CN1528329A - Ivermectin slow-release injecta, and preparing process and use method thereof - Google Patents
Ivermectin slow-release injecta, and preparing process and use method thereof Download PDFInfo
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- CN1528329A CN1528329A CNA031602924A CN03160292A CN1528329A CN 1528329 A CN1528329 A CN 1528329A CN A031602924 A CNA031602924 A CN A031602924A CN 03160292 A CN03160292 A CN 03160292A CN 1528329 A CN1528329 A CN 1528329A
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- 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 title claims abstract description 57
- 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 title claims abstract description 57
- 229960002418 ivermectin Drugs 0.000 title claims abstract description 57
- 238000000034 method Methods 0.000 title claims abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000002347 injection Methods 0.000 claims abstract description 50
- 239000007924 injection Substances 0.000 claims abstract description 50
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 238000010254 subcutaneous injection Methods 0.000 claims abstract description 12
- 239000007929 subcutaneous injection Substances 0.000 claims abstract description 12
- 229910052782 aluminium Inorganic materials 0.000 claims abstract description 11
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 241001465754 Metazoa Species 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 11
- 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 9
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- 230000037396 body weight Effects 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000008595 infiltration Effects 0.000 claims description 3
- 238000001764 infiltration Methods 0.000 claims description 3
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- 238000010792 warming Methods 0.000 claims description 3
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- 208000030852 Parasitic disease Diseases 0.000 abstract 1
- 235000019438 castor oil Nutrition 0.000 abstract 1
- 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 abstract 1
- 244000144977 poultry Species 0.000 abstract 1
- 230000001225 therapeutic effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- AZSNMRSAGSSBNP-XPNPUAGNSA-N 22,23-dihydroavermectin B1a Chemical compound 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 AZSNMRSAGSSBNP-XPNPUAGNSA-N 0.000 description 4
- 229930192734 Avilamycin Natural products 0.000 description 3
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- 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 3
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Abstract
The present invention relates to an invermectin slowly-released injection for curing animal and poultry parasitosis, its preparation process and application method. Said injection composition contains (wt%) 5% of ivermectin, 5%-15% of ethyl acetate, 1%-5% of aluminium monostrearate and the rest is injection castor oil glue. Its preparation process includes preparation of aluminium monostrearate-castor oil glue and preparation of ivermectin slowly-released injection, and its application method is subcutaneous injection. Said injection is safe and reliable in therapeutic effect.
Description
Technical field
The present invention relates to be used to prevent and treat injection and the preparation technology and the using method of verminosis of animal, is a kind of Ivermectin HCL slow-release injection and preparation technology and using method.
Background technology
Merk company obtained gang's (8 kinds) new compound from actinomycetes novel species Streptomyces avermitilis fermentation liquid in 1976, the called after avilamycin (Avermectins, AVM), its chemical constitution and component are:
AVM R
1 X-Y R
2
A1a CH
3 CH＝CH C
2H
5
A1b CH
3 CH＝CH CH
3
A2a CH
3 CH
2-CH(OH) C
2H
5
A2b CH
3 CH
2-CH(OH) CH
3
B1a H CH＝CH C
2H
5
B1b H CH＝CH CH
3
B2a H CH
2-CH(OH) C
2H
5
B2b H CH
2-CH(OH) CH
3
The C of avilamycin component " AVMB1 "
22=C
23Hydrogenation is C
22-C
23Product claim that (Ivermectin IVM), contains 22 to Ivermectin HCL, 23-dihydro AVMB1a＞80% and 22,23-dihydro AVMB1b＜20%.
Ivermectin HCL has dosage forms such as tablet, injection, and is oral or subcutaneous injection is effective to the enteron parasite of animals such as cattle, sheep, pig, Canis familiaris L., and all effective to the parasite of lung, the heart, blood vessel, lymphoid tissue, skin.Treatment back the weight of animals increases, and the fur quality improves, and it have higher safety and curative effect than avermitilis strain, becomes the upgraded product of avilamycin, and its pest-resistant spectrum has 3 cardinal guides (Nematoda, Insecta, spider Piroplasmea), 12 orders, and 73 belong to parasite; To in the nematicide body and γ-An Jidingsuan neurotransmitter reaction in the arthropod body, cause nerve conduction to be obstructed, cause that the polypide paralysis is dead.
But there is effective drug duration short (9-7 days) in the existing conventional formulation of Ivermectin HCL, does not have the long-term insecticidal action that continues.Repeated drug taking often.Long-acting slow releasing preparation such as Ivermectin HCL implants, bolus, micro-balloon injection have come out, but have problems such as administration difficulty or technical sophistication and fail to popularize.
