WO2013066277A1 - Synergic compositions - Google Patents
Synergic compositions Download PDFInfo
- Publication number
- WO2013066277A1 WO2013066277A1 PCT/TR2012/000152 TR2012000152W WO2013066277A1 WO 2013066277 A1 WO2013066277 A1 WO 2013066277A1 TR 2012000152 W TR2012000152 W TR 2012000152W WO 2013066277 A1 WO2013066277 A1 WO 2013066277A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nateglinide
- metformin hydrochloride
- pharmaceutical composition
- composition
- tablet
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 39
- 230000002195 synergetic effect Effects 0.000 title description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 85
- 229960000698 nateglinide Drugs 0.000 claims abstract description 81
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 claims abstract description 81
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 77
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 76
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 60
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 8
- 239000003826 tablet Substances 0.000 claims description 28
- 239000002552 dosage form Substances 0.000 claims description 22
- 239000013543 active substance Substances 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 10
- -1 glidant Substances 0.000 claims description 9
- 230000002035 prolonged effect Effects 0.000 claims description 8
- 239000008187 granular material Substances 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000007938 effervescent tablet Substances 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 230000003115 biocidal effect Effects 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
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- 239000000796 flavoring agent Substances 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 235000013355 food flavoring agent Nutrition 0.000 claims description 3
- 235000003599 food sweetener Nutrition 0.000 claims description 3
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- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 2
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 2
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 2
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- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 2
- 239000002269 analeptic agent Substances 0.000 claims description 2
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- 230000000202 analgesic effect Effects 0.000 claims description 2
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- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 230000001078 anti-cholinergic effect Effects 0.000 claims description 2
- 230000001142 anti-diarrhea Effects 0.000 claims description 2
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- 230000003556 anti-epileptic effect Effects 0.000 claims description 2
- 230000001567 anti-fibrinolytic effect Effects 0.000 claims description 2
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- 230000000118 anti-neoplastic effect Effects 0.000 claims description 2
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- 230000002785 anti-thrombosis Effects 0.000 claims description 2
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 2
- 229960001438 immunostimulant agent Drugs 0.000 claims description 2
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- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
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- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 claims description 2
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- 229960002477 riboflavin Drugs 0.000 claims description 2
- 229910052711 selenium Inorganic materials 0.000 claims description 2
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- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Definitions
- the present invention relates to combinations comprising nateglinide and metformin or a pharmaceutically acceptable salt thereof; use of said combinations in treatment of type 2 diabetes and pharmaceutical combinations comprising these.
- Nateglinidine chemical name of which is N-(4-isopropylcyclohexylcarbonyl)-D-phenylalanine, is a molecule belonging to meglitinide class. It was first disclosed in the patent numbered EP0196222. It is explained in said document that nateglinidine is effective in its use as a hypoglycemic agent in diabetic organisms and in lowering blood sugar and use in the treatment of type-2 diabetes.
- nateglinide can be found in film tablet forms of 60, 120 and 180 mg.
- Metformin chemical name of which is N,N-dimethylimidodicarbonimidic diamide, is a molecule belonging to biguanide class. It was first disclosed in the application numbered US3174901. It is known that metformin is especially effective in the treatment of type-2 diabetic patients who are overweight and obese but have healthy kidney functions. It is also explained in different sources that this active substance can also be used in the treatment of diseases caused by insulin resistance and polycystic ovary syndrome.
- metformin On the market, metformin can be found in metformin hydrochloride form of 500 mg, 750 mg and 1000 mg film tablet and prolonged-release tablets.
- an unexpected therapeutic benefit can be obtained in the treatment of type-2 diabetes by combination therapy where nateglinide and metformin hydrochloride are used.
- nateglinide and metformin hydrochloride are used.
- the pharmaceutical composition in which nateglinide or metformin hydrochloride are used together or simultaneously presents more therapeutic benefit compared to the compositions where these two agents are used separately.
