CN101278937A - Clear eye lotion containing latanoprost as effective ingredient - Google Patents
Clear eye lotion containing latanoprost as effective ingredient Download PDFInfo
- Publication number
- CN101278937A CN101278937A CNA2008100902128A CN200810090212A CN101278937A CN 101278937 A CN101278937 A CN 101278937A CN A2008100902128 A CNA2008100902128 A CN A2008100902128A CN 200810090212 A CN200810090212 A CN 200810090212A CN 101278937 A CN101278937 A CN 101278937A
- Authority
- CN
- China
- Prior art keywords
- latanoprost
- bak
- concentration
- preparation
- eye drop
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- GGXICVAJURFBLW-CEYXHVGTSA-N latanoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1CC[C@@H](O)CCC1=CC=CC=C1 GGXICVAJURFBLW-CEYXHVGTSA-N 0.000 title claims abstract description 70
- 229960001160 latanoprost Drugs 0.000 title claims abstract description 70
- 239000004615 ingredient Substances 0.000 title description 3
- 235000002911 Salvia sclarea Nutrition 0.000 title 1
- 244000182022 Salvia sclarea Species 0.000 title 1
- 239000006210 lotion Substances 0.000 title 1
- 239000000203 mixture Substances 0.000 claims abstract description 39
- 229960000686 benzalkonium chloride Drugs 0.000 claims abstract description 18
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000002360 preparation method Methods 0.000 claims description 47
- 239000003889 eye drop Substances 0.000 claims description 37
- 241001249696 Senna alexandrina Species 0.000 claims description 27
- 239000007951 isotonicity adjuster Substances 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 230000002421 anti-septic effect Effects 0.000 claims description 8
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 5
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 5
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 238000009472 formulation Methods 0.000 abstract description 17
- 239000004480 active ingredient Substances 0.000 abstract 1
- 229940110775 latanoprost ophthalmic solution Drugs 0.000 abstract 1
- 229940054534 ophthalmic solution Drugs 0.000 abstract 1
- 239000002997 ophthalmic solution Substances 0.000 abstract 1
- 239000003755 preservative agent Substances 0.000 abstract 1
- 230000002335 preservative effect Effects 0.000 abstract 1
- 239000012929 tonicity agent Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 67
- 239000000243 solution Substances 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 37
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 19
- 235000019799 monosodium phosphate Nutrition 0.000 description 19
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 19
- 235000011121 sodium hydroxide Nutrition 0.000 description 16
- -1 alkali metal salt Chemical class 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 15
- 239000011780 sodium chloride Substances 0.000 description 15
- 230000001186 cumulative effect Effects 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000007864 aqueous solution Substances 0.000 description 11
- 239000004094 surface-active agent Substances 0.000 description 11
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical class CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 10
- 238000002156 mixing Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000011521 glass Substances 0.000 description 8
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- 229920001214 Polysorbate 60 Polymers 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000233866 Fungi Species 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 230000003260 anti-sepsis Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 229940012356 eye drops Drugs 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 125000006177 alkyl benzyl group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 229910021538 borax Inorganic materials 0.000 description 2
- 208000021921 corneal disease Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 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 2
- 235000011083 sodium citrates Nutrition 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 235000010339 sodium tetraborate Nutrition 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical group OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 102000000471 Prostaglandin F receptors Human genes 0.000 description 1
- 108050008995 Prostaglandin F receptors Proteins 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229920013820 alkyl cellulose Polymers 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000002526 disodium citrate Substances 0.000 description 1
- 235000019262 disodium citrate Nutrition 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
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229920001038 ethylene copolymer Polymers 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229920001246 polyethylene glycol monostearate Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WUUHFRRPHJEEKV-UHFFFAOYSA-N tripotassium borate Chemical compound [K+].[K+].[K+].[O-]B([O-])[O-] WUUHFRRPHJEEKV-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
An object of the present invention is to provide better formulations of a latanoprost ophthalmic solution. The present invention provides a clear ophthalmic solution comprising latanoprost as an active ingredient and benzalkonium chloride as a preservative wherein white turbidity due to a change of formulation is prevented by adding non-ionic tonicity agent.
Description
The application is to be JIUYUE in 2003 8 days, application number the dividing an application for the application of " the clear and bright eye drop that contains effective composition latanoprost " that be 03823948.5 (international application no is PCT/JP2003/011402), denomination of invention the applying date.
Technical field
The present invention relates to a kind of clear and bright and stable eye drop that contains treatment glaucoma medicine latanoprost as effective ingredient.
Background technology
Latanoprost is a kind of with chemistry isopropyl (Z) by name-7[(1R, 2R, 3R, 5S) 3,5-dihydroxy-2-[(3R)-3-hydroxyl-penta phenyl] cyclopenta] the 5-enanthic acid is the glaucomatous prostaglandin type of the treatment medicine of representative.Latanoprost is a kind of optionally FP receptor stimulating agent and reduces intraocular pressure (referring to, Japan Patent No.2721414 for example) by the outflow that promotes aqueous body fluid.The route of administration of latanoprost is an eye drip, and in the commercial eye drop (trade name: the smooth eye drop of hila) that obtains to contain latanoprost 0.005%.
One object of the present invention is to provide a kind of latanoprost eye drop better preparation.
As the antiseptic of eye drop, benzalkonium chloride (being abbreviated as " BAK " hereinafter) is most widely used general from the angle of effect and its similar (purposes).Yet although BAK has good antisepsis, BAK can cause disorder of cornea when it is used with high concentration.Therefore, when BAK joins eye drop, then wish to reduce as much as possible its concentration.
BAK described in the description refers to contain [C
6H
5CH
2N (CH
3)
2R] the compound product of the represented chemical constitution of Cl, wherein alkyl (representing with R) is C
8H
12-C
18H
37
BAK is defined as follows in Japan in the US and European pharmacopeia:
Pharmacopeia of Japan: BAK is by [C
6H
5CH
2N (CH
3)
2R] Cl represents that wherein R is meant C
8H
12-C
18H
37And mainly comprise C
12H
25And C
14H
29
American Pharmacopeia: BAK is a kind of by [C
6H
5CH
2N (CH
3)
2R] the alkyl benzyl dimethyl ammonium chloride mixture represented of Cl.Wherein R be all or some than C
8H
17High-grade alkyl functional group's mixture also mainly comprises C
12H
25, C
14H
29And C
16H
33
European Pharmacopoeia: BAK is a kind of mixture of alkyl benzyl dimethyl ammonium chloride, and wherein alkyl has C
8To C
18Chain length.
On the other hand, add usually isotonic agent in the eye drop to keep isotonicity and to be example with the alkali metal salt example of inorganic salt such as sodium chloride with as the alkali salt of magnesium chloride.
Further, add usually buffer in the eye drop preventing the variation of pH, and with as the inorganic salt of sodium phosphate, sodium borate with as sodium acetate, the organic salt of sodium citrate and sodium carbonate is example.
All comprise isotonic agent and buffer agent in the commercially available latanoprost eye drop.
The present invention prepares and has studied the latanoprost eye drop of the additive that contains these extensive uses.
As a result, astoundingly it be proved to be 0.015% or the BAK of higher concentration in do not find white casse, but 0.01% or the BAK of lower concentration in discovery is arranged.That is because hydrophobic latanoprost and BAK have formed a kind of complex, and simultaneously because the salt caused salting out of additive for example, latanoprost-BAK complex is precipitated.The present invention has disclosed should the fact, beat allly is, is low to moderate 0.01% or this complex precipitation not when lower up to BAK concentration.Though commercially available latanoprost eye drop (trade name: the smooth eye drop of hila) contain 0.02% BAK, do not produce the problem of white casse.Yet as mentioned above, although BAK is a kind of good antiseptic, it can cause disorder of cornea when using with high concentration.Therefore, when BAK joins in the eye drop, then wish to reduce as much as possible its concentration.
