MACROMOLECULAR PRODRUGS FOR LIGHT-EMITTING DIODES AND USES THEREOF

Abstract

Provided herein are compositions comprising macromolecular photocleavable prodrug compounds of Formula (I), and pharmaceutically acceptable salts, co-crystals, tautomers, stereoisomers, solvates, hydrates, polymorphs, and isotopically enriched derivatives thereof. Also provided are methods, uses, pharmaceutical compositions, and kits involving the inventive compounds or compositions for treating and/or preventing a disease and/or condition (e.g., inflammatory disease, infectious disease, pain) in a subject, optionally comprising illumination of the compound, composition, or pharmaceutical composition with light of an absorption wavelength sufficient to cleave the bonds between each instance of L and each instance of X upon illumination with the light (e.g., light between approximately 200 nm to 500 nm).

Claims

1. A composition comprising a compound of Formula (I):
P(-L-X).sub.n  (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, wherein: n is an integer of 1 or more; each instance of X is independently an anesthetic compound; each instance of L is independently a photocleavable linker; and P is a polymer.

2. The composition of claim 1, wherein n is an integer between 1 and 100,000, inclusive.

3. The composition of claim 1 or 2, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

4. The composition of any one of claims 1-3, wherein the compound is of Formula (I-A):
X-L-P-L-X  (I-A), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

5. The composition of any one of claims 1-4, wherein the bonds between each instance of L and each instance of X is cleaved upon illumination with light at an absorption wavelength between approximately 200 nm to 500 nm.

6. The composition of any one of claims 1-5, wherein the composition forms a gel at temperatures above a phase transition temperature; and the phase transition temperature is about 37° C.

7. The composition of any one of claims 1-6, wherein at least one instance of X is a local anesthetic compound.

8. The composition of any one of claims 1-7, wherein at least one instance of X is an amino ester compound.

9. The composition of any one of claims 1-8, wherein at least one instance of X is a local anesthetic compound with a primary amine group or a local anesthetic compound with a secondary amine group.

10. The composition of claim 9, wherein the local anesthetic compound with a primary amine group is of formula: ##STR00092##

11. The composition of any one of claims 1-9, wherein the local anesthetic compound with a secondary amine group is of formula: ##STR00093##

12. The composition of any one of claims 1-11, wherein at least one instance of X is of formula: ##STR00094##

13. The composition of any one of claims 1-7, wherein at least one instance of X is an amino amide compound.

14. The composition of claim 13, wherein the amino amide compound is of formula: ##STR00095## ##STR00096##

15. The composition of claim 13 or 14, wherein the amino amide compound is ##STR00097##

16. The composition of any one of claims 1-15, wherein both instances of X are the same.

17. The composition of any one of claims 1-16, wherein both instances of X are ##STR00098##

18. The composition of any one of claims 1-17, wherein P is a hydrophilic or amphiphilic polymer.

19. The composition of any one of claims 1-6 or 18, wherein the compound is of Formula (I-A):
X-L-P-L-X  (I-A), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, each instance of X is independently a local anesthetic compound; each instance of L is independently a photocleavable linker; and P is a hydrophilic or amphiphilic polymer.

20. The composition of any one of claims 1-19, wherein P is a block copolymer comprising at least one polyether.

21. The composition of any one of claims 1-20, wherein P is a block copolymer comprising a poloxamer.

22. The composition of claim 21, wherein the poloxamer is poloxamer P407, poloxamer P331, poloxamer P188, poloxamer P182, poloxamer P124, poloxamer P338, or poloxamer P237 (F87).

23. The composition of claim 22, wherein the poloxamer is poloxamer P407.

24. The composition of any one of claims 1-23, wherein at least one instance of L comprises coumarin, o-nitrobenzyl, benzoin, 7-nitroindoline, or p-hydroxyphenacyl.

25. The composition of any one of claims 1-24, wherein at least one instance of L comprises coumarin.

26. The composition of claim 19, wherein at least one instance of the moiety ##STR00099## is of formula: ##STR00100## wherein L1 is an alkylene linker wherein one or more carbon atoms of the hydrocarbon chain are optionally replaced with —O—, —N(R.sup.a)—, —C(═O)—, optionally substituted phenyl, or ##STR00101## lp indicates the attachment to P; R.sup.1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; R.sup.a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group; each instance of R is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, or —CN; R.sup.c1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom; each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R.sup.c2 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and x is 0, 1, 2, 3, 4, 5, 6, or 7, as valency permits.

27. The composition of claim 26, wherein at least one instance of the moiety ##STR00102## is of the formula: ##STR00103##

28. The composition of 26 or 27, wherein at least one instance of the moiety ##STR00104## is of the formula: ##STR00105##

29. The composition of any one of claims 1-28, wherein both instances of L are the same.

30. The composition of any one of claims 1-29, wherein at least one instance of the moiety ##STR00106## is of the formula: ##STR00107## wherein: rl indicates the attachment to another instance of L; each instance of n1 is independently 0 or 1; and n2 is 0 or 1.

31. The composition of any one of claims 1-26, wherein at least one instance of the moiety ##STR00108## is of the formula: ##STR00109## wherein: Y is —O— or —NR.sup.a—; rl indicates the attachment to another instance of L; R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl; m1 is 0 or 1; n1 is 0 or 1; and n3 is 0 or 1.

32. The composition of any one of claims 1-26, wherein at least one instance of the moiety ##STR00110## is of the formula: ##STR00111## wherein: rl indicates the attachment to another instance of L; R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl; and n1 is 0, 1, or 2.

33. The composition of any one of claims 1-26, wherein at least one instance of the moiety ##STR00112## is of the formula: ##STR00113## wherein: rl indicates the attachment to another instance of L; R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl; m1 is 0 or 1; and n1 is 0, 1, or 2.

34. The composition of any one of claims 1-26, wherein at least one instance of the moiety ##STR00114## is of the formula: ##STR00115##

35. The composition of any one of claims 1-26 or 30-34, wherein Y is —O—.

36. The composition of any one of claims 1-26 or 30-34, wherein Y is —N(Et)-.

37. The composition of any one of claims 1-26 or 30-36, wherein at least one instance of n1 is 0.

38. The composition of any one of claims 1-26 or 30-36, wherein at least one instance of n1 is 1.

39. The composition of any one of claims 1-26 or 30-36, wherein at least one instance of n1 is 2.

40. The composition of any one of claims 1-26 or 30-39, wherein at least one instance of n2 is 0.

41. The composition of any one of claims 1-26 or 30-39, wherein at least one instance of n2 is 1.

42. The composition of any one of claims 1-26 or 30-41, wherein n3 is 0.

43. The composition of any one of claims 1-26 or 30-41, wherein n3 is 1.

44. The composition of any one of claims 1-26 or 30-43, wherein m1 is 1.

45. The composition of any one of claims 1-26 or 30-44, wherein n1 is 1, m1 is 1, and n3 is 1.

46. The composition of any one of claims 1-26 or 30-44, wherein n1 is 1 and n3 is 0.

47. The composition of any one of claims 1-26 or 30-44, wherein both instances of n1 are 2 and m1 is 1.

48. The composition of any one of claims 1-26 or 30-47, wherein at least one instance of R.sup.a is hydrogen.

49. The composition of any one of claims 1-26 or 30-48, wherein at least one instance of R.sup.a is optionally substituted C.sub.1-6 alkyl.

50. The composition of any one of claims 1-26 or 30-49, wherein at least one instance of the moiety ##STR00116## is of the formula: ##STR00117##

51. The composition of any one of claims 1-50, wherein the absorption wavelength is about 350 nm to about 530 nm.

52. The composition of any one of claims 1-51, wherein the absorption wavelength is about 450 nm to 475 nm.

53. The composition of claim 52, wherein the absorption wavelength is about 400 nm.

54. The composition of any one of claims 1-53, wherein the bonds between each instance of L and each instance of X are cleaved upon illumination with light from a light emitting diode (LED).

55. The composition of claim 54, wherein the LED is a blue LED.

56. The composition of any one of claims 1-55, wherein the compound of Formula (I) is of formula (I-a): ##STR00118## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, wherein: each instance of R.sup.3 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteryaryl, optionally substituted acyl, —OR.sup.b, or —N(R.sup.b).sub.2; each instance of R.sup.b is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.b taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl ring; each of q, r, and s is independently an integer between 0 and 200; and the sum of q, r, and s is at least 1.

57. The composition of claim 56, wherein at least one instance of R.sup.3 is unsubstituted C.sub.1-6 alkyl.

58. The composition of claim 56 or 57, wherein q and s are the same.

59. The composition of any one of claims 1-26 or 30-58, wherein x is 0.

60. The composition of any one of claims 1-26 or 30-58, wherein x is 1.

61. The composition of any one of claims 1-26 or 30-60, wherein at least one instance of R is —N(R.sup.c2).sub.2 and at least one instance of R.sup.c2 is optionally substituted alkyl.

62. The composition of claim 61, wherein at least one instance of R is —NEt.sub.2.

63. The composition of any one of claims 1-62, wherein the compound of Formula (I) is of formula (I-a): ##STR00119## or a pharmaceutically acceptable salt thereof.

64. The composition of any one of claims 1-63, wherein the compound of Formula (I) is of formula: ##STR00120## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

65. The composition of any one of claims 1-64, wherein the compound of Formula (I) is of formula: ##STR00121## or a pharmaceutically acceptable salt thereof.

66. The composition of any one of claims 1-65, wherein the compound of Formula (I) is of formula: ##STR00122## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

67. The composition of any one of claims 1-66, wherein the compound of Formula (I) is of formula: ##STR00123## ##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130## or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

68. The composition of any one of claims 1-67, wherein both instances of the active local anesthetic compound X are released upon the illumination with light.

69. The composition of any claims 1-68, wherein the composition forms a gel at a phase transition temperature between about 0° C. and about 37° C.

70. The composition of any one of claims 1-69, wherein the composition is in the form of a particle.

71. The composition of claim 70, wherein the particle is a nanoparticle or a microparticle.

72. A pharmaceutical composition comprising a composition of any one of claims 1-71, and optionally a pharmaceutically acceptable excipient.

73. The pharmaceutical composition of claim 72, wherein the pharmaceutical composition comprises a therapeutically effective amount of the composition for use in treating a disease and/or condition in a subject in need thereof.

74. The pharmaceutical composition of claim 73, wherein the condition is pain.

75. The pharmaceutical composition of claim 73 or 74, wherein the condition is pain associated with an infectious disease.

76. The pharmaceutical composition of any one of claim 73 or 74, wherein the condition is pain associated with an ear disease.

77. The pharmaceutical composition of claim 73, wherein the disease is an infectious disease.

78. The pharmaceutical composition of claim 73, wherein the disease is an ear disease.

79. The pharmaceutical composition of claim 74, wherein the pain is associated with a medical procedure.

80. The pharmaceutical composition of claim 79, wherein the medical procedure is surgery.

81. The pharmaceutical composition of claim 80, wherein the surgery is dental surgery.

82. The pharmaceutical composition of claim 79, wherein the medical procedure is a dental medical procedure.

83. The pharmaceutical composition of claim 73, wherein the condition is pain associated with trauma.

84. The pharmaceutical composition of claim 83, wherein the trauma is injury.

85. A method of treating a disease and/or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of any one of claims 1-71, or a pharmaceutical composition of claim 72 or 73.

86. The method of claim 85, wherein the method further comprises illumination of the composition or the pharmaceutical composition with light at an absorption wavelength between approximately 200 nm to 500 nm.

