CN103705454A - Oily injection containing valnemulin hydrochloride/poloxamer 407 - Google Patents
Oily injection containing valnemulin hydrochloride/poloxamer 407 Download PDFInfo
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- CN103705454A CN103705454A CN201410005517.XA CN201410005517A CN103705454A CN 103705454 A CN103705454 A CN 103705454A CN 201410005517 A CN201410005517 A CN 201410005517A CN 103705454 A CN103705454 A CN 103705454A
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- valnemulin hydrochloride
- valnemulin
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- MFBPRQKHDIVLOJ-AFFLPQGKSA-N 133868-46-9 Chemical compound Cl.CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 MFBPRQKHDIVLOJ-AFFLPQGKSA-N 0.000 title claims abstract description 59
- 238000002347 injection Methods 0.000 title claims abstract description 52
- 239000007924 injection Substances 0.000 title claims abstract description 52
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 title abstract description 7
- 229920001992 poloxamer 407 Polymers 0.000 title abstract 3
- 229940044476 poloxamer 407 Drugs 0.000 title abstract 3
- 238000002360 preparation method Methods 0.000 claims abstract description 75
- 239000003814 drug Substances 0.000 claims abstract description 51
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- 235000019198 oils Nutrition 0.000 claims description 28
- 239000006104 solid solution Substances 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 16
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- 235000012424 soybean oil Nutrition 0.000 claims description 5
- 239000003549 soybean oil Substances 0.000 claims description 5
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 claims description 4
- 210000000582 semen Anatomy 0.000 claims description 4
- 239000010419 fine particle Substances 0.000 claims description 3
- -1 hydroxypropyl Chemical group 0.000 claims description 3
- CTKXFMQHOOWWEB-UHFFFAOYSA-N Ethylene oxide/propylene oxide copolymer Chemical compound CCCOC(C)COCCO CTKXFMQHOOWWEB-UHFFFAOYSA-N 0.000 claims 7
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- 239000002245 particle Substances 0.000 abstract description 21
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- 229940079593 drug Drugs 0.000 abstract description 6
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- 238000013268 sustained release Methods 0.000 abstract 2
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- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 abstract 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 abstract 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 abstract 1
- 230000002427 irreversible effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 39
- LLYYNOVSVPBRGV-MVNKZKPCSA-N valnemulin Chemical compound CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 LLYYNOVSVPBRGV-MVNKZKPCSA-N 0.000 description 18
- 229950008166 valnemulin Drugs 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000084 colloidal system Substances 0.000 description 8
- 239000004576 sand Substances 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
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- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 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 description 1
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
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- 229920005601 base polymer Polymers 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 238000004587 chromatography analysis Methods 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000007908 nanoemulsion Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
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- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses an oily long-acting injection containing valnemulin hydrochloride/poloxamer 407 drug-loading particles, which is prepared by combining the valnemulin hydrochloride with poloxamer 407 into drug-loading particles and further dispersing the drug-loading particles into an oily medium and grinding. Hydroxypropyl methyl cellulose or high-substituted hydroxypropyl cellulose also can be added into the drug-loading particles, and the sustained-release effect of the preparation is obviously enhanced. The preparation process of the injection is simple, the drug release is uniform, the biocompatibility is good, irreversible damage to the tissue of the injection part is avoided, and the adopted sustained-release carrier can be degraded and excreted.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, being specifically related to poloxamer188 and oil medium is carrier, prepares the long-acting veterinary injection of hydrochloric valnemulin.
Background technology
Valnemulin hydrochloride is the semi-synthetic antibacterials of animal specific, there is has a broad antifungal spectrum, activity is high, toxic and side effects is lower, be difficult for to produce drug resistance, the residual feature such as low, is mainly used in preventing and treating the mycoplasma of pig, cattle, sheep and poultry and the infection of gram positive bacteria.At present there is pre-mixing agent and the valnemulin hydrochloride injection being added in feedstuff to feeding animal commercially available prod.
