CN1166362C - Solution agent of antiallergi medicine contg. levocetirizine - Google Patents
Solution agent of antiallergi medicine contg. levocetirizine Download PDFInfo
- Publication number
- CN1166362C CN1166362C CNB021308233A CN02130823A CN1166362C CN 1166362 C CN1166362 C CN 1166362C CN B021308233 A CNB021308233 A CN B021308233A CN 02130823 A CN02130823 A CN 02130823A CN 1166362 C CN1166362 C CN 1166362C
- Authority
- CN
- China
- Prior art keywords
- cetirizine hydrochloride
- group
- levo
- oral administration
- solution
- 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.)
- Expired - Lifetime
Links
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 title claims abstract description 65
- 229960001508 levocetirizine Drugs 0.000 title claims abstract description 65
- 239000003814 drug Substances 0.000 title abstract description 26
- 239000003795 chemical substances by application Substances 0.000 title description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 18
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229920001983 poloxamer Polymers 0.000 claims abstract description 16
- 229960000502 poloxamer Drugs 0.000 claims abstract description 16
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 16
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 16
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 15
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 14
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 14
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 claims description 14
- 239000000872 buffer Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 9
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 8
- 239000003889 eye drop Substances 0.000 claims description 2
- 239000007923 nasal drop Substances 0.000 claims description 2
- 230000003266 anti-allergic effect Effects 0.000 abstract description 4
- 239000002131 composite material Substances 0.000 abstract description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 82
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 44
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 43
- 229960004342 cetirizine hydrochloride Drugs 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 25
- 239000012153 distilled water Substances 0.000 description 25
- 229960001340 histamine Drugs 0.000 description 21
- 239000000126 substance Substances 0.000 description 21
- 239000000203 mixture Substances 0.000 description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- 239000002671 adjuvant Substances 0.000 description 11
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 9
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 238000007865 diluting Methods 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229960001660 histamine phosphate Drugs 0.000 description 9
- ZHIBQGJKHVBLJJ-UHFFFAOYSA-N histamine phosphate Chemical compound OP(O)(O)=O.OP(O)(O)=O.NCCC1=CNC=N1 ZHIBQGJKHVBLJJ-UHFFFAOYSA-N 0.000 description 9
- 229940085605 saccharin sodium Drugs 0.000 description 9
- 239000000600 sorbitol Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 206010037660 Pyrexia Diseases 0.000 description 8
- 230000008485 antagonism Effects 0.000 description 8
- 229940046978 chlorpheniramine maleate Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 230000001954 sterilising effect Effects 0.000 description 8
- 238000004659 sterilization and disinfection Methods 0.000 description 8
- 230000037396 body weight Effects 0.000 description 7
- 229960001803 cetirizine Drugs 0.000 description 7
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000012467 final product Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000012982 microporous membrane Substances 0.000 description 7
- 239000004334 sorbic acid Substances 0.000 description 7
- 235000010199 sorbic acid Nutrition 0.000 description 7
- 229940075582 sorbic acid Drugs 0.000 description 7
- 238000005303 weighing Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 6
- 241000220223 Fragaria Species 0.000 description 6
- 235000016623 Fragaria vesca Nutrition 0.000 description 6
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- RLLPVAHGXHCWKJ-UHFFFAOYSA-N permethrin Chemical compound CC1(C)C(C=C(Cl)Cl)C1C(=O)OCC1=CC=CC(OC=2C=CC=CC=2)=C1 RLLPVAHGXHCWKJ-UHFFFAOYSA-N 0.000 description 6
- 230000000903 blocking effect Effects 0.000 description 5
- 239000006196 drop Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 230000035939 shock Effects 0.000 description 4
- COXVTLYNGOIATD-HVMBLDELSA-N CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O Chemical compound CC1=C(C=CC(=C1)C1=CC(C)=C(C=C1)\N=N\C1=C(O)C2=C(N)C(=CC(=C2C=C1)S(O)(=O)=O)S(O)(=O)=O)\N=N\C1=CC=C2C(=CC(=C(N)C2=C1O)S(O)(=O)=O)S(O)(=O)=O COXVTLYNGOIATD-HVMBLDELSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 229960003699 evans blue Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 210000003405 ileum Anatomy 0.000 description 3
- 210000000627 locus coeruleus Anatomy 0.000 description 3
- 210000002460 smooth muscle Anatomy 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 229960004249 sodium acetate Drugs 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000007974 sodium acetate buffer Substances 0.000 description 3
