WO2018033808A1 - Improved composition of teneligliptin and metformin and method for preparing same - Google Patents
Improved composition of teneligliptin and metformin and method for preparing same Download PDFInfo
- Publication number
- WO2018033808A1 WO2018033808A1 PCT/IB2017/053749 IB2017053749W WO2018033808A1 WO 2018033808 A1 WO2018033808 A1 WO 2018033808A1 IB 2017053749 W IB2017053749 W IB 2017053749W WO 2018033808 A1 WO2018033808 A1 WO 2018033808A1
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- WIPO (PCT)
- Prior art keywords
- metformin
- pharmaceutical composition
- therapeutically effective
- teneligliptin
- effective amount
- Prior art date
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 115
- 229950000034 teneligliptin Drugs 0.000 title claims abstract description 101
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical group O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 title claims abstract description 97
- 229960003105 metformin Drugs 0.000 title claims abstract description 71
- 239000000203 mixture Substances 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 33
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 20
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 11
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 11
- 229940069328 povidone Drugs 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 48
- 239000008187 granular material Substances 0.000 claims description 37
- 239000011248 coating agent Substances 0.000 claims description 29
- 238000000576 coating method Methods 0.000 claims description 29
- 235000019441 ethanol Nutrition 0.000 claims description 26
- 239000003472 antidiabetic agent Substances 0.000 claims description 18
- 230000003178 anti-diabetic effect Effects 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 8
- 238000001033 granulometry Methods 0.000 claims description 7
- 238000013265 extended release Methods 0.000 claims description 5
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 239000002700 tablet coating Substances 0.000 claims 1
- 238000009492 tablet coating Methods 0.000 claims 1
- 239000003826 tablet Substances 0.000 abstract description 82
- 238000000338 in vitro Methods 0.000 abstract description 11
- 239000004480 active ingredient Substances 0.000 abstract description 10
- 239000000843 powder Substances 0.000 abstract description 6
- 238000007906 compression Methods 0.000 abstract description 4
- 230000006835 compression Effects 0.000 abstract description 4
- 238000005550 wet granulation Methods 0.000 abstract description 3
- 239000007935 oral tablet Substances 0.000 abstract 1
- 229940096978 oral tablet Drugs 0.000 abstract 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 46
- 229960004329 metformin hydrochloride Drugs 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 24
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 22
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000004090 dissolution Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 13
- 238000009472 formulation Methods 0.000 description 12
- 239000004408 titanium dioxide Substances 0.000 description 12
- 229920003081 Povidone K 30 Polymers 0.000 description 9
- 239000012530 fluid Substances 0.000 description 8
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 7
- 229950004221 besilate Drugs 0.000 description 7
- 235000013773 glyceryl triacetate Nutrition 0.000 description 7
- 239000001087 glyceryl triacetate Substances 0.000 description 7
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- 229960002622 triacetin Drugs 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 201000000083 maturity-onset diabetes of the young type 1 Diseases 0.000 description 5
- 229940098805 metformin hydrochloride 850 mg Drugs 0.000 description 5
- 230000002035 prolonged effect Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 229960003943 hypromellose Drugs 0.000 description 4
- 229940103788 metformin hydrochloride 1000 mg Drugs 0.000 description 4
- 229940103776 metformin hydrochloride 500 mg Drugs 0.000 description 4
- 238000001223 reverse osmosis Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000012812 general test Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229940126904 hypoglycaemic agent Drugs 0.000 description 3
- 229940123208 Biguanide Drugs 0.000 description 2
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 2
- -1 Teneligliptin compound Chemical class 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 230000000291 postprandial effect Effects 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000051325 Glucagon Human genes 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229960004666 glucagon Drugs 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 230000004190 glucose uptake Effects 0.000 description 1
- 230000004116 glycogenolysis Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 230000037356 lipid metabolism Effects 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical group O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000003979 response to food Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
Classifications
-
- 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
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
Definitions
- the present invention relates to an improved fixed dose composition
- an improved fixed dose composition comprising the combination of two hypoglycemic active ingredients, one of the gliptin family, Teneliglipt ina and the other of the biguanide family, Metformin, for treatment by Oral route of diabetes mellitus type 2 (DM2) in humans, the process to obtain such an improved composition, and its uses.
- DM2 diabetes mellitus type 2
- the Teneligliptin compound whose IUPAC nomenclature is Methanone, [(2S, 4S) -4- [4- (3-meti 1-1-phenyl-lH-pyrazol-5-i 1) -1-piperazinyl] -2-pyrrolidinyl ] -3-thiazolidini 1, represented by formula (I), was disclosed as a product in European patent EP 1 308439 Bl and its equivalents, the holder of which is MITSUBISHI TANABE PHARMA and the priority date is 10-8-00 and 28 -12-00 (JP).
- Teneligliptin is an oral hypoglycemic agent, a dipeptidyl peptidase 4 (DPP-4) inhibitor.
- DPP-4 dipeptidyl peptidase 4
- the pharmacological action of Teneligliptin is described as follows: the glucagon-like peptide type 1 (GLP-1) is secreted by the gastrointestinal tract in response to food, promotes insulin secretion from the pancreas and, by suppression of glucagon secretion, adjust postprandial glycemia.
- GLP-1 glucagon-like peptide type 1
- DPP-4 dipeptidyl peptidase 4
- Metformin is an antihyperglycemic agent belonging to the group of biguanides, which lowers basal and postprandial glycemia. It does not stimulate insulin secretion, thus not producing hypoglycemia.
- the mechanism of action is not known exactly and it is considered that it could act: 1) decreasing hepatic glucose production by inhibition of glycogenolysis and gluconeogenesis, 2) in the muscle, increasing the sensitivity or amount of insulin receptors, improving glucose uptake and utilization and 3) decreasing the intestinal absorption of glucose.
- Metformin has been shown to produce a favorable effect on lipid metabolism, independent of its effect on blood glucose.
- Administered in therapeutic doses Metformin lowers total cholesterol, LDL cholesterol and plasma t-riglycerides.
- the usual initial dose of treatment is 500 mg or 850 mg two or three times per day administered during or after meals. Increased doses can be evaluated based on tolerance and blood glucose levels. The dose can be increased to 3000 mg per day, always divided every 8 or 12 hours.
- the object of the present invention relates to an improved formulation in the form of a coated tablet, in a unit dose, comprising two agents.
- hypoglycemic agents namely Teneliglipt ina or any of its pharmaceutically acceptable salts, and Metformin, such as Metformin hydrochloride, in a therapeutically effective amount, for the treatment of type 2 diabetes mellitus (DM2), further comprising a low content of excipients.
- Metformin such as Metformin hydrochloride
- the obtained tablets were highly friable, took very low hardness working with high compression force, and also pickled (they opened in sheets).
- the physical characteristics of Metformin hydrochloride were studied thoroughly, observing that it was usually acicular crystalline powder, which tended to form lumps and compact into the container container.
- tests were carried out, reducing the granulometry of Metformin hydrochloride by calibrating it in the Fitz Mili mill, varying the meshes and speeds. Although the compressibility improved, the hardness obtained was not optimal and the process was far from reproducible.
- the granulate was then calibrated by a 2 mm mesh, and subsequently, dried by using a fluid bed until a residual humidity between 1.5 and 2% was obtained, taken at 105 2 C. Then the dry granulate was calibrated. using a 1 mm mesh, and after adding a small aliquot of Magnesium Stearate, it was mixed for 2 minutes at 12 rpm. It was subsequently compressed with a rotary compressor, obtaining very good hardness tablets (around 20 kp), with brightness, low friability (less than 1% P / P), without presence of decape or laminate working with standard compression force. Also, the disintegration time was less than 15 minutes. The tablets obtained perfectly complied with the content uniformity test of both active ingredients.
- the usual methodology when developing a tablet formulation To vehicle one or more active ingredients it is to use one or more diluents, a binder, a disintegrant, a lubricant, and it is expected that as we increase the amount of excipients, compressibility improves. In the case object of this patent, the opposite happened, the compressibility decreased, that is why we affirm that it was an unexpected event.
- the invention relates to an improved pharmaceutical composition for oral administration, in the form of a coated tablet, for the treatment of DM2, which comprises the combination of a therapeutically effective amount of the antidiabetic Teneliglipt ina or its pharmaceutically salts. acceptable, with a therapeutically effective amount of the antidiabetic Metformin hydrochloride, with a low content of pharmaceutically acceptable excipients.
- the invention also relates to the therapeutically effective doses of Teneliglipt ina or its pharmaceutically acceptable salts, which may be in the range of 10 mg to 20 mg and the therapeutically effective doses of Metformin hydrochloride, which may be in the range of 500 to 2000 mg
- the invention relates to processes for obtaining an improved pharmaceutical composition of oral administration, in the form of a coated tablet, for the treatment of DM2, which comprises grinding Metformin, mixing, granulating, mixing again and compressing therapeutically effective amounts of the active ingredients Teneliglipt ina or its pharmaceutically acceptable salts and Metformin hydrochloride together with low content of pharmaceutically acceptable excipients and coating, the tablets obtained.
- DM2 a pharmaceutically acceptable pharmaceutically acceptable salts and Metformin hydrochloride
- Teneliglipt ina mixed with Metformin in another variant, it includes dissolved in the binder solution, and finally, in another variant, incorporates Teneligliptin from the suspension of the coating.
- the industrial lot is per 200 kg, it was kneaded in two aliquots of 100 kg each, in a Zanchetta rotator with a capacity of 300 liters.
- Titanium dioxide 9.00 0.81
- Weight of the coated tablet 1112 mg
- the industrial batch is for 200 kg, it was kneaded in two aliquots of 100 kg each, in a Zanchetta rotogranuladora of 300 liters of capacity.
- the industrial lot is for 200 kg, and was mixed in two aliquots of 100 kg each, in a Zanchetta rotogranuladora of 300 liters of capacity.
- the process for preparing a formulation of coated tablets for administration every 12 hours comprising 10 mg of Teneliglipt ina its pharmaceutically acceptable salts and 500 mg of Metformin, in which, Metformin hydrochloride will be compressed and Teneligliptin will be applied together with the covering.
- Metformin hydrochloride will be compressed and Teneligliptin will be applied together with the covering.
- the formula described below is per unit of Dosing, the industrial batch is per 100 kg, and it was kneaded in a Zanchetta rotogranuladora of 300 Liters of capacity.
- Example 5 The methodology described in Example 5 is applicable for doses of 10 mg of Teneliglipt ina its pharmaceutically acceptable salts, combined with 850 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride (to be administered every 12 hr.) , and 20 mg of Teneliglipt ina combined with 850 mg of Metformin hydrochloride (to be administered every 24 hr).
- the industrial batch is 200 kg, Knead in two aliquots of 100 kg each,
- Example 7 The methodology applied in Example 7, is applicable for the doses of 10 mg of Teneliglipt ina or its pharmaceutically acceptable salts combined with 500 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride, and 10 mg of Teneligliptin combined with 850 mg of Metformin hydrochloride.
- EXAMPLE 9 The methodology applied in Example 7, is applicable for the doses of 10 mg of Teneliglipt ina or its pharmaceutically acceptable salts combined with 500 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride, and 10 mg of Teneligliptin combined with 850 mg of Metformin hydrochloride.
- Titanium dioxide 3.75 6, 25 7.00
- Friability Friabilómet ro type "ROCHE” equipment, according to USP General Tests and Assays ⁇ 1216>
- composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 500 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride.
- composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 1000 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 1000 mg of Metformin hydrochloride.
- hydrochloride Q 70% Average: 99.3% Average: 100%
- composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 850 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride.
- composition in the form of a coated tablet comprising Teneligliptin 20 mg and Metformin hydrochloride 850 mg, compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride.
- composition in the form of a coated tablet comprising Teneligliptin 10 mg in the coating and Metformin hydrochloride 500 mg, in the core compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride.
- composition in the form of a coated tablet comprising Teneligliptin 20 mg added dissolved in the binder solution and Metformin hydrochloride 850 mg, granulated in a similar manner to the previous examples, compared with coated tablets containing 20 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride .
- composition in the form of a coated tablet comprising Teneligliptin 20 mg in the coating and Metformin hydrochloride 500 mg, in the core prolonged deliberation compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride extended release.
- Parameters Example 1 Teneligliptin 20 mg Metformin
- composition in the form of a coated tablet comprising Teneligliptin 20 mg in the coating and Metformin hydrochloride 1000 mg, in the core prolonged deliberation compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 1000 mg of Metformin hydrochloride extended release.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an improved pharmaceutical composition in the form of a coated oral tablet, with teneligliptin or the pharmaceutically acceptable salts thereof and metformin or the pharmaceutically acceptable salts thereof, for the treatment of type 2 diabetes mellitus. The pharmaceutical composition is obtained by means of wet granulation, using metformin ground to a fine powder and a low load of excipients consisting of a binder, in this case povidone, and magnesium stearate as a lubricant during compression. The use of ground metformin considerably improves the compressibility of same, allowing operative conditions to be optimised. Compared with the two active ingredients separately and vehiculised in the form of coated tablets, the improved pharmaceutical composition comprising the combination of teneligliptin and metformin show no differences in in vitro release (solution), and, moreover, improved the compressibility of the powder and the friability of the tablets. The features mentioned distinguish this improved composition from other compositions containing the same active ingredients and using more excipients. Said composition is therefore the main subject matter of the present invention.
