EP1931359A2 - Thérapie combinatoire pour une digestion contrôlée des glucides - Google Patents

Thérapie combinatoire pour une digestion contrôlée des glucides

Info

Publication number
EP1931359A2
EP1931359A2 EP06803558A EP06803558A EP1931359A2 EP 1931359 A2 EP1931359 A2 EP 1931359A2 EP 06803558 A EP06803558 A EP 06803558A EP 06803558 A EP06803558 A EP 06803558A EP 1931359 A2 EP1931359 A2 EP 1931359A2
Authority
EP
European Patent Office
Prior art keywords
agent
pharmaceutical preparation
group
agents
administered
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.)
Withdrawn
Application number
EP06803558A
Other languages
German (de)
English (en)
Other versions
EP1931359A4 (fr
Inventor
Alan Watson
Laura Brass
Bard J. Geesaman
Vaughn Kailian
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.)
Elixir Pharmaceuticals Inc
Original Assignee
Elixir Pharmaceuticals Inc
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 Elixir Pharmaceuticals Inc filed Critical Elixir Pharmaceuticals Inc
Publication of EP1931359A2 publication Critical patent/EP1931359A2/fr
Publication of EP1931359A4 publication Critical patent/EP1931359A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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

Definitions

  • Alpha glucosidase inhibitors are compounds that inhibit digestive enzymes such as amylase, sucrase, maltase, and ⁇ -dextrinase, to reduce the digestion of starch and sugars. These enzymes catalyze the decomposition of disaccharides in the intestine to monosaccharides. By slowing this process, alpha glucosidase inhibitors reduce acute post-prandial hyperglycemia.
  • alpha glucosidase inhibitors examples include acarbose, miglitol, and voglibose (N-l(l,3-dihydroxy-2-propyl)valiolamitie, and N-substituted derivatives thereof (see, e.g., U.S. 5,004,838), and N-substituted pseudo-amino sugars (see, e.g., US 4,595,678)).
  • Acarbose is an inhibitor of the glucosidase class of enzymes in the small intestine as well as an inhibitor of pancreatic alpha amylase.
  • Acarbose is O-4,6-didesoxy-4- [(lS,4R,5S,6S)-4,5,6-1xmydroxy-3-(>ydroxymetiiyl)-2-cyclo hexen-l-yl amino]- ⁇ -D- glucopyranosyl-(l- ⁇ 4)-O- ⁇ -D-glucopyranosyl(l ->4)-D-glucopyranose.
  • the inhibitor can be obtained by fermentation of Actinoplanes species (see German Patent Specification 2,209,832, German Patent Specification 2,209,834, German Patent Specification 2,064,092) and can be isolated from the fermentation broth. Purification processes have been described for this purpose (see German Patent Specification 2,347,782 and German Patent Specification 2,719,912).
  • U.S. 4,904,769 describes a method for preparing a highly purified preparation of acarbose. See also, e.g., U.S. 6,150,568.
  • acarbose is an example of an inhibitor of carbohydrate digestion, e.g., saccharidase activity.
  • Other exemplary inhibitors of carbohydrate digestion include voglibose (valiolamine) , miglitol, and N-substituted derivatives thereof (see, e.g., U.S. 5,004,838), and N-substituted pseudo-amino sugars (see, e.g., US 4,595,678).
  • acarbose delays digestion of complex carbohydrates and the subsequent absorption of glucose, resulting in a smaller rise in blood glucose concentration following meals.
  • Acarbose can decrease post-prandial glucose (PPG) spikes.
  • this disclosure features a method for modulating insulin signalling or blood glucose levels, e.g., post-prandial glucose and/or fasting glucose levels.
  • the method includes: administering, to the subject, two or more of: (i) a first agent that inhibits carbohydrate degradation, (ii) a second agent that decreases formation or severity of intestinal gas, and (iii) a third agent that modulates insulin signalling or blood glucose levels, preferably all three of the above agents, e.g., a combination of the three above agents.
  • the administration of these agents can be tailored to reduce or prevent postprandial glucose spikes.
  • administered in combination means that two or more agents are administered to a subject at the same time or within an interval, such that there is overlap of an effect of each agent on the patient.
  • the administrations of the agents are spaced sufficiently close together such that a combinatorial effect is achieved.
  • the interval can be an interval of minutes, hours, days or weeks.
  • the agents are concurrently bioavailable, e.g., detectable, in the subject.
  • the first, second, and third agents can be administered in any order, or as one or more preparations that includes two more of the agents.
  • At least one administration of one of the agents is made within minutes, one, two, three, or four hours, or even within one or two days of the other agent, e.g., the second agent or third agent.
  • combinations can achieve synergistic results, i.e., greater than additive results, e.g., at least 20, 50, 70, or 100% greater than additive.
  • a single pill e.g., tablet or gel
  • an adequate dose e.g., for an adult or child
  • the first, second, and third agents are co-formulated as a single pill (e.g., tablet, gel, or other dosage unit) for administration together.
  • the alpha glucosidase inhibitor and the third agent e.g., a meglitmide
  • the second agent e.g., BEANO® or simethicone
  • the administration can be two or three times daily, e.g., as required depending on the number and volume of meals.
  • the method can modulate carbohydrate usage in the gastro-intestinal tract of the subject.
  • the subject is a human subject.
  • the subject can be a subject with normal or abnormal characteristics, e.g., with respect to a metabolic characteristic, e.g., normal or abnormal glucose tolerance.
  • the subject can have normal blood glucose response.
  • the subject is glucose intolerant relative to the norm or has impaired glucose tolerance (IGT).
  • IGT impaired glucose tolerance
  • the subject has or is at risk for diabetes, e.g., type II diabetes mellitus.
  • the subject has or is at risk for a large vessel disorder or a metabolic disorder, e.g., syndrome X.
  • the subject is generally a human, e.g., a human adult or child.
  • the second agent is administered in a manner such that the second agent acts preferentially in a specific part of the intestine, such as the ileum.
  • the first and second agents are administered at the same time.
  • the first and second agents are co-formulated.
  • the first and second agents are administered at different times.
