WO2004045581A1

WO2004045581A1 - Veterinary antiparasite suspension injection

Info

Publication number: WO2004045581A1
Application number: PCT/CN2003/000390
Authority: WO
Inventors: Yuwan Wang; Zhende Pan; Xiaoxi Dai; Yan Xue
Original assignee: Yuwan Wang; Zhende Pan; Xiaoxi Dai; Yan Xue
Priority date: 2002-11-18
Filing date: 2003-05-26
Publication date: 2004-06-03
Also published as: AU2003234895A1

Abstract

The invention relates to a suspension injection comprising macrolide or N-phenylpyrazol insect repellents. The major dispersion medium is glycerol, propylene glycol, glycerol formal or dimethicone; the process for the preparation of active component particles is mechanical milling method or solution particle crystallization, preferred solution particle crystallization (e.g. solvent-nonsolvent method or fast temp-reducing method). The present formulation can be injected subcutaneously or intravenously for preventing and treating parasitosis in animal, it has the period of validity about 30-100 days or more after a single dosege, and the period can further be controlled by adjusting dosege of injection.

Description

Veterinary suspension injection containing antiparasitic drugs

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. 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.

Background technique

1. 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 μηι) is precipitated, and in the case where no suspending agent is added, 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 μm, and a solution of hydrogenated castor oil in a triacetin solution is added to obtain a preparation of the present invention. Or 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 μm), 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. 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. In the preparation of a suspension containing avermectin and ivermectin, 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).

2. When preparing a veterinary suspension injection containing a macrolide or an N-phenylpyrazole anthelmintic, one of the key steps to overcome the mediation of the suspension and the precipitation of the drug particles is to prepare a fineness of less than 30 μm. Drug particles. 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. Ingredients: 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. 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 30μπι) 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 μm.

3. When preparing a veterinary suspension injection containing a macrolide or a quinone-phenylpyrazole anthelmintic, 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. When the specific gravity of the component granules is the same or similar, the preparation is still very stable without adding or adding a small amount of the suspending agent. Therefore, 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. .

4. 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). For example, 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%. This is an organic solvent such as 1, 2-propanediol, which is prepared by the method of micro-powder crystallization (solvent-non-solvent method) to prepare a macrolide-containing anthelmintic or N-phenylpyrazole anthelmintic drug suspension injection. The basis of chemistry.

5. When preparing the preparation of the present invention, adding a stabilizer such as hydrogenated castor oil or polyvinylpyrrolidone or sulfhydryl cellulose while 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 30μηι; and third, their presence can serve as a suspending effect.

Summary of the invention

The veterinary long-acting injection containing the macrolide-based anthelmintic drug or the quinone-phenylpyrazole-based anthelmintic drug of the present invention is characterized in that:

(1) It is a suspension in which the active ingredient is mainly present in the form of fine particles.

(2), the composition of the preparation is:

a, macrolide anti-insecticide or N-phenylpyrazole anthelmintic 0.3-25% (W / V); b. 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);

c. Other 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;

d. 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).

(3), preparation method, preferred preparation methods are as follows:

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 μm (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 condensate, polyoxyethylene hydrogenated castor oil condensate, Pluronic).

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. Other 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.

Formulation 1:

(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);

c, ethanol, isopropanol, dimercaptoacetamide, N-methylpyrrolidone 0-30% (V / V); d, water for injection to 100% (V / V);

e. 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.

(2), preparation method:

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 2:

(1), 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

(2) 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.

Formulation 3:

(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);

d. An appropriate amount of stabilizer (such as hydrogenated castor oil), an antioxidant, and a local pain alleviator may be added to the preparation.

(2), preparation method:

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 ΙΟΟμιη, 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, When it is viscous or semi-cured or cured, add 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. Or 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.

Formulation 4:

(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);

c. Mineral oil or dimethicone is added to 100% (V/V);

d. Other additives (such as water, ethanol, 1,2-propanediol, glycerol or other cosolvents, stabilizers, antioxidants, etc.) may be added to the preparation.