87. The method of claim 85, wherein the absorption wavelength is about 400 nm.

88. The method of claim 87, wherein the light is a blue LED.

89. The method of claim 85, wherein the condition is pain.

90. The method of claim 89, wherein the condition is pain associated with an infectious disease.

91. The method of claim 89, wherein the condition is pain associated with an ear disease.

92. The method of any one of claims 85-91, wherein the method comprises sustained treatment of pain.

93. The method of claim 92, wherein the pain is associated with a medical procedure.

94. The method of claim 93, wherein the medical procedure is surgery.

95. The method of claim 94, wherein the surgery is dental surgery.

96. The method of claim 93, wherein the medical procedure is a dental medical procedure.

97. The method of claim 89, wherein the condition is pain associated with trauma.

98. The method of claim 97, wherein the trauma is injury.

99. The method of claim 85, wherein the disease is an infectious disease.

100. The method of claim 85, wherein the disease is an ear disease.

101. Use of a composition to treat and/or prevent a disease and/or condition in a subject in need thereof, the use comprising administering to the subject a therapeutically effective amount of a composition of any one of claims 1-71, or a pharmaceutical composition of claim 72 or 73.

102. The use of claim 101, wherein the use further comprises illumination of the composition or the pharmaceutical composition with light at an absorption wavelength between approximately 200 nm to 500 nm.

103. The use of claim 102, wherein the absorption wavelength is about 400 nm.

104. The use of claim 103, wherein the light is a LED.

105. A kit for treating a disease and/or condition comprising a container, a composition of any one of claims 1-71, and instructions for administering the composition or pharmaceutical composition thereof to a subject in need thereof.

106. The kit of claim 105, further comprising light of an absorption wavelength between approximately 200 nm to 500 nm.

107. The kit of claim 105 or 106, further comprising a dropper, syringe, or catheter.

108. The kit of claim 106, wherein the light is a LED.

109. The kit of claim 108, wherein the light is a blue LED.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0095] The accompanying drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures is represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. 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. In the drawings:

[0096] FIGS. 1A-1C show the synthesis and characterization of the light-triggerable tetracaine-polymer prodrug. FIG. 1A shows the synthesis of P407-CM-T through alkyne-azide “click” reaction. FIG. 1B shows the photocleavage reaction of P407-CM-T. FIG. 1C shows the .sup.1H NMR of P407-CM-T.

[0097] FIGS. 2A-2B show the physical properties of P-CM-T. FIG. 2A shows the UV-vis absorption spectra of aqueous solutions of P-CM-T (0.3 mg/mL), tetracaine hydrochloride (0.01 mg/mL) and NH.sub.2—CM-OH (0.01 mg/mL). FIG. 2B shows the rheology of 20 wt % P-CM-T as a function of temperature.

[0098] FIGS. 3A-3C show the in vitro photocleavage of P407-CM-T. FIG. 3A shows the liquid chromatography curve of tetracaine, P407-CM-T before and after cleavage under 400 nm LED irradiation. FIG. 3B shows the mass spectrum corresponding to the peak at 5 min in the curve of P407-CM-T+light in panel a. FIG. 3C shows the photocleavage of P407-CM-T solution (10 mg/mL) over time under 400 nm LED at different irradiances.

[0099] FIGS. 4A-4D show the cytotoxicity of P407-CM-T. FIGS. 4A-4B show the cell survival (determined by MTS cell proliferation assay) of C2C12 and PC12 cells in direct contact with various concentrations of tetracaine, P407 and P407-CM-T for 24 h. FIGS. 4C-4D show the cell survival (determined by MTS cell proliferation assay) of C2C12 and PC12 cells exposed to tetracaine (0.5% wt %), P407 (20% wt %) and P407-CM-T (20% wt %) in Transwells® for 24 h.* indicates p<0.05 compared to untreated cells.

[0100] FIGS. 5A-5E show the phototriggered local anesthesia in the rat footpad. FIG. 5A shows the time courses of nerve block after injection of tetracaine, CM-T (tetracaine bound to coumarin without P407) and P407-CM-T with or without 2 min irradiation (as depicted in the graph) at 300 mW/cm.sup.2, immediately after injection. FIG. 5B shows the nerve block after irradiation of P407-CM-T with irradiation at various irradiances and durations. (The 300 mW/cm.sup.2, 2 min plot is also in FIG. 5A) FIG. 5C shows the effect of energy density on the duration of the triggered nerve block. FIG. 5D shows the representative time course of nerve block with multiple light triggering events (arrows represent LED triggering for 2 min at 300 mW/cm.sup.2). FIG. 5E shows the mean duration of block after each triggering event in FIG. 5D. Data are means±SD (n≥4).

[0101] FIG. 6 shows the tissue reaction to rat foot pad injections on day 4 after injection of P407-CM-T (with/without irradiation) or tetracaine. Inflammation at the injection site was characterized by lymphocytes and macrophages extending from the sub-epidermal layers into the deeper muscular layer.

[0102] FIG. 7 shows the exemplary synthetic route to P407-CM-T. The conditions for the reactions are: (i) SeO.sub.2, 1,4-dioxane, reflux; (ii) CH.sub.3NO.sub.2, N,N,N′N′-tetramethylethylenediamine, THF; (iii) Zn, acetic acid; (iv) 4-azidobenzoic acid, DIC, DMAP, DCM; (v) tetracaine, triphosgene, DIPEA, DBU, DCM; (vi) sodium hydride, THF; (vii) Copper (II) sulfate pentahydrate, (+)-sodium L-ascorbate, methanol/H.sub.2O.

[0103] FIG. 8 shows the exemplary synthetic route to CM-T. The conditions for the reactions are depicted.

[0104] FIG. 9 shows the .sup.1H NMR spectrum of compound 1 (shown in FIG. 7).

[0105] FIG. 10 shows the .sup.1H NMR spectrum of compound 2 (shown in FIG. 7).

[0106] FIG. 11 shows the .sup.1H NMR spectrum of compound 3 (shown in FIG. 7).

[0107] FIG. 12 shows the .sup.1H NMR spectrum of compound 4 (shown in FIG. 7).

[0108] FIG. 13 shows the .sup.1H NMR spectrum of compound 5 (shown in FIG. 7).

[0109] FIG. 14 shows the .sup.1H NMR spectrum of compound 6 (shown in FIG. 7).

[0110] FIG. 15 shows the .sup.1H NMR spectrum of compound 7 (P407-CM-T) (shown in FIG. 7).

[0111] FIG. 16 shows the .sup.1H NMR spectrum of compound 8 (shown in FIG. 8).

[0112] FIG. 17 shows the .sup.1H NMR spectrum of compound 9 (CM-T) (shown in FIG. 8).

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0113] The present disclosure provides compositions comprising macromolecular prodrug compounds with photocleavable linkers that may be cleaved to release an anesthetic compound X (e.g., local anesthetic), upon illumination with light, for example, light at an absorption wavelength between approximately 200 nm to 500 nm (e.g., a LED (e.g., a blue LED)). In certain embodiments, the composition forms a gel at temperatures above a phase transition temperature; and the phase transition temperature is about 37° C. In certain embodiments, the composition comprises an anesthetic compound X that is a local anesthetic compound, for example, but not limited to, an amino ester compound (e.g., procaine, tetracaine, chloroprocaine, benzocaine, butacaine, dimethocaine) or an amino amide compound (e.g., procainamide, lidocaine). The composition comprises a polymer P (e.g., hydrophilic or amphiphilic polymer), which in certain embodiments, is a block copolymer comprising at least one polyether, for example, a poloxamer (e.g., poloxamer P407). In certain embodiments, P is a hydrophobic polymer. The composition comprises a photocleavable linker connecting the polymer P and anesthetic compound X, which in certain embodiments, coumarin, o-nitrobenzyl, benzoin, 7-nitroindoline, or p-hydroxyphenacyl, or a derivative thereof.

[0114] The present disclosure further provides pharmaceutical compositions comprising a composition of a compound described herein, for treating a disease or condition (e.g., pain) in a subject in need thereof. Other aspects of the disclosure provide methods of treating a disease or condition (e.g., inflammatory disease, infectious disease, or pain) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition of a compound described herein, optionally further comprising illumination of the composition or the pharmaceutical composition with light at an absorption wavelength between approximately 200 nm to 500 nm (e.g., with a LED (e.g., blue LED)). In certain embodiments, the diseases treated and/or prevented include, but are not limited to, inflammatory disease, infectious disease, or pain, for example, pain associated with an infectious disease (e.g., infection by bacteria, virus, or other microbe), ear disease, pain associated with a medical procedure (e.g., surgery (e.g., dental surgery)), pain associated with trauma (e.g., injury), and/or sustained pain. The present disclosure further provides uses of the compounds, compositions, or pharmaceutical compositions thereof described herein, for treating a disease or condition (e.g., inflammatory disease, infectious disease, or pain) in a subject in need thereof, optionally further comprising illumination of the composition or the pharmaceutical composition with light at an absorption wavelength between approximately 200 nm to 500 nm (e.g., with a LED (e.g., blue LED)). Also provided are kits comprising a container with the compounds, compositions, and pharmaceutical compositions described herein, optionally further comprising a light of an absorption wavelength between approximately 200 nm to 500 nm (e.g., with a LED (e.g., blue LED)).

Compositions with Compounds

[0115] Certain aspects of the present disclosure relate to the compounds described herein. Provided are compositions comprising macromolecular prodrug compounds described herein. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments, a composition described herein comprises a compound of Formula (I):

P(-L-X).sub.n  (I),

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, wherein:

[0117] n is an integer of 1 or more;

[0118] each instance of X is independently an anesthetic compound;

[0119] each instance of L is independently a photocleavable linker; and

[0120] P is a polymer.

[0121] In certain embodiments, a composition described herein comprises a compound of Formula (I):

P(-L-X).sub.n  (I),

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, wherein:

[0122] n is an integer between 1 and 100,000, inclusive;

[0123] each instance of X is independently an anesthetic compound;

[0124] each instance of L is independently a photocleavable linker; and

[0125] P is a polymer.

[0126] In certain embodiments, in Formula (I), n is an integer of 1 or more. In certain embodiments, in Formula (I), n is an integer between 1 and 100,000, inclusive. In certain embodiments, in Formula (I), n is an integer between 1 and 10,000, inclusive. In certain embodiments, in Formula (I), n is an integer between 1 and 9,000, inclusive. In certain embodiments, in Formula (I), n is an integer between 1 and 1,000; between 1,000 and 2,000; between 2,000 and 3,000; between 3,000 and 4,000; between 4,000 and 5,000; between 5,000 and 6,000; between 6,000 and 7,000; between 7,000 and 8,000; between 9,000 and 10,000; between 10,000 and 12,000; between 12,000 and 14,000; between 10,000 and 15,000; between 14,000 and 16,000; between 16,000 and 18,000; between 18,000 and 20,000; between 20,000 and 30,000; between 30,000 and 40,000; between 40,000 and 50,000; between 50,000 and 60,000; between 60,000 and 70,000; between 70,000 and 80,000; between 80,000 and 90,000; or between 90,000 and 100,000. In certain embodiments, in Formula (I), n is an integer between 1 and 200,000, inclusive. In certain embodiments, in Formula (I), n is an integer that is 1 or more, and P is a cross-linked polymer. In certain embodiments, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1, 2, 3, or 4. In certain embodiments, n is 1.

[0127] In certain embodiments, a compound of Formula (I) is of Formula (I-A):

X-L-P-L-X  (I-A),

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

[0128] In some embodiments, the compound is of Formula (I-A):

X-L-P-L-X  (I-A),

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof,

[0129] each instance of X is independently a local anesthetic compound;

[0130] each instance of L is independently a photocleavable linker; and

[0131] P is a hydrophilic or amphiphilic polymer.

[0132] In certain embodiments, each instance of L is independently a photocleavable linker; and the bonds between each instance of L and each instance of X is cleaved upon illumination with light at an absorption wavelength between approximately 200 nm to 500 nm.

[0133] The terms “sol-gel transition temperature,” “phase transition temperature,” and “gelation temperature” are used interchangeably. In certain embodiments, the composition forms a gel at a phase transition temperature between about 0° C. and about 40° C. In certain embodiments, the composition forms a gel at a phase transition temperature between about 0° C. and about 39° C. In certain embodiments, the composition forms a gel at a phase transition temperature between about 0° C. and about 37° C. In certain embodiments, the composition forms a gel at a phase transition temperature between about 0° C. and about 35° C. In certain embodiments, the composition forms a gel at temperatures above a phase transition temperature; and the phase transition temperature is about 37° C.