  • the first agent can be administered prior to or during a meal, e.g., with the initial bite, and the second agent can be administered subsequent to a meal.
  • the first and second agents can be administered together in conjunction with each meal, e.g., prior to each meal, e.g., about two, three, or four times a day.
  • the first and third agents are administered at the same time.
  • the first and third agents are co-formulated.
  • the first and third agents are administered at different times.
  • the first agent is an inhibitor of a glucosidase, e.g., alpha-glucosidase.
  • the first agent includes:
  • Each R 1 is independently H, Ci-C 6 alkyl, C(O)R 3 , or arylalkyl;
  • R 2 is C 1 -C 6 alkyl;
  • each R 3 is independently C 1 -C 6 alkyl or aryl,
  • each X, Y, and Z is independently NR 4 or O;
  • each R 4 is independently H, alkyl, or arylalkyl.
  • X is NR , for example, NH.
  • Y and Z are O.
  • at least 3 R 1 moieties are H, for example, each R 1 is H.
  • R 2 is methyl.
  • Examples of preferred alkyl moieties include methyl, ethyl, and propyl.
  • Examples of preferred arylalkyl moieties include benzyl and phenylethyl.
  • An example of a preferred C(O)R 3 moiety includes acetyl.
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C 1 -C 1 O indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it.
  • arylalkyl refers to alkyl substituted with an aryl.
  • aryl refers to a 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like.
  • Voglibose a disaccharide
  • Voglibose inhibitor inhibits alpha-glucosidases. These enzymes catalyze the decomposition of disaccharides in the intestine to monosaccharides. By slowing this process, voglibose reduces acute post-prandial hyperglycemia
  • the first agent is acarbose.
  • the first agent is voglibose, miglitol, and so forth.
  • Miglitol is a desoxynojirimycin derivative, and is chemically known as 3,4,5-piperidinetriol, l-(2-hydroxyethyl)-2- (hydroxymethyl)-, [2R-(2 ⁇ ,3 ⁇ ,4 ⁇ , 5 ⁇ )]. It can be prepared from a white to pale-yellow powder. It has a molecular weight of 207.2. Miglitol is soluble in water and has a pKa of 5.9. Its empirical formula is C 8 H I7 NO 5 .
  • the first agent is a compound extracted from a naturally occurring source, such as a Salacia plant (e.g., Salacia prinoides, Salacia reticulata, or Salacia oblongd).
  • a Salacia plant e.g., Salacia prinoides, Salacia reticulata, or Salacia oblongd.
  • the first agent is:
  • the compound can be a compound extracted from Cinnamomum zeylanicum, Artocarpus heterophyllus, ⁇ nospora cordifolia, or Pterocarpus marsupium.
  • the second agent includes an enzyme that digests carbohydrate.
  • a plurality of different second agents can be administered, e.g., a mixture of enzymes that digest carbohydrate.
  • Exemplary enzymes include an alpha galactosidase, an alpha glucosidase, and a beta glucosidase.
  • a representative example is BEANO®.
  • the second agent includes or can be an anti-foaming agent, e.g., simethicone.
  • anti-foaming agents are ones that are not absorbed by the intestine.
  • the second agent can be formulated to preferentially deliver the second agent to the distal region of the colon.
  • the second agent can be formulated as a time delayed-release composition or a location-dependent release composition.
  • location-dependent release compositions include pH sensitive formulations and enzyme triggered-formulations.
  • the second agent is formulated by enteric encapsulation.
  • the third agent is an insulin secretion enhancer that promotes secretion of insulin from pancreatic beta cells.
  • An insulin secretion enhancer is a sulfonylurea drug, e.g., tolbutamide; chlorpropamide; tolazamide; acetohexamide; 4-chloro-N[( 1 -pyrolidinylamino)carbonyl] -benzenesulfonamide (generic name: glycopyramide) or its ammonium salt; glibenclamide (glyburide); gliclazide; 1- butyl-3-metanilylurea; carbutamide; glibonuride; glipizide; gliquidone; glisoxepid; glybuthiazole; glibuzole; glyhexamide; glymidine; glypinamide; phenbutamide; tolcyclamide, etc, or salts thereof.
  • a sulfonylurea drug e.g
  • Insulin secretion enhancers also include N-[4-(l- methylethyl)cyclohexyl)carbonyl]-D-phenylalanine (AY-4166); calcium (2S)-2-benzyl- 3-(cis-hexahydro-2-isoindolinylcarbonyl)propionate dihydrate (KAD-1229); and glimepiride (Hoe 490).
  • the third agent is a biguanide drug such as metformin (GLUCOPHAGE®), metformin hydrochloride, or long-acting QD metformin (GLUCOPHAGE-XL®).
  • the third agent is an insulin sensitizer, such as rosiglitazone or pioglitizone.
  • Additional exemplary insulin sensitizers include 4-[4-[2-(5-methyl-2- phenyloxazol-4-yl)ethoxy]benzyl]isoxazolidin-3,5 -dione (JTT-501) or its salt; 5-[[3,4- dihydro-2-(phenylmethyl)-2H-l-benzopyran-6-yl]methyl]-2,4-thiazolidinedione (generic name: englitazone) or its salt (preferably sodium salt); 5-[[4-[3-(5-methyl-2-phenyl-4- oxazolyl)-l-oxopropyl]phenyl]methyl]-2,4-thiazolidinedione (generic name: darglitazone/CP-86325) or its salt (preferably sodium salt); 5-[2-(5-methyl-2-phenyl-4- oxazolylmethyl)benzofuran-5-ylmethyl]-2,4-oxazolidinedione (CP-9276
  • the third agent is an agent that increases insulin production, e.g., a meglitinide, e.g., nateglinide, repaglinide, or mitiglinide.
  • a meglitinide e.g., nateglinide, repaglinide, or mitiglinide.
  • the third agent is a compound of the formula:
  • A represents a heterocyclic group, a 3 to 8-membered cycloalkyl group or a phenyl group which may have one or more substituents selected from the group of a halogen atom, a lower alkyl group having 1 to 6 carbon atoms and a lower alkoxy group having 1 to 6 carbon atoms;
  • B represents a bicyclic amino group which may have 1 or 2 unsaturated bonds, with the proviso that B bonds to the carbon atom of the carbonyl group at the nitrogen atom;
  • R represents a hydrogen atom or combines each other to form a chemical bond
  • R 1 represents a hydrogen atom, a lower alkyl group having 1 to 6 carbon atoms or an aralkyl group having 7 to 10 carbon atoms; when there is an asymmetric carbon atom, enantiomers thereof and racemic mixtures thereof.
  • the compound can be of each geometrical isomer, E-isomers thereof, Z-isomers thereof, cis-isomers thereof and trans-isomers thereof; and pharmaceutically acceptable salts thereof.
  • Examples of compounds of formula (I) include those represented by the formulae:
  • Y represents a halogen atom, a lower alkyl group having 1 to 6 carbon atoms, or a lower alkoxy group having 1 to 6 carbon atoms
  • n represents 0, 1, or 2 and other groups are as defined for formula (I);
  • Y and n are as above defined and Z presents an ethylene group or a vinylene group
  • C marked with (S) represents a carbon atom in S-configuration; and the pharmaceutically acceptable salts thereof.
  • the agent that increases insulin production is: (E)-2- benzylidene-3 -(cis-hexahydro-2-isoindolinylcarbonyl)propionic acid, (E)-2-benzylidene- 3-(cis-3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)-prop ionic acid, (E)-2-benzylidene-3- (trans-decahydro-2-isoquinolylcarbonyl)propionic acid, (E)-2-benzylidene-3-(trans- hexahydro-2-isoindolinylcarbonyl)propionic acid, (E)-2-(4-methylbenzylidene)-3-(cis- 3a,4,7,7a-tetrahydro-2-isoindolinylcarbonyl)propionic acid, (E)-3-(cis-hexahydro-2- isoindolinylcarbonyl)propi
  • the third agent is generally an agent that functions by a mechanism other than by inhibiting carbohydrate degradation.
  • the methods can include administering acarbose or another first agent, e.g., an effective amount of acarbose or the first agent, e.g., in combination with a second agent, in combination with a third agent, or in combination with both the second and third agent.
  • the methods can be used, e.g., to treat or prevent a metabolic disorder, e.g., metabolic syndrome (e.g., Syndrome X), obesity, diabetes, etc.
  • a metabolic disorder refers to a disorder in which one skilled in the art would detect a physiological change in the subject that alters metabolism of at least one substance, e.g., carbohydrates or fats.
  • a metabolic syndrome (e.g., Syndrome X and syndrome-associated insulin resistance) is manifested in a patient who presents a group of metabolic risk factors. These factors include: central obesity (excessive fat tissue in and around the abdomen), atherogenic dyslipidemia (blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls); insulin resistance or glucose intolerance (e.g., the body cannot properly use insulin or blood sugar); prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor [-1] in the blood); raised blood pressure (130/85 mmHg or higher); and proinflammatory state (e.g., elevated high- sensitivity C-reactive protein in the blood).
  • central obesity excessive fat tissue in and around the abdomen
  • atherogenic dyslipidemia blood fat disorders — mainly high triglycerides and low HDL cholesterol — that foster plaque buildups in artery walls
  • insulin resistance or glucose intolerance e.g.
  • Overweight/obesity, physical inactivity and genetic factors can contribute to the syndrome.
  • People with a metabolic syndrome are at increased risk of coronary heart disease, other diseases related to plaque buildups in artery walls (e.g., stroke and peripheral vascular disease) and type 2 diabetes.
  • Metabolic syndrome can be closely associated insulin resistance.
  • the metabolic disorder is diabetes, e.g., type 2 diabetes mellitus.
  • the patients can be normal (e.g., with respect to blood glucose levels), have impaired glucose tolerance (IGT), so-called pre-diabetic subjects, or diabetic subjects.
  • the patients can have fasting' hyperglycemia, e.g., patients that do not otherwise have diabetic characteristics and with fasting glucose levels between 100-125 mg/dL.
  • diabetes examples include insulin dependent diabetes mellitus and non-insulin dependent diabetes.
  • the method includes administering to a patient having diabetes or at risk of diabetes a combination of compounds described herein.
  • a patient can be identified as being at risk of developing diabetes by having impaired glucose tolerance (IGT), or fasting hyperglycemia.
  • ITT impaired glucose tolerance
  • the compounds described herein can be administered to a subject in a therapeutically effective amount to decrease gluconeogenesis, improve glycemic control (e.g., lower fasting blood glucose), or normalize insulin sensitivity.
  • the compounds can be administered to a subject suffering from diabetes or obesity.
  • Insulin dependent diabetes mellitus is an autoimmune disease, where insulitis leads to the destruction of pancreatic J-cells.
  • type 1 diabetes mellitus significant number of insulin producing beta cells are destroyed and only 15% to 40% are still capable of insulin production (McCulloch et al. (1991) Diabetes 40:673-679).
  • Beta cell failure results in a life long dependence on daily insulin injections and exposure to the acute and late complication of the disease.
  • Type 2 diabetes mellitus is a metabolic disease of impaired glucose homeostasis characterized by hyperglycemia, or high blood sugar, as a result of defective insulin action which manifests as insulin resistance, defective insulin secretion, or both.
  • a patient with Type 2 diabetes mellitus has abnormal carbohydrate, lipid, and protein metabolism associated with insulin resistance and/or impaired insulin secretion. The disease leads to pancreatic beta cell destruction and eventually absolute insulin deficiency. Without insulin, high glucose levels remain in the blood.
  • the long term effects of high blood glucose include blindness, renal failure, and poor blood circulation to these areas, which can lead to foot and ankle amputations. Early detection is critical in preventing patients from reaching this severity. The majority of patients with diabetes have the non- insulin dependent form of diabetes, currently referred to as Type 2 diabetes mellitus.
  • Acarbose or other inhibitors of alpha-glucosidase activity can be used, in combination with the second agent or the third agent, or both, to treat or prevent a large vessel disorder, e.g., atherosclerosis, stroke, peripheral vascular disease, myocardial infarction, and renal-vascular disease.
  • a large vessel disorder e.g., atherosclerosis, stroke, peripheral vascular disease, myocardial infarction, and renal-vascular disease.
  • the method can be used in a variety of subjects, e.g., in normal subjects, in subjects with a genetic predisposition for the disorder, or in subjects who have a symptom or medical history indicative of the disorder, e.g., subjects who have had a heart attack or who have been diagnosed with the disorder.
  • Acarbose can have side effects, including flatulence and abdominal pain.
  • Acarbose treatment has gastrointestinal (GI) side effects, including flatus, abdominal pain, and diarrhea.
