WO2010020978A1 - Methods and compositions for oral administration of proteins - Google Patents
Methods and compositions for oral administration of proteins Download PDFInfo
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- WO2010020978A1 WO2010020978A1 PCT/IL2009/000786 IL2009000786W WO2010020978A1 WO 2010020978 A1 WO2010020978 A1 WO 2010020978A1 IL 2009000786 W IL2009000786 W IL 2009000786W WO 2010020978 A1 WO2010020978 A1 WO 2010020978A1
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- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- 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
-
- 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
- A61K38/29—Parathyroid hormone (parathormone); Parathyroid hormone-related peptides
-
- 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
-
- 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
- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K9/20—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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- 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
-
- 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
-
- 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
- A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
Definitions
- compositions comprising a protein, an absorption enhancer, and a protease inhibitor and a method for administering same.
- Insulin is a medicament used to treat patients suffering from diabetes, and is the only treatment for insulin-dependent diabetes mellitus.
- Diabetes Mellitus is characterized by a pathological condition of absolute or relative insulin deficiency, leading to hyperglycemia, and is one of the main threats to human health in the 21 st century.
- the global figure of people with diabetes is set to rise to 220 million in 2010, and 300 million in 2025.
- Type I diabetes is caused primarily by the failure of the pancreas to produce insulin.
- Type II diabetes involves a lack of responsiveness of the body to the action of insulin.
- This invention provides, in one embodiment, a composition
- a composition comprising a protein having a molecular weight of up to 100,000 Daltons, a protease inhibitor, and an absorption enhancer, wherein the absorption enhancer enhances the absorption of a protein through an intestinal mucosal barrier.
- the present invention provides a composition comprising a protein having a molecular weight of up to 100,000 Daltons, a protease inhibitor, and SNAC or SNAD.
- the present invention provides amethod for oral administration of a protein having a molecular weight up to 100,000 Daltons to a subj ect, whereby a substantial fraction of said protein retains its activity after absorption, through an intestinal mucosal barrier of a subject, comprising administering orally to a subject a pharmaceutical composition comprising a protein, a protease inhibitor, and an absorption enhancer, wherein an absorption enhancer enhances the absorption of a protein through an intestinal mucosal barrier.
- the present invention provides a method for treating diabetes mellitus in a subject, comprising administering orally to a subject a pharmaceutical composition comprising insulin, Exenatide, or a combination thereof a protease inhibitor, and a absorption enhancer, wherein an absorption enhancer enhances the absorption of a protein through an intestinal mucosal barrier, thereby treating diabetes mellitus.
- Figure 1 is a graph showing the changes in blood glucose levels after treatment with the formulations of the invention.
- Figure 2 is a graph showing the changes in blood C-peptide levels after treatment with the formulations of the invention. DETAILED DESCRIPTION OF THE INVENTION
- compositions and methods comprising a protein, a protease inhibitor, and a absorption enhancer.
- the present invention provides compositions and methods comprising a protein having a molecular weight of up to 100,000 Daltons, a protease inhibitor, and a absorption enhancer.
- the absorption enhancer enhances the absorption of the protein through an intestinal mucosal barrier.
- the absorption enhancer enhances the absorption of a protein having a molecular weight of up to 100,000 Daltons through an intestinal mucosal barrier.
- compositions of the present invention include an active agent, a protease inhibitor, and a carrier.
- the compositions of the present invention are used to deliver various proteins through various biological, chemical, and physical barriers and are particularly suited for delivering proteins which are subject to environmental degradation.
- the compositions of the present invention are used to deliver active proteins through various biological, chemical, and physical barriers and are particularly suited for delivering active proteins which are subject to environmental degradation.
- the compositions comprise an active protein, SNAC, a protease inhibitor, and EDTA or Na-EDTA.
- the compositions comprise an active protein, SNAC, a protease inhibitor, and an omega-3 fatty acid.
- compositions comprise an active protein, SNAC, a protease inhibitor, EDTA or Na-EDTA, and an omega-3 fatty acid.
- the composition as described herein is an oral pharmaceutical composition.
- the composition as described herein is an encapsulated oral pharmaceutical composition.
- the composition as described herein is in a liquid oral dosage form.
- the composition as described herein is in a dry oral dosage form (tablet etc.).
- the protein of the present invention has a molecular weight of 1 ,000- 5,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 5,000-10,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 10,000-20,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 20,000-30,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 40,000-50,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 50,000-60,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 60,000-70,000 Daltons.
- the protein of the present invention has a molecular weight of 70,000-80,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 80,000-90,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 90,000- 100,000 Daltons. In another, embodiment, the protein of the present invention has a molecular weight of 100,000-150,000 Daltons.
- the protein has amolecular weight (MW) of 1-50 kilodalton (kDa).
- the MW is 1-45 kDa.
- the MW is 1-40 kDa.
- the MW is 1-35 kDa.
- the MW is 1-30 kDa.
- the MW is 1-25 kDa.
- the MW is 1-20 kDa.
- the MW is 10-50 kDa.
- the MW is 15-50 kDa.
- the MW is 20-50 kDa.
- the MW is 25-50 kDa.
- the MW is 30-50 kDa. hi another embodiment, the MW is 35-50 kDa. hi another embodiment, the MW is 1-100 kDa. In another embodiment, the MW is 1-90 kDa. hi another embodiment, the MW is 1-80 kDa. In another embodiment, the MW is 1-70 kDa. hi another embodiment, the MW is 1-60 kDa. hi another embodiment, the MW is 10-100 kDa. hi another embodiment, the MW is 15-100 kDa. hi another embodiment, the MW is 20-100 kDa. In another embodiment, the MW is 25-100 kDa. In another embodiment, the MW is 30-100 kDa.
- the MW is 10-80 kDa. hi another embodiment, the MW is 15-80 kDa. hi another embodiment, the MW is 20-80 kDa. hi another embodiment, the MW is 25-80 kDa. In another embodiment, the MW is 30-80 kDa. Each possibility represents a separate embodiment of the present invention. [0017] hi another embodiment, the MW is less than 20 kDa. hi another embodiment, the MW is less than 25 kDa. In another embodiment, the MW is less than 30 kDa. hi another embodiment, the MW is less than 35 kDa. hi another embodiment, the MW is less than 40 kDa. hi another embodiment, the MW is less than 45 kDa.