Patent CN102119919B discloses the agent of a kind of valnemulin oily injection, and said preparation is that to take ethanol or glycerol be cosolvent, the solution-type oil injection that the Oleum Ricini of take is prepared as solvent.Patent CN101756899A discloses a kind of valnemulin nano-emulsion antibacterial medicine preparation, and said preparation is to be become with surfactant, water and line of oils by valnemulin.Patent CN101947203A discloses a kind of valnemulin Emulsion, and said preparation is comprised of valnemulin hydrochloride and emulsifying agent, ethanol, oil for injection and water.Patent CN101744799B discloses the novel liposome formulation of a kind of veterinary valnemulin and salt thereof, this liposome is comprised of valnemulin and soybean phospholipid, cholesterol and finishing thing, take rat as laboratory animal, by per kilogram of body weight 10mg injection said preparation, within after administration 48 hours, in lung tissue, still can detect valnemulin.
Poloxamer is polyoxyethylene polyoxypropylene ether analog copolymer, this base polymer has plurality of specifications, wherein the aqueous solution of poloxamer188 (hereinafter to be referred as P407) has " characteristic that raises and transformed to gel by colloidal sol with temperature ", generally at 30 ℃, there is above gelling in certain density P407 aqueous solution, characteristic accordingly, P407 is used to the preparation of slow releasing injection, and said preparation is referred to as in-situ gelling preparation.After being injected in vivo containing the in-situ gelling injection of P407, under the effect of body temperature, generally, about 1 minute, by colloidal sol, change gel (semisolid) into, medicine is wrapped in gel, thereby has slowed down rate of releasing drug, and duration of efficacy is extended.The disclosed in-situ gelling injection containing P407 of document and patent, is to take water as primary solvent, and in preparation, the concentration of P407 will reach and more than 20% just have good slow releasing function; In preparation, add the blocker such as a certain amount of methylcellulose, sodium carboxymethyl cellulose, Hydroxypropylcelliloxe (H-HPC) or hydroxypropyl emthylcellulose (HPMC), can strengthen slow releasing function, but can cause preparation viscosity to raise, make injection more difficult.
P407 is also the good non-ionic surface active agent of a kind of water solublity, is to be more used to prepare Emulsion, ointment, aqueous suppository, drop pill etc.; P407 is also used as the dispersible carrier of insoluble medicine (medicine that water solublity is very poor), and for the preparation of solid solution, mostly the published solid solution of preparing with P407, be the preparation for oral preparations.
Preparation of the present invention is different from the injection of published hydrochloric valnemulin and contains the in-situ gelling injection of P407, also be different from traditional oily injection, the present invention forms medicine and P407 (or with P407 and cellulose ethers) medicine carrying microgranule (as agglomerate) of solid solution or other form, and (isopropyl myristate, hereinafter to be referred as IPM with oil medium; Injection vegetable oil) place of water is prepared the oily injection containing P407.This better stability of preparation, through valnemulin hydrochloride and P407 combination are prepared into medicine carrying microgranule, and is scattered in oil medium, thereby overcome, valnemulin hydrochloride is easily degraded, unsettled defect; This preparation injects under animal skins or intramuscular, medicine carrying microgranule is after " breakthrough " oil phase contact body fluid (water), by means of P407 " water suction (body fluid) " or water absorption and swelling (when HPMC or H-HPC exist), " adhesive aggregation " together, in injection site, form high concentration and full-bodied and there is the semi-solid agglomerate of " bioadhesive " (when HPMC or H-HPC exist), medicine is wrapped in agglomerate, thereby effectively extended the release time of medicine, therefore, this medicament also has good slow releasing function.
Summary of the invention
Valnemulin hydrochloride and P407 or valnemulin hydrochloride and P407 and HPMC (or H-HPC) form medicine carrying microgranule, and are suspended in oil medium, and this is the prominent features of this preparation.This preparation composition and preparation method are as follows:
Preparation forms: this preparation is mainly comprised of valnemulin hydrochloride, P407 and oil medium.In every liter of injection, hydrochloric valnemulin 50-150g, P40725-150g, oil medium add to 1 liter.
Described oil medium is a kind of in IPM or injection soybean oil, Semen Maydis oil, Oleum Camelliae.