Description
COMPOSICIÓN MEJORADA DE TENELIGLIPTINA Y METFORMINA Y PROCESO IMPROVED COMPOSITION OF TENELIGLIPTINE AND METFORMIN AND PROCESS
PARA PREPARARLA. TO PREPARE IT.
CAMPO TÉCNICO DE LA INVENCIÓN TECHNICAL FIELD OF THE INVENTION
La presente invención se refiere a una composición mejorada a dosis fija que comprende la combinación de dos principios activos hipoglucemiantes , uno de la familia de las gliptinas, la Teneliglipt ina y el otro de la familia de las biguanidas, la Metformina, para el tratamiento por vía oral de la diabetes mellitus tipo 2 (DM2) en humanos, el proceso para obtener dicha composición mejorada, y sus usos. The present invention relates to an improved fixed dose composition comprising the combination of two hypoglycemic active ingredients, one of the gliptin family, Teneliglipt ina and the other of the biguanide family, Metformin, for treatment by Oral route of diabetes mellitus type 2 (DM2) in humans, the process to obtain such an improved composition, and its uses.
ANTECEDENTES DE LA INVENCIÓN BACKGROUND OF THE INVENTION
El compuesto Teneligliptina, cuya nomenclatura IUPAC es Metanona, [ (2S, 4S) -4- [4- ( 3-meti 1-1-fenil-lH-pirazol-5-i 1 ) -1- piperazinil ] -2-pirrolidinil ] -3-tiazolidini 1 , representado por la fórmula (I), fue revelado como producto en la patente europea EP 1 308439 Bl y sus equivalentes, cuyo titular es MITSUBISHI TANABE PHARMA y la fecha de prioridad es 10-8-00 Y 28-12-00 (JP) . The Teneligliptin compound, whose IUPAC nomenclature is Methanone, [(2S, 4S) -4- [4- (3-meti 1-1-phenyl-lH-pyrazol-5-i 1) -1-piperazinyl] -2-pyrrolidinyl ] -3-thiazolidini 1, represented by formula (I), was disclosed as a product in European patent EP 1 308439 Bl and its equivalents, the holder of which is MITSUBISHI TANABE PHARMA and the priority date is 10-8-00 and 28 -12-00 (JP).
Formula (I)
La Teneligliptina es un hipoglucemiante oral, inhibidor de la dipeptidil peptidasa 4 (DPP-4) . La acción farmacológica de la Teneligliptina se describe de la siguiente manera: el péptido similar al glucagón tipo 1 (GLP-1) es secretado por el tracto gastrointestinal en respuesta a los alimentos, promueve la secreción de insulina desde el páncreas y, mediante la supresión de la secreción de glucagón, ajusta la glucemia postprandial . La Teneligliptina al inhibir la actividad de la dipeptidil peptidasa 4 (DPP-4), suprime la degradación del GLP-1 mediada por esta peptidasa, aumentando la concentración sanguínea de GLP-1 activado, mediante la cual despliega el efecto hipoglucémico . Formula (I) Teneligliptin is an oral hypoglycemic agent, a dipeptidyl peptidase 4 (DPP-4) inhibitor. The pharmacological action of Teneligliptin is described as follows: the glucagon-like peptide type 1 (GLP-1) is secreted by the gastrointestinal tract in response to food, promotes insulin secretion from the pancreas and, by suppression of glucagon secretion, adjust postprandial glycemia. Teneligliptin by inhibiting the activity of dipeptidyl peptidase 4 (DPP-4), suppresses the degradation of GLP-1 mediated by this peptidase, increasing the blood concentration of activated GLP-1, through which it displays the hypoglycemic effect.
El compuesto Metformina, cuya nomenclatura IÜPAC esThe Metformin compound, whose IÜPAC nomenclature is
Imidodicarbonimidic diamida, N, -dimetil, fue descripto como producto en la patente US 3 174 901, el titular es Jan Marcel Didier Aron Samuel y la fecha de prioridad es 31-01-1963. Su fórmula estructural está representada por la fórmula (II) .
Imidodicarbonimidic diamide, N, -dimethyl, was described as a product in US Patent 3 174 901, the owner is Jan Marcel Didier Aron Samuel and the priority date is 01/31-1963. Its structural formula is represented by formula (II).
Formula (II) Formula (II)
La Metformina es un antihiperglucemiante perteneciente al grupo de las biguanidas, que disminuye la glucemia basal y postprandial. No estimula la secreción de insulina, no produciendo, por lo tanto, hipoglucemia . No se conoce con exactitud el mecanismo de acción y se considera que podría actuar: 1) disminuyendo la producción hepática de glucosa por inhibición de la glucogenólisis y la gluconeogénesis, 2) en
el músculo, aumentando la sensibilidad o la cantidad de receptores de la insulina, mejorando la captación y la utilización de la glucosa y 3) disminuyendo la absorción intestinal de la glucosa. La Metformina ha demostrado producir un efecto favorable sobre el metabolismo de los lipidos, independiente de su efecto sobre la glucemia. Administrada en dosis terapéuticas, la Metformina disminuye el colesterol total, el colesterol LDL y los t riglicéridos plasmáticos. La dosis usual inicial del tratamiento es de 500 mg u 850 mg dos o tres veces por día administradas durante o después de las comidas. El incremento de las dosis pueden ser evaluadas en base a la tolerancia y niveles de glucemia. La dosis puede incrementarse hasta los 3000 mg por día, siempre fraccionadas cada 8 u 12 horas. Metformin is an antihyperglycemic agent belonging to the group of biguanides, which lowers basal and postprandial glycemia. It does not stimulate insulin secretion, thus not producing hypoglycemia. The mechanism of action is not known exactly and it is considered that it could act: 1) decreasing hepatic glucose production by inhibition of glycogenolysis and gluconeogenesis, 2) in the muscle, increasing the sensitivity or amount of insulin receptors, improving glucose uptake and utilization and 3) decreasing the intestinal absorption of glucose. Metformin has been shown to produce a favorable effect on lipid metabolism, independent of its effect on blood glucose. Administered in therapeutic doses, Metformin lowers total cholesterol, LDL cholesterol and plasma t-riglycerides. The usual initial dose of treatment is 500 mg or 850 mg two or three times per day administered during or after meals. Increased doses can be evaluated based on tolerance and blood glucose levels. The dose can be increased to 3000 mg per day, always divided every 8 or 12 hours.
La solicitud de patente internacional WO 2010/079197 Al, cuyo titular es Boehringer Ingelheim International GMBH, y cuya fecha de prioridad es 07-01-2009 (EP) , reivindica un método de tratamiento a partir de la administración de un inhibidor DPP IV solo o combinado con otro hipoglucemiante . International patent application WO 2010/079197 Al, whose owner is Boehringer Ingelheim International GMBH, and whose priority date is 07-01-2009 (EP), claims a method of treatment from the administration of a DPP IV inhibitor alone or combined with another hypoglycemic.
La solicitud de patente internacional WO 2010/092163 A2, cuyo titular es Boehringer Ingelheim International GMBH, y cuya fecha de prioridad es 13-02-2009 (EP) , reivindica una combinación comprendiendo un inhibidor DPP IV, opcionalmente , un segundo agente hipoglucemiante, y opcionalmente, un tercer agente hipoglucemiante. International patent application WO 2010/092163 A2, whose owner is Boehringer Ingelheim International GMBH, and whose priority date is 13-02-2009 (EP), claims a combination comprising a DPP IV inhibitor, optionally, a second hypoglycemic agent, and optionally, a third hypoglycemic agent.
DESCRIPCIÓN DETALLADA DE LA INVENCIÓN DETAILED DESCRIPTION OF THE INVENTION
El objeto de la presente invención se refiere a una formulación mejorada bajo la forma de comprimido recubierto, en una dosis unitaria, comprendiendo dos agentes
hipoglucemiantes , a saber de Teneliglipt ina o cualquiera de sus sales farmacéuticamente aceptables, y Metformina, como Metformina clorhidrato, en una cantidad terapéuticamente efectiva, para el tratamiento de diabetes mellitus tipo 2 (DM2), comprendiendo además, un bajo contenido de excipientes . The object of the present invention relates to an improved formulation in the form of a coated tablet, in a unit dose, comprising two agents. hypoglycemic agents, namely Teneliglipt ina or any of its pharmaceutically acceptable salts, and Metformin, such as Metformin hydrochloride, in a therapeutically effective amount, for the treatment of type 2 diabetes mellitus (DM2), further comprising a low content of excipients.
Con la finalidad de desarrollar una formulación que vehiculizara, Teneliglipt ina y sus sales farmacéuticamente aceptables y Metformina clorhidrato, se realizaron una serie de pre formulaciones y ensayos galénicos en los que se halló una importante dificultad técnica: la baja compresibilidad de la Metformina clorhidrato. A este inconveniente, se le sumó la disparidad en la dosis de ambos principios activos, ya que cada dosis unitaria comprende un rango entre 10 y 20 mg de Teneliglipt ina y un rango entre 500 y 2000 mg de Metformina clorhidrato. Además, como consecuencia de la elevada dosis de la Metformina clorhidrato, el comprimido obtenido resultó ser muy voluminoso . In order to develop a formulation that vehiculized, Teneliglipt ina and its pharmaceutically acceptable salts and Metformin hydrochloride, a series of pre-formulations and galenic tests were carried out in which an important technical difficulty was found: the low compressibility of Metformin hydrochloride. To this inconvenience, the disparity in the dose of both active ingredients was added, since each unit dose includes a range between 10 and 20 mg of inactive Teneliglipt and a range between 500 and 2000 mg of Metformin hydrochloride. In addition, as a result of the high dose of Metformin hydrochloride, the tablet obtained proved to be very bulky.
En el afán de encontrar una solución al problema planteado, inicialmente se trabajó con formulaciones conteniendo excipientes convencionales utilizados habitualmente en galénica y en cantidades variables, a saber de, celulosa microcristalina, almidón pregelatinizado, como diluyentes, croscarmelosa sódica como desintegrante, povidona como aglutinante y Estearato de Magnesio como lubricante. Los principios activos y excipientes se calibraron por malla 18 (1 mm según Estándares de los Estados Unidos), se mezclaron y granularon la mezcla de excipientes y
principios activos, con una solución alcohólica de Povidona utilizando una rotoglanuladora . Este granulado fue calibrado, secado y vuelto a calibrar. Al momento de comprimirlo con una comprimidora rotativa, el granulado presentaba grandes inconvenientes de compresibilidad. Por lo tanto, los comprimidos obtenidos eran altamente friables, tomaban muy baja dureza trabajando con elevada fuerza de compresión, y además decapaban (se abrían en láminas) . Como primer paso, se estudió minuciosamente las características físicas de la Metformina clorhidrato, observando que habitualmente era polvo cristalino acicular, que tendía a formar terrones y a compactarse en el recipiente contenedor. Luego de analizar el inconveniente, se realizaron ensayos, disminuyendo la granulometría de la Metformina clorhidrato mediante su calibrado en molino tipo Fitz Mili, variando las mallas y las velocidades. Si bien mejoró la compresibilidad, la dureza obtenida no era óptima y el proceso distaba de ser reproducible . In an effort to find a solution to the problem posed, we initially worked with formulations containing conventional excipients commonly used in galenic and in variable amounts, namely, microcrystalline cellulose, pregelatinized starch, as diluents, croscarmellose sodium as a disintegrant, povidone as a binder and Magnesium Stearate as a lubricant. The active ingredients and excipients were calibrated by 18 mesh (1 mm according to United States Standards), the mixture of excipients was mixed and granulated and active ingredients, with an alcoholic solution of Povidone using a rotoglanuladora. This granulate was calibrated, dried and re-calibrated. At the time of compressing it with a rotary compressor, the granulate presented great compressibility problems. Therefore, the obtained tablets were highly friable, took very low hardness working with high compression force, and also pickled (they opened in sheets). As a first step, the physical characteristics of Metformin hydrochloride were studied thoroughly, observing that it was usually acicular crystalline powder, which tended to form lumps and compact into the container container. After analyzing the problem, tests were carried out, reducing the granulometry of Metformin hydrochloride by calibrating it in the Fitz Mili mill, varying the meshes and speeds. Although the compressibility improved, the hardness obtained was not optimal and the process was far from reproducible.