- 210000002784 stomach Anatomy 0.000 description 3
- -1 4-(diphenyl methyl) Piperazino alkoxy acetic acid derivatives Chemical class 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 102000002322 Egg Proteins Human genes 0.000 description 2
- 108010000912 Egg Proteins Proteins 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- XINCECQTMHSORG-UHFFFAOYSA-N Isoamyl isovalerate Chemical compound CC(C)CCOC(=O)CC(C)C XINCECQTMHSORG-UHFFFAOYSA-N 0.000 description 2
- 208000030961 allergic reaction Diseases 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 239000000043 antiallergic agent Substances 0.000 description 2
- 238000002144 chemical decomposition reaction Methods 0.000 description 2
- 238000006757 chemical reactions by type Methods 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 238000000151 deposition Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 229940100688 oral solution Drugs 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
- 239000002904 solvent Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000008728 vascular permeability Effects 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000588832 Bordetella pertussis Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 244000283207 Indigofera tinctoria Species 0.000 description 1
- 240000008790 Musa x paradisiaca Species 0.000 description 1
- 235000018290 Musa x paradisiaca Nutrition 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000053227 Themus Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 238000010241 blood sampling Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 210000003767 ileocecal valve Anatomy 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003186 pharmaceutical solution Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 235000019640 taste Nutrition 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides an antiallergic medicine solution preparation containing levocetirizine. One L of the medicine composite solution contains 0.5g to 20g of zocetirizine or acceptable salt thereof in pharmacology, 20g to 100 g of polyvinyl pyrrolidone, 5g to 50g of poloxamer and 10g to 250g of polyethylene glycol 400.
Description
Technical field:
The present invention relates to contain the antiallergic agent compositions of levocetirizine, particularly be suitable for solution oral and a usefulness.
Background technology:
The chemical name that European patent EP 058146 has been illustrated cetirizine is: 4-(diphenyl methyl) Piperazino alkoxy acetic acid derivatives has antiallergic action and spasmolysis.
The chemical constitution of cetirizine has left-handed and dextroisomer, and levocetirizine is cetirizine R-isomer.
CN 1094614 A disclose a kind of cetirizine raceme that contains for the antiallergic composition that eye is used or nose is used, and said composition includes cyclodextrin compound, and a kind of surfactant or/or a kind of water-soluble polymer.
CN 1175413 A disclose a kind of eye that contains the cetirizine raceme and have used or nasal composition, and said composition includes the surfactant poloxamer.
The active ingredient of the compositions of above-mentioned two patent disclosures is the cetirizine raceme, and the antiallergic activity of cetirizine mainly is its laevoisomer.As everyone knows, with raceme drug dose is strengthened, therefore the problem of thereupon bringing toxic and side effects to increase.
The preparation of the compositions of above-mentioned two patent disclosures is the external used medicine that eye is used or nose is used.
WO9406429 and US5698558 disclose the peroral dosage form of levocetirizine, for tablet and capsule preparations, are solid preparation, and absorption rate is low, and bioavailability is less.Because chemical degradation easily takes place in levocetirizine in water, will lessen the curative effect and increase toxicity, and the molecular aggregates phenomenon can take place, and makes the solution muddiness.Levocetirizine has stronger bitterness in addition, and the mouthfeel of pharmaceutical solutions is relatively poor, is difficult to accept for the patient.Therefore the preparation of its oral solution has certain difficulty technically.
Summary of the invention:
The technical problem to be solved in the present invention provides the pharmaceutical composition that contains levocetirizine, particularly provides to absorb the oral administration solution dosage form fast, that bioavailability is high, mouthfeel is good, is suitable for the child and the old man takes.
Active ingredient in pharmaceutical of the present invention is levocetirizine or its pharmaceutically acceptable salt.Described pharmaceutically acceptable salt comprises: hydrochlorate, sulfate, phosphate, maleate, citrate, tartrate, palmitate, acetate, nitrate.
Include polyvinylpyrrolidone (PVP K in the adjuvant of said composition
30) as protecting colloid, nonionic surfactant poloxamer as solubilizing agent, PEG400 as stabilizing agent.
Pharmaceutical composition of the present invention is a solution.
Described solution is oral liquid and drop (nasal drop or eye drop).
