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WO2016066666A1 - Combinaisons pharmaceutiques de sitagliptine et d'agonistes de ppar - Google Patents

Combinaisons pharmaceutiques de sitagliptine et d'agonistes de ppar Download PDF

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Publication number
WO2016066666A1
WO2016066666A1 PCT/EP2015/074930 EP2015074930W WO2016066666A1 WO 2016066666 A1 WO2016066666 A1 WO 2016066666A1 EP 2015074930 W EP2015074930 W EP 2015074930W WO 2016066666 A1 WO2016066666 A1 WO 2016066666A1
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WIPO (PCT)
Prior art keywords
pharmaceutical combination
pharmaceutically acceptable
acceptable salt
sitagliptin
combination according
Prior art date
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PCT/EP2015/074930
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English (en)
Inventor
Ali TÜRKYILMAZ
Gülay Yelken
Sevgi Gökcek
Original Assignee
Sanovel Ilac Sanayi Ve Ticaret A.S.
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Application filed by Sanovel Ilac Sanayi Ve Ticaret A.S. filed Critical Sanovel Ilac Sanayi Ve Ticaret A.S.
Priority to EP15797263.9A priority Critical patent/EP3212234A1/fr
Publication of WO2016066666A1 publication Critical patent/WO2016066666A1/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
    • A61K31/33—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
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic 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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • the present invention relates to a pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt thereof in combination with a PPAR dual agonist or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is an oral antihyperglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class.
  • DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme which destroys the hormone incretin.
  • DPP-4 dipeptidyl peptidase-4
  • Sitagliptin works by binding to DPP-4 and preventing it from breaking down the GLP-1 and GIP. This increases the levels of these hormones in the body and so increases their effect on controlling blood sugar.
  • Sitagliptin is licensed as its phosphate monohydrate salt in the US and EU under the name of JANUVIA in the strength of 100 mg, 50 mg, and 25 mg. The recommended dose is 100 mg once daily.
  • JANUMET® sitagliptin and metformin combination
  • DPP-4 dipeptidyl peptidase-4
  • biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
  • JUVISYNC® sitagliptin and simvastatin combination
  • DPP-4 dipeptidyl peptidase-4
  • HMG-CoA reductase inhibitor combination indicated in patients for whom treatment of hypercholesterolemia and type 2 diabetes mellitus.
  • sitagliptin and PPAR dual agonists in prior art or in the market for the treatment of cardiovascular disease in patients with type-2 diabetes mellitus.
  • Sitagliptin increases plasma GLP-1 concentration and elevate cellular cAMP levels in pancreatic beta-cells leading to potentiate insulin secretion, whereas PPAR agonists regulate lipid homeostasis, cellular differentiation, proliferation and the immune response. Therefore, it is anticipated that a combination therapy of sitagliptin and PPAR agonists may synergistically represents a novel approach to modifying metabolic risk factors associated with adverse cardiovascular outcomes in patients with type 2 diabetes.
  • PPAR agonists are drugs which act upon the peroxisome proliferator-activated receptor. Over the last decade, the members of the peroxisome proliferator-activated receptor (PPAR) subclass have emerged as valuable pharmacological targets whose activation can normalize metabolic dysfunctions and reduce some cardiovascular risk factors associated with type-2 diabetes mellitus.
  • PPAR peroxisome proliferator-activated receptor
  • PPARa alpha
  • PPARy gamma
  • PPAR5 delta
  • dual acting PPARa/ ⁇ alpha/gamma
  • PPAR pan alpha/delta/gamma
  • PPAR alpha agonists are used for dyslipidemia to increase HDL (High Density Lipoprotein), decrease TG (Triglycerides) without effect on LDL (Low Density Lipoprotein).
  • PPAR gamma agonists are insulin sensitizers for type 2 diabetes.
  • PPAR delta agonists are developed to deal with glucose resulting in insulin resistance and diabetes.
  • PPAR dual (alpha and gamma) agonists are for combined treatment of type 2 diabetes and dyslipidemia.
  • PPAR pan (alpha/delta/gamma) agonists are for combined treatment of type 2 diabetes and dyslipidemia.
  • PPAR alpha agonists are also known as glitazones or thiazolidinediones (TZDs). They comprise pioglitazone, rosiglitazone, ciglitazone, darglitazone, englitazone, lobeglitazone, mitaglitazone, netoglitazone and troglitazone.