  • GI gastrointestinal
  • Such side effects are experienced by many patients, particularly at the initiation of therapy and at higher doses.
  • the side effects are likely caused when excess undigested carbohydrates enter the lower part of the intestine, are not entirely broken down by the enzymes in the lower intestine, and so are metabolized by bacteria, producing carbon dioxide.
  • the side effects can be modulated to some extent by starting at a low dose and slowly titrating the dose upward, e.g., during the course of multiple months.
  • Disclosed herein are a variety of methods for alleviating side effects of acarbose or another agent that inhibits carbohydrate degradation, e.g., alpha-glucosidase activity.
  • the disclosure features a method of administering acarbose to a subject.
  • the method includes: administering, to the subject, acarbose in combination with an agent that decreases formation or severity of intestinal gas, the agent being administered in a manner such that the agent functions preferentially in intestine or colon.
  • the method can also include administering a third agent, e.g., agent that modulates insulin signalling or blood glucose levels, e.g., by altering insulin secretion or insulin sensitivity.
  • Examples of an agent that decreases formation of intestinal gas include enzymes that digest carbohydrate.
  • a plurality of different second agents can be administered, e.g., a mixture of enzymes that digest carbohydrate.
  • Exemplary enzymes include an alpha galactosidase, alpha-glucosidase, and a beta-glucosidase.
  • Examples of an agent that decreases severity of intestinal gas include anti-foaming agents, e.g., simethicone.
  • the agent can be formulated to preferentially deliver the agent to the distal region of the colon.
  • the agent is formulated as a time delayed-release composition or a location-dependent release composition.
  • location-dependent release compositions include pH sensitive formulations and enzyme triggered-formulations.
  • the second agent is formulated by enteric encapsulation.
  • the agent that decreases formation of intestinal gas is administered subsequent to a meal, whereas acarbose is delivered prior to the meal.
  • the disclosure features a method of administering acarbose to a subject. The method includes: administering, to the subject, acarbose in combination with an anti-foaming agent.
  • the subject can be administered acarbose and the anti- foaming agent prior to each major meal for an interval, e.g., of at least 10, 20, 30, or 50 days.
  • the dose of acarbose is increased in one or more increments during the interval, e.g., during the initial 30 days.
  • the dose of the anti-foaming agent is decreased in one or more decrements during the interval, e.g., during the initial 30 days.
  • acarbose is administered without the anti-foaming agent.
  • the disclosure features a method of modulating blood glucose levels.
  • the method includes: administering, to a subject, acarbose in combination with an agent that decreases formation or severity of intestinal gas, the agent being administered in a manner such that the agent functions preferentially in intestine or colon.
  • the disclosure features a method of treating or preventing diabetes or a diabetes-related disorder.
  • the method includes: administering, to a subject having diabetes, IGT, or fasting hyperglycemia, acarbose in combination with an agent that decreases formation or severity of intestinal gas, the agent being administered in a manner such that the agent functions preferentially in intestine or colon.
  • the disclosure features a method of treating or preventing a large vessel disorder, e.g., stroke, myocardial infarction, or peripheral vascular disease.
  • the method includes: administering, to a subject, an alpha glucosidase inhibitor (e.g., acarbose) in combination with an agent that decreases formation or severity of intestinal gas, the agent being administered in a manner such that the agent functions preferentially in intestine or colon, whereby at least one symptom or predisposition of the large vessel disorder is ameliorated.
  • an alpha glucosidase inhibitor e.g., acarbose
  • agents include a sugar cleaving enzyme (e.g., an alpha-galactosidase or beta-glucosidase) and an anti-foaming agent, e.g., simethicone.
  • the disclosure features a pharmaceutical preparation that includes two or more of (e.g., all three of): a first agent that inhibits saccharase activity; a second agent that decreases formation or severity of intestinal gas; and a third agent that modulates insulin signalling or blood glucose levels.
  • the preparation can be liquid, semi-solid, or solid. Examples include a tablet or gel.
  • the first agent is acarbose.
  • the second agent includes a sugar cleaving enzyme (e.g., an alpha-galactosidase or beta-glucosidase), an agent aids expulsion of gas from the gastro-intestinal tract, or an anti-foaming agent.
  • the preparation can include the first and second agent, the first and third agent, the second and third agent, or all three of the first, second, and third agents.
  • the alpha-galactosidase enzyme can be from a non-human organism, e.g., a non- mammalian organism, e.g., from Aspergillus niger. Mammalian, e.g., human, enzymes can also be used.
  • An exemplary composition is BEANO®, a mixture of about four enzymes.
  • Exemplary components can include one or more of xylitol, invertase, disodium citrate, gelatin, and potassium sorbate.
  • the anti-foaming agent can be a silicone based antifoam.
  • exemplary anti- foaming agents include: ANTIFOAM FG- 10TM made by Dow Corning, compositions containing a hydrocarbon-silicon copolymer, a hydrophobic filler, an organo-silicone surfactant, a hydrocarbon carrier oil, and, optionally, a silicone oil (see, e.g., US 4,514,319), compositions comprising mineral oil-containing dispersed hydrophobic solid particles; hydrophobic silica in fluid hydrocarbon oil (see, e.g., US 3,714,068); compositions comprising polyoxyethylene-polypropylene copolymers containing dispersed hydrophobic silica (see, e.g., US 3,959,176); compositions containing a non- silicone water insoluble polyalkylene containing an alkoxysilicon chloride as the hydrophobic agent (see, e.g., G.B.
