Note: Descriptions are shown in the official language in which they were submitted.
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FAST-ACTING TOPICAL ANESTHETIC FORMULATIONS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority of U.S. Provisional
Patent
Application No. 63/019,042, filed May 1, 2020, and U.S. Provisional Patent
Application No.
63/139,224, filed January 19, 2021, each of which is hereby expressly
incorporated by reference
in its entirety.
FIELD
[0002] The present disclosure relates to formulations and devices suitable for
providing
rapid local anesthesia. More specifically, the present disclosure relates to
formulations including
a local anesthetic such as lidocaine and other compounds, molecules, or
excipients that improve
desirable characteristics such as solubility, bioavailability, efficacy,
tolerability, stability, or
improved dosages. The formulations may be made into a spray, a cream, a
lotion, an emulsion, a
microemulsion, a gel, a lacquer, an ointment, a solution, a patch, film or
mask, or other topical
application. Further disclosed are methods for using such formulations for
providing rapid local
anesthesia.
BACKGROUND
[0003] A local anesthetic ("LA") is a medication that moderates or eliminates
the
sensation of pain in the tissues that are local to the site of medication
application. Clinical local
anesthetics belong to one of two classes: aminoesters and aminoamides. Local
anesthetic drugs act
mainly by inhibiting sodium influx through sodium-specific ion channels in the
neuronal cell
membrane, in particular voltage-gated sodium channels. When the influx of
sodium is interrupted,
an action potential cannot develop and signal conduction is inhibited. The
receptor site is thought
to be located at the cytoplasmic or cell-interior portion of the sodium
channel. Local anesthetic
drugs bind more readily to sodium channels in an activated state. Onset of
neuronal blockade is
then faster in rapidly firing neurons, termed a state-dependent blockade.
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SUMMARY
[0004] The present disclosure relates to formulations of a local anesthetic
that provide
prompt local anesthesia following topical administration and methods of using
such formulations.
[0005] Several embodiments disclosed herein provide a topical formulation that
comprises an aminoamide or an aminoester local anesthetic with an anesthesia
onset of less than
one hour.
[0006] Several embodiments disclosed herein provide a topical formulation that
comprises an aminoamide or an aminoester local anesthetic with an anesthesia
onset of less than
thirty minutes.
[0007] Several embodiments disclosed herein provide a topical formulation that
comprises lidocaine.
[0008] Several embodiments disclosed herein provide a topical formulation that
further
comprises a C2-C4 monohydric alcohol and a monohydric C14-C20 alcohol.
[0009] Several embodiments disclosed herein provide a topical formulation that
further
comprises an isopropyl ester of a C14-C18 fatty acid.
[0010] Several embodiments disclosed herein provide a topical formulation that
further
comprises limonene.
[0011] Several embodiments disclosed herein provide a topical formulation that
further
comprises a polyethylene glycol dodecyl ether.
[0012] Several embodiments disclosed herein provide a topical formulation that
comprises lidocaine, a C2-C4 monohydric alcohol, limonene, an isopropyl ester
of a C14-C18 fatty
acid, and a monohydric C14-C20 alcohol.
[0013] Several embodiments disclosed herein provide a topical formulation that
comprises lidocaine, ethanol, limonene, isopropyl myristate, isopropyl
palmitate, and isostearyl
alcohol.
[0014] Several embodiments disclosed herein provide a topical formulation that
further
comprises a polyethylene glycol dodecyl ether.
[0015] Several embodiments disclosed herein provide a topical formulation
further
comprising a thickening agent.
[0016] Several embodiments disclosed herein provide a topical formulation
further
comprising an emollient, a preservative, or mixtures thereof.
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[0017] Several embodiments disclosed herein provide a topical formulation that
comprises lidocaine, a C2-C4 monohydric alcohol, limonene, an isopropyl ester
of a C14-C18 fatty
acid, a monohydric C14-C20 alcohol, and a pressure-sensitive adhesive.
[0018] Several embodiments disclosed herein provide a use of the topical
formulation of
the application for administration to a subject in need thereof.
[0019] Several embodiments disclosed herein provide a topical formulation
comprising
(i) at least one active agent, (ii) a C2-C4 monohydric alcohol, (iii)
limonene, (iv) an isopropyl ester
of a C14-C18 fatty acid, and (v) a monohydric C14-C20 alcohol.
[0020] Several embodiments disclosed herein provide a topical formulation of
local
anesthetic comprising one or more of (i) at least one active agent, (ii) a C2-
C4 monohydric alcohol,
(iii) limonene, (iv) an isopropyl ester of a C14-C18 fatty acid, and (v) a
monohydric C14-C20
alcohol that is suitable for immediate sale in the United States as an over
the counter drug product
subject to the provisions of an FDA monograph.
[0021] Certain features are briefly described in the following non-limiting
numbered
embodiments:
[0022] 1. A topical formulation comprising:
lidocaine present in an amount of 1% to 10% or about 1% to about 10% vv/w;
limonene present in an amount of 5% to 20% or about 5% to about 20% w/w; and
at least one C2-C4 monohydric alcohol present in an amount of 40% to 60% or
about 40%
to about 60% w/w.
[0023] 2. The topical formulation of alternative 1, wherein the at least
one C2-C4
monohydric alcohol comprises ethanol.
[0024] 3. The topical formulation of alternative 1 or 2, wherein the at
least one C2-
C4 monohydric alcohol is ethanol.
[0025] 4. The topical formulation of any one of alternatives 1-3, wherein
the lidocaine
is present in an amount of 4% or about 4% w/w.
[0026] 5. .. The topical formulation of any one of alternatives 1-4, wherein
the limonene
is present in an amount of 10% or about 10% w/w.
[0027] 6. The topical formulation of any one of alternatives 1-5, wherein
the at least
one C2-C4 monohydric alcohol is present in an amount of 51% or about 51% w/w.
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[0028] 7. The topical formulation of any one of alternatives 1-6, further
comprising
at least one isopropyl ester of a C14-C18 fatty acid.
[0029] 8. The topical formulation of alternative 7, wherein the at least
one isopropyl
ester of a C14-C18 fatty acid is present in an amount of 10% to 30% or about
10% to about 30%
w/w.
[0030] 9. The topical formulation of alternative 7 or 8, wherein the at
least one
isopropyl ester of a C14-C18 fatty acid comprises isopropyl palmitate or
isopropyl myristate, or
both.
[0031] 10. The topical formulation of alternative 9, wherein the isopropyl
palmitate
and the isopropyl myristate are each present in an amount of 5% to 15% or
about 5% to about 15%
w/w.
[0032] 11. The topical formulation of alternative 9 or 10, wherein the
isopropyl
palmitate is present in an amount of 7% or about 7% w/w.
[0033] 12. The topical formulation of any one of alternatives 9-11, wherein
the
isopropyl myristate is present in an amount of 11% or about 11% w/w.
[0034] 13. The topical formulation of any one of alternatives 9-12, wherein
the
lidocaine is present in an amount of 4% or about 4% w/w, the limonene is
present in an amount of
10% or about 10% w/w, the at least one C2-C4 monohydric alcohol is present in
an amount of
51% or about 51% w/w, the isopropyl palmitate is present in an amount of 7% or
about 7% w/w,
and the isopropyl myristate is present in an amount of 11% or about 11% w/w.
[0035] 14. The topical formulation of any one of alternatives 1-13, further
comprising
at least one monohydric C14-C20 alcohol.
[0036] 15. The topical formulation of alternative 14, wherein the at least one
monohydric C14-C20 alcohol is present in an amount of 5% to 15% or about 5% to
about 15%
w/w.
[0037] 16. The topical formulation of alternative 14 or 15, wherein the at
least one
monohydric C14-C20 alcohol comprises isostearyl alcohol.
[0038] 17. The topical formulation of any one of alternatives 14-16, wherein
the at
least one monohydric C14-C20 alcohol is isostearyl alcohol.
[0039] 18. The topical formulation of alternative 16 or 17, wherein the
isostearyl
alcohol is present in an amount of 10% or about 10% w/w.
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[0040] 19. The topical formulation of any one of alternatives 14-18, wherein
the
lidocaine is present in an amount of 4% or about 4% w/w. the limonene is
present in an amount of
10% or about 10% w/w, the at least one C2-C4 monohydric alcohol is present in
an amount of
51% or about 51% w/w, the isopropyl palmitate is present in an amount of 7% or
about 7% w/w,
the isopropyl myristate is present in an amount of 11% or about 11% w/w, and
the at least one
monohydric C14-C20 alcohol is present in an amount of 10% or about 10% w/w.
[0041] 20. The topical formulation of any one of alternatives 1-19, further
comprising
at least one polyalkylene glycol alkyl ether.
[0042] 21. The topical formulation of alternative 20, wherein the at least one
polyalkylene glycol alkyl ether is present in an amount of 0% to 10% or about
0% to about 10%.
[0043] 22. The topical formulation of alternative 20 or 21, wherein the at
least one
polyalkylene glycol alkyl ether comprises polyethylene glycol dodecyl ether.
[0044] 23. The topical formulation of any one of alternatives 20-22, wherein
the at
least one polyalkylene glycol alkyl ether is polyethylene glycol dodecyl
ether.
[0045] 24. The topical formulation of alternative 22 or 23, wherein the
polyethylene
glycol dodecyl ether is present in an amount of 5% or about 5% w/w.
[0046] 25. The topical formulation of any one of alternatives 20-24, wherein
the
lidocaine is present in an amount of 4% or about 4% w/w, the limonene is
present in an amount of
10% or about 10% w/w, the at least one C2-C4 monohydric alcohol is present in
an amount of
51% or about 51% w/w, the isopropyl palmitate is present in an amount of 7% or
about 7% w/w,
the isopropyl myristate is present in an amount of 11% or about 11% w/w, the
at least one
monohydric C14-C20 alcohol is present in an amount of 10% or about 10% w/w,
and the at least
one polyalkylene glycol alkyl ether is present in an amount of 5% or about 5%
w/w.
[0047] 26. The topical formulation of any one of alternatives 1-25, further
comprising
a cellulosic thickening agent.
[0048] 27. The topical formulation of alternative 26, wherein the cellulosic
thickening
agent is present in an amount of 0% to 5% or about 0% to about 5%.
[0049] 28. The topical formulation of alternative 25 or 26, wherein the
cellulosic
thickening agent comprises hydroxypropyl cellulose.
[0050] 29. The topical formulation of alternative 28, wherein the
hydroxypropyl
cellulose is present in an amount of 2% or about 2%.
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[0051] 30. The topical formulation of any one of alternatives 26-29, wherein
the
lidocaine is present in an amount of 4% or about 4% w/w. the limonene is
present in an amount of
10% or about 10% w/w, the at least one C2-C4 monohydric alcohol is present in
an amount of
51% or about 51% w/w, the isopropyl palmitate is present in an amount of 7% or
about 7% w/w,
the isopropyl myristate is present in an amount of 11% or about 11% w/w, the
at least one
monohydric C14-C20 alcohol is present in an amount of 10% or about 10% w/w,
the at least one
polyalkylene glycol alkyl ether is present in an amount of 5% or about 5% w/w,
and the cellulosic
thickening agent is present in an amount of 2% or about 2%.
[0052] 31. A topical formulation comprising:
lidocaine present in an amount of 1% to 10% or about 1% to about 10% w/w;
a pressure sensitive adhesive present in an amount of 70% to 90% or about 70%
to about
90% w/w;
a molecular penetration enhancer present in an amount of 0% to 5% or about 0%
to about
5% w/w; and
at least one polyalkylene glycol alkyl ether present in an amount of 0% to 5%
or about 0%
to about 5% w/w.
[0053] 32. The topical formulation of alternative 31, wherein the lidocaine is
present
in an amount of 4% or about 4% w/w.
[0054] 33. The topical formulation of alternative 31 or 32, wherein the
pressure
sensitive adhesive is present in an amount of 83% or about 83% w/w.
[0055] 34. The topical formulation of any one of alternatives 31-33, wherein
the
pressure sensitive adhesive comprises DURO-TAK 87-4098.
[0056] 35. The topical formulation of any one of alternatives 31-34, wherein
the
molecular penetration enhancer is present in an amount of 3% or about 3% w/w.
[0057] 36. The topical formulation of any one of alternatives 31-35, wherein
the
molecular penetration enhancer comprises levulinic acid.
[0058] 37. The topical formulation of any one of alternatives 31-36, wherein
the at
least one polyalkylene glycol alkyl ether is present in an amount of 2% or
about 2%.
[0059] 38. The topical formulation of any one of alternatives 31-37, wherein
the at
least one polyalkylene glycol alkyl ether comprises polyethylene glycol
dodecyl ether.
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[0060] 39. The topical formulation of any one of alternatives 31-38, wherein
the at
least one polyalkylene glycol alkyl ether is polyethylene glycol dodecyl
ether.
[0061] 40. The topical formulation of any one of alternatives 31-39, further
comprising
at least one isopropyl ester of a C14-C18 fatty acid.
[0062] 41. The topical formulation of alternative 40, wherein the at least one
isopropyl
ester of a C14-C18 fatty acid is present in an amount of 5% to 10% or about 5%
to about 10%
w/w.
[0063] 42. The topical formulation of alternative 40 or 41, wherein the at
least one
isopropyl ester of a C14-C18 fatty acid comprises isopropyl palmitate or
isopropyl myristate, or
both.
[0064] 43. The topical formulation of alternative 42, wherein the isopropyl
palmitate
and the isopropyl myristate are each present in an amount of 2.5% to 5% or
about 2.5% to about
5% w/w.
[0065] 44. The topical formulation of alternative 42 or 43, wherein the
isopropyl
palmitatc or the isopropyl myristatc, or both, arc present in an amount of 4%
or about 4% w/w.
[0066] 45. The topical formulation of any one of alternatives 31-44, wherein
the
lidocaine is present in an amount of 4% or about 4% w/w, the pressure
sensitive adhesive is present
in an amount of 83% or about 83% w/w, the molecular penetration enhancer is
present in an
amount of 3% or about 3% w/w, the polyalkylene glycol alkyl ether is present
in an amount of 2%
or about 2% w/w, the isopropyl palmitate is present in an amount of 4% or
about 4% w/w, and the
isopropyl myristate is present in an amount of 4% or about 4% w/w.
[0067] 46. A method of preventing local pain in a subject, comprising the
topical
administration to said subject of a therapeutically effective amount of the
topical formulation of
any one of alternatives 1-45.
[0068] 47. A device suitable for providing rapid local anesthesia comprising
an
annulus of pressure sensitive adhesive, within the inner circumference of
which is provided the
topical formulation of any one of alternatives 1-45.
[0069] 48. The device of alternative 47, further comprising a backing film on
which
the topical formulation is applied, wherein the backing film covers the inner
circumference of the
annulus of pressure sensitive adhesive.
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[0070] 49. The device of alternative 48, wherein the backing film is intended
to be
removed after application of the device such that the inner circumference of
the annulus of pressure
sensitive adhesive is exposed to allow access with a needle.
[0071] 50. The device of any one of alternatives 47-49, wherein the topical
formulation
is provided as a single dose packet.
[0072] 51. A kit for use in anesthetizing a target area of skin of a subject,
the kit
comprising:
(i) a predetermined dose of a topical anesthetic; and
(ii) an annulus of pressure sensitive adhesive comprising an outer
perimeter that
adheres to the skin of the subject, and an open center region in which the
skin is exposed.
[0073] 52. The kit of alternative 51, further comprising (iii) an occlusive,
waterproof
dressing or a backing film to cover the patch and target area.
[0074] 53. The kit of alternative 51 or 52, wherein the topical anesthetic
comprises a
topical formulation of any one of alternatives 1-45.
[0075] 54. The kit of any one of alternatives 51-53, wherein the topical
anesthetic
comprises lidocaine and wherein the lidocaine is optionally in gel format.
[0076] 55. The kit of any one of alternatives 51-54, wherein the annulus of
pressure
sensitive adhesive comprises a silicone ring.
[0077] 56. The kit of any one of alternatives 51-54, wherein the predetermined
dose of
the topical anesthetic is provided as a single packet (e.g., single use).
[0078] 57. A topical formulation comprising
lidocaine,
wherein the lidocaine is present in an amount of 1% to 10% or about 1% to
about 10%
w/w;
limonene,
wherein the limonene is present in an amount of 5% to 20% or about 5% to about
20%
w/w;
DMS 0,
wherein the DMSO is present in an amount of 40% to 70% or about 40% to about
70%
w/w; and
at least one C2-C4 monohydric alcohol,
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wherein the at least one C2-C4 monohydric alcohol comprises ethanol, and
wherein the
ethanol is present in an amount of 10% to 50% or about 10% to 50% w/w.
[0079] 58. The topical formulation of alternative 57, wherein
(i) lidocaine is in an amount of 4% or about 4%;
(ii) limonene is in an amount of 10% or about 10%;
(iii) DMSO is in an amount of 66% or about 66%; and
(iv) ethanol is in an amount of 20% or about 20%.
[0080] 59. The topical formulation of alternative 57, wherein
(i) lidocaine is in an amount of 4% or about 4%;
(ii) limonene is in an amount of 10% or about 10%;
(iii) DMSO is in an amount of 45% or about 45%; and
(iv) ethanol is in an amount of 41% or about 41%.
[0081] 60. The topical formulation of alternative 57, further comprising at
least one
isopropyl ester of a C14-C18 fatty acid.
[0082] 61. The topical formulation of alternative 60, wherein the at least one
isopropyl
ester of a C14-C18 fatty acid comprises isopropyl myristate, or isopropyl
palmitate, or both.
[0083] 62. The topical formulation of alternative 61, wherein isopropyl
myristate and
isopropyl palmitate are each in an amount of 0% to 15% or about 0% to about
15%.
[0084] 63. The topical formulation of alternative 62, wherein
(i) lidocaine is in an amount of 4% or about 4%;
(ii) limonene is in an amount of 10% or about 10%;
(iii) DMSO is in an amount of 45% or about 45%;
(iv) ethanol is in an amount of 31% or about 31%;
(v) isopropyl myristate is in an amount of 10% or about 10%; and
(vi) isopropyl palmitate is in an amount of 0% or about 0%.
[0085] 64. The topical formulation of alternative 62, wherein
(i) lidocaine is in an amount of 4% or about 4%;
(ii) limonene is in an amount of 10% or about 10%;
(iii) DMSO is in an amount of 45% or about 45%;
(iv) ethanol is in an amount of 31% or about 31%;
(v) isopropyl myristate is in an amount of 0% or about 0%; and
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(vi) isopropyl palmitate is in an amount of 10% or about 10%.
[0086] 65. The topical formulation of alternative 60, further comprising at
least one
monohydric C14-C20 alcohol.
[0087] 66. The topical formulation of alternative 65, wherein the at least one
monohydric C14-C20 alcohol comprises isostearyl alcohol.
[0088] 67. The topical formulation of any one of alternatives 57-66, further
comprising
polyethylene glycol dodecyl ether.
[0089] 68. A method of preventing local pain in a subject, said method
comprising the
topical administration to said subject of a therapeutically effective amount
of the formulation of
any one of Alternatives 57-67.
[0090] 69. A device suitable for providing rapid local anesthesia comprising
an
annulus of pressure-sensitive adhesive, within the inner circumference of
which is provided the
topical formulation of any one of Alternatives 57-67.
[0091] 70. A topical formulation comprising lidocaine, at least one C2-C4
monohydric
alcohol, limonene, at least one isopropyl ester of a C14-C18 fatty acid, and
at least one monohydric
C14-C20 alcohol.
[0092] 71. The topical formulation of Alternative 70, wherein the at least one
C2-C4
monohydric alcohol comprises ethanol.
[0093] 72. The topical formulation of Alternative 70, wherein the at least one
isopropyl
ester of the C14-C18 fatty acid comprises isopropyl myristate.
[0094] 73. The topical formulation of Alternative 70, wherein the at least one
isopropyl
ester of the C14-C18 fatty acid comprises isopropyl palmitate.
[0095] 74. The topical formulation of Alternative 70, wherein the at least one
isopropyl
ester of the C14-C18 fatty acid comprises both isopropyl myristate and
isopropyl palmitate.
[0096] 75. The topical formulation of Alternative 70, wherein the at least one
monohydric C14-C20 alcohol comprises isostcaryl alcohol.
[0097] 76. The topical formulation of any one of Alternatives 70-75, further
comprising polyethylene glycol dodecyl ether.
[0098] 77. A method of preventing local pain in a subject, said method
comprising the
topical administration to said subject of a therapeutically effective amount
of the formulation of
any one of Alternatives 70-76.
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[0099] 78. A device suitable for providing rapid local anesthesia comprising
an
annulus of pressure-sensitive adhesive, within the inner circumference of
which is provided the
topical formulation of any one of Alternatives 70-76.
[0100] 79. A formulation suitable for topical administration, comprising:
(i) at least one active agent;
(ii) at least one C2-C4 monohydric alcohol;
(iii) limonene;
(iv) the isopropyl esters of at least two C14-C18 fatty acids; and
(v) at least one monohydric C14-C20 alcohol.
[0101] Several embodiments disclosed herein relate to a kit for use in
anesthetizing a
target area of tissue, the kit comprising:
a predetermined dose of a topical anesthetic;
a self-adhesive patch comprising an outer perimeter which adheres to the skin
and an open
center region in which skin is exposed;
an occlusive, waterproof dressing to cover the patch and target area.
[0102] In several embodiments, the topical anesthetic comprises a formulation
(e.g., a
fast acting anesthetic formulation) according to embodiments disclosed herein.
In several
embodiments, the topical anesthetic comprises lidocaine, wherein the lidocaine
is optionally in gel
format. In several embodiments, the self-adhesive patch comprises a silicone
ring.
BRIEF DESCRIPTION OF THE DRAWINGS
[0103] In addition to the features described above, additional features and
variations will
be readily apparent from the following descriptions of the drawings and non-
limiting
embodiments. It is to be understood that these drawings depict non-limiting
embodiments and are
not intended to be limiting in scope.