- the MW is less than 50 kDa. In another embodiment, the MW is less than 55 kDa. In another embodiment, the MW is less than 60 kDa. hi another embodiment, the MW is less than 65 kDa. hi another embodiment, the MW is less than 70 kDa. In another embodiment, the MW is less than 75 kDa. hi another embodiment, the MW is less than 80 kDa. In another embodiment, the MW is less than 85 kDa. In another embodiment, the MW is less than 90 kDa. In another embodiment, the MW is less than 95 kDa. hi another embodiment, the MW is less than 100 kDa.
- the protein of the present invention is insulin.
- the insulin of methods and compositions of the present invention is human insulin.
- the insulin is recombinant insulin.
- the insulin is recombinant human insulin.
- the insulin is bovine insulin.
- the insulin is porcine insulin.
- the insulin is whale insulin, hi another embodiment, the insulin is a metal complex of insulin (e.g. a zinc complex of insulin, protamine zinc insulin, or globin zinc).
- the insulin is endogenous insulin, hi another embodiment, the insulin is fast-acting insulin, hi another embodiment, the insulin is lente insulin. In another embodiment, the insulin is semilente insulin, hi another embodiment, the insulin is ultralente insulin. In another embodiment, the insulin is NPH insulin. In another embodiment, the insulin is glargine insulin, hi another embodiment, the insulin is lispro insulin, hi another embodiment, the insulin is aspart insulin. In another embodiment, the insulin is a combination of two or more of any of the above types of insulin. In another embodiment, the insulin is any other type of insulin known in the art. Each possibility represents a separate embodiment of the present invention.
- the amount of insulin utilized in the methods and compositions of the present invention is 0.5-3 units (u)/kg in humans
- the units used to measure insulin in methods and compositions of the present invention are USP Insulin Units.
- the units used to measure insulin are milligrams.
- one international Unit (IU) of Insulin is equivalent to 45.5 mg insulin.
- the amount of insulin is 0.1-1 u/kg. hi another embodiment, the amount is 0.2-1 u/kg. hi another embodiment, the amount is 0.3-1 u/kg. hi another embodiment, the amount is 0.5-1 u/kg. In another embodiment, the amount is 0.1-2 u/kg. hi another embodiment, the amount is 0.2- 2 u/kg. In another embodiment, the amount is 0.3-2 u/kg. hi another embodiment, the amount is 0.5-2 u/kg. hi another embodiment, the amount is 0.7-2 u/kg. hi another embodiment, the amount is 1-2 u/kg. hi another embodiment, the amount is 1.2-2 u/kg. In another embodiment, the amount is 1-1.2 u/kg.
- the amount is 1-1.5 u/kg. hi another embodiment, the amount is 1-2.5 u/kg. hi another embodiment, the amount is 1-3 u/kg. In another embodiment, the amount is 2-3 u/kg. In another embodiment, the amount is 1-5 u/kg. In another embodiment, the amount is 2-5 u/kg. hi another embodiment, the amount is 3-5 u/kg.
- the amount of insulin is 0.1 u/kg. In another embodiment, the amount is 0.2 u/kg. In another embodiment, the amount is 0.3 u/kg. In another embodiment, the amount is 0.4 u/kg. hi another embodiment, the amount is 0.5 u/kg. hi another embodiment, the amount is 0.6 u/kg. In another embodiment, the amount is 0.8 u/kg. hi another embodiment, the amount is 1 u/kg. In another embodiment, the amount is 1.2 u/kg. In another embodiment, the amount is 1.4 u/kg. In another embodiment, the amount is 1.6 u/kg. In another embodiment, the amount is 1.8 u/kg. In another embodiment, the amount is 2 u/kg.
- the amount is 2.2 u/kg. In another embodiment, the amount is 2.5 u/kg. In another embodiment, the amount is 3 u/kg. [0023] hi another embodiment, the amount of insulin is 1-10 u. In another embodiment, the amount is 2-10 u. hi another embodiment, the amount is 3-10 u. hi another embodiment, the amount is 5-10 u. Li another embodiment, the amount is 1-20 u. In another embodiment, the amount is 2-20 u. In another embodiment, the amount is 3-20 u. In another embodiment, the amount is 5-20 u. hi another embodiment, the amount is 7-20 u. hi another embodiment, the amount is 10-20 u. In another embodiment, the amount is 12-20 u. In another embodiment, the amount is 10-12 u.
- the amount is 10-15 u. hi another embodiment, the amount is 10-25 u. In another embodiment, the amount is 10-30 u. In another embodiment, the amount is 20-30 u. In another embodiment, the amount is 10-50 u. hi another embodiment, the amount is 20-50 u. In another embodiment, the amount is 30-50 u. In another embodiment, the amount is 20-100 u. In another embodiment, the amount is 30-100 u. hi another embodiment, the amount is 100-150 u. In another embodiment, the amount is 100-250 u. hi another embodiment, the amount is 100-300 u. In another embodiment, the amount is 200-300 u. hi another embodiment, the amount is 100-500 u. In another embodiment, the amount is 200-500 u.
- the amount is 300-500 u. In another embodiment, the amount is 200-1000 u. In another embodiment, the amount is 300-1000 u. [0024] hi another embodiment, the amount of insulin is 1 u. hi another embodiment, the amount is 2 u. In another embodiment, the amount is 3 u. In another embodiment, the amount is 4 u. In another embodiment, the amount is 5 u. hi another embodiment, the amount is 6 u. In another embodiment, the amount is 8 u. In another embodiment, the amount is 10 u. In another embodiment, the amount is 12 u. In another embodiment, the amount is 14 u. In another embodiment, the amount is 16 u. In another embodiment, the amount is 18 u. In another embodiment, the amount is 20 u.
- the amount is 22 u. In another embodiment, the amount is 25 u. In another embodiment, the amount is 30 u. In another embodiment, the amount is 50 u. In another embodiment, the amount is 80 u. In another embodiment, the amount is 100 u. In another embodiment, the amount is 120 u. In another embodiment, the amount is 140 u. In another embodiment, the amount is 160 u. hi another embodiment, the amount is 180 u. hi another embodiment, the amount is 200 u. hi another embodiment, the amount is 300 u. hi another embodiment, the amount is 500 u.
- the protein is an insulin secretagogue.
- the protein is GLP-I .
- the protein is a GLP-I analogue.
- the protein is a GLP-I mimetic.
- the protein is an incretin mimetic, hi another embodiment, the protein mimics the GLP-I incretin.
- the protein is GLP -2.
- the protein is a GLP-2 analogue, hi another embodiment, the protein is a GLP-2 mimetic.
