US2009060989A1PendingUtilityA1
Nsaid formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
Est. expiryOct 11, 2022(expired)· nominal 20-yr term from priority
A61K 47/34A61K 9/127A61K 47/10A61K 47/12A61K 31/196A61K 47/16A61K 47/26A61K 31/405A61K 9/1272A61K 47/20A61P 29/00A61K 31/5415A61K 31/192
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Claims
Abstract
The invention describes novel formulations of nonsteroidal anti-inflammatory drugs (NSAIDs) based on complex aggregates with at least three amphipatic components suspended in a suitable, e.g. pharmaceutically acceptable, polar liquid medium. A suitably ionised NSAID is one of the two, amongst said three, components that tends to destabilise lipid membranes, the other system component with such activity being typically a surfactant. In contrast, the remaining amongst said at least three amphipatic components typically forms a stable lipid membrane on it's own. An essential characteristics of the resulting, relatively large, aggregates is an improved ability to penetrate pores, in a semi-permeable barrier, at least 30%, and often much smaller than the average diameter of the complex aggregate. This enables said aggregates to mediate NSAID transport through semi-permeable barriers including mammalian skin. As a result of the skin penetration by NSAID loaded large aggregates, the drug delivered transcutaneously with such carriers gets deeper into the tissue than the corresponding NSAID from a solution on the skin surface. This is believed to be due to the special ability of suitable large carriers to bypass the local sink of blood capillaries at the epidermal-dermal junction in the skin. The carrier-mediated delivery of locally applied NSAIDs thus allows therapy of deep tissues under the drug administration site, which is medically highly desirable.
Claims
exact text as granted — not AI-modified1 - 5 . (canceled)
6 . The composition of claim 38 , wherein the NSAID is ketoprofen, ibuprofen, diclofenac, indomethacin, or naproxen.
7 . (canceled)
8 . The composition of claim 38 , wherein the phosphatidylcholine is from soy bean, coconut, olive, safflower, sunflower, linseed, evening primrose, primrose, or castor oil.
9 - 17 . (canceled)
18 . The composition of claim 38 , wherein the total dry mass of the phosphatidylcholine, the surfactant, and the NSAID is between 0.01 weight-% and 50 weight-% of the composition.
19 . (canceled)
20 . The composition of claim 38 , further comprising a lower aliphatic alcohol.
21 - 25 . (canceled)
26 . The composition of claim 20 , wherein the alcohol is n-propanol, isopropanol, 2-propanol, n-butanol, 2-butanol, 1,2-propanediol, 1,2-butanediol, or ethanol.
27 . (canceled)
28 . The composition of claim 38 , wherein the pH of the composition is between 6.4 and 8.3.
29 . The composition of claim 38 , wherein the ionic strength of the composition is between 0.005 and 0.3.
30 . The composition of claim 38 , wherein the viscosity of the composition is between 50 mPa s and 30,000 mPa s.
31 . (canceled)
32 . (canceled)
33 . A kit comprising the composition of claim 38 .
34 . A method for treating peripheral pain or inflammation comprising applying the composition of claim 38 to the skin of a warm blooded mammal.
35 . (canceled)
36 . A non-occlusive patch comprising the composition of claim 38 .
37 . (canceled)
38 . A vesicular composition comprising:
1) vesicles having a lipid bilayer and comprising:
i) a phosphatidylcholine;
ii) a polyethyleneglycol-sorbitan-10 to 24 carbon atom fatty chain ester, a polyethyleneglycol-10 to 24 carbon atom fatty chain ether, or a nonaethyleneglycol octylphenyl ether surfactant; and
iii) an NSAID that has an acid group that is in its salt form; and
2) a pharmaceutically acceptable, polar liquid medium, wherein
the phosphatidylcholine and the surfactant of the vesicles are present in a molar ratio of between about 40/1 and about 7.5/1,
the lipid bilayer is in the fluid lamellar phase, and
the pH of the composition is above the pKa of the NSAID.
39 . The composition of claim 38 , wherein the NSAID is ketoprofen, ibuprofen, diclofenac, naproxen, indomethacin, acetaminophen, diflunisal, etodolac, flurbiprofen, mefenamic acid, salsalate, tiaprofenic acid; or the salt form is choline salicylate-Mg salicylate, fenoprofen calcium, ketorolac tromethamine, magnesium salicylate, sodium salicylate, or tolmetin sodium.
40 . The composition of claim 38 , wherein the total dry mass of the polyethyleneglycol-sorbitan-10 to 24 carbon atom fatty chain ester, polyethyleneglycol-10 to 24 carbon atom fatty chain ether, or nonaethyleneglycol octylphenyl ether-surfactant; and the NSAID is between 0.01 weight-% and 50 weight-%.
41 . The composition of claim 38 , wherein the phosphatidylcholine is soy phosphatidylcholine or egg lecithin.
