CN103720652B - Prepare containing Avermectins medicine injection with poloxamer and oil medium - Google Patents
Prepare containing Avermectins medicine injection with poloxamer and oil medium Download PDFInfo
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- CN103720652B CN103720652B CN201410005519.9A CN201410005519A CN103720652B CN 103720652 B CN103720652 B CN 103720652B CN 201410005519 A CN201410005519 A CN 201410005519A CN 103720652 B CN103720652 B CN 103720652B
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Abstract
Avermectins medicine is combined with poloxamer188, is prepared as medicine carrying microgranule；Further medicine carrying microgranule is scattered in oil medium, ground, it is prepared as the oily long-acting injection containing Avermectins medicine/poloxamer188 medicine carrying microgranule.Also can add hydroxypropyl methyl cellulose or Hydroxypropylcelliloxe in medicine carrying microgranule, their membership that adds significantly strengthens the slow releasing function of preparation.This process for preparation of injection is simple, uniform drug release, good biocompatibility, to the tissue reversible damage invariably of injection site, injection part used and excretion.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, being specifically related to poloxamer188 and oil medium is carrier, preparation containing Ah
The long-acting veterinary injection of dimension bacteriums medicine.
Background technology
Poloxamer is polyoxyethylene polyoxypropylene ether analog copolymer, and this base polymer has plurality of specifications, wherein poloxamer
The aqueous solution of 407 (hereinafter referred to as P407) has " raising by colloidal sol to the characteristic of gel conversion with temperature ", certain density P407
Aqueous solution is typically i.e. gelled more than 30 DEG C, accordingly characteristic, and P407 is used for the preparation of slow releasing injection, and said preparation is referred to as
For in-situ gelling preparation.After in-situ gelling injection containing P407 is injected in vivo, under the effect of body temperature, typically at about 1 minute,
I.e. being changed into gel (semi-solid) by colloidal sol, medicine is wrapped in gel, thus slow down rate of releasing drug, makes duration of efficacy
Extend.Document and the disclosed in-situ gelling injection containing P407 of patent, the solvent of its preparation is water, the concentration of P407 in preparation
Reach more than 20% and just have preferable slow releasing function；Add a certain amount of methylcellulose, carboxymethyl cellulose in the formulation
The blocker such as sodium, Hydroxypropylcelliloxe (H-HPC) or hydroxypropyl methyl cellulose (HPMC), can strengthen slow releasing function, but meeting
Cause formulation viscosity to raise, make injection more difficult.
P407 is also a kind of good nonionic surfactant of water solublity, be more used to prepare Emulsion, ointment,
Aqueous suppository, drop pill etc.；P407, also by the dispersible carrier as insoluble medicine (medicine that water solublity is very poor), is used for preparing admittedly
Solution, it has been disclosed that the solid solution prepared with P407, be mostly the preparation for oral preparations.
The present invention is different from published technology, and the present invention is by medicine and P407 (or with P407 and cellulose ethers) composition
The medicine carrying microgranule (such as agglomerate) of solid solution or other form, and with oil medium (isopropyl myristate, hereinafter referred to as IPM；Note
Penetrate with vegetable oil) substitute water prepare the oily injection containing P407 medicine carrying microgranule.This preparation injects animal subcutaneously or intramuscularly, medicine carrying
Microgranule, after " breakthrough " oil phase contact body fluid (water), " absorbs water (body fluid) " by means of P407 or water absorption and swelling is (at HPMC or H-HPC
In the presence of), " adhesive aggregation " together, forms high concentration with full-bodied and have " bioadhesive " (at HPMC in injection site
Or in the presence of H-HPC) semi-solid agglomerate, medicine is wrapped in agglomerate, thus effectively extends drug release time.And due to
The peptizaiton of P407, makes insoluble medicine release relatively complete, thus improves the bioavailability of hydrophobic drug, decrease injection
Fraction medicine remains.