[0134] Compounds of Formula (I) include at least two instances of X. In certain embodiments, at least one instance of X is a local anesthetic compound. In certain embodiments, both instances of X are each a local anesthetic compound. In certain embodiments, both instances of X are each the same local anesthetic compound. In certain embodiments, all instances of X are each a local anesthetic compound. In certain embodiments, all instances of X are each the same local anesthetic compound. In certain embodiments, at least one instance of X is an amino ester compound. In certain embodiments, at least one instance of X is a local anesthetic compound that is an amino ester compound with a primary amine group or a local anesthetic compound with a secondary amine group. In certain embodiments, the local anesthetic compound with a primary amine group is of formula:

##STR00006##

In certain embodiments, the local anesthetic compound with a secondary amine group is of formula:

##STR00007##

In certain embodiments, at least one instance of X is a local anesthetic compound of formula:

##STR00008##

In certain embodiments, the local anesthetic compound with a primary amine group is of formula:

##STR00009##

[0135] In certain embodiments, the local anesthetic compound with a secondary amine group is of formula:

##STR00010##

In certain embodiments, at least one instance of X is a local anesthetic compound of formula:

##STR00011##

In certain embodiments, both instances of X are each tetracaine. In certain embodiments, both instances of X are each procaine. In certain embodiments, both instances of X are each tetracaine. In certain embodiments, both instances of X are each chloroprocaine. In certain embodiments, both instances of X are each benzocaine. In certain embodiments, both instances of X are each butacaine. In certain embodiments, both instances of X are each dimethocaine. In certain embodiments, all instances of X are each procaine. In certain embodiments, all instances of X are each tetracaine. In certain embodiments, all instances of X are each chloroprocaine. In certain embodiments, all instances of X are each benzocaine. In certain embodiments, all instances of X are each butacaine. In certain embodiments, all instances of X are each or dimethocaine.

[0136] In certain embodiments, at least one instance of X is an amino amide compound. In certain embodiments, both instances of X are each an amino amide compound. In certain embodiments, both instances of X are each the same amino amide compound. In certain embodiments, all instances of X are each an amino amide compound. In certain embodiments, all instances of X are each the same amino amide compound. In certain embodiments, at least one instance of the local anesthetic compound X is an amino amide compound of formula:

##STR00012## ##STR00013##

In certain embodiments, at least one instance of the local anesthetic compound X is an amino amide compound of formula:

##STR00014##

In certain embodiments, at least one instance of the local anesthetic compound X is an amino amide compound of formula:

##STR00015##

In certain embodiments, at least one instance of the local anesthetic compound X is an amino amide compound of formula:

##STR00016##

In certain embodiments, at least one instance of the local anesthetic compound X is an amino amide compound of formula:

##STR00017##

In certain embodiments, both instances of X are each procainamide. In certain embodiments, both instances of X are each lidocaine. In certain embodiments, both instances of X are each prilocaine. In certain embodiments, all instances of X are each procainamide. In certain embodiments, all instances of X are each lidocaine. In certain embodiments, all instances of X are each prilocaine.

[0137] Compounds of Formula (I) include polymer P. In certain embodiments, P is a hydrophilic or amphiphilic polymer. In certain embodiments, P is a hydrophilic polymer. In certain embodiments, P is an amphiphilic polymer. In certain embodiments, the amphiphilic polymer is a poloxamer (Pluronics®). In certain embodiments, P is a copolymer. In certain embodiments, the polymer is biodegradable. In certain embodiments, the polymer is a copolymer. In certain embodiments, the copolymer is biodegradable or comprises biodegradable monomers. In certain embodiments, the copolymer is a block copolymer. In certain embodiments the copolymer comprises at least one block of hydrophobic monomers. In certain embodiments, the copolymer comprises at least one block of hydrophobic monomers, and at least one block of non-hydrophobic monomers. In certain embodiments, the copolymer comprises at least one block of hydrophobic monomers, and at least one block of hydrophilic monomers. In certain embodiments, P is a hydrophobic polymer. In certain embodiments, P is a cross-linked polymer. In certain embodiments, P is a polysaccharide or a polypeptide. In certain embodiments, P is hyaluronic acid. In certain embodiments, P is polyglutamic acid. In certain embodiments, P is a brush polymer, for example, a bottle-brush polymer. In certain embodiments, P is not a hydrophobic polymer. In certain embodiments, P is not hyaluronic acid or polyglutamic acid.

[0138] In certain embodiments, the copolymer comprises polyethylene oxide, polypropylene oxide, and/or a poloxamer, or copolymers of combinations thereof. In certain embodiments, the copolymer comprises a poloxamer. In certain embodiments, the poloxamer is poloxamer P407, poloxamer P331, poloxamer P188, poloxamer P182, poloxamer P124, poloxamer P338, or poloxamer P237 (F87), or combinations thereof. In certain embodiments, P is poloxamer P407, poloxamer P331, poloxamer P188, poloxamer P182, poloxamer P124, poloxamer P338, or poloxamer P237 (F87). In certain embodiments, P is poloxamer P407 (P407). In certain embodiments, P is poloxamer P331. In certain embodiments, P is poloxamer P188. In certain embodiments, P is poloxamer P182. In certain embodiments, P is poloxamer P124. In certain embodiments, P is poloxamer P338. In certain embodiments, P is poloxamer P237 (F87).

[0139] Compounds of Formula (I) include at least two instances of photocleavable linker L connecting polymer P and the anesthetic compound X. In certain embodiments, both instances of L are the same. In certain embodiments, all instances of L are the same. In certain embodiments, L comprises L1, which comprises an aryl- or heteroaryl-containing moiety. In certain embodiments, at least one instance of L comprises coumarin, o-nitrobenzyl, benzoin, 7-nitroindoline, or p-hydroxyphenacyl, or a derivative thereof. In certain embodiments, at least one instance of L comprises coumarin, o-nitrobenzyl, benzoin, 7-nitroindoline, or p-hydroxyphenacyl. In certain embodiments, at least one instance of L comprises coumarin. In certain embodiments, at least one instance of L1 comprises coumarin, o-nitrobenzyl, benzoin, 7-nitroindoline, or p-hydroxyphenacyl, or a derivative thereof. In certain embodiments, at least one instance of L1 comprises coumarin, o-nitrobenzyl, benzoin, 7-nitroindoline, or p-hydroxyphenacyl. In certain embodiments, at least one instance of L1 comprises coumarin. In certain embodiments, at least one instance of the moiety

##STR00018##

is of formula:

##STR00019##

wherein L1 is an alkylene linker wherein one or more carbon atoms are optionally replaced with —O—, —N(R.sup.a)—, —C(═O)—, optionally substituted phenyl, or

##STR00020##

and

[0140] lp indicates the attachment to P; R.sup.1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;

[0141] R.sup.a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group;

[0142] each instance of R is independently halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR.sup.c1, —NO.sub.2, —N(R.sup.c2).sub.2, —SR.sup.c1, or —CN;

[0143] R.sup.c1 is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom;

[0144] each instance of R.sup.c2 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; or optionally two instances of R.sup.c2 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and

[0145] x is 0, 1, 2, 3, 4, 5, 6, or 7, as valency permits.

[0146] In certain embodiments, at least one instance of L1 is an alkylene linker wherein one or more carbon atoms of the hydrocarbon chain are optionally replaced with —O—, —N(R.sup.a)—, —C(═O)—, optionally substituted phenyl, or

##STR00021##

In certain embodiments, at least one instance of L1 is a C.sub.1-20 alkylene linker wherein one or more carbon atoms of the hydrocarbon chain are optionally replaced with —O—, —N(R.sup.a)—, —C(═O)—, optionally substituted phenyl, or

##STR00022##

and R.sup.a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In certain embodiments, at least one instance of L1 is a C.sub.1-10 alkylene linker wherein one or more carbon atoms of the hydrocarbon chain are optionally replaced with —O—, —N(R.sup.a)—, —C(═O)—, optionally substituted phenyl, or

##STR00023##

and R.sup.a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group.

[0147] In certain embodiments, L1 comprises up to 20 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 14 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 15 in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 12 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 10 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 9 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 6 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 5 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents. In certain embodiments, L1 comprises up to 3 atoms in the hydrocarbon chain, excluding hydrogen atoms and substituents.

[0148] In certain embodiments, any of the atoms in L1 can be substituted. In certain embodiments, none of the atoms in the linker L1 are substituted. In certain embodiments, none of the carbon atoms in the linker are substituted.

[0149] In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of —O—. In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of —C═O—. In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of —NR.sup.a—, wherein R.sup.a is hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or a nitrogen protecting group. In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of —NR.sup.a—, wherein R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl. In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of optionally substituted phenyl. In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of unsubstituted phenyl. In certain embodiments, one or more carbon units of the hydrocarbon chain L1 are independently replaced with at least one instance of the moiety

##STR00024##

In certain embodiments, at least one carbon unit of the hydrocarbon chain L1 are independently replaced with at least one instance of the moiety

##STR00025##

In certain embodiments, one carbon unit of the hydrocarbon chain L1 are independently replaced with at least one instance of the moiety

##STR00026##

[0150] In certain embodiments, R.sup.a is hydrogen. In certain embodiments, R.sup.a is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.a is optionally substituted C.sub.1-6 alkyl. In certain embodiments, R.sup.a is substituted or unsubstituted methyl. In certain embodiments, R.sup.a is substituted or unsubstituted ethyl. In certain embodiments, R.sup.a is unsubstituted ethyl. In certain embodiments, R.sup.a is substituted or unsubstituted propyl. In certain embodiments, R.sup.a is unsubstituted n-propyl. In certain embodiments, R.sup.a is unsubstituted methyl or isopropyl. In certain embodiments, R.sup.a is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.a is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.a is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)).

[0151] In certain embodiments, L1 is of the formula:

##STR00027##

wherein:

[0152] Y is —O— or —NR.sup.a—;

[0153] R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl;

[0154] m1 is 0 or 1;

[0155] each instance of n1 is independently 0, 1, or 2;

[0156] n2 is 0 or 1;

[0157] n3 is 0 or 1; and

[0158] .sup.lp indicates the point of attachment to P and .sup.lx indicates the point of attachment to X.

[0159] In certain embodiments, at least one instance of the moiety

##STR00028##

is of the formula:

##STR00029##

wherein: each instance of n1 is independently 0 or 1; and n2 is 0 or 1.

[0160] In certain embodiments, at least one instance of the moiety

##STR00030##

is of the formula:

##STR00031##

wherein: Y is —O— or —NR.sup.a—; R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl; m1 is 0 or 1; n1 is 0 or 1; and n3 is 0 or 1.

[0161] In certain embodiments, at least one instance of the moiety

##STR00032##

is of the formula:

##STR00033##

wherein: R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl; and n1 is 0, 1, or 2.

[0162] In certain embodiments, at least one instance of the moiety

##STR00034##

is of the formula:

##STR00035##

wherein: R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl; m1 is 0 or 1; and n1 is 0, 1, or 2.

[0163] In certain embodiments, at least one instance of the moiety

##STR00036##

is of the formula:

##STR00037##

[0164] In certain embodiments, at least one instance of Y is —O—. In certain embodiments, at least one instance of Y is —NR.sup.a—, and R.sup.a is hydrogen, optionally substituted acyl, or optionally substituted alkyl. In certain embodiments, at least one instance of Y is —NH—. In certain embodiments, all instances of Y are —NH—. In certain embodiments, at least one instance of Y is —N(CH.sub.2).sub.1-6—. In certain embodiments, at least one instance of Y is —N(optionally substituted C.sub.1-6 alkyl)-. In certain embodiments, at least one instance of Y is —N(Me)-. In certain embodiments, at least one instance of Y is —N(Et)-. In certain embodiments, at least one instance of Y is —NR.sup.a—, and R.sup.a is hydrogen or optionally substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of Y is —NH— and another instance of Y is —N(optionally substituted C.sub.1-6 alkyl)-. In certain embodiments, at least one instance of Y is —NH— and another instance of Y is —N(Et)-.

