TR202009946A2 - A STABLE COMBINATION WITH VILDAGLIPTIN AND METFORMIN HCI - Google Patents
A STABLE COMBINATION WITH VILDAGLIPTIN AND METFORMIN HCIInfo
- Publication number
- TR202009946A2 TR202009946A2 TR2020/09946A TR202009946A TR202009946A2 TR 202009946 A2 TR202009946 A2 TR 202009946A2 TR 2020/09946 A TR2020/09946 A TR 2020/09946A TR 202009946 A TR202009946 A TR 202009946A TR 202009946 A2 TR202009946 A2 TR 202009946A2
- Authority
- TR
- Turkey
- Prior art keywords
- sodium
- vildagliptin
- feature
- tablet formulation
- formulation according
- Prior art date
Links
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 57
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 48
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 229960003105 metformin Drugs 0.000 title description 19
- 239000007916 tablet composition Substances 0.000 claims abstract description 21
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002535 acidifier Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 60
- 238000009472 formulation Methods 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- -1 polyethylene Polymers 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 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 claims description 10
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 10
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 9
- 229920001223 polyethylene glycol Polymers 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 239000000314 lubricant Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 6
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 6
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 6
- 229940105329 carboxymethylcellulose Drugs 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 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 6
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 6
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 5
- 239000008109 sodium starch glycolate Substances 0.000 claims description 5
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 5
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 5
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 229920002261 Corn starch Polymers 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 108010010803 Gelatin Proteins 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 4
- 235000010443 alginic acid Nutrition 0.000 claims description 4
- 229920000615 alginic acid Polymers 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- 239000008120 corn starch Substances 0.000 claims description 4
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 4
- 229960000878 docusate sodium Drugs 0.000 claims description 4
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 4
- 229920000159 gelatin Polymers 0.000 claims description 4
- 239000008273 gelatin Substances 0.000 claims description 4
- 229940014259 gelatin Drugs 0.000 claims description 4
- 235000019322 gelatine Nutrition 0.000 claims description 4
- 235000011852 gelatine desserts Nutrition 0.000 claims description 4
- 150000004676 glycans Chemical class 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 229960000502 poloxamer Drugs 0.000 claims description 4
- 229920001983 poloxamer Polymers 0.000 claims description 4
- 229920001282 polysaccharide Polymers 0.000 claims description 4
- 239000005017 polysaccharide Substances 0.000 claims description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229940005550 sodium alginate Drugs 0.000 claims description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 4
- 239000004299 sodium benzoate Substances 0.000 claims description 4
- 235000010234 sodium benzoate Nutrition 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 229960004793 sucrose Drugs 0.000 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
- 235000013539 calcium stearate Nutrition 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229960001021 lactose monohydrate Drugs 0.000 claims description 3
- 229960001855 mannitol Drugs 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- BZSXEZOLBIJVQK-UHFFFAOYSA-N 2-methylsulfonylbenzoic acid Chemical compound CS(=O)(=O)C1=CC=CC=C1C(O)=O BZSXEZOLBIJVQK-UHFFFAOYSA-N 0.000 claims description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 2
- 229920001817 Agar Polymers 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 239000005995 Aluminium silicate Substances 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- 229930091371 Fructose Natural products 0.000 claims description 2
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- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 2
- 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 claims description 2
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 claims description 2
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 2
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004698 Polyethylene Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
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- 229940072056 alginate Drugs 0.000 claims description 2
- 150000005215 alkyl ethers Chemical class 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
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- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 claims description 2
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- XCOBTUNSZUJCDH-UHFFFAOYSA-B lithium magnesium sodium silicate Chemical compound [Li+].[Li+].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Na+].[Na+].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3.O1[Si](O2)([O-])O[Si]3([O-])O[Si]1([O-])O[Si]2([O-])O3 XCOBTUNSZUJCDH-UHFFFAOYSA-B 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- 229960002160 maltose Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 238000007909 melt granulation Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000004260 weight control Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
Mevcut buluş, vildagliptin ve metformin hidroklorür içeren bir tablet formülasyonu ile ilgili olup, burada vildagliptin ve en az bir asitleştirici ajan bir çözücü içinde çözünmektedir. Mevcut buluş ayrıca, basit, hızlı, uygun maliyetli, zaman tasarrufu sağlayan ve endüstriyel olarak uygun bir proses ile de ilgilidirThe present invention relates to a tablet formulation containing vildagliptin and metformin hydrochloride, wherein vildagliptin and at least one acidifying agent are dissolved in a solvent. The present invention also relates to a simple, fast, cost-effective, time-saving and industrially suitable process.
Description
TARFNAME VILDAGLIPTIN VE METFORMIN Hci IÇEREN BIR STABIL KOMBINASYON Bulusun Alani Mevcut bulus, vildagliptin ve metformin hidroklorür içeren bir tablet formülasyonu ile ilgili olup, burada vildagliptin ve en az bir asitlestirici ajan bir çözücü içinde çözünmektedir. DESCRIPTION A STABLE COMBINATION CONTAINING VILDAGLIPTIN AND METFORMIN Hci Field of Invention The present invention relates to a tablet formulation comprising vildagliptin and metformin hydrochloride. wherein vildagliptin and at least one acidifying agent are dissolved in a solvent.
Mevcut bulus ayrica, basit, hizli, uygun maliyetli, zaman tasarrufu saglayan ve endüstriyel olarak uygun bir proses ile de ilgilidir. The present invention is also simple, fast, cost-effective, time-saving and industrial It is also related to a suitable process.
