WO2019023791A1 - Levothyroxine formulations - Google Patents
Levothyroxine formulations Download PDFInfo
- Publication number
- WO2019023791A1 WO2019023791A1 PCT/CA2018/050923 CA2018050923W WO2019023791A1 WO 2019023791 A1 WO2019023791 A1 WO 2019023791A1 CA 2018050923 W CA2018050923 W CA 2018050923W WO 2019023791 A1 WO2019023791 A1 WO 2019023791A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- sodium
- acid
- phosphate
- levothyroxine
- dibasic
- Prior art date
Links
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 title claims abstract description 231
- 239000000203 mixture Substances 0.000 title claims abstract description 203
- 238000009472 formulation Methods 0.000 title claims abstract description 188
- 229950008325 levothyroxine Drugs 0.000 title claims abstract description 90
- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 238000000034 method Methods 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 393
- 239000000243 solution Substances 0.000 claims description 267
- 229960003918 levothyroxine sodium Drugs 0.000 claims description 138
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 137
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 137
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 104
- 239000001488 sodium phosphate Substances 0.000 claims description 88
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 85
- 239000008215 water for injection Substances 0.000 claims description 82
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 77
- 235000010265 sodium sulphite Nutrition 0.000 claims description 69
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 claims description 62
- 235000009518 sodium iodide Nutrition 0.000 claims description 46
- 229940083599 sodium iodide Drugs 0.000 claims description 46
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 45
- 229940124274 edetate disodium Drugs 0.000 claims description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- 229940061607 dibasic sodium phosphate Drugs 0.000 claims description 29
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 28
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 26
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 26
- 235000011008 sodium phosphates Nutrition 0.000 claims description 26
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 24
- PYLIXCKOHOHGKQ-UHFFFAOYSA-L disodium;hydrogen phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O PYLIXCKOHOHGKQ-UHFFFAOYSA-L 0.000 claims description 22
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 20
- 229940001482 sodium sulfite Drugs 0.000 claims description 19
- SHWNNYZBHZIQQV-UHFFFAOYSA-J EDTA monocalcium diisodium salt Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-J 0.000 claims description 18
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 239000003963 antioxidant agent Substances 0.000 claims description 15
- 235000006708 antioxidants Nutrition 0.000 claims description 15
- 229960004217 benzyl alcohol Drugs 0.000 claims description 15
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 15
- 239000006172 buffering agent Substances 0.000 claims description 15
- 239000002738 chelating agent Substances 0.000 claims description 15
- 239000004310 lactic acid Substances 0.000 claims description 15
- 239000003002 pH adjusting agent Substances 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 15
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 15
- 229960000281 trometamol Drugs 0.000 claims description 15
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 14
- 210000001685 thyroid gland Anatomy 0.000 claims description 14
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 13
- XYQRXRFVKUPBQN-UHFFFAOYSA-L Sodium carbonate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]C([O-])=O XYQRXRFVKUPBQN-UHFFFAOYSA-L 0.000 claims description 13
- 229910021529 ammonia Inorganic materials 0.000 claims description 13
- 229940075564 anhydrous dibasic sodium phosphate Drugs 0.000 claims description 13
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 13
- 239000000920 calcium hydroxide Substances 0.000 claims description 13
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 13
- 229940111685 dibasic potassium phosphate Drugs 0.000 claims description 13
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 13
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 claims description 13
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 claims description 13
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 claims description 13
- 229960003194 meglumine Drugs 0.000 claims description 13
- 229940001593 sodium carbonate Drugs 0.000 claims description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 13
- 229940018038 sodium carbonate decahydrate Drugs 0.000 claims description 13
- 229940076133 sodium carbonate monohydrate Drugs 0.000 claims description 13
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 235000011187 glycerol Nutrition 0.000 claims description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 12
- 230000015556 catabolic process Effects 0.000 claims description 11
- 238000006731 degradation reaction Methods 0.000 claims description 11
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 claims description 11
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 claims description 10
- 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 10
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 10
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 10
- 229960004543 anhydrous citric acid Drugs 0.000 claims description 10
- 229960002303 citric acid monohydrate Drugs 0.000 claims description 10
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 10
- 208000003532 hypothyroidism Diseases 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000001509 sodium citrate Substances 0.000 claims description 10
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 10
- 239000011975 tartaric acid Substances 0.000 claims description 10
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 claims description 10
- 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 10
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 9
- 229940095629 edetate calcium disodium Drugs 0.000 claims description 9
- 229940085673 edetate calcium disodium anhydrous Drugs 0.000 claims description 9
- 229960001484 edetic acid Drugs 0.000 claims description 9
- 229940045641 monobasic sodium phosphate Drugs 0.000 claims description 9
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 claims description 9
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 claims description 9
- 229940043349 potassium metabisulfite Drugs 0.000 claims description 9
- 235000010263 potassium metabisulphite Nutrition 0.000 claims description 9
- 229940001607 sodium bisulfite Drugs 0.000 claims description 9
- BBMHARZCALWXSL-UHFFFAOYSA-M sodium dihydrogenphosphate monohydrate Chemical compound O.[Na+].OP(O)([O-])=O BBMHARZCALWXSL-UHFFFAOYSA-M 0.000 claims description 9
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 9
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 9
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 9
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 9
- 229940050865 sodium phosphate,monobasic,monohydrate Drugs 0.000 claims description 9
- 229940089687 anhydrous monobasic sodium phosphate Drugs 0.000 claims description 8
- 239000003381 stabilizer Substances 0.000 claims description 8
- 235000013772 propylene glycol Nutrition 0.000 claims description 7
- 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 6
- 206010060819 Myxoedema coma Diseases 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 230000002989 hypothyroidism Effects 0.000 claims description 6
- 239000000600 sorbitol Substances 0.000 claims description 6
- PMUNIMVZCACZBB-UHFFFAOYSA-N 2-hydroxyethylazanium;chloride Chemical compound Cl.NCCO PMUNIMVZCACZBB-UHFFFAOYSA-N 0.000 claims description 5
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 claims description 5
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 5
- 239000004322 Butylated hydroxytoluene Substances 0.000 claims description 5
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 108010024636 Glutathione Proteins 0.000 claims description 5
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 5
- UEZVMMHDMIWARA-UHFFFAOYSA-N Metaphosphoric acid Chemical compound OP(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-N 0.000 claims description 5
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 claims description 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 5
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
- 229940045942 acetone sodium bisulfite Drugs 0.000 claims description 5
- 239000001361 adipic acid Substances 0.000 claims description 5
- 235000011037 adipic acid Nutrition 0.000 claims description 5
- 229940087168 alpha tocopherol Drugs 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 5
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 5
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 5
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004327 boric acid Substances 0.000 claims description 5
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 5
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 5
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- AYFCVLSUPGCQKD-UHFFFAOYSA-I calcium;trisodium;2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate Chemical compound [Na+].[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC(=O)[O-])CCN(CC([O-])=O)CC([O-])=O AYFCVLSUPGCQKD-UHFFFAOYSA-I 0.000 claims description 5
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- 239000002526 disodium citrate Substances 0.000 claims description 5
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- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 claims description 5
- XNZQCYSOYHAYII-UHFFFAOYSA-L disodium;3-carboxy-3-hydroxypentanedioate;hydrate Chemical compound [OH-].[Na+].[Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O XNZQCYSOYHAYII-UHFFFAOYSA-L 0.000 claims description 5
- 229940073579 ethanolamine hydrochloride Drugs 0.000 claims description 5
- 229960005219 gentisic acid Drugs 0.000 claims description 5
- 229960002717 gluceptate sodium Drugs 0.000 claims description 5
- 229960003180 glutathione Drugs 0.000 claims description 5
- 235000014655 lactic acid Nutrition 0.000 claims description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 5
- 239000011976 maleic acid Substances 0.000 claims description 5
- PFJSMHLYLWDDPG-UHFFFAOYSA-N methanesulfonic acid;nitric acid Chemical compound O[N+]([O-])=O.CS(O)(=O)=O PFJSMHLYLWDDPG-UHFFFAOYSA-N 0.000 claims description 5
- 229930182817 methionine Natural products 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N monoethanolamine hydrochloride Natural products NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- LQPLDXQVILYOOL-UHFFFAOYSA-I pentasodium;2-[bis[2-[bis(carboxylatomethyl)amino]ethyl]amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC(=O)[O-])CCN(CC([O-])=O)CC([O-])=O LQPLDXQVILYOOL-UHFFFAOYSA-I 0.000 claims description 5
- 229940119446 pentetate calcium trisodium Drugs 0.000 claims description 5
- 229960003330 pentetic acid Drugs 0.000 claims description 5
- 235000007715 potassium iodide Nutrition 0.000 claims description 5
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 claims description 5
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 5
- 239000001632 sodium acetate Substances 0.000 claims description 5
- 235000017281 sodium acetate Nutrition 0.000 claims description 5
- 235000010378 sodium ascorbate Nutrition 0.000 claims description 5
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 claims description 5
- 229960005055 sodium ascorbate Drugs 0.000 claims description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
- 235000011083 sodium citrates Nutrition 0.000 claims description 5
- 239000001540 sodium lactate Substances 0.000 claims description 5
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- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
Definitions
- the present description relates generally to the field of levothyroxine. More particularly, the description relates to pharmaceutical formulations containing levothyroxine.
- Thyroid hormones mediate important physiological processes such as development, growth, and metabolism in many tissues of the body.
- T4 levothyroxine
- T3 tri-iodothyronine
- the concentrations of T4 and T3 in the blood are regulated by the hypothalamic/pituitary/thyroid (HPT) axis.
- HPT hypothalamic/pituitary/thyroid
- TRH thyrotropin-releasing hormone
- TSH thyroid-stimulating hormone
- TH synthesis in the thyroid gland requires several steps which includes the uptake of iodide by active transport, thyroglobulin (Tg) biosynthesis, oxidation and binding of iodide to Tg, and oxidative coupling of two iodotyrosines into iodothyronines.
- Tg thyroglobulin
- the synthesis of TH in thyroid gland is unilateral as evidenced by the iodide uptake, which leads to a 30-fold increase in intracellular iodide concentration in thyrocyte vs. serum.
- the release of TH from the thyroid gland is stimulated by TSH and followed by intracellular proteolysis and hydrolysis.
- THs are transported by specific carrier proteins via the circulation to tissues throughout the body and also must pass the blood/brain barrier for delivery to the Central Nervous System (CNS).
- CNS Central Nervous System
- TH binding to these carrier proteins ensures an even distribution and delivery of hormone throughout the body.
- Intracellular uptake of TH occurs by specific TH transporters, and the intracellular concentration of TH is further regulated by intracellular deiodinases that convert T4 to T3 to increase the TH activity or transform the THs to inert metabolites to reduce it.
- Intracellular THs then bind to nuclear thyroid hormone receptors (TRs), members of the nuclear receptor superfamily. TRs activate the gene transcription and synthesis of messenger RNA and cytoplasmic proteins.
- TRs nuclear thyroid hormone receptors
- TH activity is an important determinant of development and growth, and in adults plays a critical role in the regulation of the function and metabolism of virtually every organ system.
- Hypothyroid patients are deficient in endogenously produced THs.
- There are many causes to hypothyroidism including but not limited to, autoimmune disease, e.g. Hashimoto's thyroiditis and atrophic thyroiditis; surgical removal of part or all of the thyroid gland; radiation treatment; congenital hypothyroidism; and antithyroid medicines.