[0165] In certain embodiments, the moiety

##STR00038##

includes one or more of m1, n1, n2, and n3. In certain embodiments, m1 is 0. In certain embodiments, m1 is 1. In certain embodiments, at least one instance of n1 is 0. In certain embodiments, at least one instance of n1 is 1. In certain embodiments, at least one instance of n1 is 2. In certain embodiments, both instances of n1 are 2. In certain embodiments, n2 is 0. In certain embodiments, n2 is 1. In certain embodiments, n3 is 0. In certain embodiments, n3 is 1. In certain embodiments, n1 is 1, m1 is 1, and n3 is 1. In certain embodiments, n1 is 2, m1 is 1, and n3 is 1. In certain embodiments, n1 is 1 and n3 is 0. In certain embodiments, n1 is 0 and n3 is 1. In certain embodiments, both instances of n1 are 2 and m1 is 1. In certain embodiments, both instances of n1 are 2 and m1 is 0. In certain embodiments, at least one instance of n1 is 1 and m1 is 1. In certain embodiments, one instance of n1 is 1, a second instance of n1 is 2, and m1 is 1.

[0166] In certain embodiments, the photocleavable linker L includes substituent R.sup.1. In certain embodiments, R.sup.1 is hydrogen. In certain embodiments, R.sup.1 is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.1 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.1 is substituted or unsubstituted methyl. In certain embodiments, R.sup.1 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.1 is unsubstituted ethyl. In certain embodiments, R.sup.1 is substituted or unsubstituted propyl. In certain embodiments, R.sup.1 is unsubstituted n-propyl. In certain embodiments, R.sup.1 is unsubstituted methyl or isopropyl. In certain embodiments, R.sup.1 is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.1 is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.1 is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.1 is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.1 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.1 is benzyl. In certain embodiments, R.sup.1 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.1 is unsubstituted phenyl. In certain embodiments, R.sup.1 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.1 is an oxygen protecting group (e.g., methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM)), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS)).

[0167] In certain embodiments, the photocleavable linker L includes one or more instances of substituent R, as valency permits. In certain embodiments, x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is 6. In certain embodiments, x is 7. In certain embodiments, at least one instance of R is halogen (e.g., F, Cl, Br, or I).

[0168] In certain embodiments, at least one instance of R is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R is optionally substituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R is optionally substituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R is benzyl. In certain embodiments, at least one instance of R is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R is —OR.sup.c1 (e.g., —OH or —OMe). In certain embodiments, at least one instance of R is —N(R.sup.c2).sub.2 (e.g., —NMe.sub.2, —NEt.sub.2). In certain embodiments, at least one instance of R is —N(R.sup.c2).sub.2 and at least one instance of R.sup.c2 is optionally substituted alkyl. In certain embodiments, at least one instance of R is —NEt.sub.2. In certain embodiments, x is 1 and R is —NEt.sub.2. In certain embodiments, at least one instance of R is —SR.sup.c1 (e.g., —SMe). In certain embodiments, at least one instance of R is —CN. In certain embodiments, at least one instance of R is —SCN.

[0169] In certain embodiments, at least one instance of R is —OR.sup.c1, —N(R.sup.c2).sub.2, or —SR.sup.c1 and R.sup.c1 is as defined herein. In certain embodiments, R.sup.c1 is hydrogen. In certain embodiments, R.sup.c1 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, R.sup.c1 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, R.sup.c1 is substituted or unsubstituted methyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted ethyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted propyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, R.sup.c1 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, R.sup.c1 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, R.sup.c1 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.c1 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, R.sup.c1 is benzyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted phenyl. In certain embodiments, R.sup.c1 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, R.sup.c1 is an oxygen protecting group (e.g., methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM)), trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS)) when attached to an oxygen atom. In certain embodiments, R.sup.c1 is a sulfur protecting group when attached to a sulfur atom.

[0170] In certain embodiments, at least one instance of R.sup.c2 is hydrogen. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one R.sup.c2 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic carbocyclyl comprising zero, one, or two double bonds in the carbocyclic ring system). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.c2 is benzyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.c2 is substituted or unsubstituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.c2 is a nitrogen protecting group (e.g., benzyl (Bn), t-butyl carbonate (BOC or Boc), benzyl carbamate (Cbz), 9-fluorenylmethyl carbonate (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl, or p-toluenesulfonamide (Ts)). In certain embodiments, two instances of R.sup.c2 are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic ring (e.g., substituted or unsubstituted, 5- to 10-membered monocyclic or bicyclic heterocyclic ring, wherein one or two atoms in the heterocyclic ring are independently nitrogen, oxygen, or sulfur) or substituted or unsubstituted heteroaryl ring (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur).

[0171] In certain embodiments, at least one instance of the moiety

##STR00039##

is of the formula:

##STR00040##

[0172] In certain embodiments, at least one instance of the moiety

##STR00041##

of the formula:

##STR00042##

In certain embodiments, at least one instance of the moiety

##STR00043##

is of the formula:

##STR00044##

In certain embodiments, at least one instance of the moiety

##STR00045##

is of the formula:

##STR00046##

In certain embodiments, at least one instance of the moiety

##STR00047##

is of the formula:

##STR00048##

In certain embodiments, at least one instance of the moiety

##STR00049##

is of the formula:

##STR00050##

In certain embodiments, at least one instance of the moiety

##STR00051##

is of the formula:

##STR00052##

[0173] In certain embodiments, at least one instance of the moiety

##STR00053##

is of the formula:

##STR00054##

In certain embodiments, at least one instance of the moiety

##STR00055##

is of the formula:

##STR00056##

In certain embodiments, at least one instance of the moiety

##STR00057##

is of the formula:

##STR00058##

In certain embodiments, at least one instance of the moiety

##STR00059##

is of the formula:

##STR00060##

In certain embodiments, both instances of L are the same. In certain embodiments, all instances of L are the same. In certain embodiments, both instances of the moiety

##STR00061##

are the same. In certain embodiments, all instances of the moiety

##STR00062##

are the same. In certain embodiments, both instances of the moiety

##STR00063##

are the same. In certain embodiments, all instances of the moiety

##STR00064##

are the same.

[0174] In certain embodiments, the compound of Formula (I) is of formula (I-A):

##STR00065##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, wherein:

[0175] each instance of R.sup.3 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.b, or —N(R.sup.b).sub.2;

[0176] each instance of R.sup.b is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.b taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;

[0177] each of q, r, and s is independently an integer between 0 and 200; and the sum of q, r, and s is at least 1.

[0178] In certain embodiments, the compound of Formula (I) is of formula (I-a):

##STR00066##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, wherein:

[0179] each instance of R.sup.3 is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, —OR.sup.b, or —N(R.sup.b).sub.2;

[0180] each instance of R.sup.b is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, an oxygen protecting group, or a nitrogen protecting group, or two R.sup.b taken together with the nitrogen to which they are attached form an optionally substituted heterocyclic or optionally substituted heteroaryl ring;

[0181] each of q, r, and s is independently an integer between 0 and 200; and the sum of q, r, and s is at least 1.

[0182] In certain embodiments, the compound of Formula (I) is of formula (I-A):

##STR00067##

or a pharmaceutically acceptable salt thereof.

[0183] In certain embodiments, the compound of Formula (I) is of formula (I-a):

##STR00068##

or a pharmaceutically acceptable salt thereof.

[0184] In certain embodiments, at least one instance of R.sup.3 is optionally substituted acyl (e.g., —C(═O)Me). In certain embodiments, at least one instance of R.sup.3 is optionally substituted alkyl (e.g., substituted or unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted methyl. In certain embodiments, at least one instance of R.sup.3 is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted ethyl. In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted propyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted alkenyl (e.g., substituted or unsubstituted C.sub.2-6 alkenyl). In certain embodiments, at least one instance of R.sup.3 is optionally substituted alkynyl (e.g., substituted or unsubstituted C.sub.2-6 alkynyl). In certain embodiments, at least one instance of R.sup.3 is optionally substituted aryl (e.g., substituted or unsubstituted, 6- to 10-membered aryl). In certain embodiments, at least one instance of R.sup.3 is benzyl. In certain embodiments, at least one instance of R.sup.3 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.3 is optionally substituted heteroaryl (e.g., substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur; or substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently nitrogen, oxygen, or sulfur). In certain embodiments, at least one instance of R.sup.3 is —OR.sup.b (e.g., —OH or —OMe). In certain embodiments, at least one instance of R.sup.3 is —N(R.sup.b).sub.2 (e.g., —NMe.sub.2).

[0185] In certain embodiments, q is 0. In some embodiments, q is an integer between 10 and 50, inclusive. In some embodiments, q is an integer between 10 and 25, inclusive. In some embodiments, q is an integer between 1 and 10, inclusive. In certain embodiments, q is an integer between 1 and 100, inclusive. In some embodiments, q is an integer between 10 and 100, inclusive. In some embodiments, q is an integer between 50 and 75, between 75 and 100, between 100 and 125, between 125 and 150, between 150 and 175, or between 175 and 200, inclusive. In certain embodiments, q is 100. In certain embodiments, q is 101.

[0186] In certain embodiments, r is 0. In certain embodiments, r is an integer between 1 and 100, inclusive. In some embodiments, r is an integer between 10 and 100, inclusive. In some embodiments, r is an integer between 10 and 50, inclusive. In some embodiments, r is an integer between 10 and 25, inclusive. In some embodiments, r is an integer between 1 and 10, inclusive. In some embodiments, r is an integer between 25 and 75, r is an integer between 25 and 50, r is an integer between 50 and 60, r is an integer between 50 and 70, r is an integer between 50 and 75, between 75 and 100, between 100 and 125, between 125 and 150, between 150 and 175, or between 175 and 200, inclusive. In certain embodiments, r is 50. In certain embodiments, r is 55. In certain embodiments, r is 56.

[0187] In certain embodiments, s is 0. In certain embodiments, s is an integer between 1 and 100. In some embodiments, s is an integer between 10 and 100, inclusive. In some embodiments, s is an integer between 10 and 50, inclusive. In some embodiments, s is an integer between 10 and 25, inclusive. In some embodiments, s is an integer between 1 and 10, inclusive. In certain embodiments, q is an integer between 1 and 100, inclusive. In some embodiments, q is an integer between 10 and 100, inclusive. In some embodiments, q is an integer between 50 and 75, between 75 and 100, between 100 and 125, between 125 and 150, between 150 and 175, or between 175 and 200, inclusive. In certain embodiments, q is 100. In certain embodiments, q is 101. In certain embodiments, both q and s are 0. In certain embodiments, exactly one of q and s is 0. In certain embodiments, q and s are the same. In certain embodiments, q and s are different. The sum of q, r, and s is at least 1.

[0188] In certain embodiments, the compound of Formula (I) is of formula:

##STR00069## ##STR00070##

wherein q, r, and s are as defined herein.

[0189] In certain embodiments, the compound of Formula (I) is of formula:

##STR00071##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

[0190] In certain embodiments, the compound of Formula (I) is of formula:

##STR00072##

or a pharmaceutically acceptable salt thereof.

[0191] In certain embodiments, the compound of Formula (I) is of formula:

##STR00073##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

[0192] In certain embodiments, the compound of Formula (I) is of formula:

##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081##

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof.

[0193] In certain embodiments, the compound of Formula (I) is of formula:

##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088## ##STR00089##

or a pharmaceutically acceptable salt thereof.

[0194] In certain embodiments, the compound of Formula (I) is a compound provided in any one of the Examples below. In certain embodiments, the compound of Formula (I) is a compound provided in Examples 1 and 2 below. In certain embodiments, the compound of Formula (I) is a compound provided in Example 1 below.

