CN103721266A - In-situ gelation injection containing avermectin medicine/hydrogenated castor oil - Google Patents
In-situ gelation injection containing avermectin medicine/hydrogenated castor oil Download PDFInfo
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- CN103721266A CN103721266A CN201410003912.4A CN201410003912A CN103721266A CN 103721266 A CN103721266 A CN 103721266A CN 201410003912 A CN201410003912 A CN 201410003912A CN 103721266 A CN103721266 A CN 103721266A
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Abstract
The invention relates to an in-situ gelation injection containing avermectin medicine/hydrogenated castor oil drug-loading particles. The injection is prepared by forming drug-loading particles through avermectin medicines and hydrogenated castor oil and suspending the particles in 18-22 percent poloxamer 407 aqueous solution. The injection is simple in preparation process and uniform in release, realizes one-step administration and is used for preventing and treating nematodosis and ectozoic parasite diseases of pigs, cattle and sheep, the effective rate is 95 percent or higher, and the drug effect duration can be 60 days or longer. The injection is high in biocompatibility and does not have irreversible damage to tissues on an injection part, and the used controlled release carrier can be degraded and excreted.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, be specifically related to Avermectins medicine and castor oil hydrogenated (hereinafter to be referred as HCO) to be prepared into medicine carrying microgranule, medicine carrying microgranule is suspended in poloxamer188 (hereinafter to be referred as P407) aqueous solution, and preparation is containing the in-situ gelling injection of Avermectins medicine.
Background technology
Avermectins medicine comprises: ivermectin Ivermectin, avilamycin Avermectin, Eprinomectin Eprinomectin, doractin Doramectin, milbemycin oxime Milbemycin Oxime, moxidectin Moxidectin.These Avermectins medicines are mainly used in preventing and treating nematicide and the epizootic disease of the animals such as pig, cattle, sheep at veterinary clinic, their " character, pharmacology and purposes " etc. are < < veterinary drug handbook > > (Zhu Mozhong chief editor, Chemical Industry Press, July in 2002 the 1st edition, 167-174 page) all on the books and describe and in open source literature.Containing the commercially available injection of Avermectins medicine, majority is to be solution type preparation prepared by solvent with organic solvent (as 1,2-PD, N-Methyl pyrrolidone, formal glycerine etc.) or the grease compounds of synthetic; The disclosed injection containing Avermectins medicine of document or patent has solution type preparation, suspension type preparation, Emulsion, have containing microsphere or microcapsule or containing the long-acting injection of different slow-released carriers (as polyvinylpyrrolidone, polylactic acid, PLGA, Sucrose acetoisobutyrate, castor oil hydrogenated, Semen Ricini wet goods).The long-acting injection of containing hydrogenated Oleum Ricini mainly contains: castor oil hydrogenated and Avermectins medicine are prepared into solid dispersion, suspend in water or the complex media of water and 1,2-PD in, or be suspended in dimethyl-silicon wet goods oil medium; Also have castor oil hydrogenated is dissolved in and in oil medium, prepares slow releasing injection.
Injection of the present invention and technology of preparing thereof are different from published injection and technology of preparing thereof containing Avermectins medicine, feature of the present invention is: Avermectins medicine/HCO medicine carrying microgranule is suspended in the P407 aqueous solution of 18-22%, be prepared into the in-situ gelling injection containing Avermectins medicine/HCO medicine carrying microgranule, after this preparation injects in animal body, under body temperature effect, P407 is converted into gel by colloidal sol, Avermectins medicine/HCO medicine carrying microgranule is wrapped in by gel lump, medicine need slowly decompose just and can complete dispose procedure with the slow dissolving of gel and HCO.Therefore, this preparation is different from the simple in-situ gelling injection containing P407, is also different from the simple slow releasing injection containing HCO solid dispersion.
This process for preparation of injection is simple, and release is even, and single administration reaches 95% or higher for preventing and treating pig, cattle, sheep nematicide and ectoparasite disease effective percentage, effectively sustainable 60 days of drug release time or longer.This injection good biocompatibility, to the tissue of injection site without irreversible damage, slow-released carrier degradable and excretion used.