- Synthetic levothyroxine is a recommended replacement therapy for acute and chronic cases of hypothyroidism, providing patients long term control of their symptoms with a favourable side effect profile and a long serum half-life.
- levothyroxine sodium tablet or solution can restore the steady-state levels of T4 and TSH within 6 weeks.
- intravenous levothyroxine is administered initially with a loading dose followed by a daily maintenance dose until the patient's thyroid levels and symptoms are controlled where they are then transitioned to oral levothyroxine replacement therapy.
- Levothyroxine sodium for injection is a sterile, lyophilized product for parental administration of levothyroxine sodium for thyroid replacement therapy in primary, secondary and tertiary hypothyroidism.
- Levothyroxine sodium for injection is particularly useful when thyroid replacement is needed on an emergency basis, for short term thyroid replacement, and/or when oral administration is not possible.
- Administration of the conventional lyophilized formulation involves reconstitution of the lyophilized powder in 5 mL of 0.9% sodium chloride injection (USP), to provide injectable solutions having levothyroxine sodium concentrations of 20 ⁇ g/mL, 40 ⁇ g/mL or 100 ⁇ g/mL for the 10Omcg/vial,
- USP 0.9% sodium chloride injection
- Levothyroxine sodium is not a very stable compound. It is very hygroscopic and degrades rapidly under conditions of high humidity or in the presence of other moisture sources or light and under conditions of high temperature, especially in the presence of moisture or other pharmaceutical excipients such as certain
- Won CM et al. studied the kinetics of the levothyroxine degradation and concluded that levothyroxine sodium in solution degraded by deiodination. The degradation was pH dependent and followed first order kinetics. The log k - pH profile of deiodination of levothyroxine sodium showed a plateau in the acidic pH region, dropped off sigmoidally in the neutral pH region and showed another plateau in the alkaline region. The authors concluded that the kinetics of deiodination include proton attack on the anion and dianion in acidic solution and water attack on the anion and dianion in basic solution. Won CM et al.
- Wortsman J et al. Thermal inactivation of L-thyroxin. Clin Chem. 1989; 35:90-2) concluded that upon heating levothyroxine sodium rapidly degrades at >90°C, and fully decomposes at melting point (148.81 °C).
- Kazemiford et al. 2001 . "Identification and quantitation of sodium-thyroxine and its degradation products by LC using electrochemical and MS detection". J. Pharm. Biomed.
- an aqueous parenteral formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
- the pharmaceutically acceptable salt of levothyroxine is levothyroxine sodium.
- the concentration of levothyroxine sodium in the formulation is between about 5 and about 500 ⁇ g/mL.
- the formulation comprises: (i) levothyroxine sodium; (ii) one or more antioxidants; (iii) one or more chelating agents; (iv) one or more buffering agents; (v) one or more pH adjusting agents; and (vi) one or more solvents.
- the formulation comprises (i) levothyroxine sodium; (ii) one or more antioxidants; (iii) one or more chelating agents; (iv) one or more stabilizing agents; (v) one or more buffering agents; (vi) one or more pH adjusting agents; and (vii) one or more solvents.
- the one or more antioxidants is selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and sodium formaldehyde sulfoxylate.
- the one or more chelating agents is selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and pentetic acid.
- the one or more buffering agents is selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate;
- the one or more pH adjusting agents is selected from sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid;
- benzenesulfonic acid boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid; metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and trifluoroacetic acid.
- the one or more solvents is selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
- the one or more stabilizing agents is selected from sodium iodide, potassium iodide, povidone, povidone K12, povidone K17, crospovidone, sorbitol, and sorbitol solution.
- the formulation comprises (i) levothyroxine sodium; (ii) one or more antioxidants selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium metabisulfite; (iii) one or more chelating agents selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, and edetic acid; (iv) one or more buffering agents selected from sodium phosphate, dibasic,
- the formulation comprises (i)
- levothyroxine sodium (ii) one or more antioxidants selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium metabisulfite; (iii) one or more chelating agents selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid; (iv) one or more stabilizing agents selected from sodium iodide and potassium iodide; (v) one or more buffering agents selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium
- bicarbonate sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and (vii) one or more solvents selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
- USP water for injection
- propylene glycol propylene glycol
- glycerin glycerin
- benzyl alcohol selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
- the formulation comprises (i)
- levothyroxine sodium (ii) sodium sulfite; (iii) edetate disodium, edetate disodium anhydrous, or edetate sodium; (iv) sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; or dibasic potassium phosphate; (v) sodium
- hydroxide calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate;
- the formulation comprises (i)
- levothyroxine sodium (ii) sodium sulfite; (iii) edetate disodium, edetate disodium anhydrous, or edetate sodium; (iv) sodium iodide or potassium iodide; (v) sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; or dibasic potassium phosphate; (vi) sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and (vii) water for injection (USP).
- USP water for injection
- the formulation comprises (i) levothyroxine sodium; (ii) sodium sulfite; (iii) edetate disodium; (iv) sodium phosphate, dibasic, heptahydrate; (v) sodium hydroxide; and (vi) water for injection (USP).
- the formulation comprises (i) levothyroxine sodium; (ii) sodium sulfite; (iii) edetate disodium; (iv) sodium iodide; (v) sodium phosphate, dibasic, heptahydrate; (vi) sodium hydroxide; and (vii) water for injection (USP).
- the formulation comprises between about 5 and about 500 ⁇ g/mL of levothyroxine sodium.
- the formulation comprises between about 0.01 % and about 0.5% w/v of sodium sulfite. In an embodiment of the formulation, the formulation comprises between about 0.005% and about 0.5% w/v of edetate disodium.
- the formulation comprises between about 0.01 % and about 5% w/v of sodium phosphate, dibasic, heptahydrate.
- the formulation comprises between about 0.01 % and about 5% w/v of sodium iodide.
- the pH of the formulation is between about 9.5 and about 1 1 .5.
- levothyroxine e.g. , levothyroxine sodium
- less than 0.15% liothyronine and/or less than ⁇ 0.61 % total impurity levels are present in the formulation.
- levothyroxine e.g., levothyroxine sodium
- less than 0.1 1 % liothyronine and/or less than ⁇ 0.18% total impurity levels are present in the formulation.
- levothyroxine e.g. , levothyroxine sodium
- less than 0.16% liothyronine and/or less than ⁇ 0.32% total impurity levels are present in the formulation.
- levothyroxine e.g., levothyroxine sodium
- the formulation when the formulation is stored at 25°C/60% RH conditions for a period of 24 months, less than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 20%, 25%, 30% or 35% of the
- levothyroxine e.g., levothyroxine sodium
- the dosage strength of the formulation is 20 mcg/mL, 40 mcg/mL or 100 mcg/mL.
- the formulation does not contain a cyclodextrin, such as hydroxypropyl- -cyclodextrin. In an embodiment of the formulation, the formulation does not contain tromethamine. In an aspect there is provided a method of treating myxedema coma in a subject by administering to the subject the aqueous parenteral formulation as disclosed herein.
- a method of treating primary, secondary or tertiary hypothyroidism in a subject by administering to the subject the aqueous parenteral formulation as disclosed herein.
- the formulation is for use as replacement or supplemental therapy.
- the formulation is administered intravenously to provide an initial loading dose of about 300 to about 500 ⁇ g of levothyroxine or a pharmaceutically acceptable salt to the subject.
- the formulation is administered intravenously to provide a maintenance daily dose of about 50 to about 100 ⁇ g of levothyroxine to the subject.
- the levothyroxine is levothyroxine sodium.
- the inventors have provided stable aqueous pharmaceutical formulations of levothyroxine or a pharmaceutically acceptable salt thereof. These are available in an aqueous solution with a sufficient shelf-life that is commercially viable for parenteral or oral use.
- the advantages of the formulations disclosed herein compared to conventional formulations include: a) the formulations do not need to undergo an expensive lyophilisation process that results in increased manufacturing cost per vial on an industrial scale; b) the formulations do not need to be reconstituted, a process that requires aseptic technique on the part of the health care practitioners, and which can lead to sterility compromise; c) the formulations are ready for administration, and do not require reconstitution, that can delay treatment in an emergency setting; d) the formulations reduce administration errors associated with levothyroxine because the formulations do not require reconstitution using aseptic technique in an emergency setting.
- formulations of the disclosure provide for stabilization of
- levothyroxine in an aqueous solution within the solubility profile of the active ingredient (levothyroxine).
- Such formulation provide for levothyroxine in ready-to- use solutions.
- levothyroxine refers to a synthetic or endogenous thyroid hormone with the general formula of (S)-2-Amino-3-[4-(4-hydroxy-3,5- diiodophenoxy)-3,5-diiodophenyl]propanoic acid.
- levothyroxine sodium refers to the sodium salt of levothyroxine with the general formula of L-Tyrosine-0-(4-hydroxy-3,5-diiodophenyl)- 3,5-diiodo-monosodium salt.
- subject refers to a mammal. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rats, rabbits, and aquatic mammals.
- treat means the treatment of a disease in a subject, for example, a human, and includes inhibiting the disease (e.g., decreasing its rate of progression); regressing the disease; relieving or decreasing the severity of one or more symptoms of the disease; and/or curing the disease.
- prevent means the prevention of a disease in a subject, and includes inhibiting initiation of the disease; decreasing a predisposition toward the disease; and/or delaying the onset of at least one symptom of the disease.
- the term “about” is synonymous with “approximately” and is used to provide flexibility to a numerical value or range endpoint by providing that a given value may be “a little above” or “a little below” the value stated.
- “About” can mean, for example, within 3 or more than 3 standard deviations.
- “About” can mean within a percentage range of a given value. For example, the range can be ⁇ 1 %, ⁇ 5%, ⁇ 10%, ⁇ 20%, ⁇ 30%, ⁇ 40% or ⁇ 50% of a given value.
- “About” can mean with an order of magnitude of a given value, for example, within 2-fold, 3-fold, 4-fold or 5-fold of a value.
- TSH thyroid-stimulating hormone
- aqueous formulations of levothyroxine or a pharmaceutically acceptable salt thereof that are stable for extended storage in high temperature. These formulations are not only stable, but are formulated as, injectable and ready to administer aqueous compositions. Such formulation are also formulated as, oral and ready to administer aqueous compositions. In a preferred embodiment, the formulation is a parenteral formulation.
- the aqueous formulations of the present invention comprise levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
- the salt of levothyroxine is levothyroxine sodium.
- the aqueous formulation comprises: (i) levothyroxine or a pharmaceutically acceptable salt thereof
- the levothyroxine may be the free base or may be a pharmaceutically acceptable salt thereof.
- the levothyroxine is levothyroxine sodium.
- Antioxidants used in the formulations include, but are not limited to sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and/or sodium formaldehyde sulfoxylate.
- Chelating agents used in the formulations include, but are not limited to edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and/or pentetic acid.
- Buffering agents used in the formulations include, but are not limited to sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate;
- potassium phosphate monobasic; sodium acetate; sodium acetate anhydrous;
- ammonium acetate sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesqui hydrate; trisodium citrate dehydrate; sodium lactate;
- the pH adjusting agents used in the formulations include, but are not limited to sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid; benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid;
- metaphosphoric acid methanesulfonic acid
- nitric acid phosphoric acid
- succinic acid sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and/or
- Solvents used in the formulations include, but are not limited to water for injection (USP), propylene glycol, glycerin, and/or benzyl alcohol.
- the aqueous formulation comprises: (i) levothyroxine sodium
- the levothyroxine may be the free base or may be a pharmaceutically acceptable salt thereof.