The medicine that the present invention relates to is Avermectins medicine, including ivermectin Ivermectin, avilamycin
Avermectin, Eprinomectin Eprinomectin, doractin Doramectin, milbemycin oxime Milbemycin
Oxime, moxidectin Moxidectin.This experiment show, Avermectins medicine can with P407 or with P407/HPMC (or
H-HPC) it is combined into medicine carrying microgranule, and is scattered in oil medium, prepare outstanding slow releasing injection.Above Avermectins medicine
Thing is mainly used in preventing and treating nematicide and epizootic disease, their " character, the pharmacology of the animals such as pig, cattle, sheep at veterinary clinic
And purposes " etc. at " veterinary drug handbook ", (Zhu Mozhong edits, Chemical Industry Press, July in 2002 the 1st edition, 167-174
Page) and open source literature in the most on the books and description.Commercially available injection containing Avermectins medicine, majority be with organic solvent (such as 1,
2-propylene glycol, N-Methyl pyrrolidone, formal glycerine etc.) or the grease compounds of synthetic be solution-type prepared by solvent
Preparation；Document or the disclosed injection containing Avermectins medicine of patent have solution type preparation, suspension type preparation, Emulsion, have
Containing microsphere or microcapsule or containing different slow-released carriers (such as polyvinylpyrrolidone, polylactic acid, PLGA, acetic acid
Isopropylformic acid. sucrose ester, castor oil hydrogenated, Oleum Ricini etc.) long-acting injection.But containing Avermectins medicine/P407 medicine carrying microgranule
Or the oily long-acting injection containing Avermectins medicine/P407/HPMC (or H-HPC) medicine carrying microgranule has no report.
Summary of the invention
In this preparation, medicine forms medicine carrying microgranule with P407 or medicine with P407 and HPMC (or H-HPC), and micro-with medicine carrying
Granular state is suspended in oil medium, and therefore, this preparation is i.e. different from the in-situ gelling preparation containing P407 with water for medium, also different
In traditional oily injection.Invention formulation composition and preparation method are as follows:
Preparation forms: this preparation is mainly made up of Avermectins medicine, P407 and oil medium.Every liter of injection contains
Avermectins medicine 25-100g, P40725-100g, oil medium add to 1 liter.
Described Avermectins medicine includes: ivermectin Ivermectin, avilamycin Avermectin, acetamide
Base avilamycin Eprinomectin, doractin Doramectin, milbemycin oxime Milbemycin Oxime, Moses bacterium
Element Moxidectin.The commercialization the most of these Avermectins medicines, at " Chinese veterinary pharmacopoeia " and veterinary drug handbook and pertinent literature
In all can find.
Described oil medium is IPM or injection soybean oil or Semen Maydis oil or Oleum Camelliae.
In above-described every liter of injection, also can add 20-70g HPMC or H-HPC, HPMC or H-HPC need and P407
It is combined into solid solution or forms medicine carrying microgranule together with P407 and Avermectins medicine, the preparation of this preparation could be used for.H-HPC
Having good dissolubility in the low boiling point organic solvent such as methanol, ethanol, Avermectins medicine is in these low boiling point organic solvents
Having good dissolubility equally, this is that H-HPC, P407, Avermectins medicine three can make up one, is prepared as medicine carrying micro-
The important foundation of grain.
H-HPC and HPMC be nontoxic, without pharmacological action, physiologically active shows extreme inertia.HPMC, H-HPC or P407
In the oil mediums such as IPM insoluble, therefore, H-HPC or HPMC and P407 are formed microgranule, even if being scattered in higher concentration
In oil medium, formulation viscosity also will not be made significantly raised, but the medicine carrying microgranule containing high concentration H-HPC or HPMC can be inhaled in injection part
Water-swellable, form full-bodied agglomerate, full-bodied agglomerate has an effect of higher retardance (slowing down) drug release, therefore, according to
Requirement, adds appropriate H-HPC and HPMC in medicine carrying microgranule and can reach intended slow release effect.
Avermectins medicine in this preparation with medicine carrying microgranule state exist, medicine carrying microgranule be by Avermectins medicine with
P407 forms, or forms with P407/H-HPC (or and P407/HPMC).
At Avermectins medicine with the medicine carrying microgranule of P407 composition, its weight ratio is 1: 0.5-1, and medicine carrying microgranule is at preparation
In weight/volume percent content be 5-20%, surplus is oil medium.
In the medicine carrying microgranule of Avermectins medicine and P407 and HPMC composition, Avermectins medicine, P407, HPMC
The weight ratio of three is 1: 0.5-1: 0.3-0.7, and medicine carrying microgranule weight/volume percent content in the formulation is 5.5-20%, excellent
The weight/volume percent content of choosing is 8-16%, and surplus is oil medium.
In the medicine carrying microgranule of Avermectins medicine/P407/H-HPC composition, Avermectins medicine, P407, H-HPC tri-
The weight ratio of person is 1: 0.5-1: 0.3-0.7, and medicine carrying microgranule weight/volume percent content in the formulation is 5.5-20%, preferably
Weight/volume percent content be 8-16%, surplus is oil medium.
Preparation method: be summed up and mainly have following two.
