WO2018142334A1 - Formulations comprenant des sels d'oxalate de ténéligliptine et des solvates correspondants - Google Patents

Formulations comprenant des sels d'oxalate de ténéligliptine et des solvates correspondants Download PDF

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WO2018142334A1
WO2018142334A1 PCT/IB2018/050662 IB2018050662W WO2018142334A1 WO 2018142334 A1 WO2018142334 A1 WO 2018142334A1 IB 2018050662 W IB2018050662 W IB 2018050662W WO 2018142334 A1 WO2018142334 A1 WO 2018142334A1
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Prior art keywords
oxalate
pharmaceutical compositions
weight
teneligliptin
hydrate
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PCT/IB2018/050662
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English (en)
Inventor
Suresh Mahadev Kadam
Bipin Parsottam Kansagra
Shrikrishna Kantilal KALE
Shekhar Bhaskar Bhirud
Rajesh Kumar DWIVEDI
Ulhas Rameshchandra Dhuppad
Nitin Shivajirao DESHMUKH
Krishna Prakashrao SADAPHAL
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Glenmark Pharmaceuticals Limited
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Application filed by Glenmark Pharmaceuticals Limited filed Critical Glenmark Pharmaceuticals Limited
Priority to BR112018010759A priority Critical patent/BR112018010759A2/pt
Priority to KR1020187016406A priority patent/KR20180100554A/ko
Priority to AU2018202960A priority patent/AU2018202960A1/en
Priority to MX2018006005A priority patent/MX2018006005A/es
Priority to CN201880000703.0A priority patent/CN108697707A/zh
Priority to RU2018120214A priority patent/RU2742418C1/ru
Priority to JP2018537629A priority patent/JP2019512460A/ja
Publication of WO2018142334A1 publication Critical patent/WO2018142334A1/fr

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—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
    • 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
    • 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
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders
    • G01N2800/042—Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism

Definitions

  • the present invention relates to pharmaceutically acceptable formulations comprising oxalate salts of Teneligliptin and solvates thereof, optionally further comprising biguanides class of molecules. Also provided are uses of said formulations and treatment of glucose metabolism disorder in patients in need.
  • Dipeptidyi peptidase-4 (DPP-IV) inhibitors is a class of anti-diabetic drugs act by inhibiting the degradation of the incretins, glucagon-like peptide- 1 (G LP-1) and glucose-dependent insulinotropic peptide (G !P). Genericaily these compounds are termed as "gliptins”.
  • DPP-IV inhibitors are commonly used in a combination therapy along with other antidiabetic drugs
  • compositions comprising oxalate salts of the compound of Formula (!) and solvates thereof, and at least one or more pharmaceutically acceptable carriers, diluents, binder, lubricant, disintegrant and stabilizing agent.
  • the diluent is selected from group comprising of mannitol, sorbitol, xylitoi, starch, lactose, cellulose, calcium dihydrogen phosphate and like, preferable, mannitol or lactose
  • binder is selected from group comprising of hydroxypropy!
  • lubricant is glyceryl dibehenate, sodium or calcium stearyl fu ma rate, magnesium stearate, stearic acid, glyceryl palmitostearate and like, preferably glyceryl dibehenate.
  • disintegrant is selected from group comprising of Low- Substituted Hydroxypropyl Cellulose, Crospovidone, Croscarmeilose sodium, Sodium Starch Giycolate and like, preferably Low-Substituted Hydroxypropyl Cellulose
  • stabilizing agent is selected from at least one stabilizer; at least one compiexing agent; at least one polymer; at least one chelating agent; and combinations thereof.
  • the present invention provides pharmaceutical composition wherein (a) oxalate salt of compound (I) and solvate thereof selected from Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof
  • diluent is selected from mannitol or lactose
  • binder is selected from hydroxypropyl cellulose or hypromellose
  • Lubricant is selected from glyceryl dibehenate, or magnesium stearate
  • disintegrant is selected from Low-Substituted Hydroxypropyl Cellulose, Crospovidone, Croscarmellose sodium
  • stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof
  • a pharmaceutical composition comprising,
  • diluent is mannitol
  • binder is hypromellose
  • Lubricant is glyceryl dibehenate
  • disintegrant is Low-Substituted Hydroxypropyl Cellulose
  • stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof
  • a pharmaceutical composition comprising,
  • binder is hypromellose
  • Lubricant is glyceryl dibehenate
  • disintegrant is Low-Substituted Hydroxypropyl Cellulose
  • stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof.
  • compositions comprising about 0.5 % to about 80.0 % by weight of oxalate salt of compound (I) and solvate thereof, about 10 % to about 95 % by weight of diluent, about 0.1% to about 10.0 % by weight of binder, about 0.1 % to about 20.0 % by weight of lubricant, about 0.1 % to about 30 % by weight of disintegrant and about 0.05 % to about 30 % by weight stabilizing agent.
  • the oxalate salt of compound (I) and solvate thereof is Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof.
  • solvate is n. hydrate.
  • oxalate salt of compound (I) and solvate thereof is Teneligliptin 2.5 oxalate n. hydrate or Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
  • compositions comprising about 5 % to about 40.0 % by weight of oxalate salt of compound (I) and solvate thereof, about 15 % to about 95 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 0.1 % to about 20.0 % by weight of lubricant, about 0.1 % to about 30 % by weight of disintegrant and about 0.1 % to about 20 % by weight stabilizing agent.
  • the oxalate salt of compound (I) and solvate thereof is Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof.
  • solvate is n. hydrate.
  • oxalate salt of compound (I) and solvate thereof is Teneligliptin 2.5 oxalate n. hydrate or Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0
  • compositions comprising about 5 % to about 40.0 % by weight of oxalate salt of compound (I) and solvate thereof, about 30 % to about 80 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 0.1 % to about 20.0 % by weight of lubricant, about 0.1 % to about 30 % by weight of disintegrant and about 0.1 % to about 20 % by weight stabilizing agent.
  • the oxalate salt of compound (I) and solvate thereof is Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof.
  • solvate is n. hydrate.
  • oxalate salt of compound (I) and solvate thereof is Teneligliptin 2.5 oxalate n. hydrate or Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0
  • compositions comprising about 5 % to about 15.0 % by weight of Teneligliptin 3.0 oxalate n. hydrate, about 30 % to about 80 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 1.0 % to about 15.0 % by weight of lubricant, about 1.0 % to about 20 % by weight of disintegrant and about 0.5 % to about 15 % by weight stabilizing agent.
  • compositions comprising about 0.5 % to about 10.0 % by weight of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, about 5 % to about 40 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 0.5 % to about 5.0 % by weight of lubricant, about 0.5 % to about 10 % by weight of disintegrant and about 0.1 % to about 10 % by weight stabilizing agent and one or more anti-diabetic agent.
  • one or more anti-diabetic agents comprised in pharmaceutical composition of present invention is selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof.