[0195] In certain embodiments, each instance of L is independently a photocleavable linker; and the bonds between each instance of L and each instance of X are cleaved upon illumination with light at an absorption wavelength between approximately 200 nm to 500 nm. In certain embodiments, the light absorption wavelength is about 300 nm to about 550 nm. In certain embodiments, both instances of L are each a photocleavable linker. In certain embodiments, the light absorption wavelength is about 350 nm to about 530 nm. In certain embodiments, the light absorption wavelength is about 450 nm to 475 nm. In certain embodiments, the light absorption wavelength is about 400 nm. In certain embodiments, the light absorption wavelength is about 200 nm to about 550 nm, about 200 nm to about 250 nm, about 250 nm to about 300 nm, about 300 nm to about 350 nm, about 200 nm to about 300 nm, about 300 nm to about 400 nm, about 300 nm to about 500 nm, about 350 nm to about 400 nm, about 400 nm to about 500 nm, about 400 nm to about 450 nm, about 450 nm to about 500 nm, about 550 nm to about 600 nm, or about 500 nm to about 600 nm. In certain embodiments, the light absorption wavelength is about 200 nm, about 300 nm, about 400 nm, about 500 nm, or about 600 nm. In certain embodiments, the light is a LED. In certain embodiments, the light is a blue LED. In certain embodiments, the light is a yellow LED. In certain embodiments, the light is a yellow-green LED. In certain embodiments, the light is a green LED. In certain embodiments, the light is an orange LED.

[0196] In certain embodiments, both instances of the active local anesthetic compound X are released upon the illumination with light. In certain embodiments, all instances of the active local anesthetic compound X are released upon the illumination with light. In certain embodiments, the bonds between each instance of L and each instance of X are cleaved upon illumination with light from a light emitting diode (LED). In certain embodiments, the bonds between each instance of L and each instance of X are cleaved upon illumination with light from a blue LED. In certain embodiments, the bonds between each instance of L and both instances of X are cleaved upon illumination with light from the same color of LED. In certain embodiments, the bonds between each instance of L and both instances of X are cleaved upon illumination with light from a blue LED. In certain embodiments, the bonds between each instance of L and each instance of X are cleaved upon illumination with light from a different color of LED.

[0197] The compounds and compositions described herein may be useful in treating and/or preventing diseases and/or conditions in a subject in need thereof, for example, in treating pain, such as pain associated with an infectious disease, pain associated with an ear disease, pain associated with a medical procedure (e.g., dental procedure, surgery), pain associated with trauma (e.g., injury), and/or sustained pain.

Pharmaceutical Compositions, Kits, and Administration

[0198] The present disclosure also provides pharmaceutical compositions comprising a compound described herein and optionally a pharmaceutically acceptable excipient. In certain embodiments, a compound described herein is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0199] In certain embodiments, the composition is in the form of a particle. In certain embodiments, the composition is in the form of a nanoparticle or a microparticle. In certain embodiments, the composition is encapsulated in the form of a particle. In certain embodiments, the particle encapsulates the composition, as described herein. In certain embodiments, provided are compositions in the form of a plurality of particles. In certain embodiments, the particle is a nanoparticle or a microparticle. In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, a therapeutically effective amount is an amount effective for treating and/or preventing a disease and/or condition, for example, in treating pain, such as pain associated with an infectious disease, pain associated with an ear disease, pain associated with a medical procedure (e.g., dental procedure, surgery), pain associated with trauma (e.g., injury), and/or sustained pain. In certain embodiments, the condition is pain. In certain embodiments, the condition is pain associated with an infectious disease (e.g. infection by a virus, bacteria, microbe). In certain embodiments, the condition is pain associated with an ear disease (e.g., otitis media). In certain embodiments, the disease is an infectious disease (e.g. infection by a virus, bacteria, microbe). In certain embodiments, the condition is pain associated with a medical procedure, for example, surgery (e.g., dental surgery). In certain embodiments, the medical procedure is a dental medical procedure. In certain embodiments, the medical procedure is surgery. In certain embodiments, the surgery is dental surgery. In certain embodiments, the surgery is facial surgery. In certain embodiments, the surgery is cosmetic surgery. In certain embodiments, the condition is pain associated with trauma (e.g., injury). In certain embodiments, the condition is pain associated with an injury. In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) is associated with an infectious disease and/or ear disease. In certain embodiments, the pain is chronic pain related to one or more of the following conditions, including, but not limited to, lower back pain, arthritis (e.g., osteoarthritis), headaches, multiple sclerosis, fibromyalgia, shingles, cancer, surgery, or other medical procedures, amputation; surgery, invasive medical procedures, toxins, burns, infection, and nerve damage (e.g., neuropathy). In certain embodiments, the pain is pain associated with psychological factors, which is psychogenic pain related to one or more of the following conditions including headaches, muscle pains, back pains, or stomach pains. In certain embodiments, the pain is neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawal symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental/maxillofacial pain, and/or visceral pain. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an infectious disease. In certain embodiments, the disease is an infectious disease. In certain embodiments, the disease is a bacterial infectious disease. In certain embodiments, the disease is a viral infectious disease. In certain embodiments, the disease is an ear disease (e.g, otitis media).

[0200] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0201] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.

[0202] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0203] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.

[0204] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0205] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0206] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0207] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60), polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate (Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

[0208] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

[0209] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0210] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0211] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0212] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0213] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0214] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0215] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant® Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®, Kathon®, and Euxyl®.

[0216] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0217] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0218] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0219] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0220] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0221] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0222] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0223] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0224] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0225] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0226] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0227] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.

[0228] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0229] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0230] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0231] Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0232] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0233] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure.

[0234] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.

[0235] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0236] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0237] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the biological sample, tissue, or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 pg and 1 pg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0238] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0239] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, as well as improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject, biological sample, tissue, or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.

[0240] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease and/or condition (e.g., inflammatory disease, infectious disease, pain). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0241] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, pain-relieving agents, and a combination thereof. In certain embodiments, the additional pharmaceutical agent is an anti-inflammatory agent. In certain embodiments, the additional pharmaceutical agent is a pain-relieving agent.

Kits

[0242] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.

[0243] Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease and/or condition (e.g., inflammatory disease, infectious disease, pain) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease and/or condition (e.g., inflammatory disease, infectious disease, pain) in a subject in need thereof. In certain embodiments, the kits comprise a container, a composition of a compound described herein, and instructions for administering the composition or pharmaceutical composition thereof to a subject in need thereof. In certain embodiments, the kits comprise a container, a composition of a compound described herein, and instructions for administering the composition or pharmaceutical composition thereof to a subject in need thereof, and light of an absorption wavelength sufficient to cleave the bonds between each instance of L and each instance of X upon illumination with the light (e.g., light between approximately 200 nm to 500 nm). In certain embodiments, the light is a LED. In certain embodiments, the light is a blue LED. In certain embodiments, the light is a yellow LED. In certain embodiments, the light is a yellow-green LED. In certain embodiments, the light is a green LED. In certain embodiments, the light is an orange LED. In certain embodiments, the light absorption wavelength is about 300 nm to about 550 nm. In certain embodiments, the light absorption wavelength is about 350 nm to about 530 nm. In certain embodiments, the light absorption wavelength is about 450 nm to 475 nm. In certain embodiments, the light absorption wavelength is about 400 nm. In certain embodiments, the light absorption wavelength is about 200 nm to about 550 nm, about 200 nm to about 250 nm, about 250 nm to about 300 nm, about 300 nm to about 350 nm, about 200 nm to about 300 nm, about 300 nm to about 400 nm, about 300 nm to about 500 nm, about 350 nm to about 400 nm, about 400 nm to about 500 nm, about 400 nm to about 450 nm, about 450 nm to about 500 nm, about 550 nm to about 600 nm, or about 500 nm to about 600 nm. In certain embodiments, the light absorption wavelength is about 200 nm, about 300 nm, about 400 nm, about 500 nm, or about 600 nm.

[0244] In certain embodiments, a kit described herein further includes instructions for using the compound or pharmaceutical composition included in the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits and instructions provide for treating a disease and/or condition (e.g., inflammatory disease, infectious disease, pain) in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease and/or condition (e.g., inflammatory disease, infectious disease, pain) in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. In certain embodiments, a kit described herein further includes a dropper, syringe, or catheter. In certain embodiments, a kit described herein further includes a syringe.

Methods of Treatment and Uses

[0245] The present disclosure provides methods of treating a disease and/or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of a compound (e.g., a compound of Formula (I)) described herein, and optionally further comprising illumination of the composition or the pharmaceutical composition with light of an absorption wavelength sufficient to cleave the bonds between each instance of L and each instance of X upon illumination with the light (e.g., light between approximately 200 nm to 500 nm). In certain embodiments, the composition is illuminated with light that is a LED. In certain embodiments, the light is a blue LED. In certain embodiments, the light is a yellow LED. In certain embodiments, the light is a yellow-green LED. In certain embodiments, the light is a green LED. In certain embodiments, the light is an orange LED. In certain embodiments, the light absorption wavelength is about 300 nm to about 550 nm. In certain embodiments, the light absorption wavelength is about 350 nm to about 530 nm. In certain embodiments, the light absorption wavelength is about 450 nm to 475 nm. In certain embodiments, the light absorption wavelength is about 400 nm. In certain embodiments, the light absorption wavelength is about 200 nm to about 550 nm, about 200 nm to about 250 nm, about 250 nm to about 300 nm, about 300 nm to about 350 nm, about 200 nm to about 300 nm, about 300 nm to about 400 nm, about 300 nm to about 500 nm, about 350 nm to about 400 nm, about 400 nm to about 500 nm, about 400 nm to about 450 nm, about 450 nm to about 500 nm, about 550 nm to about 600 nm, or about 500 nm to about 600 nm. In certain embodiments, the light absorption wavelength is about 200 nm, about 300 nm, about 400 nm, about 500 nm, or about 600 nm.

[0246] The present disclosure also provides a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, an isotopically enriched derivative, or composition thereof, for use in the treatment of diseases and/or conditions, such as inflammatory disease, infectious disease, pain, in a subject in need thereof. The present disclosure also provides a composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, for use in the treatment of diseases, such as inflammatory disease, infectious disease, pain, in a subject in need thereof.

[0247] The present disclosure also provides uses of a compound of Formula (I), pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, an isotopically enriched derivative, or composition thereof, in the manufacture of a medicament for the treatment and/or prevention of diseases and/or conditions, such as inflammatory disease, infectious disease, pain, in a subject in need thereof. In certain embodiments, provided are uses of compositions comprising a compound of Formula (I), pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, for the treatment and/or prevention of diseases and/or conditions, such as inflammatory disease, infectious disease, pain, in a subject in need thereof. In certain embodiments, provided are uses of compositions comprising a compound of Formula (I), pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, or an isotopically enriched derivative thereof, for the treatment and/or prevention of diseases and/or conditions, such as inflammatory disease, infectious disease, pain, in a subject in need thereof, comprising illumination of the composition or the pharmaceutical composition with light sufficient to cleave the bonds between each instance of L and each instance of X upon illumination with the light (e.g., light between approximately 200 nm to 500 nm). In certain embodiments, the composition is illuminated with light that is a LED. In certain embodiments, the light is a blue LED. In certain embodiments, the light is a yellow LED. In certain embodiments, the light is a yellow-green LED. In certain embodiments, the light is a green LED. In certain embodiments, the light is an orange LED. In certain embodiments, the light absorption wavelength is about 300 nm to about 550 nm. In certain embodiments, the light absorption wavelength is about 350 nm to about 530 nm. In certain embodiments, the light absorption wavelength is about 450 nm to 475 nm. In certain embodiments, the light absorption wavelength is about 400 nm. In certain embodiments, the light absorption wavelength is about 200 nm to about 550 nm, about 200 nm to about 250 nm, about 250 nm to about 300 nm, about 300 nm to about 350 nm, about 200 nm to about 300 nm, about 300 nm to about 400 nm, about 300 nm to about 500 nm, about 350 nm to about 400 nm, about 400 nm to about 500 nm, about 400 nm to about 450 nm, about 450 nm to about 500 nm, about 550 nm to about 600 nm, or about 500 nm to about 600 nm. In certain embodiments, the light absorption wavelength is about 200 nm, about 300 nm, about 400 nm, about 500 nm, or about 600 nm.