(1) in a heated condition, by Avermectins medicine and P407 or Avermectins medicine and P407 and HPMC or
Avermectins medicine and P407 and H-HPC mono-reinstate low boiling point solvent and dissolve, and distillation of then reducing pressure removes low boiling point solvent,
Avermectins medicine/P407 solid solution or Avermectins medicine/P407/HPMC solid solution or Avermectins medicine
/ P407/H-HPC solid solution；The solid solution of preparation is pulverized 40 mesh sieves, obtains medicine carrying microgranule；Medicine carrying microgranule is scattered in part
In oil medium, it is ground to particle diameter with colloid mill and is less than 100 μm, then be ground to particle diameter less than 20 μm, addition residue with sand mill
Medium, to final volume, homogenizes further under 5000-10000rpm with high-shear homogenizing machine and i.e. obtains this preparation.
(2) by Avermectins medicine and P407 or Avermectins medicine and solid solution (P407/HPMC or P407/H-HPC)
It is scattered in part oil medium, is ground to particle diameter with colloid mill and sand mill and is less than 20 μm, add remaining media, equal with high shear
Matter machine homogenizes and i.e. obtains this preparation.
Prepared by P407/H-HPC or P407/HPMC solid solution: in a heated condition, is dissolved in by HPMC or H-HPC and P407
Methanol or be dissolved in 80% ethanol solution, mixing, under agitation removal of solvent under reduced pressure and get final product.
This formulation process need to aseptically be carried out, and during grinding, temperature of charge may not exceed 40 DEG C, solid particle in preparation
Particle diameter should be less than 20 μm, with appropriate less than 10 μm.
This preparation characteristic is summarized as follows:
This medicament drug release process is different from the in-situ gelling preparation with water as medium, also different from traditional oil preparation, main difference
Part is to there is medicine carrying microgranule " to break through " oil phase and bioresorbable water absorption and swelling formation high viscosity agglomerate process.
Appropriate H-HPC or HPMC and P407 is formed solid solution pellet, is scattered in oil phase, solve simple use
H-HPC (or HPMC) packaging medicine is difficult to grind to form the technical barrier of fine particle (less than 20 μm), remain simultaneously H-HPC and
HPMC has water absorption and swelling, forms the characteristic of high viscosity agglomerate.Pastille " agglomerate " adheres in injection site tissue, beneficially medicine
Thing preferably absorbs, and ensure that a certain degree of slow release effect, and this is that this agent has bioavailability height, has again long-acting
Basis.
Avermectins medicine is practically insoluble in water, by Avermectins medicine and P407 composition solid solution application, can reduce note
Penetrate site drug residue.
Substituting water with oil medium and prepare the slow releasing injection containing P407, can reduce the consumption of P407, P407 consumption is at 5-10%
Time, preparation just has good slow releasing function.Contain the in-situ gelling injection of P407 with water for solvent preparation, the consumption of P407 to reach
To 20～45%, preparation just can demonstrate good slow releasing function.Current domestic P407 is expensive, and (medical grade is at 160～200 yuan
/ kg), therefore, P407 consumption in the formulation is the most, and preparation cost is the highest, is unfavorable in veterinary applications popularization and application.
Detailed description of the invention
Embodiment 1, prepare 6% ivermectin injection
Preparation forms: ivermectin 60g, P40750g, H-HMC45g, IPM add to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added about 100ml methanol after adding H-HMC mixing, treats H-HMC by (1)
After dissolving, add ivermectin, fully mix, after ivermectin dissolves, decompression distillation, Ex-all methanol, cooling, pulverize after solidification,
Cross 40 mesh sieves, the medicine carrying microgranule of ivermectin must be contained.(2) medicine carrying microgranule is scattered in part IPM, crosses colloid mill and be ground to grain
Footpath is less than 50 μm, grinds with sand mill further, grinds to particle diameter less than 20 μm, adds remaining media, exist with high-shear homogenizing machine
Under the conditions of about 5000rpm, after repeatedly homogenizing, prepare the particle diameter ivermectin injection less than 20 μm.
Embodiment 2, prepare 3% avilamycin injection
Preparation forms: avilamycin 30g, P40730g, injection soybean oil adds to 1 liter.
Preparation method: P407 in 60-70 DEG C of thawing, is added avilamycin and is equivalent to avilamycin 4-5 times amount by (1)
Ethanol, fully mixes, and is allowed to dissolve, cooling, and natural drying after solidification is pulverized, and crosses 40 mesh sieves, and the medicine carrying that must contain avilamycin is micro-
Grain.(2) being scattered in by medicine carrying microgranule in part soybean oil, colloid mill excessively is ground to particle diameter and is less than 100 μm, uses sand mill further
Grind, grind to particle diameter less than 20 μm, add remaining media, with high-shear homogenizing machine under the conditions of about 5000rpm, through repeatedly homogenizing
After change, prepare the particle diameter avilamycin injection less than 20 μm.
