CN103417559B

CN103417559B - Animal compound suspension injection containing ivermectin and praziquantel and preparation method thereof

Info

Publication number: CN103417559B
Application number: CN201210150256.1A
Authority: CN
Inventors: 肖希龙; 汤树生; 陈琳琳; 郭召绪
Original assignee: BEIJING ZHONGNONGDA ANIMAL HEALTH-CARE PRODUCT TECHNOLOGY RESEARCH INSTITUTE
Current assignee: BEIJING ZHONGNONGDA ANIMAL HEALTH-CARE PRODUCT TECHNOLOGY RESEARCH INSTITUTE
Priority date: 2012-05-15
Filing date: 2012-05-15
Publication date: 2016-07-13
Anticipated expiration: 2032-05-15
Also published as: CN103417559A

Abstract

The invention discloses a kind of animal compound suspension injection containing ivermectin and praziquantel and preparation method thereof.The effective ingredient of animal compound suspension injection of the present invention is ivermectin and praziquantel.Its preparation method comprises the following steps: 1) takes suspending agent, antioxidant and preservative and is dissolved or dispersed in the dissipation of heat matchmaker of 3 20%, obtains A liquid；2) the dispersion matchmaker taking formula ratio 30 90% pours in colloid mill, starts colloid mill, is then slowly added into above-mentioned A liquid, treats all to add completely, adds wetting agent while stirring；3) treating that whole supplementary material adds completely, be sequentially added into ivermectin and praziquantel, the mode then using circular grinding and acyclic grinding to alternate is ground；4) check fineness of the particles, stop after meeting the requirements grinding, add and disperse matchmaker to formula ratio, mixing, fill, seal, sterilizing, obtain the animal compound suspension injection that the present invention contains ivermectin and praziquantel.Present invention is mainly used for preventing and treating the mixed infection that domestic animal trematodiasis, cestode, nematicide and vermin cause.

Description

Animal compound suspension injection containing ivermectin and praziquantel and preparation method thereof

Technical field

The invention belongs to pharmaceutic preparation for livestock field, be specifically related to a kind of animal compound containing ivermectin and praziquantel and mix Outstanding injection and preparation method thereof.

Background technology

China pig, cattle, sheep parasitic disease fairly common, present infection rate high, infection intensity is big and trematodiasis, cestode, Nematicide and the feature of vermin mixed infection.At present, the main means of prevention of parasitic disease is chemical prevention, but research and development tool Having the new raw material medicine of unique mechanism of action, required fund is huge, and chance of success is little.Therefore, based on existing old medicine, pass through Changing formulation factors or apply novel drug-loading system, old medicine is newly used so that it is effect is preferably played significant. At present, wide variety of several big class animal antiparasitic mainly has: praziquantel；Benzimidazoles residues such as albendazole, first Parbendazole；Tetrahydropyrimidine class；Macrocyclolactone lactone kind medicine such as ivermectin and doractin.The each not phase of every class mechanism of drug action With, pest-resistant spectrum is the most different, clinically generally by the Drug combination of two or more model of action to expand pest-resistant spectrum, treat The mixed infection that multiple parasite causes.

Praziquantel is the anti-trematodiasis of wide spectrum and cestode medicine, invalid to nematicide；Macrocyclolactone lactone kind medicine is (such as ivermectin and Duola Rhzomorph) nematicide and vermin had efficiently effect, and low to cestode and trematodiasis effect, to suction after both drug combinations Worm, cestode, nematicide and vermin are all effective, are the classical prescriptions of clinical treatment parasite mixed infection.Domestic existing Multiple ivermectin and the listing of praziquantel compound preparation, be mainly used in the Iverheart of dog cat and equus, such as Canis familiaris L.Chewable tablet (Virbac AH, Inc.), horse ZimecterinPaste (Merial Ltd., Duluth) andDrop (AST Farma, Dutchland) etc., but not yet have for domestic animal (such as pig, cattle, sheep etc.) at present Ivermectin and the listing of praziquantel compound preparation.

But, above several compound preparations are mainly used in treating nematicide, vermin and taeniasis, invalid to trematodiasis. Reason is that these compound recipes are oral formulations, and two medicines all use according to clinical recommended dose, dynamic after ivermectin oral administration Long half time in object, efficiency time is long, and single administration can treat nematicide and epizootic disease, and praziquantel is oral rear first Crossing effect serious, the half-life is short, and efficiency time is short in vivo, and only once when medication treatment trematodiasis and taeniasis, curative effect is undesirable. All there is half-life short lacking in China's veterinary drug market visible Droncit either single preparations of ephedrine or compound preparation at present Fall into.

Summary of the invention

For problem above, develop the half-life of praziquantel in compound preparation, extend the praziquantel time in animal body, Making its curative effect Tong Bu with ivermectin, a drug i.e. can be treated nematicide, trematodiasis, cestode and epizootic disease and be had reality Border meaning.

It is an object of the invention to provide longer ivermectin of a kind of praziquantel half-life and praziquantel compound preparation, specifically For a kind of determined curative effect, a drug be used for treating domestic animal nematicide, cestode, trematodiasis and vermin mixed infection containing her Dimension rhzomorph and the animal compound suspension injection of praziquantel so that it is use can extend praziquantel time in animal body and with The curative effect of ivermectin synchronizes.