  • PPAR gamma agonists (also known as fibrates) comprise bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, simfibrate, lifibrate, pirifibrate, theofibrate, tiafibrate, timofibrate, tocofibrate.
  • PPAR delta agonists comprise endurobol.
  • PPAR dual (alpha and gamma) agonists comprise saroglitazar, aloglitazar, chiglitazar, farglitazar (faraglitazar), imiglitazar, muraglitazar, naveglitazar, ragaglitazar, reglitazar, peliglitazar, pemoglitazar, sodelglitazar, tesaglitazar, oxeglitazar, imiglitazar and sipoglitazar.
  • PPAR dual agonists are the glitazars that combine increased insulin sensitization with lipid control. They bind and activate both the alpha and gamma PPAR isoforms and improvement is achieved both in lipid profiles and insulin sensitization while avoiding dyslipidemia and weight gain.
  • Glitazars are ideally suitable drugs in treatment of type 2 diabetic patients who have cardiovascular risk secondary to elevated triglyceride concentration. These molecules do not only target the dyslipidemia but also contribute to improved glycemic control.
  • Lipaglyn recommended in strength of 4 mg, developed by the Zydus Cadila. Lipaglyn has been approved for the treatment of Type II diabetes by the Drug Controller General of India in 2013. Lipaglyn is indicated for the treatment of diabetic dyslipidemia and hypertriglyceridemia with Type 2 diabetes mellitus not controlled by statin therapy. In clinical studies, Lipaglyn has demonstrated reduction of
  • triglycerides TG
  • low density lipoprotein LDL
  • VLDL very low density lipoprotein
  • non- HDL non- high density lipoprotein
  • saroglitazar 2S-2-ethoxy-3-[4-[2-[2-methyl-5-(4- methylsulfanylphenyl)pyrrol-1 -yl]ethoxy]phenyl] propanoic acid and the chemical structure is shown in Formula III.
  • Ragaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and ameliorate diabetic dyslipidemia. It is first disclosed in the patent numbered W09919313 in 1997.
  • the chemical name of Ragaglitazar is (2S)-2-ethoxy-3-[4-(2-phenoxazin-10- ylethoxy)phenyl]propanoic acid and the chemical structure is shown in Formula IV.
  • Reglitazar is a PPAR dual agonist which is first disclosed in the patent numbered W09518125 in 1993.
  • the chemical name of Reglitazar is 4-[[4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4-yl)ethoxy]phenyl]methyl]-1 ,2-oxazolidine-3,5-dione and the chemical structure is shown in Formula V.
  • imiglitazar is (4E)-4-[[4-[(5-methyl-2-phenyl-1 ,3-oxazol-4- yl)methoxy]phenyl]methoxyimino]-4-phenylbutanoic acid and the chemical structure is shown in Formula VI.
  • a pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt thereof in combination with a PPAR dual agonist or a pharmaceutically acceptable salt has been developed to achieve a stable pharmaceutical combination therapy with a safe and effective release.
  • the main embodiment of this present invention is to provide a pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt thereof in combination with a PPAR dual agonist or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
  • PPAR (peroxisome proliferator-activated receptor) dual agonist in the pharmaceutical combination of this present invention is selected from the group comprising saroglitazar, ragaglitazar, reglitazar, imiglitazar, aloglitazar, chiglitazar, farglitazar (faraglitazar), muraglitazar, naveglitazar, peliglitazar, pemoglitazar, sodelglitazar, tesaglitazar, oxeglitazar, imiglitazar sipoglitazar or pharmaceutically acceptable salt thereof.
  • sitagliptin or a pharmaceutically acceptable salt thereof is present in an amount of between 1 .5 - 90%, preferably 15 - 50% and more preferably 25 - 35% by weight of total formulation.
  • a PPAR dual agonist is present in an amount of between 0.5 - 90.0 %, preferably 1 .0 - 50.0 % and more preferably 10.0 - 45.0 % by weight of total formulation.
  • the PPAR dual agonist is preferably saroglitazar or reglitazar or ragaglitazar or imiglitazar or their acceptable salts thereof.
  • saroglitazar or a pharmaceutically acceptable salt used in the formulation is saroglitazar magnesium salt.
  • the pharmaceutical combination of this present invention comprises sitagliptin or a pharmaceutically acceptable salt thereof and saroglitazar or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination of this present invention comprises sitagliptin or a pharmaceutically acceptable salt thereof and reglitazar or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination of this present invention comprises sitagliptin or a pharmaceutically acceptable salt thereof and ragaglitazar or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical combination of this present invention comprises sitagliptin or a pharmaceutically acceptable salt thereof and imiglitazar or a pharmaceutically acceptable salt thereof.
