Chronotherapeutic dosage forms containing glucocorticosteroid and methods of treatment

Abstract

A chronotherapeutic pharmaceutical formulation comprising a core containing an active agent (e.g., a drug) and a delayed release compression coating comprising a natural or synthetic gum applied onto the surface of the core.

What is claimed is:  
     
         1 . A delayed release oral solid dosage form comprising: 
 a core comprising a therapeutically effective amount of a glucocorticosteroid drug, and a delayed release material compression coated onto said core, said delayed release material comprising one or more natural or synthetic gums, said compression coating delaying the release of said drug from said dosage form until after a period of time from about 2 to about 18 hours after exposure of the dosage form to an aqueous solution.    
     
     
         2 . The delayed release oral solid dosage form of  claim 1 , wherein said glucocorticosteroid drug is selected from the group consisting of prednisolone, prednisone, cortisone, hydrocortisone, methylprednisolone, betametasone, dexamethasone, triamcinolone, pharmaceutically acceptable salts thereof, and mixtures thereof.  
     
     
         3 . The delayed release oral solid dosage form of  claim 1 , wherein said glucocorticosteroid drug is prednisolone.  
     
     
         4 . The delayed release oral solid dosage form of  claim 1 , wherein said one or more natural or synthetic gums are agglomerated with a saccharide material prior to being compression coated onto said core.  
     
     
         5 . The delayed release oral solid dosage form of  claim 1 , which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to an aqueous solution.  
     
     
         6 . The delayed release oral solid dosage form of  claim 1 , wherein said gums comprise a mixture of xanthan gum and locust bean gum.  
     
     
         7 . The delayed release oral solid dosage form of  claim 1 , wherein said delayed release material further comprises an ionizable gel strength enhancing agent selected from the group consisting of calcium sulfate, sodium chloride, potassium sulfate, sodium carbonate, lithium chloride, tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride, sodium bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium acetate, calcium lactate, magnesium sulfate, sodium fluoride, and mixtures thereof.  
     
     
         8 . The delayed release oral solid dosage form of  claim 7 , wherein said ionizable gel strength enhancing agent is calcium sulfate.  
     
     
         9 . The delayed release oral solid dosage form of  claim 1 , wherein said delayed release material further comprises a surfactant selected from the group consisting of anionic surfactants, cationic surfactants, amphoteric (amphipathic/amphophilic) surfactants, and non-ionic surfactants.  
     
     
         10 . The delayed release oral solid dosage form of  claim 1 , wherein said delayed release material further comprises a hydrophobic material.  
     
     
         11 . The delayed release oral solid dosage form of  claim 10 , wherein said hydrophobic material is selected from the group consisting of an alkylcellulose, a copolymer of acrylic and methacrylic acid esters, waxes, shellac, zein, hydrogenated vegetable oil, and mixtures thereof, in an amount effective to slow the hydration of said gelling agent when exposed to an environmental fluid.  
     
     
         12 . The delayed release oral solid dosage form of  claim 11 , wherein said hydrophobic material is ethylcellulose.  
     
     
         13 . The delayed release oral solid dosage form of  claim 4 , wherein said saccharide is selected from the group consisting of sucrose, dextrose, lactose, fructose, mannitol, and mixtures thereof.  
     
     
         14 . The delayed release oral solid dosage form of  claim 1 , wherein said core further comprises from about 5 to about 20 percent disintegrant, by weight.  
     
     
         15 . The delayed release oral solid dosage form of  claim 14 , wherein said disintegrant is selected from the group consisting of starch, veegum, crospovidone, cellulose, kaolin, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone, and mixtures thereof.  
     
     
         16 . The delayed release oral solid dosage form of  claim 14 , wherein said disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, crosslinked carboxy methyl cellulose, sodium starch glycolate, and mixtures thereof.  
     
     
         17 . The delayed release oral solid dosage form of  claim 1 , wherein said inner core further comprises an inert diluent selected from the group consisting of sucrose, dextrose, lactose, microcrystalline cellulose, fructose, xylitol, sorbitol, mannitol, starches, mixtures thereof.  
     
     
         18 . The delayed release oral solid dosage form of  claim 1 , wherein said inner core is an immediate release core.  
     
     
         19 . The delayed release oral solid dosage form of  claim 1 , wherein said inner core is further comprises a sustained release carrier.  
     
