WO2007099431A2 - An aqueous liquid pharmaceutical compositions of gatifloxacin - Google Patents
An aqueous liquid pharmaceutical compositions of gatifloxacin Download PDFInfo
- Publication number
- WO2007099431A2 WO2007099431A2 PCT/IB2007/000465 IB2007000465W WO2007099431A2 WO 2007099431 A2 WO2007099431 A2 WO 2007099431A2 IB 2007000465 W IB2007000465 W IB 2007000465W WO 2007099431 A2 WO2007099431 A2 WO 2007099431A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- aqueous liquid
- liquid pharmaceutical
- pharmaceutically acceptable
- pharmaceutical composition
- gatifloxacin
- Prior art date
Links
- 229960003923 gatifloxacin Drugs 0.000 title claims abstract description 48
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical group FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 title claims abstract description 47
- 239000007788 liquid Substances 0.000 title claims abstract description 42
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims description 66
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 54
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 27
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 17
- 239000003755 preservative agent Substances 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 16
- 239000004094 surface-active agent Substances 0.000 claims description 15
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 14
- 230000002708 enhancing effect Effects 0.000 claims description 14
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 14
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 13
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 13
- 239000004296 sodium metabisulphite Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 abstract description 6
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 210000001519 tissue Anatomy 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 238000001556 precipitation Methods 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 6
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000003078 antioxidant effect Effects 0.000 description 4
- 229960000686 benzalkonium chloride Drugs 0.000 description 4
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 4
- 230000009977 dual effect Effects 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000001509 sodium citrate Substances 0.000 description 4
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- -1 (±)- 1 -cyclopropyl- Chemical group 0.000 description 3
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000007794 irritation Effects 0.000 description 3
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 description 3
- 229940001584 sodium metabisulfite Drugs 0.000 description 3
- 239000008137 solubility enhancer Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- OVBJJZOQPCKUOR-UHFFFAOYSA-L EDTA disodium salt dihydrate Chemical compound O.O.[Na+].[Na+].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O OVBJJZOQPCKUOR-UHFFFAOYSA-L 0.000 description 2
- 208000023146 Pre-existing disease Diseases 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 230000001010 compromised effect Effects 0.000 description 2
- 231100000478 corneal permeability Toxicity 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 229960003376 levofloxacin Drugs 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 229960003702 moxifloxacin Drugs 0.000 description 2
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 description 2
- 229960001699 ofloxacin Drugs 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 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 description 1
- FGBGEKHVEJJJLT-LLVKDONJSA-N 1-cyclopropyl-7-[(3r)-3-ethylpyrrolidin-1-yl]-6-fluoro-8-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1[C@H](CC)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC FGBGEKHVEJJJLT-LLVKDONJSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 210000001742 aqueous humor Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940082649 blood substitutes and perfusion irrigating solutions Drugs 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 229940088515 ciloxan Drugs 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940124274 edetate disodium Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229940066153 iquix Drugs 0.000 description 1
- 239000013010 irrigating solution Substances 0.000 description 1
- 229960002422 lomefloxacin Drugs 0.000 description 1
- ZEKZLJVOYLTDKK-UHFFFAOYSA-N lomefloxacin Chemical compound FC1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNC(C)C1 ZEKZLJVOYLTDKK-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229960001180 norfloxacin Drugs 0.000 description 1
- 229940099980 ocuflox Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000006195 ophthalmic dosage form Substances 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 229940054534 ophthalmic solution Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229940067107 phenylethyl alcohol Drugs 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229940072132 quinolone antibacterials Drugs 0.000 description 1
- 229940112957 quixin Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940034215 vigamox Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940109235 zymar Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/724—Cyclodextrins
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/734—Alginic acid
-
- 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
- A61K9/0043—Nose
-
- 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
- A61K9/0046—Ear
Definitions
- the present invention relates to aqueous liquid pharmaceutical compositions that include gatifloxacin and pharmaceutically acceptable salts thereof.
- the invention also relates to processes for the preparation of the pharmaceutical compositions.
- Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent. Chemically, gatifloxacin is ( ⁇ )- 1 -cyclopropyl- ⁇ -fluoro- 1 ,4-dihydro-8-methoxy-7-(3- methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of Formula 1. Gatifloxacin is indicated for the treatment of infections due to susceptible strains of microorganisms of gram-positive bacteria and some gram-negative bacteria such as Haemophilus influenzae.