Summary of the invention
The invention provides a kind of Ivermectin HCL slow-release injection and preparation technology and using method, it has solved the existing conventional formulation of Ivermectin HCL and has had the knotty problem that effective drug duration is short, do not have long-term lasting insecticidal action.
One of technical scheme of the present invention is achieved like this: a kind of Ivermectin HCL slow-release injection, it contains by weight percentage: 5% Ivermectin HCL, 5 to 15% ethyl acetate, 1 to 5% aluminum monostearate and the injection Oleum Ricini of surplus.
Two of technical scheme of the present invention is achieved like this: a kind of above-mentioned Ivermectin HCL release injectable liquid preparing process carries out according to the following steps:
The first step, the preparation of aluminum monostearate-Semen Ricini factice: at first aluminum monostearate and the injection Oleum Ricini with aequum stirred the infiltration swelling 3 to 8 hours, next is warming up to 120 to 130 ℃ and stirred 0.5 to 2 hour, put then and be chilled to 35 to 80 ℃, get aluminum monostearate-clear and bright solution of Semen Ricini factice after the filtration;
Second step, the preparation of Ivermectin HCL slow-release injection: at first the Ivermectin HCL of aequum and ethyl acetate are heated to 80 to 100 ℃ with water-bath and dissolve, after next is put and is chilled to room temperature, aluminum monostearate-Oleum Ricini the sol solution that adds first step gained, filter then the Ivermectin HCL slow-release injection.
Three of technical scheme of the present invention is achieved like this: a kind of above-mentioned Ivermectin HCL slow-release injection using method is at the Ivermectin HCL slow-release injection of animal subcutaneous injection amount for 0.05 to 0.10 milliliter of per kilogram of body weight amount injection or 2.5 to 5.0 milligrams.
Ivermectin HCL slow-release injection of the present invention not only kept Ivermectin HCL have now the conventional formulation wide spectrum, efficient, toxic and side effects is low, safe and to characteristics such as environmental effect are minimum, and overcome the short defective existing conventional formulation of Ivermectin HCL action time, at the relaxed and comfortable subcutaneous injection of animal cervical region Ivermectin HCL slow-release injection of the present invention, form the storage storehouse, drug slow discharges and reaches 100 days, convenient drug administration, safe and effective.
Description of drawings
Accompanying drawing 1 is a blank plasma extract chromatogram,
Accompanying drawing 2 is a mark extract chromatogram in the IVM+,
Accompanying drawing 3 is mark extraction-chromatography figure in blood plasma+IVM+
Accompanying drawing 4 is six average blood drug level-time graphs of sheep.
The specific embodiment
The present invention is not subjected to the restriction of following embodiment, can determine concrete embodiment according to the technical scheme and the practical situation of the invention described above.
Embodiment 2, and this Ivermectin HCL slow-release injection contains by weight percentage: 5% Ivermectin HCL, 15% ethyl acetate, 5% aluminum monostearate and the injection Oleum Ricini of surplus.
Embodiment 3, and this Ivermectin HCL slow-release injection contains by weight percentage: 5% Ivermectin HCL, 5% ethyl acetate, 5% aluminum monostearate and the injection Oleum Ricini of surplus.
Embodiment 4, and this Ivermectin HCL slow-release injection contains by weight percentage: 5% Ivermectin HCL, 15% ethyl acetate, 1% aluminum monostearate and the injection Oleum Ricini of surplus.
The Ivermectin HCL slow-release injection of the foregoing description obtains by following preparation technology:
The first step, the preparation of aluminum monostearate-Semen Ricini factice: at first aluminum monostearate and the injection Oleum Ricini with aequum stirred the infiltration swelling 3 hours or 5 hours or 8 hours, next is warming up to 120 ℃ or 130 ℃ and stirs 0.5 hour or 1 hour or 1.5 hours or to 2 hours, put then and be chilled to 35 ℃ or 50 ℃ or 65 ℃ or 80 ℃, get aluminum monostearate-clear and bright solution of Semen Ricini factice after the filtration;
Second step, the preparation of Ivermectin HCL slow-release injection: at first the Ivermectin HCL of aequum and ethyl acetate are heated to 80 ℃ or 90 ℃ or 100 ℃ with water-bath and dissolve, after next is put and is chilled to room temperature, aluminum monostearate-Oleum Ricini the sol solution that adds first step gained, filter then the Ivermectin HCL slow-release injection.
The using method of above-mentioned gained Ivermectin HCL slow-release injection is: at the Ivermectin HCL slow-release injection of animal subcutaneous injection amount for 0.05 milliliter of per kilogram of body weight amount injection or 0.08 milliliter or 0.10 milliliter or 2.5 milligrams or 3 milligrams or 5.0 milligrams.