- the protein is Exenatide.
- the oral formulations of the present invention protect Exenatide breakdown in the stomach, hi another embodiment,
- Exenatide formulation of the invention controls blood sugar levels, hi another embodiment, Exenatide formulation of the invention helps control blood sugar levels, hi another embodiment, Exenatide formulation of the invention induces pancreatic production of insulin, hi another embodiment,
- Exenatide formulation of the invention is used to treat type-2 (non-insulin dependent) diabetes.
- Exenatide formulation of the invention is used in conjunction with other diabetes medicines.
- the amount of Exenatide in a formulation as described herein is 10 meg tol mg. hi another embodiment, the amount of Exenatide in aformulation as described herein is 10 meg to25 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 25 meg to50 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 50 meg to 60 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 60 meg to70 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 70 meg to 80 meg.
- the amount of Exenatide in a formulation as described herein is 80 meg to 90 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 90 meg to 100 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 100 meg tol lO meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 110 meg to 125 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 125 meg to 150 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 150 meg to 175 meg.
- the amount of Exenatide in a formulation as described herein is 175 meg to200 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 200 meg to220 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 220 meg to240 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 240 meg to260 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 260 meg to300 meg.
- the amount of Exenatide in a formulation as described herein is 300 meg to350 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is350 meg to 400 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 400 meg to 450 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 450 meg to 500 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 550 meg to 600 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 600 meg to700 meg.
- the amount of Exenatide in a formulation as described herein is 700 meg to 800 meg. hi another embodiment, the amount of Exenatide in a formulation as described herein is 800 meg to 900 meg. In another embodiment, the amount of Exenatide in a formulation as described herein is 900 meg to 1 mg.
- the Exenatide formulation as described herein is taken twice a week, hi another embodiment, the Exenatide formulation as described herein is taken once every two days, hi another embodiment, 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. hi another embodiment, the Exenatide formulation as described herein is taken three times a day. hi another embodiment, the Exenatide formulation as described herein is taken four times a day. hi another embodiment, the Exenatide formulation as described herein is taken five times a day.
- one of skill in the art determines the dosage of a Exenatide formulation as described herein, hi 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.
- the Exenatide formulation as described herein is taken at least 75 minutes before a meal, hi another embodiment, the Exenatide formulation as described herein is taken at least 90 minutes before a meal, hi another embodiment, the Exenatide formulation as described herein is taken at least 100 minutes before a meal, hi another embodiment, the Exenatide formulation as described herein is taken at least 120 minutes before a meal, hi 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. [0031] In another embodiment, the Exenatide formulation as described herein reduces the side effects associated with an injectable dosage form comprising Exenatide.
- the Exenatide formulation as described herein reduces nausea as a side effect which is associated with an injectable dosage form comprising Exenatide.
- the Exenatide formulation as described herein does not induce nausea as a side effect which is associated with an injectable dosage form comprising Exenatide.
- the protein is glucagon.In another embodiment, the protein is interferon gamma, hi another embodiment, the protein is interferon alpha. In another embodiment, the protein is a growth hormone. In another embodiment, the protein is erythropoietin, hi another embodiment, the protein is granulocyte colony stimulating factor (G-CSF). In another embodiment, the protein is omentin.In another embodiment, the protein is calcitonin. In another embodiment, the protein is PTH. In another embodiment, the protein is PYY.
- the protein is any other protein known in the art.
- the protein is a growth hormone.
- the growth hormone is somatotropin.
- the growth hormone is Insulin Growth Factor-I (IGF-I).
- the growth hormone is any other growth hormone known in the art.
- methods and compositions of the present invention are used to administer a human serum albumin.
- Human serum albumin is not, in one embodiment, considered to be a pharmaceutically-active component; however, it can be used in the context of the present invention as a therapeutically-beneficial carrier for an active component.
- Each type of protein represents a separate embodiment of the present invention.
- the protein is an enzyme.
- the protein is a receptor ligand, transporter, or a storage protein, hi one embodiment, the protein is a structural protein.
- the enzyme is an oxidoreductase, transferase, hydrolase, lyase, isomerase, or ligase.
- oxidoreductases act on the aldehyde or oxo group of donors, on the CH-CH group of donors, on the CH-NH(2) group of donors, on the CH-NH group of donors, on NADH or NADPH, on the CH-OH group of donors, on nitrogenous compounds as donors, on a sulfur group of donors, on a heme group of donors, on diphenols and related substances as donors, on a peroxide as acceptor, on hydrogen as donor, on single donors with incorporation of molecular oxygen, on paired donors, on superoxide as acceptor, oxidizing metal ions, on CH or CH(2) groups, on iron-sulfur proteins as donors, on reduced fiavodoxin as donor, on phosphorus or arsenic in donors, or on x-H and y-H to form an x-y bond.
- transferases are acyltransferases or glycosyltransferases. In some embodiments, transferases transfer aldehyde or ketone residues, hi some embodiments, transferases transfer alkyl or aryl groups, other than methyl groups. In some embodiments, transferases transfer nitrogenous, phosphorous, sulfur or selenium containing groups.
- hydrolases are glycosylases or act on ether bonds, on peptide bonds, on carbon-nitrogen bonds, other than peptide bonds, on acid anhydrides, on carbon-carbon bonds, on halide bonds, on phosphorus-nitrogen bonds, on sulfur-nitrogen bonds, on carbon-phosphorus bonds, on sulfur-sulfur bonds, or on carbon-sulfur bonds.
- lyases are carbon-carbon lyases, carbon-oxygen lyases, carbon-nitrogen lyases, carbon-sulfur lyases, carbon-halide lyases, phosphorus-oxygen lyases, or other lyases.
- isomerases are racemases or epimerases, cis-trans-isomerases, intramolecular oxidoreductases, intramolecular transferases, intramolecular lyases, or other isomerases.
- ligases form carbon-sulfur bonds, carbon-nitrogen bonds, carbon-carbon bonds, phosphoric ester bonds, or nitrogen-metal bonds.
- transporter proteins are annexins, ATP-binding cassette transporters, hemoglobin, ATPases, calcium channels, potassium channels, sodium channels, or solute carriers.
- storage proteins comprise albumins, lactoglobulins,casein ovomucin, ferritin, phosvitin, lactoferrin, or vitellogenin.
- albumins comprise avidin, ovalbumin, serum albumin, parvalbumin, c-reactive proteinprealbumin, conalbumin, ricin, lactalbumin, methemalbumin, or transthyretin.
