Pharmaceutical compositions for inhibiting inflammatory cytokines

Abstract

Pharmaceutical compositions comprising specific tetrapeptides, for use in reducing the release or inhibiting the activity of inflammatory cytokines and mediator and treatment of diseases and disorders associated with these cytokines and mediators.

1 . A method of treating an inflammatory disease or disorder selected from the group consisting of: an eye inflammatory disease or disorder, an ear inflammatory disease or disorder, a lung inflammatory disease or disorder, a bowel inflammatory disease or disorder, or an inflammatory autoimmune disease or disorder, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of a tetrapeptide according to Formula I: pGlu-X 1 -X 2 -X 3 —OH, or a pharmaceutically acceptable salt or derivative thereof, wherein X 1  is selected from the group consisting of Asn and Thr; X 2  is selected from the group consisting of Trp, Phe and Tyr; and X 3  is selected from the group consisting of Lys, Lys derivative and Thr, thereby treating the inflammatory disease or disorder. 
     
     
         2 . The method of  claim 1 , wherein administration is via a route selected from the group consisting of topical, ophthalmic, oral, nasal, and parenteral administration. 
     
     
         3 . The method of  claim 1 , wherein the eye inflammatory disease or disorder is selected from the group consisting of uveitis, dry eye syndrome, inflammatory symptoms associated with an infectious eye disease, an allergic eye disease, keratitis, conjunctivitis, meibomian gland dysfunction and Sjogren syndrome. 
     
     
         4 . The method of  claim 1 , wherein the inflammatory autoimmune disease or disorder is selected from the group consisting of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Sjogren syndrome and lupus. 
     
     
         5 . The method of  claim 1 , wherein the bowel inflammatory disease or disorder is selected from the group consisting of Crohn's disease and ulcerative colitis. 
     
     
         6 . The method of  claim 1 , wherein the lung inflammatory disease or disorder is selected from the group consisting of asthma, bronchitis, pleurisy, alveolitis, vasculitis, pneumonia, chronic bronchitis, bronchiectasis, diffuse panbronchiolitis, hypersensitivity pneumonitis, idiopathic pulmonary fibrosis and cystic fibrosis. 
     
     
         7 . The method of  claim 1 , wherein the ear inflammatory disease or disorder is selected from the group consisting of inflammatory symptoms associated with ear infection, otitis media, otitis externa, mastoiditis and otomastoiditis. 
     
     
         8 . The method of  claim 1 , wherein the derivative comprises an alkyl group attached via an amide bond to an amino group of a side chain or a terminal amine of the tetrapeptide. 
     
     
         9 . The method of  claim 8 , wherein the alkyl is a C 4  to C 30  alkyl. 
     
     
         10 . The method of  claim 9 , wherein the alkyl is a C 8  alkyl (octanoyl), attached to the side chain of a Lys residue. 
     
     
         11 . The method of  claim 1 , wherein the tetrapeptide is selected from the group consisting of pGlu-Asn-Trp-Lys-OH (SEQ ID NO: 3) and pGlu-Asn-Trp-Thr-OH (SEQ ID NO: 2), or a pharmaceutically acceptable salt or derivative thereof, wherein the derivative is selected from the group consisting of aliphatic ester of the carboxyl group, amide of the carboxyl group, N-acyl derivatives of free amino group, and O-acyl derivative of free hydroxyl group. 
     
     
         12 . The method of  claim 11 , wherein the tetrapeptide is selected from the group consisting of pGlu-Asn-Trp-Lys(Octanoyl)-OH (SEQ ID NO: 1), pGlu-Asn-Trp-Thr-OH (SEQ ID NO: 2), or a pharmaceutically acceptable salt or derivative thereof. 
     
     
         13 . The method of  claim 11 , wherein the pharmaceutically acceptable salt is a sodium salt of the tetrapeptide. 
     
     
         14 . The method of  claim 13 , wherein the tetrapeptide is the sodium salt of a peptide having a sequence as set forth in SEQ ID NO: 1. 
     
     
         15 . The method of  claim 13 , wherein the tetrapeptide is the sodium salt of a peptide having a sequence as set forth in SEQ ID NO: 2. 
     
     
         16 . The method of  claim 1 , wherein the peptide is administered in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. 
     
     
         17 . The method of  claim 16 , wherein the pharmaceutical composition has a pH in the range of about 4 to about 8. 
     
     
         18 . The method of  claim 16 , wherein the pharmaceutical composition is formulated for topical administration as a cream, an ointment, a paste, a lotion, a gel or in the form of eyedrops. 
     
     
         19 . The method of  claim 16 , wherein the pharmaceutical composition is formulated as a cream comprising 0.1-5% w/w of the tetrapeptide, derivative or pharmaceutically acceptable salt. 
     
     
         20 . An isolated sodium salt of a tetrapeptide having a sequence as set forth in SEQ ID NO: 1.