  • the pharmaceutical compositions comprises stabilizing agent, wherein stabilizing agent is oxalic acid is present in an amount about 0.5% to about 5.0 % by weight
  • the pharmaceutical compositions comprises stabilizing agent, wherein stabilizing agent is beta-cyclodextrin present in an amount about 0.5 % to about 5.0% by weight
  • the pharmaceutical compositions comprises stabilizing agent, wherein stabilizing agent is hydroxy-propyl cellulose present in an amount about 0.1 % to about 5.0 % by weight
  • the pharmaceutical compositions comprises stabilizing agent, wherein stabilizing agent is EDTA present in an amount about 0.5% to about 5.0% by weight
  • stabilizing agent is EDTA present in an amount about 0.5% to about 5.0% by weight
  • oxalate salts of the compound of Formula (I) in pharmaceutical composition of present invention is Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, characterized by X ray powder diffraction pattern comprising reflections at 5.68°, 6.56°, 16.44°, 17.72°, 18.34°, 21.12°, 21.67°, 23.15°, 23.86°, 24.99° ⁇ 26
  • oxalate salts of the compound of Formula (I) in pharmaceutical composition of present invention is Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, characterized by X ray powder diffraction pattern comprising reflections at 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99° ⁇ 26
  • compositions comprising oxalate salts of the compound of Formula (I)
  • compositions said oxalate salts of the compound of Formula (I) and solvates thereof comprised in pharmaceutical composition of present invention are substantially pure.
  • the present invention provides, pharmaceutical composition comprising oxalate salt of compound of formula (I)
  • compositions comprise sulfonyl urea class of compounds comprises glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide and the like.
  • compositions comprise glitazone class of compounds comprising pioglitazone, rosiglitazone and the like.
  • pharmaceutical compositions comprise biguanide class of compounds comprises metformin, buformin, phenformin and like or pharmaceutically acceptable salt thereof.
  • pharmaceutical compositions comprise alpha-glucosidase inhibitor class of compounds comprising voglibose, acarbose, miglitol and the like.
  • compositions comprise SG LT2 inhibitor class of compounds comprises remogliflozin, dapagliflozin, canagliflozin, empagliflozin, luseogliflozin and the like, salt, ester or solvate thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 and extended release metformin, wherein Teneligliptin 2.5 oxalate n. hydrate to metformin or w/w ratio is in the range of 1:10-1:50.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 and metformin, wherein Teneligliptin 3.0 oxalate n. hydrate to metformin w/w ratio is in the range of 1:10-1:50.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a mixture of Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0; and metformin, wherein mixture to metformin w/w ratio is in the range of 1:10-1:50.
  • the present invention provides, pharmaceutical compositions comprising oxalate salt of compound of formula (I) and solvate thereof, wherein said oxalate salt is at least 99% pure and content of compound of formula (I I) is less than 1.0 %.
  • compositions comprising: (i) at least one of (a) oxalate salts of the compound of Formula (I) and solvates thereof; (b) Teneligliptin 2.5 oxalate n.
  • n is 1.0 to 4.0, preferably 1.0;
  • Teneligliptin 3.0 oxalate wherein n is 1.0 to 4.0, preferably 1.0;
  • at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SGLT2 inhibitor class of compounds and salts thereof, and combinations thereof; and
  • at least one or more pharmaceutically acceptable carriers, diluents and excipients selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SGLT2 inhibitor class of compounds and salts thereof, and combinations thereof;
  • compositions comprising (i) comprising oxalate salts of the compound of Formula (I) and solvates thereof; or (ii), Teneligliptin 2.5 oxalate n. hydrate wherein n is 1.0 to 4.0, preferably 1.0; or (iii) Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0; or (iv) Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n.
  • n is 1.0 to 4.0, preferably 1.0; or (v) any one of (i) to (iv) and ) at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof for use in prophylactic or curative treatment of glucose metabolism disorder in a patient.
  • anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof for use in prophylactic or curative treatment
  • a method of prophylactic or curative treatment of a patient with glucose metabolism disorder comprising administering a physiologically relevant amount of pharmaceutical compositions comprising (i) comprising oxalate salts of the compound of Formula (I) and solvates thereof; or (ii) Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0; or (iii) Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0; or (iv) Teneligliptin 2.5 oxalate n.
  • n is 1.0 to 4.0, preferably 1.0; or (v) any one of (i) to (iv) and at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SGLT2 inhibitor class of compounds and salts thereof, and combinations thereof.
  • An object of the present invention is to provide pharmaceutically acceptable formulations comprising oxalate salts of Teneligliptin and solvates thereof with superior processability.
  • An object of the present invention is to provide pharmaceutically acceptable formulations comprising oxalate salts of Teneligliptin and solvates thereof with superior stability.
  • Yet another object of the present invention is to provide pharmaceutically acceptable formulations comprising oxalate salts of Teneligliptin and solvates thereof and at least one or more antidiabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof with superior characteristics such as processability, and stability.
  • antidiabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof with superior characteristics such as processability, and stability.
  • Still another object of the present invention is to provide pharmaceutically acceptable formulations comprising oxalate salts of Teneligliptin and solvates thereof, optionally further comprising at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof, useful in treatment or control of glucose metabolism disorders in patients.
  • anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof, useful in treatment or control
  • FIG. 1 depicts the X ray powder diffraction pattern of crystalline Teneligliptin 2.5 oxalate n. hydrate, in accordance with an embodiment of the present invention.
  • FIG. 2 depicts the differential scanning calorimetry of crystalline Teneligliptin 2.5 oxalate n. hydrate, in accordance with an embodiment of the present invention.
  • FIG. 3 depicts the FT-I R spectrum of crystalline Teneligliptin 2.5 oxalate n. hydrate, in accordance with an embodiment of the present invention.
  • FIG. 4 depicts the depicts the X ray powder diffraction pattern of crystalline Teneligliptin 3.0 oxalate n. hydrate, in accordance with an embodiment of the present invention.
  • FIG. 5A-B depicts the differential scanning calorimetry of crystalline Teneligliptin 3.0 oxalate n. hydrate, in accordance with an embodiment of the present invention.
  • FIG.6 depicts the FT-IR spectrum of crystalline Teneligliptin 3.0 oxalate n. hydrate, in accordance with an embodiment of the present invention.
  • solvate means an aggregate consisting of a solute ion or molecule with one or more solvent molecules.
  • Solvates can be, but are not limited to, acetone solvate, etanol solvate, methanol solvate, butanol solvate, TBA solvate, chloroform solvate, and other organic and inorganic solvates.
  • hydrate means a compound, typically a crystalline one, in which one or more water molecules are chemically bound to another compound or molecule or element.
  • salt or “pharmaceutically acceptable salt” as used herein, is intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • crystalline means having a regularly repeating arrangement of molecules or external face planes.
  • amorphous as used herein, means essentially without regularly repeating arrangement of molecules or external face planes.
  • stabilizing agents means a pharmaceutically acceptable excipient which stabilizes the pharmaceutical composition and restricts or prevents chemical degradation of active pharmaceutical ingredient comprised in the said composition.