For solving above-mentioned technical problem, the present invention takes techniques below scheme:

A kind of animal compound suspension injection containing ivermectin and praziquantel, be with ivermectin and praziquantel be effective The animal compound suspension injection of composition.

In described animal compound suspension injection, the content of each effective ingredient is: ivermectin 0.05-2% (weight/volume Percent concentration, g/100mL), preferably 0.1-0.5% (g/100mL)；Praziquantel 10-50% (g/100mL), preferably 15- 30% (g/100mL).

The present invention utilizes compound medicine to combine suitable pharmaceutic adjuvant and makes animal compound suspension injection, divides including using Dissipate the excipient substances such as matchmaker, suspending agent, wetting agent, antioxidant and preservative.

Dispersion matchmaker: be selected from injection glyceryl triacetate, ethyl oleate, medium chain triglyceride, injection soybean oil and One or both compound in Oleum Ricini, the composite diffusion matchmaker of preferred oil acetoacetic ester and injection soybean oil, compositely proportional is not Limit；But preferably compositely proportional is volume ratio 5:3-4.In the present invention, particularly preferred oil-based solvent is as the dispersion of preparation Matchmaker so that ivermectin and praziquantel the most slowly discharge, blood drug level is steady, reduces the toxic and side effects of two medicines.

Suspending agent: be selected from vaseline, polyvinylpyrrolidone, aluminium stearate, lecithin, cholesterol, carboxymethyl cellulose One or both compound in element sodium and castor oil hydrogenated, the kind of suspending agent and consumption are according to drug dose and dispersion matchmaker's kind Class is adjusted, and is beneficial to form stable injection.In injection, suspending agent content is 0.1-2% (g/100mL).

Wetting agent: be selected from the one in tween 80, Arlacel-60, Arlacel-80 and oxireme-40-castor oil hydrogenated Or two kinds compound, pharmacy procedure is selected one-component as far as possible, but is not excluded for using multiple compound mode.In injection In liquid, wetting agent content is 0.5-1.5% (mL/100mL).

Antioxidant: be selected from vitamin E, ascorbic acid, butylhydroxy anisole, dibenzylatiooluene and Galla Turcica (Galla Helepensis) One or both compound in acid the third fat, selects one-component in pharmacy procedure as far as possible, but is not excluded for using multiple multiple The mode closed.In injection, antioxidant content is 0.01-0.5% (g/100mL).

Preservative: one or both compound, in pharmacy being selected from benzyl alcohol, methyl hydroxybenzoate and propylparaben During select one-component as far as possible, but be not excluded for using multiple compound mode.In injection, the content of preservative is 0.005-1% (g/100mL).

According to the content of each composition in the animal compound suspension injection that the present invention is formed can be: ivermectin 0.05-2 % (weight/volume percent concentration, g/100mL), praziquantel 10-50% (g/100mL), suspending agent 0.1-2% (g/ 100mL), wetting agent 0.5-1.5% (mL/100mL), antioxidant 0.01-0.5% (g/100mL), preservative 0.005-1% (g/ 100mL), remaining is dispersion matchmaker；

Preferred version: ivermectin 0.1-0.25% (g/100mL), praziquantel 15-40% (g/100mL), suspending agent 0.1-2% (g/100mL), wetting agent 0.5-1.5% (mL/100mL), antioxidant 0.01-0.5% (g/100mL), preservative 0.005-0.5% (g/100mL), remaining is dispersion matchmaker；

Most preferably scheme: ivermectin 0.1-0.25% (g/100mL)；Praziquantel 15-25% (g/100mL)；Suspending agent 0.1-0.5% (g/100mL), suspending agent is lecithin or aluminium stearate and the mixing of cholesterol；Wetting agent 0.5-1.0% (mL/ 100mL), wetting agent is oxireme-40-castor oil hydrogenated；Antioxidant 0.01-0.05% (g/100mL), antioxidant is tertiary fourth Base BHA or gallic acid third lipoprotein；Preservative 0.01-0.02% (g/100mL), preservative is methyl hydroxybenzoate；Remaining For dispersion matchmaker, dispersion matchmaker is the composite diffusion matchmaker of ethyl oleate and injection soybean oil, wherein the 50% of suspension injection cumulative volume For ethyl oleate, surplus is injection soybean oil.

Present invention also offers and a kind of prepare the above-mentioned animal compound suspension injection containing ivermectin and praziquantel Method.

Preparation method provided by the present invention, it may include following steps:

1) take suspending agent, antioxidant and preservative to be dissolved or dispersed in total formula ratio 3-20% dissipation of heat matchmaker, obtain A Liquid；

2) the dispersion matchmaker taking total formula ratio 30-90% pours in colloid mill, starts colloid mill, is then slowly added into above-mentioned A Liquid, treats all to add completely, adds wetting agent while stirring；

3) treat that whole supplementary material adds completely, be sequentially added into ivermectin and praziquantel, then use circular grinding and non-follow Ring grinds the mode alternated and is ground；

4) checking fineness of the particles, meet the requirements (standard be particle diameter be more than the granule number of 15 μm should be less than 10%) stops grinding afterwards Mill, adds surplus and disperses matchmaker to total formula ratio, mixing, fill, seal, sterilizing, obtain the present invention and contain ivermectin and praziquantel Animal compound suspension injection.