A continuación se optó por quitar los excipientes de la composición, con excepción de la solución aglutinante, y calibrar la Metformina clorhidrato, y Teneligliptina por malla de 0,5 mm (20 pulgadas) mediante la utilización de un molino Fitz Mili, con los martillos adelante y a máxima velocidad (4.800 r.p.m.) . Esta molienda, previo mezclado, se granuló mediante el uso de una rotogranuladora, estableciendo el mixer a 125 r.p.m., con el chopper detenido, en vacío, durante 2 minutos y posteriormente, se realizaron dos etapas de granulado/amasado, estableciendo el mixer a 125 r.p.m., el chopper a 700 rpm 100 %, en vacío durante 5 y 2 minutos respectivamente y con la adición de una alícuota de alcohol
en ambas etapas. Luego se calibró el granulado por una malla de 2 mm, y posteriormente, se secó mediante el uso de lecho fluido hasta obtener una humedad residual entre 1,5 y 2 %, tomada a 105 2C. A continuación el granulado seco, se calibró mediante una malla de 1 mm, y previa adición de una pequeña alícuota de Estearato de Magnesio, se mezcló durante 2 minutos a 12 r.p.m. Posteriormente se comprimió con una comprimidora rotativa, obteniéndose comprimidos de muy buena dureza, (alrededor de 20 kp) , con brillo, de baja friabilidad (menos del 1 % P/P) , sin presencia de decape ni laminado trabajando con fuerza de compresión estándar. Asimismo, el tiempo de desintegración fue menor a 15 minutos. Los comprimidos obtenidos cumplieron perfectamente el ensayo de uniformidad de contenido de ambos principios activos. Next, it was decided to remove the excipients from the composition, with the exception of the binder solution, and calibrate the Metformin hydrochloride, and Teneligliptin by mesh of 0.5 mm (20 inches) by using a Fitz Mili mill, with the hammers forward and at maximum speed (4,800 rpm). This grinding, after mixing, was granulated by using a rotogranulator, setting the mixer at 125 rpm, with the chopper stopped, in vacuum, for 2 minutes and subsequently, two granulating / kneading stages were performed, setting the mixer at 125 rpm, the chopper at 700 rpm 100%, in vacuum for 5 and 2 minutes respectively and with the addition of an aliquot of alcohol in both stages. The granulate was then calibrated by a 2 mm mesh, and subsequently, dried by using a fluid bed until a residual humidity between 1.5 and 2% was obtained, taken at 105 2 C. Then the dry granulate was calibrated. using a 1 mm mesh, and after adding a small aliquot of Magnesium Stearate, it was mixed for 2 minutes at 12 rpm. It was subsequently compressed with a rotary compressor, obtaining very good hardness tablets (around 20 kp), with brightness, low friability (less than 1% P / P), without presence of decape or laminate working with standard compression force. Also, the disintegration time was less than 15 minutes. The tablets obtained perfectly complied with the content uniformity test of both active ingredients.
Inesperadamente, se halló que utilizando un solo excipiente, en este caso el aglutinante Povidona, disuelto en alcohol etílico, y granulando la mezcla de principios activos con dicha solución, previa molienda de la Metformina a polvo fino, (granulometría menor de 300 micrones) el inconveniente técnico fue salvado, mejoró la uniformidad de contenido de la Teneligliptina y disminuyó el tamaño del comprimido. Unexpectedly, it was found that using a single excipient, in this case the Povidone binder, dissolved in ethyl alcohol, and granulating the mixture of active ingredients with said solution, after grinding the Metformin to fine powder, (granulometry less than 300 microns) the Technical inconvenience was saved, the content uniformity of Teneligliptin improved and the tablet size decreased.
Por medio de este proceso, se logró aumentar la fuerza de cohesión entre las partículas y por la tanto disminuir la tensión superficial entre las mismas y como consecuencia aumentar notablemente la compresibilidad del granulado. Como consecuencia, se obtuvieron mayores durezas a menores fuerzas de compresión. Through this process, it was possible to increase the cohesion force between the particles and therefore decrease the surface tension between them and as a consequence significantly increase the compressibility of the granulate. As a result, higher hardness was obtained at lower compression forces.
Es importante destacar que la metodología habitual cuando se desarrolla una formulación en forma de comprimido
para vehiculizar uno o más principios activos, es utilizar uno o más diluyentes, un aglutinante, un desintegrante, un lubricante, y es esperado que a medida que aumentamos la cantidad de excipientes, mejore la compresibilidad. En el caso objeto de esta patente, ocurrió lo contrario, disminuyó la compresibilidad, por eso es que afirmamos que fue un hecho inesperado . Importantly, the usual methodology when developing a tablet formulation To vehicle one or more active ingredients, it is to use one or more diluents, a binder, a disintegrant, a lubricant, and it is expected that as we increase the amount of excipients, compressibility improves. In the case object of this patent, the opposite happened, the compressibility decreased, that is why we affirm that it was an unexpected event.
Finalmente, luego de evaluar los resultados se optó por procesar la composición por granulación húmeda, previa molienda de la Metformina a polvo fino según las condiciones mencionadas previamente, y utilizando bajo contenido de excipientes. La granulometria de la Metformina molida a polvo fino es de no más de 300 micrones. Finally, after evaluating the results, it was decided to process the composition by wet granulation, after grinding the Metformin to fine powder according to the previously mentioned conditions, and using low excipient content. The granulometry of finely ground ground Metformin is no more than 300 microns.
Por lo tanto en un aspecto, la invención se refiere a una composición farmacéutica mejorada de administración oral, bajo la forma de comprimido recubierto, para el tratamiento de DM2, que comprende la combinación de una cantidad terapéuticamente efectiva del antidiabético Teneliglipt ina o sus sales farmacéuticamente aceptables, con una cantidad terapéuticamente efectiva del antidiabético Metformina clorhidrato, con bajo contenido de excipientes farmacéuticamente aceptables. La invención se refiere también a las dosis terapéuticamente efectivas de Teneliglipt ina o sus sales farmacéuticamente aceptables, las que pueden estar comprendidas en el rango de 10 mg a 20 mg y a las dosis terapéuticamente efectivas de Metformina clorhidrato, las que pueden estar en el rango de 500 a 2000 mg. Therefore, in one aspect, the invention relates to an improved pharmaceutical composition for oral administration, in the form of a coated tablet, for the treatment of DM2, which comprises the combination of a therapeutically effective amount of the antidiabetic Teneliglipt ina or its pharmaceutically salts. acceptable, with a therapeutically effective amount of the antidiabetic Metformin hydrochloride, with a low content of pharmaceutically acceptable excipients. The invention also relates to the therapeutically effective doses of Teneliglipt ina or its pharmaceutically acceptable salts, which may be in the range of 10 mg to 20 mg and the therapeutically effective doses of Metformin hydrochloride, which may be in the range of 500 to 2000 mg
En otro aspecto, la invención se refiere a los procesos para obtener una composición farmacéutica mejorada de
administración oral, bajo la forma de comprimido recubierto, para el tratamiento de DM2, que comprende moler Metformina, mezclar, granular, mezclar nuevamente y comprimir cantidades terapéuticamente efectivas de los principios activos Teneliglipt ina o sus sales farmacéuticamente aceptables y Metformina clorhidrato junto a bajo contenido de excipientes farmacéuticamente aceptables y recubrir, los comprimidos obtenidos . En una de las variantes de la invención, se incorpora laIn another aspect, the invention relates to processes for obtaining an improved pharmaceutical composition of oral administration, in the form of a coated tablet, for the treatment of DM2, which comprises grinding Metformin, mixing, granulating, mixing again and compressing therapeutically effective amounts of the active ingredients Teneliglipt ina or its pharmaceutically acceptable salts and Metformin hydrochloride together with low content of pharmaceutically acceptable excipients and coating, the tablets obtained. In one of the variants of the invention, the
Teneliglipt ina mezclada con Metformina. En otra variante, la incluye disuelta en la solución aglutinante, y por último, en otra variante, incorpora la Teneligliptina a partir de la suspensión del recubrimiento. Teneliglipt ina mixed with Metformin. In another variant, it includes dissolved in the binder solution, and finally, in another variant, incorporates Teneligliptin from the suspension of the coating.
En los Ejemplos 1, 2, 3, 4, 5, 6, 7, 8 y 9 se describen los procesos en detalle. The processes are described in detail in Examples 1, 2, 3, 4, 5, 6, 7, 8 and 9.
EJEMPLOS DE REALIZACION EXAMPLES OF REALIZATION
EJEMPLO 1 EXAMPLE 1
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 12 horas, comprendiendo Teneligliptina o sus sales farmacéuticamente aceptables 10 mg y Metformina clorhidrato 500 mg . Si bien la fórmula descripta a continuación es por unidad de dosis, el lote industrial es por 100 kg, y se amasó en una rotogranuladora Zanchetta de 300 Litros de capacidad.
NUCLEO mg por comprimido % en el The process for preparing a formulation of coated tablets for administration every 12 hours, comprising Teneligliptin or its pharmaceutically acceptable salts 10 mg and Metformin hydrochloride 500 mg, is described. Although the formula described below is per unit dose, the industrial lot is per 100 kg, and it was kneaded in a Zanchetta rotogranulator with a capacity of 300 liters. NUCLEO mg per tablet% in
recubierto núcleo core coated
Teneligliptina Bromhidrato 15, 50 2, 83 Teneligliptin Hydrochloride 15, 50 2, 83
(1) (one)
Metformina Clorhidrato 500,00 91,24 Metformin Hydrochloride 500.00 91.24
Povidona K30 29, 80 5, 43 Povidona K30 29, 80 5, 43
Estearato de Magnesio 2,70 0,49 Magnesium Stearate 2.70 0.49
Alcohol etílico (solvente c . s . Ethyl alcohol (solvent c. S.
que se evapora) that evaporates)
RECUBRIMIENTO mg % en el COATING mg% in the
comprimido recubierto coated tablet
Hipromelosa 9, 40 1, 67 Hypromellose 9, 40 1, 67
Dióxido de titanio 4,50 0,80 Titanium Dioxide 4.50 0.80
Triacet ina 1,40 0,25 Triacet ina 1.40 0.25
Óxido de hierro amarillo 0,70 0, 12 Yellow Iron Oxide 0.70 0.12
Agua de osmosis inversa 159 Reverse Osmosis Water 159
Peso del núcleo: 548 mg Core Weight: 548 mg
Peso del comprimido recubierto: 564 mg Weight of the coated tablet: 564 mg
1) Equivale a 10 mg de Teneligliptina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato. 1) Equivalent to 10 mg of Teneligliptin, another salt can be used, as is the case with Teneligliptin Besilate.
c.s.: Cantidad suficiente
MÉTODO DE ELABORACIÓN cs: Enough quantity ELABORATION METHOD
I. Disolver la Povidona K30 en el alcohol etílico. I. Dissolve Povidone K30 in ethyl alcohol.
2. Moler Metformina clorhidrato por Fitz Mili con malla 0.020 (0, 5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora. 2. Grind Metformin hydrochloride by Fitz Mili with 0.020 (0.5 mm) mesh hammers forward, at 4800 rpm and transfer to the mixer.
3. Tamizar Teneligliptina, por Fitz Mili, por malla de 1 mm . 3. Sift Teneligliptina, by Fitz Mili, by 1 mm mesh.
4. Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 1. Amasar 5 minutos . 4. Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 1. Knead 5 minutes.
5. Agregar una alícuota de alcohol etílico de 12 litros y amasar 2 minutos más o hasta obtener el punto de granulación . 5. Add an aliquot of ethyl alcohol of 12 liters and knead 2 more minutes or until the point of granulation is obtained.
6. Calibrar el granulado por una malla de 2 mm. 6. Calibrate the granulate by a 2 mm mesh.
7. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad. 7. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
8. Calibrar el granulado seco por una malla de 1,5 mm. 8. Calibrate the dry granulate by a 1.5 mm mesh.
9. Mezclar el granulado calibrado con el Estearato de Magnesio previamente tamizado por malla de 0,25 mm.9. Mix the calibrated granulate with the Magnesium Stearate previously sieved by 0.25 mm mesh.
10. Comprimir a 548 mg ± 5% mg de peso teórico. 10. Compress at 548 mg ± 5% mg of theoretical weight.
II. Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio en el agua y adicionando posteriormente hidroxipropilmetilcelulosa y la triacetina. II. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in the water and subsequently adding hydroxypropylmethylcellulose and triacetin.
12. Recubrir los comprimidos hasta obtener un peso teórico de alrededor de 564 mg ± 5%. 12. Coat the tablets until a theoretical weight of about 564 mg ± 5% is obtained.
EJEMPLO 2 EXAMPLE 2
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 12 horas,
comprendiendo Teneliglipt ina 10 o sus sales farmacéuticamente aceptables mg y Metformina clorhidrato 1000 mg . The process for preparing a formulation of coated tablets for administration every 12 hours is described, Teneliglipt ina 10 or its pharmaceutically acceptable salts mg and Metformin hydrochloride 1000 mg.
Si bien la fórmula descripta a continuación es por unidad de dosis, el lote industrial es por 200 kg, se amasó en dos alícuotas de 100 kg cada una, en una rot ogranuladora Zanchetta de 300 Litros de capacidad. Although the formula described below is per unit dose, the industrial lot is per 200 kg, it was kneaded in two aliquots of 100 kg each, in a Zanchetta rotator with a capacity of 300 liters.