Summary of the invention
1. preparation forms:
This preparation comprises Avermectins medicine, P407, HCO and water; HCO and Avermectins medicine are prepared to medicine carrying microgranule, with medicine carrying microgranule state, are suspended in P407 aqueous solution, are prepared into in-situ gelling injection.
In every liter of injection, containing Avermectins medicine/HCO medicine carrying microgranule 50-150g, P407180-220g, water for injection adds to 1 liter; In medicine carrying microgranule, the weight ratio of Avermectins medicine and HCO is 1: 0.5-1.
In above-described every liter of injection, can also add hydroxypropyl emthylcellulose (HPMC) 10-30g.
In above-described every liter of injection, can also add 5-10g PLURONICS F87 (P188).
2. preparation method:
(1) by HCO and Avermectins medicine in low boiling point organic solvent (low boiling point organic solvent comprises: methanol, ethanol, ethyl acetate, acetone, chloroform), reflux is treated to dissolve completely, do not stopping under stirring, removal of solvent under reduced pressure, obtain solids, solids is pulverized, crossed 40 mesh sieves, obtain Avermectins medicine/HCO medicine carrying microgranule.
(2) will be about medicine carrying microgranule weight 1.5-2 P407 aqueous solution doubly (containing P407 approximately 10%; weight/volume) mix with medicine carrying microgranule; crossing high-shear homogenizing machine (15000-17000rpm) homogenizes; with colloid mill, be ground to particle diameter afterwards and be less than 80 μ m; with sand mill, be ground to particle diameter again and be less than 30 μ m; add residue composition; after homogenizing with homogenizer; degassed under 5-15 ℃, negative pressure 0.06-0.08mpa condition, must be containing the in-situ gelling injection of Avermectins medicine/HCO medicine carrying microgranule.
The specific embodiment
Embodiment 1,10% avilamycin in-situ gelling injection preparation
Preparation forms: every liter of preparation adds to 1 liter containing avilamycin/HCO (weight ratio is 1: 0.5) medicine carrying microgranule 150g, P407180g, water for injection.
Preparation method: (1) by castor oil hydrogenated in 90-95 ℃ of thawing, be cooled to 70 ℃ of left and right, add avilamycin and appropriate ethanol, reflux avilamycin is dissolved completely, afterwards at stirring condition borehole cooling to 40-55 ℃, distilling under reduced pressure, Ex-all ethanol, obtains solids, pulverizes, cross 40 mesh sieves, obtain avilamycin/HCO medicine carrying microgranule.(2) the 10%P407 aqueous solution with appropriate (being about the 1.5-2 of medicine carrying microgranule amount doubly) by medicine carrying microgranule, cross high-shear homogenizing machine and shear 3-5 time, with colloid mill, be ground to particle diameter afterwards and be less than 80 μ m, then with sand mill, be ground to particle diameter and be less than 20 μ m, obtain dense thick suspension.(3) in suspension, add remaining P407 aqueous solution, after homogenizing with homogenizer, degassed under 5-15 ℃, negative pressure 0.06-0.08mpa condition, must be containing the in-situ gelling injection of avilamycin/HCO medicine carrying microgranule.
Embodiment 2,7% ivermectin in-situ gelling injection preparation
Ivermectin/HCO (weight ratio is 1: 1) medicine carrying microgranule 140g, P407180g, water for injection add to 1 liter.
Preparation method: (1) by castor oil hydrogenated in 90-95 ℃ of thawing, be cooled to 70C left and right, add ivermectin and the suitable ethanol of ivermectin triplication, reflux ivermectin is dissolved completely, afterwards at stirring condition borehole cooling to 40-55 ℃, distilling under reduced pressure, Ex-all ethanol, obtains solids, pulverizes, cross 40 mesh sieves, obtain ivermectin/HCO medicine carrying microgranule.(2) the 10%P407 aqueous solution with appropriate (being about the 1.5-2 of medicine carrying microgranule amount doubly) by medicine carrying microgranule, cross high-shear homogenizing machine and shear 3-5 time, with colloid mill, be ground to particle diameter afterwards and be less than 80 μ m, then with sand mill, be ground to particle diameter and be less than 20 μ m, obtain dense thick suspension.(3) in suspension, add remaining P407 aqueous solution, after homogenizing with homogenizer, degassed under 5-15 ℃, negative pressure 0.06-0.08mpa condition, must be containing the in-situ gelling injection of ivermectin/HCO medicine carrying microgranule.
