Systems for delivery and release of angiotensin-(1-7)

Abstract

The prior art lacks a formulation, application or product of D-Ala7-Angiotensin-(1-7) (A- 779 ) and analogues and derivatives, D-Pro7-Angiotensin-(1-7) and analogues or derivatives or of Ang-(1-7) analogues or derivatives using cyclodextrins, liposomes, biodegradable polymers and its derivatives for the study or treatment of arterial hypertension and other cardiovascular diseases, wounds, burns, arrhythmia, tumors, diabetes mellitus, sperm mobility, nephropathy, gastrointestinal and gynecological disorders, angiogenesis, angioplatsy, alopecia and blood diseases in warm blooded animals, or as ligands for de G-protein-coupled receptor MAS. This characterizes the present invention as a more effective option for the study and treatment of pathologies associated or not to this receptor. A combination of two different technologies are provided: the molecular encapsulation of the peptide angiotensin-(1-7) and its analogues and derivates in cyclodextrin and the microencapsulation in biodegradable polymers and liposomes. It is also characterized by the increase of this peptides and its analogues and derivatives using the formulation.

1 . A pharmaceutical formulation comprising Angiotensin-(1-7) or an analogue or derivative thereof encapsulated in a liposome. 
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the Angiotensin-(1-7), analogue or derivative thereof is complexed with a hydrophilic cyclodextrin. 
     
     
         3 . The pharmaceutical formulation of  claim 1 , wherein the analogue or derivative of Angiotensin-(1-7) is a member selected from the group comprising Sar 1 -Angiotensin-(1-7), D-Ala 7 -Ang-(1-7) and D-Pro 7 -Ang-(1-7). 
     
     
         4 . The pharmaceutical formulation of  claim 1 , wherein the liposome comprises one or more lipids selected from the group comprising phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, cardiolipin, cholesterol, phosphatidic acid, sphingolipids, glycolipids, fatty acids, sterols, phosphatidylethanolamine, polymerizable lipids in their polymerized or non-polymerized form, and combinations thereof. 
     
     
         5 . The pharmaceutical formulation of  claim 1 , wherein the liposome is sterically-stabilized with a polyethylene glycol-lipid. 
     
     
         6 . The pharmaceutical formulation of  claim 1 , wherein the diameter of the liposome is below about 200 nm. 
     
     
         7 . The pharmaceutical formulation of  claim 2 , wherein the hydrophilic cyclodextrin is an alpha-, beta- or gamma-cyclodextrin. 
     
     
         8 . The pharmaceutical formulation of  claim 2 , wherein the hydrophilic cyclodextrin is a member selected from the group comprising 6-O-maltosyl-,-cyclodextrin, sulfobutyl-,-cyclodextrin, 2-hydroxyethyl cyclodextrin, 2-hydroxypropyl cyclodextrin, 3-hydroxypropyl cyclodextrin, and 2,3- dihydroxypropyl cyclodextrin. 
     
     
         9 . A pharmaceutical formulation, comprising Angiotensin-(1-7) or an analogue or derivative thereof encapsulated in synthetic biodegradable polymer or derivative thereof 
     
     
         10 . The pharmaceutical formulation of  claim 9 , wherein the Angiotensin-(1-7) or an analogue or derivative thereof is complexed with a hydrophilic cyclodextrin. 
     
     
         11 . The pharmaceutical formulation of  claim 9 , wherein the polymer is a member selected from the group comprising polyanhydrides, poly(hydroxy acids), poly(hydroxyl)acids, polyuretans, polysyloxana, polymethacrylates, polyvinyl alcohol, poly(2-hydroxy-ethylmethacrylate), polyacrylamide, lactic acid polymers (PLA), glycolic acid polymers (PGA), and co-polymers thereof. 
     
     
         12 . The pharmaceutical formulation of  claim 10 , wherein the hydrophilic cyclodextrin is an alpha-, beta- or gamma-cyclodextrin. 
     
     
         13 . The pharmaceutical formulation of  claim 10 , wherein the hydrophilic cyclodextrin is a member selected from the group comprising 6-O-maltosyl-,-cyclodextrin, sulfobutyl-,-cyclodextrin, 2-hydroxyethyl cyclodextrin, 2-hydroxypropyl cyclodextrin, 3-hydroxypropyl cyclodextrin, and 2,3- dihydroxypropyl cyclodextrin. 
     
     
         14 . The pharmaceutical formulation of  claim 9 , wherein the analogue or derivative of Angiotensin-(1-7) is a member selected from the group comprising Sar 1 -Angiotensin-(1-7), D-Ala 7 -Ang-(1-7) and D-Pro 7 -Ang-(1-7). 
     
     
         15 . A medical device for controlled-release of Angiotensin-(1-7), an analogue or a derivative thereof, comprising Angiotensin-(1-7), the analogue or the derivative thereof encapsulated in a synthetic biodegradable polymer or derivative thereof. 
     
     
         16 . A medical device for controlled-release of Angiotensin-(1-7), an analogue or a derivative thereof, comprising Angiotensin-(1-7), the analogue or the derivative thereof complexed with a hydrophilic cyclodextrin. 
     
     
         17 . The device of  claim 15 , wherein the synthetic biodegradable polymer is selected from the group comprising polyanhydrides, poly(hydroxy acids), poly(hydroxyl)acids, polyuretans, polysyloxana, polymethacrylates, polyvinilalcholy, poly(2-hydroxy-ethylmethacrylate), polyacrylamide, lactic acid polymers (PLA), glycolic acid polymers (PGA), and co-polymers thereof. 
     
     
         18 . The device of  claim 16 , wherein the hydrophilic cyclodextrin is an alpha-, beta- or gamma-cyclodextrin. 
     
     
         19 . The device of  claim 16 , wherein the hydrophilic cyclodextrin is a member selected from the group comprising 6-O-maltosyl-,-cyclodextrin, sulfobutyl-,-cyclodextrin, 2-hydroxyethyl cyclodextrin, 2-hydroxypropyl cyclodextrin, 3-hydroxypropyl cyclodextrin, and 2,3-dihydroxypropyl cyclodextrin. 
     
     
         20 . The device of  claim 15 , wherein the analogue or derivative of Angiotensin-(1-7) is a member selected from the group comprising Sar 1 -Angiotensin-(1-7), D-Ala 7 -Ang-(1-7) and D-Pro 7 -Ang-(1-7). 
     
     
         21 . A method for treating or preventing a cardiovascular disease or cancer in an animal, comprising administering to the animal a therapeutically effective amount of Angiotensin-(1-7) or an analogue or derivative thereof. 
     
     
         22 . The method of  claim 21 , wherein the Angiotensin-(1-7) or an analogue or derivative thereof is complexed with a hydrophilic cyclodextrin. 
     
     
         23 . The method of  claim 22 , wherein the hydrophilic cyclodextrin is an alpha-, beta- or gamma-cyclodextrin. 
     
     
         24 . The method of  claim 22 , wherein the hydrophilic cyclodextrin is a member selected from the group comprising 6-O-maltosyl-,-cyclodextrin, sulfobutyl-,-cyclodextrin, 2-hydroxyethyl cyclodextrin, 2-hydroxypropyl cyclodextrin, 3-hydroxypropyl cyclodextrin, and 2,3-dihydroxypropyl cyclodextrin. 
     
     
         25 . The method of  claim 21 , wherein the Angiotensin-(1-7) or the analogue or derivative thereof is encapsulated in a synthetic biodegradable polymer or derivative thereof. 
     
     
         26 . The method of  claim 25 , wherein the synthetic biodegradable polymer or derivative thereof is a member selected from the group comprising polyanhydrides, poly(hydroxy acids), poly(hydroxyl)acids, polyuretans, polysyloxana, polymethacrylates, polyvinyl alcohol, poly(2-hidroxi-ethylmetacrilate), polyacrylamide, lactic acid polymers (PLA), glycolic acid polymers (PGA), and co-polymers thereof. 
     
     
         27 . The method of  claim 21 , wherein the Angiotensin-(1-7) or the analogue or derivative thereof is encapsulated in a liposome. 
     
     
         28 . The method of  claim 27 , wherein the liposome comprises one or more lipids selected from the group comprising phosphatidylcholine, phosphatidylserine, phosphatidylglycerol, cardiolipin, cholesterol, phosphatidic acid, sphingolipids, glycolipids, fatty acids, sterols, phosphatidylethanolamine, polymerizable lipids in their polymerized or non-polymerized form, and combinations thereof. 
     
     
         29 . The method of  claim 21 , wherein the analogue or derivative of Angiotensin-(1-7) is a member selected from the group comprising Sar 1 -Angiotensin-(1-7), D-Ala 7 -Ang-(1-7) and D-Pro 7 -Ang-(1-7). 
     
     
         30 . The method of  claim 21 , wherein the cardiovascular disorder is selected from the group comprising left ventricular hypertrophy, myocardial ischemia, stroke, heart failure, atherosclerosis, coronary heart disease, myocardial infarction (not specifically enumerated), angina pectoris, endothelial dysfunction. 
     
     
         31 . A method for treating or preventing a disease in an animal caused by a reduced function or stimulation of the G-protein-coupled receptor MAS, comprising administering a therapeutically effective amount of a pharmaceutical formulation comprising Angiotensin-(1-7) or an analogue or derivative thereof encapsulated in liposomes or bound to a biodegradable polymer. 
     
     
         32 . The device of  claim 16 , wherein the analogue or derivative of Angiotensin-(1-7) is a member selected from the group comprising Sar 1 -Angiotensin-(1-7), D-Ala 7 -Ang-(1-7) and D-Pro 7 -Ang-(1-7).