(12) Patent Application Publication (10) Pub. No.: US 2011/0014247 A1 Kidron (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2011/0014247 A1 Kidron (43) Pub US 2011 0014247A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0014247 A1 Kidron (43) Pub. Date: Jan. 20, 2011 (54) METHODS AND COMPOSITIONS FOR ORAL Related U.S. Application Data ADMINISTRATION OF PROTEINS (60) Provisional application No. 61/064,779, filed on Mar. 26, 2008. (75) Inventor: Miriam Kidron, Jerusalem (IL) Publication Classification (51) Int. Cl. Correspondence Address: A638/16 (2006.01) WOLF GREENFIELD & SACKS, PC. A6IR 9/00 (2006.01) 6OO ATLANTIC AVENUE A638/19 (2006.01) BOSTON, MA 02210-2206 (US) A638/2 (2006.01) A638/43 (2006.01) A638/28 (2006.01) (73) Assignee: ORAMED LTD., Jerusalem (IL) A638/27 (2006.01) A6IP3/10 (2006.01) (21) Appl. No.: 12/934,754 (52) U.S. Cl. ...... 424/400; 424/85.1; 424/85.5; 424/85.7; 424/94.1: 514/1.1 : 514/6.5: 514/6.9; 514/11.3 (22) PCT Fled: Feb. 26, 2009 (57) ABSTRACT This invention provides compositions that include a protein (86) PCT NO.: PCT/IL09/00223 and at least two protease inhibitors, method for treating dia betes mellitus, and methods for administering same, and S371 (c)(1), methods for oral administration of a protein with an enzy (2), (4) Date: Sep. 27, 2010 matic activity, including orally administering same. Patent Application Publication Jan. 20, 2011 Sheet 1 of 3 US 2011/0014247 A1 Figure 1A 8 mg insulin/150 mg EDTA 125 mg SBTI 10 105 100 95 90 85 80 Time (min.) Figure 1B 8 mg insulin/150 mg EDTA/150000 KIU Aprotinin S is S S S eS & KS & S Time (min.) Figure 1C 8 mg insulin/150 mg EDTA/150000 KIU Aprotinin/125 mg SBTI Time (min.) Patent Application Publication Jan. 20, 2011 Sheet 2 of 3 US 2011/0014247 A1 Figure 1D 8 mg insulin/150 mg EDTA/125 mg SBTI 14 is 12 g O E i 4 - 2 - O Time (min.) Figure E 8 mg insulin/150 mg EDTA/150000 KUAprotinin SS O E 5 2 Time (min.) Figure 1F 8 mg insulin/150 mg EDTA/150000 KIU Aprotinin/125 mg SBTI 2O 1 O O Time (min.) Patent Application Publication Jan. 20, 2011 Sheet 3 of 3 US 2011/0014247 A1 Figure 1G 8 mg insulin/150 mg EDTA/125 mg SBTI 2. Time (min.) Figure 1H 8 mg insulin/150 mg EDTA/150000 KIU Aprotinin 2 O Q s Time (min.) Figure 1I 8 mg insulin/150 mg EDTA/150000 KIU Aprotinin/125 mg SBTI SS 2 1.5 3 i 0.5 cs 0 Time (min.) US 2011/0014247 A1 Jan. 20, 2011 METHODS AND COMPOSITIONS FOR ORAL thereof and a first protease inhibitor and a second protease ADMINISTRATION OF PROTEINS inhibitor, thereby treating diabetes mellitus. FIELD OF INVENTION BRIEF DESCRIPTION OF THE DRAWINGS 0010 FIG.1. is a set of bar graphs showing the changes in 0001. This invention provides oral compositions compris blood glucose levels after treatment with the formulations of ing a protein and at least two protease inhibitors and a method the invention. for administering same. 0011. In FIG. 1 A-C blood glucose levels were signifi cantly reduced in human subjects treated with formulation (3) BACKGROUND OF THE INVENTION (8 mg insulin, 150 mg EDTA, 150000 KIU Aprotinin, 125 mg SBTI in 1 ml fish oil in a soft-gel capsule (SwissCup). 0002. Due to improved biotechnology, the accessibility of 0012 FIG. 1D-F shows that total blood insulin was sig biologically active peptides to the pharmaceutical industry nificantly higher especially between 220-300 minutes in has increased considerably. However, a limiting factor in the human subjects treated with formulation (3). development of peptide drugs is the relative ineffectiveness (0013 FIG. 1G-I, shows that blood C-peptide levels were when given perorally. Almost all peptide drugs are parenter significantly reduced in human Subjects treated with formu ally administered, although parenterally administered pep tide drugs are often connected with low patient compliance. lation (3) 0003 Insulin is a medicament used to treat patients suf DETAILED DESCRIPTION OF THE INVENTION fering from diabetes, and is the only treatment for insulin dependent diabetes mellitus. Diabetes Mellitus is character 0014. This invention provides compositions and methods ized by a pathological condition of absolute or relative insulin comprising a protein and at least two protease inhibitors. In deficiency, leading to hyperglycemia, and is one of the main another, embodiment, the present invention provides compo threats to human health in the 21st century. The global figure sitions and methods comprising a protein and a first protease of people with diabetes is set to rise to 220 million in 2010, inhibitor and a second protease inhibitors. In another, and 300 million in 2025. Type I diabetes is caused primarily embodiment, the present invention provides compositions by the failure of the pancreas to produce insulin. Type II and methods comprising a protein having a molecular weight diabetes, involves a lack of responsiveness of the body to the of up to 100,000 Daltons and a first protease inhibitor and a action of insulin. second protease inhibitors. 