- the levothyroxine is levothyroxine sodium.
- Antioxidants used in the formulations include, but are not limited to sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and/or sodium formaldehyde sulfoxylate.
- Chelating agents used in the formulations include, but are not limited to edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and/or pentetic acid.
- Stabilizing agents used in the formulations include, but are not limited to sodium iodide, potassium iodide, povidone, povidone K12, povidone K17, crospovidone, sorbitol, and/or sorbitol solution.
- Buffering agents used in the formulations include, but are not limited to sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate;
- potassium phosphate monobasic; sodium acetate; sodium acetate anhydrous; ammonium acetate; sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesquihydrate; trisodium citrate dehydrate; sodium lactate; (L)-sodium lactate; sodium tartrate; ammonium sulfate; and/or ethanolamine hydrochloride.
- the pH adjusting agents used in the formulations include, but are not limited to sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid; benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid; metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and/or
- Solvents used in the formulations include, but are not limited to water for injection (USP), propylene glycol, glycerin, and/or benzyl alcohol.
- the formulation is a parenteral formulation.
- composition invention embodiments are sterile.
- one or all of the composition invention embodiments are free of particulate matter.
- one or all of the composition invention embodiments are packaged in an amber glass container.
- one or all of the composition invention embodiments are aseptically packaged in an amber glass container.
- composition invention embodiments are packaged in an amber glass container and terminally sterilized.
- the formulations described here can be prepared using conventional techniques known to the person skilled in the art.
- the formulations may be prepared by dissolving levothyroxine or a pharmaceutically acceptable salt thereof in water, dissolving one or more pharmaceutically acceptable excipients, optionally adjusting the pH of the solution.
- the formulations may be prepared by dissolving one or more pharmaceutically acceptable excipients prior to dissolving the levothyroxine or pharmaceutically acceptable salt thereof, optionally adjusting the pH of the solution.
- the composition can be aseptically filled into a container that facilitates ready to administration.
- the composition can be filled into a container that facilitates ready to administration, and sterilizing said container.
- aqueous formulation e.g., parenteral or oral
- levothyroxine or a pharmaceutically acceptable salt thereof examples include, but are not limited to, those described herein.
- the formulation when the formulation is stored at 60°C for a period of 40 days, less than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 20%, 25%, 30% or 35% of the levothyroxine sodium undergoes degradation.
- the formulation when the formulation is stored at 60°C for a period of 40 days, less than 5%, of the levothyroxine undergoes degradation.
- Such formulations are particularly advantageous in emergency situations, because they are in a ready-to-administer parenteral or oral solution.
- Such solutions save time in emergency situations because the levothyroxine does not have to be reconstituted, there is no concern whether the drug has been reconstituted correctly and aseptically in the emergency situation. These characteristics improve the safety of patients in need of levothyroxine, particularly in emergency situations.
- the formulations can be provided in various dosage strengths. In some embodiments,
- the dosage strength is 10 mcg/mL, 15 mcg/ml_, 20 mcg/mL, 25 mcg/mL, 30mcg/ml_, 35 mcg/mL, 40 mcg/mL, 45 mcg/mL, 50 mcg/mL, 55 mcg/mL, 60 mcg/mL, 65 mcg/mL, 70 mcg/mL, 75 mcg/mL, 80 mcg/mL, 85 mcg/mL, 90 mcg/mL, 95 mcg/mL, 100 mcg/mL, 150 mcg/mL, or 200 mcg/mL of levothyroxine (e.g., levothyroxine sodium) in an IV direct inject or oral solution.
- levothyroxine e.g., levothyroxine sodium
- the formulation is provided at 20mcg/mL, 40mcg/mL, or 100mcg/mL, of levothyroxine (e.g., levothyroxine sodium) in an IV direct inject solution, which will provide a dosing regimen of 300-500 meg initial (e.g., loading) dose followed by 50- 1 10 meg daily (e.g. , maintenance) dose.
- levothyroxine e.g., levothyroxine sodium
- IV direct inject solution which will provide a dosing regimen of 300-500 meg initial (e.g., loading) dose followed by 50- 1 10 meg daily (e.g. , maintenance) dose.
- the formulations may be packaged in a storage container standardly used for packaging pharmaceuticals (e.g., sterile packaging), particularly liquid formulations.
- the storage contain may be a glass or plastic vial or ampoule (e.g. , 2ml, 4mL or 6mL volume).
- the packaging protects its contents from light.
- the vial is an amber glass vial.
- the packaging includes a closure system that is compatible for storage and transport of the formulation.
- Suitable caps include those from West Pharmaceutical (size 13mm; sample ID: I3FO LQ LGTE (6B) 767 RED MT STEAM RU/RP; Formula: IP, STM 13FO LNG TE (6B) 3767 RED MATTE).
- Suitable stoppers include those from West Pharmaceutical (size 13mm; sample ID: 13mm Serum Novapure V-35 4031/45 or RP S2-F451 4432/50 G; Formula: 13mm Serum NovaPure (Bromobutyl/Chlorobutyl) Stopper).
- Suitable vials include those from Schott (size: 2mL, 4mL, 6mL; sample ID: Fiolax amber Type I glass vial/ Schott; Formula: Type I Amber glass).
- the aqueous levothyroxine formulations disclosed herein may be used to treat a disease or condition that is treatable using other levothyroxine formulations.
- diseases include, but are not limited to, myxedema coma.
- an initial intravenous loading dose of the levothyroxine formulation may be about 30C ⁇ g to about 50C ⁇ g followed by once daily intravenous maintenance doses of between about 50 and about 100 ⁇ g should be administered to the subject.
- the aqueous levothyroxine formulations disclosed herein may be used for replacement or supplemental therapy in primary, secondary or tertiary
- aqueous levothyroxine formulations of the present invention may be used for severe hypothyroid subjects or subjects with myxedema coma requiring
- the aqueous parenteral formulations of the present invention may be administered intravenously to provide an initial loading dose of about 300 to about 500 ⁇ g of levothyroxine sodium to the subject.
- the aqueous parenteral levothyroxine formulation may be administered intravenously to provide a maintenance daily dose of about 50 to about 100 ⁇ g of levothyroxine sodium to the subject.
- the dose(s) of the disclosed levothyroxine formulations for treating a subject with one or more of the above-described diseases or conditions will depend on the mode of delivery and is within the skill of the skilled person to determine.
- the formulation may comprise one or more flavoring, sweetening or taste-making agents, known to those skilled in the art.
- the correct dose to be administered to the subject should be aseptically withdrawn from the vial and inspected visually for particulate matter and discoloration prior to administration into the subject.
- Example 7 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 7
- Example 9 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 9
- Example 1 1 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 1 1
- Example 13 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5 ⁇ 0.5. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 13
- Example 15 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 15
- Example 17 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 17 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 19 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0 ⁇ 0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 19
- Example 21 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5 ⁇ 0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 21 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5 ⁇ 0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 25 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0 ⁇ 0.5. Glycerin was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
- Example 25 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0 ⁇ 0.5. Glycerin was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. Example 25
- Example 26 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Glycerin was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
- Example 26 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Glycerin was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. Example 26
- Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
- Examples 1 - 26 were tested for osmolarity, pH, appearance and potency of levothyroxine sodium. All samples of Examples 1 - 26 were placed in a 50°C oven, and potency of levothyroxine sodium was tested after 3 days (see Table 1 ).
- the mobile phase used for the gradient assay HPLC method was a mixture of acetonitrile and sulfamic acid buffer adjusted to pH 2.0 with sodium hydroxide.
- the diluent for HPLC analysis had same composition as levothyroxine sodium
- the levothyroxine stock standard solution was 0.1 mg/mL of USP levothyroxine reference standard in the diluent.
- the sample solutions were injected onto HPLC without further dilution or
- the concentration of levothyroxine in the sample was determined by the external standard calibration method, where the peak area of levothyroxine in sample injections was compared to the peak area of levothyroxine reference standards in a solution of known concentration.
- Example 29 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 29 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 32 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5 ⁇ 0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Levothyroxine sodium was added to the above solution and mixed until dissolved.
- the pH of the solution was adjusted to 12.0 ⁇ 0.5 by addition of sodium hydroxide if necessary.
- the solution was filtered and filled into containers.
- Levothyroxine sodium was added to the above solution and mixed until dissolved.
- the pH of the solution was adjusted to 10.5 ⁇ 0.5 by addition of sodium hydroxide if necessary.
- the solution was filtered and filled into containers.
- Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
- Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
- Example 45 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5 ⁇ 0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Benzyl alcohol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. Example 45
- Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
- Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. All samples of Examples 27 - 46 were tested for osmolarity, pH, appearance and potency of levothyroxine sodium (see Table 2). All samples of Examples 27 - 46 were placed in the following storage conditions: ambient room temperature under ambient light in clear vials; 2-8°C under refrigeration in amber vials; 60°C/ambient RH in amber vials. The potency of levothyroxine sodium (Assay %, described above) and appearance were tested at selected stability storage time point (see Tables 3 - 5). Table 2: Examples 27 - 46 Test Results at Initial Time
- Example 48 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite was added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 48 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite was added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into
- Levothyroxine sodium was added to the above solution and mixed until dissolved.
- the pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary.
- the solution was filtered and filled into containers.
- Example 51 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 51 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was
- Examples 47 - 52 were placed in 121 °C oven for 30min, which simulated heat sterilization conditions, in both upright and inverted orientations.
- the potency (Assay %, described above) and impurity of levothyroxine sodium were tested (see Table 6).
- gradient HPLC method was employed to separate levothyroxine and impurities from formulation components.
- the gradient HPLC parameters and gradient table are depicted as follows:
- the mobile phase A used for the gradient HPLC method was prepared by dissolving 9.7 g of sulfamic acid in 2000 mL of water, followed by adding 1 .5 g of sodium hydroxide and mixing to dissolve. Mobile phase A was adjusted to pH of 2.0 with 2N sodium hydroxide. Mobile phase B is 100% acetonitrile.
- Diluent was dibasic sodium phosphate heptahydrate adjusted to pH 10.5.
- the levothyroxine stock standard solution was 0.1 mg/mL of USP levothyroxine reference standard in the Diluent.
- To prepare levothyroxine stock standard solution accurately weighed and transferred about 1 1 mg of levothyroxine USP reference standard into a 100 mL volumetric flask. Dissolved and diluted to volume with Diluent and mixed well.
- the levothyroxine working standard solution was 0.001 mg/mL of USP levothyroxine reference standard.
- To prepare levothyroxine working standard solution pipetted 2.0 mL of the levothyroxine stock standard solution to a 200 mL volumetric flask and diluted to volume with Diluent. Mixed well.
- the sensitivity and identification standard solution was 0.1 ⁇ g/mL of USP
- levothyroxine reference standard and liothyronine reference standard.
- sample solutions were injected onto HPLC without further dilution or
- the concentration of levothyroxine in the sample was determined by the external standard calibration method, where the peak area of impurity peaks in sample injections was compared to the peak area of levothyroxine reference standard in a solution of known concentration.
- Formulations containing propylene glycol showed more impurities compared to formulation the did not contain propylene glycol.
- Example 55 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 55 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydro
- Example 57 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 57
- Example 58 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
- Example 58 To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the
- Example 53 - 58 The samples of Examples 53 - 58 were stored in 2ml_ Type I Clear Glass Vials and placed in 60°C oven for about 40 days. All storage conditions were void of light exposure. Vials were stored in both upright and inverted orientations. The osmolarity, pH, appearance, potency and impurity of levothyroxine sodium were tested (as described herein) at selected stability storage time point (see Table 8).
