CN104666244A - Veterinary anti-parasitic preparation containing carnauba wax - Google Patents
Veterinary anti-parasitic preparation containing carnauba wax Download PDFInfo
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- CN104666244A CN104666244A CN201510118056.1A CN201510118056A CN104666244A CN 104666244 A CN104666244 A CN 104666244A CN 201510118056 A CN201510118056 A CN 201510118056A CN 104666244 A CN104666244 A CN 104666244A
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- Prior art keywords
- preparation
- injection
- oil
- brazil wax
- oil preparation
- Prior art date
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- 239000004203 carnauba wax Substances 0.000 title claims abstract description 76
- 230000002141 anti-parasite Effects 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title abstract description 168
- 239000003096 antiparasitic agent Substances 0.000 title abstract description 6
- 235000013869 carnauba wax Nutrition 0.000 title abstract 5
- 239000003814 drug Substances 0.000 claims abstract description 62
- 238000002347 injection Methods 0.000 claims abstract description 57
- 239000007924 injection Substances 0.000 claims abstract description 57
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 21
- 239000008158 vegetable oil Substances 0.000 claims abstract description 21
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000005660 Abamectin Substances 0.000 claims abstract description 15
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 claims abstract description 12
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 claims abstract description 12
- 229940093471 ethyl oleate Drugs 0.000 claims abstract description 12
- FSVJFNAIGNNGKK-UHFFFAOYSA-N 2-[cyclohexyl(oxo)methyl]-3,6,7,11b-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4-one Chemical compound C1C(C2=CC=CC=C2CC2)N2C(=O)CN1C(=O)C1CCCCC1 FSVJFNAIGNNGKK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960002903 benzyl benzoate Drugs 0.000 claims abstract description 8
- BEZZFPOZAYTVHN-UHFFFAOYSA-N oxfendazole Chemical compound C=1C=C2NC(NC(=O)OC)=NC2=CC=1S(=O)C1=CC=CC=C1 BEZZFPOZAYTVHN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960004454 oxfendazole Drugs 0.000 claims abstract description 8
- 229960002957 praziquantel Drugs 0.000 claims abstract description 8
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 5
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 5
- 239000003921 oil Substances 0.000 claims description 100
- 235000019198 oils Nutrition 0.000 claims description 98
- 239000000203 mixture Substances 0.000 claims description 43
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 36
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 36
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 36
- 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 description 20
- 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 description 20
- 229960002418 ivermectin Drugs 0.000 claims description 20
- 229930192734 Avilamycin Natural products 0.000 claims description 19
- 239000004190 Avilamycin Substances 0.000 claims description 19
- 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 group 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 claims description 19
- 229960005185 avilamycin Drugs 0.000 claims description 19
- 235000019379 avilamycin Nutrition 0.000 claims description 19
- 235000012424 soybean oil Nutrition 0.000 claims description 7
- 239000003549 soybean oil Substances 0.000 claims description 7
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 6
- WPNHOHPRXXCPRA-TVXIRPTOSA-N eprinomectin Chemical compound O1[C@@H](C)[C@@H](NC(C)=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 WPNHOHPRXXCPRA-TVXIRPTOSA-N 0.000 claims description 5
- 229960002346 eprinomectin Drugs 0.000 claims description 5
- 210000000582 semen Anatomy 0.000 claims description 4
- 239000000473 propyl gallate Substances 0.000 claims description 3
- 229940075579 propyl gallate Drugs 0.000 claims description 3
- 235000010388 propyl gallate Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound 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 2
- QSHVAZMOLNGWSY-UHFFFAOYSA-N 3-butyl-4-methoxyphenol Chemical group CCCCC1=CC(O)=CC=C1OC QSHVAZMOLNGWSY-UHFFFAOYSA-N 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
- 230000000694 effects Effects 0.000 abstract description 12
- RZRNAYUHWVFMIP-KTKRTIGZSA-N 1-oleoylglycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-KTKRTIGZSA-N 0.000 abstract 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract 3
- RZRNAYUHWVFMIP-HXUWFJFHSA-N glycerol monolinoleate Natural products CCCCCCCCC=CCCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-HXUWFJFHSA-N 0.000 abstract 3
- 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 abstract 1
- 229950008167 abamectin Drugs 0.000 abstract 1
- 235000019445 benzyl alcohol Nutrition 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 description 45
- 239000008280 blood Substances 0.000 description 45
- 241001494479 Pecora Species 0.000 description 43
- 229940079593 drug Drugs 0.000 description 26
- 238000009472 formulation Methods 0.000 description 22
- 238000012360 testing method Methods 0.000 description 20
- 210000002381 plasma Anatomy 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 230000000895 acaricidal effect Effects 0.000 description 11
- 239000000642 acaricide Substances 0.000 description 11
- 238000001514 detection method Methods 0.000 description 10
- 238000010254 subcutaneous injection Methods 0.000 description 10
- 239000007929 subcutaneous injection Substances 0.000 description 10