[0104] The embodiments of the application will now be described in greater
detail with
reference to the attached drawings in which:
[0105] FIG. 1 illustrates cumulative amounts of lidocaine that are found to be
retained in
porcine skin 60 minutes following topical administration of the Example 1
formulations. All
retention amounts are provided as lag per cm2 of administration area.
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[0106] FIG. 2 illustrates cumulative amounts of lidocaine that are found to be
retained in
porcine skin 60 minutes following topical administration of the Example 2
formulations. All
retention amounts are provided as lag per cm2 of administration area.
[0107] FIG. 3 illustrates cumulative amounts of lidocaine that are found to he
retained in
porcine skin 60 minutes following topical administration of the Example 3
formulations. All
retention amounts are provided as i g per cm2 of administration area.
[0108] FIG. 4 illustrates cumulative amounts of lidocaine that are found to be
retained in
porcine skin 60 minutes following topical administration of the Example 4
formulations. All
retention amounts are provided as lag per cm2 of administration area.
[0109] FIG. 5 illustrates cumulative amounts of lidocaine that are found to be
retained in
porcine skin 60 minutes following topical administration of the Example 5
formulations. All
retention amounts are provided as ug per cm2 of administration area.
[0110] FIG. 6 illustrates cumulative amounts of lidocaine that are found to be
retained in
porcine skin 30 minutes following topical administration of the Example 6
formulations. All
retention amounts arc provided as ug per cm2 of administration area.
110111_1 FIG. 7 illustrates cumulative amounts of lidocaine that are found to
be in porcine
skin 30 minutes following topical administration of the Example 7
formulations. All retention
amounts are provided as pg per cm2 of administration area.
[0112] FIG. 8 illustrates cumulative amounts of lidocaine that are found to be
retained in
porcine skin 30 minutes following topical administration of the Example 8
formulations. All
retention amounts are provided as ug per cm2 of administration area.
[0113] FIG. 9 illustrates cumulative amounts of lidocaine that are found to be
retained in
within the epidermal and dermal compartments of human cadaver at 30 mins
following topical
administration of the Example 9 formulations. All retention amounts are
provided as ug per cm2
of administration area.
110114_1 FIG. 10 illustrates cumulative amounts of lidocaine that are found to
be retained
within the epidermal and dermal compartments of human cadaver at 30 minutes
following topical
administration of the Example 10 formulations. All retention amounts are
provided as lig per cm2
of administration area.
[0115] FIG. 11 illustrates cumulative amounts of lidocaine that are found to
be retained
in human cadaver skin (the combined epidellual and dermal tissue) at 30 mins
following topical
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administration of the Example 11 formulations. All retention amounts are
provided as ug per cm2
of administration area.
[0116] FIG. 12 illustrates cumulative amounts of lidocaine that are found to
be retained
within human cadaver skin (the combined epidermal and dermal tissue) at 30
minutes following
topical administration of the Example 12 formulations. All retention amounts
are provided as ps
per cm2 of administration area.
[0117] FIG. 13 show an example of a kit comprising a topical patch with an
annulus of
pressure-sensitive adhesive and a topical formulation in use according to
several embodiments
disclosed herein.
[0118] FIG. 14 shows a schematic of a kit comprising a topical patch with an
annulus of
pressure-sensitive adhesive and a topical formulation in use and various
features according to
embodiments disclosed herein.
[0119] FIG. 15A-D shows the process of using an topical patch according to
embodiments disclosed herein with an annulus of pressure-sensitive adhesive
and a topical
formulation. FIG. 15A shows the topical patch comprising the annulus of
pressure-sensitive
adhesive and a backing film covering the interior open region of the annulus.
FIG. 15B shows the
application of the topical formulation onto the surface of the backing film.
FIG. 15C shows
application of the topical patch to a target dermal region of the subject,
where the topical
formulation is allowed to contact the skin at the target dermal region. The
backing film may be
used to hold the topical formulation in place and cause occlusion, enhancing
the kinetics,
penetration, and extent of delivery of the active agent into the target dermal
region. The design on
the backing film may be merely decorative and have no functional influence on
the device once
applied to a subject. FIG. 15D shows the removal of the backing film, exposing
the affected skin
following local anesthetization. FIG. 15E shows the injection with a syringe
as an exemplary
subsequent application, where local anesthetization with the topical
formulation ameliorates or
eliminates needle pain during injection.
DETAILED DESCRIPTION
[0120] Disclosed herein are embodiments of formulations that are exceptionally
effective at delivering local anesthetics such as lidocaine or other
aminoamide or aminoester
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anesthetics, rapidly into the skin of a subject, such that local anesthesia is
realized in less than, for
example, one hour.
[0121] Aminoester local anesthetics include but are not limited to: procaine,
benzocaine,
chloroprocaine, cocaine, cyclomethycaine, dimethocaine (or I arocaine),
piperocaine,
propoxycaine, procaine (or novocaine), proparacaine and tetracaine (or
amethocaine).
Aminoamide local anesthetics include but are not limited to: articaine,
bupivacaine, cinchocaine
(or dibucaine), etidocaine, levobupivacaine, lidocaine (or lignocaine),
mepivacaine, prilocaine,
ropivacaine and trimecaine.
[0122] Aminoester and aminoamide anesthetics can be administered topically to
noninvasively block pain in humans and other animals. There is an ongoing need
for a topical
formulation that can deliver an amount of the local anesthetic to the
epidermal and dermal tissues
sufficient to provide anesthesia at an onset time of less than one hour, while
otherwise being
suitable for clinical use. Embodiments provided for herein satisfies these and
other needs.
[0123] Owing to the huge benefit of using local anesthetics to treat pain in
patients,
numerous examples of topical and transdermal formulations of aminoester and
aminoamide local
anesthetics, alone and in various combinations, have been developed, for
example: U.S. patents
5411738, 5827529, 6673363, 7883488, 9186334 and publications 2011/0288123,
2013/0184351,
2014/0141056, 2018/0326068, each of which is hereby expressly incorporated by
reference in its
entirety.
[0124] Several factors should be considered in assessing the utility of a
local anesthetic
product such as: (i) the potency of the local anesthetic and (ii) the mode of
administration. One
mode of administration for various dosage forms is topical, wherein the drug
product is applied to
the skin exterior and the active ingredient(s) diffuse from the formulation
into the skin.
[0125] The skin, however, presents a formidable barrier to the delivery of
drugs.
Structurally, the skin consists of three principle parts: (i) a relatively
thin outermost layer, the
epidermis, (ii) a thicker inner region, the dermis, and (iii) the subcutaneous
tissue, the lowermost
layer also called the hypodermis or subcutis. The outermost layer of the
epidermis, the stratum
corneum, consists of comeocytes, flattened dead cells which are filled with
keratin. The
comeocytes are interconnected by corneodesmosomes and surrounded by lipids
which form
lamellar phases. The highly impermeable character of skin derives primarily
from the stratum
corneum. The viable epidermis underlying the stratum corneum is akin to other
living tissue. The
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dermis provides the skin's structural strength as well as the nerve and
vascular networks that
support the epidermis. In a topical mode of administration, the intended
target tissue is the viable
epidermis or, more typically, the dermis. This is in contrast to transdermal
administration, in which
the active ingredient permeates through the skin to he provided systemically
via the vasculaturc or
lymphatic system.
[0126] Delivering an active agent into (or through) the skin in sufficient
concentration to
provide therapeutic benefit usually requires some means for reducing the
stratum corneum's
hindrance to ingress of the active agent. A number of physical methods for
lowering the stratum
corneum's barrier properties have been developed, including electrically-
assisted techniques such
as iontophoresis or electroporation, ultrasound, heat, puncturing the stratum
corneum with
microneedle arrays, or ablation. Even for a single, non-repeated application,
though, such physical
methods have limitations, leading to very restricted use by patients in
practice.
[0127] Even when physical methods are not deployed, it is well known that
various
factors can affect the permeation and absorption of an active agent from a
skin-applied
pharmaceutical preparation, including the nature of the active ingredient, the
nature of the vehicle,
the pH, and the relative solubility of the active molecule in the vehicle
versus the skin. More
specifically, active agent attributes such as molecular weight, lipophilicity
or hydrophilicity,
solubility, size and charge, melting point, as well as vehicle attributes such
as active agent
solubility and dissolution rate, ability to modulate the permeability of the
stratum corneum, and
physical characteristics such as occlusivity, spreadability and adhesion, can
each have significant
effects on permeability. Unfortunately, although skin permeability can be
estimated for certain
molecules under model conditions, it is generally not possible to predict such
permeability from a
practicable formulation.
[0128] Certain molecular agents, often termed penetration enhancers, chemical
penetration enhancers, sorption promoters, sorption accelerants, or molecular
penetration
enhancers ("MPE 1m"S) can modulate skin permeability for a given molecule by,
for example,
disrupting the lipid bilayers of the stratum corneum. Over 600 substances have
been identified as
MPEs but few have been successfully developed into practical formulations.
Many potent
enhancers are irritating to the cells of the epidermis which limits both the
choice and concentration
of MPEs suitable for topical formulations. The MPEs of most practical utility
are those that are
known to cause at most limited irritation and sensitization of the skin, such
as those provided in
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the 'Inactive Ingredient Database' ("IID") published by the FDA. Notably, it
is known in the art:
(i) that the best skin permeation enhancement is typically found with
combinations of MPEs, rather
than by use of individual MPEs alone, (ii) that, in general, the penetration-
enhancing roles of
neither individual MPEs nor MPE combinations (typically termed 'multiplexed
MPE's or
"MMPETm"s) can be predicted, and (iii) that an MPE combination, or even an
individual MPE,
that performs well for one particular active compound will often perform
substantially less well
for a different active compound, especially one of a different molecular
class.
[0129] Beyond the potency and extent of delivery of the active ingredient(s),
other
factors that need to be satisfied for a skin-applied drug formulation to be
practicable include (i)
chemical and physical stability, especially in the container-closure system in
which the drug
product will be distributed, stored and provided to subjects, (ii) what is
termed the 'esthetic
profile', the set of observations made by a subject when dispensing the
product from the container-
closure system and applying the product to the skin, including color,
appearance, smell, sensation
upon skin contact, ease and feel when spreading, rubbing and how these various
characteristics
develop with time (in the case of a patch or plaster product format, the
equivalent attributes are
more commonly termed 'wear' characteristics, including the ease of removal of
the product from
the packaging, application to the area of skin indicated by the package
insert, the comfort during
the period of application, whether there is discomfort or itch under the
patch, the presence of
'creep' namely lateral reach of the adhesive leading to a dark tacky perimeter
around the patch,
and the ease and discomfort associated with removal at the end of the
administration period), and
(iii) the potential to irritate or sensitize the skin (and, if components in
the product formulation
absorb electromagnetic radiation in the visible or ultraviolet ("UV") regions,
the potential to
irritate or sensitize the skin under photoirradiation).
[0130] Regulatory compliance is another important factor. It is the duty of a
given
regulatory agency, such as the United States Food and Drug Administration
("FDA") to ensure
that only pharmaceutical products that are safe and effective are made
available to patients and
consumers. A product might follow several routes to satisfy such FDA
requirements. A product
that adheres to the conditions stipulated in an FDA over the counter ("OTC")
monograph that
provides acceptable ingredients, indication( s), doses, formulations, labeling
and testing is
generally regarded as safe and effective ("GRASE") for the uses set forth in
such monograph. A
GRASE product may be marketed and sold in the US without the need for further
regulatory filing.
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The OTC monograph for topical anesthetics lists benzocaine, cyclomethycaine
sulfate, tetracaine,
tetracaine hydrochloride, lidocaine, lidocaine hydrochloride, dibucaine and
dibucaine
hydrochloride as active ingredients that might be used prospectively in a
monograph-compliant
product. In the case of both lidocaine and lidocaine hydrochloride, monograph-
compliant
concentrations are in the range 0.4 to 4 % w/w.
[0131] The utility of a local anesthetic product is heavily dependent on
another key
parameter, namely the onset.
[0132] Amongst the many topical and transdermal formulations of local
anesthetics
taught in the prior art, few mention onset. It is, in fact, often accepted
that the onset following
topical administration of a lidocaine-comprising formulation is a
characteristic of the lidocaine
itself, and then largely independent of the details of the formulation from
which it is provided.
101331 When administered directly into a tissue provided with sensory nerves,
lidocaine
is known to have an onset of less than 2 min and a duration of 1 h to 2 h,
although the
pharmacokinetic ("PK") and pharmacodynamic ("PD") properties depend to some
degree on the
volume and concentration infused, the location of administration, and the
tissue pH. The half-life
of lidocaine elimination from the plasma following intravenous administration
is approximately
1.8 h, with lidocaine and its metabolites being excreted by the kidneys.
[0134] In case of a formulation of lidocaine applied to the skin exterior, the
availability
of the lidocaine to nerve endings in the epidermis and dermis is subject to a
lag time. The onset of
action will always be longer than the lag time, as the concentration of active
in the viable epidermis
or dermis (or which is available to deeper tissue or systemically) must build
from zero to a level
at which a noticeable effect is evident.
[0135] Kreilgaard measured unbound cutaneous concentrations of lidocaine and
prilocaine in rats by in vivo microdialysis following topical application of
microemulsions,
commercially available creams, and a hydrogel. Lidocaine lag times from each
of the formulations
(without recovery correction) arc reported to be: Microemulsion A 21( 1) min,
Microemulsion
24( 7) min, Microemulsion G 15( 7) min, Xylocaine 20( 6) mm, EMLA 38( 15) mm
were
observed, where the compositions of microemulsions expressed as
water:isostearylic isostearate:
Labrasol/ Plurol Isostearique: lidocaine: prilocaine hydrochloride were A
20:10:70:23:5; D
7:70:23:17:0; E 11:26:63:0:2.4; and G 65:3:32:9.1/7.5:14.
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[0136] Yamamoto et al. compared the permeation of five different drugs through
cryopreserved excised human skin. They reported lag times for lidocaine of
0.5h (from Tenles
tape 18 mg') and of 1.4h (from 'Ernla cream') (these values compare with lag
times reported for
Bisoprolol of 4.0h (from 'Bison tape 8 mg'), ; Nicotine of 0.7h (from
'NicotineII TTS20');
Rivastigmine of 1.6h (from `Rivastach patch 18 mg'), and Diclofenac 3.5h (from
`Voltaren tape
30 mg') and of 8.1h (from `Voltaren gel 1%').
[0137] In the following detailed description, reference is made to the
accompanying
drawings, which form a part hereof. In the drawings, similar symbols typically
identify similar
components, unless context dictates otherwise. The illustrative embodiments
described in the
detailed description, drawings, and claims are not meant to be limiting. Other
embodiments may
be utilized, and other changes may be made, without departing from the spirit
or scope of the
subject matter presented herein. It will be readily understood that the
aspects of the present
disclosure, as generally described herein, and illustrated in the Figures, can
be arranged,
substituted, combined, separated, and designed in a wide variety of different
configurations, all of
which are explicitly contemplated herein.
[0138] Unless defined otherwise, technical and scientific terms used herein
have the
same meaning as commonly understood by one of ordinary skill in the art to
which the present
disclosure belongs. For purposes of the present disclosure, the following
terms are defined below.
Definition of Terms
[0139] The terms "an", or "the as used herein not only
include aspects with one
member, but also include aspects with more than one member. For example, an
embodiment
including "a cellulosic thickening agent and a lower monohydric alcohol"
should be understood to
present certain aspects with at least a second cellulosic thickening agent, at
least a second lower
monohydric alcohol, or both. An embodiment including "an active agent" should
be understood to
present certain aspects with at least a second active agent, which may be of a
different class (e.g.,
lidocaine with a non-steroidal anti-inflammatory drug, or with an anti-
inflammatory steroid, or
with a local anesthetic, or with a sunscreen agent).
[0140] The term "about" as used herein to modify a numerical value indicates a
defined
range around that value. If "X" were the value, "about X" would generally
indicate a value from
0.95X to 1.05X. Any reference to "about X" specifically indicates at least the
values X, 0.95X,
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0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus,
"about X" is intended
to teach and provide written description support for a claim limitation of,
e.g., "0.98X". When the
quantity "X" only includes whole-integer values (e.g., "X carbons"), "about X"
indicates from
(X-1) to (X+1). In this case, "about X" as used herein specifically indicates
at least the values X,
X-1, and X+1. When "about" is applied to the beginning of a numerical range,
it applies to both
ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5%
to about 20%."
When "about" is applied to the first value of a set of values, it applies to
all values in that set. Thus,
"about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."
[0141] Throughout this specification, unless the context requires otherwise,
the words
"comprise,- "comprises,- and "comprising- will be understood to imply the
inclusion of a stated
step or element or group of steps or elements but not the exclusion of any
other step or element or
group of steps or elements.
[0142] By -consisting of' is meant including, and limited to, whatever follows
the phrase
"consisting of." Thus, the phrase "consisting of" indicates that the listed
elements are required or
mandatory, and that no other elements may be present. By "consisting
essentially of' is meant
including any elements listed after the phrase, and limited to other elements
that do not interfere
with or contribute to the activity or action specified in the disclosure for
the listed elements. Thus,
the phrase "consisting essentially of' indicates that the listed elements are
required or mandatory,
but that other elements are optional and may or may not be present depending
upon whether or not
they materially affect the activity or action of the listed elements.
[0143] As used herein the term "Molecular Accelerant" or "MolAccTm" means an
agent
that reduces onset and/or lag time when incorporated within a topical
fmmulation.
[0144] In compositions comprising an "additional" or "second" component, the
second
component, unless otherwise indicated, as used herein is chemically different
from the other
components or first component. A "third" component, unless otherwise
indicated, is different from
the other, first, and second components, and further enumerated or
"additional" components are
similarly different.
[0145] "Agent" as used herein indicates a compound or mixture of compounds
that,
when added to a composition, tend to produce a particular effect on the said
composition's
properties or performance. For example, a composition comprising a thickening
agent is likely to
be more viscous than an otherwise identical comparative composition that lacks
the thickening
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agent; a composition comprising an active agent is more likely to provide a
beneficial effect in the
subject to which the composition is administered that otherwise.
[0146] "Carbon atom number" or "C" is used in its conventional sense to mean
the
number of carbon atoms in an organic compound such as a fatty alcohol or fatty
acid. Thus, stcary I
alcohol (1-octadecanol), isostearyl alcohol (1-Heptadecanol, 16-methyl-), and
oleyl alcohol (1-
octadecenol) might each be referred to as C18 fatty alcohols; cetyl alcohol (1-
hexadecanol) and
palmitoleyl alcohol (cis-9-hexadecen- 1 -ol) might both be referred to as C16
fatty alcohols; lauric
acid, myristic acid, palmitic acid and stearic acid might be referred to as a
C12, a C14, a C16 and
C18 fatty acid , respectively. In the conventional designation of fatty acids
and fatty alcohols, the
number of double bonds in the carbon chain is also provided. Thus oleic acid
with a single carbon-
carbon double bond is designated by (C18:1), and arachidonic acid with four
carbon-carbon double
bonds is designated by (C20:4).
[0147] "C2-C4" as used herein refers to the group of organic compounds that
have 2, 3,
or 4 carbon atoms. "C2-C4 monohydric alcohol" as used herein refers to the
group of monohydric
alcohols that have 2, 3, or 4 carbon atoms, which includes but is not limited
to ethanol, 1-propanol,
2-propanol (isopropanol), 1-butanol (n-butanol), 2-butanol (sec-butanol), 2-
methylpropan-1-ol
(isobutanol), or 2-methylpropanol (tert-butanol), or any combination or
mixture thereof. "C14-
C18" as used herein refers to the group of organic compounds that have 14, 15,
16, 17, or 18 carbon
atoms. "C14-C18 fatty acid" as used herein refers to the group of fatty acids
that have 14, 15, 16,
17, or 18 carbon atoms, which includes but is not limited to myristic acid,
pentadecanoic
(pentadecylic) acid, palmitic acid, margaric acid, stearic acid, isostearic
acid, myristoleic acid,
myristovaccenic acid, myristolinolenic acid, 8-tetradecenoic acid,
pentadecanoic acid,
palmitolinolenic acid, palmitidonic acid, palmitovaccenic acid, palmitoleic
acid, sapienic acid, 4-
hexadecanoic acid, a-linolenic acid, stearidonic acid, a-eleostearic acid, 13-
eleostearic acid,
punicic acid, 7,10,13-ocadecatrienoic acid, 12-octadecenoic acid, linoleic
acid, linolelaidic acid,
y-linolenic acid, calendic acid, pinolenic acid, vacccnic acid, rumcnic acid,
oleic acid, claidic acid,
or petroselenic acid, or any combination or mixture thereof. "C14-C20" as used
herein refers to
the group of organic compounds that have 14, 15, 16, 17, 18, 19, or 20 carbon
atoms. "Monohydric
C14-C20 alcohol" as used herein refers to the group of monohydric alcohols
that have 14, 15, 16,
17, 18, 19, or 20 carbon atoms and includes but is not limited to myristyl
alcohol, pentadecyl
alcohol, palmityl alcohol (cetyl alcohol), margaryl alcohol, stearyl alcohol,
isostearyl alcohol,
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nonadecyl alcohol, arachidyl alcohol, myristoleyl alcohol, myristovaccenyl
alcohol,
myristolinolenyl alcohol, 8-tetradecenyl alcohol, pentadecanyl alcohol,
palmitolinolenyl alcohol,
palmitidonyl alcohol, palmitovaccenyl alcohol, palmitoleyl alcohol, sapienyl
alcohol, 4-
hexadecanyl alcohol, a-linolenyl alcohol, stearidonyl alcohol, a-eleostearyl
alcohol, P-eleostearyl
alcohol, punicyl alcohol, 7,10.13-ocadecatrienyl alcohol, 12-octadecenyl
alcohol, linoleyl alcohol,
linolelaidyl alcohol, y-linolenyl alcohol, calendyl alcohol, pinolenyl
alcohol, vaccenyl alcohol,
rumenyl alcohol, oleyl alcohol, elaidyl alcohol, petroselenyl alcohol, 1-
tetradecanol, cetostearyl
alcohol, dihomo-a-linolenyl alcohol, eicosatetraenyl alcohol, eicosapentaenyl
alcohol, 9,12,15-
eicosatrienyl alcohol, p-eicosatetraenyl alcohol, dihomo-linoleyl alcohol,
dihorno-y-linoley1
alcohol, arachidonyl alcohol, paullinyl alcohol, 7,10,13-eicosatrienyl
alcohol, gondoyl (11-
eicosenoyl) alcohol, 8-11-eicosadienyl alcohol, gadoleyl alcohol, 8-eicosenyl
alcohol, or any
combination or mixture thereof. In general, the term "C(A)-C(B)" as used
herein refers to the
group of organic compounds that have (A) carbon atoms, (B) carbon atoms, or
between (A) and
(B) carbon atoms, or any combination or mixture thereof.