Inventor of the present invention is through intensive studies show that, in the aqueous solution of levocetirizine, add polyvinylpyrrolidone, PEG400 and poloxamer, can prevent the chemical degradation of levocetirizine, reduce the generation of related substance, thereby the toxicity of reduction medicine, make it have good safety.Also can reduce the molecular aggregates phenomenon and take place, make solution keep clarification, improve stability of formulation.
In the 1000ml solution, the content of described levocetirizine or its pharmaceutically acceptable salt is that the content of 0.5～20g, polyvinylpyrrolidone is that the content of 20～100g, poloxamer is that the content of 5～50g, PEG400 is 10～250ml.
Contain acetic acid-sodium acetate or citric acid-sodium citrate buffer in the pharmaceutical composition of the present invention.The preferred pH value of drug solution is 4.5～6.5.The citric acid-sodium citrate buffer is a preferred reducing agents.
Pharmaceutical composition of the present invention also can comprise various oral liquids adjuvant and other pharmaceutically acceptable adjuvant commonly used, and as correctives, buffer agent, antiseptic, pH regulator agent, the consumption of adjuvant amount ranges is routinely determined.These adjuvant comprise sorbitol, glycerol, propylene glycol, sodium benzoate, methyl hydroxybenzoate, propylparaben, saccharin sodium, strawberry essence etc.
Preparation of drug combination method of the present invention is: levocetirizine, polyvinylpyrrolidone, PEG400, poloxamer and pharmaceutical adjuvant are dissolved in an amount of distilled water, slight fever and stirring make dissolving, add other adjuvant after cold slightly again, stirring makes dissolving, regulating pH value with buffer is 4.5～6.5, adds distilled water diluting to full dose.Filter sterilization.
Liquid preparation of the present invention has good to eat fruit aroma, comfortable taste, and the patient is easy to accept.
The specific embodiment:
Embodiment 1 levo-cetirizine hydrochloride oral solution
Prescription:
Levo-cetirizine hydrochloride 0.5g
Sorbitol 250g
PEG400 150ml
Polyvinylpyrrolidone 25g
Poloxamer (model is F68) 10g
Propanoic acid 1ml
Saccharin sodium 0.1g
Strawberry essence 1ml
Citric acid-sodium citrate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get citric acid 30g, add water 200ml, pH is 5.5 ± 0.2 with the sodium hydroxide adjusting, and is standby with the citric acid-sodium citrate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 2 levo-cetirizine hydrochloride oral solutions
Prescription:
Levo-cetirizine hydrochloride 1g
Propylene glycol 100ml
Sorbitol 250g
PEG400 100ml
Polyvinylpyrrolidone 20g
Poloxamer 5g
Sorbic acid 2g
Saccharin sodium 0.1g
Strawberry essence 1ml
Citric acid-sodium citrate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get citric acid 30g, add water 200ml, pH is 5.5 ± 0.2 with the sodium hydroxide adjusting, and is standby with the citric acid-sodium citrate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 3 levo-cetirizine hydrochloride oral solutions
Prescription:
Levo-cetirizine hydrochloride 0.5g
Sorbitol 180g
PEG400 10ml
Polyvinylpyrrolidone 100g
Poloxamer (model is F68) 5g
Sorbic acid 2g
Saccharin sodium 0.2g
Apple essence 1ml
Citric acid-sodium citrate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get citric acid 30g, add water 200ml, pH is 5.5 ± 0.2 with the sodium hydroxide adjusting, and is standby with the citric acid-sodium citrate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 4 levo-cetirizine hydrochloride oral solutions
Prescription:
Levo-cetirizine hydrochloride 2g
Propylene glycol 100ml
Sorbitol 250g
PEG400 120ml
Polyvinylpyrrolidone 30g
Poloxamer 10g
Sorbic acid 2g
Saccharin sodium 0.2g
Strawberry essence 1ml
Acetic acid-sodium acetate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get sodium acetate 30g, add water 200ml, pH is 5.5 ± 0.2 with the glacial acetic acid adjusting, and is standby with acetic acid-sodium-acetate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 5 levo-cetirizine hydrochloride drops
Prescription:
Levo-cetirizine hydrochloride 10g
Propylene glycol 50ml
Sorbitol 200g