  • Patent No. 1,166,877 compositions containing finely divided polyolefm polymers or polyesters dispersed in organic liquids (see, e.g., U.S. 3,705,859); compositions containing silicone oil-silica compounds and organo silicone compounds (see, e.g., US 3,691,091); and compositions containing silicone-glycol copolymers in association with silicone oil and silica (see, e.g., US 3,865,544).
  • US 5,458,886 describes some useful anti-foaming agents, including ones that contain titanium dioxide.
  • the preparation can also include one or more of: calcium silicate and a water-soluble agglomerated maltodextrin. See, e.g., US 5,073,384.
  • An anti-foaming agent can include, e.g., a mixture of from 92 to 98 percent by weight of one or more polydimethylsiloxanes and from 2 to 8 percent by weight of a high surface area silica (at least 50 m 2 /g).
  • An exemplary anti-foaming agent is simethicone. Simethicone is described in the NATIONAL FORMULARY, 14th Edition, American Pharmaceutical Association, Washington, D.C., 1975, at page 648, as a mixture of not less than 93% and not more than 99% of dimethylpolysiloxane and not less than 4% and not more than 4.5% of silicon dioxide.
  • Dimethylpolysiloxane is sometimes referred to as polysiloxane or organopolysiloxane.
  • Related mixtures can also be used, e.g., another mixture of polydimethylsiloxane and a high surface area silica.
  • Simethicone can be present at various ratios with respect to the first agent (e.g., acarbose), e.g., on a weight-to-weight basis of about 10:1 to 2:1 or 1:1 or about 1:2 to 1:7.
  • the first agent e.g., acarbose
  • the preparation is formulated as a tablet, gel, or other fashion suitable for ingestion.
  • the first and second agent are partitioned from one another in the tablet.
  • the second agent can be contained in an inner layer and the first agent can be contained in an outer layer.
  • the preparation can contain between 10-20 mg (e.g., about 12.5 mg), 20-40 mg (e.g., about 25 mg), 40-65 mg (e.g., about 50 mg), or 80- 120 mg (e.g., 100 mg) of the first agent.
  • US 5,456,920 describes an exemplary method for producing a tablet.
  • the disclosure features a kit that includes: a pharmaceutical composition including a first agent that inhibits carbohydrate digestion activity, e.g., acarbose; a pharmaceutical composition including a second agent that decreases formation or severity of intestinal gas (e.g., alpha-glucosidase or simethicone); and a third agent that modulates insulin signalling or blood glucose levels,.
  • a kit that includes: a plurality of compartments, each including one or more units of a pharmaceutical composition. A first subset of the compartments of the plurality include units of the composition at a first dosage, and a second subset of the compartments of the plurality include units of the composition at a second dosage.
  • the pharmaceutical composition includes a first agent that inhibits carbohydrate digestion activity and a second agent that decreases formation or severity of intestinal gas.
  • Acarbose or other glucosidase inhibitor is preferably administered such that it decreases carbohydrate degradation, e.g., glucosidase activity, in the proximal part of the colon.
  • carbohydrate degradation e.g., glucosidase activity
  • carbohydrate would be less available to bacterial flora in the distal part of the colon.
  • a first agent e.g., the agent that decreases carbohydrate degradation, e.g., acarbose
  • the second agent can be formulated in a variety forms to control release of one or both of the agents, either separately or in combination.
  • the second agent can be a compound (e.g., a commercially available compound) for decreasing intestinal gas.
  • Particular examples include BEANO® and simethicone.
  • any formulation can be adapted for formulating one or both of the first and second agents.
  • one of the formulations described in the following patent documents can be so adapted: US 4,863,744 describes a delivery system for delivering an agent to a selected environment of use having a pH of greater than 3.5, e.g., a gastrointestinal location after the stomach.
  • US 2004-0062804 describes modified release dosage forms, including a slow release form for simethicone.
  • US 2003-0108743 describes methods for intestinal release of an agent.
  • US 5,637,319 describes oral controlled-release preparations for drug delivery to various sites in the gastrointestinal tract, including the lower part of the intestine or colon.
  • the formulation includes an enteric coating.
  • US 5,840,332 describes exemplary formulations for delivery of an agent to distal parts of the alimentary canal.
  • the delivery system allows delivery to the duodenum, jejunum, ileum, ascending colon, transverse colon, and descending colon as the site for drug delivery.
  • the low stomach pH and presence of gastric enzymes have led to the development of enteric coatings. Such coatings protect the gastric mucosa from drug irritation and protect drugs from inactivation by gastric enzymes and/or low pH. Coatings can be prepared using a selectively insoluble substance.
  • Exemplary enteric coatings include methacrylic acid copolymers (EUDRAGITSTM), cellulose acetate phthalate, cellulose acetate succinate, and styrol maleic acid co-polymers (Ritschel, W. A., Angewante Biopharmazie, Stuttgart (1973), pp. 396-402; Agyilirah, G. A., et al., "Polymers for Enteric Coating Applications” in Polymers for Controlled Drug Delivery, Tarcha, P. J. ed., CRC Press, (1991) Boca Raton, pp.39-66).
  • the second agent is a protein, e.g., a glucosidase or an galactosidase.
  • the protein can be provided in a crystalline form, a cross-linked form, or combinations thereof.
  • US 6,541,606 describes an exemplary stabilized protein crystals formulation.
  • Another exemplary approach is crosslinked enzyme crystal technology. See, e.g., N. L. St. Clair et al., J. Am. Chem. Soc, 114, pp. 4314-16 (1992) and PCT/US91/05415.
  • Crosslinked enzyme crystals can retain their activity in environments that are normally incompatible with enzyme function. Such environments include prolonged exposure to proteases, organic solvents, high temperature or extremes of pH. In such environments, crosslinked enzyme crystals remain insoluble, stable and active.
  • crystals are produced by combining the protein to be crystallized with an appropriate aqueous solvent or aqueous solvent containing appropriate crystallization agents, such as salts or organic solvents.