- nateglinide and metformin hydrochloride provides that the therapeutic effect is seen in a shorter time and the effect is stronger compared to separate use of these two active substances. In this way, it is possible to provide a more effective treatment for patients. Surprisingly, all these positive effects are not only seen in the combinations where these two active substances are given sequentially but also seen when both active substances are given simultaneously in a single dosage form or in independent dosage forms. High therapeutic benefit can also be observed as a longer therapeutic effect.
- the present invention relates to pharmaceutical compositions which comprise nateglinide and metformin hydrochloride in separate dosage forms for sequential administration; together in independent dosage forms for simultaneous administration or in the same dosage form for simultaneous administration.
- the present invention provides a method that treats type-2 diabetes by administering efficient amounts of nateglinide and metformin hydrochloride.
- the present invention relates to pharmaceutical compositions comprising the pharmaceutically efficient amounts of nateglinide and metformin hydrochloride and at least one pharmaceutically acceptable substance.
- Nateglinide and metformin hydrochloride in said pharmaceutical compositions can be together in a single formulation with at least one pharmaceutically acceptable excipient while nateglinide and metformin hydrochloride can also be formulated separately with at least one pharmaceutically acceptable excipient.
- the different formulations obtained can be combined in a single dosage form or can be prepared in separate dosage forms. In the case that the formulations are in different dosage forms, the said dosage forms can be the same or different.
- the present invention also relates to use of nateglinide and metformin hydrochloride according to the invention for preparation of a drug that shall be used in the combination therapy as administered simultaneously, sequentially or separately in the treatment of type-2 diabetes.
- Nateglinide in the pharmaceutical compositions according to the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or any polymorphic forms like amorphous, crystalline forms or a combination thereof.
- nateglinide is in free form.
- Metformin hydrochloride in the pharmaceutical compositions of the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or any polymorphic forms like amorphous, crystalline forms or a combination thereof.
- compositions of the invention comprising nateglinide and metformin hydrochloride can be prepared in any dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged-release tablet, modified-release tablet, delayed-release tablet, orodispersible tablet, chewable tablet. While pharmaceutical formulations comprising nateglinid and metformin hydrochloride can be together in any of these dosage forms, said formulations can be in any of these dosage forms in the case that nateglinid and metformin hydrochloride are stored in separate dosage forms. In other words, compositions comprising the combination of the invention can be in any of the abovementioned dosage forms or in combination forms of these dosage forms or a treatment package consisted of this combination.
- compositions comprising nateglinide and metformin hydrochloride of the invention is preferably in form of film tablet, prolonged-release tablet or effervescent tablet.
- compositions comprising nateglinide are preferably in form of tablet, film tablet, capsule or prolonged-release tablet.
- pharmaceutical compositions comprising metformin hydrochloride are preferably in form of tablet, prolonged-release tablet, film tablet or effervescent tablet.
- compositions comprising nateglinide and metformin hydrochloride of the invention can comprise pharmaceutically acceptable excipients along with the active substances nateglinide and metformin hydrochloride.
- compositions comprising nateglinide and metformin hydrochloride of the invention can comprise at least one pharmaceutically acceptable excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic and one basic agent, coloring agent, PH regulating agent, surfactant, stabilizer, sweetener and/or taste regulating agent, flavoring agent in addition to the active substances.
- the disintegrant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
- the diluent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, ma odextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
- the lubricant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
- the glidant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc.
- the binder that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, mahodextrin, methyl cellulose, povidone, starch.
- the effervescent couple comprising at least one acidic and one basic agent that can be used in the pharmaceutical compositions of the invention comprises an acidic agent selected from a group of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid, maleic acid and a basic agent selected from a group of agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
- the pH regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartrate, fumarate, acetate, maleate and amino acid salts.
- the surfactant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
- the stabilizer that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
- the sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
- the flavoring agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising menthol, lemon, orange, vanillin, strawberry, raspberry, caramel and similar flavors.
- compositions of the invention comprise nateglinide in the range of 0,1% and 99%, preferably in the range of 1% and 98%, more preferably in the range of 5% and 95%; for example in the range of 10, 15% and 25, 30, 40, 45, 50, 55, 60, 65, 70, 75, 80% by weight.
