OA17935A - Solid dosage forms of oleyl phosphocholine - Google Patents
Solid dosage forms of oleyl phosphocholine Download PDFInfo
- Publication number
- OA17935A OA17935A OA1201300213 OA17935A OA 17935 A OA17935 A OA 17935A OA 1201300213 OA1201300213 OA 1201300213 OA 17935 A OA17935 A OA 17935A
- Authority
- OA
- OAPI
- Prior art keywords
- solid dosage
- dosage form
- weight
- cellulose
- sodium
- Prior art date
Links
- 239000007909 solid dosage form Substances 0.000 title claims abstract description 125
- SLVOKEOPLJCHCQ-SEYXRHQNSA-N [(Z)-octadec-9-enyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C SLVOKEOPLJCHCQ-SEYXRHQNSA-N 0.000 title claims abstract description 92
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 59
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 29
- 239000001913 cellulose Substances 0.000 claims abstract description 27
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 25
- 239000000314 lubricant Substances 0.000 claims abstract description 25
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 24
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 24
- 229920002678 cellulose Polymers 0.000 claims abstract description 19
- 229960005168 Croscarmellose Drugs 0.000 claims abstract description 17
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims abstract description 17
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims abstract description 15
- 239000008101 lactose Substances 0.000 claims abstract description 15
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 15
- 208000004554 Leishmaniasis Diseases 0.000 claims abstract description 7
- 208000006551 Parasitic Disease Diseases 0.000 claims abstract description 4
- 201000004792 malaria Diseases 0.000 claims abstract description 4
- 201000011510 cancer Diseases 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 96
- 229960001681 Croscarmellose Sodium Drugs 0.000 claims description 42
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 42
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 32
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 32
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 32
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 239000003085 diluting agent Substances 0.000 claims description 23
- 239000011230 binding agent Substances 0.000 claims description 22
- 239000000945 filler Substances 0.000 claims description 22
- WSVLPVUVIUVCRA-RJMJUYIDSA-N (2R,3R,4S,5R,6S)-2-(hydroxymethyl)-6-[(2R,3S,4R,5R)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol;hydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-RJMJUYIDSA-N 0.000 claims description 21
- 229960001021 Lactose Monohydrate Drugs 0.000 claims description 21
- 235000010980 cellulose Nutrition 0.000 claims description 18
- 229960001375 Lactose Drugs 0.000 claims description 14
- 239000007884 disintegrant Substances 0.000 claims description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 229920002472 Starch Polymers 0.000 claims description 12
- 229940032147 Starch Drugs 0.000 claims description 12
- 239000008107 starch Substances 0.000 claims description 12
- 235000019698 starch Nutrition 0.000 claims description 12
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 11
- -1 disintégrants Substances 0.000 claims description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 238000007873 sieving Methods 0.000 claims description 9
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 8
- XJKJWTWGDGIQRH-BFIDDRIFSA-N Alginic acid Chemical compound O1[C@@H](C(O)=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](C)[C@@H](O)[C@H]1O XJKJWTWGDGIQRH-BFIDDRIFSA-N 0.000 claims description 8
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 8
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims description 8
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 8
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 claims description 8
- 229960001031 Glucose Drugs 0.000 claims description 8
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 8
- 229920002774 Maltodextrin Polymers 0.000 claims description 8
- 239000005913 Maltodextrin Substances 0.000 claims description 8
- GUBGYTABKSRVRQ-YOLKTULGSA-N Maltose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)O[C@H]1CO)[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 GUBGYTABKSRVRQ-YOLKTULGSA-N 0.000 claims description 8
- 229960002900 Methylcellulose Drugs 0.000 claims description 8
- 229920000881 Modified starch Polymers 0.000 claims description 8
- 229940083542 Sodium Drugs 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 8
- 229940033134 Talc Drugs 0.000 claims description 8
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 8
- 235000010443 alginic acid Nutrition 0.000 claims description 8
- 229920000615 alginic acid Polymers 0.000 claims description 8
- 239000000783 alginic acid Substances 0.000 claims description 8
- 229960001126 alginic acid Drugs 0.000 claims description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- 239000001506 calcium phosphate Substances 0.000 claims description 8
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 8
- 235000011010 calcium phosphates Nutrition 0.000 claims description 8
- 229940035034 maltodextrin Drugs 0.000 claims description 8
- 229920000609 methyl cellulose Polymers 0.000 claims description 8
- 239000001923 methylcellulose Substances 0.000 claims description 8
- 235000010981 methylcellulose Nutrition 0.000 claims description 8
- 235000019814 powdered cellulose Nutrition 0.000 claims description 8
- 229920003124 powdered cellulose Polymers 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 239000005720 sucrose Substances 0.000 claims description 8
- 239000000454 talc Substances 0.000 claims description 8
- 229910052623 talc Inorganic materials 0.000 claims description 8
- 235000012222 talc Nutrition 0.000 claims description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 238000000748 compression moulding Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000006186 oral dosage form Substances 0.000 claims description 5
- YJISHJVIRFPGGN-UHFFFAOYSA-N 5-[5-[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxy-6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)O)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 YJISHJVIRFPGGN-UHFFFAOYSA-N 0.000 claims description 4
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 claims description 4
- 241000220479 Acacia Species 0.000 claims description 4
- PZZYQPZGQPZBDN-UHFFFAOYSA-N Aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 4
- 239000004135 Bone phosphate Substances 0.000 claims description 4
- 229940084030 CARBOXYMETHYLCELLULOSE CALCIUM Drugs 0.000 claims description 4
- 229960005069 Calcium Drugs 0.000 claims description 4
- 229960003563 Calcium Carbonate Drugs 0.000 claims description 4
- JHLNERQLKQQLRZ-UHFFFAOYSA-N Calcium silicate Chemical compound [Ca+2].[Ca+2].[O-][Si]([O-])([O-])[O-] JHLNERQLKQQLRZ-UHFFFAOYSA-N 0.000 claims description 4
- 229960001631 Carbomer Drugs 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 4
- 229960000913 Crospovidone Drugs 0.000 claims description 4
- 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 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 4
- 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 4
- 229940096516 Dextrates Drugs 0.000 claims description 4
- 239000001856 Ethyl cellulose Substances 0.000 claims description 4
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 4
- 239000005715 Fructose Substances 0.000 claims description 4
- 229960002737 Fructose Drugs 0.000 claims description 4
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N Glyceryl behenate Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 4
- FETSQPAGYOVAQU-UHFFFAOYSA-N Glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 4
- 229920002907 Guar gum Polymers 0.000 claims description 4
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 4
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 229940031703 LOW SUBSTITUTED HYDROXYPROPYL CELLULOSE Drugs 0.000 claims description 4
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims description 4
- 229960002160 Maltose Drugs 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229920000715 Mucilage Polymers 0.000 claims description 4
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical class N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 claims description 4
- 229920001100 Polydextrose Polymers 0.000 claims description 4
- 229940093429 Polyethylene Glycol 6000 Drugs 0.000 claims description 4
- 229940069328 Povidone Drugs 0.000 claims description 4
- 229940005550 Sodium alginate Drugs 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 4
- 229960004274 Stearic acid Drugs 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 229960002675 Xylitol Drugs 0.000 claims description 4
- 229940046282 Zinc Drugs 0.000 claims description 4
- 229940091251 Zinc Supplements Drugs 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- 239000000853 adhesive Substances 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 239000000378 calcium silicate Substances 0.000 claims description 4
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 4
- 229960003340 calcium silicate Drugs 0.000 claims description 4
- 235000012241 calcium silicate Nutrition 0.000 claims description 4
- 239000001175 calcium sulphate Substances 0.000 claims description 4
- 235000011132 calcium sulphate Nutrition 0.000 claims description 4
- 229920001531 copovidone Polymers 0.000 claims description 4
- 239000008121 dextrose Substances 0.000 claims description 4
- 238000007922 dissolution test Methods 0.000 claims description 4
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 4
- 229920001249 ethyl cellulose Polymers 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 235000001727 glucose Nutrition 0.000 claims description 4
- 229940049654 glyceryl behenate Drugs 0.000 claims description 4
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 4
- 239000000665 guar gum Substances 0.000 claims description 4
- 235000010417 guar gum Nutrition 0.000 claims description 4
- 229960002154 guar gum Drugs 0.000 claims description 4
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 4
- 229940071826 hydroxyethyl cellulose Drugs 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- 239000000832 lactitol Substances 0.000 claims description 4
- 235000010448 lactitol Nutrition 0.000 claims description 4
- 229960003451 lactitol Drugs 0.000 claims description 4
- 235000010449 maltitol Nutrition 0.000 claims description 4
- 239000000845 maltitol Substances 0.000 claims description 4
- 229940035436 maltitol Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- 229920001888 polyacrylic acid Polymers 0.000 claims description 4
- 235000013856 polydextrose Nutrition 0.000 claims description 4
- 239000001259 polydextrose Substances 0.000 claims description 4
- 229940035035 polydextrose Drugs 0.000 claims description 4
