CN106377498A - Anti-parasites injection containing glyceryl triacetate, benzyl benzoate and castor oil - Google Patents
Anti-parasites injection containing glyceryl triacetate, benzyl benzoate and castor oil Download PDFInfo
- Publication number
- CN106377498A CN106377498A CN201611014168.3A CN201611014168A CN106377498A CN 106377498 A CN106377498 A CN 106377498A CN 201611014168 A CN201611014168 A CN 201611014168A CN 106377498 A CN106377498 A CN 106377498A
- Authority
- CN
- China
- Prior art keywords
- preparation
- injection
- glyceryl triacetate
- benzyl benzoate
- ivermectin
- 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.)
- Granted
Links
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 title claims abstract description 95
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 title claims abstract description 80
- 238000002347 injection Methods 0.000 title claims abstract description 67
- 239000007924 injection Substances 0.000 title claims abstract description 67
- 239000001087 glyceryl triacetate Substances 0.000 title claims abstract description 48
- 235000013773 glyceryl triacetate Nutrition 0.000 title claims abstract description 48
- 229960002622 triacetin Drugs 0.000 title claims abstract description 48
- 229960002903 benzyl benzoate Drugs 0.000 title claims abstract description 40
- 230000002141 anti-parasite Effects 0.000 title claims abstract description 4
- 239000004359 castor oil Substances 0.000 title abstract description 9
- 235000019438 castor oil Nutrition 0.000 title abstract description 9
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 title abstract description 9
- 229960001777 castor oil Drugs 0.000 title abstract 3
- 239000003814 drug Substances 0.000 claims abstract description 51
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 claims abstract description 44
- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229960002418 ivermectin Drugs 0.000 claims abstract description 35
- 239000006184 cosolvent Substances 0.000 claims abstract description 8
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 6
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical group 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 claims description 38
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 241001465754 Metazoa Species 0.000 claims description 9
- -1 benzyl ester Chemical class 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- QSHVAZMOLNGWSY-UHFFFAOYSA-N 3-butyl-4-methoxyphenol Chemical group CCCCC1=CC(O)=CC=C1OC QSHVAZMOLNGWSY-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- YZBLFMPOMVTDJY-CBYMMZEQSA-N moxidectin Chemical compound O1[C@H](C(\C)=C\C(C)C)[C@@H](C)C(=N/OC)\C[C@@]11O[C@H](C\C=C(C)\C[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 YZBLFMPOMVTDJY-CBYMMZEQSA-N 0.000 claims description 2
- 229960004816 moxidectin Drugs 0.000 claims description 2
- AFJYYKSVHJGXSN-KAJWKRCWSA-N selamectin Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1C(/C)=C/C[C@@H](O[C@]2(O[C@@H]([C@@H](C)CC2)C2CCCCC2)C2)C[C@@H]2OC(=O)[C@@H]([C@]23O)C=C(C)C(=N\O)/[C@H]3OC\C2=C/C=C/[C@@H]1C AFJYYKSVHJGXSN-KAJWKRCWSA-N 0.000 claims description 2
- 229960002245 selamectin Drugs 0.000 claims description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical group OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims 2
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims 1
- 239000003096 antiparasitic agent Substances 0.000 claims 1
- 229940074391 gallic acid Drugs 0.000 claims 1
- 235000004515 gallic acid Nutrition 0.000 claims 1
- 238000001802 infusion Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 133
- 239000003921 oil Substances 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 23
- 230000000202 analgesic effect Effects 0.000 abstract description 2
- 239000000203 mixture Substances 0.000 description 41
- 210000004369 blood Anatomy 0.000 description 31
- 239000008280 blood Substances 0.000 description 31
- 238000009472 formulation Methods 0.000 description 27
- 241001494479 Pecora Species 0.000 description 25
- 235000019198 oils Nutrition 0.000 description 23
- 229940079593 drug Drugs 0.000 description 22
- 238000012360 testing method Methods 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 210000002381 plasma Anatomy 0.000 description 16
- 239000012071 phase Substances 0.000 description 15
- 238000000034 method Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 230000000857 drug effect Effects 0.000 description 10
- 210000000582 semen Anatomy 0.000 description 8
- 230000008569 process Effects 0.000 description 7
- 229930192734 Avilamycin Natural products 0.000 description 6
- 239000004190 Avilamycin Substances 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 6
- XIRGHRXBGGPPKY-OTPQUNEMSA-N [(2r,3s,4r,6s)-6-[(2'r,3's,3ar,4r,4'r,6s,7ar)-6-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4s,5s,6s)-6-[(2r,3as,3'ar,6'r,7r,7's,7ar,7'ar)-7'-acetyl-7'-hydroxy-6'-methyl-7-(2-methylpropanoyloxy)spiro[4,6,7,7a-tetrahydro-3ah-[1,3]dioxolo[4,5-c]pyran-2,4'-6,7a-dihydro-3ah- Chemical compound O([C@H]1[C@H](O)C[C@@H](O[C@@H]1C)O[C@H]1[C@H](O)CC2(O[C@]3(C)C[C@@H](O[C@H](C)[C@H]3O2)O[C@H]2[C@@H](OC)[C@@H](C)O[C@H]([C@@H]2O)O[C@H]2[C@H](O)[C@H](OC)[C@H](OC3[C@@H]([C@@H]4O[C@]5(O[C@H]4CO3)[C@@H]3OCO[C@H]3[C@@](O)([C@@H](C)O5)C(C)=O)OC(=O)C(C)C)O[C@@H]2COC)O[C@@H]1C)C(=O)C1=C(C)C(Cl)=C(O)C(Cl)=C1OC XIRGHRXBGGPPKY-OTPQUNEMSA-N 0.000 description 6
- 229960005185 avilamycin Drugs 0.000 description 6
- 235000019379 avilamycin Nutrition 0.000 description 6
