WO2015160678A1 - Sitagliptin tannate complex - Google Patents

Sitagliptin tannate complex Download PDF

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Publication number
WO2015160678A1
WO2015160678A1 PCT/US2015/025504 US2015025504W WO2015160678A1 WO 2015160678 A1 WO2015160678 A1 WO 2015160678A1 US 2015025504 W US2015025504 W US 2015025504W WO 2015160678 A1 WO2015160678 A1 WO 2015160678A1
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WO
WIPO (PCT)
Prior art keywords
sitagliptin
tannate complex
sitagliptin tannate
effective amount
oral dosage
Prior art date
Application number
PCT/US2015/025504
Other languages
French (fr)
Inventor
Wycliffe OMWANCHA
Rubi Burlage
Original Assignee
Merck Sharp & Dohme Corp.
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 Merck Sharp & Dohme Corp. filed Critical Merck Sharp & Dohme Corp.
Priority to KR1020167028345A priority Critical patent/KR102351813B1/en
Priority to US15/302,211 priority patent/US9833463B2/en
Priority to CN201580020211.4A priority patent/CN106456998B/en
Priority to AU2015247921A priority patent/AU2015247921B2/en
Priority to ES15780045T priority patent/ES2932383T3/en
Priority to MX2016013588A priority patent/MX2016013588A/en
Priority to EP15780045.9A priority patent/EP3131631B1/en
Priority to RU2016144695A priority patent/RU2696588C2/en
Priority to BR112016023839A priority patent/BR112016023839A8/en
Priority to JP2016562508A priority patent/JP6523328B2/en
Priority to CA2945681A priority patent/CA2945681A1/en
Publication of WO2015160678A1 publication Critical patent/WO2015160678A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present application relates to a complex of sitagliptin (4-oxo-4-[3-(trifluroromethyl)- 5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H ⁇ ) and tannic acid (“sitagliptin tannate complex”), which is a potent inhibitor of dipeptidyl peptidase-IV (“DPP-IV").
  • DPP-IV dipeptidyl peptidase-IV
  • This invention further relates to an oral dosage form comprising an effective amount of the sitagliptin tannate complex, a pharmaceutical intermediate comprising an effective amount of the sitagliptin tannate complex, methods of treating, controlling or preventing a disease or condition for which a DPP-IV inhibitor is indicated by administering an effective amount of the sitagliptin tannate complex to a patient in need thereof, and a process to prepare the sitagliptin tannate complex.
  • DPP-IV glucose-dependent insulinotropic peptide
  • GLP-1 glucose-dependent insulinotropic peptide 1
  • NIDDM non-insulin dependent diabetes mellitus
  • WO2003/004498 assigned to Merck Sharp & Dohme Corp., describes a class of beta- amino tetrahydrotriazolo[4,3-a]pyrazines, which are potent inhibitors of DPP-IV, and therefore are useful for the treatment of type 2 diabetes.
  • WO 03/004498 is 4-oxo- 4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine. While pharmaceutically acceptable salts of this compound are generically encompassed within the scope of WO 03/004498, there is no specific disclosure the sitagliptin tannate complex.
  • dihydrogenphosphonate salt is a potent inhibitor of DPP-IV and, therefore, is useful for the treatment and prevention of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes, obesity and high blood pressure.
  • WO2005/003135 also describes a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation,
  • WO2005/003135 does not describe a sitagliptin tannate complex.
  • Tannic acid also known as tannin, gallotannin, glycerite or gallotannin, is a yellowish to light brown amorphous powder having the approximate composition of C76H52O46 and a molecular weight of about 1701 grams/mol.
  • tannic acid is typically produced from Turkish or Chinese nutgall, it can be derived from the bark and fruit of many plants. Tannic acid is very soluble in water, glycerin or alcohol. Tannic acid may be obtained either by extraction from natural products or through synthetic chemical synthesis.
  • Tannate complexes comprising pharmaceutically active compounds are known in the art. See, e.g., US 5,663,415; US 6,881,741 B2; US 6,939,856 B2; US 6,670,370 Bl; and US
  • Tannate salts have been found to have better organoleptic properties, such as taste, in comparison to other salts or free base forms. See, e.g., US 2005/0202050 Al or US
  • Sitagliptin as a monohydrate phosphate salt is the active ingredient in JANUVIA ® and one of the active agents in JANUMET ® AND JANUMET XR ® , all marketed by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., to improve glycemic control in adults with type 2 diabetes mellitus.
  • An unintended effect of sitagliptin monohydrate phosphate is that it has an intense, lingering bitter taste.
  • drug products containing sitagliptin monohydrate phosphate are formulated as a film-coated tablet. Marketing sitagliptin monohydrate phosphate as a film-coated tablet is not always ideal as an estimated 20% of the patients taking JANUMET ® experience a difficulty in swallowing the tablet.