PEG400 180ml
Polyvinylpyrrolidone 40g
Poloxamer 10g
Sorbic acid 2g
Saccharin sodium 0.5g
Strawberry essence 1ml
Acetic acid-sodium acetate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get sodium acetate 30g, add water 200ml, pH is 5.5 ± 0.2 with the glacial acetic acid adjusting, and is standby with acetic acid-sodium-acetate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 6 levo-cetirizine hydrochloride drops
Prescription:
Levo-cetirizine hydrochloride 10g
Glycerol 20ml
Sorbitol 150g
PEG400 200ml
Polyvinylpyrrolidone 50g
Poloxamer 20g
Sorbic acid 2g
Saccharin sodium 0.5g
Flavoring banana essence 1ml
Acetic acid-sodium acetate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get sodium acetate 30g, add water 200ml, pH is 5.5 ± 0.2 with the glacial acetic acid adjusting, and is standby with acetic acid-sodium-acetate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 7 levo-cetirizine hydrochloride drops
Prescription:
Levo-cetirizine hydrochloride 20g
Glycerol 10ml
Sorbitol 150g
PEG400 250ml
Polyvinylpyrrolidone 60g
Poloxamer 50g
Sorbic acid 2g
Saccharin sodium 0.5g
Apple essence 1ml
Citric acid-sodium citrate is an amount of
Distilled water adds to 1000ml
Preparation: take by weighing (or measuring) supplementary material by formula ratio, get an amount of distilled water, slight fever and stirring make dissolving, and (get citric acid 30g, add water 200ml, pH is 5.5 ± 0.2 with the sodium hydroxide adjusting, and is standby with the citric acid-sodium citrate buffer.) to regulate pH value be 4.5～6.5, adds distilled water diluting to full dose, with 0.45 μ m filtering with microporous membrane, fill is jumped a queue, and rolls lid, and sterilization (the ASM water-bath is sterilized, 115.5 ℃, 30min) gets final product.
Embodiment 8 stable contrast experiments
The fill of control oral liquid bottle is adopted in all preparations on request of compositions 1～8 in the table 1, the sillicon rubber blocking sealing, and easy-to-draw plastic-aluminum composite cover fore shaft places under the condition of 40 ± 1 ℃ of temperature, RH75% accelerated test 6 months.Investigate: the clarity of solution, content, related substance.The results are shown in Table 2.
The composition of table 1 compositions (%)
| Compositions | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| Levo-cetirizine hydrochloride | 0.1 | 1.0 | 0.1 | 1.0 | 0.1 | 1.0 | 0.1 | 1.0 |
| Propylene glycol | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
| Glycerol | 5 | 5 | 5 | 5 | 5 | 5 | 5 | 5 |
| Sorbitol | 25 | 25 | 25 | 25 | 25 | 25 | 25 | 25 |
| PEG400 | - | - | - | - | - | - | 10 | 10 |
| Polyvinylpyrrolidone | - | - | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 | 2.5 |
| Poloxamer | - | - | - | - | 2.5 | 2.5 | 2.5 | 2.5 |
| Sorbic acid | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 | 0.2 |
| Saccharin sodium | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 | 0.05 |
| Strawberry essence | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
| Citric acid-sodium citrate | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount |
| Distilled water | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount | In right amount |
Annotate: the citric acid-sodium citrate buffer (get citric acid 30g, add water 200ml, regulate pH with sodium hydroxide and be 5.5 ± 0.2, standby.) regulate pH to 5.5 ± 0.2, add distilled water diluting to full dose 500ml.
Table 2 accelerated test is investigated the result
| Compositions | 0 day | 6 months | ||||
| Clarity | Content (%) | Related substance (%) | Clarity | Content (%) | Related substance (%) | |
| 1 | Qualified | 100.15 | 0.31 | ++ | 98.32 | 1.91 |
| 2 | Qualified | 99.64 | 0.34 | ++ | 97.96 | 1.86 |
| 3 | Qualified | 99.89 | 0.41 | + | 98.47 | 1.74 |
| 4 | Qualified | 101.16 | 0.31 | + | 99.53 | 1.71 |
| 5 | Qualified | 99.72 | 0.32 | Qualified | 98.43 | 1.27 |
| 6 | Qualified | 100.37 | 0.30 | Qualified | 98.98 | 1.32 |
| 7 | Qualified | 100.54 | 0.40 | Qualified | 99.93 | 0.65 |
| 8 | Qualified | 99.38 | 0.38 | Qualified | 98.87 | 0.54 |
Annotate 1: "+" representative produces a small amount of insoluble substance; " ++ " representative produces more insoluble substance.
