Method and compositions employing formulations of lecithin oils and nsaids for protecting the gastrointestinal tract and providingenhanced therapeutic activity

Abstract

A novel pharmaceutical composition is provided by which nonsteroidal anti-inflammatory drugs (NSAIDs) are added directly to phospholipid-containing oil such as lecithin oils or to a bio-compatible oil to which an phospholipid has been added to make a NSAID-containing formulation that possess low gastrointestinal (GI) toxicity and enhanced therapeutic activity to treat or prevent inflammation, pain, fever, platelet aggregation, tissue ulcerations and/or other tissue disorders. The composition of the invention are in the form of a non-aqueous solution, paste, suspension, dispersion, colloidal suspension or in the form of an aqueous emulsion or microemulstion for internal, oral, direct or topical administration.

We claim:  
     
         1 . A composition comprising a non-aqueous carrier including a phospholipid and a therapeutically effective amount of an NSAID, where the phospholipid is present in an amount sufficient to reduce pathogenic effects of the NSAID including GI ulceration, bleeding, liver damage, kidney damage, and/or cardiovascular side-effects, and where the composition prevents, reduces and/or treats tissue ulceration, tissue inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's Disease.  
     
     
         2 . The composition of  claim 1 , wherein the carrier comprises a bio-compatible oil, a phospholipid-containing bio-compatible oil, or a mixture thereof.  
     
     
         3 . The composition of  claim 1 , wherein the phospholipid-containing bio-compatible oil is a lecithin oil including a concentration of phospholipids between about 10 and about 40 wt. %  
     
     
         4 . The composition of  claim 3 , wherein the concentration is from about 10 to about 30 wt. %.  
     
     
         5 . The composition of  claim 3 , wherein the concentration is from about 10 to about 20 wt. %.  
     
     
         6 . The composition of  claim 1 , wherein the weight ratio of NSAID to carrier is between about 10:1 to about 1:10.  
     
     
         7 . The composition of  claim 6 , wherein the weight ratio is between about 2:1 to about 1:1.  
     
     
         8 . The composition of  claim 1 , wherein the NSAID is selected from the group consisting of aspirin, salicylate, naproxen, diclof enac, indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozen, ketorolac, sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, COX2 inhibitors, acetaminophen, or mixtures and combinations thereof.  
     
     
         9 . The compositions of claims  1  through  16 , wherein the phospholipid reduces the GI toxicity of the NSAID.  
     
     
         10 . The compositions of claims  1  through  16 , where the composition increases the therapeutic activity and/or potency of the NSAID to treat/prevent inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's Disease.  
     
     
         11 . A method of preparing NSAID-containing formulations comprising the step of adding a therapeutically effective amount of an NSAID to a non-aqueous carrier including a sufficient amount of a phospholipid to form a non-aqueous solution, paste, semi-solid, suspension, dispersion, colloidal suspension or mixtures thereof, where the composition has low NSAID pathogenic effects including GI ulceration, bleeding, liver damage, kidney damage, and/or cardiovascular side-effects and/or enhanced NSAID therapeutic activity and/or potency and treats, prevents or reduces inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's Disease.  
     
     
         12 . The method of  claim 11 , wherein the carrier comprises a bio-compatible oil and a phospholipid, a phospholipid-containing bio-compatible oil, or a mixture thereof.  
     
     
         13 . The method of  claim 12 , wherein the phospholipid-containing bio-compatible oil is a lecithin oil having a concentration between about 10 and about 40 wt. % of phospholipids.  
     
     
         14 . The method of  claim 13 , wherein the concentration is from about 10 to about 30 wt %.  
     
     
         15 . The method of  claim 13 , wherein the concentration is from about 10 to about 20 wt %.  
     
     
         16 . The method of  claim 11 , wherein the weight ratio of NSAID:carrier is from about 10:1 to about 1:10.  
     
     
         17 . The method of  claim 16 , wherein the weight ratio is from about 2:1 to about 1:1.  
     
     
         18 . The method of  claim 11 , wherein the NSAID is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac, indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozen, ketorolac, sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, COX2 inhibitors, acetaminophen, or mixtures and combinations thereof.  
     
     
         19 . A composition comprising an aqueous emulsion or microemulsion including an aqueous phase and a non-aqueous phase and optionally an emulsifying agent, where the aqueous phase is a bio-compatible aqueous solution and the non-aqueous phase comprises a non-aqueous carrier including a phospholipid and optionally a therapeutically effective amount of an NSAID, where the phospholipid is present in an amount sufficient to prevent or reduce tissue ulceration, and when the NSAID is present to reduce pathogenic effects of the NSAID including GI ulceration, bleeding, liver damage, kidney damage, and/or cardiovascular side-effects, and where the composition prevents, reduces and/or treats tissue ulceration, tissue inflammation, pain, fever, cardiovascular disease ovarian cancer, colon cancer, and/or Alzheimer's Disease.  
     
     
         20 . The composition of  claim 19 , where the carrier comprises a bio-compatible oil, a phospholipid-containing bio-compatible oil, or a mixture thereof.  
     
     
         21 . The composition of  claim 19 , wherein the phospholipid-containing bio-compatible oil a lecithin oil including a concentration of phospholipids between about 10 and about 40 wt. %  
     
     
         22 . The composition of  claim 21 , wherein the concentration is from about 10 to about 30 wt. %.  
     
     
         23 . The composition of  claim 21 , wherein the concentration is from about 10 to about 20 wt. %.  
     
     
         24 . The composition of  claim 19 , wherein the weight ratio of NSAID to carrier is between about 10:1 to about 1:10.  
     
     
         25 . The composition of  claim 24 , wherein the weight ratio is between about 2:1 to about 1:1.  
     
     
         26 . The composition of  claim 19 , wherein the NSAID is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac, indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozen, ketorolac, sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, COX2 inhibitors, acetaminophen, or mixtures and combinations thereof.  
     
     
         27 . The compositions of claims  19  through  26 , wherein the phospholipid reduces the GI toxicity of the NSAID.  
     
     
         28 . The compositions of claims  19  through  26 , which composition increases the therapeutic activity and/or potency of the NSAID to treat/prevent inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's Disease.  
     
     
         29 . The compositions of claims  19  through  28 , wherein the composition is a mouth wash or rinse for oral treatment of the mouth ulceration and/or inflammation due to mucositis where the mouth includes the oral cavity, gums and teeth.  
     
     
         30 . The compositions of claims  19  through  28 , wherein the composition is an eye drop or wash for treatment of inflammation of the eye due to uveitis.  
     
     
         31 . The compositions of claims  19  through  28 , wherein the composition is drinkable for treatment of the mouth, esophagus and/or GI tract due to mucositis.  
     
     
         32 . A method of preparing NSAID-containing formulations comprising the steps of: 
 adding a therapeutically effective amount of an NSAID to a non-aqueous carrier including a sufficient amount of a phospholipid to form a non-aqueous composition in the form of a solution, a paste, a semi-solid, a-suspension, a dispersion, a colloidal suspension or a mixture thereof ; and    emulsifying the non-aqueous composition in a bio-compatible aqueous solution in the presence or absence of an emulsifying agent,    where the composition has low NSAID pathogenic effects including GI ulceration, bleeding, liver damage, kidney damage, and/or cardiovascular side-effects, and/or enhanced NSAID therapeutic activity and/or potency and treats, prevents or reduces inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's Disease.    
     
     
         33 . The method of  claim 29 , wherein the carrier comprises a bio-compatible oil and a phospholipid, a phospholipid-containing bio-compatible oil, or a mixture thereof.  
     
     
         34 . The method of  claim 30 , wherein the phospholipid-containing bio-compatible oil is a lecithin oil having a concentration between about 10 and about 40 wt. % of phospholipids.  
     
     
         35 . The method of  claim 31 , wherein the concentration is from about 10 to about 30 wt. %.  
     
     
         36 . The method of  claim 31 , wherein the concentration is from about 10 to about 20 wt. %.  
     