(2), preparation method:

Method a:

Take a macrolide-based anthelmintic drug and an appropriate amount of antioxidant, add about twice the amount of ethyl acetate, heat, dissolve the macrolide anti-insecticide and antioxidant, and obtain a macrolide-containing anthelmintic And an ethyl acetate solution of the antioxidant.

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 b:

Mixing macrolide anthelmintics or N-phenylpyrazole anthelmintics with vegetable oil or mineral oil or dimercaptosilicone oil containing 3% aluminum stearate or 1-1.5% hydrogenated castor oil , made into a paste, then ground, homogenized, so that the fineness of the active ingredient is less than ΙΟΟμηι, and then the remaining medium and auxiliary agent are added to the final volume.

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.

Formulation 5:

(1), the composition of the preparation:

a, ivermectin or doramectin 2-10% (W / V)

b, sorbitol 5-15% (W/V)

c, 1, 2-propanediol 10-30% (V/V)

d, glycerin 5-30% (V/V)

c, phenyl sterol 1% (V / V)

f, water to 100% (V/V)

(2), preparation method:

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.

Or 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:

a, ivermectin or doramectin 2-10% (W / V)

b, polyethylene glycol 200-600 5-15% (W/V)

c, 1, 2-propanediol 10-30% (V/V)

e, phenylhydrin 1 % (V/V)

f, dimercaptoacetamide or N-methylpyrrolidone 0-15% (V/V)

Up to 100% (V/V)

(2), preparation method:

Dissolve ivermectin or doramycin with 1,2-propanediol or N-methylpyrrolidone or dimethylacetamide under heating or no heating, then add polyethylene glycol and mix well. Add glycerin or glycerin and water, homogenize and add the remaining dispersion medium and auxiliary to the final volume.

Formulation 7:

(1), the composition of the preparation:

a, ivermectin or doramycin 2-10% (W / V) b, hydrogenated castor oil 0.2-3.5% (W / V) c, benzyl alcohol or chlorobutanol 0.5-1% (V /V) d, Di-based silicone oil with viscosity less than 100mm ² /S to 100% (V/V)

(2), preparation method:

Take ivermectin or doramycin and ethanol equivalent to about 3 times, put it in a preparation container, add hydrogenated castor oil, dissolve and melt it under conditions of about 85 ( (refer to Hydrogenated castor oil), then the liquid is rapidly cooled under stirring and added with dimethyl silicone oil, stirring is continued, ethanol is removed under reduced pressure or no reduced pressure, and about 1% benzyl alcohol or chlorobutanol is added. And add the remaining dimercaptosilicone oil to the final volume. Or 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 ΟΟμιη, add the remaining medium and additives to the final volume.

Formulation 8:

(1) 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).

(2) Preparation method: Dissolve ivermectin with dimercaptoacetamide, then mix with molten polyethylene glycol, cool down, add water and glycerol to the final volume under stirring, and shield , that is.

Detailed ways

The invention is illustrated by the following examples, but the examples are not intended to limit the scope of the invention, and the scope and the core of the invention are determined according to the claims.

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 40μηι, 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

Take 8.5g of ivermectin with a purity of 90%, 4.5g of PVP-k30, add 30ml of 1,2-propanediol, 10ml of glycerol, and dissolve at 95°C, then cool the solution to below 30°C (not visible) Crystallization), under stirring, add 40 ml of sterile water, homogenize, then add 43 ml of water for injection containing 0.3 g of sodium thiosulfate and 15 ml of glycerol, homogenize, to obtain 5% Ivermella Suspension injection.

Example 8. 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 9. Preparation of a suspension containing 10% ivermectin

Take lg ivermectin, 0.07g hydrogenated castor oil, add 3ml ethanol, dissolve at 90 ° C, then cool to a viscous condition under stirring, add 2ml liquid paraffin oil, continue to stir, then add 8ml corn oil, Ethanol is removed under reduced pressure.