  • sitagliptin or a pharmaceutically acceptable salt used in the formulation is sitagliptin phosphate monohydrate. While combining more than one molecule in one dosage form is increasing the patients' quality of life, many challenges also occur such as the physicochemical compatibility and the therapeutical compatibility between the two active agents. It is essential to achieve the compatibility between different active agents and/or between active agents and excipients used. The scientific literature is full of examples wherein compounds of different classes cannot be combined into safe and efficacious dosage forms thereby resulting in incompatible drug combinations. Due to chemical interaction between active agents or between active agents and excipients, stability and release problems may occur. According to this embodiment, sitagliptin phosphate monohydrate present in an amount of between 25 mg and 200 mg and the saroglitazar is present in an amount of 0.1 mg and 5 mg.
  • sitagliptin phosphate monohydrate present in an amount of between 25 mg and 200 mg and the reglitazar is present in an amount of 0.5 mg and 100 mg.
  • sitagliptin phosphate monohydrate present in an amount of between 25mg and 200 mg and the ragaglitazar is present in an amount of 0.5 and 100 mg.
  • sitagliptin phosphate monohydrate present in an amount of between 25 and 200 mg and the imiglitazar is present in an amount of 0.5 and 100 mg.
  • the pharmaceutical combination is in the form of tablets (including compressed, coated or uncoated), bilayer tablets, multilayer tablets, orally disintegrating tablets, mini tablets, capsules, pellet, sugar pellet, buccal tablets, sublingual tablets, effervescent compositions, effervescent tablets, immediate release tablets, modified release tablets, film-coated tablets, gastric disintegrating tablets, pills, hard or soft gelatin capsules, oral granules, powders, mini tablets, pellets, coated bead systems, granules, microspheres, sachet, tablet in tablet or an inlay tablets, ion exchange resin systems, sterile solutions or suspensions, steril ocular solutions, aerosols, sprays, drops, ampoules, suppositories, ocular systems, parenteral systems, creams, gels, ointments, dragees, films, orally administrable films, solutions, solids; elixirs, tinctures, suspensions, syrups, colloidal dispersions,
  • pharmaceutical combination is formulated preferably in the form of tablet or capsule or multilayer tablet or tablet in tablet or orally disintegrating tablet comprising sitagliptin or a pharmaceutically acceptable salt and PPAR dual agonist or a pharmaceutically acceptable salt.
  • One embodiment of the present invention is to obtain a stable pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt and a PPAR dual agonist or a pharmaceutically acceptable salt in one dosage form.
  • Sitagliptin has also a primary amine group on its chemical structure. In solid dosage forms, it may react with many excipients or impurities of excipients, although sitagliptin itself is very stable. Especially decomposition which may be caused by reaction (e.g. by acylation, urea formation or Maillard reaction, or the like) of free base type sitagliptin when combined with an incompatible drug molecule, or its impurity and/or a pharmaceutical excipient to form derivatives with the free base type sitagliptin, such as N-acetyl or N-carbamoyl derivatives. Therefore, by the use of suitable excipients within these pharmaceutical combinations, protection against decomposition and degradation can be achieved.
  • reaction e.g. by acylation, urea formation or Maillard reaction, or the like
  • a pharmaceutical excipient to form derivatives with the free base type sitagliptin, such as N-acetyl or N-carbamoyl derivatives. Therefore, by the
  • Another embodiment of the present invention is to obtain a pharmaceutical combination comprising sitagliptin or a pharmaceutically acceptable salt and a PPAR dual agonist or a pharmaceutically acceptable salt which provides the desired release profile.
  • pharmaceutical combination of this present invention comprise at least one pharmaceutical excipient selected from the group comprising disintegrants, binders, diluents, glidants, lubricants, super-disintegrant, acidifying agent, alkalizing agent, sweeteners, aromas or mixtures thereof.
