US20110046053A1 - Methods and compositions for oral administration of exenatide - Google Patents

Methods and compositions for oral administration of exenatide Download PDF

Info

Publication number
US20110046053A1
US20110046053A1 US12/990,097 US99009709A US2011046053A1 US 20110046053 A1 US20110046053 A1 US 20110046053A1 US 99009709 A US99009709 A US 99009709A US 2011046053 A1 US2011046053 A1 US 2011046053A1
Authority
US
United States
Prior art keywords
another embodiment
exenatide
amount
dosage unit
oral
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/990,097
Other languages
English (en)
Inventor
Miriam Kidron
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Oramed Ltd
Original Assignee
Oramed Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Oramed Ltd filed Critical Oramed Ltd
Priority to US12/990,097 priority Critical patent/US20110046053A1/en
Assigned to ORAMED LTD. reassignment ORAMED LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KIDRON, MARIAM
Publication of US20110046053A1 publication Critical patent/US20110046053A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/56—Protease inhibitors from plants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention provides oral compositions comprising Exenatide, and a method for administering same.
  • peptide drugs Due to improved biotechnology, the accessibility of biologically active peptides to the pharmaceutical industry has increased considerably. However, a limiting factor in the development of peptide drugs is the relative ineffectiveness when given perorally. Almost all peptide drugs are parenterally administered, although parenterally administered peptide drugs are often connected with low patient compliance.
  • Exenatide is a glucagon-like peptide (GLP-1) agonist that was approved by the Food and Drug Administration for adjunctive therapy when patients with type 2 diabetes have not been optimally controlled on metformin. It is an incretin mimetic and potentiates exenatide secretion while inhibiting glucagon secretion and slowing gastric emptying.
  • GLP-1 glucagon-like peptide
  • Exenatide (marketed as Byetta) is manufactured and marketed by Amylin Pharmaceuticals and Eli Lilly and Company. Exenatide is a synthetic version of exendin-4, a hormone in the saliva of the Gila monster, a lizard native to several Southwestern American states. Typical human responses to exenatide include improvements in the initial rapid release of endogenous insulin, suppression of pancreatic glucagon release, delayed gastric emptying, and reduced appetite—all of which function to lower blood glucose. Unlike sulfonylureas and meglitinides, exenatide increases insulin synthesis and secretion in the presence of glucose only, lessening the risk of hypoglycemia. Byetta is also being used by some physicians to treat insulin resistance.
  • Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; however, other drugs (like injectable insulin) are effective at lowering blood sugar, but can “overshoot” their target and cause blood sugar to become too low, resulting in the dangerous condition of hypoglycemia.
  • Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels).
  • Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream.
  • Exenatide has a subtle yet prolonged effect to reduce appetite and thus may prevent weight gain. Most people using Exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated that the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss and the lowest 25% experience no loss or small weight gain.
  • Exenatide reduces liver fat content. Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice and more recently in man.
  • NASH non-alcoholic fatty liver disease
  • Exenatide is a polypeptide consisting of 39 amino acids with a molecular weight of 4186.6.
  • Ex vivo human placental perfusion studies detected minimal levels on the fetal side (fetal: maternal ratio 0.017).
  • Exenatide is currently administered as a subcutaneous injection, generally concomitantly with a sulfonylurea or metformin. Although it has a modest effect on lowering fasting glucose levels, it markedly reduces postprandial glucose.
  • the present invention addresses the need for an alternate solution for administration of exenatide.
  • composition comprising an exenatide and a protease inhibitor, wherein the composition is an oral pharmaceutical composition or a rectal pharmaceutical composition.
  • the present invention provides a method for oral or rectal administration of exenatide to a subject, whereby a substantial fraction of exenatide retains its activity after absorption, through an intestinal mucosal barrier or through a rectal tissue of said subject, comprising administering orally or rectally to a subject a pharmaceutical composition comprising said exenatide.
  • the present invention provides a method for treating diabetes mellitus in a subject, comprising administering orally or rectally to a subject a pharmaceutical composition comprising exenatide, thereby treating diabetes mellitus.
  • the present invention provides a method for reducing food intake in a subject, comprising administering orally or rectally to a subject a pharmaceutical composition comprising exenatide, thereby reducing food intake in a subject.
  • the present invention provides a method for reducing gastric motility in a subject, comprising administering orally or rectally to a subject a pharmaceutical composition comprising exenatide, thereby reducing gastric motility in a subject.
  • the present invention provides a method for lowering plasma glucagon in a subject, comprising administering orally or rectally to said subject a pharmaceutical composition comprising exenatide, thereby lowering plasma glucagon in a subject.
  • FIG. 1 Is a graph showing the blood glucose lowering effect of an Exendin-4-oral dosage form compared to control in dogs.
  • FIG. 2 Is a graph comparing the blood glucose lowering effect of an Exendin-4 in a rectal dosage form (hard gelatin capsule, 100 ⁇ g Excedrin-4), injectable dosage forms (2.5 ⁇ g Byetta GeneScript and 2.5 ⁇ g Byetta Commercial), and control in dogs, the values are calculated as ⁇ time 0 (the concentration of blood glucose at time 0 was deducted from each value obtained at a given time).
  • FIG. 3 Is a graph comparing the blood glucose lowering effect of an Exendin-4 in an oral dosage form (100 ⁇ g Excedrin-4), control, and injectable dosage forms (2.5 ⁇ g Byetta GeneScript and 2.5 ⁇ g Byetta Commercial) in dogs (the concentration of blood glucose at time 0 was deducted from each value obtained at a given time).
  • compositions and methods comprising exenatide and an omega-3 fatty acid.
  • the present invention provides compositions and methods comprising exenatide and a protease inhibitor.
  • the present invention provides compositions and methods comprising exenatide and an enhancer such as EDTA and salts thereof such as Na-EDTA.
  • the present invention provides compositions and methods comprising exenatide and Na-EDTA.
  • the present invention provides compositions and methods comprising exenatide, omega-3 fatty acid, and Na-EDTA.
  • the present invention provides oral compositions comprising exenatide.
  • the present invention provides oral compositions comprising exenatide and Na-EDTA.
  • the present invention provides oral compositions comprising exenatide, omega-3 fatty acid, and Na-EDTA. In another embodiment, the present invention provides rectal compositions comprising exenatide and Na-EDTA. In another embodiment, the present invention provides rectal compositions comprising exenatide, omega-3 fatty acid, and Na-EDTA. In one embodiment, the present invention provides a composition comprising exenatide and an omega-3 fatty acid. As provided herein (Examples), such compositions have utility in the oral administration of exenatide, whereby the exenatide is absorbed by the intestines into the bloodstream in an active form.
  • exenatide is designated AC2993 and is a synthetic exendin-4.
  • exenatide is a 39—amino acid peptide.
  • exenatide comprises the amino acid sequence: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 1).
  • exenatide comprises an amino acid sequence having at least 70% identity to SEQ ID NO: 1.
  • exenatide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 1.
  • exenatide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 1. In another embodiment, exenatide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 1. In another embodiment, exenatide comprises an amino acid sequence having at least 99% identity to SEQ ID NO: 1.
  • exenatide oral or rectal formulation of the invention is effective for diabetic therapy.
  • exenatide oral or rectal formulation of the invention enhances insulin secretion.
  • exenatide enhances glucose-dependent insulin secretion.
  • exenatide oral or rectal formulation of the invention suppresses high glucagon secretion.
  • exenatide oral or rectal formulation of the invention slows of gastric-emptying rate.
  • exenatide oral or rectal formulation of the invention binds to the pancreatic glucagon-like peptide-1 (GLP-1) receptor.
  • exenatide oral or rectal formulation of the invention reduces food intake.
  • exenatide oral or rectal formulation of the invention causes weight loss.
  • exenatide oral or rectal formulation of the invention comprises an insulin-sensitizing effect.
  • exenatide oral or rectal formulation of the invention improves glycemic control among patients with type 2 diabetes.
  • exenatide oral or rectal formulation of the invention improves glycemic control among patients with type 2 diabetes treated with sulfonylureas or metformin, alone or in combination.
  • exenatide is Exendin-4 comprising 53% amino acid sequence overlap with mammalian GLP-1.
  • oral or rectal formulation comprising exenatide is resistant to DPP-IV degradation.
  • oral or rectal formulation comprising exenatide reduces postprandial glycemia.
  • oral or rectal formulation comprising exenatide induces the release of insulin and Amylin.
  • oral or rectal formulation comprising exenatide is not associated with weight gain.
  • oral or rectal formulation comprising exenatide reduces postprandial serum triglyceride concentrations.
  • oral or rectal formulation comprising exenatide cause less adverse events than an injectable formulation comprising exenatide.
  • treatment with oral or rectal formulation comprising exenatide does not cause nausea. In another embodiment, treatment with oral or rectal formulation comprising exenatide cause only mild nausea. In another embodiment, treatment with oral or rectal formulation comprising exenatide does not cause gastroparesis.
  • the amount of Exenatide in a formulation as described herein is 10 mcg to 1 mg. In another embodiment, the amount of Exenatide in a formulation as described herein is 10 mcg to 25 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 25 mcg to 50 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 50 mcg to 60 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 60 mcg to 70 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 70 mcg to 80 mcg.
  • the amount of Exenatide in a formulation as described herein is 80 mcg to 90 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 90 mcg to 100 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 100 mcg to 110 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 110 mcg to 125 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 125 mcg to 150 mcg.
  • the amount of Exenatide in a formulation as described herein is 150 mcg to 175 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 175 mcg to 200 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 200 mcg to 220 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 220 mcg to 240 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 240 mcg to 260 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 260 mcg to 300 mcg.
  • the amount of Exenatide in a formulation as described herein is 300 meg to 350 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 350 mcg to 400 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 400 mcg to 450 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 450 mcg to 500 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 550 mcg to 600 mcg.
  • the amount of Exenatide in a formulation as described herein is 600 mcg to 700 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 700 mcg to 800 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 800 mcg to 900 mcg. In another embodiment, the amount of Exenatide in a formulation as described herein is 900 mcg to 1 mg.
  • the Exenatide formulation as described herein is taken once a day. In another embodiment, the Exenatide formulation as described herein is taken twice a day. In another embodiment, the Exenatide formulation as described herein is taken three times a day. In another embodiment, the Exenatide formulation as described herein is taken four times a day. In another embodiment, the Exenatide formulation as described herein is taken five times a day. In another embodiment, one of skill in the art determines the dosage of Exenatide formulation as described herein. In another embodiment, one of skill in the art determines the daily dose of a Exenatide formulation as described herein. In another embodiment, one of skill in the art determines the daily dosing regimen of a Exenatide formulation as described herein.
  • the Exenatide formulation as described herein is taken at least 15 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 30 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 45 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 60 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 75 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 90 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 100 minutes before a meal.
  • the Exenatide formulation as described herein is taken at least 120 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 150 minutes before a meal. In another embodiment, the Exenatide formulation as described herein is taken at least 180 minutes before a meal.
