Classifications

• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
• • 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
  • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • 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
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • 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
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • 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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • 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
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

• This invention relates to the field of pharmaceutical chemistry and, more specifically, to pharmaceutical formulations as well as to intermediates used to prepare such formulations and to methods for manufacturing such formulations.
• This compound is an agonist of GPR119, a GPCR that is expressed in the pancreatic islets and the gastrointestinal tract.
• GPR agonists have been shown to stimulate glucose-dependent insulin secretion and release of incretin hormones leading to a preservation of beta cell health.
• This invention provides pharmaceutical formulations comprising a
• Figure 1 provides a non-sink dissolution profile for compound A melt extruded compositions tested in simulated gastric fluid.
• Figure 2 provides a non-sink dissolution profile for Compound A melt extruded compositions tested in simulated fed state intestinal fluid.
• Figure 3 provides a non-sink dissolution profile for Compound A melt extruded compositions tested in simulated fasted state intestinal fluid.
• Figure 4 provides a flow chart for a manufacture process of the 25% Compound A:CAP spray-dried dispersion (SDD).
• Figure 5 illustrates the residual acetone content as a function of tray-drying time at 40°C/30% relative himidity (RH) for the 25% Compound A:CAP SDD, based on a headspace gas chromatography (GC) analysis.
• Figure 6 provides the in vitro dissolution results for the 25% Compound A:CAP SDD and crystalline Compound A.
• Figure 7 provides a flow chart for a manufacture process of uncoated Compound A SDD 25 mg tablets.
• Figure 8 provides a flow chart for a manufacture process of uncoated Compound A SDD 100 mg tablets.
• Figure 9 provides a process flow chart for film coating of uncoated Compound A SDD (spray dried dispersion) 25 and 100 mg tablets.
• Figure 10 provides the concentration-time profile after administration of repeat (5) daily doses of compound A to subjects with IFG.
• Figure 11 provides a comparison of the AUC of microcrystalline and SDD (spray dried dispersion) formulation of Compound A as a single dose.
• Figure 12 provides a comparison of Cmax of microcrystalline and SDD (spray dried dispersion) formulation Compound A as a single dose.
• Figure 13 provides a graphical representation of the percent reduction in glucose excursion during a MMTT after administration of repeat (4) daily doses of Compound A to subjects with pre-diabetes.
• Figure 14 provides the Percent Reduction in glucose excursion during a MMTT after administration of repeat (4) daily doses of Compound A in pooled subsets of subjects with increasing degrees of glucose intolerance at baseline.
• the invention is directed to a pharmaceutical formulation comprising a
• compositions and methods are intended to mean that the compositions and methods include the recited elements, but not excluding others.
• compositions and methods shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.
• Compound A referes to 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l- yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine
• crystalline refers to solid 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l- yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine, wherein the solid exhibits long-range order in three dimensions of at least about 100 repeat units in each dimension.
• non-crystalline refers to solid 5-ethyl-2- ⁇ 4-[4-(4- tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine, that does not exhibit any long range order in the positions of the atoms.
• non-crystalline is intended to include not only solid which has essentially no order, but also solid which may have some small degree of order, but the order is in less than three dimensions and/or is only over short distances.
• Non-crystalline compound may be characterized by techniques known in the art such as powder x-ray diffraction (PXRD) crystallography, solid state NMR, or thermal techniques such as differential scanning calorimetry (DSC).
• solid dispersion refers to a dispersion in which at least a portion of the 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l- yl ⁇ -pyrimidine, is non-crystalline and dispersed in a water soluble, biologically compatible polymer.
• the solid dispersions of the invention can be prepared by methods known in the art, including, but not limited to, solid dispersions formed by mechanical, thermal and solvent processes.
• Exemplary mechanical processes include milling and extrusion; melt processes, such as high temperature fusion, solvent-modified fusion and melt-congeal processes; and solvent processes, such as non-solvent precipitation, spray coating and spray drying.
• melt processes such as high temperature fusion, solvent-modified fusion and melt-congeal processes
• solvent processes such as non-solvent precipitation, spray coating and spray drying.
• the solid dispersion is formed by spray drying, as disclosed in European Patent Application Publication No. 0 901 786 A2.
• the 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]- piperidin-l-yl ⁇ -pyrimidine with or without the water soluble, biologically compatible polymer are dissolved in a suitable solvent, such as acetone, acetonitrile, methanol, ethanol, and methylethylketone, and the solvent is then rapidly removed from the solution by spray drying to form the solid dispersion.