NUCLEO mg por comprimido % en el NUCLEO mg per tablet% in
recubierto núcleo core coated
Teneligliptina Bromhidrato 15, 50 1, 44 Teneligliptin Hydrochloride 15, 50 1, 44
(1) (one)
Metformina Clorhidrato 1000,00 92, 60 Metformin Hydrochloride 1000.00 92, 60
Povidona K30 59, 00 5,46 Povidone K30 59.00 5.46
Estearato de Magnesio 5,50 0, 51 Magnesium Stearate 5.50 0.51
Alcohol etílico (solvente c . s . Ethyl alcohol (solvent c. S.
que se evapora) that evaporates)
RECUBRIMIENTO mg % en el COATING mg% in the
comprimido recubierto coated tablet
Hipromelosa 18, 80 1, 69 Hypromellose 18, 80 1, 69
Dióxido de titanio 9, 00 0,81 Titanium dioxide 9.00 0.81
Triacet ina 2,80 0,25 Triacet ina 2.80 0.25
Óxido de hierro amarillo 1,40 0, 13 Yellow Iron Oxide 1.40 0.13
Agua de osmosis inversa 318
Peso del núcleo: 1080 mg Reverse osmosis water 318 Core Weight: 1080 mg
Peso del comprimido recubierto: 1112 mg Weight of the coated tablet: 1112 mg
1) Equivale a 10 mg de Teneligliptina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato. 1) Equivalent to 10 mg of Teneligliptin, another salt can be used, as is the case with Teneligliptin Besilate.
c.s.: Cantidad suficiente c.s .: sufficient quantity
METODO DE ELABORACION ELABORATION METHOD
1. Disolver la Povidona K30 en el alcohol etílico. 1. Dissolve Povidone K30 in ethyl alcohol.
2. Moler Metformina clorhidrato por Fitz Mili con malla. 2. Grind Metformin Hydrochloride by Fitz Mili with mesh.
0.020 (0,5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora. 0.020 (0.5 mm) hammers forward, at 4800 rpm and transfer to the mixer.
3. Tamizar Teneligliptina, por Fitz Mili, por malla de 3. Sift Teneligliptina, by Fitz Mili, by mesh
1 mm . 1 mm
4. Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 1. Amasar 5 minutos . 4. Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 1. Knead 5 minutes.
5. Agregar un alícuota de alcohol etílico de 24 litros y amasar 2 minutos más o hasta obtener el punto de granulación . 5. Add an aliquot of ethyl alcohol of 24 liters and knead 2 more minutes or until the point of granulation is obtained.
6. Calibrar el granulado por una malla de 2 mm. 6. Calibrate the granulate by a 2 mm mesh.
7. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad. 7. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
8. Calibrar el granulado seco por una malla de 1,5 mm. 8. Calibrate the dry granulate by a 1.5 mm mesh.
9. Mezclar el granulado calibrado con el estearato de Magnesio previamente tamizado por malla de 0,25 mm.9. Mix the calibrated granulate with the magnesium stearate previously sieved by 0.25 mm mesh.
10. Comprimir a 1080 mg ± 5% mg de peso teórico. 10. Compress at 1080 mg ± 5% mg of theoretical weight.
11. Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio
en el agua y adicionando posteriormente hidroxipropilmet ilcelulosa y la triacetina. 11. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in the water and subsequently adding hydroxypropylmethylcellulose and triacetin.
12. Recubrir los comprimidos hasta obtener un peso promedio de 1112 mg ± 5%. 12. Coat the tablets until an average weight of 1112 mg ± 5% is obtained.
EJEMPLO 3 EXAMPLE 3
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 12 horas, comprendiendo Teneliglipt ina 10 mg o sus sales farmacéuticamente aceptables o sus sales farmacéuticamente aceptables y Metformina clorhidrato 850 mg . The process for preparing a formulation of coated tablets for administration every 12 hours is described, comprising Teneliglipt ina 10 mg or its pharmaceutically acceptable salts or pharmaceutically acceptable salts and Metformin hydrochloride 850 mg.
Si bien la fórmula descripta a continuación es por comprimido recubierto, el lote industrial es por 200 kg, se amasó en dos alícuotas de 100 kg cada una, en una rotogranuladora Zanchetta de 300 Litros de capacidad. Although the formula described below is per coated tablet, the industrial batch is for 200 kg, it was kneaded in two aliquots of 100 kg each, in a Zanchetta rotogranuladora of 300 liters of capacity.
NUCLEO mg por comprimido % NUCLEO mg per tablet%
recubierto covered
Teneligliptina Bromhidrato 15, 50 1, 68 Teneligliptin Hydrochloride 15, 50 1, 68
(1) (one)
Metformina Clorhidrato 850,00 92, 29 Metformin Hydrochloride 850.00 92, 29
Povidona K30 50, 00 5, 43 Povidona K30 50, 00 5, 43
Estearato de Magnesio 5,50 0, 60 Magnesium Stearate 5.50 0.60
Alcohol etílico (solvente c . s . Ethyl alcohol (solvent c. S.
que se evapora)
RECUBRIMIENTO mg % that evaporates) COATING mg%
Hipromelosa 16, 45 1, 90 Hypromellose 16, 45 1, 90
Dióxido de titanio 7, 90 7,80 Titanium dioxide 7, 90 7.80
Triacet ina 2,45 2,36 Triacet ina 2.45 2.36
Óxido de hierro amarillo 1,20 1, 18 Yellow Iron Oxide 1,20 1, 18
Agua de osmosis inversa 278 Reverse osmosis water 278
Peso del núcleo: 921 mg Core Weight: 921 mg
Peso del comprimido recubierto: 949 mg Weight of the coated tablet: 949 mg
1) Equivale a 10 mg de Teneliglipt ina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato. 1) Equivalent to 10 mg of Teneliglipt ina, another salt can be used, as is the case with Teneligliptin Besilate.
c.s.: Cantidad suficiente c.s .: sufficient quantity
MÉTODO DE ELABORACIÓN ELABORATION METHOD
1. Disolver la Povidona K30 en el alcohol etílico. 1. Dissolve Povidone K30 in ethyl alcohol.
2. Moler Metformina clorhidrato por Fitz Mili con malla 2. Grind Metformin Hydrochloride by Fitz Mili with Mesh
0.020 (0, 5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora. 0.020 (0.5 mm) hammers forward, at 4800 rpm and transfer to the mixer.
3. Tamizar Teneligliptina, por Fitz Mili, por malla de 1 mm . 3. Sift Teneligliptina, by Fitz Mili, by 1 mm mesh.
4. Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 1. Amasar 5 minutos . 4. Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 1. Knead 5 minutes.
5. Agregar un alícuota de alcohol etílico de 24 litros y amasar 2 minutos más o hasta obtener el punto de granulación .
6. Calibrar el granulado por una malla de 2 mm. 5. Add an aliquot of ethyl alcohol of 24 liters and knead 2 more minutes or until the point of granulation is obtained. 6. Calibrate the granulate by a 2 mm mesh.
7. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad. 7. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
8. Calibrar el granulado seco por una malla de 1,5 mm. 8. Calibrate the dry granulate by a 1.5 mm mesh.
9. Mezclar el granulado calibrado con el estearato de Magnesio previamente tamizado por malla de 0,25 mm.9. Mix the calibrated granulate with the magnesium stearate previously sieved by 0.25 mm mesh.
10. Comprimir a 921 mg ± 5% mg de peso teórico. 10. Compress at 921 mg ± 5% mg of theoretical weight.
11. Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio en el agua y adicionando posteriormente hidroxipropilmet ilcelulosa y la triacetina. 11. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in water and subsequently adding hydroxypropylmethylcellulose and triacetin.
12. Recubrir los comprimidos hasta obtener un peso promedio de 949 mg ± 5%. 12. Coat the tablets until an average weight of 949 mg ± 5% is obtained.
EJEMPLO 4 EXAMPLE 4
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 24 horas, comprendiendo Teneligliptina 20 mg sus sales farmacéuticamente aceptables y Metformina clorhidrato 850 mg . The process for preparing a formulation of coated tablets for administration every 24 hours is described, Teneligliptin 20 mg comprising its pharmaceutically acceptable salts and Metformin hydrochloride 850 mg.
Si bien la fórmula descripta a continuación, es por unidad de dosificación, el lote industrial es por 200 kg, y se amasó en dos alícuotas de 100 kg cada una, en una rotogranuladora Zanchetta de 300 Litros de capacidad. Although the formula described below, is per unit of dosage, the industrial lot is for 200 kg, and was mixed in two aliquots of 100 kg each, in a Zanchetta rotogranuladora of 300 liters of capacity.
NUCLEO mg por comprimido % NUCLEO mg per tablet%
recubierto covered
Teneligliptina Bromhidrato 31, 00 3, 31 Teneligliptin Hydrochloride 31, 00 3, 31
(1)
Metformina Clorhidrato 850,00 90, 80 (one) Metformin Hydrochloride 850.00 90, 80
Povidona K30 50, 00 5, 34 Povidona K30 50, 00 5, 34
Estearato de Magnesio 5,00 0,053 Magnesium Stearate 5.00 0.053
Alcohol etílico (solvente c . s . Ethyl alcohol (solvent c. S.
que se evapora) that evaporates)
RECUBRIMIENTO mg % COATING mg%
Hipromelosa 16, 45 1,70 Hypromellose 16, 45 1.70
Dióxido de titanio 7, 90 0,82 Titanium dioxide 7, 90 0.82
Triacet ina 2,45 0,25 Triacet ina 2.45 0.25
Óxido de hierro amarillo 1,23 0, 12 Yellow Iron Oxide 1.23 0.12
Agua de osmosis inversa 278 Reverse osmosis water 278
Peso del núcleo: 936 mg Core Weight: 936 mg
Peso del comprimido recubierto: 964 mg Weight of the coated tablet: 964 mg
1) Equivale a 20 mg de Teneliglipt ina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato. 1) Equivalent to 20 mg of Teneliglipt ina, another salt can be used, as is the case with Teneligliptin Besilate.
c.s.: Cantidad suficiente c.s .: sufficient quantity
MÉTODO DE ELABORACIÓN ELABORATION METHOD
1. Disolver la Povidona K30 en el alcohol etílico. 1. Dissolve Povidone K30 in ethyl alcohol.
2. Moler Metformina clorhidrato por Fitz Mili con malla 0.020 (0, 5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora.
3. Tamizar Teneliglipt ina, por Fitz Mili, por malla de 1 mm . 2. Grind Metformin hydrochloride by Fitz Mili with 0.020 (0.5 mm) mesh hammers forward, at 4800 rpm and transfer to the mixer. 3. Sift Teneliglipt ina, by Fitz Mili, by 1 mm mesh.
4. Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 1. Amasar 5 minutos . 4. Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 1. Knead 5 minutes.
5. Agregar un alícuota de alcohol etílico de 24 litros y amasar 2 minutos más o hasta obtener el punto de granulación . 5. Add an aliquot of ethyl alcohol of 24 liters and knead 2 more minutes or until the point of granulation is obtained.
6. Calibrar el granulado por una malla de 2 mm. 6. Calibrate the granulate by a 2 mm mesh.
7. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad. 7. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
8. Calibrar el granulado seco por una malla de 1,5 mm. 8. Calibrate the dry granulate by a 1.5 mm mesh.
9. Mezclar el granulado calibrado con el Estearato de Magnesio previamente tamizado por malla de 0,25 mm.9. Mix the calibrated granulate with the Magnesium Stearate previously sieved by 0.25 mm mesh.
10. Comprimir a 936 mg ± 5% mg de peso teórico. 10. Compress at 936 mg ± 5% mg of theoretical weight.
11. Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio en el agua y adicionando posteriormente hidroxipropilmetilcelulosa y la triacetina. 11. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in the water and subsequently adding hydroxypropyl methylcellulose and triacetin.
12. Recubrir los comprimidos hasta obtener un peso promedio 964 mg ± 5%. 12. Coat the tablets until an average weight of 964 mg ± 5% is obtained.
EJEMPLO 5 EXAMPLE 5
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 12 horas, comprendiendo 10 mg de Teneliglipt ina sus sales farmacéuticamente aceptables y 500 mg de Metformina, en la cual, la Metformina clorhidrato se comprimirá y la Teneligliptina será aplicada junto con el recubrimiento. La fórmula descripta a continuación es por unidad de
dosificación, el lote industrial es por 100 kg, y se amasó en una rotogranuladora Zanchetta de 300 Litros de capacidad. The process for preparing a formulation of coated tablets for administration every 12 hours is described, comprising 10 mg of Teneliglipt ina its pharmaceutically acceptable salts and 500 mg of Metformin, in which, Metformin hydrochloride will be compressed and Teneligliptin will be applied together with the covering. The formula described below is per unit of Dosing, the industrial batch is per 100 kg, and it was kneaded in a Zanchetta rotogranuladora of 300 Liters of capacity.
Peso del núcleo: 548 mg Core Weight: 548 mg
Peso del comprimido recubierto: 564 mg Weight of the coated tablet: 564 mg
1) Equivale a 10 mg de Teneligliptina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato.
c.s.: Cantidad suficiente 1) Equivalent to 10 mg of Teneligliptin, another salt can be used, as is the case with Teneligliptin Besilate. cs: Enough quantity
MÉTODO DE ELABORACIÓN . Disolver la Povidona K30 en el alcohol etílico.METHOD OF ELABORATION. Dissolve Povidone K30 in ethyl alcohol.
. Moler Metformina clorhidrato por Fitz Mili con malla 0.020 (0, 5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora.. Grind Metformin Hydrochloride by Fitz Mili with 0.020 (0.5 mm) mesh hammers forward, at 4800 rpm and transfer to the kneader.
. Tamizar Teneligliptina, por Fitz Mili, por con malla de 1 mm.. Sieve Teneligliptina, by Fitz Mili, with 1 mm mesh.
. Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 1. Amasar 5 minutos .. Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 1. Knead 5 minutes.
. Agregar un alícuota de alcohol etílico de 12 litros y amasar 2 minutos más o hasta obtener el punto de granulación .. Add an aliquot of ethyl alcohol of 12 liters and knead 2 more minutes or until the point of granulation is obtained.
. Calibrar el granulado por una malla de 2 mm. . Calibrate the granulate by a 2 mm mesh.
. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad.. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
. Calibrar el granulado seco por una malla de 1,5 mm.. Mezclar el granulado calibrado con el estearato de Magnesio previamente tamizado por malla de 0,25 mm.0. Comprimir a 548 mg ± 5% mg de peso teórico.. Calibrate the dry granulate by a 1.5 mm mesh. Mix the calibrated granulate with the magnesium stearate previously sieved by 0.25 mm mesh. Compress at 548 mg ± 5% mg of theoretical weight.
1. Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio en el 80 % del agua y adicionar posteriormente hidroxipropilmetilcelulosa y la triacetina.1. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in 80% of the water and then add hydroxypropyl methylcellulose and triacetin.
2. Dividir la suspensión anterior en tres alícuotas.2. Divide the previous suspension into three aliquots.
3. Disolver la Teneligliptina Bromhidrato en el 20 % del agua restante del punto 11 y adicionar a una de las
alícuotas de la suspensión de recubrimiento, mezclar hasta uniformidad. 3. Dissolve Teneligliptin Hydrochloride in 20% of the water remaining in point 11 and add to one of the Aliquots of the coating suspension, mix until uniform.
14. Recubrir los comprimidos con una alícuota de suspensión de recubrimiento hasta obtener un peso teórico de alrededor de 553 mg ± 5%. 14. Coat the tablets with an aliquot of coating suspension until a theoretical weight of about 553 mg ± 5% is obtained.
15. A continuación recubrir con la alícuota de recubrimiento que contiene la Teneliglipt ina . 15. Then coat with the coating aliquot that contains the ina Teneliglipt.
16. Y finalmente, recubrir con la alícuota restante de recubrimiento hasta obtener un peso promedio de 564 mg ± 5 %. 16. And finally, coat with the remaining coating aliquot until an average weight of 564 mg ± 5% is obtained.
EJEMPLO 6 EXAMPLE 6
La metodología descripta en el ejemplo 5 es aplicable para las dosis de 10 mg de Teneliglipt ina sus sales farmacéuticamente aceptables, combinada con 850 mg de Metformina, 10 mg de Teneliglipt ina combinada con 1000 mg de Metformina clorhidrato (para administrar cada 12 hr . ) , y 20 mg de Teneliglipt ina combinada con 850 mg de Metformina clorhidrato (para administrar cada 24 hr) . The methodology described in Example 5 is applicable for doses of 10 mg of Teneliglipt ina its pharmaceutically acceptable salts, combined with 850 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride (to be administered every 12 hr.) , and 20 mg of Teneliglipt ina combined with 850 mg of Metformin hydrochloride (to be administered every 24 hr).
EJEMPLO 7 EXAMPLE 7
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 24 horas, comprendiendo Teneligliptina 20 mg sus sales farmacéuticamente aceptables adicionada junto con la solución aglutinante y 850 mg de Metformina granulada de forma similar a los procesos descriptos en los ejemplos previos. The process for preparing a formulation of coated tablets for administration every 24 hours is described, Teneligliptin 20 mg comprising its pharmaceutically acceptable salts added together with the binder solution and 850 mg of granulated Metformin in a manner similar to the processes described in the previous examples.
Si bien la fórmula descripta a continuación, es por unidad de dosificación, el lote industrial es por 200 kg, se
amasó en dos alícuotas de 100 kg cada una, Although the formula described below is per dosage unit, the industrial batch is 200 kg, Knead in two aliquots of 100 kg each,
rot ogranuladora Zanchetta de 300 Litros de capacidad. rotator Zanchetta 300 liter capacity.
Peso del núcleo: 936 mg Core Weight: 936 mg
Peso del comprimido recubierto: 948 mg Weight of the coated tablet: 948 mg
1) Equivale a 10 mg de Teneligliptina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato.
c.s.: Cantidad suficiente MÉTODO DE ELABORACIÓN . Tamizar Teneligliptina, por Fitz Mili, por malla de 1 mm y disolverla en el alcohol etílico.1) Equivalent to 10 mg of Teneligliptin, another salt can be used, as is the case with Teneligliptin Besilate. cs: Sufficient quantity METHOD OF ELABORATION. Sift Teneligliptina, by Fitz Mili, by 1 mm mesh and dissolve it in ethyl alcohol.
. Adicionar la Povidona K30 a la solución del paso uno.. Moler Metformina clorhidrato por Fitz Mili con malla. Add the Povidone K30 to the solution in step one .. Grind Metformin hydrochloride by Fitz Mili with mesh
0.020 (0,5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora.0.020 (0.5 mm) hammers forward, at 4800 rpm and transfer to the mixer.
. Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 2. Amasar 5 minutos .. Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 2. Knead 5 minutes.
. Agregar un alícuota de alcohol etílico de 24 litros y amasar 2 minutos más o hasta obtener el punto de granulación .. Add an aliquot of ethyl alcohol of 24 liters and knead 2 more minutes or until the point of granulation is obtained.
. Calibrar el granulado por una malla de 2 mm. . Calibrate the granulate by a 2 mm mesh.
. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad.. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
. Calibrar el granulado seco por una malla de 1,5 mm.. Mezclar el granulado calibrado con el estearato de Magnesio previamente tamizado por malla de 0,25 mm.0. Comprimir a 936 mg ± 5% mg de peso teórico.. Calibrate the dry granulate by a 1.5 mm mesh. Mix the calibrated granulate with the magnesium stearate previously sieved by 0.25 mm mesh. Compress at 936 mg ± 5% mg of theoretical weight.
1. Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio en el agua y adicionando posteriormente hidroxipropilmetilcelulosa y la triacetina.1. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in water and subsequently adding hydroxypropyl methylcellulose and triacetin.
2. Recubrir los comprimidos hasta obtener un peso promedio de 948 mg ± 5%.
EJEMPLO 8 2. Coat the tablets until an average weight of 948 mg ± 5% is obtained. EXAMPLE 8
La metodología aplicada en el Ejemplo 7, es aplicable para las dosis de 10 mg de Teneliglipt ina o sus sales farmacéuticamente aceptables combinada con 500 mg de Metformina, 10 mg de Teneliglipt ina combinada con 1000 mg de Metformina clorhidrato, y 10 mg de Teneligliptina combinada con 850 mg de Metformina clorhidrato. EJEMPLO 9 The methodology applied in Example 7, is applicable for the doses of 10 mg of Teneliglipt ina or its pharmaceutically acceptable salts combined with 500 mg of Metformin, 10 mg of Teneliglipt ina combined with 1000 mg of Metformin hydrochloride, and 10 mg of Teneligliptin combined with 850 mg of Metformin hydrochloride. EXAMPLE 9
Se describe el proceso para preparar una formulación de comprimidos recubiertos para administrar cada 24 horas, en la cual, la Metformina clorhidrato se procesará de tal forma de obtener un comprimido de liberación prolongada y la Teneligliptina sus sales farmacéuticamente aceptables será aplicada junto con el recubrimiento. La fórmula descripta a continuación es por unidad de dosificación, el lote industrial es por 100 kg, y se amasó en una rotogranuladora Zanchetta de 300 Litros de capacidad. The process for preparing a formulation of coated tablets for administration every 24 hours is described, in which, Metformin hydrochloride will be processed in such a way as to obtain a prolonged-release tablet and Teneligliptin its pharmaceutically acceptable salts will be applied together with the coating. The formula described below is per dosage unit, the industrial lot is per 100 kg, and it was kneaded in a Zanchetta rotogranulator with a capacity of 300 liters.
NUCLEO mg por c . r . mg por c . r . mg por c . r . NUCLEO mg per c. r. mg per c. r. mg per c. r.
20 mg de 20 mg de 20 mg de 20 mg of 20 mg of 20 mg of
Teneligliptina Teneligliptin TeneligliptTeneligliptina Teneligliptin Teneliglipt
+ 500 mg de a + 850 mg de ina + 1000+ 500 mg of a + 850 mg of ina + 1000
Metformina Metformina mg de clorhidrato clorhidrato Metformina clorhidrato Metformin Metformin Hydrochloride Hydrochloride Metformin Hydrochloride
Teneligliptina 31,00 31,00 31,00Teneligliptina 31.00 31.00 31.00
Bromhidrato (1)
Metformina 500,00 850,00 1.000, 00 Clorhidrato Hydrochloride (1) Metformin 500.00 850.00 1,000.00 Hydrochloride
Povidona K30 14, 70 25,00 29,40 Povidone K30 14, 70 25.00 29.40
Hidroxipropilme- 223,50 292 312 tilcelulosa Hydroxypropyl- 223.50 292 312 tilcellulose
K 100 M K 100 M
Estearato de 1,80 3,00 3, 60 Magnesio Stearate 1.80 3.00 3.60 Magnesium
Alcohol c . s . c . s . c . s . isopropilico Alcohol c. s. C . s. C . s. isopropyl
(solvente que (solvent that
se evapora) evaporates)
Agua purificada c . s . c . s . c . s . Purified water c. s. C . s. C . s.
RECUBRIMIENTO 15 mg 25 mg 28 mg COATING 15 mg 25 mg 28 mg
Alcohol 6,00 10, 00 11,20 Alcohol 6.00 10.00 11.20
Dióxido de titanio 3,75 6, 25 7,00 Titanium dioxide 3.75 6, 25 7.00
Poliet ilenglicol 3, 02 5,04 5, 64 3000 Polyethylene glycol 3, 02 5.04 5, 64 3000
Talco 2,22 3,71 4, 15 Talc 2.22 3.71 4.15
Agua de osmosis 102 170 190 inversa Osmosis water 102 170 190 reverse
Peso del núcleo 771 mg 1201 mg 1376 mg Core weight 771 mg 1201 mg 1376 mg
Peso del comprimido 786 mg 1226 mg 1404 mg recubierto
1) Equivale a 20 mg de Teneligliptina, puede utilizarse otra sal, como es el caso de Teneligliptina Besilato. Tablet weight 786 mg 1226 mg 1404 mg coated 1) Equivalent to 20 mg of Teneligliptin, another salt can be used, as is the case with Teneligliptin Besilate.
c.s.: Cantidad suficiente c.s .: sufficient quantity
c.r.: comprimido recubierto c.r .: coated tablet
MÉTODO DE ELABORACIÓN ELABORATION METHOD
Disolver la Povidona K30 en el alcohol etílico. Moler Metformina clorhidrato por Fitz Mili con malla 0.020 (0, 5 mm) martillos adelante, a 4800 rpm y transferir a la amasadora. Dissolve Povidone K30 in ethyl alcohol. Grind Metformin Hydrochloride by Fitz Mili with 0.020 (0.5 mm) mesh hammers forward, at 4800 rpm and transfer to the kneader.
Tamizar Teneligliptina, por Fitz Mili, por con malla de 1 mm. Sieve Teneligliptina, by Fitz Mili, with 1 mm mesh.
Mezclar con el mixer a 125 r.p.m. durante 2 minutos y adicionar la solución obtenida en el punto 1. Amasar 5 minutos . Mix with the mixer at 125 r.p.m. for 2 minutes and add the solution obtained in point 1. Knead 5 minutes.
Agregar un alícuota de alcohol etílico de 12 litros y amasar 2 minutos más o hasta obtener el punto de granulación . Add an aliquot of ethyl alcohol of 12 liters and knead 2 more minutes or until the point of granulation is obtained.
Calibrar el granulado por una malla de 2 mm. Secar el granulado calibrado en una secadora de lecho fluido, hasta obtener entre 1,5 y 2 % de humedad. Calibrate the granulate by a 2 mm mesh. Dry the calibrated granulate in a fluid bed dryer, until 1.5 to 2% moisture is obtained.
Calibrar el granulado seco por una malla de 1,5 mm. Mezclar el granulado calibrado con el estearato de Magnesio previamente tamizado por malla de 0,25 mm. Comprimir al peso teórico estipulado ± 5% mg . Preparar el recubrimiento suspendiendo perfectamente el óxido de hierro amarillo y el dióxido de titanio en el 80 % del agua y adicionar posteriormente hidroxipropilmetilcelulosa y la triacetina. Calibrate the dry granulate by a 1.5 mm mesh. Mix the calibrated granulate with the magnesium stearate previously sieved by 0.25 mm mesh. Compress to the theoretical weight stipulated ± 5% mg. Prepare the coating by perfectly suspending yellow iron oxide and titanium dioxide in 80% of the water and subsequently add hydroxypropyl methylcellulose and triacetin.
Dividir la suspensión anterior en tres alícuotas.
13. Disolver la Teneligliptina Bromhidrato en el 20 % del agua restante del punto 11 y adicionar a una de las alícuotas de la suspensión de recubrimiento, mezclar hasta uniformidad. Divide the previous suspension into three aliquots. 13. Dissolve the Teneligliptin Hydrochloride in 20% of the remaining water of point 11 and add to one of the aliquots of the coating suspension, mix until uniform.