Embodiment 3,5% doramectin in-situ gelling injection preparation
Doramectin/HCO (weight ratio is 1: 0.8) medicine carrying microgranule 90g, P407200g, water for injection add to 1 liter.
Embodiment 4,7.5% Eprinomectin injection
Eprinomectin/HCO (weight ratio is 1: 1) medicine carrying microgranule 150g, P407180g, P18810g, HPMC22g, water for injection adds to 1 liter.
Embodiment 5,5% ivermectin in-situ gelling injection preparation
Ivermectin/HCO (weight ratio is 1: 1) medicine carrying microgranule 50g, ivermectin/HCO (weight ratio is 1: 0.5) medicine carrying microgranule 37.5g, P407180g, P18810g, HPMC20g, glycerol 65g, water for injection adds to 1 liter.
Injection described in above embodiment 3 to embodiment 5, preparation method is with embodiment 1.
Embodiment 6, the embodiment 5 preparations blood drug level in sheep body detects
Experimental animal grouping and result of the test: select 9 of healthy sheep, be divided into 3 groups, every group 3, cervical region subcutaneous injection embodiment 5 preparations, dosage is respectively 0.5mg/kg b.w. (A group), 0.8mg/kg b.w. (B group), 1.2mg/kg b.w. (C group), blood sampling on time, separated plasma, and after the plasma sample of same time is on the same group mixed with acetonitrile extraction, through centrifugal, purify (C
18post), the process such as concentrated, derivatization, make detection sample, adopt ivermectin content in HPLC (fluorescence detector) working sample.
Testing result is as shown in the table:
More than in table, numerical value is the meansigma methods of every group of 3 sheep blood plasma drug level.
Claims (5)
1. containing a long-acting injection for Avermectins medicine, it is characterized in that Avermectins medicine and castor oil hydrogenated combination, with medicine carrying microgranule state, be suspended in the aqueous solution that comprises poloxamer188, be prepared into in-situ gelling injection.
2. by injection claimed in claim 1, it is characterized in that every liter of injection comprises following component:
Weight ratio is 1: Avermectins medicine/castor oil hydrogenated medicine carrying microgranule 50-150g of 0.5-1
Poloxamer188 180-220g
Water for injection adds to 1 liter.
3. by injection claimed in claim 2, it is characterized in that preparation method is as follows:
A puts into castor oil hydrogenated and Avermectins medicine to be equivalent in ethanol or acetone or ethyl acetate that Avermectins medicine 2.5-4 doubly measures, be heated to 80 ℃ of left and right, treat to dissolve completely, under agitation, distilling under reduced pressure is except desolventizing, obtain solids and pulverize, cross 40 mesh sieves, obtain Avermectins medicine/castor oil hydrogenated medicine carrying microgranule;
B mixes the 10% poloxamer188 aqueous solution that is equivalent to medicine carrying microgranule 1.5-2 times weight with medicine carrying microgranule; cross high-shear homogenizing machine; shear 3-5 time; with colloid mill, be ground to particle diameter and be less than 80 μ m; with sand mill, grind particle diameter again and be less than 30 μ m, add residue composition, after homogenizing with homogenizer; degassed under 5-15 ℃, negative pressure 0.06-0.08mpa condition, make the in-situ gelling injection containing Avermectins medicine/castor oil hydrogenated medicine carrying microgranule.
4. by the injection described in claim 2-3 any one, it is characterized in that can also adding 10-30g hydroxypropyl emthylcellulose in every liter of injection.