In every liter of described injection, also can add 20-60g HPMC or H-HPC, HPMC or H-HPC need be combined into solid solution or form medicine carrying microgranule with P407 together with valnemulin hydrochloride with P407, could be used for the preparation of this preparation.H-HPC has good dissolubility in the low boiling point organic solvents such as methanol, ethanol, valnemulin hydrochloride has equally good dissolubility in these low boiling point organic solvents, this is that H-HPC, P407, valnemulin hydrochloride three can form one, is prepared into the important foundation of medicine carrying microgranule.
H-HPC and HPMC be nontoxic, without pharmacological action, on physiologically active, show extreme inertia.HPMC, H-HPC or P407 are insoluble in the oil mediums such as IPM, therefore, by H-HPC or HPMC and P407 composition microgranule, even be scattered in oil medium with higher concentration, can not make preparation viscosity obviously raise yet, but contain the medicine carrying microgranule of high concentration H-HPC or HPMC at injection part potential energy water absorption and swelling, form full-bodied agglomerate, full-bodied agglomerate has the effect of stronger retardance (slowing down) drug release, therefore, as requested, in medicine carrying microgranule, add the slow release effect that appropriate H-HPC and HPMC can reach expection.
In the medicine carrying microgranule of valnemulin hydrochloride and P407 composition, valnemulin hydrochloride and P407 weight ratio are 1: 0.5-1, and the weight/volume percent content of medicine carrying microgranule in preparation is 7.5-25%, surplus is oil medium.
In the medicine carrying microgranule that valnemulin hydrochloride and P407 and HPMC (or H-HPC) form, the weight ratio of valnemulin hydrochloride and P407 and HPMC (or H-HPC) is 1: 0.5-1: 0.3-0.5, the weight/volume percent content of medicine carrying microgranule in preparation is 9-25%, preferred weight/volume percent content is 12-20%, and surplus is oil medium.
Preparation method: be summed up mainly contain following several.
(1) under heating condition, valnemulin hydrochloride and P407 or valnemulin hydrochloride and P407 and HPMC or valnemulin hydrochloride and P407 and H-HPC mono-are reinstated to methanol or dissolve with ethanol, then removal of solvent under reduced pressure, obtains valnemulin hydrochloride/P407 solid solution or valnemulin hydrochloride/P407/HPMC solid solution or valnemulin hydrochloride/P407/H-HPC solid solution; The solid solution of preparation was pulverized to 40 mesh sieves, obtained medicine carrying microgranule; Medicine carrying microgranule is scattered in part oil medium, with colloid mill, be ground to particle diameter and be less than 100 μ m, with sand mill, be ground to particle diameter again and be less than 20 μ m, add remaining media to final volume, with high-shear homogenizing machine, at 5000-10000rpm, further homogenize and obtain this preparation.
(2) medicine and P407 or medicine and solid solution (P407/HPMC or P407/H-HPC) are scattered in part oil medium, with colloid mill and sand mill, are ground to particle diameter and are less than 20 μ m, add remaining media, with homogenizer this preparation that homogenizes to obtain.
(3) medicine superfine powder (particle diameter is less than 1 μ m) is mixed homogeneously with the P407 having melted, coolingly make it curing, pulverize, sieve, obtain medicine carrying microgranule, medicine carrying microgranule is scattered in oil medium through grinding to obtain this preparation.
P407/H-HPC or P407/HPMC solid solution fine particle preparation: under heating condition, HPMC or H-HPC and P407 be dissolved in to methanol or be dissolved in 80% alcoholic solution, mixing, under agitation removal of solvent under reduced pressure, pulverizes, sieves and get final product.
This preparation preparation process need be carried out under aseptic condition, and during grinding, temperature of charge can not surpass 40 ℃, and in preparation, the particle diameter of solid particle should be less than 20 μ m, more suitable to be less than 10 μ m.
This preparation characteristic is summarized as follows:
This medicament drug release process is different from take in-situ gelling preparation that water is medium and traditional oily injection, and main difference part is to exist medicine carrying microgranule " breakthrough " oil phase to contact with body fluid and absorb water to form high viscosity agglomerate process.