14. Recubrir los comprimidos con una alícuota de suspensión de recubrimiento. A continuación recubrir con la alícuota de recubrimiento que contiene la Teneligliptina . 14. Coat the tablets with an aliquot of coating suspension. Then coat with the coating aliquot that contains Teneligliptin.
15. Finalmente recubrir con la alícuota restante de recubrimiento hasta obtener el peso promedio estipulado ± 5 %. 15. Finally, coat with the remaining coating aliquot until the stipulated average weight ± 5% is obtained.
DETERMINACIONES FARMACOTECNICAS Y PRÜEBAS IN VITRO IN VITRO PHARMACOTECHNICAL DETERMINATIONS AND TESTS
Se realizaron determinaciones farmacotécnicas y pruebas in vitro para evaluar los parámetros farmacotécnicos y analíticos comparando la composición mejorada conteniendo Teneligliptina y Metformina clorhidrato, obtenidas en los Ejemplos 1, 2, 3, 4, 5 ,7 y 9 con las composiciones de ambos principios activos consideradas por separado. Pharmaco-technical determinations and in vitro tests were performed to evaluate the pharmaco-technical and analytical parameters comparing the improved composition containing Teneligliptin and Metformin hydrochloride, obtained in Examples 1, 2, 3, 4, 5, 7 and 9 with the compositions of both active principles considered separately.
Determinaciones farmacotécnicas : metodología y equipos Pharmaco-technical determinations: methodology and equipment
Dureza: Equipo Schleuniger 2E, Erweka TBH-30 Hardness: Schleuniger 2E team, Erweka TBH-30
Friabilidad: Equipo Friabilómet ro tipo "ROCHE", según USP General Tests and Assays <1216> Friability: Friabilómet ro type "ROCHE" equipment, according to USP General Tests and Assays <1216>
Velocidad: 25 r.p.m. Speed: 25 r.p.m.
Tempo de ensayo: 4 minutos
Determinaciones analíticas : Rehearsal time: 4 minutes Analytical Determinations:
-Valoración Teneligliptina: por HPLC (Cromatografía líquida de alta performance) -Teneligliptin assessment: by HPLC (High performance liquid chromatography)
-Valoración Metformina clorhidrato: por HPLC (Cromatografía líquida de alta performance) -Valueration Metformin hydrochloride: by HPLC (High performance liquid chromatography)
-Test de disolución Teneligliptina: según USP General Test Assays <711> -Teneligliptin dissolution test: according to USP General Test Assays <711>
-Test de disolución Metformina según USP General Test Assays <711> - Metformin dissolution test according to USP General Test Assays <711>
-Uniformidad de contenido Teneligliptina: por HPLC (Cromatografía líquida de alta performance) -Teneligliptin content uniformity: by HPLC (High performance liquid chromatography)
Determinaciones y pruebas IN VITRO correspondientes al Ejemplo 1 IN VITRO determinations and tests corresponding to Example 1
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 10 mg y Metformina clorhidrato 500 mg, comparado con comprimidos recubiertos conteniendo 10 mg de Teneligliptina y comprimidos recubiertos conteniendo 500 mg de Metformina clorhidrato. Improved composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 500 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride.
Parámetros Ejemplo 1 Teneligliptina 10 mg Metformina Parameters Example 1 Teneligliptin 10 mg Metformin
Teneligliptina 10 mg comprimido recubierto clorhidrato 500 mg Metformina comprimido recubierto clorhidrato 500 mg Teneligliptin 10 mg hydrochloride coated tablet 500 mg Metformin hydrochloride coated tablet 500 mg
Comprimido Compressed
recubierto covered
Dureza Hardness
(valores promedio 15 kp 13 kp 12, 6 Kp (average values 15 kp 13 kp 12, 6 Kp
sobre 20 about 20
determinaciones ) determinations)
Friabilidad Friability
(valores promedio 0,1 % 0,1 % 0,2 % (average values 0.1% 0.1% 0.2%
sobre 20 about 20
determinaciones )
Valoración determinations) Assessment
Teneligliptina 9, 8 mg 10,1 mg Teneligliptin 9.8 mg 10.1 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 490 mg 493 mg clorhidrato Metformin 490 mg 493 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 101%-99%-100%-98%- 103-101-102-99-102- Teneligliptin 101% -99% -100% -98% - 103-101-102-99-102-
Q=75% 102%-99- 101- Promedio: 101,3% Q = 75% 102% -99- 101- Average: 101.3%
Valores Promedio: 99,8% Average Values: 99.8%
individuales Q+5% individual Q + 5%
Disolución 98%-99%-99%-101%- 100%-99%-99%-100%- Dissolution 98% -99% -99% -101% - 100% -99% -99% -100% -
Metformina 101%-100% 99%-100% clorhidrato Q=70% Promedio: 99,7% Promedio: 100%Metformin 101% -100% 99% -100% hydrochloride Q = 70% Average: 99.7% Average: 100%
Valores Values
individuales Q+5% individual Q + 5%
Determinaciones y pruebas IN VITRO correspondientes alIN VITRO determinations and tests corresponding to
Ejemplo 2 Example 2
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 10 mg y Metformina clorhidrato 1000 mg, comparado con comprimidos recubiertos conteniendo 10 mg de Teneligliptina y comprimidos recubiertos conteniendo 1000 mg de Metformina clorhidrato. Improved composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 1000 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 1000 mg of Metformin hydrochloride.
Parámetros Ejemplo 2 Teneligliptina 10 mg Metformina Parameters Example 2 Teneligliptin 10 mg Metformin
Teneligliptina 10 mg comprimido recubierto clorhidrato 1000 mg Metformina comprimido recubierto clorhidrato 1000 mg Teneligliptin 10 mg hydrochloride coated tablet 1000 mg Metformin hydrochloride coated tablet 1000 mg
Comprimido Compressed
recubierto covered
Dureza Hardness
(valores promedio 25 kp 13 kp 23 Kp (average values 25 kp 13 kp 23 Kp
sobre 20 about 20
determinaciones ) determinations)
Friabilidad Friability
(valores promedio 0,1 % 0,1 % 0,1 %
sobre 20 (average values 0.1% 0.1% 0.1% about 20
determinaciones ) determinations)
Valoración Assessment
Teneligliptina 9, 9 mg 10,1 mg Teneligliptin 9.9 mg 10.1 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 991 mg 995 mg clorhidrato Metformin 991 mg 995 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 99%-101%-100%-98%- 103-101-102-99-102-Teneligliptin 99% -101% -100% -98% - 103-101-102-99-102-
Q=75% 102%-98- 101- Promedio: 101,3% Q = 75% 102% -98- 101- Average: 101.3%
Valores Promedio: 99,7% Average Values: 99.7%
individuales Q+5% individual Q + 5%
Disolución 99%-98%-101%-101%- 100%-99%-99%-100%- Solution 99% -98% -101% -101% - 100% -99% -99% -100% -
Metformina 100%-97% 99%-100% Metformin 100% -97% 99% -100%
clorhidrato Q=70% Promedio: 99,3% Promedio: 100% hydrochloride Q = 70% Average: 99.3% Average: 100%
Valores Values
individuales Q+5% individual Q + 5%
Determinaciones y pruebas IN VITRO correspondientes alIN VITRO determinations and tests corresponding to
Ejemplo 3 Example 3
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 10 mg y Metformina clorhidrato 850 mg, comparado con comprimidos recubiertos conteniendo 10 mg de Teneligliptina y comprimidos recubiertos conteniendo 850 mg de Metformina clorhidrato. Improved composition in the form of a coated tablet comprising Teneligliptin 10 mg and Metformin hydrochloride 850 mg, compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride.
Parámetros Ejemplo 3 Teneligliptina 10 mg Metformina Parameters Example 3 Teneligliptin 10 mg Metformin
Teneligliptina 10 mg comprimido recubierto clorhidrato 850 mg Metformina comprimido recubierto clorhidrato 850 mg Teneligliptin 10 mg hydrochloride coated tablet 850 mg Metformin hydrochloride coated tablet 850 mg
Comprimido Compressed
recubierto covered
Dureza Hardness
(valores promedio 23 kp 13 kp 21 Kp (average values 23 kp 13 kp 21 Kp
sobre 20 about 20
determinaciones )
Friabilidad determinations) Friability
(valores promedio 0,1 % 0,1 % 0,2 % (average values 0.1% 0.1% 0.2%
sobre 20 about 20
determinaciones ) determinations)
Valoración Assessment
Teneligliptina 10,4 mg 10,1 mg Teneligliptin 10.4 mg 10.1 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 845 mg 840 mg clorhidrato Metformin 845 mg 840 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 99%-101%-99%-102%- 103-101-102-99-102- Teneligliptin 99% -101% -99% -102% - 103-101-102-99-102-
Q=75% 102%-99- 101- Promedio: 101,3% Q = 75% 102% -99- 101- Average: 101.3%
Valores Promedio: 100,3% Average Values: 100.3%
individuales Q+5% individual Q + 5%
Disolución 98%-97%-100%-102%- 98%-99%-98%-100%-97%- Dissolution 98% -97% -100% -102% - 98% -99% -98% -100% -97% -
Metformina 98%-101% 100% Promedio: clorhidrato Q=70% Promedio: 99,3% 98, 6% Metformin 98% -101% 100% Average: hydrochloride Q = 70% Average: 99.3% 98.6%
Valores Values
individuales Q+5% individual Q + 5%
Determinaciones y pruebas IN VITRO correspondientes alIN VITRO determinations and tests corresponding to
Ejemplo 4 Example 4
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 20 mg y Metformina clorhidrato 850 mg, comparado con comprimidos recubiertos conteniendo 20 mg de Teneligliptina y comprimidos recubiertos conteniendo 850 mg de Metformina clorhidrato. Improved composition in the form of a coated tablet comprising Teneligliptin 20 mg and Metformin hydrochloride 850 mg, compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride.
Parámetros Ejemplo 4 Teneligliptina 20 mg Metformina Parameters Example 4 Teneligliptin 20 mg Metformin
Teneligliptina 20 mg comprimido recubierto clorhidrato 850 mg Metformina comprimido recubierto clorhidrato 850 mg Teneligliptin 20 mg hydrochloride coated tablet 850 mg Metformin hydrochloride coated tablet 850 mg
Comprimido Compressed
recubierto covered
Dureza Hardness
(valores promedio 24 kp 14 kp 21 Kp
sobre 20 (average values 24 kp 14 kp 21 Kp about 20
determinaciones ) determinations)
Friabilidad Friability
(valores promedio 0,1 % 0,1 % 0,2 % (average values 0.1% 0.1% 0.2%
sobre 20 about 20
determinaciones ) determinations)
Valoración Assessment
Teneligliptina 20,2 mg 20,8 mg Teneligliptin 20.2 mg 20.8 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 839 mg 840 mg clorhidrato Metformin 839 mg 840 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 98%-99%-97%-99%-99%- 103-102-102-100-101- Teneligliptin 98% -99% -97% -99% -99% - 103-102-102-100-101-
Q=75% 100 100- Promedio: 101,3% Q = 75% 100 100- Average: 101.3%
Valores Promedio: 98,7% Average Values: 98.7%
individuales Q+5% individual Q + 5%
Disolución 98%-97%-99%-98%-98%- 98%-99%-98%-100%-97%- Dissolution 98% -97% -99% -98% -98% - 98% -99% -98% -100% -97% -
Metformina 97% 100% Promedio: clorhidrato Q=70% Promedio: 97,8% 98, 6% Metformin 97% 100% Average: hydrochloride Q = 70% Average: 97.8% 98, 6%
Valores Values
individuales Q+5% individual Q + 5%
Determinaciones y pruebas IN VITRO correspondientes alIN VITRO determinations and tests corresponding to
Ejemplo 5 Example 5
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 10 mg en el recubrimiento y Metformina clorhidrato 500 mg, en el núcleo comparado con comprimidos recubiertos conteniendo 10 mg de Teneligliptina y comprimidos recubiertos conteniendo 500 mg de Metformina clorhidrato . Improved composition in the form of a coated tablet comprising Teneligliptin 10 mg in the coating and Metformin hydrochloride 500 mg, in the core compared to coated tablets containing 10 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride.