[0148] -Cellulosic thickening agent" as used herein includes a
thickening agent that is
a natural or synthetic oligomeric or polymeric carbohydrate (e.g., cellulose
and pharmaceutically
acceptable vegetable gums) or a polymeric or oligomeric derivative of a
polymeric carbohydrate
that is produced by chemical modification (e.g., hydroxypropyl cellulose,
hydroxypropyl methyl
cellulose, hydroxyethyl cellulose). Representative cellulosic thickening
agents include cellulose,
hydroxypropyl cellulose ("HPC"), hydroxypropyl methyl cellulose ("HPMC"),
hydroxyethyl
cellulose ("HEC"), methyl cellulose, carboxymethyl cellulose, and the like.
[0149] The terms "chassis", "vehicle" and -base formulation" as used
interchangeably
herein are equivalent terms that include a plurality of solvents or other
excipients that comprise
the bulk of a formulation, into which one or more active agents or additional
agents might be
introduced.
[0150] As used herein the term "comparative formulation" as it relates to a
first
formulation containing an active ingredient refers to a second formulation
containing the same
active ingredient. Generally, for the second formulation to qualify as a
comparative formulation
the concentration of the active ingredients should be approximately the same
in the first and second
formulation.
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[0151] As used herein, the phrase "effective amount" or "effective dose" means
an
amount sufficient to achieve the desired result and accordingly will depend on
the ingredient and
its desired result. Nonetheless, once the desired effect is known, determining
the effective amount
is within the skill of a person skilled in the art.
[0152] Unless otherwise indicated, the "error bars" provided in the figures
represent the
standard error of the mean value, whereas the top of the solid, shaded bar
represents a single data
value, which is the mean value of the distribution of data values.
P153] "Finite dosing" as used herein generally includes an application of a
limited
formulation dose such as to provide a limited reservoir of an active agent,
other agents and chassis.
The active agent or one or more other agents in the reservoir is depleted with
time, leading to a
decrease of the delivery rate after a maximum rate has been reached and
perhaps maintained for a
period. Similarly "infinite dosing" as used herein generally includes an
application of a substantial
formulation dose such as to provide an effectively non-limited reservoir of an
active agent, or one
or more other agents. The agent(s) in the reservoir is little depleted with
time, potentially allowing
a delivery rate to be maintained for a longer period.
[01541 "Flux" as used herein refers to the amount of a substance delivered
into or
through a unit area of a membrane in unit time. Flux measurements may be made
in vitro using
Franz diffusion cells. Suitable membranes for flux studies include synthetic
membranes and
mammalian skin including human cadaver skin and porcine skin. Flux
measurements may also be
made in vivo using pharmacokinetic studies and the like.
O155] "Formulation," "pharmaceutical composition," and "composition" as used
interchangeably herein are equivalent terms referring to a composition of
matter for administration
to a subject.
[0156] "Gel" as used herein means a semisolid system consisting of either a
suspension
made up of small inorganic particles or large organic molecules
interpenetrated by a liquid. The
viscosity of a gel may be such that it is either flowable or non-flowable.
[01571 "Irritancy Score" as used herein means a subjective rating of the
extent of skin
irritation caused by a test composition after such composition is applied to
the human forearm.
The value of the Irritancy Score ranges from 1 (no detectable irritation) to
10 (severe irritation
prompting premature removal of the test composition).
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[0158] The term "lagtime" or "lag time" as used herein means the x-axis
intercept that
results from extrapolating the steady-state line of a plot of the cumulative
amount of active that
has permeated through the membrane or membrane section (y-axis) against time
(x-axis). For skin
as the membrane, lag time may, as stipulated by the context, refer to
permeation through the
stratum corneuni, through the stratum corneum and epidermis, or through the
stratum corneuni,
epidermis and dermi s
[0159] "Lower alcohol" as used herein includes straight- or branched-chain
alkyl
alcohols with one or more hydroxyl groups that comprise less than seven (7)
carbon atoms.
Representative lower alcohols include methanol, ethanol, n-propanol,
isopropanol, n-butanol, t-
butanol, n-pentanol, 3-pentanol, n-hexanol. 2-methoxyethanol, 2-(2-
ethoxyethoxy)ethanol,
propylene glycol (propane-1,2-diol), butanediol, butynediol, pentanediol,
hexanediol, hexane triol
and the like.
[0160] The prefix -micro" as used herein can be alternatively abbreviated as -
1.t" or -u."
For example, micrograms are typically abbreviated as lag, but can
alternatively be abbreviated as
44
ug .
[0161] "Monohydric alcohol" as used herein includes straight- or branched-
chain alkyl
alcohols with a single hydroxyl group. Representative monohydric alcohols
include methanol,
ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, 3-
pentanol, n-hexanol, 2-
methoxyethanol, 2-(2-ethoxyethoxy)ethanol, hexadecan- 1 -ol, oleyl alcohol,
isostearyl alcohol and
the like.
[0162] As used herein the term "multiplexed molecular penetration enhancer" or
"MMPE" means a penetration enhancer system comprising two or more substances
wherein each
of the two or more substances is also a molecular penetration enhancer.
[0163] The term "onset of action" as used herein means the amount of time it
takes for
the effects of an active to become noticeable after administration in a
formulation to the skin.
[0164] The term "or" as used herein should in general be construed non-
exclusively. For
example, an embodiment of "a composition comprising A or B" would typically
present an aspect
with a composition comprising both A and B. "Or" should, however, be construed
to exclude those
aspects presented that cannot be combined without contradiction (e.g., a
composition pH that is
between 9 and 10 or between 7 and 8).
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[0165] The term "organic solvent" as used herein refers to a pure substance or
a mixture
of substances that is (a) a liquid at an operating temperature such as room
temperature, (b) contains
at least one carbon atom, and optionally at least one hydrogen atom, and (c)
is capable of dissolving
another substance to create a solution. Organic solvents have different
volatilities. Dimethy I
sulfoxide ("DMSO"), for example, has a lower volatility than acetone.
[0166] "Pain Score" as used herein means a subjective rating of
effectiveness of a test
composition at inducing local anesthesia in a subject 45 minutes after such
composition is applied
to the human forearm. The value of the Pain Score ranges from 1 (no detectable
numbness or
anesthesia) to 10 (complete local anesthesia and numbness).
[0167] "Penetration enhancer", "chemical penetration enhancer-, "molecular
penetration enhancer" or "MPE" as used interchangeably herein includes an
agent or a
combination of agents that improves the transport of molecules such as a
pharmaceutically or
cosmetically active agent into or through a natural membrane such as skin or
nail. A molecular
penetration enhancer may be used to assist in the delivery of an active agent
topically, regionally,
or transdermally. A molecular penetration enhancer may be a pure substance or
may comprise a
mixture of different chemical entities. Examples of substances that may act as
MPEs include, but
are not limited to: (+/-)-limonene; lauric acid; glycerol; isopropyl alcohol;
isopropyl myri state;
oleic acid; propylene glycol; Transcutol (di(ethylene glycol) ethyl ether);
and azone (1-
dodecylazacycloheptan-2-one).
[0168] The term "pH adjusting agent" as used herein refers to an agent added
to the
compositions of the present application for the purpose of changing the pH of
the composition.
Examples of such agents include acids, bases, and buffers that are each
pharmaceutically
acceptable or cosmetically acceptable.
[0169] The term "pharmaceutically acceptable" means compatible with the
treatment of
animals, and in particular, humans.
[0170] The term "pharmaceutically acceptable salt" means a pharmaceutically
acceptable acid addition salt or a pharmaceutically acceptable base addition
salt. The formation of
a desired compound salt is achieved using standard techniques. For example,
the neutral compound
is treated with an acid or base in a suitable solvent and the formed salt is
isolated by filtration,
extraction, or by any other suitable method.
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[01711 The term "potency" is interpreted herein to mean the specific ability
or capacity
of the product, as indicated by appropriate laboratory tests or by adequately
controlled clinical data
obtained through the administration of the product in the manner intended, to
effect a given result.
[0172] -Regional delivery" as used herein means delivery of an
agent through the skin
but concentrating in proximate tissue or joint.
[0173] "Saturation concentration" of a solute as used herein
means the concentration of
a solution at which no more the solute will dissolve in the solution.
0174] "Strength" as used herein when applied to a formulation means the amount
of a
substance per unit amount of the formulation. For semisolid dosage forms and
solutions, the
strength of a particular substance can be conveniently characterized as the
concentration of the
substance usually expressed as a percentage of weight by weight.
0175] "Solubilizing agent" as used herein means an agent that is added to a
solvent
system to enhance the solubility of a given active agent in the resulting
medium. Examples of
solubilizing agents include, but are not limited to, 2-hydroxypropy1-13-
cyclodextrin; sorbitan
monolaurate; sulfobutylether-13-cyclodextrin (Captisol); Transcutol P and
Twcen 80.
[0176_1 The term "subject" as used herein includes all members of the animal
kingdom,
preferably mammals, and most preferably, humans.
0177] "Superficial delivery" as used herein means delivery of an agent to the
skin
exterior surface only.
0178] "Surfactant" as used herein includes a surface-active
agent. Surfactants reduce
the surface tension of a solvent in which they are dissolved.
0179] "Thickening agent" as used herein includes an agent or combination of
agents
that increases the viscosity of a composition. A thickening agent may be a
pure substance, or it
may comprise, consist essentially of, or consist of a mixture of different
chemical entities.
Exemplary thickening agents include cellulosic thickening agents, other
polysaccharides such as
chitosan and the like, carbomer polymers, carbomer derivatives, polyvinyl
alcohol, poloxamers,
natural gums, as well as mixtures thereof.
[0180] "Topical delivery" is used in its conventional sense to mean delivery
of an agent,
such as a therapeutically active agent, into the viable skin. The outermost
layer of the epidermis,
the stratum corneurn, is lifeless and topical delivery then refers to delivery
into the viable epidermis
and/or dermis. Topical delivery of a drug may be the advantageous basis, for
example, for
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treatment of various skin disorders. Topical delivery also refers to delivery
of an agent into other
tissues that are exposed to the environment exterior to the body, such as
nail, mucosa or eye.
[0181] "Topical formulation" as used herein includes, in one aspect, a
composition that
is suitable for topical application to the skin, nail, or mucosa. A topical
formulation may, for
example, be used to confer a therapeutic or cosmetic benefit to its user.
Specific topical
formulations can be used for superficial, local, regional, or transdermal
delivery of substances. The
term "topical formulation" as used herein also encompasses the compositions
that are formed once
a composition that is suitable for topical application to the skin, nail or
mucosa is applied to the
skin, nail or mucosa. The composition of the topical formulation resulting
from such application
to the skin, nail or mucosa may differ from the originally applied
formulation. For example,
components from the originally applied formulation may undergo differential
evaporation causing
the relative amounts of the ingredients in the formulation to change.
Additionally, components
from the originally applied formulation may diffuse into the skin, nail or
mucosa. Further,
compounds that are on or within the substrate to which the formulation is
applied may become
incorporated into the formulation. For example, linolcnic acid and
cholesterol, which are natural
components of skin, may become incorporated into the formulation.
[0182] The term "topical administration" or equivalently "topical application"
is used in
its conventional sense to mean application of a substance, such as a
formulation containing an
active agent, to the skin or to a localized more or less external region of
the body such as the nail,
mucosa or eye. Topical administration may result in any one or more of
superficial, topical,
regional or transdermal delivery the active agent.
P183] "Transdermal" as used herein includes a process that occurs through the
skin.
The terms "transdermal," "percutaneous," and "transcutaneous" can be used
interchangeably. In
certain embodiments, "transdermal" may also include epicutaneous.
[0184] "Transdermal delivery" is used in its conventional sense to mean
provision of an
agent transdermally, that is through the skin, for systemic availability.
Following passage through
the skin the agent is made available to tissues throughout the body via the
lymphatic system and/or
the vasculature.
[0185] The term "treating" or "treatment" as used herein (and as well
understood in the
art) means an approach for obtaining beneficial or desired results in a
subject's condition, including
clinical results. Beneficial or desired clinical results can include, but are
not limited to, alleviation
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or amelioration of one or more symptoms or conditions, diminishment of the
extent of a disease,
stabilizing (e.g., not worsening) the state of disease, prevention of a
disease's transmission or
spread, delaying or slowing of disease progression, amelioration or palliation
of the disease state,
diminishment of the reoccurrence of disease, and remission, whether partial or
total and whether
detectable or undetectable. "Treating" and "treatment" as used herein also
include prophylactic
treatment. Treatment methods comprise administering to a subject a
therapeutically effective
amount of an active agent. The administering step may consist of a single
administration or may
comprise a series of administrations. The compositions are administered to the
subject in an
amount and for a duration sufficient to treat the patient. The length of the
treatment period depends
on a variety of factors, such as the severity of the condition, the age and
genetic profile of the
patient, the concentration of active agent, the activity of the compositions
used in the treatment, or
a combination thereof. It will also be appreciated that the effective dosage
of an agent used for the
treatment or prophylaxis may increase or decrease over the course of a
particular treatment or
prophylaxis regime. Changes in dosage may result and become apparent by
standard diagnostic
assays known in the art. In some instances, chronic administration may be
required.
[0186_1 The term "volatility" as used herein refers to the rate at which a
substance
evaporates. A more volatile organic solvent evaporates more rapidly than a
less volatile solvent
when each is held at room temperature and pressure.
[0187] The term "solubility" as used herein has its ordinary meaning as
understood in
light of the specification and refers to the ability or extent to which a
compound (solute) can
dissolve in a solvent. The United States Pharmacopeia and British Pharmacopeia
categorize
solubility as follows: very soluble, less than 1 parts solvent per 1 part
solute; freely soluble, from
1 to 30 parts solvent per 1 part solute; soluble, from 10 to 30 parts solvent
per 1 part solute;
sparingly soluble, from 30 to 100 parts solvent per 1 part solute; slightly
soluble, from 100 to 1000
parts solvent per 1 part solute; very slightly soluble, from 1000 to 10000
parts solvent to 1 part
solute; practically insoluble or insoluble, 10000 or more parts solvent per 1
part solute. The
solubility properties of an active pharmaceutical ingredient affect its
pharmacokinetics and
pharmacodynamics, e.g., dissolution rate, transdermal absorption, absorption
in the digestive tract,
metabolism, excretion and clearance, petmeability throughout the body, transit
across the blood-
brain barrier. In some embodiments, solubility of the local anesthetics and
formulations
comprising a local anesthetic describe herein is improved with the addition of
excipients including
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but not limited to monohydric alcohols, terpenes, terpenoids, isopropyl esters
of fatty acids,
nonionic surfactants, MolAccs, MPEs, emollients, solubilizing agents,
antioxidants, preservatives,
chelating agents, organic solvents, or any combination thereof.
[0188] As used herein, the term -hioavailability" has its ordinary meaning as
understood
in light of the specification and refers to the measure of the percentage of
active pharmaceutical
ingredient that reaches systemic circulation compared to the total dose amount
administered, which
can be determined by measuring drug concentration in plasma quantitatively.
Intravenous
administration results in a bioavailability of 100%. Bioavailability of other
administration
methods, e.g. topical, are dictated by factors including but not limited to
solubility, permeability,
metabolism, degradation, excretion and clearance, or modified release
formulations. High
bioavailability of topical formulations may be a good indicator for potential
toxicity and unwanted
adverse effects. In some embodiments, bioavailability of the local anesthetics
and formulations
comprising a local anesthetic described herein may be modulated with the
addition of excipients
including but not limited to monohydric alcohols, terpenes, terpenoids,
isopropyl esters of fatty
acids, nonionic surfactants, MolAccs, MPEs, emollients, solubilizing agents,
antioxidants,
preservatives, chelating agents, organic solvents, or any combination thereof.
[0189] As used herein, the terms "efficacy", "intrinsic activity", and
"potency" have their
ordinary meaning as understood in light of the specification and refers to the
amount of active
pharmaceutical ingredient that is needed to achieve a desired effect. In some
embodiments, the
desired effect is sufficient local loss of sensation or pain in a patient and
can be quantified with a
Pain Score. Efficacy or potency can be quantified as the median or 50%
effective dose (ED50), the
dose that imparts a measurable effect in 50% of a population, or the 95%
effective dose, the dose
that imparts a measurable effect in 95% of a population. In some embodiments,
efficacy or potency
of the local anesthetics and formulations comprising a local anesthetic
described herein may be
improved with the addition of excipients including but not limited to
monohydric alcohols,
terpenes, terpenoids, isopropyl esters of fatty acids, nonionic surfactants.
MolAccs, MPEs,
emollients, solubilizing agents, antioxidants, preservatives, chelating
agents, organic solvents, or
any combination thereof.
[0190] As used herein, the term "tolerability" has its ordinary meaning as
understood in
light of the specification and refers to the extent to which a patient will
willingly withstand adverse
or side effects of an active compound to achieve the desired therapeutic
effect, and can refer to
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short-term or long-term side effects. In some embodiments, tolerability of the
local anesthetics and
formulations comprising a local anesthetic described herein may be improved
with the addition of
excipients including but not limited to monohydric alcohols, terpenes,
terpenoids, isopropyl esters
of fatty acids, nonionic surfactants, MolAccs, MPEs, emollients, solubi li
zing agents, antioxidants,
preservatives, chelating agents, organic solvents, or any combination thereof.
[0191] As used herein, the term "stability" has its ordinary meaning as
understood in
light of the specification and refers to the ability for the active compound
or the formulation
containing the active compound to remain effective, intact, and safe for
consumption or
administration over time under the influence of environmental factors such as
temperature,
humidity, and light. Stability can be assessed by forced degradation studies
according to
parameters, conditions, and standards set forth by the Food and Drug
Administration (FDA) and
International Council for Harmonisation (ICH). In some embodiments, stability
of the local
anesthetics and formulations comprising a local anesthetic described herein
may be improved with
the addition of excipients including but not limited to monohydric alcohols,
terpenes, terpenoids,
isopropyl esters of fatty acids, nonionic surfactants, MolAccs, MPEs,
emollients, solubilizing
agents, antioxidants, preservatives, chelating agents, organic solvents, or
any combination thereof.
[0192] As used herein, the term "dosage forms" has its ordinary meaning as
understood
in light of the specification and refers to the methods of delivering the
active pharmaceutical
ingredient and any excipients to an individual. Methods of delivery include
but are not limited to
oral, pills, tablets, capsules, films, drinks, syrups, powders, pastes,
inhalation, aerosol, smoke,
vapor, mist, buccal, sublingual, nasal, suppository, parenteral, intradermal,
subcutaneous,
intramuscular, intraosseous, intraperitoneal, intravenous, topical, cream,
gel, liniment, balm,
lotion, ointment, liquid drops, or patches. Certain methods of delivery may be
preferential to
others, for reasons such as comfort to the patient, invasiveness, side
effects, level of degradation,
e.g. in the digestive tract, level of absorption, onset of action, local vs.
general effect, duration of
effect, effective dose amount, or therapeutic index. In some embodiments,
dosage forms of the
local anesthetics and formulations comprising a local anesthetic described
herein may be improved
with the addition of excipients including but not limited to monohydric
alcohols, terpenes,
terpenoids, isopropyl esters of fatty acids, nonionic surfactants, MolAccs,
MPEs, emollients,
solubilizing agents, antioxidants, preservatives, chelating agents, organic
solvents, or any
combination thereof.
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[0193] The term "% w/w" or "% wt/wt" means a percentage expressed in terms of
the
weight of the ingredient or agent over the total weight of the composition
multiplied by 100.
Compositions
[0194] The present application includes compositions comprising one or more
active
ingredients for topical administration and for topical, regional or
transdermal delivery.
[0195] In an embodiment, the composition is a pharmaceutical composition for
human
or veterinary use.
[0196] In another embodiments the composition comprises a local anesthetic
drug.
Active Agent
[0197] The present disclosure provides for compositions and formulations
comprising at
least one active agent.
[0198] In one embodiment, the at least one active agent is a pharmaceutical
agent, a
cosmeceutical agent, a cosmetic agent, a nutritional supplement, or a
diagnostic agent.
[0199] Non-limiting examples of active agents include aminoamide and
aminoester local
anesthetics.
[0200] In some embodiments, the active agent is an aminoamide or aminoester
local
anesthetic.
[0201] In one embodiment, the active agent is lidocaine.
[0202] In additional embodiments, the compositions of the formulation comprise
two or
more active agents. More preferably one of the two or more active agents
comprises an
aminoamide or aminoester local anesthetics. Still more preferably one of the
two or more active
agents comprises lidocaine.
[0203] In additional embodiments, the compositions of the formulation comprise
lidocaine and a second aminoamide or aminoester local anesthetic.
Alternatively, the second
aminoamide or aminoester local anesthetic comprises prilocaine or tetracaine.
[0204] In embodiments provided for in the present disclosure, the active agent
may be
present in an amount sufficient to provide a physiological, health, skin care
and/or cosmetic
benefit. In some embodiments, the active agent is present in an amount of
0.0001, 0.001, 0.01,0.1,
1, 5, 10, 12, 25, 30, 40, or 50 % w/vv or any value within the range defined
by any two of the
aforementioned values. In some embodiments, the active agent is present in an
amount of at least
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0.001% w/w. In some embodiments, the active agent is present in an amount of
at least 0.01% w/w
or at least 0.1% w/w. In some embodiments, the active agent is present in an
amount of at least 1%
w/w. In some embodiments, the active agent is present in an amount of about 1%
w/w to about
12% w/w, including any amount between those listed. In some embodiments, the
active agent is
present in an amount of about 5% w/w to about 25% w/w, including any amount
between those
listed. In a particular embodiment of the disclosure, the active agent is used
at a concentration of
about 1% to about 20% w/w, including any amount between those listed.
