample of surfactant-lipid alloy drug substance can be attributed to the presence of a surfactant-lipid alloy according to the disclosure in the instant sample.

[00286] As shown in FIG. 20J, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to absorption of water between 10% RH and 30% RH that was less than approximately 2.5%. Thus, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to absorption of water between 10% RH and 30% RH that was less than 2.9% ( compare FIG. 20F). As also shown in FIG. 20J, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to desorption of water between 0% RFI and 10% RFI that was less than approximately 2.5%. Thus, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to desorption of water between 0% RFI and 10% RFI that was less than 4.5% ( compare FIG. 25F). Without wishing to be bound by theory, these differences in the absorption and desorption kinetics between the instant sample of spray- dried powder of surfactant-lipid alloy drug substance and the comparative composition comprising a non-alloyed mixture of DPPC:CP in a 16: 1 ratio described above can be attributed to the presence of a surfactant-lipid alloy according to the disclosure in the instant sample.

[00287] FIG. 20K depicts water sorption results from a DVS experiment conducted using a sample of spray-dried powder of surfactant-lipid alloy drug substance from batch 099#025. As described elsewhere herein, batch 099#025 was prepared using a 20: 1 ratio of DPPC:CP. As shown in FIG. 20K, upon exposure to 0% RFI, the test material lost approximately 3.5% (w/w) water. Upon exposure to 90% RFI, the test material took up approximately 15.0% (w/w) water.

[00288] FIG. 20L depicts a water sorption isotherm for a sample of spray-dried powder of surfactant-lipid alloy drug substance according to the disclosure from batch 099#025. The water sorption isotherm includes results from four separate runs, two of which measured absorption and two of which measured desorption. As shown therein, there existed substantial overlap with regard to the absorption and desorption behaviors of the spray-dried powder of surfactant-lipid alloy drug substance. As described and illustrated elsewhere herein, samples of DPPC, CP, and the comparative composition comprising a non-alloyed mixture of DPPC and CP in a 16: 1 ratio did not exhibit such a marked degree of overlap with regard to their absorption and desorption behaviors. Without wishing to be bound by theory, this substantial overlap with regard to the absorption and desorption behaviors of the instant sample of surfactant-lipid alloy drug substance can be attributed to the presence of a surfactant-lipid alloy according to the disclosure in the instant sample.

[00289] As shown in FIG. 20L, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to absorption of water between 10% RH and 30% RH that was less than 2.9% ( compare FIG. 20F). As also shown in FIG. 20L, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to desorption of water between 0% RFI and 10% RFI that was less than approximately 4.0%. Thus, this sample of spray-dried powder of surfactant-lipid alloy drug substance exhibited a percent mass change due to desorption of water between 0% RFI and 10% RFI that was less than 4.5% ( compare FIG. 20F). Without wishing to be bound by theory, these differences in the absorption and desorption kinetics between the instant sample of spray-dried powder of surfactant-lipid alloy drug substance and the comparative composition comprising a non-alloyed mixture of DPPC:CP in a 16: 1 ratio described above can be attributed to the presence of a surfactant-lipid alloy according to the disclosure in the instant sample.

[00290] Example 12 - Surface Tension Activity

[00291] As described elsewhere herein, and without wishing to be bound by theory, it is believed that certain surfactants and lipids are miscible with the mucosal air-liquid interface and capable of reducing the interfacial surface tension of the ET. As a person having ordinary skill in the art would understand, experimental models and methods can be used to study the surface activity of compositions comprising surfactants and/or lipids and to study the changes in surface tension that they effect. For example, a skilled artisan would understand that techniques for measuring surface tension activity include use of a Langmuir-Wilhelmy surface balance or a captive bubble tensiometer (see, e.g., Veldhuizen, et al.,“The Role of Lipids in Pulmonary Surfactant” (1998) 1408 Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 90 and SchOrch, et al. ,“A Captive Bubble Method Reproduces the In Situ Behavior of Lung Surfactant Monolayers” (1989) Journal of Applied Physiology 2389).