     
         37 . The method of  claim 29 , wherein the weight ratio of NSAID:carrier is from about 10:1 to about 1:10.  
     
     
         38 . The method of  claim 34 , wherein the weight ratio is from about 2:1 to about 1:1.  
     
     
         39 . The method of  claim 29 , wherein the NSAID is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac, indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozen, ketorolac, sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, COX2 inhibitors, acetaminophen, or mixtures and combinations thereof.  
     
     
         40 . The method of  claim 29 , further comprising the step of: 
 shearing the emulsified material to form a microemulsion.    
     
     
         41 . A method of treating inflammation comprising the steps of: 
 administering to an animal including a human a composition comprising a non-aqueous carrier including a therapeutically effective amount of an NSAID and an amount of a phospholipid sufficient to reduce NSAID pathogenic effects including GI ulceration, bleeding, liver damage, kidney damage, and/or cardiovascular side-effects, and/or enhanced NSAID therapeutic activity and/or potency and treats, prevents or reduces inflammation, pain, fever, cardiovascular disease, ovarian cancer, colon cancer, and/or Alzheimer's Disease.    
     
     
         42 . The method of  claim 41 , wherein the carrier comprises a bio-compatible oil and a phospholipid, a phospholipid-containing bio-compatible oil, or a mixture thereof.  
     
     
         43 . The method of  claim 42 , wherein the phospholipid-containing bio-compatible oil is a lecithin oil having a concentration between about 10 and about 40 wt. % of phospholipids.  
     
     
         44 . The method of  claim 43 , wherein the concentration is from about 10 to about 30 wt. %.  
     
     
         45 . The method of  claim 43 , wherein the concentration is from about 10 to about 20 wt. %.  
     
     
         46 . The method of  claim 41 , wherein the weight ratio of NSAID:carrier is from about 10:1 to about 1:10.  
     
     
         47 . The method of  claim 46 , wherein the weight ratio is from about 2:1 to about 1:1.  
     
     
         48 . The method of  claim 41 , wherein the NSAID is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac, indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozen, ketorolac, sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, COX2 inhibitors, acetaminophen, or mixtures and combinations thereof.  
     
     
         49 . A method of preventing or treating tissue ulceration and/or inflammation comprising the steps of: 
 administering to an animal including a human a composition comprising a non-aqueous carrier including optionally a therapeutically effective amount of an NSAID and an amount of a phospholipid. sufficient to prevent ulceration and/or inflammation due to mucositis caused by chemo- and/or radiotherapy and, when the NSAID is present, to reduce NSAID pathogenic effects including GI ulceration, bleeding, liver damage, kidney damage, and/or cardiovascular side-effects, and/or enhanced NSAID therapeutic activity and/or potency of the NSAID in reducing inflammation, pain, and/or fever associated with chemo- and/or radiotherapy.    
     
     
         50 . The method of  claim 49 , wherein the carrier comprises a bio-compatible oil and a phospholipid, a phospholipid-containing bio-compatible oil, or a mixture thereof  
     
     
         51 . The method of  claim 50 , wherein the phospholipid-containing bio-compatible oil is a lecithin oil having a concentration between about 10 and about 40 wt. % of phospholipids.  
     
     
         52 . The method of  claim 51 , wherein the concentration is from about 10 to about 30 wt. %.  
     
     
         53 . The method of  claim 51 , wherein the concentration is from about 10 to about 20 wt. %.  
     
     
         54 . The method of  claim 49 , wherein the weight ratio of NSAID:carrier is from about 10:1 to about 1:10.  
     
     
         55 . The method of  claim 54 , wherein the weight ratio is from about 2:1 to about 1:1.  
     
     
         56 . The method of  claim 49 , wherein the NSAID is selected from the group consisting of aspirin, salicylate, naproxen, diclofenac, indomethacin, sulindac, ibuprofen, ketoprofen, oxaprozen, ketorolac, sulindac, nabumetone, meclofenamic, piroxicam, diflunisal, oxyphenbutazone, phenylbutazone, celecoxib, rofecoxib, COX2 inhibitors, acetaminophen, or mixtures and combinations thereof.