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WO2004045581A1 - Injection d'une suspension d'un antiparasite veterinaire - Google Patents

Injection d'une suspension d'un antiparasite veterinaire Download PDF

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Publication number
WO2004045581A1
WO2004045581A1 PCT/CN2003/000390 CN0300390W WO2004045581A1 WO 2004045581 A1 WO2004045581 A1 WO 2004045581A1 CN 0300390 W CN0300390 W CN 0300390W WO 2004045581 A1 WO2004045581 A1 WO 2004045581A1
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Prior art keywords
preparation
added
water
ethanol
anthelmintic
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PCT/CN2003/000390
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English (en)
Chinese (zh)
Inventor
Yuwan Wang
Zhende Pan
Xiaoxi Dai
Yan Xue
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Individual
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Individual
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Priority claimed from CNA031045855A external-priority patent/CN1500492A/zh
Priority claimed from CNA031045847A external-priority patent/CN1522704A/zh
Application filed by Individual filed Critical Individual
Priority to AU2003234895A priority Critical patent/AU2003234895A1/en
Publication of WO2004045581A1 publication Critical patent/WO2004045581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

Definitions

  • the preparation of the invention is a veterinary suspension injection containing an anti-parasitic drug, which is a macrolide-based anthelmintic or N-phenylpyrazole anthelmintic and liquid dispersion shield and auxiliary agent A long-acting injection of veterinary composition.
  • an anti-parasitic drug which is a macrolide-based anthelmintic or N-phenylpyrazole anthelmintic and liquid dispersion shield and auxiliary agent
  • the preparation of several long-acting injections described in the present invention differs from the long-acting injections described in the patents EP 0413538 A1, EP 0 535 734 A1, WO 99/27906 and CN 1241404.
  • Patent EP 0413538 A1 discloses a veterinary injection containing abamectin or ivermectin using triacetin as a main medium, which is a solution-type injection, and its outstanding features The prevention period is up to 42 days.
  • the preparation of the present invention is different from the preparation described in the patent, and the main difference is: a small amount of ethanol (about 5% or so) or water/ethanol is added to the supersaturated abamectin triacetin solution, and abamectin is microscopically
  • the crystal fineness is less than 30 ⁇
  • the crystal can be uniformly dispersed in a medium mainly composed of triacetin, and the physical properties of the obtained suspension are obtained. stable.
  • the suspension is used to control animal parasitic infections, subcutaneously, for up to 60 days or longer.
  • Patent EP 0 535 734 A1 discloses a long-acting injection containing abamectin or ivermectin prepared by a sustained-release medium consisting of triacetin and hydrogenated castor oil (HCO), which is unstable due to its physical properties (HCO aggregation is floating). It has not been commercialized yet and has been put on the market.
  • the long-acting injection described in the patent WO99/27906 is The formulation described in the patent EP0535734A1 is improved on the basis of the addition of acetylated monoglyceride in the formulation described in the EP 0 535 734 A1 patent, so that the formulation stability and the shelf life are significantly improved, and the formulation is fluid.
  • the preferred colloidal state, physical properties are stable, and the 3.15% ivermectin-containing formulation described in this patent has been commercialized by Merial Corporation under the trade name Ivomec-gold.
  • the long-acting injection containing abamectin or ivermectin of the present invention is also an improvement of the preparation of EP0535734A1, but the production process and clinical effect of the preparation are different from the preparation described in WO99/27906, which is characterized by: in the case of supersaturated avermectin When a small amount (1-10%, V/V) of ethanol or water/ethanol is added to the triacetin solution, the active compound precipitates 80% or more in a very short period of time (about 0.5-2 minutes).
  • the drug granules have a fineness of less than 30 ⁇ m, and a solution of hydrogenated castor oil in a triacetin solution is added to obtain a preparation of the present invention.
  • ivermectin and hydrogenated castor oil can be dissolved (melted) with 2-3 times of ethanol under heating conditions, and then rapidly cooled under stirring conditions, and ivermectin is precipitated in a state of fine powder in a very short period of time. (The fineness is less than 30 ⁇ m), and then the triglyceride is added and a part of the ethanol is removed under reduced pressure to obtain a preparation of the present invention.