[0205] In several embodiments the compositions of the formulation comprise an
aminoamide or aminoester local anesthetic that is provided in the FDA
monograph referring to
'External Analgesic Drug Products For Over-The Counter Human Use' and the
concentration of
said aminoamide or aminoester local anesthetic is within the composition range
provide for such
agent in said monograph.
[0206] In several embodiments, the compositions of the formulation comprise
lidocaine
in an amount of between 0.5 and 5.0% w/w, including for example, 0.5%, 1%,
1.5%, 2%, 2.5%,
3%, 3.5%, 4%, 4.5%, 5%, about 0.5%, about 1%, about 1.5%. about 2%, about
2.5%, about 3%,
about 3.5%, about 4%, about 4.5%, or about 5%, including any amount between
those listed.
[0207] An embodiment including "an active agent" should he understood to
present
certain aspects with at least a second active agent, which may be the same
class or a different class
(for example, lidocaine with an anti-inflammatory agent, or with a cannabinoid
such as
cannabidiol).
Monohydric Alcohol
[0208] In several embodiments, the compositions and formulations include at
least one
monohydric alcohol. Suitable monohydric alcohols include, but are not limited
to, ethanol,
propanol, propan-2-ol. (isopropanol), butanol, butan-2-ol (isobutanol),
pentanol, pentan-2-ol,
pentan-3-ol, 3-methyl-2-butanol, hexanol, hexan-2-ol, hexan-3-ol, benzyl
alcohol, stearyl alcohol
(1-octadecanol). isostearyl alcohol (1-Heptadecanol, 16-methyl-), olcyl
alcohol (1-octadecenol),
cetyl alcohol (1-hexadecanol), palmitoleyl alcohol and the like, as well as a
mixture thereof.
[0209] In some embodiments, the formulations include at least one lower
monohydric
alcohol. Example lower monohydric alcohols include, but are not limited to,
ethanol, propanol,
propan-2-ol, (isopropanol), butanol, butan-2-ol (isobutanol), pentanol, pentan-
2-ol, pentan-3-ol, 3-
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methyl-2-butanol, hexanol, hexan-2-ol, hexan-3-ol, benzyl alcohol and the
like, as well as a
mixture thereof.
[0210] In some embodiments, the monohydric alcohol is ethanol.
[0211] In several such embodiments, the ethanol is present in an amount of
between 0%
and about 90% w/w or between 0% and about 90%. In some embodiments, ethanol is
present in
an amount of about 0%, 10%, 20%, 30%, 31%, 32%, 34%, 35%, 36%, 37%, 38%, 39%,
40%,
41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%,
56%, 57%,
58%, 59%, 60%, 64%, 69%, 72%, 80%, 86%, 90% w/w, or about 0%, about 10%, about
20%,
about 30%, about 31%, about 32%, about 34%, about 35%, about 36%, about 37%.
about 38%,
about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%.
about 46%,
about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%.
about 54%,
about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 64%.
about 69%,
about 72%, about 80%, about 86%, or about 90% w/w, or any amount between a
range defined by
any two aforementioned numbers.
[0212] In some embodiments, the monohydric alcohol is benzyl alcohol.
[0213] In several embodiments, the benzyl alcohol is present in an amount
between 0%
and 20% w/w. In certain such embodiments, benzyl alcohol is present in an
amount of 0%, 5%,
10%, 15%, or 20% w/w, or about 0%, about 5%, about 10%, about 15%, or about
20% w/w or any
amount within a range defined by any two of the aforementioned numbers.
[0214] In some embodiments, the foimulations include a fatty alcohol.
[0215] Example fatty alcohols include but are not limited to stearyl alcohol
(1-
octadecanol), isostearyl alcohol (1-Heptadecanol. 16-methyl-), oleyl alcohol
(1-octadecenol), cetyl
alcohol (1-hexadecanol), palmitoleyl alcohol and the like, as well as a
mixture thereof.
[0216] In several embodiments, the fatty alcohol is a C14, a C16, a C18 or a
C20 fatty
alcohol.
[0217] In some embodiments, the fatty alcohol is a C18 fatty alcohol.
[0218] In some embodiments, the fatty alcohol is isostearyl alcohol.
[0219] In some embodiments, the isostearyl alcohol is present in an amount of
between
0% and 30% w/w. In certain such embodiments, isostearyl alcohol is present in
an amount of 0%,
1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 21%, 25%, or 30% w/w, or
about 0%,
about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about
8%, about 9%,
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about 10%, about 15%, about 20%, about 21%, about 25%, or about 30% w/w or any
amount
within a range defined by any two of the aforementioned numbers.
Combination of Monohydric Alcohols
[0220] In some embodiments, the compositions and formulations include more
than one
monohydric alcohol.
[0221] In additional embodiments, the compositions and formulations include a
lower
monohydric alcohol and a fatty alcohol.
[0222] In several embodiments, the formulations include a lower monohydric
alcohol
including but not limited to ethanol, propanol, propan-2-ol, (isopropanol),
butanol, butan-2-ol
(isobutanol), pentanol, pentan-2-ol, pentan-3-ol, 3-methy1-2-butanol, hexanol,
hexan-2-ol, hexan-
3-ol, benzyl alcohol, or any combination or mixture thereof, as well as a
combination or mixture
thereof with a fatty alcohol.
[0223] In some embodiments, the monohydric alcohol included in combination
with a
fatty alcohol is ethanol.
[0224] In some embodiments, the monohydric alcohol included in combination
with a
fatty alcohol is benzyl alcohol.
[0225] In some embodiments, the fatty alcohol combined with a lower monohydric
alcohol is a C14, a C16, a C18 or a C20 fatty alcohol.
[0226] In some embodiments, the fatty alcohol combined with a lower monohydric
alcohol is a C18 fatty alcohol.
[0227] In some embodiments, the fatty alcohol combined with a lower monohydric
alcohol is isostearyl alcohol.
[0228] In some embodiments, the compositions and formulations include ethanol
and
isostearyl alcohol.
[0229] In some embodiments, the ethanol is present in an amount between 0% and
90%
w/vv or between about 0% and about 90%. In some embodiments, ethanol is
present in an amount
of 0%, 10%. 20%, 30%. 31%, 32%. 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%,
43%,
44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%. 55%, 56%, 57%, 58%,
59%, 60%,
64%, 69%, 72%, 80%, 86%, 90% w/w, or about 0%. about 10%, about 20%, about
30%, about
31%, about 32%, about 34%, about 35%, about 36%, about 37%, about 38%, about
39%, about
40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about
47%, about
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48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about
55%, about
56%, about 57%, about 58%, about 59%, about 60%, about 64%, about 69%, about
72%, about
80%, about 86%, or about 90% w/w, or any amount between a range defined by any
two
aforementioned numbers.
[0230] In some embodiments, the isostearyl alcohol is present in an amount
between 0%
and 30% w/w or about 0% and about 30% w/w. In certain such embodiments,
isostearyl alcohol
is present in an amount of 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,
20%, 21%,
25%, or 30% w/w, or about 0%, about 1%, about 2%, about 3%, about 4%, about
5%, about 6%,
about 7%, about 8%. about 9%, about 10%, about 15%, about 20%, about 21%,
about 25%, or
about 30% w/w or any amount within a range defined by any two of the
aforementioned numbers.
Terpene and Terpenoid
[0231] In some embodiments, the compositions and formulations include a light
terpene
or terpenoid. Terpenes are organic compounds produced by plants or some
insects and animals
and include but are not limited to light terpenes, hemiterpenes, monoterpenes,
sesquiterpenes,
diterpenes, sesterterpenes, triterpenes, sesquarterpenes, tetraterpenes,
polyterpenes,
norisoprenoids, isoprene, prenol, isovaleric, geraniol, terpineol, limonene,
myrcene, linalool,
pinene, iridoids, humulene, farnesenes, famesol, cafesol, kahweol, cembrene,
taxadiene or
squalene, or any combination or mixture thereof. Terpenoids, or isoprenoids,
are molecules or
compounds derived from terpenes, and include but are not limited to
hemiterpenoids,
monoterpenoids, sesquiterpenoids, diterpenoids, sesterterpenoids,
triterpenoids, tetraterpenoids,
polyterpenoids, citral, menthol, camphor, cannabinoids, ginkgolide,
bilobalide, cucurminoids,
retinol, retinal, phytol, lanosterol, cycloartenol, steroids, lycopene, a-
carotene, I3-carotene, or y-
carotene, or any combination or mixture thereof.
[0232] In some embodiments, suitable light terpenes and terpenoids include
geraniol,
terpineol, limonene, myrcene, linalool and pinene.
[0233] In some embodiments, the light terpene is limonene.
[0234] In some embodiments, the limonene is present in an amount between 0%
and
60% w/w, or between about 0% and 60%. In some embodiments, the limonene is
present in an
amount of 0%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%
w/w or
about 0%, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%,
about 30%, about
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35%, about 40%, about 45%, about 50%, about 55%, about 60% w/w or any amount
within a range
defined by any two of the aforementioned numbers.
Isopropyl Ester of a Fatty Acid
[0235] In some embodiments, the composition includes an ester of a fatty acid.
[0236] In some embodiments, the composition includes an isopropyl ester of a
fatty acid
selected lauric acid (C12:0), tridecylic acid (C13:0), myristic acid (C14:0),
pentadecylic acid
(C15:0), palmitic acid (C16:0), rnargaric acid (C17:0), stearic acid (C18:0),
nonadecylic acid
(C19:0), arachidic acid (C20:0), ct-linolenic acid (C18:3), stearidonic acid
(C18:4), linoleic acid
(C18:2), linolelaidic acid (C18:2), y-linolenic acid (C18:3), palmitoleic acid
(C16:1), vaccenic acid
(C18:1), oleic acid (C18:1) and elaidic acid (C18:1).
[0237] In some embodiments, compositions include isopropyl myristate,
isopropyl
palmitate, diisopropyl adipate, glycerol monooleate, or diethyl sebacate.
[0238] In some embodiments, the ester of a fatty acid is present in an amount
between
0% and 30% w/w or between about 0% and about 30% w/w. In some embodiments, the
ester of a
fatty acid is present in an amount of 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%,
10%, 11%, 12%,
13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 25%, 26%, or 30% w/w, or about
0%, about
1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%,
about 9%, about
10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about
17%, about
18%, about 19%, about 20%, about 21%, about 25%, about 26%, or about 30% w/w,
or an amount
within a range defined by any two of the aforementioned numbers.
Combination of Fatty Acid Isopropyl Esters
[0239] In some embodiments, the compositions and formulations include at least
one
ester of a fatty acid.
[0240] In some embodiments, the composition includes the esters of at least
one fatty
acid selected from lauric acid (C12:0), tridecylic acid (C13:0), myristic acid
(C14:0), pentadecylic
acid (C15:0), palmitic acid (C16:0), margaric acid (C17:0), stearic acid
(C18:0). nonadecylic acid
(C19:0), arachidic acid (C20:0), cc-linolenic acid (C18:3), stearidonic acid
(C18:4)õ linoleic acid
(C18:2), linolelaidic acid (C18:2), y-linolenic acid (C18:3), palmitoleic acid
(C16:1), vaccenic acid
(C18:1), oleic acid (C18:1) and elaidic acid (C18:1)..
[0241] In some embodiments, the composition includes the isopropyl esters of
two fatty
acids.
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[0242] In some embodiments, the composition includes isopropyl myristate and
isopropyl palmitate.
[0243] In some embodiments, the isopropyl myristate is present in an amount
greater
than that of the isopropyl palmitatc, or the isopropyl myri state is present
in an amount lesser than
that of the isopropyl palmitate.
[0244] In some embodiments, the isopropyl myristate and isopropyl palmitate
are each
present in an amount between 0% and 30% w/w or between about 0% and about 30%
w/w. In
some embodiments, the isopropyl myristate or isopropyl palmitate are each
present in an amount
of 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,
17%,
18%, 19%, 20%, 21%, 25%, 26%, or 30% w/w, or about 0%, about 1%, about 2%,
about 3%,
about 4%, about 5%. about 6%, about 7%. about 8%, about 9%. about 10%, about
11%, about
12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about
19%, about
20%, about 21%, about 25%, about 26%, or about 30% w/w, or an amount within a
range defined
by any two of the aforementioned numbers.
Nonionic Surfactant
[0245] In some embodiments, the composition includes at least one
pharmaceutically
acceptable surfactant that is a nonionic surfactant.
[0246] In the present invention the nonionic surfactant may be one or more of
2,4,7,9-
tetramethy1-5-decyne-4,7-diol ethoxylate average Mn 670; 2,4,7,9-tetramethy1-5-
decyne-4,7-diol,
mixture of ( ) and meso 98%; Adogen 464; ALKANOL 6112; alkyl polyglycoside;
anhydrosorbitol ester; Brij 58; Brij 93; Brij C10; Brij L4 (polyethylene
glycol dodecyl
ether); Brij 010; Brij 020; Brij S100; Brij S10; Brij S20; carboxylic
amides; carboxylic
esters; Cetomacrogol 1000; cetostearyl alcohol; cetyl alcohol; Cocamide
diethanolamine
("DEA"); Cocamide monoethanolamine ("MEA"); decyl glucoside; decyl
polyglucose; disodium
cocoamphodiacetate; ethoxylated aliphatic alcohol; ethoxylated derivatives of
anhydrosorbitol
ester; ethylenediamine tetrakis(ethoxylate-block-propoxylate) tetrol average
Mn -7,200;
ethylenediamine tetrakis(ethoxylate-block-propoxylate) tetrol average Mn -
8,000;
ethylenediamine tetrakis(propoxylate-block-ethoxylate) tetrol average Mn -
3,600; glycerol
monostearate; glycol esters of fatty acids; IGEPAL CA-630; IGEPAL CA-520;
IGEPAL CA-
720; IGEPAL CO-520; IGEPAL CO-630; IGEPAL CO-720; IGEPAL CO-890;
IGEPAL DM-970; isoceteth-20; lauryl glucoside; maltosilles; MERPOLO A; MERPOL
DA;
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MERPOLO HCS; MERPOLO OJ; MERPOLO SE; MERPOLO SH; monoalkanolamine
condensates; monolaurin; mycosubtilin; narrow-range ethoxylate; N-octyl beta-D-
thioglucopyranoside; Nonidet P-40; Nonoxyno1-9; Nonoxynols; NP-40;
octaethylene glycol
monododecyl ether; octyl glucoside; ley' alcohol; polyethylene glycol (-PEG")-
10 sunflower
glycerides; pentaethylene glycol monododecyl ether; polidocanol; Poloxamer;
Poloxamer 407;
poly(ethylene glycol) (12) tridecyl ether mixture of C11 to C14 iso-alkyl
ethers with C13 iso-alkyl
predominating; poly(ethylene glycol) (18) tridecyl ether mixture of C11 to C14
iso-alkyl ethers
with C13 iso-alkyl predominating; poly(ethylene glycol) sorbitan tetraoleate;
poly(ethylene
glycol) sorbitol hexaoleate; polyethoxylated tallow amine; polyethylene glycol
dodecyl ether;
polyethylene glycol esters; polyethylene-block-poly(ethylene glycol) average
Mn -1,400;
polyethylene-block-poly(ethylene glycol) average Mn -575; polyethylene-block-
poly(ethylene
glycol) average Mn -875; polyethylene-block-poly(ethylene glycol) average Mn -
920;
polyglycerol polyricinoleate; polyoxyethylene fatty acid amides;
polyoxyethylene surfactants;
Polysorbate; Polysorbate 20; Polysorbate 80; sorbitan; sorbitan monolaurate
(Span 20); sorbitan
monopalmitatc (Span 40); sorbitan monostcaratc (Span 60); sorbitan monoolcatc
(Span 80);
sorbitan sesquioleate (Span 83); sorbitan trioleate (Span 85); sorbitan
isostearate (Span 120); SP
Brij C2 MBAL-S0-(SG); SP Brij C2 MBAL-S0-(SG); SP Brij S2 MBAL; SPAN 20;
stearyl
alcohol; Surfactin; Triton N-101; Triton X-100; Triton X-100; Triton X-114;
Triton X-405;
Tween 20; Tween0 40; Tween0 60; Tween0 80; and Tween0 85.
[0247] In some embodiments, the nonionic surfactant is a polyalkylene glycol
alkyl
ether.
[0248] In some embodiments, the nonionic surfactant may be present at up to
about 20%
w/w, such as 0.1, 0.15,0.2, 0.3,0.4, 0.5, 1.0, 1.5,2, 2.5, 3, 3.5,4, 4.5, 5,
5.5, 6, 6.5, 7, 8, 9, 19, 12,
14, 16, 18 or 20% w/w or about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2,
2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6,
6.5,7, 8, 9, 19, 12, 14, 16, 18 or 20% w/w. In some embodiments, the nonionic
surfactant is present
at up to about 10% w/w, such as 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0,
4.0, 5.0, 6.0, 7.0, 8Ø 9.0
or 10.0% w/w or about 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0,
6.0, 7.0, 8.0, 9.0 or 10.0%
w/w. In some embodiments, the nonionic surfactant is present at up to about 5%
w/w, such as 0.1,
0.15, 0.2, 0.3, 0.4, 0.5, 1.0, 2.0, 3.0, 4.0, 5.0% w/w or about 0.1, 0.15,
0.2, 0.3, 0.4, 0.5, 1.0, 2.0,
3.0, 4.0, 5.0% w/w.
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[0249] In some embodiments, the polyalkylene glycol alkyl ether is a
polypropylene
oxide alkyl ether or a polyethylene glycol alkyl ether. Some non-limiting
examples of polyalkylene
glycol alkyl ethers include poly(oxyethylene) cetyl ether, poly(oxyethylene)
palmityl ether,
polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, Brij 30
(Brij L4), Brij 38, Brij
52, Brij 56, Brij 58, Brij 78, Brij 98, Brij 700, Brij 700P, Brij 721, Brij
S20, and Brij W1 . In some
embodiments, the polyalkylene glycol alkyl ether is a Brij group polyalkylene
glycol alkyl ether.
In some embodiments, the polyalkylene glycol alkyl ether is Brij L4.
Pressure Sensitive Adhesive
[0250] In some embodiments, the composition includes at least one
pharmaceutically
acceptable pressure sensitive adhesive.
[0251] In some embodiments, the pressure sensitive adhesive is a pressure
sensitive
adhesive based on polyacrylate. In some embodiments, said pressure sensitive
adhesive based on
polyacrylate forms a matrix in which is embedded the active ingredient. In
some embodiments,
the pressure sensitive adhesives are polyacrylate based and available
commercially, for example
the Galva and Durotak brands, especially the series 87 and GMS, for example
DURO-TAK 87-
900A, DURO-TAK 87-9301, DURO-TAK 87-4098, GELVA GMS 3083, DURO-TAK 387-2510
/ 87-2510, DURO-TAK 387-2287 / 87-2287, DURO-TAK 87-4287, GELVA GMS 788, DURO-
TAK 387-2516 / 87-2516, DURO-TAK 87-2074, DURO-TAK 87-235A, DURO-TAK 387-2353
/ 87-2353, GELVA GMS 9073, DURO-TAK 87-2852, DURO-TAK 387-2051 / 87-2051, DURO-
TAK 387-2052 / 87-2052, DURO-TAK 387-2054 / 87-2054, DURO-TAK 87-2194, DURO-
TAK
87-2196.
[0252] The pressure sensitive adhesive based on polyacrylate may contain one
or more
acrylate homopolymers or copolymers of one or more acrylate or any combination
or mixture
thereof.
[0253] In some embodiments, the acrylate pressure sensitive adhesive is DURO-
TAK
UN1133, DURO-TAK 387-2516, DURO-TAK 87-4098, DURO-TAK 387-2054 or GELVA CiMS
7883.
MolAccs
[0254] In some embodiments, the compositions and formulations of the present
invention may include one or more MolAccs. Examples of molecular entities that
serve as
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MolAccs include, but are not limited to lower monohydric alcohols, lower
terpenes, lower fatty
acids, and DMSO.
[0255] DMSO is a polar aprotic solvent characterized as having low surface
tension.
DMSO permeates readily through skin and is known to function in some instances
as a penetration
enhancer.
[0256] In some embodiments, the MolAcc may be present in an amount between 0%
and
99% w/w or about 0% and about 99% w/w. In some embodiments, the MolAcc is
present in an
amount of 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,
70%,
75%, 80%, 85%, 90%, 95%, or 99% w/w or about 0%, about 5%, about 10%, about
15%, about
20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about
55%, about
60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about
95%, or about
99% w/w or any amount within a range defined by any two of the aforementioned
numbers.
[0257] In some embodiments, the MolAcc has a secondary function in the
composition,
including but not limited to a solvent, MPE, solubilizing agent, antioxidant,
emollient or
preservative.
Molecular Penetration Enhancers ("MPE-)
[0258] In some embodiments, the compositions and formulations for the present
invention may include one or more MPEs. Examples of MPEs include, but are not
limited to 1,3-
butanediol, alpha-tocopherol, ceteth-2, coco-caprylate/caprate,
cocodiethanolamide,
diethanolamine, diethylsebacate, dimethyl sulfoxide, dipropylene glycol, ethyl
acetate, ethyl
oleate, ethylene glycol, glycerol, hexylene glycol, isopropyl alcohol,
Labrasol , lactic acid,
laureth-2, lauric diethanolamide, lauryl lactate, levulinic acid, L-menthol,
oleic acid, oleth-5, oleyl
alcohol, propylene glycol, steareth-20 and Transcutol.
[0259] In some embodiments, the MPE has a dual role including but not limited
to a
MolAcc.
Emollients
110260_1 Emollients can optionally be added to the formulations of the
invention so that
the formulations can maintain or increase the moisture content of the stratum
corneum when the
composition is applied to the skin. Emollients may be added to the
formulations in addition to the
components already described, which may also aid in maintaining or improving
the skin condition
of the user.