- structural proteins comprise amyloid, collagen elastin, or fibrillin.
- the protein is a viral protein, bacterial protein, invertebrate protein, or vertebrate protein, hi some embodiments, the protein is a recombinant protein, hi one embodiment, the protein is a recombinant protein, hi one embodiment, the recombinant protein is a recombinant human protein.
- the molecular weights of some of the proteins mentioned above are as follows: insulin-6 kilodalton (kDa); glucagon-3.5 kDa; interferon, 28 kDa, growth hormone- 21.5-47 kDa; human serum albumin- 69 kDa; erythropoietin- 34 kDa; G-CSF- 30-34 kDa.
- the molecular weight of these proteins is appropriate for administration by methods of the present invention.
- a protease inhibitor protects the protein of the present invention from cleavage
- the present invention provides that a protease inhibitor protects insulin of the present invention from cleavage.
- the present invention provides that a protease inhibitor facilitates the protein absorption in the intestine of a subject. In another, embodiment, the present invention provides that a protease inhibitor facilitates the absorption of insulin in the intestine of a subj ect.
- a serpin is : Alpha 1 -antitrypsin, Antitrypsin-related protein, Alpha 1 - antichymotrypsin, Kallistatin, Protein C inhibitor, Cortisol binding globulin, Thyroxine-binding globulin, Angiotensinogen, Centerin, Protein Z-related protease inhibitor, Vaspin, Monocyte neutrophil elastase inhibitor, Plasminogen activator inhibitor-2, Squamous cell carcinoma antigen-1 (SCCA-I), Squamous cell carcinoma antigen-2 (SCCA-2), Maspin, PI-6, Megsin, PI-8, PI-9, Bomapin, Yukopin, Hurpin/Headpin, Antithrombin, Heparin cofactor II, Plasminogen activator inhibitor 1, Glia derived nexin / Protease nexin I, Pigment epithelium derived factor, Alpha 2-antiplasmin, Complement 1- inhibitor, 47 kDa Heat
- the present invention provides that the protease inhibitor is a trypsin inhibitor such as but not limited to: Lima bean trypsin inhibitor, Aprotinin, soy bean trypsin inhibitor (SBTI), or Ovomucoid.
- a trypsin inhibitor such as but not limited to: Lima bean trypsin inhibitor, Aprotinin, soy bean trypsin inhibitor (SBTI), or Ovomucoid.
- the present invention provides that the protease inhibitor is a Cysteine protease inhibitor.
- Cysteine protease inhibitors of the invention comprise: cystatin,type 1 cystatins (or stefins), Cystatins of type 2,human cystatins C, D, S, SN, and SA, cystatin E/M, cystatin F, type 3 cystatins, or kininogens.
- the present invention provides that the protease inhibitor is a Threonine protease inhibitor.
- the present invention provides that Threonine protease inhibitors of the invention comprise: Bortezomib, MLN-519, ER-807446, TMC-95 A.
- the present invention provides that the protease inhibitor is an Aspartic protease inhibitor.
- Aspartic protease inhibitors of the invention comprise: ⁇ 2 -Macroglobulin, Pepstatin A, Aspartic protease inhibitor 11, Aspartic protease inhibitor 1, Aspartic protease inhibitor 2, Aspartic protease inhibitor 3, Aspartic protease inhibitor 4, Aspartic protease inhibitor 5, Aspartic protease inhibitor 6, Aspartic protease inhibitor 7, Aspartic protease inhibitor 8, Aspartic protease inhibitor 9, Pepsin inhibitor Dit33, Aspartyl protease inhibitor, or Protease A inhibitor 3.
- the present invention provides that the protease inhibitor is a Metalloprotease inhibitor.
- Metalloprotease inhibitors of the invention comprise: Angiotensin- 1 -converting enzyme inhibitory peptide, Antihemorragic factor BJ46a, Beta-casein, Proteinase inhibitor CeKI, Venom metalloproteinase inhibitor DM43, Carboxypeptidase A inhibitor, smpl, IMPI, Alkaline proteinase, inh, Latexin, Carboxypeptidase inhibitor, Antihemorragic factor HSF, Testican-3, SPOCK3, TIMPl, Metalloproteinase inhibitor 1, Metalloproteinase inhibitor 2, TIMP2, Metalloproteinase inhibitor 3, TIMP3, Metalloproteinase inhibitor 4, TIMP4, Putative metalloproteinase inhibitor tag-225, Tissue inliibitor of metalloprotease, WAP, kazal, immunoglobulin,
- a protease inhibitor is a suicide inhibitor, a transition state inhibitor, or a chelating agent.
- the protease inliibitor of the present invention is: AEBSF- HCl,(epsilon)-aminocaproic acid, (alpha) 1-antichymotypsin, antipain, antithrombin III,(alpha) 1- antitrypsin ([alpha] 1 -proteinase inhibitor), APMSF-HCl (4-amidinophenyl-methane sulfonyl- fluoride), ' sprotinin, benzamidine-HCl,chymostatin, DFP (diisopropylfluoro-phosphate), leupeptin, PEFABLOC® SC (4-(2-Aminoethyl)-benzenesulfonyl fluoride hydrochloride), PMSF (phenylmethyl sulfonyl fluoride
- the amount of a protease inhibitor utilized in methods and compositions of the present invention is 0.1 mg/dosage unit, hi another embodiment, the amount of a protease inhibitor is 0.2 mg/dosage unit, hi another embodiment, the amount is 0.3 mg/dosage unit, hi 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, hi 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, hi another embodiment, the amount is 5 mg/dosage unit.
- 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, hi 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, hi another embodiment, the amount is
- the amount of aprotease inhibitor is 0.1-1 mg/dosage unit, hi another embodiment, the amount of a 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, hi another embodiment, the amount is 0.3-2 mg/dosage unit, hi 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, hi another embodiment, the amount is 3-10 mg/dosage unit, hi another embodiment, the amount is 5-10 mg/dosage unit, hi another embodiment, the amount is 1-20 mg/dosage unit, hi another embodiment, the amount is 2-20 mg/dosage unit, hi another embodiment, the amount is 3-20 mg/dosage unit, hi another embodiment, the amount is 5-20 mg/dosage unit, hi another embodiment, the amount is 10-20 mg/dosage unit, hi another embodiment, the amount is 10-100 mg/dosage unit. In another embodiment, the amount is 20-100 mg/dosage unit, hi 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, hi another embodiment, the amount is 20-200 mg/dosage unit. In another embodiment, the amount is 30-200 mg/dosage unit, hi another embodiment, the amount is 50-200 mg/dosage unit. In another embodiment, the amount is 100-200 mg/dosage unit.
