Pharmaceutical compositions for poorly soluble drugs

Abstract

The present invention provides a pharmaceutical composition of a practically insoluble drug, wherein the composition may be administered with food or without food. The composition may be in the form of a solid dispersion of the practically insoluble drug and a polymer having acidic functional groups, and the composition may in vitro form a suspension.

1 . A pharmaceutical composition in the form of a solid dispersion of a practically insoluble drug and a polymer having acidic functional groups, wherein in vitro the composition forms a suspension.  
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is such that, upon administration, a suspension is formed in vivo, the suspension being a homogeneous dispersion of particles.  
     
     
         3 . A pharmaceutical composition according to  claim 2 , wherein the particles of the suspension, formed in vitro, are at least of a size where they in vitro diffract light such that the suspension presents as a cloudy suspension.  
     
     
         4 . A pharmaceutical composition according to  claim 2  wherein the particles of the suspension are of a size less than 10 micrometer but greater than 1 nm.  
     
     
         5 . A pharmaceutical composition according to  claim 3  wherein the particles of the suspension are of a size less than 10 micrometer but greater than 1 nm.  
     
     
         6 . A pharmaceutical composition according to  claim 2  wherein a portion of the particles is in microparticulate form and a portion of the particles is in nanoparticulate form.  
     
     
         7 . A pharmaceutical composition according to  claim 3  wherein a portion of the particles is in microparticulate form and a portion of the particles is in nanoparticulate form.  
     
     
         8 . A pharmaceutical composition according to  claim 2  wherein at least a portion of the particles of the suspension are of a size less than 450 nm but greater than 1 nm, such that after passing the cloudy suspension through a 450 nm filter, the suspension remains cloudy.  
     
     
         9 . A pharmaceutical composition according to  claim 3  wherein at least a portion of the particles of the suspension are of a size less than 450 nm but greater than 1 nm, such that after passing the cloudy suspension through a 450 nm filter, the suspension remains cloudy.  
     
     
         10 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the suspension is present during in vitro dissolution testing at a pH in the range of 4.0 to 8.0.  
     
     
         11 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the suspension is present during in vitro dissolution testing at a pH in the range of 5.5 to 7.5.  
     
     
         12 . A pharmaceutical composition according to  claim 10  wherein the in vitro dissolution testing includes an acidic pre-treatment step.  
     
     
         13 . A pharmaceutical composition according to  claim 11  wherein the in vitro dissolution testing includes an acidic pre-treatment step.  
     
     
         14 . A pharmaceutical composition according to  claim 12  wherein the acidic pre-treatment step is suspension in a dissolution medium at a pH of about 1.2 for a period of about 20 minutes.  
     
     
         15 . A pharmaceutical composition according to  claim 13  wherein the acidic pre-treatment step is suspension in a dissolution medium at a pH of about 1.2 for a period of about 20 minutes.  
     
     
         16 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the drug is an azole antifungal drug.  
     
     
         17 . A pharmaceutical composition according to  claim 16  wherein the azole antifungal drug is itraconazole.  
     
     
         18 . A pharmaceutical composition according to  claim 16  wherein the azole antifungal drug is saperconazole.  
     
     
         19 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the polymer is one or more of the group comprising hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate, starch glycolate, polacrylin, cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.  
     
     
         20 . A pharmaceutical composition according to  claim 16  wherein the polymer is one or more of the group comprising hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate, starch glycolate, polacrylin, cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.  
     
     
         21 . A pharmaceutical composition according to  claim 17  wherein the polymer is one or more of the group comprising hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate, starch glycolate, polacrylin, cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.  
     
     
         22 . A pharmaceutical composition according to  claim 18  wherein the polymer is one or more of the group comprising hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, alginate, carbomer, carboxymethyl cellulose, methacrylic acid copolymer, shellac, cellulose acetate phthalate, starch glycolate, polacrylin, cellulose acetate phthalate, methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate, cellulose acetate terephthalate, cellulose acetate isophthalate and cellulose acetate trimellitate.  
     
     
         23 . A pharmaceutical composition according to  claim 19  wherein the polymer is a hydroxypropyl methylcellulose phthalate.  
     
     
         24 . A pharmaceutical composition according to any one of  claims 20  to  22  wherein the polymer is a hydroxypropyl methylcellulose phthalate.  
     
     
         25 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the ratio of drug to polymer is in the range of from 3:1 to 1:20.  
     
     
         26 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the ratio of drug to polymer is in the range of from 1:1 to 1:3.  
     
     
         27 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the solid dispersion is formed by spray drying techniques.  
     
     
         28 . A pharmaceutical composition according to  claim 27  wherein the polymer is dispersed within a solvent prior to dispersion of the drug, wherein the solvent is one or more of the group comprising methylene chloride, chloroform, ethanol, methanol, propan-2-ol, ethylacetate, acetone and water.  
     
     
         29 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the bioavailability of the drug in the pharmaceutical composition is at least twice the bioavailability of the drug per se.  
     
     
         30 . A pharmaceutical composition according to  claim 16  wherein the bioavailability of the drug in the pharmaceutical composition is at least twice the bioavailability of the drug per se.  
     
     
         31 . A pharmaceutical composition according to  claim 17  wherein the bioavailability of the drug in the pharmaceutical composition is at least twice the bioavailability of the drug per se.  
     
     
         32 . A pharmaceutical composition according to  claim 18  wherein the bioavailability of the drug in the pharmaceutical composition is at least twice the bioavailability of the drug per se.  
     
     
         33 . A pharmaceutical composition according to any one of  claims 1  to  9  wherein the composition has an AUC under fed conditions that is 80 to 125% of the composition's AUC under fasted conditions.  
     
     
         34 . A pharmaceutical composition according to  claim 16  wherein the composition has an AUC under fed conditions that is 80 to 125% of the composition's AUC under fasted conditions.  
     
     
         35 . A pharmaceutical composition according to  claim 17  wherein the composition has an AUC under fed conditions that is 80 to 125% of the composition's AUC under fasted conditions.  
     
     
         36 . A pharmaceutical composition according to  claim 18  wherein the composition has an AUC under fed conditions that is 80 to 125% of the composition's AUC under fasted conditions.  
     
     
         37 . A pharmaceutical dosage form according to any of  claims 1  to  9  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         38 . A pharmaceutical dosage form according to  claim 16  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         39 . A pharmaceutical dosage form according to  claim 17  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         40 . A pharmaceutical dosage form according to  claim 18  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         41 . A pharmaceutical dosage form containing a therapeutically effective amount of the pharmaceutical composition of any one of  claims 1  to  9 .  
     
     
         42 . A pharmaceutical dosage form containing a therapeutically effective amount of the pharmaceutical composition of  claim 16 .  
     
     
         43 . A pharmaceutical dosage form containing a therapeutically effective amount of the pharmaceutical composition of  claim 17 .  
     
     
         44 . A pharmaceutical dosage form containing a therapeutically effective amount of the pharmaceutical composition of  claim 18 .  
     
     
         45 . A pharmaceutical dosage form according to  claim 41  including one or more excipients such as disintegrants, diluents, fillers, lubricants, glidants, colourants and flavours.  
     
     
         46 . A pharmaceutical dosage form according to  claim 41  wherein the dosage form is a capsule or a tablet.  
     
     
         47 . A pharmaceutical composition in the form of a solid dispersion of an azole antifungal drug and a polymer having acidic functional groups, wherein in vitro the composition forms a suspension.  
     
     
         48 . A pharmaceutical composition according to  claim 47  wherein the suspension is present during in vitro dissolution testing at a pH in the range of 4.0 to 8.0.  
     
     
         49 . A pharmaceutical composition according to  claim 47  wherein the suspension is present during in vitro dissolution testing at a pH in the range of 5.5 to 7.5.  
     
     
         50 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein the polymer is a hydroxypropyl methylcellulose phthalate.  
     
     
         51 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein the drug is itraconazole.  
     
     
         52 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein in vivo the composition provides a mean C max  of at least 100 ng/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         53 . A pharmaceutical composition according to  claim 50  wherein in vivo the composition provides a mean C max  of at least 100 ng/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         54 . A pharmaceutical composition according to  claim 51  wherein in vivo the composition provides a mean C max  of at least 100 ng/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         55 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein in vivo the composition provides a mean C max  of at least 150 to 250 ng/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         56 . A pharmaceutical composition according to  claim 50  wherein in vivo the composition provides a mean C max  of at least 150 to 250 ng/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         57 . A pharmaceutical composition according  claim 51  wherein in vivo the composition provides a mean C max  of at least 150 to 250 ng/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         58 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein the composition provides a mean AUC of at least 800 ng.h/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         59 . A pharmaceutical composition according to claims  50  wherein the composition provides a mean AUC of at least 800 ng.h/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         60 . A pharmaceutical composition according to  claim 51  wherein the composition provides a mean AUC of at least 800 ng.h/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         61 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein the composition provides a mean AUC of 1300 to 2300 ng.h/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         62 . A pharmaceutical composition according to  claim 50  wherein the composition provides a mean AUC of 1300 to 2300 ng.h/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         63 . A pharmaceutical composition according to  claim 51  wherein the composition provides a mean AUC of 1300 to 2300 ng.h/ml, after administration of a 100 mg dose of the azole antifungal drug in the fasted state.  
     
     
         64 . A pharmaceutical composition according to any one of  claims 47  to  49  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         65 . A pharmaceutical composition according to  claim 50  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         66 . A pharmaceutical composition according to  claim 51  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         67 . A pharmaceutical composition including about 100 mg of an azole antifungal drug -wherein in vivo the composition provides a mean C max  of at least 100 ng/ml, after administration in the fasted state.  
     
     
         68 . A pharmaceutical composition according to  claim 67  wherein in vivo the composition provides a mean C max  of at least 150 to 250 ng/ml, after administration of the azole antifungal drug in the fasted state.  
     
     
         69 . A pharmaceutical composition including about 100 mg of an azole antifungal drug wherein the composition provides a mean AUC of at least 800 ng.h/ml, after administration in the fasted state.  
     
     
         70 . A pharmaceutical composition according to  claim 69  wherein the composition provides a mean AUC of 1300 to 2300 ng.h/ml, after administration of the azole antifungal drug in the fasted state.  
     
     
         71 . A pharmaceutical composition according to  claim 61  wherein the azole antifungal drug is itraconazole.  
     
     
         72 . A pharmaceutical composition according to  claim 62  wherein the azole antifungal drug is itraconazole.  
     
     
         73 . A pharmaceutical composition according to  claim 63  wherein the azole antifungal drug is itraconazole.  
     
     
         74 . A pharmaceutical composition according to  claim 64  wherein the azole antifungal drug is itraconazole.  
     
     
         75 . A pharmaceutical composition according to  claim 65  wherein the azole antifungal drug is itraconazole.  
     
     
         76 . A pharmaceutical composition according to  claim 66  wherein the azole antifungal drug is itraconazole.  
     
     
         77 . A pharmaceutical composition according to  claim 67  wherein the azole antifungal drug is itraconazole.  
     
     
         78 . A pharmaceutical composition according to  claim 68  wherein the azole antifungal drug is itraconazole.  
     
     
         79 . A pharmaceutical composition in the form of a solid dispersion of a hydroxypropyl methylcellulose phthalate and a practically insoluble drug, wherein the composition forms a suspension in vitro in the pH range of 4.0 to 8.0 and provides acceptable absorption in the intestines.  
     
     
         80 . A pharmaceutical composition according to  claim 79  wherein the drug is itraconazole.  
     
     
         81 . A pharmaceutical composition according to  claim 79  wherein the suspension is present during in vitro dissolution testing at a pH in the range of 5.5 to 7.5.  
     
     
         82 . A pharmaceutical composition according to  claim 80  wherein the suspension is present during in vitro dissolution testing at a pH in the range of 5.5 to 7.5.  
     
     
         83 . A pharmaceutical composition according to any one of  claims 67  to  70  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         84 . A process for preparing a pharmaceutical composition of a practically insoluble drug, the process including the steps of: 
 (a) adding a polymer having acidic functional groups to a solvent to form a dispersion;    (b) adding the drug to the dispersion to form a suspension or solution; and    (c) spray drying the suspension or solution to form the pharmaceutical composition in the form of a solid dispersion.    
     
     
         85 . A process according to  claim 84  wherein step (a) is conducted so as not to dissolve the polymer acid.  
     
     
         86 . A process according to  claim 84  wherein the polymer is a hydroxypropyl methylcellulose phthalate.  
     
     
         87 . A process according to  claim 85  wherein the polymer is a hydroxypropyl methylcellulose phthalate.  
     
     
         88 . A process according to any one of  claims 84  to  87  wherein the solvent is methylene chloride.  
     
     
         89 . A process according to any one of  claims 84  to  87  wherein the drug is itraconazole.  
     
     
         90 . A process according to any one of  claims 84  to  87  wherein the solid dispersion is subsequently blended with one or more excipients to produce a powder for use in a pharmaceutical dosage form.  
     
     
         91 . A process according to  claim 90  wherein the blending occurs with grinding.  
     
     
         92 . A process for preparing a pharmaceutical composition of a practically insoluble drug, the process including dispersing in a solvent the drug and a polymer having acidic functional groups, and spray drying the dispersion to form a solid dispersion.  
     
     
         93 . A pharmaceutical composition of a practically insoluble drug, the composition having an AUC under fed conditions that is 80 to 125% of the composition's AUC under fasted conditions.  
     
     
         94 . A pharmaceutical composition according to  claim 93  wherein the composition is a solid dispersion of the practically insoluble drug and a polymer having acidic functional groups.  
     
     
         95 . A pharmaceutical composition according to  claim 94  wherein the polymer is a hydroxypropyl methylcellulose phthalate.  
     
     
         96 . A pharmaceutical composition according to  claim 94  wherein in vitro the composition forms a suspension.  
     
     
         97 . A pharmaceutical composition according to  claim 95  wherein in vitro the composition forms a suspension.  
     
     
         98 . A pharmaceutical composition according to any one of  claims 93  to  97  wherein the drug is an azole antifungal drug.  
     
     
         99 . A pharmaceutical composition according to  claim 98  wherein the drug is itraconazole.  
     
     
         100 . A pharmaceutical composition according to  claim 98  wherein the drug is saperconazole.  
     
     
         101 . A pharmaceutical composition of a practically insoluble drug, wherein in vitro the composition forms a suspension.  
     
     
         102 . A pharmaceutical composition according to  claim 101  wherein the drug is an azole antifungal drug.  
     
     
         103 . A pharmaceutical composition according to  claim 102  wherein the drug is itraconazole.  
     
     
         104 . A pharmaceutical composition according to  claim 102  wherein the drug is saperconazole.  
     
     
         105 . A pharmaceutical composition according to any one of  claims 93  to  97  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         106 . A pharmaceutical composition according to  claim 98  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         107 . A pharmaceutical composition according to any one of  claims 99  to  104  wherein the composition has a reduced food effect compared to the drug per se.  
     
     
         108 . A process for preparing a pharmaceutical composition of a practically insoluble drug, the process including the steps of: 
 (a) adding the drug to a solvent to form a dispersion;    (b) adding a polymer having acidic functional groups to the dispersion to form a suspension or solution; and    (c) spray drying the suspension or solution to form the pharmaceutical composition in the form of a solid dispersion.