  • Suitable disintegrants are selected from the group comprising crospovidon (cross- linked polyvinylpyrrolidone), copovidon, polyvinylpyrrolidone (povidone), croscarmellose sodium, low-substitue HPC (hydroxylpropyl cellulose), poloxomer, sodium starch glycolate, microcristalline cellulose, starch, alginic acid and alginates, ion-exchange resins, magnesium aluminum silica, sodium dodecyl sulphate, sodium carboxy methyl cellulose, carboxy methyl cellulose calcium, docusate sodium, guar gum, polyacrylin potasium, sodium alginate, sodium glysin carbonate, sodium lauryl sulphate or mixtures thereof.
  • disintegrant used in the formulation is crospovidon.
  • release profile of both sitagliptin phosphate monohydrate and PPAR dual agonist may be changed.
  • crospovidon is used as a disintegrant, stability and desired release profile could be achieved at the same time.
  • crospovidon is used as a disintegrant and the amount of crospovidon by the weight of total formulation is in the range of % 0.25 - 30.
  • Suitable binders are selected from the group comprising crospovidon (cross-linked polyvinylpyrrolidone), polyvinylpyrrolidone (povidone), pullulan, polymethacrylate, glyceryl behenate, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose (CMC), methyl cellulose (MC), hydroxyethyl cellulose, sodium carboxymethyl cellulose (Na CMC), carboxymethyl cellulose calcium, ethyl cellulose and other cellulose derivatives, polymetacrylates, polyethylene oxide, polyvinyl alcohol, polyvinyl acetate and their copolymers, gelatin, starch, xanthan gum, guar gum, alginate, carrageen, kollagen, agar, pectin, hyaluronic acid, carbomer, cellulose acetate phthalate, hydroxypropyl starch, hydroxyethyl methyl cellulose,
  • Suitable diluents are selected from the group comprising dibasic calcium phosphate, xylitol, microcrystalline cellulose (MCC), mannitol, lactose, spray-dried lactose, sorbitol, sucrose, trehalose, isomalt, starch, calcium phosphate anhydrate, calcium phosphate dihydrate, calcium phosphate trihydrate, tribasic calcium phosphate, calcium carbonate, calcium sulfate, carboxymethyl cellulose calcium, powdered cellulose, cellulose acetate, pregelatinized starch, lactose monohydrate, sodium carbonate, sodium bicarbonate, isomalt, maltodextrine, dextrose, calcium carbonate, sugars, magnesium carbonate, corn starch or mixtures thereof.
  • MCC microcrystalline cellulose
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, talc, aluminum silicate, powdered cellulose, calcium phosphate tribasic, hydrophobic colloidal silica, magnesium oxide, magnesium trisilicate, magnesium silicate or mixtures thereof.
  • Suitable lubricants are selected from the group comprising magnesium stearate, calcium stearate, mineral oil, sodium stearyl fumarate, talc, polyethylene glycol, glyceryl monostearate, glyceryl palmitostearate, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, zinc stearate, stearic acid, hydrogenated natural oils, silica, paraffin or mixtures thereof.
  • Super-disintegrant is selected from the group comprising calcium silicate, sodium starch glycolate, croscarmellose sodium, carboxymethyl cellulose calcium, sodium carboxymethyl starch, sodium glycine carbonate, sodium lauryl sulphate, soy polysaccharide, alginic acids and algynates, cross-linked alginic acid, polyacrylin potasium, poloxomer, crospovidone, gellan gum, guar gum, xanthan gum, docusate sodium, magnesium alumina, sodium dodecyl sulfate, ion exchange resins or mixtures thereof.
  • Acidifying agent is selected from the group comprising fumaric acid, tartaric acid, citric acid, citric acid monohydrate, citric acid anhydrate, adipic acid, ascorbic acid, acetic acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, nicotinic acid, acetyl salicylic acid, sulfuric acid, acid salts (such as amino acid hydrochlorides, sodium citrates, sodium citrate dihydrate, disodium citrate, disodium dihydrogen citrate, sodium acid phosphate) or mixtures thereof, preferably it is fumaric acid.
  • Alkalizing agent is selected from the group comprising sodium glycine carbonate, ammonia solution, ammonium carbonate, diethanolamine, diisopropanolamine, potassium hydroxide, potassium bicarbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine or mixtures thereof, preferably it is sodium glycine carbonate.
  • Suitable sweeteners may include but not limited to sucralose, thaumatin, mogroside, inuline, erythritol, sucralose, mogroside, acesulfame-K, aspartame, saccharin or its sodium and calcium salts, sodium cyclamate, sucrose, fructose, glucose, sorbitol or mixtures thereof;
  • Suitable aromas may include but not limited to fruit aromas such as orange, banana, strawberry, cherry, wild cherry, lemon, etc., and other aromas such as cardamom, anis, mint, menthol, vanillin or the mixtures thereof.
  • Coating may also preferably be used for the protection from the moisture. It can be selected from the group comprising polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat IR), polyvinyl alcohol or copolymers or mixtures thereof (Opadry AMB), polymethylmetacrylate derivatives, Ethylcellulose Dispersions (Surelease), Kerry- HPC, polyethylene glycol, polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA) and all kinds of OpadryTM, as well as pigments, dyes, titanium dioxide, iron oxide, talc or polymethylmetacrylate copolymers (Eudragit).
  • these formulations have been designed, comprising the following: tablet:
  • coating bilayer tablet h. preferably, coating bilayer tablet:
  • binder i. 0.1 - 30.0 % by weight of binder
  • coating capsule I. 0.1 - 5.0 % by weight of lubricant m. preferably, coating capsule:
  • Example 1 tablet ingredients Amount (%) sitagiiptin phosphate monohydrate 1 .5 - 90.0 saroglitazar 0.5-90.0 starch 5.0-90.0
  • the production of the formulation is carried out as follows: sitagliptin phosphate monohydrate, saroglitazar, starch, crospovidon, copovidon and dibasic calcium phosphate are mixed. Colloidal silicon dioxide is added and mixed. Then, magnesium stearate is added therein and mixed for a short time.. Tablet compression is performed and tablets are preferably coated.
  • Example 2 tablet ingredients Amount (%) sitagliptin phosphate monohydrate 1.5-90.0 ragaglitazar 0.5-90.0 xylitol 5.0-90.0 dibasic calcium phosphate 5.0-90.0 crospovidon 1.0-30.0 pullulan 0.2-5.0 colloidal silicon dioxide 0.1 - 0.2 magnesium stearate 0.25-2.0 coating 0.2-10.0
  • the production of the formulation is carried out as follows: ragaglitazar, a part of crospovidon and xylitol are mixed together. The mixture is granulated with pullulan solution (pullulan is solved in a proper solvent) and dried then sieved.
  • Sitagliptin phosphate monohydrate, dibasic calcium phosphate and other part of crospovidon are mixed. Colloidal silicon dioxide is added to the mixture and mixed. Then, magnesium stearate is added and and mixed for a short time.. Tablet compression is performed and tablets are preferably coated.
  • Example 3 bilaver tablet
  • the production of the formulation is carried out as follows: First layer: sitagliptin phosphate monohydrate, starch, crospovidon and colloidal silicon dioxide are mixed. Then, magnesium stearate is added and mixed again. The mixture pass through the roller compactor.
  • Second layer saroglitazar, dibasic calcium phosphate, crospovidon, sodium starch glycolate, copovidone and colloidal silicon dioxide are mixed. Then, magnesium stearate is added and and mixed for a short time. The mixture pass through the roller compactor.
  • Granules are sieved and mixed with magnesium stearate. Then, they compressed into bilayer tablets. Tablets are preferably coated.
  • sitagliptin phosphate monohydrate and saroglitazar solution is prepared with polyvinylpyrrolidone (solved in a proper solvent) separately. Separately, sugar pellets are coated. Solution of polymethyl methacrylate is prepared and sugar pellets comprising active agents are coated. Pellets are first mixed with crospovidon, colloidal silicon dioxide and then magnesium stearate for a short time. Then, they are filled into capsules and preferably, coated.
  • Example 5 tablet in tablet
  • the production of the formulation is carried out as follows: Core tablet: sitagliptin phosphate monohydrate, mannitol, crospovidon and colloidal silicon dioxide are mixed. Then, magnesium stearate is added and mixed again. The mixture is compressed into tablets and core tablet is prepared.
  • Outer layer imiglitazar, microcrystalline cellulose, crospovidon and colloidal silicon dioxide are mixed. Then, magnesium stearate is added and mixed again.
  • a part of powder mixture comprising imiglitazar is filled into tablet cavity of machine. Then core tablet comprising sitagliptin is put into it and other part of powder mixture comprising imiglitazar is filled into it. Final tablets are pressed. Tablets are preferably coated.
  • Example 6 orally disintegrating tablet
  • the production of the formulation is carried out as follows: sitagliptin phosphate monohydrate, saroglitazar, crospovidon, mannitol, calcium silicate, sucralose and aroma are mixed. Sodium stearyl fumarate is added and mixed for a short time. Tablet compression is performed.
  • Example 7 tablet - Hot melt process
  • sitagliptin phosphate monohydrate, saroglitazar and poloxamer are passed through the extruder, cooled and sieved.
  • Crospovidon, microcrystalline cellulose and colloidal silicon dioxide are added to mixture and mixed.
  • magnesium stearate is added therein and mixed for a short time.
  • Tablet compression is or capsule filling performed. Tablets are preferably coated.