Detailed Description Of The Invention
At first research prevents the various additives of white casse, and the inventor finds and can prevent white casse by adding surfactant.
Find that by the further investigation that the kind of being absorbed in BAK is finished the mixing cpd that can not adopt the above-mentioned chemical constitution form that contains 8 to 18 carbon atom alkyls to represent occurs but the BAK that adopts alkyl to contain 12 carbon atoms can prevent white casse.
Further, the present invention considers that the use of salt such as isotonic agent can cause white casse and is absorbed in this isotonic agent and finishes accurate research.As a result, find to adopt the nonionic isotonic agent can prevent white casse as isotonic agent.
That is, found to obtain to contain the clear and bright eye drop of effective composition latanoprost and antiseptic benzalkonium chloride, wherein adopted at least aly to be selected from following 1) to 3) method prevent to change the white casse that causes by preparation;
1) add surfactant,
2) adopt by formula [C
6H
5CH
2N (CH
3)
2R] benzalkonium chloride of Cl (wherein R is the alkyl that contains 12 carbon atoms) expression do antiseptic and
3) add the nonionic isotonic agent as isotonic agent.
Above-mentioned three kinds of modes can separately or be share.
Preferred 0.001 to 0.01% (W/V) of the concentration of the effective ingredient latanoprost of eye drop of the present invention, especially preferred 0.005% (W/V).
First method of the present invention is to add surfactant.When adding surfactant, can not rely on the isotonic agent and the BAK that are adopted, prevent the clear and bright latanoprost eye drop of white casse.
The example of surfactant is a polyoxyethylene sorbitan monoleate, polyoxyethylene hydrogenated Oleum Ricini 60, polyoxy 35 Oleum Ricini, the polyglycol monostearate ester, macrogol (macrogol) 4000, lecithin, sucrose ester, polyoxyethylene alkyl ether, the polyoxy stearate, polyoxyethylene polyoxypropylene glycol and analog thereof, preferred polyoxyethylene sorbitan monoleate, polyoxyethylene hydrogenated Oleum Ricini 60, polyoxy 35 Oleum Ricini.Surfactant concentrations preferred 0.001 to 0.5%.
Second method of the present invention is to adopt [C
6H
5CH
2N (CH
3)
2R] benzalkonium chloride of Cl (wherein R is the alkyl that contains 12 carbon atoms) structural formula representative makes antiseptic.(be abbreviated as " BAK-C hereinafter at the benzalkonium chloride that contains 12 carbon atoms described in the description
12") refer to from [C
6H
5CH
2N (CH
3)
2R] benzalkonium chloride represented of Cl chemical structural formula, and its alkyl (representing with R in the structural formula) is C
12H
25
Adopt BAK-C
12Make antiseptic and can not rely on the isotonic agent that is adopted, prevent the clear and bright latanoprost eye drop of white casse.
Adopt commercially available BAK-C
12BAK-C
12Preferred 0.01% (W/V) of concentration or lower.Cross when low when BAK concentration, can not show enough antisepsises.Therefore, preferred BAK concentration is in the scope of 0.003 to 0.01 (W/V).
The third method of the present invention is to add the nonionic isotonic agent as isotonic agent.Adopt the nonionic isotonic agent can not rely on the BAK that is adopted, prevent the clear and bright latanoprost eye drop of white casse.When using the nonionic isotonic agent, can reduce the total amount of salt in the eye drop.As a result, the influence of salting out reduces, and prevents white casse by this.
The nonionic isotonic agent can be any material that is generally used for eye drop, and especially with glycerol, mannitol, Polyethylene Glycol, propylene glycol, trehalose, sucrose and analog thereof.The concentration of nonionic isotonic agent can be adjusted to every kind of material can isoosmotic concentration.
By adding a kind of pH buffer, a kind of pH regulator agent, a kind of solubilizing agent or a kind of viscosifier can at random prepare eye drop of the present invention.The example of PH buffer is as sodium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium phosphate, the phosphate of potassium dihydrogen phosphate and dipotassium hydrogen phosphate; As the borate of sodium borate and potassium borate, as the sal limonis of sodium citrate and disodium citrate with as the carbonate of sodium carbonate and sodium bicarbonate.The example of PH regulator is a hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide and analog thereof.The example of cosolvent is a polyoxyethylene sorbitan monoleate, polyoxyethylene hydrogenated Oleum Ricini 60, macrogol 4000 and analog thereof.The example of viscosifier is hydroxypropyl alkyl methyl celluloses, hydroxypropyl alkylcellulose, polyvinyl alcohol, carboxyl ethylene copolymer, polyvinylpyrrolidone and analog thereof.
In first and second kinds of methods, can add as sodium chloride, potassium chloride, the salt of calcium chloride or magnesium chloride is as isotonic agent.
Eye drop pH of the present invention preferably is adjusted to 3 to 8, and more preferably 4 to 7.
Eye drop of the present invention can adopt the prepared of extensive use.
Realize optimal mode of the present invention
Method 1) embodiment
Embodiment 1-1
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), sodium chloride (0.8g), polyoxyethylene sorbitan monoleate (0.01g) and benzalkonium chloride (0.01g) are regulated pH to 6.7, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 1-2
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), sodium chloride (0.8g), polyoxyethylene hydrogenated Oleum Ricini 60 (0.01g) and benzalkonium chloride (0.01g) are regulated pH to 6.7, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 1-3
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), sodium chloride (0.8g), polyoxy 35 Oleum Ricini 60 (0.01g) and benzalkonium chloride (0.01g) are regulated pH to 6.7, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Method 2) embodiment
Embodiment 2-1
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), sodium chloride (0.8g), polyoxyethylene hydrogenated Oleum Ricini 60 (0.01g) and BAK-C
12(0.01g), regulate pH to 6.7, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution with the 1N sodium hydrate aqueous solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 2-2
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), sodium chloride (0.8g), and BAK-C
12(0.005g), regulate pH to 6.7, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution with the 1N sodium hydrate aqueous solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Method 3) embodiment
Embodiment 3-1
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), thick glycerol (2.3g) and BAK (0.01g) regulate pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 3-2
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), mannitol (4.5g) and BAK (0.01g) regulate pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 3-3
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), PEG400 (8.0g) and BAK (0.01g) regulate pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 3-4
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), propylene glycol (2.0g) and BAK (0.01g) regulate pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Embodiment 3-5
Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water (about 90ml), trehalose (9.0g) and BAK (0.01g) regulate pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.
Experiment 1:
The mensuration of latanoprost residual ratio and the observation of outward appearance
1) is prepared as follows Comparative formulation 1 to 4.
In the 100ml glass beaker, put into pure water (about 90ml).Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water, sodium chloride (0.9g) is regulated pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.Add water for injection in the solution adjusted volume to 100ml.The accurate latanoprost solution of putting into 10ml in teat glass wherein adds 50,100,100 or 1% the BAK solution (alkyl R contains the mixing cpd of 12,14 and 16 carbon atoms in above chemical structural formula) of 200 μ l, and with its mixing.These preparations are as shown in table 1.
2) be prepared as follows preparation 1 to 3.
In the 100ml glass beaker, put into pure water (about 90ml).Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water, sodium chloride (0.9g) and various surfactant, its concentration separately is as shown in table 2.Regulate pH to 6.7 with sodium hydrate aqueous solution or dilute hydrochloric acid, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.Add water for injection in the solution adjusted volume to 100ml.The accurate latanoprost solution of putting into 10ml in teat glass wherein adds 1% the BAK solution (alkyl R contains the mixing cpd of 12,14 and 16 carbon atoms in above chemical structural formula) of 100 μ l, and with its mixing.These preparations are as shown in table 2.
3) be prepared as follows preparation 4 and 5.
In the 100ml glass beaker, put into pure water (about 90ml).Dissolving crystallized sodium dihydrogen phosphate (0.2g) in pure water, sodium chloride (0.9g) is regulated pH to 6.7 with the 1N sodium hydrate aqueous solution, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.Add water for injection in the solution adjusted volume to 100ml.The accurate latanoprost solution of putting into 10ml in teat glass wherein adds 1% the BAK-C of 50 or 100 μ l
12Solution, and with its mixing.These preparations are as shown in table 3.
4) be prepared as follows preparation 6 to 10.
In the 100ml glass beaker, put into pure water (about 90ml).Dissolving crystallized sodium dihydrogen phosphate (0.2g) and various nonionic isotonic agent are so that various concentration value as shown in table 4 in pure water, regulate pH to 6.7 with sodium hydrate aqueous solution or dilute hydrochloric acid, and the adding pure water makes that cumulative volume is that 100ml produces a kind of carrier in solution.Carrier (100ml) joins latanoprost (5mg), and stirs the mixture when about 80 ℃ of heating in water bath latanoprost is dissolved in carrier.Solution temperature returns to room temperature, and determines that subsequently pH is 6.7.Add water for injection in the solution adjusted volume to 100ml.The accurate latanoprost solution of putting into 10ml in teat glass wherein adds 1% the BAK solution (alkyl R contains the mixing cpd of 12,14 and 16 carbon atoms in above chemical structural formula) of 100 μ l, and with its mixing.These preparations are as shown in table 4.
5) observe outward appearance by every kind of solution of method for preparing, and in 25ml mixings flask every kind of solution of accurate extraction 1ml.Filter membrane with 0.22-μ m filters 9 milliliters of every kind of rest solution.
6) adopt high effective liquid chromatography for measuring to filter the concentration of latanoprost in the solution of front and back, and calculate residual ratio.
Table 1
Comparative formulation 1 | Comparative formulation 2 | Comparative formulation 3 | Comparative formulation 4 | |
Latanoprost | 0.005 | 0.005 | 0.005 | 0.005 |
The crystallization sodium dihydrogen phosphate | 0.2 | 0.2 | 0.2 | 0.2 |
Sodium chloride | 0.9 | 0.9 | 0.9 | 0.9 |
BAK | 0.02 | 0.015 | 0.01 | 0.005 |
Dilute hydrochloric acid | q.s | q.s | q.s | q.s |
Sodium hydroxide | q.s | q.s | q.s | q.s |
Pure water | q.s | q.s | q.s | q.s |
(unit in the table: % (W/V), q.s: capacity)
Table 2
Preparation 1 | Preparation 2 | Preparation 3 | |
Latanoprost | 0.005 | 0.005 | 0.005 |
The crystallization sodium dihydrogen phosphate | 0.2 | 0.2 | 0.2 |
Sodium chloride | 0.9 | 0.9 | 0.9 |
BAK | 0.01 | 0.01 | 0.01 |
Polyoxyethylene sorbitan monoleate | 0.01 | - | - |
Polyoxyethylene hydrogenated Oleum Ricini 60 | - | 0.01 | - |
Polyoxy 35 Oleum Ricini | - | - | 0.01 |
Dilute hydrochloric acid | q.s | q.s | q.s |
Sodium hydroxide | q.s | q.s | q.s |
Pure water | q.s | q.s | q.s |
(unit in the table: % (W/V), q.s: capacity)
Table 3
Preparation 4 | Preparation 5 | |
Latanoprost | 0.005 | 0.005 |
The crystallization sodium dihydrogen phosphate | 0.2 | 0.2 |
Sodium chloride | 0.9 | 0.9 |
BAK C 12 | 0.01 | 0.005 |
Dilute hydrochloric acid | q.s | q.s |
Sodium hydroxide | q.s | q.s |
Pure water | q.s | q.s |
(unit in the table: % (W/V), q.s: capacity)
Table 4
Preparation 6 | Preparation 7 | Preparation 8 | Preparation 9 | Preparation 10 | |
Latanoprost | 0.005 | 0.005 | 0.005 | 0.005 | 0.005 |
The crystallization sodium dihydrogen phosphate | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
BAK | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
Thick glycerol | 2.5 | ||||
Mannitol | 5 | ||||
PEG400 | 8.5 | ||||
Propylene glycol | 2.1 | ||||
Trehalose | 9.25 | ||||
Dilute hydrochloric acid | q.s | q.s | q.s | q.s | q.s |
Sodium hydroxide | q.s | q.s | q.s | q.s | q.s |
Pure water | q.s | q.s | q.s | q.s | q.s |
(unit in the table: % (W/V), q.s: capacity)
The result
The outward appearance observed result and the residual ratio of table 5 expression Comparative formulation 1 to 4 are measured.Contain 0.02% or the Comparative formulation 1 and 2 of 0.015%BAK join latanoprost, outward appearance is a water white transparency, and residual ratio is 96.8 to 99.4%.That is to say, preparation does not change.Yet, contain 0.01% or the Comparative formulation 3 and 4 of 0.005%BAK in observe white casse, and residual ratio reduces.That is to say, preparation changes.
The outward appearance observed result of table 6 expression preparation 1 to 3 (method 1) and residual ratio are measured.In Comparative formulation 3 and 4, observe white casse, and residual ratio reduces.On the contrary, contain in the preparation 1 to 3 of surfactant and do not find white casse, and residual ratio keeps high value, that is: 97.2 to 99.8%.These results show that surfactant prevents that preparation from changing, and obtains stable and clear and bright eye drop by this when adding surfactant in the preparation that contains latanoprost and BAK.
The outward appearance observed result of table 7 expression preparation 4 to 5 (method 2) and residual ratio are measured.Adopt the Comparative formulation 3 and 4 of BAK, find white casse, and residual ratio reduces.On the contrary, containing BAKC
12Substitute in the preparation 4 and 5 of BAK, do not find white casse, and residual ratio is 97.3 to 98.2%.That is to say, preparation does not change.These results show the BAKC that substitutes BAK when adding
12In the preparation that contains latanoprost, BAKC
12Prevent that preparation from changing, and obtain stable and clear and bright eye drop by this.
The outward appearance observed result and the residual ratio of table 8 expression preparation 6 to 10 are measured.Adopt the Comparative formulation 3 and 4 of sodium chloride, find white casse, and residual ratio reduces as isotonic agent.On the contrary, in the preparation 6 to 10 that contains the alternative sodium chloride of nonionic isotonic agent, do not find white casse, and residual ratio is 94.6 to 98.6%.That is to say, preparation does not change.These results show that this agent prevents that preparation from changing, and obtains stable and clear and bright eye drop by this when adding isotonic agent in the preparation that contains latanoprost and BAK.
Table 5
Comparative formulation 1 | Comparative formulation 2 | Comparative formulation 3 | Comparative formulation 4 | |
Outward appearance | Water white transparency | Water white transparency | White casse | White casse |
Residual ratio (%) | 99.4 | 96.8 | 67.3 | 83.5 |
Table 6
Preparation 1 | Preparation 2 | Preparation 3 | |
Outward appearance | Water white transparency | Water white transparency | Water white transparency |
Residual ratio (%) | 99.8 | 98.0 | 97.2 |
Table 7
Preparation 4 | Preparation 5 | |
Outward appearance | Water white transparency | Water white transparency |
Residual ratio (%) | 97.3 | 98.2 |
Table 8
Preparation 6 | Preparation 7 | Preparation 8 | Preparation 9 | Preparation 10 | |
Outward appearance | Water white transparency | Water white transparency | Water white transparency | Water white transparency | Water white transparency |
Residual ratio (%) | 98.6 | 96.0 | 94.6 | 98.2 | 96.2 |
Experiment 2: the antimicrobial detection of tiring
Correct the described antimicrobial of the version detection method of tiring according to Pharmacopeia of Japan the 13 and finish the foregoing description 1-1, the detection of tiring of the antimicrobial of 2-1 and 3-1.