[0248] In certain embodiments, the compounds described herein are used in applications where the nerves of interest are relatively close to the body surface, e.g. dental applications. In certain embodiments, the disease and/or condition (e.g., inflammatory disease, infectious disease, pain) to be treated or prevented using the compounds and compositions described herein is pain associated with an infectious disease, pain associated with an ear disease, pain associated with a medical procedure (e.g., dental procedure, surgery), pain associated with trauma (e.g., injury), and/or sustained pain. In certain embodiments, the condition is pain. In certain embodiments, the condition is pain associated with an infectious disease (e.g. infection by a virus, bacteria, microbe). In certain embodiments, the condition is pain associated with an ear disease (e.g., otitis media). In certain embodiments, the disease is an infectious disease (e.g. infection by a virus, bacteria, microbe). In certain embodiments, the condition is pain associated with a medical procedure, for example, surgery (e.g., dental surgery). In certain embodiments, the medical procedure is a dental medical procedure. In certain embodiments, the medical procedure is surgery. In certain embodiments, the surgery is dental surgery. In certain embodiments, the surgery is facial surgery. In certain embodiments, the surgery is cosmetic surgery. In certain embodiments, the condition is pain associated with trauma (e.g., injury). In certain embodiments, the condition is pain associated with an injury. In certain embodiments, the painful condition is inflammatory pain. In certain embodiments, the painful condition (e.g., inflammatory pain) is associated with an infectious disease and/or ear disease. In certain embodiments, the pain is chronic pain related to one or more of the following conditions, including, but not limited to, lower back pain, arthritis (e.g., osteoarthritis), headaches, multiple sclerosis, fibromyalgia, shingles, cancer, surgery, or other medical procedures, amputation; surgery, invasive medical procedures, toxins, burns, infection, and nerve damage (e.g., neuropathy). In certain embodiments, the pain is pain associated with psychological factors, which is psychogenic pain related to one or more of the following conditions including headaches, muscle pains, back pains, or stomach pains. In certain embodiments, the pain is neuropathic pain (e.g., peripheral neuropathic pain), central pain, deafferentiation pain, chronic pain (e.g., chronic nociceptive pain, and other forms of chronic pain such as post-operative pain, e.g., pain arising after hip, knee, or other replacement surgery), pre-operative pain, stimulus of nociceptive receptors (nociceptive pain), acute pain (e.g., phantom and transient acute pain), noninflammatory pain, inflammatory pain, pain associated with cancer, wound pain, burn pain, postoperative pain, pain associated with medical procedures, pain resulting from pruritus, painful bladder syndrome, pain associated with premenstrual dysphoric disorder and/or premenstrual syndrome, pain associated with chronic fatigue syndrome, pain associated with pre-term labor, pain associated with withdrawal symptoms from drug addiction, joint pain, arthritic pain (e.g., pain associated with crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral pain, musculo-skeletal pain, headache, migraine, muscle ache, lower back pain, neck pain, toothache, dental/maxillofacial pain, and/or visceral pain. In certain embodiments, the disease is an inflammatory disease. In certain embodiments, the disease is an infectious disease. In certain embodiments, the disease is an infectious disease. In certain embodiments, the disease is a bacterial infectious disease. In certain embodiments, the disease is a viral infectious disease. In certain embodiments, the disease is an ear disease (e.g, otitis media). In certain embodiments, the method comprises sustained treatment of pain.

EXAMPLES

[0249] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Synthesis of Exemplary Prodrug Compounds

[0250] Compounds of Formulas (I) may be prepared in view of the following synthetic schemes, and by using synthetic schemes and procedures recognized by one of ordinary skill in the art.

[0251] Unless otherwise noted, reagents and solvents were obtained from commercial suppliers and were used without further purification. .sup.1H NMR spectra were recorded on 500 MHz (Varian AS600), and chemical shifts are reported in parts per million (ppm, 6) downfield from tetramethylsilane (TMS). Coupling constants (J) are reported in Hz. Spin multiplicities are described as s (singlet), br (broad singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). Mass spectra were obtained on a Waters Micromass ZQ instrument. Preparative HPLC was performed on a Waters Sunfire C18 column (19 mm×50 mm, 5 μM) using a gradient of 15-95% methanol in water containing 0.05% trifluoroacetic acid (TFA) over 22 min (28 min run time) at a flow rate of 20 mL/min. Purities of assayed compounds were in all cases greater than 95%, as determined by reverse-phase HPLC analysis.

[0252] Compounds of Formula (I) may be prepared using the synthetic scheme2 shown below (Schemes 1 and 2) and procedures known by one of ordinary skill in the art.

##STR00090##

[0253] Synthesis of Compound 1 (CM-CHO). 7-Diethylamino-4-methylcoumarin (2.31 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL). Selenium dioxide (2.00 g, 18 mmol) was added. The mixture was refluxed overnight before filtered through celite. The filtrate was concentrated and purified by silica gel chromatography (dichloromethane:hexane 3:1) to give the product as a red crystal (860 mg, 35%). .sup.1H NMR (CDCl.sub.3, 400 MHz, ppm, δ) 9.95 (s, 1H), 8.21-8.19 (d, 1H), 6.60-6.57 (d, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 3.40-3.34 (m, 4H), 1.18-1.14 (m, 6H). .sup.13C NMR (CDCl.sub.3, 100 MHz, ppm, δ) 192.39, 161.60, 157.15, 150.57, 143.68, 126.93, 117.27, 109.83, 104.06, 97.98, 45.04, 12.34. ESI-MS: m/z calculated for C.sub.14H.sub.16NO.sub.3 [M+H].sup.+: 246.1; observed: 246.1

[0254] Synthesis of Compound 2 (NO.sub.2—CM-OH). Compound 1 (245 mg, 1.0 mmol) was dissolved in tetrahydrofuran (THF, 2 mL). In an ice-water bath, a solution of nitromethane (610 mg, 10 mmol) in THF (2 mL) was added dropwise. Then, a solution of N,N,N′N′-tetramethylethylenediamine (35 mg, 0.3 mmol) in THF (2 mL) was added dropwise. The reaction mixture was allowed to warm up to ambient temperature and stirred for another 4 h. The solvent was removed by a rotatory evaporator. The residue was re-dissolved in a small amount of dichloromethane and purified by silica gel chromatography (dichloromethane:ethyl acetate 10:1) to give the product as an orange solid (220 mg, 76%). .sup.1H NMR (CDCl.sub.3, 400 MHz, ppm, δ) 7.42-7.40 (d, 1H), 6.64-6.62 (dd, 1H), 6.54 (s, 1H), 6.38 (s, 1H), 5.82-5.80 (m, 1H), 4.66-4.59 (m, 2H), 3.47-3.41 (m, 4H), 3.18-3.17 (d, 1H), 1.24-1.21 (t, 6H). .sup.13C NMR (CDCl.sub.3, 100 MHz, ppm, δ) 161.97, 156.50, 151.84, 150.84, 123.95, 109.12, 106.64, 104.96, 98.13, 79.70, 67.06, 44.82, 12.41. ESI-MS: m/z calculated for C.sub.15H.sub.19N.sub.2O.sub.5 [M+H].sup.+: 307.1; observed: 307.1

[0255] Synthesis of Compound 3 (NH.sub.2—CM-OH). Compound 2 (920 mg, 3.2 mmol) was suspended in acetic acid (15 mL). The suspension was placed in an ice-water bath. Then zinc powder (1.35 g, 20.8 mmol) was added. After 30 min, the reaction mixture was allowed to warm up to ambient temperature and stirred for another 2 h. The solid was removed by filtration. The filtrate was neutralized by saturated Na.sub.2CO.sub.3 aqueous solution. The mixture was extracted with dichloromethane (200 mL) and then washed with saturated Na.sub.2CO.sub.3 aqueous solution (100 mL) and saturated NaCl aqueous solution (100 mL×2). The organic phase was dried by anhydrous Na.sub.2SO.sub.4 and concentrated by vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol 5:1) to give the product as a yellow solid (550 mg, 65%). .sup.1H NMR (CDCl.sub.3, 400 MHz, ppm, δ) 7.38-7.36 (d, 1H), 6.53-6.52 (dd, 1H), 6.43 (s, 1H), 6.30 (s, 1H), 5.03-5.01 (m, 1H), 3.44-3.34 (m, 6H), 3.16-3.13 (m, 1H), 2.87-2.85 (m, 1H), 1.17-1.15 (t, 6H). .sup.13C NMR (CDCl.sub.3, 100 MHz, ppm, δ) 162.65, 156.46, 156.30, 150.36, 124.75, 108.66, 106.12, 105.54, 97.75, 68.86, 46.77, 44.47, 44.65, 12.43. ESI-MS: m/z calculated for C.sub.15H.sub.21N.sub.2O.sub.3 [M+H].sup.+: 277.2; observed: 277.1.

[0256] Synthesis of Compound 4 (N.sub.3—CM-OH). To a suspension of 4-azidobenzoic acid (65 mg, 0.40 mmol) in dichloromethane (2 mL) in an ice-water bath, triethylamine (80 mg, 0.8 mmol) was added, followed by HATU (170 mg, 0.44 mmol). After 5 min, Compound 3 (100 mg, 0.36 mmol) in dichloromethane (5 mL) was added. The mixture was then stirred for 2 h at ambient temperature. Dichloromethane (80 mL) was used to dilute the reaction mixture, which was then washed by saturated NaCl aqueous solution (100 mL×3). The organic phase was dried by anhydrous Na.sub.2SO.sub.4 and concentrated using a rotatory evaporator. The residue was purified by silica gel chromatography (dichloromethane:methanol 20:1) to give the product as a yellow solid (130 mg, 86%). .sup.1H NMR (CDCl.sub.3, 500 MHz, ppm, δ) 7.83-7.82 (d, 2H), 7.75-7.73 (d, 1H), 7.07-7.05 (d, 2H), 7.05-7.03 (m, 1H), 6.67-6.65 (m, 1H), 6.47-6.46 (d, 1H), 6.37 (s, 1H), 5.32-5.30 (m, 1H), 4.20-4.15 (m, 1H), 3.88-3.86 (d, 1H), 3.44-3.39 (m, 4H), 3.31-3.26 (m, 1H), 1.23-1.20 (t, 6H). .sup.13C NMR (CDCl.sub.3, 125 MHz, ppm, δ) 167.94, 162.83, 156.31, 156.10, 150.88, 143.82, 129.94, 128.90, 125.05, 119.09, 109.06, 106.02, 105.33, 97.69, 69.15, 46.74, 44.75, 12.46. ESI-MS: m/z calculated for C.sub.22H.sub.24N.sub.5O.sub.4 [M+H].sup.+: 422.2; observed: 422.2.

