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(12) Patent Application Publication (10) Pub. No.: US 2015/0017238 A1 Kidron (43) Pub

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(12) Patent Application Publication (10) Pub. No.: US 2015/0017238 A1 Kidron (43) Pub US 2015.0017238A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0017238 A1 Kidron (43) Pub. Date: Jan. 15, 2015 (54) METHODS AND COMPOSITIONS FOR Publication Classification TREATING DABETES (51) Int. Cl. (71) Applicant: Oramed Ltd., Jerusalem (IL) A638/28 (2006.01) A638/57 (2006.01) (72) Inventor: Miriam Kidron, Jerusalem (IL) A638/55 (2006.01) A638/56 (2006.01) (73) Assignee: Oramed, Ltd., Jerusalem (IL) 469/48 (2006.01) A638/26 (2006.01) (21) Appl. No.: 14/370,452 (52) U.S. Cl. CPC ............... A61K 38/28 (2013.01); A61 K9/4808 (22) PCT Filed: Jan. 3, 2013 (2013.01); A61 K38/26 (2013.01); A61K38/55 (2013.01); A61 K38/56 (2013.01); A61K38/57 S371 (c)(1), USPC ............................................ 424/455; 514/6.5 Related U.S. Application Data d herein a methods and compositions for treating iabetes mellitus, concerning oral pharmaceutical composi (60) Provisional application No. 61/631,339, filed on Jan. tions comprising insulin in combination with a GLP-1 ana 3, 2012. logue. Patent Application Publication Jan. 15, 2015 Sheet 1 of 5 US 2015/001 7238A1 Patent Application Publication Jan. 15, 2015 Sheet 2 of 5 US 2015/0017238A1 Z-|| *| Patent Application Publication Jan. 15, 2015 Sheet 3 of 5 US 201S/0017238A1 e C r 5 e E O " c 3 CS S E S. s N d S 3S 3 g S S S S S. S S E R S S S Se Glucose (mg/dL) Glucose (mg/dL) d ve e 2 9. s s E cd E od s g E. E o d 833 t Sg o o d go o do o c do n r Y N were S. Glucose (mg/dL) Glucose (mg/dL) Patent Application Publication Jan. 15, 2015 Sheet 4 of 5 US 201S/0017238A1 i 2 w s E s S Glucose (mg/dL) 3 g O d C c s 3 d vs. N Glucose (mg/dL) Patent Application Publication Jan. 15, 2015 Sheet 5 of 5 US 2015/001 7238A1 control Exenatide insulin Exenatide+ insulin Glucose (mg/dL -20 O 50 100 150 Time (min) Figure 3 US 2015/001 7238 A1 Jan. 15, 2015 METHODS AND COMPOSITIONS FOR mimics physiological first-pass metabolism of insulin and TREATING DABETES GLP-1. These results provide a route to an entirely new class 0001 Benefit is claimed to U.S. Provisional Application of therapeutic modalities. 61/631,339, filed Jan. 3, 2012, which is incorporated herein 0009. The terms “protein’ and “peptide' are used inter by reference in its entirety. changeably herein. Neither term is intended to confer a limi tation of the number of amino acids present, except where a FIELD limitation is explicitly indicated. 0002. Described herein are methods and compositions for BRIEF DESCRIPTION OF THE DRAWINGS treating diabetes mellitus. 0010. The following figures are by way of illustrative BACKGROUND example and are not meant to be taken as limiting the claimed invention. 0003 Diabetes, specifically the Type II (NIDDM) variety, 0011 FIG. 1. Testing of various emulsifier formulations. has emerged in the twenty-first century as an epidemic of Foam buildup score was from 1-5, where 1 indicates no foam, global proportions. Numerous long-term complications, and 5 indicates no liquid visible because of the foam. For the including those affecting the kidneys, legs, feet, eyes, heart, Suspension test, the numbers 1-5 indicate full phase separa nerves, and blood circulation, may result from uncontrolled tion; partial phase separation with Some larger oil bubbles; diabetes. Prevention of these conditions requires comprehen small oil bubble, milky consistency; no bubbles initially, with sive treatment, requiring life style modification and medica later phase separation; and stable emulsion, respectively. tion. A number of effective anti-diabetic drugs are available and are generally safe and well tolerated. All the medications 0012 FIGS. 2A and 2B. Blood glucose profiles following become less effective as the disease progresses, and most administration of oral insulin formulations containing vari patients eventually require insulin. Most of the medications ous emulsifiers. 2A: Formulations A (upper left), B (lower are associated with risks of hypoglycemia and weight gain, left), C (upper right), and D (lower right).2B: Formulations E yet do not alter the inexorable progression of diabetes. (left) and F (right). 0004 Orally-delivered formulations for protein-based 0013 FIG. 3. Blood glucose profiles following oral drugs such as insulin are being developed by the present exenatide and oral insulin administration to pigs. Fasting, inventor (Ziv et al 1994: Nissan et al 2000, Kidronetal 2004, commercial pigs were treated with 150 mcg.eXenatide, 8 mg. Eldor et al 2010B, Eldor etal 2010C). One such oral insulin insulin, or the combination thereof, 30 minutes before caloric product is scheduled to be tested in Phase II trials and is intake. 