- U.S. Patent No. 6,333,045 discloses an aqueous liquid pharmaceutical composition of gatifloxacin for topical administration.
- the patent further points out that by incorporating disodium edetate into an aqueous liquid preparation containing gatifloxacin or its salt raises the corneal permeability of gatifloxacin and prevents precipitation of gatifloxacin crystals and coloration of gatifloxacin.
- U.S. Patent Application No. 20050009836 discloses ophthalmic compositions that include a quinolone compound and a polyhydric alcohol at a concentration that renders the composition substantially isoosmotic.
- EP 1,627,637 discloses an aqueous ophthalmic solution that includes a quinolone antimicrobial compound or salt thereof, a water-soluble vinyl polymeric compound and a water-soluble cellulose derivative.
- European Patent EP 275,515 and U.S. Patent No. 4,923,862 disclose aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salt thereof.
- US Patent No 6,716,830 disclose ophthalmic dosage forms of moxifloxacin or salt thereof in a concentration of 0.1% to 1% w/w and pharmaceutically acceptable vehicle.
- quinolone antibiotics to treat eye infections is known in the ophthalmic art.
- Several quinolone antibacterial compositions available in the market include gatifloxacin (Zymar®), Levofloxacin (Quixin® or Iquix®), Ciprofloxacin (Ciloxan®), Ofloxacin (Ocuflox®), Lomefloxacin (Lomeflox®), Moxifloxacin (Vigamox®) and Norfloxacin (available as Chibroxin®).
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and hydroxypropyl beta cyclodextrin (hereinafter referred as HP- ⁇ -CD).
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- the gatifloxacin may be present from about 0.01 to about 1.0% w/v. More particularly, it may be present from about 0.1 to 0.8% w/v, for example 0.3% w/v.
- HP- ⁇ -CD acts as a solubility enhancer component and further helps to prevent precipitation of gatifloxacin.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, and citric acid or a pharmaceutically acceptable salt thereof.
- Citric acid along with HP- ⁇ -CD acts as a permeability-enhancing component and provides high permeability to gatifloxacin.
- present invention provides a method for increasing corneal permeability.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-D-CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
- Sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and as an antioxidant.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and polyvinyl alcohol.
- Polyvinyl alcohol provides the increased bioavailability to gatifloxacin or its pharmaceutically acceptable salt thereof by prolonging the retention time.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and citric acid or a pharmaceutically acceptable salt thereof.
- Citric acid provides increased permeation to poorly permeable drug gatifloxacin.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and sodium metabisulphite.
- composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, and polyvinyl alcohol.
- Polyvinyl alcohol acts as a viscosity-increasing agent, and provides the increased bioavailability by prolonging the retention time.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, polyvinyl alcohol, and citric acid or a pharmaceutically acceptable salt thereof.
- Embodiments of the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, polyvinyl alcohol, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
- the composition may include one or more of the following features.
- the composition may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- the permeability enhancer component which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin or a pharmaceutically acceptable salt thereof.
- the presence of sodium mctabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
- the aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use.
- the compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
- aqueous liquid pharmaceutical compositions containing gatifloxacin or a pharmaceutically acceptable salt thereof which eliminates the problems of poor membrane permeability; precipitation of dosage form at physiological pH and coloration of the tissue and the formulation. This was achieved by formulating aqueous liquid pharmaceutical composition containing gatifloxacin or a salt thereof with one or more of HP- ⁇ -CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
- compositions may further include other pharmaceutically acceptable excipients.
- the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
- aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers.
- Gatifloxacin or a pharmaceutically acceptable salt thereof includes free base, salts, solvates, hydrates, polymorphs or mixtures thereof that may be used to prepare the compositions according to the invention.
- solubility enhancer component such as HP- ⁇ -CD not only prevents the precipitation of gatifloxacin or a pharmaceutically acceptable salt thereof, but also decreases the irritation associated with the said drug.
- the permeability enhancer component which includes citric acid or its salt thereof, provides a high permeation to an otherwise poor pe ⁇ neable drug like gatifloxacin.
- the presence of sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
- the aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use.
- the compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
- compositions are typically administered to the affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution or suspension, or a comparable amount of an ointment, gel or other solid or semisolid composition, one to four times per day.
- the compositions may also be formulated as irrigating solutions that are applied to the affected ophthalmic, otic or nasal tissues during surgical procedures.
- the amount of gatifloxacin or its salt to be formulated in the aqueous liquid pharmaceutical composition of the present invention is varied according to the degree of infection of a particular subject, but generally, the gatifloxacin is formulated within the range from about 0.01% to about 1.0% w/v. More particularly, it may be present from about 0.1 to about 0.8% w/v, for example 0.3% w/v of the composition.
- the concentration of gatifloxacin or its salt and all other excipients used in the composition is expressed in the %w/v of the composition i.e. certain mass of dry solute is dissolved in the fixed volume of the composition and then the concentration is expressed in terms of percentage.
- the ophthalmic, otic and nasal compositions of the present invention may have a pH in the range of 4.0 to 6.0.
- the ophthalmic compositions may also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water (“mOsm/kg”), but will preferably be about 300 mOsm/kg.
- the ophthalmic, otic and nasal pharmaceutical products are typically packaged in a multidose form.
- the preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. In general, such preservatives can be employed at an amount from about 0.001% to about 1.0% by weight of the composition. A surfactant or other appropriate co-solvent in the composition may enhance the solubility of the components of the present compositions.
- co-solvents or complex forming agents helps in achieving the desired results.
- co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrin, especially HP- ⁇ -CD, or other agents known to those skilled in the art.
- co-solvents can be employed at an amount from about 0.01% to about 5% by weight of the composition.
- HP- ⁇ -CD has a tendency to form inclusion complex with many drugs including gatifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of gatifloxacin can be further reduced based on complexation with HP- ⁇ -CD.
- viscosity enhancing agents to provide the compositions of the invention with viscosities greater than the viscosity of simple aqueous solutions is desirable to increase ocular absorption, and reduce irritability of the active compounds by the target tissues or increase the retention time in the eye, ear or nose.
- agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents known to those skilled in the art.
- Such agents can be employed at an amount from about 0.01% to about 2% by weight of the composition.
- solubility enhancer component which includes HP-D-CD, not only prevents the precipitation of gatifloxacin, but also decreases the irritation associated with the said drug.
- the viscosity-increasing agent which includes polyvinyl alcohol, provides the increased bioavailability by prolonging the retention time.
- the permeability enhancer component which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin.
- Citric acid or a pharmaceutically acceptable salt thereof comprises one or more of sodium citrate and the like.
- Sodium chloride used in the composition helps to maintain the required osmolality of the composition and also acts a buffering agent.
- Table 1 provides composition of batches of the present invention.
- Citric acid (0.08% w/v) and sodium citrate (0.18% w/v) were dissolved in water for injection.
- a blend of gatifloxacin (0.3% w/v) and HP- ⁇ -CD in concentration of 1-1.5% w/v was dissolved.
- a previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution.
- a previously dissolved solution of benzalkonium chloride in hot water was added.
- the pH was determined and it was adjusted to 4-6 using NaOH/HCl solution.
- the final volume was adjusted with water for injection.
- the resultant solution was aseptically filtered through 0.2 ⁇ filter, filled and packed in a suitable container and closure system.
- Table 2 provides composition of batches of the present invention.
- Table 3 provides composition of batches of the present invention.
- Citric acid (0.08% w/v) and sodium citrate (0.18%v) were dissolved in water for injection.
- a blend of gatifloxacin (0.3% w/v) and HP- ⁇ -CD in concentration of 1-1.5% w/v was dissolved.
- Polyvinyl alcohol was dissolved in prefiltered hot water under continuous stirring.
- a previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution.
- benzalkonium chloride in hot water was added.
- the pH was determined and it was adjusted to 4-6 using NaOH /HcI solution.
- the final volume was adjusted with water for injection.
- the resultant solution was aseptically filtered through 0.2 ⁇ filter, filled and packed in suitable container and closure system.
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Abstract
The present invention relates to aqueous liquid pharmaceutical compositions that include gatifloxacin and pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of the pharmaceutical compositions.
Description
AN AQUEOUS LIQUID PHARMACEUTICAL COMPOSITIONS OF
GATIFLOXACIN
Field of the Invention
The present invention relates to aqueous liquid pharmaceutical compositions that include gatifloxacin and pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of the pharmaceutical compositions.
Background of the Invention
Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent. Chemically, gatifloxacin is (±)- 1 -cyclopropyl-ό-fluoro- 1 ,4-dihydro-8-methoxy-7-(3- methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of Formula 1. Gatifloxacin is indicated for the treatment of infections due to susceptible strains of microorganisms of gram-positive bacteria and some gram-negative bacteria such as Haemophilus influenzae.
FORMULA I
U.S. Patent No. 6,333,045 discloses an aqueous liquid pharmaceutical composition of gatifloxacin for topical administration. The patent further points out that by incorporating disodium edetate into an aqueous liquid preparation containing gatifloxacin or its salt raises the corneal permeability of gatifloxacin and prevents precipitation of gatifloxacin crystals and coloration of gatifloxacin.
U.S. Patent Application No. 20050009836 discloses ophthalmic compositions that include a quinolone compound and a polyhydric alcohol at a concentration that renders the composition substantially isoosmotic.
European Patent Application No. EP 1,627,637 discloses an aqueous ophthalmic solution that includes a quinolone antimicrobial compound or salt thereof, a water-soluble vinyl polymeric compound and a water-soluble cellulose derivative.
European Patent EP 275,515 and U.S. Patent No. 4,923,862 disclose aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salt thereof. US Patent No 6,716,830 disclose ophthalmic dosage forms of moxifloxacin or salt thereof in a concentration of 0.1% to 1% w/w and pharmaceutically acceptable vehicle.
The use of quinolone antibiotics to treat eye infections is known in the ophthalmic art. Several quinolone antibacterial compositions available in the market include gatifloxacin (Zymar®), Levofloxacin (Quixin® or Iquix®), Ciprofloxacin (Ciloxan®), Ofloxacin (Ocuflox®), Lomefloxacin (Lomeflox®), Moxifloxacin (Vigamox®) and Norfloxacin (available as Chibroxin®).
It was noticed from U.S. Patent No. 6,333,045 that gatifloxacin aqueous liquid pharmaceutical compositions have poor membrane permeability. Also, there exist a problem of precipitation at the physiological pH and coloration of the tissue and formulation. The present invention addresses and overcomes these problems.
Summary of the Invention
Li one aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and hydroxypropyl beta cyclodextrin (hereinafter referred as HP-β-CD).
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The gatifloxacin may be present from about 0.01 to about 1.0% w/v. More particularly, it may be present from about 0.1 to 0.8% w/v, for example 0.3% w/v. HP-β-CD acts as a solubility enhancer component and further helps to prevent precipitation of gatifloxacin.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- β -CD, and citric acid or a pharmaceutically acceptable salt thereof.
Citric acid along with HP-β-CD acts as a permeability-enhancing component and provides high permeability to gatifloxacin. Thus present invention provides a method for increasing corneal permeability.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-D-CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
Sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and as an antioxidant.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable
excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and polyvinyl alcohol.
Polyvinyl alcohol provides the increased bioavailability to gatifloxacin or its pharmaceutically acceptable salt thereof by prolonging the retention time.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
hi another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and citric acid or a pharmaceutically acceptable salt thereof.
Citric acid provides increased permeation to poorly permeable drug gatifloxacin.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
hi another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and sodium metabisulphite.
Sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD, and polyvinyl alcohol.
Polyvinyl alcohol, acts as a viscosity-increasing agent, and provides the increased bioavailability by prolonging the retention time.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD, polyvinyl alcohol, and citric acid or a pharmaceutically acceptable salt thereof.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD, polyvinyl alcohol, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The permeability enhancer component, which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin or a pharmaceutically acceptable salt thereof. The presence of sodium mctabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
The aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use. The compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description of the Invention
The inventors have now developed aqueous liquid pharmaceutical compositions containing gatifloxacin or a pharmaceutically acceptable salt thereof, which eliminates the problems of poor membrane permeability; precipitation of dosage form at physiological pH and coloration of the tissue and the formulation. This was achieved by formulating aqueous liquid pharmaceutical composition containing gatifloxacin or a salt
thereof with one or more of HP-β-CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
The compositions may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers.
Gatifloxacin or a pharmaceutically acceptable salt thereof includes free base, salts, solvates, hydrates, polymorphs or mixtures thereof that may be used to prepare the compositions according to the invention.
The present inventors found that the solubility enhancer component such as HP-β-CD not only prevents the precipitation of gatifloxacin or a pharmaceutically acceptable salt thereof, but also decreases the irritation associated with the said drug. The permeability enhancer component, which includes citric acid or its salt thereof, provides a high permeation to an otherwise poor peπneable drug like gatifloxacin. The presence of sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
The aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use. The compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
The compositions are typically administered to the affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution or suspension, or a
comparable amount of an ointment, gel or other solid or semisolid composition, one to four times per day. However, the compositions may also be formulated as irrigating solutions that are applied to the affected ophthalmic, otic or nasal tissues during surgical procedures.
hi general, the amount of gatifloxacin or its salt to be formulated in the aqueous liquid pharmaceutical composition of the present invention is varied according to the degree of infection of a particular subject, but generally, the gatifloxacin is formulated within the range from about 0.01% to about 1.0% w/v. More particularly, it may be present from about 0.1 to about 0.8% w/v, for example 0.3% w/v of the composition.
The concentration of gatifloxacin or its salt and all other excipients used in the composition is expressed in the %w/v of the composition i.e. certain mass of dry solute is dissolved in the fixed volume of the composition and then the concentration is expressed in terms of percentage.
The ophthalmic, otic and nasal compositions of the present invention may have a pH in the range of 4.0 to 6.0. The ophthalmic compositions may also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water ("mOsm/kg"), but will preferably be about 300 mOsm/kg.
The ophthalmic, otic and nasal pharmaceutical products are typically packaged in a multidose form. The preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. In general, such preservatives can be employed at an amount from about 0.001% to about 1.0% by weight of the composition.
A surfactant or other appropriate co-solvent in the composition may enhance the solubility of the components of the present compositions. In case of gatifloxacin due to its poor water solubility, use of co-solvents or complex forming agents helps in achieving the desired results. Such co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrin, especially HP-β-CD, or other agents known to those skilled in the art. In general, such co-solvents can be employed at an amount from about 0.01% to about 5% by weight of the composition. HP-β-CD has a tendency to form inclusion complex with many drugs including gatifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of gatifloxacin can be further reduced based on complexation with HP-β-CD.
The use of viscosity enhancing agents to provide the compositions of the invention with viscosities greater than the viscosity of simple aqueous solutions is desirable to increase ocular absorption, and reduce irritability of the active compounds by the target tissues or increase the retention time in the eye, ear or nose. Such agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents known to those skilled in the art. Such agents can be employed at an amount from about 0.01% to about 2% by weight of the composition.
It was also found by the present inventors that the solubility enhancer component, which includes HP-D-CD, not only prevents the precipitation of gatifloxacin, but also decreases the irritation associated with the said drug. The viscosity-increasing agent, which includes polyvinyl alcohol, provides the increased bioavailability by prolonging the retention time. The permeability enhancer component, which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin.
Citric acid or a pharmaceutically acceptable salt thereof comprises one or more of sodium citrate and the like.
Sodium chloride used in the composition helps to maintain the required osmolality of the composition and also acts a buffering agent.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 ;
Table 1 provides composition of batches of the present invention.
Table 1
Procedure: Citric acid (0.08% w/v) and sodium citrate (0.18% w/v) were dissolved in water for injection. To the clear solution so obtained, a blend of gatifloxacin (0.3% w/v)
and HP-β-CD in concentration of 1-1.5% w/v was dissolved. A previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution. To this, a previously dissolved solution of benzalkonium chloride in hot water was added. The pH was determined and it was adjusted to 4-6 using NaOH/HCl solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2μ filter, filled and packed in a suitable container and closure system.
Example 2:
Table 2 provides composition of batches of the present invention.
Table 2
Procedure: Polyvinyl alcohol was dissolved in prefiltered hot water under continuous stirring. Citric acid (0.08% w/v) and sodium citrate (0.18% w/v) were dissolved in hot water for injection in a separate vessel. To the clear solution so obtained, a blend of gatifloxacin (0.3% w/v) was dissolved. A previously stirred solution of sodium chloride (0.8% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution. To
this, the polyvinyl alcohol solution was added. To this, a previously dissolved solution of benzalkonium chloride in hot water was added. The pH was determined and it was adjusted to 4-6 using sodium hydroxide or hydrochloric acid solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2μ filter, filled and packed in suitable container and closure system.
Example 3:
Table 3 provides composition of batches of the present invention.
Table 3
Procedure: Citric acid (0.08% w/v) and sodium citrate (0.18%v) were dissolved in water for injection. To the clear solution so obtained, a blend of gatifloxacin (0.3% w/v) and HP-β-CD in concentration of 1-1.5% w/v was dissolved. Polyvinyl alcohol was dissolved in prefiltered hot water under continuous stirring. A previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution. To this, a previously dissolved solution of benzalkonium chloride in hot water
was added. The pH was determined and it was adjusted to 4-6 using NaOH /HcI solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2μ filter, filled and packed in suitable container and closure system.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
Claims
We claim:
1 An aqueous liquid pharmaceutical composition comprising gatifloxacin or a pharmaceutically acceptable salt thereof and HP-β-CD.
2 The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof.
3 The aqueous liquid pharmaceutical composition according to claim 2, wherein the composition further comprises sodium metabisulphite.
4 The aqueous liquid pharmaceutical composition according to claim 1, wherein the HP-β-CD is present in a concentration of about 1.0% to about 1.5% w/v.
5 The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
6 The aqueous liquid pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable excipients comprise one or more of preservatives, surfactants/co-solvents, and viscosity enhancing agents.
7 The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition is having osmolality of about 200 mθsm/kg to about 400 mθsm/kg.
8 An aqueous liquid pharmaceutical composition comprising gatifloxacin or a pharmaceutically acceptable salt thereof and polyvinyl alcohol.
9 The aqueous liquid pharmaceutical composition according to claim 8, wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof.
10 The aqueous liquid pharmaceutical composition according to claim 9, wherein the composition further comprises sodium metabisulphite.
11 The aqueous liquid pharmaceutical composition according to claims 8, wherein the polyvinyl alcohol is present in a concentration of about 0.2% w/v to about 0.4%w/v.
12 The aqueous liquid pharmaceutical composition according to claim 8, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
13 The aqueous liquid pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable excipients comprise one or more of preservatives, surfactants/co-solvents, and viscosity enhancing agents.
14 The aqueous liquid pharmaceutical composition according to claim 8, wherein the composition is having osmolality of about 200 mOsm/kg to about 400 mθsm/kg.
15 An aqueous liquid pharmaceutical composition comprising gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD and polyvinyl alcohol.
16 The aqueous liquid pharmaceutical composition according to claim 15, wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof.
17 The aqueous liquid pharmaceutical composition according to claim 16, wherein the composition further comprises sodium metabisulphite.
18 The aqueous liquid pharmaceutical composition according to claim 15, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
19 The aqueous liquid pharmaceutical composition according to claim 18, wherein the pharmaceutically acceptable excipients comprise one or more of preservatives, surfactants/co-solvents, and viscosity enhancing agents.
20 The aqueous liquid pharmaceutical composition according to claim 15, wherein the composition is having osmolality of about 200 mOsm/kg to about 400 mOsm/kg.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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IN450/MUM/06 | 2006-02-28 | ||
IN450MU2006 | 2006-02-28 | ||
IN459MU2006 | 2006-03-28 | ||
IN458/MUM/06 | 2006-03-28 | ||
IN459/MUM/06 | 2006-03-28 | ||
IN458MU2006 | 2006-03-28 |
Publications (2)
Publication Number | Publication Date |
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WO2007099431A2 true WO2007099431A2 (en) | 2007-09-07 |
WO2007099431A3 WO2007099431A3 (en) | 2008-02-07 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/IB2007/000465 WO2007099431A2 (en) | 2006-02-28 | 2007-02-27 | An aqueous liquid pharmaceutical compositions of gatifloxacin |
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WO (1) | WO2007099431A2 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004087043A2 (en) * | 2003-02-21 | 2004-10-14 | Sun Pharmaceutical Industries Limited | Stable ophthalmic formulation containing an antibiotic and a corticosteroid |
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2007
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2004087043A2 (en) * | 2003-02-21 | 2004-10-14 | Sun Pharmaceutical Industries Limited | Stable ophthalmic formulation containing an antibiotic and a corticosteroid |
Also Published As
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WO2007099431A3 (en) | 2008-02-07 |
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