  • any of these alternative intra-oral dosage forms must be relatively easy to
  • the present invention is directed to a tannate complex of sitagliptin, to an oral dosage form comprising an effective amount of the sitagliptin tannate complex, a pharmaceutical intermediate comprising an effective amount of the sitagliptin tannate complex, and to methods of treating, controlling, or preventing a disease or condition for which a DPP-IV inhibitor is indicated by administering an effective amount of the sitagliptin tannate complex to a patient in need thereof.
  • This invention further relates to processes to prepare the sitagliptin tannate complex.
  • the sitagliptin tannate complex possesses a release property or profile in which the sitagliptin tannate complex exhibits a negligible release rate at neutral pH, such as that found in the mouth, and immediate release in acidic pH, such as that found in the stomach.
  • This release property allows one to formulate sitagliptin in oral dosage form that is easier to swallow and does not need a film layer, e.g., a dosage form such as a chewable tablet, soft chew, medicated gum or disintegrating table, because the sitagliptin tannate complex has a neutral taste in the mouth.
  • oral dosage forms that have a neutral taste would be expected to improve patient compliance in taking the medicine.
  • tannate complexes impart extended release properties to a pharmaceutical formulation comprising an active pharmaceutical ingredient (API) (see, e.g., US 6,670,370 and US 6,939,856).
  • API active pharmaceutical ingredient
  • Exhibiting extended release properties implies that the API in an extended release pharmaceutical formulation is stable (i.e., exhibits negligible dissociation) in acidic pH, such as that found in the stomach, and dissociates in a predefined manner over time in neutral pH, such as that found in the intestine.
  • the release property of the inventive sitagliptin tannate complex unexpectedly the opposite occurs in that the immediate release occurs at acidic pH.
  • FIG. 1 is graph depicting the two-stage dissolution profile for the sitagliptin tannate complex of Example 1. The graph plots the percentage (%) of sitagliptin released from the sitagliptin tannate complex versus time.
  • FIG. 2 is a graph depicting the two-stage dissolution profile for the sitagliptin tannate complex of Example 2. The graph plots the percentage (%) of sitagliptin released from the sitagliptin tannate complex versus time.
  • FIG. 3 is a graph depicting the two-stage dissolution profile for a soft-chew formulation comprising the sitagliptin tannate complex of Example 3. The graph plots the percentage (%) of sitagliptin released from the sitagliptin tannate complex in the soft-chew formulation versus time.
  • this invention provides for a sitagliptin tannate complex.
  • sitagliptin tannate complex wherein the sitagliptin content is between about 25% and about 75% by weight or between about 29% and 33%) by weight.
  • Another embodiment of the present invention is a sitagliptin tannate complex wherein the ratio of sitagliptin to tannic acid is about 3 : 1 to about 1 :4 by weight; for example about 1 :2 by weight.
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 and an inert carrier.
  • Another embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 , a therapeutically effective amount of at least one additional pharmaceutically active ingredient (e.g., a biguanide such as metformin or a pharmaceutically acceptable salt thereof) and an inert carrier.
  • a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 a therapeutically effective amount of at least one additional pharmaceutically active ingredient (e.g., a biguanide such as metformin or a pharmaceutically acceptable salt thereof) and an inert carrier.
  • Another embodiment of the present invention is a pharmaceutical intermediate, which comprises a pharmaceutically effective amount of a sitagliptin tannate complex, a
  • pharmaceutically acceptable polymer e.g., polyethylene glycol (PEG), such as PEG 3350, PEG 6000 or PEG 8000
  • pharmaceutically acceptable polyols e.g., mannitol or maltitol
  • high intensity sweeteners e.g., sucralose
  • flavorants e.g., mint, cherry or banana flavor
  • an oral dosage form e.g. a tablet, capsule, pellet or powder
  • the pharmaceutical intermediate comprising a therapeutically effective amount of a sitagliptin tannate complex.
  • Another embodiment of the present invention is an oral dosage form, which comprises the pharmaceutical intermediate comprising a therapeutically effective amount of a sitagliptin tannate complex and the oral dosage form is in the form of a soft chew, medicated gum, chewable tablet, disintegrating tablet, syrup, sachet, oral film, gel or lyosphere.
  • an oral dosage form e.g., a soft chew, medicated gum, oral film, disintegrating tablet or syrup
  • the pharmaceutical intermediate comprising a therapeutically effective amount of a sitagliptin tannate complex, wherein the sitagliptin has negligible release in the mouth and immediate release in the stomach.
  • Another embodiment of the present invention is a method for treating, controlling or preventing of one or more diseases for which an inhibitor of DPP-IV is indicated comprising the administration a therapeutically effective amount of the sitagliptin tannate complex to a patient in need thereof.
  • Another embodiment of the present invention is a method for treating, controlling or preventing type 2 diabetes, obesity and high blood pressure comprising the administration of a therapeutically effective amount of the sitagliptin tannate complex to a patient in need thereof.