Annotate 2: " related substance " mainly is meant the raw material brought in process of production, intermediate, degradation product, isomer, polymer, side reaction product etc.
The result is as follows: compositions 1 and 2 promptly began to produce insoluble substance after 4 months, and it is nearly 2% that active ingredient content descends, and related substance increases about 1.5%; When compositions 3 and 4 is deposited to 6 months, produce a small amount of insoluble substance, active ingredient content descends about 1.6%, and related substance increases about 1.4%; Compositions 5 and 6 when depositing to 6 months, does not see that insoluble substance produces, and content descends about 1.3%, and related substance increases about 1.0%; Compositions 7 and 8 when depositing to 6 months, does not see that insoluble substance produces, and content descends about 0.6%, and related substance increases about 0.3%.
This experiment shows: the oral liquid of levo-cetirizine hydrochloride is easy to generate insoluble substance; only add the protecting colloid polyvinylpyrrolidone; can not avoid the generation of insoluble substance; and the increase of the decline of active ingredient content, related substance; and after having increased the solubilizing agent poloxamer; though can guarantee the clear and bright of liquid; but the active ingredient fall is still very big; related substances increases nearly 1%; and PEG400 is also joined in the compositions simultaneously, can prepare the oral liquid of metastable levo-cetirizine hydrochloride.
Embodiment 9: pharmaceutical composition pharmacodynamics test of the present invention
Levo-cetirizine hydrochloride is third generation H
1The receptor blocking medicine can be special and the H of the mucocutaneous blood vessel of antagonism effectively
1Receptor, clinical allergic rhinitis and the various Mucocutaneous allergic disease that causes by histamine that be used for the treatment of.For verifying the H of pharmaceutical composition of the present invention
1Receptor antagonism and effect characteristics thereof, the spy carries out following test.
(1) isolated guinea pig ileum test
1, animal: 12 of healthy qualified one-level Cavia porcelluss, body weight 300-400g, male and female half and half.
2, medicine: levo-cetirizine hydrochloride oral administration solution (10ml:5mg is 0.5mg/ml) Cetirizine hydrochloride Tablets (10mg/ sheet): the normal saline solution that is made into 0.5mg/ml with normal saline is standby; Chlorpheniramine maleate tablets (4mg/ sheet): the normal saline solution that is made into 0.5mg/ml with normal saline is standby; Blank oral administration solution: for not containing the oral administration solution that medicine only contains adjuvant; The histamine phosphate normal saline solution: concentration is 0.5mg/ml.
3, method: method is put to death Cavia porcellus to tap the head, dissect immediately after the execution, take out ileum, discard near the intestinal segment in the ileocecal valve 10cm, get the intestinal segment of 3cm, put into the little glass dish that fills krebs solution, wherein pass to 95% oxygen and 5% carbon dioxide, bath temperature is 37 ± 0.5 ℃, and specimen preload 2-3g makes 24 specimen altogether.
24 isolated guinea pig ileum specimen are divided into histamine group, histamine at random add that levo-cetirizine hydrochloride oral administration solution group, histamine add the Cetirizine hydrochloride Tablets group, histamine adds the chlorpheniramine maleate tablets group, totally 4 groups, every group of 6 specimen.Add relative medicine respectively in each little glass dish, dosage is respectively histamine group 0.03mg histamine phosphate normal saline solution, histamine adds levo-cetirizine hydrochloride oral administration solution group adding 0.03mg histamine phosphate normal saline solution and 1ml levo-cetirizine hydrochloride oral administration solution, histamine add Cetirizine hydrochloride Tablets group adding 0.03mg histamine phosphate normal saline solution and 2ml levo-cetirizine hydrochloride sheet normal saline solution, histamine add chlorpheniramine maleate tablets group adding histamine phosphate normal saline solution 0.03ml and 2ml chlorpheniramine maleate tablets normal saline solution.Make the antagonism curve of each group respectively, calculate the pA that is subjected to reagent thing and control drug
2Value (amount effect curve that makes agonist is to the parallel negative logarithm that moves the molal quantity of 2 times of required competitive antagonists of high dose direction).
4, result: press pA
2Being worth descending arrangement is successively: histamine add the chlorpheniramine maleate tablets group＞＞histamine adds Cetirizine hydrochloride Tablets group＞histamine and adds levo-cetirizine hydrochloride oral administration solution group, histamine adds chlorpheniramine maleate tablets group and histamine and adds the difference that Cetirizine hydrochloride Tablets group, histamine add between levo-cetirizine hydrochloride oral administration solution group and have statistical significance, adds difference not statistically significant between levo-cetirizine hydrochloride oral administration solution group but histamine adds Cetirizine hydrochloride Tablets group and histamine.