- Table 8 Stability results of samples of Examples 53 - 58 in 60°C oven
- Formulation development and R&D Scale-up data indicates there is an underlying interaction within the formulation with the three key excipients; sodium iodide, disodium edetate and sodium sulfite.
- a multivariate statistical design studies was carried out as two sets of experimental trials: 2 3 Full Factorial DoE Study #1 and 2 3 Full Factorial DoE Study #2.
- DoE #1 was carried out to evaluate/identify if an interaction effect is present within the formulation variables.
- DoE study #2 was to further optimize the composition of sodium iodide, sodium sulfite and disodium edetate as per the results of DoE study #1 .
- concentration levels of three excipients (sodium iodide, sodium sulfite and disodium edetate) were different from that of DoE #1 .
- Sodium iodide was evaluated at higher levels, while sodium sulfite and disodium edetate were evaluated at lower levels (see Table 10).
- Example 61 After 4 weeks of storing samples at 60°C stability conditions, all samples exhibited >90% assay, ⁇ 0.15% liothyronine and ⁇ 0.61 % total impurity levels.
- Example 61 After 4 weeks of storing samples at 60°C stability conditions, all samples exhibited >90% assay, ⁇ 0.15% liothyronine and ⁇ 0.61 % total impurity levels.
- Control Formulation containing: 20 mcg/mL Levothyroxine sodium, USP; 6.48 mg/mL sodium chloride; 0.14 mg/mL sodium iodide; 10 mg/ml
- Example 60 Trial 8 (“Formulation E60/T8") was also prepared. The solution was filled into containers. Stability of the samples was evaluated, as described herein, initially and after 4 weeks storage in a 60°C oven.
- Formulation E60/T8 exhibited superior stability compared to the Control Formulation, and had an Assay % within the USP acceptable range of 90% - 1 10% and low impurity levels at elevated temperatures of 60°C for 4 weeks. Even under these high stress conditions, Formulation E60/T8 is robust.
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Abstract
An aqueous formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients and methods of using such formulation to treat a subject.
Description
LEVOTHYROXINE FORMULATIONS
CROSS REFERENCE TO PRIOR APPLICATIONS
This application claims priority under the Paris Convention to US provisional Patent Application Serial No. 62/538,912, filed July 31 , 2017, which is incorporated herein by reference as if set forth in its entirety.
FIELD OF THE DISCLOSURE
The present description relates generally to the field of levothyroxine. More particularly, the description relates to pharmaceutical formulations containing levothyroxine.
BACKGROUND OF THE DISCLOSURE
Thyroid hormones (THs) mediate important physiological processes such as development, growth, and metabolism in many tissues of the body. There are two major THs secreted by the thyroid gland, levothyroxine (T4) and tri-iodothyronine (T3), with the latter serving as the more biologically active form. The concentrations of T4 and T3 in the blood are regulated by the hypothalamic/pituitary/thyroid (HPT) axis. The hypothalamus secrets thyrotropin-releasing hormone (TRH) which is transported via the hypothalamic-hypophyseal portal system to the anterior pituitary gland where it binds to TRH receptors. This induces thyroid-stimulating hormone (TSH) release from pituitary thyrotroph cells. After TSH is released into the circulation, it eventually binds to TSH receptors located primarily in the thyroid gland. The activation of TSH receptors leads to thyrocyte proliferation, thyroglobulin and sodium-iodide symporter gene transcription, and stimulation of TH synthesis and secretion.
The majority of TH secreted by the thyroid gland is T4. TH synthesis in the thyroid gland requires several steps which includes the uptake of iodide by active transport, thyroglobulin (Tg) biosynthesis, oxidation and binding of iodide to Tg, and oxidative coupling of two iodotyrosines into iodothyronines. The synthesis of TH in thyroid gland is unilateral as evidenced by the iodide uptake, which leads to a 30-fold
increase in intracellular iodide concentration in thyrocyte vs. serum. The release of TH from the thyroid gland is stimulated by TSH and followed by intracellular proteolysis and hydrolysis.
THs are transported by specific carrier proteins via the circulation to tissues throughout the body and also must pass the blood/brain barrier for delivery to the Central Nervous System (CNS). Approximately 0.03% of the total serum T4 and 0.3% of the total serum T3 are present in free or unbound form in human. TH binding to these carrier proteins ensures an even distribution and delivery of hormone throughout the body. Intracellular uptake of TH occurs by specific TH transporters, and the intracellular concentration of TH is further regulated by intracellular deiodinases that convert T4 to T3 to increase the TH activity or transform the THs to inert metabolites to reduce it. Intracellular THs then bind to nuclear thyroid hormone receptors (TRs), members of the nuclear receptor superfamily. TRs activate the gene transcription and synthesis of messenger RNA and cytoplasmic proteins. The physiological actions of THs are produced predominately by T3, the majority of which is derived from T4 by deiodination in peripheral tissues.
TH activity is an important determinant of development and growth, and in adults plays a critical role in the regulation of the function and metabolism of virtually every organ system. Hypothyroid patients are deficient in endogenously produced THs. There are many causes to hypothyroidism, including but not limited to, autoimmune disease, e.g. Hashimoto's thyroiditis and atrophic thyroiditis; surgical removal of part or all of the thyroid gland; radiation treatment; congenital hypothyroidism; and antithyroid medicines. Synthetic levothyroxine is a recommended replacement therapy for acute and chronic cases of hypothyroidism, providing patients long term control of their symptoms with a favourable side effect profile and a long serum half-life.
For less severe hypothyroidism patients, oral administration of levothyroxine sodium tablet or solution can restore the steady-state levels of T4 and TSH within 6 weeks. For severe hypothyroid patients or patients with myxedema coma requiring hospitalization, intravenous levothyroxine is administered initially with a loading dose followed by a daily maintenance dose until the patient's thyroid levels and symptoms
are controlled where they are then transitioned to oral levothyroxine replacement therapy.
Levothyroxine sodium for injection is a sterile, lyophilized product for parental administration of levothyroxine sodium for thyroid replacement therapy in primary, secondary and tertiary hypothyroidism. Levothyroxine sodium for injection is particularly useful when thyroid replacement is needed on an emergency basis, for short term thyroid replacement, and/or when oral administration is not possible.
Conventional formulations of levothyroxine sodium for injection are preservative-free lyophilized powders containing synthetic crystalline levothyroxine sodium and the excipients mannitol, tribasic sodium phosphate or dibasic sodium phosphate and sodium hydroxide. In some conventional lyophilized formulations contain 10 mg of mannitol, 700 μg of tribasic sodium phosphate and either 200 μg or 500 μg of levothyroxine sodium. In some conventional lyophilized formulations contain 1 to 5 mg of mannitol, 400 to 600 μg of dibasic sodium phosphate and 100 to 500 μg of levothyroxine sodium. Administration of the conventional lyophilized formulation involves reconstitution of the lyophilized powder in 5 mL of 0.9% sodium chloride injection (USP), to provide injectable solutions having levothyroxine sodium concentrations of 20 μg/mL, 40 μg/mL or 100 μg/mL for the 10Omcg/vial,
200mcg/vial and 500mcg/vial presentations, respectively. Levothyroxine sodium is not a very stable compound. It is very hygroscopic and degrades rapidly under conditions of high humidity or in the presence of other moisture sources or light and under conditions of high temperature, especially in the presence of moisture or other pharmaceutical excipients such as certain
carbohydrates. Won CM et al. studied the kinetics of the levothyroxine degradation and concluded that levothyroxine sodium in solution degraded by deiodination. The degradation was pH dependent and followed first order kinetics. The log k - pH profile of deiodination of levothyroxine sodium showed a plateau in the acidic pH region, dropped off sigmoidally in the neutral pH region and showed another plateau in the alkaline region. The authors concluded that the kinetics of deiodination include proton attack on the anion and dianion in acidic solution and water attack on the anion and dianion in basic solution. Won CM et al. ("Kinetics of degradation of levothyroxine in aqueous solution and in solid state". Pharm Res. 1992;9: 131 -7)
further concluded that in solid state, the degradation of levothyroxine sodium indicated a deamination reaction following bi-phasic degradation pattern.
Levothyroxine sodium degraded at a faster rate as the temperature increased and showed bi-phasic degradation kinetics. There was little or no degradation observed at 50°C, above which temperature, levothyroxine sodium degradation was observed. In another example, Wortsman J et al. ("Thermal inactivation of L-thyroxin". Clin Chem. 1989; 35:90-2) concluded that upon heating levothyroxine sodium rapidly degrades at >90°C, and fully decomposes at melting point (148.81 °C). Kazemiford et al. (2001 . "Identification and quantitation of sodium-thyroxine and its degradation products by LC using electrochemical and MS detection". J. Pharm. Biomed. Anal., 25, 697-71 1 ) studied the photo-degradation of levothyroxine sodium tablets from three manufacturers. The extracted levothyroxine sodium solution was irradiated with a 500W Xenon lamp at 320 nm for 2 hours. The observed degradation products were Liothyroxine, Diiodothyronine, lodothyronine, Diiodotyrosine, lodotyrosine and Tyrosine. It was concluded that levothyroxine sodium is photosensitive.
There are no current marketed solutions of levothyroxine in the US and Canadian Market. Previous liquid formulation inventions have been developed that focus on obtaining sufficient solubility of levothyroxine in oral solution through reliance of solubility enhances such as cyclodextrins, complexing agents or co-polymers. There is a need for improved and stable formulations of levothyroxine.
SUMMARY OF THE INVENTION
The details of one or more embodiments are set forth in the accompanying description below. Other features and advantages will become apparent from the description, and the claims.
In an aspect there is provided an aqueous parenteral formulation comprising levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In an embodiment of the formulation, the pharmaceutically acceptable salt of levothyroxine is levothyroxine sodium.
In an embodiment of the formulation, the concentration of levothyroxine sodium in the formulation is between about 5 and about 500 μg/mL.
In an embodiment of the formulation, the formulation comprises: (i) levothyroxine sodium; (ii) one or more antioxidants; (iii) one or more chelating agents; (iv) one or more buffering agents; (v) one or more pH adjusting agents; and (vi) one or more solvents.
In an embodiment of the invention, the formulation comprises (i) levothyroxine sodium; (ii) one or more antioxidants; (iii) one or more chelating agents; (iv) one or more stabilizing agents; (v) one or more buffering agents; (vi) one or more pH adjusting agents; and (vii) one or more solvents.
In various embodiments of the formulation, the one or more antioxidants is selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and sodium formaldehyde sulfoxylate.
In various embodiments of the formulation, the one or more chelating agents is selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and pentetic acid.
In various embodiments of the formulation, the one or more buffering agents is selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate;
sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate; sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate; potassium phosphate, monobasic; sodium acetate; sodium acetate anhydrous; ammonium acetate; sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesquihydrate; trisodium citrate
dehydrate; sodium lactate; (L)-sodium lactate; sodium tartrate; ammonium sulfate; and ethanolamine hydrochloride.
In various embodiments of the formulation, the one or more pH adjusting agents is selected from sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid;
benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid; metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and trifluoroacetic acid.
In various embodiments of the formulation, the one or more solvents is selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
In various embodiments of the formulation, wherein the one or more stabilizing agents is selected from sodium iodide, potassium iodide, povidone, povidone K12, povidone K17, crospovidone, sorbitol, and sorbitol solution.