In made as described above method, when using composite diffusion matchmaker, a kind of consumption in two kinds of dispersion matchmakers is fixed, another Plant consumption to float, in operation, first disperse matchmaker by suspending agent, resist by a small amount of (the 3% of total formula ratio) one of which in described step 1) Oxygen agent, preservative etc. dissolve, in step 2) in first use the fixing that dispersion matchmaker of consumption, re-use that consumption floats that point Dissipate matchmaker to step 2) dispersion matchmaker's consumption (47-60% of total formula ratio) of setting, finally use consumption to float in step 4) The surplus of that dispersion matchmaker is settled to total formula ratio.

The usage of above-mentioned animal compound suspension injection is generally single-dose, and dosage is 0.1-0.2mL/kg body weight, note Penetrate dosage and the course for the treatment of suitably can adjust according to practical situation.

The invention provides a kind of animal compound suspension injection containing ivermectin and praziquantel and preparation method thereof.This Advantage and the good effect of invention are as follows:

(1) utilize ivermectin and praziquantel to have different pest-resistant spectrums, be used in combination and expand pest-resistant scope, make single Administration can treat trematodiasis, cestode, nematicide and epizootic disease simultaneously.

(2) present invention is oil for injection suspensoid, good stability, and drug loading is high, overcomes praziquantel injection solution and carries Dose is low, and big animal dosage is big, the drawback that clinical practice is inconvenient.Suspensoid has the advantages that drug loading is big, wherein with The oil suspension that oil is made as medium must first dissolve using the drug particles being suspended in oil phase as " bank ", drug molecule In oil phase, then distribute in aqueous body fluid from oil phase.Compared with conventional oil pharmaceutical solutions, Oil suspensions is at oil phase The course of dissolution that Chinese medicine is many additionally, therefore has longer pharmaceutical release time.Suspensoid technique is simple, and cost is relatively low, To big animal convenient drug administration, it is easy to promote clinically.

(3) ivermectin and praziquantel are used in combination, have widened pest-resistant spectrum, it is to avoid the limitation that single medicine uses, delay The generation of parasite drug resistance, additionally, this compound preparation only needs single administration, both can reduce due to frequent drug administration (former pyrrole quinoline Ketone single therapy trematodiasis and taeniasis need be administered three times every day, serve on 3 days) to animal produce stress, save again people Power, material resources and financial resources.

(4) suspension of the present invention uses oil-based solvent as the dispersion matchmaker of preparation, forms medicine after administration in injection site The bank of thing, after ivermectin and praziquantel blood drug level reach peak, medicine still slowly discharges from medicine-feeding part, and therefore it is to prolong Grow the elimination half-life of medicine.

(5) this compound injection is used for intramuscular injection, it is to avoid first mistake serious after praziquantel traditional oral formulation application Effect, absorbs fast after administration, blood drug level is high, and bioavailability is high, long half time, the time of maintenance valid density in vivo Extend.

Additionally, the animal compound suspension injection of this ivermectin and praziquantel is to use dispersion method by ivermectin and pyrrole Quinoline ketone is scattered in solvent, and adds suspending agent, wetting agent and antioxidant, utilizes colloid mill to grind and obtain, and production technology is simple, Low cost, it is easy to accomplish industrialization.

In sum, the present invention, by ivermectin and praziquantel use in conjunction, expands pest-resistant spectrum, makes a drug can be right Anti-all of anthelmintic and epizootic disease；Using oil-based solvent as solvent, making suspensoid, drug loading is big, overcomes common Solution injection praziquantel concentration is low, dosage is high, the shortcoming big to Animal stress, and forms storage after drug injection in tissue Storehouse, makes ivermectin and praziquantel slowly can discharge from medicine-feeding part, extends the valid density time；Intramuscular injection is avoided again First pass effect after praziquantel oral administration, significantly improves its bioavailability, extends its half-life, after making single administration Praziquantel maintains the time of effective blood drug concentration internal all of trematodiasis, cestode etc. to be killed.For China's veterinary clinic The sick epidemic characteristic in mixed infection of animal parasite, the present invention be mainly used in clinically preventing and treating domestic animal trematodiasis, cestode, nematicide and The mixed infection that vermin causes.Production technology of the present invention is simple, it is easy to accomplish industrialization, and low cost, low toxicity and high Effect, has high application value.

Below in conjunction with specific embodiment, the present invention is described in further details.

Accompanying drawing explanation

Fig. 1 is ivermectin blood concentration-time after pig muscle injection IVM/PZQ compound preparation and subcutaneous injection Ivomec Curve.

Fig. 2 is praziquantel blood concentration-time curve after pig muscle injection IVM/PZQ compound preparation and oral PZQ tablet.

Detailed description of the invention

The present invention is in order to provide a kind of compound recipe suspension injection that can treat domestic animal mixed infection parasitic disease, by looking into Read the document of a large amount of external and internal test of pesticide effectiveness about variety classes anti-parasite medicine two or more use in conjunction, with And the novel compound preparation with reference to external listing, it is first determined the optimum prescription as effective ingredient with ivermectin and praziquantel.