- 229940057838 polyethylene glycol 4000 Drugs 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 claims description 4
- 235000010413 sodium alginate Nutrition 0.000 claims description 4
- 239000000661 sodium alginate Substances 0.000 claims description 4
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 4
- 239000008109 sodium starch glycolate Substances 0.000 claims description 4
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 4
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 4
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 claims description 4
- 239000000600 sorbitol Substances 0.000 claims description 4
- 235000010356 sorbitol Nutrition 0.000 claims description 4
- 239000008117 stearic acid Substances 0.000 claims description 4
- 239000006188 syrup Substances 0.000 claims description 4
- 235000020357 syrup Nutrition 0.000 claims description 4
- 239000000811 xylitol Substances 0.000 claims description 4
- 235000010447 xylitol Nutrition 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 4
- 239000011701 zinc Substances 0.000 claims description 4
- 229910052725 zinc Inorganic materials 0.000 claims description 4
- 235000016804 zinc Nutrition 0.000 claims description 4
- 229960002598 Fumaric acid Drugs 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 3
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 3
- 235000015424 sodium Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 229960002668 sodium chloride Drugs 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 3
- 229960002920 sorbitol Drugs 0.000 claims description 3
- 229940091252 Sodium supplements Drugs 0.000 claims 2
- 239000004698 Polyethylene (PE) Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 229920000573 polyethylene Polymers 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 241001465754 Metazoa Species 0.000 abstract 1
- 239000008187 granular material Substances 0.000 description 27
- 238000009472 formulation Methods 0.000 description 25
- 238000000034 method Methods 0.000 description 24
- 229940079593 drugs Drugs 0.000 description 21
- 239000012071 phase Substances 0.000 description 20
- 238000007906 compression Methods 0.000 description 19
- PQLXHQMOHUQAKB-UHFFFAOYSA-N Miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 0.000 description 17
- 229960003775 miltefosine Drugs 0.000 description 17
- 239000000843 powder Substances 0.000 description 17
- 210000000952 Spleen Anatomy 0.000 description 15
- 230000035492 administration Effects 0.000 description 15
- 210000004185 Liver Anatomy 0.000 description 14
- 210000001185 Bone Marrow Anatomy 0.000 description 13
- 239000000523 sample Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000005550 wet granulation Methods 0.000 description 11
- 201000009910 diseases by infectious agent Diseases 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000002502 liposome Substances 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 244000045947 parasites Species 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 230000001965 increased Effects 0.000 description 7
- 210000000056 organs Anatomy 0.000 description 7
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Abstract
The present invention relates to solid dosage
forms of oleyl phosphocholine (C18 : 1-PC), or
O1PC, for oral administration. Further, the present
invention relates to methods for the preparation of
the present solid dosage forms and the use
thereof as a medicament and especially a
medicament for treatment of parasitic diseases,
such as leishmaniasis, chagas and malaria, and
cancer both in humans and animals. Specifically,
the present invention relates to a solid dosage
form comprising: 6 to 25 weight % of the solid
dosage form oleyl phosphocholine; 20 to 35
weight% of the solid dosage form lactose; 35 to
50 weight % of the solid dosage form cellulose; 5
to 20 weight% of the solid dosage form
croscarmellose; 1 to 10 weight% of the solid
dosage form hydroxypropylmethyl cellulose; and
0.05 to 1 weight% of the solid dosage form of a
lubricant.
Description
SOLID DOSAGE FORMS OF OLEYL PHOSPHOCHOLINE
Description
The présent invention relates to solid dosage forms of oleyl phosphocholine (C18:1-PC), or O1PC, for oral administration. Further, the présent invention relates to methods for the préparation of the présent solid dosage forms and the use thereof as a médicament and especially a médicament for the treatment of parasitic diseases, such as leishmaniasis, chagas and malaria, and cancer both in humans and animais.
. Miltefosine (MIL) belongs to the chemical group of· alkylphosphocholines and is generally used for the treatment of viscéral leishmaniasis (VL) . Its particular advantages are an oral route of administration and no cross-résistance is observed with any other first- and second-line antileishmaniasis therapy.
Although three new drugs or drug formulations including miltefosine (liposomal amphotericin B, miltefosine and paromomycin) are currently available for the treatment of leishmaniasis, they ail suffer either from limitations of cost, toxicity or the need for parentéral administration.
An alternative for miltefosine is the alkylphosphocholine oleyl phosphocholine (C18:1-PC), or O1PC, providing, amongst others, a more effective treatment of parasitic diseases such as leishmaniasis and malaria both in humans and animais.
Although the use of oleyl phosphocholine for the treatment of several diseases is suggested, the suggested formulations of oleyl phosphocholine are generally solutions, suspensions or émulsions. Especially for oral administration, there is a need in the art to provide oleyl
J phosphocholine in solid dosage forms such as in the form of tablets.
Oleyl phosphocholine has a low melting point (56.3°C), irregular particle size and shape and is very hygroscopic. These characteristics greatly limit the development of solid dosage forms, such as tablets or capsule fillings, due to difficulties in obtaining a homogeneous dry powder mixture allowing, for example, compression molding into tablets or loading of capsules.
With respect to solid dosage forms of oleyl phosphocholine, it is also important to consider the stability of the formulation. For example, a solid dosage form of oleyl phosphocholine is preferably stable for prolonged periods of time, such as at least 1 year, in a température range of 0°C to 40°C and a relative humidity in the range of 20% to 80%.
Additional factors to consider in the design of solid dosage forms of oleyl phosphocholine are friability solubility and disintegration characteristics.
It is an object of the présent invention, amongst other objects, to provide solid dosage forms of oleyl phosphocholine, and especially solid dosage forms of oleyl phosphocholine for oral administration to both humans and animais meeting at least one, if not ail, of the above stated considérations.
The above object, amongst other objects, is met by a solid dosage form of oleyl phosphocholine for oral administration as defined in the appended daims.
Specifically, the above object, amongst other objects, is met by a solid dosage form of oleyl phosphocholine for oral administration comprising-.
to 25 weight% of the solid dosage form oleyl phosphocholine;
I
t. i to 94 weight% of the solid dosage form of one or more pharmaceutically acceptable fillers, disintegrants, binders, lubricants and/or diluents;
Unless indicated otherwise, the weight percentages presented herein are weight percentages as compared to the total weight of the final oral dosage form.
Suitable diluents or fillers according to the présent invention are preferably selected from the group consisting of'calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic) , calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnésium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol and combinations thereof.
Suitable binders according to the présent invention
0 are preferably selected from the group consisting of water, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethycellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gélatine, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnésium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, sucrose (syrup) and combinations thereof.
Suitable lubricants according to the présent invention are preferably selected from the group consisting of calcium stéarate, fumaric acid, glyceryl behenate, tI glyceryl palmitostearate, hydrogenated vegetable oil, magnésium lauryl sulphate, magnésium stéarate, polyethylene glycol 4000 or 6000, sodium lauryl sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stéarate and combinations thereof.
Suitable disintegrants according to the présent invention are preferably selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and combinations thereof.
The présent solid dosage form provides a friability of less than 1 weight%, preferably less than 0.5 weight%, of the solid dosage form as determined in accordance with the European Pharmacopoeia 2.9.7 standard friability test and/or the présent solid dosage form provides a disintegration of less than 15 minutes, preferably less than 10 minutes, as determined in accordance with the European Pharmacopoeia
2.9.1 standard disintegration test (dissolution in 900 ml HCl 0.1 N).
According to a'preferred embodiment of the présent solid dosage forms, the solid dosage forms provide at least 85 weight% oleyl phosphocholine release within 30 minutes as determined in accordance with the European Pharmacopoeia 2.9.3 standard dissolution test.
According to another preferred embodiment of the présent invention, the présent solid dosage forms comprise:
to 25 weight% of the solid dosage form oleyl phosphocholine;
to 35 weight% of the solid dosage form of a diluents or filler, preferably selected from the group consisting of calcium carbonate, calcium phosphate (dibasic) , calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnésium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres,.talc, xylitol and combinations thereof.
to 60 weight% of the solid dosage form of a binder, preferably selected from the group consisting of water, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium,· carboxymethycellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gélatine, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnésium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, Sucrose (syrup) and combinations thereof.
to 20 weight% of the solid dosage form of a disintegrants, preferably selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and combinations thereof; and
0.05 to 1 weight% of the solid dosage form of a lubricant, selected from the group consisting
I of calcium stéarate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnésium lauryl sulphate, magnésium stéarate, polyethylene glycol 4000 or 6000, sodium lauryl sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stéarate and combinations thereof.
According to still another preferred embodiment of the présent invention, the présent solid dosage forms comprise:
to 25 weight% of the solid dosage form oleyl phosphocholine;
0 to 35 weight% ofthe solid dosage form lactose, preferably lactose monohydrate;
to 50 weight% of the solid dosage form cellulose, preferably microcrystalline cellulose ;
to 20 weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
to 10 weight% of the solid dosage form hydroxypropylmethyl cellulose; and
0.05 to 1 weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
According to yet another preferred embodiment of the présent invention, the présent solid dosage forms comprise :
to 15 weight% of the solid dosage form oleyl phosphocholine;
to 30 weight% of the solid dosage form lactose, preferably lactose monohydrate;
* t to 47 weight% of the solid dosage form cellulose, preferably microcrystalline cellulose ;
to 15 weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
to 5 weight% of the solid dosage form hydroxypropylmethyl cellulose; and ;
0.1 to 0.3 weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
According to a particularly preferred embodiment of the présent invention, the solid dosage forms comprise:
to 14, preferably 13, weight% of the solid dosage form oleyl phosphocholine;
to 29, preferably 28, weight% of the solid dosage form lactose, preferably lactose monohydrate;
to 45, preferably 44, weight% of the solid dosage form cellulose, preferably microcrystalline cellulose;
to 13, preferably 12, weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
to 4, preferably 3, weight% of the solid dosage form hydroxypropylmethyl cellulose; and
0.1 to 0.3, preferably 0.2, weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
The présent solid dosage forms preferably are in the form of a tablet, more preferably a tablet comprising an inner core comprised of:
» V to 14, preferably 13, weight% of the solid dosage form oleyl phosphocholine;
to 29, preferably 28, weight%· of the solid dosage form lactose, preferably lactose monohydrate ;
to 45, preferably 44, weight% of the solid dosage form cellulose, preferably microcrystalline cellulose;
to 7, preferably 6, weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
to 4, preferably 3, weight% of the solid dosage form-hydroxypropylmethyl cellulose; and an outer layer comprised of:
to 7, preferably 6, weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium; and
0.1 to 0.3, preferably 0.2, weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
According to another aspect, the présent invention relates to a method for the préparation of the présent solid dosage forms, using the weight percentages presented above, comprising the steps of:
a) adding to a dry mixture comprising one or more pharmaceutically acceptable diluents/fillers, disintegrants and/or binders water comprising 6 to 25 weight% of the solid dosage form oleyl phosphocholine;
b) drying and sieving the mixture obtained in step (a) ;
t
t.
c) adding one or more désintégrants and/or lubricants to the mixture obtained in step (b) ;
d) mixing the mixture obtained in step (c) ;
e) preparing an oral dosage form of the mixture of step (d) , preferably by compression molding.
The présent O1PC solid dosage forms are obtained by means of compression of granules' resulting from wet granulation. This process of pre-treatment of solids prior to compression serves several purposes:
increasing the particle size to improve flowability;
improving compression characteristics; and preventing particle ségrégation.
A classic wet granulation process, in a first step, involves the préparation of a dry powder mixture containing the active pharmaceutical ingrédient (API) , one or more fillers/diluents, a binder, and a disintegrant.
The inability to produce a homogeneous dry mixture with O1PC led to the development of the présent alternative wet granulation process. In this novel process, a dry powder mixture is prepared without the presence of the API. The API is dissolved in the granulation liquid and the solution obtained is used to granulate the previously prepared dry powder mixture. This allows a homogeneous distribution of the API in the formulation preventing ségrégation due to its irregular particle size/shape.
According to a preferred embodiment of this aspect, the présent invention relates to a method for the préparation of the présent solid dosage forms, using the weight percentages presented above, comprising the steps of:
i
a) adding to a dry mixture comprising lactose, preferably lactose monohydrate, cellulose, preferably microcrystalline cellulose, croscarmellose, preferably croscarmellose sodium and hydroxypropylmethyl cellulose water comprising 6 to 25 weight% of the solid dosage form oleyl phosphocholine;
b) drying and sieving the mixture obtained in step (a);
c) adding croscarmellose, preferably croscarmellose sodium and a lubricant, preferably magnésium stéarate, to the mixture obtained in step (b) ;
d) mixing the composition obtained in step (c) ;
. and
e) preparing an oral dosage form of the mixture of step (d) , preferably by compression molding.
The methods according to the présent invention preferably comprise a first sieving step, preferably through a·1400 mm sieve, before drying and a second sieving step after drying, preferably through a 710 nm sieve.
According to yet another aspect, the présent invention relates to solid dosage forms obtainable by the présent methods.
The présent invention will be further detailed in the examples below showing non limiting preferred embodiments of the présent invention. In the examples presented below, reference is made to figures wherein:
l
4L
Figure 1:
Figure 2 :
Figure 3 :
shows the structural formula of O1PC (C23H48NO4P) ;
shows a schematic représentation of a preferred formulation process of the présent solid dosages forms of oleyl phosphocholine;
shows the average dissolution profile of the O1PC tablets;
Figure 4: shows dose-efficacy comparing single and multiple oral administrations of 25, 50, and 100 mg/kg total dose compared to VIC control in A) liver, B) spleen and C) bone marrow.
EXAMPLES
List of pharmaceutically acceptable excipients tested in the formulation processes
1) Microcrystalline cellulose (Avicel® PH 101) was used as binder/diluents. Avicel PH 101 has an average particle size of 5 0 μπι and is mostly used for wet-granulation.
2) Lactose monohydrate (Pharmatose®2 00M) was used as binder/fHier. The compound generally improves the tabletting properties of the powder mixture and granules.
3) Polyvinylpyrrolidone (Kollidon®3 0) is a soluble polyvinylpyrrolidone, which is obtained by radical polymerization of N-vinylpyrrolidone with a molecular weight Mv of 31.700-51.400 Da.
4) Hydroxypropylmethylcellulose (Methocel® E15 LV) . Hydroxypropylmethylcellulose is used as tablet binder. Concentration between 2 - 5 % w/w may be used in either wet- or dry granulation.
5) | Croscarmellose sodium (Ac-di-sol®) is used as disintegrant. In the production of tablets, croscarmellose sodium may be used in both direct compression and wet granulation processes. When used in direct granulation, the croscarmellose sodium could be added in both the wet and dry stages of the process (intra and extra granular) so that .the full wicking/swelling ability of the disintegrant can be used. |
6) | Purified water. Purified water can be prepared by distillation, by ion exchange, by reverse osmosis or by any other suitable method from water that compiles with the -régulations on water intended for human consumption. |
Techniques used to assess the suitability of the présent formulations
1) | Disintegration, Ph. Eur. 2.9.1. This test détermines whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium under the experimental conditions. For the purposes of this test, disintegration does not imply complété dissolution of the unit or even of its active constituent. Complété disintegration is defined as that state in which any residue of the unit, except fragments of insoluble coating or capsule shell, remaining on the screen of the test apparatus or adhering to the lower surface of the dises, if used, is a soft mass having no palpably firm core. |
2) | Flowability, Ph. Eur. 2.9.16. This test détermines ability of divided solids (for example, powders |
and granules) to flow vertically under defined conditions.
3) Friability, Ph. Eur. 2.9.7. This test is designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping
4) Hardness - Tablet Hardness testing is also called tablet breaking force and measures tablet mechanical integrity. ;
5) Bulk density, Ph. Eur. 2.9.34. The bulk density of a powder is the ratio of the mass of an untapped powder sample to its volume, including the contribution of the interparticulate void volume. Hence, the bulk density dépends on both the density of powder particles and the spatial arrangement of particles in the powder bed. The bulking properties of a powder are dépendent upon the préparation, treatment and storage of the sample, i.e. how it has been handled.
6) Dissolution test, Ph. Eur. 2.9.3. Tablets taken
0 orally remain one of the most effective means of treatment available. The effectiveness of such dosage forms relies on the drug dissolving in the fluids of the gastrointestinal tract prior to absorption into the systemic circulation. The rate 25 of dissolution of the tablet or capsule is therefore crucial.
Melting point détermination and thermogravimetric study
0 The thermal behavior of O1PC was evaluated using a
2920 Modulated DSC (TA Instruments, Leatherhead, UK) equipped with a refrigerated cooling System (RCS) . Dry hélium at a flow rate of 40 mL/min was used as the purge gas
through the DSC cell and 150 Ml/min of nitrogen through the RCS unit.
Samples (±6 mg) were run in closed aluminium pans supplied by TA Instruments; the mass of each empty sample pan was matched with the mass of the empty reference pan to ± 0.10 mg. The experimental method consisted of an initial 5 min isothermal équilibration period at 0°C. During the subséquent heating -run the following experimental parameters were used: an underlying heating rate of 2°C/min from 0 to 350°C, modulation amplitude of 0.212°C and a period of 40s.
Température and enthalpic calibration was performed with an indium standard, whereas calibration of the heat capacity was performed with a- sapphire standard. The results were analyzed using the TA Instruments Universal Analysis Software.
It was determined that O1PC has a melting point of 56.3°C. Further trials were performed to evaluate the dégradation température using thermogravimetric analysis (TGA) .
Thermogravimetric Analysis (TGA) measures weight changes in a material as a function of température (or time) under a controlled atmosphère. Its principal use includes measurement of a material1 s thermal stability and composition. The TGA analysis was performed using a HR TGA 2950 (TA Instruments, Leatherhead, UK) . Samples (±15 mg) were equilibrated at 50°C and then heated to 500°C at a heating rate of 10°C/min and the percentage of weight loss was recorded. The O1PC compound show thermal dégradation at 159.27°C with 1% of mass loss.
Spectroscopic fingerprinting of 01PC
NIR and Raman spectroscopic techniques allow a detailed finger printing of a compound molecular structure 5 and possible changes upon processing.
Raman spectroscopy is a light-scattering process in which the substance under examination is irradiated with intense monochromatic light (usually laser light) and the· light scattered from the specimen is analyzed for frequency shift. Raman . spectroscopy is a complementary technique to infrared spectroscopy since the two techniques prone the molecular vibrations in a material, nevertheless both hâve different relative sensitivity for different functional groups.
A RamanRxnl spectrometer (Kaiser Optical Systems,
Ann Arbor, MI, USA) , equipped with an air-cooled charge coupled device (CCD) detector (back-illuminated deep déplétion design) was used in combination with afiber-optic non-contact probe to collect the powder spectrum. The laser
0 wavelength during the experiments was the 785 nm line from a 7 85 nm Invictus NIR diode laser. The spectrum was recorded at a resolution of 4 cm’1 using a laser power of 4 00 mW. Data collection, data transfer, and data analysis were automated using the HoloGRAMS data collection software (Kaiser Optical
Systems), the HoloREACT reaction analysis and profiling software (Kaiser Optical Systems) and the Matlab software (The Mathworks; version 7.7). A 10 second laser exposure time were used. A Raman spectrum characteristic from O1PC was obtained.
A diffuse réflectance NIR spectrum was collected using a Fourier-Transform NIR spectrometer (Thermo Fisher Scientific, Nicolet Antaris II near-IR analyzer) equipped with an InGaAS detector, a quartz halogen lamp and a fiber optic non-contact probe. Data analysis was done using Thermo Fisher Scientifics' Resuit software. The spectrum was collected in the 10000 - 4000 cm’1 région with a resolution of 16 cm’1 and averaged over 32 scans. A NIR spectrum characteristic from O1PC was obtained.
O1PC hygroscopicity
Active pharmaceutical ingrédients (API) frequently show a propensity to interact with water molécules,· leading to absorption of moisture in their bulk structure or adsorption on their surfaces. Such behaviour can critically affect many pharmaceutical properties such as purity, solubility and chemical stability, density, surface area, powder flow, compact ability and crystal form. Compounds may be classified as non-hygroscopic, slightly hygroscopic, moderately hygroscopic, or very hygroscopic, based on the percentage of weight gain during exposure to define humidity conditions at a spécifie température. Dynamic vapor sorption (DVS) analyzes détermine hygroscopicity profiles using a very small sample (~ 15mg), and provide both qualitative and quantitative information on water uptake.
Water sorption/desorption isotherm of O1PC was determined gravimetrically at 25°C (SD, 0.1°C) using a DVS Advantage 1 with a Cahn D2 00 microbalance (Surface Measurement Systems, London, UK) . Between 10 and 2 0 mg was weighed in the sample cup of the instrument, subjected to a drying step in order to bring the sample to a constant weight and subsequently exposed to increasing relative humidity (RH) (using 10% incréments up to 90%) . Following the sorption phase, the sample was exposed to a decreasing RH (in steps of 10% until 0% RH) . Each step continued until equilibrium was reached (i.e. when the change in mass smaller than 0.002% per minute during at least 10 min) or until 6h had passed. The mass change was recorded every minute with a resolution of ±0.1 ^g.
The water sorption and desorption profiles of O1PC show that O1PC is a very hygroscopic compound, absorbing 41.67% of water when exposed to 90% RH.
Flow properties and corresponding angle of repose
Flow properties and corresponding angle of response were determined as described Carr RL. Evaluating flow properties of solids. Chem. Eng 1965; 72: 163-168 using the following criteria:
Flow properties | Angle of repose (degrees) |
Excellent | 25-30 |
Good | 31-35 |
Fair( aid not needed) | 36-40 |
Passable (may hang up) | 41-45 |
Poor ( must agitate, vibrate) | 46-55 |
Very poor | 56-65 |
Very, very poor | >66 |
HPLC method for O1PC quantification in tablets/mixture
Equipment conditions :
Detector type: UV
Wavelength: 206 nm '18
Column: Lichrosphere® 100rp-8 endcapped (5μιη) , Merck, cat. no. 1.50827.0001
Guard column - Lichrosphere® Guard Column RP-8 end-capped, Merck, cat. no. 1.50961.0001
Column température: 25°C
Flow rate: 0.75mL/min
Injection volume: 3 0/iL
Mobile phase: Methanol (87.5%)/0.01N HCl (12.5%)
O1PC approximate elution time: 5.30 min
Sample préparation:
Disperse the amount correspondent to 1 tablet (3 85.15 mg) in 5 0 mL of HPLC grade methanol (in case of the tablet it needs to be previously pulverized in a mortar) . Sonicate the obtained suspension for 15 min. Stir for 5 min. Afterwards centrifuge at 4000rpm for 10 minutes. Carefully remove the upper transparent phase and place in a vial for inj ection.
HPLC method for O1PC quantification in 0.1 N HCl
Equipment conditions :
Detector type: PDA and MS detector
DAD Wavelength: 196 nm
Column: Supleco Discovery HPLC column C8 150*4.6mm*5^m Column température: 15°C
Flow rate: isocratic 1.5 mL/min
Injection volume: 50^L
Mobile phase: 8 00 mL acetonitrile. 200 mL water (Mili Q Grade), 500 μΗ Formic Acid, 100 μ1> Triethylamine.
Sample préparation.· The samples are homogenized, filled into vials and injected.
Formulation of solid dosage forms
Figure 2 shows a schematic représentation of the formulation process used to provide the oleyl phosphocholine solid dosage forms exemplified below.
Example 1
The wet granulation process for O1PC solid dosage formulation requires that O1PC is solubilised in water. O1PC as a water solubility of 0.2 g/ml, which implies that for each tablet with 50 mg of O1PC at least 250μ1 of water per tablet has to be incorporated in the dry powder mixture.
A wet granulation mixture was developed (Table 1) . The referred dry mixture allows the incorporation (per tablet weight of 315 mg) of 250μ1 of O1PC solution for a final dosage of 50mg. The obtained wet mass was easily passed through a sieve of 1400mm. After the 12 hours drying period good quality granules were obtained.
Table 1: Description of basic, OlPC-free, wet granulation mixture.
Example 2 Incorporation of O1PC into the formulation
Upon the production of good quality placebo granules, O1PC was introduced into the formulation solubilised in the granulation aqueous solution (Table 2).
Table 2 : Introduction of 01PC in the granulation aqueous solution.
Formulation 02 | mg/tablet | Function | Procès s and. conditions | ||
Lactose Monohydrate | 100 | Filler/diluent | |||
(Pharmatose°200M ) | a) > | ||||
Microcrystalline | 200 | Filler/diluent | a | (D H U) | ►b ¢2. o\o LH |
Cellulose | •H ε | ε | |||
04 | ε | ||||
(Avicel PH101) | tn β •H | ο | U | ||
Croscarmellose Sodium | 12 | Super | r-{ | 0 o· m | |
(Ac-di-Sols) | disintegrant | •H ε | c 0 | 12h | |
Polyvinylpyrrolidone | 3 | Binder | 4J | ||
Q | |||||
(Kollidon 30) | Granu | >1 | |||
Dry phase weight: 315 | tug | Q | |||
O1PC aqueous solution | (50mg OlPC/250/zL purified water) | ||||
Granules weight: 365mg |
The wet mass obtained was less easy to granulate, nevertheless good granules were obtained. After a drying period, the granules were compressed into tablets with a 10 mm concave punch and using 1KN compression force, üpon 10 compression, tablets of 3S5mg were obtained. Tablet friability and disintegration time were evaluated.
The tablets produced presented high levels of friability and high disintegration time. It was observed that the presence of polyvynilpyrrolidone in solution with 15 O1PC induces the formation of an unknown precipitated which indicates the presence of an incompatibility between the two compounds.
Another binder, hydroxypropylmethylcellulose, was tested and no such incompatibility was observed.
Hydroxypropylmethylcellulose was then selected to replace polyvynilpyrrolidone as a binder in the subséquent formulation assays.
I.
Example 3 Replacement of polyvinylpyrrolidone by hydroxypropylmethyl cellulose
In example 2 the need was demonstrated for the replacement of polyvinylpyrrolidone by hydroxypropylmethylcellulose (HPMC) due to incompatibility of polyvinylpyrrolidone with O1PC in solution. To produce suitable granules with the use of HPMC E15, a higher amount of binder is needed (Table 3).
Table 3 : Use of hydroxypropylmethycellulose as a binder in the granulation mixture
Formulation 03 | mg/tablet | Function | Process and conditions | ||
Lactose Monohydrate | 100 | Filler/diluent | (V î> G) | ||
(Pharmatose's200M ) | m S | ||||
Microcrystalline Cellulose | 200 | Filler/diluent | £ •H | •ri Ifl | oV> |
(Avicel°PH101) | Ê CN | 1 O | in r4 \ U 0 O | ||
Croscarmellose Sodium | 12 | Super | CD a | O r4 | |
(Ac-di-Sol0) | disintégrant | x} | |||
ε | P Q | (N | |||
Hydroxypropylmethycellulose | 11.25 | Binder | >1 | •ri | r4 |
(Methocel^ElS Premium LV) | X Q | ulat | tn P •H M Q | ||
Dry phase weight: 323.25 mg | P ré x | ||||
O1PC aqueous solution (50mg OlPC/250/iL purified water) | U | ||||
Granules weight: 373.25mg |
The wet mass produced was easy to granulate and good quality granules were obtained. After 12 hour drying period, the produced granules showed an enhance hardness to the touch, and when placed in water at 37°C; did not to disintegrate before 15 minutes. To obtain good granule disintegration, the amount of Croscarmellose Sodium was selected to be increased.
Example 4
Increasing the amount of superdi s intégrant
Croscarmellose Sodium.
The loss of dis intégrât ion capability due to the introduction of HPMC was compensated by increasing the amount of Croscarmellose Sodium (Table 4) .
Table 4: Increasing the amount of the disintegrant croscarmellose Sodium in the granulation mixture.
10.
Formulation 04 | mg/tablet | Function | Process and conditions | ||
Lactose Monohydrate | 100 | Filler/ | |||
(Pharmatose°200M ) | diluents | a) s | |||
Microcrystalline | 200 | Filler/ | 0) •ri W | P4 | |
Cellulose (Avicel°PH101) | diluents | a | e | o\O LD | |
g | h | ||||
Croscarmellose Sodium | 22.5 | Super | (Ί | O O | O 0 |
(Ac-di-Sol°) | disintegrant | tn a | H | o CO | |
Hydroxypropylme thycellui | 11.25 | Binder | •H •H | il 0 | Λ OJ |
ose (Methocel°E15 Premium | g | 4-J | tn £ | ||
LV) | 1 3 ΰ | •H ί>Ί H | |||
Dry phase weight: 333.75 mg | M O | Q | |||
O1PC aqueous solution (50mg OlPC/250gL purified water) | |||||
Granules weight: 383.75mg |
The increase of the amount of croscarmellose sodium greatly enhanced the disintegration in water to 2 minutes. Tablets prepared by compression at 1KN were therefore evaluated regarding disintegration time.
Although the produced granules readily disintegrated in water, upon compression such capability was impaired. To potentiate disintegration capability of the produced tables a similar amount of croscarmellose sodium
0 was then mixed with the dried granules.
Example 5 Incorporation of croscarmellose sodium as external phase
Aiming to improve table disintegration upon compression, an equal amount of croscarmellose sodium was dry mixed with the prepared granules. Due to the particle size différence between croscarmellose sodium and the obtained granules, a step. of granule calibration was included to prevent ségrégation during mixing process. This process includes that the dry granules are force through a sieve of 710mm and then mixed for 1 minute with croscarmellose sodium (Table 5) .
Table 5: Incorporation of croscarmellose sodium as external phase to improve disintegration time of the tablets.
Formulation 05 | mg/tabl et | Function | Process flow and conditions | ||||||
Inner phase 1 | Lactose Monohydrate (Pharmatose°200M ) Microcrystalline Cellulose (Avicel®PH101) Croscarmellose Sodium (Ac-di-Sol0) Hydroxypropyl methycellulose (Methocel^ElS Premium LV) | 100 200 22.5 11.25 | Filler/ diluent Filler/ diluent Super désintégrant Binder | •H ε CN CD C •H X •H S | anulation 1400mm sieve | Drying 12h 30°C/15% RH | Calibration 710 mm sieve | •r4 ε rH CD S •H X •H S | Compression lkN |
Dry mixed phase weight: 333.75 mg | O | ||||||||
O1PC aqueous solution (50mg OlPC/250^L purified water) | |||||||||
Granules weight: 383.75mg | |||||||||
H (U tu ω • U (ϋ | Croscarmellose Sodium (Ac-di-Sol®) | 22.5 | Super désintégrant | ||||||
O | Dry mixed phase for 406.25 mg | compression weight: |
The obtained mixture was compressed at 1KN to produce tablets of 384.25 mg. The obtained tablets were evaluated regarding disintegration time and friability.
With the introduction of an external phase of croscarmellose sodium, tablet disintegration time was greatly decreased. However, during the compression process it was observed that the tablets had the tendency to stick to the lower punch. Such situation was fixed by the introduction of a lubricant agent such as magnésium stéarate on the outer phase of the tablets.
Example 6 Incorporation of a lubricant agent (magnésium stéarate.) on the outer phase of the tablets.
Magnésium stéarate was incorporated into the external phase together with croscarmellose sodium to prevent the adhesion of the tablet to the lower punch (Table 6).
'
Table 6: Incorporation of a lubricant agent on the outer phase of the tablets.
Formulation 06 | mg/tablet | Function |
Lactose | 100 | Filler/ |
Monohydrate | diluent | |
(Pharmatoses2 0 0M | ||
Microcrystalline | 200 | Filler/ |
Cellulose | diluent | |
(Avicel®PH101) | ||
Croscarmellose | 22.5 | Super |
Sodium | disin- | |
(Ac-di-Sol°) | tegrant | |
Hydroxypropyl methycellulose (ΜβΡίιοοβΙθΕΙδ Premium EL) | 11.25 | Binder |
Dry mixed phase weight: 333.75 mg’
O1PC aqueous solution (50mg OlPC/250jéL purified water)
Granules weight: 383.75mg
Croscarmellose Sodium (Ac-di-Sol°) | 22.5 | Super désintégrant |
Magnésium Stéarate | 0.9 | Lubricant |
Process flow and conditions
Dry mixed phase for compression weight: 406.25 mg
The obtained tablets were evaluated regarding disintegration and friability and no effect was observed due to the introduction of the lubricant. No adhesion was observed during compression. However, the obtained tablets still presented high friability.
Example 7 Decreasing of tablet friability
Aiming to decrease tablet friability, a change was made in the ratio of the two diluents. Microcrystalline cellulose (MCC) is frequently used with lactose in wet granulation processes. Lactose is known to compact predominantly by brittle fracture while microcrystalline cellulose has a more plastic deformation. This way the ratio of these two fillers is known to affect tablet properties.
The wet granulation of mixture with higher ratios of MCC leads to granule densification, loss of compact ability and increased tablet friability. Therefore by reducing the ratio 5 of MCC decrease tablet friability is expected (Table 7).
Table 7: Modification of the ratio between Microcrystalline cellulose and Lactose Monohydrate in order to decrease tablet friability.
Granules weight: 361.75mg
Formulation 07 | mg/tablet | Function |
Lactose | 106.9 | Filler/ |
Monohydrate | diluents | |
(Pharmatose’i’OOM ) | ||
Microcrys talline | 171.1 | Filler/ |
Cellulose | diluents | |
(Avicel®PH101) | ||
Croscarmellose | 22.5 | Super disin- |
Sodium | tegrants | |
(Ac-di-Sol°) | ||
Hydroxyp ropy1 | 11.25 | Binder |
methycellulose (Methocel^ElS | ||
Premium LV) |
Process flow and
Dry mixed phase weight: 311.75 mg
O1PC aqueous solution (50mg OlPC/250^L purified water) conditions
Croscarmellose Sodium (Ac-di-Sol°) | 22.5 | Super désintégrants |
Magnésium Stéarate | 0.9 | Lubricant |
Dry mixed phase for compression weight: 385.15 mg
The obtained tablets (weight 385.15mg) were evaluated and evaluated for friability and disintegration time. They presented satisfactory results (Table 8).
Table 8: Evaluation of experimental Formulation 07
Characteristics Spécifications | Tablet | Results |
Dosage | 50mg Oleylphosphocoline | Not evaluated |
Drug release | 85% in the first 30 min. | Not evaluated |
Friability | Less than 1% of the total weight | 0.45% |
Disintegration
Less than 15 min.
min
Example 8 Préparation of a 150 tablet batch based on Formulation 7
For further évaluation of mixture and tablet characteristics a batch of 150 tablets was produced based on Formulation 7 . The préparation was evaluated for mass-volume relationship (Bulk Density, Tapped Density, Hausner's Ratio, and Compressibility Index) and flow properties (Angle of Repose) . The results regarding the O1PC powder/granule mixture for compression are displayed in Table 9.
Table 9 : Powder mixture for compression rheological évaluation
Parameter Results
Flowability Excellent
Angle of repose 29.7°
Tablet uniformity of mass was performed according to: Uniformity of mass of single dosage préparations,
Ph.Eur. 2.9.5. 20 tablets were weighed and a déviation of 19.26mg (+ 5%) was considered. The uniformity of mass test demonstrated little variation among tablets within the batch.
Tablet drug content was determined to evaluate content uniformity of the tablets,
The content uniformity test demonstrates that every tablet contains the amount of drug substance intended (50 mg) with little variation among tablets.
Example 9 Préparation of a 1000 tablet batch based on formulation 7
Based on the data obtained in example 8, a batch 1000 tablets produced for stability testing after packaging in aluminium bags (VaporFlex® VBVF5800-159) . The rheological properties of the mixture were determined prior to compression (Table 10).
Table 10: Powder mixture for compression rheological évaluation
Parameter | Results |
Flowability | Excellent (Annex V) |
Angle of repose | 29.5° |
Bulk density | 0.43 g/mL |
Tapped density | 0.49 g/mL |
Hausner's ratio | 1.14 |
Compressibility index | 12% |
Upon the détermination of bulk and tapped density the calculâted Hausner's ratio, compressibility index and angle of repose are indicators of an excellent flowability.
Tablet drug content was determined to évaluâte content uniformity of the tablets. The content uniformity test demonstrates that every tablet contains the amount of drug substance intended (50 mg) with little variation among .tablets.
Average uniformity of content in the mixture was performed by means of HPLC. This test is based on the assay of the individual contents of active substance from 3 samples of mixture (each équivalent to the tablet theoretical weight) obtained from 20 tablets pulverized and mixed in a mortar. The average content uniformity in the mixture test confirms the high degree of homogeneity in the distribution of the O1PC within the mixture.
Tablet uniformity of mass was performed according to: Uniformity of mass of single dosage préparations, Ph.Eur. 2.9.5. 2 0 tablets were weighed and a déviation of 19.26mg (± 5%) was considered. The uniformity of mass in the O1PC tablets shows a reproducible compression process without significant variations.
Drug release from the tablets (Dissolution test for solid dosage forms, Ph. Eur. 2.9.3) was performed in 900 mL 0. IN HCl, (37.5 + 0.5°C), using a paddle apparatus (Ph. Eur. Apparatus 2) at lOOrpm. O1PC aqueous concentration was determined by means of HPLC. Individual and average (Figure 3) dissolution profiles were determined. The tablets achieve an O1PC release of >85% in less than 30 minutes in compliance with Ph. Eur. 5.17.1.
IL
Example 10 Comparative curative efficacy of miltefosine (MIL) and oleylphosphocholine (O1PC) against Leishmania infantum in the hamster model after oral administration at 20 and 4 0 mg/kg for 5 days using different formulations.
Miltefosine (MIL) belongs to the chemical group of the alkylphosphocholines and is a marketed drug for the treatment of viscéral leishmaniasis (VL) . Its particular advantages are oral route of administration and the fact that no cross-resistance exists with any other first-line and second-line anti-leishmania therapy.
Although three new drugs or drug formulations (liposomal amphotericin B, miltefosine and paromomycin) are currently available for the treatment of VL, they ail suffer either from limitations of cost, toxicity or the need for parentéral administration. Novel alkylphosphocholines and alternative potentially cheaper formulations are being explored as potential added value to the current therapeutic options.
Animais
Golden hamsters (female, 75 g) were allocated randomly to 7 groups with 8 animais per group.
G1 : vehicle infected control (VIC) : 200 μΐ blank vehicle orally 5 days
G2 : MIL-PBS: 5 x 40 mg/kg (= 98.1 ^mol/kg) orally for 5 days
G3 : MIL-PBS: 5 x 20 mg/kg (= 49.1 μπιοί /kg) orally for 5 days
G4 : O1PC-PBS: 5 x 42.5 mg/kg (= 98.1 μπιοί /kg) orally for 5 days
G5: O1PC-PBS: 5 x 21.2 mg/kg (= 49.1 μπιοί /kg) orally for 5 days
G6 : OlPC-liposomes : 5 x 2.4 ml/kg (= 98.1 μπιοί /kg) orally for 5 days
G7 : OIPC-liposomes: 5 x 1.2 ml/kg ( = 49.1 μτηοΐ /kg) orally for 5 days
Drinking water and food were available ad libitum throughout 5 the experiment. The weight of the individual animais did not differ too much from the group mean.
Artificial infection
Leishmania infantuxn (MHOM/MA (BE)/67) amastigotes were obtained from the spleen of heavily infected donor hamsters. The total parasite burden was'determined on Giemsa-stained smears. Amastigotes in the spleen homogenate were concentrated using two centrifugation steps (low speed (3 00 rpm) with collection of the supernatant - high speed (4200 rpm) with collection of the pellet) . The parasite burdens in the spleen were estimated using the Stauber technique and the amastigote suspension was diluted to préparé the infection inocula for intracardial infection containing 2 x 107 amastigotes/ΙΟΟμΙ. At 21 days post infection (= start of treatment), the levels infection were checked in 4 randomly chosen animais by making a smear from a liver biopsy for détermination of the parasite burden (cfr. infra).
Test substances and formulations
Miltefosine was formulated at 2 0 mg/ml and 10 mg/ml in PBS and stored at room température in the dark. A clear transparent solution was obtained.
- O1PC-PBS was formulated at 21.25 mg/ml and 10.63 mg/ml in PBS and stored at room température in the dark. A clear transparent solution was obtained.
OlPC-liposome formulation was prepared at 18 mg/ml (dosed at 2.4 ml/kg = 120 μ1/50 gram). The formulation was diluted 2 times in PBS to obtain a O1PC-formulation of 9 mg/ml (dosed at 1.2 ml/kg = 120 μ1/50 gram) )
Treatment
Oral treatment started 21 days after infection (dpi) and was continued for 5 consecutive days. Dosing volume was 100 μΐ per 50 gram BW (bodyweight) .
- | Group 1 : | PBS: 100 μΐ per 50 gram |
- | Group 2 : | MIL: 20 mg/ml PBS: 100 μΐ per 50 gram |
- | Group 3 : | MIL: 10 mg/ml PBS: 100 μΐ per 50 gram |
- | Group 4 : | O1PC-PBS: 21.5 mg/ml PBS: 100 μΐ per 50 gram |
- | Group 5 : | O1PC-PBS: 10.6 mg/ml PBS: 100 μΐ per 50 gram |
- | Group 6 : | OlPC-liposomes : 18 mg/ml: 120 μΐ per 50 gram |
Group 7: O1PC-liposomes : 9 mg/ml: 12 0 μΐ per 50 gram
Evaluation parameters
Clinical symptorns: the animais were observed daily for the occurrence/presence of clinical or adverse effects during the 5-week course of the experiment. Body weight: ail animais were weighed twice weekly during the course of the experiment to monitor their general health status (severity of infection and toxicity of médication) .
Parasite burden: amastigote burdens in the different target organs (liver, spleen, bone-marrow) were determined 10 days after the last treatment (ï.e. day 35 of the experiment) . The organs of individual animais were weighed (except bone-marrow); impression smears were fixed in methanol and stained with Giemsa for microscopie évaluation of the number of amastigotes per cell by counting a minimum of 500 nucleil. The results are expressed as Leishman Donovan Units (LDU) = mean number of amastigotes per nucléus x mg organ weight. Percentage réduction as compared to vehicle-treated infected control animais (VIC) is used as a measure for drug activity. Particularly for spleen and bone-marrow, the viability of possible residual burdens was assessed using the promastigote transformation assay.
Results and discussion
Treatment was started after vérification of the liver parasite burdens 21 days after infection. Ail four positive controls were adequately infected (1.30+0.3 amastigotes/nucleus in a liver biopsy) . Ail the results are summarized in Table 11 :
The vehicle-treated infected controls (VIC) developed high infection levels in ail target organs (liver, spleen and bone marrow) The reference drug MIL at 4 0 mg/kg showed 65 % réduction of LDU-values in the liver, 99% in the spleen and 95% in the bone-marrow. At 2 0 mg/kg, no réduction was obtained in the liver, 61% in the spleen and 39% in the bone marrow.
O1PC-PBS at 40 mg/kg showed 100 % réduction of LDU-values in the liver, spleen and bone-marrow. At 2 0 mg/kg, 91% réduction was obtained in the liver, 99% in the spleen and 98% in the bone marrow. Minor adverse reactions (closed eyes, agitation) were noted immediately after gavage, disappearing within about half an hour. In the 4 0mg/kg group, one hamster died two days after the end of treatment, but is considered not to be drug related.
O1PC-liposomes at 40 mg/kg showed 100 % réduction of LDU-values in the liver, spleen and bone17935 marrow. At 2 0 mg/kg, 71% réduction was obtained in the liver, 99% in the spleen and 93% in the bone marrow.
At necropsy, no gross-pathological lésions were noted in any of the treated animais.
It is concluded that both O1PC formulations are about equipotent, with markedly higher efficacy compared to the reference drug MIL at équivalent dose levels.
Table 11: Parasite burdens in leishmania-infected hamsters treated orally for 5 days
Liver | Spleen | Bone marrow | ||||
Mean + SE of LDU | %red | Mean + SE of LDU | %red | Mean + SE of amastigotes per nucléus | %red | |
VIC - PBS | 7981+1366 | 479±72 | 1.5+0.5 | |||
Miltefosine 98.1 /zmol/kg | 2764+847 | 65 | 3.7+1.67 | 99.2 | 0.1+0,014 | 95 |
Miltefosine 49.1 μιηοΐ/kg | 9017+1489 | 0 | 188±44 | 61 | 1.0 + 0.34 | 39 |
O1PC/PBS 98.1 μπιοΐ/kg | 29 + 15 | 99.6 | 0 | 100 | 0 | 100 |
O1PC/PBS 49.1 μπιοΐ/kg | 717±295 | 91 | 3.0+1.45 | 99.4 | 0.03 + 0.014 | 98 |
O1PC/liposome 98.1 μπιοΐ/kg | 0 | 100 | 0 | 100 | 0 | 100 |
OlPC/liposome 49.1 μτηοΐ/kg | 2283+889 | 71 | 6.0±2.4 | 98.7 | 0.1 + 0.03 | 93 |
In a follow up experiment, the same experimental protocol was used to compare the efficacy of oral oleyl phosphocholine (O1PC) at total doses of 25, 50 and 100 mg/kg when given as single or multiple oral administrations (5X5, 10 and 20 mg/kg, respectively) .
The results show that the overall parasite suppression levels were similar when the doses were given as single or multiple administrations, suggesting that the total exposure (AUC) was more important than high plasmatic concentration (Cmax) for parasite killing.
Interestingly, even single administrations as high as 100 mg/kg were well tolerated in the hamsters and no sign of toxicity was observed during the experiment. Once again the two oleylphosphocholine formulations tested (aqueous and liposomes) were equally well-tolerated.
Female hamsters (n - 60) were intracardially infected with 2 x 107 Leishmania ïnfantum (MHOM/MA (BE)/67)· amastigotes on day 0. Treatment started at day +21 post infection for 5 consecutive days once daily with a total dose of 25, 50 and 100 m/kg given as single or multiple oral administrations. Amastigote burdens in the different target organs (liver, spleen, bone-marrow) were determined 10 days after the last treatment (day+35) . The organs of individual animais were weighed (except bone-marrow) ; impression smears were fixed in methanol and stained with Giemsa for microscopie évaluation of the number of amastigotes per cell by counting a minimum of 5 00 nuclei. The results (Figure 4) are expressed as Leishman Donovan Units (LDU) = mean number of amastigotes per nucléus x mg organ weight.
Treatment of naturally infected dogs
The dose of 4 mg/kg/day oleylphosphocholine was used to treat orally during 14 days a cohort of 6 dogs from a shelter naturally infected with L. ïnfantum and classified as clinically sick. The dogs were assessed at the clinical (physical examination and clinic-pathological abnormalities) and parasitological levels at the beginning of the treatment (day 0) and on day 15, 30 and 90.
Regarding tolérance, two of the six dogs treated experienced diarrhea during the first week post-treatment, and a third one had diarrhea and 1 épisode of vomiting. The other three dogs tolerated the treatment without any side effect. On day 0 the average clinical score (CS) of the dogs was 19 (range 14-31; severe) . This CS went down to 12 (range
7-16) at the end of the treatment period (day 15) , then to 5 (range 1-10) on day 30 and to 2 on day 90 (range 0-5) , translating an excellent clinical improvement after treatment.
Example 11 Stability of the solid dosage 01PC formulation
1. Aim
To monitor the drug content of O1PC tablets over a 12 month period during storage under controlled environmental conditions.
. Formulation
Oleylphosphocholine50 mg
Lactose monohydrate (Pharmatose 200M) 106.9mg
Microcrystalline cellulose (Avicel PH101) 171.1mg
Croscarmellose sodium (Ac-di-Sol)45 mg
Hydroxypropylmethylcellulose (Methocel E15 LV) 11.25mg
Magnésium stéarate 0.9 mg τ
3. Methods
Tablet manufacturing
The tablets (0 10 mm, weight 385.15 mg) were manufactured according to the process described in example 7 A batch of 1000 tablets (batch 01101007) was prepared under for stability testing under controlled environmental conditions. After manufacturing, the . tablets were packaged in hermetically sealed Aluminum sachet (Vaporflex VBVF5800159) and stored at controlled environmental conditions until. further analysis.
Quantification of O1PC content in tablets
After 0, 1, 3, 6 and 12 months storage under controlled environmental conditions the drug content of individual O1PC tablets (10 tablets per storage condition) was determined using a HPLC method.
A single O1PC tablet was crushed using mortar and pestle, and an accurately weighed amount was transferred in to a 50ml volumétrie flask. About 35 ml of mobile phase (see below for composition) was added. After 15 min sonication in an ultrasound bath and 5 min stirring to dissolve the API, mobile phase was added to obtain a total volume of 50.0 ml. A homogeneous sample of about 5 ml was transferred to a vial.
To remove the insoluble fraction the sample was centrifuged for 10 min at 4000 rpm. Afterwards an aliquot of the clear supernatant was transferred to an HPLC vial. Standard solutions corresponding to 40, 60, 80, 100 and 120% of the theoretical drug content were prepared by dissolving the required amount of O1PC in methanol.
HPLC settings:
39 | |
Column: | LichroCart 125-4, Licrospher 100 RP-8 endcapped 5/zm |
Pre-column: | LichroCart 4-4, Licrospher 100 RP-8 endcapped 5/zm |
Mobile phase: | Methanol/0.01N HCl (875/125, v/v) |
Flow rate: | 0.75 ml/min |
Injection volume: | 30 μΐ |
Détection wavelength: | 206 nm |
O1PC elution time: | + 5.3 min |
4. Results
The stability study monitored the drug content per tablet (average + standard déviation) in function of storage
conditions and storage | time. The drug content is expressed |
as a percentage of the | theoretical drug content, i.e. 50 mg |
per tablet. The results are summarized in table 12 below.