5, conclusion: levo-cetirizine hydrochloride oral administration solution and Cetirizine hydrochloride Tablets are than first generation H
1The receptor-selective of receptor blocking medicine chlorpheniramine maleate tablets is stronger, and the above two are to the H of intestinal smooth muscle
1The effect of receptor acting is faint, and chlorpheniramine maleate tablets is to the H of intestinal smooth muscle
1Receptor then has tangible blocking effect.The levo-cetirizine hydrochloride oral administration solution is compared the former with Cetirizine hydrochloride Tablets receptor-selective is stronger.
(2) rat passive cutaneous anaphylaxis, PCA of the same race (Rat PCA) test (I allergic reaction type model)
1, animal: body weight is 1 of the healthy qualified rat of 90-100g, and body weight is 40 of the healthy qualified rats of 150-200g, male and female half and half.
2, medicine: levo-cetirizine hydrochloride oral administration solution (10ml: 5mg is 0.5mg/ml)
Cetirizine hydrochloride Tablets (10mg/ sheet): the normal saline solution that is made into 0.5mg/ml with normal saline is standby.
Pounce on and quick (4mg/ sheet): the normal saline solution that is made into 0.5mg/ml with normal saline is standby.
Blank oral administration solution: for not containing the oral administration solution that medicine only contains adjuvant.
3, method:
A. sero-fast preparation: getting body weight is the healthy qualified rat of 90-100g, and antigen is the egg protein through sodium sulfate recrystallization 3-5 time, and adjuvant is the daytime to cough the bacillus vaccine, to rat muscle injection 10mg/kg, lumbar injection 2 * 10 simultaneously
10/ bordetella pertussis is put to death the animal blood sampling after 10-14 days, through low-speed centrifugal, and separation of serum, it is standby to put refrigerator.
B. passive sensitization of skin and antigen are attacked: getting body weight is the healthy qualified rat of 150-200g, is divided into 4 groups at random, 10 every group, and totally 40.Under etherization cut off the hair at back, with the dilution antiserum (1: 40 and 1: 60) intradermal injection in the Mus back, each dilution factor is injected 2 points, every some 0.1ml.Irritate stomach to animal after 47 hours and be subjected to the reagent thing, dosage is respectively: levo-cetirizine hydrochloride oral administration solution group 0.6mg/kg; Cetirizine hydrochloride Tablets group 1.1mg/kg; Pounce on and quick group 0.5mg/kg; Blank oral administration solution group 5ml/ only.48 hours posterior veins injection 1ml, 0.5% azovan blue solution (including egg protein 1mg) carry out antigen and attack.Sacrificed by decapitation animal after 20 minutes, the upset skin of back is measured blue diameter of reacting speckle.Its PCA suppresses percentage rate and calculates with following formula:
Suppress percentage rate=(matched group locus coeruleus diameter-medication group locus coeruleus diameter)/matched group locus coeruleus diameter * 100%.
4, result: arrange from big to small and be followed successively by by suppressing percentage rate: levo-cetirizine hydrochloride oral administration solution group＞Cetirizine hydrochloride Tablets group＞pounce on and quick group＞blank oral administration solution group.Wherein the difference of levo-cetirizine hydrochloride oral administration solution group and Cetirizine hydrochloride Tablets group does not have significance (p＞0.05), cetirizine hydrochloride oral administration solution, Cetirizine hydrochloride Tablets group and pounce on and quick group with barren difference significance (p≤0.01) is arranged, cetirizine hydrochloride oral administration solution group, Cetirizine hydrochloride Tablets group and pounce on and quick group difference also has significance (p≤0.01).
5, conclusion: cetirizine hydrochloride oral administration solution, Cetirizine hydrochloride Tablets and pounce on and quick the I allergic reaction type all had obvious curative effects, quick curative effect is stronger than pouncing on for cetirizine hydrochloride oral administration solution and Cetirizine hydrochloride Tablets, and the cetirizine hydrochloride oral administration solution dosage be Cetirizine hydrochloride Tablets two/once situation under can bring into play equal or higher with it curative effect.
(3) skin heart permeability test
1, animal: 50 of healthy qualified rats, body weight 160-240g, male and female half and half.