  • the Exenatide formulation as described herein reduces the side effects associated with an injectable dosage form comprising Exenatide. In another embodiment, the Exenatide formulation as described herein reduces nausea as a side effect which is associated with an injectable dosage form comprising Exenatide. In another embodiment, the Exenatide formulation as described herein does not induce nausea as a side effect which is associated with an injectable dosage form comprising Exenatide.
  • sustained release dosage forms e.g. sustained release micro encapsulation
  • the use of sustained release dosage forms enables the treatment frequency to be reduced to once or twice a day.
  • the exenatide dosage is increased correspondingly with decreasing frequency of administration.
  • exenatide levels represent a separate embodiment of the present invention.
  • Methods of measuring exenatide levels are well known in the art.
  • levels of C peptide are measured as well, to determine the relative contributions of endogenous and exogenous exenatide to observed rises in exenatide levels.
  • exenatide levels are measured by any other method known in the art. Each possibility represents a separate embodiment of the present invention.
  • omega-3 fatty acid is derived from vegetable sources such as the seeds of chia, perilla, flax, walnuts, purslane, lingonberry, seabuckthorn, and hemp. In some embodiments, omega-3 fatty acids can also be found in the fruit of the acai palm. In another embodiment, the omega-3 fatty acid has been provided in the form of a synthetic omega-3 fatty acid. In one embodiment, the omega-3 fatty acid of methods and compositions of the present invention has been provided to the composition in the form of a fish oil. In another embodiment, the omega-3 fatty acid has been provided in the form of canola oil. In another embodiment, the omega-3 fatty acid has been provided in the form of flaxseed oil.
  • omega-3 fatty acid has been provided in the form of any other omega-3 fatty acid-rich source known in the art.
  • the omega-3 fatty acid has been provided in the form of a synthetic omega-3 fatty acid.
  • Each form of omega-3 fatty acids represents a separate embodiment of the present invention.
  • the omega-3 fatty acid of methods and compositions of the present invention is an omega-3 polyunsaturated fatty acid.
  • the omega-3 fatty acid is DHA, an omega-3, polyunsaturated, 22-carbon fatty acid also referred to as 4, 7, 10, 13, 16, 19-docosahexaenoic acid.
  • the omega-3 fatty acid is ⁇ -linolenic acid (9, 12, 15-octadecatrienoic acid).
  • the omega-3 fatty acid is stearidonic acid (6, 9, 12, 15-octadecatetraenoic acid).
  • the omega-3 fatty acid is eicosatrienoic acid (ETA; 11, 14, 17-eicosatrienoic acid). In another embodiment, the omega-3 fatty acid is eicosatetraenoic acid (8, 11, 14, 17-eicosatetraenoic acid). In one embodiment, the omega-3 fatty acid is eicosapentaenoic acid (EPA; 5, 8, 11, 14, 17-eicosapentaenoic acid): In another embodiment, the omega-3 fatty acid is eicosahexaenoic acid (also referred to as “EPA”; 5, 7, 9, 11, 14, 17-eicosahexaenoic acid).
  • the omega-3 fatty acid is docosapentaenoic acid (DPA; 7, 10, 13, 16, 19-docosapenatenoic acid). In another embodiment, the omega-3 fatty acid is tetracosahexaenoic acid (6, 9, 12, 15, 18, 21-tetracosahexaenoic acid). In another embodiment, the omega-3 fatty acid is any other omega-3 fatty acid known in the art. Each omega-3 fatty acid represents a separate embodiment of the present invention.
  • compositions of the present invention further comprise a protease inhibitor.
  • compositions of the present invention further comprise a combination of at least two protease inhibitors.
  • protease inhibitors enhance the ability of omega-3 fatty acids to protect exenatide and facilitate its absorption in the intestine.
  • protease inhibitor inhibits the function of peptidases.
  • protease inhibitors enhance the ability of omega-3 fatty acids to protect the protein of the present invention and facilitate its absorption in the intestine.
  • the protease inhibitor of the present invention is a protein.
  • protease inhibitors comprise cysteine protease inhibitors, serine protease inhibitors (serpins), trypsin inhibitors, threonine protease inhibitors, aspartic protease inhibitors, metallo protease inhibitors.
  • protease inhibitors comprise suicide inhibitor, transition state inhibitor, or chelating agents.
  • the protease inhibitor is soybean trypsin inhibitor (SBTI).
  • the protease inhibitor is AEBSF-HCl.
  • the inhibitor is (epsilon)-aminocaproic acid.
  • the inhibitor is (alpha) 1-antichymotypsin.
  • the inhibitor is antipain.
  • the inhibitor is antithrombin III.
  • the inhibitor is (alpha) 1-antitrypsin ([alpha] 1-proteinase inhibitor).
  • the inhibitor is APMSF-HCl (4-amidinophenyl-methane sulfonyl-fluoride).
  • the inhibitor is sprotinin.
  • the inhibitor is benzamidine-HCl. In another embodiment, the inhibitor is chymostatin. In another embodiment, the inhibitor is DFP (diisopropylfluoro-phosphate). In another embodiment, the inhibitor is leupeptin. In another embodiment, the inhibitor is PEFABLOC® SC (4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride). In another embodiment, the inhibitor is PMSF (phenylmethyl sulfonyl fluoride). In another embodiment, the inhibitor is TLCK (1-Chloro-3-tosylamido-7-amino-2-heptanone HCl).
  • the inhibitor is TPCK (1-Chloro-3-tosylamido-4-phenyl-2-butanone).
  • the inhibitor is trypsin inhibitor from egg white (Ovomucoid).
  • the inhibitor is trypsin inhibitor from soybean.
  • the inhibitor is aprotinin.
  • the inhibitor is pentamidine isethionate.
  • the inhibitor is pepstatin.
  • the inhibitor is guanidium. In another embodiment, the inhibitor is alpha2-macroglobulin. In another embodiment, the inhibitor is a chelating agent of zinc. In another embodiment, the inhibitor is iodoacetate. In another embodiment, the inhibitor is zinc.
  • the amount of protease inhibitor utilized in methods and compositions of the present invention is 0.1 mg/dosage unit. In another embodiment, the amount of protease inhibitor is 0.2 mg/dosage unit. In another embodiment, the amount is 0.3 mg/dosage unit. In another embodiment, the amount is 0.4 mg/dosage unit. In another embodiment, the amount is 0.6 mg/dosage unit.
  • the amount is 0.8 mg/dosage unit. In another embodiment, the amount is 1 mg/dosage unit. In another embodiment, the amount is 1.5 mg/dosage unit. In another embodiment, the amount is 2 mg/dosage unit. In another embodiment, the amount is 2.5 mg/dosage unit. In another embodiment, the amount is 3 mg/dosage unit. In another embodiment, the amount is 5 mg/dosage unit. In another embodiment, the amount is 7 mg/dosage unit. In another embodiment, the amount is 10 mg/dosage unit. In another embodiment, the amount is 12 mg/dosage unit. In another embodiment, the amount is 15 mg/dosage unit.
  • the amount is 20 mg/dosage unit. In another embodiment, the amount is 30 mg/dosage unit. In another embodiment, the amount is 50 mg/dosage unit. In another embodiment, the amount is 70 mg/dosage unit. In another embodiment, the amount is 100 mg/dosage unit.
  • the amount of protease inhibitor is 0.1-1 mg/dosage unit. In another embodiment, the amount of protease inhibitor is 0.2-1 mg/dosage unit. In another embodiment, the amount is 0.3-1 mg/dosage unit. In another embodiment, the amount is 0.5-1 mg/dosage unit. In another embodiment, the amount is 0.1-2 mg/dosage unit. In another embodiment, the amount is 0.2-2 mg/dosage unit. In another embodiment, the amount is 0.3-2 mg/dosage unit. In another embodiment, the amount is 0.5-2 mg/dosage unit. In another embodiment, the amount is 1-2 mg/dosage unit. In another embodiment, the amount is 1-10 mg/dosage unit.
  • the amount is 2-10 mg/dosage unit. In another embodiment, the amount is 3-10 mg/dosage unit. In another embodiment, the amount is 5-10 mg/dosage unit. In another embodiment, the amount is 1-20 mg/dosage unit. In another embodiment, the amount is 2-20 mg/dosage unit. In another embodiment, the amount is 3-20 mg/dosage unit. In another embodiment, the amount is 5-20 mg/dosage unit. In another embodiment, the amount is 10-20 mg/dosage unit. In another embodiment, the amount is 10-100 mg/dosage unit. In another embodiment, the amount is 20-100 mg/dosage unit. In another embodiment, the amount is 30-100 mg/dosage unit.
  • the amount is 50-100 mg/dosage unit. In another embodiment, the amount is 10-200 mg/dosage unit. In another embodiment, the amount is 20-200 mg/dosage unit. In another embodiment, the amount is 30-200 mg/dosage unit. In another embodiment, the amount is 50-200 mg/dosage unit. In another embodiment, the amount is 100-200 mg/dosage unit.
  • the amount of protease inhibitor utilized in methods and compositions of the present invention is 1000 k.i.u. (kallikrein inactivator units)/pill. In another embodiment, the amount is 10 k.i.u./dosage units. In another embodiment, the amount is 12 k.i.u./dosage unit. In another embodiment, the amount is 15 k.i.u./dosage units. In another embodiment, the amount is 20 k.i.u./dosage unit. In another embodiment, the amount is 30 k.i.u./dosage units. In another embodiment, the amount is 40 k.i.u./dosage unit.
  • the amount is 50 k.i.u./dosage units. In another embodiment, the amount is 70 k.i.u./dosage units. In another embodiment, the amount is 100 k.i.u./dosage unit. In another embodiment, the amount is 150 k.i.u./dosage unit. In another embodiment, the amount is 200 k.i.u./dosage units. In another embodiment, the amount is 300 k.i.u./dosage unit. In another embodiment, the amount is 500 k.i.u./dosage units. In another embodiment, the amount is 700 k.i.u./dosage units.
  • the amount is 1500 k.i.u./dosage unit. In another embodiment, the amount is 3000 k.i.u./dosage unit. In another embodiment, the amount is 4000 k.i.u./dosage unit. In another embodiment, the amount is 5000 k.i.u./dosage unit.
  • protease inhibitor represents a separate embodiment of the present invention.
  • the protease targeted by the protease inhibitor of methods and compositions of the present invention is a serine protease.
  • the protease is trypsin.
  • the protease is chymotrypsin.
  • the protease is carboxypeptidase.
  • the protease is aminopeptidase.
  • the protease is any other protease that functions in the duodenum or the small intestine. Each possibility represents a separate embodiment of the present invention.
  • compositions of the present invention further comprise a substance that enhances absorption of the exenatide through an intestinal mucosal barrier.
  • a substance that enhances absorption of the exenatide through an intestinal mucosal barrier is referred to herein as an “enhancer.”
  • enhancers when used together with omega-3 fatty acids, enhance the ability of exenatide to be absorbed in the intestine.
  • the enhancer is didecanoylphosphatidylcholine (DDPC).
  • the enhancer is a chelating agent such as ethylenediaminetetraacetic acid (EDTA) or egtazic acid EGTA.
  • EDTA is sodium-EDTA.
  • the enhancer is NO donor.
  • the enhancer is a bile acid, glycine-conjugated form of a bile acid, or an alkali metal salt.
  • absorption enhancement is achieved through utilization of a combination of ⁇ -galactosidase and ⁇ -mannanase.
  • the enhancer is a fatty acid such as sodium caprate. In one embodiment, the enhancer is sodium glycocholate. In one embodiment, the enhancer is sodium salicylate. In one embodiment, the enhancer is n-dodecyl- ⁇ -D-maltopyranoside. In some embodiments, surfactants serve as absorption enhancer. In one embodiment, the enhancer is chitisan such as N,N,N-trimethyl chitosan chloride (TMC).
  • TMC N,N,N-trimethyl chitosan chloride
  • NO donors of the present invention comprise 3-(2-Hydroxy-1-(1-methylethyl)-2-nitrosohydrazino)-1-propanamine, N-ethyl-2-(1-ethyl-hydroxy-2-nitro sohydrazino)-ethanamine, or S-Nitroso-N-acetylpenicillamine
  • the bile acid is cholic acid. In another embodiment, the bile acid is chenodeoxycholic acid. In another embodiment, the bile acid is taurocholic acid. In another embodiment, the bile acid is taurochenodeoxycholic acid. In another embodiment, the bile acid is glycocholic acid. In another embodiment, the bile acid is glycochenocholic acid. In another embodiment, the bile acid is 3 beta-monohydroxychloric acid. In another embodiment, the bile acid is lithocholic acid. In another embodiment, the bile acid is 5 beta-cholanic acid. In another embodiment, the bile acid is 3,12-diol-7-one-5 beta-cholanic acid.
  • the bile acid is 3 alpha-hydroxy-12-ketocholic acid. In another embodiment, the bile acid is 3 beta-hydroxy-12-ketocholic acid. In another embodiment, the bile acid is 12 alpha-3 beta-dihydrocholic acid. In another embodiment, the bile acid is ursodesoxycholic acid.
  • the enhancer is a nonionic surfactant.
  • the enhancer is a nonionic polyoxyethylene ether surface active agent (e.g one having an HLB value of 6 to 19, wherein the average number of polyoxyethylene units is 4 to 30).
  • the enhancer is an anionic surface active agent.
  • the enhancer is a cationic surface active agent.
  • the enhancer is an ampholytic surface active agent.
  • zwitteruionic surfactants such as acylcarnitines serve as absorption enhancers.
  • the amount of enhancer utilized in methods and compositions of the present invention is 0.1 mg/dosage unit. In another embodiment, the amount of enhancer is 0.2 mg/dosage unit. In another embodiment, the amount is 0.3 mg/dosage unit. In another embodiment, the amount is 0.4 mg/dosage unit. In another embodiment, the amount is 0.6 mg/dosage unit. In another embodiment, the amount is 0.8 mg/dosage unit. In another embodiment, the amount is 1 mg/dosage unit. In another embodiment, the amount is 1.5 mg/dosage unit. In another embodiment, the amount is 2 mg/dosage unit. In another embodiment, the amount is 2.5 mg/dosage unit.
  • the amount is 3 mg/dosage unit. In another embodiment, the amount is 5 mg/dosage unit. In another embodiment, the amount is 7 mg/dosage unit. In another embodiment, the amount is 10 mg/dosage unit. In another embodiment, the amount is 12 mg/dosage unit. In another embodiment, the amount is 15 mg/dosage unit. In another embodiment, the amount is 20 mg/dosage unit. In another embodiment, the amount is 30 mg/dosage unit. In another embodiment, the amount is 50 mg/dosage unit. In another embodiment, the amount is 70 mg/dosage unit. In another embodiment, the amount is 100 mg/dosage unit.