  • the preparation of the invention is essentially a suspension, and the HCO mainly plays a suspending role in the preparation, and at the same time, also plays a certain sustained release effect.
  • avermectin In the preparation of a suspension containing avermectin, avermectin is precipitated from the triacetin solution in a fine powder state, and ethanol is indispensable and is the key to preparing the preparation.
  • the formulation overcomes the deficiencies of the formulation described in patent EP0535734A1 after the addition of ethanol or water/ethanol, that is, the physical properties of the preparation are stable;
  • the clinical feature of the preparation is that it has both a quick-acting effect and a sustained-release long-acting effect. It is used to control the infection of cattle and sheep parasites, and the prevention period can reach 90 days. Above (for different parasites, the length of the control period is different).
  • the preparation method can adopt the mechanical pulverization method (for example, pulverization by a jet mill or a fluid energy mill or a ball mill or a colloid mill) or the fine powder crystallization method, and the preparation of the micro powder crystallization method (solvent-nonsolvent method or rapid cooling method) is preferred.
  • Fine particles which is one of the characteristics of the present invention, which is prepared by: adding a supersaturated solution or a high-concentration solution containing a macrolide-based anthelmintic or a quinone-phenylpyrazole anthelmintic.
  • ethanol a small amount of ethanol (5-10%) or water/ethanol (5-30%) or glycerin or glycerol/water solution or water, so that the active ingredient is precipitated in the form of fine particles (fineness less than 30 ⁇ ) in a very short time; or
  • the active ingredient is dissolved in a low-boiling organic solvent such as ethanol under heating to prepare a supersaturated solution, and then rapidly cooled under stirring to rapidly decrystallize, which can also prepare active ingredient particles having a fineness of less than 30 ⁇ m.
  • the key steps to overcome the precipitation of the suspension medium and the precipitation of the drug particles are: selecting a suitable liquid as the dispersion medium
  • the specific gravity of the medium is adjusted to approximate the specific gravity of the suspended particles to control the stability of the preparation.
  • the invention adopts an organic solvent such as glycerol, propylene glycol, furfural glycerin or polyethylene glycol as a main shield, and prepares a suspension preparation containing a macrolide-based anthelmintic drug, and adjusts the specific gravity of the preparation medium to an activity.
  • the preparation of the present invention is superior to the aqueous suspension and oil suspension containing avermectin or ivermectin described in the patent CN1241404, and the preparation needs to add more suspending agent or thickener to be able to Media or drugs are not Precipitation and other issues. Therefore, using glycerol, formaldehyde glycerol, polyethylene glycol, propylene glycol, triacetin as the main dispersion medium, the stability of the suspension is controlled by adjusting the specific gravity of the dispersion medium, which is one of the characteristics of the present invention. .
  • the organic liquid used in the present invention may be a solvent of an active ingredient at different temperatures and under different conditions, or may be a dispersion medium (non-solvent).
  • a dispersion medium non-solvent
  • formaldehyde glycerol and 1,2-propanediol are good solvents for ivermectin (solution solubility greater than 8% at room temperature, solubility greater than 30% at 90 °C), but mixed with a certain amount of water (water content up to 30) Above %, the solubility of ivermectin in it is less than 0.1%.
  • solvent-non-solvent method a method of micro-powder crystallization (solvent-non-solvent method) to prepare a macrolide-containing anthelmintic or N-phenylpyrazole anthelmintic drug suspension injection.
  • solvent-non-solvent method solvent-non-solvent method
  • a stabilizer such as hydrogenated castor oil or polyvinylpyrrolidone or sulfhydryl cellulose
  • dissolving the active ingredient, and dissolving or swelling together with the active ingredient can play three roles: The first is dispersion, to prevent the active ingredients from agglomerating with water; the second is to prevent the growth of the nucleus and ensure that the active ingredients are fine powder with a fineness of less than 30 ⁇ ; and third, their presence can serve as a suspending effect.
