NANO-EMULSION BASED COMPOSITIONS, METHODS FOR THEIR PREPARATION AND THEIR USE IN DELIVERY OF ACTIVE INGREDIENTS

COMPOSITIONS A BASE DE NANOEMULSIONS, PROCEDES DE LEUR PREPARATION ET LEUR UTILISATION DANS LA LIVRAISON D`INGREDIENTS ACTIFS

English Abstract

The present disclosure relates to compositions comprising an oil-in-water nano- emulsion dispersed in an external oil phase, methods for the preparation of such compositions as well as uses of such compositions, for example, for delivery of active ingredients to a subject. The methods comprise combining a first mixture comprising a liquid oil and a charged lipid with a second mixture that is an aqueous mixture comprising a film-forming themoreversible emulsifier to prepare an oil-in-water nano-emulsion; and combining the oil-in-water nano- emulsion with a third mixture comprising a combination of solid lipids to prepare the composition.

French Abstract

Il est décrit des compositions qui consistent en une nano-émulsion dhuile et deau propagée dans une phase huileuse externe, des modes de préparation de ces compositions ainsi que des modes dutilisation de ces compositions, comme la libération dingrédients actifs dans un sujet. Les méthodes comprennent la combinaison dun premier mélange composé dune huile à létat liquide et dun lipide chargé à un deuxième mélange aqueux constitué dun émulsifiant thermoréversible qui forme un film en vue de préparer une nano-émulsion dhuile et deau, suivie par la combinaison de la nano-émulsion dhuile et deau à un troisième mélange composé dune combinaison de lipides à létat solide en vue de préparer la composition.

Claims

CA 3091186
CLAIMS
What is claimed is:
1. A composition comprising an oil-in-water nano-emulsion dispersed in an
external oil
phase, the oil-in-water nano-emulsion comprising an internal oil phase
dispersed in an
aqueous phase and stabilized by a film-forming thennoreversible emulsifier,
wherein
the internal oil phase comprises a liquid oil in combination with a charged
lipid;
the external oil phase comprises a combination of solid lipids;
the ratio by weight of the oil-in-water nano-emulsion to the external oil
phase is in
a range of from about 2:3 to about 8.5:3; and the ratio by weight of the
liquid oil to the
charged lipid is in a range of from about 5:1 to about 50:1.
2. The composition of claim 1, wherein the aqueous phase further comprises
a humectant.
3. The composition of claim 2, wherein the humectant is glycerin.
4. The composition of any one of claims 1 to 3, wherein the liquid oil is a
synthetic oil,
mineral oil, natural oil or combinations thereof.
5. The composition of claim 4, wherein the liquid oil is a vegetable oil or
combination thereof.
6. The composition of any one of claims 1 to 5, wherein the liquid oil is
medium-chain
triglyceride (MCT) oil.
7. The composition of any one of claims 1 to 6, wherein the charged lipid
is a negatively
charged lipid.
8. The composition of claim 7, wherein the negatively charged lipid is
oleic acid.
9. The composition of any one of claims 1 to 8, wherein the film-forming
thennoreversible
emulsifier is an amphoteric tri-block copolymer that is a polyethylene
glycol¨b¨
polypropylene glycol¨b¨polyethylene glycol (poloxamer).
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10. The composition of any one of claims 1 to 9, wherein the ratio by
weight of the film-
forming thermoreversible emulsifier to the internal oil phase is at least 0.1
: 10.
11. The composition of any one of claims 1 to 10, wherein the combination
of solid lipids is a
combination of at least two of:
glyceryl dibehenate, glyceryl palmitostearate or combinations thereof;
(ii) petrolatum, cetyl palmitate, beeswax or combinations thereof;
(iii) a hydrogenated vegetable oil or combinations thereof;
(iv) a fatty alcohol or combinations thereof; and
(v) glyceryl stearate, polyethylene glycol (PEG)-40 glyceryl stearate, PEG-
100
stearate or combinations thereof.
12. The composition of claim 11, wherein the petrolatum, cetyl palmitate,
beeswax or
combin an on s thereof i s petrol atum
13. The composition of claim 11 or 12, wherein the ratio by weight of (i) :
[(ii) + (iii)] : (v) in
the combination of solid lipids is about 2 : 1 : 2.
14. The composition of any one of claims 11 to 13, wherein the solid lipids
are glyceryl dibehenate,
petrolatum, hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-
100 stearate.
15. The composition of any one of claims 1 to 14, wherein the composition
further comprises
a multifunctional polymer, a liquid emollient, a penetration enhancer, a
chelating agent,
an antioxidant, a preservative or combinations thereof.
16. The composition of claim 15, wherein the composition comprises:
a combination of multifunctional polymers that is polyacrylate crosspolymer-6
and hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer;
(ii) the liquid emollient isopropyl lauroyl sarcosinate;
(iii) the penetration enhancer ethoxy diglycol;
(iv) the chelating agent disodium ethylenediaminetetraacetic acid (EDTA);
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(v) the antioxidant butylated hydroxytoluene; and
(vi) a combination of preservatives that is caprylyl glycol and phenoxy
ethanol.
17. The composition of claim 15, wherein the composition comprises,
consists essentially of
or consists of:
water in an amount of from about 50 wt% to about 80 wt%;
glycerin in an amount of from about 1 wt% to about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about 0.05 wt% to about 5 wt%;
oleic acid in an amount of from about 0.1 wt% to about 10 wt%;
MCT oil in an amount of from about 1 wt% to about 10 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to about 5 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 5 wt%;
disodium EDTA in an amount of from about 0.005 wt% to about 0.05 wt%;
glyceryl dibehenate in an amount of from about 1 wt% to about 10 wt%;
petrolatum in an amount of from about 0.5 wt% to about 10 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%;
cetyl alcohol in an amount of from about 0.5 wt% to about 10 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 1 wt% to
about 10 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 1 wt% to about 5 wt%;
ethoxy diglycol in an amount of from about 1 wt% to about 10 wt%;
butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%; and
phenoxy ethanol in an amount of from about 0.05 wt% to about 1 wt%.
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18. The composition of claim 15, wherein the composition comprises:
water in an amount of from about 60 wt% to about 70 wt%;
glycerin in an amount of from about 1.5 wt% to about 5 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about 0.1 wt% to about 0.5 wt%;
oleic acid in an amount of from about 0.5 wt% to about 2.5 wt%;
MCT oil in an amount of from about 7 wt% to about 9 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.2 wt% to about 1 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 1 wt%;
disodium ethylenediaminetetraacetic acid in an amount of from about 0.01 wt%
to
about 0.03 wt%;
glyceryl dibehenate in an amount of from about 5 wt% to about 6 wt%;
petrolatum in an amount of from about 0.75 wt% to about 1.25 wt%;
hydrogenated castor oil in an amount of from about 1.25 wt% to about 2.25 wt%;

cetyl alcohol in an amount of from about 0.75 wt% to about 5 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 5 wt% to
about 6 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 2 wt% to about 4 wt%;
ethoxy diglycol in an amount of from about 4 wt% to about 6 wt%;
butylated hydroxytoluene in an amount of from about 0.05 wt% to less than 0.1
wt%;
caprylyl glycol in an amount of from about 0.4 wt% to about 0.6 wt%; and
phenoxy ethanol in an amount of from about 0.85 wt% to about 0.95 wt%.
19. The composition of claim 15, wherein the composition comprises:
water in an amount of about 62 wt%;
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glycerin in an amount of about 2 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of about 0.3 wt%;
oleic acid in an amount of about 1 wt%;
MCT oil in an amount of about 8 wt%;
polyacrylate crosspolymer-6 in an amount of about 0.6 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of about 0.2 wt%;
disodium ethylenediaminetetraacetic acid in an amount of about 0.02 wt%;
glyceryl dibehenate in an amount of about 5.5 wt%;
petrolatum in an amount of about 1 wt%;
hydrogenated castor oil in an amount of about 1.75 wt%;
cetyl alcohol in an amount of about 2 wt%;
glyceryl stearate and PEG-100 stearate in an amount of about 5.5 wt%;
isopropyl lauroyl sarcosinate in an amount of about 3 wt%;
ethoxy diglycol in an amount of about 5 wt%;
butylated hydroxytoluene in an amount of 0.1 wt% or less than 0.1 wt%;
caprylyl glycol in an amount of about 0.5 wt%; and
phenoxy ethanol in an amount of about 0.9 wt%.
20. The composition of any one of claims 1 to 19, wherein the ratio by
weight of the oil-in-
water nano-emulsion to the external oil phase is about 8.5:3.
21. A composition comprising an oil-in-water nano-emulsion dispersed in an
external oil
phase, the oil-in-water nano-emulsion comprising an internal oil phase
dispersed in an
aqueous phase and stabilized by a film-forming thennoreversible emulsifier,
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wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is about 8.5:3; the ratio by weight of the liquid oil to the charged
lipid is in a range of
from about 5:1 to about 50:1; and the composition comprises:
water in an amount of from about 50 wt% to about 80 wt%;
glycerin in an amount of from about 1 wt% to about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about 0.05 wt% to about 5 wt%;
oleic acid in an amount of from about 0.1 wt% to about 10 wt%;
MCT oil in an amount of from about 1 wt% to about 10 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to about 5 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 5 wt%;
disodium EDTA in an amount of from about 0.005 wt% to about 0.05 wt%;
glyceryl dibehenate in an amount of from about 1 wt% to about 10 wt%;
petrolatum in an amount of from about 0.5 wt% to about 10 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%;
cetyl alcohol in an amount of from about 0.5 wt% to about 10 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 1 wt% to
about 10 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 1 wt% to about 5 wt%;
ethoxy diglycol in an amount of from about 1 wt% to about 10 wt%;
butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%; and
phenoxy ethanol in an amount of from about 0.05 wt% to about 1 wt%.
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22. A
composition comprising an oil-in-water nano-emulsion dispersed in an external
oil
phase, the oil-in-water nano-emulsion comprising an internal oil phase
dispersed in an
aqueous phase and stabilized by a film-forming thennoreversible emulsifier,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is about 8.5:3; the ratio by weight of the liquid oil to the charged
lipid is in a range of
from about 5:1 to about 50:1; and the composition comprises:
water in an amount of from about 60 wt% to about 70 wt%;
glycerin in an amount of from about 1.5 wt% to about 5 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about 0.1 wt% to about 0.5 wt%;
oleic acid in an amount of from about 0.5 wt% to about 2.5 wt%;
MCT oil in an amount of from about 7 wt% to about 9 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.2 wt% to about 1 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 1 wt%;
disodium ethylenediaminetetraacetic acid in an amount of from about 0.01 wt%
to
about 0.03 wt%;
glyceryl dibehenate in an amount of from about 5 wt% to about 6 wt%;
petrolatum in an amount of from about 0.75 wt% to about 1.25 wt%;
hydrogenated castor oil in an amount of from about 1.25 wt% to about 2.25 wt%;

cetyl alcohol in an amount of from about 0.75 wt% to about 5 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 5 wt% to
about 6 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 2 wt% to about 4 wt%;
ethoxy diglycol in an amount of from about 4 wt% to about 6 wt%;
butylated hydroxytoluene in an amount of from about 0.05 wt% to less than 0.1
wt%;
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caprylyl glycol in an amount of from about 0.4 wt% to about 0.6 wt%; and
phenoxy ethanol in an amount of from about 0.85 wt% to about 0.95 wt%.
23. A
composition comprising an oil-in-water nano-emulsion dispersed in an external
oil
phase, the oil-in-water nano-emulsion comprising an internal oil phase
dispersed in an
aqueous phase and stabilized by a film-forming themioreversible emulsifier,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is about 8.5:3; the ratio by weight of the liquid oil to the charged
lipid is about 8:1,
and the composition comprises:
water in an amount of about 62 wt%;
glycerin in an amount of about 2 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of about 0.3 wt%;
oleic acid in an amount of about 1 wt%;
MCT oil in an amount of about 8 wt%;
polyacrylate crosspolymer-6 in an amount of about 0.6 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of about 0.2 wt%;
disodium ethylenediaminetetraacetic acid in an amount of about 0.02 wt%;
glyceryl dibehenate in an amount of about 5.5 wt%;
petrolatum in an amount of about 1 wt%;
hydrogenated castor oil in an amount of about 1.75 wt%;
cetyl alcohol in an amount of about 2 wt%;
glyceryl stearate and PEG-100 stearate in an amount of about 5.5 wt%;
isopropyl lauroyl sarcosinate in an amount of about 3 wt%;
ethoxy diglycol in an amount of about 5 wt%;
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butylated hydroxytoluene in an amount of 0.1 wt% or less than 0.1 wt%;
caprylyl glycol in an amount of about 0.5 wt%; and
phenoxy ethanol in an amount of about 0.9 wt%.
24. The composition of any one of claims 1 to 23, wherein the oil droplets
of the internal oil
phase dispersed in the aqueous phase have a mean droplet size of less than
about 700 nm.
25. The composition of any one of claims 1 to 24, wherein the composition
is devoid of
active ingredients.
26. The composition of claim 25, wherein the composition has up to 2 years
shelf life.
27. A composition comprising the composition of any one of claims 1 to 24,
and further
comprising one or more active ingredients.
28. The composition of claim 27, wherein the composition releases the one
or more active
ingredients for a time of up to about 24 hours.
29. The composition of claim 27 or 28, wherein the composition has at least
6 months shelf life.
30. The composition of any one of claims 27 to 29, wherein the active
ingredient is
diclofenac or a pharmaceutically acceptable salt thereof.
31. The composition of claim 30, wherein the diclofenac or pharmaceutically
acceptable salt
thereof is diclofenac sodium present in an amount of from about 5 wt% to about
10 wt%.
32. The composition of any one of claims 27 to 29, wherein the active
ingredients are
lidocaine, benzocaine, tetracaine or pharmaceutically acceptable salts thereof
or
combinations thereof, wherein the lidocaine, benzocaine, tetracaine or
pharmaceutically
acceptable salts thereof are present in an amount of up to about 20 wt%, with
the total
concentration of the lidocaine, benzocaine, tetracaine or pharmaceutically
acceptable
salts thereof being no more than 30 wt%, based on the total weight of the
composition.
33. The composition of any one of claims 27 to 29, wherein the active
ingredient is
tetrahydrocannabinol (THC), cannabidiol (CBD) or combinations thereof.
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34. The composition of claim 33, wherein the composition comprises CBD
isolate in an
amount of up to about 20 wt%, CBD oil in an amount of up to about 15 wt%,
and/or THC
distillate in an amount of up to 20 wt%.
35. The composition of any one of claims 27 to 29, wherein the composition
further
comprises one or more natural and/or herbal active agents with anti-
inflammatory,
analgesic or anesthetic effect; terpenoids; essential oils or combinations
thereof.
36. A use of the composition of any one of claims 1 to 26 for preparing a
compound
comprising one or more active ingredients.
37. A use of a composition of any one of claims 27 to 35 on the skin of a
subject for delivering
the one or more active ingredients to the subject.
38. A use of a composition of any one of claims 27 to 35 for preparation of
a medicament for
the skin of a subject for delivering the one or more active ingredients to the
subject.
39. The use of claim 37 or 38, wherein the composition is for
administration once per day.
40. A use of a compound as defined in claim 36 on the skin of a subject for
delivering the one
or more active ingredients to the subject.
41. A use of a compound as defined in claim 36 for preparation of a
medicament for the skin
of a subject for delivering the one or more active ingredients to the subject.
42. The use of claim 40 or 41, wherein the compound is for administration
once per day.
43. The use of any one of claims 37 to 42, wherein the subject is a human.
44. A method of preparing a composition comprising an oil-in-water nano-
emulsion
dispersed in an external oil phase, the oil-in-water nano-emulsion comprising
an internal
oil phase dispersed in an aqueous phase, the method comprising:
combining a first mixture comprising a liquid oil and a charged lipid with a
second mixture that is an aqueous mixture comprising a film-forming
thennoreversible
emulsifier to prepare an oil-in-water nano-emulsion; and
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combining the oil-in-water nano-emulsion with a third mixture comprising a
combination of solid lipids to prepare the composition,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is in a range of from about 2:3 to about 8.5:3; and the ratio by weight
of the liquid
oil to the charged lipid is in a range of from about 5:1 to about 50:1.
45. The method of claim 44, wherein the aqueous mixture comprising the film-
forming
thermoreversible emulsifier further comprises a humectant.
46. The method of claim 45, wherein the humectant is glycerin.
47. The method of any one of claims 44 to 46, wherein the liquid oil is a
synthetic oil,
mineral oil, natural oil or combinations thereof.
48. The method of claim 47, wherein the liquid oil is a vegetable oil or
combination thereof.
49. The method of any one of claims 44 to 48, wherein the liquid oil is
medium-chain
triglyceride (MCT) oil.
50. The method of any one of claims 44 to 49, wherein the charged lipid is
a negatively
charged lipid.
51. The method of claim 50, wherein the negatively charged lipid is oleic
acid.
52. The method of any one of claims 44 to 51, wherein the film-forming
thermoreversible
emulsifier is an amphoteric tri-block copolymer that is a polyethylene
glycol¨b¨
polypropylene glycol¨b¨polyethylene glycol (poloxamer).
53. The method of any one of claims 44 to 52, wherein the ratio by weight
of the film-
forming thermoreversible emulsifier to the internal oil phase is at least 0.1
: 10.
54. The method of any one of claims 44 to 53, wherein the combination of
solid lipids is a
combination of at least two of:
(i) glyceryl dibehenate, glyceryl palmitostearate or combinations
thereof;
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(ii) petrolatum, cetyl palmitate, beeswax or combinations thereof;
(iii) a hydrogenated vegetable oil or combinations thereof;
(iv) a fatty alcohol or combinations thereof; and
(v) glyceryl stearate, polyethylene glycol (PEG)-40 glyceryl stearate, PEG-
100
stearate, or combinations thereof.
55. The method of claim 54, wherein the petrolatum, cetyl palmitate,
beeswax or
combinations thereof is petrolatum.
56. The method of claim 54 or 55, wherein the ratio by weight of (i) :
[(ii) + (iii)] : (v) in the
combination of solid lipids is about 2 : 1 : 2.
57. The method of any one of claims 54 to 56, wherein the solid lipids are
glyceryl dibehenate,
petrolatum, hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-
100 stearate.
58. The method of any one of claims 44 to 57, wherein the third mixture
comprising the
combination of solid lipids further comprises a liquid emollient, a
penetration enhancer,
an antioxidant, or combinations thereof.
59. The method of claim 58, wherein the third mixture comprising the
combination of solid
lipids comprises: the liquid emollient isopropyl lauroyl sarcosinate; the
penetration
enhancer ethoxy diglycol; and the antioxidant butylated hydroxytoluene.
60. The method of any one of claims 44 to 59, wherein subsequent to
preparing the oil-in-
water nano-emulsion, the method further comprises:
combining the oil-in-water nano-emulsion with a fourth mixture comprising one
or
more of a multifunctional polymer and a chelating agent with the oil-in-water
nano-emulsion.
61. The method of claim 60, wherein the multifunctional polymer is a
combination of
multifunctional polymers that is polyacrylate crosspolymer-6 and hydroxyethyl
acrylate/sodium acryloyldimethyl taurate copolymer and the chelating agent is
disodium
ethylenediaminetetraacetic acid (EDTA).
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62. The method of any one of claims 44 to 61, wherein subsequent to
combining the oil-in-water
nano-emulsion with the third mixture comprising a combination of solid lipids,
the method
further comprises combining the composition thereby obtained with a
preservative.
63. The method of claim 62, wherein the preservative is a combination of
preservatives that is
caprylyl glycol and phenoxy ethanol.
64. The method of claim 63, wherein the composition comprises, consists
essentially of or
consists of:
water in an amount of from about 50 wt% to about 80 wt%;
glycerin in an amount of from about 1 wt% to about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about 0.05 wt% to about 5 wt%;
oleic acid in an amount of from about 0.1 wt% to about 10 wt%;
MCT oil in an amount of from about 1 wt% to about 10 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to about 5 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 5 wt%;
disodium EDTA in an amount of from about 0.005 wt% to about 0.05 wt%;
glyceryl dibehenate in an amount of from about 1 wt% to about 10 wt%;
petrolatum in an amount of from about 0.5 wt% to about 10 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%;
cetyl alcohol in an amount of from about 0.5 wt% to about 10 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 1 wt% to
about 10 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 1 wt% to about 5 wt%;
ethoxy diglycol in an amount of from about 1 wt% to about 10 wt%;
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butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%; and
phenoxy ethanol in an amount of from about 0.05 wt% to about 1 wt%.
65. The method of claim 63, wherein the composition comprises:
water in an amount of from about 60 wt% to about 70 wt%;
glycerin in an amount of from about 1.5 wt% to about 5 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about 0.1 wt% to about 0.5 wt%;
oleic acid in an amount of from about 0.5 wt% to about 2.5 wt%;
MCT oil in an amount of from about 7 wt% to about 9 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.2 wt% to about 1 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 1 wt%;
disodium ethylenediaminetetraacetic acid in an amount of from about 0.01 wt%
to
about 0.03 wt%;
glyceryl dibehenate in an amount of from about 5 wt% to about 6 wt%;
petrolatum in an amount of from about 0.75 wt% to about 1.25 wt%;
hydrogenated castor oil in an amount of from about 1.25 wt% to about 2.25 wt%;