- the amount of a protease inhibitor utilized in the methods and compositions of the present invention is 1000 ki.u. (kallikrein inactivator units)/ dosage unit, hi another embodiment, the amount is 10 k.i.u./dosage unit, hi another embodiment, the amount is 12 k.i.u./dosage unit, hi another embodiment, the amount is 15 k.i.u./dosage unit, hi another embodiment, the amount is 20 k.i.u./dosage unit, hi another embodiment, the amount is 30 k.i.u./dosage unit, hi another embodiment, the amount is 40 k.i.u./dosage unit, hi another embodiment, the amount is 50 k.i.u./dosage unit.
- the amount is 70 k.i.u./dosage unit. 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 unit. Li another embodiment, the amount is 300 k.i.u./dosage unit, hi another embodiment, the amount is 500 k.i.u./dosage unit. In another embodiment, the amount is 700 k.i.u./dosage unit. La another embodiment, the amount is 1500 k.i.u./dosage unit.
- the amount is 3000 k.i.u./dosage unit, hi another embodiment, the amount is 4000 k.i.u./dosage unit, hi another embodiment, the amount is 5000 k.i.uVdosage unit.
- Each amount of a first or a second protease inhibitor represents a separate embodiment of the present invention.
- the amount is 50-5000 k.i.u./dosage unit.
- the amount is 500-4000 k.i.u./dosage unit.
- the amount is 100-1000 k.i.u./dosage unit.
- the amount is 200-1500 ki.u./dosage unit.
- compositions of the present invention comprise a substance that enhances absorption of a protein of the invention through an intestinal mucosal barrier
- compositions of the present invention further comprise a substance that enhances absorption of insulin through an intestinal mucosal barrier.
- compositions of the present invention further comprise a substance that enhances absorption of Exenatide through an intestinal mucosal barrier.
- compositions of the present invention further comprise a substance that reduces the degradation of Exenatide in the digestive system.
- compositions of the present invention further comprise a substance that reduces the degradation of Exenatide in the stomach.
- compositions of the present invention further comprise a substance that reduces the degradation of Exenatide in the intestine.
- a substance is referred to herein as an "enhancer.”
- enhancers when used together with omega-3 fatty acids or a protease inhibitor, enhance the ability of a proitein to be absorbed in the intestine.
- enhancers when used together with omega-3 fatty acids and a protease inhibitor, enhance the ability of insulin to be absorbed in the intestine.
- enhancers, when used together with omega-3 fatty acids and a protease inhibitor 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, hi some embodiments, the enhancer is a bile acid, gly cine-conjugated form of a bile acid, or an alkali metal salt, hi one embodiment, absorption enhancement is achieved through utilization of a combination of ⁇ -galactosidase and ⁇ -mannanase.
- the enhancer is a fatty acid such as sodium caprate.
- the enhancer is sodium glycocholate.
- the enhancer is sodium salicylate.
- the enhancer is n-dodecyl- ⁇ -D- maltopyranoside.
- surfactants serve as absorption enhancer
- the enhancer is chitisan such as N, N, N- trimethyl chitosan chloride (TMC).
- TMC chitosan chloride
- NO donors of the present invention comprise 3-(2-Hydroxy-l-(l- methylethyl)-2-nitrosohydrazino)- 1 -propanamine, N-ethyl-2-( 1 -ethyl-hydroxy-2-nitrosohydrazino)- 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. La 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 agents, hi another embodiment, the enhancer is a cationic surface active agent, hi another embodiment, the enhancer is an ampholytic surface active agent.
- zwitteruionic surfactants such as acylcarnitines serve as absorption enhancers.
- the absorption enhancer is an effective oral absorption enhancer for macromolecular drugs.
- the absorption enhancer is veiy water soluble.
- the absorption enhancer is fully, i. e. greater than 85%, absorbed by the gastro-intestinal tract.
- the absorption enhancer is a coarse form, hi another embodiment, the absorption enhancer is micronized. hi another embodiment, the absorption enhancer is amorphous.
- the absorption enhancer is N- (5-chlorosalicyloyl)-8-aminocaprylic acid (5- CNAQ.
- the absorption enhancer is N- (10-[2-hydroxybenzoyl] amino) decanoic acid (SNAD).
- the absorption enhancer is N- (8- [2-hydroxybenzoyl] amino) caprylic acid (SNAC).
- the absorption enhancer is CNAC, SNAD, SNAC, a monosodium and/or disodium salts thereof, ethanol . solvates of sodium salts thereof and the
- the absorption enhancer is 8-(N-2-hydroxy-4-methoxybenzoyl)-aminocaprylic acid (4-MOAC) and pharmaceutically acceptable salts thereof and/or amorphous and polymorphic forms of 4-MOAC.
- the absorption enhancer is N-(8-[2-hydroxy-5-chlorobenzoyl]-amino)octanoic acid (also known as 8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid)) (5-CNAC) and pharmaceutically acceptable salts thereof and/or amorphous and polymorphic forms of 5-CNAC.
- the absorption enhancer is 4-[(2-hydroxy-4- chlorobenzoyl)amino]butanoate (also known as 4-[(4-chloro-2-hydroxy- benzoyl)amino]butanoic acid) (4-CNAB) and pharmaceutically acceptable salts thereof, including its monosodium salt and/or amorphous and polymorphic forms of 4- CNAB.
- the pharmaceutical compositions of the present invention comprise a delivery effective amount of one or more of the absorption enhancers.
- the pharmaceutical compositions of the present invention comprise an amount sufficient to deliver the active agent for the desired effect.
- the pharmaceutical compositions of the present invention comprise an amount of 2.5% to 99.4% by weight of an absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 2.5% to 10% by weight of a absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 8% to 15% by weight of a absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 10% to 20% by weight of a absorption enhancer, hi another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 15% to 30% by weight of an absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 20% to 40% by weight of an absorption enhancer.
- the pharmaceutical compositions of the present invention comprise an amount of 30% to 50% by weight of an absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 40% to 60% by weight of an absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 50% to 70% by weight of an absorption enhancer. In another embodiment, the pharmaceutical compositions of the present invention comprise an amount of 70% to 99.4% by weight of an absorption enhancer. In another embodiment, the amount of an absorption enhancer in the present composition is a delivery effective amount and can be determined for any particular carrier or biologically or chemically active agent by methods known to those skilled in the art.