  • terapéuticaally effective amount is intended to mean the amount of oxalate salt of compound of Formula (I) or solvate thereof, which will elicit a biological response in tissue of a patient.
  • prophylactic in the context of treatment is intended to mean the amount of oxalate salt of compound of Formula (I) or solvate thereof, which will prevent or reduce occurrence of glucose metabolism disorder in a patient or onset of clinical symptoms of glucose metabolism disorder in a patient.
  • curative in the context of treatment is intended to mean the amount of oxalate salt of compound of Formula (I) or solvate thereof, which will cure or manage glucose metabolism disorder in a patient.
  • metalformin as used herein, unless mentioned otherwise, means metformin, its pharmaceutically acceptable salt or hydrate thereof.
  • excipients refers generally to substances other than pharmaceutically active ingredients which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form.
  • carriers refers generally to any substance or substrate used in the process of drug delivery which serves to improve the selectivity, effectiveness and/or safety of drug administration.
  • glucose metabolism disorder is intended to cover various metabolic disorders involving glucose in human beings like diabetes mellitus, hyperglycemia, hypoglycemia, glycosuria and like. Further, diabetes mellitus includes Type I and Type I I diabetes mellitus.
  • dients refers generally to filler/diluents which can be used to increase the bulk volume or improve flow properties.
  • the present invention provides pharmaceutical compositions comprising oxalate salts of the compound of Formula (I)
  • the solvate is preferably n. hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, n is 1.0.
  • the diluent is selected from group comprising of mannitol, sorbitol, xyiitol, starch, lactose, cellulose, calcium dihydrogen phosphate and like, preferable, mannitol or lactose
  • binder is selected from group comprising of hydroxypropyi cellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose, hypromeilose and like, preferably hypromellose or hydroxypropyi cellulose.
  • lubricant is glyceryl dibehenate, sodium or calcium stearyl fumarate, magnesium stearate, stearic acid, glyceryl pa!mitostearate and like, preferably glyceryl dibehenate.
  • disintegrant is selected from group comprising of Low-Substituted Hydroxypropyi Cellulose, Crospovidone, Croscarmellose sodium, Sodium Starch Glycolate and like, preferably Low-Substituted Hydroxypropyi Cellulose.
  • stabilizing agent is selected from at least one stabilizer; at least one complexing agent; at least one polymer; at least one chelating agent; and combinations thereof.
  • the pharmaceutical composition comprises Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition comprises Teneligliptin 2.5 oxalate 1.0 hydrate.
  • the pharmaceutical composition comprises Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0. In a preferred embodiment, the pharmaceutical composition comprises Teneligliptin 3.0 oxalate 1.0 hydrate.
  • the pharmaceutical composition comprises Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0 and Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
  • the pharmaceutical composition comprises Teneligliptin 2.5 oxalate monohydrate and Teneligliptin 3.0 oxalate monohydrate.
  • the solvated oxalate salt of Teneligliptin comprised in pharmaceutical composition is 10-100% pure. In another embodiment, the purity level is 20-100%. In another embodiment, the purity is 30-100%. In another embodiment, the purity is 40-100%. In another embodiment, the purity is 50-100%. In another embodiment, the purity is 60-100%. In another embodiment, the purity is 70-100%. In another embodiment, the purity is 80-100%. In another embodiment, the purity is 90-100%. In a preferred embodiment, purity is more than 99%. In a more preferred embodiment, purity is more than 99.5%. In an embodiment, the solvated oxalate salt of Teneligliptin comprised in pharmaceutical composition is substantially pure.
  • Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprised in pharmaceutical composition is 10-100% pure.
  • the purity level is 20-100%.
  • the purity is 30-100%.
  • the purity is 40-100%.
  • the purity is 50-100%.
  • the purity is 60-100%.
  • the purity is 70-100%.
  • the purity is 80-100%.
  • the purity is 90-100%.
  • purity is more than 99%.
  • purity is more than 99.5%.
  • Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprised in pharmaceutical composition is substantially pure.
  • Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprised in pharmaceutical composition is 10-100% pure.
  • the purity level is 20-100%.
  • the purity is 30-100%.
  • the purity is 40-100%.
  • the purity is 50-100%.
  • the purity is 60-100%.
  • the purity is 70-100%.
  • the purity is 80-100%.
  • the purity is 90-100%.
  • purity is more than 99%.
  • purity is more than 99.5%.
  • Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprised in pharmaceutical composition is substantially pure.
  • Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 comprised in pharmaceutical compositions as described herein is in crystalline form.
  • Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 comprised in pharmaceutical compositions as described herein is in amorphous form.
  • Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0, comprised in pharmaceutical compositions as described herein is in amorphous form.
  • compositions as described herein, wherein Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 is characterized by X-ray powder diffraction pattern comprising reflections at 5.68°, 6.56°, 16.44°, 17.72°, 18.34°, 21.12°, 21.67°, 23.15°, 23.86°, 24.99° ⁇ 2 ⁇ and having an X-ray powder diffraction pattern as represented in FIG. 1.
  • compositions as described herein, wherein Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 is characterized by differential scanning calorimetry (DSC) thermogram with an endotherm at 152.76°C and 169.68°C and represented by DSC curve in FIG. 2.
  • DSC differential scanning calorimetry
  • compositions as described herein, wherein Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 is characterized by infra-red absorption (I R) peaks at 3452.22, 3011.77, 2540.88, 1721.37, 1650.04, 1207.43, 922.34, 708.96, 477.35cm 1 and represented in FIG. 3.
  • I R infra-red absorption
  • compositions as described herein, wherein Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 is characterized by X-ray powder diffraction pattern comprising reflections at 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99° ⁇ 2 ⁇ and having an X-ray powder diffraction pattern as represented in FIG. 4.
  • compositions as described herein, wherein Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 is characterized by differential scanning calorimetry (DSC) thermogram with an endotherm at 177.34 °C and represented by DSC curve in FIG. 5A and at 171.6°C as represented in FIG. 5B.
  • DSC differential scanning calorimetry
  • compositions as described herein, wherein Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 is characterized by infra-red absorption (I R) peaks at 3464.93, 3011.34, 2537.55, 1911.30, 1720.10, 1651.64, 1456.82, 1363.34, 1209.29, 922.88, 709.74, 475.21 cm “1 and represented in FIG. 6.
  • I R infra-red absorption
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0 and at least one or more pharmaceutically acceptable carriers, diluents and excipients. In one preferred embodiment, n is 1.0
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, wherein the said salt exists in crystalline or amorphous form
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, characterized by X-ray powder diffraction pattern comprising reflections at 5.69°, 6.57°, 16.43°, 17.71°, 21.66°, 23.15°, 23.86°, 24.99° ⁇ 2 ⁇ and having an X-ray powder diffraction pattern as represented in FIG. 4.
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, which is substantially pure.
  • the present invention provides pharmaceutical compositions comprising Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0 and at least one or more pharmaceutically acceptable carriers, diluents and excipients. In on preferred aspect of this embodiment, n is 1.0. In preferred aspect of this embodiment, Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n. hydrate are substantially pure.
