Solid drug form of n-(2,6-bis(1-methylethyl)phenyl)-n'-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride and compositions, methods and kits related thereto

Abstract

A novel solid drug form of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride (also referred to “ATR-101”) suitable for oral dosing, and to compositions, methods and kits relating thereto. ATR-101 has particular utility in the treatment of, for example, aberrant adrenocortical cellular activity, including adrenocortical carcinoma (ACC), congenital adrenal hyperplasia (CAH) and Cushing's syndrome.

1 . A solid drug form of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride having a particle size distribution as follows: d(0.1) of about 2 μm, d(0.5) of about 12 μm, and a d(0.9) of about 49 μm. 
     
     
         2 . A solid drug form of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride having a d(0.5) particle size distribution ranging from 5 to 20 μm. 
     
     
         3 . The solid drug form of  claim 2  wherein the d(0.5) particle size distribution ranges from 6 to 18 μm. 
     
     
         4 . The solid drug form of  claim 2  wherein the d(0.5) particle size distribution ranges from 8 to 16 μm. 
     
     
         5 . The solid drug form of  claim 2  wherein the d(0.5) particle size distribution ranges from 10 to 14 μm. 
     
     
         6 . The solid drug form of any one of  claims 2 - 5  wherein the d(0.1) particle size distribution is greater than 1 μm. 
     
     
         7 . The solid drug form of any one of  claims 2 - 6  wherein the d(0.9) particle size distribution is less than 60 μm. 
     
     
         8 . A solid drug form of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride having differential scanning calorimetry (DSC) onset at about 228.28° C. and endotherm at about 230.93° C. 
     
     
         9 . A solid drug form of N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride having a purity in excess of 98% (w/w). 
     
     
         10 . An oral dosage product comprising the solid drug form of any one of  claims 1 - 9 . 
     
     
         11 . The oral dosage product of  claim 10 , wherein the product is a capsule containing from 25 to 750 mg of the solid drug form. 
     
     
         12 . The oral dosage product of  claim 10 , wherein the product is a tablet or a pill containing from 25 to 750 mg of the solid drug form. 
     
     
         13 . A solid pharmaceutical composition in a unit dosage form suitable for oral administration, comprising N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)methyl)urea hydrochloride (ATR-101) in combination with one or more pharmaceutically acceptable carriers or excipients, wherein ATR-101 is present in the unit dosage form at a level ranging from about 250-750 mg as measured as the free base form of ATR-101. 
     
     
         14 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 is present in the unit dosage form at a level of about 500 mg as measured as the free base form of ATR-101. 
     
     
         15 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 is present in the unit dosage form at a level of about 700 mg as measured as the free base form of ATR-101. 
     
     
         16 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 50% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form. 
     
     
         17 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 60% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form. 
     
     
         18 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 65% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form. 
     
     
         19 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 is present in the unit dosage form at a level at or in excess of 70% by weight, as measured as the free base form of ATR-101, of the total weight of the unit dosage form. 
     
     
         20 . The solid pharmaceutical composition of  claim 13 , wherein ATR-101 has a particle size distribution as follows: d(0.1) of about 2 μm, d(0.5) of about 12 μm, and a d(0.9) of about 49 μm. 
     
     
         21 . The solid pharmaceutical composition of  claim 13  wherein the unit dosage form is formulated for dosing once daily. 
     
     
         22 . The solid pharmaceutical composition of  claim 13  wherein the unit dosage form is formulated for dosing twice daily. 
     
     
         23 . The solid pharmaceutical composition of  claim 13 , wherein the unit dosage form is formulated for dosing three or four times daily. 
     
     
         24 . The solid pharmaceutical composition of  claim 13 , wherein the one or more pharmaceutically acceptable carriers or excipients are selected from one or more diluents, binding agents, adhesives, disintegrants, wetting agents, lubricants, anti-adherents, glidants, and surfactants. 
     
     
         25 . The solid pharmaceutical composition of  claim 13  in tablet form. 
     
     
         26 . The solid pharmaceutical composition of  claim 25 , wherein the tablet has a disintegration time of less than 30 minutes. 
     
     
         27 . The solid pharmaceutical composition of  claim 25 , wherein the tablet has a friability of less than 0.5%. 
     
     
         28 . The solid pharmaceutical composition of  claim 25 , wherein the tablet is a coated tablet. 
     