  • the solvent is combined with the protein and may be subjected to agitation at a temperature determined experimentally to be appropriate for the induction of crystallization and acceptable for the maintenance of protein activity and stability.
  • the solvent can optionally include co-solutes, such as divalent cations, co-factors or chaotropes, as well as buffer species to control pH. The need for co-solutes and their concentrations are determined experimentally to facilitate crystallization.
  • Crosslinking may be carried out using reversible crosslinkers, in parallel or in sequence.
  • the resulting crosslinked protein crystals are characterized by a reactive multifunctional linker, into which a trigger is incorporated as a separate group.
  • the reactive functionality is involved in linking together reactive amino acid side chains in a protein and the trigger consists of a bond that can be broken by altering one or more conditions in the surrounding environment (e.g., pH, temperature, or thermodynamic water activity).
  • the bond between the crosslinking agent and the protein may be a covalent or ionic bond, or a hydrogen bond. The change in surrounding environment results in breaking of the trigger bond and dissolution of the protein.
  • Protein crystals or formulations can themselves be encapsulated, e.g., in a polymeric coating to form a microsphere.
  • the crystals are suspended in a polymeric carrier which is dissolved in an organic solvent.
  • the polymer solution can be in an amount that provides a weight ratio of protein crystals to polymer between about 0.02 and about 20, preferably between about 0.1 and about 2.
  • the protein crystals can be contacted with polymer in solution for a period of time between about 0.5 minutes and about 30 minutes, preferably between about 1 minutes and about 3 minutes.
  • the crystals become coated and are referred to as nascent microspheres.
  • the nascent microspheres increase in size while coating occurs.
  • the suspended coated crystals or nascent microspheres along with the polymeric carrier and organic solvent are transferred to a larger volume of an aqueous solution containing a surface active agent, known as an emulsifier.
  • the suspended nascent microspheres are immersed in the aqueous phase, where the organic solvent evaporates or diffuses away from the polymer. Eventually, a point is reached where the polymer is no longer soluble and forms a precipitated phase encapsulating the protein crystals or formulations to form a composition.
  • the emulsifier can reduce the interfacial surface tension between the various phases of matter in the system during the hardening phase of the process.
  • the coating polymer has some inherent surface activity, there may be no need for addition of a separate surface active agent.
  • exemplary emulsifiers include poly(vinyl alcohol), surfactants and other surface active agents which can reduce the surface tension between the polymer coated protein crystals or polymer coated crystal formulations and the solution.
  • the crystal is a crystal that includes at least one or more enzymes present in BEANO®.
  • Example Administration of an alpha-glucosidase inhibitors (such as acarbose) and a carbohydrate-cleaving enzyme (CCE)
  • an alpha-glucosidase inhibitors such as acarbose
  • CCE carbohydrate-cleaving enzyme
  • An alpha-glucosidase inhibitors can be administered in combination with an CCE, for example, at the beginning of a meal.
  • the two agents can be administered to minimize the possibility of a cancellation effect, e.g., to prevent the inhibitor from inactivating the enzyme.
  • Either or both agents can be formulated using a time delayed release formulation.
  • the agents can be formulated to have different release profiles, e.g., such that the profiles favor the inhibitor being released in the upper part of the intestine or the proximal colon and the CCE being released further down the GI tract, e.g., in the distal colon.
  • the inhibitor is formulated for typical release whereas the CCE is formulated for time delayed release.
  • the CCE is formulated for pH sensitive release, e.g., such that the CCE would not be released or activated until it hit a certain pH level characteristic of the lower part of the intestine.
  • the release could be triggered by time, pH, other enzyme activation (i.e., the CCE-type agent would be bound up until enzymes or conditions in the lower intestine released or activated it), the dissolution of certain coatings on the molecule or pill, etc.
  • Simethicone or another anti-foaming agent can be used to ameliorate effects of excess gas in the intestinal tract.
  • Anti-foaming agents can alleviate froth in the stomach or lower bowel, e.g., by facilitating expulsion of the gas by belching or passing flatus.
  • Simethicone and other anti-foaming agents reduce surface tension and thereby disrupt or break bubbles.
  • Simethicone for example, is not absorbed from the intestine, nor is it known to have adverse side effects, e.g., with a condition or medication.
  • Simethicone could be in a regular or controlled release formulation, e.g., a time delayed release or pH dependent release formulation.
  • a features a package (e.g., a blister pack) that includes a plurality of compartments.
  • Each compartment can include at least one unit dosage of a glucosidase inhibitor (e.g., acarbose).
  • the compartments can be ordered, e.g., to have low dosages in one area of the package, medium doses in another area, and high doses in a third area.
  • the compartment can be presented sequentially, e.g., going left to right and then down, or going in a circle, e.g., clockwise.
  • compartments can be organized such that compartments early in the sequence have a low dose (e.g., 25 mg), compartments midway through the sequence have a second dose (e.g., 50 mg) and compartments later in the sequence have a third dose (e.g., 100 mg).
  • the package can be used to provide a gradually increasing dosage of the glucosidase inhibitor.
  • Unit doses can be prepared for each of two or three meals anticipated during the diurnal cycle.
  • a tablet is produced containing 25 mg acarbose, 20 mg mitiglinide, and 300 GaIU BEANO®. It can be administered three times a day with meals. For example, it can be taken prior to meals.
  • a tablet is produced containing 0.2 mg voglibose, 20 mg mitiglinide, and 300 GaIU BEANO®. It can be administered three times a day with meals. For example, it can be taken prior to meals.

