Use of Calcitonin for the Treatment of RA

Abstract

The present invention relates to a novel use of calcitonin in rheumatoid arthritis, and to methods of treating and/or preventing rheumatoid arthritis and conditions associated therewith in mammals, particularly humans. In particular, a method is provided of preventing or/and treating rheumatoid arthritis in a patient in need thereof comprising administering to said patient a therapeutically effective amount of calcitonin, e.g. salmon calcitonin in free form or salt form, in a pharmaceutically acceptable oral delivery form, wherein the therapeutically effective amount of a calcitonin is delivered orally in a composition comprising the calcitonin and a delivery agent for calcitonin.

1 . A method of preventing or treating Rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form and a delivery agent for calcitonin. 
     
     
         2 . A method for inhibiting inflammation of the joints associated with rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form and a delivery agent for calcitonin. 
     
     
         3 . A method for inhibiting swelling of skeletal joints associated with rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form and a delivery agent for calcitonin. 
     
     
         4 . A method for inhibiting, halting or reversing the cartilage and bone erosion and destruction associated with rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form and a delivery agent for calcitonin. 
     
     
         5 . A method for decreasing pain, associated with rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form and a delivery agent for calcitonin. 
     
     
         6 . The method according to  claim 1 , wherein said calcitonin is salmon calcitonin. 
     
     
         7 . The method according to  claim 1 , wherein the delivery agent is a compound of the following formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , and R 4  are independently hydrogen, —OH, —NR 6 R 7 , halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; 
 R 5  is a substituted or unsubstituted C 2 -C 16 alkylene, substituted or unsubstituted C 2 -C 16 alkenylene, substituted or unsubstituted C 1 -C 12 alkyl(arylene), or substituted or unsubstituted aryl(C 1 -C 12 alkylene); and 
 R 6  and R 7  are independently hydrogen, oxygen, or C 1 -C 4  alkyl; and hydrates and alcohol solvates thereof. 
 
     
     
         8 . The method according to  claim 7 , wherein the delivery agent is a disodium salt, an alcohol solvate or a hydrate of a compound of formula I. 
     
     
         9 . The method according to  claim 1 , wherein the delivery agent is selected from the group of 5-CNAC, SNAD, and SNAC and their pharmaceutically acceptable salts. 
     
     
         10 . The method according to  claim 1 , wherein said pharmaceutical composition comprises a delivery agent selected from the group consisting of a disodium salt of 5-CNAC, a disodium salt of SNAD, and a disodium salt of SNAC. 
     
     
         11 . The method according to  claim 1 , wherein said pharmaceutical composition comprises a delivery agent in micronized form. 
     
     
         12 . The method according to  claim 11  wherein said micronized delivery agent has an average particle size of less than 40, particularly of less than 20, more particularly of less than 10 micrometers. 
     
     
         13 . The method according to  claim 1 , wherein the therapeutically effective amount of a calcitonin is delivered orally in a composition comprising the calcitonin which is conjugated to a polymer molecule. 
     
     
         14 . The method according to  claim 1 , wherein the therapeutically effective amount of a calcitonin is delivered with an effective dosage of an oral pharmaceutical composition comprising calcitonin, at least one pharmaceutically acceptable pH-lowering agent, at least one absorption enhancer, and an enteric coating. 
     
     
         15 . The method according to  claim 1 , for preventing or treating Rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form in a dosage range of between 0.4 mg and 2.5 mg and a delivery agent for calcitonin. 
     
     
         16 . The method according to  claim 15 , wherein the dosage range is of between 0.6 mg and 1.2 mg. 
     
     
         17 . The method according to  claim 15 , wherein said dose is administered once per day. 
     
     
         18 . The method according to  claim 15 , wherein said dose is administered twice a day. 
     
     
         19 - 32 . (canceled) 
     
     
         33 . A pharmaceutical composition for use in the oral treatment or prevention of Rheumatoid arthritis in a patient in need thereof, comprising a calcitonin in free or salt form and a delivery agent for calcitonin together with one or more pharmaceutically acceptable diluents or carriers therefore. 
     
