RU2453316C2 - Фармацевтическая композиция с длительным постепенным высвобождением, содержащая водную суспензию бисфосфоната - Google Patents
Фармацевтическая композиция с длительным постепенным высвобождением, содержащая водную суспензию бисфосфоната Download PDFInfo
- Publication number
- RU2453316C2 RU2453316C2 RU2009128023/15A RU2009128023A RU2453316C2 RU 2453316 C2 RU2453316 C2 RU 2453316C2 RU 2009128023/15 A RU2009128023/15 A RU 2009128023/15A RU 2009128023 A RU2009128023 A RU 2009128023A RU 2453316 C2 RU2453316 C2 RU 2453316C2
- Authority
- RU
- Russia
- Prior art keywords
- salt
- pharmaceutical composition
- calcium
- acid
- salts
- Prior art date
Links
- 229940122361 Bisphosphonate Drugs 0.000 title claims abstract description 74
- 150000004663 bisphosphonates Chemical class 0.000 title claims abstract description 71
- 239000007900 aqueous suspension Substances 0.000 title claims abstract description 33
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 32
- 230000002035 prolonged effect Effects 0.000 title abstract description 6
- 239000003814 drug Substances 0.000 claims abstract description 81
- 239000000203 mixture Substances 0.000 claims abstract description 71
- 150000003839 salts Chemical class 0.000 claims abstract description 66
- 239000011575 calcium Substances 0.000 claims abstract description 49
- -1 phosphorus oxoacid Chemical class 0.000 claims abstract description 44
- 239000011574 phosphorus Substances 0.000 claims abstract description 39
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 39
- 239000007787 solid Substances 0.000 claims abstract description 39
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 30
- 208000001132 Osteoporosis Diseases 0.000 claims abstract description 25
- 239000002253 acid Substances 0.000 claims abstract description 23
- 239000006185 dispersion Substances 0.000 claims abstract description 18
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 239000007924 injection Substances 0.000 claims abstract description 17
- 238000002347 injection Methods 0.000 claims abstract description 17
- 159000000007 calcium salts Chemical class 0.000 claims abstract description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 13
- 208000020084 Bone disease Diseases 0.000 claims abstract description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims abstract description 10
- 239000011780 sodium chloride Substances 0.000 claims abstract description 10
- 239000012736 aqueous medium Substances 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 6
- 229940079593 drug Drugs 0.000 claims description 80
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 claims description 38
- 239000001506 calcium phosphate Substances 0.000 claims description 21
- 229960004343 alendronic acid Drugs 0.000 claims description 19
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 18
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 238000013268 sustained release Methods 0.000 claims description 17
- 239000012730 sustained-release form Substances 0.000 claims description 17
- 229910019142 PO4 Inorganic materials 0.000 claims description 15
- 235000021317 phosphate Nutrition 0.000 claims description 15
- 239000002504 physiological saline solution Substances 0.000 claims description 14
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 claims description 13
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 claims description 12
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 claims description 12
- 229960004276 zoledronic acid Drugs 0.000 claims description 12
- 150000004677 hydrates Chemical class 0.000 claims description 10
- 235000011010 calcium phosphates Nutrition 0.000 claims description 9
- 239000007927 intramuscular injection Substances 0.000 claims description 9
- 150000001447 alkali salts Chemical class 0.000 claims description 8
- 238000010255 intramuscular injection Methods 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 235000011180 diphosphates Nutrition 0.000 claims description 7
- 229960000759 risedronic acid Drugs 0.000 claims description 7
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 239000004034 viscosity adjusting agent Substances 0.000 claims description 6