- an absorption enhancer is a peptide.
- an absorption enhancer is an amino acid.
- a absorption enhancer is derived from amino acids.
- the amount of enhancer utilized in methods and compositions of the present invention is 0.1 mg/dosage unit, hi 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, hi 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, hi another embodiment, the amount is 7 mg/dosage unit. In another embodiment, the amount is 10 mg/dosage unit. hi another embodiment, the amount is 12 mg/dosage unit. In another embodiment, the amount is 15 mg/dosage unit, hi another embodiment, the amount is 20 mg/dosage unit. In another embodiment, the amount is 30 mg/dosage unit, hi another embodiment, the amount is 50 mg/dosage unit, hi another embodiment, the amount is 70 mg/dosage unit, hi 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, hi another embodiment, the amount is 0.3-1 mg/dosage unit, hi another embodiment, the amount is 0.5-1 mg/dosage unit, hi another embodiment, the amount is 0.1-2 mg/dosage unit. In another embodiment, the amount is 0.2-2 mg/dosage unit, hi another embodiment, the amount is 0.3-2 mg/dosage unit, hi 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, hi 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, hi another embodiment, the amount is 30-200 mg/dosage unit, hi another embodiment, the amount is 50-200 mg/dosage unit, hi another embodiment, the amount is 100-200 mg/dosage unit.
- Each type and amount of enhancer represents a separate embodiment of the present invention.
- omega-3 fatty acid can be found in vegetable sources such as the seeds of chia, perilla, flax, walnuts, purslane, lingonberry, seabuckthorn, and hemp, hi some embodiments, omega-3 fatty acids can also be found in the fruit of the acai palm.
- the omega-3 fatty acid has been provided in the form of a synthetic omega-3 fatty acid.
- the omega-3 fatty acid of methods and compositions of the present invention has been provided to the composition in the form offish oil.
- the omega-3 fatty acid has been provided in the form of canola oil.
- 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
- 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), hi another embodiment, the omega-3 fatty acid is eicosatrienoic acid (ETA; 11, 14, 17-eicosatrienoic acid). In another embodiment, the omega-3 fatty acid is eicsoatetraenoic 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).
- 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).
- the omega-3 fatty acid is tetracosahexaenoic acid (6, 9, 12, 15, 18, 21- tetracosahexaenoic acid).
- 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 coating that inhibits digestion of the composition in a subject's stomach.
- coating inhibits digestion of the composition in a subject's stomach.
- the coated dosage forms of the present invention release drug when pH move towards alkaline range, hi one embodiment, 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, liydroxypropylmethyl 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 JP. 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 is used as the enteric coating.
- 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 insulin against decomposition in the stomach.
- the coating is a gelatin coating.
- microencapsulation is used to protect Exenatide against decomposition in the stomach.
- the coating is a film-coating.
- the coating is ethylcellulose.
- the coating is a water-based dispersion of ethylcellulose, e.g. hydroxypropylmethylcellulose (HPMC) E 15.
- the coating is a gastro-resistant coating, e.g. a polymer containing carboxylic acid groups as a functional moiety.
- the coating is a monolithic matrix.
- the coating is cellulose ether (e.g. hypromellose (HPMC).
- HPMC hypromellose
- the present invention provides a composition comprising an active protein of the invention, a protease inhibitor, and an absorption enhancer.
- the present invention provides a composition comprising an active protein of the invention, a protease inhibitor, an omega-3 fatty acid, and an absorption enhancer.
- the present invention provides a composition comprising an active protein of the invention, a protease inhibitor, an omega-3 fatty acid, EDTA or Na-EDTA, and an absorption enhancer.
- the present invention provides that the use of at least one protease inhibitor and an absorption enhancer in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the inventionJn another embodiment, the present invention provides that the use of at least one protease inhibitor and an absorption enhancer in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin. In another embodiment, the present invention provides that the use of at least one protease inhibitor and an absorption enhancer in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of at least one protease inhibitor and an absorption enhancer in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of at least one protease inhibitor and an absorption enhancer in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of at least one protease inhibitor and an absorption enhancer in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of at least one protease inhibitor and SNAC in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of at least one protease inhibitor and SNAC in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of at least one protease inhibitor and SNAC in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of at least one protease inhibitor and SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of at least one protease inhibitor and SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of at least one protease inhibitor and SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of a serpin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of a serpin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of a serpin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of a serpin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase ' the bioavailability of a protein of the invention.
- the present invention provides that the use of a trypsin inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of a trypsin inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of SBTI or Aprotinin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention, hi another embodiment, the present invention provides that the use of SBTI or Aprotinin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin, hi another embodiment, the present invention provides that the use of SBTI or Aprotinin and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of a Cysteine protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of a a Cysteine protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of a Cysteine protease inliibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of a Threonine protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of a Threonine protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin
- the present invention provides that the use of a Threonine protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of a Metalloprotease protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention
- the present invention provides that the use of a Metalloprotease protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of a Metalloprotease protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of an Aspartic protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of a protein of the invention.
- the present invention provides that the use of an Aspartic protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin.
- the present invention provides that the use of an Aspartic protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subj ect by at least 10%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 10%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subj ect by at least 20%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 20%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 30%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 30%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 40%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subj ect by at least 40%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 50%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 50%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 60%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 60%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 70%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 70%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 80%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 80%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 90%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 90%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 100%.
- the present invention provides that the use of a protease inhibitor and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of Exenatide in a human subject by at least 100%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 10%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 20%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 30%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 40%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 50%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 60%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition in a single oral composition in a
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 80%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 90%.
- the present invention provides that the use of Aprotinin or SBTI and SNAC or SNAD in a single oral composition dramatically, unexpectedly, increase the bioavailability of insulin in a human subject by at least 100%.
- this invention further provides the use of sustained release dosage forms (e.g. sustained release microencapsulation) that enable the treatment frequency to be reduced to once or twice a day.
- sustained release dosage forms e.g. sustained release microencapsulation
- the insulin dosage is increased correspondingly with decreasing frequency of administration.
- the Exenatide dosage is increased correspondingly with decreasing frequency of administration.
- levels of recombinant insulin are measuring using a human insulin radioimmunoassay (RIA) kit, e.g. the kit manufactured by Linco Research Inc, (St. Charles, Missouri).