  • the amount of enhancer is 0.1-1 mg/dosage unit. In another embodiment, the amount of enhancer is 0.2-1 mg/dosage unit. In another embodiment, the amount is 0.3-1 mg/dosage unit. In another embodiment, the amount is 0.5-1 mg/dosage unit. In another embodiment, the amount is 0.1-2 mg/dosage unit. In another embodiment, the amount is 0.2-2 mg/dosage unit. In another embodiment, the amount is 0.3-2 mg/dosage unit. In another embodiment, the amount is 0.5-2 mg/dosage unit. In another embodiment, the amount is 1-2 mg/dosage unit. In another embodiment, the amount is 1-10 mg/dosage unit.
  • the amount is 2-10 mg/dosage unit. In another embodiment, the amount is 3-10 mg/dosage unit. In another embodiment, the amount is 5-10 mg/dosage unit. In another embodiment, the amount is 1-20 mg/dosage unit. In another embodiment, the amount is 2-20 mg/dosage unit. In another embodiment, the amount is 3-20 mg/dosage unit. In another embodiment, the amount is 5-20 mg/dosage unit. In another embodiment, the amount is 10-20 mg/dosage unit. In another embodiment, the amount is 10-100 mg/dosage unit. In another embodiment, the amount is 20-100 mg/dosage unit. In another embodiment, the amount is 30-100 mg/dosage unit.
  • the amount is 50-100 mg/dosage unit. In another embodiment, the amount is 10-200 mg/dosage unit. In another embodiment, the amount is 20-200 mg/dosage unit. In another embodiment, the amount is 30-200 mg/dosage unit. In another embodiment, the amount is 50-200 mg/dosage unit. In another embodiment, the amount is 100-200 mg/dosage unit.
  • compositions of the present invention further comprise a coating that inhibits digestion of the composition in the stomach of a subject.
  • coating inhibits digestion of the composition in the stomach of a subject.
  • the coated dosage forms of the present invention release drug when pH move towards alkaline range.
  • coating is a monolayer, wherein in other embodiments coating applied in multilayers.
  • coating is a bioadhesive polymer that selectively binds the intestinal mucosa and thus enables drug release in the attachment site.
  • the enteric coating is an enteric film coating.
  • coating comprises biodegradable polysaccharide, chitosan, aquateric aqueous, aquacoat ECD, azo polymer, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropylmethyl cellulose phthalate, gelatin, poly vinyl acetate phthalate, hydrogel, pulsincap, or a combination thereof.
  • pH sensitive coating will be used according to the desired release site and/or profile as known to one skilled in the art.
  • the coating is an enteric coating.
  • Methods for enteric coating are well known in the art, and are described, for example, in Siepmann F, Siepmann J et al, Blends of aqueous polymer dispersions used for pellet coating: importance of the particle size. J Control Release 2005; 105(3): 226-39; and Huyghebaert N, Vermeire A, Remon J P. In vitro evaluation of coating polymers for enteric coating and human ileal targeting. Int J Pharm 2005; 298(1): 26-37. Each method represents a separate embodiment of the present invention.
  • Eudragit® an acrylic polymer
  • enteric coating an acrylic polymer
  • acrylic polymers for the coating of pharmaceutical preparations is well known in the art.
  • Eudragit Acrylic Polymers have been shown to be safe, and are neither absorbed nor metabolized by the body, but rather are eliminated.
  • the coating is a gelatin coating.
  • microencapsulation is used to protect the exenatide against decomposition in the stomach. Methods for applying a gelatin coating and for microencapsulation are well known in the art. Each method represents a separate embodiment of the present invention.
  • the coating is a film-coating.
  • the coating is ethylcellulose.
  • the coating is a water-based dispersion of ethylcellulose, e.g. hydroxypropylmethylcellulose (HPMC) E15.
  • the coating is a gastro-resistant coatings, e.g. a polymer containing carboxylic acid groups as a functional moiety.
  • the coating is a monolithic matrix.
  • the coating is a cellulose ether (e.g. hypromellose (HPMC).
  • HPMC hypromellose
  • a multiparticulate dosage forms is used to inhibit digestion of the composition in the stomach.
  • Each type of coating, dosage form, etc, that inhibits digestion of the composition in the stomach represents a separate embodiment of the present invention.
  • the present invention provides a method for oral or rectal administration of a exenatide to a subject, whereby a substantial fraction of the exenatide retains its activity after absorption through an intestinal mucosal barrier or rectal mucosal barrier of the subject, comprising administering orally or rectally to the subject a pharmaceutical composition comprising exenatide and a protease inhibitor, thereby orally or rectally administering exenatide to a subject.
  • the present invention provides a method for oral or rectal administration of a exenatide to a subject, whereby a substantial fraction of the exenatide retains its activity after absorption through an intestinal mucosal barrier or rectal mucosal barrier of the subject, comprising administering orally or rectally to the subject a pharmaceutical composition comprising exenatide and an omega-3 fatty acid.
  • the present invention provides a method for treating diabetes mellitus in a subject, comprising administering orally or rectally to the subject a pharmaceutical composition comprising an exenatide and an omega-3 fatty acid, thereby treating diabetes mellitus.
  • the diabetes mellitus is Type I diabetes. In another embodiment, the diabetes mellitus is Type II diabetes. In another embodiment, the diabetes mellitus is insulin-dependent diabetes. In another embodiment, the diabetes mellitus is non-insulin-dependent diabetes. In another embodiment, the diabetes mellitus is any other type of diabetes known in the art. Each possibility represents a separate embodiment of the present invention.
  • six treatments a day of the exenatide composition are administered. In one embodiment, five treatments a day of the exenatide composition are administered. In another embodiment, four treatments a day of the exenatide composition are administered. In another embodiment, three treatments a day of the exenatide composition are administered. In another embodiment, two treatments a day are administered. In another embodiment, four treatments a day are administered. In another embodiment, one treatment a day is administered. In another embodiment, more than four treatments a day are administered. Each possibility represents a separate embodiment of the present invention.
  • exenatide plasma concentrations rise rapidly and reach median peak plasma concentrations in 1.5-3 hours. In another embodiment, following oral or rectal administration exenatide concentrations are measurable for approximately 10 hours postdose.
  • following 2 days of exenatide oral or rectal administration a reduction in mean HbAlC is observed. In another embodiment, following 3 days of exenatide oral or rectal administration a reduction in mean HbAlC is observed. In another embodiment, following 4 days of exenatide oral or rectal administration a reduction in mean HbAlC is observed. In another embodiment, following 5 days of exenatide oral or rectal administration a reduction in mean HbAlC is observed.
  • exenatide 20-300 mcg dosed administered before a meal results in reduction in postprandial glucose excursions. Additionally, the incidence of transient low blood glucose was higher when patients received exenatide administered after a meal.
  • exenatide 20-300 mcg should be administered within the 180 minute period before the meal.
  • exenatide 20-300 mcg should be administered within the 150 minute period before the meal.
  • exenatide 20-300 mcg should be administered within the 120 minute period before the meal.
  • exenatide 20-300 mcg should be administered within the 90 minute period before the meal.
  • exenatide 20-300 mcg should be administered within the 60 minute period before the meal.
  • exenatide 20-300 mcg should be administered within the 30 minute period before the meal.
  • Exenatide is indicated for treatment of type 1 diabetes mellitus. In another embodiment, Exenatide is indicated for treatment of type 2 diabetes mellitus (DM) in combination with metformin, and/or sulfonylureas in patients who have not achieved adequate glycemic control on maximally tolerated doses. In another embodiment, Exenatide is indicated for treatment of type 2 diabetes mellitus (DM) in combination with metformin. In another embodiment, Exenatide is indicated for treatment of type 2 diabetes mellitus (DM) in combination with sulfonylureas. In another embodiment, Exenatide of the invention is formulated in a single dosage form in combination with a sulfonylurea. In another embodiment, Exenatide of the invention is formulated in a single dosage form in combination with metformin.
  • Exenatide formulations of the present invention are useful in view of their pharmacological properties.
  • Exenatide formulations of the present invention possess glucagon levels reduction activity.
  • Exenatide formulations of the present invention suppress glucagon secretion.
  • Exenatide formulations of the present invention suppress glucagon secretion, as evidenced by the ability to lower glucagon levels in animals and humans.
  • Exenatide formulations of the present invention are used to treat conditions or diseases that can be alleviated by reducing glucagon levels and suppressing glucagon secretion.
  • the compounds referenced above may form salts with various inorganic and organic acids and bases.
  • Such salts include salts prepared with organic and inorganic acids, for example, HCl, HBr, H 2 SO 4 , H 3 PO 4 , trifluoroacetic acid, acetic acid, formic acid, methanesulfonic acid, toluenesulfonic acid, maleic acid, fumaric acid and camphorsulfonic acid.
  • Salts prepared with bases include ammonium salts, alkali metal salts, e.g., sodium and potassium salts, and alkali earth salts, e.g., calcium and magnesium salts.
  • Acetate, hydrochloride, and trifluoroacetate salts are preferred.
  • the salts may be formed by conventional means, as by reacting the free acid or base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the ions of an existing salt for another ion on a suitable ion exchange resin.
  • Exenatide formulations of the present invention are useful in preventing obesity. In another embodiment, Exenatide formulations of the present invention are useful in preventing excess adipose tissue. In another embodiment, Exenatide formulations of the present invention are useful in preventing health risks associated with enhanced food intake. In another embodiment, Exenatide formulations of the present invention are useful in preventing diseases associated with obesity such as Type 2 diabetes, increased cardiac risk, hypertension, atherosclerosis, degenerative arthritis, and increased incidence of complications of surgery involving general anesthesia. In another embodiment, Exenatide formulations of the present invention are useful in treating diseases associated with obesity such as Type 2 diabetes, increased cardiac risk, hypertension, atherosclerosis, degenerative arthritis, and increased incidence of complications of surgery involving general anesthesia.
  • Exenatide formulations of the present invention are useful in reducing the risk of developing diseases associated with obesity such as Type 2 diabetes, increased cardiac risk, hypertension, atherosclerosis, degenerative arthritis, and increased incidence of complications of surgery involving general anesthesia.
  • Exenatide formulations of the present invention are useful in controlling body weight. In another embodiment, Exenatide formulations of the present invention are useful in maintaining body weight. In another embodiment, Exenatide formulations of the present invention are useful in reducing food intake. In another embodiment, Exenatide formulations of the present invention are useful in reducing food intake in obese subjects. In another embodiment, Exenatide formulations of the present invention are useful in decreasing the plasma glucose level. In another embodiment, Exenatide formulations of the present invention are useful in decreasing the plasma lipid level. In another embodiment, Exenatide formulations of the present invention are useful in preventing hypernutrition. In another embodiment, Exenatide formulations of the present invention are useful in treating hypernutrition.
  • the present invention provides a composition for oral or rectal administration of exenatide, comprising an exenatide protein and a protease inhibitor, whereby a substantial fraction of the exenatide retains the enzymatic activity after absorption through an intestinal mucosal barrier of a subject.
  • the present invention provides a composition for oral or rectal administration of exenatide, comprising an exenatide protein and an enhancer, whereby a substantial fraction of the exenatide retains the enzymatic activity after absorption through an intestinal mucosal barrier of a subject.
  • the present invention provides a composition for oral or rectal administration of exenatide, comprising an exenatide protein and an omega-3 fatty acid, whereby a substantial fraction of the exenatide retains the enzymatic activity after absorption through an intestinal mucosal barrier of a subject.
  • the present invention provides the use of exenatide and a protease inhibitor in the manufacture of a medicament for oral or rectal administration of exenatide to a subject, whereby a substantial fraction of exenatide retains its activity after absorption through an intestinal mucosal barrier of the subject.
  • the present invention provides the use of exenatide and an enhancer in the manufacture of a medicament for oral or rectal administration of exenatide to a subject, whereby a substantial fraction of exenatide retains its activity after absorption through an intestinal mucosal barrier of the subject.