[0257] Synthesis of Compound 5 (N3-CM-tetracaine). To a solution of triphosgene (73 mg, 0.25 mmol) in anhydrous dichloromethane (2 mL) in an ice-water bath, a solution of tetracaine (190 mg, 0.72 mmol) and N,N-diisopropylethylamine (100 mg, 0.77 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred for 1 h at ambient temperature. The resulted solution was withdrawn in a syringe and then added into a solution of Compound 4 (120 mg, 0.28 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (250 mg, 1.67 mmol) in dichloromethane (5 mL). The reaction mixture then was stirred for 7 days. Dichloromethane (100 mL) was used to dilute the reaction mixture. The solution was washed by saturated NaCl aqueous solution (100 mL×3). The organic phase was dried by anhydrous Na.sub.2SO.sub.4 and concentrated by vacuum. The residue was re-dissolved in a small amount of dichloromethane and purified by silica gel chromatography (dichloromethane:methanol 10:1) to give the product as a light-yellow solid (38 mg, 19%). .sup.1H NMR (CDCl.sub.3, 500 MHz, ppm, δ) 8.07-8.05 (d, 2H), 7.77-7.75 (d, 2H), 7.73-7.72 (d, 1H), 7.30-7.28 (d, 2H), 7.08-7.06 (d, 2H), 6.63-6.61 (dd, 1H), 6.45 (s, 1H), 6.25-6.23 (m, 1H), 6.80-5.70 (m, 1H), 4.54-4.52 (t, 2H), 3.94-3.64 (m, 4H), 3.41-3.37 (m, 4H), 3.08-3.05 (m, 2H), 2.60 (s, 6H), 1.48-1.26 (m, 4H), 1.20-1.17 (t, 3H), 0.84-0.82 (t, 3H). .sup.13C NMR (CDCl.sub.3, 125 MHz, ppm, δ) 166.97, 165.53, 162.46, 156.37, 153.90, 152.99, 150.90, 145.78, 143.60, 130.91, 130.15, 128.92, 127.14, 125.38, 119.05, 109.37, 105.69, 104.62, 97.55, 71.53, 65.84, 60.48, 57.29, 50.19, 44.75, 30.22, 19.78, 15.27, 13.65, 13.41. ESI-MS: m/z calculated for C.sub.38H.sub.46N.sub.7O.sub.7 [M+H].sup.+: 712.3; observed: 712.3.

[0258] Synthesis of Compound 6 (P407-yne). P407 (1.2 g) was dissolved in anhydrous THF (10 mL), then NaH (24 mg, 1 mmol) was added at 0° C. The mixture was stirred for 2 h. Propargyl bromide (100 uL 80 wt % in toluene) was added dropwise. The reaction was stirred overnight. A few drops of water were added dropwise to quench the reaction. Then, the mixture was pass through a short silica gel column (dichloromethane:methanol 2:1). The solution was concentrated and precipitated into cold diethyl ether. The product was collected by filtration as an off-white solid in 90% yield. .sup.1H NMR (CDCl.sub.3, 500 MHz, ppm, δ) 4.21 (m, 4H), 3.77-3.36 (m, 1050H), 2.45 (m, 2H), 1.16-1.12 (m, 180H). GPC:M.sub.n=12.6 kg/mol, Ð=1.40.

[0259] Synthesis of Compound 7 (P407-CM-T). Copper (II) sulfate pentahydrate (10 mg, 0.06 mmol) was dissolved in water (0.5 mL), then (+)-sodium L-ascorbate (20 mg, 0.1 mmol) was added. After 5 min, the mixture was added to a methanol solution (10 mL) containing Compound 6 (P407-yne, 200 mg, 0.013 mmol) and Compound 5 (N.sub.3—CM-tetracaine, 40 mg, 0.056 mmol). After 12 h, the mixture was diluted by dichloromethane (100 mL) and washed with saturated NaCl aqueous solution (100 mL×3). The organic phase was dried by anhydrous Na.sub.2SO.sub.4 and concentrated by vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol 8:1). The collected solution was concentrated by a rotatory evaporator and precipitated in cold ether. The product was collected by filtration as a light-yellow solid (180, 85%). .sup.1H NMR (CDCl.sub.3, 400 MHz, ppm, δ) 8.23-8.24 (m, 2H), 8.15-8.13 (m, 4H), 8.04-8.03 (m, 4H), 7.89-7.87 (m, 6H), 7.35-7.34 (m, 4H), 6.70-6.68 (m, 2H), 6.49-6.48 (m, 2H), 6.31-6.29 (m, 2H), 5.92-5.81 (m, 2H), 5.59-5.57 (m, 2H), 4.79-4.68 (m, 4H), 4.25-3.20 (m, 1060H), 1.58-0.82 (m, 190H). GPC:M.sub.n=13.6 kg/mol, Ð=1.41.

##STR00091##

[0260] Synthesis of Compound 8 (CM-OH). Compound 1 (350 mg, 1.43 mmol) was dissolved in methanol (5 mL). Sodium borohydride (170 mg, 4.50 mmol) was added slowly into the above solution in an ice-water bath. After 2 h, water (1 mL) was added to quench the reaction. Then, the mixture was diluted with dichloromethane (100 mL), followed by washed with saturated NaCl aqueous solution (100 mL×3). The organic phase was dried by anhydrous Na.sub.2SO.sub.4 and concentrated by vacuum. The residue was purified by silica gel chromatography (dichloromethane:ethyl acetate 5:1) to give the product as a yellow solid (250 mg, 71%). .sup.1H NMR (CDCl.sub.3, 500 MHz, ppm, δ) 7.33-7.31 (d, 1H), 6.58-6.57 (dd, 1H), 6.51-6.50 (d, 1H), 6.27 (s, 1H), 4.84 (s, 2H), 3.43-3.39 (q, 4H), 1.23-1.20 (t, 6H). .sup.13C NMR (CDCl.sub.3, 125 MHz, ppm, δ) 162.52, 156.17, 154.59, 150.49, 124.36, 108.53, 106.29, 105.48, 97.77, 60.99, 44.72, 12.45. ESI-MS: m/z calculated for C.sub.14H.sub.18NO.sub.3 [M+H].sup.+: 248.1; observed: 248.1

[0261] Synthesis of Compound 9 (CM-T). To a solution of triphosgene (36 mg, 0.12 mmol) in anhydrous dichloromethane (2 mL) in an ice-water bath, a solution of tetracaine (90 mg, 0.34 mmol) and triethylamine (50 mg, 0.50 mmol) in dichloromethane (5 mL) was added dropwise. The reaction mixture was stirred for 1 h at ambient temperature. The resulted solution was withdrawn in a syringe and then added into a solution of Compound 8 (65 mg, 0.26 mmol) and triethylamine (120 mg, 1.2 mmol) in dichloromethane (5 mL). After 24 h, the reaction mixture was diluted by dichloromethane (100 mL) and washed by saturated NaCl aqueous solution (100 mL×3). The organic phase was dried by anhydrous Na.sub.2SO.sub.4 and concentrated by vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol 20:1) to give the product as a yellow solid (60 mg, 45%). .sup.1H NMR (CDCl.sub.3, 500 MHz, ppm, δ) 8.07-8.05 (d, 2H), 7.32-7.30 (d, 2H), 7.24-7.22 (d, 1H), 8.54-8.51 (dd, 1H), 6.49-6.48 (d, 1H), 5.91 (m, 1H), 5.25 (s, 2H), 4.44-4.41 (t, 2H), 3.76-3.72 (t, 2H), 3.42-3.37 (q, 4H), 2.73-2.70 (t, 2H), 2.33 (s, 6H), 1.56-1.50 (m, 2H), 1.34-1.28 (m, 2H), 1.21-1.18 (t, 6H), 0.90-0.86 (t, 3H).sup.13C NMR (CDCl.sub.3, 125 MHz, ppm, δ) 165.80, 161.83, 159.19, 154.18, 150.61, 149.91, 131.63, 130.68, 128.70, 124.36, 108.56, 106.08, 105.91, 97.77, 63.05, 62.79, 57.76, 50.29, 45.78, 44.73, 30.36, 29.69, 19.84, 13.71, 12.42. ESI-MS: m/z calculated for C.sub.30H.sub.40N.sub.3O.sub.6 [M+H].sup.+: 538.3; observed: 538.3.

Example 2. Light-Triggered Release of Conventional Local Anesthetics from a Macromolecular Progdrug for On-Demand Local Anesthesia

Results and Discussions

[0262] The molecular design and synthesis of the polymer-drug conjugate (P407-couramin-tetracaine; P407-CM-T) are shown in FIG. 1A. The photo-cleavage reaction is shown in FIG. 1B. In brief, a coumarin derivative bi-functionalized at the 4-position of the coumarin ring was synthesized, then an azide group was introduced for click reaction with the P407. Then, tetracaine was connected to the coumarin through a carbamate linkage. The resulting coumarin-tetracaine conjugate was then conjugated onto an alkyl-functionalized P407 through azide-alkyne “click” cycloaddition..sup.22,23 After the reaction, the molecular weight of the polymer (determined with a polystyrene standard) as measured by gel permeation chromatography (GPC) increased from 12.6 k to 13.6 k. In the .sup.1H NMR spectrum of P407-CM-T (FIG. 1C), peaks could be clearly assigned to each moiety of the molecule, indicating its successful synthesis: the peak at 8.03-8.04 ppm is representative of the tetracaine moiety; the peaks at 6.70-6.68 ppm, 6.49-6.48 ppm and 6.31-6.29 ppm are representative of the coumarin moiety;.sup.24 and the large peaks at 3-4 ppm and 1-2 ppm are attributable to P407 by comparing to the spectrum of alkyne terminated P407 in FIG. 15..sup.25 These results demonstrated the successful synthesis of the designed material. More detailed chemical characterization of all compounds are available in FIGS. 10-17.

[0263] P407-CM-T aqueous solution showed strong absorption in the blue range with a maximum at 394 nm and a full width at half-maximum (fwhm) of 64 nm (FIG. 2A). By comparing to the absorption spectra of coumarin and tetracaine, the absorption peak of P407-CM-T at around 400 nm can be attributable to the coumarin moiety, and the peak at around 300 nm to the tetracaine moiety. DEACM derivatives are known to be cleavable by 400 nm LED..sup.24, 26 Therefore, a 400 nm LED with tunable intensity was used in the triggering experiments.

[0264] The reverse thermal gelation property of P407-CM-T (20 wt % in aqueous) was verified by oscillatory shear rheology (10 rads.sup.−1, 1% strain, 1° C. min.sup.−1). The loss modulus (G″) was higher than the storage modulus (G′) at <30° C., indicating a liquid-like property, which ensured the material would be injectable. G′ became greater than G″ at about 33° C., indicating gelation (FIG. 2B). This property could be beneficial for the material to be retained at the site of injection,.sup.27 where drug release could subsequently be triggered.

[0265] The ability of P407-CM-T to release tetracaine under 400 nm light was studied in vitro (FIG. 3A). Irradiation of P407-CM-T (10 mg/mL) with 400 nm light at 50 mW/cm.sup.2 revealed a peak on liquid chromatography that was not seen in unirradiated P407-CM-T and that co-migrated with free tetracaine. The small molecule released from P407-CM-T after irradiation had the molecular weight of tetracaine ion (m/z of 265.1) by liquid chromatography-mass spectroscopy (LC-MS) (FIG. 3B), indicating that P407-CM-T can release tetracaine in its native form. Almost all the conjugated drug was cleaved from P407-CM-T (10 mg/mL) within 120 s of irradiation at 50 mW/cm.sup.2, and approximately 40% of cleavage occurred within 120 s at 25 mW/cm.sup.2 (FIG. 3C). When P407-CM-T solution was kept in the dark at 37° C. for two weeks, no tetracaine was released, indicating good stability in the dark.

[0266] Before testing the material in vivo, test materials were evaluated in vitro with C2C12 and PC12 cells to assess cytotoxicity to muscle and nerve cells respectively. Different compounds were directly added into the cell culture media (1 mg/mL, 0.33 mg/mL and 0.11 mg/mL) and incubated in the media bathing the cells (i.e. in direct contact with them) in conventional cell culture wells. After 24 h, cell viabilities were evaluated with the MTS assay, and their survival expressed as percentages of results in untreated cells. Free tetracaine showed high cytotoxicity in both cell lines, while P407 and P407-CM-T showed little cytotoxicity (FIGS. 4A-4B). Due to the high molecular weight of the polymer-containing samples, their molar concentrations were perforce lower than that of the small molecule tetracaine. It would not be practical to culture cells in media containing the polymer concentration to be used in vivo (20 wt %), which would be very viscous. Therefore, test materials were placed in Transwell® inserts such that they were in continuity with the cell culture media. Here, also both P407 and P407-CM-T had no effect on cell viability (p>0.05 compared to untreated cells) while tetracaine greatly reduced cell survival (p<0.05 compared to untreated cells) in both cell lines (FIGS. 4C-4D). These results indicated that covalently linking tetracaine onto P407 can effectively reduce its cytotoxicity, presumably because there was little free tetracaine.