- 230000036765 blood level Effects 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 230000037396 body weight Effects 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 230000000590 parasiticidal effect Effects 0.000 description 5
- 239000002297 parasiticide Substances 0.000 description 5
- 229920001993 poloxamer 188 Polymers 0.000 description 5
- 229940044519 poloxamer 188 Drugs 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IBSREHMXUMOFBB-JFUDTMANSA-N 5u8924t11h Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O3)C=C[C@H](C)[C@@H](C(C)C)O4)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1=C[C@H](C)[C@@H]([C@@H](C)CC)O[C@]11O[C@H](C\C=C(C)\[C@@H](O[C@@H]2O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C2)[C@@H](C)\C=C\C=C/2[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\2)O)C[C@H]4C1 IBSREHMXUMOFBB-JFUDTMANSA-N 0.000 description 4
- 241000283690 Bos taurus Species 0.000 description 4
- 206010059866 Drug resistance Diseases 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- KMZHZAAOEWVPSE-UHFFFAOYSA-N 2,3-dihydroxypropyl acetate Chemical compound CC(=O)OCC(O)CO KMZHZAAOEWVPSE-UHFFFAOYSA-N 0.000 description 3
- 239000005660 Abamectin Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229950008167 abamectin Drugs 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N Benzylformate Chemical compound O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000009514 concussion Effects 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical group CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 244000045947 parasite Species 0.000 description 2
- 230000000149 penetrating effect Effects 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- MERJTCXDDLWWSK-UHFFFAOYSA-N 1-methylpyrrole pyrrolidin-2-one Chemical compound CN1C=CC=C1.N1C(CCC1)=O MERJTCXDDLWWSK-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- XRYKMKMQJBOVES-UHFFFAOYSA-N C(C1=CC=CC=C1)OC=O.C1=CC=CC=C1 Chemical compound C(C1=CC=CC=C1)OC=O.C1=CC=CC=C1 XRYKMKMQJBOVES-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000507 anthelmentic effect Effects 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000003950 cyclic amides Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 239000005645 nematicide Substances 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000009304 pastoral farming Methods 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000009781 safety test method Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
By aiming at the problem of too slow medicine release of ivermectin oil injection prepared from benzyl benzoate and castor oil, the invention provides anti-parasites injection prepared by adding a certain amount of glyceryl triacetate into benzyl benzoate and castor oil, so that the fast-acting performance of the preparation is improved; in addition, the preparation still has the good long-acting effect. 0.1 to 10 percent (weight/volume ratio) of ivermectin medicine and cosolvents prepared from benzyl benzoate, glyceryl triacetate and castor oil are contained in the injection provided by the invention; in the cosolvents prepared from benzyl benzoate, glyceryl triacetate and castor oil, the volume percentage of the glyceryl triacetate is 10 to 38 percent; the volume percentage of castor oil is 15 to 40 percent; the balance is benzyl benzoate. Antioxidants and local analgetics can also be added in the injection.
Description
Technical field
The present invention relates to field of veterinary medicine preparation is and in particular to one kind is used for preventing and treating nematicide and ectozoa sense in animal body
The oily injection of the medicine of class containing ivermectin of dye, said preparation feature is that long-acting and quick-acting effects are had both.
Background technology
The preventing and treating verminosis of the grazing animals such as cattle, sheep are typically more convenient with injection system administration, and use has
The injection of long-acting can reduce times for spraying, thus reducing use cost.Therefore, it is subject to very much in veterinary clinic long-acting injection
Welcome.Since the listing of ivermectin class medicine, research worker has been working hard preferably contain it is intended to develop parasiticide effect
The long-acting injection of ivermectin class medicine, has contained the long-acting oil injection of ivermectin or avilamycin in the area such as South America
Agent is allowed for cattle preventing and treating verminosis.But during the research in decades and Clinical practice, people's further insight
Arrive, the long-acting injection of the medicine of class containing ivermectin remains a need for certain quick-acting effects and under secure conditions as far as possible
Raising blood levels, the especially blood levels of peak phase.Otherwise, slow due to drug effect, peak phase blood medicine is dense
Degree level is low, is unfavorable for the timely treatment of severe infection animal, is especially detrimental to killing and control to drug resistance worm strain
The generation of drug resistance and development.
The studies and clinical application in past finds, the Yi Wei being prepared for slow-released carrier with Oleum Ricini or castor oil hydrogenated
Although rhzomorph injection duration of efficacy is long, there is a problem of that the slow and blood peak concentration of drug level that drug effect is come is low.WO
99/27906 3.15% Yi Wei disclosing the preparations such as a kind of use acetylated monoglyceride, castor oil hydrogenated, glyceryl triacetate
Rhzomorph oil injection, due to the addition of castor oil hydrogenated and acetylated monoglyceride, makes the rate of releasing drug of preparation significantly slow.