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[0261] In some embodiments, added emollients are included in the compositions
of the
invention at a concentration between 0% and 99% w/w or about 0% and about 99%
w/w, such as
0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,
45%, 50%,
55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% w/w, or
about 0%,
about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about
8%, about 9%,
about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%,
about 45%,
about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,
about 85%,
about 90%, about 95%, about 96%, about 97%, about 98%, or about 99% w/w or any
concentration
within a range defined by any two of the aforementioned values.
[0262] Example emollients may be selected from any of the classes known in the
art. A
general list of useful emollients appears, for example, in U.S. Pat. No.
4,478,853 and in EP patent
application 0 522 624A1 as well as in the CTFA Cosmetic Ingredient Handbook
published by The
Cosmetic, Toiletry, and Fragrance Association, Washington D.C. (1992) under
listings including
but not limited to "Skin Conditioning agents", "emollients", "humectants",
"miscellaneous" and
-occlusive."
[0263] In some embodiments, the addition of one or more emollients may affect
the
viscosity and stability of the compositions of the present invention. In some
embodiments, a single
emollient may be added to the composition. In other embodiments, two or more
emollients may
be added to the composition. While any of a variety of emollients may be added
to the formulations
of the present invention, some embodiments will include wax and oil type
emollients either alone
or combined with water soluble emollients. In some embodiments of the
invention, emollient
systems can be comprised of humectants in addition to occlusive wax and oil
emollients in
concentrations that achieve a moisturizing effect and which maintain and
improve the condition
of the skin upon repeated use. Emollients may be non-comedogenic and chosen to
avoid skin
irritation or sensitization reactions.
Solubilizing Agent
[0264] In some embodiments, the formulations and compositions of the present
invention may include a solubilizing agent. Examples of solubilizing agents
include, but are not
limited to: 2-hydroxypropy1-13-cyclodextrin; Cremophor EL; dimethylsulfoxide;
docusate sodium;
ethanol; Gelucire 44/14; Labrasol; Nonoxynol 9; Octoxymol 9; PEG-60
Hydrogenated Castor Oil
(HCO-60); Poloxamer 124; Poloxamer 188; Poloxamer 237; Poloxamer 338;
Poloxamer 407;
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Poloxamer; Polyethylene glycol 400 (PEG 400); Polyoxyl 10 Oleyl Ether;
Polyoxyl 20 Cetostearyl
Ether; Polyoxyl 35 Castor Oil; Polyoxyl 40 Hydrogenated Castor Oil; Polyoxyl
40 Stearate;
Polysorbate 20; Polysorbate 40; Polysorbate 60; Polysorbate 80; propylene
glycol; sodium lauryl
sulfate; sodium taurochol ate; sorbitan monolaurate; sorbitan monooleate;
sorbitan monopalmitate;
sorbitan monostearate; sulfobutylether-13-cyclodextrin (Captisol); Transcutol
P; Tween 80;
Tylox apol
Antioxidant
[0265] In some embodiments, the formulation additionally comprises an anti-
oxidant.
Example anti-oxidants include but are not limited to ascorbic acid, ascorbyl
linoleate, ascorbyl
dipalmitate, ascorbyl palmitate, ascorbyl tocopherol maleate, butylated
hydroxytoluene, butylated
hydroxyanisole (BHA), calcium ascorbate, carotenoids, kojic acid and its
pharmaceutically
acceptable salts, propyl gallate, sodium thiosulfate, thioglycolic acid and
its pharmaceutically
acceptable salts (e.g., ammonium), tocopherol (including a, 13, y and 6
forms), tocopherol acetate,
tocophereth-5, tocophereth-12, tocophereth-18, or tocophereth-80.
Preservative
[0266] In some embodiments, the formulation additionally comprises at least
one
preservative. Example preservatives include hut are not limited to
benzalkonium chloride,
cetrimonium bromide (aka cetyltrimethylammonium bromide), cetylpyridinium
chloride,
benzethonium chloride, alkyltrimethylammonium bromide, methyl paraben, ethyl
paraben, propyl
paraben, butyl paraben, benzyl alcohol, cetyl alcohol, steryl alcohol, benzoic
acid, sorbic acid,
chloroacetamide, trichlorocarban, thimero sal, imidurea, bronopol,
chlorhexidine, 4-chlorocresol,
4-chloroxylenol, dichlorophene and hexachlorophene. Especially preferred are
cetylpyridinium
chloride, methyl paraben and propyl paraben, or mixtures thereof.
Chelating Agent
[0267] Chelating agents form complexes with metal ions, for example, to
improve
stability of a composition comprising metals or to improve excretion of metal
ions. In some
embodiments, the formulation comprises at least one chelating agent. Example
chelatin2 agents
include but are not limited to ethylenediaminetetraacetic acid ("EDTA"),
disodium edetate, sodium
calcium edetate, dimercaprol, succimer, 2.3 -dimercapto- 1-propanesulfonic
acid, alpha lipoic acid,
citric acid, phosphonates, or porphyrins.
Organic Solvents
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[0268] In some embodiments, the compositions of the present invention are
formulated
with organic solvents. Examples of organic solvents include but are not
limited to acetic acid;
acetone; acetonitrile; 1-butanol; 2-butanol; 2-butanone; tert-butyl alcohol;
cyclohexane; diethylene
glycol; diethyl ether; diglymc (dicthylenc glycol); dimethyl ether; dimethyl
isosorhide; 1,2-
dimethoxy-ethane (glyme or "DME"); dimethylformamide ("DMF"); DMSO; 1,4-
dioxane;
ethanol; ethyl acetate; ethylene glycol; glycerin; heptane;
Hexamethylphosphoramide (HMPA);
Hexamethylphosphorous triamide (HMPT); hexane; methanol; methyl t-butyl ether
(MTBE);
methylene chloride; N-methyl-2-pyrrolidinone ("NMP"); nitromethane; pentane;
petroleum ether
(ligroine); 1-propanol; 2-propanol; pyridine; tetrahydrofuran ("THF");
toluene; triethylamine; o-
xylene; m-xylene; p-xylene. In some embodiments, organic solvents for use in
the compositions
are substances that are pharmaceutically acceptable for application to the
skin. In some
embodiments, the compositions include at least two organic solvents. In some
embodiments, the
formulations may have different volatilities. In some embodiments, one of the
solvents is highly
volatile such that the formulation substantially dries relatively quickly on
application to the skin
of a subject while the second solvent is less volatile and serves to maintain
the lidocainc and/or
congener thereof in a substantially solubilized form in order that the
lidocaine and/or congener
thereof can continue to be efficiently delivered into the skin of the subject.
In some embodiments,
one of the solvents is highly volatile such that the formulation substantially
dries when applied to
a suitable substrate, such as a polymeric backing film, to provide an adhesive
film suitable for later
application to the skin of a subject while the second solvent is less volatile
and serves to maintain
the lidocaine and/or congener thereof in a substantially solubilized form in
the film in order that
the lidocaine can continue to be efficiently delivered into the skin of the
subject.
[0269] Some embodiments provided herein relate to topical compositions. In
some
embodiments, the compositions include a topical anesthetic, at least one
monohydric alcohol, a
terpene or terpenoid, at least one isopropyl ester of a fatty acid, and at
least one monohydric
alcohol.
1102701 In some embodiments, the compositions include at least one topical
anesthetic,
each present in a weight percent ranging from 1 to 99% w/w, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50. 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97,
98, or 99% w/w, or in a
percent within a range defined by any two of the aforementioned values. In
other embodiments,
the at least one topical anesthetic includes lidocaine.
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[0271] In some embodiments, the compositions include at least one monohydric
alcohol,
each present in a weight percent ranging from 1 to 99% w/w, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50. 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97,
98, or 99% w/w, or in a
percent within a range defined by any two of the aforementioned values. In
some embodiments,
the at least one monohydric alcohol includes at least one C2-C4 monohydric
alcohol. In some
embodiments, the at least one C2-C4 monohydric alcohol includes ethanol.
[0272] In some embodiments, the compositions include at least one terpene or
terpenoid,
each present in a weight percent ranging from 1 to 99% w/w, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97,
98, or 99% w/w, or in a
percent within a range defined by any two of the aforementioned values. In
some embodiments,
the at least one terpene or terpenoid includes limonene.
[0273] In some embodiments, the compositions include at least one isopropyl
ester of a
fatty acid, each present in a weight percent ranging from 1 to 99% w/w, such
as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
96, 97, 98, or 99% w/w,
or in a percent within a range defined by any two of the aforementioned
values. In some
embodiments, the at least one isopropyl ester of a fatty acid includes at
least one isopropyl ester
of a C14-C18 fatty acid. In some embodiments, the at least one isopropyl ester
of a C14-C18 fatty
acid includes isopropyl myristate and/or isopropyl palmitate.
[0274] In some embodiments, the compositions include at least one monohydric
alcohol,
each present in a weight percent ranging from 1 to 99% w/w, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97,
98, or 99% w/w, or in a
percent within a range defined by any two of the aforementioned values. In
some embodiments,
the at least one monohydric C14-C20 alcohol includes at least one monohydric
C14-C20 alcohol.
In some embodiments, the at least one monohydric C14-C20 alcohol includes
isostearyl alcohol.
[0275] In some embodiments, the compositions additionally include at least one
nonionic
surfactant, each present in a weight percent ranging from 1 to 99% w/w, such
as 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
96, 97, 98, or 99% w/w,
or in a percent within a range defined by any two of the aforementioned
values. In some
embodiments, the at least one nonionic surfactant includes polyethylene glycol
dodecyl ether.
[0276] In some embodiments, the compositions additionally include at least one
MolAcc, each present in a weight percent ranging from 1 to 99% w/w, such as 1,
2, 3, 4, 5, 6, 7,
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8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
96, 97, 98, or 99% w/w,
or in a percent within a range defined by any two of the aforementioned
values. In some
embodiments, the at least one MolAcc includes DMSO.
[0277] In some embodiments, the compositions additionally include at least one
MPE,
each present in a weight percent ranging from 1 to 99% w/w, such as 1, 2, 3,
4, 5, 6, 7, 8, 9, 10,
15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97,
98, or 99% w/w, or in a
percent within a range defined by any two of the aforementioned values.
[0278] In some embodiments, the compositions additionally include at least one
emollient, each present in a weight percent ranging from 1 to 99% w/w, such as
1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
96, 97, 98, or 99% w/w,
or in a percent within a range defined by any two of the aforementioned
values.
[0279] In some embodiments, the compositions additionally include at least one
solubilizing agent, each present in a weight percent ranging from 1 to 99%
w/w, such as 1, 2, 3, 4,
5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,
90, 95, 96, 97, 98, or 99%
w/w, or in a percent within a range defined by any two of the aforementioned
values.
[0280] In some embodiments, the compositions additionally include at least one
antioxidant, each present in a weight percent ranging from 1 to 99% w/w, such
as 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, 96, 97, 98, or 99% w/w,
or in a percent within a range defined by any two of the aforementioned
values.
[0281] In some embodiments, the compositions additionally include at least one
preservative, each present in a weight percent ranging from 1 to 99% w/w, such
as 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,
95, 96, 97, 98, or 99% w/w,
or in a percent within a range defined by any two of the aforementioned
values.
[0282] In some embodiments, the compositions additionally include at least one
chelating agent, each present in a weight percent ranging from 1 to 99% w/w,
such as 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75. 80, 85,
90, 95, 96, 97, 98, or 99%
w/w, or in a percent within a range defined by any two of the aforementioned
values.
[0283] In some embodiments, the compositions additionally include at least one
organic
solvent, each present in a weight percent ranging from 1 to 99% w/w, such as
1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 96,
97, 98, or 99% w/w, or
in a percent within a range defined by any two of the aforementioned values.
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[0284] Some embodiments provided herein relate to methods of preventing local
pain in
a subject by administering a therapeutically effective amount of the topical
formulations described
herein to the subject. The topical formulation is applied to the subject for
1, 5, 10, 15, 20, 25, 30,
35, 40, 50, 55, or 60 seconds, or 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40,
45, 50, 60 minutes, or 1, 2,
3, 4, 5 hours, or for a duration within a range defined by any two of the
aforementioned values, or
until the subject is sufficiently relieved of local pain.
[0285] Some embodiments provided herein relate to a device suitable for
providing rapid
local anesthesia using the topical formulations described herein. The device
comprises a pressure-
sensitive adhesive formed into an annulus, circle, square, rectangle, polygon,
or any other
appropriate shape to cover the area to be affected, wherein the topical
formulations described
herein are applied to the inner circumference of the annulus, or any other
appropriate region of the
pressure-sensitive adhesive.
Non-limiting Formulations
[0286] Disclosed herein arc various embodiments of topical formulations for
rapid onset
topical anesthesia. The embodiments may include any one of the active agents
(such as one or
more aminc-)amide or aminc-)ester anesthetics) as well as one or more
excipients disclosed herein or
otherwise known in the art for various purposes including but not limited to
improving
permeability across the skin, increasing duration of the effect by releasing
the active agent at a
reduced rate, improving the stability of the formulation, either at the time
of use or in storage,
increasing the viscosity of the formulation for improved handling, or
providing adhesive properties
to the formulation. Non-limiting embodiments of the topical formulations are
provided throughout
the disclosure, and particularly in the Examples. It is envisioned that the
described ratios for any
one or more constituent compounds of each formulation may be adjusted within a
reasonable
range, for example, increasing or decreasing the relative % w/w of a compound
by 0.5%, 1%, 2%,
3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w, or any % w/w within a range defined by
any two of
the aforementioned percentages.
[0287] Disclosed herein are topical formulations comprising lidocaine present
in an
amount of 1% to 10% or about 1% to about 10% w/w (for example, about 1%, 2%,
3%, 4%, 5%,
6%, 7%, 8%, 9%, or 10% w/w), limonene present in an amount of 5% to 20% or
about 5% to about
20% w/w (for example, about 5%, 6%,7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%,
16%, 17%,
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18%, 19%, or 20% w/w), and at least one C2-C4 monohydric alcohol present in an
amount of 40%
to 60% or about 40% to about 60% w/w (for example, about 40%, 41%, 42%, 43%,
44%, 45%,
46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60%
w/w). In
some embodiments, the at least one C2-C4 monohydric alcohol comprises ethanol.
In some
embodiments, the at least one C2-C4 monohydric alcohol is ethanol. In some
embodiments, the
lidocaine is present in an amount of 4% or about 4% w/w. In some embodiments,
the limonene is
present in an amount of 10% or about 10% w/w. In some embodiments, the at
least one C2-C4
monohydric alcohol is present in an amount of 51% or about 51% w/w. In some
embodiments, the
lidocaine may be substituted for any one or more other active agents, such as
another aminoamide
or aminoester anesthetic. In some embodiments, the limonene may be substituted
for any one or
more other molecular penetration enhancers or terpenes. In some embodiments,
the at least one
C2-C4 monohydric alcohol may be substituted for any one or more other C2-C4
monohydric
alcohols.
[0288] In some embodiments, the topical formulations disclosed herein further
comprise
at least one isopropyl ester of a C14-C18 fatty acid. In some embodiments, the
at least one
isopropyl ester of a C14-C18 fatty acid is present in an amount of 10% to 30%
or about 10% to
about 30% w/w (for example, about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%,
19%,
20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% w/w). In some
embodiments, the
at least one isopropyl ester of a C14-C18 fatty acid comprises isopropyl
palmitate or isopropyl
myristate, or both. In some embodiments, the isopropyl palmitate and the
isopropyl myristate are
each present in an amount of 5% to 15% or about 5% to about 15% w/w (for
example, about 5%,
6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w/w). In some embodiments, the
isopropyl
palmitate is present in an amount of 7% or about 7% w/w. In some embodiments,
the isopropyl
myristate is present in an amount of 11%, or about 11% w/w. In some
embodiments, the lidocaine
is present in an amount of 4% or about 4% w/w, the limonene is present in an
amount of 10% or
about 10% w/w, the at least one C2-C4 monohydric alcohol is present in an
amount of 51% or
about 51% w/w, the isopropyl palmitate is present in an amount of 7% or about
7% w/w, and the
isopropyl myristate is present in an amount of 11% or about 11% w/w. In some
embodiments, the
at least one isopropyl ester of a C14-C18 fatty acid may be substituted for
any one or more other
isopropyl ester of a C14-C18 fatty acid.
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[0289] In some embodiments, the topical formulations disclosed herein further
comprise
at least one monohydric C14-C20 alcohol. In some embodiments, the at least one
monohydric
C14-C20 alcohol is present in an amount of 5% to 15% or about 5% to about 15%
w/w (for
example, about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% w/w). In
some
embodiments, the at least one monohydric C14-C20 alcohol comprises isostearyl
alcohol. In some
embodiments, the at least one monohydric C14-C20 alcohol is isostearyl
alcohol. In some
embodiments, the isostearyl alcohol is present in an amount of 10% or about
10% w/w. In some
embodiments, the lidocaine is present in an amount of 4% or about 4% w/w, the
limonene is
present in an amount of 10% or about 10% w/w, the at least one C2-C4
monohydric alcohol is
present in an amount of 51% or about 51% w/w, the isopropyl palmitate is
present in an amount
of 7% or about 7% w/w, the isopropyl myristate is present in an amount of 11%
or about 11%
w/w, and the at least one monohydric C14-C20 alcohol is present in an amount
of 10% or about
10% w/w. In some embodiments, the at least one monohydric C14-C20 alcohol may
be substituted
for any one or more other monohydric C14-C20 alcohols.
[0290] In some embodiments, the topical formulations disclosed herein further
comprise
at least one polyalkylene glycol alkyl ether. In some embodiments, the at
least one polyalkylene
glycol alkyl ether is present in an amount of 0% to 10% or about 0% to about
10% w/w (for
example, about 0%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w/w). In some
embodiments,
the at least one polyalkylene glycol alkyl ether comprises polyethylene glycol
dodecyl ether. In
some embodiments, the polyethylene glycol dodecyl ether is present in an
amount of 5% or about
5% w/w. In some embodiments, the lidocaine is present in an amount of 4% or
about 4% w/w, the
limonene is present in an amount of 10% or about 10% w/w, the at least one C2-
C4 monohydric
alcohol is present in an amount of 51% or about 51% w/w, the isopropyl
palmitate is present in an
amount of 7% or about 7% w/w, the isopropyl myristate is present in an amount
of 11% or about
11% w/w, the at least one monohydric C14-C20 alcohol is present in an amount
of 10% or about
10% w/w, and the at least one polyalkylene glycol alkyl ether is present in an
amount of 5% or
about 5% w/w. In some embodiments, the at least one polyalkylene glycol alkyl
ether may be
substituted for any one or more other polyalkylene glycol alkyl ethers.
[0291] In some embodiments, the topical formulations disclosed herein further
comprise
a cellulosic thickening agent. In some embodiments, the cellulosic thickening
agent is present in
an amount of 0% to 5% or about 0% to about 5% w/w (for example, about 0%, 1%,
2%, 3%, 4%,
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or 5% w/w). In some embodiments, the cellulosic thickening agent comprises
hydroxypropyl
cellulose. In some embodiments, the hydroxypropyl cellulose is present in an
amount of 2% or
about 2%. In some embodiments, the lidocaine is present in an amount of 4% or
about 4% w/w,
the limonene is present in an amount of 10% or about 10% w/w, the at least one
C2-C4 monohydric
alcohol is present in an amount of 51% or about 51% w/w, the isopropyl
palmitate is present in an
amount of 7% or about 7% w/w, the isopropyl myristate is present in an amount
of 11% or about
11% w/w, the at least one monohydric C14-C20 alcohol is present in an amount
of 10% or about
10% w/w, the at least one polyalkylene glycol alkyl ether is present in an
amount of 5% or about
5% w/w, and the cellulosic thickening agent is present in an amount of 2% or
about 2%. In some
embodiments, the cellulosic thickening agent may be substituted for any one or
more other
thickening agents.
[0292] Also disclosed herein are topical formulations comprising lidocaine
present in an
amount of 1% to 10% or about 1% to about 10% w/w (for example, about 1%, 2%,
3%, 4%, 5%,
6%, 7%, 8%, 9%, or 10% w/w), a pressure sensitive adhesive present in an
amount of 70% to 90%
or about 70% to about 90% w/w (for example. about 70%, 71%, 72%, 73%, 74%,
75%, 76%, 77%,
78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% w/w), a
molecular
penetration enhancer present in an amount of 0% to 5% or about 0% to about 5%
w/w (for example,
about 0%, 1%, 2%, 3%, 4%, or 5% w/w), and at least one polyalkylene glycol
alkyl ether present
in an amount of 0% to 5% or about 0% to about 5% w/w (for example, about 0%,
1%, 2%, 3%,
4%, or 5% w/w). In some embodiments, the lidocaine is present in an amount of
4% or about 4%
w/w. In some embodiments, the pressure sensitive adhesive is present in an
amount of 83% or
about 83% w/w. In some embodiments, the pressure sensitive adhesive comprises
DURO-TAK
87-4098. In some embodiments, the molecular penetration enhancer is present in
an amount of 3%
or about 3% w/w. In some embodiments, the molecular penetration enhancer
comprises levulinic
acid. In some embodiments, the at least one polyalkylene glycol alkyl ether is
present in an amount
of 2% or about 2%. In some embodiments, the at least one polyalkylene glycol
alkyl ether
comprises polyethylene glycol dodecyl ether. In some embodiments, the at least
one polyalkylene
glycol alkyl ether is polyethylene glycol dodecyl ether. In some embodiments,
the lidocaine may
be substituted for any one or more other active agents, such as another
aminoamide or aminoester
anesthetic. In some embodiments, the pressure sensitive adhesive may be
substituted for any one
or more other pressure sensitive adhesives. In some embodiments, the molecular
penetration
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enhancer may be substituted for any one or more other molecular penetration
enhancers. In some
embodiments, the at least one polyalkylene glycol alkyl ether may be
substituted for any one or
more other polyalkylene glycol alkyl ethers.
