Poorly soluble drug containing microsphere with improved bioavailabilty and method of preparing the same

Abstract

A poorly soluble drug containing microsphere with improved bioavailability, an oral formulation comprising the same, and a method of preparing the same are provided, wherein the poorly soluble drug containing microsphere is a solid dispersion wherein the poorly soluble drug is dispersed in the water-soluble polymer carrier in a noncrystalline form by spray drying, thus increasing bioavailability of the poorly soluble drug.

1 . A poorly soluble drug containing micro sphere, comprising a water-soluble polymer carrier and a poorly soluble drug,
 wherein the poorly soluble drug is dispersed in the water-soluble polymer carrier in a non-crystalline form by spray drying a mixed solution of the water-soluble polymer carrier and the poorly soluble drug wherein the water-soluble polymer carrier and the poorly soluble drug are dissolved in a mixed solvent of water and an organic solvent.   
     
     
         2 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the microsphere does not comprise a seed. 
     
     
         3 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the water-soluble polymer carrier is one or more selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), cellulose polymer, and a combination thereof. 
     
     
         4 . The poorly soluble drug containing microsphere according to  claim 3 , wherein the water-soluble polymer carrier is hydroxypropylmethylcellulose. 
     
     
         5 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the weight ratio of the poorly soluble drug and the water-soluble polymer carrier is 1:1 to 1:15. 
     
     
         6 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the organic solvent is selected from the group consisting of C 1 - C 4  linear or branched alcohol, dichloromethane, and a combination thereof. 
     
     
         7 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the weight ratio of the organic solvent and water is 0.5:1 to 5:1. 
     
     
         8 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the poorly soluble drug is one or more selected from the group consisting of acyclovir, allopurinol, amiodarone, azathioprine, benazepril, calcitriol, candesartan, eprosartan, carbidopa/levidopa, clarithromycin, clozapine, desmopressin acetate, diclofenac, enalapril, famotidine, felodipine, fenofibrate, fentanyl, fexofenadine, fosinopril, furosemide, glyburide, hyoscyamine, imipramine, itraconazole, levothyroxine, atorvastatin, lovastatin, meclizine, megesterol, mercaptopurine, metolazone, mometasone, nabumetasone, omeprazole, paroxetine, propafenone, quinapril, simvastatin, sirolimus, tacrolimus, tizanidine, and a combination thereof. 
     
     
         9 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the microsphere has an average particle diameter of 500 μm or less. 
     
     
         10 . The poorly soluble drug containing microsphere according to  claim 1 , wherein the mixed solution is
 a mixed solution of an aqueous solution of the polymer carrier wherein the water-soluble polymer carrier is dissolved in water and a solution of the poorly soluble drug wherein the poorly soluble drug is dissolved in the organic solvent; or   a mixed solution of the poorly soluble drug dissolved in a solution of the polymer carrier wherein the water-soluble polymer carrier is dissolved in a mixed solvent of the organic solvent and water.   
     
     
         11 . An oral formulation comprising the poorly soluble drug containing microsphere according to  claim 1 . 
     
     
         12 . A method for preparing a poorly soluble drug containing microsphere, comprising
 a) dissolving a water-soluble polymer carrier and a poorly soluble drug in water and an organic solvent to prepare a mixed solution; and   b) spray drying the mixed solution.   
     
     
         13 . The method according to  claim 12 , wherein a seed and a surfactant are not used. 
     
     
         14 . The method according to  claim 12 , wherein the water-soluble polymer carrier is one or more selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP), cellulose polymer, and a combination thereof. 
     
     
         15 . The method according to  claim 14 , wherein the water-soluble polymer carrier is hydroxypropylmethylcellulose. 
     
     
         16 . The method according to  claim 12 , wherein the weight ratio of the poorly soluble drug and the water-soluble polymer carrier is 1:1 to 1:15. 
     
     
         17 . The method according to  claim 12 , wherein the organic solvent is selected from the group consisting of C 1 -C 4  linear or branched alcohol, dichloromethane, and a combination thereof. 
     
     
         18 . The method according to  claim 12 , wherein the weight ratio of the organic solvent and water is 0.5:1 to 5:1. 
     
     
         19 . The method according to  claim 12 , wherein the poorly soluble drug is one or more selected from the group consisting of acyclovir, allopurinol, amiodarone, azathioprine, benazepril, calcitriol, candesartan, eprosartan, carbidopa/levidopa, clarithromycin, clozapine, desmopressin acetate, diclofenac, enalapril, famotidine, felodipine, fenofibrate, fentanyl, fexofenadine, fosinopril, furosemide, glyburide, hyoscyamine, imipramine, itraconazole, levothyroxine, atorvastatin, lovastatin, meclizine, megesterol, mercaptopurine, metolazone, mometasone, nabumetasone, omeprazole, paroxetine, propafenone, quinapril, simvastatin, sirolimus, tacrolimus, tizanidine, and a combination thereof. 
     
     
         20 . The method according to  claim 12 , wherein the b) spray drying is conducted at an injection temperature of 80 to 120° C., at an injection speed of 1 to 10 ml/min, using a nozzle type spray dryer, or
 at a spray temperature of 80 to 120° C., a spray speed of 3,000 to 5,000 rpm, and an injection speed of 10 to 100 ml/min, using an atomizer type spray dryer. 
 
     
     
         21 . The method according to  claim 12 , wherein the step a) comprises
 dissolving the water-soluble polymer carrier in water to prepare an aqueous solution of the polymer carrier, dissolving the poorly soluble drug in an organic solvent to prepare a solution of the poorly soluble drug, and mixing the aqueous solution of the polymer carrier and the solution of the poorly soluble drug to prepare a mixed solution; or   dissolving the water-soluble polymer carrier in a mixed solvent of water and an organic solvent to prepare a solution of the polymer carrier, and dissolving the poorly soluble drug in the polymer carrier solution to prepare a mixed solution.   
     
     
         22 . A fenofibrate containing microsphere, comprising a water-soluble polymer carrier and fenofibrate,
 wherein fenofibrate is dispersed in the water-soluble polymer carrier in a noncrystalline form by spray drying, and   the microsphere has a dissolution pattern that 10 wt % or more of contained fenofibrate is dissoluted within 5 minutes, 30 wt % or more is dissoluted within 15 minutes, and 40 wt % or more is dissoluted within 30 minutes, when tested according to the second method (paddle method: 100 rotations per minute, tertiary distilled water 500 ml) of Korean Pharmacopoeia 9 th  Revision.   
     
     
         23 . An oral formulation comprising the fenofibrate containing microsphere according to  claim 22 .