Sterilisation of s-nitrosothiols

Abstract

This invention provides a method of sterilising an S-nitrosothiol, for example S-nitrosoglutathione, without reduction of purity by more than about 5.0% through degradation. The invention allows sterile S-nitrosothiol or a sterile pharmaceutical pre-composition comprising S-nitrosothiol, wherein the S-nitrosothiol is in dry solid form, to be produced. The sterile pharmaceutical pre-composition is mixed with one or more diluents, excipients, carriers, additional active agents, or any combination thereof, for example sterile saline, to prepare a pharmaceutical composition of S-nitrosothiol for use.

1 . A sterile S-nitrosothiol or a sterile pharmaceutical pre-composition comprising S-nitrosothiol, wherein the S-nitrosothiol is in dry solid form and the sterile S-nitrosothiol or sterile pharmaceutical pre-composition has an S-nitrosothiol purity of at least about 95% and a sterility assurance level (SAL) of 10 −6  or lower. 
     
     
         2 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , wherein the sterile S-nitrosothiol or the sterile pharmaceutical pre-composition comprising S-nitrosothiol is in a dry sterile environment in a sealed container. 
     
     
         3 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 2 , wherein the seal is arranged so that the container can be opened, for example pierced, under sterile conditions to allow the sterile S-nitrosothiol or a sterile pharmaceutical pre-composition comprising S-nitrosothiol to be formulated with other desired ingredients to make a final pharmaceutical composition for administration. 
     
     
         4 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 2 , wherein the seal is arranged so that a sterile liquid can be introduced into the container, for example using a syringe provided with a hollow needle, to dissolve or suspend the sterile dry solid S-nitrosothiol or the sterile pharmaceutical pre-composition in situ within the container. 
     
     
         5 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , wherein the said material has been sterilised by exposure to a sterilising dose of ionising radiation in an environment sealed from external contamination. 
     
     
         6 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 2 , wherein the said material has been sterilised by exposure to a sterilising dose of ionising radiation in the said sealed container. 
     
     
         7 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , wherein the S-nitrosothiol has an S-nitrosothiol purity of at least about 98.0%, for example at least about 98.5%. 
     
     
         8 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , wherein the amount of the S-nitrosothiol or the pharmaceutical pre-composition comprising S-nitrosothiol contains a known weight of S-nitrosothiol selected according to an ultimate desired medical use. 
     
     
         9 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , wherein the S-nitrosothiol is selected from: S-nitrosoglutathione (GSNO); S-nitroso-L-cysteine (CySNO); S-nitroso-N-acetyl-cysteine (SNAC); S-nitroso-L-cysteinemethyl-ester (CMESNO); S-nitroso-D,L-penicillamine (PSNO); S-nitroso-N-acetyl-D,L-penicillamine (SNAP); S-nitroso-N-acetylcysteamine (ACSNO); S-nitroso-beta-mercaptosuccinic acid; 1-S-nitrosothio-beta-D-galactopyranose; S-nitrosothioglycerol; S-nitrosohomocysteine; S-nitrosocysteinylglycine; S-nitrosocaptopril; alkyl, cycloalkyl or aryl thionitrites, such as, for example, methyl thionitrite, ethyl thionitrite, n-propyl thionitrite, s-propyl thionitrite, n-butyl thionitrite, s-butyl thionitrite, tert-butyl thionitrite, n-pentyl thionitrite, n-hexyl thionitrite, cyclohexyl thionitrite, phenyl thionitrite; S-nitroso derivatives of cysteine-containing proteins, oligo- and poly-peptides, for example S-nitrosoalbumin, poly-S-nitrosoalbumin or S-nitrosohemoglobin; and any derivative thereof; and a salt of any of the foregoing. 
     
     
         10 . The sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , wherein the S-nitrosothiol is S-nitrosoglutathione. 
     
     
         11 . A kit comprising a container or containers containing sterile the sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , together with instructions for mixing the sterile S-nitrosothiol or a sterile pharmaceutical pre-composition comprising S-nitrosothiol with one or more sterile pharmaceutical diluents, excipients, carriers, additional active agents, or any combination thereof, to obtain a pharmaceutical composition for a pharmaceutical use containing S-nitrosothiol in a desired concentration. 
     
     
         12 . A method for preparing a sterile pharmaceutical composition for human or veterinary use, comprising mixing the sterile S-nitrosothiol or sterile pre-composition containing S-nitrosothiol of  claim 1  with one or more sterile pharmaceutical diluents, excipients, carriers, additional active agents, or any combination thereof, to obtain a pharmaceutical composition for a pharmaceutical use containing S-nitrosothiol in a desired concentration. 
     
     
         13 . A pharmaceutical composition comprising a desired concentration of the sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1  mixed with one or more sterile pharmaceutical diluents, excipients, carriers, additional active agents, or any combination thereof. 
     
     
         14 . A method of treating or preventing a disease or disorder of a human or animal subject which responds to S-nitrosothiol or NO therapy, said method comprising administering the sterile S-nitrosothiol or sterile pharmaceutical pre-composition comprising S-nitrosothiol of  claim 1 , to a human or animal subject in need thereof. 
     
     
         15 . The method of  claim 14 , the method comprising administering a pharmaceutical composition comprising the sterile S-nitrosothiol or sterile pre-composition containing S-nitrosothiol mixed with one or more sterile pharmaceutical diluents, excipients, carriers, additional active agents, or any combination thereof. 
     
     
         16 . The method of  claim 14 , wherein the sterile S-nitrosothiol or a sterile pharmaceutical pre-composition comprising S-nitrosothiol results in inducing arterial or venous smooth muscle relaxation, reducing augmentation index, reducing augmentation pressure, reducing arterial stiffness, inhibiting platelet aggregation, inducing T cell apoptosis or activating guanylate cyclase in the human or animal subject in need thereof. 
     
     
         17 . The method of  claim 14 , wherein the disease or disorder which responds to S-nitrosothiol or NO therapy is selected from pre-eclampsia, severe pre-eclampsia, eclampsia, HELLP syndrome, organ transplantation perfusion, organ dialysis, post-operative conditions of balloon angioplasty, acute myocardial infarction, unstable angina, cerebral embolism, hypertension, atherosclerosis, restenosis, ischemia and heart failure, other cardiovascular proliferative, inflammatory, contractile and hypertensive disorders, and pre-conditioning related disorders of the heart and brain, oesophageal spasm, biliary spasm, colic and other motility and smooth muscle disorders of the gastrointestinal tract, erectile dysfunction, stroke, bronchial constriction, cystic fibrosis, pneumonia, asthma, pulmonary fibrosis, and other pulmonary disorders involving diminished gas exchange or inflammation, as well as infectious diseases of viral, bacterial and other origin, disorders of red blood cells characterised by S-nitrosothiol deficiency, abnormal rheology or impaired vasodilation, and thrombotic disorders.