- 238000011282 treatment Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 241000283690 Bos taurus Species 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 230000036765 blood level Effects 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- XINQFOMFQFGGCQ-UHFFFAOYSA-L (2-dodecoxy-2-oxoethyl)-[6-[(2-dodecoxy-2-oxoethyl)-dimethylazaniumyl]hexyl]-dimethylazanium;dichloride Chemical compound [Cl-].[Cl-].CCCCCCCCCCCCOC(=O)C[N+](C)(C)CCCCCC[N+](C)(C)CC(=O)OCCCCCCCCCCCC XINQFOMFQFGGCQ-UHFFFAOYSA-L 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000013019 agitation Methods 0.000 description 5
- 238000010171 animal model Methods 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 4
- 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 4
- 229960001008 heparin sodium Drugs 0.000 description 4
- 210000004731 jugular vein Anatomy 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 241000238876 Acari Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 108010006025 bovine growth hormone Proteins 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 230000023597 hemostasis Effects 0.000 description 3
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- 239000004033 plastic Substances 0.000 description 3
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- 238000010008 shearing Methods 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000000273 veterinary drug Substances 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 241000509427 Sarcoptes scabiei Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- -1 doractin Chemical compound 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
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- 238000012216 screening Methods 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- NOYRGONWBIVLEL-SNAWJCMRSA-N (e)-1,1-dimethoxybut-2-ene Chemical compound COC(OC)\C=C\C NOYRGONWBIVLEL-SNAWJCMRSA-N 0.000 description 1
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical class OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
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- 238000010241 blood sampling Methods 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention relates to a veterinary anti-parasitic injection containing carnauba wax. The preparation is mainly prepared from anti-parasitic medicine, the carnauba wax and an oily medium, wherein the anti-parasitic medicine is avermectins, praziquantel and oxfendazole; the oily medium is vegetable oil, ethyl oleate or benzyl benzoate, and more than one of the vegetable oil, ethyl oleate or benzyl benzoate can be combined to use. Glycerol mono-oleate can be added in the preparation, the carnauba wax and the glycerol mono-oleate are compositely applied, and the slow-release effect of the preparation is better. The selected preparation is prepared from 36-80 g of abamectin anti-parasitic medicine, 10-70 g of the carnauba wax, 80-120 g of the glycerol mono-oleate, 0.1-0.3 g of an antioxidant, 10-20 g of benzyl alcohol and the balance of the oily medium (per 1000ml).
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, being specifically related to brazil wax or brazil wax and glyceryl monooleate is slow-release material, and preparation is containing the long-acting veterinary injection of anti-parasite medicine.
Background technology
Brazil wax is also known as Brazil wax, it is nontoxic, nonirritant, and being recognized is safe pharmaceutic adjuvant, be often used as the polishing agent of tablet or coating of pill, ointment base, suppository base in a medicament, and the disperse medium of solid dispersion and the slow-release material of oral formulations.About the application of brazil wax in injection, report few.Patent CN86105087C discloses a kind of technical scheme prepared containing bovine growth hormone long-acting injection, bovine growth hormone is suspended in the oil medium be made up of brazil wax and vegetable oil, brazil wax Optimum Contents is 5-10%, this oil preparation of subcutaneous injection, single-dose, effective sustained release time of bovine growth hormone can reach about 28 days.Some patents (as: patent CN1572302A, CN1698637A, CN1236758A, CN1461640A, CN1444925A, CN1421199A, CN1572300A) are also had to refer to available brazil wax as the slow-release material of injection or suspending agent etc., but all open or discuss clearly for core contents such as concrete technology of preparing scheme (composition etc. as formula) and clinical effectiveness thereof.
We observe in the process of exploitation anti-parasite medicine long-acting injection: (1), containing the oily injection of vegetable oil and brazil wax, the oily injection prepared than alone vegetable oil has more obvious long-acting; (2) slow releasing function of drug level to preparation has a significant effect, and when preparation of Chinese medicine concentration brings up to certain level, the effective blood drug concentration persistent period in sheep body obviously extends; (3) brazil wax and glyceryl monooleate Combination application, slow release effect is better.As can be seen here, with vegetable oil and brazil wax or the veterinary injection preparing the Avermectins anti-parasite medicine containing higher concentration with vegetable oil, brazil wax and glyceryl monooleate (GMO), good commercial promise is had.
Summary of the invention
The present invention is by introduction brazil wax in detail or prepare the long-acting injection containing anti-parasite medicine with brazil wax/glyceryl monooleate.
1, preparation composition:
Preparation comprises anti-parasite medicine; Brazil wax; Vegetable oil or ethyl oleate or benzyl benzoate, but they more than one use together.