The advantage that the two kinds of drug developments of ivermectin and praziquantel are become compound preparation is to overcome treatment mixed infection to need To give the stress that animal is caused by multi-medicament simultaneously, reduce the workload of veterinary personnel.Provided by the present invention Dosage form (compound recipe suspension injection) can also significantly extend the elimination half-life of praziquantel, improves its bioavailability, makes administration one Secondary rear blood drug level maintains the effective time to be enough to kill all trematodiasiss and cestode, so that single dose uses the compound recipe of the present invention During preparation, praziquantel is Tong Bu with the curative effect of ivermectin.

The present invention provides a kind of compound recipe suspension injection containing ivermectin and praziquantel.During compound recipe assembles, remove Concertedness between medicine to be considered, forms determined curative effect, has good stability by screening appropriate pharmaceutic adjuvant especially Preparation, and finally give suitable Praziquantel long-acting preparation.

First, the present invention according to the clinical test of pesticide effectiveness according to the literature, obtain ivermectin and praziquantel optimum to Pharmaceutical quantities, and by investigating the stability of preparation under medicine different content proportioning, it is determined that each content of active component in injection: Ivermectin 0.05-2% (weight/volume percent concentration, g/100mL), preferably 0.1-0.5% (g/100mL)；Praziquantel 10-50% (g/100mL), preferably 15-40% (g/100mL).

Dispersion matchmaker: the present invention determine from numerous dispersion matchmakers use selected from injection glyceryl triacetate, ethyl oleate, One or both compound in medium chain triglyceride, injection soybean oil and Oleum Ricini, preferred oil acetoacetic ester is big with injection The composite diffusion matchmaker of Oleum Glycines, preferable compositely proportional is volume ratio 5:3-4.The present invention selects above oil-based solvent conduct especially The dispersion matchmaker of preparation so that ivermectin and praziquantel medicine in such dispersion matchmaker are able to the most slowly discharge, Blood drug level is steady, reduces the toxic and side effects of two medicines.

Suspending agent: be selected from vaseline, polyvinylpyrrolidone, aluminium stearate, lecithin, cholesterol and castor oil hydrogenated In one or both compound, the kind of suspending agent and consumption are adjusted according to dispersion matchmaker's kind of drug dose and selection Whole, it is beneficial to form stable injection.In the present invention, above suspending agent content in injection is 0.1-2% (g/ 100mL)。

According to the content of each component in the animal compound suspension injection that the present invention is formed can be: ivermectin 0.05- 2% (weight/volume percent concentration, g/100mL), preferably 0.1-0.5% (g/100mL)；Praziquantel 10-50% (g/ 100mL), preferably 15-40% (g/100mL), suspending agent 0.1-2% (g/100mL), wetting agent 0.5-1.5% (mL/ 100mL), antioxidant 0.01-0.5% (g/100mL), preservative 0.005-1% (g/100mL), remaining is dispersion matchmaker.

Concrete, in described animal compound suspension injection, the content of each component is: ivermectin 0.1-0.25% (g/ 100mL), praziquantel 15-40% (g/100mL), suspending agent 0.1-2% (g/100mL), wetting agent 0.5-1.5% (mL/ 100mL), antioxidant 0.01-0.5% (g/100mL), preservative 0.005-0.5% (g/100mL), remaining is dispersion matchmaker；

Preferably, in described animal compound suspension injection, the content of each component is: ivermectin 0.1-0.25% (g/ 100mL)；Praziquantel 15-25% (g/100mL)；Suspending agent 0.1-0.5% (g/100mL), suspending agent is lecithin or stearic acid Aluminum and the mixing of cholesterol；Wetting agent 0.5-1.0% (mL/100mL), wetting agent is oxireme-40-castor oil hydrogenated；Anti- Oxygen agent 0.01-0.05% (g/100mL), antioxidant is butylhydroxy anisole or gallic acid third lipoprotein；Preservative 0.01- 0.02% (g/100mL), preservative is methyl hydroxybenzoate；Remaining is dispersion matchmaker, and dispersion matchmaker is ethyl oleate and injection Semen sojae atricolor The composite diffusion matchmaker of oil, wherein the 50% of suspension injection cumulative volume is ethyl oleate, and surplus is injection soybean oil.

The preparation of the above-mentioned animal compound suspension injection containing ivermectin and praziquantel, it may include following steps:

For using the situation of composite diffusion matchmaker, a kind of consumption in two kinds of dispersion matchmakers is fixing, and another kind of consumption can To float, its concrete consumption is depending on final step.Specifically, in step 1) first with a small amount of one of which dispersion matchmaker (strictly according to the facts Execute the ethyl oleate in example 8-9, the injection Oleum Ricini in embodiment 5) suspending agent, antioxidant, preservative etc. are dissolved, in step Rapid 2) (first with fixing that of consumption, deficiency is used again to use one dispersion matchmaker (consumption fixing that) or two kinds of dispersion matchmakers in It is that consumption floats, and as fixed the ethyl oleate first use of consumption in embodiment 5, then uses injection Oleum Ricini) it is stirred, After in step 4) use surplus dispersion matchmaker (the dispersion matchmaker that consumption can float, such as the injection Oleum Ricini in embodiment 5 and reality Execute the injection soybean oil in example 8-9) add to total formula ratio (being settled to 100L as in embodiment).