In various embodiment of the formulation, the formulation comprises (i) levothyroxine sodium; (ii) one or more antioxidants selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium metabisulfite; (iii) one or more chelating agents selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, and edetic acid; (iv) one or more buffering agents selected from sodium phosphate, dibasic,
heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate; sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate; and potassium phosphate, monobasic; (v) one or more pH adjusting agents selected from sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine;
meglumine; tromethamine; and ammonia; and (vi) one or more solvents selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
In various embodiments of the formulation, the formulation comprises (i)
levothyroxine sodium; (ii) one or more antioxidants selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium metabisulfite; (iii) one or more chelating agents selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid; (iv) one or more stabilizing agents selected from sodium iodide and potassium iodide; (v) one or more buffering agents selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium
phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate;
sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate; and potassium phosphate, monobasic; (vi) one or more pH adjusting agents selected from sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium
bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and (vii) one or more solvents selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
In various embodiments of the formulation, the formulation comprises (i)
levothyroxine sodium; (ii) sodium sulfite; (iii) edetate disodium, edetate disodium anhydrous, or edetate sodium; (iv) sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; or dibasic potassium phosphate; (v) sodium
hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate;
diethanolamine; meglumine; tromethamine; or ammonia; and (vi) water for injection (USP).
In various embodiments of the formulation, the formulation comprises (i)
levothyroxine sodium; (ii) sodium sulfite; (iii) edetate disodium, edetate disodium
anhydrous, or edetate sodium; (iv) sodium iodide or potassium iodide; (v) sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; or dibasic potassium phosphate; (vi) sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and (vii) water for injection (USP).
In an embodiment of the formulation, the formulation comprises (i) levothyroxine sodium; (ii) sodium sulfite; (iii) edetate disodium; (iv) sodium phosphate, dibasic, heptahydrate; (v) sodium hydroxide; and (vi) water for injection (USP).
In an embodiment of the formulation, the formulation comprises (i) levothyroxine sodium; (ii) sodium sulfite; (iii) edetate disodium; (iv) sodium iodide; (v) sodium phosphate, dibasic, heptahydrate; (vi) sodium hydroxide; and (vii) water for injection (USP).
In an embodiment of the formulation, the formulation comprises between about 5 and about 500 μg/mL of levothyroxine sodium.
In an embodiment of the formulation, the formulation comprises between about 0.01 % and about 0.5% w/v of sodium sulfite. In an embodiment of the formulation, the formulation comprises between about 0.005% and about 0.5% w/v of edetate disodium.
In an embodiment of the formulation, the formulation comprises between about 0.01 % and about 5% w/v of sodium phosphate, dibasic, heptahydrate.
In an embodiment of the formulation, the formulation comprises between about 0.01 % and about 5% w/v of sodium iodide.
In an embodiment of the formulation, the pH of the formulation is between about 9.5 and about 1 1 .5.
In an embodiment of the formulation, when the formulation is stored at 60°C for a period of 4 weeks, at least 90% levothyroxine (e.g. , levothyroxine sodium) remains. In other embodiments, when the formulation is stored at 60°C for a period of 4
weeks, less than 0.15% liothyronine and/or less than <0.61 % total impurity levels are present in the formulation.
In an embodiment of the formulation, when the formulation is stored at 60°C for a period of 2 weeks, at least 90% levothyroxine (e.g., levothyroxine sodium) remains. In other embodiments, when the formulation is stored at 60°C for a period of 2 weeks, less than 0.1 1 % liothyronine and/or less than <0.18% total impurity levels are present in the formulation.
In an embodiment of the formulation, when the formulation is stored at 60°C for a period of 2 weeks, at least 90% levothyroxine (e.g. , levothyroxine sodium) remains. In other embodiments, when the formulation is stored at 60°C for a period of 2 weeks, less than 0.16% liothyronine and/or less than <0.32% total impurity levels are present in the formulation.
In an embodiment of the formulation, when the formulation is stored at 60°C for a period of 40 days, less than about 5% of levothyroxine (e.g., levothyroxine sodium) undergoes degradation.
In other embodiments of the formulation, when the formulation is stored at 25°C/60% RH conditions for a period of 24 months, less than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 20%, 25%, 30% or 35% of the
levothyroxine (e.g., levothyroxine sodium) undergoes degradation. In other embodiments of the formulation, the dosage strength of the formulation is 20 mcg/mL, 40 mcg/mL or 100 mcg/mL.
In an embodiment of the formulation, the formulation does not contain a cyclodextrin, such as hydroxypropyl- -cyclodextrin. In an embodiment of the formulation, the formulation does not contain tromethamine. In an aspect there is provided a method of treating myxedema coma in a subject by administering to the subject the aqueous parenteral formulation as disclosed herein.
In an aspect there is provided a method of treating primary, secondary or tertiary hypothyroidism in a subject by administering to the subject the aqueous parenteral formulation as disclosed herein. In an embodiment, the wherein the formulation is for use as replacement or supplemental therapy.
In an embodiment of the method, the formulation is administered intravenously to provide an initial loading dose of about 300 to about 500 μg of levothyroxine or a pharmaceutically acceptable salt to the subject. In an embodiment of the method, the formulation is administered intravenously to provide a maintenance daily dose of about 50 to about 100 μg of levothyroxine to the subject. In an embodiment of the method, the levothyroxine is levothyroxine sodium.
Detailed Description of the Invention
As described herein the inventors have provided stable aqueous pharmaceutical formulations of levothyroxine or a pharmaceutically acceptable salt thereof. These are available in an aqueous solution with a sufficient shelf-life that is commercially viable for parenteral or oral use. The advantages of the formulations disclosed herein compared to conventional formulations include: a) the formulations do not need to undergo an expensive lyophilisation process that results in increased manufacturing cost per vial on an industrial scale; b) the formulations do not need to be reconstituted, a process that requires aseptic technique on the part of the health care practitioners, and which can lead to sterility compromise; c) the formulations are ready for administration, and do not require reconstitution, that can delay treatment in an emergency setting; d) the formulations reduce administration errors associated with levothyroxine because the formulations do not require reconstitution using aseptic technique in an emergency setting.
Surprisingly, the formulations of the disclosure provide for stabilization of
levothyroxine in an aqueous solution within the solubility profile of the active ingredient (levothyroxine). Such formulation provide for levothyroxine in ready-to- use solutions.
Definitions
As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a container" includes one or more of such containers and reference to "the excipient" includes reference to one or more of such excipients.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set forth below.
As used herein, the term "levothyroxine" refers to a synthetic or endogenous thyroid hormone with the general formula of (S)-2-Amino-3-[4-(4-hydroxy-3,5- diiodophenoxy)-3,5-diiodophenyl]propanoic acid.
As used herein, the term "levothyroxine sodium" refers to the sodium salt of levothyroxine with the general formula of L-Tyrosine-0-(4-hydroxy-3,5-diiodophenyl)- 3,5-diiodo-monosodium salt.
As used herein, the term "subject" refers to a mammal. Examples of subjects include humans, and may also include other animals such as horses, pigs, cattle, dogs, cats, rats, rabbits, and aquatic mammals.
As used herein, "treat", "treating" and "treatment", means the treatment of a disease in a subject, for example, a human, and includes inhibiting the disease (e.g., decreasing its rate of progression); regressing the disease; relieving or decreasing the severity of one or more symptoms of the disease; and/or curing the disease.
As used herein, "prevent," "preventing," and "prevention" means the prevention of a disease in a subject, and includes inhibiting initiation of the disease; decreasing a predisposition toward the disease; and/or delaying the onset of at least one symptom of the disease.
As used herein, the term "about" is synonymous with "approximately" and is used to provide flexibility to a numerical value or range endpoint by providing that a given value may be "a little above" or "a little below" the value stated. "About" can mean, for example, within 3 or more than 3 standard deviations. "About" can mean within a percentage range of a given value. For example, the range can be ±1 %, ±5%, ±10%, ±20%, ±30%, ±40% or ±50% of a given value. "About" can mean with an order of magnitude of a given value, for example, within 2-fold, 3-fold, 4-fold or 5-fold
of a value. However, it is to be understood that even when a numerical value is accompanied by the term "about" in this specification, that express support shall be provided at least for the exact numerical value as well as though the term "about" were not present. As used herein, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in patent law and can mean "includes,"
"including," and the like, and are generally interpreted to be open ended terms. The terms "consisting of" or "consists of" are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with patent law. "Consisting essentially of" or "consists essentially of" have the meaning generally ascribed to them by patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the composition's nature or characteristics would be permissible if present under the "consisting essentially of" language, even though not expressly recited in a list of items following such terminology. When using an open ended term, like "comprising" or "including," it is understood that direct support should be afforded also to "consisting essentially of" language as well as "consisting of" language as if stated explicitly and vice versa. In essence, use of one of these terms in the specification provides support for all of the others.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary. Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include
not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1 -3, from 2-4, and from 3-5, etc. , as well as 1 , 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
Abbreviations
The following abbreviations are used throughout the disclosure:
CMC - Chemistry, Manufacturing and Control
CNS - Central Nervous System
EDTA - edetate disodium
HPLC - High Performance Liquid Chromatography
HPT - hypothalami ic/pituitary/thyroid
ID - Identification
kg - kilogram
meg - microgram
mg - milligram
ml_ - milliliter
mm - millimeter
mOsm - milliosmoles
Na2S03 - Sodium sulfite
Nal - Sodium Iodide
NDA - New Drug Application
NLT - No Less Than
nm - nanometer
NMT - No More Than
Out of Range - Out of Range
PG - Propylene Glycol
qs - quantum sufficit
RH - Relative Humidity
RNA - ribonucleic acid
RS - Reference Standard
T3 - tri-iodothyronine
T4 - levothyroxine
Tg - thyroglobulin
Th - Thyroid hormone
TR - nuclear thyroid hormone receptor
TRH - thyrotropin-releasing hormone
TSH - thyroid-stimulating hormone
μg - microgram
μιη - micrometer
USP - United States Pharmacopeia
UV - Ultra violet
w/v - weight by volume
Levothyroxine Formulations
As described herein the inventors have provided aqueous formulations of levothyroxine or a pharmaceutically acceptable salt thereof that are stable for extended storage in high temperature. These formulations are not only stable, but are formulated as, injectable and ready to administer aqueous compositions. Such formulation are also formulated as, oral and ready to administer aqueous compositions. In a preferred embodiment, the formulation is a parenteral formulation.
The aqueous formulations of the present invention comprise levothyroxine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. In a preferred embodiment, the salt of levothyroxine is levothyroxine sodium. In one embodiment, the aqueous formulation comprises: (i) levothyroxine or a pharmaceutically acceptable salt thereof
(ii) one or more antioxidants
(iii) chelating agents
(iv) one or more buffering agents
(v) one or more pH adjusting agents and
(vi) one or more solvents The levothyroxine may be the free base or may be a pharmaceutically acceptable salt thereof. In a preferred embodiment, the levothyroxine is levothyroxine sodium.
Antioxidants used in the formulations include, but are not limited to sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and/or sodium formaldehyde sulfoxylate.
Chelating agents used in the formulations include, but are not limited to edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and/or pentetic acid.
Buffering agents used in the formulations include, but are not limited to sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate;
sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate;
potassium phosphate, monobasic; sodium acetate; sodium acetate anhydrous;
ammonium acetate; sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesqui hydrate; trisodium citrate dehydrate; sodium lactate;
(L)-sodium lactate; sodium tartrate; ammonium sulfate; and/or ethanolamine hydrochloride.
The pH adjusting agents used in the formulations include, but are not limited to sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate;
diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid; benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid;
metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and/or
trifluoroacetic acid.