Described anti-parasite medicine comprises one or more the compositions in Avermectins medicine, praziquantel, oxfendazole.Avermectins medicine comprises avilamycin, ivermectin, doractin, Eprinomectin, moxidectin.They are mainly used in animal parasitosis control (Zhu Mozhong edits, veterinary drug handbook, Chemical Industry Press, July in 2002 the 1st edition, 167-174 page) at veterinary clinic.In the formulation, the concentration of Avermectins medicine is 1-15%, weight/volume.Find under study for action, when in preparation, avilamycin concentration reaches more than 3% or 3%, the slow releasing function of preparation is obviously strengthened (see embodiment 3).Therefore, consider from preparing durative action preparation angle, the concentration of Avermectins medicine in oil preparation is greater than 3% better.Consider the weight of animals size, wish the factors such as the duration of efficacy that reaches and dosage, for the preparation of pig or sheep, drug level at 3-4% (weight/volume) as well; For the preparation of the large animal such as cattle, horse, drug level is suitable in 6% (weight/volume) left and right; Preparation is containing the semi-solid oil preparation of high concentration brazil wax, and drug level is that 10-15% is suitable.Praziquantel or oxfendazole suitable concentration is in the formulation 8-20%, weight/volume.
Described brazil wax is also known as Brazil wax, and its concentration is in the formulation 0.7-10%.Within the scope of finite concentration, the concentration of brazil wax is larger, the release of preparation is held time also longer (see embodiment 2), but during brazil wax excessive concentration, can make preparation too thickness, adhesion rate increases, and needs larger thrust during injection, and need the longer time just can complete injection process, bring inconvenience to use.In this preparation, the upper limit of brazil wax concentration should have good mobility by preparation or easily by No. 16 needle for injections (semi-solid preparation), also can determine with reference to the key factor such as the cohesiveness of medicinal liquid and the duration of efficacy of hope simultaneously.Test shows, brazil wax good concentration range in this preparation is 0.7-6%, weight/volume, when in preparation, brazil wax concentration is less than 2%, the mobility of preparation and cohesiveness are in acceptable state, along with the further increase of concentration, viscosity increases significantly, when brazil wax concentration is greater than 5%, applicable preparation semi-solid state, require the oil preparation that the release phase is longer, the applicable syringe of oil preparation of this semi-solid state is as packing container (by direct for oil preparation fill in syringe), and drug level should improve as much as possible, the oil preparation loss caused because of cohesiveness can be overcome like this, and volume injected can be reduced by improving drug level, to overcome the deficiencies such as administration difficulty.Be applicable to preparation to contain high concentration brazil wax, should possess containing the anti-parasite medicine of the semi-solid oil preparation of high concentration medicine the feature that activity is high, safety is good, Avermectins medicine is the broad-spectrum anti-parasite medicine being applied to clinical activity the highest (minimum effective dose is 0.01mg/kg b.w.) up to now.With semi-solid oil preparation prepared by Avermectins medicine, with high dose subcutaneous administrations, duration of efficacy significant prolongation, as the semi-solid oil preparation containing ivermectin 15% and brazil wax 6.5%, for the control of Wintering Period sheep parasite disease, by 1.5mg/kg b.w. dosage, single subcutaneous injection, duration of efficacy is 103 days or longer (see embodiments 10); Press 1.5mg/kg b.w. dosage for cattle, single subcutaneous injection (implantation) is containing the semi-solid oil preparation of ivermectin 15% and brazil wax 6.5%, and holding time of effective blood drug concentration reaches 125 days (see embodiment 11).In addition, brazil wax also can play the effect of suspending agent in this oil preparation.
GMO is a kind of monoglyceride compounds synthesized by glycerol and oleic acid, general as emulsifying agent or dispersant use in a medicament.Because GMO has the characteristic (being converted into full-bodied Emission in Cubic by laminar flow shape) absorbing in vivo and undergo phase transition after moisture reaches the balanced contents of 35%, therefore, inquired in recent years and utilize GMO to prepare the report of in-situ gelling long-acting injection a lot, and have commodity to go on the market.We find in recipe determination process, appropriate GMO is added in preparation, not only can overcome the medicament adhesion rate caused because adding brazil wax in vegetable oil to increase not enough (see embodiment 1), more importantly, contain the oil preparation of GMO and brazil wax simultaneously, its slow releasing function obviously strengthens, and is better than the oil preparation only containing brazil wax, is also better than the oil preparation (see embodiment 4) only containing vegetable oil and GMO.Therefore, when preparing invention formulation, by adding GMO to improve the slow release effect of preparation.In preparation, the suitable concentration of GMO is 3-20%, and better concentration is 8-12%, weight/volume.In addition, also observe in test, the oil preparation containing GMO and brazil wax is injected water, the hydrophobicity agglomerate formed closely does not fall apart, and moisture not easily infiltrates, and this points out us, add the raising of slow releasing function after GMO, seem to have with GMO the characteristic of phase transformation without direct substantial connection.