Teknigin Bilinen Durumu Diabetes mellitus, sekresyon degisimi sonucunda insülin etkisinin azaldigi veya yok oldugu ve/veya insülin aktivitesinin azaldigi bir grup karbonhidrat metabolizmasi bozuklugudur. Tip 1 ve Tip 2 olmak üzere iki ana diyabet tipi bulunmaktadir: Tip 1 diyabet, pankreasin insülin üreten hücrelerinin (beta hücreleri) hasar görmesi nedeniyle olusur. Tip 1 diyabette ise pankreas az insülin üretimi yapar veya hiç yapmaz, böylece seker, enerji olarak kullanilmak üzere vücut hücrelerine giremez. Tip 'I diyabetli kisiler, kan sekerini kontrol etmek için insülin enjeksiyonlari kullanmalidir. Known Status of the Technique Diabetes mellitus is a condition in which the effect of insulin decreases or disappears as a result of secretion changes. It is a group of carbohydrate metabolism disorders in which insulin and/or insulin activity is reduced. Type 1 There are two main types of diabetes: Type 2 and Type 2: Type 1 diabetes is caused by damage to the insulin-producing cells of the pancreas (beta cells). consists of In type 1 diabetes, the pancreas produces little or no insulin, so sugar, It cannot enter body cells to be used as energy. People with type 1 diabetes, blood sugar Must use insulin injections to control
Tip 2 diyabette pankreas insülin üretir, ancak üretilen insülin ya yetersiz kalir ya da düzgün etki göstermez. Bu diyabet tipi en çok 40 yasin üzerindeki ve asiri kilolu kisilerde görülür. Tip 2 diyabet bazen diyet, kilo kontrolü ve egzersiz kombinasyonu ile kontrol altina alinabilir. In type 2 diabetes, the pancreas produces insulin, but the insulin produced is either insufficient or not produced properly. does not show any effect. This type of diabetes is most common in people over the age of 40 and in people who are overweight. Medicine Type 2 diabetes can sometimes be controlled with a combination of diet, weight control and exercise.
Bununla birlikte, oral glikoz düsürücü ilaçlar veya insülin enjeksiyonlarindan olusan bir tedavi uygulanabilir. However, a treatment consisting of oral glucose-lowering medications or insulin injections applicable.
Vildagliptin, tip 2 diyabetin (insüline bagimli olmayan diyabet) tedavisinde kullanilmak üzere gelistirilmis bir dipeptidil dipeptidaz-IV (DPP-IV) inhibitörüdür. Vildagliptin, dipeptidil dipeptidaz-IV enziminin bozunmasini önler, böylece inkretin hormonlarinin, glukagon benzeri peptid-1'in (GLP-i) ve glukoz bagimli insülinotropik peptidin (GIP) etkilerini inhibe eder. Vildagliptin, for use in the treatment of type 2 diabetes (non-insulin dependent diabetes) It is an improved dipeptidyl dipeptidase-IV (DPP-IV) inhibitor. Vildagliptin, dipeptidyl It prevents the degradation of the dipeptidase-IV enzyme, thus inhibiting the release of incretin hormones, such as glucagon. It inhibits the effects of peptide-1 (GLP-i) and glucose-dependent insulinotropic peptide (GIP).
Vildagliptin'in kimyasal adi (S) - {[(3-hidroksiadamantan-1-iI) amino] asetil} pirolidin-2- karbonitrildir ve asagida Formül 1'de gösterilen kimyasal yapiya sahiptir. Chemical name of vildagliptin (S) - {[(3-hydroxyadamantane-1-yl)amino] acetyl} pyrrolidine-2- It is carbonitrile and has the chemical structure shown in Formula 1 below.
Formül 1 Vildagliptin, suda ve organik polar çözücüler içinde çözünürdür. Formula 1 Vildagliptin is soluble in water and organic polar solvents.
Vildagliptin, Galvus® markasiyla 50 mg dozaj formlarinda pazarlanmaktadir. Özellikle tip 2 diyabet olmak üzere diabetes mellitus tedavisinde kullanilmaktadir. Vildagliptin is marketed in 50 mg dosage forms under the brand name Galvus®. Especially type 2 It is used in the treatment of diabetes mellitus.
Metformin, oral yoldan uygulanan bir biguanid yapisina sahip bir antidiyabetiktir. Metformin hidroklorür beyaz ila beyazimsi kristalin bir bilesiktir ve suda kolaylikla çözünür ve aseton, eter ve kloroformda hemen hemen çözünmez. Metforminin oral dozlarinin genellikle günde degisebilir. Tek basina veya sülfonilüre, alfa-glukosidaz inhibitörleri veya insülin ile kombinasyon halinde kullanilir. Metformin is an antidiabetic with a biguanide structure that is administered orally. metformin hydrochloride is a white to off-white crystalline compound that is readily soluble in water and acetone, It is practically insoluble in ether and chloroform. Oral doses of metformin are usually administered daily. It may change. Alone or with sulfonylurea, alpha-glucosidase inhibitors or insulin used in combination.
Metformin hidroklorürün kimyasal adi, 1,1-dimetilbiguanid hidroklorürdür ve kimyasal yapisi asagida Formül Il'de gösterilmektedir.. The chemical name of metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride and its chemical structure It is shown below in Formula II.