• a suitable solvent such as acetone, acetonitrile, methanol, ethanol, and methylethylketone
• An example of a solid dispersion of this invention is the spray-dried solid dispersion comprising about 25 weight percent of Compound A
• the term "pharmaceutically inert carrier” refers to carriers which are inert, in the sense that they do not chemically react with 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl- phenoxymethyl)-thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine in an adverse manner, are pharmaceutically acceptable, and have at least some solubility in aqueous solution at physiologically relevant pHs (e.g. pHl-8).
• Examples of pharmaceutically inert carriers are well known in the literature and, include by way of example only, cellulose acetate phthalate, magnesium stearate, lactose, lactose monohydrate, crospovidone,
• microcrystalline cellulose microcrystalline cellulose, colloidal silica dioxide, and the like.
• water soluble, biologically compatible polymer refers to polymers which do not interact with 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)- thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine in an adverse manner that is detrimental to its use in vivo, are pharmaceutically acceptable, have at least some solubility in aqueous solution at physiologically relevant pHs (e.g. pHl-8) and which, when combined with Compound A to form a solid dispersion as that term is defined above, impart enhanced solubility to
• the water soluble, biologically compatible polymer can be neutral or ionizable, and have an aqueous-solubility of at least 0.1 mg/mL over at least a portion of the pH range of 1 to 8.
• the glass-transition temperature (Tg) of the polymer is great enough so that the resulting solid dispersion has a relatively high Tg
• the polymer may have a Tg of at least 100 °C at 50% RH, at least 105 °C at 50% RH, or even at least 110 °C at 50% RH.
• substantially homogeneous refers to solid dispersions as defined above wherein Compound A is dispersed in the solid dispersion such that the concentration of Compound A in any given amount of the solid dispersion is substantially uniform to that of any other given amount of the solid dispersion.
• the phrase "therapeutically effective amount” means the amount of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the attending clinician.
• a therapeutically effective amount includes the amount of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l- yl ⁇ -pyrimidine that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease.
• the “therapeutically effective amount” will vary depending on the pharmaceutically inert carrier, the disease and its severity and the age, weight, etc., of the mammal to be treated.
• This invention is predicated in part on the discovery that the water solubility and the bioavailability of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]- piperidin-l-yl ⁇ -pyrimidine is enhanced when at least a portion (e.g., more than 25%) of the compound is non-crystalline and preferably employed in combination with a water soluble, biologically compatible polymer. Without being limited to any theory, it is believed that the water soluble, biologically compatible polymer assists in maintaining the non-crystallinity of this compound.
• the invention is directed to a pharmaceutical formulation comprising a pharmaceutically inert carrier, and a therapeutically effective amount of 5- ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l -yl ⁇ -pyrimidine
• This invention is further directed to intermediates useful in this invention wherein said intermediate is a solid dispersion comprising a water soluble, biologically compatible polymer 5 -ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ - pyrimidine wherein at least a portion of said 5 -ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl- phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine is non-crystalline.
• a pharmaceutical formulation comprising a
• from about 50%> to about 100%, by weight, of the 5-ethyl- 2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine is noncrystalline. In some embodiments, from about 75%> to about 100%, by weight, of the 5- ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l -yl ⁇ -pyrimidine is non-crystalline.
• about 95%>, by weight, of the 5-ethyl-2- ⁇ 4-[4-(4- tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine is non-crystalline.
• the invention further comprises solid dispersions of 5-ethyl- 2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine substantially homogenously dispersed throughout the solid dispersion wherein the solid dispersion further comprises a water soluble, biologically compatible polymer.
• formulations of the present invention may be cellulosic or non-cellulosic.
• the polymers are neutral or ionizable in aqueous solution.
• ionizable and cellulosic polymers are preferred, with ionizable cellulosic polymers being more preferred.
• Exemplary water-soluble polymers include hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, carboxy methyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, and mixtures thereof.
• said water soluble polymer is selected from the group consisting of povidone, copovidone, hypromellose acetate succinate, polyethylene glycol, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, carboxy methyl ethyl cellulose, cellulose acetate trimellitate and cellulose acetate phthalate.
• said water soluble, biologically compatible polymer is selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, carboxy methyl ethyl cellulose, cellulose acetate trimellitate and cellulose acetate phthalate.
• said polymer is cellulose acetate phthalate.
• the solid dispersion comprises from about 5% to about 75%, by weight, of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l- yl ⁇ -pyrimidine .
• the solid dispersion is employed to provide for
• compositions further comprising a pharmaceutically inert carrier wherein the formulation comprises from about 10%> to about 50%>, by weight, of 5-ethyl-2- ⁇ 4-[4-(4- tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine.
• the pharmaceutical formulation comprises from about 20% to about 30%, by weight, of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]- piperidin- 1 -yl ⁇ -pyrimidine.
