Methods and compositions for oral administration of proteins

Abstract

This invention provides compositions comprising a protein and an omega-3 fatty acid, method for treating diabetes mellitus, comprising administering same, and methods for oral administration of a protein with an enzymatic activity, comprising orally administering same.

1 . A composition comprising a protein having a molecular weight of up to 100,000 Daltons and an omega-3 fatty acid. 
     
     
         2 . The composition of  claim 1 , wherein
 (a) said protein is insulin;   (b) said omega-3 fatty acid is derived from fish oil; or   (c) said inhibitor is soybean trypsin inhibitor (SBTI).   
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , further comprising an inhibitor of a protease. 
     
     
         5 . (canceled) 
     
     
         6 . The composition of  claim 4 , wherein
 (a) said inhibitor is AEBSF-HCI; (epsilon)-aminocaproic acid; (alpha)1-antichymotypsin; antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCI (4-amidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCI; chymostatin; DFP (diisopropylfluoro-phosphate); leupeptin; PEFABLOC® SC (4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride); PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-beptanone HCI); TPCK (1-Chloro-3-tosylarnido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); trypsin inhibitor from soybean; aprotinin; pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin; a chelating agent of zinc; iodoacetate; or zinc;   (b) said protease is a serine protease; or   (c) said protease is trypsin.   
     
     
         7 - 8 . (canceled) 
     
     
         9 . The composition of  claim 1 , further comprising a substance that enhances absorption of said insulin protein through an intestinal mucosal barrier. 
     
     
         10 . The composition of  claim 9 , wherein said substance is EDTA 
     
     
         11 . The composition of  claim 9 , wherein said substance is a bile acid or alkali metal salt thereof. 
     
     
         12 . The composition of  claim 11 , wherein said bile acid is cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3.beta.-monohydroxychloric acid, lithocholic acid, 3.alpha.-hydroxy-12-ketocholic acid, 3.beta.-hydroxy-12-ketocholic acid, 12.alpha.-3.beta.-dihydrocholic acid, or ursodesoxycholic acid. 
     
     
         13 . The composition of  claim 1 , further comprising a coating that inhibits digestion of said composition in a stomach of a subject. 
     
     
         14 . The composition of  claim 13 , wherein said coating is an enteric coating or gelatin coating. 
     
     
         15 . A method for oral administration of a protein having a molecular weight up to 100,000 Daltons to a subject, whereby a substantial fraction of said protein retains its activity after absorption, through an intestinal mucosal barrier of said subject, comprising administering orally to said subject a pharmaceutical composition comprising said protein and an omega-3 fatty acid. 
     
     
         16 . The method of  claim 15 , wherein
 (a) said protein is an enzyme;   (b) said protein is insulin;   (c) said protein is a glucagon, an interferon gamma, an interferon alpha, a growth hormone, an erythropoietin, or granulocyte colony stimulating factor (G-CSF);   (d) said protein has a molecular weight of 1-50 kilodalton;   (e) said protein is a receptor ligand, transport protein, storage protein or a combination thereof; or   (f) said composition further comprises omega-3 fatty acid derived from fish oil.   
     
     
         17 - 21 . (canceled) 
     
     
         22 . The method of  claim 15 , wherein said pharmaceutical composition further comprises a protease inhibitor. 
     
     
         23 . The method of  claim 22 , wherein
 (a) said inhibitor is soybean trypsin inhibitor (SBTI);   (b) said inhibitor is AEBSF-HCI; (epsilon)-aminocaproic acid; (alpha)1-antichymotypsin; antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCI (4-amidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCI; chymostatin; DFP (diisopropylfluoro-phosphate); leupeptin; PEFABLOC® SC (4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride); PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-heptanone HCI); TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); trypsin inhibitor from soybean; aprotinin; pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin; a chelating agent of zinc; iodoacetate; or zinc;   (c) wherein said protease is a serine protease; or   (d) wherein said protease is trypsin.   
     
     
         24 - 26 . (canceled) 
     
     
         27 . The method of  claim 5 , wherein said pharmaceutical composition further comprises a substance that enhances absorption of said protein through an intestinal mucosal barrier. 
     
     
         28 . The method of  claim 27 , wherein said substance is EDTA. 
     
     
         29 . The method of  claim 27 , wherein said substance is a bile acid or alkali metal salt thereof. 
     
     
         30 . The method of  claim 29 , wherein said bile acid is cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3.beta.-monohydroxychloric acid, lithocholic acid, 3.alpha.-hydroxy-12-ketocholic acid, 3.beta.-hydroxy-12-ketocholic acid, 12.alpha.-3.beta.-dihydrocholic acid, or ursodesoxycholic acid. 
     
     
         31 . The method of  claim 15 , wherein said pharmaceutical composition further comprises a coating that inhibits digestion of said composition in a stomach of a subject. 
     
     
         32 . The method of  claim 31 , wherein said coating is an enteric coating or gelatin coating. 
     
     
         33 . A method for treating diabetes mellitus in a subject, comprising administering orally to said subject a pharmaceutical composition comprising insulin and an omega-3 fatty acid, thereby treating diabetes mellitus. 
     
     
         34 . The method of  claim 33 , wherein
 (a) said composition further comprises omega-3 fatty acid derived from fish oil; or   (b) said pharmaceutical composition further comprises a coating that inhibits digestion of said composition in a stomach of a subject.   
     
     
         35 . The method of  claim 33 , wherein said pharmaceutical composition further comprises an inhibitor of a protease. 
     
     
         36 . The method of  claim 35 , wherein
 (a) said inhibitor is soybean trypsin inhibitor (SBTI);   (b) said inhibitor is AEBSF-HCI; (epsilon)-aminocaproic acid; (alpha)1-antichymotypsin; antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCI (4-ainidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCI; chymostatin; DFP (diisopropylfluoro-phosphate); leupeptin; PEFABLOC® SC (4-(2 Aminoethyl)-benzenesulfonyl fluoride hydrochloride); PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-heptanone HCI); TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); trypsin inhibitor from soybean; aprotinin; pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin; a chelating agent of zinc; iodoacetate; or zinc;   (c) said protease is a serine protease; or   (d) said protease is trypsin.   
     
     
         37 - 39 . (canceled) 
     
     
         40 . The method of  claim 33 , wherein said pharmaceutical composition further comprises a substance that enhances absorption of said insulin protein through an intestinal mucosal barrier. 
     
     
         41 . The method of  claim 40 , wherein said substance is EDTA. 
     
     
         42 . The method of  claim 40 , wherein said substance is a bile acid or alkali metal salt thereof. 
     
     
         43 . The method of  claim 42 , wherein said bile acid is cholic acid, chenodeoxycholic acid, taurncholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3.beta.-monohydroxychloric acid, lithocholic acid, 3.alpha.-hydroxy-12-ketocholic acid, 3.beta.-hydroxy-12-ketocholic acid, 12.alpha.-3.beta.-dihydrocholic acid, or ursodesoxycholic acid. 
     
     
         44 . (canceled) 
     
     
         45 . The method of  claim 41 , wherein said coating is an enteric coating or gelatin coating.