HSC"`NJLNJLNH2 Formül ll Vildagliptin ve metformin hidroklorür içeren kombinasyon, Eucreas® ticari markasi altinda dozaj formlari). Kombinasyon halinde ilgili etkin maddelerin farmasötik formülasyonlari ve bunlarin hazirlanmasina yönelik proses EP 1948149 sayili patent basvurusunda açiklanmaktadir. basvurusunda açiklanmaktadir. Açiklanan tablet, etkin maddelere ek olarak dolgu maddeleri, baglayicilari dagiticilari Iubrikanlar ve renklendirme maddeleri gibi olagan eksipiyanlar içerebilir. Bahsedilen Iubrikanlara örnekler; koloidal silika, magnezyum trisilikat, nisasta, talk, kalsiyum fosfat, magnezyum stearat, alüminyum stearat, kalsiyum stearat, magnezyum karbonat, magnezyum oksit, polietilen glikol, selüloz ve mikrokristalin selülozdur. HSC"`NJLNJLNH2 formula ll The combination containing vildagliptin and metformin hydrochloride is available under the trademark Eucreas® dosage forms). Pharmaceutical formulations of relevant active substances in combination and The process for their preparation is described in patent application numbered EP 1948149. is explained. It is explained in the application. The described tablet contains, in addition to the active ingredients, fillers, binders dispersants usual excipients such as lubricants and coloring agents may contain. Examples of the mentioned Iubricans; colloidal silica, magnesium trisilicate, starch, talc, calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, cellulose and microcrystalline cellulose.
EP sayili patent basvurusunda etkin madde olarak sitagliptin veya Vildagliptin veya sitagliptinin veya vildagliptinin tuzu ile kombinasyon halinde metformin etkin maddesi veya metforminin tuzunu ve bir Iubrikan (kompozisyonun toplam agirligina göre agirlikça glikoldür veya en az bir baska Iubrikan ile polietilen glikolün bir karisimidir. Sitagliptin or Vildagliptin as the active ingredient in the patent application numbered EP or the active substance metformin in combination with sitagliptin or vildagliptin salt or the salt of metformin and a lubricant (by weight relative to the total weight of the composition glycol or a mixture of polyethylene glycol with at least one other lubricant.
Hem metformin HCI hem de vildagliptin bazi yapisal problemler barindirmaktadir. Stabilite ile ilgili sorunlar, çevre ve fiziksel kosullarin etkisine bagli olarak vildagliptin dahil olmak üzere birçok etkin maddede ortaya çikmaktadir. Vildagliptin, hava ve nem kosullarina karsi oldukça duyarli bir etkin maddedir. Vildagliptin hava ve neme maruz kaldiginda, yapisal olarak bozunur ve kimyasal davranisi degisir. Gelistirilen vildagliptin ürünlerinin stabilitesi istenilen düzeyde degildir ve söz konusu ürünlerin raf ömrü kisalmistir. Ek olarak, vildagliptin formülasyon gelistirmede kullanilan eksipiyanlara karsi reaktiftir. Bu durum, formülasyonda safsizliklarin olusmasina neden olmakta ve istenmeyen bilesenlerin formülasyona girmesine yol açmaktadir. Both metformin HCl and vildagliptin have some structural problems. with stability related problems, including vildagliptin, depending on the influence of the environment and physical conditions It occurs in many active substances. Vildagliptin is highly resistant to weather and moisture conditions. It is a sensitive active ingredient. Vildagliptin becomes structurally unstable when exposed to air and moisture. It decomposes and its chemical behavior changes. The stability of the developed vildagliptin products is as desired. and the shelf life of the products in question is shortened. Additionally, vildagliptin It is reactive towards excipients used in formulation development. This situation is in the formulation It causes impurities to form and undesirable components enter the formulation. It gives way.
Bu kombinasyonun stabilitesi açisindan, vildagliptinin yukaridaki dezavantajlarinin üstesinden gelmek için alternatif yaklasimlara ihtiyaç duyulmustur. In terms of the stability of this combination, the above disadvantages of vildagliptin are Alternative approaches were needed to overcome this problem.
Bazi tuzlarin veya bazi tuz hidratlarinin iyilestirilmis fizikokimyasal özellikleri, hem farmasötik açidan aktif bir madde olarak üretildiginde hem de üretim ve saklama sirasinda büyük önem tasimaktadir. The improved physicochemical properties of some salts or some salt hydrates are useful both in pharmaceutical applications. It is of great importance both during production and storage when it is produced as an active substance in terms of is carrying.
Mevcut bulusta, vildagliptin tuzu elde edilmis ve formülasyon hazirlanirken test edilmis olup, ölçülebilir bir nem absorpsiyonu veya kaybi göstermemesi yönünden avantajli oldugu görülmüstür. Bu sekilde vildagliptinin bozunmasi önlenmis ve formülasyonun stabilize edilmesi saglanmistir. In the present invention, vildagliptin salt was obtained and tested while preparing the formulation. It is advantageous in that it does not show any measurable moisture absorption or loss. has been seen. In this way, degradation of vildagliptin was prevented and the formulation was stabilized. It has been ensured.
Mevcut bulusta, vildagliptin ve en az bir asitlestirici ajan. bir çözücü içinde çözündürülmekte ve daha sonra vildagliptin tuzu elde edilmektedir. Yani, bu formülasyon yukaridaki sorunlarin üstesinden gelmektedir. Bu sekilde, fiziksel parametrelerin daha sabit tutulmasi ile baslayarak, formülasyonlarin daha da yüksek kalitede olmasi garanti edilebilir. In the present invention, vildagliptin and at least one acidifying agent. being dissolved in a solvent and then vildagliptin salt is obtained. So, this formulation solves the above problems is overcoming it. In this way, by keeping the physical parameters more constant By starting with this, even higher quality of the formulations can be guaranteed.
Bulusun Ayrintili Açiklamasi Mevcut bulusun ana amaci, istenen stabiliteye, hizli dagilma süresine ve kabul edilebilir bir dissolüsyon profiline sahip bir tablete basilabilen vildagliptin ve metformin HCI içeren bir tablet sunulmasidir. Detailed Description of the Invention The main object of the present invention is to achieve the desired stability, rapid dispersion time and acceptable A tablet containing vildagliptin and metformin HCl that can be compressed into a tablet with a dissolution profile. is the presentation of tablets.