• the pharmaceutical formulation comprises about 5%, by weight, of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ - pyrimidine, or alternatively, about 10%> by weight, or about 15% by weight, or about 20%> by weight, or about 25% by weight, or about 30% by weight, or about 35% by weight, or about 40%) by weight, or about 45% by weight, or about 50% by weight, or about 55% by weight, or about 60% by weight, or about 65% by weight, or about 70% by weight, or about 75%) by weight, or about 80% by weight, or about 85% by weight, or about 90% by weight, or about 95% by weight.
• the 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)- thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine can exist within the solid dispersion in relatively pure non-crystalline domains, or, in some embodiments, is distributed substantially homogeneously throughout the solid dispersion.
• the solid dispersions of this invention are substantially homogenous and comprising a water soluble, biologically compatible polymer and a therapeutically effective amount of 5 -ethyl-2- ⁇ 4- [4-(4-tetrazol- 1 -yl-phenoxymethyl)- thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine.
• the fraction of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine that is present in relatively pure non-crystalline domains or regions within the solid dispersion is relatively small, on the order of less than 20% by weight, and preferably less than 10% by weight of the total amount of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2- yl]-piperidin-l-yl ⁇ -pyrimidine in the composition.
• the invention is directed to a method of producing solid dispersions comprising a therapeutically effective amount of 5-ethyl-2- ⁇ 4-[4-(4- tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine and a water soluble, biologically compatible polymer, wherein from about 25% to about 100% by weight of the 5-ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine is non-crystalline, which method comprises the steps of:
• the non-crystalline form of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl- phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine can be prepared by combining crystalline 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l-yl ⁇ - pyrimidine with a solvent to form solution C and rapidly removing solution C.
• the present invention is directed to a method of producing solid dispersions wherein from about 25%> to about 100% by weight of the 5- ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin-l -yl ⁇ -pyrimidine is non-crystalline, which method comprises the steps of: a) combining non-crystalline 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)- thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine and a solvent to form solution A;
• solution A b) combining solution A and a water soluble, biologically compatible polymer to form solution B;
• the 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)- thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine step a) is crystalline.
• the 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l-yl-phenoxymethyl)- thiazol-2-yl]-piperidin-l-yl ⁇ -pyrimidine step a) is crystalline.
• the non-crystalline form of this compound can be used.
• any suitable water soluble, biologically compatible polymer can be used in step b).
• Non-limiting examples include, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, carboxy methyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate and cellulose acetate phthalate.
• the water soluble, biologically compatible polymer is cellulose acetate phthalate.
• the step of rapidly removing the solvent from solution B employs a spray-dryer.
• a spray dryer combines a liquid stream (e.g., solution A or B, above) with a drying gas, and separates the solute or suspension as a solid and the solvent into a vapor.
• the solid can be collected in a drum or cyclone.
• the liquid input stream is sprayed through a nozzle into a hot vapor stream and vaporized. Solids form as moisture quickly leaves the droplets.
• a nozzle is usually used to make the droplets as small as possible, maximising heat transfer and the rate of water vaporization. When a flammable solvent is used, oxygen is normally excluded from all parts of the spray drying apparatus.
• suitable drying gases for use in the methods disclosed herein include inert gases, such as nitrogen, argon, carbon dioxide, helium, krypton, and xenon, at a flow rate of about 1200 g/min to about 2500 g/min. In some embodiments, the flow rate is about 1850 g/min.
• Typical droplet sizes can range from about 1 to about 500 micrometers, depending on the nozzle selected.
• the smallest diameter of the solid dispersion is from about 1 to about 500 micrometers, or from about 1 to about 400 micrometers, or from about 5 to about 300 micrometers, or from about 5 to about 200 micrometers, or from about or 5 to about 100 micrometers, or from about or 5 to about 80 micrometers, or from about or 5 to about 60 micrometers, or from about or 5 to about 40 micrometers, or from about or 5 to about 50 micrometers, or from about or 10 to about 40 micrometers, or from about or 15 to about 35 micrometers, or about 25 micrometers.
• solution B is delivered to the spray-dryer at a rate of from about 175 grams/min to about 250 g/min. In some embodiments, solution B is delivered to the spray-dryer at a rate of from about 200 grams/min to about 230 g/min. In some embodiments, solution B is delivered to the spray-dryer at a pressure of from about 150 psi to about 500 psi. In some embodiments, solution B is delivered to the spray-dryer at a pressure of from about 200 psi to about 450 psi. In some embodiments, solution B is delivered to the spray-dryer at a pressure of from about 300 psi to about 315 psi. For commercial scale manufacturing, the drying gas flow rate can be significantly higher. The above provides for rapid removal of the solvent such that at least a portion of Compound A remains non-crystalline.