Said preparation commercialization, by 0.63mg/kg b.w. dosage to a cattle shot, duration of efficacy is up to more than 70 day.This system
Although agent dosage is 3.15 times of ordinary preparation (with 1% ivermectin injection of propylene glycol, formal glycerine preparation),
But peak phase blood drug level (about 25ng/ml) is close with ordinary preparation.It is reported that, said preparation can be only achieved upon administration on the 28th day
More than 90% anthelminthic effect.It is solvent preparation that patent CN 102316876A discloses one kind Oleum Gossypii semen with benzyl benzoate
The oily injection containing doractin, said preparation with Oleum Ricini and ethyl oleate be solvent preparation preparation compare, it is steady
Qualitative more preferably, it is fast that in addition, said preparation also has, the off-drug period is short, drug effect is come, and preparation still remains good slow release effect
The feature of fruit.CN 104168886A discloses by non-aqueous carrier and the length comprising Oleum Ricini and at least one cyclic amides form
Effect compositionss, it is said that said composition is used for animal parasitosis preventing and treating, have " quickly knocking down " (i.e. the quick-acting meaning) and " pole
Good long-lasting nature ".CN 101703776A discloses a kind of infection long-acting injection, and the preparation method of injection is：To live
Sexual element is dissolved in N-Methyl pyrrolidone and benzyl alcohol, is settled to 1000 milliliters with Oleum Ricini after stirring.Special at this
Be related to the preparation of ivermectin durative action preparation in profit, but to described ivermectin formulation clinicing aspect feature not
There is specific discussion.CN 1867341B discloses and comprises abamectin (AVERMECTIN B1) and Yi Wei for control parasite
The compositionss of rhzomorph, the purpose that abamectin and ivermectin are applied in combination is the rapid release effect in order to improve preparation, A Ba
Gram fourth rate of release in the oil medium being made up of Oleum Ricini is very fast, can make up ivermectin rate of release in Oleum Ricini
Excessively slow defect, so that the injection containing Oleum Ricini has slow releasing function and is also provided with quick-acting effects.US
The 6552002 parasiticide long-acting injections disclosing surfactant containing span and high drug load；Patent CN
104095812A disclose by oil medium add Poloxamer 188 (a kind of nonionic surfactant) method Lai
Solve the problems, such as that oil preparation quick-acting difference and peak phase blood levels are low；Prepare the long-acting of high drug load with surfactant
Injection, it is critical that sport technique segment, application is or not the control of the determination of dosage, the selection of surfactant and content
When, it is understood that there may be problem include leading to preparation storage life to shorten, preparation character changes, inject after position increased response
Even produce toxicity, these are all the problems that people are unwilling to accept.
Further, since Oleum Ricini has higher viscosity and it is limited to the solvability of ivermectin class medicine, therefore,
In the disclosed long-acting injection containing Oleum Ricini (for example：CN 1215331A、CN 1293921C、CN 1197583C、CN
1867341B、CN 101312710A、CN 102316876A、WO 99/27906、CN 104095812A、CN 104168886A、
CN 101703776A, WO 97/11709, US 6552002 etc.), majority all applies and can reduce oil preparation viscosity and increase dissolving
The auxiliary agent of degree, applies more auxiliary agent to be N-Methyl pyrrolidone, dimethyl acetylamide, ethyl acetate, ethyl oleate, benzoic acid
Benzyl ester, also useful ethanol.Add these solvents in the formulation, the species due to adding is different, and addition is different, often carries
It is only possible to some ill effects finding when coming commonly used.For example, ethanol, ethyl acetate, dimethyl acetylamide, N- methyl pyrrole
Pyrrolidone etc. is not the good solvent of tissue tolerance, their application and need in terms of usage amount strict control, application
Improper or because of animal difference, frequently can lead to animal injection site and the serious position reactions such as red and swollen and inflammation occur.Only use benzene
Benzyl formate and vegetable oil to prepare during the long-acting injection of the medicine of class containing ivermectin although formulation An injection portion as solvent
The zest of position is inconspicuous, but preparation lacks the stability stored, and deposits easy appearance precipitation and even occur to coagulate below 4 DEG C
Gu.Especially only with the ivermectin injection of benzyl benzoate and the preparation of more Oleum Ricini, it is very slow that drug effect is come, blood medicine peak
Concentration is low, bioavailability low (as the control formulation of embodiment 5).Poloxamer 188 is added to solve oil note in oil preparation
When penetrating the low problem of the slow and peak phase blood drug level that agent drug effect comes, as with benzyl benzoate as solvent, when poloxamer in preparation
When 188 contents are more than 3% about, place for a long time in low temperature, Poloxamer 188 can separate out, therefore, this kind of preparation is not suitable for
Deposit under low temperature, this makes the application of commodity receive certain restriction, is unfavorable for commercialization popularization and application.
Glyceryl triacetate be a kind of prepare oily injection commonly use oil medium, be related to oily injection system in many
All refer in standby patent application to prepare long-acting oil injection with glyceryl triacetate for medium, including with three second
The injection that acid glyceride to prepare the medicine of class containing ivermectin for solvent (proposes to make with glyceryl triacetate for solvent earliest
The patent application of standby ivermectin injection is EP 0 413538A1, EP 0 535734A1 and patent WO 99/27906).?
In the patent application of the oily injection to prepare the medicine of class containing ivermectin with oil medium for solvent, many also all carries simultaneously
To oily injection is prepared (such as oil medium with glyceryl triacetate, benzyl benzoate, vegetable oil (inclusion Oleum Ricini)
The of CN 104168886A【0081】With【0099】Section), but all lack clearly discussion and the test support of concrete technical scheme.
In other words, do not express the bacterium containing Yi Wei prepared by with benzyl benzoate, glyceryl triacetate, Oleum Ricini as oil medium
The technical characteristic of the oily injection of element, the such as relation to the ratio of three kinds of oil mediums in preparation and preparation clinic drug effect,
With the relation of internal blood drug level Changing Pattern, and the special role played of glyceryl triacetate etc. all specifically do not retouch
State.
Content of the invention
Only release is had for the drug injection of class containing ivermectin prepared by solvent by benzyl benzoate and Oleum Ricini too slow
Problem.The present invention proposes specific solution to this.This programme is by substituting part benzoic acid with glyceryl triacetate
Benzyl ester, and suitable adjustment Oleum Ricini content in the formulation, in combination with the change of dosage, thus improve certain in preparation
The rate of release of amount ivermectin class medicine, on the premise of maintaining long-acting, makes the quick-acting of preparation and peak phase blood medicine dense
Degree level is improved；In solution proposed by the present invention, quick-acting and long-acting components are more specifically specify that
And consumption, so that preparation has controllable slow releasing function and controllable initial release amount；By technology proposed by the present invention
The preparation of scheme preparation also has the more preferable feature of stability (during preservation, to be prepared than with N-Methyl pyrrolidone and Oleum Ricini
Preparation produce 2- epimer ivermectin less)；With containing ethanol, dimethyl acetylamide, N-Methyl pyrrolidone
Preparation compares, and invention formulation has also obtained further improvement in terms of tissue tolerance.