Mevcut bulusun bir baska amaci, önceki teknikteki problemleri ortadan kaldirmak ve ilgili önceki teknige ek avantajlar getirmektir. Another purpose of the present invention is to eliminate the problems in the prior art and to to bring additional advantages to the prior art.
Mevcut bulusun ana amaci, stabil bir kombinasyon prosesi sunulmasidir. Proses, basit, hizli, uygun maliyetli, zaman tasarrufu saglayan ve endüstriyel olarak uygun bir yöntemdir. The main purpose of the present invention is to provide a stable combination process. The process is simple, fast, It is a cost-effective, time-saving and industrially suitable method.
Bu tarifnamede kullanildigi sekliyle "çözelti", vildagliptin, en az bir asitlestirici ajan ve en az bir baglayici içeren, tercihen %65 etil alkol-su olmak üzere bir çözücü içinde çözünen bir form anlamina gelmektedir. As used herein, "solution" means vildagliptin, at least one acidifying agent and at least containing a binder, dissolved in a solvent, preferably 65% ethyl alcohol-water It means form.
Bulusun bir uygulamasina göre, bir tablet formülasyonu, bir çözelti içinde vildagliptin ve metformin hidroklorür içermekte olup, burada vildagliptin ve en az bir asitlestirici ajan ve en az bir baglayici bir çözücü içinde çözünmüstür. According to one embodiment of the invention, a tablet formulation contains vildagliptin and metformin hydrochloride, comprising vildagliptin and at least one acidifying agent and A little binder is dissolved in a solvent.
Mevcut bulusta, vildagliptin ve en az bir asitlestirici ajan, bir çözücü içinde çözündürülmekte ve daha sonra vildagliptin tuzu elde edilmektedir. Böylece, tablet formülasyonunun stabilitesi saglanir, çünkü vildagliptin tuzu ölçülebilir bir nem absorpsiyonu veya kaybi göstermemesi açisindan avantajlidir ve vildagliptin etkin maddesi bozunmaya ugramaz. Bu özellik üretimde çok önemlidir. Ayrica, vildagliptin tuzlarini içeren çözelti, kristalizasyona gerek kalmadan dogrudan proseste kullanilmistir. Bu da bize çözücü kullanmadan zaman kazandirmistir. In the present invention, vildagliptin and at least one acidifying agent are dissolved in a solvent. and then vildagliptin salt is obtained. Thus, the stability of the tablet formulation This is achieved because the vildagliptin salt does not show any measurable moisture absorption or loss. and the active ingredient of vildagliptin does not undergo degradation. This feature is in production It is very important. Moreover, the solution containing vildagliptin salts can be produced without the need for crystallization. used directly in the process. This saved us time without using solvents.
Böylelikle hizli, pratik ve maliyeti düsük stabil bir kombinasyon elde edilmistir. Thus, a fast, practical and low-cost, stable combination has been achieved.
Ayrica, vildagliptin tuzu, baska bir etkin madde olan metformin HCI içeren bir formülasyonda bulundugunda stabilite ve dissolüsyon profilini gelistirmeye yardimci olur. Sasirtici bir sekilde, mevcut bulusta, vildagliptin tuzunun baska bir etkin maddenin bozunmasini önleme veya indirgeme avantajina sahip oldugu görülmüstür. Additionally, vildagliptin salt can be used in a formulation containing another active ingredient, metformin HCl. When present, it helps improve stability and dissolution profile. a surprising one Thus, in the present invention, vildagliptin salt prevents the degradation of another active substance. It has been observed that it has a reduction advantage.
Uygun asitlestirici ajan; hidroklorik asit, sitrik asit, sitrik asit anhidrat, tartarik asit, askorbik asit, malik asit, oksalik asit, süksinat, asetik asit, bütirik asit, malonik asit, formik asit, fumarik asit veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable acidifying agent; hydrochloric acid, citric acid, citric acid anhydrate, tartaric acid, ascorbic acid, malic acid, oxalic acid, succinate, acetic acid, butyric acid, malonic acid, formic acid, fumaric is selected from the group consisting of acids or mixtures thereof.
Mevcut bulusun bir uygulamasina göre asitlestici ajanin miktari, toplam formülasyonun agirliginca %0.1 ile %50 arasindadir. According to one embodiment of the present invention, the amount of acidifying agent is It is between 0.1% and 50% by weight.
Mevcut bulusun bir uygulamasina göre, içindeki asitlestirici ajanin miktari vildagliptin molü basina 1 mol ila 1.5 mol, tercihen vildagliptin molü basina 1.0 ila 1.3 mol arasindadir. Bu oranlar, vildagliptin tuzunun hazirlanmasi için ve dolayisiyla stabil bir kombinasyon için çok önemlidir. According to one embodiment of the present invention, the amount of acidifying agent in the mole of vildagliptin 1 mole to 1.5 moles per mole of vildagliptin, preferably 1.0 to 1.3 moles per mole of vildagliptin. This ratios are too high for the preparation of vildagliptin salt and therefore for a stable combination It is important.
Mevcut bulusun bu uygulamasina göre, asitlestirici ajan hidroklorik asittir. According to this embodiment of the present invention, the acidifying agent is hydrochloric acid.