Solvents used in the formulations include, but are not limited to water for injection (USP), propylene glycol, glycerin, and/or benzyl alcohol.
In another embodiment, the aqueous formulation comprises: (i) levothyroxine sodium
(ii) one or more antioxidants
(iii) one or more chelating agents
(iv) one or more stabilizing agents
(v) one or more buffering agents (vi) one or more pH adjusting agents and
(vii) one or more solvents
The levothyroxine may be the free base or may be a pharmaceutically acceptable salt thereof. In a preferred embodiment, the levothyroxine is levothyroxine sodium.
Antioxidants used in the formulations include, but are not limited to sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and/or sodium formaldehyde sulfoxylate.
Chelating agents used in the formulations include, but are not limited to edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and/or pentetic acid.
Stabilizing agents used in the formulations include, but are not limited to sodium iodide, potassium iodide, povidone, povidone K12, povidone K17, crospovidone, sorbitol, and/or sorbitol solution.
Buffering agents used in the formulations include, but are not limited to sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate;
sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate;
potassium phosphate, monobasic; sodium acetate; sodium acetate anhydrous; ammonium acetate; sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesquihydrate; trisodium citrate dehydrate; sodium lactate; (L)-sodium lactate; sodium tartrate; ammonium sulfate; and/or ethanolamine hydrochloride. The pH adjusting agents used in the formulations include, but are not limited to sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid; benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid; metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and/or
trifluoroacetic acid.
Solvents used in the formulations include, but are not limited to water for injection (USP), propylene glycol, glycerin, and/or benzyl alcohol.
In a preferred embodiment, the formulation is a parenteral formulation.
In another aspect, one or all of the composition invention embodiments are sterile.
In another aspect, one or all of the composition invention embodiments are free of particulate matter. In another aspect, one or all of the composition invention embodiments are packaged in an amber glass container.
In another aspect, one or all of the composition invention embodiments are aseptically packaged in an amber glass container.
In another aspect, one or all of the composition invention embodiments are packaged in an amber glass container and terminally sterilized. The formulations described here can be prepared using conventional techniques known to the person skilled in the art. For example, the formulations may be prepared by dissolving levothyroxine or a pharmaceutically acceptable salt thereof in water, dissolving one or more pharmaceutically acceptable excipients, optionally adjusting the pH of the solution. Alternatively, the formulations may be prepared by dissolving one or more pharmaceutically acceptable excipients prior to dissolving the levothyroxine or pharmaceutically acceptable salt thereof, optionally adjusting the pH of the solution. The composition can be aseptically filled into a container that facilitates ready to administration. Alternatively, the composition can be filled into a container that facilitates ready to administration, and sterilizing said container.
Examples of processes to prepare an aqueous formulation (e.g., parenteral or oral) of levothyroxine or a pharmaceutically acceptable salt thereof include, but are not limited to, those described herein.
In various embodiments, when the formulation is stored at 60°C for a period of 40 days, less than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 20%, 25%, 30% or 35% of the levothyroxine sodium undergoes degradation. In a preferred embodiment, when the formulation is stored at 60°C for a period of 40 days, less than 5%, of the levothyroxine undergoes degradation. In other various embodiments after having been terminally sterilized at about 121 °C for about 30 minutes less than 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 1 1 %, 12%, 13%, 14%, 15%, 20%, 25%, 30% or 35% of the levothyroxine has undergone degradation. In a preferred embodiment, after having been terminally sterilized at about 121 °C for about 30 minutes less than 5% of the levothyroxine has undergone degradation. Such stability characteristics allow the formulations to be stored as aqueous formulations for immediate administration to a patient in need thereof. Such formulations are particularly advantageous in emergency situations, because they are in a ready-to-administer parenteral or oral solution. Such solutions save time in emergency situations because the levothyroxine does not have to be
reconstituted, there is no concern whether the drug has been reconstituted correctly and aseptically in the emergency situation. These characteristics improve the safety of patients in need of levothyroxine, particularly in emergency situations.
The formulations can be provided in various dosage strengths. In some
embodiments, the dosage strength is 10 mcg/mL, 15 mcg/ml_, 20 mcg/mL, 25 mcg/mL, 30mcg/ml_, 35 mcg/mL, 40 mcg/mL, 45 mcg/mL, 50 mcg/mL, 55 mcg/mL, 60 mcg/mL, 65 mcg/mL, 70 mcg/mL, 75 mcg/mL, 80 mcg/mL, 85 mcg/mL, 90 mcg/mL, 95 mcg/mL, 100 mcg/mL, 150 mcg/mL, or 200 mcg/mL of levothyroxine (e.g., levothyroxine sodium) in an IV direct inject or oral solution. Preferably, the formulation is provided at 20mcg/mL, 40mcg/mL, or 100mcg/mL, of levothyroxine (e.g., levothyroxine sodium) in an IV direct inject solution, which will provide a dosing regimen of 300-500 meg initial (e.g., loading) dose followed by 50- 1 10 meg daily (e.g. , maintenance) dose.
The formulations may be packaged in a storage container standardly used for packaging pharmaceuticals (e.g., sterile packaging), particularly liquid formulations. For example, the storage contain may be a glass or plastic vial or ampoule (e.g. , 2ml, 4mL or 6mL volume). In some embodiments, the packaging protects its contents from light. In a preferred embodiment, the vial is an amber glass vial.
Preferably the packaging includes a closure system that is compatible for storage and transport of the formulation.
Suitable caps include those from West Pharmaceutical (size 13mm; sample ID: I3FO LQ LGTE (6B) 767 RED MT STEAM RU/RP; Formula: IP, STM 13FO LNG TE (6B) 3767 RED MATTE). Suitable stoppers include those from West Pharmaceutical (size 13mm; sample ID: 13mm Serum Novapure V-35 4031/45 or RP S2-F451 4432/50 G; Formula: 13mm Serum NovaPure (Bromobutyl/Chlorobutyl) Stopper). Suitable vials include those from Schott (size: 2mL, 4mL, 6mL; sample ID: Fiolax amber Type I glass vial/ Schott; Formula: Type I Amber glass).
Methods of Treatment
The aqueous levothyroxine formulations disclosed herein may be used to treat a disease or condition that is treatable using other levothyroxine formulations. Such diseases include, but are not limited to, myxedema coma.
To treat myxedema coma, an initial intravenous loading dose of the levothyroxine formulation may be about 30C^g to about 50C^g followed by once daily intravenous maintenance doses of between about 50 and about 100μg should be administered to the subject. The aqueous levothyroxine formulations disclosed herein may be used for replacement or supplemental therapy in primary, secondary or tertiary
hypothyroidism.
The aqueous levothyroxine formulations of the present invention may be used for severe hypothyroid subjects or subjects with myxedema coma requiring
hospitalization. The aqueous parenteral formulations of the present invention may be administered intravenously to provide an initial loading dose of about 300 to about 500 μg of levothyroxine sodium to the subject. The aqueous parenteral levothyroxine formulation may be administered intravenously to provide a maintenance daily dose of about 50 to about 100 μg of levothyroxine sodium to the subject. The dose(s) of the disclosed levothyroxine formulations for treating a subject with one or more of the above-described diseases or conditions will depend on the mode of delivery and is within the skill of the skilled person to determine.
When used orally, the formulation may comprise one or more flavoring, sweetening or taste-making agents, known to those skilled in the art. The correct dose to be administered to the subject should be aseptically withdrawn from the vial and inspected visually for particulate matter and discoloration prior to administration into the subject.
EXAMPLES
Example 1
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Benzyl alcohol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 2
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Benzyl alcohol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 3
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Monothioglycerol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 4
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 5
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Monothioglycerol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 6
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 7
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Monothioglycerol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 8
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 9
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Monothioglycerol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 10
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 1 1
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Monothioglycerol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 12
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 13
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 14
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 15
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 16
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 17
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 18
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 1 .0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 19
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 20
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 21
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Propylene glycol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 22
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Propylene glycol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 23
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Propylene glycol was added to the above solution and
mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 24
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 1 1 .0±0.5. Glycerin was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. Example 25
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Glycerin was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 26
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Glycerin was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
All samples of Examples 1 - 26 were tested for osmolarity, pH, appearance and potency of levothyroxine sodium. All samples of Examples 1 - 26 were placed in a 50°C oven, and potency of levothyroxine sodium was tested after 3 days (see Table 1 ).
To analyze the potency of levothyroxine sodium that can be present in an illustrative formulation of levothyroxine sodium, gradient assay HPLC method was employed to separate levothyroxine from formulation components. The HPLC column is Zorbax SB-C18, 4.6x150 mm, 5 μιη. Column temperature is ambient room temperature. Flow rate was 1 .0 mL/min. Levothyroxine was detected in the eluent using UV absorbance. UV Detector wavelength was set at 225 nm. Injection volume was 5 μί for assay determination.
The mobile phase used for the gradient assay HPLC method was a mixture of acetonitrile and sulfamic acid buffer adjusted to pH 2.0 with sodium hydroxide. The diluent for HPLC analysis had same composition as levothyroxine sodium
formulation and it was dibasic sodium phosphate heptahydrate having a pH of 10.5..
The levothyroxine stock standard solution was 0.1 mg/mL of USP levothyroxine reference standard in the diluent.
The sample solutions were injected onto HPLC without further dilution or
preparation.
The concentration of levothyroxine in the sample was determined by the external standard calibration method, where the peak area of levothyroxine in sample injections was compared to the peak area of levothyroxine reference standards in a solution of known concentration.
To calculate the potency of levothyroxine sodium (or Assay %) in the sample solutions, the following formula was used:
Result = {ru/rs) * {Cs/Cu) * 100
Where:
ru = peak response of levothyroxine from the Sample solution
rs = peak response of levothyroxine from the Standard solution
Cs = concentration of USP Levothyroxine RS in the Standard solution ( Q/mL)
Cu = concentration of Levothyroxine Sodium in the Sample solution ^g/mL)
Table 1 : Examples 1 to 26 - Stability Results
1 1 338 10.00 Cloudy 93.3 NA
12 68 7.91 Cloudy 94.3 NA
13 104 10.82 Clear 94.6 95.3
14 232 1 1 .67 Clear 95.3 94.0
15 84 10.58 Clear 92.9 95.4
16 374 1 1 .71 Clear 93.0 NA
17 129 10.29 Cloudy 91 .2 98.3
18 404 10.65 Cloudy 77.3 NA
19 219 10.43 Cloudy 95.7 94.7
20 495 10.31 Cloudy 93.0 NA
Out of
21 NA Clear 96.3 98.2 range
Out of NA
22 Clear 95.9 98.3 range
Out of NA
23 Clear 89.9 98.9 range
24 635 NA Clear 101 .5 78.5
25 707 NA Clear 96.1 97.7
26 795 NA Clear 92.0 90.8
NA - Not tested
Primary observations from the above analyses include the following: Levothyroxine was light sensitive. Monothioglycerol caused the pH to drop in the formulation, resulting in precipitation of levothyroxine sodium. EDTA also caused the pH to drop and precipitation of levothyroxine. Sodium sulfite didn't change the pH or osmolality significantly an appeared to provide stabilizing activity to the formulation. Sodium iodide also did not change the pH and osmolality. Levothyroxine sodium did not degrade whenever Nal was present in the solution.
