U.S. patent application number 10/388371 was filed with the patent office on 2004-01-15 for water-based delivery systems.
Invention is credited to Skold, Thomas.
Application Number | 20040009213 10/388371 |
Document ID | / |
Family ID | 28042008 |
Filed Date | 2004-01-15 |
United States Patent
Application |
20040009213 |
Kind Code |
A1 |
Skold, Thomas |
January 15, 2004 |
Water-based delivery systems
Abstract
The invention relates to a water-based delivery system for an
active substance, characterized by enhancing skin barrier
restoration in the stratum corneum comprising water, a fatty acid,
cholesterol, a ceramide and at least one skin lipid precursor.
Inventors: |
Skold, Thomas; (Norrtalje,
SE) |
Correspondence
Address: |
HOFFMANN & BARON, LLP
6900 JERICHO TURNPIKE
SYOSSET
NY
11791
US
|
Family ID: |
28042008 |
Appl. No.: |
10/388371 |
Filed: |
March 13, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60365059 |
Mar 13, 2002 |
|
|
|
Current U.S.
Class: |
424/449 |
Current CPC
Class: |
A61K 8/42 20130101; A61Q
19/00 20130101; A61K 9/0014 20130101; A61K 47/24 20130101; A61K
8/553 20130101; A61K 9/1272 20130101; A61K 8/68 20130101; A61K 8/63
20130101; A61K 47/28 20130101; A61P 17/00 20180101; A61K 47/12
20130101; A61Q 17/00 20130101; A61K 47/18 20130101 |
Class at
Publication: |
424/449 |
International
Class: |
A61K 009/70 |
Claims
We claim:
1. A water-based topical delivery system for an active substance,
capable of enhancing skin barrier restoration in the stratum
corneum comprising water; fatty acids; cholesterol; and a
ceramide/phospholipid portion.
2. A delivery system according to claim 1 wherein the ratio of
ceramide/phospholipid portion:cholesterol:fatty acid is
approximately between 2:1:1 and 2.35:1:1.
3. A delivery system according to claim 1 further comprising at
least one skin lipid precursor.
4. A delivery system according to claim 3 wherein the fatty acid is
between 0.5-10%; the cholesterol is between 0.5-10%; the lipid
precursors are between 0.000001-10%; and the ceramide/phospholipid
portion is between 0.005-20%.
5. A delivery system according to claim I wherein the fatty acid
comprises ten to twenty-four carbon atoms.
6. A delivery system according to claim 5 wherein the fatty acid
comprises sixteen to eighteen carbon atoms.
7. A delivery system according to claim I wherein the fatty acid is
lauric acid, myristic acid, palmitic acid, stearic acid, arachidic
acid, behenic acid, lignoceric acid, oleic acid, palmitoleic acid,
linoleic acid, linolenic acid, arachidonic acid, precursors
thereof, and/or unsaturated derivatives thereof, and/or mixtures
thereof.
8. A delivery system according to claim 1, wherein said fatty acid
is selected from a group consisting of linoleic acid,
.gamma.-linolenic acid, homo-.gamma.-linolenic acid, columbinic
acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, timnodonic
acid, hexaenoic acid and mixtures thereof.
9. A delivery system according to claim 6 wherein the ceramide is
ceramide 1, ceramide 3, ceramide 4, ceramide 5, ceramide 6A, a
cerebroside, ceramide 6B, a pseudoceramide, a neoceramide, or
mixtures thereof.
10. A delivery system according to claim 9 wherein the
pseudoceramide is N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl
)hexadecanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)butanamide;
N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)heptanamide;
N-(2-hydroxyoctadecyl)-N-(2-bydroxyethyl)ethanamide;
N-(2-hydroxyoctadecyl)-N-(2-O-glucopyranosyl)ethylpentanamide;
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)hexanamide;
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2butylhexanamide;
N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2-hydroxyhexanamide;
N-(2-hydroxytetraadecyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxyhexadecyl)-N-(2-sulfoethyl)hexadecanamide;
N-(2-hydroxyoctadecyl)-N-(2-phosphoethyl)butanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;
N-(2-hydroxy-3-nonanyloxypropyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)butanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-sulfohydroxyethyl)decanamide;
N-(2-hydroxy-3-decyloxypropyl)-N-(2-hydroxyethyl)hexanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)butanamide;
N-(2-hydroxy-3-octadecyloxypropyl
)-N-(2-hydroxyethyl)co-o-linoleoyldocos- anamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)-2-methylpropanamide-
;
N-(2-hydroxy-3-tetraadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)heptanamide;
N-(2-bydroxy-3-hexadecyloxypropyl)-N-(2-phosphoethyl)hexadecanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-)-glucopyranosyl)ethyl-2-hydroxyp-
ropanamide; or
N-(2-hydroxy-3-octyloxypropyl)-N-(2-hydroxyethyl)pentanamid- e.
11. A delivery system according to claim 9 wherein the neoceramide
is: N-(2,3-dihydroxypropyl)-N-(hexadecyl)butanamide;
N-(2,3-dihydroxypropyl)-- N-(tetradecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyp- ropanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-(2-ethylhexadecyl)hexanamide;
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyoctanamide;
N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(dodecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-- (hexadecyl)-2-hydroxyhexanamide;
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-- (hexadecyl)octanamide;
N-(2-hydroxy-3-phosphopropyl)-N-(octadecyl)ethanami- de;
N-(2-hydroxy-3-sulfopropyl)-N-(hexadecyl)butanamide;
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)decanamide;
N-(2,3-dihydroxypropyl)-N-(heptadecyl)ethanamide;
N-(2,3-dihydroxypropyl)- -N-(3-methylhexadecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(heptadecyl)bu- tanamide;
N-(2,3-dihydroxypropyl)-N-(6-dodecenyl)hexadecan-amide;
N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxy-ethanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)2-hydroxypropan-amide;
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(heptadecyl)-ethanamide;
N-(2-hydroxy-3-sulfopropyl)-N-(dodecyl)heptanamide;
N-(2,3-dihydroxypropyl)-N-(tetradecyl)-4-hydroxybutan-amide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)-(t)-O-linoleoyl-docosanamide;
N-(2,3-dihydroxypropyl)-N-(linoleyl)ethanamide;
N-(2,3-dihydroxypropyl)-N- -(oleyl)-2-hydroxy-heptan-amide;
N-(2,3-dihydroxypropyl)-N-iyiodecyl)-(t)-- O-linoleoyldocosanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)-3-hyrdoxybu- tanamide;
N-(2-phospho-3hydroxypropyl)-N-(heptadecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-(2-methylheptadecyl)propanamide;
N-(2,3-dihydroxypropyl)-N-(3-ethylheptadecyl)butanamide;
N-(2-sulfo-3-hydroxypropyl)-N-(1-octadecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)propanamide;
N-(2,3-dihydroxypropyl)- -N-(dodecyl)decanamide;
N-(2,3-dihydroxypropyl)-N-(3-ethyldodecyl)butanami- de;
N-(2-O-glucopyranosyl-3-hydroxy propyl)-N-(heptadecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxypropanamide;
N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxyheptanamide;
N-(2,3-dihydroxypropyl)-N-(dodecyl)-2-hydroxyoctanamide;
N-(2,3-dihydroxypropyl)-N(hexadecyl)-2-methylheptanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)-2-hydroxypentanamide;
N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxyheptanamide;
N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxypropanamide; or N-(2;
3-dihydroxypropyl)-N-(tetradecyl)ethanamide.
12. A delivery system according to claim 1, wherein said
phospholipid is selected from a group consisting of
phosphatidylcholine, DSPC 18, phosphatidic acid, inositol
phosphate, phosphatidylglycerol, phosphatidylinositol,
phosphatidylserine, phosphatidylethanolamine and mixtures
thereof.
13. A delivery system according to claim 12, wherein said
phospholipid comprises at least one lysophospholipid.
14. A delivery system according to claim 13 wherein the
lysophospholipid is selected from the group consisting of
monopalmitoylphosphatidylcholine (MPPC), lysophosphatidylcholines,
lysophosphatidylglycerols, lysophosphatidylethanolamines,
lysophosphatidylinositols, lysophosphatidylserines,
lysophosphatidic acid, and mixtures thereof.