     
         20 . A delayed release oral solid dosage form comprising: 
 a core comprising a therapeutically effective amount of a glucocorticosteroid drug, and an agglomerated delayed release material compression coated onto said core, said agglomerated delayed release material comprising a gum selected from the group consisting of a homopolysaccharide, a heteropolysaccharide, and a mixture of a homopolysaccharide and a heteropolysaccharide, together with a pharmaceutically acceptable excipient, said compression coating delaying the release of said drug from said dosage form for a predetermined period of time after exposure of the dosage form to an aqueous solution.    
     
     
         21 . The delayed release oral solid dosage form of  claim 1 , wherein said heteropolysaccharide gum is in an amount of from about 20 to about 80 percent of the delayed release coating and said homopolysaccharide gum is in an amount of from about 80 to about 20 percent of the delayed release coating.  
     
     
         22 . The delayed release oral solid dosage form of  claim 21 , wherein said heteropolysaccharide gum is xanthan gum and said homopolysaccharide gum is locust bean gum.  
     
     
         23 . The delayed release oral solid dosage form of  claim 20 , wherein said glucocorticosteroid is prednisolone.  
     
     
         24 . The delayed release oral solid dosage form of  claim 20 , wherein said core further comprises an effective amount of disintegrant.  
     
     
         25 . A delayed release oral solid dosage form comprising: 
 a core comprising a therapeutically effective amount of a glucocorticosteroid drug and an effective amount of a disintegrant, and an agglomerated delayed release material compression coated onto said core, said agglomerated delayed release material consisting essentially of one or more natural or synthetic pharmaceutically acceptable gums and one or more optional pharmaceutically acceptable excipients, said compression coating delaying the release of said drug from said dosage form for a predetermined period of time after exposure of the dosage form to an aqueous solution.    
     
     
         26 . The delayed release oral solid dosage form of  claim 26 , wherein said core further comprises from about 5 to about 20 percent disintegrant, by weight.  
     
     
         27 . The delayed release oral solid dosage form of  claim 27 , wherein said disintegrant is selected from the group consisting of starch, veegum, crospovidone, cellulose, kaolin, microcrystalline cellulose, crosslinked polyvinyl pyrrolidone, and mixtures thereof.  
     
     
         28 . The delayed release oral solid dosage form of  claim 27 , wherein said disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, crosslinked carboxy methyl cellulose, sodium starch glycolate, and mixtures thereof.  
     
     
         29 . The delayed release oral solid dosage form of  claim 25  which delays the release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to an aqueous solution.  
     
     
         30 . The delayed release oral solid dosage form of  claim 25 , wherein said gums comprise a mixture of xanthan gum and locust bean gum.  
     
     
         31 . A delayed release oral solid dosage form comprising: 
 a core comprising a therapeutically effective amount of a glucocorticosteroid drug and a disintegrant, and a delayed release material compression coated onto said core, said delayed release material comprising one or more natural or synthetic gums, said compression coating delaying the release of said drug from said dosage form for a predetermined period of time after exposure of the dosage form to an aqueous solution, said disintegrant being included in said core in an amount effective to cause the release of at least about 50 percent of said drug into said aqueous solution within one hour after said predetermined period of time.    
     
     
         32 . The delayed release oral solid dosage form of  claim 31 , wherein said disintegrant comprises from about 5 to about 20 percent of said core, by weight.  
     
     
         33 . The delayed release oral solid dosage form of  claim 27 , wherein said disintegrant comprises from about about 0.1 to about 5 percent of said oral solid dosage form, by weight.  
     
     
         34 . The delayed release oral solid dosage form of  claim 32 , wherein said disintegrant is a superdisintegrant.  
     
     
         35 . The delayed release oral solid dosage form of  claim 34 , wherein said superdisintegrant is selected from the group consisting of croscarmellose sodium, crospovidone, crosslinked carboxy methyl cellulose, sodium starch glycolate, and mixtures thereof.  
     
     
         36 . The delayed release oral solid dosage form of  claim 34 , wherein said gums comprise a mixture of xanthan gum and locust bean gum.  
     
     
         37 . The delayed release oral solid dosage form of  claim 36 , wherein said xanthan gum and said locust bean gum are agglomerated with a saccharide material prior to compression coating onto said core.  
     