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Abstract

L'invention concerne une combinaison pharmaceutique comprenant de la sitagliptine ou un sel pharmaceutiquement acceptable de celle-ci en combinaison avec un agoniste double de PPAR ou un sel pharmaceutiquement acceptable.
PCT/EP2015/074930 2014-10-30 2015-10-28 Combinaisons pharmaceutiques de sitagliptine et d'agonistes de ppar WO2016066666A1 (fr)

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Application Number Priority Date Filing Date Title
EP15797263.9A EP3212234A1 (fr) 2014-10-30 2015-10-28 Combinaisons pharmaceutiques de sitagliptine et d'agonistes de ppar

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TR2014/12671 2014-10-30
TR201412671 2014-10-30

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WO2016066666A1 true WO2016066666A1 (fr) 2016-05-06

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019154895A1 (fr) * 2018-02-08 2019-08-15 Strekin Ag Formulation en gel pour la prévention ou le traitement de la perte auditive

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018125A1 (fr) 1993-12-27 1995-07-06 Japan Tobacco Inc. Derive d'isoxazolidinedione et son utilisation
WO1999019313A1 (fr) 1997-10-27 1999-04-22 Dr. Reddy's Research Foundation Nouveaux composes tricycliques et leur utilisation en medecine, procede de preparation de ces derniers et compositions pharmaceutiques les contenant
US20060270722A1 (en) * 2005-05-31 2006-11-30 Thornberry Nancy A Combination of a dipeptidyl peptidase-IV inhibitor and a dual PPAR agonist for the treatment of diabetes and obesity
EP2578208A1 (fr) * 2011-10-06 2013-04-10 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations posologiques solides d'inhibiteurs DPP-IV

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995018125A1 (fr) 1993-12-27 1995-07-06 Japan Tobacco Inc. Derive d'isoxazolidinedione et son utilisation
WO1999019313A1 (fr) 1997-10-27 1999-04-22 Dr. Reddy's Research Foundation Nouveaux composes tricycliques et leur utilisation en medecine, procede de preparation de ces derniers et compositions pharmaceutiques les contenant
US20060270722A1 (en) * 2005-05-31 2006-11-30 Thornberry Nancy A Combination of a dipeptidyl peptidase-IV inhibitor and a dual PPAR agonist for the treatment of diabetes and obesity
EP2578208A1 (fr) * 2011-10-06 2013-04-10 Sanovel Ilac Sanayi ve Ticaret A.S. Formulations posologiques solides d'inhibiteurs DPP-IV

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019154895A1 (fr) * 2018-02-08 2019-08-15 Strekin Ag Formulation en gel pour la prévention ou le traitement de la perte auditive

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MA40868A (fr) 2017-09-05

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