The present invention is further illustrated below with specific embodiment.Following embodiment 1-10 uses the optimal test of the present invention Scheme, those of ordinary skill in the art can be apparent from some identical, replacements according to present disclosure Scheme, all should belong to the disclosure.In embodiment, method therefor is conventional method if no special instructions.

Embodiment 1, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

The formula of the animal compound suspension injection that the present invention contains ivermectin and praziquantel is as follows:

Ivermectin	0.2kg,
		Praziquantel	15kg,
Aluminium stearate	1kg,
		Arlacel-80	0.5L,
Vitamin E	0.02kg,
		Benzyl alcohol	0.5kg,
Injection soybean oil	Add to 100L.

Preparing the animal compound suspension injection containing ivermectin and praziquantel by the present invention, concrete grammar includes following Step:

1) aluminium stearate of formula ratio, vitamin E and benzyl alcohol being added in 3L injection soybean oil, heated and stirred makes it It is completely dissolved, obtains A liquid；

2) take 60L injection soybean oil and pour in colloid mill, start colloid mill, be then slowly added into above-mentioned A liquid, treat all Add completely, add the Arlacel-80 of formula ratio while stirring；

3) treat that whole supplementary material adds completely, be sequentially added into ivermectin and the praziquantel of formula ratio, then use circulation to grind The mode that mill and acyclic grinding alternate is ground；

4) checking fineness of the particles, result meets the requirements (standard be particle diameter be more than the granule number of 15 μm should be less than 10%), stops Only grind, inject with soybean oil to 100L, mixing, fill, seal, sterilizing, obtain the present invention containing ivermectin and pyrrole The animal compound suspension injection of quinoline ketone.

Embodiment 2, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.2kg,
		Praziquantel	30kg,
Castor oil hydrogenated	1kg,
		Arlacel-80	0.5L,
Ascorbic acid	0.02kg,
		Methyl hydroxybenzoate	0.05kg,
Glyceryl triacetate	Add to 100L.

The animal compound suspension injection containing ivermectin and praziquantel, concrete grammar bag is prepared by the method for the present invention Include following steps:

1) take the castor oil hydrogenated of formula ratio, ascorbic acid and methyl hydroxybenzoate and add in 3L glyceryl triacetate, heating Stirring makes it be completely dissolved to obtain A liquid；

2) take 40L glyceryl triacetate and pour in colloid mill, start colloid mill, be then slowly added into above-mentioned A liquid, treat all Add completely, add the Arlacel-80 of formula ratio while stirring；

4) checking fineness of the particles, result meets the requirements (standard be particle diameter be more than the granule number of 15 μm should be less than 10%), stops Only grind, add glyceryl triacetate to 100L, mixing, fill, seal, sterilizing, obtain the present invention containing ivermectin and pyrrole The animal compound suspension injection of quinoline ketone.

Embodiment 3, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.2kg,
		Praziquantel	40kg,
Castor oil hydrogenated	0.3kg,

Lecithin	0.2kg,
		Arlacel-80	0.6L,
Dibenzylatiooluene	0.05kg,
		Methyl hydroxybenzoate	0.05kg,
Medium chain triglyceride	20L,
		Ethyl oleate	Add to 100L.

1) take the castor oil hydrogenated of formula ratio, lecithin, dibenzylatiooluene and methyl hydroxybenzoate and be dissolved in the acid of 3L deep fat In ethyl ester, for A liquid；

2) medium chain triglyceride and the 60L ethyl oleate that take 20L formula ratio are poured in colloid mill, start colloid mill, then It is slowly added into above-mentioned A liquid, treats all to add completely, add the Arlacel-80 of formula ratio while stirring；

3) treating that whole supplementary material adds completely, be sequentially added into ivermectin and the praziquantel of formula ratio, starting to grind, employing follows The mode that ring grinds and acyclic grinding alternates is ground；

4) checking fineness of the particles, result meets the requirements (standard be particle diameter be more than the granule number of 15 μm should be less than 10%), stops Only grind, add ethyl oleate to 100L, mixing, fill, seal, sterilizing, obtain the present invention containing ivermectin and praziquantel Animal compound suspension injection.

Embodiment 4, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.2kg,
		Praziquantel	15kg,
Vaseline	0.5kg,
		Castor oil hydrogenated	0.3kg,
Tween 80	0.5L,
		Ascorbic acid	0.2kg,
Methyl hydroxybenzoate	0.05kg,
		Glyceryl triacetate	50L,
Injection Oleum Ricini	Add to 100L.

1) take the castor oil hydrogenated of formula ratio, vaseline, ascorbic acid and methyl hydroxybenzoate and add 3L injection Oleum Ricini In, heated and stirred makes it be completely dissolved, and obtains A liquid；

2) glyceryl triacetate and the 30L injection Oleum Ricini that take formula ratio are poured in colloid mill, start colloid mill, then It is slowly added into above-mentioned A liquid, treats all to add completely, add the tween 80 of formula ratio while stirring；

4) checking fineness of the particles, result meets the requirements (standard be particle diameter be more than the granule number of 15 μm should be less than 10%), stops Only grind, inject with Oleum Ricini to 100L, mixing, fill, seal, sterilizing, obtain the present invention containing ivermectin and pyrrole The animal compound suspension injection of quinoline ketone.