- compositions of the invention comprise metformin hydrochloride in the range of 0,1% and 99%, preferably in the range of 1% and 98%, more preferably in the range of 5% and 95%; for example in the range of 10, 15, 20, 25% and 30, 40, 45, 50, 55, 60, 65, 70, 75, 80% by weight.
- Nateglinide can be found in the range of 1 mg and 1000 mg, preferably in the range of 50 mg and 800 mg, more preferably in the range of 100 mg and 500 mg in the pharmaceutical compositions of the invention.
- Metformin hydrochloride can be found in the range of 100 mg and 2000 mg, preferably in the range of 250 mg and 1500 mg, more preferably in the range of 400 mg and 1200 mg in pharmaceutical compositions of the invention.
- the present invention relates to the pharmaceutical compositions comprising a combination of 50 - 300 mg nateglinide and 400 - 1200 mg metformin hydrochloride as active agent.
- the present invention relates to pharmaceutical compositions comprising nateglinide and metformin hydrochloride combinations, particle size (d 5 o) of which are in the range of 1-200 ⁇ , preferably in the range of 3-150 ⁇ , more preferably in the range of 5-100 ⁇ .
- compositions comprising nateglinide and metformin hydrochloride of the invention can optionally comprise a third active substance along with nateglinide and metformin hydrochloride.
- the third active substance can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion,
- composition of the invention can be obtained by a method comprising the steps of;
- the obtained pharmaceutical composition or compositions can be converted into any dosage form stated above.
- the obtained tablets can be treated with film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed-release coating agents or coating compositions comprising any combination thereof.
- Saccharose can be used alone or optionally along with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof as a sugar-based coating agent.
- agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof as a sugar-based coating agent.
- Water-soluble coating agent can be selected from a group comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers like polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides like pullulan or a combination thereof.
- cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
- synthetic polymers like polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides like pullulan or a combination thereof.
- Enteric coating agent can be selected from a group comprising cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives like methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances like shellac or a combination thereof.
- cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
- acrylic acid derivatives like methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances like shellac or a combination thereof.
- Delayed-release coating agent can be selected from a group comprising cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer S, ethyl acrylate methyl methacrylate copolymer emulsion or a combination thereof.
- composition of the invention can be used for treating and preventing type-2 diabetes.
- Nateglinide, metformin hydrochloride and the diluent are mixed. They are granulated with a granulation solution comprising a binder. The obtained granules are dried and mixed with the disintegrant and other excipients. The final composition obtained is compressed in tablet compression machine and coated with coating agent.
- EXAMPLE 2 Effervescent Tablet Formulation Comprising Nateglinide and Metformin
- Nateglinide, metformin hydrochloride and the effervescent couple are mixed. They are granulated with a granulation solution comprising binder. The obtained granules are dried and mixed with disintegrant and other excipients. The final mixture obtained is compressed in tablet compression machine.
- the first mixture is obtained by adding the lubricant into the mixture.
- Metformin hydrochloride and the diluent are mixed.
- the obtained mixture is granulated with a granulation solution comprising binder.
- the obtained granules are dried and the second mixture is obtained by mixing them with the glidant and the other excipients.
- Both the mixtures obtained are fed to tablet compression machine and compressed in bilayer tablet form.
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Abstract
The present invention relates to pharmaceutical compositions comprising nateglinide and metformin hydrochloride that shall be used in the treatment of type-2 diabetes.
Description
SYNERGIC COMPOSITIONS
The present invention relates to combinations comprising nateglinide and metformin or a pharmaceutically acceptable salt thereof; use of said combinations in treatment of type 2 diabetes and pharmaceutical combinations comprising these. Nateglinidine, chemical name of which is N-(4-isopropylcyclohexylcarbonyl)-D-phenylalanine, is a molecule belonging to meglitinide class. It was first disclosed in the patent numbered EP0196222. It is explained in said document that nateglinidine is effective in its use as a hypoglycemic agent in diabetic organisms and in lowering blood sugar and use in the treatment of type-2 diabetes.