0004. Approximately 20%-30% of all diabetics use daily 0015. In another, embodiment, the protein of the present insulin injections to maintain their glucose levels. An esti invention has a molecular weight of 1,000-5,000 Daltons. In mated 10% of all diabetics are totally dependent on insulin another, embodiment, the protein of the present invention has injections. a molecular weight of 5,000-10,000 Daltons. In another, 0005. Currently, the only route of insulin administration is embodiment, the protein of the present invention has a injection. Daily injection of insulin is causes considerable molecular weight of 10,000-20,000 Daltons. In another, suffering for patients. Side effects such as lipodystrophy at embodiment, the protein of the present invention has a the site of the injection, lipatrophy, lipohypertrophy, and molecular weight of 20,000-30,000 Daltons. In another, occasional hypoglycemia are known to occur. In addition, embodiment, the protein of the present invention has a Subcutaneous administration of insulin does not typically molecular weight of 40,000-50,000 Daltons. In another, provide the fine continuous regulation of metabolism that embodiment, the protein of the present invention has a occurs normally with insulin secreted from the pancreas molecular weight of 50,000-60,000 Daltons. In another, directly into the liver via the portal vein. embodiment, the protein of the present invention has a molecular weight of 60,000-70,000 Daltons. In another, 0006. The present invention addresses the need for an embodiment, the protein of the present invention has a alternate solution for administration of insulin. molecular weight of 70,000-80,000 Daltons. In another, embodiment, the protein of the present invention has a SUMMARY OF THE INVENTION molecular weight of 80,000-90,000 Daltons. In another, embodiment, the protein of the present invention has a 0007. This invention provides, in one embodiment, a com molecular weight of 90,000-100,000 Daltons. In another, position comprising a protein or a combination of proteins embodiment, the protein of the present invention has a having a molecular weight of up to 100,000 Daltons and a first molecular weight of 100,000-150,000 Daltons. protease inhibitor and a second protease inhibitor. 0016. In another embodiment, the protein has a molecular 0008. In another embodiment, the present invention pro weight (MW) of 1-50 kilodalton (kDa). In another embodi vides a method for oral administration of a protein having a ment, the MW is 1-45 kDa. In another embodiment, the MW molecular weight up to 100,000 Daltons to a subject, whereby is 1-40 kDa. In another embodiment, the MW is 1-35kDa. In a substantial fraction of the protein retains its activity after another embodiment, the MW is 1-30 kDa. In another absorption, through an intestinal mucosalbarrier of a subject, embodiment, the MW is 1-25 kDa. In another embodiment, comprising administering orally to a Subject a pharmaceutical the MW is 1-20 kDa. In another embodiment, the MW is composition comprising the protein and a first protease 10-50 kDa. In another embodiment, the MW is 15-50kDa. In inhibitor and a second protease inhibitor. another embodiment, the MW is 20-50 kDa. In another 0009. In another embodiment, the present invention pro embodiment, the MW is 25-50 kDa. In another embodiment, vides a method for treating diabetes mellitus in a subject, the MW is 30-50 kDa. In another embodiment, the MW is comprising administering orally to a Subject a pharmaceutical 35-50kDa. In another embodiment, the MW is 1-100kDa. In composition comprising insulin, Exenatide, or a combination another embodiment, the MW is 1-90 kDa. In another US 2011/0014247 A1 Jan. 20, 2011 embodiment, the MW is 1-80 kDa. In another embodiment, ment, the amount is 0.1-2 u?kg. In another embodiment, the the MW is 1-70kDa. In another embodiment, the MW is 1-60 amount is 0.2-2 u?kg. In another embodiment, the amount is kDa. In another embodiment, the MW is 10-100 kDa. In 0.3-2 u/kg. In another embodiment, the amount is 0.5-2 u/kg. another embodiment, the MW is 15-100 kDa. In another In another embodiment, the amount is 0.7-2 u/kg. In another embodiment, the MW is 20-100kDa. In another embodiment, embodiment, the amount is 1-2 u?kg. In another embodiment, the MW is 25-100 kDa. In another embodiment, the MW is the amount is 1.2-2 u?kg.
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