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(12) Patent Application Publication (10) Pub. No.: US 2007/0087957 A1 Kidron (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2007/0087957 A1 Kidron (43) Pub US 20070087957A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0087957 A1 Kidron (43) Pub. Date: Apr. 19, 2007 (54) METHODS AND COMPOSITIONS FOR Publication Classification ORAL ADMINISTRATION OF PROTENS (51) Int. Cl. (76) Inventor: Miriam Kidron, (US) A6II 38/28 (2006.01) A6II 3L/22 (2006.01) Correspondence Address: A6II 3L/202 (2006.01) PEARL COHEN ZEDEK LATZER, LLP (52) U.S. Cl. ................. 514/3: 514/4; 514/547: 514/560; 15OO BROADWAY 12TH FLOOR 514f12 NEW YORK, NY 10036 (US) (21) Appl. No.: 11/513,343 (57) ABSTRACT (22) Filed: Aug. 31, 2006 This invention provides compositions comprising a protein Related U.S. Application Data and an omega-3 fatty acid, method for treating diabetes mellitus, comprising administering same, and methods for (60) Provisional application No. 60/713,716, filed on Sep. oral administration of a protein with an enzymatic activity, 6, 2005. comprising orally administering same. US 2007/0087957 A1 Apr. 19, 2007 METHODS AND COMPOSITIONS FOR ORAL 0010. In another embodiment, the present invention pro ADMINISTRATION OF PROTEINS vides a method for oral administration of a protein with an enzymatic activity to a subject, whereby a Substantial frac CROSS-REFERENCE TO RELATED tion of the protein retains the enzymatic activity after APPLICATIONS absorption through an intestinal mucosal barrier of the Subject, comprising administering orally to the Subject a 0001. This Application claims priority of U.S. Provi pharmaceutical composition comprising the protein and an sional Ser. No. 60/713,716, filed on Sep. 6, 2005, which is omega-3 fatty acid, thereby orally administering a protein included in its entirety by reference herein. with an enzymatic activity to a subject. FIELD OF INVENTION 0011. In another embodiment, the present invention pro vides a method for treating diabetes mellitus in a Subject, 0002 This invention provides compositions comprising a comprising administering orally to the Subject a pharmaceu protein and an omega-3 fatty acid, and a method for admin tical composition comprising insulin and an omega-3 fatty istering same. acid, thereby treating diabetes mellitus. BACKGROUND OF THE INVENTION DETAILED DESCRIPTION OF THE INVENTION 0003. Due to improved biotechnology, the accessibility of biologically active peptides to the pharmaceutical indus 0012. This invention provides compositions and methods try has increased considerably. However, a limiting factor in comprising a protein and an omega-3 fatty acid. In one the development of peptide drugs is the relative ineffective embodiment, the protein having a molecular weight up to ness when given perorally. Almost all peptide drugs are 200,000 Daltons. In a preferred embodiment, the protein parenterally administered, although parenterally adminis having a molecular weight up to 100,000 Daltons. In one tered peptide drugs are often connected with low patient embodiment, the present invention further provides an compliance. enhancer which enhances absorption through the intestines. 0004 Insulin is a medicament used to treat patients 0013 In one embodiment, the protein is an enzyme. In Suffering from diabetes, and is the only treatment for insulin Some embodiments, the protein is a receptor ligand, trans dependent diabetes mellitus. Diabetes Mellitus is character porter, or a storage protein. In one embodiment, the protein ized by a pathological condition of absolute or relative is a structural protein. insulin deficiency, leading to hyperglycemia, and is one of 0014. In some embodiments, the enzyme is an oxi the main threats to human health in the 21st century. The doreductase, transferase, hydrolase, lyase, isomerase, or global figure of people with diabetes is set to rise to 220 ligase. In some embodiments, oxidoreductases act on the million in 2010, and 300 million in 2025. Type I diabetes is aldehyde or oxo group of donors, on the CH-CH group of caused primarily by the failure of the pancreas to produce donors, on the CH-NH(2) group of donors, on the insulin. Type II diabetes, involves a lack of responsiveness CH-NH group of donors, on NADH or NADPH, on the of the body to the action of insulin. CH-OH group of donors, on nitrogenous compounds as 0005) Approximately 20%-30% of all diabetics use daily donors, on a Sulfur group of donors, on a heme group of insulin injections to maintain their glucose levels. An esti donors, on diphenols and related Substances as donors, on a mated 10% of all diabetics are totally dependent on insulin peroxide as acceptor, on hydrogen as donor, on single donors injections. with incorporation of molecular oxygen, on paired donors, on Superoxide as acceptor, oxidizing metal ions, on CH or 0006 Currently, the only route of insulin administration CH(2) groups, on iron-sulfur proteins as donors, on reduced is injection. Daily injection of insulin is causes considerable flavodoxin