[0267] The effectiveness of light-triggered anesthesia using P407-CM-T was assessed in vivo after footpad injection in the rat (Table 1);.sup.17, 28-32 this model was selected because it was anticipated that 400 nm light would not penetrate deeply into tissue..sup.33

TABLE-US-00001 TABLE 1 Duration of block for different compounds without or with a single irradiation event Irradiance Irradiation Duration Duration of Block Compound (W/cm.sup.2) (min) (min) Tetracaine 0 0 28.6 ± 7.1 CM-T 0 0  43.9 ± 11.4 P407-CM-T 0 0 0 P407-CM-T 0.2 2 19.5 ± 4.5 P407-CM-T 0.3 2 36.5 ± 8.9 P407-CM-T 0.3 5 66.7 ± 24  saline 0.3 2 0

[0268] A hundred microliters of 20 wt % P407-CM-T were injected into the plantar aspect of the rat hind paw. Neurobehavioral testing was performed by stimulating the rat footpad with a Touch Test sensory evaluator and noting the vocal and/or motor response (foot withdrawal) of the rat, maximum peak effect (MPE) and duration of block was calculated..sup.17, 28 In the absence of irradiation, P407-CM-T did not cause local anesthesia (FIG. 5A). Irradiation of the site of administration immediately after injection with a 400 nm LED at 200 mW/cm.sup.2 for two minutes caused local anesthesia lasting 19.5±4.5 min (FIGS. 5A-5B). Local anesthesia was prolonged to 36.5±8.9 min (FIG. 5B) by increasing the irradiance to 300 mW/cm.sup.2 also for 2 minutes (p<0.05 compared to 200 mW/cm.sup.2). Extending the irradiation time to five minutes at 300 mW/cm.sup.2 further extended local anesthesia to 66.7±24 min (p<0.05 compared to 300 mW/cm.sup.2 for 2 min, FIG. 5B). Tetracaine conjugated to coumarin without P407 (chemical structure shown in FIG. 8) produced local anesthesia slightly longer than from tetracaine (p<0.05), possibly due to the large hydrophobic addition to the tetracaine. This indicated that conjugation of the polymer is necessary to inactivate the drug. The duration of local anesthesia bore an almost linear relationship to the irradiation energy density (the product of irradiance and irradiation duration; FIG. 4C), suggesting that the degree of anesthesia could be modulated by varying the irradiance and/or irradiation duration according to patients' changing needs.

[0269] It would be important for a light-triggerable local anesthetic system to be triggered repeatedly, so as to be able to treat pain over an extended period. To assess the ability of P407-CM-T to provide repeated on-demand local anesthesia, animals were injected in the footpad with 0.1 mL of 20 wt % P407-CM-T (FIG. 4D). No nerve block ensued. The animal was then irradiated at the site of injection with 400 nm light at 300 mW/cm.sup.2 for 2 min. Subsequently, irradiation was repeated five times, fifteen min after the anesthetic effect from the preceding irradiation event wore off. The duration of block generally decreased with successive triggering events (FIG. 5E). This was possibly because of drug depletion after each triggering event. Triggering could also be delayed for 2 h or 6 h after injection; there was no nerve block until irradiation occurred. Delays in triggering led to fewer triggerable peaks, presumable because of the polymer depletion and loss of triggerable material.

[0270] To assess tissue reaction to the formulations, rats were euthanized 4 days and 14 days after injections, and their foot pads were harvested. Saline injections resulted in a very mild localized chronic inflammation (i.e. lymphocytes and macrophages) in the subcutaneous layer on day 4 which decreased to a minimal chronic inflammation with mild fibrosis by day 14. P407-CM-T injections without irradiation caused mild-moderate chronic inflammation on days 4 (FIG. 6) and decreased to very mild inflammation with fibrosis on day 14, which was similar to that from P407 injections. P407-CM-T injections with irradiation on the first day caused moderate chronic inflammation on day 4 extending from the sub-epidermal layers into the deeper muscular layers (FIG. 6). This inflammation also decreased to mild by day 14. The greater inflammation in animals P407-CM-T that were irradiated was probably due to the release of tetracaine since the tissue reaction was similar to that of tetracaine injection (FIG. 6).

[0271] Triggered local anesthesia would allow patients to adjust their pain relief as needed without needing systemic medications such as opioids or procedures requiring skilled personnel (at least after the initial application). Light, due to its tunable wavelength, irradiance, area and duration of exposure, is a suitable trigger. Laser sources are commonly used in light-triggered drug delivery systems due to their monochromaticity, coherence and high intensity. However, laser sources can be expensive and relatively bulky, and their high intensity can cause tissue injury. Light from LEDs is not monochromatic, coherent, and is generally comparatively low in intensity. However, LEDs are cheaper and can be small, efficient, and inexpensive. The light source in the current exemplary system was a blue light LED so that it could be potentially used on a larger scale, making them suitable for real-world applications. In certain embodiments, LEDs at 400 nm light do not penetrate deeply into tissue. However, demonstrated here was that the light that penetrated through the skin was sufficient to cleave the bonds between tetracaine and coumarin and release the free drug. Described herein is a macromolecular prodrug of tetracaine that did not cause local anesthesia in the absence of photo-triggering, and provided LED-triggered local anesthesia in proportion to the intensity and duration of irradiation.

Materials and Characterizations

Materials

[0272] The other chemical and solvents were used as received: 7-diethylamino-4-methylcoumarin (Sigma-Aldrich, 99%), selenium dioxide (Sigma-Aldrich, 99.8%), celite (Sigma-Aldrich), nitromethane (Alfa Aesar, 98%), N,N,N′N′-tetramethylethylenediamine (Alfa Aesar, 99%), acetic acid (Sigma-Aldrich, 99%), zinc (purum, powder, Sigma-Aldrich), sodium carbonate (Sigma-Aldrich, 99%), sodium chloride (Sigma-Aldrich, 99%), sodium sulfate anhydrous (Sigma-Aldrich, 99%), 4-azidobenzoic acid (TCI America, 97%), triethylamine (TCI America, 99%), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, Chem-Impex International, 99%), triphosgene (Chem-Impex International, 99%), N,N-diisopropylethylamine (DIPEA, Sigma-Aldrich, 99%), 1,8-diazabicyclo[5.4.0]undec-7-ene (Alfa Aesar, 99%), Poloxamer 407 (from BASF), sodium hydride (Sigma-Aldrich, dry, 90%), propargyl bromide (Sigma-Aldrich, 80 wt % in toluene), Copper (II) sulfate pentahydrate (Sigma-Aldrich, 99%), sodium (+)-L-ascorbate (Sigma-Aldrich, 99%), sodium borohydride (Sigma-Aldrich, 98%), tetracaine (Sigma-Aldrich, 98%), tetracaine hydrochloride (Sigma-Aldrich, meets United States Pharmacopeia specifications), dichloromethane (Sigma-Aldrich, 99% or anhydrous), hexane (Sigma-Aldrich, mixture of isomers, 99%), ethyl acetate (Sigma-Aldrich, 99%), dioxane (Sigma-Aldrich, 99%), tetrahydrofuran (Sigma-Aldrich, 99%), diethyl ether (Sigma-Aldrich, 99%), methanol (Sigma-Aldrich, 99%), d-chloroform (Cambridge Isotope Laboratories Inc., 99%). NO2-CM-OH was synthesized according previously reported method with some modifications.

Characterizations

[0273] .sup.1H and .sup.13C NMR experiments were measured on a Varian 400 M or 500 NMR spectrometer. The spectra were referenced to the residual solvent peak in CDCl.sub.3 at δ 7.27 ppm for .sup.1H proton and δ 77.00 ppm for .sup.13C, respectively.

[0274] An Agilent 1260 series High Performance Liquid Chromatography (HPLC) with a UV-vis detector was used for analyzing the released drug in the releasing experiments. The mobile phase was 40/60 acetonitrile/water with flow rate of 0.5 mL/min. An Anilent 1200 Series Liquid chromatography-mass spectrometry (LC-MS) with a 6130 Quadrupole MS detector was used for the LC-MS experiments. Gel permeation chromatography (GPC) were measured in THF at 35° C. on Tosoh EcoSEC instrument. The flow rate was 0.35 mL/min.

[0275] UV-vis absorption spectra were measured on an Agilent 8453 UV-vis G1103A spectrometry.

[0276] Photo-triggering experiments were performed using a BLS-13000-1 LED driver and an LCS-0405-50-XX lamp from MIGHTEX.

[0277] Rheology experiments were tested on a TA DHR-2 rheometer with a frequency of 1 Hz, shear strain of 1% and a temperature ramp between 10° C. and 45° C.

[0278] Sample preparation. Tetracaine hydrochloride, P407 or P407-CM-T were direct dissolved in water. CM-T was dissolved in a small amount of ethanol, and equal molar of HCl (2 M in ethanol) was added. The solvent was completely removed by a rotatory evaporator and oil pump, and the resulted CM-T hydrochloride salt was re-dissolved in water.

[0279] Photocleavage of P407-CM-T in vitro. To demonstrate the capability of P407-CM-T to release tetracaine in the native form, 100 uL P407-CM-T solution (10 mg/mL) was placed in a 2 mL centrifuge tube and irradiated with 400 nm LED light with designed intensity and time. The solution was then diluted into 1 mL for HPLC or LC-MS measurements to verify the release of tetracaine and determine the concentrations. Dark stability of P407-CM-T was evaluated by placing the solution of P407-CM-T in a 37° C. oven for designed days, followed by HPLC measurements.

[0280] Cytotoxicity analysis. For the “direct contact” experiments, the cells were incubated in 48-well plates with concentration of formulations of 1, 0.33, 0.11 mg/mL in the media for all samples. For the “indirect contact” experiments, the cells were incubated in 24-well plates with a transwell in each well, in which 50 μL of tetracaine (0.5% wt %) or P407 (20% wt %) or P407-CM-T (20% wt %) was applied. After 24 h, the cell viabilities were evaluated with MTS assay as percentages of the control.

[0281] Animal studies. Animal studies were performed according to standard protocols approved by the Boston Children's Hospital Animal Care and Use Committee. Adult Sprague-Dawley rats (300-400 g, from Charles River Laboratories) were housed in groups under a 12 h/12 h light/dark cycle. Under brief isoflurane-oxygen anesthesia, 100 μL of solution were injected into the plantar aspect of the rat hind paw. Neurobehavioral testing was performed at predetermined intervals according to previously reported method by stimulating the rat footpad with Touch Test sensory evaluators (filament with target force of 180 g) and noting the vocal or motor response (foot withdrawal) of the rat according to previous reports,.sup.34,35 modified from previous reports..sup.36-39 An absence of vocalization or withdrawal after five trials was defined as complete nerve block or 100% maximum possible effect (MPE). In photo triggered anesthesia experiments, the hind paw of the rat with injected formulations was irradiated by the LED at designed intensity for 2-5 min under brief isoflurane-oxygen anesthesia.

[0282] Statistics. Data were described with means and standard deviations calculated from Microsoft excel.

[0283] Histology. The rats were euthanized with carbon dioxide 4 days or 14 days after injection. The rat foot pads were dissected, fixed by formalin, embedded in paraffin and underwent standard haematoxylin and eosin (H&E) stain.

REFERENCES

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EQUIVALENTS AND SCOPE

[0323] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0324] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects described herein, is/are referred to as comprising particular elements and/or features, certain embodiments described herein or aspects described herein consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments described herein, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0325] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment described herein can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0326] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.