By appropriate H-HPC or HPMC and P407 composition solid solution pellet, be scattered in oil phase, solved the simple technical barrier that is difficult to grind to form fine particle (being less than 20 μ m) with H-HPC (or HPMC) packaging medicine, retain H-HPC and HPMC has water absorption and swelling simultaneously, formed the characteristic of high viscosity agglomerate.Pastille " agglomerate " adheres in injection site tissue, is conducive to medicine and better absorbs, and guaranteed slow release effect to a certain degree, and it is high that this is that this agent has bioavailability, has again the basis of long-acting.
By oil medium place of water, prepare the slow releasing injection containing P407, can reduce the consumption of P407, P407 consumption is when 5-10%, and preparation just has good slow releasing function.Take water as the in-situ gelling injection of solvent preparation containing P407, and the consumption of P407 will reach 20～45%, and preparation just can demonstrate good slow releasing function.Current domestic P407 price more expensive (medical grade is at 160～200 yuan/kg), therefore, P407 consumption in preparation is more, and preparation cost is higher, is unfavorable for applying in veterinary applications.
The specific embodiment
Embodiment 1, preparation 15% valnemulin hydrochloride injection
Preparation forms: valnemulin hydrochloride 150g, P407100g, injection soybean oil add to 1 liter.
Preparation method: melt P407 at 65-75 ℃ (1), then add valnemulin hydrochloride and be equivalent to the methanol that valnemulin hydrochloride 2-3 doubly measures, fully stir, cooling and decompression, remove methanol, make solid solution, solid solution is pulverized, cross 40 mesh sieves, obtain valnemulin hydrochloride/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in appropriate soybean oil, while being ground to particle diameter approximately 100 μ m with colloid mill, with sand mill, be further ground to particle diameter and be less than 10 μ m, then add remaining soybean oil, with high-shear homogenizing machine under 5000rpm condition after repeatedly homogenizing, make 15% valnemulin hydrochloride injection.
Embodiment 2, preparation 10% valnemulin hydrochloride injection
Preparation forms: every liter of hydrochloric valnemulin 100g, P40760g, HPMC30g, IPM add to final volume.
Preparation method: melt P407 at 65-75 ℃ (1), then add valnemulin hydrochloride, HPMC, after fully mixing, add and be equivalent to the methanol that valnemulin hydrochloride 2-3 doubly measures, fully stir, cooling and decompression, removes methanol, make solid solution, solid solution is pulverized, crossed 40 mesh sieves, obtain the medicine carrying microgranule of hydrochloric valnemulin.(2) medicine carrying microgranule is scattered in appropriate IPM, while being ground to particle diameter approximately 100 μ m with colloid mill, with sand mill, be further ground to particle diameter and be less than 8 μ m, then add remaining IPM, with high-shear homogenizing machine under 5000rpm condition after repeatedly homogenizing, make 10% valnemulin hydrochloride injection.
Embodiment 3, preparation 13% valnemulin hydrochloride injection
Preparation forms: every liter of hydrochloric valnemulin 130g, P40765g, H-HPC40g, IPM adds to final volume.
Preparation method: melt P407 at 65-75 ℃ (1), then add valnemulin hydrochloride, H-HPC, after fully mixing, add and be equivalent to the methanol that valnemulin hydrochloride 2-3 doubly measures, fully stir, cooling and decompression, removes methanol, make solid solution, solid solution is pulverized, crossed 40 mesh sieves, obtain the medicine carrying microgranule of hydrochloric valnemulin.(2) medicine carrying microgranule is scattered in appropriate IPM, while being ground to particle diameter approximately 100 μ m with colloid mill, with sand mill, be further ground to particle diameter and be less than 8 μ m, then add remaining IPM, with high-shear homogenizing machine under 5000rpm condition after repeatedly homogenizing, make 6.5% valnemulin hydrochloride injection.
Embodiment 4, preparation 13% valnemulin hydrochloride injection
Preparation forms: valnemulin hydrochloride 130g, P40765g, IPM adds to 1 liter.