  • the present invention provides pharmaceutical compositions comprising oxalate salts of the compound of Formula (I) comprising
  • the pharmaceutical compositions further comprise at least one stabilizer which is pharmaceutically acceptable organic acid selected from group comprising of oxalic acid, citric acid, tartaric acid.
  • the stabilizer is oxalic acid.
  • the pharmaceutical compositions further comprise at least one complexing agent selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma cyclodextrin, methyl beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, their derivatives and combinations thereof.
  • the complexing agent is hydroxypropyl-beta-cyclodextrin.
  • the pharmaceutical compositions further comprise at least one polymer selected from the group comprising of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxyl propyl methyl cellulose, and combinations thereof.
  • the polymer is hydroxypropyl cellulose.
  • the pharmaceutical compositions further comprise at least one chelating agent selected from the group consisting of EDTA, zinc sulfate, ferrous ascorbate, calcium carbonate, sodium chloride, potassium chloride, and combinations thereof.
  • the chelating agent is EDTA.
  • the pharmaceutical compositions further comprise stabilizer and at least one polymer.
  • the stabilizer is oxalic acid.
  • the polymer is selected from the group comprising of gelatin, polyvinyl alcohol, copovidone, hydroxyl propyl cellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxyl propyl methyl cellulose, and combinations thereof, preferably hydroxyl propyl celluose.
  • the pharmaceutical compositions further comprise at least one stabilizer, at least one polymer, and at least one complexing agent.
  • the stabilizer is oxalic acid.
  • the polymer is selected from the group comprising of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxyl propyl methyl cellulose, and combinations thereof, preferably hydroxypropyl cellulose.
  • the complexing agent is selected from the group comprising of beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, and combinations thereof, preferably hydroxypropyl beta cyclodextrin.
  • the pharmaceutical compositions of present invention further comprise at least one polymer and at least one chelating agent.
  • the polymer is selected from the group comprising of gelatin, polyvinyl alcohol, copovidone, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, hydroxyl propyl methyl cellulose, and combinations thereof, preferably hydroxypropyl cellulose.
  • the chelating agent is selected from the group consisting of EDTA, zinc sulfate, ferrous ascorbate, calcium carbonate, sodium chloride, potassium chloride, and combinations thereof, preferably EDTA.
  • the present invention provides a pharmaceutical compositions comprising (a) oxalate salt of compound (I) and solvate thereof selected from Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof
  • diluent is selected from mannitol or lactose
  • binder is selected from hydroxypropy! cellulose or hypromellose
  • Lubricant is selected from glyceryl dibehenate, or magnesium stearate
  • disintegrant is selected from Low-Substituted Hydroxypropyl Cellulose, Crospovidone, Croscarmellose sodium
  • the present invention provides a pharmaceutical compositions comprising
  • diluent is mannitol
  • binder is hypromellose
  • Lubricant is glyceryl dibehenate
  • disintegrant is Low-Substituted Hydroxypropyl Cellulose
  • stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose,
  • the present invention provides a pharmaceutical compositions comprising
  • oxalate salt of compound (I) and solvate thereof is Teneligliptin 3.0 oxalate n. hydrate, wherein 1.0 to 4.0
  • binder is hypromellose
  • Lubricant is glyceryl dibehenate
  • disintegrant is Low-Substituted Hydroxypropyl Cellulose
  • stabilizing agent is selected from oxalic acid, beta-cyclodextrin, hydroxypropyl cellulose, EDTA and combinations thereof.
  • compositions comprising about 0.5 % to about 80.0 % by weight of oxalate salt of compound (I) and solvate thereof, about 10 % to about 95 % by weight of diluent, about 0.1% to about 10.0 % by weight of binder, about 0.1 % to about 20.0 % by weight of lubricant, about 0.1 % to about 30 % by weight of disintegrant and about 0.05 % to about 30 % by weight stabilizing agent.
  • compositions comprising about 5 % to about 40.0 % by weight of oxalate salt of compound (I) and solvate thereof, about 15 % to about 95 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 0.1 % to about 20.0 % by weight of lubricant, about 0.1 % to about 30 % by weight of disintegrant and about 0.1 % to about 20 % by weight stabilizing agent.
  • compositions comprising about 5 % to about 40.0 % by weight of oxalate salt of compound (I) and solvate thereof, about 30 % to about 80 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 0.1 % to about 20.0 % by weight of lubricant, about 0.1 % to about 30 % by weight of disintegrant and about 0.1 % to about 20 % by weight stabilizing agent.
  • compositions comprising about 5 % to about 15.0 % by weight of Teneligliptin 3.0 oxalate n. hydrate, about 30 % to about 80 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 1.0 % to about 15.0 % by weight of lubricant, about 1.0 % to about 20 % by weight of disintegrant and about 0.5 % to about 15 % by weight stabilizing agent.
  • Teneligliptin 3.0 oxalate n. hydrate is crystalline Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
  • compositions comprising about 0.5 % to about 10.0 % by weight of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, about 5 % to about 40 % by weight of diluent, about 0.1% to about 10 % by weight of binder, about 0.5 % to about 5.0 % by weight of lubricant, about 0.5 % to about 10 % by weight of disintegrant and about 0.1 % to about 10 % by weight stabilizing agent and one or more anti-diabetic agent.
  • Teneligliptin 3.0 oxalate n. hydrate is crystalline Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0.
  • the present invention provides pharmaceutical compositions comprising substantially pure oxalate salt of compound of formula (I) and solvates thereof
  • the present invention provides pharmaceutical compositions wherein purity of oxalate salt of compound of formula (I) is greater than 98.0 %.
  • the present invention provides pharmaceutical compositions wherein purity of oxalate salt of compound of formula (I) is greater than 99.0 %.
  • the present invention provides pharmaceutical compositions wherein purity of oxalate salt of compound of formula (I) is greater than 99.5 %.
  • the present invention provides pharmaceutical compositions comprising substantially pure oxalate salt of compound of formula (I) and solvates thereof, wherein oxalate salt of compound of formula (I) is Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof.
  • the present invention also provides pharmaceutical compositions as described herein, further comprising at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof.
  • anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha-glucosidase inhibitor class of compounds and salts thereof, SG LT2 inhibitor class of compounds and salts thereof, and combinations thereof.
  • the present invention provides pharmaceutical compositions comprising oxalate salt of compound of formula (I) and solvates thereof and at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha- glucosidase inhibitor class of compounds and salts thereof, SGLT2 inhibitor class of compounds and salts thereof, and combinations thereof.
  • anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha- glucosidase inhibitor class of compounds and salts thereof, SGLT2 inhibitor class of compounds and salts thereof, and combinations thereof.
  • said sulfonyl urea class of compounds used in pharmaceutical compositions of present invention comprises glimepiride, glipiride, tolbutamide, tolazamide, glibenclamide, gliclazide and the like.
  • sulfonyl urea compound is glimepiride.
  • said glitazone class of compounds used in pharmaceutical compositions of present invention comprises pioglitazone, rosiglitazone and the like.
