EP3764989A1 - Stable liquid suspension composition of fludrocortisone - Google Patents
Stable liquid suspension composition of fludrocortisoneInfo
- Publication number
- EP3764989A1 EP3764989A1 EP19713218.6A EP19713218A EP3764989A1 EP 3764989 A1 EP3764989 A1 EP 3764989A1 EP 19713218 A EP19713218 A EP 19713218A EP 3764989 A1 EP3764989 A1 EP 3764989A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- fludrocortisone
- liquid suspension
- stable liquid
- suspension composition
- parahydroxybenzoate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 77
- AAXVEMMRQDVLJB-BULBTXNYSA-N fludrocortisone Chemical group O=C1CC[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 AAXVEMMRQDVLJB-BULBTXNYSA-N 0.000 title claims abstract description 45
- 229960002011 fludrocortisone Drugs 0.000 title claims abstract description 44
- 239000006194 liquid suspension Substances 0.000 title claims abstract description 44
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 32
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 29
- 239000002518 antifoaming agent Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 23
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 21
- SYWHXTATXSMDSB-GSLJADNHSA-N fludrocortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O SYWHXTATXSMDSB-GSLJADNHSA-N 0.000 claims description 20
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 19
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 19
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 19
- 239000000375 suspending agent Substances 0.000 claims description 19
- 229960003336 fluorocortisol acetate Drugs 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 239000003755 preservative agent Substances 0.000 claims description 14
- 230000002335 preservative effect Effects 0.000 claims description 14
- 239000008213 purified water Substances 0.000 claims description 13
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 12
- 235000011187 glycerol Nutrition 0.000 claims description 12
- 235000003599 food sweetener Nutrition 0.000 claims description 11
- 239000003765 sweetening agent Substances 0.000 claims description 11
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims description 10
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 10
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 10
- 229960002216 methylparaben Drugs 0.000 claims description 10
- 229940083037 simethicone Drugs 0.000 claims description 10
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 9
- -1 veegum Polymers 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- MOZDKDIOPSPTBH-UHFFFAOYSA-N Benzyl parahydroxybenzoate Chemical compound C1=CC(O)=CC=C1C(=O)OCC1=CC=CC=C1 MOZDKDIOPSPTBH-UHFFFAOYSA-N 0.000 claims description 6
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 6
- XPJVKCRENWUEJH-UHFFFAOYSA-N Isobutylparaben Chemical compound CC(C)COC(=O)C1=CC=C(O)C=C1 XPJVKCRENWUEJH-UHFFFAOYSA-N 0.000 claims description 6
- CMHMMKSPYOOVGI-UHFFFAOYSA-N Isopropylparaben Chemical compound CC(C)OC(=O)C1=CC=C(O)C=C1 CMHMMKSPYOOVGI-UHFFFAOYSA-N 0.000 claims description 6
- 229920002125 Sokalan® Polymers 0.000 claims description 6
- 239000006185 dispersion Substances 0.000 claims description 6
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 claims description 6
- 239000004376 Sucralose Substances 0.000 claims description 5
- 239000003963 antioxidant agent Substances 0.000 claims description 5
- 235000006708 antioxidants Nutrition 0.000 claims description 5
- 239000006172 buffering agent Substances 0.000 claims description 5
- 235000019408 sucralose Nutrition 0.000 claims description 5
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 claims description 5
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 239000013029 homogenous suspension Substances 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 4
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 4
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- 229920002907 Guar gum Polymers 0.000 claims description 3
- GZYFIMLSHBLMKF-REOHCLBHSA-N L-Albizziine Chemical compound OC(=O)[C@@H](N)CNC(N)=O GZYFIMLSHBLMKF-REOHCLBHSA-N 0.000 claims description 3
- 229920001615 Tragacanth Polymers 0.000 claims description 3
- 239000000305 astragalus gummifer gum Substances 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 3
- 239000000796 flavoring agent Substances 0.000 claims description 3
- 150000002334 glycols Chemical class 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 229940113094 isopropylparaben Drugs 0.000 claims description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 229920001296 polysiloxane Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 235000010241 potassium sorbate Nutrition 0.000 claims description 3
- 239000004302 potassium sorbate Substances 0.000 claims description 3
- 229940069338 potassium sorbate Drugs 0.000 claims description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 3
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 3
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 3
- 235000010234 sodium benzoate Nutrition 0.000 claims description 3
- 239000004299 sodium benzoate Substances 0.000 claims description 3
- 239000000230 xanthan gum Substances 0.000 claims description 3
- 235000010493 xanthan gum Nutrition 0.000 claims description 3
- 229920001285 xanthan gum Polymers 0.000 claims description 3
- 229940082509 xanthan gum Drugs 0.000 claims description 3
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical class [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 3
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 2
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical group [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims description 2
- 108010011485 Aspartame Proteins 0.000 claims description 2
- 235000010358 acesulfame potassium Nutrition 0.000 claims description 2
- 229960004998 acesulfame potassium Drugs 0.000 claims description 2
- 239000000619 acesulfame-K Substances 0.000 claims description 2
- 239000000605 aspartame Substances 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims description 2
- 229960003438 aspartame Drugs 0.000 claims description 2
- 239000003086 colorant Substances 0.000 claims description 2
- 229940109275 cyclamate Drugs 0.000 claims description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 235000019204 saccharin Nutrition 0.000 claims description 2
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229940081974 saccharin Drugs 0.000 claims description 2
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 claims description 2
- 229940085605 saccharin sodium Drugs 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 8
- 239000000725 suspension Substances 0.000 description 20
- 239000007788 liquid Substances 0.000 description 14
- 239000006260 foam Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- 239000012669 liquid formulation Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000013530 defoamer Substances 0.000 description 5
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 208000026872 Addison Disease Diseases 0.000 description 4
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 4
- 229960002303 citric acid monohydrate Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 208000036647 Medication errors Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 235000010323 ascorbic acid Nutrition 0.000 description 3
- 239000011668 ascorbic acid Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229960005219 gentisic acid Drugs 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 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 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- 208000005676 Adrenogenital syndrome Diseases 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- 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 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 206010039807 Secondary adrenocortical insufficiency Diseases 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 2
