Nsaid formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery

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.

1 - 37 . (canceled) 
   
   
       38 . A method for inducing analgesia comprising applying to the skin of a warm blooded mammal a vesicular composition comprising:
 a) 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. 
 
   
   
       39 . The method of  claim 38 , wherein the phosphatidylcholine is from soy bean, coconut, olive, safflower, or sunflower, linseed, evening primrose, primrose, or castor oil. 
   
   
       40 . The method 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. 
   
   
       41 . The method of  claim 38 , wherein the composition further comprises a lower aliphatic alcohol. 
   
   
       42 . The method of  claim 41 , wherein the alcohol is n-propanol, isopropanol, 2-propanol, n-butanol, 2-butanol, 1,2-propanediol, 1,2-butanediol, or ethanol. 
   
   
       43 . The method of  claim 38 , wherein the pH of the composition is between 6.4 and 8.3. 
   
   
       44 . The method of  claim 38 , wherein the ionic strength of the composition is between 0.005 and 0.3. 
   
   
       45 . The method of  claim 38 , wherein the viscosity of the composition is between 50 mPa s and 30,000 mPa s. 
   
   
       46 . The method of  claim 38 , wherein the composition is applied in a non-occlusive patch. 
   
   
       47 . The method of  claim 38 , wherein the total dry mass of, the polyethyleneglycol-sorbitan-monooleate, polyoxyethylene-oleoyl ether, or nonaethyleneglycol octylphenyl ether surfactant; and the NSAID is between 0.01 weight-% and 50 weight-%. 
   
   
       48 . The method of  claim 38 , wherein the phosphatidylcholine is soy phosphatidylcholine or egg lecithin. 
   
   
       49 . The method of  claim 38  wherein the salt of the NSAID is the sodium salt of ketoprofen. 
   
   
       50 . The method of  claim 38 , wherein the phosphatidylcholine is soy phosphatidylcholine, the surfactant is polyethyleneglycol-sorbitan-monooleate, and the salt of the NSAID is the sodium salt of ketoprofen. 
   
   
       51 . The method of  claim 38 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1. 
   
   
       52 . The method of  claim 51 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1. 
   
   
       53 . The method of  claim 52 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1. 
   
   
       54 . The method of  claim 53 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1. 
   
   
       55 . The method of  claim 50 , 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 . The method of  claim 38 , wherein the pH of the composition is between 0.2 and 2.2 pH units above the pKa of the NSAID. 
   
   
       60 . The method of  claim 59 , wherein the pH of the composition is between 0.5 and 1.9 pH units above the pKa of the NSAID. 
   
   
       61 . The method of  claim 60 , wherein the pH of the composition is between 0.8 and 1.6 pH units above the pKa of the NSAID. 
   
   
       62 . The method of  claim 38 , wherein the phosphatidylcholine is from egg or soya beans. 
   
   
       63 . The method of  claim 38 , wherein the composition further comprises a thickening agent; an antioxidant, or a microbicide. 
   
   
       64 . The method of  claim 38 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 14/1 and about 10/1. 
   
   
       65 . The method of  claim 38 , wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID. 
   
   
       66 . A method for inducing analgesia comprising applying to the skin of a warm blooded mammal a vesicular composition comprising:
 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. 
 
   
   
       67 . The method of  claim 66 , wherein the phosphatidylcholine is from soy bean, coconut, olive, safflower, or sunflower, linseed, evening primrose, primrose, or castor oil. 
   
   
       68 . The method of  claim 66 , wherein the total dry mass of the phosphatidylcholine, the surfactant, and the NSAID is between 0.01 weight-% and 50 weight-% of the composition. 
   
   
       69 . The method of  claim 66 , wherein the composition further comprises a lower aliphatic alcohol. 
   
   
       70 . The method of  claim 69 , wherein the alcohol is n-propanol, isopropanol, 2-propanol, n-butanol, 2-butanol, 1,2-propanediol, 1,2-butanediol, or ethanol. 
   
   
       71 . The method of  claim 66 , wherein the pH of the composition is between 6.4 and 8.3. 
   
   
       72 . The method of  claim 66 , wherein the ionic strength of the composition is between 0.005 and 0.3. 
   
   
       73 . The method of  claim 66 , wherein the viscosity of the composition is between 50 mPa s and 30,000 mPa s. 
   
   
       74 . The method of  claim 66 , wherein the total dry mass of, the phosphatidylcholine; the polyethyleneglycol-sorbitan-monooleate, polyoxyethylene-oleoyl ether, or nonaethyleneglycol octylphenyl ether surfactant; and the NSAID is between 0.01 weight-% and 50 weight-%. 
   
   
       75 . The method of  claim 66 , wherein the phosphatidylcholine is soy phosphatidylcholine or egg lecithin. 
   
   
       76 . The method of  claim 66 , wherein the salt of the NSAID is the sodium salt of ketoprofen. 
   
   
       77 . The method of  claim 66 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1. 
   
   
       78 . The method of  claim 77 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1. 
   
   
       79 . The method of  claim 78 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1. 
   
   
       80 . The method of  claim 79 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1. 
   
   
       81 . The method of  claim 66 , wherein the phosphatidylcholine is soy phosphatidylcholine, the surfactant is polyethyleneglycol-sorbitan-monooleate, and the salt of the NSAID is the sodium salt of ketoprofen. 
   
   
       82 . The method of  claim 81 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 3/1 to about 1/1. 
   
   
       83 . The method of  claim 82 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2.5/1 to about 1/1. 
   
   
       84 . The method of  claim 83 , wherein the molar ratio of phosphatidylcholine to NSAID is between about 2/1 to about 1/1. 
   
   
       85 . The method of  claim 84 , wherein the molar ratio of phosphatidylcholine to NSAID is about 1/1. 
   
   
       86 . The method of  claim 66 , wherein the pH of the composition is between 0.2 and 2.2 pH units above the pKa of the NSAID. 
   
   
       87 . The method of  claim 86 , wherein the pH of the composition is between 0.5 and 1.9 pH units above the pKa of the NSAID. 
   
   
       88 . The method of  claim 87 , wherein the pH of the composition is between 0.8 and 1.6 pH units above the pKa of the NSAID. 
   
   
       89 . The method of  claim 66 , wherein the phosphatidylcholine is from egg or soya beans. 
   
   
       90 . The method of  claim 66 , wherein the composition further comprises a thickening agent, an antioxidant, or a microbicide. 
   
   
       91 . The method of  claim 66 , wherein the phosphatidylcholine and the surfactant are present in a molar ratio of between about 14/1 and about 10/1. 
   
   
       92 . The method of  claim 91 , wherein the pH is between 0.2 and 2.2 pH units above the pKa of the NSAID. 
   
   
       93 . The method of  claim 66 , wherein the composition is applied in a non-occlusive patch.