Preparation proposed by the present invention comprises the ivermectin class medicine of 0.1-10% (weight/volume) and by Benzyl Benzoate
Ester, glyceryl triacetate, the cosolvent of Oleum Ricini composition；Antioxidant and local analgesic also can be added in preparation.By volume hundred
Divide than calculating, in the described cosolvent being made up of benzyl benzoate, glyceryl triacetate, Oleum Ricini, glyceryl triacetate
Content be 10-38%, the content of Oleum Ricini is 15-40%, balance of benzyl benzoate.
Described ivermectin class medicine include ivermectin, doractin, moxidectin, acetylamino evericin,
The compositionss of one of avilamycin, selamectin or two kinds.They belong to Macrolide anti-parasite medicine.
Described glyceryl triacetate is a kind of zest very little to body tissue, have no toxic side effect, metabolizable oil
Property solvent.It can use as solvent, cosolvent or diluent in the preparation of injection, because its safety is good, therefore, can
Used as exclusive solvents in injection.In invention formulation, the Main Function of glyceryl triacetate has three aspects：
(1) combine the solvent as dissolving ivermectin class medicine with benzyl benzoate and Oleum Ricini, its addition is not only further
Reduce the viscosity of preparation, the shortcoming also overcoming benzyl benzoate easily solidification under cryogenic；(2) divided by blood drug level
Analysis test, is found surprisingly that, adds a certain amount of triacetic acid in the ivermectin injection containing benzyl benzoate and Oleum Ricini
After glyceride, can obviously improve the rapid release effect of preparation, and bioavailability significantly improves (see embodiment 5 and Fig. 1).Pass through
The content ratio of glyceryl triacetate, benzyl benzoate and Oleum Ricini three in adjustment formula, and combine on the premise of safety
Improve dosage, gratifying clinical effectiveness (see embodiment 6) can be obtained；(3) present invention utilize glyceryl triacetate and
Benzyl benzoate combination to substitute ethanol, dimethyl acetylamide or N-Methyl pyrrolidone it will be apparent that reducing note as solvent
Pain reaction when penetrating, makes injection be in tolerable level (see embodiment 7) to the zest of tissue.
The present invention select glyceryl triacetate replace Poloxamer 188 come to prepare have the long-acting effect that also has immediate effect containing her
The reason dimension bacteriums drug injection, is, Poloxamer 188 is insoluble in vegetable oil, when with benzyl benzoate as hydrotropy
During agent, preparation is deposited below 5 DEG C and is tended to have sticky material and separate out, and that is, preparation lacks the stability of storage, exist need in 5 DEG C with
The deficiency of upper preservation, this is unfavorable for popularization and application.
According to information, in the oily injection of preparation, the consumption of benzyl benzoate reaches 70% still without observing
Bad toxic and side effects.Effect played in this agent for the benzyl benzoate mainly has three aspects：(1) combine with Oleum Ricini, make
For preparing slow-released carrier and the solvent of this agent.Test display, meltage in this system for the medicine such as ivermectin is up to 13%
More than；In preparation, Semen Ricini oil content increases, and drug releasing rate slows down；When Semen Ricini oil content is constant, by Benzyl Benzoate ester content
Improve, glyceryl triacetate content is reduced, drug releasing rate equally slows down；(2) unexpectedly observe in research process,
Substitute ethanol, dimethyl acetylamide or N-Methyl pyrrolidone by the use of glyceryl triacetate and benzyl benzoate as solvent,
The 2- epimer H2B1a (the 1% about of only H2B1a activity) producing during preserving is less, so that preparation has
More preferable stability (see embodiment 7).(3) although relevant books are recorded glyceryl triacetate and are dissolved in Oleum Ricini, we
Test display, both are simultaneously immiscible, and therefore, benzyl benzoate also acts as the effect of bridging solvent in this agent, that is, pass through benzene
The addition of benzyl formate makes the heterogeneity liquid containing glyceryl triacetate and Oleum Ricini become homogeneous, stable, clear
Liquid.The addition of benzyl benzoate should be not less than the 60% of glyceryl triacetate addition in the formulation, and otherwise preparation can divide
Layer.
Described antioxidant include dibenzylatiooluene, tertiary butyl-4-hydroxy methoxybenzene, in propylgallate one
Plant or more than one compositionss.Antioxidant content in the formulation is 0.02-0.5% (weight/volume percent).
Described local analgesia agent selects benzyl alcohol, and its addition in the formulation is 1-3% (percent by volume).
Preparation proposed by the present invention is applied to the preventing and treating of animal parasitosis, is particularly suited for pig, cattle, sheep parasite disease anti-
Control, subcutaneously or intramuscularly to inject this agent, single administration, the preventing and treating phase can maintain 35-90 days even longer.When using, pass through
Change dosage can adjust duration of efficacy, that is, in certain scope, dosage is bigger, the drug effect duration longer (see
Embodiment 6).In medicament preparation process, by improving Semen Ricini oil content, the drug effect phase can be made to extend；Sweet by improving triacetic acid
Glyceride content can make the rapid release effect of medicine strengthen, and can carry peak period blood levels, improves bioavailability (see enforcement
Example 5).Therefore, by the change connected applications of glyceryl triacetate, the adjustment of Semen Ricini oil content and dosage in formula, can make
The different clinical parasiticide injections needing must be practically applicable to, this is the technical characteristics feature of the present invention.
Brief description
Fig. 1 is preparation 15,16, the 17 and Comparative formulation blood concentration-time curve chart in sheep body.
Specific embodiment
With reference to specific embodiment, the technical characteristic of the present invention is further described.