- GRWZHXKQBITJKP-UHFFFAOYSA-L dithionite(2-) Chemical compound [O-]S(=O)S([O-])=O GRWZHXKQBITJKP-UHFFFAOYSA-L 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000002395 mineralocorticoid Substances 0.000 description 2
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 238000009256 replacement therapy Methods 0.000 description 2
- 235000010378 sodium ascorbate Nutrition 0.000 description 2
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 2
- 229960005055 sodium ascorbate Drugs 0.000 description 2
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 2
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- WHBMMWSBFZVSSR-GSVOUGTGSA-M (R)-3-hydroxybutyrate Chemical compound C[C@@H](O)CC([O-])=O WHBMMWSBFZVSSR-GSVOUGTGSA-M 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 description 1
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 1
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-UHFFFAOYSA-N Galactaric acid Natural products OC(=O)C(O)C(O)C(O)C(O)C(O)=O DSLZVSRJTYRBFB-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 241000446313 Lamella Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 229940045942 acetone sodium bisulfite Drugs 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- 229960002478 aldosterone Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- OENHQHLEOONYIE-UKMVMLAPSA-N all-trans beta-carotene Natural products CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 235000013734 beta-carotene Nutrition 0.000 description 1
- 239000011648 beta-carotene Substances 0.000 description 1
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 description 1
- 229960002747 betacarotene Drugs 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical group 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-L cysteinate(2-) Chemical compound [S-]CC(N)C([O-])=O XUJNEKJLAYXESH-UHFFFAOYSA-L 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- HRKQOINLCJTGBK-UHFFFAOYSA-L dioxidosulfate(2-) Chemical compound [O-]S[O-] HRKQOINLCJTGBK-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- DSLZVSRJTYRBFB-DUHBMQHGSA-N galactaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O DSLZVSRJTYRBFB-DUHBMQHGSA-N 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940001607 sodium bisulfite Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 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 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- VYGBQXDNOUHIBZ-UHFFFAOYSA-L sodium formaldehyde sulphoxylate Chemical compound [Na+].[Na+].O=C.[O-]S[O-] VYGBQXDNOUHIBZ-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- YNJORDSKPXMABC-UHFFFAOYSA-N sodium;2-hydroxypropane-2-sulfonic acid Chemical compound [Na+].CC(C)(O)S(O)(=O)=O YNJORDSKPXMABC-UHFFFAOYSA-N 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
Definitions
- the present invention contemplates a stable liquid suspension composition of fludrocortisone or pharmaceutically acceptable salts thereof.
- the present invention contemplates more particularly a stable liquid composition of fludrocortisone or pharmaceutically acceptable salts thereof suitable for oral administration.
- Fludrocortisone (9-a-fluorocortisol) A synthetic analog of aldosterone that acts on the kidney so as to conserve sodium and excrete potassium. This definition includes derivatives of fludrocortisone, such as fludrocortisone acetate (which goes by the brand name Florinef®. Fludrocortisone in the form of its acetate salt has the chemical name 9- fluoro- 1 1 b.17.21 -trihydroxypregn-4-ene-3.20-dione 2l-acetate; its molecular formula is C23H31F06, and its molecular weight is 422.493. The structural formula is shown below;
- Fludrocortisone is prescribed for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease and for the treatment of salt-losing adrenogenital syndrome.
- the usual dose is 0.1 mg of fludrocortisone acetate daily, although dosage ranging from 0.1 mg three times a week to 0.2 mg daily has been employed. In the event transient hypertension develops as a consequence of therapy, the dose should be reduced to 0.05 mg daily.
- Fludrocortisone acetate is preferably administered in conjunction with cortisone (10 mg to 37.5 mg daily in divided doses) or hydrocortisone (10 mg to 30 mg daily in divided doses).
- Fludrocortisone Products comprising fludrocortisone are marketed under the trade name FLORINEF ® .
- Various tablet formulations of fludrocortisone have been approved for marketing, for instance, conventional compressed instant release (IR) tablets comprising 0.1 mg of active ingredient. These are administered once, twice or three times daily.
- IR compressed instant release
- preparing extemporaneous suspension may result in degradation of the active ingredients, if the active ingredient is sensitive to water or any other solvent exposure which may result in a decrease in concentration of the active ingredient in extemporaneous suspension and patient may get less dose compared to the prescribed one for effective treatment.
- solvent vehicle which is usually water or a medium comprised mostly of water
- water or the solvent medium is usually the reason for the instability.
- the solvent medium such as water may lead todegradation of the active ingredient. This is a potential issue for fludrocortisone.
- the present invention relates a stable liquid suspension composition
- a stable liquid suspension composition comprising fludrocortisone present in the range from 0.001 mg/ml to 1 mg/ml, a vehicle for fludrocortisone or salts thereof, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
- said stable liquid suspension composition comprises;
- the stable liquid suspension composition comprises;
- the stable liquid suspension is formulated in water or an aqueous medium including water.
- One more aspect of the present invention is to provide process for preparing said stable liquid suspension composition comprising steps of;
- step b) adding a suspending agent to the solution of step a) optionally with continuous stirring,
- step d) adding sweetener to the solution produced in step c), optionally with continuous stirring,
- step e dispersing fludrocortisone acetate in a mixture of vehicle and purified water, f) adding the dispersion produced in step e) in to the suspension produced in step d) to get an homogenous suspension, optionally with continuous stirring, g) adding buffering agent to the suspension produced in step f) to adjust the pH to from 3 to 5, and
- continuous stirring may be employed in order to ensure good dissolution or suspension of the relevant component.
- Stable liquid pharmaceutical composition of fludrocortisone is the invention as further described herein.
- the invention provides a stable liquid suspension composition comprising fludrocortisone present in the range from about 0.001 mg/ml to 1 mg/ml.
- the composition includes a vehicle for fludrocortisone, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
- pharmaceutically-acceptable salts as used herein includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases.
- Suitable pharmaceutically-acceptable acid addition salts of fludrocortisone may be prepared from an inorganic acid or from an organic acid.
- inorganic acids examples include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
- Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, malonic, galact
- composition refers to a system in which small solid particles are essentially uniformly dispersed in a liquid medium.
- stable suspension describes a suspension that shows no separation after being stored for at least 1 week at ambient temperature.
- pH of the composition should be from 3 to 5, preferably the pH is from 3.8 to 4.2, and ideally about 4.