Embodiment 3, prepare 9% Eprinomectin injection
Preparation forms: Eprinomectin 90g, P40790g, injection Semen Maydis oil adds to 1 liter.
Preparation method: (1) by P407 in 60-70 DEG C of thawing, add Eprinomectin and be equivalent to acetamido Ah
The ethanol of dimension rhzomorph 3-5 times amount, backflow is dissolved, and reduces pressure and ethanol is distilled off, and pulverizes after cooling and solidifying, crosses 40 mesh sieves, must contain acetyl
The medicine carrying microgranule of amido avilamycin.(2) being scattered in by medicine carrying microgranule in part Semen Maydis oil, mistake colloid mill is ground to particle diameter and is less than
100 μm, grind with sand mill further, grind to particle diameter less than 20 μm, add remaining media, with high-shear homogenizing machine about
Under the conditions of 5000rpm, after repeatedly homogenizing, prepare the particle diameter Eprinomectin injection less than 20 μm.
Embodiment 4, prepare 5% doractin injection
Preparation forms: containing doractin 5g, P407/HPMC (2: 1) solid solution 10g, camellia oleosa seed in every 100ml injection
Oil adds to final volume.
Preparation method: doractin and solid solution are scattered in part Oleum Camelliae, are ground to particle diameter with colloid mill and sand mill
Less than 20 μm, add remaining media, homogenize with high-shear homogenizing machine and i.e. obtain this preparation.
Embodiment 5,8% Eprinomectin injection
Preparation includes Eprinomectin medicine carrying microgranule 160g, and it is to be moored Lip river by 80g Eprinomectin, 45g
Husky nurse 407,35g HPMC composition；IPM adds to 1 liter.
Embodiment 6,8% ivermectin injection
Preparation includes ivermectin medicine carrying microgranule 160g, and it is by 80g ivermectin, 45g poloxamer188,35g HPMC
Composition；IPM adds to 1 liter.
Embodiment 7,8% ivermectin injection
Preparation includes ivermectin medicine carrying microgranule 120g, and it is made up of 80g ivermectin, 40g poloxamer188；IPM
Add to 1 liter.
Embodiment 8, embodiment 1 preparation and Comparative formulation determination of plasma concentration in sheep body
Comparative formulation forms: Comparative formulation contains ivermectin ultramicro powder 6%, P4075%, H-HMC4.5%, water for injection
Add to 100%.
Experimental animal packet and result of the test: the healthy sheep 10 of choosing, be divided into 2 groups, often group 5, and cervical region is subcutaneous to be injected respectively
Embodiment 1 preparation and Comparative formulation, dosage is 1.2mg/kg b.w., takes a blood sample on time, separated plasma, and will be with group with for the moment
Between plasma sample mixing after with acetonitrile extraction, by centrifugation, purify (C18Post), concentration, the process such as derivatization, prepare detection sample
Product, use HPLC (fluorescence detector) to measure ivermectin content in sample.Testing result is as shown in the table:
In above table, numerical value is the meansigma methods often organizing 5 sheep blood plasma drug level.
Claims (3)
1. one kind contains Avermectins medicine and the veterinary antiparasitic oil injection of poloxamer188, it is characterised in that:
A. in every liter of injection, comprise 25-100 gram of Avermectins medicine, 25-100 gram of poloxamer188, oil medium
Add to 1 liter；
B. the Avermectins medicine comprised in described injection and poloxamer188 are to be scattered in medicine carrying microgranule state
In oil medium；
C. in comprising the medicine carrying microgranule of Avermectins medicine and poloxamer188, Avermectins medicine and poloxamer
The weight ratio of 407 is 1: 0.5-1, and medicine carrying microgranule content in the formulation is 5-20%, weight/volume percent；
Described oil medium is the one in isopropyl myristate, injection soybean oil, Semen Maydis oil, Oleum Camelliae；
Described Avermectins medicine is that ivermectin, avilamycin, Eprinomectin, doractin, U.S. shellfish are mould
One in element oxime, moxidectin.