  • glitazone compound is pioglitazone.
  • said alpha-glucosidase inhibitor class of compounds used in pharmaceutical compositions of present invention comprises voglibose, acarbose, miglitol and the like.
  • alpha-glucosidase inhibitor is voglibose.
  • said SG LT2 inhibitor class of compounds comprises remogliflozin, dapagliflozin, canagliflozin, empagliflozin, luseogliflozin and the like.
  • said biguanide class of compounds comprises metformin, buformin, phenformin and the like.
  • the member of the biguanides class of molecules is metformin or its pharmaceutically acceptable salt.
  • member of biguanide class is metformin hydrochloride.
  • member of biguanide class is mixture of metformin and metformin hydrochloride.
  • metformin part of pharmaceutical composition of present invention is immediate release layer or extended release layer.
  • metformin part comprised in the pharmaceutical compositions is immediate release layer.
  • metformin part comprised in the pharmaceutical compositions is extended release layer.
  • metformin comprised in the pharmaceutical compositions is a mixture of immediate and extended release layer of metformin.
  • compositions as described herein further comprise at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof.
  • compositions of present invention comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent or combinations thereof stabilize solvated oxalate salts of Teneligliptin and inhibit formation of compound of Formula (II) in said pharmaceutical compositions.
  • compositions comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof function to stabilize Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof function to stabilize Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising at least one stabilizer, at least one complexing agent, at least one polymer, at least one chelating agent, and combinations thereof function to stabilize the mixture of Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising Oxalate salt of compound of formula (I) and solvate thereof, wherein said oxalate salt is at least 99% pure and content of compound of formula (I I) is less than 1.0 %.
  • compositions comprising oxalate salt of compound of formula (I) and solvate thereof, wherein said oxalate salt is at least 99.5 % pure and content of compound of formula (II) is less than 0.5.0 %.
  • compositions comprising Oxalate salt of compound of formula (I) and solvate thereof, wherein said oxalate salt is at least 99.9 % pure and content of compound of formula (II) a is less than 0.1 %.
  • compositions comprising Teneligliptin 2.5 oxalate and solvate thereof, wherein said oxalate salt is at least 99% pure and content of compound of formula (I I) is less than 1.0 %.
  • compositions comprising Teneligliptin 2.5 oxalate and solvate thereof, wherein said oxalate salt is at least 99.5 % pure and content of compound of formula (II) is less than 0.5.0 %.
  • solvate is n. hydrate.
  • pharmaceutical compositions comprising Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising Teneligliptin 2.5 oxalate and solvate thereof, wherein said oxalate salt is at least 99.9 % pure and content of impurity B is less than 0.1 %.
  • solvate is n. hydrate.
  • pharmaceutical compositions comprising Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising Teneligliptin 3.0 oxalate and solvate thereof, wherein said oxalate salt is at least 99% pure and content of compound of formula (II) is less than 1.0 %.
  • solvate is n. hydrate.
  • pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising Teneligliptin 3.0 oxalate and solvate thereof, wherein said oxalate salt is at least 99.5 % pure and content of impurity B is less than 0.5.0 %.
  • solvate is n. hydrate.
  • pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • compositions comprising Teneligliptin 3.0 oxalate and solvate thereof, wherein said oxalate salt is at least 99.9 % pure and content of impurity B is less than 0.1 %.
  • solvate is n. hydrate.
  • pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • the present invention provides pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein said oxalate salt is at least 99% pure and content of compound of formula (II) is less than 1.0 %.
  • the present invention provides pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein said oxalate salt is at least 99.5 % pure and content of compound of formula (II) is less than 0.5 %.
  • the present invention provides pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein said oxalate salt is at least 99.9 % pure and content of compound of formula (II) is less than 0.1 %.
  • the present invention provides pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate which is at least 99.0% pure, at least 99.5 % pure, at least 99.9 % pure, in crystalline form.
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate wherein n is 1.0 to 4.0 preferably 1.0 and extended release metformin, wherein Teneligliptin to metformin w/w ratio is in the range of 1:10-1:50, preferably in the range of 1:10-1:40, particularly about 1:15 or 1:31.
  • compositions comprising Teneligliptin 2.5 oxalate n. hydrate wherein n is 1.0 to 4.0 preferably 1.0 and extended release metformin, wherein Teneligliptin to metformin w/w ratio is in the range of 1:10-1:50, preferably in the range of 1:10-1:40, particularly about 1:15 or 1:31.
  • compositions comprising a mixture of Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n. hydrate wherein n is 1.0 to 4.0, preferably 1.0 and extended release metformin, wherein Teneligliptin to metformin w/w ratio is in the range of about 1:10-1:50, preferably in the range of about 1:10-1:40, particularly about 1:15 or 1:31.
  • compositions comprising Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 and extended release metformin and at least one or more pharmaceutically acceptable carriers, diluents and excipients.
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 and extended release metformin and at least one or more pharmaceutically acceptable carriers, diluents and excipients.
  • compositions comprising a mixture of Teneligliptin 2.5 oxalate n. hydrate and Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0 and extended release metformin and at least one or more pharmaceutically acceptable carriers, diluents and excipients.
  • the present invention provides pharmaceutical compositions as described herein for use in prophylactic treatment of glucose metabolism in a patient.
  • the present invention provides pharmaceutical compositions as described herein for use in curative treatment of glucose metabolism in a patient.
  • the present invention provides a method of prophylactic curative treatment of a patient with glucose metabolism disorder comprising administering a physiologically relevant amount of pharmaceutical compositions as described herein.
  • the present invention provides a method of curative treatment of a patient with glucose metabolism disorder comprising administering a physiologically relevant amount of pharmaceutical compositions as described herein.
  • compositions as described herein comprising granules of n. hydrate oxalate salts of Teneligliptin, wherein n is 1.0 to 4.0, preferably 1.0.
  • pharmaceutical compositions as described herein comprising granules of Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • pharmaceutical compositions as described herein comprising granules of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • the present invention provides process for preparing pharmaceutical composition of oxalate salt of compound of formula (I) wherein said process steps comprises of:
  • step (b) Granulating sifted material of step (a) with binder solution;
  • step (c) Drying and sifting granulate obtained in step (b);
  • step (d) lubricating sifted granulate of step (c) with suitable lubricant to obtain blend;
  • step (e) compressing lubricated blend of step (d) to form tablet or filling blend of step (d) into capsules
  • Step (f) optionally compressing lubricated blend of step (d) with blend of one or more antidiabetic agents to form tablet or filling blend mixture into capsules
  • Step (a) of above process involves sifting of oxalate salt of compound of formula (I) and solvate thereof with suitable excipients.
  • oxalate salt of compound of formula (I) and solvate thereof is Teneligliptin 2.5 oxalate or Teneligliptin 3.0 oxalate and solvate thereof.
  • the solvate is n. hydrate.