Represent testing result in the table 9.Under the situation of antibacterial, in any embodiment, all do not detect antibacterial.Under the situation of fungus, not detecting the fungus that fungus or quantity inoculated at inoculation four stars after date has significant minimizing.Therefore, find to have showed enough antisepsises.
Table 9
Industrial applicibility
Also can then can provide clear and bright Latanoprost eye drops by adding surfactant even reduce BAK concentration. In addition, by adopting BAKC12As anticorrisive agent, even reducing, BAK concentration also can provide clear and bright Latanoprost eye drops. Further, add the nonionic isotonic agent, also can provide clear and bright Latanoprost eye drops and BAK concentration even lower even BAK concentration reduces.
Claims (10)
1, contains the clear and bright eye drop of effective composition latanoprost and antiseptic benzalkonium chloride, it is characterized in that, prevent that by containing the nonionic isotonic agent preparation from changing the white casse that causes.
2, eye drop as claimed in claim 1 is characterized in that, benzalkonium chloride is by formula [C
6H
5CH
2N (CH
3)
2R] Cl represents that wherein R is the alkyl that contains 12 carbon atoms.
3, eye drop as claimed in claim 1 is characterized in that, the concentration of latanoprost is 0.001~0.01%W/V, and the concentration of benzalkonium chloride is 0.003~0.01%W/V.
4, eye drop as claimed in claim 1 is characterized in that, the concentration of latanoprost is 0.005%W/V, and the concentration of benzalkonium chloride is 0.003~0.01%W/V.
5, eye drop as claimed in claim 1 is characterized in that, the nonionic isotonic agent is a glycerol, mannitol, Polyethylene Glycol, propylene glycol, trehalose or sucrose.
6, prevent to contain the method that changes the white casse that causes in the eye drop of effective composition latanoprost and antiseptic benzalkonium chloride by preparation by adding the nonionic isotonic agent.
7, the method that prevents white casse as claimed in claim 6 is characterized in that, benzalkonium chloride is by formula [C
6H
5CH
2N (CH
3)
2R] Cl represents that wherein R is the alkyl that contains 12 carbon atoms.
8, the method that prevents white casse as claimed in claim 6 is characterized in that, the concentration of latanoprost is 0.001~0.01%W/V, and the concentration of benzalkonium chloride is 0.003~0.01%W/V.
9, the method that prevents white casse as claimed in claim 6 is characterized in that, the concentration of latanoprost is 0.005%W/V, and the concentration of benzalkonium chloride is 0.003 to 0.01%W/V.
10, the method that prevents white casse as claimed in claim 6 is characterized in that, the nonionic isotonic agent is a glycerol, mannitol, Polyethylene Glycol, propylene glycol, trehalose or sucrose.
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CN2008100902128A Expired - Fee Related CN101278937B (en) | 2002-09-09 | 2003-09-08 | Clear eye lotion containing latanoprost as effective ingredient |
CNB038239485A Expired - Fee Related CN100389770C (en) | 2002-09-09 | 2003-09-08 | Transparent eye drops containing latanoprost |
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CN102716074B (en) * | 2012-06-28 | 2013-10-16 | 武汉武药科技有限公司 | Bimatoprost eye drops and preparation method thereof |
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CN100389770C (en) | 2008-05-28 |
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