Existing Ivermectin HCL preparation oral administration all absorbs well, is distributed widely in whole body.Because subcutaneous tissue is more loose, be rich in fat, absorb slowlyer, blood level is more steadily and can be digestive tract or liver metabolism destruction.Therefore subcutaneous injection is safer effectively.
Internal metabolism situation test at sheep subcutaneous injection Ivermectin HCL slow-release injection of the present invention is as follows:
(1), the pre-treatment of plasma sample
The accurate blood plasma sample 2.0ml that draws puts centrifuge tube, adds ethyl acetate 2.0ml, vortex concussion 2min, centrifugal (12000r/min) 15min.Divide and get upper strata liquid (organic facies).Lower floor adds ethyl acetate 1.5ml once more, and the same operation is totally three (ethyl acetate 2.0ml, 1.5ml, 1.5ml; Centrifugal (12000r/min) 15min, 10min, 10min).Merge upper strata liquid, 50 ℃ of water-bath N
2Stream dries up.Remnant adds 100 μ l methanol before measuring, vortex dissolving 2min, centrifugal (12000r/min) 15min, sample introduction 20 μ l.
(2), the preparation of interior mark storing solution
Precision takes by weighing internal standard substance 5.0mg, adds dissolve with methanol in the 50ml volumetric flask, is diluted to scale.Make standard reserving solution (100.0ng/ml).Accurate absorption is gone up liquid 2.0ml and is put in the 10ml volumetric flask, adds methanol and shakes up, is diluted to scale, makes 20.0ng/ml standard inner mark solution.
(3), chromatographic condition
Zirchrom C
18Post (5 μ m, 250mm * 4.6mm); Mobile phase: methanol: water=92: 8; Flow velocity: 1ml/min; Detect wavelength 245nm.Column temperature: 40 ℃; Sample size: 20 μ l, quantitative with the ratio of IVM and internal standard substance peak area.Retention time is respectively: interior mark t
R=8.877min; AVMt
R=11.372min blank plasma does not have an Interference Peaks inferior.
(4), working curve preparation
The accurate blank plasma 2.0ml (n=6) that draws, add reference substance storing solution (4ng/ml) 2,5,10,25,50,100 μ l, each 20 μ l of inner mark solution respectively, vortex mixing 2min adds ethyl acetate 2.0ml, vortex concussion 2min, centrifugal (12000r/min) 15min.Divide and get upper strata liquid (organic facies).Add ethyl acetate 1.5ml in the subnatant again, the same operation is totally three (ethyl acetate 2.0ml, 1.5ml, 1.5ml; Centrifugal (12000r/min) 15min, 10min), merge upper strata liquid, 50 ℃ of water-bath N
2Stream dries up.Remnant adds 100 μ l methanol before measuring, vortex dissolving 2min, centrifugal (12000r/min) 15min, sample introduction 20 μ l.Get standard working curve, return agenda, detectability and precision.
Regression equation: A=0.0049C+0.0304, r=0.9993
Detectability: 2ng/ml.RSD：12％(4.0-200ng/ml，n＝6)。Background recovery of standard addition: 102 ± 3.5%
(5), medication, get blood time, blood sample and handle and record the blood drug level data
6 of sheep, press 0.1ml/kg (5.0mg/kg) cervical region subcutaneous injection Ivermectin HCL slow-release injection, respectively 1,2,4,8,15,22,29,36,43,50,57,64,71,78,85,92,99,106,113,120 day venous blood collection 15ml after administration.Heparinization, the centrifugal blood plasma of telling.Pre-treatment in accordance with the law, sample introduction 20 μ l under the HPLC condition.Obtain blood drug level (internal metabolism) data such as the following table of sheep subcutaneous injection Ivermectin HCL slow-release injection.