     
         29 . A method of administering a solid pharmaceutical composition of any one of  claims 13 - 28 , comprising orally administering to a subject in need thereof ATR-101 in unit dosage form. 
     
     
         30 . The method of administering the solid pharmaceutical composition of  claim 29 , further comprising oral administration of an acidic agent at or near the time of oral administration of ATR-101 in unit dosage form. 
     
     
         31 . The method of  claim 30 , wherein the acidic agent is an acidic aqueous solution. 
     
     
         32 . The method of  claim 31 , wherein the acidic aqueous solution has a pH in the range of 2.0 to 3.5, inclusive. 
     
     
         33 . The method of  claim 31 , wherein the acidic aqueous solution has a pH in the range of 2.2 to 3.0, inclusive. 
     
     
         34 . The method of  claim 31 , wherein the acidic aqueous solution has a pH in the range of 2.3 to 2.7, inclusive. 
     
     
         35 . The method of  claim 31 , wherein the acidic aqueous solution is a non-diet cola beverage. 
     
     
         36 . The method of  claim 30 , wherein the acid agent is in a solid dosage form. 
     
     
         37 . The method of  claims 36 , wherein the solid dosage form is a solid dosage form of citric acid. 
     
     
         38 . The method of  claim 29 , wherein the subject has a non-cancerous disorder. 
     
     
         39 . The method of  claim 38 , wherein the subject has a non-cancerous endocrine disorder. 
     
     
         40 . The method of  claim 38 , wherein the subject has Cushing's syndrome, congenital adrenal hyperplasia and/or 21-hydroxylase deficiency. 
     
     
         41 . The method of  claim 29 , wherein the subject has a cancerous disorder. 
     
     
         42 . The method of  claim 41 , wherein the subject has ACC. 
     
     
         43 . The method of  claim 41 , wherein the subject has prostate cancer. 
     
     
         44 . A method for treating adrenocortical carcinoma in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid drug form of  claims 1 - 9 , the oral dosage product of  claims 10 - 12 , or the solid pharmaceutical composition of  claims 13 - 28 . 
     
     
         45 . A method for treating Cushing's syndrome in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid drug form of  claims 1 - 9 , the oral dosage product of  claims 10 - 12 , or the solid pharmaceutical composition of  claims 13 - 28 . 
     
     
         46 . A method for treating benign adenoma, increased hormone production, adrenocortical carcinoma, congenital adrenal hyperplasia, excess cortisol production, symptoms associated with excess cortisol production, hyperaldosteronism or 21-hydroxylase deficiency in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid drug form of  claims 1 - 9 , the oral dosage product of  claims 10 - 12 , or the solid pharmaceutical composition of  claims 13 - 28 . 
     
     
         47 . A method for reducing adrenocortical tumor size in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the solid drug form of  claims 1 - 9 , the oral dosage product of  claims 10 - 12 , or the solid pharmaceutical composition of  claims 13 - 28 . 
     
     
         48 . A kit comprising a plurality of oral unit dosage forms of the solid pharmaceutical composition of any one of  claims 13 - 28  in combination with an acidic agent for co-administration, or instructions for co-administration with an acidic agent, at or near the time of oral administration of ATR-101 in unit dosage form. 
     
     
         49 . A method for making N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea hydrochloride at a purity level in excess of 98% (w/w), comprising the step of employing crystalized 2,6-diisopropylanaline hydrochloride salt as an intermediate in the synthesis. 
     
     
         50 . The method of  claim 49  wherein 2,6-diisopropylanaline hydrochloride salt is employed in an isocyanate coupling step to form N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)cyclopentyl)methyl)urea as the free base. 
     
     
         51 . The method of  claim 50 , wherein the isocyanate of the isocyanate coupling step is generated in situ. 
     
     
         52 . N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)methyl)urea hydrochloride at a purity level in excess of 98% (w/w) made according to the method of any one  claims 49 - 51 . 
     
     
         53 . N-( 2 , 6 -bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)methyl)urea hydrochloride at a purity level in excess of 98% (w/w). 
     
     
         54 . N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)methyl)urea hydrochloride of  claim 53  at a purity level in excess of 98.5% (w/w). 
     
     
         55 . N-(2,6-bis(1-methylethyl)phenyl)-N′-((1-(4-(dimethylamino)phenyl)-cyclopentyl)methyl)urea hydrochloride of  claim 53  at a purity level in excess of 99% (w/w).