  • the present invention provides the use of exenatide and an omega-3 fatty acid in the manufacture of a medicament for oral or rectal administration of exenatide to a subject, whereby a substantial fraction of exenatide retains its activity after absorption through an intestinal mucosal barrier of the subject.
  • the present invention provides the use of an exenatide protein and a protease inhibitor in the manufacture of a medicament for treating diabetes mellitus in a subject. In one embodiment, the present invention provides the use of an exenatide protein and an enhancer in the manufacture of a medicament for treating diabetes mellitus in a subject. In one embodiment, the present invention provides the use of an exenatide protein and an omega-3 fatty acid in the manufacture of a medicament for treating diabetes mellitus in a subject.
  • compositions of the present composition are absorbed at different rates from the intestinal lumen into the blood stream.
  • the absorption of the bile acid in one embodiment, is significantly faster than the absorption of exenatide.
  • a drug regimen involving ingestion of a pair of pills at spaced intervals e.g., a second pill containing a higher concentration of enhancer is taken at a defined interval (e.g. 30 minutes) after the first pill.
  • a defined interval e.g. 30 minutes
  • certain of the constituents are microencapsulated to enhance the absorption of the exenatide into the system.
  • a treatment protocol of the present invention is therapeutic. In another embodiment, the protocol is prophylactic. Each possibility represents a separate embodiment of the present invention.
  • the present invention provides oral or rectal administration of exenatide which is comparable to previous injectable dosage forms of exenatide. In another embodiment, the present invention provides superior oral or rectal administration of exenatide compared to previous injectable dosage forms of exenatide. In another embodiment, oral or rectal administration of exenatide is cheaper than injectable dosage forms of exenatide. In another embodiment, oral or rectal administration of exenatide provides better compliance than injectable dosage forms of exenatide. In another embodiment, oral or rectal administration of exenatide provides fewer side effects than injectable dosage forms of exenatide.
  • solid carriers/diluents for use in methods and compositions of the present invention include, but are not limited to, a gum, a starch (e.g. corn starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e.g. polymethylacrylate), calcium carbonate, magnesium oxide, talc, or mixtures thereof.
  • a gum e.g. corn starch, pregeletanized starch
  • a sugar e.g., lactose, mannitol, sucrose, dextrose
  • a cellulosic material e.g. microcrystalline cellulose
  • an acrylate e.g. polymethylacrylate
  • compositions further comprise binders (e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g.
  • binders e.g. acacia, cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone
  • disintegrating agents e.g.
  • cornstarch potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate), buffers (e.g., Tris-HCl, acetate, phosphate) of various pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g.
  • sodium lauryl sulfate permeation enhancers
  • solubilizing agents e.g., glycerol, polyethylene glycerol
  • anti-oxidants e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole
  • stabilizers e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose
  • viscosity increasing agents e.g. carbomer, colloidal silicon dioxide, ethyl cellulose, guar gum
  • sweeteners e.g. aspartame, citric acid
  • preservatives e.g., Thimerosal, benzyl alcohol, parabens
  • lubricants e.g.
  • stearic acid magnesium stearate, polyethylene glycol, sodium lauryl sulfate), flow-aids (e.g. colloidal silicon dioxide), plasticizers (e.g. diethyl phthalate, triethyl citrate), emulsifiers (e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e.g., poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethacrylates) and/or adjuvants.
  • plasticizers e.g. diethyl phthalate, triethyl citrate
  • emulsifiers e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate
  • polymer coatings e.g., poloxamers or poloxamines
  • coating and film forming agents e.g. ethyl cellulose
  • the dosage forms of the present invention are formulated to achieve an immediate release profile, an extended release profile, or a delayed release profile.
  • the release profile of the composition is determined by using specific excipients that serve for example as binders, disintegrants, fillers, or coating materials.
  • the composition will be formulated to achieve a particular release profile as known to one skilled in the art.
  • the oral or rectal formulation of the present invention is further formulated to accomplish sustained release of Exenatide. In another embodiment, the oral or rectal formulation of the present invention is further formulated to accomplish immediate release of Exenatide. In another embodiment, the oral or rectal formulation of the present invention is further formulated to accomplish slow release of Exenatide. In another embodiment, the oral or rectal formulation of the present invention is further formulated to accomplish a combination of sustained and immediate release of Exenatide. In another embodiment, the release rate of Exenatide can be manipulated by various formulatory methods known to one of skill in the art of the invention.
  • the composition is formulated as an oral dosage form.
  • the composition is a solid oral dosage form comprising tablets, chewable tablets, suppositories, or capsules.
  • the capsules are soft gelatin capsules.
  • controlled- or sustained-release coatings utilized in methods and compositions of the present invention include formulation in lipophilic depots (e.g. fatty acids, waxes, oils).
  • compositions also include, in another embodiment, incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.) Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.
  • particulate compositions of the active ingredients are coated with polymers (e.g. poloxamers or poloxamines)
  • compositions containing the exenatide and omega-3 fatty acid are delivered in a vesicle, e.g. a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez—Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • a vesicle e.g. a liposome
  • compositions that contain an active component for example by mixing, granulating, or tablet-forming processes, is well understood in the art.
  • the active therapeutic ingredient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient.
  • the active ingredients of compositions of the present invention are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • the formulation of the present invention further comprises a base.
  • the base used in the pharmaceutical composition of this invention may be those which are known as bases of suppositories for intrarectal administration.
  • base include oils and fats comprising triglycerides as main companothernts such as cacao butter, palm fat, palm kernel oil, coconut oil, fractionated coconut oil, lard and WITEPSOL®TM, waxes such as lanolin and reduced lanolin; hydrocarbons such as Vaseline, squalene, squalane and liquid paraffin; long to medium chain fatty acids such as caprylic acid, lauric acid, stearic acid and oleic acid; higher alcohols such as lauryl alcohol, cetanol and stearyl alcohol; fatty acid esters such as butyl stearate and dilauryl malonate; medium to long chain carboxylic acid esters of glycerin such as triolein and tristearin; glycerin-
  • composition of this invention may further include a surface-active agent, preservative, and coloring agent, which are ordinarily used in suppositories.
  • the unit dosage forms of the pharmaceutical composition of this invention include a solid suppository having as a base a solid fat which when administered to the rectum, becomes flowable within the rectum, such as cacao butter and WITEPSOL, a solid suppository having as a base a hydrophilic solid substance which becomes flowable in the rectum in the same way, such as macrogol, and a gelatin capsule suppository having a normally liquid substance (liquid at room temperature) such as neutral fatty acid triglycerides and vegetable oils as a base and coated with a gelatin film.
  • a normally liquid substance liquid at room temperature
  • the term “treating” refers to curing a disease. In another embodiment, “treating” refers to preventing a disease. In another embodiment, “treating” refers to reducing the incidence of a disease. In another embodiment, “treating” refers to ameliorating symptoms of a disease. In another embodiment, “treating” refers to inducing remission. In another embodiment, “treating” refers to slowing the progression of a disease.
  • a formulation containing 150 milligram (mg) Na-EDTA (Sigma-Aldrich, St. Louis, Mo.), 125 mg soybean trypsin inhibitor (SBTI; Sigma), 50 ⁇ g exenatide, and 0.8 milliliter (ml) fish oil was prepared.
  • a formulation containing 150 milligram (mg) Na-EDTA (Sigma-Aldrich, St. Louis, Mo.), 125 mg soybean trypsin inhibitor (SBTI; Sigma), 100 ⁇ g exenatide, and 0.8 milliliter (ml) fish oil was prepared.
  • formulation 1 treatment or 3 (control) were administered directly to the duodenum of about 9 kg beagle dogs or by an endoscope to about 16 kg pigs.
  • FIG. 1 The ability of formula 1 to substantially reduce blood glucose levels is also shown in FIG. 1 in dogs. Similar results were obtained in pigs. Moreover, FIG. 3 shows that an oral dosage form of Exendin-4 can replace injectable dosage forms of Exendin-4(see Example 2) in reducing blood glucose levels.
  • oral compositions comprising a protease inhibitor and Na-EDTA can protect exenatide from proteases in the small intestine and enable direct absorption of orally administered exenatide.
  • oral and rectal formulations comprising exenatide
  • oral and rectal formulations were compared to commercially available injectable formulations.
  • compositions comprising a protease inhibitor and Na-EDTA can protect exenatide from proteases in the small intestine and enable direct absorption of orally administered exenatide.
  • the Exendin-4-used for the oral and rectal dosage forms was obtained from GeneScript.
  • the results presented show that Exendin-4-purchased from GeneScript is effective as the commercial Exendin-4(Eli Lilly, USA).
  • the oral and/or rectal routes of administration are favorable over the injectable route of administration for many reasons that are known to one of skill in the art.
  • the unexpected results presented herein demonstrate the ability to effectively administer Exendin-4-via an oral or rectal route of administration.
  • Results are shown in Table 2 and FIG. 4 .
  • Tablet cores comprising exenatide and a protease inhibitor are prepared using methods well known in the art.
  • the coating may be any delayed release coating known in the art.
  • the coating may be a polymer composed of the following ingredients:
  • a solution of the enteric coated polymer is prepared by dissolving the polymer in a methylene chloride+isopropyl alcohol mixture.
  • the tablets are coated by spraying the solution within a mildly warmed jar under constant agitation. The solvent vapors are continuously aspirated.
  • a mixture of Na-EDTA, SBTI, and exenatide and fish oil is formulated into tablet or capsule cores, coated with an enteric coating or gelatin coating, and administered to human subjects. Blood glucose levels of the subjects are measured periodically as described in the previous Examples. In addition, the subjects' plasma levels of recombinant exenatide and its activity are tested. The coated pills are shown to deliver functional exenatide to the subjects, and the exenatide significantly lowers their blood glucose levels, showing that active exenatide can be delivered to the bloodstream via oral administration. Different types of commercially available delayed release coatings are tested to determine which coating provides the best delivery of exenatide, and this coating is used in subsequent Examples.
  • omega-3 fatty acids or sources of omega-3 fatty acids are compared for their ability to preserve exenatide following oral administration in methods and compositions of the present invention.
  • Exenatide tablets or capsules are formulated as described in the above Examples, except that the exenatide is combined with alternate source instead of in fish oil. The most effective source of omega-3 fatty acids is used in subsequent Examples.
  • protease inhibitors either non-toxic or having an acceptable toxicity profile; e.g. those listed above in the specification
  • Exenatide tablets or capsules are formulated as described in the above Examples, except that the alternate protease inhibitors are substituted for SBTI.
  • Amounts of the protease inhibitors are also varied, to determine the optimal amounts. The most effective protease inhibitor/amount is used in subsequent Examples.
  • enhancers are compared for their ability to facilitate absorption of exenatide following oral administration in methods and compositions of the present invention.
  • Exenatide tablets or capsules are formulated as described in the above Examples, except that the alternate enhancers are substituted for EDTA.
  • Amounts of the enhancers are also varied, to determine the optimal amounts. The most effective enhancer/amount is used in subsequent experiments.
  • exenatide tablets or capsules are formulated as described in the above Examples, except that the type and amount of exenatide is varied. The most effective type/amount of exenatide is used in clinical trials.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Zoology (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Botany (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Vascular Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
US12/990,097 2008-05-05 2009-05-03 Methods and compositions for oral administration of exenatide Abandoned US20110046053A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/990,097 US20110046053A1 (en) 2008-05-05 2009-05-03 Methods and compositions for oral administration of exenatide