[0293] In some embodiments, the topical formulations disclosed herein further
comprise
at least one isopropyl ester of a C14-C18 fatty acid. In some embodiments, the
at least one
isopropyl ester of a C14-C18 fatty acid is present at an amount of 5% to 10%
or about 5% to about
10% w/w (for example, about 5%, 6%, 7%, 8%, 9%, or 10% w/w). In some
embodiments, the at
least one isopropyl ester of a C14-C18 fatty acid comprises isopropyl
palmitate or isopropyl
myristate, or both. In some embodiments, the isopropyl palmitate and the
isopropyl myristate are
each present in an amount of 2.5% to 5% or about 2.5% to about 5% w/w (for
example, about
2.5%, 3%, 3.5%, 4%, 4.5%, or 5% w/w). In some embodiments, the isopropyl
palmitate or the
isopropyl myristate, or both, are present in an amount of 4% or about 4% w/w.
In some
embodiments, the lidocaine is present in an amount of 4% or about 4% w/w, the
pressure sensitive
adhesive is present in an amount of 83% or about 83% w/w, the molecular
penetration enhancer is
present in an amount of 3% or about 3% w/w, the polyalkylcnc glycol alkyl
ether is present in an
amount of 2% or about 2% w/w, the isopropyl palmitate is present in an amount
of 4% or about
4% w/w, and the isopropyl myristate is present in an amount of 4% or about 4%
w/w. In some
embodiments, the at least one isopropyl ester of a C14-C18 fatty acid may be
substituted for any
one or more other isopropyl esters of a C14-C18 fatty acid.
[0294] In some embodiments of the present application, a pharmaceutical
composition
comprises lidocaine, ethanol, limonene, isopropyl palmitate, isopropyl
myristate, and isostearyl
alcohol.
[0295] According to some embodiments disclosed herein, there is provided a
pharmaceutical composition comprising, consisting essentially of, or
consisting of:
about 4% w/w lidocaine;
about 30% w/w to about 65% w/w ethanol;
about 10% w/w limonene;
about 4% w/w to about 15% w/w isopropyl myristate;
about 4% w/w to about 15% w/w isopropyl palmitate;
about 5% w/w to about 15% w/w of isostearyl alcohol.
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[0296] In some embodiments, there is further included in said pharmaceutical
composition: about 1% w/w to about 8% w/w polyethylene glycol dodecyl ether.
In some
embodiments, there is further included in said pharmaceutical composition:
about 1% w/w to about
5% w/w hydroxypropyl cellulose.
[0297] In some embodiments, there is provided a pharmaceutical composition
comprising lidocaine, a C2-C4 monohydric alcohol, limonene, an isopropyl ester
of a C14-C18
fatty acid, and a monohydric C14-C20 alcohol.
[0298] According to some embodiments disclosed herein, there is provided a
pharmaceutical composition comprising, consisting essentially of, or
consisting of:
about 1% w/w to about 5% w/w lidocaine;
about 30% w/w to about 65% w/w of a C2-C4 monohydric alcohol;
about 2% w/w to about 20% w/w of limonene;
about 2% w/w to about 20% w/w of an isopropyl ester of a C14-C18 fatty acid;
about 2% w/w to about 15% w/w of a monohydric C14-C20 alcohol
[0299] In some embodiments, there is further included in said pharmaceutical
composition: about 1% w/w to about 10% w/w polyethylene glycol dodecyl ether.
In some
embodiments, there is further included in said pharmaceutical composition:
about 1% w/w to about
5% w/w hydroxypropyl cellulose.
[0300] In some embodiments of the present application, there is provided a
pharmaceutical composition comprising lidocaine, a C2-C4 monohydric alcohol,
limonene, the
isopropyl esters of two C14-C18 fatty acids, and a monohydric C14-C20 alcohol.
[0301] According to some embodiments disclosed herein, there is provided a
pharmaceutical composition comprising, consisting essentially of, or
consisting of:
about 1% w/w to about 5% w/w lidocaine;
about 30% w/w to about 65% w/w of a C2-C4 monohydric alcohol;
about 2% w/w to about 20% w/w of limonene;
about 2% w/w to about 15% w/w of the isopropyl ester of a first C14-C18 fatty
acid;
about 2% w/w to about 15% w/w of the isopropyl ester of a second C14-C18 fatty
acid;
about 2% w/w to about 15% w/w of a monohydric C14-C20 alcohol
[0302] In some embodiments, there is further included in said pharmaceutical
composition: about 1% w/w to about 10% w/w polyethylene glycol dodecyl ether.
In some
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embodiments, there is further included in said pharmaceutical composition:
about 1% w/w to about
5% w/w hydroxypropyl cellulose.
[0303] In some embodiments, there is provided a pharmaceutical composition
suitable
for topical administration comprising an active agent, a C2-C4 monohydric
alcohol, limonene, the
isopropyl esters of two C14-C18 fatty acids, and a monohydric C14-C20 alcohol.
[0304] According to some embodiments disclosed herein, there is provided a
pharmaceutical composition comprising, consisting essentially of, or
consisting of:
about 0.01% w/w to about 25% w/w of an active agent;
about 30% w/w to about 65% w/w of a C2-C4 monohydric alcohol;
about 2% w/w to about 20% w/w of limonene;
about 2% w/w to about 15% w/w of the isopropyl ester of a first C14-C18 fatty
acid;
about 2% w/w to about 15% w/w of the isopropyl ester of a second C14-C18 fatty
acid;
about 2% w/w to about 15% w/w of a monohydric C14-C20 alcohol
[0305] In some embodiments, there is further included in said pharmaceutical
composition: about 1% w/w to about 10% w/w polyethylene glycol dodecyl ether.
In some
embodiments, there is further included in said pharmaceutical composition:
about 1% w/w to about
5% w/w hydroxypropyl cellulose.
Characteristics of Compositions Disclosed Herein
(a) Delivery of the Active Agent
[0306] In some embodiments, the composition provides substantially reduced
onsets
relative to comparative formulations. This substantially reduced onset derives
from dual benefits
of the inventive composition, namely substantially reduced lag times combined
with substantially
accelerated delivery kinetics relative to comparative formulations.
(b) Stability
[0307] The stability of a drug product composition can have a significant
impact on the
length and cost of drug development, the nature of the studies required to
support regulatory
submissions, and the ultimate safety and approvability.
[0308] In some embodiments, the topical formulations disclosed herein exhibit
chemical
and physical characteristics suitable for clinical development and
commercialization.
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[0309] In some embodiments, there is provided a lidocaine formulation wherein
the
lidocaine degrades by less than 5% over the course of 6 months at room
temperature. More
preferably, the rate of degradation is less than 5.0, 4.0, 3.0, 2.0, 1.0, 0.9,
0.8, 0.7, 0.6, 0.5, 0.4, 0.3,
0.2, or less than 0.1%, and all fractions in between, over the course of 6
months at room
temperature.
[0310] In some embodiments, the composition remains stable for an acceptable
time
period between preparation and use when stored in a closed container at normal
ambient
temperature. In some embodiments, an "acceptable time period" is at least
about 30 days, at least
about six months, at least about one year, or at least about two years.
[0311] In some embodiments, the composition maintains at least 75%, 80%, 85%,
90%
or 95% strength of the active ingredient following storage for two weeks at 25
C. In some
embodiments, the composition maintains at least 75%. 80%, 85%. 90% or 95%
strength of the
active ingredient following storage for two weeks at 40 C. In some
embodiments, the composition
maintains at least 75%, 80%, 85%, 90% or 95% strength of the active ingredient
following storage
for 16 days at 40 C. In some embodiments, the composition maintains at least
75%, 80%, 85%,
90% or 95% strength of the active ingredient following storage for 43 days at
40 C.
(c) Phartnacokinetic Properties
[0312] In some embodiments, the composition provides substantially reduced
onsets
relative to comparative formulations. This substantially reduced onset derives
from dual benefits
of the inventive composition, namely substantially reduced lag times combined
with substantially
accelerated delivery kinetics relative to comparative formulations. In some
embodiments, the
compositions provide onsets of less than one hour, for example, within 5, 10,
15, 20, 25, 30, 35,
40, 45, 50, 55, or 60 minutes, or any time of onset within a range defined by
any two of the
aforementioned times.
[0313] In some embodiments, following topical administration the composition
provides
substantially increased proportionate delivery into viable epidet
___________________ -nal and dermal tissue relative to
transdeinial permeation, compared with comparator formulations.
[0314] In some embodiments, the composition provides no more than minor skin
irritation, evidenced by a score in a Draize test in albino rabbit skin or
human volunteers of no
more than 2 in erythema, no more than 2 in edema, and no more than 2 in
combined Draize score.
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(d) Viscosity
[0315] In some embodiments, the composition of the present application is more
viscous
than water at standard temperature and pressure ("STP"). In some embodiments,
the composition
has a kinematic viscosity of more than about 1 centistokes ("cSt") or a
dynamic viscosity of more
than about 1 centipoise (cP). In some embodiments, the dynamic viscosity of
the composition is
at most about 2, 3, 4, 5, 7, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70,
75, 80, 90, 100, 150, 200,
250, 500, 1,000, 2,000, 3,000, 5,000, 10,000, 20,000, 50,000, 100,000,
200,000, 500,000 or
1,000,000 cP at STP. In some embodiments, the dynamic viscosity is at most
about 2, 3, 4, 5, 7,
10, 12, 15, 20, 25, 30, 35, 40, 45 or 50 cP at STP. In some embodiments, the
dynamic viscosity is
at most about 2, 3, 4, 5, 7, 10, 12, 15 or 20 cP at STP. In some embodiments,
the composition is
thixotropic (i.e., it decreases in viscosity upon being stirred or shaken).
The composition's viscosity
can be adjusted by the addition of a thickening agent, such as a cellulosic
thickening agent, for
example, hydroxypropyl cellulose, or other thickening agents, or mixtures
thereof.
[0316] In some embodiments the composition is provided in the form of a
topical patch.
[0317] In some embodiments, the composition is provided in the form of a
viscous gel,
suitable for provision in the reservoir of a topical patch of a reservoir
design.
[0318] In some embodiments, the composition is provided in the form of a
viscous gel,
suitable for within an annulus of pressure-sensitive adhesive.
Methods of Preparation
[0319] In embodiments of the present application, the pharmaceutical
compositions are
formulated as a spray, a cream, a lotion, an emulsion, a microemulsion, a gel,
a lacquer, an
ointment, a solution, or a patch, film or mask for topical administration. In
a suitable embodiment,
the composition is a topical patch.
[0320] Methods of preparing compositions for transdermal administration are
known in
the art (see, for example, Remington's Pharmaceutical Sciences, 2000-20th
edition, and The United
States Pharmacopeia: The National Formulary, USP 24 NF19, published in 1999).
[0321] In some embodiments, the formulation is prepared in the form of a
topical film
or patch. Appropriate amounts of the liquid ingredients as taught herein are
added to an amount of
lidocaine in a container and appropriate amounts of the chosen acrylate
copolymer solution or
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solutions are added. The container is covered to prevent evaporative losses
and the container
contents are intimately mixed. Any air bubbles in the resulting homogeneous
solution are removed.
The resulting solution is applied to a backing film and spread over the
surface of a suitable
substrate, such as a backing film, a release film or a transfer film, to
provide a formulation film of
a suitable uniform thickness. The application and spreading process may be
achieved manually.
For preparing larger amounts of film, a semi-automated or automated process is
preferred, as is
well-known in the art. After the film has been deposited, it is subjected to a
controlled period of
heating to evaporate the volatile solvents. Conveniently, another substrate,
such as a release film,
a backing film, or a transfer film is applied to the exposed formulation film
surface to protect the
formulation prior to use. Conveniently, the film composite is then sealed in a
suitable pouch
container to further protect the film from dirt, air, moisture and other
possible contaminants.
Methods of Treatment
[0322] In some embodiments, the invention describes a method for providing
local
anesthesia in a subject comprising the step of applying a therapeutically
effective amount of a
topical formulation to a subject to provide a topical anesthetic
intradermally. In some non-limiting
embodiments, the topical anesthetic is lidocaine. In some embodiments, the
topical formulation is
any one of the topical formulations disclosed herein.
[0323] In some embodiments, the pharmaceutical composition is applied to a
limb or
other suitable body area of the subject.
[0324] In some embodiments, the subject is a human. Alternatively, the subject
is a non-
human mammal.
[0325] In some embodiments, the volume of transdermal formulation that is
applied to
the skin in each dose is in the range of about 0.01 to 10 mL. In a preferred
embodiment the volume
of drug applied to the skin in each dose is in the range of about 0.1 to 5.0
mL and in a yet more
particularly preferred embodiment is in the range of about 0.2 to 2.0 mL.
[0326] In some embodiments, the formulation is applied to an area of skin of
about 0.5,
1, 2, 5, 10, 20, 50, 100, 140 or 200 cm2 or any area between these numbers.
[0327] The compositions of the invention are suitable for use on mammalian
skin.
[0328] In some embodiments, the compositions of the invention are suitable for
acute or
temporary use.
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Packaging
[0329] Compositions of the present disclosure may, if desired, be presented in
a sealed
pouch, each pouch containing a single dose of the inventive formulation. More
than one sealed
pouch may, if desired, be packaged to provide, in one package, multiple
individual doses of the
inventive formulation.
Devices and Kits
[0330] In some embodiments, the topical formulations are prepared as part of a
device
suitable for providing rapid local anesthesia. In some embodiments, the device
comprises an
annulus of pressure sensitive adhesive, within the inner circumference of
which is provided any
one of the topical formulations disclosed herein. In some embodiments, in lieu
of the annulus, the
pressure sensitive adhesive may be any other shape to cover the area to be
affected. In some
embodiments, the device further comprises a backing film on which the topical
formulation is
applied, where the backing film covers the inner circumference of the annulus
of pressure sensitive
adhesive. In some embodiments, the backing film is intended to be removed
after application of
the device such that the inner circumference of the annulus of pressure
sensitive adhesive is
exposed. This exposure allows for subsequent actions, such as allowing access
with a needle. In
some embodiments, the topical formulation is provided as a single dose packet
(e.g., a packet for
a single use). In some embodiments, the backing film may be substituted for or
used in conjunction
with an occlusive, waterproof dressing to cover the affected area for the
duration of anesthetization
by the topical formulation.
[0331] Compositions provided for herein are, in some embodiments, sold or
otherwise
provided in the form of a kit. In some embodiments, the kit comprises a sealed
sachet or pouch
which holds the inventive formulation. Alternatively, the kit may comprise
several sealed sachets
or pouches, each holding the inventive formulation. In some embodiments, the
sachet or pouch
substantially protects the formulation from atmospheric oxygen until the
sachet or pouch is opened
and the inventive fatmulation applied to a subject. In some embodiments, the
kit comprises one or
more of the devices disclosed herein, which may comprise the topical
formulation, pressure
sensitive adhesive, and/or backing film or occlusive, waterproof dressing. In
some embodiments
are disclosed kits for use in anesthetizing a target area of skin in a
subject. In some embodiments,
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the kits comprise a predetermined dose of a topical anesthetic, an annulus of
pressure sensitive
adhesive comprising an outer perimeter that adheres to the skin of the
subject, and an open center
region in which the skin is exposed. In some embodiments, the kits further
comprises an occlusive,
waterproof dressing or a backing film to cover the open center region and
target area. In some
embodiments, the topical anesthetic is any one of the topical formulations
disclosed herein. In
some embodiments, the topical anesthetic comprises lidocaine. In several
embodiments, the
topical anesthetic is present in the topical formulation in an amount about 4
% or less than about
4%. In some embodiments, the lidocaine is optionally in gel format. In some
embodiments, the
annulus of pressure sensitive adhesive comprises a silicone ring. In some
embodiments, the
predetermined dose of the topical anesthetic is provided as a single dose/use
packet.
[0332] In some embodiments, the kit additionally comprises a notice. The
notice may be
in a form approved by a governmental agency regulating the manufacture, use,
or sale of
pharmaceuticals, the notice indicating approval by the agency. In one aspect
the notice may contain
information about how to safely apply the formulation. The notice may include
information
concerning the identity of the active ingredients in the formulation. In one
embodiment the active
ingredient listed on the notice comprises or consists of lidocaine.
[0333] The invention is generally disclosed herein using affirmative language
to describe
the numerous embodiments. The invention also includes embodiments in which
subject matter is
excluded, in full or in part, such as substances or materials, method steps
and conditions, protocols,
or procedures.
[0334] The following non-limiting examples are illustrative of the present
application:
EXAMPLES
[0335] Some of the embodiments discussed above are elaborated upon in further
detail
in the following examples, which are not in any way intended to limit the
scope of the present
disclosure. Those in the art will appreciate that many other embodiments that
not be specifically
discussed in the examples are also provided for herein as described above and
in the claims.
Example 1. Formulation Preparation and Assessment
[0336] Formulations of compositions as provided in Table 1 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
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into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 60
mins following formulation application as measured by extraction from the skin
according to the
procedure described under Example 22 are provided in Figure 1, expressed in
lag per cm2 of
application area.
[0337] The concentration of acrylate pressure-sensitive adhesive in Table 1 is
provided
on a 'wet' basis and the solids content of the adhesives is, on average, 42%,
so that after dry-down,
the lidocaine concentration in the films used in this skin delivery study is
about 9.5% w/w. Figure
1 illustrates that the intrinsic extent of lidocaine delivery from a simple
patch formulation is
relatively low and it varies little as the nature of the acrylate polymer
system is changed. The
embodiments in the subsequent examples demonstrate compositions comprising
lidocaine that
improve topical bioavailability and efficacy.
Table 1: Lidocaine formulation compositions. All amounts are given in % w/w.
LdF1 LdlF3 LdF4 LdF5 LdF6
Lidocainc 4 4 4 4 4
DURO-TAK UN1133 96
DURO-TAK 387-2516 96
DURO-TAK 87-4098 96
DURO-TAK 387-2054 96
GELVA GMS 7883 96
Example 2. Formulation Preparation and Assessment
[0338] Formulations of compositions as provided in Table 2 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 60
mins following formulation application as measured by extraction from the skin
according to the
procedure described under Example 22 are provided (referenced to EMLAO Cream
(lidocaine
2.5% and prilocaine 2.5%)) in Figure 2, expressed in lag per cm2 of
application area.
[0339] It is frequently stated in the art that a solution of an active agent
in pure DMSO
will provide the highest possible levels of dermal delivery and transdermal
permeation. Figure 2
illustrates that a solution of lidocaine in DMSO is less effective at
delivering lidocaine into porcine
skin over 60 minutes than EMLAO, which has only 2.5% w/w of lidocaine. More
surprisingly, the
introduction of D-limonene provides a substantial increase in delivery, even
though other
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molecular accelerants and MPEs have little effect in the same system. Figure 2
shows that
composition LdF26, composed of 4% lidocaine, 86% DMSO, and 10% limonene
exhibit
significantly enhanced (about 233 lag/cm2) delivery of lidocaine, relative to
the LdF25 DMSO and
EMLA controls. Composition LdF29, which contains the surfactant Brij L4, also
exhibits a modest
advantage over control formulations.
Table 2. Lidocaine foimulation compositions. All amounts are given in % w/w.
...................... LdF25 LdF26 ' LdF27 LdF28 ' LdF29 LdF30 LdF31 LdF32
LdF33
Lidocaine 4 4 4 4 4 4 4 4
4
DMSO 96 86 86 86 86 86 86 86
86
Limonene 10
Ethanol 10 --
Transcutol 10
Brij L4 10
Levulinic acid 10
Propylene glycol 10
Dimethyl
isosorbide
Benzyl alcohol
10
Example 3. Formulation Preparation and Assessment
[0340] Formulations of compositions as provided in Table 3 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 60
mins following formulation application as measured by extraction from the skin
according to the
procedure described under Example 22 are provided in Figure 3, expressed in
iLtg per cm2 of
application area.
[0341] Figure 3 illustrates that several of the MPEs known in the prior art
have little
effect on the delivery of lidocaine into the skin over 60 minutes. While the
overall delivery
numbers are lower than in Figure 2 (reflecting the donor to donor variability
of natural animal
skin), formulation LdF36 comprising 10% w/w of isopropyl palmitate and
formulation LdF42
comprising 10% w/w of isopropyl myris tale both evidence enhanced lidocaine
delivery levels as
compared to LdF26. These results show that, in accordance with several
embodiments disclosed
herein, addition of fatty acid esters improve topical delivery of lidocaine
compositions, with
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isopropyl palmitate and isopropyl myristate (isopropyl esters of a C14-C18
fatty acid) having the
greatest effect under the conditions tested.
Table 3. Lidocaine formulation compositions. All amounts are given in % w/w.
al. al, sm- al. cl. cl.
al, al. sm-
.ri
CS' -r-, (.11 C1 ----1 00
Lidocaine 4 4 4 4 4 4 4 4 4
4
DMSO
86 61 56 45 45 45 45 45 45 45
Ethanol 20 20 31 31 31 31 31
31 31
Limonene 10 10 10 10 10 10 10 10
10 10
Menthol 5
a-Terpineol 10
Isopropyl palmitate 10
Hexylene glycol 10
Diisopropyl adipate 10
Glycerol monooleate 10
Diethyl sehacate 10
Octyldodecanol 10
Isopropyl myrist ate
10
Example 4. Formulation Preparation and Assessment
[0342] Formulations of compositions as provided in Table 4 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 60
mins following formulation application as measured by extraction from the skin
according to the
procedure described under Example 22 are provided (referenced to EMLAO Cream
(lidocaine
2.5% and prilocaine 2.5%)) in Figure 4, expressed in lag per cm2 of
application area.
[0343] Figure 4 further illustrates that the effect of a given MPE that is
known in the
prior art on the delivery of lidocaine into the skin over 60 minutes, that is
its effectiveness as a
molecular accelerant for lidocaine, can vary broadly from that of another MPE,
even those that are
nominally similar. Amongst the MPEs considered in Table 4, dipropylene glycol,
PEG-7 methyl
ether, lauryl lactate and oleyl oleate evidence some role as molecular
pentrations, but are inferior
(in this study) to D-limonene.
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Table 4. Lidocaine formulation compositions. All amounts are given in % w/w.
t-' t-'
sa. sa. sa sa. sa. sa. ca.
sa. sa. sa.
"r1 '11 "r1 '11 "r1 "r1 -r1
"r1 '71 "r1
-P c_ c_s, t, -P -P -P -P -P=
- c.s, P
w -P c_il ct --I
Lidocaine HCL 4 4 4 4 4 4 4 4 4 4
DMSO 66 56 56 52 45 45 45 45 45 45
Ethanol 20 20 20 31 31 31 31 31 31 31
Limonene 10 10 10 10 10 10 10 10 10 10
Dipropylene glycol 10
PEG-7 methyl ether 10
Lauryl lactate 1
Laurie cliethanolamide 10
Oleic acid 10
Octyldodecanol 10
Ceraphyl 41 10
Oleyl oleate 10
Capric/caprylic
triglyceride
Example 5. Formulation Preparation and Assessment
[0344] Formulations of compositions as provided in Table 5 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 60
ruins following formulation application as measured by extraction from the
skin according to the
procedure described under Example 22 are provided (referenced to EMLAO Cream
(lidocaine
2.5% and prilocaine 2.5%)) in Figure 5, expressed in ps per cm2 of application
area.
0345] Figure 5 further illustrates that several MPEs that are known in the
prior art have
little incremental effect on the delivery of lidocaine into the skin over 60
minutes, relative to the
simpler formulation comprising DMSO, ethanol and to D-limonene.
Table 5. Lidocaine formulation compositions. All amounts are given in % w/w.
LdF43 LdF53 LdF54 LdF55 LdF56 LdF57 LdF58 LdF59 LdF60
Lidocaine 4 4 4 4 4 4 4 4
4
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DMSO 66 61 61 61 61 61 61 61
61
Ethanol 20 20 20 20 20 20 20 20
20
Limonene 10 10 10 10 10 10 10 10
10
Cyclomethicone 5
PPG 15 stearyl
ether
Span 20 (sorbitan
monolaurate)
Brij L 23 69 LQ
5
(Laureth-23)
Brij S 20 So MH
5
(Steareth-21)
Cocamide DEA 5
Polysorbate 80 5
Ethyl oleate
5
Example 6. Formulation Preparation and Assessment
[0346] Formulation LdF43 (Table 5) was prepared using the general procedure
described
under Example 21. The amounts of lidocaine that have permeated into and which
are retained
within porcine skin at 30 mins following formulation application from LdF43,
referenced to
EMLAO Cream (lidocaine 2.5% and prilocaine 2.5%), LMX Lidocaine 4% topical
anesthetic
cream, Aspercreme Lidocaine Patch 4%, and Salonpas Lidocaine 4% Pain relieving
gel patch
(measured according to the procedure described under Example 22) are provided
in Figure 6,
expressed in vg per cm2 of application area.
[0347] The data presented in Figure 6 illustrates the superiority of several
embodiments
of the formulations disclosed herein (using LdF43 as a non-limiting example)
relative to
commercial lidocaine formulations with respect to providing active agent
delivery into skin.
Example 7. Formulation Preparation and Assessment
[0348] Formulations of compositions as provided in Table 6 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 30
mins following formulation application as measured by extraction from the skin
according to the
procedure described under Example 22 are provided (referenced to EMLAC) Cream
and LMX
Lidocaine 4% topical anesthetic cream) in Figure 7, expressed in tg per cm2 of
application area.
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[0349] Figure 7 further illustrates the superiority of several embodiments of
the
formulations disclosed herein (using LdF43 as a non-limiting example) relative
to commercial
lidocaine formulations with respect to providing active agent delivery into
skin. This data also
shows that, surprisingly, in accordance with several embodiment, incorporation
of additional
individual excipients does not further enhance such delivery.
Table 6. Lidocaine formulation compositions All amounts are given in % w/w.
LdF43 LdF61 LdF62 LdF6 3 LdF64 LdF65 LdF66 LdF67 LdF68
Lidocaine 4 4 4 4 4 4 4 4
4
DMSO 66 56 56 61 61 56 56 59
56
Ethanol 20 20 20 20 20 20 20 20
20
Limonene 10 10 10 10 10 10 10 10
10
Ethanol 10
Transcutol 10
Brij L4 LQ (Laureth-
4)
Levulinic acid 5
Propylene glycol 10
Dimethyl isosorbide
(DMI)
Isopropyl palmitate 7
Hex yl ene glycol
10
Example 8. Formulation Preparation and Assessment
[0350] Formulations of compositions as provided in Table 7 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within porcine skin (the combined epidermal and
dermal tissue) at 30
mins following formulation application as measured by extraction from the skin
according to the
procedure described under Example 22 are provided (referenced to EMLAO Cream
and LMX
Lidocaine 4% topical anesthetic cream) in Figure 8, expressed in lag per cm2
of application area.
[0351] Figure 8 further illustrates the superiority of several embodiments of
the
formulations disclosed herein (using LdF43 as a non-limiting example) relative
to commercial
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lidocaine formulations with respect to providing active agent delivery into
skin. This data also
shows that, surprisingly, in accordance with several embodiment, incorporation
of additional
individual excipients does not further enhance such delivery.
Table 7. Lidocaine formulation compositions. All amounts are given in % w/w.
LdF43 LdF69 LdF70 LdF71 LdF72 LdF73 LdF74 LdF75
Lidocaine 4 4 4 4 4 4 4
4
DMSO 66 56 63 56 56 61 56
61
Ethanol 20 20 20 20 20 20 20
20
Limonene 10 10 10 10 10 10 10
10
Diisopropyl adipate 10
Glycerol monooleate 4
Diethyl sebacate 10
Isopropyl myristate 10
Polysorbate 20 5
Glycerin 10
Propylene Carbonate
5
Example 9. Formulation Preparation and Assessment
[03521 Formulations of compositions as provided in Table 8 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within the epidermal and dermal compartments of
human cadaver at
30 mins following formulation application as measured according to the
procedure described under
Example 22 are provided (referenced to EMLAO Cream) in Figure 9, expressed in
pg per cm2 of
application area.
[0353] Figure 9 illustrates that selected patch formulation compositions do
not provide
enhanced level of lidocaine delivery into the epidermal and dermal
compartments of human
cadaver over a 30 minute period relative to a commercial lidocaine cream
formulation.
Table 8. Lidocaine formulation compositions. All amounts are given in % w/w.
LdF76 LdF77 LdF78 LdF79 LdF80 LdF81 LdF83
Lidocaine 4 4 4 4 4 4
4
Gelva GMS 788 96 86 76 66 56 46
56
Limonene 10 20 30 40 50
20
DMSO
20
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Example 10. Formulation Preparation and Assessment
[0354] Formulations of compositions as provided in Table 9 were prepared using
the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within the epidermal and dermal compartments of
human cadaver at
30 mins following formulation application as measured according to the
procedure described under
Example 22 are provided (referenced to EMLACD Cream) in Figure 10, expressed
in lug per cm2 of
application area.
[0355] Figure 10 illustrates the superiority of the several embodiments of the
formulations disclosed herein, with LdF43 (and a modification, LdF84, that has
altered proportions
of DMSO and ethanol) as non-limiting examples, at providing enhanced active
agent delivery into
the epidermal and dermal compartments of human skin.
Table 9. Lidocaine formulation compositions. All amounts are given in % w/w.
LdF43 LdF84 LdF85 LdF86 LdF87
Lidocainc 4 4 4 4 4
DMSO 66 45 16 6
Ethanol 20 41 50 50 36
Limonene 10 10 10 10 20
Eudragit S 100 20 20 30
Propylene glycol 10 10
Example 11. Formulation Preparation and Assessment
[0356] Formulations of compositions as provided in Table 10 were prepared
using the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within human cadaver skin (the combined epidermal
and dermal tissue)
at 30 mills following formulation application as measured according to the
procedure described
under Example 22 are provided (referenced to SYNERAO (lidocaine and
tetracaine) Topical Patch
and EMLAO Cream) in Figure 11, expressed in ug per cm2 of application area.
[0357] Figure 11 illustrates the superiority of several embodiments of the
formulations
disclosed herein, with LdF84 (and a modification, LdF89, that has higher
viscosity following
incorporation of hydroxypropyl cellulose ("HPC")) as non-limiting examples, at
providing
enhanced active agent delivery into human skin.
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Table 10. Lidocaine formulation compositions. All amounts are given in % w/w.
LdF36 LdF84 LdF88 LdF89
Lidocaine 4 4 2 4
DMSO 45 45 45 45
Ethanol 34 41 36 32
Limonene 10 10 10 10
Isopropyl palmitate 7 7 7
HPC 2
Isopropyl myristate
Example 12. Formulation Preparation and Assessment
[0358] Formulations of compositions as provided in Table 11 were prepared
using the
general procedure described under Example 21. The amounts of lidocaine that
have permeated
into and which are retained within human cadaver skin (the combined epidermal
and dermal tissue)
at 30 mins following formulation application as measured according to the
procedure described
under Example 22 are provided (referenced to EMLAO Cream) in Figure 12,
expressed in lag per
cm2 of application area.
[0359] Figure 12 illustrates that increased concentration of HPC leads to
enhanced levels
of active agent delivery into human skin (over a 30 minute period).
Table 11. Lidocaine formulation compositions. All amounts are given in % w/w.
LdF101 LdF102 LdF103 LdF104 LdF105
Lidocaine 4 4 4 4 4
DMSO 34 34 34 44 34
Ethanol 32 32 37 37 37
Limonene 10 10 5 5 5
Isopropyl palmitate 7 7 7 7 7
Propylene glycol 10 10
HPC 3 3 3 3 3
Croda GTCC 10 10
Example 13. Formulation Preparation and in vivo Assessment
[0360] Formulations of compositions as provided in Table 12 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23. The results here
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indicate that, according to several embodiments, excipients such as isopropyl
myristate and
isopropyl palmitate used in compositions with high transdermal permeation do
not cause undue
irritation.
Table 12. Lidocaine formulation compositions. All amounts are given in % w/w.
c'E; 1¨, 1¨, 1¨, 1¨, 1¨,
k 1¨, NJ
00 l`J LA CP, Oc
,C)
Lidocaine
4 4 4 4 4 4 4 4 4 4 4 4 4 4 4
DMS 0 18 16
Ethanol 50 50 50 50 50 50 50
Limonene
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
Isopropyl
7 7 7 7 7 7 7 7 7 7 7 7 7 7 7
palmitatc
Brij L4 5 5 5 5 5 5 5 5 5
5 5 5 5
Isopropyl
21
26 16 11 11 11 7 7 7
myristate
Propylene
21
glycol
Lauryl lactate 3
Cyclomethicone 5
Peg-7 methyl
21 10 10 7 7
ether
Isostearic acid 21 10 7
7
Iso stearyl
alcohol 21 10
7 7
HPC
3 3 3 3 3 3 3 3 3 3 3 3 3 3 3
Ethanol
50 50 50 50 50 50 50 50
Pain Score 6 10 4 3 4 8 7 5 8 6
6 7 7
Irritancy Score 0 1 7 7 1 1 1 0 0 0 0
0 0 0 0
Example 14. Formulation Preparation and in vivo Assessment
[03611 Formulations of compositions as provided in Table 13 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23.
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Table 13. Lidocaine formulation compositions. All amounts are given in % w/w.
'71 '71 '71 '71 '71 '71 '71 '71
'71 '71 '71 '71
-1;k= 4 Lti. Li,
LA.
cr\
Lidocaine 4 4 4 4 4 4 4 4 4 4 4 4 4
Gelva GMS 788 41 44 44 44 42 42 40
DURO-TAK 87-
4098 41 44 44 44 42 42 40 89 89 89 85 85 81
DMSO 5
Diethyl sebacate 5
Levulinic acid 3 3 3 3 3 3 3 1.5 1.5
1.5 1.5 1.5 1.5
Brij L4 LQ 1 2 2 2 2 2 2 1.5 1.5 1.5 1.5
1.5 1.5
Isopropyl
palmitate 4 4 4 4 4
4 4 4
Isopropyl
myristate 4 4 4 4 4
4
Isostearyl alcohol 4 4 4 4 4
4
Eudragit S100
Ethanol
Pain Score 2 2 2 2 2 2 2 2 2 2
2 2 2
T1 T1 rjaL. aL. al.
P-Ti Pal Pal ,-.11
'(-_-Ak 'ENL C:7; C:7; '-a;
Lidocaine 4 4 4 4 4 4
4 4 2
Gelva GMS 788
DURO-TAK 87-4098 87 87 87 83 83 79 81 85
DMSO
Diethyl sebacate
Levulinic acid 3 3 3 3 3 3 1.5 1.5 3
Brij L4 LQ 2 2 2 2 2 2 1.5 1.5 2
Isopropyl palmitate 4 4 4 4 4 4 4
Isopropyl myristate 4 4 4 4 4 4
Isostearyl alcohol 4 4 4 4 4
Eudragit S100 12
Ethanol 69
Pain Score 2 2 2 1 2 2 2 2 2
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Example 15. Formulation Preparation and in vivo Assessment
[0362] Formulations of compositions as provided in Table 14 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23.
Table 14. Lidocaine formulation compositions. All composition amounts are
given in % w/w.
1 Tj T1 T1 T1 T1 T1 T1,r1 '71 '71
O cc Go Go co co co co co cc co -rc
co
Lidocaine
4 4 4 4 4 4 4 4 4 4 4 4 4
Ethanol
51 40 40 40 40 40 40 46 39 39 46 46 39
Limonene
10 10 10 10 10 10 10 10 10 10 10 10 10
Isopropyl palmitate 7 7 7 7 7 7 7 7 7 7
7 7 7
Brij L4 5 5 5 5 5 5 5 5 5 5
5 5 5
Isopropyl myristate 11 11 11 11 11 11 11 11
11 11 11 11 11
Isostearyl alcohol
10 10 10 10 10 10 10 10 10 10 10 10 10
Klucel MF 2
4 4 4 4 4 4
Lauryl lactate 10 3
Diisopropyl adipate 10 10
Propylene glycol
10
monolaurate
Glyceryl monolinoleate 10
Levulinic acid 10
3
Dimethyl isosorbide 10
10
HPC HY119 3 3 3 3 3 3
Pain Score 1 3 3 2 3 3 3 3 1 3
3 2 3
Example 16. Formulation Preparation and in vivo Assessment
[0363] Formulations of compositions as provided in Table 15 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23. The results here
indicate that DMSO at low concentrations is useful as a permeating agent, as
in accordance with
several embodiments .
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Table 15. Lidocaine formulation compositions. All compositions amounts are
given in % w/w.
s=1. s=1. cL, sm- aL.
P-11 P-11 P-11 Pm P-11 P-Ti P-Ti
P-11 ,- -1 ,- -1 P-11
7,-. -7:: -7:: -7:: 47 -7=: 5 :1 `:--1 .7) .7)
c, c, LA
C71
Lidocaine 4 4 4 4 4 4 4 4 4 4 4 4 4
Ethanol 70 40 72 69 64 64 86 72 80 35 35
Eudragit RSPO 10 15 15
Eudragit NE 30D 10 16
Eudragit S100 9 9 7 7 7 7
Limonene 10 10 10 10 10 10 10 10
Isopropyl palmitate 7 7 7 7 7 7 1
7
Brij L4 1
Isopropyl myristate 1
Isostearyl alcohol 1
DMSO 5
45 45
Water 10 10
Span 40 2 2
Urea 4
Transcutol 30
Glycerin
37 40
Menthol 4
Ethyl acetate 30 30
Transcutol 5
Klucel ME 4
4
HPC 3 3 3
Pain Score 3 2 3 3 1 3 3 3 3 4
4 4 4
Example 17. Formulation Preparation and in vivo Assessment
[0364] Formulations of compositions as provided in Table 16 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23. Compositions
LdF123, LdF124, LdF125, LdF126, LdF128 and LdF129 evidence phase separation.
Table 16. Lidocaine formulation compositions. All composition amounts arc
given in % w/w.
'71 '71 '71
') ') N-)k
W c..n ass ceD
Lidocaine 4 4 4 4 4 4 4 4 4
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Limonene 10 10 10 10 10 10 10 10 10
Isopropyl palmitate 7 7 7 7 7 7 7 7 7
Ethanol 50 50 50 50 50 50 50
Transcutol 26 10 20 45 45
Propylene glycol 26 9 9 6 6 16 11
Glycerin 26
Urea 5 5 5
Sodium lauryl sulphate 5 5
Water 12 12 10 10 10
HPC 3 3 3 3 3 3 3 3 3
Pain Score 3 3 3 3 3 3 3 3 3
Example 18. Formulation Preparation and in vivo Assessment
[0365] Formulations of compositions as provided in Table 17 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23.
Table 17. Lidocaine formulation compositions. All composition amounts are
given in % w/w.
sP.
'71n-
r1 71 r1 r1
W 4 A .C)
Lidocaine 4 4 4 4 4 4 4 4 4 4
Limonene 10 10 10 10 10 10 10 10 10 10
Isopropyl palmitate 7 7 7 7 7 7 7 7 7 7
Ethanol 40 40 40 40 40
Isostearic acid 29 24 19 14 9
Transcutol 34 29 24 19 14 45 45 45 45 45
DMSO 5 10 15 20 25 5 10 15 20 25
Pain Score 3 3 3 3 3 3 3 3 3 3
Example 19. Formulation Preparation and in vivo Assessment
[0366] Formulations of compositions as provided in Table 18 were prepared
using the
general procedure described under Example 21. Each was evaluated in vivo for
numbing potential
and irritation potential according to the procedure described under Example
23. Formulations
LdF201, LdF202 and LdF203 are creams. The results here indicate that, in
accordance with several
embodiments disclosed herein, hexylene glycol enhances skin permeation.
In several
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embodiments, this is accomplished with relatively nominal, to no, irritation
at the application site
as well.
Table 18. Lidocaine formulation compositions. All composition amounts arc
given in % w/w.
s=?.., CI. CI.
'71 '71 '71 '71 '71 '71 '71
'71 ti
\ \ \ \ C)
00 \ D (.4-)
Lidocaine 4 4 4 4 4 4 4 4 4
Limonene 5 10 10 10 10 10
Isopropyl palmitate 4
Isopropyl myristate 8 15
Isostearyl alcohol 8
DMSO 10 45 45 20
Hexylene glycol 37
Glycerin 5 37 30
Diisopropyl adipate 8
Laureth-4 2.3
Laurcth-23 5.7
Choline-generic acid 92
Gelot 64 11
Schercemol GMIS ester 5.3
PEG-40 Stearate 4.7 6 6 6 6
Menthol 4 4 4
Cetostearyl alcohol 6 6 10
Water 40 80 70 76
Water at pH 12 (NaOH) 80
HPC (HY119) 4 4 4
Pain Score 4 1 5 5 3 3 3 3 3
Irritancy Score 5 1 1 1 1 1 1 1
[0367] The formulation compositions disclosed in the above Examples
demonstrate
superior lidocainc delivery compared to commercially available products.
Compositions
comprising lidocaine, DMSO, ethanol, and limonene offer efficient transderrnal
permeation, while
additional MPEs or excipients typically (hut not always) cause a reduction in
efficacy. Thus, in
several embodiments, the compositions are MPE-free. In several embodiments,
the compositions
are excipient-free. Non-limiting examples of compositions according to
embodiments provided
for herein are: LdF43 (4% lidocaine, 66% DMSO, 20% ethanol, 10% limonene) and
LdF84 (4%
lidocaine, 45% DMSO, 41% ethanol, 10% limonene). Addition of at least one
isopropyl ester of a
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C14-C18 fatty acid or HPC further improves permeation, in several embodiments,
as seen with
compositions LdF36 (4% lidocaine, 45% DMSO, 31% ethanol, 10% limonene, 10%
isopropyl
palmitate), LdF42 (4% lidocaine, 45% DMSO, 31% ethanol, 10% limonene, 10%
isopropyl
myristate), and LdF89 (4% lidocaine, 45% DMSO, 32% ethanol, 10% limonene, 7%
isopropyl
palmitate, 2% HPC).
Example 20. Lidocaine Analytical Methods
[0368] A sample of lidocaine was obtained from Sigma (Catalog#: L7757). Assays
of
lidocaine in the various matrices generated in the examples were made using
high performance
liquid chromatography ("HPLC-) using ultraviolet ("UV-) detection at 220 nm or
360 nm using
an Agilent 1100 system and an Agilent ZORBAX Eclipse Plus Phenyl Hexyl 5 m,
4.6x100 mm
column maintained at 40 C, with an Agilent ZORBAX Eclipse Plus 4.6x12.5 nun, 5
i_tm guard
column. Mobile phase A comprised water with 0.1% phosphoric acid and mobile
phase B
comprised acetonitrile, at a flow rate of 1 mL min-1. The gradient consisted
of 5%, 5%, 95% and
95% mobile phase B at each of 0 mm, 1 mm, 6 mm and 7 mm with a post time of
2.5 min. Injection
volumes were 5 or 10 L. The calibration curve was developed using five
standards with lidocaine
concentrations ranging from 0.064 to 40 pg mL-1 , using linear fitting force
through zero.
Example 21. General Procedure for Formulation Preparation
(a) Solutions
[0369] The requisite amount of each excipient required for the given
formulation
composition is provided by accurate volumetric or gravimetric means, as
appropriate, into a
suitable container, such as a glass vial or media bottle. Appropriate solvents
include but are not
limited to water, oil, wax, fatty acids, lipids, detergents, nonpolar solvent,
polar solvent, organic
solvent, inorganic solvent, alcohol, ethanol, DMSO, isopropyl alcohol,
propylene glycol, isopropyl
myristate, polyethylene glycols, terpenes, limonene, esters, ethers, ketones,
aldehydes, carboxylic
acids, acids, bases or any combination or mixtures thereof. The requisite
amount of lidocaine by
accurate weighing is introduced. The suitable container is capped and the
contents sonicated at
room temperature until the lidocaine fully dissolves in the solvent.