[00292] In a set of experiments, the surface tension of a PBS (phosphate-buffered saline) medium was measured as a function of the number of shots of one of CP only, DPPC only, a non-alloyed mixture of DPPC and CP, or a surfactant-lipid alloy drug substance according to the disclosure that were introduced to the medium. An integrated dissolution and surface tension monitoring system was utilized to measure the surface tension of the PBS medium (pFH 7) into which the shots were introduced. The system was a modified USP Type 2 dissolution bath containing a direct dosing system. The media was maintained at 37°C with stirring, and the surface tension of the PBS was measured using a bubble pressure tensiometer. FIG. 21 A depicts the configuration of the integrated dissolution and surface tension monitoring system. The bubble pressure method for measuring surface tension enables high precision and flexibility without a requirement for exact immersion depth of the system in the media. This is done by pumping air through a capillary into the liquid being analyzed. The pressure within the bubble changes continuously with its radius. Therefore, the surface tension is calculated from the deviation between pressure maximum and minimum. A calibration is automatically carried out with water, establishing a known capillary radius.

[00293] Results from these experiments are depicted in FIG. 21 B, FIG. 21 C, and FIG. 21 D. As shown therein, administration of surfactant-lipid alloy drug substances, wherein the surfactant is DPPC and the lipid is CP, that were produced from either ethanol:dichloromethane or ethanol:ethyl acetate produced a greater decrease in surface tension compared to DPPC alone, CP alone, or non-alloyed mixtures of DPPC and CP. The reduction in surface tension produced by the surfactant-lipid alloy drug substances was significant at the first dose and far greater than comparative non-alloyed mixtures of DPPC and CP. This reduction in surface tension by surfactant-lipid alloy drug substances was greater than was observed using the comparative non-alloyed mixtures of DPPC and CP.

[00294] As also shown therein, administration of surfactant-lipid alloy drug substances that were produced from either ethanol:dichloromethane or ethanol:ethyl acetate using a 40: 10 or 30: 10 ratio of DPPC:CP produced a greater decrease in surface tension compared to DPPC alone, CP alone, or non-alloyed mixtures of DPPC and CP at 20: 1 or 10: 1 ratios of DPPC:CP. The reduction in surface tension exhibited by the surfactant-lipid alloy drug substances produced using DPPC: CP at a 40: 10 or 30: 10 ratio was less pronounced than that exhibited by surfactant-lipid alloy drug substances produced using other ratios of DPPC:CP, but more pronounced than DPPC alone, CP alone, or non-alloyed mixtures of DPPC and CP at 20: 1 or 10: 1 following the second dose.

[00295] As demonstrated by the foregoing non-limiting Examples and embodiments, the disclosed novel surfactant-lipid alloy, surfactant-lipid alloy drug substance, and pharmaceutical compositions comprising the same exhibited physical and/or chemical properties that differed from the corresponding properties of the surfactant DPPC alone, and/or the lipid CP alone, and/or non-alloyed mixtures of DPPC and CP.

[00296] Example 13 - XRPD and Raman Analysis

Definitions [00297] As used herein, the terms “X-ray powder diffraction” and “XRPD” interchangeably refer to the analytical characterization method of X-ray powder diffraction. Patterns from such a method can be recorded at ambient conditions in transmission or reflection geometry using a diffractometer.

[00298] As used herein, the terms“X-ray powder diffractogram,” “X-ray powder diffraction pattern,”“XRPD pattern” interchangeably refer to an experimentally obtained pattern from the analytical characterization method of X-ray powder diffraction. The pattern is a plot of signal positions (on the abscissa) versus signal intensities (on the ordinate). For a material, an X-ray powder diffractogram may include one or more signals, each identified by its angular value as measured in degrees 2Q (° 2Q) depicted on the abscissa of an X-ray powder diffractogram, which may be expressed as“a signal at ... degrees two-theta” and/or“a signal at [a] two-theta value(s) of ...”.

[00299] With reference to XRPD, a“signal” or“peak” as used herein refers to a point in the XRPD pattern where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in an XRPD pattern may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art-recognized methods are capable of and suitable for determining whether a signal exists in a pattern, such as Rietveld refinement.

[00300] As used herein,“a signal at ... degrees two-theta” and“a signal at [a] two- theta value[] of ...” refer to X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2Q).

[00301] The repeatability of the angular values in X-ray powder diffraction experiments is in the range of ± 0.2 °2Q, i.e. , the angular value can be at the recited angular value + 0.2 degrees two-theta, the angular value - 0.2 degrees two-theta, or any value between those two end points (angular value +0.2 degrees two-theta and angular value -0.2 degrees two-theta).

