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
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).