15. A delivery system according to claim 3 wherein the lipid
precursor comprises mevalonic acid or
25-hydroxycholecalciferol.
16. A delivery system according to claim 3 wherein the lipid
precursor comprises deoxyacetein cimifugoside, adapalene,
adenosine, aloe derived lectins, 3-aminopropyl dihydrogen
phosphate, anise extracts, ascorbic acid and derivatives thereof,
ascorbyl palmitate, asiatic acid, benzoic acid derivatives, biotin,
butanoyl betulinic acid, cathecholamines, coenzyme Q10,
dehydrocholesterol, dehydroascorbic acid and derivatives thereof,
estrogen and derivatives, eythrobic acid, genistein, lipoic acid,
4-methoxy salicylic acid, N-acetyl cysteine, panthetine,
pregnenolone and derivatives, retinal, retinoates, retinal, retinyl
acetate, retinyl glucuronate, retinyl linoleate, retinyl palmitate,
retinyl proprionate, phytosphingosine, or sphingosine.
17. A delivery system according to claim 1 further comprising
triethanolamine.
18. A delivery system according to claim 1, wherein the water
content exceeds 50%.
19. A delivery system according to claim 1, wherein the water
content exceeds 75%.
20. A delivery system according to claim 1, wherein the water
content exceeds 79%.
21. A delivery system according to claim 1, wherein the water
content exceeds 90%.
22. A delivery system according to claim 3, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
2-20%.
23. A delivery system according to claim 3, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
5-20%.
24. A delivery system according to claim 3, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
5-15%.
25. A delivery system according to claim 3, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
6-13%.
26. A delivery system according to claim 3, comprising a
combination of:
10 Fatty Acid 0.5-10% Phospholipid 0.5-10% Cholesterol 0.5-7% Lipid
precursor 0.000001-10% Ceramide 0.005%-7%.
27. A delivery system according to claim 26 wherein the lipid
precursor is mevalonic acid.
28. A delivery system according to claim 26, further comprising
11 Glycerine 0-5% Propylene glycol 0-48% PVP (M weight 40.000) 0-5%
TEA 0-3%.
29. A delivery system according to claim 26, further comprising
12 25-Hydroxycholecalciferol 0.015% Acylceramides 0.025%.
30. A delivery system according to claim 26, wherein the lipid
precursor comprises 0.01% of Mevalonic acid, 0.0015%
25-Hydroxycholecalciferol, or a combination of Mevalonic acid, and
25-Hydroxycholecalciferol.
31. A delivery system according to claim 3, wherein said skin
barrier restoration is enhanced by in situ promotion of cholesterol
synthesis in the stratum corneum.
32. A delivery system according to claim 3, wherein said skin
barrier restoration is enhanced by in situ promotion of ceramide
synthesis in the stratum corneum.
33. A delivery system according to claim 3, wherein said skin
barrier restoration is enhanced by in situ promotion of
sphingolipid synthesis in the stratum corneum.
34. A delivery system according to claim 1, wherein said system
further comprises one or more therapeutically active substances
selected from the group consisting of peptides, proteins,
sunscreens, tanning agents, skin anti-wrinkling agents,
anti-dandruff agents, anti-acne agents, hair growth stimulants,
hormones, vaccines, nicotine, interferon, pain killers, vitamins;
and substances which treat eczema, dry skin, itchy skin, fungal
infections, acne, skin cancer, hair loss, louse infections,
psoriasis, and skin lesions.
35. A delivery system according to claim 3, wherein the lipids of
said system blend with the lipids present in the cornea stratum,
resulting in a temporary and reversible atrophy in the lipid
bilayer, thereby enhancing possibility for penetration of
therapeutic substances delivered by the system.
36. A delivery system according to claim 3, wherein the system does
not comprise alcohol.
37. A delivery system according to claim 36, wherein the alcohol is
ethanol.
38. A delivery system according to claim 3, wherein the system
comprises less than 10% alcohol.
39. A delivery system according to claim 38 wherein the alcohol is
ethanol.
40. A topical delivery system for an active substance comprising
water and lipophilic components, wherein the lipophilic components
comprise fatty acids, cholesterol, and a ceramide/phospholipid
portion, and wherein the lipophilic components are in the form of
lipid particles, and gas spheres or vesicles.
41. A topical delivery system according to claim 40 further
comprising at least one skin lipid precursor.
42. A topical delivery system for an active substance comprising
water and lipophilic components, wherein the lipophilic components
comprise fatty acids, cholesterol, and a ceramide/phospholipid
portion, and wherein the lipophilic components are in the form of
lipid particles, gas spheres and vesicles.
43. A topical delivery system according to claim 42 further
comprising at least one skin lipid precursor.
44. A topical delivery system according to claim 40 wherein the
diameter of the gas spheres is approximately 1 .mu.m to 500
.mu.m.
45. A topical delivery system according to claim 40 wherein the
diameter of the vesicles is approximately 0.02 .mu.m to 0.5
.mu.m.
46. A topical delivery system according to claim 40 wherein the
diameter of the lipid particles is approximately less than 1 .mu.m
to 150 .mu.m.
47. A delivery system according to claim 41 wherein the fatty acid
is between 0.5-10%; the cholesterol is between 0.5-10%; the lipid
precursors are between 0.000001-10%; and the ceramide/phospholipid
portion is between 0.005-20%.
48. A delivery system according to claim 40 wherein the fatty acid
comprises ten to twenty-four carbon atoms.
49. A delivery system according to claim 48 wherein the fatty acid
comprises sixteen to eighteen carbon atoms.
50. A delivery system according to claim 40 wherein the fatty acid
is lauric acid, myristic acid, palmitic acid, stearic acid,
arachidic acid, behenic acid, lignoceric acid, oleic acid,
palmitoleic acid, linoleic acid, linolenic acid, arachidonic acid,
precursors thereof, and/or unsaturated derivatives thereof, and/or
mixtures thereof.
51. A delivery system according to claim 40, wherein said fatty
acid is selected from a group consisting of linoleic acid,
.gamma.-linolenic acid, homo-.gamma.-linolenic acid, columbinic
acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid, timnodonic
acid, hexaenoic acid and mixtures thereof.
52. A delivery system according to claim 43 wherein the ceramide is
ceramide 1, ceramide 3, ceramide 4, ceramide 5, ceramide 6A, a
cerebroside, ceramide 6B, a pseudoceramide, a neoceramide, or
mixtures thereof.
53. A delivery system according to claim 52 wherein the
pseudoceramide is N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl
)hexadecanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)butanamide;
N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)heptanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxyoctadecyl)-N-(2-O-glucopyranosyl)ethylpentanamide;
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)hexanamide;
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2butylhexanamide;
N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2-hydroxyhexanamide;
N-(2-hydroxytetraadecyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxyhexadecyl)-N-(2-sulfoethyl)hexadecanamide;
N-(2-hydroxyoctadecyl)-N-(2-phosphoethyl)butanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;
N-(2-hydroxy-3-nonanyloxypropyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)butanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-sulfohydroxyethyl)decanamide;
N-(2-hydroxy-3-decyloxypropyl)-N-(2-hydroxyethyl)hexanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-bydroxyethyl)hexadecanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)butanamide;
N-(2-hydroxy-3-octadecyloxypropyl
)-N-(2-hydroxyethyl)co-o-linoleoyldocos- anamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)-2-methylpropanamide-
;
N-(2-hydroxy-3-tetraadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)heptanamide;
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-phosphoethyl)hexadecanamide;
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide;
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-)-glucopyranosyl)ethyl-2-hydroxyp-
ropanamide; or
N-(2-hydroxy-3-octyloxypropyl)-N-(2-hydroxyethyl)pentanamid- e.
54. A delivery system according to claim 52 wherein the neoceramide
is: N-(2,3-dihydroxypropyl)-N-(hexadecyl)butanamide;
N-(2,3-dihydroxypropyl)-- N-(tetradecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyp- ropanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-(2-ethylhexadecyl)hexanamide;
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyoctanamide;
N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(dodecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-- (hexadecyl)-2-hydroxyhexanamide;
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-- (hexadecyl)octanamide;
N-(2-hydroxy-3-phosphopropyl)-N-(octadecyl)ethanami- de;
N-(2-hydroxy-3-sulfopropyl)-N-(hexadecyl)butanamide;
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)decanamide;
N-(2,3-dihydroxypropyl)-N-(heptadecyl)ethanamide;
N-(2,3-dihydroxypropyl)- -N-(3-methylhexadecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(heptadecyl)bu- tanamide;
N-(2,3-dihydroxypropyl)-N-(6-dodecenyl)hexadecan-amide;
N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxy-ethanamide;
N-(2,3-dihydroxypropyl)-N-(cctadecyl)2-hydroxypropan-amide;
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(heptadecyl)-ethanamide;
N-(2-hydroxy-3-sulfopropyl)-N-(dodecyl)heptanamide;
N-(2,3-dihydroxypropyl)-N-(tetradecyl)-4-hydroxybutan-amide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)-(t)-O-linoleoyl-docosanamide;
N-(2,3-dihydroxypropyl)-N-(linoleyl)ethanamide;
N-(2,3-dihydroxypropyl)-N- -(oleyl)-2-hydroxy-heptan-amide;
N-(2,3-dihydroxypropyl)-N-iyiodecyl)-(t)-- O-linoleoyldocosanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)-3-hyrdoxybu- tanamide;
N-(2-phospho-3hydroxypropyl)-N-(heptadecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-(2-methylheptadecyl)propanamide;
N-(2,3-dihydroxypropyl)-N-(3-ethylheptadecyl)butanamide;
N-(2-sulfo-3-hydroxypropyl)-N-(1-octadecyl)ethanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)propanamide;
N-(2,3-dihydroxypropyl)- -N-(dodecyl)decanamide;
N-(2,3-dihydroxypropyl)-N-(3-ethyldodecyl)butanami- de;
N-(2-O-glucopyranosyl-3-hydroxy propyl)-N-(heptadecyl)butanamide;
N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxypropanamide;
N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxyheptanamide;
N-(2,3-dihydroxypropyl)-N-(dodecyl)-2-hydroxyoctanamide;
N-(2,3-dihydroxypropyl)-N(hexadecyl)-2-methylheptanamide;
N-(2,3-dihydroxypropyl)-N-(octadecyl)-2-hydroxypentanamide;
N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxyheptanamide;
N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxypropanamide; or
N-(2;3-dihydroxypropyl)-N-(tetradecyl)ethanamide.
55. A delivery system according to claim 40, wherein said
phospholipid is selected from a group consisting of
phosphatidylcholine, DSPC 18, phosphatidic acid, inositol
phosphate, phosphatidylglycerol, phosphatidylinositol,
phosphatidylserine, phosphatidylethanolamine and mixtures
thereof.
56. A delivery system according to claim 55, wherein the
phospholipids comprises at least one lysophospholipid.
57. A delivery system according to claim 56 wherein the
lysophospholipid is selected from the group consisting of
monopalmitoylphosphatidylcholine (MPPC), lysophosphatidylcholines,
lysophosphatidylglycerols, lysophosphatidylethanolamines,
lysophosphatidylinositols, lysophosphatidylserines,
lysophosphatidic acid, and mixtures thereof.
58. A delivery system according to claim 41 wherein the lipid
precursor comprises mevalonic acid or
25-hydroxycholecalciferol.
59. A delivery system according to claim 41 wherein the lipid
precursor comprises deoxyacetein cimifugoside, adapalene,
adenosine, aloe derived lectins, 3-aminopropyl dihydrogen
phosphate, anise extracts, ascorbic acid and derivatives thereof,
ascorbyl palmitate, asiatic acid, benzoic acid derivatives, biotin,
butanoyl betulinic acid, cathecholamines, coenzyme Q10,
dehydrocholesterol, dehydroascorbic acid and derivatives thereof,
estrogen and derivatives, eythrobic acid, genistein, lipoic acid,
4-methoxy salicylic acid, N-acetyl cysteine, panthetine,
pregnenolone and derivatives, retinal, retinoates, retinal, retinyl
acetate, retinyl glucuronate, retinyl linoleate, retinyl palmitate,
retinyl proprionate, phytosphingosine, or sphingosine.
60. A delivery system according to claim 40 further comprising
triethanolamine.
61. A delivery system according to claim 40, wherein the water
content exceeds 50%.
62. A delivery system according to claim 40, wherein the water
content exceeds 75%.
63. A delivery system according to claim 40, wherein the water
content exceeds 79%.
64. A delivery system according to claim 40, wherein the water
content exceeds 90%.
65. A delivery system according to claim 40, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
2-20%.
66. A delivery system according to claim 41, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
5-20%.
67. A delivery system according to claim 41, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
5-15%.
68. A delivery system according to claim 41, wherein the combined
content of a fatty acid, cholesterol, a ceramide/phospholipid
portion, and a skin lipid precursor in said system is between about
6-13%.
69. A delivery system according to claim 41, comprising a
combination of:
13 Fatty Acid 0.5-10% Phospholipid 0.5-10% Cholesterol 0.5-7% Lipid
precursor 0.000001-10% Ceramide 0.005% -7%.
70. A delivery system according to claim 69 wherein the lipid
precursor is mevalonic acid.
71. A delivery system according to claim 69, further comprising
14 Glycerine 0-5% Propylene glycol 0-48% PVP (M weight 40.000) 0-5%
TEA 0-3%.
72. A delivery system according to claim 69, wherein the lipid
precursor comprises 0.01% of Mevalonic acid; 0.0015% of
25-Hydroxycholecalciferol or a mixture of both.
73. A delivery system according to claim 41, wherein said skin
barrier restoration is enhanced by in situ promotion of cholesterol
synthesis in the stratum corneum.
74. A delivery system according to claim 41, wherein said skin
barrier restoration is enhanced by in situ promotion of ceramide
synthesis in the stratum corneum.
75. A delivery system according to claim 41, wherein said skin
barrier restoration is enhanced by in situ promotion of
sphingolipid synthesis in the stratum corneum.
76. A delivery system according to claim 40, wherein said system
further comprises one or more therapeutically active substances
selected from the group consisting of: peptides, proteins,
sunscreens, tanning agents, skin anti-wrinkling agents,
anti-dandruff agents, anti-acne agents, hair growth stimulants,
hormones, vaccines, nicotine, interferon, pain killers, vitamins;
and substances which treat eczema, dry skin, itchy skin, fungal
infections, acne, skin cancer, hair loss, louse infections,
psoriasis, and skin lesions.
77. A delivery system according to claim 40, wherein the system
does not comprise alcohol.
78. A delivery system according to claim 77, wherein the alcohol is
ethanol.
79. A delivery system according to claim 40, wherein the system
comprises less than 10% alcohol.
80. A delivery system according to claim 79 wherein the alcohol is
ethanol.
Description
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/365,059, filed Mar. 13, 2002, which is
incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel topical and mucosal
delivery systems for drugs or any other active substance.
BACKGROUND OF THE INVENTION
[0003] The main demands on human skin are to prevent loss of water,
and to prevent water and other matter of the environment from
entering the body indiscriminately. The human skin thus forms a
selectively permissible physical barrier between the human body and
its surroundings.
[0004] The barrier function has been shown to reside in the stratum
corneum. The stratum corneum is the topmost layer of the skin, and
is built of corneocytes. Corneocytes are cells that contain
extensively cross-linked proteins, surrounded by a highly resistant
cell envelope. The corneocytes are embedded in a bed of specific
lipid structures of long chain lipids. These long chain lipids are
organized as bilamellar structures stacked on top of each other.
The bilamellar structures fill the intercellular spaces between the
corneocytes.
[0005] To account for the skin's barrier properties, and for its
selective hydrophilic and hydrophobic pathways, the skin has been
described as a mosaic barrier model. This model envisages barrier
lipids to exist predominantly in crystalline (gel) form. Such a
form provides water impermeable domains, which are surrounded by
so-called grain borders of lipids in a liquid crystalline state.
This arrangement provides an effective, water tight barrier that
still allows a minute but controlled loss of water through the
liquid crystalline interdomains. This controlled water loss is
enough to keep the keratin of the stratum corneum hydrated. The
liquid character of the interdomain grain borders allows passage of
hydrophilic and hydrophobic molecules on down-hill gradients, i.e.
passage by passive diffusion.
[0006] Dermal delivery systems are compositions which deliver
active substances to, or through, the skin. These compositions
typically contain skin permeation enhancers. Permeation enhancers
may induce structural transformations of the bilamellar structure
in the liquid crystalline interdomain regions, and thus promote
transdermal delivery of, for example, pharmacological
substances.
[0007] Typical dermal delivery systems have an alcohol or petroleum
base, with little consideration given to the biological properties
of the vehicle itself. For example, emulsified fatty acids can
inherit certain detergent properties if their structure is
significantly altered from those in the normal skin. The detergent
properties can lead to disruption of the normal barrier function,
which is counteractive to the potential benefit of the delivery
system. Disruption of the normal barrier function often causes the
stratum corneum to lose its natural potential to function properly
as a barrier. As a result, the skin becomes either too dry or too
permeable to environmental substances.
[0008] Other conventional delivery systems that are thought to
protect the skin from harmful substances are barrier ointments. The
purpose of barrier ointments is to provide a film, and thereby
create a layer which is impermeable to environmental substances.
Due to the impermeability, though, these ointments both increase
the body temperature of the treated body part, as well as prevent
perspiration, and thus render an uncomfortable sensation.
[0009] The dermal delivery systems described above are not
formulated to deliver a substance to, or through, the human skin
without permanently disrupting the stratum corneum's natural
barrier function.
SUMMARY OF THE INVENTION
[0010] In one embodiment, the invention relates to a water-based
delivery system for an active substance, characterized by enhancing
skin barrier restoration in the stratum corneum comprising water, a
fatty acid, cholesterol, and a ceramide. In another embodiment, the
delivery system also comprises at least one skin lipid
precursor.
[0011] In an additional embodiment, the invention relates to
delivery system for an active substance comprising water and
lipophilic components, wherein the lipophilic components comprise
fatty acids, cholesterol, and a ceramide/phospholipid portion, and
wherein the lipophilic components are in the form of lipid
particles, and gas spheres or vesicles. This delivery system can
also comprise at least one skin lipid precursor.
BRIEF DESCRIPTION OF DRAWINGS
[0012] FIG. 1 is a diagram showing the gas spheres, lipid
particles, vesicles and hydrophilic phase of the delivery
systems.
[0013] FIG. 2 is a diagram showing the components of the gas
spheres of the delivery systems.
[0014] FIG. 3 is a diagram showing the components of the lipid
particles and of the vesicles of the delivery systems.
[0015] FIG. 4 is a diagram showing the location of active
substances within the various microcompartments of the delivery
systems.
DETAILED DESCRIPTION OF INVENTION
[0016] The present invention provides an improved topical delivery
system (skin preparation) formulated to deliver a substance to, or
through, the human skin without permanently disrupting the stratum
corneum's natural barrier function. Additionally, the topical
delivery system of the present invention provides unique skin
barrier restoration properties.
[0017] All percentages given below are indicated in percent by
weight. All numbers are approximate.
[0018] The topical delivery system of the present invention is a
water-based formulation comprising hydrophilic and lipophilic
components. In a preferred embodiment, the delivery system
comprises a water content exceeding 50%, such as more than 55%,
60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 85%, 87%, 90%, 94%,
95% and 98%. Preferably, the water content is between 60-80%, more
preferably, between 70 and 80%.
[0019] The topical delivery system is preferably designed, in its
choice and composition of lipids, to resemble the normal lipid
organization of the stratum corneum (horny layer), as much as
possible. Upon administration, the system (formulation) blends with
the lipids naturally present in the stratum comeum, and easily
penetrates the lipid bilayer of the skin. In doing so, the system
carries along with it one or more active substances to be
administered. The system enhances penetration of active substances
into and/or through the stratum corneum, while the normal barrier
properties of the stratum corneum are left intact, and/or are even
functionally enhanced.
[0020] The lipophilic component (i.e. lipids) of the system
comprises fatty acids, cholesterol and a ceramide/phospholipid
portion. The lipids are similar to those which make up the normal
stratum comeum. The preferred ratio of the ceramide/phospholipid
portion:cholesterol:fatty acid is in the range of approximately
2:1:1.5 to approximately 2.95:0.5:0.5. Preferably, for example, the
ratio is approximately 2:1:1; more preferably the ratio is
approximately 2.35:1:1.
[0021] The fatty acids of the present invention can be any fatty
acid, mixtures of fatty acids, salts of fatty acids, or mixtures of
fatty acids and salts of fatty acids. The fatty acids can be
saturated or unsaturated. Additionally, the fatty acids can
comprise precursors of fatty acids. In a preferred embodiment, the
fatty acids comprise ten, twelve, fourteen, sixteen, eighteen,
twenty, twenty-two, or twenty-four carbon atoms, or any mixture of
such fatty acids. A fatty acid mixture with a predominant portion
of fatty acids which comprise a chain of sixteen or eighteen carbon
atoms is most preferred.
[0022] For example, the delivery system can be prepared from a
mixture of fatty acids of the following composition: at most about
2% of a component comprising a chain of fourteen carbon atoms,
between about 47 and about 52% of a component comprising a chain of
sixteen carbon atoms, between about 43 and about 48% of a component
comprising a chain of eighteen carbon atoms, and at most about 1%
of a component comprising a chain of twenty carbon atoms.
[0023] Examples of suitable saturated fatty acids for use in the
delivery system include lauric acid, myristic acid, palmitic acid,
stearic acid, arachidic acid, behenic acid, and lignoceric acid.
Examples of suitable unsaturated fatty acids include oleic acid,
palmitoleic acid, linoleic acid, linolenic acid, and arachidonic
acid. Preferably, the delivery system contains an essential
portion, such as about 90%, of such fatty acids.
[0024] The preferred fatty acids are the essential fatty acids
(EFAs). EFAs are essential for the plasma membrane formation of all
cells. In keratinocytes, EFA deficiency makes cells
hyperproliferative. Supplementation of EFAs reverses the
hyperproliferation. EFAs also enhance lipid biosynthesis of the
epidermis and provide lipids for the barrier formation of the
epidermis. The essential fatty acids are preferably chosen from
linoleic acid, .gamma.-linolenic acid, homo-.gamma.-linolenic acid,
columbinic acid, eicosa-(n-6,9,13)-trienoic acid, arachidonic acid,
timnodonic acid, hexaenoic acid, and mixtures thereof.
[0025] The delivery system also comprises cholesterol, or
derivatives of cholesterol such as, for example, lipid esters of
cholesterol.
[0026] The ceramide/phospholipid portion can comprise 100%
ceramide, 100% phospholipids, or any other percent combination of
ceramide and phospholipids. For example, the ceramide/phospholipid
portion can comprise 95% ceramide and 5% phospholipids, 90%
ceramide and 10% phospholipids, 85% ceramide and 15% phospholipids,
or 80% ceramide and 20% phospholipids.
[0027] The ceramide component of the delivery system can be any
ceramide or any mixture of ceramides. In this specification,
ceramides include pseudoceramides and neoceramides.
[0028] For example, the ceramide may be any of ceramide 1-7; and/or
mixtures thereof. 5 Some specific examples of ceramides include
ceramide 1, ceramide 3, ceramide 4, ceramide 5, ceramide 6A,
cerebrosides and ceramide 6B.
[0029] Some examples of pseudoceramides include:
[0030] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)hexadecanamide
[0031] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)propanamide
[0032] N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)butanamide
[0033] N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)heptanamide
[0034] N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)ethanamide
[0035]
N-(2-hydroxyoctadecyl)-N-(2-O-glucopyranosyl)ethylpentanamide
[0036] N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)hexanamide
[0037] N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2butylhexanamide
[0038] N-(2-hydroxyhexadecyl)-N-(2-hydroxyethyl)ethanamide
[0039]
N-(2-hydroxydodecyl)-N-(2-hydroxyethyl)-2-hydroxyhexanamide
[0040] N-(2-hydroxytetraadecyl)-N-(2-hydroxyethyl)propanamide
[0041] N-(2-hydroxyhexadecyl)-N-(2-sulfoethyl)hexadecanamide
[0042] N-(2-hydroxyoctadecyl)-N-(2-phosphoethyl)butanamide
[0043]
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide
[0044]
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyetbyl)hexadecanamide
[0045]
N-(2-hydroxy-3-nonanyloxypropyl)-N-(2-hydroxyethyl)propananide
[0046]
N-(2-hydroxyoctadecyl)-N-(2-hydroxyethyl)-2-hydroxypropanamide
[0047]
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide
[0048]
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)butanamide
[0049]
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide
[0050]
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-sulfohydroxyethyl)decanamide
[0051]
N-(2-hydroxy-3-decyloxypropyl)-N-(2-hydroxyethyl)hexanamide
[0052]
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-hydroxyethyl)hexadecanamide
[0053]
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)butanamide
[0054] N-(2-hydroxy-3-octadecyloxypropyl
)-N-(2-hydroxyethyl)co-o-linoleoy- ldocosanamide
[0055]
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide
[0056]
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-hydroxyethyl)-2-methylpropa-
namide
[0057]
N-(2-hydroxy-3-tetraadecyloxypropyl)-N-(2-hydroxyethyl)ethanamide
[0058]
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)heptanamide
[0059]
N-(2-hydroxy-3-hexadecyloxypropyl)-N-(2-phosphoethyl)hexadecanamide
[0060]
N-(2-hydroxy-3-dodecyloxypropyl)-N-(2-hydroxyethyl)propanamide
[0061]
N-(2-hydroxy-3-octadecyloxypropyl)-N-(2-)-glucopyranosyl)ethyl-2-hy-
droxypropanamide
[0062]
N-(2-hydroxy-3-octyloxypropyl)-N-(2-hydroxyethyl)pentanamide
[0063] Some examples of neoceramides include:
[0064] N-(2,3-dihydroxypropyl)-N-(hexadecyl)butanamide
[0065] N-(2,3-dihydroxypropyl)-N-(tetradecyl)ethanamide
[0066]
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxypropanamide
[0067] N-(2,3-dihydroxypropyl)-N-(octadecyl)butanamide
[0068] N-(2,3-dihydroxypropyl)-N-(2-ethylhexadecyl)hexanamide
[0069]
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyoctanamide
[0070] N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide
[0071] N-(2,3-dihydroxypropyl)-N-(dodecyl)butanamide
[0072]
N-(2,3-dihydroxypropyl)-N-(hexadecyl)-2-hydroxyhexanamide
[0073]
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)octanamide
[0074] N-(2-hydroxy-3-phosphopropyl)-N-(octadecyl)ethanamide
[0075] N-(2-hydroxy-3-sulfopropyl)-N-(hexadecyl)butanamide
[0076]
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(hexadecyl)decanamide
[0077] N-(2,3-dihydroxypropyl)-N-(heptadecyl)ethanamide
[0078] N-(2,3-dihydroxypropyl)-N-(3-methylhexadecyl)ethanamide
[0079] N-(2,3-dihydroxypropyl)-N-(heptadecyl)butanamide
[0080] N-(2,3-dihydroxypropyl)-N-(6-dodecenyl)hexadecan-amide
[0081]
N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxy-ethanamide
[0082]
N-(2,3-dihydroxypropyl)-N-(ectadecyl)2-hydroxypropan-amide
[0083]
N-(2-hydroxy-3-O-glucopyranosylpropyl)-N-(heptadecyl)-ethanamide
[0084] N-(2-hydroxy-3-sulfopropyl)-N -(dodecyl)heptanamide
[0085]
N-(2,3-dihydroxypropyl)-N-(tetradecyl)-4-hydroxybutanamide
[0086]
N-(2,3-dihydroxypropyl)-N-(octadecyl)-(t)-O-linoleoyl-docosanamide
[0087] N-(2,3-dihydroxypropyl)-N-(linoleyl)ethanamide
[0088] N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxy-heptan-amide
[0089]
N-(2,3-dihydroxypropyl)-N-iyiodecyl)-(t)-O-linoleoyldocosanamide
[0090]
N-(2,3-dihydroxypropyl)-N-(octadecyl)-3-hyrdoxybutanamide
[0091] N-(2-phospho-3hydroxypropyl)-N-(heptadecyl)butanamide
[0092]
N-(2,3-dihydroxypropyl)-N-(2-methylheptadecyl)propanamide
[0093] N-(2,3-dihydroxypropyl)-N-(3-ethylheptadecyl)butanamide
[0094] N-(2-sulfo-3-hydroxypropyl)-N-(1-octadecyl)ethanamide
[0095] N-(2,3-dihydroxypropyl)-N-(octadecyl)propanamide
[0096] N-(2,3-dihydroxypropyl)-N-(dodecyl)decanamide
[0097] N-(2,3-dihydroxypropyl)-N-(3-ethyldodecyl)butanamide
[0098] N-(2-O-glucopyranosyl-3-hydroxy
propyl)-N-(heptadecyl)butanamide
[0099] N-(2,3-dihydroxypropyl)-N-(oleyl)-2-hydroxypropanamide
[0100]
N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxyheptanamide
[0101] N-(2,3-dihydroxypropyl)-N-(dodecyl)-2-hydroxyoctanamide
[0102] N-(2,3-dihydroxypropyl)-N(hexadecyl)-2-methylheptanamide
[0103]
N-(2,3-dihydroxypropyl)-N-(octadecyl)-2-hydroxypentanamide
[0104]
N-(2,3-dihydroxypropyl)-N-(2-methylhexadecyl)-2-hydroxyheptanamide
[0105]
N-(2,3-dihydroxypropyl)-N-(linoleyl)-2-hydroxypropanamide
[0106] N-(2;3-dihydroxypropyl)-N-(tetradecyl)ethanamide.
[0107] The phospholipid component may contain any phospholipid or
mixtures of phospholipids. Preferably the phospholipid component
comprises phosphatidylcholine (PC). Other examples of phospholipids
include distearoylphosphatidylcholine (DSPC 18), phosphatidic acid,
inositol phosphate, phosphatidylglycerol, phosphatidylinositol,
phosphatidylserine, and phosphatidylethanolamine.
[0108] Additionally, the phospholipid component can comprise one or
more lysophospholipids. Lysophospholipids are single chain
phospholipids. Examples of lysophospholipids include
lysophosphatidylcholines, such as monopalmitoylphosphatidylcholine
(MPPC); lysophosphatidylglycerols; lysophosphatidylethanolamines;
lysophosphatidylinositols; lysophosphatidylserines; and
lysophosphatidic acid. Mixtures of different types of phospholipids
and/or lysophospholipids can also be used.
[0109] In a preferred embodiment, the present system also comprises
skin lipid precursors. The lipid precursors include any compound
that promotes in situ cholesterol, ceramide or sphingolipid
synthesis. The preferred lipid precursors are mevalonic acid, which
promotes in situ cholesterol synthesis; and
25-hydroxycholecalciferol, which promotes in situ ceramide
synthesis in the skin. Other preferred precursors are palmitoyl CoA
and serine, which together are converted to 3-ketosphinganine,
which promotes in situ ceramide synthesis in the skin.
[0110] By the promotion of in situ cholesterol and ceramide
synthesis in the skin, the overall content of lipid in the system
can be maintained in a range as low as approximately 2-20%.
Therefore, the water content of the delivery system can be as high
as 80-98%. The high water content enables the skin to "breathe"
normally, and enhances its ability to restore its normal barrier
function rapidly.
[0111] Other lipid precursors useful in the present invention
include, for example: acylceramides; deoxyacetein cimifugoside,
adapalene, adenosine, aloe derived lectins, 3-aminopropyl
dihydrogen phosphate, anise extracts, ascorbic acid and derivatives
thereof, ascorbyl palmitate, asiatic acid, benzoic acid
derivatives, biotin, butanoyl betulinic acid, cathecholamines,
coenzyme Q10, dehydrocholesterol, dehydroascorbic acid and
derivatives thereof, estrogen and derivatives, eythrobic acid,
genistein, lipoic acid, 4-methoxysalicylic acid, N-acetylcysteine,
panthetine, pregnenolone and derivatives, retinal, retinoates,
retinal, retinyl acetate, retinyl glucuronate, retinyl linoleate,
retinyl palmitate, retinyl proprionate, phytosphingosine,
sphingosine, and others.
[0112] Preferably, an alkaline compound, or buffer system, is
included in the formulation to adjust the pH. Examples of alkaline
compounds include triethanolamine (TEA), sodium hydroxide, sodium
acetate, and sodium bicarbonate. Examples of buffer systems include
carbonic acid/potassium carbonate, phosphoric acid/potassium
phosphate, and acetic acid/sodium acetate.