Example 10. Suspension injection containing 10% ivermectin

Take lg ivermectin, 0.15 g of hydrogenated castor oil, add 3 ml of ethanol, dissolve at 90 ° C, then cool to a viscous state under stirring, add 0.6 ml of water, continue stirring until the paste, and remove under reduced pressure Partial ethanol (about 1-1.5 ml), adding 4 ml of triacetin, homogenization After adding glycerol triacetate to the final volume, it is obtained.

Example 11. Preparation of a suspension injection containing 5% ivermectin

Take lg ivermectin, 0.25g hydrogenated castor oil, add 3ml ethanol, dissolve at 90 ° C, then cool under stirring, and add 9ml of dimercapto silicone oil with a viscosity of 100mm ² /S, continue to stir, and reduce The ethanol is removed by pressure, and then the dimercaptosilicone oil is added to the final volume.

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). Long-acting suspension injection; Group 2 20 sheep, subcutaneous injection of 1% avermectin injection at a dose of 2ml/10kg (equivalent to 2mg/kg avermectin) (Beijing Agricultural University New Technology Development Corporation) Production); Group 3 20 sheep, subcutaneously injected with 1% avermectin injection at a dose of 0.2ml/10kg (corresponding to 0.2mg/kg avermectin) (produced by Beijing Agricultural University New Technology Development Corporation); Group 4 10 sheep were not administered to the control group. The effects of the drugs in each administration group on the pruritus of the sheep were observed regularly. The results of the drug efficacy are shown in Table 1. At the same time, three sheep were taken from each drug-administered group and blood was collected periodically. Fluorescence-high performance liquid chromatography was used to determine avermectin in plasma. Concentration, its blood concentration is shown in Table 2.

It can be seen from Table 1 that in the present invention, 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. As can be seen from Table 2, 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. It can be seen from Table 1 that some sheep have only been infected with itch again. In summary, ordinary injections do not have a good sustained release effect even if the dosage is increased, and the preparation of the invention has a remarkable sustained release effect, and is very suitable for parasitic control of wintering sheep.

Table 1. Effect of 5% avermectin long-acting suspension injection and 1% avermectin injection on pruritus

Groups 1 2 3 4 3 days before the test. Number of live itch sheep 20 20 20 10 After the test, itching is relieved, and the number of sheep with biting marks is 15 4 6 10

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

10 days The number of sheep with live insects 0 0 0 10 After the test, the number of sheep with new hair growing in the original affected area is 20 20 20 -

25 days The number of sheep with live insects 0 0 0 10 After the test, the number of sheep with new hair growing in the original affected area is 20 18 16 -

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 -

65 days The number of sheep with live insects 0 8 11 10 After the test, the number of sheep with new hair growing in the original affected area is 20 7 9 -

90 days Sheep with live worms 0 13 11 10 Table 2. Comparison of blood concentrations of 5% avermectin long-acting suspension injection and 1% avermectin injection

The above examples and other contents in the specification clarify the gist of the present invention, but the contents and specific examples described in the specification do not limit the scope of the claims of the present invention. The scope of the claims of the invention is set forth in the claims.

In addition, common knowledge of the preparation of injectables (such as aseptic processing, material sterilization, etc.) well known in the art is not described in detail in the examples, which does not mean that the preparation of the preparation of the present invention is not required to be done. The problem that should be explained.

Claims

Rights request

1. A long-acting veterinary injection containing a macrolide-based anthelmintic drug or an N-phenylpyrazole-based anthelmintic drug, which is characterized by:

(2), the composition of the preparation is:

a, macrolide anti-insecticide or N-phenylpyrazole anthelmintic 0.3-25% (w / v); b, the main dispersion medium of the composition is water or benzyl benzoate or glycerol Acetate or fatty acid ester formed from monohydric or polyhydric alcohol (extracted or synthesized from plants) or mineral oil (such as liquid paraffin oil) or dimethicone or propylene glycol or glycerol, polyethylene glycol , furfural glycerol to 100% (V / V), glycerol, polyethylene glycol, formaldehyde glycerol need to be used together with water, or two or more combined with water.