- RIA human insulin radioimmunoassay
- levels of C peptide are measured as well, to determine the relative contributions of endogenous and exogenous insulin to observed rises in insulin levels.
- insulin ELISA kits are used, hi another embodiment, insulin levels are measured by any other method known in the art.
- Exenatide levels are measured by a method known in the art. Each possibility represents a separate embodiment of the present invention.
- a multiparticulate dosage forms is used to inhibit digestion of the composition in the stomach, hi another embodiment, a multiparticulate dosage forms is used to inhibit digestion of the composition in the stomach.
- the present invention provides a method for oral administration of a protein with an enzymatic activity to a subj ect, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject, comprising administering orally to the subject a pharmaceutical composition comprising the protein, a protease inhibitor, and an absorption enhancer, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for oral administration of a protein with an enzymatic activity to a subject, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject, comprising administering orally to the subject a pharmaceutical composition comprising the protein, a protease inhibitor, and SNAC or SNAD, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for oral administration of insulin to a subj ect, whereby a substantial fraction of insulin retains its activity after absorption through an intestinal mucosal barrier of the subject, comprising administering orally to the subject a pharmaceutical composition comprising insulin, a protease inhibitor, and SNAC or SNAD, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for oral 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, comprising administering orally to the subject a pharmaceutical composition comprising Exenatide at least one protease inhibitor, and SNAC or SNAD, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for oral administration of a protein with an enzymatic activity to a subject, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject, comprising administering orally to the subject a pharmaceutical composition comprising the protein, at least one protease inhibitor, SNAC or SNAD, and an omega-3 fatty acid, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for oral administration of a protein with an enzymatic activity to a subject, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject, comprising administering orally to the subject a pharmaceutical composition comprising the protein, at least one protease inhibitor, and SNAC or SNAD, EDTA (or a salt thereof), and an omega-3 fatty acid, thereby orally administering a protein with an enzymatic activity to a human subject.
- the present invention provides a method for oral administration of insulin to a subj ect, whereby a substantial fraction of insulin retains its activity after absorption through an intestinal mucosal barrier of the subject, comprising administering orally to the subject a pharmaceutical composition comprising insulin, at least one protease inhibitor, SNAC or SNAD, an omega-3 fatty acid, and Na-EDTA, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for oral 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, comprising administering orally to the subject a pharmaceutical composition comprising Exenatide, at least one protease inhibitor, SNAC or SNAD,an omega-3 fatty acid, and Na-EDTA, thereby orally administering a protein with an enzymatic activity to a subject.
- the present invention provides a method for treating diabetes mellitus in a human subject, comprising administering orally to the subject a pharmaceutical composition comprising an insulin, at least one protease inhibitor, and SNAC or SNAD, thereby treating diabetes mellitus.
- the present invention provides a method for treating diabetes mellitus in a human subject, comprising administering orally to the subject a pharmaceutical composition comprising an insulin and at least one protease inhibitor, and SNAC or SNAD, and omega-3 fatty acid thereby treating diabetes mellitus.
- the present invention provides a method for treating diabetes mellitus in a human subject, comprising administering orally to the subject a pharmaceutical composition comprising an insulin and at least one protease inhibitor, and SNAC or SNAD, EDTA (or a salt thereof), and omega-3 fatty acid thereby treating diabetes mellitus.
- the present invention provides a method for treating diabetes mellitus in a human subject, comprising administering orally to the subject a pharmaceutical composition comprising an Exenatide, at least one protease inhibitor, and SNAC or SNAD, thereby treating diabetes mellitus.
- the present invention provides a method for treating diabetes mellitus in a human subject, comprising administering orally to the subject a pharmaceutical composition comprising an Exenatide and at least one protease inhibitor, and SNAC or SNAD, and omega-3 fatty acid thereby treating diabetes mellitus.
- the present invention provides a method for treating diabetes mellitus in a human subject, comprising administering orally to the subject a pharmaceutical composition comprising an Exenatide and at least one protease inhibitor, and SNAC or SNAD 5 EDTA (or a salt thereof), and 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, hi another embodiment, the diabetes mellitus is insulin-dependent diabetes. In another embodiment, the diabetes mellitus is non-insulin-dependent diabetes, hi 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.
- the present invention provides a composition for oral administration of insulin, comprising an insulin protein at least one protease inhibitor, and SNAC or SNAD, whereby a substantial fraction of the insulin retains the enzymatic activity after absorption through an intestinal mucosal barrier of a human subject.
- the present invention provides the use of a protein, at least one protease inhibitor, and SNAC or SNAD in the manufacture of a medicament for oral administration of a protein with an enzymatic activity to a subject, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject.
- the present invention provides the use of a protein, at least one protease inhibitor, SNAC or SNAD, and an omega-3 fatty acid in the manufacture of a medicament for oral administration of a protein with an enzymatic activity to a subject, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject.
- the present invention provides the use of a protein, at least one protease inhibitor, SNAC or SNAD, Na-EDTA, and an omega-3 fatty acid in the manufacture of a medicament for oral administration of a protein with an enzymatic activity to a subject, whereby a substantial fraction of the protein retains the enzymatic activity after absorption through an intestinal mucosal barrier of the subject.
- the present invention provides the use of an insulin protein, at least one protease inhibitor, and SNAC or SNAD in the manufacture of a medicament for treating diabetes mellitus in a subject.
- the present invention provides the use of an insulin protein, at least one protease inhibitor, SNAC or SNAD, and an omega-3 fatty acid in the manufacture of a medicament for treating diabetes mellitus in a subject, hi one embodiment, the present invention provides the use of an insulin protein, at least one protease inhibitor, SNAC or SNAD, Na-EDTA, and an omega-3 fatty acid in the manufacture of a medicament for treating diabetes mellitus in a subject.
- the present invention provides the use of an Exenatide protein, at least one protease inhibitor, and SNAC or SNAD in the manufacture of a medicament for treating diabetes mellitus in a subject.
- the present invention provides the use of an Exenatide protein, at least one protease inhibitor, SNAC or SNAD 5 and an omega-3 fatty acid in the manufacture of a medicament for treating diabetes mellitus in a subject.
- the present invention provides the use of an Exenatide protein, at least one protease inhibitor, SNAC or SNAD, Na-EDTA, and an omega-3 fatty acid in the manufacture of a medicament for treating diabetes mellitus in a subject.
- methods and compositions of the present invention have the advantage of more closely mimicking physiological insulin secretion by the pancreas.