[00302] With reference to XRPD, the terms“signal intensities” and“peak intensities” interchangeably refer to relative signal intensities within a given X-ray powder diffractogram. Factors that can affect the relative signal or peak intensities include sample thickness and preferred orientation (e.g., the crystalline particles are not distributed randomly). [00303] The term “X-ray powder diffractogram having a signal at ... two-theta values” as used herein refers to an XRPD pattern that contains X-ray reflection positions as measured and observed in X-ray powder diffraction experiments (° 2Q).

[00304] As used herein, an X-ray powder diffractogram is“substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two diffractograms overlap. In determining“substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in XRPD diffractograms even for the same solid state form. Thus, those of ordinary skill in the art will understand that the signal maximum values in XRPD diffractograms (in degrees two-theta (° 2Q) referred to herein) generally mean that value reported ±0.2 degrees 2Q of the reported value, an art-recognized variance.

[00305] As used herein, “Raman spectroscopy” refers to an analytical characterization method that uses the known “Raman effect” such that light with a wavelength differing from that of incident light in scattered light is generated, when light such as a laser beam enters a chemical substance. A difference between the frequency of Raman scattering light and the frequency of incident light is referred to as“Raman shift.”“Raman shift” is specific to the structure of a molecule.

[00306] A“Raman spectrum” is a plot of signal positions (on the abscissa) versus signal intensities (on the ordinate). For a material, a Raman spectrum may include one or more signals, each identified by its chemical shift value as measured in cm ¹ depicted on the abscissa of a Raman spectrum, which may be expressed as“a signal at ... cm ¹”.

[00307] With reference to a Raman spectrum, a“signal” or“peak” as used herein refers to a point in the Raman spectrum where the intensity as measured in counts is at a local maximum. One of ordinary skill in the art would recognize that one or more signals (or peaks) in a Raman spectrum may overlap and may, for example, not be apparent to the naked eye. Indeed, one of ordinary skill in the art would recognize that some art- recognized methods are capable of and suitable for determining whether a signal exists in a pattern. The terms“signal intensities” and“peak intensities” interchangeably refer to relative signal intensities within a given spectrum.

[00308] As used herein,“a signal at ... cm ¹” refers to chemical shifts as measured and observed in Raman spectroscopy experiments (cm ¹).

[00309] The repeatability of the chemical shift values in Raman experiments is in the range of ± 0.5 cm^-1 , i.e. , the chemical shift value can be at the recited value + 0.5 cm- ¹, the chemical shift value - 0.5 cm^-1 , or any value between those two end points (recited value + 0.5 cm^-1 and recited value - 0.5 cm^-1).

[00310] As used herein, a Raman spectrum is“substantially similar to that in [a particular] Figure” when at least 90%, such as at least 95%, at least 98%, or at least 99%, of the signals in the two spectra overlap. In determining“substantial similarity,” one of ordinary skill in the art will understand that there may be variation in the intensities and/or signal positions in Raman spectra even for the same compound. Thus, those of ordinary skill in the art will understand that the signal maximum values in Raman spectra (in cm ¹) referred to herein generally mean that value reported ± cm^-1 of the reported value, an art- recognized variance.

Embodiments

[00311] In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2, 9.2 ± 0.2, and 21 .0 ± 0.2 degrees two-theta. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta.

[00312] In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least one additional signal at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2

[00313] In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least one additional signal at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least two additional signals at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least three additional signal at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X- ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least four additional signals at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5 0 ± 0.2, 9 2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least five additional signals at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2 and 21 .0 ± 0.2 degrees two-theta and at least six additional signals at two-theta values chosen from 3.1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9.2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 6.2 ± 0.2, 21.0 ± 0.2, 3 1 ± 0.2, 3.3 ± 0.2, 5.0 ± 0.2, 9 2 ± 0.2, 12.3 ± 0.2, 14.6 ± 0.2, and 23.4 ± 0.2 degrees two-theta.

[00314] In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram having a signal at 21 .0 ± 0.2 degrees two-theta. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by an X-ray powder diffractogram substantially similar to that in FIG. 22.