(3), preparation method, preferred preparation methods are as follows:

Method a is a solvent-nonsolvent method. The specific preparation process is: dissolving the active compound with a co-solvent or a solvent under heating or no heating, and then mixing with a medium (non-solvent) capable of reducing the solubility of the active compound, after the active compound is mostly precipitated in a microcrystalline state, The remaining medium and other auxiliaries 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 co-solvent or solvent under heating or no heating (referring to a suspending agent), followed by mixing with a medium (non-solvent) which reduces the solubility of the active compound, After the portion is precipitated in the microcrystalline state, 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 fine particles having a fineness of less than 80 μm (prepared by mechanical pulverization or powder crystallization), and the fine particles are suspended in the medium of the present invention to prepare a suspension.

2. The formulation of claim 1 wherein:

(1) The stabilizer is a pharmaceutically usable stabilizer; preferred stabilizers include: mercapto cellulose, carboxymethyl cellulose and sodium salts thereof, hydroxypropyl cellulose, hydroxyethyl cellulose, Sodium alginate, sodium propylene glycol alginate, sodium polyacrylate, sorbitol, mannitol, sodium metaphosphate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol having a molecular weight of more than 1000, xanthan gum, hydrogenated castor oil, Brazilian wax Nonionic surfactants (such as glycerin fatty acid esters, polyglycerol fatty acid esters, sucrose esters, sorbitan higher fatty acid esters Span, polyoxyethylene sorbitan higher fatty acid ester condensates Tween, polyoxyethylene Higher fatty acid condensate Mrjs, condensate of polyoxyethylene with higher fatty alcohol Brijs, plain plus Paregal, emulsifier OP, polyoxyethylene castor oil condensate, polyoxyethylene hydrogenated castor oil condensate, puerto ).

(2) The local pain reducing agent is preferably phenylhydrin, chlorobutanol, procaine, tetracaine or lidocaine.

(3), the cosolvent is preferably ethanol, 3-6 carbon monohydric alcohol, 1,2-propanediol, furfural glycerol and its homologue, dimethylacetamide, N-mercapto-pyrrole; 3⁄4 Ketone, azone, An aromatic alcohol, a low-boiling organic solvent (such as ethyl acetate, methyl acetate, butyl acetate, acetone, dichloromethane, trichloromethane, etc.), these low-boiling organic solvents are preferably used for the preparation of oil suspensions, After the dissolution aid is completed, it should be removed from the formulation.

(4) The macrolide-based anthelmintic drugs include: avermectin abamectin, ivermectin ivermectin, emarosin emamectin, euphorin eprinomectin, doramectin doramectin, moxi The N-phenyl group is preferably a fipronil fipronil. It said other anthelmintic agents include: albendazole sulfoxide albendazole oxide, Offenbach of ^p Jun oxfendazole, chlorine change Liu amine (# 1) closantel (sodium) , levamisole hydrochloride, coccidiostats, or insect growth regulator agents Juvenile hormone anthelmintics, which are present in the formulation at a level of 1-25% (w/v).

3. A formulation according to claim 1 wherein the optimized formulation composition and preparation method is:

(1), the composition of the preparation:

c, ethanol, isopropanol, dimercaptoacetamide, N-mercaptopyrrolidone 0-30% (V / V); d, water for injection to 100% (V / V);

(2), preparation method:

Method a, taking a macrolide anthelmintic or N-phenylpyrazole anthelmintic and hydrogenated ramie Oil or Brazilian wax or polyvinylpyrrolidone (without adding them), dissolved in ethanol or dimercaptoacetamide, N-methylpyrrolidone or formaldehyde glycerol or / and 1,2-propanediol with or without heating Mix with water or glycerin or water/glycerin or water/1,2-propanediol under stirring, and then add the solution containing phenylhydrin or other medium and residual auxiliaries, and mix well. A suspension injection of a cycloester anthelmintic or an N-phenylpyrazole anthelmintic.

Method b, dissolving or swelling a macrolide anthelmintic or N-phenylpyrazole anthelmintic and methylcellulose (also without) with N-methyl-pyrrolidone or dimercaptoacetamide, After mixing with water or glycerin/water or 1,2-propanediol/water under stirring, after homogenization, the remaining medium containing phenylhydrin 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 glycerol, followed by adding glycerol, stirring into a paste, adding water for injection and auxiliary The final volume.

4. The formulation of claim 1 wherein the selected formulation composition and preparation method are:

(1), formulation composition: macrolide-type anthelmintic 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).

(2) Preparation method: Dissolve the macrolide lactone detoxification medicinal cosolvent, mix with the melted PEG, cool down, add water or glycerin and water to the final volume under stirring, and widen, That is. 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.

5. The formulation of claim 1 wherein the optimized formulation composition and method of preparation are:

(1), the composition of the preparation:

(2), preparation method:

Method a, dissolving a macrolide-based anthelmintic drug (such as avermectin) under heating conditions with triacetin to prepare a supersaturated solution, cooling the liquid to below 30 ° C, and adding under stirring 5-10% (v / V) of ethanol or water / ethanol, after the completion of the crystallization, add cooled triacetin to about 80% of the final volume, stir, mix the hook, add triacetin ( With or without hydrogenated castor oil) and antioxidants to the final volume.

Method c, macrolides, hydrogenated castor oil and ethanol according to 1: 0.02-2: 2-3.5 Mix (W/W/V) in proportion, heat to melt and dissolve, rapidly cool under stirring, and when it is viscous or semi-cured or solidified, remove some ethanol under reduced or no pressure, then Add triacetin, grind (such as a colloid mill), add sterile water containing about 5% of the final volume of the preparation under stirring (can also be added before adding triacetin), and continue stirring for a certain period of time. The remaining medium is then added to the final volume. Or dissolve the macrolide lactone medicinal drug about 3 times of ethanol under heating, and rapidly cool under stirring conditions. When the liquid is viscous, remove some ethanol under reduced pressure, and then add triacetin to continue. Stir and depressurize, remove the ethanol, and add the remaining medium (triacetin) to the final volume.

6. The formulation of claim 1 wherein the optimized oil suspension composition and method of preparation are:

(1), the composition of the preparation:

c. Mineral oil or dimercaptosilicone oil is added to 100% (V/V);

(2), preparation method:

Method a:

Take the macrolide anti-insecticide and the right amount of antioxidants, add about twice the acetic acid Ethyl ester, heated, dissolves macrolide anti-insecticides and antioxidants to give an ethyl acetate solution containing a macrolide anti-insecticide and an antioxidant.

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, and lower the temperature to below 25 °C. Continue Stirring for 1-2 hours gave a suspension of ethyl acetate which 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-based anthelmintic.

Method b:

Mixing a macrolide anthelmintic or an N-phenylpyrazole anthelmintic with a vegetable oil or mineral oil or dimethicone containing 3% aluminum stearate or 1-1.5% hydrogenated castor oil, It is made into a paste, then ground and shielded, so that the fineness of the active ingredient is less than ΙΟΟμηι, and then the remaining medium and auxiliary agent are added to the final volume.

Method c:

Take the macrolide anti-insecticide, hydrogenated castor oil and ethanol, mix at a ratio of 1: 0.05-2: 2.5-3.5 (W/W/V), and dissolve 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 is removed and the ethanol is removed under reduced pressure, after which the remaining medium (vegetable oil or liquid paraffin oil or dimethicone) is added to the final volume.