Landscapes

  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Hematology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L’invention concerne des compositions qui comprennent des combinaisons d’agents qui inhibent la dégradation des glucides, diminuent la formation ou la gravité de gaz intestinaux et/ou modulent la signalisation de l'insuline ou des niveaux de glucose dans le sang. L’invention concerne également des procédés d'administration de ces compositions, par exemple, en vue de réduire ou empêcher des pics post-prandiaux de glucose.
EP06803558A 2005-09-14 2006-09-13 Thérapie combinatoire pour une digestion contrôlée des glucides Withdrawn EP1931359A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US71753605P 2005-09-14 2005-09-14
PCT/US2006/035761 WO2007033292A2 (fr) 2005-09-14 2006-09-13 Thérapie combinatoire pour une digestion contrôlée des glucides

Publications (2)

Publication Number Publication Date
EP1931359A2 true EP1931359A2 (fr) 2008-06-18
EP1931359A4 EP1931359A4 (fr) 2009-04-01

Family

ID=37865568

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06803558A Withdrawn EP1931359A4 (fr) 2005-09-14 2006-09-13 Thérapie combinatoire pour une digestion contrôlée des glucides

Country Status (4)

Country Link
EP (1) EP1931359A4 (fr)
CN (1) CN101325959A (fr)
CA (1) CA2622558A1 (fr)
WO (1) WO2007033292A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7888382B2 (en) 2005-04-20 2011-02-15 Kissei Pharmaceutical Co., Ltd. Combined pharmaceutical preparation for treatment of type 2 diabetes
EP1948150A4 (fr) * 2005-11-07 2010-04-14 Elixir Pharmaceuticals Inc Combinaisons de metformine et de mitiglinide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006032011A2 (fr) * 2004-09-14 2006-03-23 Elixir Pharmaceuticals, Inc. Therapie combinee destinee a la digestion controlee d'hydrates de carbone
WO2006134492A2 (fr) * 2005-04-12 2006-12-21 Agi Therapeutics Research Limited Procedes et formulations a base d'acarbose pour traiter la constipation chronique