     
         34 . A pharmaceutical composition according to  claim 33 , wherein said calcitonin is salmon calcitonin. 
     
     
         35 . A pharmaceutical composition according to claim  32 , wherein the delivery agent is a compound of the following formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1 , R 2 , R 3 , and R 4  are independently hydrogen, —OH, —NR 6 R 7 , halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; 
 R 5  is a substituted or unsubstituted C 2 -C 16 alkylene, substituted or unsubstituted C 2 -C 16 alkenylene, substituted or unsubstituted C 1 -C 12 alkyl(arylene), or substituted or unsubstituted aryl(C 1 -C 12 alkylene); and 
 R 6  and R 7  are independently hydrogen, oxygen, or C 1 -C 4  alkyl; and hydrates and alcohol solvates thereof. 
 
     
     
         36 . A pharmaceutical composition according to  claim 35 , wherein the delivery agent is a disodium salt, an alcohol solvate or a hydrate of a compound of formula I. 
     
     
         37 . A pharmaceutical composition according to claim  32 , wherein the delivery agent is selected from the group of 5-CNAC, SNAD, and SNAC and their pharmaceutically acceptable salts. 
     
     
         38 . A pharmaceutical composition according to claim  32 , wherein said pharmaceutical composition comprises a delivery agent selected from the group consisting of a disodium salt of 5-CNAC, a disodium salt of SNAD, and a disodium salt of SNAC. 
     
     
         39 . A pharmaceutical composition according to claim  32 , wherein said pharmaceutical composition comprises a delivery agent in micronized form. 
     
     
         40 . A pharmaceutical composition according to  claim 39 , wherein said micronized delivery agent has an average particle size of less than 40, particularly of less than 20, more particularly of less than 10 micrometers. 
     
     
         41 . A pharmaceutical composition according to claim  32  wherein the therapeutically effective amount of a calcitonin is delivered orally in a composition comprising the calcitonin which is conjugated to a polymer molecule. 
     
     
         42 . A pharmaceutical composition according to claim  32 , wherein the therapeutically effective amount of a calcitonin is delivered with an effective dosage of an oral pharmaceutical composition comprising calcitonin, at least one pharmaceutically acceptable pH-lowering agent, at least one absorption enhancer, and an enteric coating. 
     
     
         43 . A pharmaceutical composition according to claim  32  for preventing or treating Rheumatoid arthritis in a patient in need thereof comprising administering orally to said patient a therapeutically effective amount of a calcitonin in free or salt form in a dosage range of between 0.4 mg and 2.5 mg and a delivery agent for calcitonin. 
     
     
         44 . A pharmaceutical composition according to  claim 43 , wherein the dosage range is of between 0.6 mg and 1.2 mg. 
     
     
         45 . A pharmaceutical combination for use in the oral treatment or prevention of Rheumatoid arthritis in a patient in need thereof, comprising:
 a. a first agent which is a calcitonin, and   b. a co-agent which is selected from the group consisting of salmon, (Asu 1-7)-eel or human calcitonin; a calcitonin analogue or derivative thereof; COX-2 inhibitors, e.g. lumiracoxib (Prexige®), celecoxib (Celebrex®), rofecoxib (Vioxx®), valdecoxib (Bextra®), etoricoxib (Arcoxia®); or mixed COX-1 and COX-2 inhibitors, e.g. diclofenac; Etanercept (Enbrel®); pain killers (e.g. Aspirin, Paracetamol); bone formers and bone antiresorbers.   
     
     
         46 . A pharmaceutical combination according to  claim 45  comprising between 0.4 and 2.5 mg of a calcitonin. 
     
     
         47 - 48 . (canceled) 
     
     
         49 . A method of preventing or treating Rheumatoid arthritis in a patient in need thereof comprising administering to said patient an oral pharmaceutical composition comprising between 0.4 and 2.5 mg of a calcitonin.