Parámetros Ejemplo 1 Teneligliptina 10 mg Metformina Parameters Example 1 Teneligliptin 10 mg Metformin
Teneligliptina 10 mg comprimido recubierto clorhidrato 500 mg Teneligliptin 10 mg hydrochloride coated tablet 500 mg
Metformina comprimido recubierto clorhidrato 500 mg Metformin hydrochloride coated tablet 500 mg
Comprimido
recubierto Compressed covered
Valoración Assessment
Teneligliptina 9, 6 mg 10,1 mg Teneligliptin 9.6 mg 10.1 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 492 mg 493 mg clorhidrato Metformin 492 mg 493 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 98%-97-96%-97%-96%- 103-101-102-99-102- Teneligliptin 98% -97-96% -97% -96% - 103-101-102-99-102-
Q=75% 97- 101- Promedio: 101,3% Q = 75% 97- 101- Average: 101.3%
Valores Promedio: 96,8% Average Values: 96.8%
individuales Q+5% individual Q + 5%
Disolución 98%-97%-99%-99%- 100%-99%-99%-100%- Dissolution 98% -97% -99% -99% - 100% -99% -99% -100% -
Metformina 100%-97% 99%-100% clorhidrato Q=70% Promedio: 98,3% Promedio: 100%Metformin 100% -97% 99% -100% hydrochloride Q = 70% Average: 98.3% Average: 100%
Valores Values
individuales Q+5% individual Q + 5%
Determinaciones y pruebas IN VITRO correspondientes alIN VITRO determinations and tests corresponding to
Ejemplo 7 Example 7
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 20 mg adicionada disuelta en la solución aglutinante y Metformina clorhidrato 850 mg, granulada de forma similar a los ejemplos previos, comparado con comprimidos recubiertos conteniendo 20 mg de Teneligliptina y comprimidos recubiertos conteniendo 850 mg de Metformina clorhidrato. Improved composition in the form of a coated tablet comprising Teneligliptin 20 mg added dissolved in the binder solution and Metformin hydrochloride 850 mg, granulated in a similar manner to the previous examples, compared with coated tablets containing 20 mg of Teneligliptin and coated tablets containing 850 mg of Metformin hydrochloride .
Parámetros Ejemplo 7 Teneligliptina 20 mg Metformina Parameters Example 7 Teneligliptin 20 mg Metformin
Teneligliptina 20 mg comprimido recubierto clorhidrato 850 mg Metformina comprimido recubierto clorhidrato 850 mg Teneligliptin 20 mg hydrochloride coated tablet 850 mg Metformin hydrochloride coated tablet 850 mg
Comprimido
recubierto Compressed covered
Dureza Hardness
(valores promedio 25 kp 14 kp 21 Kp (average values 25 kp 14 kp 21 Kp
sobre 20 about 20
determinaciones ) determinations)
Friabilidad Friability
(valores promedio 0,2 % 0,1 % 0,2 % (average values 0.2% 0.1% 0.2%
sobre 20 about 20
determinaciones ) determinations)
Valoración Assessment
Teneligliptina 19, 9 mg 20,8 mg Teneligliptin 19.9 mg 20.8 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 848 mg 840 mg clorhidrato Metformin 848 mg 840 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 100%-99%-101%-98%- 103-102-102-100-101- Teneligliptin 100% -99% -101% -98% - 103-102-102-100-101-
Q=75% 99%-102 100- Promedio: 101,3% Q = 75% 99% -102 100- Average: 101.3%
Valores Promedio: 99,8% Average Values: 99.8%
individuales Q+5% individual Q + 5%
Disolución 99%-101%-102%-98%- 98%-99%-98%-100%-97%- Solution 99% -101% -102% -98% - 98% -99% -98% -100% -97% -
Metformina 97%-99% 100% Promedio: clorhidrato Q=70% Promedio: 99,3% 98, 6% Metformin 97% -99% 100% Average: hydrochloride Q = 70% Average: 99.3% 98.6%
Valores Values
individuales Q+5% individual Q + 5%
Determinaciones y pruebas IN VITRO correspondientes alIN VITRO determinations and tests corresponding to
Ejemplo 9 Example 9
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 20 mg en el recubrimiento y Metformina clorhidrato 500 mg, en el núcleo deliberación prolongada comparado con comprimidos recubiertos conteniendo 20 mg de Teneligliptina y comprimidos recubiertos conteniendo 500 mg de Metformina clorhidrato de liberación prolongada.
Parámetros Ejemplo 1 Teneligliptina 20 mg MetforminaImproved composition in the form of a coated tablet comprising Teneligliptin 20 mg in the coating and Metformin hydrochloride 500 mg, in the core prolonged deliberation compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 500 mg of Metformin hydrochloride extended release. Parameters Example 1 Teneligliptin 20 mg Metformin
Teneligliptina 20 mg de comprimido recubierto clorhidrato 500 mg liberación inmediata comprimido recubierto Metformina clorhidrato de liberación 500 mg de liberación prolongada prolongada Teneligliptin 20 mg hydrochloride coated tablet 500 mg immediate release Metformin coated tablet 500 mg prolonged extended release hydrochloride
Comprimido recubierto Coated tablet
Dureza Hardness
(valores 27 kp (values 27 kp
promedio sobre average over
20 twenty
determinaciones determinations
Friabilidad Friability
(valores 0,1% (values 0.1%
promedio sobre average over
20 twenty
determinaciones ) determinations)
Valoración Assessment
Teneligliptina 19, 8 mg 10,1 mg Teneligliptin 19.8 mg 10.1 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 498 mg 493 mg clorhidrato Metformin 498 mg 493 mg hydrochloride
(450-550 (450-550
mg/comp) mg / comp)
Disolución Dissolution
Teneligliptina 97%-99-98%-98%-97%-97- 103-101-102-99-102- Teneligliptin 97% -99-98% -98% -97% -97- 103-101-102-99-102-
Q=75% Promedio: 97,6% 101- Promedio: 101,3% Q = 75% Average: 97.6% 101- Average: 101.3%
Valores Values
individuales individual
Q+5% Q + 5%
Disolución Dissolution
Metformina Ia Hora 40 %-38%-42%-40%-39%- Ia Hora 42 %-39%-43%-43%- clorhidrato 42% 38%-40% Ia Hora 25 - 45 % 4a Hora 67 %-65%-70%-68%-70%- 4a Hora 65 %-66%-70%-69%- 4a Hora 50 - 70 % 69% 70%-68% 10a Hora No menos de 8aHora: 98%-100%-99%-104%- 8aHora: 98%-100%-99%- 85 % 102%-101% 104%-102%-101% Metformin I at Hour 40% -38% -42% -40% -39% - I at Hour 42% -39% -43% -43% - Hydrochloride 42% 38% -40% I at Hour 25 - 45% 4 to Hour 67% -65% -70% -68% -70% - 4 to Hour 65% -66% -70% -69% - 4 to Hour 50 - 70% 69% 70% -68% 10 to Hour No less than 8 a Hour: 98% -100% -99% -104% - 8 a Hour: 98% -100% -99% - 85% 102% -101% 104% -102% -101%
Composición mejorada en forma de comprimido recubierto comprendiendo Teneligliptina 20 mg en el recubrimiento y Metformina clorhidrato 1000 mg, en el núcleo deliberación prolongada comparado con comprimidos recubiertos conteniendo
20 mg de Teneligliptina y comprimidos recubiertos conteniendo 1000 mg de Metformina clorhidrato de liberación prolongada. Improved composition in the form of a coated tablet comprising Teneligliptin 20 mg in the coating and Metformin hydrochloride 1000 mg, in the core prolonged deliberation compared to coated tablets containing 20 mg of Teneligliptin and coated tablets containing 1000 mg of Metformin hydrochloride extended release.
Parámetros Ejemplo 1 Teneligliptina 20 mg Metformina Parameters Example 1 Teneligliptin 20 mg Metformin
Teneligliptina 20 mg comprimido recubierto clorhidrato 1000 mg de liberación comprimido recubierto inmediata de liberación Metformina prolongada clorhidrato 1000 mg Teneligliptin 20 mg hydrochloride coated tablet 1000 mg immediate release coated tablet extended release Metformin hydrochloride 1000 mg
de liberación release
prolongada prolonged
Comprimido Compressed
recubierto covered
Dureza Hardness
(valores promedio 29 kp (average values 29 kp
sobre 20 about 20
determinaciones determinations
Friabilidad Friability
(valores promedio 0,1% (average values 0.1%
sobre 20 about 20
determinaciones ) determinations)
Valoración Assessment
Teneligliptina 19, 8 mg 10,1 mg Teneligliptin 19.8 mg 10.1 mg
(9 -10 mg/comp) (9 -10 mg / comp)
Valoración Assessment
Metformina 997 mg 995 mg clorhidrato Metformin 997 mg 995 mg hydrochloride
(450-550 mg/comp) (450-550 mg / comp)
Disolución Dissolution
Teneligliptina 96%-98-99%-97%-99%- 103-101-102-99-102- Teneligliptin 96% -98-99% -97% -99% - 103-101-102-99-102-
Q=75% 101 101- Promedio: 101,3% Q = 75% 101 101- Average: 101.3%
Valores Promedio: 98,3% Average Values: 98.3%
individuales Q+5% individual Q + 5%
Disolución Dissolution
Metformina Ia Hora 40 %-38%-42%-40%- Ia Hora 32 %-32%-32%33%- clorhidrato 39%-42% 33%-33% Ia Hora 25 - 45 % 4a Hora 67 %-65%-70%-68%- 4a Hora 60 %-59%-62%-61%- 4a Hora 50 - 70 % 70%-69% 62%-62% 10a Hora No menos de 85 8aHora: 98%-100%-99%- 8aHora: 98%-97%-99%-97%- % 104%-102%-101% 98%-98%
Conclusión : Metformin I at Hour 40% -38% -42% -40% - I at Hour 32% -32% -32% 33% - Hydrochloride 39% -42% 33% -33% I at Hour 25 - 45% 4 a Hour 67% -65% -70% -68% - 4 to Hour 60% -59% -62% -61% - 4 to Hour 50 - 70% 70% -69% 62% -62% 10 to Hour No less from 85 8 a Hour: 98% -100% -99% - 8 a Hour: 98% -97% -99% -97% -% 104% -102% -101% 98% -98% Conclusion :
Ante los resultados galénicos obtenidos con la formulación mejorada y los resultados de las determinaciones y pruebas IN VITRO realizados sobre los mismos, se decidió procesar la composición por granulación húmeda, previa molienda de la Metformina a polvo fino ( granulometría menor a 300 micrones) según las condiciones mencionadas previamente, y utilizando únicamente Povidona como aglutinante y Estearato de Magnesio como lubricante.
Given the galenic results obtained with the improved formulation and the results of the IN VITRO determinations and tests performed on them, it was decided to process the composition by wet granulation, after milling the Metformin to fine powder (granulometry less than 300 microns) according to the conditions mentioned previously, and using only Povidone as a binder and Magnesium Stearate as a lubricant.
Claims
1. Una composición farmacéutica mejorada para ser admini strabie oralmente como hipoglucémico, que comprende la combinación de una cantidad terapéuticamente efectiva del antidiabético Teneligliptina o sus sales farmacéuticamente aceptables con una cantidad terapéuticamente efectiva del antidiabético Metformina o sus sales farmacéuticamente aceptables, junto con baja carga de excipientes farmacéuticamente aceptables. 1. An improved pharmaceutical composition to be administered orally as hypoglycemic, comprising the combination of a therapeutically effective amount of the antidiabetic Teneligliptin or its pharmaceutically acceptable salts with a therapeutically effective amount of the antidiabetic Metformin or its pharmaceutically acceptable salts, together with a low load of pharmaceutically acceptable excipients.
2. Una combinación farmacéutica para el tratamiento de diabetes mellitus tipo 2 de conformidad con la reivindicación 1, que comprende una cantidad terapéuticamente efectiva del antidiabético Teneligliptina y una cantidad terapéuticamente efectiva del antidiabético Metformina. 2. A pharmaceutical combination for the treatment of type 2 diabetes mellitus according to claim 1, which comprises a therapeutically effective amount of the antidiabetic Teneligliptin and a therapeutically effective amount of the antidiabetic Metformin.
3. Una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 1, que comprende una combinación de Teneligliptina o sus sales farmacéuticamente aceptables y Metformina o sus sales farmacéuticamente aceptables junto a un aglutinante y un lubricante . 3. An improved pharmaceutical composition for oral administration according to claim 1, comprising a combination of Teneligliptin or its pharmaceutically acceptable salts and Metformin or its pharmaceutically acceptable salts together with a binder and a lubricant.
4. Una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 1, que comprende una combinación de Teneligliptina o sus sales farmacéuticamente aceptables y Metformina o sus sales farmacéuticamente aceptables donde el aglutinante es Povidona y el lubricante es Estearato de Magnesio.
3S 4. An improved pharmaceutical composition for oral administration according to claim 1, comprising a combination of Teneligliptin or its pharmaceutically acceptable salts and Metformin or its pharmaceutically acceptable salts wherein the binder is Povidone and the lubricant is Magnesium Stearate. 3S
5. Una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 1, en donde la composición farmacéutica es un comprimido recubierto . 5. An improved pharmaceutical composition to be orally administrable according to claim 1, wherein the pharmaceutical composition is a coated tablet.
6. Una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 1, en donde la composición farmacéutica comprende una cantidad terapéuticamente efectiva de Teneliglipt ina o sus sales farmacéuticamente aceptables y una cantidad terapéuticamente efectiva de Metformina o sus sales farmacéuticamente aceptables molida a una granulometria menor de 300 micrones, incluidas en el núcleo del comprimido recubierto . 6. An improved pharmaceutical composition for oral administration according to claim 1, wherein the pharmaceutical composition comprises a therapeutically effective amount of Teneliglipt ina or its pharmaceutically acceptable salts and a therapeutically effective amount of Metformin or its pharmaceutically acceptable salts ground to a granulometry less than 300 microns, included in the core of the coated tablet.