  • Another embodiment of the present invention is the use of a sitagliptin tannate complex for the manufacture of a medicament for the treatment and/or prevention of one or more diseases for which an inhibitor of DPP-IV is indicated.
  • “Mammal” includes humans and other mammalian animals.
  • terapéuticaally effective amount is intended to mean that amount of a pharmaceutically active ingredient that will elicit the biological or medical response of a tissue or a system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician (e.g., inhibiting DPP-IV).
  • a "prophylactically effective amount” is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician.
  • preventing or "prevention” are used herein to refer to administering a compound before the onset of clinical symptoms.
  • immediate release means that at least 85% of the drug is released from the dosage form within 120 minutes or less when tested in a USP type 2 apparatus in a fasted state simulated intestinal fluid (FaSSIF) at a pH of 6.5 at room temperature (approximately 25 C), which can be made using SIFTM powder (from biorelevant.com Ltd) as follows:
  • non-ligible release means that the amount of sitagliptin dissociated from the sitagliptin tannate complex is not sufficient for the sitagliptin tannate complex to lose its tastemasking activity in a subject; e.g., up to 10% of the sitagliptin is dissociated from the sitagliptin tannate complex, up to 5% of the sitagliptin is dissociated from the sitagliptin tannate complex, or up to 3% of the sitagliptin is dissociated from the sitagliptin tannate complex.
  • composition is intended to encompass both bulk
  • compositions and individual dosage units comprised of more than one (e.g., two)
  • pharmaceutically active agents such as, for example, the sitagliptin tannate complex and an additional active ingredient.
  • examples of other pharmaceutically active ingredients that may be administered in combination with the sitagliptin tannate complex of the present invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
  • insulin sensitizers including (i) PPARy agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, including PPAR ⁇ / ⁇ dual agonists, such as KRP-297, and PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin HC1 and phenformin, and (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
  • PPARy agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like
  • a-glucosidase inhibitors such as acarbose
  • glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
  • GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as those disclosed in WO00/42026 and WO00/59887;
  • PACAP PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420;
  • cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR ⁇ / ⁇ dual agonists, such as KRP-297, (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoAxhol
  • anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, and ⁇ adrenergic receptor agonists;
  • agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors.
  • the above combinations include combinations of the sitagliptin tannate complex of the present invention not only with one other pharmaceutically active ingredient, but also with two or more different pharmaceutically active ingredients.
  • Non-limiting examples include combinations of the sitagliptin tannate complex with two or more pharmaceutically active ingredients selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DPP-IV inhibitors, and anti-obesity compounds.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day.
  • compositions are preferably provided in the form of oral dosage forms containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, and 500 milligrams of sitagliptin for the symptomatic adjustment of the dosage to the patient to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of sitagliptin, preferably, from about 1 mg to about 200 mg of active ingredient.
  • the sitagliptin tannate complex can form the active pharmaceutical ingredient, and are typically administered in admixture with suitable
  • carrier materials
  • carrier suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
  • the active pharmaceutical ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the active pharmaceutical ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like
  • any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Additional pharmaceutical adjuvants include binders, lubricants, sweeteners, flavoring agents, disintegrating agents and coloring agents, which are known in the art (see, e.g.,
  • Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • sitagliptin tannate complex of the present invention can be made by the following process:
  • step (3) Wash the residue obtained in step (2) with a polar pharmaceutically acceptable liquid (e.g., water);
  • a polar pharmaceutically acceptable liquid e.g., water
  • step (4) Dry the residue obtained in step (4), for example, in a vacuum oven (e.g. at 50°C) for about 3 to 10 hours, to provide the sitagliptin tannate complex;
  • the active solution of sitagliptin was prepared by dissolving 0.5 g of sitagliptin freebase in 20 ml of methanol. 1 g of tannic acid was dissolved in the same amount of methanol to form tannic acid dispersion. The sitagliptin solution was then added slowly to tannic acid dispersion while stirring. The mixture was allowed to stir until all the solvent evaporated under ambient conditions in a fume hood. The solid material formed was pulverized into powder. 100 ml of water was added to the powder and the mixture stirred for 30 minutes, before centrifuging at 15K rpm to remove the liquid. The washed sitagliptin tannate complex was then dried in a constant temperature oven at 50 °C.
  • Stage 1 A sample of sitagliptin tannate complex of Example 1 or 2 was placed in 10 mL of SSF, which was prepared by dissolving 8.0 g of NaCl, 0.19 g of potassium phosphate monobasic, and 2.38 g of sodium phosphate dibasic in 1 L of water, and adjusting to pH 6.8 with phosphoric acid, heated to 37 °C, for 1 minute and an aliquot was removed.