Embodiment 5, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.1kg,
		Praziquantel	15kg,
Polyvinylpyrrolidone	0.8kg,
		Tween 80	1L,
Vitamin E	0.5kg,
		Propylparaben	0.008kg,
Ethyl oleate	30L,
		Injection Oleum Ricini	Add to 100L.

1) take the polyvinylpyrrolidone of formula ratio, vitamin E and propylparaben to add in 3L injection Oleum Ricini, add Thermal agitation makes it be completely dissolved, and obtains A liquid；

2) ethyl oleate (30L) and the 30L injection Oleum Ricini that take formula ratio are poured in colloid mill, start colloid mill, so After be slowly added into above-mentioned A liquid, treat all to add completely, add the tween 80 of formula ratio while stirring；

Embodiment 6, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.1kg,
		Praziquantel	25kg,
Sodium carboxymethyl cellulose	0.3kg,
		Lecithin	0.3kg,
Arlacel-80	1.5L,
		Vitamin E	0.075kg,
Methyl hydroxybenzoate	0.05kg,
		Medium chain triglyceride	30L,
Injection soybean oil	Add to 100L.

1) take the sodium carboxymethyl cellulose of formula ratio, lecithin, vitamin E and methyl hydroxybenzoate and be dissolved in the hot medium chain triglyceride of 5L In three esters, for A liquid；

2) take 25L medium chain triglyceride and 50L injection soybean oil is poured in colloid mill, start colloid mill, the most slowly Add above-mentioned A liquid, treat all to add completely, add the Arlacel-80 of formula ratio while stirring；

Embodiment 7, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.15kg,
		Praziquantel	25kg,
Lecithin	2kg,
		Arlacel-60	0.5L,
Butylhydroxy anisole	0.075kg,
		Methyl hydroxybenzoate	0.05kg,
Glyceryl triacetate	Add to 100L.

1) take the lecithin of formula ratio, butylhydroxy anisole and methyl hydroxybenzoate and be dissolved in the hot glyceryl triacetate of 3L In, for A liquid；

2) take 60L glyceryl triacetate and pour in colloid mill, start colloid mill, be then slowly added into above-mentioned A liquid, treat all Add completely, add the Arlacel-60 of formula ratio while stirring；

4) checking fineness of the particles, result meets the requirements (standard be particle diameter be more than the granule number of 15 μm should be less than 10%), stops Only grind, inject with glyceryl triacetate to 100L, mixing, fill, seal, sterilizing, obtain the present invention containing Yi Wei bacterium Element and the animal compound suspension injection of praziquantel.

Embodiment 8, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.25kg,
		Praziquantel	25kg,
Lecithin	0.5kg,
		Oxireme-40-castor oil hydrogenated	0.5L,
Gallic acid third lipoprotein	0.05kg,
		Methyl hydroxybenzoate	0.02kg,
Benzyl alcohol	0.02kg,
		Ethyl oleate	50L,
Injection soybean oil	Add to 100L.

1) it is dissolved in 3L ethyl oleate, for A liquid by measuring lecithin, gallic acid third lipoprotein, benzyl alcohol and methyl hydroxybenzoate；

2) remainder gauging acetoacetic ester (47L) is poured in colloid mill, starts colloid mill, is then slowly added into above-mentioned A liquid, treats complete Portion adds completely, adds oxireme-40-castor oil hydrogenated the most according to quantity；

3) treat that whole supplementary material adds completely, be sequentially added into ivermectin and praziquantel, start to grind, use circular grinding and The mode that acyclic grinding alternates is ground；

Embodiment 9, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.1kg,
		Praziquantel	15kg,
Aluminium stearate	0.05kg,
		Cholesterol	0.05kg,
Oxireme-40-castor oil hydrogenated	1.0L,
		Butylhydroxy anisole	0.01kg,
Methyl hydroxybenzoate	0.01kg,
		Ethyl oleate	50L,
Injection soybean oil	Add to 100L.

1) take the aluminium stearate of formula ratio, cholesterol, methyl hydroxybenzoate and butylhydroxy anisole and be dissolved in 3L oleic acid second In ester, for A liquid；

2) remainder gauging acetoacetic ester is poured in colloid mill, starts colloid mill, is then slowly added into above-mentioned A liquid, treats all to add Enter completely, add the oxireme-40-castor oil hydrogenated of formula ratio while stirring；

Embodiment 10, preparation are containing ivermectin and the animal compound suspension injection of praziquantel

Ivermectin	0.1kg,
		Praziquantel	20kg,
Lecithin	0.2kg,
		Castor oil hydrogenated	0.6kg,
Arlacel-60	0.5L,

Butylhydroxy anisole	0.05kg,
		Methyl hydroxybenzoate	0.005kg,
Ethyl oleate	Add to 100L.