  • oxalate salt of compound of formula (I) and solvate thereof is Teneligliptin 2.5 oxalate n. hydrate or Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • the present invention provides a process for preparing pharmaceutical composition comprising oxalate salt of compound of formula (I) and solvate thereof, wherein said process steps comprises of:
  • step (c) granulating sifted pharmaceutically acceptable excipients of step (a) with binder solution of step (b);
  • step (d) Drying and sifting granulate obtained in step (c);
  • step (e) lubricating sifted granulate of step (c) with sifted pharmaceutically acceptable excipients to obtain blend;
  • step (f) compressing lubricated blend of step (d) to form tablet or filling blend of step (d) into capsules
  • the present invention provide process for preparing pharmaceutical composition comprising oxalate salt of compound of formula (I) and solvate thereof, wherein said process steps comprises of:
  • step (c) sifting the spray dried mixture obtained in step (b)
  • step (d) lubricating sifted granulate of step (c) with sifted pharmaceutically acceptable excipients
  • step (e) compressing lubricated blend of step (d) to form tablet or filling blend of step (d) into capsules.
  • the present invention provide process for preparing pharmaceutical composition comprising oxalate salt of compound of formula (I) and solvate thereof, wherein said process steps comprises of:
  • step (b) Granulating sifted material of step (a) with binder solution;
  • step (c) Drying and sifting granulate obtained in step (b);
  • step (d) lubricating sifted granulate of step (c) with suitable lubricant to obtain blend;
  • step (e) compressing lubricated blend of step (d) to form tablet or filling blend of step (d) into capsules;
  • step (f) optionally compressing lubricated blend of step (d) with blend of one or more anti-diabetic agents to form tablet or filling blend mixture into capsules.
  • the present invention provide, a process for preparing pharmaceutical composition comprising Teneligliptin 3.0 oxalate n. hydrate, wherein said process steps comprises of:
  • step (c) granulating sifted pharmaceutically acceptable excipients of step (a) with binder solution of step (b);
  • step (d) Drying and sifting granulate obtained in step (c);
  • step (e) lubricating sifted granulate of step (c) with sifted pharmaceutically acceptable excipients to obtain blend;
  • step (f) compressing lubricated blend of step (d) to form tablet or filling blend of step (d) into capsules;
  • the present invention provide, a process for preparing pharmaceutical composition comprising Teneligliptin 3.0 oxalate n. hydrate, wherein said process steps comprises of:
  • step (b) spray drying the solution obtained in step (a) ;
  • step (c) sifting the spray dried mixture obtained in step (b);
  • step (d) lubricating sifted granulate of step (c) with sifted pharmaceutically acceptable excipients
  • step (e) compressing lubricated blend of step (d) to form tablet or filling blend of step (d) into capsules.
  • granules of oxalate salt of compound (I) and solvate thereof can be made of oxalate salt of compound (I) and solvate thereof in association with suitable diluents, lubricant, binder, fluidizing agent, disintegrant, soiubilizing agent and like.
  • granules of Teneligliptin 2.5 oxalate and solvate thereof can be made Teneligliptin 2.5 oxalate and solvate thereof in association with suitable diluents, lubricant, binder, fluidizing agent, disintegrant, soiubilizing agent and like.
  • granules of Teneligliptin 3.0 oxalate and solvate thereof can be made of Teneligliptin 3.0 oxalate and solvate thereof in association with suitable diluents, lubricant, binder, fluidizing agent, disintegrant, solubi!izing agent and like.
  • granules of Teneligliptin 2.5 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0, as contemplated by this invention can be made of Teneligliptin 2.5 oxalate n. hydrate in association with suitable diluents, lubricant, binder, fluidizing agent, disintegrant, soiubilszing agent and like.
  • granules of Teneligliptin 3.0 oxalate n. hydrate can be made of Teneligliptin 3.0 oxalate n. hydrate in association with suitable diluents, lubricant, binder, fluidizing agent, disintegrant, solubiiizing agent and like.
  • Suitable binder include, but are not limited to, hydroxypropylcellulose, polyvinyl alcohol, povidone, copovidone, ethyl cellulose, hypromellose and like.
  • Suitable diluents include, but are not limited to, mannito!, sorbitol, xyiitol, starch, lactose, cellulose, calcium dihydrogen phosphate and like.
  • Suitable lubricants include but are not limited to glyceryl dibehenate, sodium or calcium stearyl fumarate, magnesium stearate, stearic acid, glyceryl palmitostearate.
  • Granules of oxalate salt of compound of formula (I) and solvate thereof can be prepared by mixing oxalate salt of compound of formula (I) and pharmaceutically acceptable excipients; adding a binder solution to the mixture of compound of formula (I) and pharmaceutically acceptable excipients and drying the wet mixture of oxalate salt of compound of formula (I) and pharmaceutically acceptable excipients followed by sieving to form granules.
  • granules of oxalate salt of compound of formula (I) and solvate thereof can be prepared after mixing oxalate salt of compound of formula (I) and pharmaceutically acceptable excipients, a binder solution can be sprayed on the mixture in a fluidized bed-processor followed by drying of the wet granules and subsequent optional sieving.
  • flakes of oxalate salt of compound of formula (I) can be prepared by dry mixing oxalate salt of compound of formula (I) and pharmaceutically acceptable excipients to form a blend; roll-compacting the blend one or more times to form flakes followed by granulating and sieving the flakes.
  • the oxalate salt of compound of formula (I) granules or flakes can be lubricated with any of the lubricants mentioned above. This mixture can then be punched in a tableting machine or can be filled into capsules by a capsule-filling machine. Optionally, a coating can be applied to the tablet.
  • the coating solution or suspension contains excipients like hypromellose, polyethylene glycol, colorant such as red or yellow iron oxide, titanium dioxide and talc. These tablets can be alternatively, filled into capsules of suitable size.
  • the capsule volume can be suitably selected, ranging from 0.13- 1.37 ml to accommodate the oxalate salt of compound of formula (I) containing lubricated blend or tablets.
  • oxalate salt of compound of formula (I) used for preparing Teneligliptin containing granules is Teneligliptin 3.0 oxalate or solvate thereof.
  • Teneligliptin 3.0 oxalate or solvate is in crystalline form.
  • a direct compression process for producing Teneligliptin tablets is also contemplated by the invention.
  • the tablets are prepared by mixing Teneligliptin with one or more pharmaceutically acceptable excipients to prepare a blend for direct compression; compressing the blend of to form a tablet; optionally a coating can be applied to the tablet, as described above.
  • compositions comprising oxalate salt of compound of formula (I) and solvate thereof and metformin or its pharmaceutically acceptable salt thereof as described herein, wherein the content of metformin or its pharmaceutically acceptable salt thereof can be suitably selected so as to deliver a dose of metformin in the range of 1 -2000 mg, preferably 250-1000 mg, more preferably 500-1000 mg, still more preferably 500 mg or 1000 mg.
  • a pharmaceutical composition contains Teneligliptin and metformin in separate portions.
  • a multi-layered composition containing Teneligliptin and metformin in separate layers of a bi- or tri-!ayered tablet a composition containing metformin in the core and Teneligliptin in the coating and other similar variants thereof.