- 239000002270 dispersing agent Substances 0.000 claims description 5
- 159000000003 magnesium salts Chemical class 0.000 claims description 5
- 230000003204 osmotic effect Effects 0.000 claims description 5
- 239000006174 pH buffer Substances 0.000 claims description 5
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 5
- 239000003755 preservative agent Substances 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 5
- 239000000375 suspending agent Substances 0.000 claims description 5
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 4
- 229920000388 Polyphosphate Polymers 0.000 claims description 4
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 claims description 4
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 4
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 4
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 4
- 229960005236 ibandronic acid Drugs 0.000 claims description 4
- 125000005341 metaphosphate group Chemical group 0.000 claims description 4
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 claims description 4
- 229960003978 pamidronic acid Drugs 0.000 claims description 4
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims description 4
- 239000001205 polyphosphate Substances 0.000 claims description 4
- 235000011176 polyphosphates Nutrition 0.000 claims description 4
- 229960005324 tiludronic acid Drugs 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 229910000392 octacalcium phosphate Inorganic materials 0.000 claims description 2
- YIGWVOWKHUSYER-UHFFFAOYSA-F tetracalcium;hydrogen phosphate;diphosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].OP([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O YIGWVOWKHUSYER-UHFFFAOYSA-F 0.000 claims description 2
- 150000003751 zinc Chemical class 0.000 claims 2
- 125000000524 functional group Chemical group 0.000 claims 1
- CMJFWZAVQWOMKU-UHFFFAOYSA-H tricalcium diphosphate tetrahydrate Chemical compound O.O.O.O.[Ca++].[Ca++].[Ca++].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O CMJFWZAVQWOMKU-UHFFFAOYSA-H 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 238000007918 intramuscular administration Methods 0.000 abstract description 4
- 239000002609 medium Substances 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 40
- 239000008186 active pharmaceutical agent Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 229960005069 calcium Drugs 0.000 description 30
- 241000700159 Rattus Species 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 238000011282 treatment Methods 0.000 description 19
- 229940062527 alendronate Drugs 0.000 description 17
- VFAZUESUCBECNE-UHFFFAOYSA-L calcium;(4-amino-1-hydroxy-1-phosphonobutyl)-hydroxyphosphinate Chemical compound [Ca+2].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O.NCCCC(O)(P(O)(O)=O)P(O)([O-])=O VFAZUESUCBECNE-UHFFFAOYSA-L 0.000 description 17
- 210000001519 tissue Anatomy 0.000 description 13
- 238000000975 co-precipitation Methods 0.000 description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 12
- 239000010452 phosphate Substances 0.000 description 12
- 206010015150 Erythema Diseases 0.000 description 10
- 206010030113 Oedema Diseases 0.000 description 10
- DCSBSVSZJRSITC-UHFFFAOYSA-M alendronate sodium trihydrate Chemical compound O.O.O.[Na+].NCCCC(O)(P(O)(O)=O)P(O)([O-])=O DCSBSVSZJRSITC-UHFFFAOYSA-M 0.000 description 10
- 231100000321 erythema Toxicity 0.000 description 10
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 10
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 210000000988 bone and bone Anatomy 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 230000007794 irritation Effects 0.000 description 9
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 8
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 8
- 230000002265 prevention Effects 0.000 description 8
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 7
- LLSDKQJKOVVTOJ-UHFFFAOYSA-L calcium chloride dihydrate Chemical compound O.O.[Cl-].[Cl-].[Ca+2] LLSDKQJKOVVTOJ-UHFFFAOYSA-L 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 230000002459 sustained effect Effects 0.000 description 7
- 229910052725 zinc Inorganic materials 0.000 description 7
- 239000011701 zinc Substances 0.000 description 7
- 229940052299 calcium chloride dihydrate Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000902 placebo Substances 0.000 description 6
- 229940068196 placebo Drugs 0.000 description 6
- 210000000689 upper leg Anatomy 0.000 description 6
- 230000036325 urinary excretion Effects 0.000 description 6
- 230000002411 adverse Effects 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 5
- 230000029142 excretion Effects 0.000 description 5
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 5
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 5
- 235000019799 monosodium phosphate Nutrition 0.000 description 5
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 5
- 238000001179 sorption measurement Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 229940043256 calcium pyrophosphate Drugs 0.000 description 4
- 238000009792 diffusion process Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 229940048084 pyrophosphate Drugs 0.000 description 4
- 238000011552 rat model Methods 0.000 description 4
- 229940089617 risedronate Drugs 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- GBNXLQPMFAUCOI-UHFFFAOYSA-H tetracalcium;oxygen(2-);diphosphate Chemical compound [O-2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GBNXLQPMFAUCOI-UHFFFAOYSA-H 0.000 description 4
- 210000002700 urine Anatomy 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 3
- 229960002713 calcium chloride Drugs 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- JUNWLZAGQLJVLR-UHFFFAOYSA-J calcium diphosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])([O-])=O JUNWLZAGQLJVLR-UHFFFAOYSA-J 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002288 cocrystallisation Methods 0.000 description 3
- 230000000052 comparative effect Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 235000019821 dicalcium diphosphate Nutrition 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000008595 infiltration Effects 0.000 description 3
- 238000001764 infiltration Methods 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 208000029985 osteonecrosis of the jaw Diseases 0.000 description 3
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- DPOPBAPQJCXAIB-UHFFFAOYSA-N 2-imidazol-1-ylethenol Chemical group OC=CN1C=CN=C1 DPOPBAPQJCXAIB-UHFFFAOYSA-N 0.000 description 2
- MAHZBSVNRNPSBZ-UHFFFAOYSA-N 2-pyridin-3-ylethenol Chemical group OC=CC1=CC=CN=C1 MAHZBSVNRNPSBZ-UHFFFAOYSA-N 0.000 description 2
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 2
- 208000037147 Hypercalcaemia Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229940037127 actonel Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229940028101 boniva Drugs 0.000 description 2
- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229940001490 fosamax Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000002657 hormone replacement therapy Methods 0.000 description 2
- 230000000148 hypercalcaemia Effects 0.000 description 2
- 208000030915 hypercalcemia disease Diseases 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 238000009806 oophorectomy Methods 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 2
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 2
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 2
- 229940048086 sodium pyrophosphate Drugs 0.000 description 2
- 235000019832 sodium triphosphate Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 2
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 2
- 229910000165 zinc phosphate Inorganic materials 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- 102000055006 Calcitonin Human genes 0.000 description 1
- 108060001064 Calcitonin Proteins 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000011327 Increased bone mineral density Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000037848 Metastatic bone disease Diseases 0.000 description 1
- 206010030201 Oesophageal ulcer Diseases 0.000 description 1
- 206010030216 Oesophagitis Diseases 0.000 description 1
- 208000010191 Osteitis Deformans Diseases 0.000 description 1
- 208000027868 Paget disease Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000011052 biological reactivity test Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 229960004015 calcitonin Drugs 0.000 description 1
- 229940069978 calcium supplement Drugs 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000028299 esophageal disease Diseases 0.000 description 1
- 208000019064 esophageal ulcer Diseases 0.000 description 1
- 208000006881 esophagitis Diseases 0.000 description 1
- 229940064258 estrace Drugs 0.000 description 1
- 229940074117 estraderm Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 238000009164 estrogen replacement therapy Methods 0.000 description 1
- JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229940085363 evista Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000027202 mammary Paget disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 229940101566 miacalcin Drugs 0.000 description 1
- 238000007431 microscopic evaluation Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- ZIPLKLQPLOWLTM-UHFFFAOYSA-N naphthalene-2,3-dicarbaldehyde Chemical compound C1=CC=C2C=C(C=O)C(C=O)=CC2=C1 ZIPLKLQPLOWLTM-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 229940063238 premarin Drugs 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 108010068072 salmon calcitonin Proteins 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- VZWGHDYJGOMEKT-UHFFFAOYSA-J sodium pyrophosphate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O VZWGHDYJGOMEKT-UHFFFAOYSA-J 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-I triphosphate(5-) Chemical compound [O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O UNXRWKVEANCORM-UHFFFAOYSA-I 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- YZYKBQUWMPUVEN-UHFFFAOYSA-N zafuleptine Chemical compound OC(=O)CCCCCC(C(C)C)NCC1=CC=C(F)C=C1 YZYKBQUWMPUVEN-UHFFFAOYSA-N 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
Images
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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
- A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87680006P | 2006-12-21 | 2006-12-21 | |
| US60/876,800 | 2006-12-21 | ||
| US11/768,181 | 2007-06-25 | ||
| US11/768,181 US8974801B2 (en) | 2006-12-21 | 2007-06-25 | Long term sustained release pharmaceutical composition containing aqueous suspension of bisphosphonate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2009128023A RU2009128023A (ru) | 2011-01-27 |
| RU2453316C2 true RU2453316C2 (ru) | 2012-06-20 |
Family
ID=39543732
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2009128023/15A RU2453316C2 (ru) | 2006-12-21 | 2007-12-13 | Фармацевтическая композиция с длительным постепенным высвобождением, содержащая водную суспензию бисфосфоната |
Country Status (14)
| Country | Link |
|---|---|
| US (3) | US8974801B2 (enExample) |
| EP (2) | EP2548441B1 (enExample) |
| JP (1) | JP5492564B2 (enExample) |
| CN (1) | CN101616591B (enExample) |
| BR (1) | BRPI0720605A2 (enExample) |
| CA (1) | CA2673058C (enExample) |
| DK (2) | DK2120585T3 (enExample) |
| ES (2) | ES2396733T3 (enExample) |
| MX (1) | MX2009006447A (enExample) |
| PL (2) | PL2548441T3 (enExample) |
| PT (2) | PT2120585E (enExample) |
| RU (1) | RU2453316C2 (enExample) |
| SI (1) | SI2120585T1 (enExample) |
| WO (1) | WO2008085281A1 (enExample) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101813728B1 (ko) * | 2009-07-31 | 2017-12-29 | 그뤼넨탈 게엠베하 | 결정화 방법 및 생체이용률 |
| US20160016982A1 (en) | 2009-07-31 | 2016-01-21 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
| US9169279B2 (en) | 2009-07-31 | 2015-10-27 | Thar Pharmaceuticals, Inc. | Crystallization method and bioavailability |
| AU2010330909B2 (en) | 2009-12-18 | 2014-09-11 | Howmedica Osteonics Corp. | Post irradiation shelf-stable dual paste direct injectable bone cement precursor systems and methods of making same |
| CN102453050B (zh) * | 2010-11-03 | 2015-01-07 | 成都云克药业有限责任公司 | 一种二膦酸化合物及其制备方法 |
| ES2714701T3 (es) | 2010-11-10 | 2019-05-29 | Stryker European Holdings I Llc | Proceso para la preparación de una espuma ósea polimérica |
| WO2012071517A2 (en) | 2010-11-24 | 2012-05-31 | Thar Pharmaceuticals, Inc. | Novel crystalline forms |
| WO2013175385A1 (en) | 2012-05-20 | 2013-11-28 | Bar-Ilan Research And Development Company Ltd. | Bisphosphonates vinylic monomers and polymers and uses thereof |
| US9492268B2 (en) | 2012-11-13 | 2016-11-15 | The Secant Group, Llc | Tapered tubular implant formed from woven fabric |
| WO2017208070A1 (en) | 2016-05-31 | 2017-12-07 | Grünenthal GmbH | Bisphosphonic acid and coformers with lysin, glycin, nicotinamide for treating psoriatic arthritis |
| CN108815117A (zh) * | 2018-08-23 | 2018-11-16 | 宁波蒙曼生物科技有限公司 | 一种镇痛药物组合物及其制备方法 |
| CN109930209B (zh) * | 2019-03-07 | 2022-02-15 | 华南理工大学 | 一种具高结晶度及长径比双膦酸盐晶体及其制备方法 |
| CN112707934A (zh) * | 2020-12-30 | 2021-04-27 | 华南理工大学 | 一种阿仑膦酸钙配合物及其制备方法 |
| CN114349786B (zh) * | 2021-12-28 | 2023-07-11 | 中国科学院上海硅酸盐研究所 | 阿仑膦酸钙超长纳米线及其制备方法和应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6201039B1 (en) * | 1993-09-21 | 2001-03-13 | The Penn State Research Foundation | Bone substitute composition comprising hydroxyapatite and a method of production therefor |
Family Cites Families (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5356887A (en) | 1990-01-31 | 1994-10-18 | Merck & Co., Inc. | Pharmaceutical compositions containing insoluble calcium salts of amino-hydroxybutylidene bisphoshonic acids |
| US5358941A (en) | 1992-12-02 | 1994-10-25 | Merck & Co., Inc. | Dry mix formulation for bisphosphonic acids with lactose |
| US5462932A (en) | 1994-05-17 | 1995-10-31 | Merck & Co., Inc. | Oral liquid alendronate formulations |
| ES2221019T3 (es) | 1996-10-31 | 2004-12-16 | Takeda Chemical Industries, Ltd. | Preparacion de liberacion mantenida. |
| EP1028712B1 (en) | 1997-09-19 | 2005-01-12 | Shire Laboratories Inc. | Solid solution beadlet |
| SE9703691D0 (sv) | 1997-10-10 | 1997-10-10 | Astra Ab | Pharmaceutical compositions |
| WO1999067809A1 (en) | 1998-06-24 | 1999-12-29 | Merck & Co., Inc. | Compositions and methods for inhibiting bone resorption |
| US6342249B1 (en) | 1998-12-23 | 2002-01-29 | Alza Corporation | Controlled release liquid active agent formulation dosage forms |
| US6706283B1 (en) | 1999-02-10 | 2004-03-16 | Pfizer Inc | Controlled release by extrusion of solid amorphous dispersions of drugs |
| US6677320B2 (en) | 2000-01-20 | 2004-01-13 | Hoffmann-La Roches Inc. | Parenteral bisphosphonate composition with improved local tolerance |
| KR100492110B1 (ko) * | 2000-05-05 | 2005-06-02 | 에프. 호프만-라 로슈 아게 | 비스포스폰산 또는 그의 염을 포함하는 피하 투여용겔-유사 약학 조성물 |
| US6350471B1 (en) | 2000-05-31 | 2002-02-26 | Pharma Pass Llc | Tablet comprising a delayed release coating |
| US6476006B2 (en) | 2000-06-23 | 2002-11-05 | Teva Pharmaceutical Industries, Ltd. | Composition and dosage form for delayed gastric release of alendronate and/or other bis-phosphonates |
| JP4161031B2 (ja) | 2000-10-31 | 2008-10-08 | 独立行政法人産業技術総合研究所 | 亜鉛含有リン酸カルシウム微粒子含有懸濁液または粒子溶媒混合系及び亜鉛欠乏症治療剤 |
| GB0029111D0 (en) | 2000-11-29 | 2001-01-10 | Novartis Ag | Organic compounds |
| US6558702B2 (en) | 2001-04-13 | 2003-05-06 | Alkermes Controlled Therapeutics, Inc. | Method of modifying the release profile of sustained release compositions |
| FR2836681B1 (fr) | 2002-03-04 | 2004-06-18 | Centre Nat Rech Scient | Compose phosphocalcique modifie, composition injectable le contenant |
| US7488496B2 (en) * | 2002-03-06 | 2009-02-10 | Christer Rosen | Effervescent compositions comprising bisphosphonates and methods related thereto |
| JP2007501241A (ja) | 2003-08-06 | 2007-01-25 | ローディア インコーポレイティド | 骨成長を促進する方法 |
| US7420000B2 (en) | 2003-09-10 | 2008-09-02 | University Of Southern California | Amino phosphonate and amino bis-phosphonate derivatives |
| US20050261250A1 (en) | 2004-05-19 | 2005-11-24 | Merck & Co., Inc., | Compositions and methods for inhibiting bone resorption |
| US8071574B2 (en) * | 2005-02-22 | 2011-12-06 | John Dennis Bobyn | Implant improving local bone formation |
-
2007
- 2007-06-25 US US11/768,181 patent/US8974801B2/en active Active
- 2007-12-13 MX MX2009006447A patent/MX2009006447A/es active IP Right Grant
- 2007-12-13 DK DK07862893.0T patent/DK2120585T3/da active
- 2007-12-13 EP EP12186963.0A patent/EP2548441B1/en active Active
- 2007-12-13 JP JP2009542815A patent/JP5492564B2/ja not_active Expired - Fee Related
- 2007-12-13 PT PT78628930T patent/PT2120585E/pt unknown
- 2007-12-13 RU RU2009128023/15A patent/RU2453316C2/ru not_active IP Right Cessation
- 2007-12-13 WO PCT/US2007/025569 patent/WO2008085281A1/en not_active Ceased