     
         38 . A delayed release oral solid tablet, comprising: 
 a tablet core comprising a therapeutically effective amount of a glucocorticosteroid drug, and a delayed release material compression coated onto said core, said delayed release material comprising one or more natural or synthetic gums, said gums comprising from about 6.5 percent to about 83 percent of the tablet by weight, said compression coating delaying the release of said drug from said dosage form for a period of time from about 2 to about 18 hours after exposure of the dosage form to an aqueous solution.    
     
     
         39 . The delayed release oral solid tablet of  claim 38 , wherein said tablet core further comprises from about 5 to about 20% superdisintegrant.  
     
     
         40 . A chronotherapeutic, delayed release oral solid dosage form comprising a core comprising from about 0.01 mg to about 40 mg glucocorticosteroid, and a delayed release material compression coated onto said core, said delayed release material comprising one or more natural or synthetic gums, said compression coating comprising from about 75 to about 94 percent by weight of the oral solid dosage form, and the ratio of the core to gum in said compression coating being from about 1:0.37 to about 1:5, by weight, said compression coating delaying the release of said glucocorticosteroid from said dosage form for a period of time from about 2 to about 18 hours after exposure of the dosage form to an aqueous solution.  
     
     
         41 . A method of preparing a chronotherapeutic oral solid dosage form of a glueocorticosteroid, comprising: 
 preparing a core comprising a therapeutically effective amount of a glucocorticosteroid and from about 5 to about 20% disintegrant, by weight of the core,    preparing a granulate of a delayed release material comprising one or more natural or synthetic gums,    compression coating said granulate onto said core, said compression coating delaying the release of said glucocorticosteroid from said dosage form until after a period of time from about 2 to about 18 hours after exposure of the dosage form to an aqueous solution.    
     
     
         42 . The method of  claim 41 , further comprising preparing said granulate of delayed release material by wet granulating one or more natural or synthetic gums together with at least one pharmaceutically acceptable excipient, and drying the resultant granulate to obtain agglomerated particles of said delayed release material.  
     
     
         43 . The method of  claim 42 , further comprising granulating said glucocorticosteroid, said disintegrant, and a pharmaceutically acceptable inert diluent prior to said compression coating step.  
     
     
         44 . The method of  claim 43 , wherein said disintegrant is a superdisintegrant incorporated into said core in an amount said disintegrant being included in said core in an amount effective to cause the release of at least about 50 percent of said glucocorticosteroid into said aqueous solution within one hour upon completion of the time period for said delayed release.  
     
     
         45 . A method of treating early morning inflammation or arthritis comprising: orally administering to a human at bedtime an oral solid dosage comprising a core comprising a therapeutically effective amount of a glucocorticosteroid; and a delayed release compression coating on said core comprising one or more natural or synthetic pharmaceutically acceptable gums; said compression coating delaying the release of said glucocortosteroid from said dosage form for a time period until at least about 4 hours after oral administration.  
     
     
         46 . The method of  claim 46 , wherein after oral administration of the dosage form, the glucocorticosteroid is not released from the dosage form for about 4 to about 12 hours.  
     
     
         47 . The method of  claim 46 , wherein after oral administration of the dosage form, the glucocorticosteroid is released over a time period of at least about 4 hours after the period of delay is completed.  
     
     
         48 . A method of chronotherapeutically treating arthritis, comprising orally administering the oral solid dosage form of  claim 1  to a human or animal at bedtime, which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to gastrointestinal fluid.  
     
     
         49 . A method of chronotherapeutically treating arthritis, comprising orally administering the oral solid dosage form of  claim 20  to a human or animal at bedtime, which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to gastrointestinal fluid.  
     
     
         50 . A method of chronotherapeutically treating arthritis, comprising orally administering the oral solid dosage form of  claim 25  to a human or animal at bedtime, which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to gastrointestinal fluid.  
     
     
         51 . A method of chronotherapeutically treating arthritis, comprising orally administering the oral solid dosage form of  claim 31  to a human or animal at bedtime, which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to gastrointestinal fluid.  
     
     
         52 . A method of chronotherapeutically treating arthritis, comprising orally administering the oral solid dosage form of  claim 38  to a human or animal at bedtime, which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to gastrointestinal fluid.  
     
     
         53 . A method of chronotherapeutically treating arthritis, comprising orally administering the oral solid dosage form of  claim 40  to a human or animal at bedtime, which delays release of said glucocorticosteroid until at least about 4 hours after exposure of the dosage form to gastrointestinal fluid.