cetyl alcohol in an amount of from about 0.75 wt% to about 5 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 5 wt% to
about 6 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 2 wt% to about 4 wt%;
ethoxy diglycol in an amount of from about 4 wt% to about 6 wt%;
butylated hydroxytoluene in an amount of from about 0.05 wt% to less than 0.1
wt%;
caprylyl glycol in an amount of from about 0.4 wt% to about 0.6 wt%; and
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phenoxy ethanol in an amount of from about 0.85 wt% to about 0.95 wt%.
66. The method of claim 63, wherein the composition comprises:
water in an amount of about 62 wt%;
glycerin in an amount of about 2 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of about 0.3 wt%;
oleic acid in an amount of about 1 wt%;
MCT oil in an amount of about 8 wt%;
polyacrylate crosspolymer-6 in an amount of about 0.6 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of about 0.2 wt%;
disodium ethylenediaminetetraacetic acid in an amount of about 0.02 wt%;
glyceryl dibehenate in an amount of about 5.5 wt%;
petrolatum in an amount of about 1 wt%;
hydrogenated castor oil in an amount of about 1.75 wt%;
cetyl alcohol in an amount of about 2 wt%;
glyceryl stearate and PEG-100 stearate in an amount of about 5.5 wt%;
isopropyl lauroyl sarcosinate in an amount of about 3 wt%;
ethoxy diglycol in an amount of about 5 wt%;
butylated hydroxytoluene in an amount of 0.1 wt% or less than 0.1 wt%;
caprylyl glycol in an amount of about 0.5 wt%; and
phenoxy ethanol in an amount of about 0.9 wt%.
67. The method of any one of claims 44 to 66, wherein the ratio by weight
of the oil-in-water
nano-emulsion to the external oil phase is about 8.5:3.
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68. A method of preparing a composition comprising an oil-in-water nano-
emulsion
dispersed in an external oil phase, the oil-in-water nano-emulsion comprising
an internal
oil phase dispersed in an aqueous phase and stabilized by a film-forming
thermoreversible emulsifier;
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is about 8.5:3; and the ratio by weight of the liquid oil to the charged
lipid is in a
range of from about 5:1 to about 50:1,
the method comprising:
combining a first mixture comprising:
(a) oleic acid in an amount of from about 0.1 wt% to about 10 wt%; and
(b) MCT oil in an amount of from about 1 wt% to about 10 wt%;
with a second mixture that is an aqueous mixture comprising:
(c) water in an amount of from about 50 wt% to about 80 wt%;
(d) glycerin in an amount of from about 1 wt% to about 10 wt%; and
(e) polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an
amount of from about 0.05 wt% to about 5 wt%;
then combining the mixture thereby obtained with a mixture comprising:
(f) polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to about
5 wt%;
(g) hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an
amount of from about 0.1 wt% to about 5 wt%; and
(h) disodium EDTA in an amount of from about 0.005 wt% to about 0.05 wt%;
to prepare an oil-in-water nano-emulsion;
combining the oil-in-water nano-emulsion with a mixture comprising:
(i) glyceryl dibehenate in an amount of from about 1 wt% to about 10 wt%;
(j) petrolatum in an amount of from about 0.5 wt% to about 10 wt%;
(k) hydrogenated castor oil in an amount of from about 1 wt% to about 10
wt%;
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CA 3091186
(1) cetyl alcohol in an amount of from about 0.5 wt% to about 10
wt%;
(m) glyceryl stearate and PEG-100 stearate in an amount of from about 1 wt%

to about 10 wt%;
(n) isopropyl lauroyl sarcosinate in an amount of from about 1 wt% to about
5 wt%;
(o) butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1
wt%; and
(1)) ethoxy diglycol in an amount of from about 1 wt% to about 10
wt%;
then combining the mixture thereby obtained with a mixture comprising:
(q) caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%;
and
(r) phenoxy ethanol in an amount of from about 0.05 wt% to about 1 wt%,
to prepare the composition.
69. A method of preparing a composition comprising an oil-in-water nano-
emulsion
dispersed in an external oil phase, the oil-in-water nano-emulsion comprising
an internal
oil phase dispersed in an aqueous phase and stabilized by a film-forming
thermoreversible emulsifier;
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is about 8.5:3; and the ratio by weight of the liquid oil to the charged
lipid is in a
range of from about 5:1 to about 50:1,
the method comprising:
combining a first mixture comprising:
(a) oleic acid in an amount of from about 0.5 wt% to about 2.5 wt%; and
(b) MCT oil in an amount of from about 7 wt% to about 9 wt%;
with a second mixture that is an aqueous mixture comprising:
(c) water in an amount of from about 60 wt% to about 70 wt%;
(d) glycerin in an amount of from about 1.5 wt% to about 5 wt%; and
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(e) polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an
amount of from about 0.1 wt% to about 0.5 wt%;
then combining the mixture thereby obtained with a mixture comprising:
(f) polyacrylate crosspolymer-6 in an amount of from about 0.2 wt% to about
1 wt%;
(g) hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an
amount of from about 0.1 wt% to about 1 wt%; and
(h) disodium ethylenediaminetetraacetic acid in an amount of from about
0.01
wt% to about 0.03 wt%;
to prepare an oil-in-water nano-emulsion;
combining the oil-in-water nano-emulsion with a mixture comprising:
(i) glyceryl dibehenate in an amount of from about 5 wt% to about 6 wt%;
(j) petrolatum in an amount of from about 0.75 wt% to about 1.25 wt%;
(k) hydrogenated castor oil in an amount of from about 1.25 wt% to about
2.25 wt%;
(1) cetyl alcohol in an amount of from about 0.75 wt% to about 5
wt%;
(m) glyceryl stearate and PEG-100 stearate in an amount of from about 5 wt%

to about 6 wt%;
(n) isopropyl lauroyl sarcosinate in an amount of from about 2 wt% to about
4 wt%;
(o) butylated hydroxytoluene in an amount of from about 0.05 wt% to less
than
0.1 wt%; and
(1)) ethoxy diglycol in an amount of from about 4 wt% to about 6
wt%;
then combining the mixture thereby obtained with a mixture comprising:
(q) caprylyl glycol in an amount of from about 0.4 wt% to about 0.6 wt%;
and
(r) phenoxy ethanol in an amount of from about 0.85 wt% to about 0.95 wt%,
to prepare the composition.
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70. A method of preparing a composition comprising an oil-in-water nano-
emulsion
dispersed in an external oil phase, the oil-in-water nano-emulsion comprising
an internal
oil phase dispersed in an aqueous phase and stabilized by a film-forming
thermoreyersible emulsifier;
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is about 8.5:3; and the ratio by weight of the liquid oil to the charged
lipid is about 8:1,
the method comprising:
combining a first mixture comprising:
(a) oleic acid in an amount of about 1 wt%; and
(b) MCT oil in an amount of about 8 wt%;
with a second mixture that is an aqueous mixture comprising:
(c) water in an amount of about 62 wt%;
(d) glycerin in an amount of about 2 wt%; and
(e) polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an
amount of about 0.3 wt%;
then combining the mixture thereby obtained with a mixture comprising:
(f) polyacrylate crosspolymer-6 in an amount of about 0.6 wt%;
(g) hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an
amount of about 0.2 wt%; and
(h) disodium ethylenediaminetetraacetic acid in an amount of about 0.02
wt%;
to prepare an oil-in-water nano-emulsion;
combining the oil-in-water nano-emulsion with a mixture comprising:
(i) glyceryl dibehenate in an amount of about 5.5 wt%;
(j) petrolatum in an amount of about 1 wt%;
(k) hydrogenated castor oil in an amount of about 1.75 wt%;
(1) cetyl alcohol in an amount of about 2 wt%;
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(m) glyceryl stearate and PEG-100 stearate in an amount of about 5.5 wt%;
(n) isopropyl lauroyl sarcosinate in an amount of about 3 wt%;
(o) butylated hydroxytoluene in an amount of 0.1 wt% or less than 0.1 wt%;
and
(1)) ethoxy diglycol in an amount of about 5 wt%;
then combining the mixture thereby obtained with a mixture comprising:
(q) caprylyl glycol in an amount of about 0.5 wt%; and
(r) phenoxy ethanol in an amount of about 0.9 wt%,
to prepare the composition.
71. The method of any one of claims 44 to 70, wherein the combining
comprises mixing with
a high shear homogenizer at a temperature of from about 35 C to about 85 C.
72. The method of any one of claims 44 to 71, wherein the method is for
preparation of a
compounding base.
73. The method of any one of claims 44 to 72, wherein the method further
comprises adding one or
more active ingredients, one or more natural and/or herbal active agents with
anti-
inflammatory, analgesic or anesthetic effect; terpenoids; essential oils or
combinations thereof.
74. The method of claim 73, wherein the addition is by a method comprising
compounding.
75. The method of claim 73, wherein the addition is during the preparation
of the composition.
76. A composition obtained by the method of any one of claims 44 to 75.
69
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Description

8000475-3 / 87073945
NANO-EMULSION BASED COMPOSITIONS, METHODS FOR THEIR
PREPARATION AND THEIR USE IN DELIVERY OF ACT WE INGREDIENTS
FIELD
[001] The present disclosure relates to compositions comprising an oil-in-
water nano-
emulsion dispersed in an external oil phase, methods for the preparation of
such compositions as
well as uses of such compositions, for example, for delivery of active
ingredients to a subject.
BACKGROUND
[002] Dermal and transdermal delivery of active ingredients such as drugs
has the advantage
of bypassing the hepatic first pass metabolism. It also can have the advantage
of local targeted
delivery of the active ingredient to the affected area. Accordingly, it may be
more effective with
less systemic side effects and drug-drug interactions than other routes of
administration such as
an oral delivery route. This may, for example, present a greater benefit in
the management of
chronic conditions such as chronic pain in elderly patients that may have high
blood pressure and
be using multiple medications resulting in increased drug-drug interactions.
[003] Skin has three different layers i.e. epidermis, dermis and
subcutaneous. The main
barrier in transdermal delivery is the stratum corneum (SC), which is the
outermost part among
the five layers of epidermis. The composition of the SC and its morphology is
unique in nature
due to the tight junctions of corneocytes and with no blood vessels so that
permeability of drugs
through this layer of the skin is less. Due to this lower permeability,
various prior formulations
were not suitable for use as dermal and transdermal drug delivery systems.
[004] Highly lipophilic drugs such as nonsteroidal anti-inflammatory drugs
(NSAIDs) and
cannabinoids have difficulty passing the stratum comeum. Therefore, if the
transdermal
delivery system is not appropriate, the desired analgesic and anti-
inflammatory effect can only
be achieved by increasing the concentration of active pharmaceutical
ingredients (APIs) for
example, to 30-40%. Incorporating a high concentration of APIs may, for
example, require a
higher concentration of solvent to levigate the dry powder prior to
incorporating into the base.
This significantly enhances the cost of a compounded drug for the patient
and/or health care
system and can also increase the risk of skin hypersensitivity reactions.
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[005] Acute and chronic inflammation and pain can be caused by many
different reasons
such as tissue or bone injury, nerve damage, arthritis and joint degeneration,
prostaglandin-
induced, neuropathic pain and/or musculoskeletal pain. Therefore, a
personalized compounded
product advantageously may contain various medications as well as optionally
natural/herbal
ingredients with a synergic effect to provide a tailored therapeutic outcome.
As such, a delivery
(e.g. transdermal) base for the management of e.g. inflammation and pain
ideally has resilience to
incorporate and deliver multiple actives without becoming unstable. These
active ingredients may
have hydrophilic and/or lipophilic physicochemical characteristics. Therefore,
a useful
compounding base for the treatment or management of inflammation and/or pain
advantageously
has the flexibility to enhance the delivery of both hydrophilic and lipophilic
active ingredients.
[006] Dermal and transdermal anti-inflammatory drugs for local pain relief
are
commercially available in the form of gels, creams, hydrogels and emulgels.
Such topical
NSAIDs in the form of gels, creams, hydrogels and emulgels provide 6 to 12
hours pain relief.
[007] Pluronic lecithin organogels (PLOs) are the most popular conventional
transdermal
drug delivery systems in pharmacy compounding. PLOs have gained significant
popularity
compared to other traditional topical and transdermal drug delivery systems
owing to their
lower cost and high transdermal permeability_ However, PLOs have a number of
disadvantages
such as a sticky tacky feeling, yellow color and short duration of action
(e.g. 6-8 hours). As a
result, patients may prefer a cosmetically appealing cream base rather than a
gel base.
Additionally, PLO gels can be difficult to mix with active ingredients at the
pharmacy level due
to a high concentration (20-30%) of a thermoreversible polymer, Poloxamer 407.
[008] Conventional creams and liposomal delivery systems available in the
market for the
transdermal delivery of compounding APIs may have various drawbacks. For
example, they may
release the active ingredient fast and therefore require application
frequently (for example, 3 to 4
times a day). They may also exhibit low rates and/or total amounts of
penetration for certain active
ingredients into the skin. Phase separation may occur if a high concentration
of APIs such as
cyclobenzaprine HC1, diclofenac Na, gabapentin, lidocaine HC1 and/or ketamine
HC1 are added. They
may also expire quickly when compounded with certain APIs (for example, 1 to 3
months). Currently
available transdermal creams that provide 12-hour release and are robust can
be expensive.
Commercially available submicron transdermal emulgels made of Carbopol'
typically create a
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8000475-3 / 87073945
sticky and tacky feeling following application on skin. Additionally, these
systems do not have the
capacity to hold higher concentrations of APIs in salt form. Emulgels
containing non-tacky colloidal
gums such as xanthan, carrageenan, and tam gum may not provide sustained drug
release.
[009] A two-step emulsion technique has been conventionally used for
creating oil-in-water-
in-oil (0/W/0) multiple emulsions, in which an oil-in-water (0/W) type
emulsion formed using a
hydrophilic surfactant is re-emulsified in an outer oil phase in which a
lipophilic surfactant has been
dissolved. However, the emulsification stability of known multiple emulsions
may be so low that,
over time, phase separation occurs. Additionally, the inner oil phase can
migrate into the outer oil
phase thereby compromising the sustained release capacity. Therefore, creating
an 0/W/0
emulsion that is, e.g. stable over a wide pH range and in the presence of a
high load of electrolytes
(e.g. an API in salt form) and also sustains the release of the API is
desirable.
SUMMARY
[0010] As described in greater detail herein below, a nano-emulsion cream
base (Nano-
Emulsion SR Cream) was prepared that is a white cream that can, for example,
be readily spread on
an affected area without leaving a tacky or sticky feeling, readily removed if
not tolerated, and
would be readily mixed with compounding APIs at the pharmacy level. The Nano-
Emulsion SR
Cream is composed of an oil-in-water (0/W) nano-emulsion core stabilized in an
external oil phase
Such oil-in-water-in-oil (0/W/O) multiple emulsions can be used, for example,
to prolong the
release of lipophilic and hydrophilic active ingredients. The Nano-Emulsion SR
Cream possessed
occlusive properties, which can enhance the percutaneous permeation of active
ingredients but was
still suitable for use on intact skin. The preservative challenge test showed
that the formulation
preserved against bacteria and mold growth. The Nano-Emulsion SR Cream was
prepared using a
low energy emulsification technique via hot stiffing and homogenization. Such
a technique can be
an easy, cost-effective method to scale up. However, the choice of emulsion
components and ratios
of these components, as well as certain steps to add ingredients is critical
in generating stable
emulsion systems with appropriate particle sizes. The stability of a topical
cream (e.g. a
compounded product) plays an important role in the therapeutic efficacy of the
formulation. The
product was stable for 3 months under accelerated conditions, which
corresponds to 2 years shelf
life for the Nano-Emulsion SR cream. The Nano-Emulsion SR Cream was
thermodynamically
stable at least for 6 months even when diclofenac sodium was added at a 10%
concentration. In
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addition, in vitro permeation release results showed that the Nano-Emulsion SR
Cream sustained
the release of diclofenac sodium for 24 hours. Such a cream can advantageously
be applied once
daily. This may, for example, result in enhanced patient adherence and
compliance in comparison
to formulations, which are only capable of release over a lower time such as 6-
12 hours. It can
also significantly reduce the cost of a drug for a patient with a chronic
condition. When the Nano-
Emulsion SR Cream was compounded with THC distillate and CBD oil, no oxidative