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3543999A1 (de) * 1985-12-13 1987-06-19 Bayer Ag Hochreine acarbose
US4898986A (en) * 1986-09-09 1990-02-06 Takeda Chemical Industries, Ltd. Inosose derivatives, production and use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006032011A2 (fr) * 2004-09-14 2006-03-23 Elixir Pharmaceuticals, Inc. Therapie combinee destinee a la digestion controlee d'hydrates de carbone
WO2006134492A2 (fr) * 2005-04-12 2006-12-21 Agi Therapeutics Research Limited Procedes et formulations a base d'acarbose pour traiter la constipation chronique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HOLMAN R R ET AL: "A RANDOMIZED DOUBLE-BLIND TRIAL OF ACARBOSE IN TYPE 2 DIABETES SHOWS IMPROVED GLYCEMIC CONTROL OVER 3 YEARS (U.K. PROSPECTIVE DIABETES STUDY 44)" DIABETES CARE, AMERICAN DIABETES ASSOCIATION, ALEXANDRIA, VA, US, vol. 22, no. 6, 1 June 1999 (1999-06-01), pages 960-964, XP008000344 ISSN: 0149-5992 *
KLEIST P ET AL: "CONCOMITANT ADMINISTRATION OF THE ALPHA-GLUCOSIDASE INHIBITOR VOGLIBOSE (AO-128) DOES NOT ALTER THE PHARMACOKINETICS OF GLIBENCLAMIDE" EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, SPRINGER VERLAG, DE, vol. 53, no. 2, 1 October 1997 (1997-10-01), pages 149-152, XP009045647 ISSN: 0031-6970 *
See also references of WO2007033292A2 *
WELBORN T A: "ACARBOSE, AN ALPHA-GLUCOSIDASE INHIBITOR FOR NON-INSULIN-DEPENDENT DIABETES" MEDICAL JOURNAL OF AUSTRALIA, AUSTRALIAN MEDICAL PUB., SYDNEY, AU, vol. 168, no. 2, 19 January 1998 (1998-01-19), pages 76-78, XP008034334 ISSN: 0025-729X *

Also Published As

Publication number Publication date
EP1931359A4 (fr) 2009-04-01
CA2622558A1 (fr) 2007-03-22
WO2007033292A2 (fr) 2007-03-22
WO2007033292A3 (fr) 2007-06-28
CN101325959A (zh) 2008-12-17

Similar Documents

Publication Publication Date Title
JP4845740B2 (ja) 糖尿病を治療するための組成物および方法
ES2302702T3 (es) Composicion farmaceutica que comprende una combinacion de metformina y glibenclamida.
ES2150889T3 (es) Combinacion de glibenclamida-metformina para el tratamiento de la diabetes mellitus tipo ii.
ES2275654T5 (es) Combinaciones que contienen inhibidores de la dipeptidilpeptidasa-IV y agentes antidiabéticos
JP6121334B2 (ja) 胃および結腸製剤ならびにそれらを作製するための方法および使用するための方法
EP1738751B1 (fr) système de libération espacée de médicaments
RU2275915C2 (ru) Способ лечения диабета
US20060193845A1 (en) Combination therapy for controlled carbohydrate digestion
RU2201272C2 (ru) Применение ингибиторов желудочно-кишечной липазы
WO2002004024A1 (fr) Composition destinee au traitement du diabete
KR20080080220A (ko) Ｄｐｉｖ 억제제 및 메트포르민 또는 티아졸리딘디온을병용한 2형 당뇨병의 치료
PT1558220E (pt) Composições orais para tratamento da diabetes
Riddle Oral pharmacologic management of type 2 diabetes
MXPA05010977A (es) Composiciones farmaceuticas que comprenden sustancias antidiabeticas combinadas para su uso en diabetes mellitus.
Rosenthal et al. Effects on blood pressure of the α-glucosidase inhibitor acarbose compared with the insulin enhancer glibenclamide in patients with hypertension and type 2 diabetes mellitus
KR20080028415A (ko) ＰＰＡＲγ 애고니스트를 함유하는 의약 조성물
CA2132427A1 (fr) Methode et composition pour supprimer les effets secondaires des medicaments anti-inflammatoires
EP1931359A2 (fr) Thérapie combinatoire pour une digestion contrôlée des glucides
Massi-Benedetti et al. Pharmacology and clinical experience with repaglinide
WO2003005994A1 (fr) Formulation de comprime-noyau comprenant de la troglitazone et un biguanide
Reasner et al. Treatment of type 2 diabetes mellitus: a rational approach based on its pathophysiology
US20120053172A1 (en) Use of a combination of diazoxide and metformin for treating obesity or obesity related disorders
WO2024055932A1 (fr) Composé azacyclique, composition pharmaceutique associée et utilisation s'y rapportant pour prévenir et/ou traiter une maladie
Sundaram et al. Newer antidiabetic drugs
Hoffer Negative and positive side effects of vitamin B3

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080312

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

RIN1 Information on inventor provided before grant (corrected)

Inventor name: KAILIAN, VAUGHN

Inventor name: GEESAMAN, BARD, J.

Inventor name: BRASS, LAURA

Inventor name: WATSON, ALAN

A4 Supplementary search report drawn up and despatched

Effective date: 20090304

RIC1 Information provided on ipc code assigned before grant

Ipc: C07H 15/12 20060101ALI20090226BHEP

Ipc: A61K 31/715 20060101AFI20080402BHEP

Ipc: A61P 3/10 20060101ALI20090226BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20090603