as donor, on phosphorus or arsenic in donors, or suffering for patients. Side effects such as lipodystrophy at the site of the injection, lipatrophy, lilpohypertrophy, and on X-H and y-H to form an x-y bond. occasional hypoglycemia are known to occur. In addition, 0015. In some embodiments, transferases are acyltrans Subcutaneous administration of insulin does not typically ferases or glycosyltransferases. In some embodiments, provide the fine continuous regulation of metabolism that transferases transfer aldehyde or ketone residues. In some occurs normally with insulin secreted from the pancreas embodiments, transferases transfer alkyl or aryl groups, directly into the liver via the portal vein. other than methyl groups. In some embodiments, trans ferases transfer nitrogenous, phosphorous, Sulfur or sele 0007. The present invention addresses the need for an nium containing groups. alternate solution for administration of insulin. 0016. In some embodiments, hydrolases are glycosylases SUMMARY OF THE INVENTION or act on ether bonds, on peptide bonds, on carbon-nitrogen bonds, other than peptide bonds, on acid anhydrides, on 0008. This invention provides compositions comprising a carbon-carbon bonds, on halide bonds, on phosphorus protein and an omega-3 fatty acid, method for treating nitrogen bonds, on Sulfur-nitrogen bonds, on carbon-phos diabetes mellitus, comprising administering same, and phorus bonds, on sulfur-sulfur bonds, or on carbon-sulfur methods for oral administration of a protein with an enzy bonds. matic activity, comprising orally administering same. 0017. In some embodiments, lyases are carbon-carbon 0009. In one embodiment, the present invention provides lyases, carbon-oxygen lyases, carbon-nitrogen lyases, car a composition comprising an insulin protein and an omega-3 bon-sulfur lyases, carbon-halide lyases, phosphorus-oxygen fatty acid. lyases, or other lyases. US 2007/0087957 A1 Apr. 19, 2007 0018. In some embodiments, isomerases are racemases or 0.5-3 units (u)/kg in humans. In one embodiment, the units epimerases, cis-trans-isomerases, intramolecular oxi used to measure insulin in methods and compositions of the doreductases, intramolecular transferases, intramolecular present invention are USP Insulin Units. In one embodiment, lyases, or other isomerases. the units used to measure insulin are milligrams. In another 0019. In some embodiments, ligases form carbon-sulfur embodiment, one USP Insulin Unit is equivalent to 45.5 mg bonds, carbon-nitrogen bonds, carbon-carbon bonds, phos insulin. phoric ester bonds, or nitrogen-metal bonds. 0029. In another embodiment, the amount of insulin is 0020. In some embodiments, transporter proteins are 0.1-1 u/kg. In another embodiment, the amount is 0.2-1 u/kg. annexins, ATP-binding cassette transporters, hemoglobin, In another embodiment, the amount is 0.3-1 u/kg. In another ATPases, calcium channels, potassium channels, sodium embodiment, the amount is 0.5-1 u/kg. In another embodi channels, or solute carriers. ment, the amount is 0.1-2 u?kg. In another embodiment, the amount is 0.2-2 u?kg. In another embodiment, the amount is 0021. In some embodiments, storage proteins comprise 0.3-2 u/kg. In another embodiment, the amount is 0.5-2 u/kg. albumins, lactoglobulins, casein ovomucin, ferritin, phos In another embodiment, the amount is 0.7-2 u/kg. In another vitin, lactoferrin, or Vitellogenin. In one embodiment, albu embodiment, the amount is 1-2 u?kg. In another embodi mins comprise avidin, ovalbumin, serum albumin, parval ment, the amount is 1.2-2 u?kg. In another embodiment, the bumin, c-reactive protein prealbumin, conalbumin, ricin, amount is 1-1.2 u/kg. In another embodiment, the amount is lactalbumin, methemalbumin, or transthyretin. 1-1.5u/kg. In another embodiment, the amount is 1-2.5u/kg. 0022. In some embodiments, structural proteins comprise In another embodiment, the amount is 1-3 u?kg. In another amyloid, collagen elastin, or fibrillin. embodiment, the amount is 2-3 u?kg. In another embodi 0023. In some embodiments, the protein is a viral protein, ment, the amount is 1-5 u/kg. In another embodiment, the bacterial protein, invertebrate protein, or vertebrate protein. amount is 2-5 u/kg. In another embodiment, the amount is In some embodiments, the protein is a recombinant protein. 3-5 u/kg. In one embodiment, the protein is a recombinant protein. In 0030. In another embodiment, the amount of insulin is one embodiment, the recombinant protein is a recombinant 0.1 u?kg. In another embodiment, the amount is 0.2 u/kg. In human protein. another embodiment, the amount is 0.3 u?kg. In another 0024. In one embodiment, the present invention provides embodiment, the amount is 0.4 u/kg. In another embodi a composition comprising an insulin protein and an omega-3 ment, the amount is 0.5 u?kg. In another embodiment, the fatty acid. As provided herein (Examples). Such composi amount is 0.6 u/kg. In another embodiment, the amount is tions have utility in the oral administration of insulin, 0.8 u?kg.
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