2, medicine: levo-cetirizine hydrochloride oral administration solution (10ml: 5mg is 0.5mg/ml)
Cetirizine hydrochloride Tablets (10mg/ sheet): the normal saline solution that is made into 0.5mg/ml with normal saline is standby.
Blank oral administration solution: for not containing the oral administration solution that medicine only contains adjuvant.
The histamine phosphate normal saline solution: concentration is 0.5mg/ml.
3, method: 50 rats are divided into the heavy dose of group of levo-cetirizine hydrochloride oral administration solution, middle dosage group, small dose group, Cetirizine hydrochloride Tablets group and blank group (blank oral administration solution), totally 5 groups, 10 every group at random.Feed earlier and observe a week, early morning on the same day was irritated corresponding trial drug of stomach or control drug to it in test, and dosage only is respectively the heavy dose of group of levo-cetirizine hydrochloride oral administration solution 1.1mg/kg, middle dosage group 0.6mg/kg, small dose group 0.3mg/kg, cetirizine hydrochloride group sheet group 2.2mg/kg, blank group 5ml/.The histamine phosphate normal saline solution 0.1ml of 1 hour intradermal injection 0.5mg/ml after the administration, the 1% azovan blue normal saline solution 1ml/kg of intravenous injection simultaneously.Put to death animal after 30 minutes, take off indigo plant and dye skin and shred, soaked 24 hours with 1: 1 acetone normal saline solution, solution centrifugal is got supernatant, with 72-1 type spectrophotometric determination optical density (640nm).Calculate the antagonism that azovan blue content causes by reagent thing and control drug to histamine with reaction vascular permeability increases according to standard curve.
4, result: large, medium and small dosage group of levo-cetirizine hydrochloride oral administration solution and Cetirizine hydrochloride Tablets group all effectively the vascular permeability that causes of antagonism histamine increase, with the blank group significant difference (p≤0.01) is arranged relatively; Wherein the antagonism of the heavy dose of group of levo-cetirizine hydrochloride oral administration solution is the strongest (compares there was no significant difference with dosage group in the levo-cetirizine hydrochloride oral administration solution with the Cetirizine hydrochloride Tablets group, compared significant difference p≤0.05 with levo-cetirizine hydrochloride oral administration solution small dose group), there was no significant difference (p 〉=0.05) between dosage group and Cetirizine hydrochloride Tablets group in the levo-cetirizine hydrochloride oral administration solution.
5, conclusion: the levo-cetirizine hydrochloride oral administration solution is to the H of skin heart smooth muscle
1Receptor has tangible antagonism, is that the antagonism of Cetirizine hydrochloride Tablets of its twice is identical with dosage.The dosage of dosage group is preferred dose in the levo-cetirizine hydrochloride oral administration solution, recommends to be used for clinical trial (being scaled human dose is: 5mg/ days).
(4) shock test due to the histamine
1, animal: 50 of healthy qualified one-level Cavia porcelluss, body weight 200-300g, male and female half and half.
2, medicine: levo-cetirizine hydrochloride oral administration solution (10ml: 5mg is 0.5mg/ml)
Cetirizine hydrochloride Tablets (10mg/ sheet): the normal saline solution that is made into 0.5mg/ml with normal saline is standby.
Blank oral administration solution: for not containing the oral administration solution that medicine only contains adjuvant.
The histamine phosphate normal saline solution: concentration is 0.5mg/ml.
3, method: 50 Cavia porcelluss are divided into the heavy dose of group of levo-cetirizine hydrochloride oral administration solution, middle dosage group, small dose group, Cetirizine hydrochloride Tablets group and blank group (blank oral administration solution), totally 5 groups, 10 every group at random.Feed earlier and observe a week, early morning on the same day was irritated corresponding trial drug of stomach or control drug to it in test, and dosage is respectively the heavy dose of group of levo-cetirizine hydrochloride oral administration solution 1.34mg/kg, middle dosage group 0.67mg/kg, small dose group 0.33mg/kg, Cetirizine hydrochloride Tablets group
2.68mg/kg, blank group 5ml/ only.1 hour intravenous injection histamine phosphate normal saline solution 0.2mg/kg causes shock (show as accelerated breathing, dyspnea, drop to even death) after the administration.Observation is subjected to the reagent thing to the incubation period of the shock due to the histamine and the influence of degree.