Embodiment 1. prepares the injection of the medicine of class containing ivermectin
Preparation composition is shown in Table 1.Described in table 1, the preparation process of preparation is as follows：Will be sweet to benzyl benzoate, Oleum Ricini and triacetic acid
Grease mixes, and stirs most homogeneous solution, adds active ingredient afterwards, is heated or not heated, and stirring is allowed to dissolve, and obtains final product this
Invention preparation.Formulation process should aseptically be carried out, and all supplementary materials all should be aseptic.This preparation also can divide
After dress sterilize, sterilising temp with 110 DEG C, 15-20 minute.
Table 1. preparation 1 forms to preparation 5
| Composition | Preparation 1 | Preparation 2 | Preparation 3 | Preparation 4 | Preparation 5 |
| Ivermectin g | 0.2 | 2 | 5 | 6 | 8 |
| Glyceryl triacetate ml | 15 | 25 | 30 | 31 | 31 |
| Oleum Ricini ml | 15 | 15 | 20 | 34 | 30 |
| Benzyl benzoate ml | 70 | 60 | 47 | 31 | 32 |
The parasiticide injection containing doractin for embodiment 2. preparation
Preparation 6 containing doractin is shown in Table 2 to preparation 10 composition, and preparation method is as follows：By benzyl benzoate, Oleum Ricini and
Glyceryl triacetate mixes, and stirs most homogeneous solution, adds doractin, antioxidant and benzyl alcohol afterwards, heating or not
Heating, stirring is allowed to dissolve, and obtains final product this agent.Formulation process should aseptically be carried out, and all supplementary materials all should
Aseptic.This preparation also can sterilize after subpackage, sterilising temp with 110 DEG C, 15-20 minute.
Table 2. preparation 6 forms to preparation 10
| Composition | Preparation 6 | Preparation 7 | Preparation 8 | Preparation 9 | Preparation 10 |
| Doractin g | 0.1 | 0.5 | 3 | 5 | 7 |
| Glyceryl triacetate ml | 15 | 25 | 36 | 25 | 28 |
| Oleum Ricini ml | 30 | 28 | 26 | 35 | 40 |
| Benzyl alcohol ml | 1.3 | 2.5 | 2 | 3 | 2 |
| BHA g | 0.01 | 0.01 | 0.01 | 0.01 | 0.01 |
| BHT g | 0.02 | 0.02 | 0.02 | 0.02 | 0.02 |
| Benzyl benzoate ml | 54 | 44 | 36 | 34 | 30 |
The injection containing acetylamino evericin for embodiment 3. preparation
Composition containing acetylamino evericin injection is shown in Table 3；Preparation method is with embodiment 2.
Table 3. preparation 11 forms to preparation 14
| Composition | Preparation 11 | Preparation 12 | Preparation 13 | Preparation 14 |
| Acetylamino evericin g | 3.5 | 6 | 8 | 10 |
| Glyceryl triacetate ml | 30 | 40 | 35 | 35 |
| Oleum Ricini ml | 15 | 18 | 18 | 25 |
| Benzyl benzoate ml | 54 | 41 | 46 | 38.5 |
| BHA g | 0.01 | 0.01 | 0.01 | 0.01 |
| BHT g | 0.02 | 0.02 | 0.02 | 0.02 |
| Benzyl alcohol ml | 1 | 1 | 1 | 1.5 |
Embodiment 4. preparation is containing 4% ivermectin oil injection
Oily injection composition containing 4% ivermectin is shown in Table 4；Formulation preparation method is with embodiment 2.
Table 4. preparation 15 is to preparation 17 and control formulation composition
| Composition | Preparation 15 | Preparation 16 | Preparation 17 | Control formulation |
| Ivermectin g | 4 | 4 | 4 | 4 |
| Glyceryl triacetate ml | 35 | 28 | 20 | 0 |
| Oleum Ricini ml | 15 | 28 | 15 | 28 |
| Benzyl alcohol ml | 1.5 | 1.5 | 1.5 | 1.5 |
| BHA g | 0.01 | 0.01 | 0.01 | 0.01 |
| BHT g | 0.02 | 0.02 | 0.02 | 0.02 |
| Benzyl benzoate ml | 46 | 40 | 61 | 68 |
Embodiment 5. preparation 15,16, the 17 and control formulation blood concentration assay in sheep body
Experimental animal and administration
The healthy sheep (Small-fat-tail sheep) 24 selecting 25-31 kg body weight is only used as test animal, correct amount.In administration
Front collection blank plasma is detected, does not contain ivermectin after testing, you can for testing in its blood plasma.Test is divided into 4 groups,
Numbering is 15 groups of preparation, 16 groups of preparation, 17 groups of preparation, control formulation group, respectively injection embodiment 4 in preparation 15, preparation 16,
Preparation 17 and control formulation, in sheep cervical region subcutaneous injection, dosage is 0.4mg/kg b.w..Note sheep only during injection
Pain reaction situation, note checking that injection site has or not redness, caking etc. when taking a blood sample every time, and make well-documented history.
Blood specimen collection and pretreatment
Injection gathered blood sample after 12 hours, 36 hours, 3 days, 5 days, 6 days, 8 days, 11 days, 16 days, 20 days, 35 days, often
Secondary every sheep extracts 5 milliliters of blood from jugular vein, is added to equipped with the centrifuge tube of heparin sodium aqua, takes supernatant liquid after centrifugation
(i.e. blood plasma) is in empty centrifuge tube.Samples taken should be carried out labelling and be stored in -20 DEG C of refrigerators.