Uygun baglayicilar; polivinilpirolidon, hidroksipropil metil selüloz, sodyum karboksimetil selüloz, polietilen glikol, polivinil alkol, polivinil asetat, önceden jelatinize edilmis nisasta, dogal zamklar, sükroz, sodyum aljinat, karboksi metil selüloz, metil selüloz, jelatin, karagenan, guar zamki, karbomer, polimetakrilatlar, metakrilat polimerler, jelatin, agar, alginat, ksantan zamki, pektin, polisakkaritler, karbomer, poloksamer, poliakrilamid, alüminyum hidroksit, laponit, bentonit, polioksietilen-alkil eter, polidekstroz, polietilen oksit veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable connectors; polyvinylpyrrolidone, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, pregelatinized starch, natural gums, sucrose, sodium alginate, carboxy methyl cellulose, methyl cellulose, gelatin, carrageenan, guar gum, carbomer, polymethacrylates, methacrylate polymers, gelatin, agar, alginate, xanthan gum, pectin, polysaccharides, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, laponite, bentonite, polyoxyethylene-alkyl ether, polydextrose, polyethylene oxide or mixtures thereof.
Mevcut bulusun bir uygulamasina göre, baglayicilarin kullanimi, çözeltinin formülasyon içinde kolay dagitilmasini saglamaktadir. Böylece formülasyonun istenen dissolüsyon profiline sahip olmasini saglamaya yardimci olmaktadir. According to one embodiment of the present invention, the use of binders may affect the formulation of the solution. It allows easy distribution inside. Thus, the desired dissolution of the formulation It helps to ensure that you have a profile.
Mevcut bulusun bir uygulamasina göre baglayicilarin miktari, toplam formülasyonun agirliginca %1.0 ile %200 arasindadir. Tercihen, toplam formülasyonda agirlikça %2.0 ile Mevcut bulusun bir uygulamasina göre, baglayici, polivinilpirolidon veya hidroksipropil metil selüloz veya bunlarin karisimlaridir. According to one embodiment of the present invention, the amount of binders is It is between 1.0% and 200% by weight. Preferably with 2.0% by weight in the total formulation According to one embodiment of the present invention, the binder is polyvinylpyrrolidone or hydroxypropyl methyl cellulose or mixtures thereof.
Mevcut bulusun bir uygulamasina göre, çözeltinin hazirlanmasi asagidaki adimlardan olusmaktadir; - Oda sicakliginda, vildagliptin, tercihen %65 etil alkol-su olmak üzere bir çözücüye eklenir, - Ardindan, en az bir asitlestirici ajan eklenir ve karistirilir, - Ardindan, en az bir baglayici eklenir ve karistirilir. According to one embodiment of the present invention, preparation of the solution consists of the following steps: is formed; - At room temperature, vildagliptin is dissolved in a solvent, preferably 65% ethyl alcohol-water. is added, - Then, at least one acidifying agent is added and mixed, - Then, at least one binder is added and mixed.
Mevcut bulusun bir uygulamasina göre metformin hidroklorürün miktari, toplam formülasyonun agirliginca %50.0 ile %90.0 arasindadir. Tercihen, toplam formülasyonda agirlikça %60.0 ile %800 arasindadir. According to one embodiment of the present invention, the amount of metformin hydrochloride is It is between 50.0% and 90.0% by weight of the formulation. Preferably in the total formulation It is between 60.0% and 800% by weight.
Mevcut bulusun bir uygulamasina göre vildagliptin miktari, toplam formülasyonun agirliginca Mevcut bulusun bir uygulamasina göre, tablet, dolgu maddeleri, dagiticilar, Iubrikanlar, glidantlar, yüzey aktif maddeleri, topaklanmayi önleyici maddeler, kaplama maddeleri veya bunlarin karisimlarini içeren gruptan seçilen en az bir farmasötik olarak kabul edilebilir eksipiyan içermektedir. According to one embodiment of the present invention, the amount of vildagliptin is determined by the weight of the total formulation. According to one embodiment of the present invention, the tablet contains fillers, disintegrants, lubricants, glidants, surfactants, anti-caking agents, coating agents or at least one pharmaceutically acceptable substance selected from the group consisting of mixtures thereof. Contains excipients.
Genel olarak, formülasyonda yer alan eksipiyanlar, etkin maddenin çözünürlügü, emilimi, biyoyararlanimi gibi fizikokimyasal ve fizikokinetik özellikleri pozitif veya negatif yönde etkileyebilir. Bu nedenle, bir etkin maddeye eslik eden eksipiyanlar, formülasyon gelistirilirken dikkatle ve bilinçli bir sekilde seçilmelidir. Formülasyonlar, etkin maddeler ile eksipiyanlar arasinda fizikokimyasal geçimsizlik göstermemelidir. In general, the excipients included in the formulation affect the solubility, absorption, Physicochemical and physicokinetic properties such as bioavailability can be affected positively or negatively. may affect. For this reason, excipients accompanying an active ingredient are considered during formulation development. should be chosen carefully and consciously. Formulations, active ingredients and excipients There should be no physicochemical incompatibility between them.
Uygun dolgu maddeleri; mikrokristalin selüloz, dibazik kalsiyum fosfat, mannitol, spreyle kurutulmus mannitol, Iaktoz, Iaktoz monohidrat, nisasta, dekstroz, sükroz, fruktoz, sodyum karbonat, maltoz, sorbitol, ksilitol, inositol, kaolin, inorganik tuzlar, kalsiyum tuzlari, polisakkaritler, sodyum klorür, dekstratlar, laktitol, maltodekstrin, sükroz-maltodekstrin karisimi, trehaloz, sodyum bikarbonat, kalsiyum karbonat içeren gruptan seçilmektedir. Suitable fillers; microcrystalline cellulose, dibasic calcium phosphate, mannitol, by spray dried mannitol, lactose, lactose monohydrate, starch, dextrose, sucrose, fructose, sodium baking soda, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin The mixture is selected from the group consisting of trehalose, sodium bicarbonate and calcium carbonate.