5. by the injection described in claim 2-3 any one, it is characterized in that can also adding 5-30g PLURONICS F87 in every liter of injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410003912.4A CN103721266A (en) | 2014-01-06 | 2014-01-06 | In-situ gelation injection containing avermectin medicine/hydrogenated castor oil |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410003912.4A CN103721266A (en) | 2014-01-06 | 2014-01-06 | In-situ gelation injection containing avermectin medicine/hydrogenated castor oil |
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| CN103721266A true CN103721266A (en) | 2014-04-16 |
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| CN201410003912.4A Pending CN103721266A (en) | 2014-01-06 | 2014-01-06 | In-situ gelation injection containing avermectin medicine/hydrogenated castor oil |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811967A (en) * | 2016-09-09 | 2018-03-20 | 中国疾病预防控制中心寄生虫病预防控制所 | Anti-parasite medicine in-situ solidification sustained-release injector and preparation method thereof |
| CN110721152A (en) * | 2018-12-29 | 2020-01-24 | 瑞普（天津）生物药业有限公司 | Sustained-release composition for treating animal skin parasite and fungus infection |
| CN113209012A (en) * | 2021-06-04 | 2021-08-06 | 湖南伟达科技有限公司 | Avermectin transdermal solution and preparation method thereof |
| WO2022254199A1 (en) * | 2021-06-01 | 2022-12-08 | Hovione Scientia Limited | Process to reduce ivermectin particle size |
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| EP0535734A1 (en) * | 1991-09-30 | 1993-04-07 | Merck & Co. Inc. | Long acting injectable formulations containing hydrogenated castor oil |
| WO1999051201A1 (en) * | 1998-04-03 | 1999-10-14 | Ashmont Holdings Limited | Sustained release formulation |
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| CN1698637A (en) * | 2004-05-17 | 2005-11-23 | 王玉万 | Powder injection of macrolides or N-phenyl pyrazoles deworming drug |
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2014
- 2014-01-06 CN CN201410003912.4A patent/CN103721266A/en active Pending
Patent Citations (9)
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| EP0535734A1 (en) * | 1991-09-30 | 1993-04-07 | Merck & Co. Inc. | Long acting injectable formulations containing hydrogenated castor oil |
| CN1283990A (en) * | 1997-12-03 | 2001-02-14 | 麦克公司 | Long cating injectable formulations contg. hydrogenated castor oil |
| WO1999051201A1 (en) * | 1998-04-03 | 1999-10-14 | Ashmont Holdings Limited | Sustained release formulation |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107811967A (en) * | 2016-09-09 | 2018-03-20 | 中国疾病预防控制中心寄生虫病预防控制所 | Anti-parasite medicine in-situ solidification sustained-release injector and preparation method thereof |
| CN107811967B (en) * | 2016-09-09 | 2021-08-24 | 中国疾病预防控制中心寄生虫病预防控制所(国家热带病研究中心) | Antiparasitic in-situ curing slow-release injection and preparation method thereof |
| CN110721152A (en) * | 2018-12-29 | 2020-01-24 | 瑞普（天津）生物药业有限公司 | Sustained-release composition for treating animal skin parasite and fungus infection |
| CN110721152B (en) * | 2018-12-29 | 2022-01-14 | 瑞普（天津）生物药业有限公司 | Sustained-release composition for treating animal skin parasite and fungus infection |
| WO2022254199A1 (en) * | 2021-06-01 | 2022-12-08 | Hovione Scientia Limited | Process to reduce ivermectin particle size |
| CN113209012A (en) * | 2021-06-04 | 2021-08-06 | 湖南伟达科技有限公司 | Avermectin transdermal solution and preparation method thereof |
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Owner name: BEIJING AGRICHINA PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: WANG YUWAN Effective date: 20150106 |
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Effective date of registration: 20150106 Address after: 102206 Beijing city Changping District Baishan Town East Village profile West Industrial Zone No. 535 Pro Applicant after: BEIJING AGRICHINA PHARMACEUTICAL CO., LTD. Address before: 100083 Beijing Qinghua East Road, No. 17,, 41-5-102 Applicant before: Wang Yuwan |
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Application publication date: 20140416 |