METHODS AND COMPOSITIONS FOR TREATING PULMONARY HYPERTENSION
Inhalable compositions for treating pulmonary hypertension comprising treprostinil, derivative thereof or analogs thereof and a method for treating pulmonary arterial hypertension and/or idiopathic pulmonary fibrosis are disclosed herein. Methods of manufacturing pharmaceutical compositions are also disclosed. Compositions are based on diketopiperazine powders for pulmonary inhalation.
1 . A process for making an inhalable dry powder composition comprising,
preparing a suspension of microcrystalline particles of (E)-3,6-bis[4-(N-carbonyl 2-propenyl)amidobutyl]-2,5-diketopiperazine in an aqueous ammonia solution and combining an acetic acid solution in a high shear mixer at a temperature ranging from 13° C. to about 20° C. while mixing in a high shear mixer to form a suspension;
washing the suspension in water; pelletizing the suspension in a cryogranulator, and drying the suspension in a lyophilizer to collect the microcrystalline particles of the diketopiperazine;
resuspending the microcrystalline particles of the diketopiperazine in in a solution of deionized water and ethanol; preparing a hydrophobic compound in in a solution of about 70% to about 100% ethanol, and adding the solution to the suspension with mixing and drying the suspension.
2 . The process of claim 1 , wherein the hydrophobic compound is a prostaglandin.
3 . The process of claim 2 , wherein the prostaglandin is treprostinil, a derivative thereof or an analog thereof.
4 . The process of claim 1 , wherein the resuspending step comprises dried crystalline particles of a diketopiperazine in a solution of deionized water and an alcohol that contains from about 0.2% to about 2% solid in the suspension, or from about 1% to about 4% solid in the suspension, or from about 1% to about 10% solid in the suspension.
5 . An inhalable dry powder composition made by the process of claim 1 .
6 . The inhalable dry powder composition of claim 5 , wherein the hydrophobic compound is a prostaglandin.
7 . The inhalable dry powder composition of claim 6 , wherein the prostaglandin is treprostinil, a derivative thereof or an analog thereof.
8 . A cartridge comprising an inhalable dry powder composition made by the process of claim 1 .
9 . The cartridge of claim 8 , wherein the hydrophobic compound is a prostaglandin.
10 . The cartridge of claim 9 , wherein the prostaglandin is treprostinil, a derivative thereof or an analog thereof.
11 . An inhaler comprising a hydrophobic compound made by the process comprising,
preparing a suspension of microcrystalline particles of (E)-3,6-bis[4-(N-carbonyl 2-propenyl)amidobutyl]-2,5-diketopiperazine in an aqueous ammonia solution and combining an acetic acid solution in a high shear mixer at a temperature ranging from 13° C. to about 20° C. while mixing in a high shear mixer to form a suspension;
washing the suspension in water; pelletizing the suspension in a cryogranulator, and drying the suspension in a lyophilizer to collect the microcrystalline particles of the diketopiperazine;
resuspending the microcrystalline particles of the diketopiperazine in in a solution of deionized water and ethanol; preparing the hydrophobic compound in in a solution of about 70% to about 100% ethanol, and adding the solution to the suspension with mixing and drying the suspension.
12 . The inhaler of claim 11 , wherein the hydrophobic compound is a prostaglandin.
13 . The inhaler of claim 12 , wherein the prostaglandin is treprostinil, a derivative thereof or an analog thereof.
14 . The inhaler of claim 11 , wherein the resuspending step comprises dried crystalline particles of a diketopiperazine in a solution of deionized water and an alcohol that contains from about 0.2% to about 2% solid in the suspension, or from about 1% to about 4% solid in the suspension, or from about 1% to about 10% solid in the suspension.
15 . A method of treating pulmonary hypertension comprising administering to a patient in need of treatment an inhalable, substantially crystalline dry powder composition comprising a treprostinil dose in an amount of up to 200 μg and one or more pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier and/or excipient, wherein said administering comprises at least one to four inhalations per day.
16 . The method of claim 15 , wherein the substantially crystalline dry powder composition comprises a diketopiperazine.
17 . The method of claim 15 , wherein the diketopiperazine is (E)-3,6-bis[4-(N-carbonyl-2-propenyl)amidobutyl]-2,5-diketopiperazine.