1-mL blood samples were periodically drawn currently being reviewed for IND status. throughout the 180-minute observation period to determine 0005. The incretin hormone Glucagon-like Peptide 1 glucose concentrations. (GLP-1), Secreted within minutes of food ingestion, is asso ciated with induction of insulin release. Therapies based on DETAILED DESCRIPTION OF THE GLP-1 are treatment options for Type 2 Diabetes Mellitus EMBODIMENTS (T2DM) that act through a variety of complementary mecha 0014 Provided herein is a pharmaceutical composition for nisms. The most intriguing aspect of the incretins is the fact oral delivery, comprising an oil-based liquid formulation, the that they cause insulin release in a glucose-dependent manner oil-based liquid formulation comprising an insulin, a GLP-1 and are thought to have a low risk of inducing hypoglycemia. analogue, a trypsin inhibitor, and a chelator of divalent cat Furthermore, the incretins seem to be weight-neutral (or ions, wherein the oil-based liquid formulation is surrounded weight-reducing), preserve beta-cell mass, and possibly also by a coating or capsule that resists degradation in the stom induce neogenesis of insulin-secreting cells. ach. 0006. However, clinical use of the native GLP-1 is limited 0015. Another embodiment provides a multi-component due to its rapid enzymatic inactivation, resulting in a half-life oral pharmaceutical composition, comprising: (a) a first oil of 2-3 minutes. To overcome this obstacle, long-acting deg based liquid formulation, the first oil-based liquid formula radation-resistant peptides, both natural and synthetic, tion comprising an insulin, a trypsin inhibitor, and a chelator referred to as GLP-1 mimetic agents or analogues, have been of divalent cations; and (b) a second oil-based liquid formu designed and tested. lation, the second oil-based liquid formulation comprising a 0007 To date, GLP-1 analogues are only available as GLP-1 analogue, a trypsin inhibitor, and a chelator of divalent injectable dosage forms. The present inventor is developing cations; wherein each of the first oil-based liquid formulation an oral exenatide GLP-1 analogue capsule. A first-in-humans and the second oil-based liquid formulation is surrounded by trial (n=4) testing its safety in healthy humans demonstrated a coating or capsule that resists degradation in the stomach. In retained biological functionality of orally delivered exenatide Some embodiments, the two liquid formulations can be in (Eldor et al 2010A). separate dosage forms. In other embodiments, the two liquid formulations are in the same dosage form; for example, in SUMMARY separate encased compartments within the same pill. 0008 To the inventor's knowledge, oral insulin formula 0016 “Liquid” as used herein refers to a phase that flows tions have not been tested in combination with oral GLP-1 freely and has a constant Volume under ambient conditions. analogue formulations. The data provided herein illustrate a Fish oil, for instance, is a liquid under ambient conditions. previously-unrecognized, strong cooperative interaction The term includes oil-based solutions, Suspensions, and com between these components when formulated as described binations thereof. In alternative embodiments, the term may herein. This enables a potent anti-diabetes effect in a conve refers to a composition that has a viscosity within the range of nient form that both facilitates patent compliance and also 1-1000 millipascal seconds, inclusive, at 20°C. US 2015/001 7238 A1 Jan. 15, 2015 0017. In certain embodiments, the different components no. 141732-76-5: SEQ ID NO: 4), lixisenatide (CAS no. of a multi-component pharmaceutical composition are indi 320367-13-3), liraglutide (CAS no. 204656-20-2), exendin-9 cated for co-administration together. "Co-administration', in (CAS no. 133514-43-9), AC3174 (Leuc14)lexendin-4, this regard, may refer either to simultaneous administration Amylin Pharmaceuticals, Inc.), taspoglutide (CAS no. or, in another embodiment, to administration within 30 min 275371-94-3), albiglutide (CAS no. 782500-75-8), sema utes of each other. In still other embodiments, the different glutide (CAS no.910463-68-2), LY2189265 (DulaglutideTM: components are indicated for administration in a particular CAS no. 923950-08-7), and CJC-1 134-PC (a modified Exen order, separated by a set time interval that will typically be 30 din-4 analogue conjugated to recombinant human albumin minutes or less. For example, the insulin-containing dosage manufactured by ConjuChemTM). All CAS records were form may be indicated for administration 2-10 minutes after accessed on Dec. 19, 2011. Thus, in certain embodiments, the the exenatide-containing dosage form; in other embodiments, described method or composition utilizes any of the above 10-20 minutes after the exenatide-containing dosage form; in listed GLP-1 analogues. In other embodiments, one of the other embodiments, 20-30 minutes after the exenatide-con above-listed GLP-1 analogues is selected. Those of skill in taining dosage form; and in other embodiments, 30-60 min the art will appreciate in light of the findings of described utes after the exenatide-containing dosage form.
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