  • composition of the preparation is:
  • the main dispersion medium constituting the preparation is water or benzyl benzoate or triacetin or a fatty acid ester (extracted or synthesized from plants) or a mineral oil (such as liquid paraffin) formed from a monohydric or polyhydric alcohol. Oil) or low viscosity dimercapto silicone oil; or glycerol, propylene glycol, polyethylene glycol, formaldehyde glycerol, they need to be used together with water, or two or more combinations with water, to 100% (V/V);
  • auxiliaries such as stabilizers, solubilizers, antioxidants, local pain alleviators or 5-20% ethanol or isopropanol in the formulation volume may be added to the preparation;
  • the compound preparation of other anthelmintic drugs may be added to the preparation, and the content of other anthelmintic drugs is 0.5-25% (W/V).
  • Method a Solvent-non-solvent method.
  • the specific preparation process is: dissolving the active compound with a cosolvent or a solvent under heating or no heating, and then mixing with a medium (non-solvent) which can reduce the solubility of the active compound, after the active compound is mostly precipitated in a microcrystalline state. Then, the remaining medium and other auxiliary agents are added to the final volume to obtain the suspension injection of the present invention. Or dissolving or swelling the active compound and the suspending agent with a cosolvent or solvent under heating or no heating, followed by mixing with a medium (non-solvent) which reduces the solubility of the active compound, and mostly precipitates in the microcrystalline state in the active compound. Thereafter, the remaining medium and other auxiliary agents are added to the final volume to obtain the suspension injection of the present invention.
  • Method b The active compound is prepared into microparticles having a particle size of less than 80 ⁇ m (which can be prepared by mechanical pulverization or micronization crystallization), and then the active compound microparticles are suspended in the medium of the present invention to prepare a suspension.
  • the stabilizer is a pharmaceutically useful stabilizer; preferred stabilizers include: sulfhydryl Cellulose, carboxymethylcellulose and its sodium salt, hydroxypropylcellulose, hydroxyethylcellulose, sodium alginate, sodium propylene glycol alginate, sodium polyacrylate, sorbitol, mannitol, sodium metaphosphate, polyethylene Pyrrolidone, polyvinyl alcohol, polyethylene glycol with a molecular weight greater than 1000, xanthan gum, hydrogenated castor oil, nonionic surfactants (eg glycerol fatty acid esters, polyglycerol fatty acid esters, sucrose esters, sorbitan higher fat) Acid ester Span, polyoxyethylene sorbitan higher fatty acid ester condensate Tween, polyoxyethylene higher fatty acid condensate Myijs, polyoxyethylene and higher fatty alcohol condensate Brijs, flat plus Paregal, emulsifier OP, poly Oxyethylene castor oil
  • the topical pain relieving agent is preferably phenylhydrin, chlorobutanol, procaine, tetracaine or lidocaine.
  • the co-solvent is preferably ethanol, 3-6 carbon monohydric alcohol, 1,2-propanediol, furfural glycerol and its homologues, dimethylacetamide, N-mercapto-pyrrolidone, azone, aromatic alcohol
  • Low boiling organic solvent such as ethyl acetate, decyl acetate, butyl acetate, acetone, dichloromethane, chloroform, etc.
  • these low boiling organic solvents are preferably used in the preparation of oil suspensions, they are completed After solubilization, it should be removed from the formulation.
  • the macrolide-based anthelmintic drugs include: avermectin abamectin, ivermectin ivermectin, emarosin ememectin, euphorin eprinomectin, doramectin doramectin, moxidectin;
  • the N-phenylpyrazine drug is preferably fipronil fipronil.
  • anthelmintic drugs include: albendazole oxide, oxfendazole, closantel (sodium), levamisole hydrochloride, anticoccidial, insect growth regulator or Young hormone-based anthelmintics, which are present in the formulation at a level of 1-25% (w/v).
  • the composition and preparation method of the optimized formulation of the present invention are as follows.
  • composition of the preparation (1), the composition of the preparation:
  • a macrolide anti-insecticide or N-phenylpyrazole anthelmintic 2-10% (w / v);
  • b propylene glycol, polyethylene glycol, glycerol, furfural glycerol, or a mixed dispersion medium composed of one or more of them, 5-50% (V/V);
  • An appropriate amount of stabilizer, antioxidant or local pain alleviating agent may be added to the preparation, and other anthelmintic drugs may be added to form a compound preparation.