- the liver is exposed to a greater insulin concentration than peripheral tissues.
- insulin administered according to the present invention reaches the intestine and is absorbed in the body through the intestine and through the portal system to the liver. This absorption route thus resembles the physiological secretion of insulin by the pancreas, enabling, in this embodiment, delicate control of the blood glucose level and the metabolic activities of the liver and the peripheral organs controlled by insulin.
- 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 insulin.
- 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.
- certain of the constituents are microencapsulated to enhance the absorption of the insulin into the system.
- 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.
- the protocol is prophylactic. Each possibility represents a separate embodiment of the present invention.
- 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. macrocrystalline 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. macrocrystalline 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, croscarmelose 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), surfactants (e.g.
- sodium lauryl sulfate permeation enhancers
- solubilizing agents e.g., glycerol, polyethylene glycerol
- anti-oxidants e.g., ascorbic acid, sodium metabisulfite, butylatedhydroxyanisole
- stabilizers e.g. hydroxypropyl cellulose, hyroxypropylmethyl 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), emulsif ⁇ ers (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
- emulsif ⁇ ers e.g. carbomer, hydroxypropyl cellulose, sodium lauryl sulfate
- polymer coatings e.g., poloxamers or poloxamines
- coating and film forming agents e.g. ethyl
- the dosage forms of the present invention are formulated to achieve an immediate release profile, an extended release profile, or a delayed release profile, hi some embodiments, the release profile of the composition is determined by using specific excipients that serve for example as binders, disintegrants, fillers, or coating materials, hi one embodiment, the composition will be formulated to achieve a particular release profile as known to one skilled in the art.
- the composition is formulated as an oral dosage form.
- the composition is a solid oral dosage form comprising tablets, chewable tablets, or capsules. In one embodiment the capsules are soft gelatin capsules.
- capsules as described herein are hard-shelled capsules. In another embodiment, capsules as described herein are soft-shelled capsules. In another embodiment, capsules as described herein are made from gelatine. In another embodiment, capsules as described herein are made from plant-based gelling substances like carrageenans and modified forms of starch and cellulose.
- 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.)
- polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts, or spheroplasts.
- polymers e.g. poloxamers or poloxamines
- compositions containing the insulin 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).
- the compositions containing the Exenatide and omega-3 fatty acid are delivered in a vesicle, e.g.
- 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 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. hi another embodiment, “treating” refers to inducing remission. In another embodiment, “treating” refers to slowing the progression of a disease.
- Formulation [00122] [please provide] dayspriorto dosing, formulation were prepared containing: (1) 6 mg insulin, 250 mg SNAC, 125 mg SBTI in [what is the exact carrier], (2). 6 mg insulin, 250 mg SNAC, 2.5 mg Aprotinin, 125 mg SBTI in [what is the exact carrier], (3) 6 mg insulin, 250 mg SNAC, 2.5 mg Aprotinin,125 mg SBTI in [what is the exact carrier]. (4) 6 mg insulin, 250 mg SNAC in [what is the exact carrier]. The formulations were stored in the refrigerator (4° C) until dosing. RESULTS
- omega-3 fatty acids or sources of omega- 3 fatty acids are compared for their ability to preserve insulin following oral administration in methods and compositions of the present invention.
- Insulin tablets or capsules are formulated as described in the above Examples, except that the insulin is dissolved in the 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
- Insulin and/or Exenatide tablets or capsules are formulated as described in the above Examples, except that the alternate protease inhibitors are substituted for SBTI and/or Aprotinin.
- 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 insulin following oral administration in methods and compositions of the present invention.
- Insulin 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.
- Insulin tablets or capsules are formulated as described in the above Examples, except that the type and amount of insulin is varied. The most effective type/amount of insulin is used in clinical trials.
Abstract
Description
Claims
Priority Applications (16)
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NZ591497A NZ591497A (en) | 2008-08-18 | 2009-08-11 | A compositions comprising a protein, a protease inhibitor and N-(8-[2-hydroxybenzoyl]amino)caprylate (SNAC) or N-(10[2-hydroxybenzoyl]amino)decanoate (SNAD) for diabetes mellitus treatment |
JP2011523481A JP5740689B2 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of proteins |
EP09807991.6A EP2331072B8 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of proteins |
CA2734442A CA2734442C (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of proteins |
CN200980132155.8A CN102123697B (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of proteins |
US13/058,259 US9186412B2 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of insulin |
EP20186801.5A EP3741359A1 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of proteins |
ES09807991T ES2823233T3 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for the oral administration of proteins |
RU2011108334/15A RU2494755C2 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral protein administration |
AU2009283821A AU2009283821B2 (en) | 2008-08-18 | 2009-08-11 | Methods and compositions for oral administration of proteins |
IL210842A IL210842A (en) | 2008-08-18 | 2011-01-24 | Single, solid composition comprising a protein, a protease inhibitor and a salt of nac or nad and uses thereof for oral administration of the protein |
US14/936,758 US10010503B2 (en) | 2008-08-18 | 2015-11-10 | Methods and compositions for oral administration |
IL245352A IL245352A (en) | 2008-08-18 | 2016-05-01 | Oral pharmaceutical composition comprising parathyroid hormome or a fragment thereof, protease inhibitor and a salt of nac or nad |
US16/000,966 US10420721B2 (en) | 2008-08-18 | 2018-06-06 | Methods and compositions for oral administration |
US16/546,375 US11246827B2 (en) | 2008-08-18 | 2019-08-21 | Methods and compositions for oral administration |
US17/588,377 US20220151919A1 (en) | 2008-08-18 | 2022-01-31 | Methods and compositions for oral administration |
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US11246827B2 (en) | 2022-02-15 |
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US20110142800A1 (en) | 2011-06-16 |
JP5981575B2 (en) | 2016-08-31 |
EP3741359A1 (en) | 2020-11-25 |
JP2015107990A (en) | 2015-06-11 |
CN102123697A (en) | 2011-07-13 |
EP2331072A1 (en) | 2011-06-15 |
JP2016185970A (en) | 2016-10-27 |
US20190380953A1 (en) | 2019-12-19 |
JP2012500254A (en) | 2012-01-05 |
AU2009283821B2 (en) | 2014-05-29 |
EP2331072B1 (en) | 2020-07-22 |
EP2331072B8 (en) | 2020-08-26 |
US20180280292A1 (en) | 2018-10-04 |
RU2011108334A (en) | 2012-09-27 |
RU2494755C2 (en) | 2013-10-10 |
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