[0113] The fatty acids of the final delivery system can be in a
free state or can form a salt. The portion of fatty acids which is
in a free state is partially dependent on the pH of the
formulation. In general, the level of free fatty acid increases as
the pH of the formulation decreases. Depending upon the particular
use of the formulation, the pH of the formulation can vary.
Preferably, the pH of the formulation is about 6.5 to 7.8.
[0114] In a preferred embodiment, the delivery system comprises
triethanolamine (TEA). It is preferred to adapt the molar ratio
between the fatty acids and triethanolamine to enable a certain
portion of the fatty acids in the final delivery system to form a
triethanolaminium salt, while another portion of the acid exists as
free fatty acid. Preferably, the delivery system is prepared from
fatty acids and triethanolamine in which the molar ratio of the
fatty acids to the triethanolamine is higher than about 2:1,
preferably higher than about 3:1.
[0115] In a preferred embodiment, the delivery system comprises a
combined content of a fatty acid, cholesterol, a
ceramide/phospholipid portion, and skin lipid precursors between
about 2-20%. A preferred low end of this range is about 2%, 3%, 4%,
5%, 6%, 7% or 8%. A preferred high end of this range is about 13%,
14%, 15%, 16%, 17%, 18%, 19% and 20%.
[0116] In another preferred embodiment, the amounts of the
components of the delivery system are as follows: fatty acid:
0.5-10%; cholesterol: 0.5-10%; a ceramide/phospholipid portion:
0.005-20%; and lipid precursors: 0.000001-10%.
[0117] In a preferred embodiment, the formulation does not contain
any irritating ingredients. Examples of irritating ingredients
include alcohols, such as isopropanol and ethanol; short chain
fatty acids; and detergents. Preferably, the formulation contains
less than 10% alcohol, more preferably less than 5% alcohol, most
preferably less than 1% alcohol, and optimally no alcohol.
[0118] Without the intention to limit the scope of the invention, a
possible theory explaining the mechanical properties of the
delivery system follows. The administered formulation easily
penetrates the lipid bilayer of the skin. In doing so, the system
creates a temporary and reversible state of enhanced atrophy among
the lipid components of the bilayer. The enhanced atrophy in itself
then gives rise to either a) enhanced energy levels, wherein the
energy could promote active transport of the to-be-carried
substances into the skin, and/or b) creates naturally and
reversibly occurring holes and disorganized patches in the lipid
bilayer through which the active substances could then pass more
easily. It is very well feasible that the temporary disarray in the
lipid bilayer will temporarily break up the organized structure of
the bilayer and create micelles of lipids with areas between them,
or surrounding them, through which lipophobic/hydrophilic
substances and/or compositions can enter through the stratum
corneum. As the lipid composition of the formulation resembles the
natural lipid composition of the skin, the so introduced new lipids
will after a short time of creative chaos easily blend in with the
natural lipid building stones of the lipid bilayer, and thus not
permanently damage the barrier function of the skin.
[0119] Following the temporary disarray in the lipid bilayer, the
normal barrier function of the cornea stratum rapidly returns.
(That is, the skin barrier restoration is rapid.) The rapid return
may be enhanced by the lipid precursors of the formulation. For
example, the in situ promotion of cholesterol synthesis in the
stratum corneum, the in situ promotion of ceramide synthesis in the
stratum corneum, and/or the in situ promotion of sphingolipid
synthesis in the stratum corneum may allow for the rapid skin
barrier restoration.
[0120] A delivery system according to the present invention
preferably comprises a combination of:
1 Fatty Acid (C16-24) 0.5-10% Phospholipid 0.5-10% Cholesterol
0.5-7% Lipid precursor: 0.000001-10% Mevalonic acid and/or
25-Hydroxycholecalciferol Ceramide 0.005%-7% (Not all components
are present are 0%.)
[0121] Another preferred embodiment of the delivery system
comprises:
2 Fatty Acid (C16-24) 0.5-10% Phospholipid 0.5-10% Cholesterol
0.5-7% Lipid precursor: 0.000001-10% Mevalonic acid and/or
25-Hydroxycholecalciferol Ceramide 0.005%-7% Glycerine 0-5%
Propylene glycol 0-48% PVP (e.g., M weight 40.000) 0-5% TEA 0-3%
(Not all components are present are 0%.)
[0122] An even more preferred embodiment of the delivery system
comprises:
3 Fatty Acid (C16-24) 2% Phospholipid 4.5% Cholesterol 2% Lipid
precursor: 0.000001-10% Mevalonic acid and/or 1% or 0.01%
25-Hydroxycholecalciferol 0.015% or 0.0015% Ceramide 3 0.015%
Glycerine 3% Propylene glycol 4% PVP (M weight 40.000) 2% TEA
0.5%
[0123] An even more preferred embodiment of the delivery system
comprises:
4 Fatty Acid (C16-24) 2% Phospholipid 4.5% Cholesterol 2% Lipid
precursor: 0.000001-10% Mevalonic acid and/or 1% or 0.01%
25-Hydroxycholecalciferol 0.015% or 0.0015% Ceramide 3 0.015%
Glycerine 3% Propylene glycol 4% PVP (M weight 40.000) 2% TEA 0.5%
Ceramide 1 0.025%
[0124] The topical delivery system according to the present
invention further comprises one or more cosmetically and/or
therapeutically active substances. Active substances are defined as
agents other than emollients and other than ingredients that merely
improve the physical characteristics of the formulation.
[0125] Some general examples of active substances include
sunscreens, tanning agents, skin anti-wrinkling agents,
anti-dandruff agents, anti-acne agents, hair growth stimulants and
vitamins. Therapeutically active substances include, but are not
limited to, substances which treat conditions such as eczema, dry
skin, itchy skin, fungal infection, acne, skin cancer, hair loss,
louse infection, psoriasis, and skin lesions (i.e. wounds).
Therapeutically active substances also include substances for
transdermal delivery, for example, interleukin, hormones, vaccines,
nicotine, interferon, pain killers, peptides, proteins and
vitamins.
[0126] Active substances also include steroid hormones. Steroid
hormones inhibit inflammation and hyperproliferation of the
epidermis thus resulting in normalization of hypersensitive skin
conditions. Examples of steroid hormones include, but are not
limited to, glucocorticoids, androgens and estrogens.
[0127] Examples of sunscreens include those materials commonly
employed to block ultraviolet light. Illustrative compounds are
derivatives of PABA, cinnamate and salicylate. For example, octyl
methoxycinnamate and 2-hydroxy-4-methoxybenzophenone (also known as
oxybenzone) can be used. Octyl methoxycinnamate and
2-hydroxy-4-methoxybenzophenone are commercially available under
the trademarks, Parsol MCX and Benzophenone-3, respectively. The
exact amount of sunscreen employed in the systems can vary
depending upon the degree of protection desired from the sun's UV
radiation.
[0128] Examples of vitamins include vitamin A and vitamin E,
preferably in the form of an ester of a fatty acid, such as vitamin
A palmitate (retinyl palmitate) and vitamin E linoleate (tocopheryl
linoleate). Other esters of vitamins A and E may also be utilized,
such as any of the fatty acids mentioned above and below.
[0129] Preservatives may also be included in the formulations of
the present invention. Suitable preservatives include alkyl esters
of p-hydroxybenzoic acid, hydantoin derivatives, propionate salts,
and a variety of quaternary ammonium compounds. Particularly
preferred preservatives of this invention are methyl paraben,
propyl paraben, imidazolidinyl urea, sodium dehydroxyacetate and
benzyl alcohol. Preservatives are typically used in amounts up to
about 2% by weight of the formulation.
[0130] Other adjunct minor components may also be incorporated into
the formulations of the present invention. These components may
include thickeners, coloring agents, opacifiers and perfumes. For
example, any thickening agent can be included in the formulation to
adjust the viscosity of the formulation. Examples of suitable
thickening agents include glycerol and xanthan gum. Some additional
adjunct minor components include chalk, talc, Fullers earth,
kaolin, starch, smectites clays, chemically modified magnesium
aluminium silicate, organically modified montmorillonite clay,
hydrated aluminium silicate, fumed silica, aluminium starch octenyl
succinate and mixtures thereof. Amounts of these adjunct minor
components may range anywhere from 0.001 up to 20% by weight of the
formulation (i.e. composition).
[0131] The delivery system can be in any form, such as a cream, a
lotion, a gel, and an aerosol foam. The amount of certain adjunct
minor components used in a particular formulation varies depending
on the desired form of the delivery system, as would be known by a
skilled artisan. For example, the amount of thickening agent used
to prepare an aerosol foam formulation is about 10 to 20% of the
amount used to prepare a cream formulation. Additionally,
emulsifiers are added to an aerosol foam formulation, such as, for
example, laureth 4.
[0132] In another embodiment, the present invention provides a
mucosal delivery system formulated to deliver a substance to, or
through, a human mucous membrane without permanently disturbing the
integrity of the mucous membrane. The mucous membrane is the moist
tissue that lines some organs and body cavities (such as nose,
mouth, lungs, rectum, stomach and vagina) and secretes mucous. The
mucosal delivery system comprises the lipophilic and hydrophilic
components, as described above. The particular formulations of the
mucosal delivery systems are varied to accommodate the particular
environment of the mucosa, as would be known by a skilled
artisan.
[0133] In a preferred embodiment, the lipophilic components of the
topical or mucosal delivery system form three types of particles:
gas spheres, vesicles, and lipid particles. These three types of
particles are within a hydrophilic phase (i.e. aqueous medium). See
FIG. 1.
[0134] The gas spheres are lipid monolayers that enclose air
bubbles. These monolayers are formed from the lipophilic
components. Negatively charged carboxylate groups stud the outer
surfaces of these gas spheres. See FIG. 2. Preferably, these gas
spheres are approximately 1 .mu.m to approximately 500 .mu.m in
diameter.
[0135] The vesicles are lipid bilayers enclosing a hydrophilic
core. These bilayers are formed from the lipophilic components.
Negatively charged carboxylate groups stud the inner and outer
surfaces of the vesicles. See FIG. 3. The vesicles can range from
approximately 0.02 .mu.m to approximately 0.5 .mu.m in
diameter.
[0136] The lipid particles are lipid monolayers enclosing fatty
acids. These monolayers are formed from the lipophilic components.
See FIG. 3. The lipid particles are less than approximately 1 to
approximately 150 .mu.m in diameter. The lipid particles may be in
the form of individual lipid particles, or the lipid particles may
aggregate to form crystals.
[0137] The various particles of the delivery system provide
microcompartments with different properties. Due to these different
microcompartments, the delivery system can be used to deliver both
hydrophilic and lipophilic active substances. For example, a water
soluble active substance can be located in the hydrophilic core of
the vesicles, or can be located in the hydrophilic phase of the
system. A lipid soluble active substance can be located within the
monolayer of the gas spheres, within the bilayer of the vesicles,
or within the monolayer or within the core of the lipid particles.
See FIG. 4.
[0138] Preferably, the delivery systems comprise three phases, i.e.
a foam phase, a vesicle phase and a hydrophilic phase. The foam
phase comprises the gas spheres and the lipid particles. The
vesicle phase comprises the vesicles and the lipid particles. The
hydrophilic phase comprises water and hydrophilic components.
[0139] In a preferred embodiment, the delivery system is produced
from three portions (i.e. fractions), in particular a hydrophilic
portion and two lipophilic portions. The two lipophilic portions
comprise the lipophilic components as defined above. Both
lipophilic portions are immersed in aqueous media. One portion is
made into the foam phase. The other portion is made into the
vesicle phase. The foam phase portion and the vesicle phase portion
can be in a ratio from about 1:7 to about 7:1. Preferably, the foam
phase portion and the vesicle phase portion are approximately equal
in amount.
[0140] Preferably, the foam phase is formed by mixing the foam
phase portion at about 65 to 85.degree. C. The pH is set to the
range of about 5.5 to 8.2. The mixing is performed under conditions
so as to allow gas spheres to form.
[0141] Preferably, the vesicle phase is formed by gently mixing the
vesicle phase portion at about 65 to 85.degree. C. The pH is set to
the range of about 5.5 to 8.2. After mixing, the vesicle phase
portion is homogenized. Homogenization can be accomplished with,
for example, a high pressure homogenizer or a sonicator. The
pressure of the homogenizer can be set, for example, from about
10,000 to 40,000 psi. Preferably, the vesicle phase is produced
under conditions which do not allow any gas to enter the
formulation, such as in a vacuum.
[0142] The lipid particles, and/or lipid particle crystals, form as
a by-product of the formation of the foam phase and vesicle phase.
In either the foam phase or vesicle phase, up to 30% of the
lipophilic components can be in the form of lipid particles and/or
lipid particle crystals.
[0143] The hydrophilic phase is formed by mixing together water
soluble components with water (i.e. hydrophilic portion). Examples
of water soluble components include propylene glycol, glycerol,
polyvinylpyrrolidone, and thickeners, e.g., xanthan gum.
[0144] The foam phase, vesicle phase and hydrophilic phases are
mixed together. Preferably, an equal amount of each phase is used
in the formulation.
[0145] The foam phase, vesicle phase and hydrophilic phases can be
mixed together in any order. For example, the foam phase and the
vesicle phase can be first mixed together, and then the resulting
mixture can be mixed with the hydrophilic phase. As another
example, the foam phase can be first mixed with the hydrophilic
phase, and then the vesicle phase can be added.
[0146] One or more active substances can be added to the foam phase
portion, the vesicle phase portion, the hydrophilic portion, or a
combination of these portions.
[0147] The specific components of a formulation, and the
formulation process, can be varied to obtain delivery systems which
allow for different rates of the release, and degrees of
penetration, of active substance(s). For example, the phase of the
system in which an active substance is placed affects release and
penetration rates. For instance, to enhance penetration rates of
either a hydrophilic or lipophilic active substance, a major
portion of the active substance is placed within the vesicle phase
portion.
[0148] Another factor which affects release and penetration rates
is the size of the micro-compartments. The size of the vesicles can
be controlled via the formulation process. For example, during
processing, as the homogenizing pressure and duration increases,
the vesicle size decreases.
[0149] An additional factor which affects release and penetration
rates is the type of phospholipids used in the formulation. For
example, penetration can be enhanced by including a greater portion
of unsaturated phospholipids within the formulation.
[0150] Also, phospholipids which include elevated levels of surface
active single chain agents enhance penetration. Surface active
single chain agents at about a level of 2% to 10% of the
phospholipids are considered to be at an elevated level. Examples
of surface active agents are lysophospholipids.
[0151] An example of a phospholipid formulation comprises 95%
phosphatidylcholine and 1.2% lysophosphatidylcholine. Such a
formulation is sold as EPIKURON.RTM. 200 SH. A phospholipid
formulation which provides enhanced penetration comprises 95%
phosphatidylcholine and 3% lysophosphatidylcholine. Such a
formulation is sold as EPIKURON.RTM. 200.
[0152] The concentration of free fatty acid is also an important
parameter affecting penetration rates. A relatively high level of
free fatty acid enhances penetration of hydrophilic active
substances.
[0153] Penetration rates can also be enhanced by the addition of
certain adjuvants. For example, an anionic surfactant can be added
to the foam phase portion. Also, incorporation of glyceryldilaurate
into the vesicle bilayers creates more flexible vesicles which can
enhance penetration.
[0154] Additional factors which affect release and penetration
rates include: the ratio between the different lipid components;
the ratio between the foam phase, the vesicle phase and the
hydrophilic phase; and the ratio between the amounts of active
substances within each phase.
[0155] In one embodiment of the present invention, the lipophilic
components of the delivery system form only two of the
above-defined particles. That is, the formulation comprises only
the gas spheres and lipid particles; or the formulation comprises
only the vesicles and lipid particles.
[0156] In this embodiment, the delivery system is produced from a
hydrophilic portion and a lipophilic portion. The lipophilic
portion is made either into the foam phase or the vesicle phase, as
described above. Preferably, the vesicle phase is produced under
conditions which do not allow any gas to enter the formulation,
such as in a vacuum. The foam phase or vesicle phase is mixed with
the hydrophilic phase. Preferably, an equal amount of either the
foam phase or vesicle phase, and the hydrophilic phase is used in
the formulation.
[0157] Thus, while there have been described what are presently
believed to be the preferred embodiments of the present invention,
other and further embodiments, modifications, and improvements will
be known to those skilled in the art, and it is intended to include
all such further embodiments, modifications, and improvements and
come within the true scope of the claims as set forth below.
EXAMPLES
Example 1
[0158] A General Method of Making:
[0159] The phospholipid, cholesterol, palmitic acid and ceramide
components are mixed together with water, and agitated at a
temperature of 70-80.degree. C. The following additional components
are added: mevalonic acid lactone, 25-hydroxycholecalciferol,
propylene glycol, glycerine, PVP, TEA added along with water, and
sodium hydroxide. Sodium hydroxide is added to adjust viscosity and
stabilize the formulation. Water is then added, and the formulation
is agitated well. The formulation is then cooled down.
[0160] An active substance can be dissolved in both the lipid phase
and/or the water phase, depending on the solubility and
concentration of the active substance.
Example 2
[0161] Formulation of a Preferred Embodiment of the Topical
Delivery System
[0162] (An active ingredient is excluded from this
formulation.)
5 Component Total amount Water 79.5% of formulation Epikuron 200SH
3.5% of formulation Palmitic acid 1.5% of formulation Cholesterol
1.5% of formulation Mevalonic acid 0.01% of formulation
Triethanolamine 0.5% of formulation Phenonip 0.4% of formulation
Xanthan gum 2.0% of formulation Skinflux 2.0% of formulation
25-hydroxycholecalciferol 0.0015% of formulation Propylene glycol
4.0% of formulation Glycerol 3.0% of formulation
Polyvinylpyrrolidone 2.0% of formulation Epikuron 200SH are
hydrogenated lecithins, i.e. phosphatidylcholine (PC). "Skinflux"
is a blend product obtainable from Degussa Goldschmidt which
contains: Ceramide 1, 3, 6II; Phytosphingosine; Cholesterol; Sodium
Lauroyl Lactylate; Carbomer; and Xanthan Gum. Mevalonic acid
lactone is a lipid precursor for cholesterol/fatty acids.
25-Hydroxycholecalciferol is a lipid precursor for ceramides
Xanthan Gum is a thickener (polysaccharide). PHENONIP .RTM. is a
preservative and a blend of parabens.
[0163] Three fractions, a vesicle fraction, a foam fraction and a
hydrophilic fraction, are first prepared separately, as described
below. Each fraction weighs 3.3 kg. Then the three fractions are
mixed together. The following tables show the percent amount of
each component contributed by each fraction to the final
formulation. Thus, for each component, the sum of the percent
amounts of all the fractions is 100%.
[0164] 1: Vesicle Fraction
6 Percent Amount in Final Component Formulation Water 33% of total
water Hydrogenated lecithins 50% of total amount Palmitic acid 50%
of total amount Cholesterol 50% of total amount Mevalonic acid 50%
of total amount Triethanol amine 50% of total amount Preservative
(e.g., Paraben mixture) 50% of total amount Xanthan gum 15% of
total amount Skinflux 33% of total amount 25-hydroxycholecalcifer-
ol 50% of total amount 5M sodium hydroxide 1.3 ml per 1000 grams of
water The "Percent Amount in Final Formulation" indicates the
percentage of each component which is contributed by the vesicle
fraction to the final formulation.
[0165] In forming the vesicle fraction, the components are mixed
and heated to the temperature range of 65 to 85.degree. C. while
gently stirring. The pH is set to the range of 5.5 to 8.2 by the
use of sodium hydroxide. The resulting mixture is then homogenized.
Homogenization can be accomplished by, for example, a homogenizer
set at a high pressure (e.g. 10,000 to 40,000 psi); or by a
sonicator. The size of the vesicles is partially dependent upon how
long the resulting mixture is agitated. For example, to obtain an
average vesicle size of 0.140 .mu.m, the resulting mixture is
agitated for 60 minutes at about 70.degree. C. The mixture is then
allowed to cool to below 40.degree. C.
[0166] 2: Foam Fraction
7 Percent Amount in Final Component Formulation Water 33% of total
water Hydrogenated lecithins 50% of total amount Palmitic acid 50%
of total amount Cholesterol 50% of total amount Mevalonic acid 50%
of total amount Triethanol amine 50% of total amount Preservative
(e.g. a paraben mixture) 50% of total amount Xanthan gum 7.5% of
total amount Skinflux 33% of total amount 25-hydroxycholecalcifer-
ol 50% of total amount 5M sodium hydroxide 1.3 ml per 1000 g of
water The "Percent Amount in Final Formulation" indicates the
percentage of each component which is contributed by the foam
fraction to the final formulation.
[0167] In forming the foam fraction, the components are mixed and
heated to the temperature range of 65 to 85.degree. C. while
stirring. The pH is set to the range of 5.5 to 8.2 by the use of
sodium hydroxide. The composition is mixed vigorously for 1 minute.
Mixing can be done with ULTRATURRAX.RTM. from IKA Werke, Janke
& Kunkel GmbH & Co KG (Staufen, Germany). The composition
is then allowed to cool to below 40.degree. C.
[0168] 3: Hydrophilic Fraction
8 Percent Amount in Final Component Formulation Water 34% of total
water Propylene glycol 100% of total amount Glycerol 100% of total
amount Polyvinylpyrrolidone 100% of total amount Xanthan gum 77.5%
of total amount Skinflux 34% of total amount 5M sodium hydroxide
3.0 ml per 1000 g of water The "Percent Amount in Final
Formulation" indicates the percentage of each component which is
contributed by the hydrophilic fraction to the final
formulation.
[0169] In forming the hydrophilic fraction, the components are
mixed and heated to the temperature range of 65 to 85.degree. C.
while stirring. The pH is set to the range of 5.5 to 8.2 by use of
sodium hydroxide. Once homogeneous, the composition is then allowed
to cool to below 40.degree. C.
[0170] In forming the final formulation, after all the fractions
are cooled down (below 40.degree. C.), the three fractions are
mixed together in any order. For example, the foam fraction is
added to the vesicle fraction and gently mixed. Then the
hydrophilic fraction is added. The resulting mixture is gently
blended for several minutes to obtain a homogeneous solution.
[0171] The delivery system of this example is in the form of a
cream. In order to produce a delivery system in an aerosol foam
form, the total amount of xanthan gum in the final formulation is
reduced from 2% to about 0.3%. Additionally, an emulsifier is
added, such as laureth 4. Preferably, the emulsifier makes up about
0.7% of the final formulation.
Example 3
[0172] Formulation with Lidocaine as an Active Ingredient
[0173] An example of a 48 kg batch of a formulation of the delivery
system follows. The three fractions used to prepare this
formulation each contain 16 kg.
9 INCI Name Trade Name Supplier CAS Amount Hydrogenated Epikuron
Degussa 1.7 kg Lecithines 200 SH Goldschmidt Cholesterol Vendico
57-88-5 0.8 kg Palmitic acid Karlshamn 57-10-3 0.8 kg Ceramide 1,
3, 6II, Skin Flux Degussa 1.0 kg Phytosphingosine, Goldschmidt
Cholesterol, Sodium Lauroyl Lactylate, Carbomer, Xanthan Gum.
Mevalonic acid Sigma 674-26-0 4.8 g lactone Aldrich 25-Hydroxy-
Solvay 19356-17-3 0.72 kg cholecalciferol Propylene glycol MB-Sveda
57-55-6 2.0 kg Glycerin, 99.5% Vendico 56-81-5 1.5 kg Polyvinyl-
Apoteket 9003-39-8 1.0 kg pyrrolidone Xanthan gum Sigma 11138-66-2
1.0 kg Aldrich Triethanolamine, MB-Sveda 102-71-6 0.3 kg 85%
Phenonip Vendico 0.2 kg Chemical Lidocain USP-grade Apoteket 2.4 kg
Purified Up to Water 48 kg
Example 4
[0174] Measurement of Skin Barrier Restoration:
[0175] In the present context enhancing skin barrier restoration
can be measured by tape and/or acetone striping of stratum corneum
skin lipid content before, during and after a treatment period with
the present invention and other systems. Then HPLC analysis of skin
lipid content of stratum corneum is conducted.
* * * * *