1) take the castor oil hydrogenated of formula ratio, lecithin, butylhydroxy anisole and methyl hydroxybenzoate and add 3L oleic acid In ethyl ester, heated and stirred makes it be completely dissolved, and obtains A liquid；

2) take 60L ethyl oleate and pour in colloid mill, start colloid mill, be then slowly added into above-mentioned A liquid, treat all to add Completely, the Arlacel-60 of formula ratio is added while stirring；

Test one, the present invention contain the animal compound suspension injection of ivermectin and praziquantel medicine generation in sheep body Dynamic test is reported

The animal compound suspension injection of ivermectin and praziquantel medicine in target animals body is contained for inquiring into the present invention For dynamic law, and compare with commercially available ivermectin and praziquantel single preparations of ephedrine, carried out containing ivermectin, pyrrole Quinoline ketone suspension injection pharmacokinetic in sheep body, concrete grammar is as follows:

1 material and method

1.1 test material embodiments 9 preparation containing ivermectin (IVM) and praziquantel (PZQ) compound injection, contain IVM 0.1% (g/100mL), PZQ 15% (g/100mL)；Ivomec (IVOMEC, control drug), containing IVM 1%, Cimmeria Animal health company limited；Praziquantel tablets in healthy volunteers, containing PZQ 100mg/ sheet, middle peasant Hua Wei pharmaceutical Co. Ltd；Ivermectin (IVM) Standard substance, content 93.9%, China Veterinery Drug Inspection Office；Praziquantel standard substance, content 100%, Sigma company；High-efficient liquid Chromatography, Waters, US；Sep-Pak alkali alumina solid-phase extraction column, Waters, US.

1.2 experimental animals and administration healthy adult sheep 18, body weight 35 ± 4.1kg, in China Agricultural University's Animal House Raise, feed the complete feed 1 week of not drug containing before administration to adapt to environment.Animal is randomly divided into A, B, C 3 groups, A group cervical region Intramuscular injection IVM/PZQ compound injection, B group cervical region subcutaneous injection Ivomec, C group is administered orally PZQ tablet.A group dosage is IVM: 0.2mg/kg, PZQ:30mg/kg.B group dosage is IVM:0.2mg/kg；C group is applied at the oral dose with PZQ:30mg/kg When PZQ tablet carries out preliminary experiment, the blood drug level recorded has mass data to be less than the quantitative limit of method, it is impossible to based on accurately Calculate pharmacokinetic parameters, thus the dosage of C group PZQ is 100mg/kg.

1.3 sample collecting A groups in be administered before and administration after 0.13,0.25,0.5,0.75,1,1.5,2,3,4,6,8,12, 24,36,48,72,96,168,240,336,504 and 672h from jugular vein blood collection 8mL of sheep；B group is before being administered and after administration 0.5,1,2,4,8,12,24,36,48,72,96,168,240,336,504 and 672h from jugular vein blood collection 8mL of sheep；C group in 0.13,0.25,0.5,0.75,1,1.5,2,3,4,6,8,12,24,36 and 48h adopt from the jugular vein of sheep before being administered and after being administered Blood 8mL.Putting into the centrifuge tube in advance with heparin sodium moistening after blood specimen collection, 3000g/min draws supernatant after being centrifuged 10min, It is placed in-20 DEG C of preservations stand-by.

1.4 blood samples process

1.4.1 ivermectin detection

Taking each group of plasma sample 1mL respectively, add 3mL acetonitrile, whirling motion is extracted 1min, 3000g/min and is centrifuged 10min, inhales Take supernatant and join the Sep-Pak alkali alumina extraction column activated with 8mL acetonitrile, collect filtrate, nitrogen under the conditions of 50 DEG C Air-blowing is done.Add 100 μ l A liquid (N-Methylimidazole.: acetonitrile=1:1), whirling motion 30s, add 150 μ l B liquid (trifluoroacetic anhydride: Acetonitrile=1:2), whirling motion 30s, it is eventually adding 750 μ l methanol, whirling motion mixes, lucifuge derivatization 30min, 0.22 μm pin hole filter membrane mistake Loading after filter.

1.4.2 praziquantel detection

Draw respectively each group of plasma sample 1mL be placed in 15mL tool plug centrifuge tube, add 6mL extracting solution (methyl tertiary butyl ether(MTBE): Dichloromethane=2:1), whirling motion 1min, machinery concussion 15min(250r/min) afterwards 2500g/min be centrifuged 30min, draw supernatant, Under 45 DEG C of water bath condition, nitrogen dries up.Redissolve mutually with 250 μ l flowings before loading, sample introduction after 0.22 μm organic facies membrane filtration.

1.5 chromatographic condition

Ivermectin detects: flowing phase: acetonitrile: water=92:8；Flow velocity: 1mL/min；Excitation wavelength: 365nm；Transmitted wave Long: 475nm；Sample size: 50 μ l.

Praziquantel detects: flowing phase: acetonitrile: water=47:53；Flow velocity: 1mL/min；Detection wavelength: 217nm；Sample size: 50 μl。

1.6 standard curve

Ivermectin standard curve takes appropriate 3 μ g/mL IVM standard solutions, is diluted to 0.5,1,2,5,10 and successively The standard working solution of 30ng/mL, respectively takes 1mL nitrogen and dries up, according to loading after 1.4.1 method derivatization, record chromatogram and Peak area.