  • Method a taking macrolide anthelmintics or N-phenylpyrazole anthelmintics and hydrogenated castor oil or Brazilian wax or polyvinylpyrrolidone (without adding them), using ethanol or dimercaptoacetamide, N-methylpyrrolidone or furfural glycerol or / and 1,2-propanediol are dissolved under heating or no heating, under stirring with water or with water / glycerol or with water / 1,2-propanediol or Glycerin is mixed, homogenized, and then added with an aqueous solution containing phenylhydrin or other medium and residual auxiliaries, and mixed to obtain a mixture of macrolide-containing anthelmintic or N-phenylpyrazole anthelmintic. Suspension injection.
  • Method b dissolving or swelling a macrolide anthelmintic or N-phenylpyrazole anthelmintic and sulfhydryl cellulose (also without) with N-mercapto-pyrrolidone or dimethylacetamide, After mixing with water or glycerin/water under stirring, after homogenization, the remaining medium containing phenyl sterol and the auxiliary agent are added to the final volume. A small amount of glycerin may be added as necessary to adjust the specific gravity of the preparation.
  • Method c dissolving the macrolide lactone medicinal 1,2-propanediol or polyethylene glycol 200-400 or furfural glycerin, and then adding glycerin, stirring into a paste, adding water for injection and assisting The final volume of the agent.
  • formulation composition macrolide anti-insecticide or N-phenylpyrazole anthelmintic 3-10% (W / V); molecular weight greater than 1000 polyethylene glycol (PEG) 3-20 % ( W / V ); Glycol 0-20% (V / V); Cosolvent 0-40% (V / V); Water for injection or glycerol and water for injection added to 100% (V / V) o
  • Preparation method Dissolve the macrolide lactone detoxification medicinal cosolvent, mix with the molten PEG, cool down, add water or water/glycerol to the final volume under stirring, homogenize, and obtain. Or the macrolide anti-insecticide and PEG are first prepared into a solid body, then the active ingredient / PEG solid dispersion is taken, water or glycerin and water are dispersed, homogenized, and the remaining medium and auxiliary agent are added. That is.
  • composition of the preparation (1), the composition of the preparation:
  • a macrolide anti-insecticide or N-phenylpyrazole anthelmintic 5-20% (w / v); b, ethanol or ethanol / water or propylene glycol and water composite medium 0-20% (V/V); c, benzyl benzoate or triacetin is added to 100% (V/V);
  • An appropriate amount of stabilizer such as hydrogenated castor oil, an antioxidant, and a local pain alleviator may be added to the preparation.
  • Method a using a macrolide anti-insecticide (such as avermectin) under heating conditions Dissolve triacetin, prepare a supersaturated solution, cool the liquid to below 30 ° C, add 5-10% (v / v) of ethanol or water / ethanol under stirring, after the completion of the crystallization, add cooling
  • the triacetin is about 80% of the final volume, stirred, mixed, and added triacetin (with or without hydrogenated castor oil) and antioxidant to the final volume.
  • Method b dispersing the macrolide-based anthelmintic drug with a small amount of triacetin, and then adding a triacetin liquid containing hydrogenated castor oil, stirring into a paste and grinding (such as a colloid mill or a ball mill, etc.) ), homogenization, when the fineness of the active ingredient is less than ⁇ , the remaining medium and the auxiliary agent are added to the final volume.
  • Method c mixing macrolides, hydrogenated castor oil and ethanol in a ratio of 1: 0.02-5: 2-3.5 (W/W/V), heating to melt and dissolve, and rapidly cooling under stirring conditions,
  • triacetin grind (such as a colloid mill), remove some ethanol under reduced pressure, and add sterile water to the final volume of about 5% of the preparation under stirring. It can be added before adding triacetin, stirring is continued for a certain period of time, and then the remaining medium is added to the final volume.
  • the macrolide-based anthelmintic drug is dissolved in 3 times of ethanol, and rapidly cooled under stirring. When the liquid is viscous into a paste, triacetin is added, stirring is continued, and ethanol is removed under reduced pressure, and then added. Triacetin to the final volume.
