Formulations from natural products, turmeric, paclitaxel, and aspirin

Abstract

The invention provides novel compounds and formulations of turmeric oil, fish oil, aspirin and anti-cancer drugs (paclitaxel) having anti-inflammatory, analgesic and/or anti-cancer activity.

1 . A process for obtaining an turmeric oil extract, the process comprising distilling turmeric oil under high vacuum distillation and collecting a distillate at 70-100° C., 105-118° C. or at 100-130° C. 
     
     
         2 . The turmeric oil extract of  claim 1 , wherein the extract has anti-inflammatory, anti-cancer and/or analgesic activity. 
     
     
         3 . The turmeric oil extract of  claim 2 , wherein the extract has anti-cancer activity against pancreatic, breast or prostate cancer. 
     
     
         4 . A composition comprising turmeric oil or a turmeric oil extract and a compound selected from the group consisting of an anti-cancer compound, an anti-inflammatory agent, curcumin, a curcumin derivative, fish oil, fish oil extract, aspirin, a salicylic acid conjugate, a curcumin ether derivative or a combinations thereof, wherein the salicylic acid conjugate is of formula (II): 
       
         
           
           
               
               
           
         
         wherein: 
         R 8  is a carbohydrate; 
         R 9  is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted acyl; and 
         analogs, derivatives, isomers, prodrugs, and pharmaceutically acceptable salts thereof, 
         wherein the curcumin ether derivative is of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein: (i) R 1 , R 2 , R 3 , and R 4  are independently H, alkyl, acyl, trialkylsilyl (—Si(alkyl) 3 ), aryl dialkylsilyl (—Si(alkyl) 2 aryl), diarylalkylsilyl (—Si(aryl) 2 alkyl), or triarylsilyl (—Si(aryl) 3 ); or (ii) R 2  and R 4  are both CH 3 , and R 1  and R 3  are both alkyl or one of R 1  and R 3  is H and the other is alkyl, 
         and wherein the curcumin derivative is of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a peptide, —C(O)R 3 , —C(O)OR 3 , or —C(O)NR 3 R 3 , provided that at least one of R 1  and R 2  is not H, or both of R 1  and R 2  are not octyl or hexadecyl, or one of R 1  or R 2  is not H and the other is not octyl or hexadecyl; 
         R 3  is independently for each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
         or R 1  and R 2  are linking groups and at least one of R 1  and R 2  is a linking group conjugated with a glyceryl lipid; and 
         analogs, derivatives, isomers, prodrugs, and pharmaceutically acceptable salts thereof. 
       
     
     
         5 . The composition of  claim 4 , wherein R 8  is selected from the group consisting of glucose, glyceraldehydes, erythrose, threose, ribulose, xylulose, ribose, arabinose, deoxyribose, xylose, lyxose, psicose, fructose, sorbose, tagatose, allose, altrose, mannose, gulose, idose, galactose, talose, fucose, fuculose, rhamnose, sedoheptulose, octose, nonose (Neuraminic acid), and the like. 
     
     
         6 . The composition of  claim 4 , wherein at least one of R 1  and R 2  of Formula (I) is selected from the group consisting of acetyl, myristoleoyl, palmitoleoyl, sapienoyl, oleoyl, linoleoyl, α-linoleoyl, α-linolenoyl, γ-linolenoyl, arcchidionoyl, eicosapentaenoyl, erucoyl, docosahexaenoyl, lauroyl, myrsitoyl, palmitoyl, stearoyl, arachidoyl, behenoyl, lignoceroyl, certoyl and any combinations thereof. 
     
     
         7 . The composition of  claim 4 , wherein at least one of R 1  and R 2  of Formula (I) is —C(O)R 3  and R 3  is an optionally substituted aryl. 
     
     
         8 . The curcumin derivative of  claim 4 , wherein the curcumin derivative is selected from the group consisting of di(acetylsalicyloyl)-curcumin monoacetylsalicyloyl-curcumin, diacetyl-curcumin, monoacetyl-curcumin, diaglutaroyl-curcumin, monoglutaroyl-curcumin, di-gluocose-glutaroyl-curcumin, mono-gluocose-glutaroyl-curcumin, monolinoleol-curcumnin, di-linoleoyl-curcumin and peptide-curcumin conjugates. 
     
     
         9 . The composition of  claim 4 , wherein the composition comprises turmeric oil extract and paclitaxel; turmeric oil extract and aspirin; turmeric oil extract and a curcumin derivative, turmeric oil extract and a salicylic acid conjugate; turmeric oil extract and curcumin; turmeric oil extract and di(acetylsalicyloyl)-curcumin; turmeric oil extract and monoacetylsalicyloyl-curcumin; turmeric oil extract and diacetyl-curcumin; turmeric oil extract and monoacetyl-curcumin; turmeric oil extract and diaglutaroyl-curcumin; turmeric oil extract and monoglutaroyl-curcumin; turmeric oil extract and di-gluocose-glutaroyl-curcumin; turmeric oil extract and mono-gluocose-glutaroyl-curcumin; turmeric oil extract and monolinoleol-curcumnin; turmeric oil extract and di-linoleoyl-curcumin; turmeric oil extract and an anticancer agent; turmeric oil extract and an anti-inflammatory agent; turmeric oil extract and fish oil; turmeric oil extract and fish oil extract; turmeric oil extract, an anti-cancer agent and an anti-inflammatory agent; turmeric oil extract, an anti-cancer agent and a curcumin derivative; turmeric oil extract, an anti-cancer agent and a salicylic acid conjugate; turmeric oil extract, an anti-inflammatory agent and a curcumin derivative; turmeric oil extract, an anti-inflammatory agent and a salicylic acid conjugate; or turmeric oil extract, a curcumin derivative and a salicylic acid conjugate. 
     
     
         10 . The composition of  claim 9 , wherein the composition has enhanced anti-cancer activity. 
     
     
         11 . The composition of  claim 4 , wherein the linking group is a glutaryl group, succinoyl group, or ether group. 
     
     
         12 . The composition of  claim 4 , wherein the glyceryl lipid comprises one or two lipids conjugated with glycerol. 
     
     
         13 . The composition of  claim 4 , wherein the lipid is a fatty acid or fatty alkyl group. 
     
     
         14 . The composition of  claim 4 , wherein R 1  and R 2  are glutaric acid and at least one of R 1  and R 2  is a glutarate conjugated with a glyceryl lipid. 
     
     
         15 . A method comprising: administering a therapeutically effective amount of:
 a. a turmeric oil extract,   b. a composition comprising: (a) turmeric oil or a turmeric oil extract, and (b) a compound selected from the group consisting of an anti-cancer compound, an anti-inflammatory agent, fish oil, fish oil extract, aspirin, a salicylic acid conjugate, a curcumin ether derivative and any combinations thereof,   c. a salicylic acid conjugate, or   d. any combinations thereof to a subject in need thereof,
 wherein the salicylic acid conjugate is of formula (II): 
   
       
         
           
           
               
               
           
         
         wherein R 8  is a carbohydrate; R 9  is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted acyl; and analogs, derivatives, isomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein the curcumin ether derivative is of formula (III): 
       
       
         
           
           
               
               
           
         
         wherein: (i) R 1 , R 2 , R 3 , and R 4  are independently H, alkyl, acyl, trialkylsilyl (—Si(alkyl) 3 ), aryl dialkylsilyl (—Si(alkyl) 2 aryl), diarylalkylsilyl (—Si(aryl) 2 alkyl), or triarylsilyl (—Si(aryl) 3 ); or (ii) R 2  and R 4  are both CH 3 , and R 1  and R 3  are both alkyl or one of R 1  and R 3  is H and the other is alkyl, 
         and wherein the curcumin derivative is of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  are independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a peptide, —C(O)R 3 , —C(O)OR 3 , or —C(O)NR 3 R 3 , provided that at least one of R 1  and R 2  is not H, or both of R 1  and R 2  are not octyl or hexadecyl, or one of R 1  or R 2  is not H and the other is not octyl or hexadecyl; 
         R 3  is independently for each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl; 
         or R 1  and R 2  are linking groups and at least one of R 1  and R 2  is a linking group conjugated with a glyceryl lipid; and 
         analogs, derivatives, isomers, prodrugs, and pharmaceutically acceptable salts thereof. 
       
     
     
         16 . The method of  claim 15 , wherein the linking group is a glutaryl group, succinoyl group, or ether group. 
     
     
         17 . The method of  claim 15 , wherein the lipid is a fatty acid or fatty alkyl group. 
     
     
         18 . The method of  claim 15 , wherein R 1  and R 2  are glutaric acid and at least one of R 1  and R 2  is a glutarate conjugated with a glyceryl lipid. 
     
     
         19 . The method of  claim 15 , wherein the subject is in need of treating inflammation or an inflammatory disease or condition. 
     
     
         20 . The method of  claim 15 , wherein the subject is in need of treating cancer or a metastasis.