2. the oily injection as described in claim 1, it is characterised in that comprise 20-60g hydroxypropyl methyl in every liter of injection
Cellulose or Hydroxypropylcelliloxe, hydroxypropyl methyl cellulose or Hydroxypropylcelliloxe are and Avermectins medicine
Thing and poloxamer188 combination, be present in preparation with medicine carrying microgranule state；In medicine carrying microgranule, Avermectins medicine/pool
The weight ratio of Luo Shamu 407/ hydroxypropyl methyl cellulose or Hydroxypropylcelliloxe is 1: 0.5-1: 0.3-0.7；Medicine carrying
Microgranule weight/volume percent content in the formulation is 5.5-20%, and surplus is oil medium.
3. the oily injection as described in claim 1 or claim 2 any one, it is characterised in that described oil injection
Agent one of by the following method preparation:
Method a. in a heated condition, by husky with pool Lip river to Avermectins medicine and poloxamer188 or Avermectins medicine
Nurse 407 and Hydroxypropylcelliloxe or Avermectins medicine are together with poloxamer188 and hydroxypropyl methyl cellulose
Dissolve with low boiling point solvent, distillation of then reducing pressure, remove low boiling point solvent, obtain Avermectins medicine/poloxamer188 solid
Solution or Avermectins medicine/poloxamer188/Hydroxypropylcelliloxe solid solution or Avermectins medicine/pool
Luo Shamu 407/ hydroxypropyl methyl cellulose solid solution；The solid solution of preparation is pulverized, crosses 40 mesh sieves, obtain medicine carrying microgranule；
Medicine carrying microgranule is scattered in part oil medium, is ground to particle diameter with colloid mill and is less than 100 μm, then be ground to grain with sand mill
Footpath is less than 20 μm, and addition remaining media, to final volume, homogenizes under 5000-10000rpm further with high-shear homogenizing machine
Obtain described oily injection；
Method b. by Avermectins medicine and poloxamer188 or by Avermectins medicine with by poloxamer188 and height
Replace the solid solution of hydroxypropyl cellulose composition or by Avermectins medicine and by poloxamer188 and hydroxypropyl methyl fiber
The solid solution of element composition is scattered in part oil medium, is ground to particle diameter with colloid mill and sand mill and remains less than 20 μm, addition
Remaining medium, homogenizes with high-shear homogenizing machine and i.e. obtains described oily injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201410005519.9A CN103720652B (en) | 2014-01-07 | 2014-01-07 | Prepare containing Avermectins medicine injection with poloxamer and oil medium |
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|---|---|---|---|
| CN201410005519.9A CN103720652B (en) | 2014-01-07 | 2014-01-07 | Prepare containing Avermectins medicine injection with poloxamer and oil medium |
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| CN103720652A CN103720652A (en) | 2014-04-16 |
| CN103720652B true CN103720652B (en) | 2016-09-28 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104095812B (en) * | 2014-07-30 | 2017-09-19 | 北京中农华威制药有限公司 | The preparation method of the emulsifiable oily injection containing Avermectins medicine |
| UY36570A (en) * | 2015-02-26 | 2016-10-31 | Merial Inc | INJECTABLE FORMULATIONS OF PROLONGED ACTION THAT INCLUDE AN ISOXAZOLINE ACTIVE AGENT, METHODS AND USES OF THE SAME |
| CN106619685B (en) * | 2016-03-07 | 2021-05-07 | 中农华威生物制药(湖北)有限公司 | Oral solid preparation containing ivermectin medicine |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1193510A (en) * | 1998-04-23 | 1998-09-23 | 王玉万 | Oily injection for preventing animals from parasites |
| KR100315465B1 (en) * | 1998-11-23 | 2002-02-19 | 성재갑 | Animal Insect Repellent Compositions Containing Water Soluble Polymer and Alcohol |
| GB0316377D0 (en) * | 2003-07-12 | 2003-08-13 | Norbrook Lab Ltd | Parasiticidal composition |
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Effective date of registration: 20170103 Address after: 102206 Beijing City, Miyun Miyun Li Ge Zhuang Cun Zhen Xi Milin No. 128 100 Patentee after: Beijing Zhongnonghuawei feed Technology Co.,Ltd. Address before: 100083 Beijing Qinghua East Road, No. 17,, 41-5-102 Patentee before: Wang Yuwan |
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Effective date of registration: 20220927 Address after: 435300 No. 008 Jinshan Road, lishizhen Pharmaceutical Industrial Park, Hexi, Qichun County, Huanggang City, Hubei Province Patentee after: Zhongnong Huawei Biopharmaceutical (Hubei) Co.,Ltd. Address before: No. 128, 100 Milin West, Ligezhuang Village, Miyun Town, Miyun County, Beijing 102206 Patentee before: Beijing Zhongnonghuawei feed Technology Co.,Ltd. |