- the stable liquid suspension composition of the present invention is chemically and physically stable without any precipitation or crystallization. This was demonstrated in a stability study. Another benefit is that the composition overcame the problem of unpleasant taste.
- a stable liquid suspension composition according to the present invention shows good stability and reproducibility even after long-term storage. This means that a liquid composition can be stored for a few days or a week or longer without significant degradation.
- the stable liquid suspension composition of present invention even though being in the form of a suspension also offers an advantage of uniform dosing, physical stability. It also reduces the chances of medication error or over dosage.
- the stable liquid suspension composition of the present invention, as described herein remains stable for longer period during stability studies performed at different temperature and humidity condition.
- Fludrocortisone acetate is a synthetic adrenocortical steroid possessing very potent mineralcorticoid properties and high glucocorticoid activity. It is used for its mineralcorticoid effects. It is a white to pale yellow, odourless or almost odourless, crystalline powder. Practically insoluble in water; soluble 1 in 50 in alcohol, 1 in 50 in chloroform; slightly soluble in ether.
- fludrocortisone to be used in the form of Fludrocortisone acetate As per one embodiment, fludrocortisone to be used in the form of Fludrocortisone acetate.
- a stable liquid suspension composition comprises fludrocortisone present in the range fromO.OOl mg/ml to 1 mg/ml, a vehicle for fludrocortisone, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
- the liquid suspension is a suspension in water or a mixture of water and a co-solvent.
- the liquid suspension is a suspension in water.
- the stable liquid suspensions of the invention remain stable and uniform when appropriate excipients are selected and are used at specific and effective concentrations.
- One of the main excipients that plays role in stabilizing the pharmaceutical composition of present invention is suspending agent and vehicle for fludrocortisone or salts thereof.
- an appropriate vehicle is required to disperse fludrocortisone acetate before preparing the final composition.
- Many vehicles are unsuitable for producing compositions of fludorocortisone.
- the inventors of the present invention tried many vehicles and surprisingly found that appropriate stability is observed when the vehicle is selected from one or more of: polyethylene glycol, glycerol and propylene glycol.
- glycerol is used as a vehicle for dispersing fludrocortisone acetate.
- the amount of the vehicle for dispersing fludrocortisone acetate is used in the range from 0.01 to 5% w/v, and is preferably in the range from 0.05 to 1% w/v.
- the suspending agent can be selected from one or more of: xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxy vinyl polymer), polyvinyl Pyrrolidone.
- the suspending agent is cellulose based, in a preferred embodiment, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose or Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose).
- HPMC hydroxypropyl methylcellulose
- the suspending agent is HPMC (hydroxypropyl methylcellulose) also known as hypromellose.
- Hypromellose is a solid, and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloids when dissolved in water. This non-toxic ingredient is combustible and can react vigorously with oxidising agents.
- HPMC is available in different grades commercially based on the viscosity for the product measured at 2% in water at 20°C.
- HPMC Different grades available are HPMC followed by K100 LV, K4M, K15M, K100M, E15 LV, E50 LV, E4M, F50 LV, F4M code.
- HPMC with low viscosity grade are preferred, including HPMC K100LV, HPMCE4M, HPMC E50LV and HPMC E15LV.
- the suspending agent is HPMC E4M.
- the concentration of the suspending agent is also important. Thisimpacts the final stability and physical characteristic of composition.
- the % of suspending agent is in the range from 0.1 to 10 % w/v, more prefearably in the range from 0.25 to 5 % w/v and most preferred is 0.5 to 2.5 % w/v.
- a substance used to reduce foam formation in liquid dosage compositions is called anti foaming agents also called as Defoamer.
- Anti foaming agents also called as Defoamer.
- a defoamer or an anti-foaming agent is a chemical additive that reduces and hinders the formation of foam in industrial process liquids.
- the terms anti-foam agent and defoamer are often used interchangeably.
- a defoamer is insoluble in the foaming medium and has surface active properties.
- An essential feature of a defoamer product is a low viscosity and a facility to spread rapidly on foamy surfaces. It has affinity to the air-liquid surface where it destabilizes the foam lamellas. This causes rupture of the air bubbles and breakdown of surface foam. Entrained air bubbles are agglomerated, and the larger bubbles rise to the surface of the bulk liquid more quickly.
- the anti-foaming agent for the present invention can be selected from one or more of: polydimethylsiloxane, simethicone, other silicones, stearates, alcohols and glycols.
- the anti -foaming agent may be of more than one of the above agents.
- the anti foaming agent is simethicone.
- the anti foaming agent is present in the range from 0.005 to 1 % w/v. In a preferred embodiment, anti foaming agent is present in the range from 0.01 to 0.5 % w/v. In a more preferred embodiment, anti foaming agent is present in the range from 0.01 to 0.1 % w/v. In a most embodiment, anti foaming agent is present in the range from 0.02 to 0.08 % w/v.
- suitable preservative for present invention can be selected from one or more of: methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof.
- the preservative is present in the range from about 0.001 %w/v to about 0.5 %w/v.
- the present stable liquid suspension composition of present invention contains one or more inactive excipients selected from buffering agent, sweetener, anti oxidant, coloring agent and flavoring agent.
- suitable buffer for present invention is selected from one or more of: Citric Acid monohydrate, Sodium Citrate, Sodium Dihydrogen Phosphate, Disodium Phosphate, Trometamol (Tris), Disodium hydrogen phosphate anhydrous, Hydrochloric Acid, Ascorbic Acid, Sodium Ascorbate and anhydrous, monohydrate or dehydrate forms thereof.
- the buffer can be single or any combination of above listed buffer. In a preferred embodiment, combination of Disodium hydrogen phosphate anhydrous and Citric Acid monohydrate is to be used.
- suitable sweetener for present invention is selected from one or more of: acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame or mixtures thereof.
- sucralose is to be used.
- the liquid pharmaceutical composition of the present invention can be prepared in absence of sweetener. However to make it more palatable and easily acceptable by patient especially children, very small amount of sweetener can be added. Sweetener for the present invention can be used in the range from about 0.01 %w/v to 0.5 % w/v.
- the liquid pharmaceutical composition may further comprise anti oxidants.
- Suitable antioxidants for the composition of the present invention can be selected from one or more of: consisting ofbutylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium/acid), bisulfite sodium, cystein/cysteinate HC1, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sul
- the vehicle or solvent for making the final volume of the composition can be selected from one or more of: glycerine, alcohols, propylene glycol, polyethylene glycol, purified water, ethanol and isopropyl alcohol.
- the vehicle or solvent may include mixtures of the above agents Preferably purified water is used as a solvent.
- said stable liquid suspension composition comprises;
- the stable liquid composition of fludrocortisone is to be used for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease. It can also be used for the treatment of salt-losing adrenogenital syndrome.
- said stable liquid suspension composition comprises;
- a suspending agent selected from xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxyvinyl polymer), polyvinyl Pyrrolidone, or mixtures thereof
- an anti foaming agent selected from polydimethylsiloxane, simethicone, other silicones, stearates, alcohols, glycols or combinations thereof,
- said stable liquid suspension composition comprises;
- said stable liquid suspension composition comprises;
- the stable liquid suspension composition is prepared by:
- step b) adding suspending agent in step a) with continuous stirring
- step b) adding antifoaming agent in step b) with continuous stirring
- step d) adding sweetener to step c) with continuous stirring
- step e) dispersing fludrocortisone acetate in mixture of vehicle and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
- step f) adding buffering agent to step f) to adjust pH to from 3 to 5 and
- the stable liquid suspension composition is prepared by a) adding methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben in water and stirring till dissolve it, b) adding HPMC (hydroxypropyl methylcellulose) E4M in step a) with continuous stirring,
- step b) adding simethicone in step b) with continuous stirring
- step d) adding sucralose to step c) with continuous stirring
- step e) dispersing fludrocortisone acetate in mixture of glycerol and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
- step f) adding citric acid monohydrate and disodium hydrogen phosphate anhydrous to step f) to adjust pH in between 3 to 5 and
- step 2 Add HPMC E4M in step 1 when temperature reaches 60-70°C and keep aside to cool at room temperature.
- step 5 Add dispersion of step 5 into step 4 and mix to get homogeneous suspension.
- Example 1 Make up to volume with purified water and stir for 10 minutes to get homogeneous suspension. Physical observations: The composition of Example 1 was observed after storing for 24 hrs at room temperature. No any sedimentation or colour change observed, hence further stability studies at different temperature/humidity and time duration was planned.
- Example 2 Comparative examples
- Example 2 The composition of Example 2 (2A, 2B and 2C) was observed after storing for 24 hrs at room temperature. There are sedimentation as well as slight color change was observed in all three composition. Therefore no further stability studies were conducted.
- Example 3 The composition of Example 3 was observed after storing for 24 hrs at room temperature. There are very little sedimentation was observed but that was redisersible on shaking. No further stability conducted.
- Example 4 Stability study of Example 1
- Example 1 shows good stability for 6 months storage when stored in the condition of
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Abstract
The present invention relates to stable liquid suspension composition suitable for oral administration comprising fludrocortisone or pharmaceutically acceptable salts thereof and process for preparing the said liquid suspension pharmaceutical composition.
Description
TITLE: STABLE LIQUID SUSPENSION COMPOSITION OF
FLUDROCORTISONE
Field of the Invention
The present invention contemplates a stable liquid suspension composition of fludrocortisone or pharmaceutically acceptable salts thereof. The present invention contemplates more particularly a stable liquid composition of fludrocortisone or pharmaceutically acceptable salts thereof suitable for oral administration. Background of the Invention
Fludrocortisone (9-a-fluorocortisol): A synthetic analog of aldosterone that acts on the kidney so as to conserve sodium and excrete potassium. This definition includes derivatives of fludrocortisone, such as fludrocortisone acetate (which goes by the brand name Florinef®. Fludrocortisone in the form of its acetate salt has the chemical name 9- fluoro- 1 1 b.17.21 -trihydroxypregn-4-ene-3.20-dione 2l-acetate; its molecular formula is C23H31F06, and its molecular weight is 422.493. The structural formula is shown below;
Fludrocortisone is prescribed for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease and for the treatment of salt-losing adrenogenital syndrome.
The usual dose is 0.1 mg of fludrocortisone acetate daily, although dosage ranging from 0.1 mg three times a week to 0.2 mg daily has been employed. In the event transient hypertension develops as a consequence of therapy, the dose should be reduced to 0.05 mg daily. Fludrocortisone acetate is preferably administered in conjunction with cortisone (10 mg to 37.5 mg daily in divided doses) or hydrocortisone (10 mg to 30 mg daily in divided doses).
Products comprising fludrocortisone are marketed under the trade name FLORINEF®. Various tablet formulations of fludrocortisone have been approved for marketing, for instance, conventional compressed instant release (IR) tablets comprising 0.1 mg of active ingredient. These are administered once, twice or three times daily.
In terms of pharmaceutical formulations, the major market is solid oral formulations or dosage forms because of ease of manufacturing, storage, stability etc. However on the other hand, there are a huge number of patients who have difficulties swallowing, for example children and aged people. Also some patients with mental disorders or nauseated patients struggle with administration of such formulations. There are also certain situations when patients may be travelling and have very little or no access of water. In all such cases, the solid formulations appears to be non viable and may result in patient non compliance and/or medication error. This may lead to discontinuation of medication. In absence of any oral liquid formulation available in the market, hospitals & dispensaries generally follow a practice of preparing extemporaneous suspensions from available solid formulations and triturating the same followed by adding water and, if required, syrup to make it palatable. For fludrocortisone such practice is followed by crushing commercially available tablet formulation and mixing with water and syrup or some sweetener to prepare a palatable oral suspension for the patient.
However, the pharmacy practice of dispensing extemporaneous suspensions from solid formulations can create medication errors in terms of accurate dosing. This could lead to
potentially fatal conditions especially for a drug of this type which falls in low therapeutic index as in the case for fludrocortisone.
Thus the practice of dispensing extemporaneous suspensions of the drug is very unsafe and may result in adverse effects.
Furthermore, preparing extemporaneous suspension may result in degradation of the active ingredients, if the active ingredient is sensitive to water or any other solvent exposure which may result in a decrease in concentration of the active ingredient in extemporaneous suspension and patient may get less dose compared to the prescribed one for effective treatment.
To overcome these problems an oral liquid formulation is required.
