Prostacyclin analogue formulations

Abstract

The present invention relates to an injectable pre-formulation comprising:a) at least one of a mono-, di- or tri-acyl lipid and/or a tocopherol;b) optionally at least one phospholipid;c) at least one biocompatible, organic solvent; andd) at least one prostacyclin analogue or a salt thereof;wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid. Such compositions may additionally comprise polar co-solvents. Methods of treatment, particularly for management of pulmonary artery hypertension (PAH), severe PAH, Raynaud's disease, ischemia and related conditions are provided, as well as corresponding uses of the compositions. Administration devices comprising the formulations and kits comprising the devices are also provided.

1 - 43 . (canceled) 
     
     
         44 . A pre-formulation comprising:
 a) at least one of a mono-, di- or tri-acyl lipid and/or a tocopherol;   b) optionally at least one phospholipid;   c) at least one biocompatible, organic solvent; and   d) at least one prostacyclin analogue or a salt thereof;   wherein the pre-formulation forms, or is capable of forming, at least one liquid crystalline phase structure upon contact with excess aqueous fluid.   
     
     
         45 . The pre-formulation of  claim 44 , wherein component d) comprises a prostacyclin analogue containing a 3,4-cis fused cyclopentane ring, an OH group at the 1-position of said cyclopentane ring and a C1-10 group at the 2-position of the cyclopentane ring,
 wherein the prostacyclin analogue has a molecular weight of less than 500 g/mol and is not a polypeptide.   
     
     
         46 . The pre-formulation of  claim 44  comprising 0.1 to 10% of component d) based on the prostacyclin analogue free acid. 
     
     
         47 . The pre-formulation of  claim 44 , wherein component d) comprises treprostinil (TPN) or a salt thereof. 
     
     
         48 . The pre-formulation of  claim 44 , wherein component a) comprises a neutral diacyl and/or monoacyl lipid. 
     
     
         49 . The pre-formulation of  claim 44 , wherein component a) comprises a diacyl glycerol. 
     
     
         50 . The pre-formulation of  claim 44 , comprising 20 to 80 wt % component a). 
     
     
         51 . The pre-formulation of  claim 44 , wherein component b) comprises a phosphatidyl choline (PC). 
     
     
         52 . The pre-formulation of  claim 44  comprising 30 to 60 wt % component b). 
     
     
         53 . The pre-formulation of  claim 44 , wherein component c) comprises at least one solvent selected from the group consisting of: alcohols, amines, amides, sulphoxides esters, and mixtures thereof. 
     
     
         54 . The pre-formulation of  claim 53  wherein component c) comprises ethanol or mixtures of ethanol and propylene glycol. 
     
     
         55 . The pre-formulation of  claim 53  wherein component c) comprises a mono-alcoholic solvent and a sulphoxide or an amide. 
     
     
         56 . The pre-formulation of  claim 44 , wherein component c) is present at a level of 1 to 30% by weight. 
     
     
         57 . The pre-formulation of  claim 44 , wherein the ratio of components a:b is in the range of 40:60 to 60:40. 
     
     
         58 . The pre-formulation of  claim 44 , wherein:
 component a) comprises soy phosphatidylcholine (PC);   component b) comprises glycerol dioleate (GDO);   component c) comprises ethanol; and   component d) comprises treprostinil (TPN) or a salt thereof.   
     
     
         59 . The pre-formulation of  claim 58  further comprising a co-solvent selected from the group consisting of propylene glycol (PG), dimethylsulphoxide (DMSO), and N-methyl-pyrrolidone (NMP), wherein the ratio of ethanol:co-solvent is in the range of 30:70 to 70:30 (w/w). 
     
     
         60 . The pre-formulation of  claim 58  wherein component d) comprises treprostinil sodium (TPN(Na)). 
     
     
         61 . A method of sustained administration of a prostacyclin analogue to a human or non-human mammalian subject, comprising administering to the subject the pre-formulation of  claim 44 . 
     
     
         62 . A medicament comprising the pre-formulation of  claim 44 . 
     
     
         63 . A method for the treatment of a human or non-human mammalian subject comprising administering to the subject the pre-formulation of  claim 44 . 
     
     
         64 . The method of  claim 63  for the treatment of a human or non-human mammalian subject in need thereof to treat at least one condition selected from pulmonary artery hypertension (PAH), severe PAH, Raynaud's disease, ischemia, and related conditions. 
     
     
         65 . The medicament of  claim 62  for use in the in vivo formation of a depot for treatment of at least one condition selected from pulmonary artery hypertension (PAH), severe PAH, Raynaud's disease, ischemia, and related conditions. 
     
     
         66 . A pre-filled administration device containing the pre-formulation of  claim 44 . 
     
     
         67 . A kit comprising an administration device as claimed in  claim 66 .