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US7153808P 2008-05-05 2008-05-05
US12/990,097 US20110046053A1 (en) 2008-05-05 2009-05-03 Methods and compositions for oral administration of exenatide
PCT/IL2009/000461 WO2009136392A2 (en) 2008-05-05 2009-05-03 Methods and compositions for oral administration of exenatide

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2009/000461 A-371-Of-International WO2009136392A2 (en) 2008-05-05 2009-05-03 Methods and compositions for oral administration of exenatide

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/855,346 Division US10350162B2 (en) 2008-05-05 2013-04-02 Methods and compositions for oral administration of exenatide

Publications (1)

Publication Number Publication Date
US20110046053A1 true US20110046053A1 (en) 2011-02-24

Family

ID=41265104

Family Applications (4)

Application Number Title Priority Date Filing Date
US12/990,097 Abandoned US20110046053A1 (en) 2008-05-05 2009-05-03 Methods and compositions for oral administration of exenatide
US13/855,346 Active 2029-07-03 US10350162B2 (en) 2008-05-05 2013-04-02 Methods and compositions for oral administration of exenatide
US16/435,854 Abandoned US20190314275A1 (en) 2008-05-05 2019-06-10 Methods and Compositions for Rectal Administration of Exenatide
US17/243,660 Abandoned US20210322305A1 (en) 2008-05-05 2021-04-29 Methods and Compositions for Oral Administration of Exenatide

Family Applications After (3)

Application Number Title Priority Date Filing Date
US13/855,346 Active 2029-07-03 US10350162B2 (en) 2008-05-05 2013-04-02 Methods and compositions for oral administration of exenatide
US16/435,854 Abandoned US20190314275A1 (en) 2008-05-05 2019-06-10 Methods and Compositions for Rectal Administration of Exenatide
US17/243,660 Abandoned US20210322305A1 (en) 2008-05-05 2021-04-29 Methods and Compositions for Oral Administration of Exenatide

Country Status (15)