In a liquid formulation, stability is the biggest challenge compared to solid formulations. This is because in liquid formulations, the active ingredient will remain in a dissolved state in solvent vehicle (which is usually water or a medium comprised mostly of water) and water or the solvent medium is usually the reason for the instability. The solvent medium such as water may lead todegradation of the active ingredient. This is a potential issue for fludrocortisone.
Formation of foam during the preparation of liquid formulation is also a quite common problem and interfere with development of stable and effective liquid formulation. The severity of foam formation depends on nature of active ingredients as well as other excipients used in the preparation.
Still a need exists for stable liquid pharmaceutical composition of fludrocortisone which overcome all the problems discussed above. There is a needfor oral administration formulations that do not have any stability or dose uniformity issue. Inventors of the present invention have addressed these issues and provided stable liquid pharmaceutical
composition suitable for oral administration comprising fludrocortisone or pharmaceutically acceptable salts thereof.
Summary of the Invention
The present invention relates a stable liquid suspension composition comprising fludrocortisone present in the range from 0.001 mg/ml to 1 mg/ml, a vehicle for fludrocortisone or salts thereof, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients. In an embodiment, said stable liquid suspension composition comprises;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) 0.01 to 5% w/v of a vehicle for fludrocortisone,
c) 0.1 to 10 % w/v of a suspending agent,
d) 0.005 to 1 % w/v of an anti-foaming agent,
e) 0.008% w/v to 0.5% w/v of a preservative, and
f) one or more inactive excipients.
In certain embodiments, the stable liquid suspension composition comprises;
g) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
h) 0.01 to 5% w/v of glycerol,
i) 0.1 to 10 % w/v of HPMC (hydroxypropyl methylcellulose) E4M,
j) 0.005 to 1 % w/v of simethicone,
k) methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben),
1) one or more inactive excipients.
The stable liquid suspension is formulated in water or an aqueous medium including water.
One more aspect of the present invention is to provide process for preparing said stable liquid suspension composition comprising steps of;
a) adding preservative in water and stirring,,
b) adding a suspending agent to the solution of step a) optionally with continuous stirring,
c) adding antifoaming agent to the solution produced in step b), optionally with continuous stirring,
d) adding sweetener to the solution produced in step c), optionally with continuous stirring,
e) dispersing fludrocortisone acetate in a mixture of vehicle and purified water, f) adding the dispersion produced in step e) in to the suspension produced in step d) to get an homogenous suspension, optionally with continuous stirring, g) adding buffering agent to the suspension produced in step f) to adjust the pH to from 3 to 5, and
h) adding purified water to make the final volume.
In any one or more of the above steps, where indicated as optional, continuous stirring may be employed in order to ensure good dissolution or suspension of the relevant component.
Detailed description of the Invention
Stable liquid pharmaceutical composition of fludrocortisone is the invention as further described herein. The invention provides a stable liquid suspension composition comprising fludrocortisone present in the range from about 0.001 mg/ml to 1 mg/ml. The composition includes a vehicle for fludrocortisone, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
The term "pharmaceutically-acceptable salts" as used herein includes salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. Suitable pharmaceutically-acceptable acid addition salts of fludrocortisone may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic, sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, alginic, b-hydroxybutyric, malonic, galactaric and galacturonic acid. The preferred salt form for the present invention is acetic and the Fludorocortisone is in the form of Fludorcortisone acetate.
The term "about" as and where used in this specification means ±10% of the mentioned value. However when the term“about” is used in connection with pH, it should be considered as ±2 unit of the pH value.
The terms“formulation” and“composition” are intended to have the same meaning and are used interchangeably throughout this specification.The term "suspension" as used herein refers to a system in which small solid particles are essentially uniformly dispersed in a liquid medium.
The term "stable suspension", as used herein describes a suspension that shows no separation after being stored for at least 1 week at ambient temperature.
To keep liquid suspension composition of present invention stable for longer period of time, the pH also plays a role. It is typically necessary to carefully control the PH of the liquid suspension. As per one embodiment, pH of the composition should be from 3 to 5, preferably the pH is from 3.8 to 4.2, and ideally about 4.
The stable liquid suspension composition of the present invention is chemically and physically stable without any precipitation or crystallization. This was demonstrated in a stability study. Another benefit is that the composition overcame the problem of unpleasant taste.
A stable liquid suspension composition according to the present invention shows good stability and reproducibility even after long-term storage. This means that a liquid composition can be stored for a few days or a week or longer without significant degradation.
The stable liquid suspension composition of present invention, even though being in the form of a suspension also offers an advantage of uniform dosing, physical stability. It also reduces the chances of medication error or over dosage. The stable liquid suspension composition of the present invention, as described herein remains stable for longer period during stability studies performed at different temperature and humidity condition.
Fludrocortisone acetate is a synthetic adrenocortical steroid possessing very potent mineralcorticoid properties and high glucocorticoid activity. It is used for its mineralcorticoid effects. It is a white to pale yellow, odourless or almost odourless, crystalline powder. Practically insoluble in water; soluble 1 in 50 in alcohol, 1 in 50 in chloroform; slightly soluble in ether.
As per one embodiment, fludrocortisone to be used in the form of Fludrocortisone acetate. The fludrocortisone acetate to be used in the range from 0.001 mg/ml to 1 mg/ml, preferably in the range from 0.005 mg/ml to 0.08 mg/ml, more preferably from 0.008 mg/ml to 0.05 mg/ml. In a most preferred embodiment, the fludrocortisone acetate is present in the range from 0.008 mg/ml to 0.02 mg/ml.
In certain embodiments, a stable liquid suspension composition comprises fludrocortisone present in the range fromO.OOl mg/ml to 1 mg/ml, a vehicle for
fludrocortisone, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients. The liquid suspension is a suspension in water or a mixture of water and a co-solvent. Preferably, the liquid suspension is a suspension in water.
