NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery
First Claim
1. A vesicular composition comprising:
- 1) vesicles having a lipid bilayer and consisting essentially of;
i) a phosphatidylcholine;
ii) a polyethyleneglycol-sorbitan-monooleate, a polyoxyethylene-oleoyl ether, or a nonaethyleneglycoloctylphenyl ether surfactant; and
iii) a salt of an NSAID wherein said NSAID is diclofenac, ibuprofen or ketoprofen; and
2) a pharmaceutically acceptable, polar liquid medium, whereinthe phosphatidylcholine and the surfactant of the vesicles are present in a molar ratio of between about 20/1 and about 7.5/1,the molar ratio of phosphatidylcholine to NSAID is between about 10/1 to about 1/1,the lipid bilayer is in the fluid lamellar phase, andthe pH of the composition is above the pKa of the NSAID.
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Accused Products
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.
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Citations
80 Claims
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1. A vesicular composition comprising:
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1) vesicles having a lipid bilayer and consisting essentially of; i) a phosphatidylcholine; ii) a polyethyleneglycol-sorbitan-monooleate, a polyoxyethylene-oleoyl ether, or a nonaethyleneglycoloctylphenyl ether surfactant; and iii) a salt of an NSAID wherein said NSAID is diclofenac, ibuprofen or ketoprofen; 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 20/1 and about 7.5/1, the molar ratio of phosphatidylcholine to NSAID is between about 10/1 to about 1/1, the lipid bilayer is in the fluid lamellar phase, and the pH of the composition is above the pKa of the NSAID. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
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41. A vesicular composition comprising:
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1) vesicles consisting essentially of; i) a phosphatidylcholine; ii) a polyethyleneglycol-sorbitan-monooleate, a polyoxyethylene-oleoyl ether, or a nonaethyleneglycoloctylphenyl ether surfactant; and iii) a salt of an NSAID wherein said NSAID is diclofenac, ibuprofen or ketoprofen; 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 20/1 and about 7.5/1, the molar ratio of phosphatidylcholine to NSAID is between about 10/1 to about 1/1, 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. - View Dependent Claims (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80)
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Specification