• Suitable solvents for use in the spray-dryer include polar organic solvents, such as alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and propyl acetate; and various other solvents, such as tetrahydrofuran, acetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane.
• the solvent of solution A is acetone.
• the temperature of the spray-dryer can be adjusted based on the solvent employed and the size of the nozzle.
• the spray drying is performed at a temperature of between about 100° C and about 150° C. In some embodiments, the spray drying is performed at a temperature of between about 115° C and about 135° C. In some embodiments, the spray drying is performed at a temperature of about 125° C.
• the solid dispersions of this invention can be prepared by hot melting the water-soluble, biologically compatible polymer, adding the desired amount of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol-l -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine to the hot melt under conditions to provide a uniform dispersion of the hot melt and then extruding the hot melt to form a solid dispersionsolid dispersion.
• the solid dispersion produced herein is sometimes referred to as a "hot melt extrudate".
• Suitable polymers for hot melt purposes include, for example, povidone, copovidone, hypromellose acetate succinate, and polyethylene glycol.
• compositions of the present invention comprise a
• the compound of Formula (IX) and (X) are contacted at a temperature of 60 °C to 100 °C. In other aspects, the temperature is 70 °C to 90 °C, 79 °C to 81 °C, or 80 °C.
• the base is NaOH, Na 2 C0 3 , NaHC0 3 , KHC0 3 , K 2 C0 3 , Cs 2 C0 3 , Et 3 N (triethylamine) and i-Pr 2 Net (diisopropylethylamine).
• the compound of Formula (IX) is prepared by contacting a compound of Formula (VIII) with acid
• the compound of Formula (VIII) is prepared by contacting a compound of Formula (VI) with a compound of Formula (VII)
• VII are contacted in a polar organic solvent selected from dimethyl formamide (DMF) and acetonitrile (MeCN) and in presence of base.
• a polar organic solvent selected from dimethyl formamide (DMF) and acetonitrile (MeCN) and in presence of base.
• the base is selected from the group consisting of NaOH, Na 2 C0 3 , K 2 C0 3 , Cs 2 C0 3 and NaH.
• the compound of the solvent is MeCN. In other aspects, the solvent is DMF.
• the base is Cs 2 C0 3 . In still other aspects the base is K 2 C0 3 .
• the compound of Formula (VI) is prepared by contacting a compound of Formula (IV) with a compound of Formula (V)
• the compounds of Formula (IV) and Formula (V) are refluxed in a polar organic solvent in presence of base.
• the base is selected from the group consisting of Na 2 C0 3 , K 2 C0 3 , Cs 2 CO and MgC0 3 .
• the compound of Formula (VII) is prepared by contacting 4-aminophenol with sodium azide and trimethylorthoformate.
• the compound of Formula (IV) is prepared by contacting a compound of Formula (II) with a compound of Formula (III)
• the compound of Formula (II) is prepared by contacting a compound of Formula (I) with di-tert-butyl dicarbonate (Boc 2 0).
• an intermediate compound for use in the preparation of 5-ethyl-2- ⁇ 4-[4-(4-tetrazol- 1 -yl-phenoxymethyl)-thiazol-2-yl]-piperidin- 1 -yl ⁇ -pyrimidine selected from the group consisting of
• the labeled compound can be prepared according to the following scheme from commercially available 14C(U)]-4-aminophenol hydrochloride (Archemi 1-800-331-6661, ARC-545):
• methods of treating a disease or condition selected from the group consisting of Type I diabetes, Type II diabetes and metabolic syndrome are provided.
• the method comprises administering to a subject in need of such treatment an effective amount of a pharmaceutical formulation of the present invention.
• methods of raising intracellular levels of Ca in a cell expressing GPRl 19 are provided.
• the method comprises exposing a cell that expresses
• the cell that expresses GPR119 is a pancreatic cell, an islet cell, or a beta cell, an intestinal endocrine cell, an L cell or a K cell.
• Another aspect of the invention provides a method of stimulating insulin production in a mammal, in particular a human.
• the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal.
• insulin is produced by the beta cells.
• the invention provides a method of stimulating insulin secretion in a mammal, in particular a human.
• the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal.
• insulin is secreted into the blood stream by the beta cells.
• a further aspect of the invention provides a method of stimulating glucose- dependent insulin secretion in a mammal, in particular a human.
• the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal. After administration to the subject, insulin is secreted into the blood stream by the beta cells in a glucose-dependent manner. Methods that show the blood glucose lowering effects of the pharmaceutical formulations of the invention are known in the art.
• the invention provides methods of lowering blood glucose in a mammal, preferably a human.
• the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal.
• blood glucose levels are lowered.
• the blood glucose in a mammal is reduced by about 5% or more, or about 15% or more, or about 25% or more, or about 35% or more, or about 45% or more, or about 50%> or more, or about 60%> or more, or about 70%> or more, or about 75% or more, or about 80% or more, or about 85% or more, or about 90% or more.
• the method further comprises steps to measure blood glucose levels before and after administration of a pharmaceutical formulation of the invention.
• Blood glucose levels are easily measured by numerous commercially available glucose monitoring devices that measure blood glucose from samples of blood or urine. Blood glucose can also be measured by commercially available glucometers that do not require blood or urine samples. Methods that teach how to measure improvements in diabetes paramaters, including blood glucose monitoring are known in the art.
• Another aspect of the invention provides a method of stimulating incretin production in a mammal, in particular a human.
• the method comprises administering an effective amount of a pharmaceutical formulation of the invention to the mammal.
• glucagon- like peptide 1 and glucose-dependent insulinotropic polypeptide is produced by the intestinal endocrine cells.
• Example 1 4-Carbamoyl-piperidine-l-carboxylic acid tert-butyl ester
• the conversion was estimated via the integral of the italicized signals: 4 hrs, 80% conversion; 6 hrs, 95% conversion.
• the reaction solution was allowed to cool to 10°C (ice-water bath temp), and then a solution of 15% (w/v) NaOH (705 mL; 2.64 mol, 2 eq. of HC1 used) in -500 mL of water was added dropwise over 15 minutes. (Diluted 15% aq. NaOH was used to ensure no precipitation (inorganic salt) in the organic phase). Immediate phase break was observed when the stirring was stopped to give a brown aqueous layer on top and a pale yellow organic layer on the bottom.
• 1,4-dioxane, 1,4- dioxane/methanol, or methylene chloride will produce a tiny amount of detectable impurity which can be seen by 1H NMR in DMSO-ife Diagnostic peaks ⁇ 6.82 (m), 6.56 (m), 4.99 (m) ppm. This impurity will be carried over to the final product in the next step, and cannot be removed by purification via recrystallization.
• reaction mixture was aliquoted and quenched into water/brine, and then extracted w/ EtOAc.
• the conversion was estimated via the integral of the italicized signals. Complete conversion was observed between 3 to 4 hours. Prolonged heating (> 5 hours) resulted in the formation of the unidentified impurity.
• reaction mixture was transferred to a 5-L 3-neck flask, and allowed to cool with stirring to rt with ice-water bath.
• the resulting slurry was stirred at rt for an additional 10-15 minutes.
• the off-white precipitate was filtered and then rinsed with water (250 mL x 2).
• the mother liquor was kept to do another recrystallization later on, and the precipitate on the filter funnel was rinsed once more time with 300 mL of heptane. After air-drying, 91.11 g of product was obtained as a white solid.
• the mother liquor (without heptane) was stripped down in vacuo until a thick slurry was formed, and the resulting precipitate was filtered and rinsed twice with EtOAc (100 mL x 2) and once with heptane (100 mL) to give another 16.84 of product as a white solid. Overall yield 78%.
• Free amine (207 mg, 0.60 mmol) was treated at 90°C with 178.3 mg of 2-chloro-5- ethylpyrimidine (2 eq.) and anhy. K 2 CO 3 (1.5 eq.) in 1 mL of DMF (the final concentration of the free amine is -0.60 M). The reaction was complete in 2 hours. However, the reaction mixture was not homogenous at the end because of the precipitation of product.
• Free amine (212 mg, 0.62 mmol) was treated at 90°C with 114.2 mg of 2-chloro-5- ethylpyrimidine (1.3 eq.) and anhy. K 2 CO 3 (1.5 eq.) in 0.5 mL of DMF (the final concentration of the free amine is -1.2 M). The reaction was achieved -85% conversion in 2 hours, and the reaction mixture was not homogenous because of the precipitation of product. Significant amount of the unidentified by-products were formed after heating at 90°C for 4 hours.
• HPMCAS-MF indicates M grade Hypromellose Acetate Succinate supplied as a fine power
• Solid dispersion formulations of Compound A in Eudragit® E PO (Formulation 2) and Kollidon® VA 64 (Formulation 3) were examined for dissolution behavior under non- sink conditions to assess oral bioavailability enhancement. Studies were conducted in three different media preparations, including: simulated gastric fluid, fed state simulated intestinal fluid and fasted state simulated intestinal fluid, which are presented in Table 2, Table 3 and Table 4 and Figure 1, Figure 2 and Figure 3.
• Example 9 Spray-Dried Dispersion Formulation with 25 % of Compound A
• the spray drying process includes preparation of the spray solution to dissolve Compound A and cellulose acetate phthalate (CAP), spray drying to form spray-dried dispersion (SDD) powder, and secondary drying of the SDD powder to remove residual solvent.
• Figure 4 provides an overview of the process used to manufacture the 25 % SDD formulation containing 250 mg/g of Compound A and 750 mg/g of CAP (referred to as 25% Compound A: CAP SDD) on a PSD-1 spray dryer.
• Spray Solution Preparation During spray solution preparation the temperature of the solution is maintained at room temperature but above 20°C to ensure the solubility of Compound A. After Compound A is added to the acetone, the solution is mixed for at least one hour, until the crystalline Compound A is completely dissolved. The CAP is then added to the solution and mixed for at least one hour until the CAP is completely dissolved. The spray solution contains 1.25 % of Compound A, 3.75 % of CAP and 95 % of acetone.
• Spray Drying The spray-drying conditions are divided into preheating, warm- up/shutdown and feed-solution processing phases. During the warm-up phase pure acetone is sprayed to thermally equilibrate the spray dryer. During the feed-solution processing phase the Compound A:CAP spray solution is sprayed.
• the spray-drying conditions are:
• Figure 5 illustrates the residue acetone content as a function of tray-drying time at 40°C/30 % RH for 25 % Compound A:CAP SDD based on headspace gas chromatography (GC) analysis under conditions having a tray-dryer bed depth of equal to or less than 2.5 cm.
• GC headspace gas chromatography
• a spray solution was formed containing 1.25 wt% Compound A, 3.75 wt% CAP, and 95% acetone as follows.
• Compound A was added to acetone in a stainless-steel solution tank with a top-mounted mixer, and mixed for at least 1 hour.
• CAP was added directly to this mixture, and the mixture stirred for at least one additional hour.
• the resulting mixture had a slight haze after the entire amount of polymer had been added.
• This mixture was then filtered by passing it through a filter with a screen size of 230 ⁇ to remove any large insoluble material from the mixture, thus forming the spray solution.
• the spray-dried dispersion was then formed using the following procedure.
• the spray solution was pumped to a spray drier (Niro type XP Portable Spray-Dryer with a Liquid-Feed Process Vessel [PSD-1]) equipped with a pressure swirl atomizer (Spraying Systems Pressure Nozzle and Body (SK 76-16)).
• PSD-1 Liquid-Feed Process Vessel
• the PSD-1 was equipped with a 9-inch chamber extension to increase the vertical length of the dryer.
• the spray drier was also equipped with a diffuser plate having a 1% open area to direct the flow of the drying gas and minimize product recirculation within the spray dryer. The nozzle sat flush with the diffuser plate during operation.
• the spray solution was pumped to the spray drier at about 215 gm/min at a pressure of about 315 psig.
• Drying gas e.g., nitrogen
• the evaporated solvent and wet drying gas exited the spray drier at a temperature of 45 ⁇ 5°C.
• the SDD formed by this process was collected in a cyclone.
• Long-term storage of the SDD may be at an average of 5°C (e.g., 2°C to 8 °C) in double low-density polyethylene (LDPE) bags inside HDPE drums with desiccant between the two bags.
• LDPE double low-density polyethylene
• the SDD may be stored for short-term, e.g., 1 week, at ambient temperature and humidity (e.g., 25°C/60% RH).
• Example 10 In vitro Analysis of Spray-Dried Dispersion Formulation with 25 % of Compound A
• Table 6 lists the general physical properties of a 25% Compound A:CAP SDD manufactured from an acetone solution.
• Tables 7a and 7b and Figure 6 compares in vitro dissolution performance of Compound A:CAP SDD with that of crystalline of Compound A, HPMCAS-MG, and HPMCAS-HG. As the figure shows, the C max and AUCo-90 (area under the curve through 90 minutes) of the SDD were more than 6-fold higher than those of crystalline of
• concentrations of Compound A obtained in these samples were used to determine the maximum concentration of Compound A and the area under the concentration- versus-time curve ("AUC 90 ") during the initial ninety minutes.
• Tablet manufacture includes blending the SDD and intragranular excipients to form a uniform blend, dry-granulating to form flowable granules, blending extragranular excipients to provide additional tableting functionality, tablet compressing to form unit dosages, and film-coating to provide a white opaque coating.
• the excipients used in the 25 and 100 mg tablets are shown in Tables 9 and 10, respectively.
• a sufficient amount of the solid dispersion of compound A was used to provide for 25 mg of the compound in the 25 mg tablet, and a sufficient amount of the solid dispersion of compound A was used to provide for 100 mg of the compound in the 100 mg tablet.
• Figure 7 provides an overview of the manufacturing process for the uncoated 25 mg tablets.
• Figure 8 provides an overview of the manufacturing process for the uncoated 100 mg tablets.
• Microcrystalline cellulose (Avicel PH-101, FMC); intragranular Lactose monohydrate, modified spray-dried (316 FastFlo,
• Crospovidone Polyplasdone XL, ISP
• Magnesium stearate (vegetable sourced); intragranular
• Crospovidone Polyplasdone XL, ISP
• Lactose monohydrate modified spray-dried (316 FastFlo,
• Microcrystalline cellulose (Avicel PH-200, FMC);
• Magnesium stearate (vegetable sourced); extragranular
• Microcrystalline cellulose (Avicel PH-101, FMC); intragranular Lactose monohydrate, modified spray-dried (316 FastFlo,
• Crospovidone Polyplasdone XL, ISP
• Magnesium stearate (vegetable sourced); intragranular
• Magnesium stearate (vegetable sourced); extragranular
• the same blending and dry-granulation process is used for the 25 mg and 100 mg active tablets (i.e., a "common granulation" is used for both tablet strengths).
• the 25 and 100 mg uncoated tablets may have identical size, shape and weight.
• the 25 mg and 100 mg tablets can be coated using a film coating compositions well known to those of skill in the art, for example, Opadry II (white 85F 18378, Colorcon) and purified water.
• the dry granulation process is carried out as follows: 1.
• the intragranular excipients are delumped by passing through a low-shear cone mill.
• the magnesium stearate is hand screened with a portion of the blend from step 2 into the bin blender and blended.
• the blend is discharged from the blender and roller-compacted.
• the roller compactor parameters are established to provide roller compacted material with a solid fraction (a
• unitless relative density parameter of 0.63. This is assured by in-process measurement.
• the roller compacted material is granulated by passing through a 0.8 mm oscillating screen mill.
• the granulation from step 5 is called the “Common Granulation” and is used to manufacture both the 25 and 100 mg active tablets.
• the extragranular final blend and tablet compression are carried out as follows:
• the granulation, extragranular lactose and extragranular micro crystalline cellulose are added to the bin blender and blended.
• the colloidal silica dioxide is hand screened with a portion of the blend from step 2 into the bin blender and blended.
• the magnesium stearate is hand screened with a portion of the blend from step 3 into the bin blender and blended.
• the powder is discharged from the blender and compressed into 800 mg total weight tablets using a rotary tablet press.
• the tablet weight, tablet weight distribution and tablet hardness are adjusted during startup and are monitored at timed intervals during compressing to assure product attributes are met.
• the tablets are de-dusted, passed through a metal detector and stored in double polyethylene bags in drums.
• microcrystalline cellulose were delumped using a comil 197 equipped with a 0.032-inch (032R) screen and 1601 impellor.
• the spray-dried dispersion was added to the delumped mixture and blended using a PK twin-shell blender, followed by addition and blending of the magnesium stearate, to form the intragranular blend.
• the intragranular blend was roller compacted and milled into granules using a Gerteis Mini-Pactor with a Gerteis Star Rotor Mill with a 0.8 mm screen, a compression force between 4 and 7 kN/cm, and a roll speed between 2 and 6 rpm.
• the milled granulation was blended with colloidal silica dioxide, followed by the addition and blending of the extragranular magnesium stearate. Tablets were compressed using a Kilian T-100 rotary press with 0.3586" X 0.7174" modified oval tooling to a hardness of 17-23 kP.
• aqueous film-coating process is the same for the 25 and 100 mg active tablets, which is described below and illustrated in Figure 9.
• the coating pan is pre-warmed and then the empty pan is spray-coated with a thin layer of Opadry II to eliminate sliding of tablets during film-coating.
• the tablets are film-coated and the coating suspension is stirred throughout the coating process to prevent settling.
• the tablets are dried with jog tumbling.
• a coating solution was formed by adding Opadry II to purified water (1 :9 w wt) in a mixing vessel with overhead propeller stirrer.
• the coating solution was pumped using a peristaltic pump to a Schlick 970 spray gun with 1.0-mm nozzle and standard air cap, and the tablets were coated in a Vector LDCS pan-coater.
• the following conditions were used: atomizing air pressure 15 psi, nozzle tip-to-bed distance 2.5", inlet air flow 45 CFM, inlet-air temperature 70 to 75 °C, exhaust temperature 46 °C, pan run speed 20 rpm, and solution flow rate 9 g/min.
• Coated tablets had a hardness of 20kP.
• a sink dissolution test was performed on 100-mgA Film-Coated SDD tablets.
• 900 mL dissolution media (0.05 M NaH 2 P0 4 , pH 6.8, containing 1 wt% sodium lauryl sulfate) was added to 1000 mL VanKel dissolution vessels and allowed to warm up for about 30 minutes. Tests were performed at 37°C. Four tablets were dropped into individual vessels containing the dissolution media at time 0. The theoretical maximum concentration of Compound A in the dissolution media was 11 ⁇ g/mL.
• Samples (10 mL) were taken at 5, 15, 30 and 45 minutes using 20 mL syringes with cannulas equipped with 10 ⁇ full flow filters. The samples were filtered through a 0.45 ⁇ nylon syringe filter into an HPLC vial for analysis. The results are shown in Table 11. The 100 mg tablets released 98.3% of theoretical by 45 minutes. Tablets were greater than 80% dissolved within 5 minutes.
• the tablets can be packed in high-density polyethylene (HDPE) bottles with polypropylene heat-induction seal caps and desiccant. Bottles can be labeled with the lot number, content, storage conditions and other information as required.
• HDPE high-density polyethylene
• Study Design This is a single center, phase 1, double-blind, placebo-controlled, multiple ascending dose study of Compound A given orally as a reformulated tablet (spray dried dispersion, or SDD) to otherwise healthy subjects with "pre-diabetes" (impaired fasting glucose, impaired glucose tolerance, or HbAlC > 5.8), or diet-controlled type 2 diabetes mellitus.
• SDD spray dried dispersion
• the study was designed to evaluate the safety, tolerability, pharmacokinetics (PK), and proof-of-concept pharmacodynamics of Compound A.
• Each dosing cohort consisted of a screening period to assess eligibility, a dosing and observational period, and a follow-up period.
• DLTs dose-limiting toxicities
• Study Procedures Screening Phase (Day -35 to -3) [0148] The initial screening visit occurred between Day -35 and Day -4, before the start of each new dose cohort, to determine subject eligibility. At the initial screening visit, subjects signed an informed consent prior to any study specific assessments or assignment of a screening number. Screening evaluations included collection of demographics and a full medical history with medication review, 12-lead ECG and vital signs (including height and weight), drug and alcohol screen, serum pregnancy test (females only), clinical laboratory evaluation and HbAlc. A minimum of 15 subjects who satisfied initial screening eligibility assessments were invited to complete the Day -3 assessments.
• Compound A was measured pre-dose (t -30 and 0 min) on Day 1 and at 20 and 40 minutes, and 1, 2, 3, 4, 6, 8, 12, and 24 hours post-dose. Compound A was measured at identical timepoints associated with the Day 4 dose, but included additional measurements at 48 and 72 hours post-dose (Day 7). Additionally, a 24 hour urine collection was completed on Day 4 for potential measurement of Compound A and its metabolites.
• MMTT was administered at baseline (Day -2 pre-dose) and at 2 hours after the Day 4 dose, at the identical time on each occasion.
• Glucose, and insulin were obtained from 7 measurements performed at 30 minutes before the meal, immediately before the meal (0 minutes), and 30, 60, 90, 120, and 240 minutes after starting the meal.
• Total GLP-1 and glucagon were obtained from 11 measurements performed at 30 minutes before the meal, immediately before the meal (0 minutes), 10, 15, 20, 30, 40, 60, and 90 minutes after starting the meal, and at 2 and 4 hours after starting the meal.
• OGTT was administered at baseline (Day -1 pre-dose) and at 2 hours after the Day 5 dose, at the identical time on each occasion.
• Glucose and insulin were obtained from 7 measurements performed at 30 minutes before the glucose ingestion, immediately before the glucose ingestion (0 minutes), and 30, 60, 90, 120, and 240 minutes after the glucose ingestion.
• Total GLP- 1 and glucagon were obtained from 11 measurements performed at 30 minutes before the meal, immediately before the meal (0 minutes), 10, 15,
• This visit included vital signs, full physical examination including funduscopic examination, clinical laboratory evaluation, serum pregnancy test (females only), ECG, concomitant medication review, and review of ongoing AE's. The completion of this visit marked the end of the subject's formal participation in the study.
• Cohort 1 25 mg (25 mg x 1) orally once daily for 5 days
• Cohort 2 100 mg (100 mg x 1) orally once daily for 5 days
• Cohort 3 300 mg (100 mg x 3) orally once daily for 5 days
• Cohort 4 600 mg (100 mg x 6) orally once daily for 5 days

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