The stable liquid suspensions of the invention remain stable and uniform when appropriate excipients are selected and are used at specific and effective concentrations. One of the main excipients that plays role in stabilizing the pharmaceutical composition of present invention is suspending agent and vehicle for fludrocortisone or salts thereof. As fludrocortisone is insoluble in water, an appropriate vehicle is required to disperse fludrocortisone acetate before preparing the final composition. Many vehicles are unsuitable for producing compositions of fludorocortisone. The inventors of the present invention tried many vehicles and surprisingly found that appropriate stability is observed when the vehicle is selected from one or more of: polyethylene glycol, glycerol and propylene glycol. Further in a preferred embodiment, glycerol is used as a vehicle for dispersing fludrocortisone acetate. The amount of the vehicle for dispersing fludrocortisone acetate is used in the range from 0.01 to 5% w/v, and is preferably in the range from 0.05 to 1% w/v. The suspending agent can be selected from one or more of: xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxy vinyl polymer), polyvinyl Pyrrolidone. In certain preferred embodiments, the suspending agent is cellulose based, in a preferred embodiment, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose or Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose). As per more preferred embodiment, the suspending agent is HPMC (hydroxypropyl methylcellulose) also known as hypromellose.
Hypromellose is a solid, and is a slightly off-white to beige powder in appearance and may be formed into granules. The compound forms colloids when dissolved in water. This non-toxic ingredient is combustible and can react vigorously with oxidising agents. HPMC is available in different grades commercially based on the viscosity for the product measured at 2% in water at 20°C. Different grades available are HPMC followed by K100 LV, K4M, K15M, K100M, E15 LV, E50 LV, E4M, F50 LV, F4M code. In a preferred embodiment, the HPMC with low viscosity grade are preferred, including HPMC K100LV, HPMCE4M, HPMC E50LV and HPMC E15LV. In a most preferred embodiment, the suspending agent is HPMC E4M.
The concentration of the suspending agent is also important. Thisimpacts the final stability and physical characteristic of composition. As per one embodiment, the % of suspending agent is in the range from 0.1 to 10 % w/v, more prefearably in the range from 0.25 to 5 % w/v and most preferred is 0.5 to 2.5 % w/v.
A substance used to reduce foam formation in liquid dosage compositions is called anti foaming agents also called as Defoamer. Commonly in process of manufacturing or when reconstituting of liquid dosage have this problem of foam formation forms needs it due to undesirable and disruptive Anti-foaming agents. These are effective to reduce foam by lowering surface tension and cohesive binding of the liquid phase.
A defoamer or an anti-foaming agent is a chemical additive that reduces and hinders the formation of foam in industrial process liquids. The terms anti-foam agent and defoamer are often used interchangeably. Generally a defoamer is insoluble in the foaming medium and has surface active properties. An essential feature of a defoamer product is a low viscosity and a facility to spread rapidly on foamy surfaces. It has affinity to the air-liquid surface where it destabilizes the foam lamellas. This causes rupture of the air bubbles and breakdown of surface foam. Entrained air bubbles are agglomerated, and the larger bubbles rise to the surface of the bulk liquid more quickly.
In certain embodiments, the anti-foaming agent for the present invention can be selected from one or more of: polydimethylsiloxane, simethicone, other silicones, stearates, alcohols and glycols. The anti -foaming agent may be of more than one of the above agents. In a preferred embodiment, the anti foaming agent is simethicone.
In an embodiment, the anti foaming agent is present in the range from 0.005 to 1 % w/v. In a preferred embodiment, anti foaming agent is present in the range from 0.01 to 0.5 % w/v. In a more preferred embodiment, anti foaming agent is present in the range from 0.01 to 0.1 % w/v. In a most embodiment, anti foaming agent is present in the range from 0.02 to 0.08 % w/v.
In certain embodiments, suitable preservative for present invention can be selected from one or more of: methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof. In one embodiment the preservative is present in the range from about 0.001 %w/v to about 0.5 %w/v.
The present stable liquid suspension composition of present invention contains one or more inactive excipients selected from buffering agent, sweetener, anti oxidant, coloring agent and flavoring agent. In certain embodiments, suitable buffer for present invention is selected from one or more of: Citric Acid monohydrate, Sodium Citrate, Sodium Dihydrogen Phosphate, Disodium Phosphate, Trometamol (Tris), Disodium hydrogen phosphate anhydrous, Hydrochloric Acid, Ascorbic Acid, Sodium Ascorbate and anhydrous, monohydrate or dehydrate forms thereof. The buffer can be single or any combination of above listed buffer. In a preferred
embodiment, combination of Disodium hydrogen phosphate anhydrous and Citric Acid monohydrate is to be used.
In certain embodiments, suitable sweetener for present invention is selected from one or more of: acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame or mixtures thereof. In a preferred embodiment, sucralose is to be used. The liquid pharmaceutical composition of the present invention can be prepared in absence of sweetener. However to make it more palatable and easily acceptable by patient especially children, very small amount of sweetener can be added. Sweetener for the present invention can be used in the range from about 0.01 %w/v to 0.5 % w/v.
In certain embodiments, the liquid pharmaceutical composition may further comprise anti oxidants.
Suitable antioxidants for the composition of the present invention can be selected from one or more of: consisting ofbutylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, alpha-tocopherol, propyl gallate, gentisic acid sodium ascorbate, sodium bisulfite, sodium metabisulfite, monothioglycero, cysteine, thioglycolate sodium, acetone sodium bisulfite, ascorbate (sodium/acid), bisulfite sodium, cystein/cysteinate HC1, dithionite sodium (Na hydrosulfite, Na sulfoxylate), gentisic acid, gentisic acid ethanolamine, glutamate monosodium, formaldehyde sulfoxylate sodium, metabisulfite potassium, metabisulfite sodium, monothioglycerol (thioglycerol), propyl gallate, sulfite sodium, tocopherol alpha and thioglycolate sodium. The antioxidant may be a mixture of more than one of the above agents.
In certain embodiments the vehicle or solvent for making the final volume of the composition can be selected from one or more of: glycerine, alcohols, propylene glycol, polyethylene glycol, purified water, ethanol and isopropyl alcohol. The vehicle or solvent may include mixtures of the above agents Preferably purified water is used as a solvent.
In one embodiment of the present invention, said stable liquid suspension composition comprises;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) vehicle for fludrocortisone or salts thereof,
c) a suspending agent,
d) an anti foaming agent,
e) at least one preservative and
f) one or more inactive excipinets. The stable liquid composition of fludrocortisone is to be used for partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison's disease. It can also be used for the treatment of salt-losing adrenogenital syndrome.