  • composition of the preparation (1), the composition of the preparation:
  • a macrolide anti-insecticide or N-phenylpyrazole anthelmintic 0.2-10% (w/v);
  • b vegetable oil or triacetin or organic acid with more than 8 carbons a liquid ester compound formed from a monohydric alcohol or propylene glycol or glycerol (extracted or synthesized from an organism) 0-95% (V/V);
  • additives such as water, ethanol, 1,2-propanediol, glycerol or other cosolvents, stabilizers, antioxidants, etc. may be added to the preparation.
  • a vegetable oil solution containing 2% aluminum stearate or 0.8-1% hydrogenated castor oil in a final volume of about 50% of the preparation is placed in a preparation tank, and when heated to about 85 ° C, the above macrolide-containing compound is added.
  • Ethyl acetate solution of anthelmintic and antioxidant reduce the liquid temperature to about 50 °C under stirring, add 110% liquid pyrolyzed liquid paraffin oil, lower the temperature to below 25 °C, continue to stir For 1-2 hours, a suspension of ethyl acetate was not removed.
  • the resulting suspension was treated under reduced pressure at 40 ° C to remove ethyl acetate to obtain an oil suspension containing a macrolide-containing anthelmintic.
  • Method c Take the macrolide anti-insecticide, hydrogenated castor oil and ethanol, mix in the ratio of 1: 0.05-2: 2-3.5 (W/W/V), and dissolve it at about 85 °C. Melt), then rapidly cool under stirring conditions, when the liquid is viscous or semi-cured, add or not add liquid paraffin oil which accounts for about 20% (V/V) of the final volume of the preparation, stir evenly, then add vegetable oil or two The mercapto silicone oil was removed and the ethanol was removed under reduced pressure, followed by the addition of the remaining shield (vegetable oil or liquid paraffin oil or dimercapto silicone oil) to the final volume.
  • the remaining shield vegetable oil or liquid paraffin oil or dimercapto silicone oil
  • composition of the preparation (1), the composition of the preparation:
  • Ivermectin or doramycin is dissolved in ethanol under heating, then uniformly mixed with molten sorbitol, cooled, dried or dried under reduced pressure, ethanol is removed, the solid is pulverized, and a dispersion medium and an auxiliary agent are added thereto. Final volume.
  • ivermectin or doramycin can be dissolved in ethanol under heating conditions, then mixed with molten sorbitol, cooled, added with glycerin or glycerin and water, homogenized and added to the remaining dispersion medium and auxiliary agent. Final volume.
  • Formulation 6 (1), the composition of the preparation:
  • composition of the preparation (1), the composition of the preparation:
  • the active ingredient, hydrogenated castor oil, and an appropriate amount of dimethyl silicone oil are mixed, heated at 90 ° C, after the hydrogenated castor oil is melted, cooled, made into a paste, and ground with a colloid mill until the fineness of the active ingredient is less than 1 When ⁇ , add the remaining medium and additives to the final volume.
  • Formulation composition ivermectin 3-7% (W/V); polyethylene glycol (4000-10000) 5-10% (W/V); glycerol 3-15% (V/ V); Dimercaptoacetamide 3-20% (V/V); Water for injection is added to 100% (V/V).
  • Example 1 This example is to prepare a long-acting suspension injection containing 5% of ivermectin to take 95% of ivermectin with a purity of 95%, and add 5L of N-mercaptopyrrolidone to make ivermectin at 60-80 °C. Dissolve, then add 20L PEG-200, mix, after cooling to room temperature, add 40L of glycerol under stirring, then add 6kg of PVP-K30 water for injection to 100L, stir and mix, degas, then Long-acting suspension injection containing 5% ivermectin.
  • Example 2 this example is to prepare a long-acting suspension injection containing avermectin 2.5% Take 2.75kg of avermectin ultrafine powder with a particle size of less than 40 ⁇ , disperse in 30L of glycerol, and then add 10L of 1,2-propanediol, 37L of PEG-200, 21L of water and 2L of Tween-80, and mix. Eliminating air bubbles, a long-acting suspension injection containing 2.5% of avermectin was obtained.