- 2007-12-13 BR BRPI0720605-4A2A patent/BRPI0720605A2/pt not_active IP Right Cessation
- 2007-12-13 PL PL12186963T patent/PL2548441T3/pl unknown
- 2007-12-13 DK DK12186963.0T patent/DK2548441T3/en active
- 2007-12-13 EP EP07862893A patent/EP2120585B1/en active Active
- 2007-12-13 PL PL07862893T patent/PL2120585T3/pl unknown
- 2007-12-13 ES ES07862893T patent/ES2396733T3/es active Active
- 2007-12-13 CA CA2673058A patent/CA2673058C/en active Active
- 2007-12-13 PT PT121869630T patent/PT2548441E/pt unknown
- 2007-12-13 CN CN200780047021.7A patent/CN101616591B/zh active Active
- 2007-12-13 SI SI200731112T patent/SI2120585T1/sl unknown
- 2007-12-13 ES ES12186963.0T patent/ES2524690T3/es active Active
-
2015
- 2015-02-13 US US14/622,749 patent/US20150157650A1/en not_active Abandoned
- 2015-02-13 US US14/622,746 patent/US20150157649A1/en not_active Abandoned
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6201039B1 (en) * | 1993-09-21 | 2001-03-13 | The Penn State Research Foundation | Bone substitute composition comprising hydroxyapatite and a method of production therefor |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2120585A4 (en) | 2011-11-23 |
| PL2120585T3 (pl) | 2013-03-29 |
| PT2120585E (pt) | 2013-01-15 |
| US20150157650A1 (en) | 2015-06-11 |
| PL2548441T3 (pl) | 2015-02-27 |
| EP2548441B1 (en) | 2014-08-27 |
| PT2548441E (pt) | 2014-11-27 |
| EP2120585A1 (en) | 2009-11-25 |
| RU2009128023A (ru) | 2011-01-27 |
| EP2120585B1 (en) | 2012-10-03 |
| CA2673058A1 (en) | 2008-07-17 |
| ES2524690T3 (es) | 2014-12-11 |
| BRPI0720605A2 (pt) | 2014-04-08 |
| US8974801B2 (en) | 2015-03-10 |
| SI2120585T1 (sl) | 2013-05-31 |
| CN101616591B (zh) | 2014-06-18 |
| CN101616591A (zh) | 2009-12-30 |
| US20080153784A1 (en) | 2008-06-26 |
| DK2548441T3 (en) | 2014-12-08 |
| JP5492564B2 (ja) | 2014-05-14 |
| MX2009006447A (es) | 2009-07-27 |
| US20150157649A1 (en) | 2015-06-11 |
| WO2008085281A1 (en) | 2008-07-17 |
| DK2120585T3 (da) | 2013-01-21 |
| CA2673058C (en) | 2015-11-24 |
| EP2548441A1 (en) | 2013-01-23 |
| ES2396733T3 (es) | 2013-02-25 |
| JP2010513483A (ja) | 2010-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK2548441T3 (en) | Long-term release of pharmaceutical composition containing aqueous slurry of bisphosphonate | |
| Adami et al. | Adverse effects of bisphosphonates: a comparative review | |
| RU2297229C2 (ru) | Фармацевтическое применение бисфосфонатов | |
| JP3062001B2 (ja) | 骨修復を促進することを意図した医薬組成物の調製のためのビスホスホン酸誘導体の使用および対応する医薬組成物 | |
| RU2465922C2 (ru) | Инъецируемый кальций-фосфатный цемент в форме апатита, высвобождающий ингибитор резорбции костной ткани | |
| EP0573604B1 (en) | Methods for the treatment of osteoporosis | |
| US5356887A (en) | Pharmaceutical compositions containing insoluble calcium salts of amino-hydroxybutylidene bisphoshonic acids | |
| JP2010513483A5 (enExample) | ||
| US20100144679A1 (en) | Medication kits and formulations for preventing, treating or reducing secondary fractures after previous fracture | |
| EP0449405B1 (en) | Use of bisphosphonic acids for the treatment of calcium metabolism disorders | |
| JP2003500352A (ja) | 血管形成を処置するためのビスホスホン酸の使用 | |
| Do et al. | Bisphosphonate-induced severe hypocalcemia-a case report | |
| WO2008116809A1 (en) | Pharmaceutical compositions comprising a bisphosphonate and vitamin d | |
| Brown et al. | Developments in the therapeutic applications of bisphosphonates | |
| US20060134190A1 (en) | Formulations of bisphosphonate drugs with improved bioavailability | |
| KR100385697B1 (ko) | 올파드로네이트를포함하는골체량동화성조성물 | |
| NZ250293A (en) | Fracture treatment using methanebisphosphonic acid derivatives and pharmaceutical compositions | |
| Sietsema et al. | Bisphosphonates in development for metabolic bone disease | |
| NZ510804A (en) | Use of bisphosphonic acid derivatives for preparing a medicine for treating lameness | |
| Pavkovic et al. | Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphanates | |
| Yeap | The Use of Bisphosphonates In Osteoporosis: A Review | |
| KR20210143382A (ko) | 탄소 형광 나노 입자-알렌드로네이트 복합체 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | The patent is invalid due to non-payment of fees |
Effective date: 20171214 |