  • Stage 2 The remaining solution transferred to 500 mL of SGF, which was prepared by dissolving 2.0 g of NaCl in 1 L of water, and adding 1.4 mL of concentrated hydrochloric acid.
  • SGF was stirred at 37 °C with apparatus 2 (paddles), and aliquots were collected at 6 time- points.
  • Fig. 1 depicts the dissolution profile of Example 1
  • Fig. 2 depicts the dissolution profile of Example 2.
  • Both profiles indicate that very little to no sitagliptin was released in SSF. This indicates that the sitagliptin-tannic acid complex is not soluble or almost not soluble at neutral pH and, hence, a subject would not be expected to taste the unpleasant flavor of sitagliptin. However, in both profiles, the sitagliptin is rapidly released from the complex at the low pH of SGF and, therefore, would be expected to be available for absorption by the subject.
  • sitagliptin tannate complexes obtained in Examples 1 and 2 were formulated as a soft chew by incorporating the sitagliptin tannate complex of the following composition:
  • the soft chew formulation was prepared as follows:
  • part A The ingredients of part A were mixed until uniform;
  • step (2) The mixed ingredients from step (2) were melted and added to the mixed ingredients of step (1) and mixed well;
  • step (3) The mixed ingredients from step (3) were added to the mixed ingredient from step (4) and mixed until uniform;

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Abstract

The present invention provides for a sitagliptin tannate complex or a pharmaceutical compositions or a pharmaceutically acceptable intermediates comprising said complex. This invention also relates to a processes to prepare the sitagliptin tannate complex as well as to methods of using the sitagliptin tannate complex to treat diabetes, obesity and high blood pressure.

Description

TITLE OF THE INVENTION
SITAGLIPTIN TANNATE COMPLEX
FIELD OF THE INVENTION
The present application relates to a complex of sitagliptin (4-oxo-4-[3-(trifluroromethyl)- 5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H^ ) and tannic acid ("sitagliptin tannate complex"), which is a potent inhibitor of dipeptidyl peptidase-IV ("DPP-IV"). This novel tannate complex is useful for the treatment, control or prevention of diseases and conditions for which an inhibitor of DPP-IV is indicated. This invention further relates to an oral dosage form comprising an effective amount of the sitagliptin tannate complex, a pharmaceutical intermediate comprising an effective amount of the sitagliptin tannate complex, methods of treating, controlling or preventing a disease or condition for which a DPP-IV inhibitor is indicated by administering an effective amount of the sitagliptin tannate complex to a patient in need thereof, and a process to prepare the sitagliptin tannate complex.
BACKGROUND OF THE INVENTION
Inhibition of DPP-IV, an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon- like peptide 1 (GLP-1), represents a novel approach to the treatment and prevention of type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). The therapeutic potential of DPP-IV inhibitors for the treatment of type 2 diabetes has been reviewed: C. F. Deacon and J.J. Hoist, "Dipeptidyl peptidase IV inhibition as an approach to the treatment and prevention of type 2 diabetes: a historical perspective," Biochem. Biophvs. Res. Commun., 294: 1-4 (2000); K. Augustyns, et al, "Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of type 2 diabetes," Expert. Opin. Ther. Patents, 13: 499-510 (2003); and D.J. Drucker, "Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of Type 2 diabetes," Expert Opin. Investig. Drugs, 12: 87-100 (2003).
WO2003/004498, assigned to Merck Sharp & Dohme Corp., describes a class of beta- amino tetrahydrotriazolo[4,3-a]pyrazines, which are potent inhibitors of DPP-IV, and therefore are useful for the treatment of type 2 diabetes. Specifically disclosed in WO 03/004498 is 4-oxo- 4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5- trifluorophenyl)butan-2-amine. While pharmaceutically acceptable salts of this compound are generically encompassed within the scope of WO 03/004498, there is no specific disclosure the sitagliptin tannate complex.
WO2005/003135, also to Merck Sharp & Dohme Corp., discloses the
dihydrogenphosphate salt of sitagliptin. The publication indicates that the
dihydrogenphosphonate salt is a potent inhibitor of DPP-IV and, therefore, is useful for the treatment and prevention of non-insulin dependent diabetes mellitus, also referred to as type 2 diabetes, obesity and high blood pressure. WO2005/003135 also describes a crystalline monohydrate of the dihydrogenphosphate salt as well as a process for its preparation,
pharmaceutical compositions containing this novel salt form, and methods of use for the treatment of type 2 diabetes, obesity, and high blood pressure. WO2005/003135 does not describe a sitagliptin tannate complex. WO2005/072530, WO2006/033848, and
WO2007/035198, all to Merck Sharp & Dohme Corp., describe salts of sitagliptin.
Tannic acid, also known as tannin, gallotannin, glycerite or gallotannin, is a yellowish to light brown amorphous powder having the approximate composition of C76H52O46 and a molecular weight of about 1701 grams/mol. Although tannic acid is typically produced from Turkish or Chinese nutgall, it can be derived from the bark and fruit of many plants. Tannic acid is very soluble in water, glycerin or alcohol. Tannic acid may be obtained either by extraction from natural products or through synthetic chemical synthesis.
Tannate complexes comprising pharmaceutically active compounds are known in the art. See, e.g., US 5,663,415; US 6,881,741 B2; US 6,939,856 B2; US 6,670,370 Bl; and US
7,547,806 B2. Tannate salts have been found to have better organoleptic properties, such as taste, in comparison to other salts or free base forms. See, e.g., US 2005/0202050 Al or US
2003/0083354 Al . Additionally, Vummaneni et al. ( International Journal of Research in Pharmaceutical and Biomedical Sciences 3(2), 510-524 (2012)) report that tannic acid acts as a taste masker for chloroquine phosphate. Moreover, as tannate salts are relatively large molecules, they afford absorption of the pharmaceutically active compound over a prolonged period of time and hence can be used in sustained release preparations. See, e.g., US 7,547,806 B2; US
2005/0202050 Al or US 2003/0083354 Al .
Sitagliptin as a monohydrate phosphate salt is the active ingredient in JANUVIA® and one of the active agents in JANUMET® AND JANUMET XR®, all marketed by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., to improve glycemic control in adults with type 2 diabetes mellitus. An unintended effect of sitagliptin monohydrate phosphate is that it has an intense, lingering bitter taste. In order to overcome this bitter taste, drug products containing sitagliptin monohydrate phosphate are formulated as a film-coated tablet. Marketing sitagliptin monohydrate phosphate as a film-coated tablet is not always ideal as an estimated 20% of the patients taking JANUMET® experience a difficulty in swallowing the tablet.
Hence, there is a need to develop alternative intra-oral dosage forms with a pleasant taste for patient populations (e.g., the elderly or children) who cannot swallow the large tablets.
Moreover, any of these alternative intra-oral dosage forms must be relatively easy to
manufacture to make the product cost effective. This and other objectives will become evident from the following description.
SUMMARY OF THE INVENTION
In its many embodiments, the present invention is directed to a tannate complex of sitagliptin, to an oral dosage form comprising an effective amount of the sitagliptin tannate complex, a pharmaceutical intermediate comprising an effective amount of the sitagliptin tannate complex, and to methods of treating, controlling, or preventing a disease or condition for which a DPP-IV inhibitor is indicated by administering an effective amount of the sitagliptin tannate complex to a patient in need thereof. This invention further relates to processes to prepare the sitagliptin tannate complex.
Applicants discovered that the sitagliptin tannate complex possesses a release property or profile in which the sitagliptin tannate complex exhibits a negligible release rate at neutral pH, such as that found in the mouth, and immediate release in acidic pH, such as that found in the stomach. This release property allows one to formulate sitagliptin in oral dosage form that is easier to swallow and does not need a film layer, e.g., a dosage form such as a chewable tablet, soft chew, medicated gum or disintegrating table, because the sitagliptin tannate complex has a neutral taste in the mouth. Moreover, oral dosage forms that have a neutral taste would be expected to improve patient compliance in taking the medicine.
Further, this release property is unexpected in view of what the prior art generally teaches about tannate complexes. The prior art discloses that tannate complexes impart extended release properties to a pharmaceutical formulation comprising an active pharmaceutical ingredient (API) (see, e.g., US 6,670,370 and US 6,939,856). Exhibiting extended release properties implies that the API in an extended release pharmaceutical formulation is stable (i.e., exhibits negligible dissociation) in acidic pH, such as that found in the stomach, and dissociates in a predefined manner over time in neutral pH, such as that found in the intestine. However, in the release property of the inventive sitagliptin tannate complex, unexpectedly the opposite occurs in that the immediate release occurs at acidic pH.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is graph depicting the two-stage dissolution profile for the sitagliptin tannate complex of Example 1. The graph plots the percentage (%) of sitagliptin released from the sitagliptin tannate complex versus time.
FIG. 2 is a graph depicting the two-stage dissolution profile for the sitagliptin tannate complex of Example 2. The graph plots the percentage (%) of sitagliptin released from the sitagliptin tannate complex versus time.
FIG. 3 is a graph depicting the two-stage dissolution profile for a soft-chew formulation comprising the sitagliptin tannate complex of Example 3. The graph plots the percentage (%) of sitagliptin released from the sitagliptin tannate complex in the soft-chew formulation versus time.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, this invention provides for a sitagliptin tannate complex.
Another embodiment of the present invention is a sitagliptin tannate complex wherein the sitagliptin content is between about 25% and about 75% by weight or between about 29% and 33%) by weight.
Another embodiment of the present invention is a sitagliptin tannate complex wherein the ratio of sitagliptin to tannic acid is about 3 : 1 to about 1 :4 by weight; for example about 1 :2 by weight.
Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 and an inert carrier.
Another embodiment of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 , a therapeutically effective amount of at least one additional pharmaceutically active ingredient (e.g., a biguanide such as metformin or a pharmaceutically acceptable salt thereof) and an inert carrier.
Another embodiment of the present invention is a pharmaceutical intermediate, which comprises a pharmaceutically effective amount of a sitagliptin tannate complex, a
pharmaceutically acceptable polymer (e.g., polyethylene glycol (PEG), such as PEG 3350, PEG 6000 or PEG 8000), and optionally, one or more pharmaceutically acceptable polyols (e.g., mannitol or maltitol), high intensity sweeteners (e.g., sucralose) or flavorants (e.g., mint, cherry or banana flavor).
Another embodiment of the present invention is an oral dosage form (e.g. a tablet, capsule, pellet or powder), which comprises the pharmaceutical intermediate comprising a therapeutically effective amount of a sitagliptin tannate complex.
Another embodiment of the present invention is an oral dosage form, which comprises the pharmaceutical intermediate comprising a therapeutically effective amount of a sitagliptin tannate complex and the oral dosage form is in the form of a soft chew, medicated gum, chewable tablet, disintegrating tablet, syrup, sachet, oral film, gel or lyosphere.
Another embodiment of the present invention is an oral dosage form (e.g., a soft chew, medicated gum, oral film, disintegrating tablet or syrup), which comprises the pharmaceutical intermediate comprising a therapeutically effective amount of a sitagliptin tannate complex, wherein the sitagliptin has negligible release in the mouth and immediate release in the stomach.
Another embodiment of the present invention is a method for treating, controlling or preventing of one or more diseases for which an inhibitor of DPP-IV is indicated comprising the administration a therapeutically effective amount of the sitagliptin tannate complex to a patient in need thereof.
Another embodiment of the present invention is a method for treating, controlling or preventing type 2 diabetes, obesity and high blood pressure comprising the administration of a therapeutically effective amount of the sitagliptin tannate complex to a patient in need thereof.
Another embodiment of the present invention is the use of a sitagliptin tannate complex for the manufacture of a medicament for the treatment and/or prevention of one or more diseases for which an inhibitor of DPP-IV is indicated.
As used throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings: "Patient" includes both human and other animals.
"Mammal" includes humans and other mammalian animals.
The term "therapeutically effective amount" is intended to mean that amount of a pharmaceutically active ingredient that will elicit the biological or medical response of a tissue or a system, animal or human, that is being sought by a researcher, veterinarian, medical doctor or other clinician (e.g., inhibiting DPP-IV). A "prophylactically effective amount" is intended to mean that amount of a pharmaceutical drug that will prevent or reduce the risk of occurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human by a researcher, veterinarian, medical doctor or other clinician. The terms "preventing" or "prevention" are used herein to refer to administering a compound before the onset of clinical symptoms.
The term "immediate release" means that at least 85% of the drug is released from the dosage form within 120 minutes or less when tested in a USP type 2 apparatus in a fasted state simulated intestinal fluid (FaSSIF) at a pH of 6.5 at room temperature (approximately 25 C), which can be made using SIF™ powder (from biorelevant.com Ltd) as follows:
Step 1. Preparation of the FaSSIF buffer (5L)
1.1 To prepare 5L, dissolve the following in approximately 4.9L of purified water:
2.10g NaOH (pellets), 19.77 g sodium hydrogen phosphate monohydrate (or alternatively, 17.19g sodium dihydrogen phosphate anhydrous), and 30.93g NaCl.
1.2 Adjust the pH of the buffer to exactly 6.5, using either IN NaOH or IN HCL, and make up to volume.
Step 2. Preparation of FaSSIF using SIF™powder (1L);
2.1 In a 1L volumetric flask, dissolve 2.24g of SIF™ powder (stored at 5 C and equilibrated at room temperature prior to use) in approximately 500 ml of the FaSSiF phosphate buffer.
2.2 Stir until the SIF™ powder has dispersed. When a clear solution is
obtained, make up to volume (1L) with the FaSSIF phosphate buffer.
The term "negligible release" means that the amount of sitagliptin dissociated from the sitagliptin tannate complex is not sufficient for the sitagliptin tannate complex to lose its tastemasking activity in a subject; e.g., up to 10% of the sitagliptin is dissociated from the sitagliptin tannate complex, up to 5% of the sitagliptin is dissociated from the sitagliptin tannate complex, or up to 3% of the sitagliptin is dissociated from the sitagliptin tannate complex.
The term "pharmaceutical composition" is intended to encompass both bulk
compositions and individual dosage units comprised of more than one (e.g., two)
pharmaceutically active agents such as, for example, the sitagliptin tannate complex and an additional active ingredient. Examples of other pharmaceutically active ingredients that may be administered in combination with the sitagliptin tannate complex of the present invention, and either administered separately or in the same pharmaceutical composition, include, but are not limited to:
(a) other DPP-IV inhibitors;
(b) insulin sensitizers including (i) PPARy agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone, and the like) and other PPAR ligands, including PPAR α/γ dual agonists, such as KRP-297, and PPARa agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (ii) biguanides such as metformin HC1 and phenformin, and (iii) protein tyrosine phosphatase- IB (PTP-1B) inhibitors;
(c) insulin or insulin mimetics;
(d) sulfonylureas and other insulin secretagogues such as tolbutamide and glipizide, meglitinide, and related materials;
(e) a-glucosidase inhibitors (such as acarbose);
(f) glucagon receptor antagonists such as those disclosed in WO 98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;
(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as those disclosed in WO00/42026 and WO00/59887;
(h) GIP and GIP mimetics such as those disclosed in WO00/58360, and GIP receptor agonists;
(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as those disclosed in WO 01/23420;
(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, rosuvastatin, and other statins), (ii) sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR γ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPAR α/γ dual agonists, such as KRP-297, (vi) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vii) acyl CoAxholesterol acyltransferase inhibitors, such as avasimibe, and (viii) anti-oxidants, such as probucol;
(k) PPAR δ agonists, such as those disclosed in W097/28149;
(1) anti-obesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, and ββ adrenergic receptor agonists;
(m) an ileal bile acid transporter inhibitor; and
(n) agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and cyclo-oxygenase 2 selective inhibitors.
The above combinations include combinations of the sitagliptin tannate complex of the present invention not only with one other pharmaceutically active ingredient, but also with two or more different pharmaceutically active ingredients. Non-limiting examples include combinations of the sitagliptin tannate complex with two or more pharmaceutically active ingredients selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPAR agonists, PTP-1B inhibitors, other DPP-IV inhibitors, and anti-obesity compounds.
The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral
administration, the compositions are preferably provided in the form of oral dosage forms containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, and 500 milligrams of sitagliptin for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of sitagliptin, preferably, from about 1 mg to about 200 mg of active ingredient.
In the method of the present invention the sitagliptin tannate complex can form the active pharmaceutical ingredient, and are typically administered in admixture with suitable
pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the active pharmaceutical ingredient can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
Moreover, when desired or necessary, additional pharmaceutically acceptable adjuvants may be added. Additional pharmaceutical adjuvants include binders, lubricants, sweeteners, flavoring agents, disintegrating agents and coloring agents, which are known in the art (see, e.g.,
Remington's Pharmaceutical Sciences (1995). Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
GENERAL METHOD FOR PREPARING A SITAGLIPTIN TANNATE COMPLEX
The sitagliptin tannate complex of the present invention can be made by the following process:
(1) Combine a solution of a salt for free base form of sitagliptin in a pharmaceutically acceptable solvent (e.g., methanol or ethanol) with a dispersion of tannic acid in a
pharmaceutically acceptable solvent (e.g., methanol or ethanol), while stirring, to form a first mixture; (2) Remove most of the liquid from the first mixture by, for example, evaporation, decantation or vacuum drying;
(3) Wash the residue obtained in step (2) with a polar pharmaceutically acceptable liquid (e.g., water);
(4) Remove all the liquid from the washed residue obtained in step (3) by, for example, evaporation, decantation or vacuum drying;
(5) Dry the residue obtained in step (4), for example, in a vacuum oven (e.g. at 50°C) for about 3 to 10 hours, to provide the sitagliptin tannate complex;
(6) Pulverize the sitagliptin tannate complex (e.g., via milling) into a free-flowing powder.
EXAMPLES
SITGLIPTIN TANNATE COMPLEXES Example 1
The active solution of sitagliptin was prepared by dissolving 0.5 g of sitagliptin freebase in 20 ml of methanol. 1 g of tannic acid was dissolved in the same amount of methanol to form tannic acid dispersion. The sitagliptin solution was then added slowly to tannic acid dispersion while stirring. The mixture was allowed to stir until all the solvent evaporated under ambient conditions in a fume hood. The solid material formed was pulverized into powder. 100 ml of water was added to the powder and the mixture stirred for 30 minutes, before centrifuging at 15K rpm to remove the liquid. The washed sitagliptin tannate complex was then dried in a constant temperature oven at 50 °C.
Example 2
A solution of 1.5 g sitagliptin freebase and a dispersion of 3 g tannic acid were prepared separately in 20 ml of ethanol. Small portions of sitagliption solution were added to tannic acid dispersion while stirring. After all the sitagliptin solution was added, the mixture was allowed to stir under ambient conditions in a fume hood until all the solvent evaporated. The solid material was further dried in a vacuum oven at 50 °C for about 3 hours. It was then pulverized into a powder. TWO STAGE DISSOLUTION PROFILE
The dissolution profile of the sitagliptin tannate complexes of Example 1 and 2 using simulated saliva fluid (SSF) and simulated gastric fluid (SGF) by using the following two stage dissolution protocol:
Stage 1 : A sample of sitagliptin tannate complex of Example 1 or 2 was placed in 10 mL of SSF, which was prepared by dissolving 8.0 g of NaCl, 0.19 g of potassium phosphate monobasic, and 2.38 g of sodium phosphate dibasic in 1 L of water, and adjusting to pH 6.8 with phosphoric acid, heated to 37 °C, for 1 minute and an aliquot was removed.
Stage 2: The remaining solution transferred to 500 mL of SGF, which was prepared by dissolving 2.0 g of NaCl in 1 L of water, and adding 1.4 mL of concentrated hydrochloric acid. The SGF was stirred at 37 °C with apparatus 2 (paddles), and aliquots were collected at 6 time- points.
The aliquots were then analyzed by HPLC to determine the amount of free sitagliptin.
Fig. 1 depicts the dissolution profile of Example 1 and Fig. 2 depicts the dissolution profile of Example 2. Both profiles indicate that very little to no sitagliptin was released in SSF. This indicates that the sitagliptin-tannic acid complex is not soluble or almost not soluble at neutral pH and, hence, a subject would not be expected to taste the unpleasant flavor of sitagliptin. However, in both profiles, the sitagliptin is rapidly released from the complex at the low pH of SGF and, therefore, would be expected to be available for absorption by the subject.
FORMULATION EXAMPLE
Soft Chew
The sitagliptin tannate complexes obtained in Examples 1 and 2 were formulated as a soft chew by incorporating the sitagliptin tannate complex of the following composition:
Figure imgf000012_0001
B PEG 8000 3.0
B glycerol monostearate 0.5
C MALTRIN® M040 (maltodextrin ) 18.4
C Starchl500® 25.0
D peppermint 0.5
The soft chew formulation was prepared as follows:
(1) The ingredients of part A were mixed until uniform;
(2) The ingredients of part B were mixed;
(3) The ingredients of part C were mixed in a turbular mixer for about 10 minutes;
(4) The mixed ingredients from step (2) were melted and added to the mixed ingredients of step (1) and mixed well;
(5) The mixed ingredients from step (3) were added to the mixed ingredient from step (4) and mixed until uniform;
(6) Peppermint was added to the mixture obtained in step (5) and mixed well to obtain a dough-like mixture;
(7) The dough-like mixture was placed into a soft-chew mold and allowed to congeal and form the soft-chew units containing the sitagliptin tannate complex of Example 1 or Example 2.
While the invention has been described with reference to certain particular embodiments thereof, numerous alternative embodiments will be apparent to those skilled in the art from the teachings described herein. The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole. All patents, patent applications and publications cited herein are incorporated by reference in their entirety.

Claims

What is claimed is:
1. Sitagliptin tannate complex.
2. The sitagliptin tannate complex according to claim 1, wherein the sitagliptin content is between about 25% and about 75% by weight.
3. The sitagliptin tannate complex according to claim 2, wherein the sitagliptin content is between about 29 and about 33% by weight.
4. The sitagliptin tannate complex according to claim 1, wherein the ratio of sitagliptin to tannic acid is about 3 : 1 to about 1 :4 by weight.
5. The sitagliptin tannate complex according to claim 4, wherein the ratio is about 2: 1 by weight.
6. A pharmaceutical composition comprising a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 and an inert carrier.
7. The pharmaceutical composition according to claim 6 that further comprises a therapeutically effective amount of an additional pharmaceutically active ingredient.
8. A pharmaceutical intermediate which comprises a therapeutically effective amount of a sitagliptin tannate complex according to claim 1 , a pharmaceutically acceptable polymer, and, optionally, one or more polyols, high intensity sweeteners, flavorants.
9. An oral dosage form which comprises the pharmaceutical intermediate according to claim 8.
10. The oral dosage form according to claim 9, which is in the form of a tablet, capsule, pellet or powder.
11. The oral dosage form according to claim 9, which is in the form of a soft chew, medicated gum, chewable tablet, disintegrating tablet, syrup, sachet, oral film, gel or lyosphere.
12. The oral dosage form according to claim 9, which has negligible release in the mouth and immediate release in the stomach
13. The oral dosage form according to claim 12, which is a soft chew, medicated gum, oral film, disintegrating tablet or syrup.
14. A method for treating, controlling, or preventing of one or more diseases for which an inhibitor of DPP-IV is indicated, comprising the administration a therapeutically effective amount of the sitagliptin tannate complex according to claim 1 to a patient in need thereof.
15. The method according to claim 14, wherein the disease is type 2 diabetes, obesity or high blood pressure.
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BR112016023839A2 (en) 2017-08-15
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RU2016144695A (en) 2018-05-21

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