Blood sample purification
Take the sheep plasma of -20 DEG C of preservations, room temperature places 1-2 hour, after making blood plasma recover room temperature, take 1 milliliter of blood plasma, plus
3.5 milliliters of methanol, concussion processes 1min, stands 20min, and 1200 × g is centrifuged 20min, takes supernatant away；Precipitation repeats previous step
Suddenly；Merge supernatant twice, add 5 milliliters of ultra-pure waters, mix, use C18SPE post (500mg) purification, method is：Activated with methanol
C18SPE post, with loading after 4 milliliters of 70% methanol aqueous solution balance, coutroi velocity about 1mL/min, afterwards successively with 4 milliliters pure
Water, 4 milliliter of 70% methanol aqueous solution drip washing, with 4 ml methanol eluting in three times, eluent is placed in N in glass tubing2(55 DEG C) blow
Dry.
Derivatization is detected with HPLC
In the glass tubing thoroughly drying up, it is initially charged N- Methylimidazole .-acetonitrile 200 μ L, concussion adds trifluoro second after mixing
Anhydride-acetonitrile 200 μ L, mixes, and puts and adds methanol 600 μ L after reacting 10min at room temperature, crosses 0.22 μm of filter membrane, filter after mixing
Liquid HPLC in time detection.Chromatographic condition is：Using SunFireTM C185 μm of 4.6 × 150mm chromatographic columns, mobile phase be water-
Acetonitrile-methanol (5.5: 32: 62.5), is measured using fluorescence detector, and excitation wavelength is 365nm, and launch wavelength is
475nm, sample size is 10 μ L；Flow velocity is 1mL/min；Column temperature is 35 DEG C.
Result of the test
Result of the test is shown in table 5 and Fig. 1.From table 5 data and Fig. 1：(1) comparing preparation 16 with control formulation can
See, when Semen Ricini oil content is the same, replace part benzyl benzoate with glyceryl triacetate, peak phase blood drug level is far above and is not added with three
The control formulation of acetin, and Double-peak Phenomenon occurs, first time blood medicine peak occurred at 36 hours about, little 144
When about again peak occurs it is believed that the appearance on first time peak is likely to mainly glyceryl triacetate and part Yi Wei
The effect that the release of rhzomorph is brought, the appearance on second peak should be that the release of benzyl benzoate/ivermectin is brought
Effect.
This points out us, and by changing the ratio of glyceryl triacetate and Oleum Ricini in preparation, the controllability release of medicine is
Can realize.This is the technical characteristics of this agent.(2) preparation 15, preparation 17 are compared visible, reduction Semen Ricini with preparation 16
Oil content, peak phase blood drug level significantly improves, and the glyceryl triacetate adding is more, and peak phase blood drug level is higher；With right
Compare according to preparation, peak reaching time of blood concentration is early, reached blood medicine peak at the 3rd day about, and does not contain glyceryl triacetate
Matched group, whole process release is gentle, but blood peak concentration of drug level is too low.Above-mentioned result of the test shows, glyceryl triacetate has
Play the role of to accelerate ivermectin release.
Ivermectin mean concentration (ng/mL) in each time point sheep plasma of table 5.
| h | Preparation 15 | Preparation 16 | Preparation 17 | Control formulation |
| 12 | 5.2 | 4.8 | 4.2 | 3.6 |
| 36 | 13.1 | 11.2 | 9.6 | 7.1 |
| 72 | 16.7 | 7.5 | 13.8 | 7.4 |
| 120 | 14.3 | 10.5 | 12.5 | 8.0 |
| 144 | 13.3 | 11.3 | 11.3 | 8.7 |
| 192 | 9.9 | 7.1 | 10.7 | 6.5 |
| 264 | 4.5 | 4.4 | 4.8 | 5.2 |
| 384 | 1.8 | 3.3 | 3.1 | 2.5 |
| 480 | 1.3 | 1.9 | 2.4 | 2.1 |
After the preparation 17 of embodiment 6. sheep injection various dose, plasma ivermectin concentrations measure
Experimental animal and administration
Select the healthy sheep 24 of 27-35 kg body weight, be divided into 3 groups (the 1st group, the 2nd group and the 3rd groups) at random.Accurately
Weigh, through the preparation 17 in cervical region skin injection embodiment 5, gather blank plasma before administration.Organizing 1 dosage is 0.4mg/kg
b.w.；Organizing 2 dosages is 0.8mg/kg b.w.；Organizing 3 dosages is 1.2mg/kg b.w..Sheep pain is noted during injection
Response situation, and record.
Blood specimen collection and the test side such as pretreatment, blood sample preservation, blood sample purification and derivatization, chromatographic condition of HPLC detection
Method is same as Example 5, and plasma ivermectin concentrations analysis result is shown in table 6.
After the preparation 17 of table 6. sheep injection various dose, plasma ivermectin concentrations measure
| Time (my god) | 2 | 5 | 10 | 15 | 20 | 35 | 55 | 75 | 90 |
| 1st group | 10.8 | 14.7 | 6.5 | 4.4 | 3.1 | 1.1 | 0.3 | ND | ND |
| 2nd group | 16.7 | 19.2 | 11.8 | 10.4 | 6.5 | 4.3 | 1.9 | 0.7 | ND |
| 3rd group | 19.5 | 27.9 | 18.5 | 15.1 | 11.2 | 7.5 | 3.8 | 1.8 | 0.6 |
From upper table data, increase with dosage, peak phase blood levels improve, effective blood drug concentration (literary composition
Offer and be recited as 0.5ng/ml) persistent period also extends, therewith with 1.2mg/kg b.w. dosed administration (the 3rd group), effective blood
Concentration can continue until 75-90 days.The upper table Notes of Key Data we：In Clinical practice, user can as needed, in 3.5mg/
In the range of the dosage of kg b.w (see the safety testing of embodiment 7), drug effect is changed by change dosage and continues
Time.This is the outstanding feature that this preparation has in terms of clinical practice.