Described vegetable oil is injection vegetable oil, the one in preferred soybean oil, Semen Maydis oil, Oleum Camelliae, Oleum Gossypii semen, Oleum Ricini.These vegetable oil as medicinal solvent or oiliness disperse medium, by the more preparation for long-acting veterinary injection (as patent CN102316876A, CN101703776A, CN104095812A, CN1215331A, CN1421199A, WO 00/35445 etc.).Appropriate ethyl oleate or benzyl benzoate is added in the oil preparation prepared with vegetable oil, the viscosity of oil preparation can be reduced, and the solvability that can improve Avermectins medicine, therefore select suitable ratio vegetable oil and benzyl benzoate or ethyl oleate to be combinationally used, the good oil preparation of mobility can be prepared; When preparation is containing the oil preparation of high concentration Avermectins medicine, adds appropriate benzyl benzoate and preparation drug effect can be made to come soon, preparation does not lose that it is long-lasting simultaneously.
Owing to there is oxidizable composition in preparation, as vegetable oil, ethyl oleate etc., therefore, where necessary (as when not inflated with nitrogen embedding), also need in oil preparation to add antioxidant, the antioxidant selected is the mixture of one or more any ratios in tertiary butyl-4-hydroxy methoxybenzene (BHA), dibenzylatiooluene (BHT) or propyl gallate (PG), and antioxidant suitable concentration is in the formulation 0.1-0.5g/1000ml.In order to the pain of bringing out when alleviating injection, also should add appropriate local analgesia agent in preparation, the local analgesia agent of selection is benzyl alcohol, and its suitable concentration is 10-20g/1000ml preparation.
2, preparation method:
This agent preparation process should aseptically be carried out, and the preparation method of selection is:
By the acetic acid ethyl dissolution of active ingredient by 1.5-2 times amount, obtain active ingredient/ethyl acetate solution; Brazil wax is mixed with vegetable oil, is heated to 85-90 DEG C, after brazil wax dissolves, mix with active ingredient/ethyl acetate solution, under agitation decompression removing ethyl acetate, cool to room temperature, add other composition remaining, homogenize with high-speed shearing machine, obtain this oil preparation.Or brazil wax is mixed with vegetable oil, be heated to 85-90 DEG C, after brazil wax dissolves, under agitation, be down to room temperature, add active ingredient and other composition remaining, be ground to active ingredient particle diameter with high-shear homogenizing machine or colloid mill and be less than 15 μm, obtain this oil preparation.Or active ingredient, brazil wax and other adjuvant composition are mixed, cross pipeline high shear grinding machine, through repeatedly grinding, diameter of aspirin particle being ground to and being less than 15 μm, obtaining this oil preparation.
3, the cohesiveness of oil preparation and easy assay method:
In general, when comprising the slow-release material having and increase formulation viscosity in oil preparation, having a certain amount of medicament and adhering on the chamber wall of splendid attire medicament, during use, extract with syringe unclean, thus cause medicament to lose; The medicament adhered on bottle wall is more, loses larger.In the present invention, the part pharmaceutical quantities adhered on bottle wall is accounted for the percentage by weight of total pharmaceutical quantities/bottle, be referred to as adhesion rate (%); The adhesion rate of oil preparation increases, its commodity value declines, and oil preparation level of adhesion is larger, show that the viscosity of oil preparation is larger, the strength extracted needed for medicinal liquid and injection liquid with syringe can be larger, cause administration to be wasted time and energy, add labor intensity and labor cost, and often bring out the stress of animal and pain reaction stronger.It is considered herein that, as the primary dcreening operation index of oil preparation, reflect the sliminess of preparation by adhesion rate, more intuitively, more practical, and measure simple, easy to operate.The mensuration of adhesion rate is in the present invention adopted and is carried out with the following method.
The oil preparation prepared is filled to (the W that weighs
1) 25ml cillin bottle in, every bottled amount is 25ml, and fill is complete, and weigh (W
2), W
2-W
1be the dose weight (W of 25ml
3).Jump a queue after weighing, Zha Gai, room temperature leave standstill 1 month.During mensuration, back and forth the every bottle liquid medicine of shake, makes it abundant mixing, leaves standstill after 10 minutes, takes off aluminium lid and plug, incline and medicinal liquid, and keep bottle upsidedown 3 minutes, weighs the dose weight (W that inclines
4), (W
3-W
4)/W
3x 100 is the adhesion rate (%) of medicament.
The cohesiveness of invention formulation is measured, result display (see embodiment 1): in (1) oil preparation, brazil wax concentration is larger, and adhesion rate is larger in order to upper method; (2) containing the oil preparation of GMO, its adhesion rate is starkly lower than not containing the oil preparation of GMO.
Detailed description of the invention
In embodiment 1, brazil wax concentration and preparation, the existence of GMO is on the impact of oil preparation adhesion rate (%)
In table, oil preparation 1 to oil preparation 7 is the final volume being disperse medium with soybean oil and adding to oil preparation with soybean oil, in oil preparation, avilamycin concentration (%), brazil wax concentration (%), GMO concentration (%), be weight/volume percent concentration; The mensuration of oil preparation adhesion rate is undertaken by the method described in above summary of the invention, is the meansigma methods of 3 parallel samples with adhesion rate (%) in following table, and mensuration temperature is room temperature (21-24 DEG C).