[00315] In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by a Raman spectrum having at least one signal in the Raman shift range of from 3000 cm ¹ to 2750 cm^-1 and at least one signal in the Raman shift range of from 1500 cm^-1 to 1250 cm ¹. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by a Raman spectrum having at least one signal in the Raman shift range of from 3000 cm ¹ to 2750 cm ¹ , at least one signal in the Raman shift range of from 1500 cm ¹ to 1250 cm^-1 , and at least one signal in the Raman shift range of from 1 100 cm^-1 to 1 150 cm ¹. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by a Raman spectrum having at least one signal in the Raman shift range of from 3000 cm^-1 to 2750 cm ¹ , at least one signal in the Raman shift range of from 1500 cm ¹ to 1250 cm ¹ , at least one signal in the Raman shift range of from 1 150 cm^-1 to 1 100 cm^-1 , and at least one signal in the Raman shift range of from 900 cm^-1 to 850 cm ¹. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by a Raman spectrum having at least one signal in the Raman shift range of from 3000 cm ¹ to 2750 cm ¹, at least two signals in the Raman shift range of from 1500 cm^-1 to 1250 cm^-1 , at least one signal in the Raman shift range of from 1 150 cm^-1 to 1 100 cm^-1 , and at least one signal in the Raman shift range of from 900 cm^-1 to 850 cm ¹. In some embodiments, the DPPC-CP surfactant-lipid alloy is characterized by a Raman spectrum substantially similar to that in FIG. 23.

Experimental [00316] X-Ray Powder Diffraction: X-ray powder diffraction (XRPD) spectra were recorded at room temperature in transmission mode using a Rigaku MiniFlex 300/600 system. The X-Ray generator operated at a voltage of 40 kV and a current of 15 mA with copper radiation (1 .541862 A). Each sample was scanned over the range of 3° to 40 °20 with a step size of 0.02 °20, scan speed of 5.00 degree/minute.

[00317] FIG. 22 depicts an X-ray powder diffractogram of a sample of a DPPC-CP surfactant-lipid alloy according to the disclosure.

[00318] Raman spectroscopy: The FT-Raman spectra were acquired using an FT- Raman accessory module interfaced to a Nicolet 6700 FT-IR spectrophotometer (Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs) detector. Wavelength verification was performed using sulfur and cyclohexane. Each sample was prepared for analysis by placing the sample into a pellet and pellet holder. Approximately 1 .0 W of Nd:YV04 laser power (1064 nm excitation wavelength) was used to irradiate the sample. Each spectrum represents 256 co-added scans collected at a spectral resolution of 4 crrr ¹. FIG. 23 was generated using OMNIC software version 7.2. FIG. 23 depicts a Raman spectrum of a sample of DPPC-CP surfactant-lipid alloy according to the disclosure.

Claims

1. A drug substance comprising a surfactant-lipid alloy, wherein the surfactant is dipalmitoylphosphatidylcholine and the lipid is cholesteryl palmitate.

2. The drug substance according to claim 1, wherein said surfactant-lipid alloy constitutes at least 70% of the drug substance by volume, at least 75% of the drug substance by volume, at least 80% of the drug substance by volume, at least 85% of the drug substance by volume, at least 90% of the drug substance by volume, at least 95% of the drug substance by volume, at least 97% of the drug substance by volume, or at least 99% of the drug substance by volume.

3. The drug substance according to claim 1 or claim 2, wherein the ratio of dipalmitoylphosphatidylcholine to cholesteryl palmitate in the surfactant-lipid alloy is selected from 40:1, 39:1, 38:1, 37:1, 36:1, 35:1, 34:1, 33:1, 32:1, 31:1, 30:1, 29:1, 28:1, 27:1,26:1,25:1,24:1,23:1,22:1,21:1,20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, and 10:1.

4. A pharmaceutical composition comprising the drug substance of any one of claims 1-3 and a propellant.

5. The pharmaceutical composition of claim 4, wherein the propellant includes 1,1,1 ,2-tetrafluoroethane.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition reduces the surface tension of a phosphate buffered saline medium to a greater degree than a pharmaceutical composition comprising a non-alloyed mixture of dipalmitoylphosphatidylcholine, cholesteryl palmitate, and 1,1,1,2-tetrafluoroethane.

7. The pharmaceutical composition of claim 6, wherein the greater reduction in surface tension occurs after a single shot of the pharmaceutical composition is introduced to the medium.

8. The pharmaceutical composition of claim 7, wherein the ratio of dipalmitoylphosphatidylcholine to cholesteryl palmitate in the surfactant-lipid alloy is 10:1 , 20:1, or 30:1.