  • compositions comprising oxalate salts of Teneligliptin and solvates thereof and at least one or more anti-diabetic agents selected from the group consisting of sulfonyl urea class of compounds and salts thereof, glitazone class of compounds and salts thereof, biguanide class of compounds and salts thereof, alpha- glucosidase inhibitor class of compounds and salts thereof, SGLT2 inhibitor class of compounds and salts thereof, and combinations thereof as described herein, wherein weight concentration of oxalate salts of Teneligliptin and solvates thereof is in the range of 0.5 to 10.0 %, preferably 0.5 to 8.0 %.
  • anti-diabetic agent is metformin and salts thereof.
  • the anti-diabetic agent is extended release metformin.
  • the dose amount of extended release metformin in said pharmaceutical formulation is 500mg. In another embodiment, the dose amount of extended release metformin in said pharmaceutical formulation is lOOOmg.
  • compositions comprising oxalate salts of Teneligliptin and solvates thereof, preferably Teneligliptin 3.0 oxalate n. hydrate and metformin or its pharmaceutically acceptable salt thereof, preferably extended release metformin as described herein, wherein Teneligliptin to metformin w/w ratio in said composition is in the range of 1:10-1:50. In an embodiment, the w/w ratio is about 1:15. In another embodiment, the w/w ratio is about 1:31. In an embodiment, the dosage amount of Teneligliptin is in the range of about 5-50%, preferably 20-40%, more preferably 25-35%. In an embodiment, the dosage amount of metformin is in the range of 100-2000mg, preferably 500-lOOOmg, more preferably SOOmg or lOOOmg.
  • the present invention provides method for treating, preventing, or slowing the progression of a metabolic disorder by administering to a patient in need thereof a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent, wherein the metabolic disorder is selected from the group consisting of type 1 diabetes meilitus, type 2 diabetes meilitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (I PG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, insulin resistance and metabolic syndrome in a patient in need thereof.
  • a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent
  • the metabolic disorder is selected from the group consisting of type 1 diabetes meilitus, type 2 diabetes meilitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (I PG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, insulin resistance and metabolic syndrome in a patient in need
  • the present invention provides a method of treating type 2 diabetes meilitus by administering to a patient in need thereof a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent or pharmaceutically acceptable salts thereof.
  • the present invention provides method for improving giycemic control in a patient treated with monotherapy of an antidiabetic drug by administering to a patient in need thereof a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent or pharmaceutically acceptable salts thereof.
  • the present invention provides method for improving giycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbAlc in a patient by administering to a patient in need thereof a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent or pharmaceutically acceptable salts thereof.
  • the present invention provides method for treating, preventing, or slowing the progression of a condition or disorder selected from the group consisting of complications of diabetes meiiitus in a patient by administering to a patient in need thereof a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent or pharmaceutically acceptable salts thereof.
  • Complications of diabetes meiiitus include cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, learning and memory impairment, neurodegenerative or cognitive disorders, cardio- or cerebrovascular diseases, tissue ischaemia, diabetic foot or ulcers, arteriosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and vascular restenosis and the likes
  • the present invention provides method for treating, preventing, or slowing the progression of degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta ceils and/or restoring the functionality of pancreatic insulin secretion in a patient by administering to a patient in need thereof a pharmaceutical composition comprising oxalate salt of compound of formula (I) and at least one other anti-diabetic agent or pharmaceutically acceptable salts thereof.
  • Example 1 Pharmaceutical compositions comprising Teneligliptin 3.0 oxalate n. hydrate
  • compositions comprising Teneligliptin 3.0 oxalate n. hydrate, preferably monohydrate.
  • Table 1 provides a formulation comprising oxalic acid as stabilizer to prevent degradation of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • Table 1 Formulation Comprising Oxalic Acid as a Stabilizer
  • binder Add and dissolve under stirring Oxalic Acid and Hydroxypropul Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2 with suitable process parameters in FBP. After completion of granulation, dry the wet mass till desired LoD is achieved;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 2 provides a formulation comprising oxalic acid, polymer and complexing agent to prevent degradation of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • binder Add and dissolve under stirring Oxalic Acid, ⁇ Cyclodextrin and Hydroxypropyl Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2 with suitable process parameters in FBP. After completion of granulation, dry the wet mass till desired LoD is achieved;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 3 provides a formulation comprising complexing agent to prevent degradation of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • Lubrication Lubricate the granules of step 3 with sifted excipients of step 4 using suitable blender;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 4 provides a formulation comprising a polymer to prevent degradation of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • binder Add and dissolve under stirring Hydroxypropyl Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2 with suitable process parameters in FBP. After completion of granulation, dry the wet mass till desired LoD is achieved;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 5 provides a formulation comprising a polymer to prevent degradation of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • Lubrication Lubricate the granules of step 3 with sifted excipients of step 4 using suitable blender;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 6 provides a formulation comprising a polymer and chelating agent to prevent degradation of Teneligliptin 3.0 oxalate n. hydrate, wherein n is 1.0 to 4.0, preferably 1.0.
  • binder Add and dissolve under stirring Oxalic Acid, EDTA and Hydroxypropyl Cellulose in purified water;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Example 2 Process for combination of Teneligliptin 3.0 oxalate and Metformin HCI
  • Metformin part (For 500 mg dose): Metformin Hydrochloride is milled using multimill. Co-sifted milled Metformin Hydrochloride and Carboxymethyl Cellulose sodium through #40 mesh s.s. sieve. Guar Gum sifted through #100 mesh s.s. sieve. Sifted Metformin Hydrochloride, Carboxymethyl Cellulose and Guar Gum granulated in rapid mixer granulator for 20 minutes. Binder solution prepared by adding Methylparaben and Propylparaben in purified water under stirring. Granulated mixture of Metformin Hydrochloride, Carboxymethyl Cellulose and Guar Gum granulated with binder solution in Fluidized Bed Dryer.
  • Granules obtained sifted through 16 # sieve using vibratory sifter. Over-sized granules collected and milled using multimill. Milled granules collected and sifted through #16 sieves using vibratory sifter. Co-sifted Hydroxypropylmethyl Cellulose, Pregelatinised starch, Polyethylene Oxide and Hydrogenated Castor Oil through sieve # 40 and Magnesium Stearate through sieve # 40 using vibratory sifter.
  • Lubrication pre-mix prepared by mixing fine granules and Co-sifted Hydroxypropylmethyl Cellulose, Pregelatinised starch, Polyethylene Oxide and Hydrogenated Castor Oil. Milled granules lubricated with lubrication pre-mix in blender to obtain metformin HCI blend.
  • Metformin part (For 1000 mg dosage form): Metformin Hydrochloride is milled using multimill and sift through #40 mesh s.s. sieve. Sift Carboxymethyl Cellulose sodium through #40 mesh s.s. sieve. Guar Gum sifted through #100 mesh s.s. sieve. Sifted Metformin Hydrochloride and Carboxymethyl Cellulose granulated in rapid mixer granulator for 20 minutes. Binder solution prepared by adding Methylparaben and Propylparaben in purified water under stirring. Granulated mixture of Metformin Hydrochloride, Carboxymethyl Cellulose with purified water using suitable process parameter.
