Methods of preparing compositions containing thymoquinone

Abstract

The invention relates to stable preparations of thymoquinone and methods of making and administering stable preparations of thymoquinone. Embodiments of the methods provide compositions comprising thymoquinone with phosphatidylcholine and/or guggulsterol and/or guggulsterol derivatives and/or sodium cholesteryl sulfate, in tablet, capsule, gel, or ointment forms, and method of administering the preparations.

What is claimed is: 
     
         1 . A method of preparing a composition comprising thymoquinone, comprising:
 i) mixing thymoquinone and vitamin E TPGS and melting it together;   ii) preparing lipid granules by sifting lipid and magnesium aluminometasilicate (Neusilin US2) and forming a mixture comprising lipid granules and melted thymoquinone of i) and sifting the resulting mixture, wherein the lipid is selected from the group consisting of phosphatidylcholine, guggulsterol, a guggulsterol derivative, and sodium cholesteryl sulfate;   iii) co-sifting magnesium aluminometasilicate, silicified microcrystalline cellulose (SMCC HD90), cross carmellose sodium, hydrophilic fumed silica; sodium lauryl sulfate, and anhydrous citric acid;   iv) sifting Poloxamer and blending with thymoquinone-lipid granules of ii) and granules of iii); and   v) sifting magnesium stearate and combining with the thymoquinone-lipid granules of iv) and mixing to form a lubricated mixture.   
     
     
         2 . The method of  claim 1 , wherein said lubricated mixture of v) is pressed into tablets. 
     
     
         3 . The method of  claim 2 , wherein said tablets are seal-coated. 
     
     
         4 . The method in  claim 3 , wherein said seal-coated tablets are enteric coated with polymers. 
     
     
         5 . The method of  claim 1 , wherein said phosphatidylcholine includes soy phosphatidylcholine, hydrogenated soyphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidycholine, egg phosphatidylcholine. 
     
     
         6 . The method of  claim 1 , wherein said guggulsterol derivative includes guggulsteryl sulfate, guggulsteryl phosphate, guggulsteryl phosphocholine, guggulsteryl phosphoglycerol, fatty acid esters of guggulsterol, and polyethylene glycol (PEG) derivatives of guggulsterol. 
     
     
         7 . The method of  claim 6 , wherein said fatty acid esters of guggulsterol include guggulsteryl acetate, guggulsteryl propionate, guggulsteryl butyrate, guggulsteryl valerate, guggulsteryl hexanoate, guggulsteryl caprylate, guggulsteryl caprates, guggulsteryl laurate, guggulsteryl myrstate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linolenate, guggulsteryl eicosapentenoate, guggulsteryl arachidonate, guggulsteryl hemisuccinate, guggulsteryl succinate. 
     
     
         8 . The method of  claim 6 , wherein the molecular weight of PEG in said PEG derivatives of guggulsterol is between 500 and 2000. 
     
     
         9 . The method of  claim 3 , wherein said seal coating comprises one or more polymers selected from hydroxymethyl propyl cellulose, methyl hydroxyethylcellulose, ethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, povidone, sodium carboxy methylcellulose, acrylate polymer, Opadri, and polyethylene glycol. 
     
     
         10 . The method of  claim 4 , wherein said enteric coating comprises one or more polymers selected from hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, acrylate polymers, and polyvinyl acetate phthalate, Opadri enteric, Eudragit, and Acryl-EZE. 
     
     
         11 . The method of  claim 1  or  claim 6  wherein guggulsterol or guggulsterol derivative is in the form of Z-isomer. 
     
     
         12 . The method of  claim 6 , wherein guggulsteryl sulfate is in the form of sodium salt. 
     
     
         13 . The method of  claim 2 , wherein the amount of thymoquinone in a single tablet is between 50 mg and 1000 mg. 
     
     
         14 . The method of  claim 2 , wherein the amount of said thymoquinone in a single tablet is at least 500 mg. 
     
     
         15 . The method of  claim 2 , wherein the amount of said thymoquinone in a single tablet is at least 1000 mg. 
     