4, result: large, medium and small dosage group of levo-cetirizine hydrochloride oral administration solution and Cetirizine hydrochloride Tablets group and blank group all do not have obvious influence, there was no significant difference between each test group and matched group (p 〉=0.05) to the incubation period and the order of severity of suffering a shock due to the histamine.
5, conclusion: levo-cetirizine hydrochloride oral administration solution and Cetirizine hydrochloride Tablets are invalid to the anaphylactic shock due to the histamine.
Above-mentioned result of the test proves that pharmaceutical composition of the present invention has the anti-H of height
1Receptor active, its H
1Receptor blocking usefulness and dosage are that the usefulness of Cetirizine hydrochloride Tablets of its twice is suitable even higher, and the dosage of recommending to be used for clinical trial is 5mg/ days; Compare the levo-cetirizine hydrochloride oral administration solution with Cetirizine hydrochloride Tablets and have higher receptor-selective, so the safety of medicine is higher.Therefore the levo-cetirizine hydrochloride oral administration solution is a kind of novel anti allergic drug of highly effective and safe.
Preparation according to the present invention is elaborated by embodiment, but it should be considered as limitation of the present invention.
Claims (6)
1, a kind of pharmaceutical composition that contains levocetirizine or its pharmaceutically acceptable salt is characterized in that described pharmaceutical composition is a liquid preparation; In the 1000ml pharmaceutical composition, the content of levocetirizine or its pharmaceutically acceptable salt is that the content of 0.5～20g, polyvinylpyrrolidone is that the content of 20～100g, poloxamer is that the content of 5～50g, PEG400 is 10～250ml.
2, the described pharmaceutical composition of claim 1 is an oral liquid.
3, the described pharmaceutical composition of claim 1 is nasal drop or eye drop.
4, the described pharmaceutical composition of claim 1 contains acetic acid-sodium acetate or citric acid-sodium citrate buffer.
5, the described pharmaceutical composition of claim 3 contains the citric acid-sodium citrate buffer.
6, the described pharmaceutical composition of claim 1, pH value is 4.5～6.5.
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| CN102133179B (en) * | 2011-03-11 | 2013-02-06 | 四川健能制药有限公司 | Stable cetirizine oral solution |
| CN103222952A (en) * | 2013-04-25 | 2013-07-31 | 北京科源创欣科技有限公司 | Stable solution preparation comprising carteolol or hydrochloride thereof |
| CN103222954A (en) * | 2013-05-15 | 2013-07-31 | 北京科源创欣科技有限公司 | Solution agent containing loperamide or hydrochloride thereof and preparation method of solution agent |
| CN103222955A (en) * | 2013-05-22 | 2013-07-31 | 北京科源创欣科技有限公司 | Stable solution containing epinastine or hydrochloride of epinastine |
| CN103860462A (en) * | 2014-01-14 | 2014-06-18 | 万特制药(海南)有限公司 | Levocetirizine hydrochloride syrup and preparation method |
| CN106491522A (en) * | 2016-09-24 | 2017-03-15 | 北京万全德众医药生物技术有限公司 | A kind of levo-cetirizine hydrochloride Oral drops and preparation method thereof |
| CN112220746B (en) * | 2020-10-20 | 2022-07-15 | 北京诚济制药股份有限公司 | Levocarnitine oral solution and preparation method thereof |
| CN113876702A (en) * | 2021-11-04 | 2022-01-04 | 南京恒道医药科技有限公司 | Levocetirizine hydrochloride eye drops and preparation method thereof |
| CN116492295A (en) * | 2023-04-18 | 2023-07-28 | 新乡医学院第三附属医院 | A kind of levocetirizine hydrochloride oral solution |
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Owner name: CHONGQING HUAPONT PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HUABANG PHARMACEUTICAL CO., LTD., CHONGQING Effective date: 20130220 |
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Free format text: CORRECT: ADDRESS; FROM: 400041 JIULONGPO, CHONGQING TO: 401121 YUBEI, CHONGQING |
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Addressee: Li Yongsheng Document name: Notification of Passing Examination on Formalities |
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Effective date of registration: 20130220 Address after: 401121 Chongqing, Yubei District and the number of stars Avenue, No. 69 Patentee after: CHONGQING HUAPONT PHARM. Co.,Ltd. Address before: Four street in Chongqing city from 400041 Science Park No. 55 Patentee before: CHONGQING HUAPONT PHARM. Co.,Ltd. |
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