Country Link
US (4) US20110046053A1 (enExample)
EP (2) EP2300031B1 (enExample)
JP (4) JP2011519915A (enExample)
CN (2) CN102026646A (enExample)
AU (1) AU2009245294B2 (enExample)
BR (1) BRPI0908292B1 (enExample)
CA (1) CA2723434C (enExample)
DK (1) DK2300031T3 (enExample)
ES (1) ES2645588T3 (enExample)
HK (1) HK1223558A1 (enExample)
NO (1) NO2300031T3 (enExample)
NZ (1) NZ589390A (enExample)
RU (1) RU2566063C2 (enExample)
WO (1) WO2009136392A2 (enExample)
ZA (1) ZA201008090B (enExample)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110160129A1 (en) * 2009-12-24 2011-06-30 Incube Labs, Llc Therapeutic Agent Preparations for Delivery Into a Lumen of the Intestinal Tract Using a Swallowable Drug Delivery Device
US20110208270A1 (en) * 2009-08-03 2011-08-25 Incube Labs, Llc Swallowable Capsule and Method for Stimulating Incretin Production Within the Intestinal Tract
WO2013003824A1 (en) * 2011-06-29 2013-01-03 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8734429B2 (en) 2010-12-23 2014-05-27 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US8765811B2 (en) 2012-07-10 2014-07-01 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US8764733B2 (en) 2010-12-23 2014-07-01 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8809271B2 (en) 2010-12-23 2014-08-19 Rani Therapeutics, Llc Therapeutic agent preparations comprising liraglutide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8809269B2 (en) 2010-12-23 2014-08-19 Rani Therapeutics, Llc Therapeutic agent preparations comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8846040B2 (en) 2010-12-23 2014-09-30 Rani Therapeutics, Llc Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8901107B2 (en) 2011-01-12 2014-12-02 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
WO2014106846A3 (en) * 2013-01-03 2015-01-29 Oramed Ltd. Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof
US8969293B2 (en) 2010-12-23 2015-03-03 Rani Therapeutics, Llc Therapeutic agent preparations comprising exenatide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8980822B2 (en) 2010-12-23 2015-03-17 Rani Therapeutics, Llc Therapeutic agent preparations comprising pramlintide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9149617B2 (en) 2010-12-23 2015-10-06 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US20150328287A1 (en) * 2014-05-15 2015-11-19 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising glucose regulating proteins
US9242008B2 (en) 2014-06-18 2016-01-26 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of fatty acids
US20160030361A1 (en) * 2013-03-14 2016-02-04 Jerome J. Schentag Cholestosome vesicles for incorporation of molecules into chylomicrons
US9259386B2 (en) 2010-12-23 2016-02-16 Rani Therapeutics, Llc Therapeutic preparation comprising somatostatin or somatostatin analogoue for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9284367B2 (en) 2010-12-23 2016-03-15 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9283179B2 (en) 2010-12-23 2016-03-15 Rani Therapeutics, Llc GnRH preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9382187B2 (en) 2012-07-10 2016-07-05 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US9402807B2 (en) 2010-12-23 2016-08-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9402806B2 (en) 2010-12-23 2016-08-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9415004B2 (en) 2010-12-23 2016-08-16 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9505709B2 (en) 2014-05-05 2016-11-29 Thetis Pharmaceuticals Llc Compositions and methods relating to ionic salts of peptides
US9629799B2 (en) 2010-12-23 2017-04-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9730951B2 (en) 2010-03-03 2017-08-15 Volant Holdings Gmbh Compositions, methods of treatment and diagnostics for treatment of hepatic steatosis alone or in combination with a Hepatitis C virus infection
US9861683B2 (en) 2010-12-23 2018-01-09 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9999626B2 (en) 2014-06-18 2018-06-19 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of active agents
US10058593B2 (en) 2008-03-26 2018-08-28 Oramed Ltd. Methods and compositions for oral administration of proteins
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US10342764B2 (en) 2012-02-01 2019-07-09 Oramed Ltd. Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same
US10350162B2 (en) 2008-05-05 2019-07-16 Oramed Ltd. Methods and compositions for oral administration of exenatide
US10398762B2 (en) 2012-01-03 2019-09-03 Oramed Ltd. Methods and compositions for treating diabetes
US10639272B2 (en) 2010-12-23 2020-05-05 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
WO2020225068A1 (en) 2019-05-06 2020-11-12 Evonik Operations Gmbh Preparation for use in weight management comprising omega-3 fatty acid salts and basic amino acids
FR3120189A1 (fr) 2021-03-01 2022-09-02 Farid Bennis Composition pharmaceutique pour une administration par voie orale d’un agoniste du récepteur du GLP-1

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9259456B2 (en) * 2005-09-06 2016-02-16 Oramed Pharmaceuticals Inc. Methods and compositions for oral administration of proteins
SG179026A1 (en) 2009-09-08 2012-04-27 Signature Therapeutics Inc Compositions comprising enzyme-cleavable ketone-modified opioid prodrugs and optional inhibitors thereof
US20110262355A1 (en) 2010-04-21 2011-10-27 Jenkins Thomas E Compositions comprising enzyme-cleavable opioid prodrugs and inhibitors thereof
CA2814763C (en) 2011-01-11 2019-05-28 Signature Therapeutics, Inc. Compositions comprising enzyme-cleavable oxycodone prodrug
ITFI20120259A1 (it) * 2012-11-27 2014-05-28 Stefano Bacci Analoghi del glucagon-like peptide (glp-1) per uso topico.
EP2799062A1 (en) * 2013-05-03 2014-11-05 Gilberto Borges de Brito Pharmaceutical product for inducing magnified release of endogenous gut hormones, pyy and glp-1, to a therapeutic effect on obesity and dm2
US10265384B2 (en) 2015-01-29 2019-04-23 Novo Nordisk A/S Tablets comprising GLP-1 agonist and enteric coating
CN104740647A (zh) * 2015-04-08 2015-07-01 东莞市麦亘生物科技有限公司 一种艾塞那肽口服制剂及其制备方法
LT3297653T (lt) 2015-05-22 2022-01-10 The Board Of Trustees Of The Leland Stanford Junior University Postbariatrinės hipoglikemijos gydymas glp-1 antagonistais
RU2702690C2 (ru) * 2015-08-13 2019-10-09 БИОЛИНГУС АйПи ЛЛСи Способ получения продуктов, содержащих стабилизированные активные вещества, и композиций, содержащих таковые
US10653753B2 (en) 2016-03-04 2020-05-19 Eiger Biopharmaceuticals, Inc. Treatment of hyperinsulinemic hypoglycemia with exendin-4 derivatives
HRP20250278T1 (hr) 2016-11-21 2025-04-25 Amylyx Pharmaceuticals, Inc. Puferovane formulacije eksendina (9-39)
CN112057619A (zh) 2019-06-10 2020-12-11 苏州兰鼎生物制药有限公司 一种具有降血糖作用的药物组合物
AU2021211236B2 (en) * 2020-01-23 2025-12-18 Axcess (UK) Ltd Cellular uptake
WO2021166899A1 (ja) * 2020-02-17 2021-08-26 宇部興産株式会社 インクレチン様物質と組み合わせて使用するための消化管プロテアーゼ阻害剤を含む薬剤
US12384744B2 (en) 2021-09-29 2025-08-12 Ensysce Biosciences Inc. Enzyme-cleavable methadone prodrugs and methods of use thereof
EP4545069A1 (en) * 2022-06-24 2025-04-30 Sunsho Pharmaceutical Co., Ltd. Pharmaceutical composition and method for producing same
WO2025090920A1 (en) * 2023-10-25 2025-05-01 Piton Therapeutics, Inc. Compositions and methods for treating dysfunction of glucose metabolism and/or regulation

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4579730A (en) * 1983-05-23 1986-04-01 Hadassah Medical Organization Pharmaceutical compositions containing insulin
US5206219A (en) * 1991-11-25 1993-04-27 Applied Analytical Industries, Inc. Oral compositions of proteinaceous medicaments
US5824638A (en) * 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US6692766B1 (en) * 1994-06-15 2004-02-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
US6858576B1 (en) * 1996-08-08 2005-02-22 Amylin Pharmaceuticals, Inc. Methods for regulating gastrointestinal motility
US20060045868A1 (en) * 2004-08-25 2006-03-02 Aegis Therapeutics Llc Absorption enhancers for drug administration
US20070077283A1 (en) * 2005-09-30 2007-04-05 Nastech Pharmaceutical Company Inc. Method of enhancing transmucosal delivery of therapeutic compounds
US20070087957A1 (en) * 2005-09-06 2007-04-19 Miriam Kidron Methods and compositions for oral administration of proteins

