Compositions and methods for producing cellular labels for nuclear magnetic resonance techniques

• US 20090074673A1
• Filed: 07/10/2008
• Published: 03/19/2009
• Est. Priority Date: 07/10/2007
• Status: Active Grant

• Current Assignee: Carnegie Mellon University
• Original Assignee: Carnegie Mellon University
• Inventors: Janjic, Jelena, Ahrens, Eric T.
• Granted Patent: US 8,227,610 B2
• Time in Patent Office: Days
• US Class Current: 424/9.370
• CPC Class Codes: A61K 49/126 Linear polymers, e.g. dextran, inulin, PEG
• CPC Class Codes: A61K 49/1806 Suspensions, emulsions, colloids, dispersions
• CPC Class Codes: A61K 49/1896 not provided for elsewhere, e.g. cells, viruses, ghosts, red blood cells, virus capsides
• CPC Class Codes: C08G 65/007 containing fluorine
• CPC Class Codes: C08L 2203/02 for biomedical use

Abstract

The disclosure provides, in part, compositions and methods for producing cellular labels for tracking cells by MRI. The disclosure provides, in part, methods for labeling, detecting and quantifying cell numbers in vivo.

Claims

1. A compound of any one of formulae 1, 2, 6-8, 10-15, 16-17, or 40-41:

45. A composition comprising

A) one or more compound of claim 1 or 4 and a compound of formula 1a,

50. An emulsion comprising a compound of any one of claims 1, 4, or 49 or a composition of claim 16 or 45, wherein the emulsion is optionally characterized by one or more of the following:

the emulsion further comprises a block copolymer;

wherein the block copolymer is optionally a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 1900, 2900, or 8400;

the emulsion further comprises a lipid;

wherein the lipid is optionally DMPC;

the emulsion further comprises polyethylamine;

the emulsion further comprises protamine sulfate;

the emulsion has a mean particle size of less than 200 nM in diameter;

the emulsion is stable at temperatures ranging from 4°

C. to 37°

C.;

or

the emulsion has a polydispersity index ranging from 0.1 to 0.2.

66. A method for preparing an emulsion of a PFPE derivative with block copolymer, or an emulsion of claim 50 or 64, comprising using low energy methods, wherein the low energy method optionally comprises a thin film method.

69. A method for preparing an emulsion of claim 50 or 64 comprising high energy methods, wherein the high energy method is optionally microfluidization or sonication.

72. A method for

I) labeling a cell, the method comprising contacting the cell ex vivo with a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49 under conditions such that the fluorocarbon imaging reagent becomes associated with the cell;

II) detecting a cell in a subject, the method comprising;

a) administering to the subject a cell that is labeled with a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49; and

b) examining at least a portion of the subject by a nuclear magnetic resonance technique, thereby detecting a labeled cell in the subject;

III) detecting transplanted cells in a transplant recipient, the method comprising;

a) administering cells for transplant to a transplant recipient, at least a portion of which cells for transplant are labeled with a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49; and

b) examining at least a portion of the subject by a nuclear magnetic resonance technique, thereby detecting the labeled cells;

IV) quantifying cell number in vivo, the method comprising;

a) administering to the subject cells that are labeled with a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49;

b) examining at least a portion of the subject by a nuclear magnetic resonance technique, thereby detecting labeled cells in the subject; and

c) quantifying the number of labeled cells in a region of interest (ROI);

V) labeling a cell, the method comprising contacting the cell in vivo with a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49 under conditions such that the fluorocarbon imaging reagent becomes associated with the cell;

or

VI) detecting a cell in a subject, the method comprising;

a) administering to the subject a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49; and

b) examining at least a portion of the subject by a nuclear magnetic resonance technique, thereby detecting a labeled cell in the subject.

78. A labeled cellular formulation for administration to a subject, the formulation comprising:

a) a cell; and

b) a fluorocarbon imaging reagent comprising a compound of any one of claims 1, 4, or 49 that is associated with the cell.

2-3. -3. (canceled)

4. A compound of

A) formula 26:

5-15. -15. (canceled)

16. A composition comprising

a compound of formula 10 and a compound of formula 1;

a compound of formula 12 and a compound of formula 1;

a compound of formula 14 and a compound of formula 1;

a compound of formula 16 and a compound of formula 1;

a compound of formula 40 and a compound of formula 1;

a compound of formula 10 and a compound of formula 20;

a compound of formula 10, a compound of formula 20, and a compound of formula 1;

compound of formula 11 and a compound of formula 21;

a compound of formula 11 and a compound of formula 22;

a compound of formula 12 and a compound of formula 23;

a compound of formula 12, a compound of formula 23, and a compound of formula 1;

a compound of formula 13 and a compound of formula 24;

a compound of formula 13 and a compound of formula 25;

a compound of formula 10 and a compound of formula 26;

a compound of formula 10, a compound of formula 26, and a compound of formula 1;

a compound of formula 11 and a compound of formula 27;

a compound of formula 11 and a compound of formula 28;

a compound of formula 12 and a compound of formula 29;

a compound of formula 12, a compound of formula 29, and a compound of formula 1;

a compound of formula 13 and a compound of formula 30;

a compound of formula 13 and a compound of formula 31;

a compound of formula 10 and a compound of formula 32;

a compound of formula 10, a compound of formula 32, and a compound of formula 1;

a compound of formula 11 and a compound of formula 33;

a compound of formula 11 and a compound of formula 34;

a compound of formula 12 and a compound of formula 35;

a compound of formula 12, a compound of formula 35, and a compound of formula 1;

a compound of formula 13 and a compound of formula 36;

or

a compound of formula 13 and a compound of formula 37.

17-44. -44. (canceled)

46-48. -48. (canceled)

49. A compound of formula:

51-63. -63. (canceled)

64. An emulsion selected from the group consisting of:

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, a compound of formula 1a, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, a compound of formula 1a, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, a compound of formula 1a, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 1a, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1a and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, perfluoro-15-crown-5 ether, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, perfluoro-15-crown-5 ether, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, perfluoro-15-crown-5 ether, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1, perfluoro-15-crown-5 ether, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1a, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising a compound of formula 1a, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising a compound of formula 1a, perfluoro-15-crown-5 ether, and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and protamine sulfate;

an emulsion comprising perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29, and polyethylamine;

an emulsion comprising perfluoro-15-crown-5 ether and a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 8400, an average number of PEO units of about 153, and an average number of PPO units of about 29;

an emulsion comprising a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1a, a compound of formula 1, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1a, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1a, a compound of formula 1, perfluoro-15-crown-ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, perfluoro-15-crown-5 ether, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1, a compound of formula 16, a compound of formula 17, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1, a compound of formula 18, a compound of formula 19, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate;

an emulsion comprising a compound of formula 1, a compound of formula 40, a compound of formula 41, a compound of formula 1a, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate; and

an emulsion comprising a compound of formula 42, a poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) tri-block copolymer with an average molecular weight of 6500, an average number of PEO units of about 74, and an average number of PPO units of about 56, and an emulsifier, wherein the emulsifier is a non-ionic solubiliser comprising glycerol polyethylene glycol ricinoleate.

65. A method for preparing a composition comprising a compound of formula 1 and a compound of formula 38:

67-68. -68. (canceled)

70-71. -71. (canceled)

73-77. -77. (canceled)