(b) Ointments and Gels
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[0370] The requisite amount of each excipient required for the given
formulation
composition is provided by accurate volumetric or gravimetric means, as
appropriate, into a
suitable container, such as a glass or plastic vial. Excipients include but
are not limited to solvents,
emollients, stiffening agents, emulsifying agents, so lubi Ii zing agents,
humectants, thickening
agents, gelling agents, preservatives, permeation enhancers, chelating agents,
antioxidants,
acidifying agents, alkalizing agents, buffering agents, vehicles, carbomers,
gums, xanthan gum,
guar gum, camauba wax, cetyl alcohol, cetyl ester wax, emulsifying wax,
hydrous lanolin, lanolin,
lanolin alcohols, microcrystalline wax, paraffin, petrolatum, polyethylene
glycol, stearic acid,
stearyl alcohol, white wax, yellow wax, wax absolute, poly sorbate 20,
polysorbate 80, polysorbate
60, poloxamer, sorbitan monostearate, sorbitan monooleate, sodium lauryl
sulfate, ethers, esters,
propylene glycol esters, propylene glycol ethers, diethylene glycol esters,
diethylene glycol ethers,
docusate, glycerin, propylene glycol, polyethylene glycol, sorbitol, methyl
cellulose, carrageenan,
colloidal silicon dioxide, gelatin, polyethylene oxide, alginic acid, alginate
salts, sodium alginate,
fumed silica, benzoic acid, propyl paraben, methyl paraben, imidurea, sorbic
acid, sorbate salts,
potassium sorbate, benzalkonium chloride, phenyl mercuric acetate,
chlorobutanol,
phenoxyethanol, ethanol, isopropyl alcohol, oleic acid,
ethylenediaminetetraacetic acid
("EDTA"), butylated hydroxyani sole, butylated hydroxytoluene, citric acid,
phosphoric acid,
sodium hydroxide, sodium phosphate, triethanolamine, water, hexylene glycol,
ley' alcohol,
propylene carbonate, or mineral oil, or any combination or mixtures thereof.
The requisite amount
of lidocaine by accurate weighing is introduced into a suitable container,
such as a glass media
bottle, with excipients. The contents are subjected to processes known in the
art to form a semi-
solid preparation, such as a water-in-oil emulsion, oil-in-water emulsion,
gel, colloid, homogenate,
ointment, cream, lotion, suspension, foam, or shampoo.
(c) Patches
[0371] Appropriate amounts of the liquid ingredients as taught herein are
added to an
amount of lidocaine in a container and appropriate amounts of the chosen
acrylate copolymer
solution or solutions are added. The container is covered or capped to prevent
evaporative losses
and the container contents are intimately mixed. Any air bubbles in the
resulting homogeneous
solution are removed, such as by a 10 minute period of sonication. A backing
film (such as CoTran
9718 from 3M (St. Paul, MN)) and bar applicator such as the bar film
applicator from Mitutoyo,
or a film applicator, such as from Byk-Gardner, are provided on a spreading
platform. The solution
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is applied under the applicator and the applicator translated to produce a
film of the uniform desired
thickness on the backing membrane. The wet film is immediately placed
horizontally for 30
minutes in an incubator or oven operating at 70 C. It is ensured that the
incubator or oven is
suitably vented to avoid exposure by the operators to the volatile solvents
that are lost on drying
of the film. The patch is removed from the incubator or oven and a suitable
release liner, such as
CoTran 9718 from 3M (St. Paul, MN), is applied to the sticky side of the
patch.
[0372] A punch is used to produce a patch of the desired area and the patch is
then heat-
sealed in a suitable laminated pouch.
Example 22. General Procedure for Skin Delivery Measurement
[0373] Different procedures were used in the skin delivery studies, depending
on the
format of the test formulation, the time period for the study, and on whether
human or porcine skin
was employed.
[0374] In first experiments with porcine skin, skin from 4 week-old pigs
sourced from
Thomas D. Morris, Inc. (Reisterstown. MD) was frozen following collection,
shipped frozen over
dry ice and stored frozen until used, when it is first allowed to thaw to room
temperature. Pieces
of skin some 1" square are cut and placed on a paper towel soaked in phosphate-
buffered saline
solution at pH 7.4 ("PBS-). Semisolid test formulations (whether solution,
cream, ointment) are
dispensed onto the skin using a Nichiryo positive displacement pipette
(Nichiryo America,
Maryland Heights, MO) at a dose corresponding to some 9 mg per cm2 of
addressed skin area and
spread over the addressed area using an instrument such as a blunt glass rod.
At the end of the
study period (30 or 60 minutes) excess formulation was wiped from the skin
surface and the surface
cleaned by applying 200 L 50:50 water:ethanol, waiting 5 mins, and wiping dry
with a Kimwipe.
For prototype reservoir patch and matrix patch compositions the procedure is
similar, with the
patch (reservoir) or a lOmm circular punch from a matrix patch formulation,
typically some 20011m
in thickness, is applied to the skin surface. At the end of the 30 or 60
minute contact time, the patch
is gently removed. After cleaning, the skin exterior is tapestripped either
three or ten times, and
the tapestrippings discarded. A punch of diameter in the range of 2 nun or
about 2 mm to 1.5 cm
or about 1.5 cm, such as 2 mm, 3 mm, 4 mm. 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10
mm, 11 mm,
12 mm, 13 mm, 14 mm or 15 mm or about 2 mm, about 3 mm, about 4 mm, about 5
mm, about 6
mm, about 7 mm, about 8 mm, about 9 mm, about 10 mm, about 11 mm, about 12 mm,
about 13
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mm, about 14 mm or about 15 mm, is taken of the central addressed area. The
punched piece
(epidermal and dermal sections are not separated) is placed into a 4 mL glass
vial. 3 mL of DMSO
(the "Extraction Fluid") is added to the vial which is then maintained at 32 C
for 24 hours on an
orbital shaker. At the end of the extraction period, aliquots of the
Extraction Fluid arc drawn and
analyzed by the verified HPLC-UV method (Example 18).
[0375] In later experiments with human skin. Franz-type vertical diffusion
cells
("FDC"s) were employed. Franz diffusion cells are a common and well-known
method for
measuring skin delivery and permeation. The general FDC procedure is described
by Franz. In the
present studies, FDCs with a 3.3mL receptor well volume are used with split
thickness human
cadaver skin (0.015"-0.018", obtained from AlloSource (Centennial, CO), Skin
Bank NY
Firefighters (New York, NY), Science Care (Phoenix, AZ), Allosource
(Centennial, CO) or
BioIVT (Westbury, NY). Skin is frozen following collection, shipped frozen
over dry ice and
stored frozen until used, when it is first allowed to thaw to room
temperature. The FDC donor well
addresses a skin area of about 0.55 cm2. The receptor wells are filled with
phosphate buffered
saline solution at pH 7.4 (-PBS") containing 0.01% sodium azide (a
preservative) (the -Receptor
Fluid"), that was verified to provide appropriate sink conditions for the
diffusing lidocaine
throughout the study. The receptor wells of the FDCs are maintained at 32( 1)
C in a stirring dry
block with continual stirring of the Receptor Fluid in the receptor well at
some 300 rpm using a
magnetic stir bar. Donor and receptor chambers are clamped about the skin
piece under uniform
pressure using a pinch clamp (SS #18 VWR 80073-350).
[0376] After the FDCs are assembled, the skin is allowed to hydrate for 20
minutes in
contact with the Receptor Fluid. Any FDCs that evidence any leakage during
this period are
discarded. The integrity and quality of each skin piece is tested prior to
application of the test
formulations through measurement of the transepidermal electrical resistance
("TEER"). Skin
pieces evidencing an excessively low TEER value are discarded and the TEER
values of accepted
skin pieces are used to guide the distribution of test formulation samples
over the skin piece set.
[0377[ Generally, six (6) replicates of each test formulation are examined,
typically in a
batch of some 36 FDCs in total. Each solution or gel test formulation is
applied using a Nichiryo
positive displacement pipette at a dose of 5 L or 10 L, corresponding to 9 or
18 mg per cm2. For
patch formulations, a lOmm circular piece is cut or punched from each prepared
patch formulation,
typically some 200pm in thickness. The patch is applied to the skin exterior
and the donor well
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then applied over the patch, the perimeter of each patch piece being situated
under the donor well
flange. Dosings of the set of FDCs in a batch are time-staggered, so as to
avoid delay in the
subsequent disassembly, skin surface cleaning and tape-tripping operations.
[0378] At the end of the experiment (30 or 60 mins depending on the study),
the FDC is
disassembled and the patch is carefully peeled away from the skin surface or,
for ointments, gels
and solutions, any residual formulation is wiped from the skin exterior with a
KimWipe. The skin
is further cleaned by applying 2001aL 50:50 water:ethanol, waiting 5 mins, and
wiping dry with a
Kimwipe. The successive topmost layers of the stratum corneum are removed by
three (3) times
applying cellophane tape to the skin and then removing the tape. Tape
strippings are discarded,
the material present in those peripheral layers being considered absorbed only
superficially. In
certain cases the epidermal and dermal compartments were separated, using mild
heating if
necessary (to 60 C for no longer than one minute). The skin sections (or
epidermal and dermal
sections separately) are placed into 4 mL glass vials. 3 mL of Extraction
Fluid is added to each
vial and the vials maintained at 32 C for 24 hours on an orbital shaker. At
the end of the extraction
period, aliquots of the Extraction Fluid are drawn and analyzed by the
verified HPLC-UV method
(Example 18).
Example 23. In vivo Assessments of Local Anesthesia Effectiveness and
Irritation Potential
[0379] To assess the effectiveness of a test formulation in causing prompt
local
anesthesia, the formulation is applied to the forearm of between one and five
human volunteer
subjects. For a solution, ointment or gel, the test formulation is applied
over an approximately 8
cm2 area of skin, at a dosing of around 8 mg per cm2. In the case of a
reservoir patch configuration,
the test formulation is introduced into the interior reservoir volume of the
reservoir patch and the
patch applied to the skin; the formulation contact area is some 3 cm2. In the
case of a matrix patch,
an approximately 2.5x2.5 cm or some 6 cm2 area of patch is cut, release liner
(if present) removed,
and the patch applied to the skin. 45 minutes following formulation
application, the test
formulation is removed and a sharp object (a Nichiryo positive pipette tip or
a 16 gauge syringe
needle) is applied to the treated skin area. Each subject rates the level of
pain sensation
subjectively, that is provides a 'Pain Score' or 'Numbness Score' on a 1-10
basis. 1 being complete
numbness and 10 being no detectable effect. The subject also rates degree of
irritation, if present,
using a similar scale from 0-10. 0 being non-irritating and 10 being
unbearably irritating. For test
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formulations that prove to be substantially irritating, the experiment is
concluded prematurely by
prompt removal of the test formulation (preventing then a comparative
assessment of numbness).
Example 24. Short Term Stability Assessment
[0380] For assessments of the short term stabilities of transdermal patch
formulations,
samples of transdermal patches are prepared according to Example 21, heat-
sealed in polybags
and placed in stability chambers operating at 30 C 2 C and 65% 5% relative
humidity ("RH")
and at 40 C 2 C/75% 5% RH. At predefined sampling times, such as 1 day, 7
days, 2 weeks,
3 weeks, 4 weeks, 1 month, 2 months, or any time within a range defined by any
two of the
aforementioned times, pouches are removed from each stability chamber, opened,
the patch inside
each removed and dissolved in an appropriate volume, e.g. 5 mL, of methanol,
and the
concentration of lidocaine measured using the verified HPLC-UV method (Example
20).
Example 25. Long Term Stability Assessment
[0381] For assessments of the longer term stabilities of transdermal patch
formulations,
samples of transdermal patches are prepared according to Example 21, heat-
sealed in polybags
and placed in stability chambers operating at 25 C 2 C and 60% 5% RH and
at 30 C
2 C/65% 5% RH. At predefined sampling times, such as 1, 2, 3, 4 weeks, or 1,
2, 3, 4, 5, 6, 7, 8,
9, 10, 11. 12 months, or any time within a range defined by any two of the
aforementioned times,
pouches are removed from each stability chamber, opened, the patch inside each
removed and
dissolved in an appropriate volume, e.g. 5 mL, of methanol, and the
concentration of lidocaine
measured using the verified HPLC-UV method (Example 20).
Example 26. Methods of Manufacturing Stable Patch Formulations
[0382] Transdermal patch formulations that provide suitable chemical and
physical
stability are conveniently prepared according to the compositions provided in
Examples 1 to 19
and the procedure provided in Example 21. A drug product must be manufactured
on a consistent
basis and subject to exacting quality conditions. To produce a composition as
disclosed herein,
preparation should be in line with the disclosed preparative procedures. Due
consideration should
be given to one or more of the following: (i) use of a pharmaceutical grade of
each excipient, (ii)
adherence to the methods of the present disclosure, (iii) achieving a
substantially homogeneous
solution following combination of all ingredients, (iv) reducing premature
evaporative losses, (v)
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substantial removal of air bubbles prior to film formation, (vi) deposition of
films of uniform
thickness on the chosen substrate, (vii) limited introduction of contaminants
or chemical changes
in the formulation by the spreading apparatus, (viii) substantially uniform
and controlled drying
conditions.
Example 27. Kit for Use in Alleviating Needle Pain
[0383] This non-limiting embodiment relates to a kit, and its use, for
reduction,
ameliorating or eliminating needle pain (e.g., pain associated with needle
sticks or skin punctures).
In several embodiments, the kit comprises (i) at least one pre-dosed tube of a
fast onset lidocaine
formulation (for example those disclosed herein) (ii) a self-adhesive gel ring
(or other shape with
an open central region), and (iii) a waterproof occlusive dressing or backing
film.
[0384] In several embodiments, the pre-dosed lidocaine is a lidocaine gel. In
several
embodiments, the lidocaine is clear, or substantially clear, for example to
aid in visual
identification of an injection site. In several embodiments, the pre-dosed
lidocaine is dosed for a
particular patient, for example a pediatric subject, an adult subject etc. In
several embodiments,
different kits are provided, for example with higher doses provided for
patients with particular
sensitivities to needle sticks or other skin punctures. In several
embodiments, at least a second
dose of lidocaine is provided in a kit, for example if additional anesthesia
is needed for a subject.
In several embodiments, the pre-dosed amount of lidocaine ensures an
appropriate dose for a given
patient to maximize efficacy and/or minimize risk for overdose.
[0385] In several embodiments, the lidocaine formulation is advantageous in
that it is
believed to be safer than available prescriptions containing tetracaine or
prilocaine (both increase
risk of potential methemoglobinemia). In several embodiments, the use of a
lidocaine gel provides
advantageous antimicrobial properties to reduce risk of infection at a site of
injection. In several
embodiments, the gel is clear, which aids in visualization of skin by a
medical provider for
monitoring of potential adverse reaction.
[0386] In several embodiments, the ring is silicone or other relatively soft
and pliable
material. Any biocompatible, flexible material is suitable, so long as it
adheres to the target site,
even during motion of the tissue surrounding the target site. In several
embodiments, the flexibility
and conformance of the ring (or other shape with an open central region) keeps
medications
localized to intended area. As such, in several embodiments, the use of the
ring (or other shape)
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minimizes the need for excessive medication, thereby enhancing safety for
patients. In several
embodiments, the ring further comprises a dye or other colorant that
temporarily marks the skin
of the subject in the shape of the ring (for example to identify the target
site for injection).
Alternatively, the kit may further comprise a skin marking pen.
[0387] In several embodiments, the occlusive dressing or backing film is
transparent, or
substantially so, to facilitate a clear visual view of the target area. This
allows, in several
embodiments, a medical provider to view the skin throughout the duration of a
procedure (from
application of anesthetic to completion of injection) to detect possible
adverse effects or reactions.
However, the occlusive dressing or backing film does not necessarily need to
be transparent.
[0388] In use, according to several embodiments, a silicone gel ring is placed
onto clean
dry skin. Gel (e.g., a lidocaine formulation as disclosed herein) is dispensed
from the pre-
determined dosing tube and is placed into center of the ring. The occlusive
dressing or backing
film is placed atop, or has been placed on the center of ring previously (e.g.
during manufacture).
Figure 13 shows a use of the kit according to several embodiments with a ring
applied to the skin
of a patient at a target site and covered with an occlusive dressing (such as
TEGADERMCD).
Figures 15A-E shows additional embodiments of a silicone gel ring with backing
film.
[0389] The system is left in place for 30-90 minutes. At the time of the
needle procedure,
the occlusive dressing or backing film is removed and the gel ring is left on
the skin in order to
delineate the site of anesthetized skin (Figure 15C-D). In several
embodiments, downward
pressure, around the anesthetized site in one or more places, is applied in
order to stimulate local
nerves that sense pressure and/or vibration, which in several embodiments,
further alleviates the
sensations of pain from a needle stick or skin puncture (see, e.g., Figure 14
and 15E). If the desired
degree of anesthesia is not met, the area can be re-dosed and/or re-occluded
for an additional period
of time. At such time that anesthesia is reached, the lidocaine gel may be
removed by the medical
provider with an alcohol pad (or by tissue or other means) and the injection
can then be
administered. Post-injection, the gel ring is removed and discarded.
[0390] In at least some of the previously described embodiments, one or more
elements
used in an embodiment can interchangeably be used in another embodiment unless
such a
replacement is not technically feasible. It will be appreciated by those
skilled in the art that various
other omissions, additions and modifications may be made to the methods and
structures described
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above without departing from the scope of the claimed subject matter. All such
modifications and
changes are intended to fall within the scope of the subject matter, as
defined by the appended
claims.
[0391] With respect to the use of substantially any plural and/or singular
terms herein,
those having skill in the art can translate from the plural to the singular
and/or from the singular to
the plural as is appropriate to the context and/or application. The various
singular/plural
permutations may be expressly set forth herein for sake of clarity.
[0392] It will be understood by those within the art that, in general, terms
used herein,
and especially in the appended claims (e.g., bodies of the appended claims)
are generally intended
as "open- terms (e.g., the term "including- should be interpreted as
"including but not limited to,"
the term "having" should be interpreted as "having at least," the term
"includes" should be
interpreted as "includes but is not limited to," etc.). It will be further
understood by those within
the art that if a specific number of an introduced claim recitation is
intended, such an intent will
be explicitly recited in the claim, and in the absence of such recitation no
such intent is present.
For example, as an aid to understanding, the following appended claims may
contain usage of the
introductory phrases "at least one" and "one or more" to introduce claim
recitations. However, the
use of such phrases should not be construed to imply that the introduction of
a claim recitation by
the indefinite articles "a" or "an" limits any particular claim containing
such introduced claim
recitation to embodiments containing only one such recitation, even when the
same claim includes
the introductory phrases "one or more" or "at least one" and indefinite
articles such as "a" or "an"
(e.g., "a" and/or "an" should be interpreted to mean "at least one or "one or
more"); the same
holds true for the use of definite articles used to introduce claim
recitations. In addition, even if a
specific number of an introduced claim recitation is explicitly recited, those
skilled in the art will
recognize that such recitation should be interpreted to mean at least the
recited number (e.g., the
bare recitation of "two recitations," without other modifiers, means at least
two recitations, or two
or more recitations). Furthermore, in those instances where a convention
analogous to "at least one
of A, B, and C, etc." is used, in general such a construction is intended in
the sense one having
skill in the art would understand the convention (e.g., "a system having at
least one of A, B, and
C" would include but not be limited to systems that have A alone, B alone, C
alone, A and B
together, A and C together, B and C together, and/or A, B, and C together,
etc.). In those instances
where a convention analogous to "at least one of A, B, or C, etc." is used, in
general such a
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construction is intended in the sense one having skill in the art would
understand the convention
(e.g., "a system having at least one of A, B, or C" would include but not be
limited to systems that
have A alone, B alone, C alone, A and B together, A and C together, B and C
together, and/or A,
B, and C together, etc.). It will be further understood by those within the
art that virtually any
disjunctive word and/or phrase presenting two or more alternative tel
_______________ iis, whether in the
description, claims, or drawings, should be understood to contemplate the
possibilities of including
one of the terms, either of the terms, or both terms. For example, the phrase
"A or B" will be
understood to include the possibilities of "A" or "B" or "A and B ."
[0393] In addition, where features or aspects of the disclosure are described
in terms of
Markush groups, those skilled in the art will recognize that the disclosure is
also thereby described
in terms of any individual member or subgroup of members of the Markush group.
[0394] Any titles or subheadings used herein are for organization purposes and
should
not be used to limit the scope of embodiments disclosed herein. Moreover, a
listing of one
ingredient under one heading does not preclude it also being considered under
another heading.
For example, an ingredient listed under the heading of -Preservative" may also
function in some
embodiments as an anti-oxidant, despite not being listed under the heading
"Anti-oxidant".
[0395] As will be understood by one skilled in the art, for any and all
purposes, such as
in terms of providing a written description, all ranges disclosed herein also
encompass any and all
possible sub-ranges and combinations of sub-ranges thereof. Any listed range
can be easily
recognized as sufficiently describing and enabling the same range being broken
down into at least
equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting
example, each range discussed
herein can be readily broken down into a lower third, middle third and upper
third, etc. As will
also be understood by one skilled in the art all language such as "up to," "at
least," "greater than,"
"less than," and the like include the number recited and refer to ranges which
can be subsequently
broken down into sub-ranges as discussed above. Finally, as will be understood
by one skilled in
the art, a range includes each individual member. Thus, for example, a group
having 1-3 articles
refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5
articles refers to groups
having 1, 2, 3, 4, or 5 articles, and so forth.
[0396] While various aspects and embodiments have been disclosed herein, other
aspects
and embodiments will be apparent to those skilled in the art. The various
aspects and embodiments
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disclosed herein are for purposes of illustration and are not intended to be
limiting, with the true
scope and spirit being indicated by the following claims.
[0397] It is understood that the examples and embodiments described herein are
for
illustrative purposes only. Various modifications or changes in light thereof
will be suggested to
persons skilled in the art and are to be included within the spirit and
purview of this application
and the scope of the appended claims. All publications, patents, and patent
applications cited herein
are hereby incorporated by reference in their entirety for all purposes.
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