Family Cites Families (34)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6350793A (ja) 1986-08-20 1988-03-03 株式会社東芝 高速増殖炉の崩壊熱除去システム
US5034415A (en) 1987-08-07 1991-07-23 Century Laboratories, Inc. Treatment of diabetes mellitus
ES2045276T3 (es) 1988-07-21 1994-01-16 Hoffmann La Roche Preparacion de insulina
JPH02250823A (ja) * 1989-03-24 1990-10-08 Tsumura & Co マイクロカプセル剤およびその製造方法
GB9007052D0 (en) 1990-03-29 1990-05-30 Skua Investments Ltd Pharmaceutical formulations
IL114673A (en) 1995-07-19 2000-12-06 Hadasit Med Res Service Pharmaceutical compositions containing protein for oral administration
JPH09208485A (ja) * 1996-01-31 1997-08-12 Teijin Ltd ペプチド・蛋白質性薬物の水難溶性組成物
JPH10330287A (ja) * 1997-03-31 1998-12-15 Nippon Suisan Kaisha Ltd 多価不飽和脂肪酸からなる消化管吸収促進剤およびそれを含有する薬剤
US5975893A (en) 1997-06-20 1999-11-02 Align Technology, Inc. Method and system for incrementally moving teeth
JP2000050793A (ja) * 1998-08-07 2000-02-22 Meiji Milk Prod Co Ltd 人工乳組成物
JP2000128805A (ja) 1998-10-27 2000-05-09 Nippon Suisan Kaisha Ltd 多価不飽和脂肪酸および高分子ゲルからなる経粘膜吸収促進剤及びそれを含有する薬剤
US6761903B2 (en) 1999-06-30 2004-07-13 Lipocine, Inc. Clear oil-containing pharmaceutical compositions containing a therapeutic agent
JP2001240558A (ja) 2000-02-29 2001-09-04 Nippon Suisan Kaisha Ltd 多価不飽和脂肪酸を経粘膜吸収促進剤として含有する固形製剤。
US6673574B2 (en) 2000-11-30 2004-01-06 Unigene Laboratories Inc. Oral delivery of peptides using enzyme-cleavable membrane translocators
KR20010069322A (ko) 2001-03-08 2001-07-25 서종수 휴대형정보단말기 또는 화상이동통신장치를 이용한전자경매방법
CN1160122C (zh) 2001-04-20 2004-08-04 清华大学 一种制备口服胰岛素油相制剂的方法
MXPA04000521A (es) 2001-07-18 2005-09-08 Solae Llc Concentrado inhibidor de bowman-birk, de alto contenido en proteinas y proceso para su manufactura.
US20030198666A1 (en) 2002-01-07 2003-10-23 Richat Abbas Oral insulin therapy
US7767828B2 (en) 2003-11-12 2010-08-03 Phenomix Corporation Methyl and ethyl substituted pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV
US20060286129A1 (en) * 2003-12-19 2006-12-21 Emisphere Technologies, Inc. Oral GLP-1 formulations
US20050143303A1 (en) * 2003-12-26 2005-06-30 Nastech Pharmaceutical Company Inc. Intranasal administration of glucose-regulating peptides
US8076288B2 (en) 2004-02-11 2011-12-13 Amylin Pharmaceuticals, Inc. Hybrid polypeptides having glucose lowering activity
AU2005329255B2 (en) 2004-04-15 2010-09-30 Chiasma, Inc. Compositions capable of facilitating penetration across a biological barrier
KR101276754B1 (ko) 2004-07-19 2013-06-19 바이오콘 리미티드 인슐린―올리고머 접합체，제형 및 이들의 용도
US20060046962A1 (en) * 2004-08-25 2006-03-02 Aegis Therapeutics Llc Absorption enhancers for drug administration
US20070086972A1 (en) 2005-09-12 2007-04-19 Jacob Birnbaum Hair growth compositions and methods for treating hair loss or related conditions
CN101095942B (zh) * 2006-06-30 2011-11-16 北京民海生物科技有限公司 一种包含稳定剂的Exendin-4注射剂药物配方
US10058593B2 (en) * 2008-03-26 2018-08-28 Oramed Ltd. Methods and compositions for oral administration of proteins
NO2300031T3 (enExample) 2008-05-05 2018-02-17
CL2009001425A1 (es) 2008-06-17 2010-04-30 Univ Indiana Res & Tech Corp Analogos de glucagon con un aminoacido aromatico grande que carece de cadena lateral de imidazol que le confiere actividad agonista del receptor gip; composiciones farmaceutica; kit que los contiene y uso para reducir el aumento de peso, tratar la diabetes o inducir paralisis del tracto intestinal.
ES2823233T3 (es) 2008-08-18 2021-05-06 Entera Bio Ltd Métodos y composiciones para la administración oral de proteínas
DK2800579T3 (da) 2012-01-03 2017-11-13 Oramed Ltd Kapsler indeholdende olie-baserede flydende sammensætninger af kombinerede terapeutiske stoffer til behandling af diabetes
JP6567827B2 (ja) 2012-02-01 2019-08-28 オラムド エルティーディー． プロテアーゼ阻害剤を含有する組成物、該組成物を含む組成物、および、該組成物を製造および使用する方法
WO2014106846A2 (en) 2013-01-03 2014-07-10 Oramed Ltd. Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4579730A (en) * 1983-05-23 1986-04-01 Hadassah Medical Organization Pharmaceutical compositions containing insulin
US5206219A (en) * 1991-11-25 1993-04-27 Applied Analytical Industries, Inc. Oral compositions of proteinaceous medicaments
US6692766B1 (en) * 1994-06-15 2004-02-17 Yissum Research Development Company Of The Hebrew University Of Jerusalem Controlled release oral drug delivery system
US5824638A (en) * 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US6858576B1 (en) * 1996-08-08 2005-02-22 Amylin Pharmaceuticals, Inc. Methods for regulating gastrointestinal motility
US20060045868A1 (en) * 2004-08-25 2006-03-02 Aegis Therapeutics Llc Absorption enhancers for drug administration
US20070087957A1 (en) * 2005-09-06 2007-04-19 Miriam Kidron Methods and compositions for oral administration of proteins
US20070077283A1 (en) * 2005-09-30 2007-04-05 Nastech Pharmaceutical Company Inc. Method of enhancing transmucosal delivery of therapeutic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Heine et al ('Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes' Annals of Internal Medicine October 18 2005 v143(8) pages 559-569) *

Cited By (140)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10058593B2 (en) 2008-03-26 2018-08-28 Oramed Ltd. Methods and compositions for oral administration of proteins
US11660327B2 (en) 2008-03-26 2023-05-30 Oramed Ltd. Methods and compositions for oral administration of proteins
US10881714B2 (en) 2008-03-26 2021-01-05 Oramed Ltd. Methods and compositions for oral administration of proteins
US10350162B2 (en) 2008-05-05 2019-07-16 Oramed Ltd. Methods and compositions for oral administration of exenatide
US12403308B2 (en) 2009-08-03 2025-09-02 Alva Therapeutics, Inc. Swallowable capsule and method for stimulating incretin production within the intestinal tract
US8682440B2 (en) 2009-08-03 2014-03-25 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US9987487B2 (en) 2009-08-03 2018-06-05 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US20110208270A1 (en) * 2009-08-03 2011-08-25 Incube Labs, Llc Swallowable Capsule and Method for Stimulating Incretin Production Within the Intestinal Tract
US8958879B2 (en) 2009-08-03 2015-02-17 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US11872396B2 (en) 2009-08-03 2024-01-16 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US9403002B2 (en) 2009-08-03 2016-08-02 Rani Therapeutics, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US8781591B2 (en) 2009-08-03 2014-07-15 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US11439817B2 (en) 2009-08-03 2022-09-13 Incube Labs, Llc Swallowable capsule and method for stimulating incretin production within the intestinal tract
US11253686B2 (en) 2009-12-24 2022-02-22 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US10252039B2 (en) 2009-12-24 2019-04-09 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US8852151B2 (en) 2009-12-24 2014-10-07 Rani Therapeutics, Llc Swallowable drug delivery device and method of delivery
US20110160129A1 (en) * 2009-12-24 2011-06-30 Incube Labs, Llc Therapeutic Agent Preparations for Delivery Into a Lumen of the Intestinal Tract Using a Swallowable Drug Delivery Device
US10987499B2 (en) 2009-12-24 2021-04-27 Rani Therapeutics, Llc Swallowable drug delivery device and method of delivery
US11376405B2 (en) 2009-12-24 2022-07-05 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US8759284B2 (en) 2009-12-24 2014-06-24 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10603475B2 (en) 2009-12-24 2020-03-31 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US10596359B2 (en) 2009-12-24 2020-03-24 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10493253B2 (en) 2009-12-24 2019-12-03 Rani Therapeutics, Llc Therapeutic agent preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US12268831B2 (en) 2009-12-24 2025-04-08 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US11338118B2 (en) 2009-12-24 2022-05-24 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US20110160699A1 (en) * 2009-12-24 2011-06-30 Incube Labs, Llc Swallowable Drug Delivery Device and Methods of Drug Delivery
US10179228B2 (en) 2009-12-24 2019-01-15 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US8721620B2 (en) 2009-12-24 2014-05-13 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US10039908B2 (en) 2009-12-24 2018-08-07 Rani Therapeutics, Llc Swallowable drug delivery device and method of delivery
US8562589B2 (en) 2009-12-24 2013-10-22 Rani Therapeutics, Llc Swallowable drug delivery device and method of delivery
US9757548B2 (en) 2009-12-24 2017-09-12 Rani Therapeutics, Llc Method for delivering a therapeutic agent into the wall of the small intestine
US9456988B2 (en) 2009-12-24 2016-10-04 Rani Therapeutics, Llc Swallowable drug delivery device and methods of drug delivery
US9730951B2 (en) 2010-03-03 2017-08-15 Volant Holdings Gmbh Compositions, methods of treatment and diagnostics for treatment of hepatic steatosis alone or in combination with a Hepatitis C virus infection
US10245277B2 (en) 2010-03-03 2019-04-02 Volant Holdings Gmbh Compositions, methods of treatment and diagnostics for treatment of hepatic steatosis alone or in combination with a hepatitis C virus infection
US9402806B2 (en) 2010-12-23 2016-08-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8846040B2 (en) 2010-12-23 2014-09-30 Rani Therapeutics, Llc Therapeutic agent preparations comprising etanercept for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9415004B2 (en) 2010-12-23 2016-08-16 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8734429B2 (en) 2010-12-23 2014-05-27 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US9457065B2 (en) 2010-12-23 2016-10-04 Rani Therapeutics, Llc Methods for delivering insulin preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US9486414B2 (en) 2010-12-23 2016-11-08 Rani Therapeutics, Llc Method for delivering liraglutide preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US9492378B2 (en) 2010-12-23 2016-11-15 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US12263325B2 (en) 2010-12-23 2025-04-01 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US9511121B2 (en) 2010-12-23 2016-12-06 Rani Therapeutics, Llc Method for delivering exenatide to a patient in need thereof
US9539207B2 (en) 2010-12-23 2017-01-10 Rani Therapeutics, Llc Method for delivering pramlintide into a lumen of the intestinal tract using a swallowable drug delivery
US9629799B2 (en) 2010-12-23 2017-04-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11844867B2 (en) 2010-12-23 2023-12-19 Rani Therapeutics, Llc Method of delivering insulin into a lumen of the intestinal tract using a swallowable drug delivery device
US11813314B2 (en) 2010-12-23 2023-11-14 Rani Therapeutics, Llc Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device
US9283179B2 (en) 2010-12-23 2016-03-15 Rani Therapeutics, Llc GnRH preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9284367B2 (en) 2010-12-23 2016-03-15 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9757514B2 (en) 2010-12-23 2017-09-12 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US11814427B2 (en) 2010-12-23 2023-11-14 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9814763B2 (en) 2010-12-23 2017-11-14 Incube Labs, Llc Method for delivery of somatostatin into a lumen of the intestinal tract
US9844655B2 (en) 2010-12-23 2017-12-19 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9844505B2 (en) 2010-12-23 2017-12-19 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US9861683B2 (en) 2010-12-23 2018-01-09 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9907747B2 (en) 2010-12-23 2018-03-06 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9956178B2 (en) 2010-12-23 2018-05-01 Rani Therapeutics, Llc Methods for delivering insulin preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US9259386B2 (en) 2010-12-23 2016-02-16 Rani Therapeutics, Llc Therapeutic preparation comprising somatostatin or somatostatin analogoue for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11806504B2 (en) 2010-12-23 2023-11-07 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US10004783B2 (en) 2010-12-23 2018-06-26 Rani Therapeutics, Llc Method for delivering pramlintide into a lumen of the intestinal tract using a swallowable drug delivery device
US10029080B2 (en) 2010-12-23 2018-07-24 Rani Therapeutics, Llc Method for delivering exenatide into a lumen of the intestinal tract using a swallowable drug delivery device
US11771879B2 (en) 2010-12-23 2023-10-03 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11684761B2 (en) 2010-12-23 2023-06-27 Rani Therapeutics, Llc Preparation comprising exanatide for delivery into a lumen of the intestinal tract
US8764733B2 (en) 2010-12-23 2014-07-01 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11654182B2 (en) 2010-12-23 2023-05-23 Rani Therapeutics, Llc Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device
US11638690B2 (en) 2010-12-23 2023-05-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11555068B2 (en) 2010-12-23 2023-01-17 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8809271B2 (en) 2010-12-23 2014-08-19 Rani Therapeutics, Llc Therapeutic agent preparations comprising liraglutide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11419812B2 (en) 2010-12-23 2022-08-23 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US9205127B2 (en) 2010-12-23 2015-12-08 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8809269B2 (en) 2010-12-23 2014-08-19 Rani Therapeutics, Llc Therapeutic agent preparations comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10300010B2 (en) 2010-12-23 2019-05-28 Rani Therapeutics, Llc Methods for delivering entanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10307579B2 (en) 2010-12-23 2019-06-04 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10314891B2 (en) 2010-12-23 2019-06-11 Rani Therapeutics, Llc Method for delivering pramlintide into a lumen of the intestinal tract using a swallowable drug delivery device
US10314892B2 (en) 2010-12-23 2019-06-11 Rani Therapeutics, Llc Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device
US10322167B2 (en) 2010-12-23 2019-06-18 Rani Therapeutics, Llc Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device
US10335463B2 (en) 2010-12-23 2019-07-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9402807B2 (en) 2010-12-23 2016-08-02 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9149617B2 (en) 2010-12-23 2015-10-06 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US10350163B2 (en) 2010-12-23 2019-07-16 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11304895B2 (en) 2010-12-23 2022-04-19 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US11229684B2 (en) 2010-12-23 2022-01-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10478396B2 (en) 2010-12-23 2019-11-19 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10487145B2 (en) 2010-12-23 2019-11-26 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10980749B2 (en) 2010-12-23 2021-04-20 Rani Therapeutics, Llc Therapeutic preparation comprising insulin for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10548850B2 (en) 2010-12-23 2020-02-04 Rani Therapeutics, Llc Therapeutic composition comprising insulin prepared for delivery into an intestinal tract
US8980822B2 (en) 2010-12-23 2015-03-17 Rani Therapeutics, Llc Therapeutic agent preparations comprising pramlintide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US8969293B2 (en) 2010-12-23 2015-03-03 Rani Therapeutics, Llc Therapeutic agent preparations comprising exenatide for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10632251B2 (en) 2010-12-23 2020-04-28 Rani Therapeutics, Llc Device, system and methods for the oral delivery of therapeutic compounds
US10639272B2 (en) 2010-12-23 2020-05-05 Rani Therapeutics, Llc Methods for delivering etanercept preparations into a lumen of the intestinal tract using a swallowable drug delivery device
US10752681B2 (en) 2010-12-23 2020-08-25 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10967050B2 (en) 2010-12-23 2021-04-06 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10864254B2 (en) 2010-12-23 2020-12-15 Rani Therapeutics, Llc Method of delivering gonadotropin releasing hormone or an analogue thereof into a lumen of the intestinal tract using a swallowable drug delivery device
US10874840B2 (en) 2010-12-23 2020-12-29 Rani Therapeutics, Llc Preparation comprising exanatide for delivery into a lumen of the intestinal tract
US10953077B2 (en) 2010-12-23 2021-03-23 Rani Therapeutics, Llc Method of delivering a somatostatin compound into a lumen of the intestinal tract using a swallowable drug delivery device
US10888517B2 (en) 2010-12-23 2021-01-12 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US10926073B2 (en) 2010-12-23 2021-02-23 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9216951B2 (en) 2011-01-12 2015-12-22 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
US8901107B2 (en) 2011-01-12 2014-12-02 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
US9012507B2 (en) 2011-01-12 2015-04-21 Thetis Pharmaceuticals Llc Lipid-lowering antidiabetic agent
WO2013003824A1 (en) * 2011-06-29 2013-01-03 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
AU2012275112B2 (en) * 2011-06-29 2017-07-06 Rani Therapeutics, Llc Therapeutic agent preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device
US9808510B2 (en) 2011-06-29 2017-11-07 Rani Therapeutics, Llc Method for delivering gonadotropin releasing hormone into a lumen of the intestinal tract
US11395848B2 (en) 2012-01-03 2022-07-26 Oramed Ltd. Methods and compositions for treating diabetes
US10398762B2 (en) 2012-01-03 2019-09-03 Oramed Ltd. Methods and compositions for treating diabetes
US10342764B2 (en) 2012-02-01 2019-07-09 Oramed Ltd. Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same
US10933022B2 (en) 2012-02-01 2021-03-02 Oramed Ltd. Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same
US8933124B2 (en) 2012-07-10 2015-01-13 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US8765811B2 (en) 2012-07-10 2014-07-01 Thetis Pharmaceuticals Llc Tri-salt form of metformin
US9382187B2 (en) 2012-07-10 2016-07-05 Thetis Pharmaceuticals Llc Tri-salt form of metformin
EP4215205A1 (en) * 2013-01-03 2023-07-26 Oramed Ltd. Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof
US10967051B2 (en) 2013-01-03 2021-04-06 Oramed Ltd. Methods and compositions for treating NAFLD, hepatic steatosis, and sequelae thereof
WO2014106846A3 (en) * 2013-01-03 2015-01-29 Oramed Ltd. Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof
US10369114B2 (en) 2013-03-14 2019-08-06 Therasyn Sensors, Inc. Cholestosome vesicles for incorporation of molecules into chylomicrons
US11633364B2 (en) 2013-03-14 2023-04-25 Therasyn Sensors, Inc. Methods of treatment using cholestosome vesicles for incorporation of molecules into chylomicrons
US12005146B2 (en) 2013-03-14 2024-06-11 Therasyn Sensors, Inc. Methods of treatment using cholestosome vesicles for incorporation of molecules into chylomicrons
US20160030361A1 (en) * 2013-03-14 2016-02-04 Jerome J. Schentag Cholestosome vesicles for incorporation of molecules into chylomicrons
US9693968B2 (en) * 2013-03-14 2017-07-04 Jerome J. Schentag Cholestosome vesicles for incorporation of molecules into chylomicrons
US12465575B2 (en) 2013-03-14 2025-11-11 Therasyn Sensors, Inc. Methods of treatment using cholestosome vesicles for incorporation of molecules into chylomicrons
US11052052B2 (en) 2013-03-14 2021-07-06 Therasyn Sensors, Inc. Cholestosome vesicles for incorporation of molecules into chylomicrons
US9505709B2 (en) 2014-05-05 2016-11-29 Thetis Pharmaceuticals Llc Compositions and methods relating to ionic salts of peptides
US11304993B2 (en) 2014-05-15 2022-04-19 Rani Therapeutics, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising polypeptides and/or proteins
US10098931B2 (en) 2014-05-15 2018-10-16 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising immunoglobulins
US10058595B2 (en) 2014-05-15 2018-08-28 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising TNF-inhibiting antibodies
US10039810B2 (en) 2014-05-15 2018-08-07 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising anti-interleukin antibodies
US12214019B2 (en) 2014-05-15 2025-02-04 Rani Therapeutics, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising polypeptides and/or proteins
US10220076B2 (en) * 2014-05-15 2019-03-05 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising glucose regulating proteins
US20150328287A1 (en) * 2014-05-15 2015-11-19 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising glucose regulating proteins
US10953075B2 (en) 2014-05-15 2021-03-23 Incube Labs, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising anti-interleukin antibodies
US11026998B2 (en) 2014-05-15 2021-06-08 Rani Therapeutics, Llc Shaped mass composition comprising exenatide
US11291709B2 (en) 2014-05-15 2022-04-05 Rani Therapeutics, Llc Pharmaceutical compositions and methods for fabrication of solid masses comprising TNF-inhibiting antibodies
US9242008B2 (en) 2014-06-18 2016-01-26 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of fatty acids
US9999626B2 (en) 2014-06-18 2018-06-19 Thetis Pharmaceuticals Llc Mineral amino-acid complexes of active agents
US11191840B2 (en) 2016-06-03 2021-12-07 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US11925688B2 (en) 2016-06-03 2024-03-12 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US10130719B2 (en) 2016-06-03 2018-11-20 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
US11135298B2 (en) 2016-06-03 2021-10-05 Thetis Pharmaceuticals Llc Compositions and methods relating to salts of specialized pro-resolving mediators
WO2020225068A1 (en) 2019-05-06 2020-11-12 Evonik Operations Gmbh Preparation for use in weight management comprising omega-3 fatty acid salts and basic amino acids
WO2022185155A1 (fr) 2021-03-01 2022-09-09 Farid Bennis Composition pharmaceutique pour une administration par voie orale d'un agoniste du recepteur du glp-1
FR3120189A1 (fr) 2021-03-01 2022-09-02 Farid Bennis Composition pharmaceutique pour une administration par voie orale d’un agoniste du récepteur du GLP-1

Also Published As

Publication number Publication date
JP2017008080A (ja) 2017-01-12
US10350162B2 (en) 2019-07-16
HK1223558A1 (zh) 2017-08-04
RU2566063C2 (ru) 2015-10-20
CN102026646A (zh) 2011-04-20
JP2018115204A (ja) 2018-07-26
JP2011519915A (ja) 2011-07-14
JP6356548B2 (ja) 2018-07-11
RU2010146372A (ru) 2012-06-20
AU2009245294A1 (en) 2009-11-12
NZ589390A (en) 2011-11-25
CN105903005A (zh) 2016-08-31
NO2300031T3 (enExample) 2018-02-17
EP3275460A1 (en) 2018-01-31
DK2300031T3 (en) 2017-10-30
BRPI0908292B1 (pt) 2022-09-20
WO2009136392A3 (en) 2010-03-11
JP6379143B2 (ja) 2018-08-22
US20190314275A1 (en) 2019-10-17
WO2009136392A2 (en) 2009-11-12
CA2723434C (en) 2018-01-23
EP2300031A2 (en) 2011-03-30
BRPI0908292A2 (pt) 2015-08-04
ES2645588T3 (es) 2017-12-05
EP2300031B1 (en) 2017-09-20
AU2009245294B2 (en) 2014-02-20
US20210322305A1 (en) 2021-10-21
ZA201008090B (en) 2012-08-29
US20130195939A1 (en) 2013-08-01
JP2015038082A (ja) 2015-02-26
EP2300031A4 (en) 2012-10-24
CA2723434A1 (en) 2009-11-12

Similar Documents

Publication Publication Date Title
US20210322305A1 (en) Methods and Compositions for Oral Administration of Exenatide
US20220151919A1 (en) Methods and compositions for oral administration
EP1933862B1 (en) Methods and compositions for oral administration of proteins
IL230392A (en) Oral Accenatide Preparations
HK1155375A (en) Methods and compositions for oral administration of exenatide
HK1119951B (en) Methods and compositions for oral administration of proteins
IL189956A (en) Compositions for oral administration of proteins

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION