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 - 45 . (canceled) 
     
     
         46 . An oral dosage form for administering a protein to be absorbed by a subject's intestines into the subject's bloodstream in an active form, the oral dosage form comprising the protein, soybean trypsin inhibitor (SBTI), EDTA and an omega-3 fatty acid in a water-free oily solution,
 wherein the protein is selected from the group consisting of a growth hormone, an enzyme, a receptor ligand, a transporter protein, a storage protein, and a structural protein,   wherein the protein has a molecular weight of 1-50 kilodaltons (kDa),   wherein the oral dosage form does not comprise aprotinin or insulin, and   wherein the water-free oily solution is surrounded by a coating that inhibits digestion of the oral dosage form in the subject's stomach.   
     
     
         47 . The oral dosage form of  claim 46 , wherein
 (a) the protein is glucagon; and   (b) the omega-3 fatty acid is in the form of fish oil.   
     
     
         48 . The oral dosage form of  claim 46 , wherein the omega-3 fatty acid is in the form of fish oil. 
     
     
         49 . The oral dosage form of  claim 46 , wherein the oral dosage form further comprises AEBSF-HCl; (epsilon)-aminocaproic acid; (alpha)l-antichymotrypsin; antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCl (4-amidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCl; chymostatin; DFP (diisopropylfluoro-phosphate); leupeptin; 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride; PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-beptanone HCl); TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin; a chelating agent of zinc; iodoacetate; or zinc. 
     
     
         50 . The oral dosage form of  claim 46 , wherein the oral dosage form further comprises a bile acid or alkali metal salt thereof. 
     
     
         51 . The oral dosage form of  claim 50 , wherein the 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. 
     
     
         52 . The oral dosage form of  claim 46 , wherein the coating is an enteric coating or gelatin coating. 
     
     
         53 . A method for oral administration of a protein to a subject, wherein the protein is to be absorbed by a subject's intestines into the subject's bloodstream in an active form, comprising administering orally to the subject an oral dosage form that comprises the protein, soybean trypsin inhibitor (SBTI), EDTA, and an omega-3 fatty acid,
 wherein the protein, SBTI, EDTA, and omega-3 fatty acid are in a water-free, oily solution,   wherein the protein is selected from the group consisting of a growth hormone, an enzyme, a receptor ligand, a transporter protein, a storage protein, and a structural protein,   wherein the protein has a molecular weight of 1-50 kDa,   wherein the oral dosage form does not comprise aprotinin or insulin, and   wherein the water-free oily solution is surrounded by a coating that inhibits digestion of the oral dosage form in the subject's stomach.   
     
     
         54 . The method of  claim 53 , wherein
 (a) the protein is glucagon; and   (b) the omega-3 fatty acid is in the form of fish oil.   
     
     
         55 . The method of  claim 53 , wherein the omega-3 fatty acid is in the form of fish oil. 
     
     
         56 . The method of  claim 53 , wherein the oral dosage form further comprises AEBSF-HCl; (epsilon)-aminocaproic acid; (alpha)l-antichymotrypsin, antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCl (4-amidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCl; chymostatin; DFP (diisopropylfluoro-phosphate); leupeptin; 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride; PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-beptanone HCl); TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin; a chelating agent of zinc; iodoacetate; or zinc. 
     
     
         57 . The method of  claim 53 , wherein the coating is an enteric coating or gelatin coating. 
     
     
         58 . The oral dosage form of  claim 46 , wherein the protein has a molecular weight of 1-20 kDa. 
     
     
         59 . An oral dosage form for administering a protein to be absorbed by a subject's intestines into the subject's bloodstream in an active form, the oral dosage form comprising the protein, SBTI, EDTA, and an omega-3 fatty acid in a water-free oily solution,
 wherein the protein is selected from the group consisting of a growth hormone, an enzyme, a receptor ligand, a transporter protein, a storage protein, and a structural protein,   wherein the protein has a molecular weight of 1-50 kDa,   wherein the oral dosage form does not comprise aprotinin or insulin, and   wherein the oral dosage form is non-alcoholic.   
     
     
         60 . The oral dosage form of  claim 59 , wherein
 (a) the protein is glucagon; and   (b) the omega-3 fatty acid is in the form of fish oil.   
     
     
         61 . The oral dosage form of  claim 59 , wherein the omega-3 fatty acid is in the form of fish oil. 
     
     
         62 . The oral dosage form of  claim 59 , wherein the oral dosage form further comprises AEBSF-HCl; (epsilon)-aminocaproic acid; (alpha)l-antichymotrypsin; antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCl (4-amidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCL; chymostatin; DFP (diisopropylfluoro-phosphate); leupeptin; 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride, PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-beptanone HCl); TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin; a chelating agent of zinc; iodoacetate; or zinc. 
     
     
         63 . The oral dosage form of  claim 59 , wherein the oral dosage form further comprises a bile acid or alkali metal salt thereof. 
     
     
         64 . The oral dosage form of  claim 63 , wherein the 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. 
     
     
         65 . The oral dosage form of  claim 59 , wherein the protein has a molecular weight of 1-20 kDa. 
     
     
         66 . A method for oral administration of a protein to a subject, wherein the protein is to be absorbed by a subject's intestines into the subject's bloodstream in an active form, comprising administering orally to the subject an oral dosage form that comprises the protein, SBTI, EDTA, and an omega-3 fatty acid,
 wherein the protein, SBTI, EDTA, and omega-3 fatty acid are in a water-free oily solution,   wherein the protein is selected from the group consisting of a growth hormone, an enzyme, a receptor ligand, a transporter protein, a storage protein, and a structural protein,   wherein the protein has a molecular weight of 1-50 kDa,   wherein the oral dosage form does not comprise aprotinin or insulin, and   wherein the oral dosage form is non-alcoholic.   
     
     
         67 . The method of  claim 66 , wherein
 (a) the protein is glucagon; and   (b) the omega-3 fatty acid is in the form of fish oil.   
     
     
         68 . The method of  claim 66 , wherein the omega-3 fatty acid is in the form of fish oil. 
     
     
         69 . The method of  claim 66 , wherein the oral dosage form further comprises AEBSF-HCl; (epsilon)-aminocaproic acid; (alpha)l-antichymotrypsin; antipain; antithrombin III; (alpha)1-antitrypsin ([alpha]1-proteinase inhibitor); APMSF-HCl (4-amidinophenyl-methane sulfonyl-fluoride); sprotinin; benzamidine-HCl; chymostatin, DFP (diisopropylfluoro-phosphate); leupeptin; 4-(2-Aminoethyl)benzenesulfonyl fluoride hydrochloride; PMSF (phenylmethyl sulfonyl fluoride); TLCK (1-Chloro-3-tosylamido-7-amino-2-beptanone HCl); TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone); trypsin inhibitor from egg white (Ovomucoid); pentamidine isethionate; pepstatin; guanidium; alpha2-macroglobulin, a chelating agent of zinc; iodoacetate; or zinc.