  • Example 3 this example is to prepare a long-acting suspension injection containing 5% of ivermectin to take 95% of ivermectin with a purity of 95%, and add 10L of furfural glycerol to heat at 80 ° C to dissolve ivermectin. Then, add 20L of PEG-200, add 30L of glycerin under stirring, then add water for injection to 100L, stir and mix, degas, and obtain.
  • Example 4 this example is to prepare a long-acting suspension injection containing avermectin 5% to take avermectin 5.5kg, add 22L of triacetin, dissolve at 80-90 ° C, and then cool it to 20 - 30 ° C, under stirring conditions (magnetic stirring), add 10 L of ethanol / water (2: 1), continue to stir the reaction for 20-40 minutes, then add the antioxidant containing triacetin to the final volume.
  • Example 5 this example is to prepare a long-acting suspension injection containing avermectin 5% to take avermectin 5.5kg, add 22L of triacetin, dissolve at 80-90 ° C, and then cool it to 20 At -30 ° C, 10 L of ethanol/water (3:1) was added under stirring (magnetic stirring). After about 20 minutes, the solution was added to 65 L of glycerol containing 1.5 kg of hydrogenated castor oil and 0.2 kg of antioxidant. In the acetate solution, the reaction was further stirred for 20 minutes to obtain a long-acting suspension injection containing 5% of avermectin.
  • Example 6 Dissolving ivermectin with 3 times of ethanol under heating to prepare a supersaturated solution, and cooling the liquid to about 30 ° C. After stirring, after the crystallizing is substantially completed, a certain amount of content is added. A triacetin solution of the antioxidant, ethanol was removed under reduced pressure, and triacetin was added to a final volume.
  • Example 7. Preparation of a suspension containing 5% ivermectin
  • Formulation composition ivermectin 5% (W/V); PEG 10000 7 % (WV); dimercaptoacetamide 10% (V/V); sodium thiosulfate 0.2% (W/V); trichloro Tert-butanol 0.5% (V/V); water for injection was added to 100% (V/V).
  • Preparation method ivermectin is dissolved in dimethylacetamide, added with chlorobutanol, then mixed with the melted PEG, stirred and mixed, and cooled to 10-40 ° C, and then injected under stirring Use water to about 70% of the final volume, pass through a colloid mill and pass through a 100 mesh sieve, and add a solution of sodium sulphate to the final volume.
  • Example 10 Suspension injection containing 10% ivermectin
  • Example 12 this example is an example 11 preparation blood concentration analysis experiment
  • the experimental animal was a sheep. 1.5 ml of the preparation of Example 11 was subcutaneously injected at a dose of 50 kg. The blood samples of the experimental sheep were collected periodically, and the concentration of ivermectin in the plasma was measured. The measurement method was fluorescence-high pressure liquid chromatography.
  • the experimental results are as follows:
  • Example 13 This example compares the efficacy and blood concentration of the formulation of Example 5 with common avermectin injection on sheep itch.
  • 70 sheep infected with natural itching were randomly divided into 4 groups, the first group of 20 sheep, subcutaneously injected with 5% of Avermectin in Example 5 at a dose of 0.4 ml/10 kg (equivalent to 2 mg/kg avermectin).
  • the 5% avermectin long-acting suspension injection can prevent and cure the pruritus for more than 90 days; and the common avermectin injection is constant (0. 2 mg / Kgb.w. dose) injection or 10 times constant administration, the prevention period is less than 45 days.
  • the effective blood concentration (about 3 ng/ml) of the 5% avermectin long-acting suspension injection of the present invention can be maintained for more than 90 days; while the common avermectin injection is injected by a constant or 10 times of constant administration, by 45 days, the blood concentration has dropped below the effective blood concentration.
