Pharmaceutical compositions for glucocorticoid replacement therapy

Abstract

The invention relates to glucocorticoid replacement therapy and provides pharmaceutical compositions and kits designed to deliver one or more glucocorticoids to a subject in need thereon in a manner that results in serum levels of the glucocorticoid that essentially mimic that of a healthy subject for a clinically relevant period of time. The pharmaceutical compositions and kits are prepared in such a way that a first part of one or more glucocorticoids is substantially immediately released and a second part of one or more glucocorticoids is released over an extended period of time of at least about 8 hours. The invention also relates to a method for treating diseases requiring glucocorticoid treatment such as in subjects having a glucocorticoid deficiency disorder.

1 .- 111 . (canceled) 
     
     
         112 . A pharmaceutical tablet composition for the treatment of a glucocorticoid deficiency disorder comprising:
 (a) 1-80 mg of hydrocortisone (HC) comprised in an extended release (ER) tablet core and an immediate release (IR) coating on said tablet core,   (b) said extended release tablet core comprising hydrocortisone, one or more of a filler or binder selected from the group consisting of hydroxypropylmethylcellulose, microcrystalline cellulose and starch or modified starch, a colloidal silica glidant, and a magnesium stearate lubricant, the amount of hydrocortisone present in said extended release core is 60% to 80% of the total amount of hydrocortisone present in said dosage form and is released over an extended period of time of at least 8 hours; and   (c) said immediate release coating material comprising hydrocortisone and at least one coating material selected from the group consisting of hydroxypropylmethylcellulose, polyvinylalcohol, polyethylene glycol, titanium dioxide and talc, with the amount of hydrocortisone present in said immediate release coating material being 20% to 40% of the total amount of hydrocortisone in said dosage form and determined as the amount of hydrocortisone released 1 hour after start of testing of the unit dosage form in an in vitro dissolution test according to USP employing USP Dissolution Apparatus No. 2. (paddle); 50 rpm and simulated intestinal fluid without enzymes as dissolution medium, wherein at least 50% of the hydrocortisone in the coating is released within the first 45 min of the dissolution test.   
     
     
         113 . A pharmaceutical tablet composition according to  claim 112 , wherein at least 50% of the hydrocortisone of the tablet coating is released within the first 30 min of the dissolution test. 
     
     
         114 . A pharmaceutical tablet composition according to  claim 112 , wherein the hydrocortisone of the tablet core is released over an extended period of time of at least 10 hours. 
     
     
         115 . A pharmaceutical tablet composition according to  claim 114 , wherein the release is determined in the dissolution test as defined in claim  1 . 
     
     
         116 . A pharmaceutical tablet composition according to  claim 112 , wherein at least 50% of hydrocortisone in the dosage form is released within 10 hours after start of the dissolution test defined in claim  1 , wherein at least 80% of the hydrocortisone in the dosage form is released within 24 hours after start of the dissolution test defined in claim  1 . 
     
     
         117 . A pharmaceutical tablet composition according to  claim 112 , wherein from 3 to 15% of the hydrocortisone contained in the tablet core is released per hour during a time period of from 1 to 8 hours after start of the dissolution test as defined in claim  1 . 
     
     
         118 . A pharmaceutical tablet composition according to  claim 112 , wherein
 (i) from 3 to 15% of the hydrocortisone contained in the tablet core is released per hour during a time period of from 1 to 6 hours,   ii) from 3 to 10% of the hydrocortisone contained in the tablet core is released per hour during a time period of from 6 to 10 hours, and   iii) from 3 to 7.5% of the hydrocortisone contained in the tablet core is released per hour during a time period of from 10 to 12 hours after start of the dissolution test as defined in claim  1 .   
     
     
         119 . A pharmaceutical composition according to any of claims 112 in unit dosage form. 
     
     
         120 . A method for the treatment of a glucocorticoid deficiency disorder in a patient in need of said treatment, comprising administering to said patient a therapeutically effective amount of a pharmaceutical tablet composition according to  claim 112 . 
     
     
         121 . The method according to  claim 120 , wherein said pharmaceutical tablet composition is administered once daily in the morning.