Example 27
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 28
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 29
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 30
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Exam le 31
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 32
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until
dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 1 0.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 33
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 34
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Benzyl alcohol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 35
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Exam le 36
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Benzyl alcohol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 10.5±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 37
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until
dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 38
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 12.0±0.5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 39
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 40
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Exam le 41
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 42
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Benzyl alcohol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 43
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Exam le 44
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 10.5±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Benzyl alcohol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. Example 45
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was
maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Edetate disodium was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers.
Example 46
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 12.0±0.5. Sodium sulfite was added to the above solution and mixed until dissolved. Sodium iodide was added to the above solution and mixed until dissolved. Propylene glycol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The solution was filtered and filled into containers. All samples of Examples 27 - 46 were tested for osmolarity, pH, appearance and potency of levothyroxine sodium (see Table 2). All samples of Examples 27 - 46 were placed in the following storage conditions: ambient room temperature under ambient light in clear vials; 2-8°C under refrigeration in amber vials; 60°C/ambient RH in amber vials. The potency of levothyroxine sodium (Assay %, described above) and appearance were tested at selected stability storage time point (see Tables 3 - 5).
Table 2: Examples 27 - 46 Test Results at Initial Time
Table 3: Examples 27 - 46 Stability Results (ambient temperature under ambient light in clear vials)
NA - Not tested
Table 4: Examples 27 - 46 Stability Results (2-8°C under refrigeration in amber vials)
Table 5: Examples 27 - 46 Stability Results (60°C/ambient RH in amber vials)
Based on the above analyses, a Prototype I study was initiated. Six formulations (see Examples 47-52) were prepared at 100 mL scale. Each sample was filled with 1 mL of fill volume of solution into 2 mL Type I Clear Glass Vials and then stoppered to represent a worst-case scenario with respect to the process of parameters (e.g., head space oxygen, light). Storage conditions were 60°C.
Example 47
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite was added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 48
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite was added to the above buffer and mixed until dissolved. Propylene glycol was added to the above solution and mixed.
Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 49
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite and edetate disodium were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 50
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 51
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was
maintained at 9.5 - 1 1 .5. Sodium sulfite and edetate disodium were added to the above buffer and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 52
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Propylene glycol was added to the above solution and mixed. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
The samples of Examples 47 - 52 were placed in 121 °C oven for 30min, which simulated heat sterilization conditions, in both upright and inverted orientations. The potency (Assay %, described above) and impurity of levothyroxine sodium were tested (see Table 6). To analyze the impurities of levothyroxine sodium that can be present in an illustrative formulation of levothyroxine sodium, gradient HPLC method was
employed to separate levothyroxine and impurities from formulation components. The gradient HPLC parameters and gradient table are depicted as follows:
The mobile phase A used for the gradient HPLC method was prepared by dissolving 9.7 g of sulfamic acid in 2000 mL of water, followed by adding 1 .5 g of sodium hydroxide and mixing to dissolve. Mobile phase A was adjusted to pH of 2.0 with 2N sodium hydroxide. Mobile phase B is 100% acetonitrile.
Diluent was dibasic sodium phosphate heptahydrate adjusted to pH 10.5. The levothyroxine stock standard solution was 0.1 mg/mL of USP levothyroxine reference standard in the Diluent. To prepare levothyroxine stock standard solution, accurately weighed and transferred about 1 1 mg of levothyroxine USP reference
standard into a 100 mL volumetric flask. Dissolved and diluted to volume with Diluent and mixed well.
The levothyroxine working standard solution was 0.001 mg/mL of USP levothyroxine reference standard. To prepare levothyroxine working standard solution, pipetted 2.0 mL of the levothyroxine stock standard solution to a 200 mL volumetric flask and diluted to volume with Diluent. Mixed well.
The sensitivity and identification standard solution was 0.1 μg/mL of USP
levothyroxine reference standard and liothyronine reference standard.
The sample solutions were injected onto HPLC without further dilution or
preparation. Injection volume for both levothyroxine working standard solution and sample solution was 50 μί.
Diluent was injected as blank injection.
The concentration of levothyroxine in the sample was determined by the external standard calibration method, where the peak area of impurity peaks in sample injections was compared to the peak area of levothyroxine reference standard in a solution of known concentration.
To calculate the percentage of liothyronine sodium (T3 %) in the sample solutions, the following formula was used:
Result = (ru/rs) * (Cs/Cu) * * 100
Where:
ru = peak response of liothyronine from the Sample solution
rs = peak response of levothyroxine from the Standard solution
Cs = concentration of USP levothyroxine RS in the Standard solution (Mg/mL)
Cu = concentration of Levothyroxine Sodium in the Sample solution ( g/mL)
To calculate the percentage of any other impurity (Impurity %) in the sample solutions, the following formula was used:
Result = {ru/rs) * {Cs/Cu) * 100
Where:
ru = peak response of any impurity from the Sample solution
rs = peak response of levothyroxine from the Standard solution
Cs = concentration of USP Levothyroxine RS in the Standard solution
(MQ/mL)
Cu = concentration of Levothyroxine Sodium in the Sample solution ^g/mL)
Any peaks corresponding to those of the blank solution were disregarded. Any peaks corresponding to less than 0.03% were disregarded. To calculate the total impurity, added Impurity % from all impurity peaks.
Table 6: Stability of Samples of Examples 47 - 52 in simulated heat sterilization condition
The samples of Examples 47 - 52 were placed in 60°C oven for about 36 days. The potency and impurity of levothyroxine sodium were tested (see Table 7).
Table 7: Stability results of samples of Examples 47- 52 in 60°C oven
EDTA and Nal positively contributed to the stability of the formulation. Formulations containing propylene glycol showed more impurities compared to formulation the did not contain propylene glycol.
Based on the above studies, a Prototype II study was initiated, to further address qualitative and quantitative aspects of the formulation. Six formulations (see Examples 47-52) were prepared at 100 mL scale. Each sample was filled with 1 mL of fill volume of solution into 2 mL Type I Clear Glass Vials and then stoppered to represent a worst-case scenario with respect to the process of parameters (e.g., head space oxygen, light). Storage conditions were 60°C.
Example 53
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was
maintained at 9.5 - 1 1 .5. Sodium sulfite and edetate disodium were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 54
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 55
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 56
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
Example 57
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers. Example 58
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was
maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filtered and filled into containers.
The samples of Examples 53 - 58 were stored in 2ml_ Type I Clear Glass Vials and placed in 60°C oven for about 40 days. All storage conditions were void of light exposure. Vials were stored in both upright and inverted orientations. The osmolarity, pH, appearance, potency and impurity of levothyroxine sodium were tested (as described herein) at selected stability storage time point (see Table 8).
Table 8: Stability results of samples of Examples 53 - 58 in 60°C oven
Table 8: Stability results of samples of Examples 53 - 58 in 60°C oven (cont'd)
No impurities were observed from a placebo sample (containing 1 .8 mg sodium sulfite; 10 mg sodium iodide; 1 mg EDTA, 10.72 mg sodium phosphate, dibasic, heptahydrate; sodium (qs); and water for injection (qs to 1 ml_)). The presence of 0.1 % EDTA, without sodium iodide, and the associated stability profile as seen in Example 53 demonstrates that this excipient has a stabilizing effect alone or in combination with sodium sulfite.
Example 59 Multivariate Statistical Design:
Formulation development and R&D Scale-up data indicates there is an underlying interaction within the formulation with the three key excipients; sodium iodide, disodium edetate and sodium sulfite. A multivariate statistical design studies was carried out as two sets of experimental trials: 23 Full Factorial DoE Study #1 and 23 Full Factorial DoE Study #2.
All the individual formulations/trials of each of the DoE were packaged in 2ml_ USP Type I amber glass, stoppered with 'Flurotec' coated 'Chlorobutyl' rubber stoppers (for improved compatibility with a high pH of 10.5 as recommended from the
supplier) and subjected to short-term stress stability at 60°C (Inverted orientation) for a period of 4 weeks (see Table 9).
23 Full Factorial DoE Study #1:
DoE #1 was carried out to evaluate/identify if an interaction effect is present within the formulation variables.
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filled into containers.
Table 9: Stability results of samples of Example 59 Initial and 60°C oven
23 Full Factorial DoE Study #2:
The goal of DoE study #2 was to further optimize the composition of sodium iodide, sodium sulfite and disodium edetate as per the results of DoE study #1 . The concentration levels of three excipients (sodium iodide, sodium sulfite and disodium edetate) were different from that of DoE #1 . Sodium iodide was evaluated at higher levels, while sodium sulfite and disodium edetate were evaluated at lower levels (see Table 10).
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filled into containers.
Table 10: Stability results of samples of Example 60 Initial and 60°C oven
After 4 weeks of storing samples at 60°C stability conditions, all samples exhibited >90% assay, <0.15% liothyronine and <0.61 % total impurity levels. Example 61
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was
adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was filled into containers. Stability of the samples was evaluated initially and after 1 or 2 weeks storage in a 60°C oven (see Table 1 1 ).
Table 11 : Stability results of sample of Example 61 Initial and 60°C oven
Time
Strength Test
Initial 1Wk 2Wk
Assay % 101.7 100.7 99.3
40 μ9/πιΙ_ Liothyronine % ND 0.08 0.1 1
Total Impurities % ND 0.15 0.18
After 2 weeks of storing samples at 60°C stability conditions, all samples
exhibited >90% assay, <0.1 1 % liothyronine and <0.18% total impurity levels.
Example 62
To a processing vessel, water for injection was added. Disodium phosphate, heptahydrate and sodium hydroxide were added and dissolved. The pH was maintained at 9.5 - 1 1 .5. Sodium sulfite, edetate disodium and sodium iodide were added to the above buffer and mixed until dissolved. Levothyroxine sodium was added to the above solution and mixed until dissolved. The pH of the solution was adjusted to 9.5 - 1 1 .5 by addition of sodium hydroxide if necessary. The solution was
filled into containers. Stability of the samples was evaluated initially and after 1 or 2 weeks storage in a 60°C oven (see Table 12).
Table 12: Stability results of sample of Example 62 Initial and 60°C oven
After 2 weeks of storing samples at 60 degrees stability conditions, all samples exhibited >90% assay, <0.16% liothyronine and <0.32% total impurity levels.
The results of the experiments described herein show, inter alia, that levothyroxine is stabilized with the use of formulations comprising sodium iodide, sodium sulfite and disodium edetate in combination and at certain ratios. Example 63
A formulation ("Control Formulation") containing: 20 mcg/mL Levothyroxine sodium, USP; 6.48 mg/mL sodium chloride; 0.14 mg/mL sodium iodide; 10 mg/ml
tromethamine, USP; sodium hydroxide (1 N) and hydrochloric acid as needed to adjust pH to 10-10.5 and purified water (q.s.). The formulation of Example 60, Trial 8 ("Formulation E60/T8") was also prepared. The solution was filled into containers. Stability of the samples was evaluated, as described herein, initially and after 4 weeks storage in a 60°C oven.
Table 13: Stability results of samples of Example 63 Initial and 60°C oven
Formulation E60/T8 exhibited superior stability compared to the Control Formulation, and had an Assay % within the USP acceptable range of 90% - 1 10% and low impurity levels at elevated temperatures of 60°C for 4 weeks. Even under these high stress conditions, Formulation E60/T8 is robust.
It is to be understood that the invention embodiments are not limited to the particular structures, process steps, or materials disclosed herein, but are extended to equivalents thereof as would be recognized by those ordinarily skilled in the relevant arts. It should also be understood that terminology employed herein is used for the purpose of describing particular embodiments only and is not intended to be limiting.