7. Composition according to claims 1 and 2, characterized by preferred formulation composition and preparation Method is

(1), the composition of the preparation:

a, ivermectin or doramectin 2-10% (W / V)

b, sorbitol 5-15% (W/V)

c, 1, 2-propanediol 10-30% (V/V)

d, glycerin 5-30% (V/V)

e, phenylhydrin 1% (V/V)

f, water to 100% (V/V)

(2), preparation method:

Ivermectin or doramycin is dissolved in ethanol under heating conditions, and then mixed with molten sorbitol, cooled, dried or dried under reduced pressure, ethanol is removed, the solid is pulverized, and the dispersion medium and auxiliary agent are added. The final volume.

8. A method according to claims 1 and 2, characterized in that the preferred formulation composition and preparation method are:

(1), the composition of the preparation:

a, ivermectin or doramectin 2-10% (W / V)

b, polyethylene glycol 200-600 5-15% (V / V)

c, 1, 2-propanediol 10-30% (V/V)

d, glycerin 5-30% (V / V) e, phenylhydrin 1% (V/V)

f, dimethylacetamide or N-decylpyrrolidone 0-15% (V/V)

g, water to 100% (V/V)

(2), preparation method:

Dissolve ivermectin or doramycin with 1,2-propanediol or N-methylpyrrolidone or dimercaptoacetamide under heating or no heating, then add polyethylene glycol, mix well, then add Glycerin or glycerin and water, after homogenization, add the remaining dispersion medium and auxiliary to the final volume.

9. The method of claim 6 wherein the preferred formulation composition and method of preparation are:

(1), the composition of the preparation:

(2), preparation method:

Take ivermectin or doracycline and ethanol equivalent to about 3 times, put it in a preparation container, add hydrogenated castor oil, dissolve and melt it at about 85 °C (refer to hydrogenated castor oil) After that, the liquid is rapidly cooled under stirring and added with dimethyl silicone oil, stirring is continued, and ethanol is removed under reduced pressure or no reduced pressure, and about 1% of benzyl alcohol or chlorobutanol is added, and Add the remaining dimethicone to the final volume. Or the active ingredient, hydrogenated castor oil, and an appropriate amount of dimercaptosilicone oil are mixed and heated at 90 ° C to be hydrogenated. After the castor oil is melted, it is cooled, made into a paste, and ground with a colloid mill until the fineness of the active ingredient is less than 1 ΟΟμηι, and the remaining medium and the auxiliary agent are added to the final volume.

10. A method according to claims 2 and 4, characterized in that the preferred formulation composition and preparation method are:

(1) Formulation composition: ivermectin 3-7% (Ψ/Υ); polyethylene glycol (4000-10000) 5-10% (W/V); glycerol 3-15% (V/ V); dimethylacetamide 3-20% (V/V); water for injection added to 100% (V/V) o

(2), preparation method: ivermectin is dissolved in dimethylacetamide, and then mixed with the molten polyethylene glycol, cooling, adding water and glycerol to the final volume under stirring, homogenization , that is.

11. A method according to claims 1-3, characterized in that the preferred formulation composition and preparation method is:

(1), formulation composition: avermectin or doramectin 3-7% (W / V); hydrogenated castor oil 0,3-7% (W / V); water for injection 0-20% (V / V); benzyl alcohol 1% (V/V); thiourea 0.3% (W/V); 1, 2-propanediol to 100% (V/V) o

(2), preparation method: take the active ingredient and hydrogenated castor oil, dissolved in ethanol under heating conditions, then quickly cool the liquid to semi-cured, add 1,2-propanediol (with or without water for injection), stir After a certain period of time, homogenization, ethanol was removed under reduced pressure, and the remaining 1,2-propanediol and the auxiliary were added to the final volume. Or take a solid dispersion ( 1: 0.3-1 ) of the active ingredient in combination with hydrogenated castor oil, add ethanol in a ratio of 1: 1-1.5 (W/V), heat it at about 80 使 to melt it, then cool it to half. When curing, a part of 1,2-propanediol is added, and ethanol is removed under reduced pressure under stirring, and then the remaining medium and auxiliary agent are added to obtain. Necessary A small amount of glycerin is added to the preparation.