On the market, nateglinide can be found in film tablet forms of 60, 120 and 180 mg.
Metformin, chemical name of which is N,N-dimethylimidodicarbonimidic diamide, is a molecule belonging to biguanide class. It was first disclosed in the application numbered US3174901. It is known that metformin is especially effective in the treatment of type-2 diabetic patients who are overweight and obese but have healthy kidney functions. It is also explained in different sources that this active substance can also be used in the treatment of diseases caused by insulin resistance and polycystic ovary syndrome.
Formula 2: Metformin On the market, metformin can be found in metformin hydrochloride form of 500 mg, 750 mg and 1000 mg film tablet and prolonged-release tablets.
Surprisingly, it has been seen that an unexpected therapeutic benefit, especially synergistic therapeutic benefit, can be obtained in the treatment of type-2 diabetes by combination therapy where nateglinide and metformin hydrochloride are used. For instance, it is possible to lower the dosages required for the desired therapeutic effect in the combination of nateglinide and metformin hydrochloride with use of nateglinide and metformin hydrochloride in comparison to treatments in which only nateglinide or
metformin hydrochloride is used; therefore, to alleviate undesired side effects. From a different aspect, the pharmaceutical composition in which nateglinide or metformin hydrochloride are used together or simultaneously presents more therapeutic benefit compared to the compositions where these two agents are used separately. In another aspect, combined use of nateglinide and metformin hydrochloride provides that the therapeutic effect is seen in a shorter time and the effect is stronger compared to separate use of these two active substances. In this way, it is possible to provide a more effective treatment for patients. Surprisingly, all these positive effects are not only seen in the combinations where these two active substances are given sequentially but also seen when both active substances are given simultaneously in a single dosage form or in independent dosage forms. High therapeutic benefit can also be observed as a longer therapeutic effect.
According to this, the present invention relates to pharmaceutical compositions which comprise nateglinide and metformin hydrochloride in separate dosage forms for sequential administration; together in independent dosage forms for simultaneous administration or in the same dosage form for simultaneous administration.
From a different aspect, the present invention provides a method that treats type-2 diabetes by administering efficient amounts of nateglinide and metformin hydrochloride.
From one aspect, the present invention relates to pharmaceutical compositions comprising the pharmaceutically efficient amounts of nateglinide and metformin hydrochloride and at least one pharmaceutically acceptable substance. Nateglinide and metformin hydrochloride in said pharmaceutical compositions can be together in a single formulation with at least one pharmaceutically acceptable excipient while nateglinide and metformin hydrochloride can also be formulated separately with at least one pharmaceutically acceptable excipient. The different formulations obtained can be combined in a single dosage form or can be prepared in separate dosage forms. In the case that the formulations are in different dosage forms, the said dosage forms can be the same or different.
The present invention also relates to use of nateglinide and metformin hydrochloride according to the invention for preparation of a drug that shall be used in the combination therapy as administered simultaneously, sequentially or separately in the treatment of type-2 diabetes. Nateglinide in the pharmaceutical compositions according to the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or any polymorphic forms like amorphous, crystalline forms or a combination thereof. Preferably, nateglinide is in free form.
Metformin hydrochloride in the pharmaceutical compositions of the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers and/or any polymorphic forms like amorphous, crystalline forms or a combination thereof.
Pharmaceutical compositions of the invention comprising nateglinide and metformin hydrochloride can be prepared in any dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged-release tablet, modified-release tablet, delayed-release tablet, orodispersible tablet, chewable tablet. While pharmaceutical formulations comprising nateglinid and metformin hydrochloride can be together in any of these dosage forms, said formulations can be in any of these dosage forms in the case that nateglinid and metformin hydrochloride are stored in separate dosage forms. In other words, compositions comprising the combination of the invention can be in any of the abovementioned dosage forms or in combination forms of these dosage forms or a treatment package consisted of this combination.