7. Una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 1, en donde la composición farmacéutica comprende una cantidad terapéuticamente efectiva de Metformina incluida en el núcleo junto con entre 5 y 6 % Povidona y entre 0,1 y 1 % Estearato de Magnesio y una cantidad terapéuticamente efectiva de Teneliglipt ina o sus sales farmacéuticamente aceptables incluida en el recubrimiento del comprimido. 7. An improved pharmaceutical composition for oral administration according to claim 1, wherein the pharmaceutical composition comprises a therapeutically effective amount of Metformin included in the core together with between 5 and 6% Povidone and between 0.1 and 1% Stearate of Magnesium and a therapeutically effective amount of Teneliglipt ina or its pharmaceutically acceptable salts included in the tablet coating.
8. Una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 1, en donde la composición farmacéutica comprende una cantidad terapéuticamente efectiva de Metformina incluida en el núcleo y una cantidad terapéuticamente efectiva de Teneliglipt ina incluida en el recubrimiento, en donde la Metformina es de liberación prolongada.
8. An improved pharmaceutical composition for oral administration according to claim 1, wherein the pharmaceutical composition comprises a therapeutically effective amount of Metformin included in the core and a therapeutically effective amount of Teneliglipt ina included in the coating, wherein Metformin It is extended release.
9. Una composición farmacéutica para ser administrabie oralmente de conformidad con las reivindicaciones 1 a 8, en donde la cantidad terapéuticamente efectiva de Teneligliptina o sus sales farmacéuticamente aceptables está comprendida entre 10 mg y 20 mg y la cantidad terapéuticamente efectiva de Metformina o sus sales farmacéuticamente aceptables está comprendida entre 500 mg y 1000 mg . 9. A pharmaceutical composition to be administered orally according to claims 1 to 8, wherein the therapeutically effective amount of Teneligliptin or its pharmaceutically acceptable salts is between 10 mg and 20 mg and the therapeutically effective amount of Metformin or its pharmaceutically acceptable salts. Acceptable is between 500 mg and 1000 mg.
10. Una composición farmacéutica para ser administrabie oralmente de conformidad con la reivindicación 9, en donde la cantidad terapéuticamente efectiva de Teneligliptina o sus sales farmacéuticamente aceptables es 10 mg por unidad de dosificación, y la cantidad terapéuticamente efectiva de Metformina o sus sales farmacéuticamente aceptables es 500 mg o preferentemente 850 mg o más preferentemente 1000 mg por unidad de dosificación. 10. A pharmaceutical composition to be administered orally according to claim 9, wherein the therapeutically effective amount of Teneligliptin or its pharmaceutically acceptable salts is 10 mg per dosage unit, and the therapeutically effective amount of Metformin or its pharmaceutically acceptable salts is 500 mg or preferably 850 mg or more preferably 1000 mg per dosage unit.
11. Una composición farmacéutica para ser administrable oralmente de conformidad con las reivindicación 9, en donde la cantidad terapéuticamente efectiva de Teneligliptina es 20 mg por unidad de dosificación, y la cantidad terapéuticamente efectiva de Metformina es 850 por unidad de dosificación. 11. A pharmaceutical composition for oral administration according to claim 9, wherein the therapeutically effective amount of Teneligliptin is 20 mg per dosage unit, and the therapeutically effective amount of Metformin is 850 per dosage unit.
12. Una composición farmacéutica para ser administrable oralmente de conformidad con las reivindicación 8, en donde la cantidad terapéuticamente efectiva de Teneligliptina es 20 mg por unidad de dosificación, y la cantidad terapéuticamente efectiva de Metformina es 500 mg o preferentemente 850 mg o mas preferentemente 1000 mg por unidad de dosificación.
12. A pharmaceutical composition for oral administration according to claim 8, wherein the therapeutically effective amount of Teneligliptin is 20 mg per dosage unit, and the therapeutically effective amount of Metformin is 500 mg or preferably 850 mg or more preferably 1000 mg per dosage unit.
13. Una composición farmacéutica para ser administrabie oralmente de conformidad con la reivindicación 7, en donde la cantidad terapéuticamente efectiva de Teneligliptina es 20 mg por unidad de dosificación, y la cantidad terapéuticamente efectiva de Metformina es 850 mg por unidad de dosificación. 13. A pharmaceutical composition to be administered orally according to claim 7, wherein the therapeutically effective amount of Teneligliptin is 20 mg per dosage unit, and the therapeutically effective amount of Metformin is 850 mg per dosage unit.
14. Una composición farmacéutica para ser administrabie oralmente de conformidad con la reivindicación 10, en donde la composición farmacéutica es administrable cada 12 horas. 14. A pharmaceutical composition for oral administration according to claim 10, wherein the pharmaceutical composition is administrable every 12 hours.
15. Una composición farmacéutica para ser administrable oralmente de conformidad con las reivindicaciones 11 y 12, en donde la composición farmacéutica además está adaptada para ser administrable una vez al día. 15. A pharmaceutical composition to be orally administrable according to claims 11 and 12, wherein the pharmaceutical composition is further adapted to be administrable once a day.
16. Un proceso para preparar una composición farmacéutica mejorada para ser administrable oralmente de conformidad con las reivindicaciones 1 a 6, que comprende granular Teneligliptina o sus sales farmacéuticamente aceptables y Metformina o sus sales farmacéuticamente aceptables previamente molida hasta granulometria inferior a 300 micrones, por malla de 0,5 mm, con una cantidad de entre 5% y 6 % de Povidona disuelta en alcohol etílico, secar el granulado, mezclarlo con una cantidad entre 0,1% y 1% de Estearato de Magnesio, y comprimir una cantidad terapéuticamente efectiva del antidiabético Teneligliptina con una cantidad terapéuticamente efectiva del antidiabético Metformina.
16. A process for preparing an improved pharmaceutical composition to be orally administrable in accordance with claims 1 to 6, which comprises granulating Teneligliptin or its pharmaceutically acceptable salts and Metformin or its pharmaceutically acceptable salts previously ground to granulometry of less than 300 microns, per mesh. 0.5 mm, with an amount of between 5% and 6% of Povidone dissolved in ethyl alcohol, dry the granulate, mix it with an amount between 0.1% and 1% of Magnesium Stearate, and compress a therapeutically effective amount of the antidiabetic Teneligliptin with a therapeutically effective amount of the antidiabetic Metformin.
17. Un proceso para preparar la composición farmacéutica para ser administrable oralmente de conformidad con la reivindicación 16, que comprende adicionalmente, recubrir la composición farmacéutica obtenida. 17. A process for preparing the pharmaceutical composition to be orally administrable in accordance with claim 16, further comprising coating the obtained pharmaceutical composition.
18. Un proceso para preparar una composición farmacéutica mejorada para ser administrable oralmente de conformidad con las reivindicaciones 1 a 6, que comprende granular Metformina con una solución aglutinante conteniendo la Teneliglipt ina o sus sales farmacéuticamente aceptables disuelta y una cantidad suficiente de Povidona disuelta en alcohol etílico, secar el granulado, mezclarlo con una cantidad suficiente de Estearato de Magnesio, y comprimir una cantidad terapéuticamente efectiva del antidiabético Teneliglipt ina con una cantidad terapéuticamente efectiva del antidiabético Metformina. 18. A process for preparing an improved pharmaceutical composition for oral administration according to claims 1 to 6, comprising granulating Metformin with a binder solution containing the inactive Teneliglipt or its pharmaceutically acceptable salts dissolved and a sufficient amount of Povidone dissolved in alcohol. ethyl, dry the granulate, mix it with a sufficient amount of Magnesium Stearate, and compress a therapeutically effective amount of the antidiabetic Teneliglipt ina with a therapeutically effective amount of the antidiabetic Metformin.
19. Un proceso para preparar la composición farmacéutica para ser administrable oralmente de conformidad con la reivindicación 18, que comprende adicionalmente recubrir la composición farmacéutica obtenida. 19. A process for preparing the pharmaceutical composition to be orally administrable according to claim 18, further comprising coating the obtained pharmaceutical composition.
20. Un proceso para preparar una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 7, que comprende granular Metformina con una solución conteniendo una cantidad suficiente de Povidona disuelta en alcohol etílico, secar el granulado, mezclarlo con una cantidad suficiente de20. A process for preparing an improved pharmaceutical composition for oral administration according to claim 7, which comprises granulating Metformin with a solution containing a sufficient amount of Povidone dissolved in ethyl alcohol, drying the granulate, mixing it with a sufficient amount of
Estearato de Magnesio, y comprimir una cantidad terapéuticamente efectiva del antidiabético Metformina y recubrir los comprimidos con una suspensión conteniendo una
cantidad terapéuticamente efectiva del antidiabético Teneligliptina . Magnesium Stearate, and compress a therapeutically effective amount of the antidiabetic Metformin and coat the tablets with a suspension containing a therapeutically effective amount of the antidiabetic Teneligliptin.
21. Un proceso para preparar una composición farmacéutica mejorada para ser administrable oralmente de conformidad con la reivindicación 8, que comprende granular Metformina molida a granulometria inferior a 300 micrones y una cantidad suficiente de hidroxipropilmetilcelulosa K 100 con una cantidad suficiente de Povidona disuelta en alcohol etílico, secar el granulado, mezclarlo con una cantidad suficiente de Estearato de Magnesio, y comprimir una cantidad terapéuticamente efectiva del antidiabético Metformina y recubrir los comprimidos con una suspensión conteniendo una cantidad terapéuticamente efectiva del antidiabético Teneligliptina .
21. A process for preparing an improved pharmaceutical composition for oral administration according to claim 8, which comprises granulating ground Metformin at granulometry of less than 300 microns and a sufficient amount of hydroxypropyl methylcellulose K 100 with a sufficient amount of Povidone dissolved in ethyl alcohol. , dry the granulate, mix it with a sufficient amount of Magnesium Stearate, and compress a therapeutically effective amount of the antidiabetic Metformin and coat the tablets with a suspension containing a therapeutically effective amount of the antidiabetic Teneligliptin.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR112019002909-5A BR112019002909A2 (en) | 2016-08-17 | 2017-06-23 | improved composition of teneligliptin and metformin, and process for preparation thereof |
| CONC2019/0001110A CO2019001110A2 (en) | 2016-08-17 | 2019-02-05 | Improved composition of teneligliptin and metformin and process to prepare it |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2016010682A MX2016010682A (en) | 2016-08-17 | 2016-08-17 | Improved composition of teneligliptin and metformin and method for preparing same. |
| MXMX/A/2016/010682 | 2016-08-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018033808A1 true WO2018033808A1 (en) | 2018-02-22 |
Family
ID=61196457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2017/053749 WO2018033808A1 (en) | 2016-08-17 | 2017-06-23 | Improved composition of teneligliptin and metformin and method for preparing same |
Country Status (9)
| Country | Link |
|---|---|
| AR (1) | AR109253A1 (en) |
| BR (1) | BR112019002909A2 (en) |
| CL (1) | CL2019000273A1 (en) |
| CO (1) | CO2019001110A2 (en) |
| DO (1) | DOP2019000035A (en) |
| EC (2) | ECSP19010066A (en) |
| MX (1) | MX2016010682A (en) |
| PE (1) | PE20190402A1 (en) |
| WO (1) | WO2018033808A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014080383A1 (en) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Pharmaceutical composition of dipeptidyl peptidase-iv (dpp-iv) inhibitors in combination with other antidiabetics |
| WO2015132679A1 (en) * | 2014-03-05 | 2015-09-11 | Glenmark Pharmaceuticals Ltd | Teneligliptin compositions |
-
2016
- 2016-08-17 MX MX2016010682A patent/MX2016010682A/en unknown
-
2017
- 2017-06-23 WO PCT/IB2017/053749 patent/WO2018033808A1/en active Application Filing
- 2017-06-23 PE PE2019000305A patent/PE20190402A1/en unknown
- 2017-06-23 BR BR112019002909-5A patent/BR112019002909A2/en active Search and Examination
- 2017-07-04 AR ARP170101849A patent/AR109253A1/en unknown
-
2019
- 2019-02-01 CL CL2019000273A patent/CL2019000273A1/en unknown
- 2019-02-05 CO CONC2019/0001110A patent/CO2019001110A2/en unknown
- 2019-02-12 EC ECSENADI201910066A patent/ECSP19010066A/en unknown
- 2019-02-18 DO DO2019000035A patent/DOP2019000035A/en unknown
- 2019-06-25 EC ECSENADI201944926A patent/ECSP19044926A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014080383A1 (en) * | 2012-11-26 | 2014-05-30 | Ranbaxy Laboratories Limited | Pharmaceutical composition of dipeptidyl peptidase-iv (dpp-iv) inhibitors in combination with other antidiabetics |
| WO2015132679A1 (en) * | 2014-03-05 | 2015-09-11 | Glenmark Pharmaceuticals Ltd | Teneligliptin compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| ECSP19044926A (en) | 2019-07-31 |
| BR112019002909A2 (en) | 2019-05-21 |
| AR109253A1 (en) | 2018-11-14 |
| ECSP19010066A (en) | 2019-11-30 |
| DOP2019000035A (en) | 2019-06-30 |
| CO2019001110A2 (en) | 2019-04-12 |
| CL2019000273A1 (en) | 2019-06-28 |
| MX2016010682A (en) | 2018-02-16 |
| PE20190402A1 (en) | 2019-03-13 |
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