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

Patent metadata

Field	Value
Publication number	US-12151998-B2
Application number	US-202117359249-A
Country	US
Kind code	B2
Filing date	Jun 25, 2021
Priority date	Sep 26, 2014
Publication date	Nov 26, 2024
Grant date	Nov 26, 2024

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.

First claim

The invention claimed is:

1. 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, 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.

2. The solid pharmaceutical composition of claim 1 , 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.

3. The solid pharmaceutical composition of claim 1 , 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.

4. The solid pharmaceutical composition of claim 1 , 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.

5. The solid pharmaceutical composition of claim 1 , 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.

6. The solid pharmaceutical composition of claim 1 wherein the unit dosage form is formulated for dosing once daily.

7. The solid pharmaceutical composition of claim 1 wherein the unit dosage form is formulated for dosing twice daily.

8. The solid pharmaceutical composition of claim 1 , wherein the unit dosage form is formulated for dosing three or four times daily.

9. The solid pharmaceutical composition of claim 1 , 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.

10. The solid pharmaceutical composition of claim 1 in tablet form.

11. The solid pharmaceutical composition of claim 10 , wherein the tablet has a disintegration time of less than 30 minutes.

12. A kit comprising a plurality of oral unit dosage forms of the solid pharmaceutical composition of claim 1 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.

Assignees

• Univ Michigan Regents

Inventors

• Hunt Iii Stephen Warren
• Phillips Martin Douglas
• Matunas Robert
• Chen Herman
• Betancourt Aimesther
• Uzarama Charles
• Thibert Roch

Classifications

• C07C273/1809

  with formation of the N-C(O)-N moiety · CPC title

• A61K31/17

  having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64) · CPC title

• A61K9/2059

  Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• A61K9/2018

  Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates · CPC title