The character of embodiment 7. preparation 17, stability, safety and irritation test
1. the character of preparation and stability test
Preparation in embodiment 5 is the slightly sticky liquid of clear, places in -18 DEG C, and formulation viscosity increases, but not
Occur to solidify and precipitation occurs, preparation is placed 12 months in 30-32 DEG C, with HPLC detection, the decrement of ivermectin is only just
The 0.49-0.72% of beginning amount, the relative amount of 2- epimer H2B1a is 0.18-0.26%, monosaccharide ivermectin relative
Content is 0.33-0.49%.Above test data shows preparation stabilization, and quality has reached commercial requirements.When with N- methyl pyrrole
When pyrrolidone is as cosolvent, the relative amount of 2- epimer H2B1a is 0.67-0.92%.
2. the safety of preparation and irritation test
Select the healthy sheep 8 that body weight is 28-33 kilogram, correct amount, by 3.5mg/kg b.w. dosage through cervical region skin
Lower ejection preparation 17, the behavior of experimental animal, the situation of change of injection site and body weight after observation medication in 30 days.Result shows
Show, upon administration, 8 sheep all search for food normally, no any Deviant Behavior；Injection site no lump；It is administered latter 30 days and weighs, put down
All daily gains 0.18-0.27 kilogram, with the matched group zero difference by 0.4mg/kg b.w. dosed administration.This result of the test explanation
3.5mg/kg b.w. dosed administration pressed by this preparation, to sheep safety.In addition, we analyze (embodiment in process of the test in blood medicine
5th, embodiment 6) to observe, when injecting, to sheep, the preparation that the present invention provides, no because the struggle phenomenon that pain leads to occurs, this says
Bright preparation zest is inconspicuous.In addition, in addition to indivedual sheep, injection site no lump produces, the sheep producing lump only (accounts for
Test sheep only 2.2%) caused by misoperation when being likely to and injecting.
Blood drug level detection in sheep body for the embodiment 8. abamectin injection (AVM)
1. the formula composition of preparation is shown in Table 7
Table 7. preparation 18,19 and the composition of Comparative formulation
2. determination of plasma concentration
Select the healthy sheep 24 of 33-37 kg body weight, divide 3 groups, every group 8, correct amount is after cervical region subcutaneous injection
Preparation 18, preparation 19 and Comparative formulation, dosage is 1.0mg/kg b.w, takes a blood sample on time, because being primary dcreening operation, in order to mitigate
Workload, is isolated and purified after same group, the plasma sample mixed in equal amounts of same time, measures AVM hereinafter in blood plasma with HPLC
Rhzomorph content (ng/ml).Isolate and purify, the specific operation process such as fluorescence derivation and HPLC measure with reference to " Pan Baoliang, Wang Ming,
Wang Yuwan, the foundation of sheep plasma avilamycin fluorescence highly effective liquid phase chromatography detection method, Chinese veterinary's science and technology, volume 32, the 11st
Phase, 2002, the 8-11 page " in method carry out.The measurement result of blood plasma avilamycin concentration (ng/ml) is shown in Table 8.
The measurement result of table 8. blood plasma avilamycin concentration (ng/ml)
| Time (my god) | 1 | 3 | 5 | 10 | 20 | 35 | 50 | 65 |
| Preparation 19 | 14.5 | 18.3 | 23.1 | 15.7 | 5.1 | 3.1 | 1.3 | 0.4 |
| Preparation 18 | 13.3 | 27.2 | 16.4 | 12.1 | 4.2 | 2.6 | 0.5 | ND |
| Comparative formulation | 8.8 | 12.1 | 16.5 | 9.4 | 5.6 | 4.3 | 2.5 | 0.6 |
As can be seen from Table 8, the Comparative formulation peak phase blood levels without glyceryl triacetate are significantly lower than containing three
The preparation 19 of acetin and preparation 18, and peak time is slow, but effective blood drug concentration level can maintain about 65 days.This
Illustrate Oleum Ricini to have significantly to slow down the effect of drug release, glyceryl triacetate has the work improving preparation initial release amount
With；Glyceryl triacetate content improves, and initial release amount improves.
The explanation of this result of the test：Oleum Ricini has good slow releasing function；Glyceryl triacetate can make preparation rapid release effect
Improved, suitable ratio is in by the content adjusting both and can prepare the long-acting injection with quick-acting effects, should
The value of preparation is that it is more suitable for generation and the development of killing and delay drug resistance of drug resistance worm strain.Through screening test table
Bright：In every 100 ml of formulation, the Optimum Contents of avilamycin are 3-6 gram, and the Optimum Contents of Oleum Ricini are 30-38 milliliter, three
Acetin 12-18 milliliter (balance of benzyl benzoate), active ingredient content, Semen Ricini oil content and glyceryl triacetate contain
Amount within this range, and adjusts dosage when being used in combination, you can ensure that preparation has drug effect next fast, peak concentration level and carries
High advantage.Also ensure that preparation still has long-acting.
Claims (3)
1. a kind of animal anti-parasitic injection, described infusion pump contains the ivermectin class medicine of 0.1-10%, weight/body
Long-pending ratio, adds to 100% by the cosolvent that benzyl benzoate, glyceryl triacetate, Oleum Ricini form, volume ratio；
In the described cosolvent being made up of benzyl benzoate, glyceryl triacetate, Oleum Ricini, the volume of glyceryl triacetate
Degree is 10-38%, and the volume percent content of Oleum Ricini is 15-40%, balance of benzyl benzoate, and benzene first
The content of acid benzyl ester is not less than the 60% of glyceryl triacetate content；
Described ivermectin class medicine includes ivermectin, doractin, moxidectin, acetylamino evericin, AVM hereinafter
The compositionss of one of rhzomorph, selamectin or two kinds.
2. the injection as described in claim 1 is it is characterised in that comprise the antioxygen of 0.02-0.5% in described injection
Agent, weight/volume percent, described antioxidant includes dibenzylatiooluene, tertiary butyl-4-hydroxy methoxybenzene, gallic acid
One of propyl ester or more than one compositionss.