Time blood drug level (ng/ml) meansigma methods ± SD
(day) 1 2 3 4 5 6
0 0 0 0 0 0 0 0
1 23.5 29.3 25.6 25.4 60.0 47.9 35±15
2 55.8 51.4 180 37.7 82.6 66.8 79±52
4 52.5 43.5 30.2 36.6 85.5 78.2 54±22
8 96.3 245 82.9 61.1 100 71.4 109±68
15 61.6 154 38.4 70.5 67.0 64.7 76±40
22 42.8 20.1 22.2 45.9 40.9 38.2 35±11
29 64.6 73.9 33.1 64.7 -- 48.6 57±16
36 79.5 22.3 51.7 64.5 57.1 35.1 51±20
43 62.1 22.6 53.8 43.1 32.5 36.8 41±14
50 58.2 12.4 33.1 25.8 18.0 23.9 28±16
57 50.4 14.5 33.1 32.5 20.4 34.0 30±12
64 47.9 9.6 19.9 9.2 20.4 30.8 23±14
71 35.1 4.5 12.1 10.7 8.4 17.2 15±11
78 40.0 4.0 20.4 6.3 5.1 11.9 15±14
85 60.2 17.4 38.8 19.7 36.8 24.9 33±16
92 52.6 16.8 21.4 14.2 13.9 18.4 23±15
99 43.4 6.4 12.0 11.3 5.5 22.8 17±14
106 43.2 4.0 7.9 10.8 2.8 2.3 12±16
113 18.3 4.5 5.3 2.4 2.2 4.0 6.1±6.1
120 10.0 0 0 2.8 0 3.4 2.7±3.9
(6), six average drug-time curves of sheep and the information that provides see accompanying drawing 4 for details
In view of following reason, mean drug concentration-time graph is rendered as a nonlinear curve:
1., Ivermectin HCL slow-release injection cervical region subcutaneous injection, the part Ivermectin HCL enters blood rapidly because ethyl acetate easily spreads absorption, first peak occurs, and the average maximum concentration of Ivermectin HCL reached 109 ± 68 (ng/ml) in the 8th day.
2., because " fat-solubility of Ivermectin HCL ", " the non-absorbent vegetable oil solvent of human body " reach the triple role of " trivalent metal soap ", most of medicine discharges in subcutaneous fat formation storage storehouse and slows down rapidly, and drug level dropped to 35 ± 11ng/ml in the 22nd day.
3., the medicine that enters blood forms the second storage storehouse in the liver enrichment, slow down drug release once more, forms long undaform simultaneously and discharges.The blood drug level release of in the 40-60ng/ml scope, fluctuating in the most of the time.
4., after the administration the 113rd day, six average blood drug level of sheep dropped to 6.1 ± 6 (ng/ml).Infer that thus slow release effective time was above 100 days behind the Ivermectin HCL slow-release injection cervical region subcutaneous injection.
Therefore, Ivermectin HCL slow-release injection of the present invention has overcome the defective that there is effective drug duration short (9-7 days) in the existing conventional formulation of Ivermectin HCL, does not have long-term lasting insecticidal action.
Claims (3)
1, a kind of Ivermectin HCL slow-release injection is characterized in that containing by weight percentage: 5% Ivermectin HCL, 5 to 15% ethyl acetate, 1 to 5% aluminum monostearate and the injection Oleum Ricini of surplus.
2, a kind of Ivermectin HCL release injectable liquid preparing process according to claim 1 is characterized in that carrying out according to the following steps:
The first step, the preparation of aluminum monostearate-Semen Ricini factice: at first aluminum monostearate and the injection Oleum Ricini with aequum stirred the infiltration swelling 3 to 8 hours, next is warming up to 120 to 130 ℃ and stirred 0.5 to 2 hour, put then and be chilled to 35 to 80 ℃, get aluminum monostearate-clear and bright solution of Semen Ricini factice after the filtration;
Second step, the preparation of Ivermectin HCL slow-release injection: at first the Ivermectin HCL of aequum and ethyl acetate are heated to 80 to 100 ℃ with water-bath and dissolve, after next is put and is chilled to room temperature, aluminum monostearate-Oleum Ricini the sol solution that adds first step gained, filter then the Ivermectin HCL slow-release injection.
3, a kind of Ivermectin HCL slow-release injection using method according to claim 1 is characterized in that the Ivermectin HCL slow-release injection of animal subcutaneous injection amount for 0.05 to 0.10 milliliter of per kilogram of body weight amount injection or 2.5 to 5.0 milligrams.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03160292 CN1197583C (en) | 2003-09-30 | 2003-09-30 | Ivermectin slow-release injecta, and preparing process and use method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03160292 CN1197583C (en) | 2003-09-30 | 2003-09-30 | Ivermectin slow-release injecta, and preparing process and use method thereof |
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| Publication Number | Publication Date |
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| CN1528329A true CN1528329A (en) | 2004-09-15 |
| CN1197583C CN1197583C (en) | 2005-04-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101214223B (en) * | 2007-12-29 | 2010-06-16 | 西北农林科技大学 | A kind of closantamide or its sodium salt long-acting sustained-release injection and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101214223B (en) * | 2007-12-29 | 2010-06-16 | 西北农林科技大学 | A kind of closantamide or its sodium salt long-acting sustained-release injection and preparation method thereof |
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