Claims
1 . An aqueous parenteral formulation comprising levothyroxine or a
pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
2. The aqueous parenteral formulation of claim 1 , wherein the pharmaceutically acceptable salt of levothyroxine is levothyroxine sodium.
3. The aqueous parenteral formulation of claim 2, wherein the concentration of levothyroxine sodium in the formulation is between about 5 and about 500 μg/mL.
4. An aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) one or more antioxidants;
(iii) one or more chelating agents;
(iv) one or more buffering agents;
(v) one or more pH adjusting agents; and
(vi) one or more solvents.
5. The aqueous parenteral formulation of claim 4, wherein the one or more
antioxidants is selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and sodium formaldehyde sulfoxylate.
6. The aqueous parenteral formulation of claim 4, wherein the one or more
chelating agents is selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium
disodium anhydrous, edetic acid, anhydrous citric acid, citric acid
monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and pentetic acid.
7. The aqueous parenteral formulation of claim 4, wherein the one or more
buffering agents is selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate; sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate;
potassium phosphate, monobasic; sodium acetate; sodium acetate anhydrous; ammonium acetate; sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesquihydrate; trisodium citrate dehydrate; sodium lactate; (L)-sodium lactate; sodium tartrate; ammonium sulfate; and ethanolamine hydrochloride.
8. The aqueous parenteral formulation of claim 4, wherein the one or more pH adjusting agents is selected from sodium hydroxide; calcium hydroxide;
potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid; benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid; metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and trifluoroacetic acid.
9. The aqueous parenteral formulation of claim 4, wherein the one or more
solvents is selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
10. The aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) one or more antioxidants selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium metabisulfite;
(iii) one or more chelating agents selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, and edetic acid;
(iv) one or more buffering agents selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate; sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate; and potassium phosphate, monobasic;
(v) one or more pH adjusting agents selected from sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and
(vi) one or more solvents selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
The aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) sodium sulfite;
(iii) edetate disodium, edetate disodium anhydrous, or edetate sodium ;
(iv) sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium
phosphate; sodium phosphate dehydrate; or dibasic potassium phosphate;
(v) sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate;
sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; or ammonia; and
(vi) water for injection (USP).
12. The aqueous parenteral formulation of claim 1 , comprising (i) levothyroxine sodium; (ii) sodium sulfite;
(iii) edetate disodium;
(iv) sodium phosphate, dibasic, heptahydrate;
(v) sodium hydroxide; and
(vi) water for injection (USP).
13. The aqueous parenteral formulation of claim 12, comprising between about 5 and about 500 μg/mL of levothyroxine sodium .
14. The aqueous parenteral formulation of claim 12, comprising between about 0.01 % and about 0.5% w/v of sodium sulfite.
15. The aqueous parenteral formulation of claim 12, comprising between about 0.005% and about 0.5% w/v of edetate disodium.
16. The aqueous parenteral formulation of claim 12, comprising between about 0.01 % and about 5% w/v of sodium phosphate, dibasic, heptahydrate.
17. The aqueous parenteral formulation of claim 12, wherein the pH of the
formulation is between about 9.5 and about 1 1 .5.
18. The aqueous parenteral formulation of claim 12, wherein, when the formulation is stored at 60°C for a period of 40 days, less than about 5% of levothyroxine sodium undergoes degradation.
19. The aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) one or more antioxidants;
(iii) one or more chelating agents;
(iv) one or more stabilizing agents;
(v) one or more buffering agents;
(vi) one or more pH adjusting agents; and
(vii) one or more solvents.
20. The aqueous parenteral formulation of claim 19, wherein the one or more antioxidants is selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, potassium metabisulfite, alpha-tocopherol, acetone sodium bisulfite, ascorbic acid, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, gentisic acid, gentisic ethanolamide, glutathione, methionine, monothioglycerol, and sodium formaldehyde sulfoxylate.
21 . The aqueous parenteral formulation of claim 19, wherein the one or more chelating agents is selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid, anhydrous citric acid, citric acid
monohydrate, gluceptate sodium, pentasodium pentetate, pentetate calcium trisodium, and pentetic acid.
22. The aqueous parenteral formulation of claim 19, wherein the one or more stabilizing agents is selected from sodium iodide, potassium iodide, povidone, povidone K12, povidone K17, crospovidone, sorbitol, and sorbitol solution.
23. The aqueous parenteral formulation of claim 19, wherein the one or more buffering agents is selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate; sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate;
potassium phosphate, monobasic; sodium acetate; sodium acetate
anhydrous; ammonium acetate; sodium citrate; disodium hydrogen citrate; anhydrous trisodium citrate; disodium citrate sesquihydrate; trisodium citrate dehydrate; sodium lactate; (L)-sodium lactate; sodium tartrate; ammonium sulfate; and ethanolamine hydrochloride.
24. The aqueous parenteral formulation of claim 19, wherein the one or more pH adjusting agents is selected from sodium hydroxide; calcium hydroxide;
potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; ammonia; hydrochloric acid; acetic acid; acetic anhydride; adipic acid; anhydrous citric acid; benzenesulfonic acid; boric acid; citric acid monohydrate; lactic acid; (DL)-lactic acid; (L)-lactic acid; maleic acid; metaphosphoric acid; methanesulfonic acid; nitric acid; phosphoric acid; succinic acid; sulfuric acid; sulfurous acid; tartaric acid; (DL)-tartaric acid; and trifluoroacetic acid.
25. The aqueous parenteral formulation of claim 19, wherein the one or more solvents is selected from water for injection (USP), propylene glycol, glycerin, and benzyl alcohol.
26. The aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) one or more antioxidants selected from sodium sulfite, sodium bisulfite, sodium metabisulfite, and potassium metabisulfite;
(iii) one or more chelating agents selected from edetate disodium, edetate disodium anhydrous, edetate sodium, edetate calcium disodium, edetate calcium disodium anhydrous, edetic acid;
(iv) one or more stabilizing agents selected from sodium iodide and potassium iodide;
(v) one or more buffering agents selected from sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; sodium phosphate, monobasic, anhydrous; sodium phosphate, monobasic, dehydrate; sodium phosphate, monobasic, monohydrate; dibasic potassium phosphate; and potassium phosphate, monobasic;
(vi) one or more pH adjusting agents selected from sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate; sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and
(vii) one or more solvents selected from water for injection (USP), propylene glycol, glycerin, benzyl alcohol.
The aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) sodium sulfite;
(iii) edetate disodium, edetate disodium anhydrous, or edetate sodium ;
(iv) sodium iodide or potassium iodide;
(v) sodium phosphate, dibasic, heptahydrate; sodium phosphate, dibasic; sodium phosphate, dibasic, anhydrous; sodium phosphate, dibasic dehydrate; sodium phosphate, dibasic dodecahydrate; sodium phosphate; sodium phosphate dehydrate; or dibasic potassium phosphate;
(vi) sodium hydroxide; calcium hydroxide; potassium hydroxide; sodium bicarbonate; sodium carbonate; sodium carbonate decahydrate;
sodium carbonate monohydrate; diethanolamine; meglumine; tromethamine; and ammonia; and
(vii) water for injection (USP).
28. The aqueous parenteral formulation of claim 1 , comprising
(i) levothyroxine sodium;
(ii) sodium sulfite;
(iii) edetate disodium;
(iv) sodium iodide;
(v) sodium phosphate, dibasic, heptahydrate;
(vi) sodium hydroxide; and
(vii) water for injection (USP).
29. The aqueous parenteral formulation of claim 28, comprising between about 5 and about 500 μg/mL of levothyroxine sodium .
30. The aqueous parenteral formulation of claim 28, comprising between about 0.01 % and about 0.5% w/v of sodium sulfite.
31 . The aqueous parenteral formulation of claim 28, comprising between about 0.005% and about 0.5% w/v of edetate disodium.
32. The aqueous parenteral formulation of claim 28, comprising between about 0.01 % and about 5% w/v of sodium iodide.
33. The aqueous parenteral formulation of claim 28, comprising between about 0.01 % and about 5% w/v of sodium phosphate, dibasic, heptahydrate.
34. The aqueous parenteral formulation of claim 28, wherein the pH of the
formulation is between about 9.5 and about 1 1 .5.
35. The aqueous parenteral formulation of claim 28, wherein, when the
formulation is stored at 60°C for a period of 40 days, less than about 5% of levothyroxine sodium undergoes degradation.
36. A method of treating myxedema coma in a subject by administering to the subject the aqueous parenteral formulation of any one of claims 1 - 35.
37. A method of treating hypothyroidism in a subject by administering to the
subject the aqueous parenteral formulation of any one of claims 1 - 35.
38. A method for treating Hashimoto's thyroiditis and atrophic thyroiditis in a subject by administering to the subject the aqueous parenteral formulation of any one of claims 1 - 35.
39. The method of claim 38, wherein the formulation is for use as replacement or supplemental therapy.
40. A method of providing replacement or supplemental therapy of
hypothyroidism resulting from surgical removal of part or all of the thyroid gland; radiation treatment; congenital hypothyroidism; and anti-thyroid medicines in a subject, the method comprising administering to the subject the aqueous parenteral formulation of any one of claims 1 - 35.
41 . The method of any one of claims 36-40, wherein the formulation is administered intravenously to provide an initial dose of about 300 to about 500 of levothyroxine or a pharmaceutically acceptable salt to the subject.
42. The method of any one of claims 36-40, wherein the formulation is
administered intravenously to provide a daily dose of about 50 to about 100 μ9 of levothyroxine to the subject.
43. The method of any one of claims 36-42 wherein the levothyroxine is
levothyroxine sodium.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2747987C1 (en) * | 2020-10-07 | 2021-05-18 | Федеральное государственное бюджетное военное образовательное учреждение высшего образования "Военно-медицинская академия имени С.М. Кирова" Министерства обороны Российской Федерации (ВМедА) | Composition for treatment of latent and subclinical papillomavirus infection of cervix and method for its application |
US11135190B2 (en) | 2016-12-01 | 2021-10-05 | Fresenius Kabi Usa, Llc | Levothyroxine liquid formulations |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007077252A1 (en) * | 2006-01-06 | 2007-07-12 | Intervet International B.V. | Concentrated liquid thyroid hormone composition |
US9345772B1 (en) * | 2015-02-27 | 2016-05-24 | Nilesh Parikh | Liquid levothyroxine formulations |
WO2017013591A1 (en) * | 2015-07-22 | 2017-01-26 | Leiutis Pharmaceuticals Pvt Ltd | Stabilized liquid formulation of levothyroxine |
-
2018
- 2018-07-30 WO PCT/CA2018/050923 patent/WO2019023791A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007077252A1 (en) * | 2006-01-06 | 2007-07-12 | Intervet International B.V. | Concentrated liquid thyroid hormone composition |
US9345772B1 (en) * | 2015-02-27 | 2016-05-24 | Nilesh Parikh | Liquid levothyroxine formulations |
WO2017013591A1 (en) * | 2015-07-22 | 2017-01-26 | Leiutis Pharmaceuticals Pvt Ltd | Stabilized liquid formulation of levothyroxine |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11135190B2 (en) | 2016-12-01 | 2021-10-05 | Fresenius Kabi Usa, Llc | Levothyroxine liquid formulations |
RU2747987C1 (en) * | 2020-10-07 | 2021-05-18 | Федеральное государственное бюджетное военное образовательное учреждение высшего образования "Военно-медицинская академия имени С.М. Кирова" Министерства обороны Российской Федерации (ВМедА) | Composition for treatment of latent and subclinical papillomavirus infection of cervix and method for its application |
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