Pharmaceutical compositions containing hyaluronic acid and carnosine and relative use

Abstract

Pharmaceutical compositions are described containing Hyaluronic Acid and Carnosine for use in the treatment and prevention of osteoarthritis (OA) and for the treatment of rheumatoid arthritis (RA).

1 . A pharmaceutical composition comprising a hyaluronic acid (HA)/carnosine conjugate with a direct amide bond between the carboxyl group of hyaluronic acid and the amine group of carnosine for use in the prevention and treatment of osteoarthritis and the treatment of rheumatoid arthritis (RA). 
     
     
         2 . The pharmaceutical composition according to  claim 1 , for use in the treatment of pathologies caused directly by RA selected from the group comprising pulmonary fibrosis, pleurisy and pleuropericarditis, xerophthalmia, uveitis and scleritis, or indirectly related to/depending on RA selected from the group comprising premature pathological aging, heart attack, stroke, arterosclerosis and coronary atherosclerosis, arterial hypertension, dementia, diabetes, osteoporosis and amyloidosis, cancer, proteinuria and nephritis, gastric lesions, cataracts, psoriatic arthritis, gastritis, vasculitis, type I diabetes and autoimmune thyroiditis. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , wherein the hyaluronic acid (HA)/carnosine conjugate is obtained by covalently conjugating the dipeptide of carnosine with hyaluronic acid by the formation of a direct amide bond between the carboxyl of HA and the amine group of carnosine, with a derivatization degree, i.e. amidation, of the carboxyl group of HA higher than 25%, preferably ranging from 30 to 100%, more preferably ranging from 30 to 60%, and even more preferably varying within the range of 35±3% or 45±5% and mixtures thereof. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , wherein the HA has an average molecular weight ranging from 400 to 3×10 6  Da, preferably ranging from 1×10 5  Da to 1×10 6  Da, even more preferably within the range of 130-220 kDa or within the range of 500-750 kDa and mixtures thereof. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , wherein the derivatization degree of HA ranges from 30 to 60% and the average molecular weight of HA ranges from 1×10 5  Da to 1×10 6 , and is preferably within the range of 130-220 kDa or 500-750 kDa and mixtures thereof. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the hyaluronic acid used for the amide derivative of HA with carnosine is the sodium salt of HA or the tetrabutylammonium salt of HA. 
     
     
         7 . The pharmaceutical composition according to  claim 1  for topical, oral, intra-articular, parenteral or surgical application. 
     
     
         8 . Biomaterials consisting of derivatives of HA conjugated with carnosine, wherein said derivatives are selected from esters of HA, amides of HA, internal esters of HA, percarboxylates of HA and sulfates of HA. 
     
     
         9 . The biomaterials consisting, of derivatives of HA conjugated with carnosine according to  claim 8 , for use in the prevention and treatment of osteoarthritis, in the treatment of rheumatoid arthritis (RA), and in the treatment of pathologies caused directly by RA selected from the group comprising pulmonary fibrosis, pleurisy and pleuropericarditis, xerophthalmia, uveitis and scleritis, or indirectly related to/depending on RA selected from the group comprising premature pathological aging, heart attack, stroke, arterosclerosis and coronary atherosclerosis, arterial hypertension, dementia, diabetes, osteoporosis and amyloidosis, cancer, proteinuria and nephritis, gastric lesions, cataracts, psoriatic arthritis, gastritis, vasculitis, type I diabetes and autoimmune thyroiditis. 
     
     
         10 . Biomaterials consisting of derivatives of HA conjugated with carnosine according to  claim 9 , in the form of fibers, gels, hydrogels, microspheres, sponges, woven or nonwoven fabrics, films, for topical, oral, intra-articular, parenteral or surgical application. 
     
     
         11 . The pharmaceutical composition according to  claim 1 , associated with pharmacologically and/or biologically active substances and/or with controlled release systems of drugs and/or natural polymers or polymers of a synthetic nature. 
     
     
         12 . The pharmaceutical composition according to  claim 2 , wherein the hyaluronic acid (HA)/carnosine conjugate is obtained by covalently conjugating the dipeptide of carnosine with hyaluronic acid by the formation of a direct amide bond between the carboxyl of HA and the amine group of carnosine, with a derivatization degree, i.e. amidation, of the carboxyl group of HA higher than 25%, preferably ranging from 30 to 100%, more preferably ranging from 30 to 60%, and even more preferably varying within the range of 35±3% or 45±5% and mixtures thereof. 
     
     
         13 . The pharmaceutical composition according to  claim 2 , wherein the HA has an average molecular weight ranging from 400 to 3×10 6  Da, preferably ranging from 1×10 5  Da to 1×10 6  Da, even more preferably within the range of 130-220 kDa or within the range of 500-750 kDa and mixtures thereof. 
     
     
         14 . The pharmaceutical composition according to  claim 3 , wherein the HA has an average molecular weight ranging from 400 to 3×10 6  Da, preferably ranging from 1×10 5  Da to 1×10 6  Da, even more preferably within the range of 130-220 kDa or within the range of 500-750 kDa and mixtures thereof. 
     
     
         15 . The pharmaceutical composition according to  claim 2 , wherein the derivatization degree of HA ranges from 30 to 60% and the average molecular weight of HA ranges from 1×10 5  Da to 1×10 6 , and is preferably within the range of 130-220 kDa or 500-750 kDa and mixtures thereof. 
     
     
         16 . The pharmaceutical composition according to  claim 3 , wherein the derivatization degree of HA ranges from 30 to 60% and the average molecular weight of HA ranges from 1×10 5  Da to 1×10 6 , and is preferably within the range of 130-220 kDa or 500-750 kDa and mixtures thereof. 
     
     
         17 . The pharmaceutical composition according to  claim 4 , wherein the derivatization degree of HA ranges from 30 to 60% and the average molecular weight of HA ranges from 1×10 5  Da to 1×10 6 , and is preferably within the range of 130-220 kDa or 500-750 kDa and mixtures thereof. 
     
     
         18 . The pharmaceutical composition according to  claim 2 , wherein the hyaluronic acid used for the amide derivative of HA with carnosine is the sodium salt of HA or the tetrabutylammonium salt of HA. 
     
     
         19 . The pharmaceutical composition according to  claim 3 , wherein the hyaluronic acid used for the amide derivative of HA with carnosine is the sodium salt of HA or the tetrabutylammonium salt of HA. 
     
     
         20 . The pharmaceutical composition according to  claim 4 , wherein the hyaluronic acid used for the amide derivative of HA with carnosine is the sodium salt of HA or the tetrabutylammonium salt of HA.