In the case that nateglinide and metformin hydrochloride are in the same dosage form, pharmaceutical compositions comprising nateglinide and metformin hydrochloride of the invention is preferably in form of film tablet, prolonged-release tablet or effervescent tablet.
In the case that nateglinide and metformin hydrochloride are in different dosage forms, pharmaceutical compositions comprising nateglinide are preferably in form of tablet, film tablet, capsule or prolonged-release tablet. In the case that nateglinide and metformin hydrochloride are in different dosage forms, pharmaceutical compositions comprising metformin hydrochloride are preferably in form of tablet, prolonged-release tablet, film tablet or effervescent tablet.
Pharmaceutical compositions comprising nateglinide and metformin hydrochloride of the invention can comprise pharmaceutically acceptable excipients along with the active substances nateglinide and metformin hydrochloride.
Pharmaceutical compositions comprising nateglinide and metformin hydrochloride of the invention can comprise at least one pharmaceutically acceptable excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic and one basic agent, coloring agent, PH regulating agent, surfactant, stabilizer, sweetener and/or taste regulating agent, flavoring agent in addition to the active substances.
The disintegrant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl
cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
The diluent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, ma odextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
The lubricant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
The glidant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, talc.
The binder that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminum silicate, mahodextrin, methyl cellulose, povidone, starch.
The effervescent couple comprising at least one acidic and one basic agent that can be used in the pharmaceutical compositions of the invention comprises an acidic agent selected from a group of organic acids such as malic acid, citric acid, tartaric acid, fumaric acid, maleic acid and a basic agent selected from a group of agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
The pH regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartrate, fumarate, acetate, maleate and amino acid salts.
The surfactant that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
The stabilizer that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
The sweetener and/or taste regulating agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol,
maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
The flavoring agent that can be used in the pharmaceutical compositions of the invention can be selected from a group comprising menthol, lemon, orange, vanillin, strawberry, raspberry, caramel and similar flavors.
Pharmaceutical compositions of the invention comprise nateglinide in the range of 0,1% and 99%, preferably in the range of 1% and 98%, more preferably in the range of 5% and 95%; for example in the range of 10, 15% and 25, 30, 40, 45, 50, 55, 60, 65, 70, 75, 80% by weight.
Pharmaceutical compositions of the invention comprise metformin hydrochloride in the range of 0,1% and 99%, preferably in the range of 1% and 98%, more preferably in the range of 5% and 95%; for example in the range of 10, 15, 20, 25% and 30, 40, 45, 50, 55, 60, 65, 70, 75, 80% by weight.
Nateglinide can be found in the range of 1 mg and 1000 mg, preferably in the range of 50 mg and 800 mg, more preferably in the range of 100 mg and 500 mg in the pharmaceutical compositions of the invention. Metformin hydrochloride can be found in the range of 100 mg and 2000 mg, preferably in the range of 250 mg and 1500 mg, more preferably in the range of 400 mg and 1200 mg in pharmaceutical compositions of the invention.
In another aspect, the present invention relates to the pharmaceutical compositions comprising a combination of 50 - 300 mg nateglinide and 400 - 1200 mg metformin hydrochloride as active agent. In a way, the present invention relates to pharmaceutical compositions comprising nateglinide and metformin hydrochloride combinations, particle size (d5o) of which are in the range of 1-200 μπι, preferably in the range of 3-150 μηι, more preferably in the range of 5-100 μπι.
Pharmaceutical compositions comprising nateglinide and metformin hydrochloride of the invention can optionally comprise a third active substance along with nateglinide and metformin hydrochloride. The third active substance can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glycosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogues
thereof, vitamin Bi, vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.
The pharmaceutical composition of the invention can be obtained by a method comprising the steps of;
• Mixing the active substances nateglinide and/or metformin hydrochloride homogenously and adding at least one of the abovementioned excipients if necessary or
• Granulating the active substances nateglinide and/or metformin hydrochloride with a
granulation solution comprising at least one of the excipients and afterwards, mixing it homogenously with the other excipients or
• Granulating a composition comprising the active substances nateglinide and/or metformin hydrochloride and at least one of the excipients with a granulation solution and afterwards, mixing it homogenously with the other excipients or
• Mixing the active substances nateglinide and/or metformin hydrochloride with at least one of the abovementioned excipients and optionally granulating it with a granulation solution comprising excipients
• Using any of the abovementioned methods separately for active substance compositions and combining the obtained formulations or storing them in different dosage forms in the case that nateglinide and metformin hydrochloride are prepared in two separate formulations.
The obtained pharmaceutical composition or compositions can be converted into any dosage form stated above. In the case that they are in tablet form, the obtained tablets can be treated with film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents, delayed-release coating agents or coating compositions comprising any combination thereof.
Saccharose can be used alone or optionally along with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatin, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof as a sugar-based coating agent.
Water-soluble coating agent can be selected from a group comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers like polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides like pullulan or a combination thereof.
Enteric coating agent can be selected from a group comprising cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives like methacrylic
acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances like shellac or a combination thereof.
Delayed-release coating agent can be selected from a group comprising cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer S, ethyl acrylate methyl methacrylate copolymer emulsion or a combination thereof.
Pharmaceutical composition of the invention can be used for treating and preventing type-2 diabetes.
The examples below are given in order to explain the formulations of the present invention; yet, the invention cannot be limited to these examples.
EXAMPLE 1 : Film Tablet Formulation Comprising Nateglinide and Metformin
Nateglinide, metformin hydrochloride and the diluent are mixed. They are granulated with a granulation solution comprising a binder. The obtained granules are dried and mixed with the disintegrant and other excipients. The final composition obtained is compressed in tablet compression machine and coated with coating agent.
EXAMPLE 2: Effervescent Tablet Formulation Comprising Nateglinide and Metformin
Nateglinide, metformin hydrochloride and the effervescent couple are mixed. They are granulated with a granulation solution comprising binder. The obtained granules are dried and mixed with disintegrant and other excipients. The final mixture obtained is compressed in tablet compression machine.
EXAMPLE 3: Bilayer Tablet Formulation Comprising Nateglinide and Metformin
Metformin hydrochloride and the diluent are mixed. The obtained mixture is granulated with a granulation solution comprising binder. The obtained granules are dried and the second mixture is obtained by mixing them with the glidant and the other excipients.
Both the mixtures obtained are fed to tablet compression machine and compressed in bilayer tablet form.
Claims
1. A pharmaceutical composition that comprises nateglinide and metformin hydrochloride combination as the active agent.
2. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claim 1 characterized in that the said composition comprises nateglinide in the range of 1-1000 mg.
3. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-2 characterized in that the said composition comprises nateglinide in the range of 50- 800 mg.
4. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-3 characterized in that the said composition comprises nateglinide in the range of 100- 500 mg.
5. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-4 characterized in that the said composition comprises metformin hydrochloride in the range of 100-2000 mg.
6. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1 -5 characterized in that the said composition comprises metformin hydrochloride in the range of 250-1500 mg.
7. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1 -6 characterized in that the said composition comprises metformin hydrochloride in the range of 400-1200 mg.
8. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-7 characterized in that nateglinide can be in any pharmaceutically acceptable form thereof such as salts, hydrates, solvates, esters, enantiomers, diastereomers and/or polymorphic forms like amorphous and crystalline forms or a combination thereof.
9. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-8 characterized in that metformin hydrochloride can be in any pharmaceutically acceptable form thereof such as salts, hydrates, solvates, esters, enantiomers, diastereomers and/or polymorphic forms like amorphous and crystalline forms or a combination thereof.
10. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-9 characterized in that nateglinide and metformin hydrochloride are in the same solution.
11. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-9 characterized in that nateglinide and metformin hydrochloride are in different solutions.
12. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-9, 11 characterized in that different formulations comprising nateglinide and metformin hydrochloride are combined in the same dosage form.
13. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-9, 11 characterized in that different formulations comprising nateglinide and metformin hydrochloride are in different dosage forms.
14. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1-13 characterized in that the said composition is in tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enteric-coated tablet, dry powder, granule, prolonged release tablet, modified release tablet, delayed release tablet, orodispersible tablet, chewable tablet form or a combination thereof.
15. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claims 1 1 -14 characterized in that the composition comprising nateglinide is in tablet, film coated tablet, capsule or prolonged-release tablet form; while the composition comprising metformin hydrochloride is in tablet, prolonged-release tablet, film coated tablet or effervescent tablet form.
16. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to any preceding claims characterized in that the said composition further comprises at least one pharmaceutically acceptable excipient along with nateglinide and metformin hydrochloride.
17. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to claim 16 characterized in that the said composition further comprises at least one pharmaceutically acceptable excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic and one basic agent, coloring agent, pH regulating agent, surfactant, stabilizer, sweetener and/or taste regulating agent, flavoring agent along with nateglinide and metformin hydrochloride.
18. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to any preceding claims characterized in that the said composition comprises nateglinide in the range of 0,1-99% by weight.
19. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to any preceding claims characterized in that the said composition comprises metformin hydrochloride in the range of 0,1-99% by weight.
20. The pharmaceutical composition comprising nateglinide and metformin hydrochloride according to any preceding claims characterized in that the said composition further comprises a third active substance selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti- Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, immunosuppressant, muscle relaxant, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogues thereof, vitamin B(, vitamin C, vitamin E, vitamin Be, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium along with nateglinide and metformin hydrochloride.
21. The pharmaceutical composition comprising nateglinide and metformin hydrochloride combination according to any preceding claims characterized in that the said composition is used for the production of a drug used in treatment of type-2 diabetes.
22. The pharmaceutical composition comprising nateglinide and metformin hydrochloride combination as active agent which is used sequentially, simultaneously or simultaneously.
23. The pharmaceutical composition comprising the combination of 50-30 mg of nateglinide and 400- 1200 mg of metformin hydrochloride as active agent.
24. The pharmaceutical composition comprising nateglinide and metformin hydrochloride composition, particle size of which is in the range of 1 and 200 μιη as active agent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201110979 | 2011-11-03 | ||
| TR2011/10979 | 2011-11-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013066277A1 true WO2013066277A1 (en) | 2013-05-10 |
Family
ID=47459074
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2012/000152 WO2013066277A1 (en) | 2011-11-03 | 2012-09-24 | Synergic compositions |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2013066277A1 (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
| EP0196222A2 (en) | 1985-03-27 | 1986-10-01 | Ajinomoto Co., Inc. | Hypoglycemic agent |
| WO2001021159A2 (en) * | 1999-09-17 | 2001-03-29 | Novartis Ag | Pharmaceutical composition of nateglinide and another antidiabetcagent |
| US20030224046A1 (en) * | 2002-06-03 | 2003-12-04 | Vinay Rao | Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent |
| WO2007056387A2 (en) * | 2005-11-07 | 2007-05-18 | Elixir Pharmaceuticals, Inc. | Combinations of metformin and meglitinide |
-
2012
- 2012-09-24 WO PCT/TR2012/000152 patent/WO2013066277A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
| EP0196222A2 (en) | 1985-03-27 | 1986-10-01 | Ajinomoto Co., Inc. | Hypoglycemic agent |
| WO2001021159A2 (en) * | 1999-09-17 | 2001-03-29 | Novartis Ag | Pharmaceutical composition of nateglinide and another antidiabetcagent |
| US20030224046A1 (en) * | 2002-06-03 | 2003-12-04 | Vinay Rao | Unit-dose combination composition for the simultaneous delivery of a short-acting and a long-acting oral hypoglycemic agent |
| WO2007056387A2 (en) * | 2005-11-07 | 2007-05-18 | Elixir Pharmaceuticals, Inc. | Combinations of metformin and meglitinide |
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