Table 12 Stability of the O1PC solid dosage forms
Storage Storage conditions time
2-8°C 25°C - 60% RH 30°C - 65% RH 40°C - 75% RH (months)
0 | 101.2 | ± | 2.3 | O, O | 101.2 | ± 2.3 | 101.2 | + 2.3 | O, 0 | 101.2 | + 2.3 | O, *o | |||
1 | 101.3 | ± | 1.7 | O. O | -- | 101.7 | + | 1.2 | O, *o | 103.0 | ± | 1.7 | 0, O | ||
3 | -- | 104.2 | + 2.9 | O. & | 102.7 | ± | 1.6 | O, Ό | 102.6 | ± | 2.0 | O, ~O | |||
6 | 100.4 | ± | 1.8 | O, o | 101.3 | + 1.3 | O, Ό | 101.4 | + | 1.2 | O O | 99.1 | ± | 5.6 | |
12 | 94.9 | ± | 1.1 | o | 95.8 | + 1.3 | *O | 97.7 | 0.7 | O. | __ |
5. Conclusion
This example indicates that the drug content remains stable in the O1PC tablet formulation over at least 12 months at ail température tested.
The réduction in average drug content after 12 months storage is most probable not indicative of drug dégradation as no additional peaks were observed in the chromatograms.
Claims (17)
1. Solid dosage form of oleyl phosphocholine for oral administration comprising:
6 to 25 weight% of the solid dosage form oleyl phosphocholine;
75 to 94 weight% of the solid dosage form of one or more pharmaceutically acceptable fillers, disintégrants, binders, lubricants and/or diluents;
said solid dosage form provides a friability of less than
1 weight%, preferably less than 0.5 weight%, of the solid dosage form as determined in accordance with the European Pharmacopoeia 2.9.7 standard friability test and/or said solid dosage form provides a disintegration of less than 15 minutes, preferably less than 10 minutes, as determined in accordance with the European Pharmacopoeia 2.9.1 standard disintegration test.
2. Solid dosage form according to claim 1, wherein said solid dosage form provides at least 85 weight% oleylphosphocholine release within 30 minutes as determined in accordance with the European Pharmacopoeia 2.9.3 standard dissolution test.
3. Solid dosage form according to claim 1 or claim
2 comprising one or more diluents or fillers selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnésium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium
REPLACEMENT SHEET chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol and combinations thereof.
5 4. Solid dosage form according to any of the daims 1 to 3 comprising one or more binders selected from the group consisting of water, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethycellulose sodium, microcrystalline cellulose,
10 powdered cellulose, ethyl cellulose, gélatine, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnésium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene
15 oxide, povidone, copovidone, sodium alginate, starch paste, pregelatinized starch, Sucrose (syrup) and combinations thereof.
5. Solid dosage form according to any of the
20 daims 1 to 4 comprising one or more lubricants selected from the group consisting of calcium stéarate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnésium lauryl sulphate, magnésium stéarate, polyethylene glycol 4000 or 6000, sodium lauryl
25 sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stéarate and combinations thereof.
6. Solid dosage form according to any of the daims 1 to 5 comprising one or more disintegrants selected
30 from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and combinations thereof.
REPLACEMENT SHEET «
7. Solid dosage form according to any of the daims 1 to 6 comprising:
6 to 25 weight% of the solid dosage form oleyl phosphocholine;
20 to 35 weight% of the solid dosage form of one or more diluents or fillers preferably selected from the group consisting of calcium carbonate, calcium phosphate (dibasic), calcium phosphate (tribasic), calcium sulphate, cellulose, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dextrates, dextrose, fructose, lactitol, lactose monohydrate, magnésium carbonate, maltitol, maltodextrin, maltose, mannitol, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, sugar spheres, talc, xylitol and combinations thereof.
36 to 60 weight% of the solid dosage form of one or more binders preferably selected from the group consisting of water, acacia mucilage, alginic acid, carbomer, carboxymethylcellulose calcium, carboxymethycellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gélatine, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, magnésium aluminum silicate, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, copovidone, sodium alginate,
REPLACEMENT SHEET starch paste, pregelatinized starch, Sucrose (syrup) and combinations thereof.
5 to 20 weight% of the solid dosage form of one or more disintegrants preferably selected from the group consisting of starch, microcrystalline cellulose, alginic acid, methyl cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, calcium silicate and combinations thereof; and
0.05 to 1 weight% of the solid dosage form of one or more lubricants preferably selected from the group consisting of calcium stéarate, fumaric acid, glyceryl behenate, glyceryl palmitostearate, hydrogenated vegetable oil, magnésium lauryl sulphate, magnésium stéarate, polyethylene glycol 4000 or 6000, sodium lauryl sulphate, sodium stearyl fumarate, starch, stearic acid, talc, zinc stéarate and combinations thereof.
8. Solid dosage form comprising:
6 to 25 weight% of the solid dosage form oleyl phosphocholine;
20 to 35 weight% of the solid dosage form lactose, preferably lactose monohydrate;
35 to 50 weight% of the solid dosage form cellulose, preferably microcrystalline cellulose;
5 to 20 weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
REPLACEMENT SHEET
I
Μ r
1 to 10 weight% of the solid dosage form hydroxypropylmethyl cellulose; and
0.05 to 1 weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
9. Solid dosage form according to claim 8, comprising:
10 to 15 weight% of the solid dosage form oleyl phosphocholine;
25 to 30 weight% of the solid dosage form lactose, preferably lactose monohydrate ;
42 to 47 weight% of the solid dosage form cellulose, preferably microcrystalline cellulose;
10 to 15 weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
1 to 5 weight% of the solid dosage form hydroxypropylmethyl cellulose; and
0.1 to 0.3 weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
10. Solid dosage form according to claim 8 or claim 9, comprising:
12 to 14, preferably 13, weight% of the solid dosage form oleyl phosphocholine;
27 to 29, preferably 28, weight% of the solid dosage form lactose, preferably lactose monohydrate;
REPLACEMENT SHEET • >
43 to 45, preferably 44, weight% of the solid dosage form cellulose, preferably microcrystalline cellulose;
11 to 13, preferably 12, weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
2 to 4, preferably 3, weight% of the solid dosage form hydroxypropylmethyl cellulose; and
0.1 to 0.3, preferably 0.2, weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
11. Solid dosage form according to any of the daims 1 to 10, wherein said form is a tablet or capsule, preferably a tablet.
12. Solid dosage form of claim 11, comprising an inner core comprised of:
12 to 14, preferably 13, weight% of the solid dosage form oleyl phosphocholine;
27 to 29, preferably 28, weight% of the solid dosage form lactose, preferably lactose monohydrate;
43 to 45, preferably 44, weight% of the solid dosage form cellulose, preferably microcrystalline cellulose;
5 to 7, preferably 6, weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium;
2 to 4, preferably 3, weight% of the solid dosage form hydroxypropylmethyl cellulose; and
REPLACEMENT SHEET *
an outer layer comprised of:
5 to 7, preferably 6, weight% of the solid dosage form croscarmellose, preferably croscarmellose sodium; and
0.1 to 0.3, preferably 0.2, weight% of the solid dosage form of a lubricant, preferably magnésium stéarate.
13. Method for the préparation of a solid dosage form according to any of the daims 1 to 12, said method comprises :
a) adding to a dry mixture comprising one or more pharmaceutically acceptable diluents/fillers, disintegrants and/or binders water as defined in any of the daims 1 to 13, water comprising 6 to 25 weight% oleyl phosphocholine;
b) drying and sieving the mixture obtained in step (a);
c) adding one or more disintegrants and/or lubricants as defined in any of the daims 1 to 13 to the mixture obtained in step (b);
d) mixing the mixture obtained in step (c) ;
e) preparing an oral dosage form of the mixture of step (d), preferably by compression molding.
14. Method according to daim 13, comprising:
a) adding to a dry mixture comprising lactose, preferably lactose monohydrate, cellulose, preferably microcrystalline cellulose, croscarmellose, preferably croscarmellose sodium and hydroxypropylmethyl cellulose
REPLACEMENT SHEET
F water comprising 6 to 25 weight% oleyl phosphocholine;
b) drying and sieving the mixture obtained in step (a);
c) adding croscarmellose, preferably croscarmellose sodium and a lubricant, preferably magnésium stéarate, to the mixture obtained in step (b);
d) mixing the composition obtained in step (c) ; and
e) preparing an oral dosage form of the mixture of step (d), preferably by compression molding.
15. Method according to claim 13 or claim 14, wherein sieving comprises a first sieving step, preferably through a 1400 mm sieve, before drying and a second sieving step after drying, preferably through a 710 nm sieve.
16. Solid dosage form obtainable by a method according to any of the claims 13 to 15.
17. Solid dosage form according to any of the claims 1 to 12 or 16 for use in human or animal medicine.
18. Solid dosage form according to any of the claims 1 to 12 or 16 for use in the treatment of parasitic diseases, preferably leishmaniasis, chagas or malaria, or cancer in humans and animais.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EPPCT/EP2010/067926 | 2010-11-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA17935A true OA17935A (en) | 2018-03-12 |
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