42 . The composition of claim 38 , wherein the NSAID is ketoprofen.
43 . The composition of claim 38 , wherein the surfactant is a polyethyleneglycol-sorbitan-10 to 24 carbon atom fatty chain ester.
44 . The composition of claim 43 , wherein the polyethyleneglycol-sorbitan-10 to 24 carbon atom fatty chain ester is polyethyleneglycol-sorbitan-monooleate.
45 . The composition of claim 44 , wherein the polyethyleneglycol-sorbitan-10 to 24 carbon atom fatty chain-ester is Tween 80.
46 . The composition of claim 38 , wherein the phosphatidylcholine is soy phosphatidylcholine, the surfactant is polyethyleneglycol-sorbitan-monooleate, and the NSAID is ketoprofen.
47 . The composition of claim 38 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
48 . The composition of claim 47 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
49 . The composition of claim 48 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
50 . The composition of claim 49 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
51 . The composition of claim 46 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
52 . The composition of claim 51 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
53 . The composition of claim 52 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
54 . The composition of claim 53 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
55 . The method of claim 34 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
56 . The method of claim 55 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
57 . The method of claim 56 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
58 . The method of claim 57 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
59 . A method for treating peripheral pain or inflammation comprising applying the patch of claim 36 to the skin of a warm blooded mammal.
60 . The method of claim 59 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
61 . The method of claim 60 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
62 . The method of claim 61 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
63 . The method of claim 62 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
64 . The composition of claim 43 , wherein the polyethyleneglycol-sorbitan-10 to 24 carbon atom fatty chain ester is polyethyleneglycol-sorbitan-monolaurate.
65 . The composition of claim 64 , wherein the polyethyleneglycol-sorbitan-monolaurate is Tween 20.
66 . The composition of claim 38 , wherein the pH of the composition is between 0.2 and 2.2 pH units above the pKa of the NSAID.
67 . The composition of claim 66 , wherein the pH of the composition is between 0.5 and 1.9 pH units above the pKa of the NSAID.
68 . The composition of claim 67 , wherein the pH of the composition is between 0.8 and 1.6 pH units above the pKa of the NSAID.
69 . The composition of claim 38 , wherein the phosphatidylcholine is from egg or soya beans.
70 . The composition of claim 38 , wherein the surfactant is a polyethyleneglycol-sorbitan-monolaurate, a polyethyleneglycol-sorbitan-monooleate, a polyethyleneglycol-monolaurate, a polyethyleneglycol-monooleate, a polyethyleneglycol-monolaurate-ether, or a polyethyleneglycol-monooleate-ether.
71 . The composition of claim 38 , further comprising a thickening agent, an antioxidant, or a microbicide.
72 . The composition of claim 38 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 40/1 and about 10/1.
73 . The composition of claim 38 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 30/1 and about 7.5/1.
74 . The composition of claim 73 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 20/1 and about 10/1.
75 . The composition of claim 74 , wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.
76 . A method for treating peripheral pain or inflammation comprising applying the composition of claim 75 to the skin of a warm blooded mammal.
77 . The method of claim 76 , wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.
78 . The kit of claim 33 , wherein the kit comprises a tube.
79 . The composition of claim 38 , wherein the NSAID is ibuprofen.
80 . The composition of claim 38 , wherein the NSAID is diclofenac.
81 . The composition of claim 38 , wherein the NSAID is indomethacin.
82 . A vesicular composition comprising:
1) vesicles comprising:
i) a phosphatidylcholine;
ii) a polyethyleneglycol-sorbitan-10 to 24 carbon atom-fatty chain ester, a polyethyleneglycol-10 to 24 carbon atom-fatty chain ether, or a nonaethyleneglycol octylphenyl ether surfactant; and
iii) an NSAID that has an acid group that is in its salt form; and
2) a pharmaceutically acceptable, polar liquid medium, wherein
the phosphatidylcholine and the surfactant of the vesicles are present in a molar ratio of between about 40/1 and about 7.5/1,
the vesicles are capable of penetrating a barrier with pores having an average pore diameter at least 50% smaller than the average vesicle diameter before the penetration, and
the pH of the composition is above the pKa of the NSAID.
83 . The composition of claim 82 , wherein the phosphatidylcholine is from soy bean, coconut, olive, safflower, or sunflower, linseed, evening primrose, primrose, or castor oil.
84 . The composition of claim 82 , wherein the total dry mass of the phosphatidylcholine, the surfactant, and the NSAID is between 0.01 weight-% and 50 weight-% of the composition.
85 . The composition of claim 82 , further comprising a lower aliphatic alcohol.
86 . The composition of claim 85 , wherein the alcohol is n-propanol, isopropanol, 2-propanol, n-butanol, 2-butanol, 1,2-propanediol, 1,2-butanediol, or ethanol.
87 . The composition of claim 82 , wherein the pH of the composition is between 6.4 and 8.3.
88 . The composition of claim 82 , wherein the ionic strength of the composition is between 0.005 and 0.3.
89 . The composition of claim 82 , wherein the viscosity of the composition is between 50 mPa s and 30,000 mPa s.
90 . The composition of claim 82 , wherein the NSAID is ketoprofen, ibuprofen, diclofenac, naproxen, indomethacin, acetaminophen, diflunisal, etodolac, flurbiprofen, mefenamic acid, salsalate, tiaprofenic acid; or the salt form is choline salicylate-Mg salicylate, fenoprofen calcium, ketorolac tromethamine, magnesium salicylate, sodium salicylate, or tolmetin sodium.
91 . The composition of claim 82 , wherein the NSAID is ketoprofen, ibuprofen, diclofenac, naproxen, or indomethacin.
92 . The composition of claim 82 , wherein the total dry mass of the phosphatidylcholine; the polyethyleneglycol-sorbitan-10 to 24 carbon atom-fatty chain ester, polyethyleneglycol-10 to 24 carbon atom-fatty chain ether, or nonaethyleneglycol octylphenyl ether surfactant; and the NSAID is between 0.01 weight-% and 50 weight-%.
93 . The composition of claim 82 , wherein the phosphatidylcholine is soy phosphatidylcholine or egg lecithin.
94 . The composition of claim 82 , wherein the NSAID is ketoprofen.
95 . The composition of claim 82 , wherein the surfactant is a polyethyleneglycol-sorbitan-10 to 24 carbon atom-fatty chain ester.
96 . The composition of claim 95 , wherein the polyethyleneglycol-sorbitan-10 to 24 carbon atom-fatty chain ester is polyethyleneglycol-sorbitan-monooleate.
97 . The composition of claim 96 wherein the polyethyleneglycol-sorbitan-10 to 24 carbon atom-fatty chain-ester is Tween 80.
98 . The composition of claim 95 , wherein the polyethyleneglycol-sorbitan-10 to 24 carbon atom-fatty chain ester is polyethyleneglycol-sorbitan-monolaurate.
99 . The composition of claim 98 , wherein the polyethyleneglycol-sorbitan-monolaurate is Tween 20.
100 . The composition of claim 82 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
101 . The composition of claim 100 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
102 . The composition of claim 101 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
103 . The composition of claim 102 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
104 . The composition of claim 82 , wherein the phosphatidylcholine is soy phosphatidylcholine, the surfactant is polyethyleneglycol-sorbitan-monooleate, and the NSAID is ketoprofen.
105 . The composition of claim 104 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
106 . The composition of claim 105 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
107 . The composition of claim 106 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
108 . The composition of claim 107 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
109 . The composition of claim 82 , wherein the pH of the composition is between 0.2 and 2.2 pH units above the pKa of the NSAID.
110 . The composition of claim 109 , wherein the pH of the composition is between 0.5 and 1.9 pH units above the pKa of the NSAID.
111 . The composition of claim 110 , wherein the pH of the composition is between 0.8 and 1.6 pH units above the pKa of the NSAID.
112 . The composition of claim 82 , wherein the phosphatidylcholine is from egg or soya beans.
113 . The composition of claim 82 , wherein the surfactant is a polyethyleneglycol-sorbitan-monolaurate, a polyethyleneglycol-sorbitan-monooleate, a polyethyleneglycol-monolaurate, a polyethyleneglycol-monooleate, a polyethyleneglycol-monolaurate-ether, or a polyethyleneglycol-monooleate-ether.
114 . The composition of claim 82 , further comprising a thickening agent, an antioxidant, or a microbicide.
115 . The composition of claim 82 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 40/1 and about 10/1.
116 . The composition of claim 82 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 30/1 and about 7.5/1.
117 . The composition of claim 116 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 20/1 and about 10/1.
118 . The composition of claim 117 , wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.
119 . A method for treating peripheral pain or inflammation comprising applying the composition of claim 82 to the skin of a warm blooded mammal.
120 . The method of claim 119 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
121 . The method of claim 120 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
122 . The method of claim 121 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
123 . The method of claim 122 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.
124 . A method for treating peripheral pain or inflammation comprising applying the composition of claim 117 to the skin of a warm blooded mammal.
125 . The method of claim 124 , wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID.
126 . A kit comprising the composition of claim 82 .
127 . The kit of claim 126 , wherein the kit comprises a tube.
128 . A non-occlusive patch comprising the composition of claim 82 .
129 . A method for treating peripheral pain or inflammation comprising applying the patch of claim 128 to the skin of a warm blooded mammal.
130 . The method of claim 129 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1.
131 . The method of claim 130 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1.
132 . The method of claim 131 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1.
133 . The method of claim 132 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1.Join the waitlist — get patent alerts
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