Preparation method: melt P407 at 65-75 ℃ (1), then add valnemulin hydrochloride and be equivalent to the methanol that valnemulin hydrochloride 2-3 doubly measures, fully stir, cooling and decompression, remove methanol, make solid solution, solid solution is pulverized, cross 40 mesh sieves, obtain valnemulin hydrochloride/P407 medicine carrying microgranule.(2) medicine carrying microgranule is scattered in appropriate IPM, while being ground to particle diameter approximately 100 μ m with colloid mill, with sand mill, be further ground to particle diameter and be less than 8 μ m, then add remaining IPM, with high-shear homogenizing machine under 5000rpm condition after repeatedly homogenizing, make 6.5% valnemulin hydrochloride injection.
Embodiment 5, preparation 8% valnemulin hydrochloride injection
Preparation forms: valnemulin hydrochloride 80g, P40780g, Oleum Camelliae adds to 1 liter.
Preparation method: valnemulin hydrochloride is scattered in the P407 having melted, after cooling curing, pulverize, ground product is scattered in the IPM of approximately 2 times of amounts, with colloid mill, be ground to particle diameter and be less than 100 μ m, with sand mill, be ground to particle diameter again and be less than 5 μ m, add remaining media, with homogenizer, homogenize and obtain this preparation.
Embodiment 6, preparation 10% valnemulin hydrochloride injection
Preparation forms: valnemulin hydrochloride 100g, P407/HPMC (1: 0.6) solid solution 50g, Semen Maydis oil adds to 1 liter.
Preparation method: (1) by P407 and HPMC mix homogeneously, adds to be equivalent to HPMC3.5-5 and doubly to measure methanol, and 70-80 ℃ of backflow, after HPMC dissolves completely, distilling under reduced pressure, removes methanol, cooling, obtain P407/HPMC solid solution, through pulverizing, sieving, obtain solid solution pellet.(2) valnemulin hydrochloride and solid solution pellet are scattered in part Semen Maydis oil, with colloid mill and sand mill, are ground to particle diameter and are less than 20 μ m, add residue composition, with high-shear homogenizing machine, homogenize and obtain this preparation.
Embodiment 7: after sheep injection embodiment 3, embodiment 4 preparations and Comparative formulation, blood drug level detects
Comparative formulation a: the hydrochloric valnemulin 13g of every 100ml preparation, P4076.5g, sterilized water add to final volume.
Comparative formulation b: the hydrochloric valnemulin 13g of every 100ml preparation, P40720g, sterilized water add to final volume.
Test method: select 12 of healthy sheep, divide 4 groups, 3 every group; Difference subcutaneous injection embodiment 3, embodiment 4 preparations and Comparative formulation, dosage is 13mg/kg b.w., blood sampling on time, centrifugal separation plasma, by the plasma sample mixed in equal amounts of same same time of test group together by extraction, centrifugalize, purification and the process such as concentrated, make detection sample, adopt high pressure lipuid chromatography (HPLC) (C
18post) measure valnemulin hydrochloride concentration in blood plasma, experimental result is as shown in the table.
In table, numerical value is the meansigma methods that every group of 3 sheep detects.
Embodiment 8: stability test
Embodiment 3 preparations, embodiment 4 preparations and Comparative formulation a, Comparative formulation b are deposited 12 months in 30-35 ℃, with HPLC, measure valnemulin hydrochloride content, to account for the percentage ratio of primary quantity, represent, the results are shown in following table.
Place the percentage ratio (%) that 12 months valnemulin content accounts for primary quantity
Claims (6)
1. an oily long-acting injection that comprises valnemulin hydrochloride/poloxamer188 medicine carrying microgranule.
2. by injection claimed in claim 1, it is characterized in that every liter of injection comprises following composition:
Valnemulin hydrochloride 50-150g
Poloxamer188 25-150g
Oil medium adds to 1 liter
Described oil medium is a kind of in isopropyl myristate, injection soybean oil, Semen Maydis oil, Oleum Camelliae.