  • the number of sheep with dead insects in 2 days is 6 6 4 10
  • the number of sheep with live insects is 0 0 0 10
  • There are no signs of biting the number of sheep with dry hair in the original affected area is 20 20 20 - Itching is relieved after the test,
  • the number of sheep with bite marks is 0 0 0
  • the number of sheep with 45 days of live insects is 0 2 4 10 After the test, the number of sheep with new hair growing in the original affected area was 20 12 9 -

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Abstract

L'invention concerne l'injection d'une suspension contenant des insectifuges à macrolides ou N-phénylpyrazol. Le milieu de dispersion principal est le glycérol, le propylène glycol, le glycérol formal ou diméthycone ; le procédé de préparation de particules de constituant actif est le procédé de broyage mécanique ou une cristallisation de particules en solution, de préférence une cristallisation de particules en solution (par exemple un procédé à solvant/non solvant ou un procédé de réduction temp rapide). La présente formulation peut être injectée par voie sous-cutanée ou intraveineuse pour prévenir et traiter la parasitose chez un animal, elle présente une durée de validité d'environ 30-100 jours ou davantage après un dosage individuel, et la durée peut être encore régulée par ajustement du dosage d'injection.
PCT/CN2003/000390 2002-11-18 2003-05-26 Injection d'une suspension d'un antiparasite veterinaire Ceased WO2004045581A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003234895A AU2003234895A1 (en) 2002-11-18 2003-05-26 Veterinary antiparasite suspension injection

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN02148804.5 2002-11-18
CN02148804 2002-11-18
CN03104584.7 2003-02-19
CNA031045855A CN1500492A (zh) 2002-11-18 2003-02-19 含抗寄生虫药物的兽用混悬注射剂
CNA031045847A CN1522704A (zh) 2003-02-19 2003-02-19 一种兽用抗寄生虫缓释注射剂
CN03104585.5 2003-02-19

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110311173A1 (en) * 2009-02-27 2011-12-22 Ntn Corporation Rolling bearing
WO2013165264A1 (fr) * 2012-05-01 2013-11-07 Nexan Corporation Limited Compositions anthelminthiques
CN107349236A (zh) * 2017-07-24 2017-11-17 佛山市南海东方澳龙制药有限公司 多拉菌素制剂及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413538A1 (fr) * 1989-08-14 1991-02-20 Merck & Co. Inc. Compositions injectables à effet prolongé à base de triacétine
EP0535734A1 (fr) * 1991-09-30 1993-04-07 Merck & Co. Inc. Formulations injectables à libération soutenue contenant de l'huile de ricine hydrogénée
CN1241404A (zh) * 1999-07-16 2000-01-19 王玉万 一种含阿维菌素或伊维菌素的注射用缓释制剂
CN1283990A (zh) * 1997-12-03 2001-02-14 麦克公司 含有氢化蓖麻油的长效注射制剂
CN1375287A (zh) * 2001-03-16 2002-10-23 王玉万 含氯氰碘柳胺或其钠盐的兽用混悬注射剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0413538A1 (fr) * 1989-08-14 1991-02-20 Merck & Co. Inc. Compositions injectables à effet prolongé à base de triacétine
EP0535734A1 (fr) * 1991-09-30 1993-04-07 Merck & Co. Inc. Formulations injectables à libération soutenue contenant de l'huile de ricine hydrogénée
CN1283990A (zh) * 1997-12-03 2001-02-14 麦克公司 含有氢化蓖麻油的长效注射制剂
CN1241404A (zh) * 1999-07-16 2000-01-19 王玉万 一种含阿维菌素或伊维菌素的注射用缓释制剂
CN1375287A (zh) * 2001-03-16 2002-10-23 王玉万 含氯氰碘柳胺或其钠盐的兽用混悬注射剂

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110311173A1 (en) * 2009-02-27 2011-12-22 Ntn Corporation Rolling bearing
US8905642B2 (en) * 2009-02-27 2014-12-09 Ntn Corporation Rolling bearing
WO2013165264A1 (fr) * 2012-05-01 2013-11-07 Nexan Corporation Limited Compositions anthelminthiques
AU2013257335B2 (en) * 2012-05-01 2017-03-02 Nexan Corporation Limited Anthelmintic compositions
CN107349236A (zh) * 2017-07-24 2017-11-17 佛山市南海东方澳龙制药有限公司 多拉菌素制剂及其制备方法和应用
CN107349236B (zh) * 2017-07-24 2020-10-23 佛山市南海东方澳龙制药有限公司 多拉菌素制剂及其制备方法和应用

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