     
         16 . The method of  claim 2 , wherein the amount of said phosphatidylcholine in a single tablet is between 10 mg and 500 mg. 
     
     
         17 . The method of  claim 2 , wherein the amount of said phosphatidylcholine in a single tablet is between 10 mg and 250 mg. 
     
     
         18 . The method of  claim 2 , wherein the amount of said phosphatidylcholine in a single tablet is between 10 mg and 100 mg. 
     
     
         19 . The method of  claim 2 , wherein the amount of said guggulsterol or guggulsterol derivative in a single tablet is between 10 mg and 1000 mg. 
     
     
         20 . The method of  claim 2 , wherein the amount of said guggulsterol or guggulsterol derivative in a single tablet is 25 mg. 
     
     
         21 . The method  claim 2 , wherein the amount of said guggulsterol or guggulsterol derivative in a single tablet is 50 mg. 
     
     
         22 . A method of preparing a gel or ointment composition comprising thymoquinone, phosphatidylcholine, guggulsterol or guggulsterol derivative or sodium cholesteryl sulfate, comprising:
 i) mixing phosphatidylcholine, guggulsterol, or guggulsterol derivative or sodium cholesteryl sulfate and thymoquinone in a first organic solvent;   ii) diluting the mixture of i) with a second organic solvent; and   iii) mixing the diluted mixture of ii) with a gelling agent to form a uniform viscous gel or ointment.   
     
     
         23 . The method of  claim 22 , wherein said phosphatidylcholine is from hydrogenated soy phosphatidylcholine or soy phosphatidylcholine. 
     
     
         24 . The method of  claim 22 , wherein said guggulsterol derivative includes guggulsteryl sulfate, guggulsteryl phosphate, guggulsteryl phosphocholine, guggulsteryl phosphoglycerol, fatty acid esters of guggulsterol, and polyethylene glycol (PEG) derivatives of guggulsterol. 
     
     
         25 . The method of  claim 24 , wherein said fatty acid esters of guggulsterol include guggulsteryl acetate, guggulsteryl propionate, guggulsteryl butyrate, guggulsteryl valerate, guggulsteryl hexanoate, guggulsteryl caprylate, guggulsteryl caprates, guggulsteryl laurate, guggulsteryl myrstate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linolenate, guggulsteryl eicosapentenoate, guggulsteryl arachidonate, guggulsteryl hemisuccinate, guggulsteryl succinate. 
     
     
         26 . The method of  claim 24 , wherein molecular weight of PEG in said PEG derivatives of guggulsterol is between 500 and 2000. 
     
     
         27 . The method of  claim 22 ,  23 , or  claim 24 , wherein said guggulsterol or guggulsterol derivative is a Z-isomer. 
     
     
         28 . The method of any one of  claims 6  and  24 , wherein the guggulsteryl sulfate is in the form of sodium salt. 
     
     
         29 . The method of  claim 22 , wherein said gelling agent is selected from hydroxypropylmethylcellulose, sodium carboxymethylcellulose, methyl cellulose, Simulgel INS 100, carbomers, Guar gum, and gelatin. 
     
     
         30 . The method of  claim 22 , wherein said first organic solvent and second organic solvent are the same or different. 
     
     
         31 . The method of  claim 22 , wherein said first organic solvent and second organic solvent is selected from isopropyl alcohol, ethanol, propylene glycol, polyethylene glycols, oleic acid, oleoyl alcohol, mineral oil, and purified water. 
     
     
         32 . The method of  claim 22 , wherein the amount of thymoquinone in said gel or ointment is between 0.1% and 10% by weight. 
     
     
         33 . The method of  claim 22 , wherein the amount of said thymoquinone in said gel or ointment is 3% by weight. 
     
     
         34 . The method of  claim 22 , wherein the quantity of said phosphatidylcholine in said gel or ointment is between 1% and 20% by weight. 
     
     
         35 . The method of  claim 18 , wherein the amount of said phosphatidylcholine in said gel or ointment is 6% by weight. 
     
     
         36 . The method of  claim 22 , wherein the amount of guggulsterol or guggulsterol derivative in a gel or ointment is between 0.1% and 10% by weight. 
     
     
         37 . The method of  claim 18  or  claim 20 , wherein the amount of guggulsterol or guggulsterol derivative is 0.5% by weight. 
     
     
         38 . A method of administering thymoquinone to a subject, comprising:
 i) providing a composition comprising thymoquinone prepared according to any one of  claims 1  to  37 ; and   ii) administering the preparation to a subject.   
     
     
         39 . The method of  claim 38 , wherein said composition is a tablet or capsule and said administering comprises oral administration. 
     
     
         40 . The method of  claim 38 , wherein said composition comprises a gel or ointment and said administering comprises topical administration. 
     
     
         41 . The method of  claim 38 , wherein said subject is a human. 
     
     
         42 . The method of any one of  claims 1 - 4 , wherein said phosphatidylcholine includes soy phosphatidylcholine, hydrogenated soyphosphatidylcholine, dimyristoylphosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dioleoylphosphatidycholine, egg phosphatidylcholine. 
     
     
         43 . The method of any one of  claims 1 - 4  and  42 , wherein said guggulsterol derivative includes guggulsteryl sulfate, guggulsteryl phosphate, guggulsteryl phosphocholine, guggulsteryl phosphoglycerol, fatty acid esters of guggulsterol, and polyethylene glycol (PEG) derivatives of guggulsterol. 
     
     
         44 . The method of any one of  claim 43 , wherein said fatty acid esters of guggulsterol include guggulsteryl acetate, guggulsteryl propionate, guggulsteryl butyrate, guggulsteryl valerate, guggulsteryl hexanoate, guggulsteryl caprylate, guggulsteryl caprates, guggulsteryl laurate, guggulsteryl myrstate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linolenate, guggulsteryl eicosapentenoate, guggulsteryl arachidonate, guggulsteryl hemisuccinate, guggulsteryl succinate. 
     
     
         45 . The method of any one of  claims 6 ,  7 ,  43 , and  44 , wherein the molecular weight of PEG in said PEG derivatives of guggulsterol is between 500 and 2000. 
     
     
         46 . The method of any one of  claims 3 ,  4 , and  42 - 45 , wherein said seal coating comprises one or more polymers selected from hydroxymethyl propyl cellulose, methyl hydroxyethylcellulose, ethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, povidone, sodium carboxy methylcellulose, acrylate polymer, Opadri, and polyethylene glycol. 
     
     
         47 . The method of any one of  claims 4  and  42 - 46 , wherein said enteric coating comprises one or more polymers selected from hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate, acrylate polymers, polyvinyl acetate phthalate, Opadri enteric, Eudragit, and Acryl-EZE. 
     
     
         48 . The method of any one of  claims 1 - 4  and  42 - 47 , wherein guggulsterol or guggulsterol derivative is in the form of Z-isomer. 
     
     
         49 . The method of claim any one of  claims 1 - 4 ,  6 , and  42 - 48 , wherein guggulsterol derivative is in the form of sodium salt. 
     
     
         50 . The method of any one of  claims 2 - 4  and  42 - 49 , wherein the amount of thymoquinone in a single tablet is at least 50 mg, preferably at least 500 mg, more preferably at least 1000 mg. 
     
     
         51 . The method of any one of  claims 2 - 4  and  42 - 50 , wherein the amount of said phosphatidylcholine in a single tablet is between 10 mg and 500 mg, preferably between 10 and 250 mg, more preferably between 10 and 100 mg. 
     
     
         52 . The method of any one of  claims 2 - 4  and  42 - 51 , wherein the amount of said guggulsterol or guggulsterol derivative in a single tablet is between 10 mg and 1000 mg, preferably between 25 mg and 50 mg. 
     
     
         53 . The method of  claim 19 - 21 , wherein said guggulsterol derivative includes guggulsteryl sulfate, guggulsteryl phosphate, guggulsteryl phosphocholine, guggulsteryl phosphoglycerol, fatty acid esters of guggulsterol, and polyethylene glycol (PEG) derivatives of guggulsterol. 
     
     
         54 . The method of  claim 53 , wherein said fatty acid esters of guggulsterol include guggulsteryl acetate, guggulsteryl propionate, guggulsteryl butyrate, guggulsteryl valerate, guggulsteryl hexanoate, guggulsteryl caprylate, guggulsteryl caprates, guggulsteryl laurate, guggulsteryl myrstate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linolenate, guggulsteryl eicosapentenoate, guggulsteryl arachidonate, guggulsteryl hemisuccinate, guggulsteryl succinate. 
     
     
         55 . The method of  claim 53  or  54 , wherein molecular weight of PEG in said PEG derivatives of guggulsterol is between 500 and 2000. 
     
     
         56 . The method of any one of  claims 19 - 21  and  53 - 55 , wherein said guggulsterol or guggulsterol derivative is a Z-isomer. 
     
     
         57 . The method of  claim 22  or  23 , wherein said guggulsterol derivative includes guggulsteryl sulfate, guggulsteryl phosphate, guggulsteryl phosphocholine, guggulsteryl phosphoglycerol, fatty acid esters of guggulsterol, and polyethylene glycol (PEG) derivatives of guggulsterol. 
     
     
         58 . The method of  claim 57 , wherein said fatty acid esters of guggulsterol include guggulsteryl acetate, guggulsteryl propionate, guggulsteryl butyrate, guggulsteryl valerate, guggulsteryl hexanoate, guggulsteryl caprylate, guggulsteryl caprates, guggulsteryl laurate, guggulsteryl myrstate, guggulsteryl palmitate, guggulsteryl stearate, guggulsteryl oleate, guggulsteryl linoleate, guggulsteryl linolenate, guggulsteryl eicosapentenoate, guggulsteryl arachidonate, guggulsteryl hemisuccinate, guggulsteryl succinate. 
     
     
         59 . The method of  claim 57  or  58 , wherein molecular weight of PEG in said PEG derivatives of guggulsterol is between 500 and 2000. 
     
     
         60 . The method of any one of  claims 57 - 59 , wherein said guggulsterol or guggulsterol derivative is a Z-isomer. 
     
     
         61 . The method of any one of  claims 57 - 60 , wherein said guggulsterol sulfate is in the form of sodium salt. 
     
     
         62 . The method of any one of  claims 22 - 29 , wherein said first organic solvent and second organic solvent are the same or different. 
     
     
         63 . The method of any one of  claims 22 - 29 , and  62 , wherein said first organic solvent and second organic solvent are selected from isopropyl alcohol, ethanol, propylene glycol, polyethylene glycols, oleic acid, oleoyl alcohol, mineral oil, and purified water. 
     
     
         64 . The method of any one of  claims 22 - 29  and  57 - 63 , wherein the amount of thymoquinone in said gel or ointment is between 0.1% and 10% by weight, preferably 3% by weight. 
     
     
         65 . The method of any one of  claims 22 - 29  and  57 - 64 , wherein the quantity of said phosphatidylcholine in said gel or ointment is between 1% and 20% by weight, preferably 6% by weight. 
     
     
         66 . The method of any one of  claims 22 - 29  and  57 - 65 , wherein the amount of guggulsterol or guggulsterol derivative in a gel or ointment is between 0.1% and 10% by weight, preferably 0.5% by weight. 
     
     
         67 . A method of administering thymoquinone to a subject, comprising:
 i) providing a composition comprising thymoquinone prepared according to any one of  claims 1  to  66 ; and   ii) administering the preparation to a subject.   
     
     
         68 . The method of  claim 67 , wherein said composition is a tablet or capsule and said administering comprises oral administration. 
     
     
         69 . The method of  claim 67 , wherein said composition comprises a gel or ointment and said administering comprises topical administration. 
     
     
         70 . The method any one of  claims 67 - 69 , wherein said subject is a human.