As follows with the preparation process of oil agent 1 to oil preparation 7:
Brazil wax is mixed with soybean oil, at 85-90 DEG C, brazil wax is dissolved, obtain clean oil solution, after being down to room temperature, add avilamycin and GMO (oil preparation 5, oil preparation 7), with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear grinding 1 hour, obtain oil preparation 1-oil preparation 7.
Relatively the formula composition of oil preparation 1 to oil preparation 3 is visible, and in oil preparation, brazil wax concentration is larger, and adhesion rate is higher; Relatively the formula composition of oil preparation 4 and oil preparation 5, oil preparation 6 and oil preparation 7 is visible, and comprise oil preparation 5 and the oil preparation 7 of GMO, its adhesion rate is lower than oil preparation 4, the oil preparation 6 not containing GMO; When brazil wax concentration reaches 5%, adhesion rate is greater than 8%, and therefore, the oil preparation that brazil wax concentration is greater than 5% is not suitable for, with bottle as packing container, being applicable to the container of special plastic injector as splendid attire oil preparation.
Blood drug level after oil preparation 1, oil preparation 2, oil preparation 3 and Comparative formulation in embodiment 2, sheep injection embodiment 1 detects.
(1) preparation of Comparative formulation: getting purity is 96% (B
1acontent) avilamycin 5.21g, mix with 497ml soybean oil, with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear 1 hour, obtain the Comparative formulation containing avilamycin 1%.
(2) experimental animal, administration and blood specimen collection: select body weight the healthy sheep (Small-fat-tail sheep) 20 of 38-45 kilogram, be divided into 4 groups at random, often organize 5, be numbered group 1, group 2, group 3, group 4 respectively, organize 1 cervical region subcutaneous injection Comparative formulation 0.4mg/kg b.w., group 2, group 3, group 4 inject oil preparation 1, oil preparation 2, oil preparation 3 in embodiment 1 respectively, and cervical region subcutaneous injection, dosage is 0.4mg/kg b.w..Take a blood sample from sheep jugular vein after administration on time, each 4ml that accurately takes a blood sample, puts into same containing in the 20ml centrifuge tube of heparin sodium, with the centrifugal 10min of 3000r/min after mixing by the blood sample that same for the same test group time gathers, get upper liquid (blood plasma), be placed in-18 to-20 DEG C of preservations.
(3) in blood sample treatments and blood plasma, avilamycin detects: in blood sample treatments and blood plasma, the detection method of avilamycin presses document [Pan Baoliang, Wang Yuwan, Wang Ming, avermectins long-effective injection (oil suspending agent) and the pharmacokinetics comparative study of normal injection in sheep body, China's veterinary drug magazine, 2003,37 (3): 18-21] method in is carried out, and testing result is in table 1.
Oil preparation 1-oil preparation 3 in table 1, sheep injection embodiment 1 and the blood drug level (ng/ml) after Comparative formulation
In general, the blood concentration-time data of slow releasing preparation are not suitable for carrying out data analysis with classical pharmacokinetic model.Do not considering under the prerequisite of carrying out pharmacokinetic parameter system-computed, when applying the method screening formula of blood levels's assessment in animal body, can only at the representational time point blood sample collection of the drug effect maintenance period requiring to reach, and by the same group of blood sample with the time to carry out blood plasma separation, pretreatment and detection after mixed in equal amounts.Do like this, the detection limit of sample can extremely significantly reduce, thus can greatly reduce workload, is of value to means that application blood drug level detects and carries out more extensive, more scientific and closer to the recipe determination of actual (comparing with external simulation test).Published result of the test and clinical practice display, commercially available with 1,2-propylene glycol and formal glycerine are the 1% ivermectin injection prepared of cosolvent or 1% avilamycin injection, with the dosage of 0.2mg/kg b.w., single is to sheepskin hemostasis, duration of efficacy can reach about 18 days, is about 0.2ng/ml about the 21st day blood levels; With the dosage of 0.4mg/kg b.w., single is to sheepskin hemostasis, and duration of efficacy can reach 26-28 days, and within about the 26th day, blood levels is about 0.5ng/ml.
Based on above-mentioned, in the formulation screening test scheme of this research, the effect that the screened preparation of the requirement drafted reaches is: with the dosed administration of 0.4mg/kg b.w., 3rd day to the 5th day blood drug level is if reach more than 10 times (being greater than 10ng/ml) of minimum effective blood drug concentration upon administration, and about the 36th day upon administration, blood drug level still can remain on 2ng/ml level (reported in literature, avilamycin or ivermectin are to cattle, in the body of sheep, nematicide and verminal minimum effective blood drug concentration are 0.5-1.0ng/ml), the screened preparation of such blood levels can be reached, just there is necessity of commercial development.Based on this, this test and Selection two representational time point blood sample collections, to understand the slow release effect of screened oil preparation.First blood sampling time point is the 3rd day and the 5th day upon administration, and the time point of second blood sample collection is the 36th day and the 38th day upon administration.Data are detected from table 1, result of the test shows certain regularity, and give the result of notable difference: the 36th day to 38 days upon administration, the oil preparation containing brazil wax is not starkly lower than containing the oil preparation blood drug level of brazil wax, along with brazil wax concentration in the formulation increases, the blood levels of 36-38 days is in raising.When brazil wax concentration in preparation reaches certain level (as oil preparation 3, brazil wax concentration is 5%), more effectively can delay drug release, the 38th day upon administration, blood drug level was still in gratifying effect level.
The detection of blood drug level after oil preparation 2 in embodiment 3, sheep injection embodiment 1, oil preparation 4, oil preparation 6.
(1) experimental animal, administration and blood specimen collection: select body weight the healthy sheep (Small-fat-tail sheep) 15 of about 40 kilograms, be divided into 3 groups at random, often organize 5, oil preparation 2 respectively in cervical region subcutaneous injection embodiment 1, oil preparation 4, oil preparation 6, dosage is 0.4mg/kg b.w..Take a blood sample from sheep jugular vein after administration on time, each 4ml that accurately takes a blood sample, puts into same containing in the 20ml centrifuge tube of heparin sodium, with the centrifugal 10min of 3000r/min after mixing by the blood sample that same for the same test group time gathers, get upper liquid (blood plasma), be placed in-18 to-20 DEG C of preservations.
(2) in blood sample treatments and blood plasma, avilamycin detects: in blood sample treatments and blood plasma, the detection method of avilamycin is with embodiment 2, and result of the test is in table 2.
Blood drug level (ng/ml) after oil preparation 2, oil preparation 4 and oil preparation 6 in table 2, sheep injection embodiment 1
As seen from Table 2, when preparation of Chinese medicine concentration reaches more than 3%, slow releasing function is significantly improved, therefore, when preparing the long-acting veterinary injection containing Avermectins anti-parasite medicine with vegetable oil and brazil wax, when drug level in preparation reaches more than 3%, better clinical effectiveness (long-acting) can be had.
The detection of blood drug level after oil preparation 4, oil preparation 5 and Comparative formulation in embodiment 4, sheep injection embodiment 1.
(1) preparation of Comparative formulation: getting purity is 96% (B
1acontent) avilamycin 9.375g mix with GMO 30g, add soybean oil to 300ml, with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear 1 hour, obtain the Comparative formulation containing avilamycin 3%.
(2) experimental animal, administration and blood specimen collection: select body weight close to the healthy sheep (Small-fat-tail sheep) 24 of (about 40 kilograms), be divided into 4 groups at random, often organize 6,1st group, the 2nd group, the 3rd group oil preparation 4, oil preparation 5 and the Comparative formulation respectively in cervical region subcutaneous injection embodiment 1, dosage is 0.4mg/kg b.w., the 4th group of injected sc oil preparation 5 pressing 0.8mg/kg b.w.; Take a blood sample from sheep jugular vein after administration on time, each 4ml that accurately takes a blood sample, puts into same containing in the 20ml centrifuge tube of heparin sodium, with the centrifugal 10min of 3000r/min after mixing by the blood sample that same for the same test group time gathers, get upper liquid (blood plasma), be placed in-18 to-20 DEG C of preservations.
(3) in blood sample treatments and blood plasma, avilamycin detects: in blood sample treatments and blood plasma, the detection method of avilamycin is with embodiment 2, and testing result is in table 3.
Blood drug level (ng/ml) after oil preparation 4, oil preparation 5 and Comparative formulation in table 3, sheep injection embodiment 1
As seen from Table 3, the slow releasing function containing the oil preparation 5 (the 2nd group) of GMO and brazil wax in preparation is better than the oil preparation 4 (the 1st group) only containing brazil wax, compare, both significant differences with the Comparative formulation (the 3rd group) only containing GMO.This result of the test shows, by GMO and brazil wax being combinationally used, can extend duration of efficacy.Relatively the 2nd group (dosage 0.4mg/kg b.w.) is visible with the 4th group of (dosage 0.8mg/kg b.w.) result of the test, increase dosage, effectively can improve the later stage blood levels of (after administration 36-45 days).This tells us, and oil preparation of the present invention by increasing dosage, can effectively extend the drug action time in use.
The result of the test of comprehensive above embodiment 2, embodiment 3, embodiment 4 is visible, by whether adding of levelling brazil wax concentration, drug level, dosage and GMO, can obtain the long-acting injection with Expected Results.
Embodiment 5, the preparation of several 3.6% ivermectin injection and the prevention effect to sheep itch mite
(1) preparation of preparation
Preparation a: get brazil wax 20g, GMO 100g, purity is 97% (B
1acontent) ivermectin 37.11g, add ethyl oleate and be settled to 1 liter, fully mix, in 80-90 DEG C, brazil wax is dissolved completely, be down to room temperature, with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear 1 hour, obtain preparation a.
Preparation b: get brazil wax 20g, purity is 97% (B
1acontent) ivermectin 37.11g, add ethyl oleate and be settled to 1 liter, fully mix, in 80-90 DEG C, brazil wax is dissolved completely, be down to room temperature, with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear 1 hour, obtain preparation b.
Preparation c: get GMO 100g, purity is 97% (B
1acontent) ivermectin 37.11g, add ethyl oleate and be settled to 1 liter, fully mix, in 80-90 DEG C, ivermectin is dissolved completely, be down to room temperature, with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear 1 hour, obtain preparation c.
Preparation d: getting purity is 97% (B
1acontent) ivermectin 37.11g, be settled to 1 liter with ethyl oleate, with high-shear homogenizer under 12000-16000r/min condition, repeatedly shear 1 hour, obtain preparation d.
(2) evaluation of clinical curative effect
Experimental animal is 50 and has made a definite diagnosis the sheep infecting acaricide, and body weight is 30-45 kilogram, random point 5 groups, often organizes 10.Do not go and buy Chinese medicine for 1st group; Sheep subcutaneous injection formulation a, preparation b, preparation c, the preparation d respectively of the 2nd group, the 3rd group, the 4th group, the 5th group.Dosage is 0.4mg/kg b.w., mixed group's stable breeding 55 days after administration.Result of the test is as follows:
1st group, 0-55 days periods, 10 sheep all can detect demodicid mite alive.
2nd group (a), the sheep of 8-11 days all infection acaricides is all controlled effectively ejection preparation upon administration, drives clean rate and reaches 100%; After administration the 47th day, have 1 tested efficient demodicid mite of sheep, this illustrates that the duration of efficacy of preparation a was close to 47 days.
3rd group (ejection preparation b), the sheep of 10-13 days all infection acaricides is all controlled effectively upon administration, drives clean rate and reaches 100%; After administration the 44th day, have 2 tested efficient demodicid mites of sheep, this illustrates that the duration of efficacy of preparation b was close to 44 days.
4th group (ejection preparation c) upon administration 7-11 days all sheep infecting acaricide is all controlled effectively, and drives clean rate and reaches 100%; After administration the 35th day, have 2 tested efficient demodicid mites of sheep, this illustrates that the duration of efficacy of preparation c was close to 35 days.
5th group (ejection preparation d) upon administration 9-12 days all sheep infecting acaricide is all controlled effectively, and drives clean rate and reaches 100%; After administration the 36th day, have 3 tested efficient demodicid mites of sheep, this illustrates that preparation d duration of efficacy was close to 36 days.
Embodiment 6, prepare 6% Eprinomectin injection
Get the Eprinomectin 13.2g that purity is 90%, use 28ml acetic acid ethyl dissolution; By brazil wax 3g, GMO 10g, mix with ethyl oleate 120ml and benzyl benzoate 60ml, in 80-90 DEG C of water-bath, brazil wax is dissolved; Mix by the solution of acetamide-containing base avilamycin with containing the solution of brazil wax, be under agitation down to room temperature, with high speed shearing abrasive machine, at 14000r/min, fully shear 1 hour, obtain 6% Eprinomectin injection.
Embodiment 7, prepare 10% oxfendazole's injection
Get 20g oxfendazole, 2g brazil wax, with Oleum Camelliae to 200ml, with high speed shearing abrasive machine, at 14000r/min, fully shear, the particle diameter to oxfendazole is less than 5 μm, obtains 10% oxfendazole's injection.
Embodiment 8, prepare 15% praziquantel oil injection
Preparation forms: praziquantel 15% (folding hundred), weight/volume; Brazil wax 6.5%, weight/volume; GMO 10%, weight/volume; BHT 0.03%, weight/volume; Injection Oleum Camelliae adds to final volume.
Preparation method: praziquantel is mixed with Oleum Camelliae, fully be ground to praziquantel particle diameter and be less than 20 μm, add brazil wax and GMO, be heated to 80-90 DEG C, brazil wax is dissolved completely, be cooled to 50-55 DEG C under agitation, with high-shear homogenizing machine, further shear treatment, and under this temperature conditions, oil preparation is filled to (sealing ring material is silica gel) in 5ml plastic injector, obtains this preparation.
Embodiment 9, prepare 15% ivermectin oil injection
Preparation forms: ivermectin 15% (folding hundred), weight/volume; Brazil wax 6.5%, weight/volume; GMO 10%, weight/volume; BHT 0.03%, weight/volume; Injection Oleum Camelliae adds to final volume.
Preparation method: ivermectin is mixed with Oleum Camelliae, fully being ground to ivermectin particle diameter is about 15 μm, add brazil wax and GMO, be heated to 80-90 DEG C, brazil wax is dissolved completely, be cooled to 50-55 DEG C under agitation, with high-shear homogenizing machine, further shear treatment, and under this temperature conditions, oil preparation is filled to (sealing ring material is silica gel) in 5ml plastic injector, obtains this preparation.
