Orally dispersible tablet

Abstract

The present invention provides a preparation with improved disintegration property, a preparation showing improved bioavailability of a medicament, production methods thereof and the like. A rapidly disintegrating preparation comprising granules comprising a medicament coated with a coating layer containing sugar or sugar alcohol; and a disintegrant. A production method of a rapidly disintegrating preparation including a step of producing granules comprising a medicament, a step of forming a coating layer containing sugar or sugar alcohol on the obtained granules and a step of mixing the coated granules with a disintegrant and molding the mixture.

1 - 4 . (canceled) 
     
     
         5 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in an amount of 0.05-1.0 mg, wherein the AUC ratio of (i) a metabolite of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide to (ii) (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 20, and wherein the metabolite consists of (2S)-2-Hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide. 
     
     
         6 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in an amount of 0.1-0.8 mg, wherein the AUC ratio of (i) a metabolite of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide to (ii) (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 20, and wherein the metabolite consists of (2S)-2-Hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide. 
     
     
         7 . The preparation according to  claim 5 , wherein the AUC ratio is not more than about 10. 
     
     
         8 . The preparation according to  claim 6 , wherein the AUC ratio is not more than about 10. 
     
     
         9 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein the AUC ratio of (i) (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide to (ii) a metabolite of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not less than about 5-fold than that by oral administration, and wherein the metabolite consists of (2S)-2-Hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl]ethyl}propanamide. 
     
     
         10 . The preparation according to  claim 9 , wherein the AUC ratio is not less than about 10-fold than that by oral administration. 
     
     
         11 . The preparation according to one of  claims 9  and  10 , wherein the AUC ratio is not more than about 30-fold than that by oral administration. 
     
     
         12 . The preparation according to  claim 11 , wherein the AUC ratio is not more than about 20-fold than that by oral administration. 
     
     
         13 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein the AUC ratio of (i) a metabolite of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide to (ii) (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 20, and wherein the metabolite consists of (2S)-2-Hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl]ethyl}propanamide. 
     
     
         14 . The preparation according to  claim 13 , wherein the AUC ratio is not more than about 10. 
     
     
         15 . The preparation according to  claim 13 , wherein the AUC ratio is not more than about 5. 
     
     
         16 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein the bioavailability of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is improved not less than about 10-fold than that by oral administration. 
     
     
         17 . The preparation according to  claim 16 , wherein the bioavailability of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is improved in a range from not less than about 10-fold to not more than about 30-fold than that by oral administration. 
     
     
         18 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein the average Tmax value of the plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         19 . The preparation according to  claim 18 , wherein the average Tmax value is not more than about 0.3 hours. 
     
     
         20 . The preparation according to  claim 18 , wherein the average Tmax value is not more than about 0.25 hours. 
     
     
         21 . The preparation according to any one of  claims 9 ,  13 , and  16 , wherein the average Tmax value of plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         22 . The preparation according to  claim 21 , wherein the average Tmax value is not more than about 0.3 hours. 
     
     
         23 . The preparation according to  claim 22 , wherein the average Tmax value is not more than about 0.25 hours. 
     
     
         24 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide, wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human subject is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         25 . The preparation according to  claim 24 , wherein the coefficient of variation is not more than about 35%. 
     
     
         26 . The preparation according to  claim 25 , wherein the coefficient of variation is nor more than about 30%. 
     
     
         27 . The preparation according to any one of  claims 9 ,  13 ,  16 , and  18 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human subject is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         28 . The preparation according to  claim 27 , wherein the coefficient of variation is not more than about 35%. 
     
     
         29 . The preparation according to  claim 28 , wherein the coefficient of variation is not more than about 30%. 
     
     
         30 . A preparation for oral-mucosal absorption, comprising (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in amount of 0.05-1.0 mg. 
     
     
         31 . The preparation according to  claim 30 , wherein (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is in amount of 0.1-0.8 mg. 
     
     
         32 . The preparation according to any one of  claims 30 - 31 , wherein the AUC ratio of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide in an unchanged form to a metabolite thereof after administration to a human is not less than about 5-fold than that by oral administration, wherein the metabolite consists of (2S)-2-Hydroxy-N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl]ethyl}propanamide. 
     
     
         33 . The preparation according to  claim 32 , wherein the AUC ratio is not less than about 10-fold than that by oral administration. 
     
     
         34 . The preparation according to  claim 32 , wherein the AUC ratio is not more than about 30-fold. 
     
     
         35 . The preparation according to  claim 34 , wherein the AUC ratio is not more than about 20-fold. 
     
     
         36 . The preparation according to  claim 33 , wherein the AUC ratio is not more than about 30-fold. 
     
     
         37 . The preparation according to  claim 36 , wherein the AUC ratio is not more than about 20-fold. 
     
     
         38 . The preparation according to any one of  claims 30 - 31 , wherein the AUC ratio of the metabolite to (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is not more than about 20. 
     
     
         39 . The preparation according to  claim 38 , wherein the AUC ratio is not more than about 10. 
     
     
         40 . The preparation according to  claim 38 , wherein the AUC ratio is not less than about 5. 
     
     
         41 . The preparation according to  claim 39 , wherein the AUC ratio is not less than about 5. 
     
     
         42 . The preparation according to any one of  claims 30 - 31 , wherein the bioavailability of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide is improved not less than about 10-fold than that by oral administration. 
     
     
         43 . The preparation according to any one of  claims 30 - 31 , wherein the bioavailability is improved within the range from not less than about 10-fold to not more than about 30-fold than that by oral administration. 
     
     
         44 . The preparation according to any one of  claims 30 - 31 , wherein the average Tmax value of plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         45 . The preparation according to  claim 44 , wherein the average Tmax is not more than about 0.3 hours. 
     
     
         46 . The preparation according to  claim 45 , wherein the average Tmax is not more than about 0.25 hours. 
     
     
         47 . The preparation according to  claim 32 , wherein the average Tmax value of plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         48 . The preparation according to  claim 47 , wherein the average Tmax is not more than about 0.3 hours. 
     
     
         49 . The preparation according to  claim 48 , wherein the average Tmax is not more than about 0.25 hours. 
     
     
         50 . The preparation according to  claim 38 , wherein the average Tmax value of plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         51 . The preparation according to  claim 50 , wherein the average Tmax is not more than about 0.3 hours. 
     
     
         52 . The preparation according to  claim 51 , wherein the average Tmax is not more than about 0.25 hours. 
     
     
         53 . The preparation according to  claim 42 , wherein the average Tmax value of plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         54 . The preparation according to  claim 53 , wherein the average Tmax is not more than about 0.3 hours. 
     
     
         55 . The preparation according to  claim 54 , wherein the average Tmax is not more than about 0.25 hours. 
     
     
         56 . The preparation according to  claim 43 , wherein the average Tmax value of plasma level of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 0.4 hours. 
     
     
         57 . The preparation according to  claim 56 , wherein the average Tmax is not more than about 0.3 hours. 
     
     
         58 . The preparation according to  claim 57 , wherein the average Tmax is not more than about 0.25 hours. 
     
     
         59 . The preparation according to any one of  claims 30 - 31 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         60 . The preparation according to  claim 59 , wherein the coefficient of variation is not more than about 35%. 
     
     
         61 . The preparation according to  claim 60 , wherein the coefficient of variation is not more than about 30%. 
     
     
         62 . The preparation according to  claim 59 , wherein the preparation further contains a disintegrant. 
     
     
         63 . The preparation according to  claim 32 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         64 . The preparation according to  claim 63 , wherein the coefficient of variation is not more than about 35%. 
     
     
         65 . The preparation according to  claim 64 , wherein the coefficient of variation is not more than about 30%. 
     
     
         66 . The preparation according to  claim 63 , wherein the preparation further contains a disintegrant. 
     
     
         67 . The preparation according to  claim 38 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         68 . The preparation according to  claim 67 , wherein the coefficient of variation is not more than about 35%. 
     
     
         69 . The preparation according to  claim 68 , wherein the coefficient of variation is not more than about 30%. 
     
     
         70 . The preparation according to  claim 67 , wherein the preparation further contains a disintegrant. 
     
     
         71 . The preparation according to  claim 42 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno [5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         72 . The preparation according to  claim 71 , wherein the coefficient of variation is not more than about 35%. 
     
     
         73 . The preparation according to  claim 72 , wherein the coefficient of variation is not more than about 30%. 
     
     
         74 . The preparation according to  claim 71 , wherein the preparation further contains a disintegrant. 
     
     
         75 . The preparation according to  claim 43 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         76 . The preparation according to  claim 75 , wherein the coefficient of variation is not more than about 35%. 
     
     
         77 . The preparation according to  claim 76 , wherein the coefficient of variation is not more than about 30%. 
     
     
         78 . The preparation according to  claim 75 , wherein the preparation further contains a disintegrant. 
     
     
         79 . The preparation according to  claim 44 , wherein the coefficient of variation of pharmacokinetic parameters of (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide after administration to a human is not more than about 45%, wherein the pharmacokinetic parameters consist of Cmax and AUC. 
     
     
         80 . The preparation according to  claim 79 , wherein the coefficient of variation is not more than about 35%. 
     
     
         81 . The preparation according to  claim 80 , wherein the coefficient of variation is not more than about 30%. 
     
     
         82 . The preparation according to  claim 79 , wherein the preparation further contains a disintegrant.