Mevcut bulusun bir uygulamasina dolgu maddelerinin miktari, toplam formülasyonun agirliginca %2.0 ile %200 arasindadir. Tercihen, toplam formülasyonda agirlikça %2.0 ile Mevcut bulusun bir uygulamasina göre dolgu maddesi, mikrokristalin selülozdur. The amount of fillers in an embodiment of the present invention depends on the total formulation. It is between 2.0% and 200% by weight. Preferably with 2.0% by weight in the total formulation According to one embodiment of the present invention, the filler is microcrystalline cellulose.
Uygun dagiticilar; kroskarmelloz sodyum, sodyum nisasta glikolat, prejelatinize nisasta, düsük sübstitüye hidroksipropil selüloz, sodyum karboksimetil selüloz, kalsiyum karboksimetil selüloz, karboksimetil selüloz, dokusat sodyum, guar zamki, poliakrilin potasyum, sodyum aljinat, misir nisastasi, aljinatlar, iyon degistirici reçineler, magnezyum alüminyum silikat, sodyum dodesil sülfat, poloksamer, sodyum glisin karbonat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable distributors; croscarmellose sodium, sodium starch glycolate, pregelatinized starch, low substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, docusate sodium, guar gum, polyacryline potassium, sodium alginate, corn starch, alginates, ion exchange resins, magnesium aluminum silicate, containing sodium dodecyl sulphate, poloxamer, sodium glycine carbonate or mixtures thereof is selected from the group.
Mevcut bulusun bir uygulamasina göre dagitici miktari, toplam formülasyonun agirliginca Mevcut bulusun bir uygulamasina göre dagitici, kroskarmeloz sodyum veya sodyum nisasta glikolat veya bunlarin karisimlaridir. According to one embodiment of the present invention, the amount of disintegrant is based on the weight of the total formulation. According to one embodiment of the present invention, the disintegrant is croscarmellose sodium or sodium starch. glycolate or mixtures thereof.
Uygun lubrikanlar; sodyum stearil fumarat, magnezyum stearat, kalsiyum stearat, çinko stearat, mumlar, hidrojenlenmis bitkisel yag, sodyum klorat, magnezyum sodyum oleat, sodyum asetat, sodyum benzoat, gliserol palmito sülfat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable lubricants; sodium stearyl fumarate, magnesium stearate, calcium stearate, zinc stearate, waxes, hydrogenated vegetable oil, sodium chlorate, magnesium sodium oleate, containing sodium acetate, sodium benzoate, glycerol palmito sulphate or mixtures thereof is selected from the group.
Mevcut bulusun bir uygulamasina göre Iubrikan miktarii toplam formülasyonun agirliginca Mevcut bulusun bir uygulamasina göre, Iubrikan, sodyum stearil fumarat veya magnezyum stearat veya bunlarin karisimlaridir. According to one embodiment of the present invention, the amount of lubricant is determined by the weight of the total formulation. According to one embodiment of the present invention, the lubricant is sodium stearyl fumarate or magnesium. stearate or mixtures thereof.
Uygun glidantlar, kolloidal silikon dioksit, misir nisastasi veya bunlarin karisimlarini içeren gruptan seçilmektedir. Containing suitable glidants, colloidal silicon dioxide, corn starch or mixtures thereof. is selected from the group.
Mevcut bulusun bir uygulamasina göre glidant miktari, toplam formülasyonun agirliginca Mevcut bulusun bir uygulamasina göre glidant, kolloidal silikon dioksittir. According to one embodiment of the present invention, the amount of glidant is determined by the weight of the total formulation. According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.
Uygun yüzey aktif maddeleri; sodyum Iauril sülfat, sodyum dokusat, gliseril monooleat, polietilen alkil eter, polioksietilen stearatlar, polietilen glikol, sodyum benzoat, dokusat sodyum, alfa tokoferol, askorbil palmitat, polioksietilen hidrojene hintyagi veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable surfactants; sodium lauryl sulfate, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene stearates, polyethylene glycol, sodium benzoate, docusate sodium, alpha tocopherol, ascorbyl palmitate, polyoxyethylene hydrogenated castor oil or any of these is selected from the group containing mixtures.
Mevcut bulusun bir uygulamasina yüzey aktif maddelerin miktari, toplam formülasyonun agirliginca %0.1 ile %20 arasindadir. The amount of surfactants in an embodiment of the present invention depends on the total formulation. It is between 0.1% and 20% by weight.
Mevcut bulusun bir uygulamasina göre yüzey aktif madde, sodyum Iauril sülfattir. According to one embodiment of the present invention, the surfactant is sodium lauryl sulfate.
Uygun topaklanmayi önleyici maddeler; talk, kalsiyum fosfat, tribazik, kalsiyum silikat, hidrofobik koloidal silika, magnezyum oksit, magnezyum silikat, magnezyum trisilikat veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable anti-caking agents; talc, calcium phosphate, tribasic, calcium silicate, hydrophobic colloidal silica, magnesium oxide, magnesium silicate, magnesium trisilicate or is selected from the group containing mixtures thereof.
Mevcut bulusun bu uygulamasina göre, topaklanmayi önleyici madde talktir. According to this embodiment of the present invention, the anticaking agent is talc.
Mevcut bulusun bir uygulamasina göre topaklanmayi önleyici madde miktari, toplam formülasyonun agirliginca %0.01 ile %31) arasindadir. According to one embodiment of the present invention, the amount of anticaking agent is the total It is between 0.01% and 31% by weight of the formulation.
Uygun kaplama ajanlari, kopovidon, polimetakrilatlar, polidekstroz, polialkilarilat kopolimerler, triasetin, hidroksil propil metil selüloz, koloidal silikon dioksit, Iaktoz monohidrat, orta Zincirli trigliseritler, hidroksipropil selüloz, beyaz mum. polivinil alkol. polietilen glikol, talk, polivinil alkol-polietilen glikol kopolimerleri (Kollicoat® IR), etilselüloz dispersiyonlari (Surelease®), polivinilprolidon, polivinilprolidon-vinil asetat kopolimeri (PVP-VA), her türlü Opadry®, pigmentleri, boyalar, titanyum dioksit, kirmizi demir oksit, siyah demir oksit veya bunlarin karisimlarini içeren gruptan seçilmektedir. Suitable coating agents include copovidone, polymethacrylates, polydextrose, polyalkylarylate copolymers, triacetin, hydroxyl propyl methyl cellulose, colloidal silicon dioxide, lactose monohydrate, medium chain triglycerides, hydroxypropyl cellulose, white wax. polyvinyl alcohol. polyethylene glycol, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), all types of Opadry®, pigments, dyes, titanium dioxide, red iron oxide, black iron oxide or their is selected from the group containing mixtures.
Mevcut bulusun bir uygulamasina göre kaplama maddeleri içeren kaplama miktari toplam formülasyonda agirlikça %20 ile %5.0 arasindadir. According to one embodiment of the present invention, the amount of coating containing coating substances is It is between 20% and 5.0% by weight in the formulation.
Mevcut bulusun bir uygulamasina göre, kaplama maddeleri; polivinil alkol, polietilen glikol, talk, titanyum dioksit, kirmizi demir oksit, siyah demir oksit veya bunlarin karisimidir. According to an embodiment of the present invention, coating materials; polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, black iron oxide or mixtures thereof.
Mevcut bulusa ait tablet, direkt baski, yas veya kuru granülasyon, isiyla eritmeli granülasyon, isiyla eritmeli ekstrüzyon, akiskan yatakli granülasyon, ekstrüzyonlküre haline getirme, çift baski (slugging), spreyle kurutma ve çözücü buharlastirma gibi teknikte iyi bilinen standart teknikler ve üretim prosesleri kullanilarak hazirlanabilir. Örnek 1: Vildagliptin ve metformin HCI içeren tablet formülasyonu Metformin HCI 50.0 - 90.0 Vildagliptin 2.0 - 20.0 Mikrokristalin selüloz 2.0 - 20.0 Kroskarmelloz sodyum 2.0 - 10.0 Polivinilpirolidon 1.0 - 20.0 .2 Hidroklorik asit 0.1- 5.0 Kolloidal silikon dioksit 0.1- 2.0 Sodyum Iauril sülfat 0.1- 2.0 .“ Sodyum stearil fumarat 0.5- 5.0 TOPLAM 100 Örnek 2: Vildagliptin ve metformin HCI içeren tablet formülasyonu Metformin HCI 76.3 Vildagliptin 3.8 Mikrokristalin selüloz 4.6 Kroskarmelloz sodyum 3.6 Polivinilpirolidon 5.0 .9 Hidroklorik asit 0.5 Kolloidal silikon dioksit 0.4 Sodyum Iauril sülfat 0.5 TOPLAM 100 Örnek 1 veya 2 için proses; Metformin elenir, Mikrokristalin selüloz ve kroskarmelloz sodyum eklenir ve ardindan karistirilir ve toz bir karisim elde edilir Çözelti hazirlanir 0 Tercihen %65 etil alkol-su olmak üzere bir çözücüye vildagliptin eklenir, o Ardindan, hidroklorik asit (%370 hidroklorik asit-su) eklenir ve karistirilir, 0 Daha sonra, polivinilpirolidon eklenir ve karistirilir, Ardindan, toz karisim ve çözelti akiskan yatakli kurutucuda granül haline getirilir ve Karisim elenir, Kalan polivinilpirolidon karisima eklenir ve akiskan yatakli kurutucuda granül haline getirilir ve kurutulur Karisim elenir ve granül elde edilir. The tablet of the present invention can be produced by direct compression, wet or dry granulation, heat melt granulation, heat melt extrusion, fluidized bed granulation, extrusion spheroidization, double standard methods well known in the art such as slugging, spray drying and solvent evaporation. It can be prepared using techniques and production processes. Example 1: Tablet formulation containing vildagliptin and metformin HCl Metformin HCI 50.0 - 90.0 Vildagliptin 2.0 - 20.0 Microcrystalline cellulose 2.0 - 20.0 Croscarmellose sodium 2.0 - 10.0 Polyvinylpyrrolidone 1.0 - 20.0 .2 Hydrochloric acid 0.1- 5.0 Colloidal silicon dioxide 0.1- 2.0 Sodium Iauryl sulfate 0.1- 2.0 .“ Sodium stearyl fumarate 0.5- 5.0 TOTAL 100 Example 2: Tablet formulation containing vildagliptin and metformin HCl Metformin HCI 76.3 Vildagliptin 3.8 Microcrystalline cellulose 4.6 Croscarmellose sodium 3.6 Polyvinylpyrrolidone 5.0 .9 Hydrochloric acid 0.5 Colloidal silicon dioxide 0.4 Sodium Iauryl sulfate 0.5 TOTAL 100 Process for example 1 or 2; Metformin is eliminated, Microcrystalline cellulose and croscarmellose sodium are added and then mixed and powdered. a mixture is obtained The solution is prepared 0 Add vildagliptin to a solvent, preferably 65% ethyl alcohol-water, o Then, hydrochloric acid (370% hydrochloric acid-water) is added and mixed, 0 Next, polyvinylpyrrolidone is added and mixed, Then, the powder mixture and solution are granulated in the fluid bed dryer and The mixture is eliminated, The remaining polyvinylpyrrolidone is added to the mixture and turned into granules in a fluid bed dryer. brought and dried The mixture is sifted and granules are obtained.
- Granüller ve kolloidal silikon dioksit ve sodyum Iauril sülfat karistirilir, - Sodyum stearil fumarat eklenir ve karistirilir, - Karisim tabletler olusturmak üzere basilir, - Tabletler, kaplama maddeleri ile kaplanir Örnek 3: Vildagliptin ve metformin HCI içeren tablet formülasyonu Metformin HCI 50.0 - 90.0 Vildagliptin 2.0 - 20.0 Mikrokristalin selüloz 2.0 - 20.0 Sodyum nisasta glikolat 2.0 - 10.0 Hidroksipropil metil selüloz 1.0 - 20.0 Hidroklorik asit 0.1 - 5.0 Kolloidal silikon dioksit 0.1- 2.0 TOPLAM 100 Örnek 4: Vildagliptin ve metformin HCI içeren tablet formülasyonu Metformin HCI 76.7 Vildagliptin 3.8 Mikrokristalin selüloz 4.6 Sodyum nisasta glikolat 3.6 Hidroksipropil metil selüloz 5.0 Hidroklorik asit 0.5 .2 Talk 0.1 Kolloidal silikon dioksit 0.4 E Magnezyum stearat 2.0 TOPLAM 100 Örnek 3 veya 4 için proses; Metformin elenir, Mikrokristalin selüloz ve sodyum nisasta glikolat eklenir ve ardindan karistirilir ve toz bir karisim elde edilir Çözelti hazirlanir 0 Tercihen %65 etil alkol-su olmak üzere bir çözücüye Vildagliptin eklenir, o Ardindan, hidroklorik asit (%370 hidroklorik asit-su) eklenir ve karistirilir. o Ardindan, hidroksipropil metil ve talk eklenir ve karistirilir. - Granules and colloidal silicon dioxide and sodium lauryl sulfate are mixed, - Sodium stearyl fumarate is added and mixed, - The mixture is pressed to form tablets, - Tablets are coated with coating agents Example 3: Tablet formulation containing vildagliptin and metformin HCl Metformin HCI 50.0 - 90.0 Vildagliptin 2.0 - 20.0 Microcrystalline cellulose 2.0 - 20.0 Sodium starch glycolate 2.0 - 10.0 Hydroxypropyl methyl cellulose 1.0 - 20.0 Hydrochloric acid 0.1 - 5.0 Colloidal silicon dioxide 0.1- 2.0 TOTAL 100 Example 4: Tablet formulation containing vildagliptin and metformin HCl Metformin HCI 76.7 Vildagliptin 3.8 Microcrystalline cellulose 4.6 Sodium starch glycolate 3.6 Hydroxypropyl methyl cellulose 5.0 Hydrochloric acid 0.5 .2Talk 0.1 Colloidal silicon dioxide 0.4 E Magnesium stearate 2.0 TOTAL 100 Process for example 3 or 4; Metformin is eliminated, Microcrystalline cellulose and sodium starch glycolate are added and then mixed and powdered. a mixture is obtained The solution is prepared 0 Vildagliptin is added to a solvent, preferably 65% ethyl alcohol-water, o Then, hydrochloric acid (370% hydrochloric acid-water) is added and mixed. o Then, hydroxypropyl methyl and talc are added and mixed.
Ardindan, toz karisim ve çözelti akiskan yatakli kurutucuda granül haline getirilir ve Karisim elenir ve granül elde edilir. Then, the powder mixture and solution are granulated in the fluid bed dryer and The mixture is sifted and granules are obtained.
Granüller ve kolloidal silikon dioksit karistirilir, Magnezyum stearat eklenir ve karistirilir, Karisim tabletler olusturmak üzere basilir, Tabletler, kaplama maddeleri ile kaplanir Granules and colloidal silicon dioxide are mixed, Magnesium stearate is added and mixed, The mixture is pressed to form tablets, Tablets are coated with coating agents
Claims (1)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2020/09946A TR202009946A2 (en) | 2020-06-25 | 2020-06-25 | A STABLE COMBINATION WITH VILDAGLIPTIN AND METFORMIN HCI |
| EP21828954.4A EP4171532A1 (en) | 2020-06-25 | 2021-05-07 | A stable combination of vildagliptin and metformin hci |
| PCT/TR2021/050442 WO2021262115A1 (en) | 2020-06-25 | 2021-05-07 | A stable combination of vildagliptin and metformin hci |
Applications Claiming Priority (1)
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|---|---|---|---|
| TR2020/09946A TR202009946A2 (en) | 2020-06-25 | 2020-06-25 | A STABLE COMBINATION WITH VILDAGLIPTIN AND METFORMIN HCI |
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| EA032126B1 (en) * | 2013-12-23 | 2019-04-30 | Крка, Д.Д. Ново Место | Solid pharmaceutical composition comprising metformin and vildagliptin and process for manufacturing same |
| MA40869A (en) * | 2014-10-30 | 2017-09-05 | Sanovel Ilac Sanayi Ve Ticaret As | PHARMACEUTICAL COMBINATIONS OF VILDAGLIPTIN AND PPAR AGONISTS |
| CN105193752B (en) * | 2015-10-27 | 2018-03-30 | 石家庄康贺威药业有限公司 | A kind of vildagliptin tablet and preparation method thereof |
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