The oily injection of embodiment 10, embodiment 9 is used for the clinical trial of sheep preventing and treating verminosis
For the test of Wintering Period sheep itch mite disease control.Select the sheep 71 (a group) put in a suitable place to breed, be divided into two groups at random, the 1st group 20, the 2nd group 51.Commercially available 1% ivermectin injection of 1st group of subcutaneous injection is (with 1, prepared by 2-propylene glycol, formal glycerine), dosage is 1.5mg/kg b.w., 2nd group of subcutaneous injection embodiment 9 oily injection 1.5mg/kg b.w., make regular check on acaricide infection conditions after administration, result of the test is as follows:
1st group has 4 sheep to infect acaricide before administration, within the 12nd day, checks upon administration, and 20 sheep all check less than demodicid mite existence of living; Within 36th day, detect 1 sheep upon administration and again infect acaricide, within the 41st day, detect 12 sheep and again infect acaricide.
2nd group has 13 sheep to infect acaricide before administration, within the 12nd day, checks upon administration, and 51 sheep all check less than the demodicid mite that lives.Within upon administration the 103rd day, on 2 sheep healths, detect demodicid mite alive, within 117 days after administration, detect 11 sheep and again infect acaricide.
The detection of oily injection blood drug level in cattle body of embodiment 11, embodiment 9
(1) experimental animal, administration and blood specimen collection: select body weight to be the healthy cattle 6 of 190-220 kilogram, respectively at the oily injection (with No. 16 syringe needles) of the ears of an ox or cow dorsal sc injection embodiment 9, dosage is 1.5mg/kg b.w., take a blood sample from bovine jugular vein after administration on time, each 3ml that accurately takes a blood sample, the blood sample of 6 cattle gathered the same time injects same the 20ml centrifuge tube containing heparin sodium, with the centrifugal 10min of 3000r/min after mixing, get upper liquid (blood plasma), be placed in-18 to-20 DEG C of preservations.
(2) in blood sample treatments and blood plasma, ivermectin detects: in blood sample treatments and blood plasma ivermectin detection reference example 2 in the detection method of avilamycin carry out, result of the test is in table 4.
Plasma ivermectin concentrations (ng/ml) after table 4 Corii Bovis seu Bubali hemostasis (1.5mg/kg b.w.) embodiment 9 preparation
Claims (5)
1., containing an injection for brazil wax, it is characterized in that comprising following component in every 1000ml injection:
Described anti-parasite medicine is one or more the compositions in Avermectins anti-parasite medicine, praziquantel, oxfendazole; Described Avermectins anti-parasite medicine is avilamycin, ivermectin, doractin, Eprinomectin, moxidectin;
Described oil medium is one or more the compositions in injection vegetable oil, ethyl oleate, benzyl benzoate; Described vegetable oil is the one in injection soybean oil, Semen Maydis oil, Oleum Camelliae, Oleum Gossypii semen, Oleum Ricini;
Described antioxidant is one or more the compositions in tertiary butyl-4-hydroxy methoxybenzene, dibenzylatiooluene or propyl gallate.
2., by injection according to claim 1, it is characterized in that also comprising glyceryl monooleate 30-200g in every 1000ml injection.
3., by injection according to claim 2, it is characterized in that comprising following component in every 1000ml injection:
4., by injection according to claim 2, it is characterized in that comprising following component in every 1000ml injection:
5., by injection according to claim 2, it is characterized in that comprising following component in every 1000ml injection:
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1444925A (en) * | 2002-03-19 | 2003-10-01 | 王玉万 | Long acting injection containing ethyl cellulose for animal |
| CN1461640A (en) * | 2002-05-31 | 2003-12-17 | 王玉万 | Slow releasing injection contg. antiparasitic medicine |
-
2015
- 2015-03-18 CN CN201510118056.1A patent/CN104666244B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1444925A (en) * | 2002-03-19 | 2003-10-01 | 王玉万 | Long acting injection containing ethyl cellulose for animal |
| CN1461640A (en) * | 2002-05-31 | 2003-12-17 | 王玉万 | Slow releasing injection contg. antiparasitic medicine |
Non-Patent Citations (1)
| Title |
|---|
| 董吉等: ""注射型原位凝胶植入剂的研究进展"", 《药学进展》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022254199A1 (en) * | 2021-06-01 | 2022-12-08 | Hovione Scientia Limited | Process to reduce ivermectin particle size |
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| CN104666244B (en) | 2017-08-08 |
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Denomination of invention: Veterinary anti-parasitic preparation containing carnauba wax Effective date of registration: 20191128 Granted publication date: 20170808 Pledgee: Huaxia Bank Beijing branch Wanliu Limited by Share Ltd Pledgor: Beijing Zhongnonghuawei pharmaceutical Limited by Share Ltd Registration number: Y2019990000606 |
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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. |
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