discoloration of the cannabinoids was observed under the conditions used.
[0011] Accordingly, the present disclosure includes a composition
comprising an oil-in-
water nano-emulsion dispersed in an external oil phase, the oil-in-water nano-
emulsion
comprising an internal oil phase dispersed in an aqueous phase and stabilized
by a film-forming
thermoreversible emulsifier,
wherein
the internal oil phase comprises a liquid oil in combination with a charged
lipid;
the external oil phase comprises a combination of solid lipids;
the ratio by weight of the oil-in-water nano-emulsion to the external oil
phase is
in a range of from about 2:3 to about 7:3; and the ratio by weight of the
liquid oil to the
charged lipid is in a range of from about 5:1 to about 50:1.
[0012] In an embodiment, the aqueous phase further comprises a humectant.
In another
embodiment, the humectant is glycerin.
[0013] In an embodiment, the liquid oil is a synthetic oil, mineral oil,
natural oil or
combinations thereof. In another embodiment, the liquid oil is a vegetable oil
or combination
thereof. In a further embodiment, the liquid oil is medium-chain triglyceride
(MCT) oil.
[0014] In an embodiment, the charged lipid is a negatively charged lipid.
In another
embodiment, the negatively charged lipid is oleic acid.
[0015] In an embodiment, the film-forming thermoreversible emulsifier is an
amphoteric
tri-block copolymer that is a polyethylene glycol¨b¨polypropylene
glycol¨b¨polyethylene
glycol (poloxamer). In another embodiment, the ratio by weight of the film-
forming
thermoreversible emulsifier to the internal oil phase is at least 0.1 : 10.
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[0016] In an embodiment, the combination of solid lipids is a combination
of at least two of:
(i) glyceryl dibehenate, glyceryl palmitostearate or combinations thereof;
(ii) petrolatum, cetyl palmitate, beeswax or combinations thereof;
(iii) a hydrogenated vegetable oil or combinations thereof;
(iv) a fatty alcohol or combinations thereof; and
(v) glyceryl stearate, polyethylene glycol (PEG)-40 glyceryl stearate, PEG-
100
stearate or combinations thereof.
[0017] In an embodiment, the cetyl palmitate, beeswax or combinations
thereof is petrolatum.
In another embodiment, the ratio by weight of (i) : [(ii) + (iii)] : (v) in
the combination of solid
lipids is about 2 : 1 : 2. In a further embodiment, the solid lipids are
glyceryl dibehenate,
petrolatum, hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-
100 stearate.
[0018] In an embodiment, the composition further comprises a
multifunctional polymer, a
liquid emollient, a penetration enhancer, a chelating agent, an antioxidant, a
preservative or
combinations thereof. In another embodiment, the composition comprises:
(i) a combination of multifunctional polymers that is polyacrylate
crosspolymer-6
and hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer;
(ii) the liquid emollient isopropyl lauroyl sarcosinate;
(iii) the penetration enhancer ethoxy diglycol;
(iv) the chelating agent disodium ethylenediaminetetraacetic acid (EDTA);
(v) the antioxidant butylated hydroxytoluene; and
(vi) a combination of preservatives that is caprylyl glycol and phenoxy
ethanol.
[0019] In a further embodiment, the composition comprises, consists
essentially of or consists of:
water in an amount of from about 50 wt% to about 80 wt%;
glycerin in an amount of from about 1 wt% to about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an
amount of from about 0.05 wt% to about 5 wt%;
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oleic acid in an amount of from about 0.1 wt% to about 10 wt%;
MCT oil in an amount of from about 1 wt% to about 10 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to about 5 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 5 wt%;
disodium EDTA in an amount of from about 0.005 wt% to about 0.05 wt%;
glyceryl dibehenate in an amount of from about 1 wt% to about 10 wt%;
petrolatum in an amount of from about 0.5 wt% to about 10 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%;
cetyl alcohol in an amount of from about 0.5 wt% to about 10 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 1 wt% to
about 10 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 1 wt% to about 5 wt%;

ethoxy diglycol in an amount of from about 1 wt% to about 10 wt%;
butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%; and
phenoxy ethanol in an amount of from about 0.05 wt% to about 1 wt%.
[0020] In an embodiment, the oil droplets of the internal oil phase
dispersed in the aqueous
phase have a mean droplet size of less than about 700 nm.
[0021] In an embodiment, the composition is devoid of active ingredients.
In another
embodiment, such a composition has up to 2 years shelf life.
[0022] In an alternative embodiment, the composition further comprises one
or more active
ingredients. In another embodiment, such a composition releases the one or
more active
ingredients for a time of up to about 24 hours. In a further embodiment of the
present
disclosure, such a composition has at least 6 months shelf life.
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[0023] In an embodiment, the active ingredient is diclofenac or a
pharmaceutically
acceptable salt thereof. In another embodiment, the diclofenac or
pharmaceutically acceptable
salt thereof is diclofenac sodium present in an amount of from about 5 wt% to
about 10 wt%.
[0024] In an embodiment, the active ingredients are lidocaine, benzocaine,
tetracaine or
pharmaceutically acceptable salts thereof or combinations thereof, wherein the
lidocaine, benzocaine,
tetracaine or pharmaceutically acceptable salts thereof are present in an
amount of up to about 20
wt%, with the total concentration of the lidocaine, benzocaine, tetracaine or
pharmaceutically
acceptable salts thereof being no more than 30 wt%, based on the total weight
of the composition.
[0025] In an embodiment, the active ingredient is tetrahydrocannabinol
(THC), cannabidiol
(CBD) or combinations thereof. In another embodiment, the composition
comprises CBD
isolate in an amount of up to about 20 wt%, CBD oil in an amount of up to
about 15 wt%,
and/or THC distillate in an amount of up to 20 wt%.
[0026] In an embodiment, the composition further comprises one or more
natural and/or
herbal active agents with anti-inflammatory, analgesic or anesthetic effect;
terpenoids; essential
oils or combinations thereof.
[0027] The present disclosure also includes a use a composition of the
present disclosure
devoid of active ingredients for preparing a compound comprising one or more
active ingredients.
[0028] The present disclosure also includes a use of a composition
comprising one or more
active ingredients of the present disclosure or a compound comprising one or
more active
ingredients of the present disclosure on the skin of a subject for delivering
the one or more active
ingredients to the subject. The present disclosure also includes a use of a
compound comprising one
or more active ingredients of the present disclosure or a compound comprising
one or more active
ingredients of the present disclosure for preparation of a medicament for the
skin of a subject for
delivering the one or more active ingredients to the subject. In an
embodiment, such a composition
or compound is for administration once per day. In another embodiment, the
subject is a human.
[0029] The present disclosure also includes a method of preparing a
composition comprising
an oil-in-water nano-emulsion dispersed in an external oil phase, the oil-in-
water nano-emulsion
comprising an internal oil phase dispersed in an aqueous phase, the method
comprising:
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combining a first mixture comprising a liquid oil and a charged lipid with a
second mixture that is an aqueous mixture comprising a film-forming
thermoreversible
emulsifier to prepare an oil-in-water nano-emulsion; and
combining the oil-in-water nano-emulsion with a third mixture comprising a
combination of solid lipids to prepare the composition,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is in a range of from about 2:3 to about 7:3; and the ratio by weight of
the liquid oil
to the charged lipid is in a range of from about 5:1 to about 50:1.
[0030] In an embodiment, the aqueous mixture comprising the film-forming
thermoreversible
emulsifier further comprises a humectant. In another embodiment, the humectant
is glycerin.
[0031] In an embodiment, the liquid oil is synthetic oil, mineral oil,
natural oil or
combinations thereof. In another embodiment, the liquid oil is a vegetable oil
or combination
thereof. In a further embodiment, the liquid oil is medium-chain triglyceride
(MCT) oil.
[0032] In an embodiment, the charged lipid is a negatively charged lipid.
In another
embodiment, the negatively charged lipid is oleic acid.
[0033] In an embodiment, the film-forming thermoreversible emulsifier is an
amphoteric
tri-block copolymer that is a polyethylene glycol¨b¨polypropylene
glycol¨b¨polyethylene
glycol (poloxamer). In another embodiment, the ratio by weight of the film-
forming
thermoreversible emulsifier to the internal oil phase is at least 0.1: 10.
[0034] In an embodiment, the combination of solid lipids is a combination
of at least two of:
(i) glyceryl dibehenate, glyceryl palmitostearate or combinations thereof;
(ii) petrolatum, cetyl palmitate, beeswax or combinations thereof;
(iii) a hydrogenated vegetable oil or combinations thereof;
(iv) a fatty alcohol or combinations thereof; and
(v) glyceryl stearate, polyethylene glycol (PEG)-40 glyceryl stearate, PEG-
100
stearate, or combinations thereof.
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[0035] In an embodiment, the cetyl palmitate, beeswax or combinations
thereof is petrolatum.
In an embodiment, the ratio by weight of (i) : [(ii) + (iii)] : (v) in the
combination of solid lipids
is about 2 : 1 : 2. In another embodiment, the solid lipids are glyceryl
dibehenate, petrolatum,
hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-100
stearate.
[0036] In an embodiment, the third mixture comprising the combination of
solid lipids
further comprises a liquid emollient, a penetration enhancer, an antioxidant,
or combinations
thereof. In another embodiment, the third mixture comprising the combination
of solid lipids
comprises: the liquid emollient isopropyl lauroyl sarcosinate; the penetration
enhancer ethoxy
diglycol; and the antioxidant butylated hydroxytoluene.
[0037] In an embodiment, subsequent to preparing the oil-in-water nano-
emulsion, the
method further comprises:
combining the oil-in-water nano-emulsion with a fourth mixture comprising one
or
more of a multifunctional polymer and a chelating agent with the oil-in-water
nano-emulsion.
[0038] In another embodiment of the present disclosure, the multifunctional
polymer is a
combination of multifunctional polymers that is polyacrylate crosspolymer-6
and hydroxyethyl
acrylate/sodium acryloyldimethyl taurate copolymer and the chelating agent is
disodium
ethylenediaminetetraacetic acid (EDTA).
[0039] In an embodiment, subsequent to combining the oil-in-water nano-
emulsion with
the third mixture comprising a combination of solid lipids, the method further
comprises
combining the composition thereby obtained with a preservative. In another
embodiment, the
preservative is a combination of preservatives that is caprylyl glycol and
phenoxy ethanol.
[0040] In an embodiment, the composition comprises, consists essentially of
or consists of:
water in an amount of from about 50 wt% to about 80 wt%;
glycerin in an amount of from about 1 wt% to about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an
amount of from about 0.05 wt% to about 5 wt%;
oleic acid in an amount of from about 0.1 wt% to about 10 wt%;
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MCT oil in an amount of from about 1 wt% to about 10 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to about 5 wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an amount
of from about 0.1 wt% to about 5 wt%;
disodium EDTA in an amount of from about 0.005 wt% to about 0.05 wt%;
glyceryl dibehenate in an amount of from about 1 wt% to about 10 wt%;
petrolatum in an amount of from about 0.5 wt% to about 10 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%;
cetyl alcohol in an amount of from about 0.5 wt% to about 10 wt%;
glyceryl stearate and PEG-100 stearate in an amount of from about 1 wt% to
about 10 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 1 wt% to about 5 wt%;

ethoxy diglycol in an amount of from about 1 wt% to about 10 wt%;
butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%; and
phenoxy ethanol in an amount of from about 0.05 wt% to about 1 wt%.
[0041] In an embodiment, the combining comprises mixing with a high shear
homogenizer
at a temperature of from about 35 C to about 85 C.
[0042] In an embodiment, the method is for preparation of a compounding
base.
[0043] In an alternative embodiment, the method further comprises adding
one or more
active ingredients, one or more natural and/or herbal active agents with anti-
inflammatory,
analgesic or anesthetic effect; terpenoids; essential oils or combinations
thereof. In an
embodiment, the addition is by a method comprising compounding. In an
alternative
embodiment, the addition is during the preparation of the composition.
Date Recue/Date Received 2020-08-26

CA 3091186
[0044]
The present disclosure also includes a composition obtained by a method of the
present disclosure for preparing a composition comprising an oil-in-water nano-
emulsion
dispersed in an external oil phase, the oil-in-water nano-emulsion comprising
an internal oil
phase dispersed in an aqueous phase.
[0044A] The present disclosure also includes a composition comprising an oil-
in-water nano-
emulsion dispersed in an external oil phase, the oil-in-water nano-emulsion
comprising an internal oil
phase dispersed in an aqueous phase and stabilized by a film-forming
thermoreversible emulsifier,
wherein the internal oil phase comprises a liquid oil in combination with a
charged lipid; the external
oil phase comprises a combination of solid lipids; the ratio by weight of the
oil-in-water nano-
emulsion to the external oil phase is in a range of from about 2:3 to about
8.5:3; and the ratio by
weight of the liquid oil to the charged lipid is in a range of from about 5:1
to about 50:1.
[0044B] The present disclosure also includes a composition comprising an oil-
in-water nano-
emulsion dispersed in an external oil phase, the oil-in-water nano-emulsion
comprising an
internal oil phase dispersed in an aqueous phase and stabilized by a film-
forming
thermoreversible emulsifier, wherein the ratio by weight of the oil-in-water
nano-emulsion to the
external oil phase is about 8.5:3; the ratio by weight of the liquid oil to
the charged lipid is in a
range of from about 5-1 to about 50-1; and the composition comprises- water in
an amount of from
about 50 wt% to about 80 wt%; glycerin in an amount of from about 1 wt% to
about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol in an amount
of from about
0_05 wt% to about 5 wt%; oleic acid in an amount of from about OA wt% to about
10 wt%; MCT
oil in an amount of from about 1 wt% to about 10 wt%; polyacrylate
crosspolymer-6 in an
amount of from about 0.1 wt% to about 5 wt%; hydroxyethyl acrylate/sodium
acryloyldimethyl
taurate copolymer in an amount of from about 0.1 wt% to about 5 wt%; disodium
EDTA in an
amount of from about 0.005 wt% to about 0.05 wt%; glyceryl dibehenate in an
amount of from
about 1 wt% to about 10 wt%; petrolatum in an amount of from about 0.5 wt% to
about 10 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%;
cetyl alcohol in an
amount of from about 0.5 wt% to about 10 wt%; glyceryl stearate and PEG-100
stearate in an
amount of from about 1 wt% to about 10 wt%; isopropyl lauroyl sarcosinate in
an amount of
from about 1 wt% to about 5 wt%; ethoxy diglycol in an amount of from about 1
wt% to about
11
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wt%; butylated hydroxytoluene in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl
glycol in an amount of from about 0.01 wt% to about 1.0 wt%; and phenoxy
ethanol in an
amount of from about 0.05 wt% to about 1 wt%.
[0044C] The present disclosure also includes a composition comprising an oil-
in-water nano-
emulsion dispersed in an external oil phase, the oil-in-water nano-emulsion
comprising an internal oil
phase dispersed in an aqueous phase and stabilized by a film-forming
thermoreversible emulsifier,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil phase is about 8.5:3;
the ratio by weight of the liquid oil to the charged lipid is in a range of
from about 5:1 to about 50:1;
and the composition comprises: water in an amount of from about 60 wt% to
about 70 wt%; glycerin in
an amount of from about 1.5 wt% to about 5 wt%; polyethylene
glycol¨b¨polypropylene glycol¨b¨
polyethylene glycol in an amount of from about 0.1 wt% to about 0.5 wt%; oleic
acid in an amount of
from about 0.5 wt% to about 2.5 wt%; MCT oil in an amount of from about 7 wt%
to about 9 wt%;
polyacrylate crosspolymer-6 in an amount of from about 0.2 wt% to about 1 wt%;
hydroxyethyl
acrylate/sodium acryloyldimethyl taurate copolymer in an amount of from about
0.1 wt% to about
1 wt%; disodium ethylenediaminetetraacetic acid in an amount of from about
0.01 wt% to about
0.03 wt%; glyceryl dibehenate in an amount of from about 5 wt% to about 6 wt%;
petrolatum in an
amount of from about 0.75 wt% to about 1.25 wt%; hydrogenated castor oil in an
amount of from
about 1.25 wt% to about 2.25 wt%; cetyl alcohol in an amount of from about
0.75 wt% to about 5
wt%; glyceryl stearate and PEG-100 stearate in an amount of from about 5 wt%
to about 6 wt%;
isopropyl lauroyl sarcosinate in an amount of from about 2 wt% to about 4 wt%;
ethoxy diglycol in
an amount of from about 4 wt% to about 6 wt%; butylated hydroxytoluene in an
amount of from
about 0.05 wt% to less than 0.1 wt%; caprylyl glycol in an amount of from
about 0.4 wt% to about
0.6 wt%; and phenoxy ethanol in an amount of from about 0.85 wt% to about 0.95
wt%.
[0044D] The present disclosure also includes a composition comprising an oil-
in-water nano-
emulsion dispersed in an external oil phase, the oil-in-water nano-emulsion
comprising an
internal oil phase dispersed in an aqueous phase and stabilized by a film-
forming
thermoreversible emulsifier, wherein the ratio by weight of the oil-in-water
nano-emulsion to the
external oil phase is about 8.5:3; the ratio by weight of the liquid oil to
the charged lipid is about
8:1; and the composition comprises: water in an amount of about 62 wt%;
glycerin in an amount
of about 2 wt%; polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene
glycol in an
amount of about 0.3 wt%; oleic acid in an amount of about 1 wt%;
ha
Date Recue/Date Received 2021-06-16

CA 3091186
MCT oil in an amount of about 8 wt%; polyacrylate crosspolymer-6 in an amount
of about 0.6
wt%; hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer in an
amount of about
0.2 wt%; disodium ethylenediaminetetraacetic acid in an amount of about 0.02
wt%; glyceryl
dibehenate in an amount of about 5.5 wt%; petrolatum in an amount of about 1
wt%;
hydrogenated castor oil in an amount of about 1.75 wt%; cetyl alcohol in an
amount of about 2
wt%; glyceryl stearate and PEG-100 stearate in an amount of about 5.5 wt%;
isopropyl lauroyl
sarcosinate in an amount of about 3 wt%; ethoxy diglycol in an amount of about
5 wt%;
butylated hydroxytoluene in an amount of 0.1 wt% or less than 0.1 wt%;
caprylyl glycol in an
amount of about 0.5 wt%; and phenoxy ethanol in an amount of about 0.9 wt%.
[0044E] The present disclosure also includes a composition comprising such a
composition,
and further comprising one or more active ingredients.
[0044F] The present disclosure also includes a method of preparing a
composition comprising
an oil-in-water nano-emulsion dispersed in an external oil phase, the oil-in-
water nano-emulsion
comprising an internal oil phase dispersed in an aqueous phase, the method
comprising: combining
a first mixture comprising a liquid oil and a charged lipid with a second
mixture that is an aqueous
mixture comprising a film-forming thermoreversible emulsifier to prepare an
oil-in-water nano-
emulsion; and combining the oil-in-water nano-emulsion with a third mixture
comprising a
combination of solid lipids to prepare the composition, wherein the ratio by
weight of the oil-in-
water nano-emulsion to the external oil phase is in a range of from about 2:3
to about 8.5:3; and the
ratio by weight of the liquid oil to the charged lipid is in a range of from
about 5-1 to about 50-1
[0044G] The present disclosure also includes a method of preparing a
composition comprising
an oil-in-water nano-emulsion dispersed in an external oil phase, the oil-in-
water nano-emulsion
comprising an internal oil phase dispersed in an aqueous phase and stabilized
by a film-forming
thermoreversible emulsifier; wherein the ratio by weight of the oil-in-water
nano-emulsion to the
external oil phase is about 8.5:3; and the ratio by weight of the liquid oil
to the charged lipid is in
a range of from about 5:1 to about 50:1, the method comprising: combining a
first mixture
comprising: (a) oleic acid in an amount of from about 0.1 wt% to about 10 wt%;
and (b) MCT oil
in an amount of from about 1 wt% to about 10 wt%; with a second mixture that
is an aqueous
mixture comprising: (c) water in an amount of from about 50 wt% to about 80
wt%; (d) glycerin
in an amount of from about 1 wt% to about 10 wt%; and (e) polyethylene
glycol¨b-
1 lb
Date Recue/Date Received 2021-04-01

CA 3091186
polypropylene glycol¨b¨polyethylene glycol in an amount of from about 0.05 wt%
to about 5
wt%; then combining the mixture thereby obtained with a mixture comprising:
(f) polyacrylate
crosspolymer-6 in an amount of from about 0.1 wt% to about 5 wt%; (g)
hydroxyethyl
acrylate/sodium acryloyldimethyl taurate copolymer in an amount of from about
0.1 wt% to
about 5 wt%; and (h) disodium EDTA in an amount of from about 0.005 wt% to
about 0.05 wt%;
to prepare an oil-in-water nano-emulsion; combining the oil-in-water nano-
emulsion with a
mixture comprising: (i) glyceryl dibehenate in an amount of from about 1 wt%
to about 10 wt%;
(j) petrolatum in an amount of from about 0.5 wt% to about 10 wt%; (k)
hydrogenated castor oil
in an amount of from about 1 wt% to about 10 wt%; (1) cetyl alcohol in an
amount of from about
0.5 wt% to about 10 wt%; (m) glyceryl stearate and PEG-100 stearate in an
amount of from
about 1 wt% to about 10 wt%; (n) isopropyl lauroyl sarcosinate in an amount of
from about 1
wt% to about 5 wt%; (o) butylated hydroxytoluene in an amount of from about
0.02 wt% to 0.1
wt%; and (p) ethoxy diglycol in an amount of from about 1 wt% to about 10 wt%;
then
combining the mixture thereby obtained with a mixture comprising: (q) caprylyl
glycol in an
amount of from about 0.01 wt% to about 1.0 wt%; and (r) phenoxy ethanol in an
amount of from
about 0.05 wt% to about 1 wt%, to prepare the composition.
[0044H] The present disclosure also includes a method of preparing a
composition comprising
an oil-in-water nano-emulsion dispersed in an external oil phase, the oil-in-
water nano-emulsion
comprising an internal oil phase dispersed in an aqueous phase and stabilized
by a film-forming
thermoreversible emulsifier; wherein the ratio by weight of the oil-in-water
nano-emulsion to the
external oil phase is about 8.5:3; and the ratio by weight of the liquid oil
to the charged lipid is in
a range of from about 5:1 to about 50:1, the method comprising: combining a
first mixture
comprising: (a) oleic acid in an amount of from about 0.5 wt% to about 2.5
wt%; and (b) MCT
oil in an amount of from about 7 wt% to about 9 wt%; with a second mixture
that is an aqueous
mixture comprising: (c) water in an amount of from about 60 wt% to about 70
wt%; (d) glycerin
in an amount of from about 1.5 wt% to about 5 wt%; and (e) polyethylene
glycol¨b¨
polypropylene glycol¨b¨polyethylene glycol in an amount of from about 0.1 wt%
to about 0.5
wt%; then combining the mixture thereby obtained with a mixture comprising:
(f) polyacrylate
crosspolymer-6 in an amount of from about 0.2 wt% to about 1 wt%; (g)
hydroxyethyl
acrylate/sodium acryloyldimethyl taurate copolymer in an amount of from about
0.1 wt% to
about 1 wt%; and (h) disodium ethylenediaminetetraacetic acid in an amount of
from about 0.01
11 c
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CA 3091186
wt% to about 0.03 wt%; to prepare an oil-in-water nano-emulsion; combining the
oil-in-water
nano-emulsion with a mixture comprising: (i) glyceryl dibehenate in an amount
of from about 5
wt% to about 6 wt%; (j) petrolatum in an amount of from about 0.75 wt% to
about 1.25 wt%; (k)
hydrogenated castor oil in an amount of from about 1.25 wt% to about 2.25 wt%;
(1) cetyl
alcohol in an amount of from about 0.75 wt% to about 5 wt%; (m) glyceryl
stearate and PEG-
100 stearate in an amount of from about 5 wt% to about 6 wt%; (n) isopropyl
lauroyl sarcosinate
in an amount of from about 2 wt% to about 4 wt%; (o) butylated hydroxytoluene
in an amount of
from about 0.05 wt% to less than 0.1 wt%; and (p) ethoxy diglycol in an amount
of from about 4
wt% to about 6 wt%; then combining the mixture thereby obtained with a mixture
comprising:
(q) caprylyl glycol in an amount of from about 0.4 wt% to about 0.6 wt%; and
(r) phenoxy
ethanol in an amount of from about 0.85 wt% to about 0.95 wt%, to prepare the
composition.
[00441]
The present disclosure also includes a method of preparing a composition
comprising an oil-
in-water nano-emulsion dispersed in an external oil phase, the oil-in-water
nano-emulsion comprising an
internal oil phase dispersed in an aqueous phase and stabilized by a film-
forming thermoreversible
emulsifier; wherein the ratio by weight of the oil-in-water nano-emulsion to
the external oil phase is about
8.5:3; and the ratio by weight of the liquid oil to the charged lipid is about
8:1, the method comprising:
combining a first mixture comprising: (a) oleic acid in an amount of about 1
wt%; and (b) MCT oil in an
amount of about 8 wt%; with a second mixture that is an aqueous mixture
comprising: (c) water in an
amount of about 62 wt%; (d) glycerin in an amount of about 2 wt%; and (e)
polyethylene glycol¨b¨
polypropylene glycol¨b¨polyethylene glycol in an amount of about 0.3 wt%; then
combining the
mixture thereby obtained with a mixture comprising: (f) polyacrylate
crosspolymer-6 in an amount of
about 0.6 wt%; (g) hydroxyethyl acrylate/sodium acryloyldimethyl taurate
copolymer in an amount of
about 0.2 wt%; and (h) disodium ethylenediaminetetraacetic acid in an amount
of about 0.02 wt%; to
prepare an oil-in-water nano-emulsion; combining the oil-in-water nano-
emulsion with a mixture
comprising: (i) glyceryl dibehenate in an amount of about 5.5 wt%; (j)
petrolatum in an amount of
about 1 wt%; (k) hydrogenated castor oil in an amount of about 1.75 wt%; (1)
cetyl alcohol in an
amount of about 2 wt%; (m) glyceryl stearate and PEG-100 stearate in an amount
of about 5.5 wt%; (n)
isopropyl lauroyl sarcosinate in an amount of about 3 wt%; (o) butylated
hydroxytoluene in an amount
of 0.1 wt% or less than 0.1 wt%; and (p) ethoxy diglycol in an amount of about
5 wt%; then combining
the mixture thereby obtained with a mixture comprising: (q) caprylyl glycol in
an amount of about 0.5
wt%; and (r) phenoxy ethanol in an amount of about 0.9 wt%, to prepare the
composition.
lid
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CA 3091186
[0045] Other features and advantages of the present disclosure will become
apparent from the
following detailed description. It should be understood, however, that the
detailed description and the
specific examples, while indicating embodiments of the disclosure, are given
by way of illustration
only and the scope of the claims should not be limited by these embodiments,
but should rather be
given the broadest interpretation consistent with the description as a whole.
BRIEF DESCRIPTION OF THE DRAWINGS
[0046] The embodiments of the disclosure will now be described in greater
detail with
reference to the attached drawings, in which:
[0047] Figure 1 is a plot showing cumulative diclofenac sodium (Diclofenac
Na, percent) release as
a function of time (hours) from a nano-emulsion SR composition according to an
embodiment of the
present disclosure tested by in vitro permeation through PermeaPad' membranes.
[0048] Figure 2 is a plot showing in vitro permeation test first order
release kinetics of the diclofenac
sodium (Diclofenac Na) from the nano-emulsion SR composition according to an
embodiment of the
present disclosure tested by in vitro permeation through PermeaPad membranes.
[0049] Figure 3 is a plot showing in vitro permeation test Higutchi release
kinetics of the diclofenac
sodium (Diclofenac Na) from the nano-emulsion SR composition according to an
embodiment of the
present disclosure tested by in vitro permeation through PermeaPad' membranes.
[0050] Figure 4 is a Korsmeyer-Peppas model plot of the release kinetics of
the diclofenac sodium
(Diclofenac Na) from the nano-emulsion SR composition according to an
embodiment of the present
disclosure tested by in vitro permeation through PermeaPad' membranes.
lie
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DETAILED DESCRIPTION
I. Definitions
[0051] Unless otherwise indicated, the definitions and embodiments
described in this and
other sections are intended to be applicable to all embodiments and aspects of
the disclosure
herein described for which they would be understood to be suitable by a person
skilled in the art.
[0052] As used herein, the words "comprising" (and any form thereof, such
as "comprise" and
"comprises"), "having" (and any form thereof, such as "have" and "has"),
"including" (and any
form thereof, such as "include" and "includes") or "containing" (and any form
thereof, such as
"contain" and "contains"), are inclusive or open-ended and do not exclude
additional, unrecited
elements or process/method steps. As used herein, the word "consisting" and
its derivatives are
intended to be close-ended terms that specify the presence of the stated
features, elements,
components, groups, integers and/or steps, and also exclude the presence of
other unstated features,
elements, components, groups, integers and/or steps. The term "consisting
essentially of', as used
herein, is intended to specify the presence of the stated features, elements,
components, groups,
integers, and/or steps as well as those that do not materially affect the
basic and novel
characteristic(s) of these features, elements, components, groups, integers
and/or steps.
[0053] Terms of degree such as "substantially", "about" and "approximately"
as used herein
mean a reasonable amount of deviation of the modified term such that the end
result is not
significantly changed. These terms of degree should be construed as including
a deviation of at least
5% of the modified term if this deviation would not negate the meaning of the
term it modifies.
[0054] As used in this disclosure, the singular forms "a", "an" and "the"
include plural
references unless the content clearly dictates otherwise.
[0055] The term "and/or" as used herein means that the listed items are
present, or used,
individually or in combination. In effect, this term means that "at least one
of" or "one or
more" of the listed items is present or used.
[0056] The term "subject" as used herein includes all members of the animal
kingdom
including mammals. In an embodiment, the subject is a human.
12
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8000475-3 / 87073945
[0057] The term "pharmaceutically acceptable salt" as used herein means a
salt of the
active ingredient that is compatible with the treatment of subjects and
includes any suitable
non-toxic organic or inorganic salt for the particular active ingredient.
II. Compositions
100581 The compositions of the present disclosure are nano-emulsion based
compositions that
may be used topically for the sustained release cutaneous (dermal) and/or
subcutaneous (transdermal)
delivery of hydrophilic and lipophilic actives. For example, they can be used
for the targeted local
delivery of pharmaceuticals, cosmeceuticals, dermaceuticals, nutraceuticals,
phytoceuticals and/or
cannabinoids. The sustained drug release of the compositions together with
enhanced permeation
through skin may, for example, provide an advantageous cost saving benefit to
patients and the health
care system, by reducing the frequency and dose of application. Patient
prescriptions may therefore
last longer and the patient may require less frequent doctor and pharmacy
visits.
[0059] Accordingly, the present disclosure includes a composition
comprising an oil-in-
water nano-emulsion dispersed in an external oil phase, the oil-in-water nano-
emulsion
comprising an internal oil phase dispersed in an aqueous phase and stabilized
by a film-forming
thermoreversible emulsifier,
wherein
the internal oil phase comprises a liquid oil in combination with a charged
lipid;
the external oil phase comprises a combination of solid lipids;
the ratio by weight of the oil-in-water nano-emulsion to the external oil
phase is in
a range of from about 2:3 to about 7:3; and the ratio by weight of the liquid
oil to the
charged lipid is in a range of from about 5:1 to about 50:1.
[0060] In an embodiment, the aqueous phase further comprises a humectant.
The term
"humectant" as used herein refers to a substance that can reduce and/or
prevent the loss of
moisture in the composition. The humectant can be any suitable humectant. In
an embodiment,
the humectant is glycerin, 1,2-propanediol, 1,3-propanediol or combinations
thereof. In another
embodiment, the humectant is glycerin. It will be appreciated by a person
skilled in the art that
glycerin is also sometimes referred to as glycerol. It will also be
appreciated by a person skilled
13
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8000475-3 / 87073945
in the art that certain compounds such as glycerin, 1,2-propanediol and 1,3-
propanediol are
useful as and referred to herein as humectants, but they may also have other
properties such as
acting as a penetration enhancer and/or co-solvent. The compositions
preferably have a low
concentration of humectant, which advantageously may, for example, reduce
transepidermal
water loss (TEWL). Accordingly, in a further embodiment, the composition
comprises less than
about 2 wt% of the humectant (such as the glycerin).
[0061]
The liquid oil is any suitable liquid oil or combination thereof. In an
embodiment, the
liquid oil is a synthetic oil, mineral oil, natural oil, essential oil or
combinations thereof. In another
embodiment, the liquid oil is synthetic oil, mineral oil, natural oil or
combinations thereof. In a
further embodiment, the liquid oil is a mineral oil, natural oil or
combinations thereof. The term
"synthetic oil" as used herein refers to a suitable cosmetic and/or
pharmaceutical grade oil
chemically synthesized from a plant, animal and/or mineral source or
combinations of such
synthetic oils. The term "mineral oil" as used herein refers to an oil made up
of light mixtures of
higher alkanes from a mineral source such as a distillate of petroleum.
Mineral oils are typically
colorless and odorless. The term "natural oil" as used herein refers to an oil
obtained from a natural
source, animal or plant. In an embodiment, the liquid oil is a natural oil.
Natural oils can be
obtained, for example, from oil-containing parts or combinations thereof of
plants. Accordingly, in
an embodiment, the natural oil is a vegetable oil or combination thereof. The
term "vegetable
oil" as used herein refers to an oil extracted from seeds and/or other oil-
containing parts of a
plant such as fruits. In another embodiment, the vegetable oil or combination
thereof is selected
from long chain triglycerides (i.e. triglycerides having an aliphatic tail of
13-21 carbon atoms),
medium chain triglycerides (i.e. triglycerides having 2 or 3 fatty acids
having an aliphatic tail
of 6-12 carbon atoms), sources thereof or combinations thereof. A person
skilled in the art
would be able to readily select a suitable source or combination thereof for a
particular
composition of triglycerides. In an embodiment, the vegetable oil or
combination thereof is
selected from olive oil, avocado oil, moringa oil, medium chain triglyceride
oil, coconut oil,
palm oil and combinations thereof. In another embodiment, the liquid oil such
as the vegetable
oil or combination thereof is a medium-chain triglyceride (MCT) oil. In a
further embodiment,
the MCT oil comprises caprylic acid (C8:0) and capric acid (C10:0) e.g. in a
ratio of about
60:40. The internal oil phase is in the range of from about 1 wt% to about 20
wt%, based on the
14
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8000475-3 / 87073945
total weight of the internal oil phase, aqueous phase and external oil phase.
The term "essential
oil" as used herein refers to a concentrated volatile composition of a plant-
based oil.
[0062] The addition of oleic acid and vegetable oils with a high content of
oleic acid in the
nano-emulsions promoted a negative surface charge that increased electrostatic
repulsive forces
between droplets avoiding destabilization phenomena such as coalescence; i.e.
the negatively
charged oil droplets can enhance the nano-emulsion stability. Accordingly, in
an embodiment,
the charged lipid is a negatively charged lipid. In an embodiment, the
negatively charged lipid
is a negatively charged fatty acid. The negatively charged fatty acid can be
any suitable
negatively charged fatty acid. Negatively charged lipids e.g. fatty acids such
as oleic acid may
also, for example, advantageously cause less skin irritation than positively
charged lipids such
as fatty amines. Accordingly, in an embodiment, the negatively charged lipid
is oleic acid. In
another embodiment, the charged lipid is a positively charged lipid. In
another embodiment, the
positively charged lipid is a positively charged fatty amine. In another
embodiment of the
present disclosure, the positively charged fatty amine is oleyl amine.
[0063] In an embodiment, the ratio by weight of the liquid oil to the
charged lipid is in a range
of from about 5:1 to about 10:1.
[0064] Non-ionic emulsifiers such as sorbital esters and their ethoxylates,
commercially
available as TweenTm and Span, amphoteric emulsifiers such as phospholipids,
lecithin,
saponin and their derivatives have also been used to make nano-emulsions.
However, in the
compositions of the present disclosure, amphoteric tri-block copolymers are
advantageously
used, for example, because they can be used at lower concentration, such as a
concentration as
low as 0.2 wt% to create a stable nano-emulsion. Such tri-block copolymers are
also preferred
in chronic conditions such as but not limited to pain, inflammation and
fibrosis as they may, for
example, have less risk of skin irritation. The thermoreversible property
(e.g. a liquid at room
temperature and a gel at body temperature) of such emulsifiers may also be
advantageous in
sustaining the release of active ingredients. Accordingly, in an embodiment,
the film-forming
thermoreversible emulsifier is an amphoteric tri-block copolymer. Certain such
film-forming
thermoreversible emulsifiers that are amphoteric tri-block copolymers such as
poloxamers
(polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol tri-block
copolymers) can
also enhance the viscosity of the water phase, thereby further enhancing the
stability of a nano-
Date Recue/Date Received 2020-08-26