3. by the injection described in claim 1 or claim 2 any one, it is characterized in that valnemulin hydrochloride and poloxamer188 form medicine carrying microgranule, in medicine carrying microgranule, the weight ratio of valnemulin hydrochloride and poloxamer188 is 1: 0.5-1, the weight/volume percent content of medicine carrying microgranule in preparation is 7.5-25%, and surplus is oil medium.
4. by injection claimed in claim 2, it is characterized in that also can adding 20-60g hydroxypropyl emthylcellulose or Hydroxypropylcelliloxe in every liter of injection, hydroxypropyl emthylcellulose or Hydroxypropylcelliloxe and poloxamer188 combination, with solid solution fine particle state, be present in preparation, or combine with valnemulin hydrochloride and poloxamer188, with medicine carrying microgranule state, be present in preparation.
5. by injection claimed in claim 4, it is characterized in that every liter of injection comprises following composition:
The medicine carrying microgranule 160g that 80g valnemulin hydrochloride, 40g poloxamer188,40g Hydroxypropylcelliloxe form, isopropyl myristate adds to 1 liter.
6. by injection claimed in claim 4, it is characterized in that every liter of injection comprises following composition:
The medicine carrying microgranule 160g that 100g valnemulin hydrochloride and 60g poloxamer188 form, isopropyl myristate adds to 1 liter.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410005517.XA CN103705454B (en) | 2014-01-07 | 2014-01-07 | The oily injection of hydrochloric valnemulin/poloxamer188 |
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| CN201410005517.XA CN103705454B (en) | 2014-01-07 | 2014-01-07 | The oily injection of hydrochloric valnemulin/poloxamer188 |
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| CN104689324A (en) * | 2014-07-30 | 2015-06-10 | 王玉万 | Preparation method of hydrophilic treatment drug containing type emulsifiable oil injection |
| CN105878176A (en) * | 2016-04-06 | 2016-08-24 | 山东胜利生物工程有限公司 | Valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
| WO2016138339A1 (en) * | 2015-02-26 | 2016-09-01 | Merial, Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| CN115068412A (en) * | 2022-07-20 | 2022-09-20 | 塔里木大学 | Valnemulin hydrochloride nano gel for treating animal proliferative enteritis and preparation method thereof |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104689324A (en) * | 2014-07-30 | 2015-06-10 | 王玉万 | Preparation method of hydrophilic treatment drug containing type emulsifiable oil injection |
| WO2016138339A1 (en) * | 2015-02-26 | 2016-09-01 | Merial, Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| AU2016222532B2 (en) * | 2015-02-26 | 2018-07-12 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| AU2018205137B2 (en) * | 2015-02-26 | 2019-08-08 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| US10561641B2 (en) | 2015-02-26 | 2020-02-18 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
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| US11484528B2 (en) | 2015-02-26 | 2022-11-01 | Boehringer Ingelheim Animal Health USA Inc. | Long-acting injectable formulations comprising an isoxazoline active agent, methods and uses thereof |
| CN105878176A (en) * | 2016-04-06 | 2016-08-24 | 山东胜利生物工程有限公司 | Valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
| CN105878176B (en) * | 2016-04-06 | 2019-01-08 | 山东胜利生物工程有限公司 | A kind of valnemulin hydrochloride injection in-situ gel preparation and preparation method thereof |
| CN115068412A (en) * | 2022-07-20 | 2022-09-20 | 塔里木大学 | Valnemulin hydrochloride nano gel for treating animal proliferative enteritis and preparation method thereof |
| CN115068412B (en) * | 2022-07-20 | 2024-01-26 | 塔里木大学 | Valnemulin hydrochloride nanogel for treating animal proliferative enteritis and preparation method thereof |
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| CN103705454B (en) | 2016-08-31 |
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Application publication date: 20140409 Assignee: Hebei Veyon Animal Pharmaceutical Co., Ltd. Assignor: Wang Yuwan Contract record no.: 2016130000019 Denomination of invention: Oily injection containing valnemulin hydrochloride/poloxamer 407 Granted publication date: 20160831 License type: Exclusive License Record date: 20161111 |
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