  • Wet granulated mass obtained is semi-dried and sifted throughl6 # sieve.
  • Semi-dried granules dried in Fluidized bed dryer. Sift the dried granules through sieve #16 using vibratory sifter. Over-sized granules collected and milled using multimill. Milled granules collected and sifted through #16 sieves using vibratory sifter. Co-sifted Hydroxypropyl methyl cellulose and Maize Starch through sieve # 40 using vibratory sifter and Magnesium Stearate through sieve # 60. Milled granules lubricated with Co-sifted Hydroxypropyl methyl cellulose and Maize Starch and sifted Magnesium Stearate in suitable blender.
  • Table 7 depicts the stability profile of the formulation of Table 1 at 1 month and 2 month.
  • Table 8 depicts a formulation which shows impermissible levels of impurity B.
  • Table 9 depicts the stability profile of the formulation of Table 8.
  • Table 10 depicts a formulation which shows impermissible levels of impurity B.
  • Table 11 depicts the stability profile of the formulation of Table 10.
  • Table 12 depicts a formulation which shows impermissible levels of impurity B.
  • Table 13a depicts the stability profile of the formulation of Table 12.
  • Table 13b depicts the stability profile of the formulation of Table 12.
  • Formulations comprising Teneligliptin 3.0 oxalate n. hydrate and Glimepiride
  • Table 14a depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Glimepiride.
  • Table 14b depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Glimepiride (monolayer strategy 2).
  • binder Add and dissolve under stirring Oxalic Acid and Hydroxypropul Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 14c depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Glimepiride.
  • Table 14d depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Glimepiride (bilayer strategy 2).
  • binder Add and dissolve under stirring Oxalic Acid and Hydroxypropul Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • binder Add and dissolve under stirring tween 80 and Hydroxypropul Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender.
  • Compression, coating, packing Compress both lubricated blends of Teneligliptin part and Glimepiride part with suitable tooling using a bilayer compression machine. Coat the compressed tablets using aqueous dispersion of opadry yellow. Pack the film coated tablets in blister pack.
  • Formulations comprising Teneligliptin 3.0 oxalate n. hydrate and Pioglitazone
  • Table 15a depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Pioglitazone (monolayer strategy 1).
  • Table 15b depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Pioglitazone.
  • binder Add and dissolve under stirring Oxalic Acid and Hydroxypropul Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender; 7. Compression: Compress the lubricated blend with suitable tooling and process parameters;
  • Table 15c depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Pioglitazone (bilayer strategy 1).
  • Table 15d depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Pioglitazone.
  • binder Add and dissolve under stirring Oxalic Acid and Hydroxypropul Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass; 4. Sift the sized granules through #030 mesh sieve. Mill the left over using 1.0 mm screen and sift through #030 mesh sieve;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender.
  • binder Add and dissolve under stirring Hydroxypropyl Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender.
  • Compression, coating, packing Compress both lubricated blends of Teneligliptin part and Pioglitazone part with suitable tooling using a bilayer compression machine. Coat the compressed tablets using aqueous dispersion of opadry yellow.
  • Formulations comprising Teneligliptin 3.0 oxalate n. hydrate and Voglibose
  • Table 16a depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Voglibose.
  • Table 16b depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Voglibose.
  • binder Add and dissolve under stirring Oxalic Acid and Hydroxypropyl Cellulose in purified water;
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Compression Compress the lubricated blend with suitable tooling and process parameters
  • Table 16c depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Voglibose.
  • Table 16d depicts a formulation comprising Teneligliptin 3.0 oxalate n. hydrate and Voglibose.
  • Granulation Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender.
  • step 3 Granulate the materials of step 1 with binder solution of step 2. After completion of granulation, dry the wet mass;
  • Lubrication Lubricate the granules of step 4 with sifted excipients of step 5 using suitable blender.

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Abstract

La présente invention concerne des formulations pharmaceutiquement acceptables comprenant des sels d'oxalate de ténéligliptine et des solvates correspondants. L'invention concerne également des combinaisons avec des biguanides et l'utilisation desdites formulations pharmaceutiquement acceptables pour la gestion de troubles du métabolisme du glucose.
PCT/IB2018/050662 2017-02-03 2018-02-02 Formulations comprenant des sels d'oxalate de ténéligliptine et des solvates correspondants WO2018142334A1 (fr)

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BR112018010759A BR112018010759A2 (pt) 2017-02-03 2018-02-02 composições farmacêuticas, processo para preparação de composição farmacêutica, e, método de tratamento curativo ou profilático
KR1020187016406A KR20180100554A (ko) 2017-02-03 2018-02-02 테넬리글립틴의 옥살레이트 염 및 이의 용매화물을 포함하는 제형
AU2018202960A AU2018202960A1 (en) 2017-02-03 2018-02-02 Formulations comprising oxalate salts of Teneligliptin and solvates thereof
MX2018006005A MX2018006005A (es) 2017-02-03 2018-02-02 Formulaciones que comprenden sales de oxalato de teneligliptin y solvatos de este.
CN201880000703.0A CN108697707A (zh) 2017-02-03 2018-02-02 包含特力利汀之草酸盐及其溶剂合物之配方
RU2018120214A RU2742418C1 (ru) 2017-02-03 2018-02-02 Лекарственные формы, содержащие оксалатные соли тенелиглиптина и их сольваты
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WO2015173779A1 (fr) * 2014-05-16 2015-11-19 Micro Labs Limited Procédé de préparation de teneliglipin et nouveaux intermédiaires correspondants

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* Cited by examiner, † Cited by third party
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WO2020209350A1 (fr) * 2019-04-12 2020-10-15 田辺三菱製薬株式会社 Comprimé oral à désintégration rapide pour le traitement du diabète
WO2021053564A1 (fr) * 2019-09-17 2021-03-25 Glenmark Pharmaceuticals Limited Composition pharmaceutique comportant de la rémogliflozine ou un sel ou un ester de celle-ci et de la ténéligliptine ou un sel de celle-ci

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CN108884089A (zh) 2018-11-23
AU2018202623A1 (en) 2018-08-23
JP2019512460A (ja) 2019-05-16
WO2018142327A1 (fr) 2018-08-09
BR112018010759A2 (pt) 2018-12-04
MX2018006006A (es) 2019-05-16
TW201831473A (zh) 2018-09-01
EA039402B1 (ru) 2022-01-24
KR20180100554A (ko) 2018-09-11
EA201992376A1 (ru) 2020-03-23
CN108697707A (zh) 2018-10-23
JP2019508385A (ja) 2019-03-28
AU2018202960A1 (en) 2018-08-23
RU2742418C1 (ru) 2021-02-05
KR20180099635A (ko) 2018-09-05

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