In another embodiment, said stable liquid suspension composition comprises;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) vehicle for fludrocortisone or salts thereof selected from polyethylene glycol, glycerol and propylene glycol, or mixtures thereof,
c) a suspending agent selected from xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxyvinyl polymer), polyvinyl Pyrrolidone, or mixtures thereof d) an anti foaming agent selected from polydimethylsiloxane, simethicone, other silicones, stearates, alcohols, glycols or combinations thereof,
e) a preservative selected from methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof, and f) one or more inactive excipients.
In another embodiment, said stable liquid suspension composition comprises;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) 0.01 to 5% w/v of glycerol,
c) 0.1 to 10 % w/v of HPMC (hydroxypropyl methylcellulose) E4M,
d) 0.005 to 1 % w/v of simethicone,
e) methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben),
f) one or more inactive excipients.
In another embodiment, said stable liquid suspension composition comprises;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) 0.05 to 1% w/v of glycerol,
c) 0.25 to 5 % w/v of HPMC (hydroxypropyl methylcellulose) E4M,
d) 0.01 to 0.5 % w/v of simethicone,
e) methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben),
f) one or more inactive excipients.
In another embodiment, the stable liquid suspension composition is prepared by
a) adding preservative in water and stirring,
b) adding suspending agent in step a) with continuous stirring,
c) adding antifoaming agent in step b) with continuous stirring,
d) adding sweetener to step c) with continuous stirring,
e) dispersing fludrocortisone acetate in mixture of vehicle and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
g) adding buffering agent to step f) to adjust pH to from 3 to 5 and
h) adding purified water to make final volume.
In another embodiment, the stable liquid suspension composition is prepared by a) adding methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben in water and stirring till dissolve it, b) adding HPMC (hydroxypropyl methylcellulose) E4M in step a) with continuous stirring,
c) adding simethicone in step b) with continuous stirring,
d) adding sucralose to step c) with continuous stirring,
e) dispersing fludrocortisone acetate in mixture of glycerol and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
g) adding citric acid monohydrate and disodium hydrogen phosphate anhydrous to step f) to adjust pH in between 3 to 5 and
h) adding purified water to make final volume. The invention is further illustrated by the following examples, which are by no means intended to limit the scope of the invention but are given by way of illustration.
Examples
Example 1: Fludrocortisone acetate Suspension 0.05 mg/5ml
*value after potency correction as per COA.
Process:
1. Add and dissolve methyl parahydroxybenzoate and ethyl parahydroxybenzoate into 60 ml purified water with the aid of heating at above 90°C to get a clear, colourless solution. Keep aside till temperature reaches 60 -70°C.
2. Add HPMC E4M in step 1 when temperature reaches 60-70°C and keep aside to cool at room temperature.
3. Add simethicon PD30 and stirr for 20- 30 minutes,
4. Add sucralose to step 3 and stir for 10-15 minutes using.
5. Separately disperse fludrocortisone acetate in glycerol and add 5ml of purified water and form uniform dispersion.
6. Add dispersion of step 5 into step 4 and mix to get homogeneous suspension.
7. Add citric acid monohydrate and disodium hydrogen phosphate anhydrous and mix to get homogeneous suspension to adjust pH in between 3-5.
8. Add caramel flavor to suspension and mix it.
9. Make up to volume with purified water and stir for 10 minutes to get homogeneous suspension. Physical observations: The composition of Example 1 was observed after storing for 24 hrs at room temperature. No any sedimentation or colour change observed, hence further stability studies at different temperature/humidity and time duration was planned. Example 2: Comparative examples
Procedure: As per Example 1
Physical observations: The composition of Example 2 (2A, 2B and 2C) was observed after storing for 24 hrs at room temperature. There are sedimentation as well as slight color change was observed in all three composition. Therefore no further stability studies were conducted.
Example 3: Fludrocortisone acetate Suspension 0.05 mg/5ml
*value after potency correction as per COA.
Procedure: As per Example 1
Physical observations: The composition of Example 3 was observed after storing for 24 hrs at room temperature. There are very little sedimentation was observed but that was redisersible on shaking. No further stability conducted.
Example 4: Stability study of Example 1
Stability study of composition of Example 1 filled in amber colour glass bottle were performed at different temperature and relative humidity conditions for 6 months and results are as described below;
Results of stability study at 25°C/60%RH and 30°C/65%RH
Result of stability study at 2-8°C
After performing stability study, it was observed that the liquid suspension composition of Example 1 shows good stability for 6 months storage when stored in the condition of
2-8°C.
Claims
1. A stable liquid suspension composition comprising fludrocortisone present in the range from about 0.001 mg/ml to 1 mg/ml, vehicle for fludrocortisone or salts thereof, a suspending agent, an anti foaming agent, at least one preservative and one or more inactive excipients.
2. The stable liquid suspension composition of claim 1, comprising;
0.001 mg/ml to 1 mg/ml of fludrocortisone,
0.01 to 5% w/v of a vehicle for fludrocortisone,
0.1 to 10 % w/v of a suspending agent,
0.005 to 1 % w/v of an anti-foaming agent,
a preservative, optionally in an amount of from 0.001% w/v to 0.5% w/v, and one or more inactive excipients.
3. The stable liquid suspension composition according to claim 1 or 2, wherein fludrocortisone is in the form of fludrocortisone acetate.
4. The stable liquid suspension composition according to any preceding claim, wherein the pH is in the range from about 3 to 5.
5. The stable liquid suspension composition according to any preceding claim, wherein liquid suspension is to be stored at condition of 2-8°C.
6. The stable liquid suspension composition according to any preceding claim, wherein vehicle for fludrocortisone is selected from polyethylene glycol, glycerol and propylene glycol.
7. The stable liquid suspension composition according to any preceding claim, wherein suspending agent is selected from xanthan gum, guar gum, tragacanth gum, veegum, HPMC (hydroxypropyl methylcellulose), microcrystalline cellulose, Avicel RC-591 (microcrystalline cellulose/ sodium carboxymethyl cellulose), Carbopol® (carboxyvinyl polymer) and polyvinyl Pyrrolidone.
8. The stable liquid suspension composition according to any preceding claim, wherein anti foaming agent is selected from polydimethylsiloxane, simethicone, other silicones, stearates, alcohols and glycols.
9. The stable liquid suspension composition according to any preceding claim, wherein preservative is selected from methyl parahydroxybenzoate (methyl paraben), ethyl parahydroxybenzoate (ethyl paraben), propyl parahydroxybenzoate (propyl paraben), butyl parahydroxybenzoate (butyl paraben), isobutyl parahydroxybenzoate (isobutyl paraben), isopropyl parahydroxybenzoate (isopropyl paraben), benzyl parahydroxybenzoate (benzyl paraben), Sodium Benzoate, Benzoic acid, Potassium Sorbate and combinations thereof
10. The stable liquid suspension composition according to any preceding claim, wherein inactive excipients is selected from buffering agent, sweetener, anti oxidant, coloring agent and flavoring agent.
11. The stable liquid suspension composition according to claim 10, wherein sweetener is selected from acesulfame potassium, sucralose, cyclamate, saccharin, saccharin sodium and aspartame or mixtures thereof.
12. The stable liquid suspension composition of claim 1, comprising;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) 0.01 to 5% w/v of glycerol,
c) 0.1 to 10 % w/v of HPMC (hydroxypropyl methylcellulose) E4M,
d) 0.005 to 1 % w/v of simethicone,
e) methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben),
f) one or more inactive excipients.
13. The stable liquid suspension composition of claim 1 comprising;
a) 0.001 mg/ml to 1 mg/ml of fludrocortisone,
b) 0.05 to 1% w/v of glycerol,
c) 0.25 to 5 % w/v of HPMC (hydroxypropyl methylcellulose) E4M,
d) 0.01 to 0.5 % w/v of simethicone,
e) methyl parahydroxybenzoate (methyl paraben) and ethyl parahydroxybenzoate (ethyl paraben),
f) one or more inactive excipients.
14. A process for preparing a stable liquid suspension composition, comprising the steps of;
a) adding preservative in water and stirring till dissolve it,
b) adding suspending agent in step a) with continuous stirring,
c) adding antifoaming agent in step b) with continuous stirring,
d) adding sweetener to step c) with continuous stirring,
e) dispersing fludrocortisone acetate in mixture of vehicle and purified water, f) adding dispersion of step e) in to step d) with continuous stirring to get homogenous suspension,
g) adding buffering agent to step f) to adjust pH in between 3 to 5 and
h) adding purified water to make final volume.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1803893.5A GB2571937B (en) | 2018-03-12 | 2018-03-12 | Stable liquid suspension composition of fludrocortisone |
| PCT/IB2019/051696 WO2019175703A1 (en) | 2018-03-12 | 2019-03-03 | Stable liquid suspension composition of fludrocortisone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP3764989A1 true EP3764989A1 (en) | 2021-01-20 |
Family
ID=61972944
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19713218.6A Withdrawn EP3764989A1 (en) | 2018-03-12 | 2019-03-03 | Stable liquid suspension composition of fludrocortisone |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP3764989A1 (en) |
| GB (1) | GB2571937B (en) |
| WO (1) | WO2019175703A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350297A (en) * | 2021-06-11 | 2021-09-07 | 河南金大众生物工程有限公司 | Tilmicosin dry suspension and preparation method thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP20231000T1 (en) * | 2020-02-25 | 2023-12-08 | Labomed Pharmaceutical Company S.A. | ORAL SOLUTIONS CONTAINING FLUDROCORTISONE ACETATE |
| CN111759814A (en) * | 2020-07-20 | 2020-10-13 | 华益药业科技(安徽)有限公司 | Fludrocortisone acetate tablet for resisting inflammation and processing technology |
| CN111759812A (en) * | 2020-07-20 | 2020-10-13 | 华益药业科技(安徽)有限公司 | Fludrocortisone acetate tablet for inhibiting proliferation of connective hoof tissue and processing technology thereof |
| CN111803457A (en) * | 2020-07-20 | 2020-10-23 | 华益药业科技(安徽)有限公司 | Fludrocortisone acetate tablet and processing technology thereof |
| KR20240042485A (en) * | 2021-07-30 | 2024-04-02 | 에피제닉스 테라퓨틱스, 인크. | Clemizole preparation |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5112604A (en) * | 1989-09-01 | 1992-05-12 | Riker Laboratories, Inc. | Oral suspension formulation |
| US7300670B2 (en) * | 2002-04-03 | 2007-11-27 | Unilab Pharmatech, Ltd. | Oral suspension formulation |
| AU2003286792A1 (en) * | 2002-10-29 | 2004-05-25 | Oregon Health And Science University | Fludrocortisone treatment for hearing loss |
| US20060093631A1 (en) * | 2004-10-29 | 2006-05-04 | Buehler Gail K | Dye-free pharmaceutical suspensions and related methods |
| JP5334588B2 (en) * | 2005-11-28 | 2013-11-06 | マリナス ファーマシューティカルズ | Ganaxolone preparation, method for producing the same, and use thereof |
| JP2010510988A (en) * | 2006-11-28 | 2010-04-08 | マリナス ファーマシューティカルズ | Nanoparticle formulation, method for producing the same and use thereof |
| WO2010068775A2 (en) * | 2008-12-11 | 2010-06-17 | Amira Pharmaceuticals, Inc. | Alkyne antagonists of lysophosphatidic acid receptors |
| US8377946B1 (en) * | 2011-12-30 | 2013-02-19 | Pharmacyclics, Inc. | Pyrazolo[3,4-d]pyrimidine and pyrrolo[2,3-d]pyrimidine compounds as kinase inhibitors |
| CA2949480A1 (en) * | 2014-02-24 | 2015-08-27 | Urigen Pharmaceuticals, Inc. | Compositions of pentosan polysulfate salts for oral administration and methods of use |
| WO2017218894A1 (en) * | 2016-06-16 | 2017-12-21 | Cutispharma, Inc. | Composition and method for proton pump inhibitor suspension |
-
2018
- 2018-03-12 GB GB1803893.5A patent/GB2571937B/en not_active Expired - Fee Related
-
2019
- 2019-03-03 WO PCT/IB2019/051696 patent/WO2019175703A1/en unknown
- 2019-03-03 EP EP19713218.6A patent/EP3764989A1/en not_active Withdrawn
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113350297A (en) * | 2021-06-11 | 2021-09-07 | 河南金大众生物工程有限公司 | Tilmicosin dry suspension and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2571937A (en) | 2019-09-18 |
| GB201803893D0 (en) | 2018-04-25 |
| GB2571937B (en) | 2021-07-14 |
| WO2019175703A1 (en) | 2019-09-19 |
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