8000475-3 / 87073945
emulsion. Accordingly, in an embodiment, the film-forming thermoreversible
emulsifier is a
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol. In another
embodiment,
the polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol is
Poloxamer 407
(Pluronic F-127), Poloxamer 188 (Pluronic' F-68) or combinations thereof.
In an
embodiment, the polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene
glycol is
Poloxamer 407. The film-forming thermoreversible emulsifier is present in an
amount suitable
to stabilize the nano-emulsion. In an embodiment, the ratio by weight of the
film-forming
thermoreversible emulsifier to the internal oil phase is at least 0.1 : 10,
e.g. at least 0.3 : 10.
[0065] The compositions of the present disclosure are sometimes referred to
as oil-in-
water-in-oil emulsions in that the oil-in-water nano-emulsion is further
dispersed in the external
oil phase. At least a portion of the solid lipids of the external oil phase
are multifunctional in
that they advantageously have more than one function in the composition; e.g.
the capability to
emulsify and stabilize the composition in addition to having thickening
properties. For
example, in some embodiments, the combination of solid lipids is a combination
of at least two
of: suitable mono-, di- and tri-glycerides or combinations thereof; a suitable
occlusive wax or
combinations thereof; a hydrogenated vegetable oil or combinations thereof; a
fatty alcohol,
fatty acid or combinations thereof; and suitable glyceryl esters, derivatives
thereof and
combinations thereof. Active pharmaceutical ingredients (APIs) in salt form
such as
cyclobenzaprine HC1, diclofenac sodium, ketamine HC1 and lidocaine HC1 are
known to create
a challenge with respect to the stability of cream dosage forms. For example,
a high
concentration of these APIs can cause breakdown of the cream due to their
interaction with
certain solid fats and thickening agents. In contrast, the compositions of the
present examples
were observed to be stable even with higher concentrations of diclofenac
sodium.
[0066] In an embodiment, the combination of solid lipids is a combination
of at least two of:
(i) glyceryl dibehenate, glyceryl palmitostearate or combinations thereof;
(ii) petrolatum, cetyl palmitate, beeswax or combinations thereof;
(iii) a hydrogenated vegetable oil or combinations thereof;
(iv) a fatty alcohol, or combinations thereof; and
16
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8000475-3 / 87073945
(v)
glyceryl stearate, polyethylene glycol (PEG)-40 glyceryl stearate, PEG-100
stearate or combinations thereof.
[0067]
For example, the glyceryl behenate and/or glyceryl palmitostearate have
gelling and
thickening properties, which may be advantageous for sustained release. In an
embodiment, the
glyceryl dibehenate, glyceryl palmitostearate or combinations thereof is
glyceryl dibehenate.
The petrolatum has thickening and semi-occlusive properties, may also enhance
sustained
release and compositions comprising petrolatum may have higher stability in
the presence of an
API in salt form than compositions comprising cetyl palmitate and/or beeswax.
Accordingly, in
an embodiment, the petrolatum, cetyl palmitate, beeswax or combinations
thereof is petrolatum.
In another embodiment, the petrolatum is petrolatum white USP. However,
beeswax may be
advantageous and/or desirable for certain compositions such as those
comprising active
ingredients that are cannabinoids. Accordingly, in another embodiment, the
petrolatum, cetyl
palmitate, beeswax or combinations thereof is beeswax. The hydrogenated
vegetable oil or
combination thereof can be useful to create a stable matrix. In an embodiment,
the hydrogenated
vegetable oil is hydrogenated castor oil, hydrogenated soy oil or combinations
thereof. In another
embodiment, the hydrogenated vegetable oil is hydrogenated castor oil. The
petrolatum and/or
hydrogenated vegetables oil(s) may also enhance the permeability of both
hydrophilic and
lipophilic drugs, for example, by hydrating the skin, dilating the SC
intercellular channels and/or
opening tight junctions. In an embodiment, the fatty alcohol or combination
thereof is cetyl
alcohol, stearyl alcohol, cetostearyl alcohol (a mixture of fatty alcohols
comprising
predominantly cetyl alcohol and stearyl alcohol) or combinations thereof. In
another
embodiment, the fatty alcohol is cetyl alcohol. The glyceryl stearate,
polyethylene glycol (PEG)-
40 glyceryl stearate, PEG-100 stearate or combinations thereof can be useful
as viscosity
enhancers and/or have self-emulsifying capability. In another embodiment, the
glyceryl stearate,
polyethylene glycol (PEG)-40 glyceryl stearate, PEG-100 stearate or
combinations thereof is a
combination of glyceryl stearate and PEG-100 stearate. In an embodiment, the
ratio of the solid
lipids (i) : [(ii) + (iii)] : (v) in the combination is about 2 : 1 : 2. Such
a ratio was observed to
create a stable and sustained release matrix. In another embodiment, the solid
lipids comprise,
consist essentially of or consist of glyceryl dibehenate, petrolatum (e.g.
petrolatum white USP),
hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-100
stearate.
17
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8000475-3 / 87073945
[0068] In another embodiment of the present disclosure, the composition
further comprises a
multifunctional polymer, a liquid emollient, a penetration enhancer, a
chelating agent, an
antioxidant, a preservative or combinations thereof. In an embodiment, the
composition further
comprises a multifunctional polymer. In another embodiment, the composition
further comprises
a liquid emollient. In another embodiment, the composition further comprises a
penetration
enhancer. In another embodiment, the composition further comprises an
antioxidant. In another
embodiment, the composition further comprises a preservative. In another
embodiment, the
composition further comprises a combination of a multifunctional polymer, a
liquid emollient, a
penetration enhancer, a chelating agent, an antioxidant and a preservative.
[0069] The "multifunctional polymer" as used herein refers to a polymer
that has more than
one function in the composition, for example, it has the capability to act as
two or more of an
emulsifier, a thickener, a stabilizer and a texturizer and includes a
composition comprising a
multifunctional polymer having such properties. In an embodiment, the
multifunctional
polymer comprises one or more tri-block copolymers having a hydrophilic-
lipophilic balance
(HLB) of about 18. In another embodiment, the multifunctional polymer is
combination of
polyacrylamide & C13-14 isoparaffin & laureth-7 (e.g. SEPIGELTM 305),
acrylamide/sodium
acryloyldimethyl taurate copolymer, isohexadecane and Polysorbate 80 (e.g.
SIMULGELTm
600), a hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer (e.g.
SEPINOVTM
WE0 and/or SEPINOV EMT-10), polyacrylate crosspolymer-6 (e.g. SEPIMAX ZENTm),
polyacrylate crosspolymer-11 (e.g. ARISTOFLEXTm Velvet) or combinations
thereof. The
multifunctional polymers are suitably selected from those that are stable in a
wide pH range.
For example, polyacrylate crosspolymer-6, has advantageous resistance to
electrolytes and is
stable in a wide pH range (from about 2 to about 8). It has the ability to
stabilize the oil phase,
provide a gel cream texture and create a pseudo-emulsion system. In an
embodiment, the
multifunctional polymer is a combination of multifunctional polymers that is
polyacrylate
crosspolymer-6 and hydroxyethyl acrylate/sodium acryloyldimethyl taurate
copolymer.
[0070] The liquid emollient can be polar or non-polar and suitably has the
ability to
dissolve soluble and poorly water-soluble active ingredients, respectively.
The liquid emollient
is advantageously of amino acid or vegetable origin or is a silicone oil and
has the advantage of
a lack of a rancid oil odor. Accordingly, in an embodiment, the liquid
emollient is isopropyl
18
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8000475-3 / 87073945
myristate, isopropyl palmitate, glycine, N-methyl-N-(1-oxododecy1)-, 1-
methylethyl ester
(isopropyl lauroyl sarcosinate), a plant-based C15-19 Alkane (e.g. EMOGREEN')
or a
silicone oil emollient. Such emollients may, for example, have enhanced
ceramide-like
emolliency (sensory effect), reduced greasy feeling and/or reduced oxidative
reactions (thereby
avoiding or reducing the development of a rancid oil smell. In an embodiment
of the present
disclosure, the liquid emollient is isopropyl lauroyl sarcosinate.
[0071] Penetration enhancers suitably create a push and pull effect. As a
result, they can
enhance the skin reservoir effect and sustain the release of poorly soluble
active ingredients.
While dimethyl sulfoxide (DMSO) is a commonly used solvent for enhancing the
penetration of
lipophilic drugs, ethoxy diglycol is advantageous in that it has less skin
toxicity. Accordingly, in
an embodiment, the penetration enhancer is ethoxy diglycol. The Nano-Emulsion
SR cream was
also compatible and stable in the presence of terpenoids useful e.g. as
natural penetration
enhancers such as cineol, eucalyptol limonene, linanool and menthol.
Accordingly, in some
embodiments of the present disclosure, the penetration enhancer comprises a
natural penetration
enhancer. In another embodiment, the natural penetration enhancer is one or
more terpenoids. In
another embodiment, the terpenoid is cineol, eucalyptol limonene, linanool,
menthol or
combinations thereof. In another embodiment, the penetration enhancer
comprises menthol.
[0072] The term "chelating agent" as used herein refers to a chemical
compound that binds
with metal ions or metallic compounds, thereby preventing or reducing
oxidative reactions,
enhancing the stability of product by improving preservative and/or
antioxidant efficacy_ The
chelating agent is any suitable chelating agent. In an embodiment of the
present disclosure, the
chelating agent is a salt (e.g. a disodium salt) of ethylenediaminetetraacetic
acid (EDTA).
[0073] Antioxidants can be useful, for example, to prevent or reduce
oxidation of oil
ingredients and/or discoloration of active ingredients such as cannabinoids.
The antioxidants
are suitably selected from natural or synthetic antioxidants. In an
embodiment, the antioxidant
is tocopherol acetate, butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA) or
combinations thereof. In another embodiment, the antioxidant is butylated
hydroxytoluene.
[0074] In some embodiments, the composition comprises a preservative that
is a wide
spectrum preservative or combination thereof capable of preserving both oil
and water phases.
19
Date Recue/Date Received 2020-08-26

8000475-3 / 87073945
The preservative is suitably selected from natural and/or synthetic
preservatives. In an
embodiment, the preservative is caprylyl glycol, pentylene glycol,
ethylhexylglycerin, vitamin
E, phenoxy ethanol or combinations thereof. In another embodiment of the
present disclosure,
the preservative is a combination of preservatives that is caprylyl glycol and
phenoxy ethanol.
[0075] The present disclosure also includes a composition comprising an oil-
in-water nano-
emulsion dispersed in an external oil phase, the oil-in-water nano-emulsion
comprising an
internal oil phase dispersed in an aqueous phase and stabilized by a film-
forming
thermoreversible emulsifier,
wherein
the internal oil phase comprises a liquid oil in combination with a charged
lipid;
the external oil phase comprises a combination of solid lipids;
the aqueous phase comprises a humectant;
the ratio by weight of the oil-in-water nano-emulsion to the external oil
phase is
in a range of from about 2:3 to about 7:3; and the ratio by weight of the
liquid oil to the
charged lipid is in a range of from about 5:1 to about 50:1,
the composition further comprising a multifunctional polymer, a liquid
emollient, a
penetration enhancer, a chelating agent, an antioxidant and a preservative.
[0076] In an embodiment, the composition comprises, consists essentially of
or consists of:
water (e.g. purified water);
the humectant glycerin;
the film-forming thermoreversible emulsifier that is a polyethylene glycol¨b¨
polypropylene glycol¨b¨polyethylene glycol (e.g. Poloxamer 407);
the charged lipid oleic acid;
the liquid oil medium chain triglyceride (MCT) oil;
the combination of multifunctional polymers that is polyacrylate crosspolymer-
6
and hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer;
Date Recue/Date Received 2020-08-26

8000475-3 / 87073945
the chelating agent disodium ethylenediaminetetraacetic acid (EDTA);
the solid lipids glyceryl dibehenate, petrolatum (e.g. petrolatum white USP),
hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-100
stearate;
the liquid emollient isopropyl lauroyl sarcosinate;
the penetration enhancer ethoxy diglycol;
the antioxidant butylated hydroxytoluene; and
the combination of preservatives that is caprylyl glycol and phenoxy ethanol.
[0077]
In an embodiment, the water is present in an amount of from about 50 wt% to
about
80 wt%, about 60 wt% to about 70 wt% or about 62 wt%. In another embodiment,
the
humectant (e.g. glycerin) is present in an amount of from about 1 wt% to about
10 wt%, about
1.5 wt% to about 5 wt% or about 2 wt%. In another embodiment, the film-forming

thermoreversible emulsifier (e.g. the polyethylene glycol¨b¨polypropylene
glycol¨b¨
polyethylene glycol such as Poloxamer 407 is present in an amount of from
about 0.05 wt% to
about 5 wt%, about 0.1 wt% to about 0.5 wt% or about 0.3 wt%. In another
embodiment, the
charged lipid (e.g. the negatively charged lipid such as oleic acid) is
present in an amount of
from about 0.1 wt% to about 10 wt%, about 0.5 wt% to about 2.5 wt% or about 1
wt%. In
another embodiment, the liquid oil (e.g. medium chain triglyceride (MCT) oil)
is present in an
amount of from about 1 wt% to about 10 wt%, about 7 wt% to about 9 wt% or
about 8 wt%. In
another embodiment, the multifunctional polymer (e.g. the combination of
multifunctional
polymers that is polyacrylate crosspolymer-6 and hydroxyethyl acrylate/sodium
acryloyldimethyl taurate copolymer) is present in a total amount of from about
0.2 wt% to
about 10 wt%, about 0.4 wt% to about 1.2 wt% or about 0.8 wt%. In some
embodiments
wherein the multifunctional polymer is a combination of polyacrylate
crosspolymer-6 and
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer, the
polyacrylate
crosspolymer-6 is present in an amount of from about 0.1 wt% to about 5 wt%,
about 0.2 wt%
to about 1 wt% or about 0.6 wt% and the hydroxyethyl acrylate/sodium
acryloyldimethyl
taurate copolymer is present in an amount of from about 0.1 wt% to about 5
wt%, about 0.1
wt% to about 1 wt% or about 0.2 wt%. In another embodiment, the chelating
agent (e.g.
disodium ethylenediaminetetraacetic acid) is present in an amount of from
about 0.005 wt% to
21
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8000475-3 / 87073945
about 0.05 wt%, about 0.01 wt% to about 0.03 wt% or about 0.02 wt%. In another