3. the injection as described in claim 1 or claim 2 any one is it is characterised in that wrap in described injection
Benzyl alcohol containing 1-3%, percent by volume.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611014168.3A CN106377498B (en) | 2016-11-18 | 2016-11-18 | Anti parasitic injection containing glyceryl triacetate, Ergol and castor oil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611014168.3A CN106377498B (en) | 2016-11-18 | 2016-11-18 | Anti parasitic injection containing glyceryl triacetate, Ergol and castor oil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106377498A true CN106377498A (en) | 2017-02-08 |
| CN106377498B CN106377498B (en) | 2019-08-13 |
Family
ID=57958968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611014168.3A Active CN106377498B (en) | 2016-11-18 | 2016-11-18 | Anti parasitic injection containing glyceryl triacetate, Ergol and castor oil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106377498B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109197882A (en) * | 2018-09-14 | 2019-01-15 | 河北威远生物化工有限公司 | A kind of emamectin benzoate B2a/B2b benzoate emulsion and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490768A (en) * | 2014-12-01 | 2015-04-08 | 上海同仁药业有限公司 | Doramectin injection and preparation method thereof |
-
2016
- 2016-11-18 CN CN201611014168.3A patent/CN106377498B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490768A (en) * | 2014-12-01 | 2015-04-08 | 上海同仁药业有限公司 | Doramectin injection and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109197882A (en) * | 2018-09-14 | 2019-01-15 | 河北威远生物化工有限公司 | A kind of emamectin benzoate B2a/B2b benzoate emulsion and preparation method thereof |
| CN109197882B (en) * | 2018-09-14 | 2021-07-30 | 河北威远生物化工有限公司 | Emamectin benzoate emulsion B2a/B2B and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106377498B (en) | 2019-08-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100917809B1 (en) | Stable Pharmaceutical Composition containing Docetaxel | |
| KR20090052920A (en) | Stable pharmaceutical composition containing taxane derivatives, and method of manufacturing the same | |
| AU2016258642B2 (en) | Cabazitaxel fat emulsion injection, and preparation method and use thereof | |
| Zeng et al. | Pharmacokinetics and safety of ginsenoside Rd following a single or multiple intravenous dose in healthy Chinese volunteers | |
| CN102697795B (en) | Anti-tumor combined medicament | |
| CN107811967A (en) | Anti-parasite medicine in-situ solidification sustained-release injector and preparation method thereof | |
| CN101926813B (en) | Veterinary compound anti-parasitic injection and preparation method thereof | |
| CN103251565A (en) | Voriconazole freeze-dried powder injection for injection and preparation method thereof | |
| WO2013143300A1 (en) | Sustained-release preparation of fulvestrant or derivatives thereof and preparation method therefor | |
| Geng et al. | Study of an injectable in situ forming gel for sustained-release of Ivermectin in vitro and in vivo | |
| CN106377498A (en) | Anti-parasites injection containing glyceryl triacetate, benzyl benzoate and castor oil | |
| CN102342931B (en) | Injectable parenteral medicinal preparation of temozolomide and preparation method thereof | |
| CN101623255B (en) | Artesunate nanoemulsion drug composition and preparation method thereof | |
| CN112957320A (en) | Pharmaceutical preparation | |
| CN102940630A (en) | Medicinal composition containing temsirolimus and preparation method of medicinal composition | |
| CN104906590B (en) | Valnemulin parenteral solution containing brazil wax | |
| CN113041222B (en) | Injection emulsion and preparation method thereof | |
| CN101455648A (en) | Puerarin freeze-drying preparation | |
| CN1867341B (en) | Compositions for controlling parasites comprising a combination of abamectin and milbemycin | |
| CN1256948C (en) | Avermectin containing parasite resisitant long-acting injectio | |
| CN108289897B (en) | Pharmaceutical composition of remazolam | |
| CN104771360A (en) | Artemether nanoemulsion pharmaceutical composition and preparation method thereof | |
| CN101485632B (en) | Nimodipine lipid microsphere injection and preparation method thereof | |
| CN104173278A (en) | Subcutaneous injection administration system based on Brij97 liquid crystal and preparation method of subcutaneous injection administration system based on Brij97 liquid crystal | |
| CN101422454A (en) | Omega-3 polyunsaturated fatty acid tanshinone IIA sub-microemulsion and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20181205 Address after: 102209 C2034 2, 16 building, No. 37 Chao Yuan Road, Changping District science and Technology Park, Beijing. Applicant after: Beijing Zhongnonghuawei pharmaceutical Limited by Share Ltd Address before: 102206 Block C 510, Zhongguancun Life Science Park, Beiqing Road, Changping District, Beijing Applicant before: Beijing Zhongnonghuawei Biological Medicine Research Institute |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Anti-parasites injection containing glyceryl triacetate, benzyl benzoate and castor oil Effective date of registration: 20191128 Granted publication date: 20190813 Pledgee: Huaxia Bank Beijing branch Wanliu Limited by Share Ltd Pledgor: Beijing Zhongnonghuawei pharmaceutical Limited by Share Ltd Registration number: Y2019990000606 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 102209 C2034 2, 16 building, No. 37 Chao Yuan Road, Changping District science and Technology Park, Beijing. Patentee after: Zhongnonghuawei Pharmaceutical Co., Ltd Address before: 102209 C2034 2, 16 building, No. 37 Chao Yuan Road, Changping District science and Technology Park, Beijing. Patentee before: Beijing Zhongnong Huawei Pharmaceutical Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20210531 Granted publication date: 20190813 Pledgee: Huaxia Bank Beijing branch Wanliu Limited by Share Ltd. Pledgor: Beijing Zhongnong Huawei Pharmaceutical Co.,Ltd. Registration number: Y2019990000606 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |