Pharmaceutical compositions with improved dissolution

Abstract

The invention relates to methods of screening mixtures containing a pharmaceutical compound and an excipient to identify properties of the pharmaceutical compound/excipient combination that retard solid-state nucleation. The invention further relates to increasing the solubility, dissolution and bioavailability of a drug with low solubility in gastric fluids conditions by combining the drug with a recrystallization/precipitation retardant and an optional enhancer.

1 . A process for producing a pharmaceutical composition, which comprises: 
 (1) providing a plurality of containers;    (2) providing a plurality of excipient solutions;    (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound;    (4) dispensing into each container at least one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, a property of each mixture being varied in different containers;    (5) incubating the mixture;    (6) determining onset of solid-state nucleation;    (7) selecting a pharmaceutical compound/excipient combination whereby onset of solid-state nucleation is retarded; and    (8) producing a pharmaceutical composition comprising the pharmaceutical compound/excipient combination.    
     
     
         2 . A process according to  claim 1 , wherein the property varied in step (4) comprises identity or amount of the excipient or the pharmaceutical compound.  
     
     
         3 . A process according to  claim 1 , wherein each solution comprises an aqueous solution.  
     
     
         4 . A process according to  claim 3 , wherein the mixture simulates gastric juices or intestinal fluids.  
     
     
         5 . A process according to  claim 1 , wherein the compound solution is supersaturated.  
     
     
         6 . A process according to  claim 1 , wherein the plurality of containers are presented in a multiple well plate format.  
     
     
         7 . A process according to  claim 1 , wherein at least the step of dispensing is performed with automated liquid handling apparatus.  
     
     
         8 . A process according to  claim 1 , wherein the intimate mixture is formed using a mixer.  
     
     
         9 . A process according to  claim 1 , wherein the step of incubating the mixture is preformed at constant temperature.  
     
     
         10 . A process according to  claim 9 , wherein the temperature is approximately 37° C.  
     
     
         11 . A process according to  claim 1 , wherein the onset of solid-state nucleation is determined by measuring the light scattering of the mixture.  
     
     
         12 . A process according to  claim 11 , wherein the light scattering is measured using a nephelometer.  
     
     
         13 . A process according to  claim 1 , which further comprises a step of determining the crystallinity of the product of solid-state nucleation before selecting the pharmaceutical compound/excipient combination.  
     
     
         14 . A process according to  claim 13 , wherein the crystallinity is determined by birefringence screening.  
     
     
         15 . A pharmaceutical composition obtained by a process according to  claim 1 .  
     
     
         16 . A process for producing a pharmaceutical composition, which comprises: 
 (1) providing a plurality of containers;    (2) providing a plurality of excipient solutions;    (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound;    (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, the excipient being varied in different containers;    (5) incubating the mixture;    (6) determining onset of solid-state nucleation;    (7) selecting an excipient which is found to retard onset of solid-state nucleation; and    (8) producing a pharmaceutical composition comprising the pharmaceutical compound and the selected excipient.    
     
     
         17 . A pharmaceutical composition obtained by a process according to  claim 16 .  
     
     
         18 . A method for assessing excipient-mediated retardation of solid-state nucleation of a pharmaceutical compound, which method comprises: 
 (1) providing a plurality of containers;    (2) providing a plurality of excipient solutions;    (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound;    (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, a property of each mixture being varied in different containers;    (5) incubating the mixture;    (6) determining onset of solid-state nucleation; and    (7) ranking the property of the mixture according to time of onset of solid-state nucleation.    
     
     
         19 . A method for screening excipients that retard solid-state nucleation of a pharmaceutical compound, which method comprises: 
 (1) providing a plurality of containers;    (2) providing a plurality of excipient solutions;    (3) providing a plurality of compound solutions, each having dissolved therein a pharmaceutical compound;    (4) dispensing into each container one of the excipient solutions with one of the compound solutions so as to form an intimate mixture, the excipient being varied in different containers;    (5) incubating the mixture;    (6) determining onset of solid-state nucleation; and    (7) ranking the excipient according to time of onset of solid-state nucleation.    
     
     
         20 . A pharmaceutical composition comprising: 
 (a) a salt form of a drug having low solubility in gastric fluid conditions;    (b) a recrystallization/precipitation retardant; and    (c) a an optional enhancer;    wherein the composition retards recrystallization/precipitation of the drug for at least 5 minutes in gastric fluid conditions.    
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein the recrystallization/precipitation retardant is a surfactant.  
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein the surfactant has an interfacial tension of less than 10 dyne/cm or a surface tension of less then 42 dyne/cm.  
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the surfactant is a poloxamer.  
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein the poloxamer has an interfacial tension of less than 10 dyne/cm or surface tension less then 42 dyne/cm.  
     
     
         25 . The pharmaceutical composition according to  claim 21 , wherein the composition comprises an enhancer.  
     
     
         26 . The pharmaceutical composition according to  claim 22 , wherein the composition comprises a cellulose ester as an enhancer.  
     
     
         27 . The pharmaceutical composition according to  claim 23 , wherein the composition comprises HPC or HPMC as an enhancer.  
     
     
         28 . The pharmaceutical composition according to  claim 24 , wherein the composition comprises HPC as an enhancer.  
     
     
         29 . The composition according to  claim 26 , wherein recrystallization/precipitation is retarded for at least 10 minutes.  
     
     
         30 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 15 minutes.  
     
     
         31 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 20 minutes.  
     
     
         32 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 25 minutes.  
     
     
         33 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 30 minutes.  
     
     
         34 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 35 minutes.  
     
     
         35 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 40 minutes.  
     
     
         36 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 45 minutes.  
     
     
         37 . The composition according to  claim 29 , wherein recrystallization/precipitation is retarded for at least 60 minutes.  
     
     
         38 . The pharmaceutical composition according to  claim 20 , wherein the drug comprises a sulfonamide drug.  
     
     
         39 . The pharmaceutical composition according to  claim 38 , wherein the sulfonamide drug is a benzene sulfonamide.  
     
     
         40 . The pharmaceutical composition according to  claim 39 , wherein the benzene sulfonamide comprises celecoxib, deracoxib, valdecoxib, rofecoxib or eturicoxib.  
     
     
         41 . The pharmaceutical composition according to  claim 39 , wherein the benzene sulfonamide is in the form of an alkali metal or alkaline earth metal salt.  
     
     
         42 . The pharmaceutical composition according to  claim 20 , wherein the aqueous solubility of the drug is not more than 0.1 mg/ml when measured at 37° C.  
     
     
         43 . The pharmaceutical composition according to  claim 20 , wherein the aqueous solubility of the drug is not more than 10 mg/ml when measured at 37° C.  
     
     
         44 . A process for producing a pharmaceutical composition for delivering a supersaturated concentration of a drug having low aqueous solubility, which process comprises intimately mixing together components (a) (b) and (c) of  claim 20 .  
     
     
         45 . The process according to  claim 44 , wherein the drug comprises a sulfonamide drug.  
     
     
         46 . A process according to  claim 45 , wherein the sulfonamide drug is a benzene sulfonamide.  
     
     
         47 . The process according to  claim 46 , wherein wherein the benzene sulfonamide comprises celecoxib, deracoxib, valdecoxib, rofecoxib or eturicoxib.  
     
     
         48 . A process according to  claim 47 , wherein the benzene sulfonamide is in the form of an alkali metal or alkaline earth metal salt.  
     
     
         49 . The process according to  claim 44 , wherein the aqueous solubility of the drug is not more than 0.1 mg/ml when measured at 37° C.  
     
     
         50 . The process according to  claim 44 , wherein the aqueous solubility of the drug is not more than 10 mg/ml when measured at 37° C.  
     
     
         51 . The pharmaceutical composition according to  claim 20 , wherein the salt is an alkali metal or alkaline earth metal salt.  
     
     
         52 . The pharmaceutical composition according to  claim 52 , wherein the metal is sodium, potassium, lithium, calcium or magnesium.  
     
     
         53 . The pharmaceutical composition according to  claim 52 , wherein the salt is crystalline.  
     
     
         54 . The pharmaceutical composition according to  claim 20 , wherein: 
 (a) the bioavailability of the composition orally administered is at least 70%;    (b) the bioavailability of the composition orally administered is as least 80%;    (c) the bioavailability of the composition orally administered is as least 85%;    (d) the bioavailability of the composition orally administered is as least 90%;    (e) the bioavailability of the composition orally administered is as least 95%;    (f) the Cmax is at least 2 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (g) the Cmax is at least 3 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (h) the Cmax is at least 4 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (i) the Cmax is at least 5 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (j) the Cmax is at least 10 fold greater than a neutral form in vivo or in an in vitro dissolution assay; the Cmax is at least 2 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (k) the Cmax is at least 25 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (l) the Cmax is at least 50 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (m)the Cmax is at least 100 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (n) the Cmax is at least 250 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (o) the Cmax is at least 500 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (p) the Cmax is at least 750 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (q) the Cmax is at least 1000 fold greater than a neutral form in vivo or in an in vitro dissolution assay;    (r) the bioavailability of the composition is at least 50% greater than a neutral form;    (s) the bioavailability of the composition is at least 75% greater than a neutral form;    (t) the bioavailability of the composition is at least 2 fold that of a neutral form;    (u) the bioavailability of the composition is at least 3 fold that of a neutral form;    (v) the bioavailability of the composition is at least 4 fold that of a neutral form;    (w) the bioavailability of the composition is at least 5 fold that of a neutral form; or    (x) the bioavailability of the composition is at least 10 fold that of a neutral form.