embodiment, the solid lipids are present in a total amount of from about 5 wt%
to about 40
wt%. In some embodiments, solid lipid (i) (e.g. glyceryl dibehenate) is
present in an amount of
from about 1 wt% to about 10 wt%, about 5 wt% to about 6 wt% or about 5.5 wt%;
solid lipid
(ii) (e.g. petrolatum such as petrolatum white USP) is present in an amount of
from about 0.5
wt% to about 10 wt%, about 0.75 wt% to about 1.25 wt% or about 1 wt%; solid
lipid (iii) (e.g.
hydrogenated castor oil) is present in an amount of from about 1 wt% to about
10 wt%, about
1.25 wt% to about 2.25 wt% or about 1.75 wt%; solid lipid (iv) (e.g. cetyl
alcohol) is present in
an amount of from about 0.5 wt% to about 10 wt%, about 0.75 wt% to about 5 wt%
or about 2
wt%; and solid lipid (v) (e.g. glyceryl stearate and PEG-100 stearate) is
present in an amount of
from about 1 wt% to about 10 wt%, about 5 wt% to about 6 wt% or about 5.5 wt%.
In another
embodiment, the liquid emollient (e.g. isopropyl lauroyl sarcosinate) is
present in an amount of
from about 1 wt% to about 5 wt%, about 2 wt% to about 4 wt% or about 3 wt%. In
another
embodiment, the penetration enhancer (e.g. ethoxy diglycol) is present in an
amount of from
about 1 wt% to about 10 wt%, about 4 wt% to about 6 wt% or about 5 wt%. In
another
embodiment, the antioxidant butylated hydroxytoluene is present in an amount
of from about
0.02 wt% to 0.1 wt%, about 0.05 wt% to less than 0.1 wt% or less than 0.1 wt%.
In another
embodiment, the preservative (e.g. the combination of preservatives that is
caprylyl glycol and
phenoxy ethanol) is present in a total amount of from about 0.06 wt% to about
2.0 wt%. In
some embodiments wherein the preservative is a combination of preservatives
that is caprylyl
glycol and phenoxy ethanol, the caprylyl glycol is present in an amount of
from about 0.01
wt% to about 1.0 wt%, about 0.4 wt% to about 0.6 wt% or about 0.5 wt% and the
phenoxy
ethanol is present in an amount of from about 0.05 wt% to about 1 wt%, about
0.85 wt% to
about 0.95 wt% or about 0.9 wt%. It will be appreciated by a person skilled in
the art that the
ranges in such embodiments can be optionally be interchanged.
[0078]
In an embodiment, the composition comprises, consists essentially of or
consists of
water in an amount of from about 50 wt% to about 80 wt%, about 60 wt% to about
70 wt% or
about 62 wt%; glycerin in an amount of from about 1 wt% to about 10 wt%, about
1.5 wt% to
about 5 wt% or about 2 wt%; polyethylene glycol-b-polypropylene glycol-b-
polyethylene
glycol (e.g. Poloxamer 407) in an amount of from about 0.05 wt% to about 5
wt%, about 0.1
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8000475-3 / 87073945
wt% to about 0.5 wt% or about 0.3 wt%; oleic acid in an amount of from about
0.1 wt% to
about 10 wt%, about 0.5 wt% to about 2.5 wt% or about 1 wt%; medium chain
triglyceride
(MCT) oil in an amount of from about 1 wt% to about 10 wt%, about 7 wt% to
about 9 wt% or
about 8 wt%; polyacrylate crosspolymer-6 in an amount of from about 0.1 wt% to
about 5 wt%,
about 0.2 wt% to about 1 wt% or about 0.6 wt%; hydroxyethyl acrylate/sodium
acryloyldimethyl taurate copolymer in an amount of from about 0.1 wt% to about
5 wt%, about
0.1 wt% to about 1 wt% or about 0.2 wt%; disodium ethylenediaminetetraacetic
acid in an
amount of from about 0.005 wt% to about 0.05 wt%, about 0.01 wt% to about 0.03
wt% or
about 0.02 wt%; glyceryl dibehenate in an amount of from about 1 wt% to about
10 wt%, about
wt% to about 6 wt% or about 5.5 wt%; petrolatum (e.g. petrolatum white USP) in
an amount
of from about 0.5 wt% to about 10 wt%, about 0.75 wt% to about 1.25 wt% or
about 1 wt%;
hydrogenated castor oil in an amount of from about 1 wt% to about 10 wt%,
about 1.25 wt% to
about 2.25 wt% or about 1.75 wt%; cetyl alcohol in an amount of from about 0.5
wt% to about
wt%, about 0.75 wt% to about 5 wt% or about 2 wt%; glyceryl stearate and PEG-
100
stearate in an amount of from about 1 wt% to about 10 wt%, about 5 wt% to
about 6 wt% or
about 5.5 wt%; isopropyl lauroyl sarcosinate in an amount of from about 1 wt%
to about 5
wt%, about 2 wt% to about 4 wt% or about 3 wt%; ethoxy diglycol in an amount
of from about 1
wt% to about 10 wt%, about 4 wt% to about 6 wt% or about 5 wt%; butylated
hydroxytoluene in
an amount of from about 0.02 wt% to 0.1 wt%, about 0.05 wt% to less than 0.1
wt% or less than
0.1 wt%; caprylyl glycol in an amount of from about 0.01 wt% to about 1.0 wt%,
about 0.4 wt%
to about 0.6 wt% or about 0.5 wt%; and phenoxy ethanol in an amount of from
about 0.05 wt% to
about 1 wt%, about 0.85 wt% to about 0.95 wt% or about 0.9 wt%.
[0079]
The term "oil-in-water nano-emulsion" as used herein refers to an emulsion in
which oil droplets of the internal oil phase dispersed in the aqueous phase
have a mean droplet
size of less than about 1 tn. In an embodiment, the oil droplets have a mean
droplet size of
less than about 700 nm. In another embodiment, the oil droplets have a mean
droplet size of
less than about 500 nm. In a further embodiment, the oil droplets have a mean
droplet size of
from about 400 nm to about 600 nm or about 500 nm. Droplet size is suitably
measured at
ambient temperature (e.g. at 25 C) using an instrument such as a Malvern
Zetasizer Nano-ZS.
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[0080] The pH of the composition may depend, for example, on whether the
composition is in
the form of a compounding base or in a form that would be directly applied to
the skin of a subject
and the skilled person would be able to select a suitable pH accordingly. For
example, the pH of a
composition that is in the form of a compounding base for use with an active
ingredient that is of
basic pH is suitably in a range that, when the active ingredient is added, the
pH of the final
composition is in a range that would be compatible with the application to the
skin of a subject.
This may, for example, be an operational advantage for compounding pharmacies
with limited
access to measuring pH devices. Alternatively, in some embodiments, a pH
adjusting agent is
added such that the pH of the final composition is in a range that would be
compatible with the
application to the skin of a subject. As a general rule, the compatible pH
range for a composition to
be applied to the skin of a subject is in a range of from greater than 4 to
less than 8. Accordingly, as
an example, a composition that is for compounding with about 10% diclofenac Na
would
optionally have a pH in a range of about 4.5 to about 5.5 which can prepare a
final composition
having a pH in a range of about 6.5 to less than 8 without the need to adjust
the pH.
[0081] The compositions of the present disclosure may permit the topical
administration of
a single active ingredient or multiple active ingredients simultaneously to
address one or more
disease conditions. For example, the composition may sustain the release of
both lipophilic and
hydrophilic active ingredients, enhance the dermal and/or transdermal
penetration of both
lipophilic and hydrophilic active ingredients, exhibit resiliency in the
presence of a salt load of
up to 20% of the total weight of the composition or greater, and/or remain
stable and/or avoid
degradation for up to six months or more. The compositions of the present
disclosure may
provide for about 70% or greater permeation of a highly lipophilic active
ingredient, such as
diclofenac sodium (diclofenac Na), beyond the stratum corneum for up to about
24 hours.
[0082] Accordingly, in some embodiments, the composition delivers one or
more active
ingredients dermally (cutaneously) and/or transdermally (subcutaneously). In
some embodiments,
the composition delivers of one or more active ingredients dermally
(cutaneously). In some
embodiments, the composition delivers one or more active ingredients
transdermally
(subcutaneously). It will be appreciated by a person skilled in the art having
regard to the present
disclosure that adapting the compositions for dermal vs transdermal delivery
of an active ingredient
involves adapting the concentration or presence of certain components of the
composition. For
24
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8000475-3 / 87073945
example, compositions for transdermal delivery would typically include the
penetration enhancer
(e.g. ethoxy diglycol) and would have higher concentrations of the liquid oil.
[0083] In an embodiment, the composition comprising one or more active
ingredients has
at least 3 months shelf life, at least 6 months shelf life and/or up to 2
years shelf file.
100841 In an embodiment, the composition releases the one or more active
ingredients for a
time of up to about 24 hours. In another embodiment, the composition releases
the one or more
active ingredients for a time of about 6 hours to about 24 hours or about 12
hours to about 24 hours.
[0085] Some compositions of the present disclosure are suitable to be used
as a base for
preparing a compound comprising one or more active ingredients (e.g.
pharmaceutical,
cosmeceutical, dermaceutical, nutraceutical, phytoceutical and/or cannabinoid
active ingredients).
Accordingly, in some embodiments, the composition is devoid of active
ingredients (is a
compounding base). In an embodiment, such a composition has up to 2 years
shelf life.
[0086] The present disclosure further includes a use of such compositions
for preparing a
compound comprising one or more active ingredients.
[0087] In alternative embodiments, the composition further comprises one or
more active
ingredients. In an embodiment, the one or more active ingredients are selected
from pharmaceutical
active ingredients, cosmeceutical active ingredients, dermaceutical active
ingredients, nutraceutical
active ingredients, phytoceutical active ingredients, cannabinoid active
ingredients and
combinations thereof. In an embodiment, the one or more active ingredients are
present in a total
amount of from about 5 wt% to about 40 wt%, based on the total weight of the
composition. In
another embodiment, the one or more active ingredients are present in a total
amount of up to 30
wt%, up to 20 wt%, or up to 10 wt% based on the total weight of the
composition.
[0088] In some embodiments, the composition comprises a single active
ingredient. In some
embodiments, the composition comprises a combination of active ingredients. In
some embodiments,
the composition comprises active ingredients that address different diseases,
conditions or symptoms.
[0089] In some embodiments, the active ingredient or combination thereof is
lipophilic. In some
embodiments, the active ingredient or combination thereof is hydrophilic. In
some embodiments, the
active ingredients are a combination of lipophilic and hydrophilic active
ingredients.
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8000475-3 / 87073945
[0090] In an embodiment, the active ingredient is a pharmaceutical active
ingredient. In an
embodiment, the pharmaceutical active ingredient is selected from a non-
steroidal anti-
inflammatory drug (NSAID), a muscle relaxant, a narcotic analgesic, an opioid
antagonist with
analgesic effect, an opioid or opiate agonist, a nerve depressant, an
antidepressant, a local
anesthetic, a peripheral vasodilator, a corticosteroid, vitamin D3, an anti-
infective drug (e.g. an
antimicrobial, antifungal and/or antiviral drug) and combinations thereof. In
an embodiment, the
pharmaceutical active ingredient is an NSAID. In another embodiment, the
pharmaceutical active
ingredient is a muscle relaxant. In another embodiment, the pharmaceutical
active ingredient is a
narcotic analgesic. In another embodiment, the pharmaceutical active
ingredient is an opioid
antagonist with analgesic effect. In another embodiment, the pharmaceutical
active ingredient is
an opioid or opiate agonist. In another embodiment, the pharmaceutical active
ingredient is a
nerve depressant. In another embodiment, the pharmaceutical active ingredient
is an
antidepressant. In another embodiment, the pharmaceutical active ingredient is
a local anesthetic.
In another embodiment, the pharmaceutical active ingredient is a peripheral
vasodilator. In
another embodiment, the pharmaceutical active ingredient is a corticosteroid.
In another
embodiment, the pharmaceutical active ingredient is vitamin D3. In another
embodiment, the
pharmaceutical active ingredient is an anti-infective drug (e.g. an
antimicrobial, antifungal and/or
antiviral drug). In another embodiment of the present disclosure, the
phannaceutical active
ingredient is a combination of two or more of an NSAID, a muscle relaxant, a
narcotic analgesic,
an opioid antagonist with analgesic effect, an opioid or opiate agonist, a
nerve depressant, an
antidepressant, a local anesthetic, a peripheral vasodilator, a
corticosteroid, vitamin D3 and an
anti-infective drug (e.g. an antimicrobial, antifungal and/or antiviral drug).
[0091] In an embodiment, the NSAID is selected from a salicylic acid
derivative (e.g.
aspirin, diflunisal, salsalate or trilisate); a propionic acid (e.g.
flurbiprofen, ibuprofen,
ketoprofen, naproxen or oxaprozin); an acetic acid (e.g. diclofenac, etodolac,
indomethacin,
ketorolac, nabumetone, sulindac or tolmetin); a fenamate (e.g. meclofenamate);
an oxicam (e.g.
meloxicam or piroxicam); and a COX-2 inhibitor (e.g. celecoxib, rofecoxib, and
valdecoxib).
In an embodiment, the composition comprises an NSAID or combination thereof in
an amount
of from about 1 wt% to about 30 wt%, based on the total weight of the
composition. In an
embodiment, the muscle relaxant is cyclobenzaprine or baclofen. In an
embodiment, the
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narcotic analgesic is ketamine or tramadol. In an embodiment, the opioid
antagonist with
analgesic effect is naltrexone. In an embodiment, the opioid or opiate agonist
is ketamine or
tramadol. In an embodiment, the nerve depressant is gabapentin, pregabalin,
topiramate or
lamotrigine. In an embodiment, the antidepressant is amitrptyline, doxepine,
bupropione or
naltrexone. For example, such antidepressants can optionally be used as
topical analgesic
drugs. In an embodiment, the local anesthetic is lidocaine (e.g. lidocaine
base or lidocaine
HC1), benzocaine, prilocaine HC1 or tetracaine }ICI. In an embodiment, the
peripheral
vasodilator is sildenafil, tadalafil or vardenafil. In an embodiment, the
corticosteroid is
hydrocortisone, betamethasone, clobetasol, desonide, fluoroquinolone or
mometasone. In an
embodiment, the anti-infective drug (e.g. the antimicrobial, antifungal and/or
antiviral drug) is
fusidic acid, mupirocin, gentamycin, neomycin or acyclovir.
[0092] In an embodiment, the active ingredient is a hormone for delivery to
the dermis, e.g. for
the management of skin aging. In another embodiment, the hormone is for
hormone-replacement
therapy. In an embodiment, the hormone is estradiol, estriol, progesterone,
dehydroepiandrosterone
(DHEA) or combinations thereof. In another embodiment, the hormone is
testosterone.
[0093] In an embodiment, the active ingredient is a lipophilic
phytoceutical. In another
embodiment, the lipophilic phytoceutical is selected from a cannabinoid,
methyl salicylates,
curcumin, terpenoids, flavonoids and combinations thereof. In an embodiment,
the cannabinoid
is selected from cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol
and combinations
thereof_ In an other embodiment of the present disclosure, the terpen oi ds
and fl avon oi ds are
selected from cineol, linanool, limonene, eucalyptol, menthol and combinations
thereof.
[0094] In an embodiment, the active ingredient is a cosmeceutical. In an
embodiment, the
cosmeceutical is selected from a lipophilic antioxidant, ceramides and
combinations thereof. In
an embodiment, the cosmeceutical is a lipophilic antioxidant or combinations
thereof. In
another embodiment, the cosmeceutical is ceramides. In another embodiment, the
lipophilic
antioxidant is selected from vitamin E derivatives (e.g. alpha-tocopherol),
vitamin A derivatives
(e.g. retinol, beta-carotene or retinoic acid), and Coenzyme Qio (e.g.
ubiquinol or ubiquinone).
[0095] In another embodiment, the active ingredient is a matrix
metalloproteinase enhancer
(e.g. stratifin), a co-enzyme for matrix metalloproteinase (e.g. zinc), a
matrix metalloproteinase
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inhibitor, an anti-aging active (e.g. vitamin C (ascorbic acid) or
glutathione), an anti-aging
amino acid, peptide, protein or derivative thereof (e.g. acetyl octapeptide-1,
the active peptide
of botulinum toxin, hyaluronic acid, denatured collagen or arginine), natural
moisturizing
factors, telomerase activators or combinations thereof.
[0096] The compositions of the present disclosure can entrap lipophilic
active ingredients
such as diclofenac sodium in both the internal and external oil phase. This
particular aspect can
result in an immediate release of diclofenac sodium from the external phase
for immediate local
pain relief, followed by sustained release of the drug from the internal oil
phase. The Nano-
Emulsion SR Cream was thermodynamically stable for at least 6 months when
diclofenac sodium
was added at a 10% concentration and was even surprisingly stable with 20%
diclofenac sodium.
[0097] Accordingly, in an embodiment, the active ingredient is diclofenac
or a
pharmaceutically acceptable salt thereof in an amount of up to 30 wt%. In an
embodiment, the
active ingredient is diclofenac or a pharmaceutically acceptable salt thereof
in an amount of
greater than about 2.3 wt%, for example, from 2.5 wt% to 30 wt%, about 5 wt%
to about 15 wt%
or about 5 wt% to about 10 wt%. In an embodiment, the diclofenac salt is
diclofenac sodium.
[0098] The Nano-Emulsion SR Cream was also compounded with Benzocaine 20
wt%,
Lidocaine 6 wt% and Tetracaine HC1 4 wt% to obtain a smooth and homogeneous
product. The
product was stable at room temperature in contrast to conventional creams and
gels that are not
resilient to such a high concentration of anesthetics and separate easily.
[0099] Accordingly, in an embodiment, the active ingredient is lidocaine,
benzocaine, tetracaine,
prilocaine or pharmaceutically acceptable salts thereof or combinations
thereof, wherein the lidocaine,
benzocaine, tetracaine, prilocaine or pharmaceutically acceptable salts
thereof are each present in an
amount of up to about 20 wt%, with the total concentration of the lidocaine,
benzocaine, tetracaine,
prilocaine or pharmaceutically acceptable salts thereof being no more than 30
wt%. In another
embodiment, the active ingredient is lidocaine, benzocaine, tetracaine or
pharmaceutically acceptable
salts thereof or combinations thereof, wherein the lidocaine, benzocaine,
tetracaine or
pharmaceutically acceptable salts thereof are each present in an amount of up
to about 20 wt%, with
the total concentration of the lidocaine, benzocaine, tetracaine or
pharmaceutically acceptable salts
thereof being no more than 30 wt%. In an embodiment, the active ingredients
are a combination of
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lidocaine, benzocaine and tetracaine or pharmaceutically acceptable salts
thereof. In another
embodiment, the active ingredients are benzocaine in an amount of about 20
wt%, lidocaine in an
amount of about 6 wt% and tetracaine HC1 in an amount of about 4 wt%.
[00100] The compositions of the present disclosure can be used for the dermal
and/or
transdermal delivery of cannabinoids (poorly water soluble, e.g. log P 6-7,
MW: 280-315
Daltons). The Nano-Emulsion SR cream was compounded with THC distillate and
CBD oil to
obtain a smooth and homogeneous product. Packaged in an opaque airless pump
and stored at
room temperature away from excessive heat and light, no color change was
observed over 12
months. Similar results were observed with a cream compounded with CBD
isolate.
[00101] Accordingly, in an embodiment, the active ingredient is
tetrahydrocannabinol
(THC), cannabidiol (CBD) or combinations thereof. In an embodiment, the active
ingredient is
THC. In another embodiment, the active ingredient is CBD. In a further
embodiment, the active
ingredients are a combination of THC and CBD. In an embodiment, the
composition comprises
CBD isolate in an amount of up to about 20 wt%. In another embodiment, the
composition
comprises CBD oil in an amount of up to about 15 wt%. In a further embodiment,
the
composition comprises THC distillate in an amount of up to 20 wt%. In an
embodiment, the
THC is present in an amount of less than 1 gram per package of the composition
[00102] In some embodiments, the composition further comprises one or more
natural and/or
herbal active agents with anti-inflammatory, analgesic or anesthetic effect.
In some embodiments,
the one or more natural and/or herbal active agents with anti-inflammatory,
analgesic or
anesthetic effect are oils (such as essential oils) and/or terpenoids or
combinations thereof. In
some embodiments, the one or more natural and/or herbal active agents with
anti-inflammatory
effect are an oil (e.g. avocado, olive or moringa oil), an essential oil
(e.g., thyme, turmeric or
rosemary essential oils) or combinations thereof. In some embodiments, the one
or more natural
and/or herbal agents with analgesic effect are an oil (e.g. wintergreen or
peppermint oil), an
essential oil (e.g. eucalyptus, lavender, thyme or rosemary essential oils) or
combinations thereof.
In some embodiments, the natural and/or herbal active agents with anesthetic
effect are clove
essential oil, menthol, or camphor or combinations thereof. In some
embodiments, the
composition further comprises one or more terpenoids with analgesic, anti-
inflammatory,
anesthetic, antioxidant, anti-infective (e.g. anti-microbial and/or anti-
viral), anti-fibrogenic and/or
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anti-aging effects. In an embodiment, the terpenoids are cineol, eucalyptol,
limonene, linanool,
menthol or combinations thereof. The Nano-Emulsion SR cream was also
compatible and stable
in the presence of oils such as avocado, olive, moringa and wintergreen,
essential oils such as
clove, lavender, rosemary, eucalyptus, thyme, turmeric, peppermint and
spearmint and terpenoids
such as cineol, eucalyptol, limonene, linanool and menthol. Accordingly, in
some embodiments
of the present disclosure, the composition further comprises one or more oils
similar to such oils
and/or essential oils. In another embodiment, the essential oil is lavender,
rosemary, eucalyptus,
thyme, turmeric, peppermint and spearmint or combinations thereof. In another
embodiment, the
oil is avocado, olive, moringa or wintergreen oil or combinations thereof.
[00103] It will be appreciated by a person skilled in the art that the
components of the
compositions of the present disclosure can be chosen from natural, organic,
cosmetic and/or
pharmaceutical grade categories and can select appropriate components
accordingly.
III. Methods of Delivering Active Ingredients
[00104] The compositions of the present disclosure can be used, for example,
for cutaneous
(dermal) and/or subcutaneous (transdermal) delivery of active ingredients,
whether compounded
or in a commercially available product. An exemplary compound with diclofenac
sodium added
at a 100/ concentration showed sustained release of the diclofenac sodium for
24 hours.
[00105]
Accordingly, the present disclosure also includes a method of delivering one
or more
active ingredients to a subject, the method comprising applying a composition
of the present
disclosure comprising the one or more active ingredients to the skin of the
subject. The present
disclosure also includes a use of a composition of the present disclosure
comprising the one or more
active ingredients on the skin of a subject for delivering the one or more
active ingredients to the
subject. The present disclosure also includes a use of a composition of the
present disclosure
comprising the one or more active ingredients for preparation of a medicament
for the skin of a
subject for delivering the one or more active ingredients to the subject. The
present disclosure also
includes a composition of the present disclosure comprising the one or more
active ingredients for
use on the skin of a subject to deliver the one or more active ingredients to
the subject.
[00106] In an embodiment, the delivery of the one or more active ingredients
is dermal. In
another embodiment, the delivery of the one or more active ingredients is
subdermal.
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[00107] In an embodiment, the composition is a commercially available product.
In another
embodiment, the composition is prepared as a compound.
[00108] In an embodiment, the composition or compound is administered to
the skin of the
subject or for use less than three times per day. In another embodiment, the
composition or compound
is administered to the skin of the subject or for use twice per day. In a
further embodiment, the
composition or compound is administered to the skin of the subject or for use
once per day.
[00109] It will be appreciated by a person skilled in the art that the use of
the composition
will depend on the active ingredient or combination of active ingredients to
be delivered to the
subject. For example, in some embodiments, the delivery of the one or more
active ingredients
is for treatment (e.g. targeted local relief) of inflammation, pain (e.g.
musculoskeletal and/or
neuropathic pain), muscle spasm, skin aging, tissue fibrosis, joint fibrosis
or combinations
thereof and the skilled person would be able to select suitable active agents
accordingly. In an
embodiment, the delivery of the one or more active ingredients is for local
analgesic effect. In
another embodiment, the delivery of the one or more active ingredients is for
local-
inflammatory effect. In a further embodiment, the delivery of the one or more
active
ingredients is for an antifibrogenic effect. In another embodiment, the
delivery of the one or
more active ingredients is for anti -aging and/or skin rejuvenation
IV. Methods of Preparation
[00110] The Nano-Emulsion SR Cream described in the examples of the present
disclosure
was prepared using a low energy emulsification technique via hot stifling and
homogenization.
Such a technique can be an easy, cost-effective method to scale up. However,
the choice of
emulsion components and ratios of these components, as well as certain steps
to add
ingredients is critical in generating stable emulsion systems with appropriate
particle sizes.
[00111] Accordingly, the present disclosure includes a method of preparing
a composition
comprising an oil-in-water nano-emulsion dispersed in an external oil phase,
the oil-in-water nano-
emulsion comprising an internal oil phase dispersed in an aqueous phase, the
method comprising:
combining a first mixture comprising a liquid oil and a charged lipid with a
second mixture that is an aqueous mixture comprising a film-forming
thermoreversible
emulsifier to prepare an oil-in-water nano-emulsion; and
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combining the oil-in-water nano-emulsion with a third mixture comprising a
combination of solid lipids to prepare the composition,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is in a range of from about 2:3 to about 7:3; and the ratio by weight of
the liquid oil
to the charged lipid is in a range of from about 5:1 to about 50:1.
[00112] It will be appreciated by a person skilled in the art that embodiments
relating to the
components of the compositions of the present disclosure may pertain to
embodiments relating
to the corresponding components in the methods herein for preparing such
compositions.
[00113] For example, in an embodiment, the aqueous mixture comprising the film-
forming
thermoreversible emulsifier further comprises a humectant. The humectant can
be any suitable
humectant. In an embodiment, the humectant is glycerin, 1,2-propanediol, 1,3-
propanediol or
combinations thereof. In another embodiment, the humectant is glycerin. The
compositions
prepared by the methods of the present disclosure preferably have a low
concentration of
humectant which advantageously may, for example, reduce transepidermal water
loss (TEWL).
Accordingly, in a further embodiment of the present disclosure, the
composition comprises less
than about 2 wt% of the humectant (such as the glycerin).
[00114] The liquid oil is any suitable liquid oil or combination thereof. In
an embodiment,
the liquid oil is a synthetic oil, mineral oil, natural oil, essential oil or
combinations thereof. In
another embodiment, the liquid oil is a synthetic oil, mineral oil, natural
oil or combinations thereof.
In a further embodiment, the liquid oil is a mineral oil, natural oil or
combinations thereof. In an
embodiment, the liquid oil is a natural oil. In an embodiment, the natural oil
is a vegetable oil
or combination thereof. In another embodiment, the vegetable oil or
combination thereof is
selected from long chain triglycerides (i.e. triglycerides having an aliphatic
tail of 13-21 carbon
atoms), medium chain triglycerides (i.e. triglycerides having 2 or 3 fatty
acids having an
aliphatic tail of 6-12 carbon atoms), sources thereof or combinations thereof.
A person skilled
in the art would be able to readily select a suitable source or combination
thereof for a
particular composition of triglycerides. In an embodiment, the vegetable oil
or combination
thereof is selected from olive oil, medium chain triglyceride oil, coconut
oil, palm oil, moringa
oil, avocado oil and combinations thereof. In another embodiment, the liquid
oil such as the
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vegetable oil or combination thereof is medium-chain triglyceride (MCT) oil.
In a further
embodiment, the MCT oil comprises caprylic acid (C8:0) and capric acid (C10:0)
e.g. in a ratio
of about 60:40. The internal oil phase is in the range of from about 1 wt% to
about 20 wt%,
based on the total weight of the internal oil phase, aqueous phase and
external oil phase.
[00115] In an embodiment, the charged lipid is a negatively charged lipid. In
an embodiment,
the negatively charged lipid is a negatively charged fatty acid. The
negatively charged fatty acid
can be any suitable negatively charged fatty acid. Negatively charged lipids
e.g. fatty acids such
as oleic acid may also, for example, advantageously cause less skin irritation
than positively
charged lipids. Accordingly, in an embodiment, the negatively charged lipid is
oleic acid. In
another embodiment, the charged lipid is a positively charged lipid. In
another embodiment, the
positively charged lipid is a positively charged fatty amine. In another
embodiment of the
present disclosure, the positively charged fatty amine is oleyl amine.
[00116] In an embodiment, the ratio by weight of the liquid oil to the charged
lipid is in a range
of from about 5:1 to about 10:1.
[00117] In an embodiment, the film-forming thermoreversible emulsifier is an
amphoteric
tri-block copolymer. In another embodiment, the film-forming thermoreversible
emulsifier is a
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol. In another
embodiment,
the polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol is
Poloxamer 407
(Pluronic F-127), Poloxamer 188 (Pluronic' F-68) or combinations thereof.
In an
embodiment, the polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene
glycol is
Poloxamer 407. The film-forming thermoreversible emulsifier is present in an
amount suitable
to stabilize the nano-emulsion. In an embodiment, the ratio by weight of the
film-forming
thermoreversible emulsifier to the internal oil phase is at least 0.1: 10,
e.g. at least 0.3 : 10.
[00118] In an embodiment, the combination of solid lipids is a combination of
at least two of:
glyceryl dibehenate, glyceryl palmitostearate or combinations thereof;
(ii) petrolatum, cetyl palmitate, beeswax or combinations thereof;
(iii) a hydrogenated vegetable oil or combinations thereof;
(iv) a fatty alcohol or combinations thereof; and
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(v)
glyceryl stearate, polyethylene glycol (PEG)-40 glyceryl stearate, PEG-100
stearate or combinations thereof.
[00119] In an embodiment, the glyceryl dibehenate, glyceryl palmitostearate or
combinations
thereof is glyceryl dibehenate. In another embodiment, the petrolatum, cetyl
palmitate, beeswax
or combinations thereof is petrolatum. In another embodiment, the petrolatum
is petrolatum
white USP. In another embodiment, the petrolatum, cetyl palmitate, beeswax or
combinations
thereof is beeswax. In an embodiment, the hydrogenated vegetable oil is
hydrogenated castor oil,
hydrogenated soy oil or combinations thereof. In another embodiment, the
hydrogenated
vegetable oil is hydrogenated castor oil. In an embodiment, the fatty alcohol
or combination
thereof is cetyl alcohol, stearyl alcohol, cetostearyl alcohol (a mixture of
fatty alcohols comprising
predominantly cetyl alcohol and stearyl alcohol) or combinations thereof. In
another embodiment,
the fatty alcohol is cetyl alcohol. In another embodiment, the glyceryl
stearate, polyethylene glycol
(PEG)-40 glyceryl stearate, PEG-100 stearate or combinations thereof is a
combination of glyceryl
stearate and PEG-100 stearate. In an embodiment, the ratio of the solid lipids
(i) : [(ii) + (iii)] : (v)
in the combination is about 2 : 1 : 2. In another embodiment, the solid lipids
comprise, consist
essentially of or consist of glyceryl dibehenate, petrolatum (e.g. petrolatum
white USP),
hydrogenated castor oil, cetyl alcohol, glyceryl stearate and PEG-100
stearate.
[00120] In an embodiment, the third mixture comprising the combination of
solid lipids
further comprises a liquid emollient, a penetration enhancer, an antioxidant,
or combinations
thereof_ In another embodiment, the third mixture comprising the combination
of solid lipids
further comprises a liquid emollient, a penetration enhancer and an
antioxidant.
[00121] The liquid emollient can be polar or non-polar and suitably has the
ability to
dissolve soluble and poorly water-soluble active ingredients, respectively.
The liquid emollient
is advantageously of amino acid or vegetable origin or is a silicone oil and
has the advantage of
a lack of a rancid oil odor. Accordingly, in an embodiment, the liquid
emollient is isopropyl
myristate, isopropyl palmitate, glycine, N-methyl-N-(1-oxododecy1)-, 1-
methylethyl ester
(isopropyl lauroyl sarcosinate) a plant-based C15-19 Alkane (e.g. EMOGREENTm)
or a
silicone oil emollient. Such emollients may, for example, have enhanced
ceramide-like
emolliency (sensory effect), reduced greasy feeling and/or reduced oxidative
reactions (thereby
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avoiding or reducing the development of a rancid oil smell. In an embodiment
of the present
disclosure, the liquid emollient is isopropyl lauroyl sarcosinate.
[00122] Penetration enhancers suitably create a push and pull effect. As a
result, they can
enhance the skin reservoir effect and sustain the release of poorly soluble
active ingredients.
While dimethyl sulfoxide (DMSO) is a commonly used solvent for enhancing the
penetration
of lipophilic drugs, ethoxy diglycol is advantageous in that it has less skin
toxicity.
Accordingly, in an embodiment, the penetration enhancer is ethoxy diglycol.
The Nano-
Emulsion SR cream was also compatible and stable in the presence of terpenoids
useful e.g. as
natural penetration enhancers such as cineol, eucalyptol limonene, linanool
and menthol.
Accordingly, in some embodiments of the present disclosure, the penetration
enhancer
comprises a natural penetration enhancer. In another embodiment, the natural
penetration
enhancer is one or more terpenoids or combinations thereof. In another
embodiment, the
terpenoid is cineol, eucalyptol limonene, linanool, menthol or combinations
thereof. In another
embodiment, the penetration enhancer comprises menthol.
[00123] Antioxidants can be useful, for example, to prevent or reduce
oxidation of oil
ingredients and/or discoloration of active ingredients such as cannabinoids.
The antioxidants
are suitably selected from natural or synthetic antioxidants In an embodiment,
the antioxidant
is tocopherol acetate, butylated hydroxytoluene (BHT), butylated
hydroxyanisole (BHA) or
combinations thereof. In another embodiment, the antioxidant is butylated
hydroxytoluene.
[00124] In an embodiment, the third mixture comprising the combination of
solid lipids
comprises: the liquid emollient isopropyl lauroyl sarcosinate; the penetration
enhancer ethoxy
diglycol; and the antioxidant butylated hydroxytoluene.
[00125] In an embodiment, subsequent to preparing the oil-in-water nano-
emulsion, the
method further comprises:
combining the oil-in-water nano-emulsion with a fourth mixture comprising
one or more of a multifunctional polymer and a chelating agent.
[00126]
Accordingly, the present disclosure also includes a method of preparing a
composition
comprising an oil-in-water nano-emulsion dispersed in an external oil phase,
the oil-in-water nano-
emulsion comprising an internal oil phase dispersed in an aqueous phase, the
method comprising:
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combining a first mixture comprising a liquid oil and a charged lipid with a
second mixture that is an aqueous mixture comprising a film-forming
thermoreversible
emulsifier to prepare an oil-in-water nano-emulsion;
combining the oil-in-water nano-emulsion with a fourth mixture comprising
one or more of a multifunctional polymer and a chelating agent; and
combining the oil-in-water nano-emulsion thereby obtained with a third mixture

comprising a combination of solid lipids to prepare the composition,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is in a range of from about 2:3 to about 7:3; and the ratio by weight of
the liquid oil
to the charged lipid is in a range of from about 5:1 to about 50:1.
[00127] In such embodiments, the multifunctional polymer is well-hydrated by
combining with
the first mixture prior to combination with the third mixture so as to obtain
a homogeneous
composition. In an embodiment, the multifunctional polymer comprises one or
more tri-block
copolymers having a hydrophilic-lipophilic balance (HLB) of about 18. In
another embodiment, the
multifunctional polymer is combination of polyacrylamide & C13-14 isoparaffin
& laureth-7 (e.g.
SEPIGELTm 305), acrylamide/sodium acryloyldimethyl taurate copolymer,
isohexadecane and
Polysorbate 80 (e.g. SIMULGELTm 600), a hydroxyethyl acrylate/sodium
acryloyldimethyl taurate
copolymer (e.g. SEPINOVIm WE0 and/or SEPINOV EMT-10), polyacrylate
crosspolymer-6 (e.g.
SEPIMAX ZEN), polyacrylate crosspolymer-11 (e.g. ARISTOFLEXIm Velvet) or
combinations
thereof. The multifunctional polymers are suitably selected from those that
are stable in a wide pH
range. For example, polyacrylate crosspolymer-6, has advantageous resistance
to electrolytes and is
stable in a wide pH range (from about 2 to about 8). It has the ability to
stabilize the oil phase,
provide a gel cream texture and create a pseudo-emulsion system. In an
embodiment, the
multifunctional polymer is a combination of multifunctional polymers that is
polyacrylate
crosspolymer-6 and hydroxyethyl acrylate/sodium acryloyldimethyl taurate
copolymer.
[00128] The chelating agent is any suitable chelating agent. In an embodiment,
the chelating
agent is a salt (e.g. a disodium salt) of ethylenediaminetetraacetic acid
(EDTA).
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[00129] In an embodiment, the multifunctional polymer is a combination of
multifunctional
polymers that is polyacrylate crosspolymer-6 and hydroxyethyl acrylate/sodium
acryloyldimethyl
taurate copolymer and the chelating agent is disodium
ethylenediaminetetraacetic acid (EDTA).
[00130] In an embodiment, subsequent to combining the oil-in-water nano-
emulsion with
the third mixture comprising a combination of solid lipids, the method further
comprises
combining the composition thereby obtained with a preservative.
[00131]
Accordingly, the present disclosure also includes a method of preparing a
composition
comprising an oil-in-water nano-emulsion dispersed in an external oil phase,
the oil-in-water nano-
emulsion comprising an internal oil phase dispersed in an aqueous phase, the
method comprising:
combining a first mixture comprising a liquid oil and a charged lipid with a
second mixture that is an aqueous mixture comprising a film-forming
thermoreversible
emulsifier to prepare an oil-in-water nano-emulsion;
combining the oil-in-water nano-emulsion thereby obtained with a fourth
mixture comprising one or more of a multifunctional polymer and a chelating
agent;
combining the oil-in-water nano-emulsion with a third mixture comprising a
combination of solid lipids; and combining the composition thereby obtained
with a
preservative to prepare the composition,
wherein the ratio by weight of the oil-in-water nano-emulsion to the external
oil
phase is in a range of from about 2:3 to about 7:3; and the ratio by weight of
the liquid oil
to the charged lipid is in a range of from about 5:1 to about 50:1.
[00132] The preservative is suitably a wide spectrum preservative or
combination thereof
capable of preserving both oil and water phases. The preservative is suitably
selected from
natural and/or synthetic preservatives. In an embodiment, the preservative is
caprylyl glycol,
pentylene glycol, ethylhexylglycerin, Vitamin E, phenoxy ethanol or
combinations thereof. In
another embodiment of the present disclosure, the preservative is a
combination of
preservatives that is caprylyl glycol and phenoxy ethanol.
[00133] In an embodiment, the composition comprises, consists essentially of
or consists of:
water e.g. in an amount of from about 50 wt% to about 80 wt%;
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glycerin e.g. in an amount of from about 1 wt% to about 10 wt%;
polyethylene glycol¨b¨polypropylene glycol¨b¨polyethylene glycol e.g. in an
amount of from about 0.05 wt% to about 5 wt%;
oleic acid e.g. in an amount of from about 0.1 wt% to about 10 wt%;
MCT oil e.g. in an amount of from about 1 wt% to about 10 wt%;
polyacrylate crosspolymer-6 e.g. in an amount of from about 0.1 wt% to about 5
wt%;
hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer e.g. in an
amount of from about 0.1 wt% to about 5 wt%;
disodium EDTA e.g. in an amount of from about 0.005 wt% to about 0.05 wt%;
glyceryl dibehenate e.g. in an amount of from about 1 wt% to about 10 wt%;
petrolatum (e.g. petrolatum white USP) e.g. in an amount of from about 0.5 wt%

to about 10 wt%;
hydrogenated castor oil e.g. in an amount of from about 1 wt% to about 10 wt%;

cetyl alcohol e.g. in an amount of from about 0.5 wt% to about 10 wt%;
glyceryl stearate and PEG-100 stearate e.g. in an amount of from about 1 wt%
to
about 10 wt%;
isopropyl lauroyl sarcosinate e.g. in an amount of from about 1 wt% to about 5
wt%;
ethoxy diglycol e.g. in an amount of from about 1 wt% to about 10 wt%;
butylated hydroxytoluene e.g. in an amount of from about 0.02 wt% to 0.1 wt%;
caprylyl glycol e.g. in an amount of from about 0.01 wt% to about 1.0 wt%; and

phenoxy ethanol e.g. in an amount of from about 0.05 wt% to about 1.0 wt%.
[00134] The speed at which the combining (e.g. mixing) in the present methods
is carried
out may, for example, have an impact on the particle size in the compositions
prepared
therefrom. For example, a higher rate of mixing may result in a smaller
particle size in the
nano-emulsions. In the examples of the present disclosure, a high shear
homogenizer was used.
However, other suitable means for combining in the methods of the present
disclosure can also
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be employed such as an ultra-sonicator or a high-pressure homogenizer. For
example, a high-
pressure homogenizer may be useful to obtain nano-emulsions having an average
droplet size
of less than about 500 nm whereas a high shear homogenizer may be useful to
obtain nano-
emulsions having an average droplet size of greater than about 500 nm.
Accordingly, in an
embodiment, the combining comprises mixing with a high shear homogenizer, an
ultra-
sonicator or a high-pressure homogenizer. In another embodiment, the combining
comprises
mixing with a high shear homogenizer. The temperature at which the combining
(e.g. mixing)
in the present methods is carried out may, for example, be selected based on
the temperature
sensitivity of the components (e.g. any active ingredients being added during
the method). In an
embodiment, the combining is carried out at a temperature of from about 35 C
to about 85 C. In
another embodiment, the combining comprises mixing with a high shear
homogenizer at a
temperature of from about 35 C to about 85 C. The time period for combining
may depend, for
example, on the components being combined and the step of the method but can
be selected by a
person skilled in the art having regard to the present disclosure. In an
embodiment, the time for
combining the first mixture with the second mixture is from about 15 minutes
to about 1 hour or
about 30 minutes. In another embodiment, the time for combining the oil-in-
water nano-emulsion
with the fourth mixture is from about 15 minutes to about 1 hour or about 30
minutes. In a further
embodiment, the time for combining the oil-in-water nano-emulsion with the
third mixture is
from about 5 minutes to about 30 minutes or about 15 minutes. In another
embodiment, the time
for combining the composition obtained from combining the oil-in-water nano-
emulsion with the
third mixture is from about 5 minutes to about 20 minutes or about 10 minutes.
[00135] The order of combining may vary. For example, the first mixture may be
added to
the second mixture or vice versa. However, adding the third mixture comprising
the
combination of solid lipids to the oil-in-water nano-emulsion may be
advantageous during
manufacturing due to the respective volumes of these components. Accordingly,
in an
embodiment, the combination of solid lipids is added to the oil-in-water nano-
emulsion.
[00136] In some embodiments, the method does not comprise adding an active
ingredient. In
an embodiment, the method is for preparation of a compounding base.
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[00137] In alternative embodiments, the method further comprises adding one or
more active
ingredients, natural and/or herbal active agents with anti-inflammatory,
analgesic, anesthetic,
anti-aging, anti-fibrogenic and/or anti-infective effect; terpenoids;
essential oils or combinations
thereof. The embodiments for the active ingredients, natural and/or herbal
active agents with anti-
inflammatory, analgesic, anesthetic, anti-aging, anti-fibrogenic and/or anti-
infective effect;
terpenoids; essential oils or combinations thereof can be varied as described
herein above.
[00138] In some embodiments, the addition is by a method comprising
compounding (i.e.
the composition is in the form of a compound base). A person skilled in the
art would be able to
readily select means and suitable conditions for compounding. In such
embodiments, additional
excipients such as a levigating agent (e.g. ethoxy diglycol) are mixed with
powdered active
ingredients or other components to be added prior to addition to the
composition.
[00139]
In alternative embodiments, the addition is during the preparation of the
composition;
i.e. the one or more active ingredients, natural and/or herbal active agents
with anti-inflammatory,
analgesic, anesthetic, anti-aging, anti-fibrogenic and/or anti-infective
effect; terpenoids; essential
oils or combinations thereof are combined with the other components of the
composition to obtain
the composition. The step at which the addition is carried out as well as the
conditions (e.g.
temperature) may vary depending on the particular active ingredients and/or
their physicochemical
stability, natural and/or herbal active agents with anti-inflammatory,
analgesic, anesthetic, anti-
aging, anti-fibrogenic and/or anti-infective effect; terpenoids; essential
oils or combinations thereof
which are being added but can be readily selected by a person skilled in the
art
[00140] The present disclosure also includes a composition obtained by a
method of the
present disclosure for preparing a composition comprising an oil-in-water nano-
emulsion
dispersed in an external oil phase, the oil-in-water nano-emulsion comprising
an internal oil
phase dispersed in an aqueous phase.
[00141] The following non-limiting examples are illustrative of the present
disclosure:
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EXAMPLES
Example 1: Preparation and characterization of a nano-emulsion cream useful
for
transdermal delivery and studies of its use for sustained release of
diclofenac sodium.
I. Materials
[00142] Phase A: Purified water (62%); glycerin (humectant; 2%); and Poloxamer
407
(thickening, stabilizing emulsifier; 0.3%). Phase B: Oleic acid (lipid
component with negative
charge; 1%); and medium chain triglyceride (non-hydrogenated oil, penetration
enhancer and
emollient; 8%). Phase C: polyacrylate crosspolymer-6 (oil and water
thickening, stabilizing
emulsifier; 0.6%); hydroxyethyl acrylate/sodium acryloyldimethyl taurate
copolymer (oil and
water thickening, stabilizing co-emulsifier; 0.2%); and disodium
ethylenediaminetetraacetic
acid (EDTA, chelating agent, 0.02%). Phase D: cetyl alcohol (fatty alcohol
thickener, 2%),
glyceryl stearate and PEG-100 stearate (emulsifying thickener; 5.5%), white
petrolatum USP
(semi-occlusive lipid component; 1%); hydrogenated castor oil (solid lipid
component; 1.75%);
glyceryl dibehenate (solid lipid with sustained release property; 5.5%);
isopropyl lauroyl
sarcosinate (amino acid based polar emollient; 3%); butylated hydroxy toluene
(anti-oxidant;
0.1%); and ethoxy diglycol (permeation enhancer, solubilizing agent; 5%).
Phase E: caprylyl
glycol preservative; 0.5%); and phenoxy ethanol (preservative; 0.9%).
II. General Preparation of Nano-Emulsion SR Cream
[00143] Phase A: Purified water was heated to 60 C then glycerin added, while
heating
continued at 60 C. Poloxamer 407 was then added as a 30% stock solution in
water while mixing
with a high shear homogenizer and heating to 80 C. the temperature was
maintained at 80 C.
[00144] Phase B: In another vessel, all of the components of Phase B were
mixed and the
temperature brought to 80 C by heating. The temperature was maintained at 80
C.
[00145] While maintaining the temperature at 80 C, the Phase B mixture was
then added
into the Phase A vessel while mixing with a high shear homogenizer at 8000 rpm
while
maintaining the temperature at 80 C. The mixture was homogenized using the
high shear
homogenizer for 30 minutes and the temperature continued to be maintained at
80 C.
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[00146] Phase C: The Phase C components were then added into the Phase A/B
(nano-
emulsion) while mixing with the high shear homogenizer while maintaining the
temperature at
80 C and mixed for 30 minutes at 8000-rpm. The temperature was maintained at
80 C.
[00147] Phase D: In another vessel, all of the components of Phase D were
mixed, and the
temperature brought to 80 C by heating. The temperature was maintained at 80
C.
[00148] At 80 C, the Phase D mixture was then added into the Phase A/B/C
mixture while
mixing with the high shear homogenizer at high speed while maintaining the
temperature at
80 C. The mixture was mixed with the high shear homogenizer for 15 minutes.
[00149] The batch was then cooled to 50 C and the temperature maintained at 50
C.
[00150] Phase E: The Phase E premix was then prepared in a separate container
and the
mixture warmed enough to melt the caprylyl glycol.
[00151] At 50 C, the Phase E premix was added into the batch containing the
remaining
phases while mixing with the high shear homogenizer. The mixture was mixed for
10 minutes
then cooled to room temperature where the initial pH was recorded (pH range:
4.5 - 5.5).
III. Thermodynamic Stability (Product Shelf Life)
[00152] An accelerated stability test was conducted for the Nano-Emulsion SR
Cream over a
period of three months as per ICH guidelines at a temperature of 40 2 C/
and 75% relative
humidity (RH). Triplicate samples were analyzed for changes in the appearance
(odor, color and
any sign of phase separation), pH and viscosity. The product was stable for 3
months under
accelerated conditions, which corresponds to 2 years shelf life for the Nano-
Emulsion SR cream.
IV. Nano-emulsion Droplet Size Measurement
[00153] A nano-emulsion composed of oleic acid (1 ml), MCT oil (8 ml),
Poloxamer 407
(30% stock Solution, 1 ml), glycerin (2 ml) and water (63 ml) was prepared.
The aqueous and
oil phases were heated separately to 80 C. The oil phase was gradually added
to aqueous phase,
mixed and homogenized at 8000 rpm using a high shear homogenizer for 30
minutes while
temperature was maintained at 80 C. Samples were cooled down, diluted 10,000-
15,000 times
using distilled water and mixed well. The Z value (droplet size) was measured
at 25 C using a
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Malvern Zetasizer Nano-ZS. Measurements were conducted using 6 preparations (n
= 6). Mean
values were calculated. The mean droplet size measured 498 nm.
Example 2: Compounding with Diclofenac Sodium
I. Preparation
[00154] Diclofenac sodium (micronized, 10 g) powder was ground using a mortar
and
pestle. Levigating agent (ethoxy diglycol, 3 mL) was added to wet the powder
and form a
smooth paste. The Nano-emulsion SR cream of Example 1 was geometrically added
and the
components mixed well until homogenous. For example, an overhead stirrer or a
compounding
mixer can be used to mix the compound. The compound was packaged in an airless
pump
container and can be suitably stored at room temperature away from excessive
heat.
II. In vitro Permeation Test through PermeaPad' Membrane
[00155] Three replicates of 10% diclofenac sodium compounded cream was tested
on a
PermeaPad biomimetic membrane. In-line diffusion cells with a diameter of
11.28 mm (1 cm')
were used for the testing. An InnoMe GmbH PermeaPad Membrane was used as a
synthetic skin
membrane. Cells were dosed by filling a syringe with the 10% diclofenac sodium
cream, and then
using the syringe to apply the material (15 mg to 40 mg) directly to each of
the membranes,
taking weights of the syringe before and after. Phosphate buffer (pH 7.4) was
used as the receptor
fluid. Flow rate was set to 1 mL/hr. Samples were collected at 1, 3, 6, 9, 12,
16, 20, and 24 hours.
Samples were refrigerated at 3 C for 6 days before high performance liquid
chromatography
HPLC analysis was performed. The HPLC method was isocratic with 72% methanol
and 28% of
a mixture of pH 2.85 phosphoric acid and 0.5% triethylamine on an Agilent
Zorbax eclipse XDB-
C18 column (5 pm 4.6 mm x 150 mm) maintained at 40 C. Retention time for
diclofenac was
determined to be 6.3 minutes. No interference compounds were present.
[00156]
The results indicated a sustained release pattern throughout 24 hours of the
study
(Figure 1). Drug (diclofenac sodium) release kinetics indicated that drug
release was best
explained by first-order kinetics, as these plots showed the highest linearity
(Correlation
Coefficient = 0.9696; Figure 2), but a close relationship was also noted with
Higutchi kinetics
(Correlation Coefficient= 0.9694; Figure 3). Korsmeyer Peppas's plot indicated
an "n" value of
0.9729 (Figure 4), which was indicative of an anomalous diffusion mechanism or
diffusion
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coupled with matrix dissolution; hence, the drug release was controlled by
more than one
process. Drug dissolution and as a result drug release from this formulation
is impacted by the
presence of penetration enhancers, such as MCT oil, ethoxy diglycol and oleic
acid.
Additionally, while not wishing to be limited by theory, the film-forming and
semi occlusive
property of the nano-emulsion SR cream impacts on the degradation of the
matrix created by
hydrogenated castor oil, glyceryl behenate, cetyl alcohol, petrolatum and
glyceryl monostearate
by creating water channels and therefore matrix porosity. The in vitro
permeation results show
that the rate of drug release is concentration dependent (first-order
kinetics). The higher rate of
release was observed for the initial 60% of drug released (16 hours) was
followed by a slightly
slower rate between 16 to 24 hours. The concentration dependent rate of
release would be a
useful tool, for example, for pharmacists and physicians in customizing the
compounding
formulation strength (% of active drug) to a patient's needs.
III. Thermodynamic Stability (Beyond Use Date)
[00157] Accelerated (40 + 2 C and 75% RH) and real time (25 C and 60% RH)
stability
tests were conducted for the Nano-Emulsion SR cream compounded with diclofenac
Na 10%.
Triplicate preparations were also analyzed for changes in the appearance
(odor, color and signs
of phase separation), pH, viscosity, microbial contamination (yeast and mold,
Staphylococcus
aureus, Escherichia coli, Salmonella, and Pseudomonas) and drug content
(potency; evaluated
using the HPLC method) of the compound. Samples were tested at time zero, and
after 7, 21
and 42 days_ The real time samples were tested after 90 and 180 days_ The
results of the
accelerated stability test were confirmed by a real time stability test.
[00158] The results showed that the Nano-Emulsion SR cream compounded with
diclofenac
Na was stable for 180 days. There was no significant change in the appearance
of the
compound, pH and viscosity of the product. The active drug content reduced by
3.7%
following 42 days kept in the accelerated condition, which is well under the
accepted limit for
compounded product potency variation limit ( 10%). Furthermore, real time
stability results
confirmed the stability of the diclofenac Na 10% compounded in the Nano-
Emulsion SR cream
up to at least 180 days. Therefore, a BUD of 180 days was assigned to this
preparation.
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[00159] Decreasing the dose frequency of drugs such as nonsteroidal anti-
inflammatory
drugs (NSAIDs) like diclofenac Na may, for example, increase patient
compliance; patients
prefer to apply the cream once daily. It can also reduce the cost of a drug
for patient
significantly. The 0/W/0 Nano-Emulsion cream sustained the release of
diclofenac Na for 24
hours. Hence, the formulation can, for example, be used as a once-daily
sustained-release
transdermal cream for targeted local pain and inflammation relief. The
formulation showed
exceptional thermodynamic stability, 6 months, when compounded with diclofenac
Na 10%.
Additionally, the full plate microbial count showed no contamination at the
end of stability test.
IV. Additional Observations
[00160] The diclofenac Na 10% compounded in Nano-Emulsion SR was dispensed to
individual patients with knee arthritis, shoulder neuropathic pain and back
pain. The patients
reported 30 minutes onset of action followed by 18-20 hours sustained pain
relief. Pain was
controlled well overnight and there was no breakthrough pain to wake up
patients. The semi-
occlusive property of the cream was noticeable and acknowledged by patients.
Example 3: Compounded anesthetic cream (BLT Cream)
[00161] Topical Benzocaine 20%, Lidocaine 6% and Tetracaine HC1 4% (BLT) is
commonly
prescribed for local anesthesia prior to dermatological procedures. However,
the conventional
creams and gels are not resilient to such a high concentration of anesthetics
and separate easily.
The Nano-Emulsion SR Cream of Example 1 was used for compounding this
prescription.
Benzocaine 20 g
Lidocaine 6 g
Tetracaine HC1 4 g
Ethoxy Diglycol 10 ml
Nano-Emulsion SR Cream (Example 1) qs to 100 g
[00162] Lidocaine crystalline powder was triturated using a mortar and pestle.
Tetracaine and
then benzocaine powders were geometrically added to the lidocaine fine powder.
The powders
were ground and blended well. Ethoxy diglycol was then added to the powders
and mixed to
form a smooth paste. The Nano-Emulsion SR Cream was geometrically added and
mixed using
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an overhead stirrer or a compounding mixer (electronic mortar and pestle). The
BLT cream was
packaged in an airless pump and can be kept at room temperature or
refrigerated.
[00163] The compounded product was smooth and homogeneous. It was stable at
room
temperature. According to USP guidelines for topical compounded products, a
BUD of 35 days
was assigned to this compound (United States Pharmacopeia, General Chapter
795,
Pharmaceutical Compounding ¨ Non-Sterile Preparations, USP 42-NF 37, 2019).
The BLT
cream was dispensed to patients. The patients reported 18-20 hours local
anesthesia.
Example 4: Compounded product containing multiple analgesic drugs
[00164] This compound contained one NSAID (diclofenac Na), one nerve
depressant
(gabapentin), and one anesthetic (lidocaine). This compound may be used for
neuropathic pain,
sciatic pain, trigeminal neuralgia and pain associated with shingles.
Diclofenac Na 10 g
Gabapentin 6 g
Lidocaine 5 g
Ethoxy Diglycol 4 ml
Nano-Emulsion SR Cream (Example 1) qs to 100 g
[00165] Gabapentin and Lidocaine crystalline powders were triturated and
blended well
using a mortar and pestle. Diclofenac Na powder was then added and blended
well. Ethoxy
diglycol was added to levigate the powders and to form a smooth paste. The
Nano-Emulsion
SR Cream was geometrically added to the powders and mixed well until a smooth
and
homogeneous mixture was achieved. The compounded cream was packaged in an
opaque
airless pump. The product was stored in room temperature away from excessive
heat.
[00166] A BUD of 90 days can be assigned to this preparation when stored at
room
temperature (25 C) due to low stability profile of gabapentin and lidocaine.
The cream was
dispensed to 5 patients. The patients reported 18-20 hours local anesthesia.
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Example 5: Compounded product containing multiple drugs
[00167] This compounded preparation contains more than one drug. In
particular, it includes
two NSAIDs (diclofenac Na and ketoprofen), one muscle relaxant (baclofen), and
one
antidepressant (amitriptyline). This compound is indicated for musculoskeletal
pain.
Diclofenac Na 10 g
Ketoprofen 10 g
Baclofen 5 g
Amitriptyline HC1 2 g
Ethoxy Diglycol 6 ml
Nano Emulsion SR Cream (Example 1) qs to 100 g
[00168] Amitriptyline HCl, baclofen, diclofenac Na and ketoprofen powders were
ground and
then geometrically blended using a mortar and pestle. Ethoxy diglycol was
added to levigate the
powders and to form a smooth paste. The Nano-Emulsion SR cream was
geometrically added to the
powders and mixed well until a smooth and homogeneous mixture was achieved.
The compounded
cream was packaged in an opaque airless pump. The product was stored in room
temperature away
from excessive heat. The BUD of this preparation is 180 days at room
temperature (25 C).
Example 6: Compounded product containing multiple analgesic drugs
[00169] This compounded preparation contains more than one analgesic drug. It
includes
one NSAID (diclofenac Na) and one muscle relaxant (cyclobenzaprine HC1). This
compound
may be used for musculoskeletal pain.
Diclofenac Na 10 g
Cyclobenzaprine HC1 2 g
Ethoxy Diglycol 3 ml
Nano Emulsion SR Cream (Example 1) qs to 100 g
[00170] Cyclobenzaprine HC1 and diclofenac Na powders were ground and
geometrically
mixed using a mortar and pestle. Ethoxy diglycol was added to levigate the
powders and to
form a smooth paste. The Nano-Emulsion SR cream was geometrically added to the
powders
and mixed well until a smooth and homogeneous mixture was achieved. The
compounded
cream was packaged in an opaque airless pump. The product was stored in room
temperature
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away from excessive heat. The BUD of this preparation is 90 days at room
temperature (25 C)
due to the low stability profile of cyclobenzaprine HC1.
Example 7: Compounded product with high concentration of an NSAID
[00171] This compounded preparation contains a higher concentration of the
NSAID
diclofenac Na than the preparations of the Examples hereinabove.
Diclofenac Na 20 g
Ethoxy Diglycol 5 ml
Nano-Emulsion SR Cream (Example 1) qs to 100 g
[00172] Diclofenac Na micronized powder was ground using a mortar and pestle.
Ethoxy
diglycol was then added to levigate the powder and to form a smooth paste. The
Nano-
Emulsion SR cream was geometrically added to the powders and mixed well until
a smooth
and homogeneous mixture was achieved. The compounded cream was packaged in an
opaque
airless pump. The product was stored at room temperature away from excessive
heat. The BUD
of this preparation is 180 days at room temperature (25 C).
Example 8: Formulation containing CBD/THC
Full spectrum 011 (3:33 % (w/v) THC:CBD in MCT Oil) 9 ml (270 mg: 891 mg
THC:CBD)
THC Distillate (99%) 230 mg
Menthol 0.5g
Nano-Emulsion SR cream (Example 1) qs to 50 g
[00173] Menthol crystals were ground using a mortar and pestle until they
became liquid. In a
glass beaker, the THC distillate and CBD oil were gently heated up to 40 C
while mixing with a
glass stirrer. This mixture was added to the menthol and mixed well. The Nano-
Emulsion SR
cream was then geometrically added to the mixture and mixed well until a
smooth and
homogeneous mixture achieved. The compounded cream was packaged in an opaque
airless
pump. The product was stored at room temperature away from excessive heat and
light.
[00174] The mixture was smooth and homogenous. The mixture was kept at room
temperature
for 12 months (tested every week for the first month and then monthly up to 12
months). The
mixture was consistent and homogenous. No color change was observed for the 12
months tested.
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Example 9: Formulation containing CBD isolate
CBD Isolate (99%) 500 mg
Menthol 0.5g
Spearmint Essential Oil 0.5 ml
Nano-Emulsion SR Cream (Example 1) qs to 50 g
[00175] Menthol crystals were ground using a mortar and pestle until they
became liquid.
Then spearmint and CBD oil were added and mixed well. The Nano-Emulsion SR
cream was
then geometrically added to the mixture and mixed well until a smooth and
homogeneous
mixture achieved. The compounded cream was packaged in an opaque airless pump.
The
product was stored at room temperature away from excessive heat and light.
[00176] The mixture was smooth and homogenous. The mixture was kept at room
temperature
for 12 months (tested every week for the first month and then monthly up to 12
months). The
mixture was consistent and homogenous. No color change was observed for the 12
months tested.
Comparative Example
[00177] Phase A: Purified water (80 wt%), glycerin (1 wt%) and Poloxamer
407 (0.3 wt%). Phase
B: Oleic acid (1 wt%), MCT (8 wt%), cetyl alcohol (2 wt%), glyceryl stearate
and PEG-100 stearate (5
wt%), and isononyl isononanoate (2 wt%). Phase C: Polyacrylate Crosspolymer-6
(0.7 wt%).
[00178] In this experiment, the oil phase (Phase B) and aqueous phase (Phase
A) were heated
to 80 C separately. Phase B was added to Phase A while homogenizing at 8000
rpm. The droplet
size of the cream was measured with a Zetasizer. The result showed that the
droplet size was in
the micrometer range (1.5 to 3 m). This formulation did not create a nano-
emulsion.
[00179] While the disclosure has been described with reference to what are
presently considered
to be the preferred examples, it is to be understood that the disclosure is
not limited to the disclosed
examples. To the contrary, the present disclosure is intended to cover various
modifications and
equivalent arrangements included within the spirit and scope of the appended
claims.
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