Praziquantel standard curve preparation PZQ concentration is respectively 0.025,0.050,0.125,0.250,0.500,1.000, The blood plasma of 2.000 and 3.000 μ g/mL adds sample, according to loading after 1.4.2 PZQ disposal methods, record chromatogram and Peak area.

1.7 data process the ivermectin obtained and praziquantel plasma drug level-time data 3P97 medicine generation dynamic Mechanics program software carries out compartment model matching, and calculates main pharmacokinetic parameter.

2 results

2.1 plasma assay results

IVM blood drug level after sheep intramuscular injection IVM/PZQ compound injection and subcutaneous injection Ivomec is shown in Fig. 1 (IVM:0.2mg/kg, n=6), it will be seen from figure 1 that the Drug-time curve basic simlarity of two medicines, wherein IVM/PZQ compound injection Efficiency time be slightly better than control drug Ivomec, when the ivermectin blood drug level of two kinds of preparations is higher than the maintenance of 1.0ng/mL Between, i.e. there is killing action to hold time all close to 350h to internal nematicide；Sheep intramuscular injection IVM/PZQ compound injection and The blood drug level of the PZQ after oral PZQ tablet is shown in Fig. 2 (PZQ:30mg/kg, PZQ:100mg/kg, n=6), can from Fig. 2 Go out, although consumption is VM/PZQ compound injection 3.3 times of oral PZQ tablet, it is multiple that its efficiency time is considerably shorter than VM/PZQ Side's injection, the efficiency time of IVM/PZQ compound injection (is higher than minimal effective concentration 100ng/mL with the blood drug level of PZQ Time note) be about 35h, and when the consumption of PZQ tablet is VM/PZQ compound injection 3.3 times, its efficiency time is only about 23h。

2.2 pharmacokinetic parameter

By the blood concentration-time data 3P97 software processes of experiment gained, the pharmacokinetics process symbol of IVM Closing the two-compartment model of the first order absorption that weight coefficient is 1/C/C, it is 1/ that the pharmacokinetics process of PZQ meets weight coefficient The one-compartment model of the first order absorption of C/C, the main pharmacokinetic parameters of two medicines is shown in Tables 1 and 2.

Table 1 intramuscular injection IVM/PZQ compound injection and subcutaneous injection Ivomec (IVM:0.2mg/kg) sheep plasma afterwards The pharmacokinetic parameters of middle IVM

Table 2 intramuscular injection IVM/PZQ compound injection PZQ:30mg/kg) and oral PZQ tablet PZQ:100mg/kg) after The pharmacokinetic parameters of PZQ in sheep plasma

3 conclusions

Ivermectin praziquantel suspension injection involved in the present invention pharmacokinetics process and two in sheep body The commercially available single preparations of ephedrine of kind of medicine is compared, every pharmacokinetic parameter of IVM and Ivomec after this compound preparation of intramuscular injection Difference is not notable, but IVM/PZQ compound injection is slightly better than control drug Ivomec, its blood drug level dimension higher than 1.0ng/mL Hold the time, i.e. have killing action to hold time all up to more than 14d internal nematicide；Sheep intramuscular injection IVM/PZQ compound recipe After injection and oral praziquantel folk prescription tablet, the peak time of PZQ is respectively 0.60h and 3.75h, i.e. pyrrole in this compound preparation The peak time of quinoline ketone is short, rapid-action, the praziquantel tablets in healthy volunteers that AUC and its 3 multiple dose are administered without significant difference, system the most of the present invention In agent, the bioavailability of praziquantel significantly improves；On the other hand, the elimination curve part of praziquantel in IVM/PZQ compound injection Dividing compared with oral tablet group more mild, its elimination half-life (11.64h) is 3.14 times of oral tablet group, the blood medicine of PZQ Concentration remains above minimal effective concentration 100ng/mL when 24h, shows that it has long-acting, and then can kill institute in sheep body Some trematodiasiss, cestode and larva thereof.

This result of the test shows that compound preparation a drug of the present invention can effectively treat the nematicide of sheep, trematodiasis, cestode And epizootic disease.

Demonstrating the suspension injection of other embodiments in the same way, result is complete with the experiment conclusion of embodiment 9 Identical.

Test two, animal compound suspension injection containing ivermectin and the praziquantel clinical trial in sheep body

For inquiring into animal compound suspension injection (the hereinafter referred to as present invention that the present invention contains ivermectin and praziquantel Medicine) pharmacokinetics rule in target animals body, and compare with commercially available ivermectin and praziquantel single preparations of ephedrine, Having carried out containing ivermectin, praziquantel suspension injection pharmacokinetic in sheep body, concrete grammar is as follows:

1 material and method

1.1 test material embodiments 9 preparation containing ivermectin (IVM) and praziquantel (PZQ) compound injection (IVM/PZQ compound preparation, medicine of the present invention), containing IVM 0.1% (g/100mL), PZQ 15% (g/100mL)；Ivomec (IVOMEC, control drug 1), containing IVM 1%, Cimmeria animal health company limited；Praziquantel tablets in healthy volunteers (control drug 2), contains PZQ 100mg/ sheet, middle peasant Hua Wei pharmaceutical Co. Ltd；Ivermectin reference substance, content 93.9%, China's veterinary medicament supervision Institute；Praziquantel standard substance, content 100%, Sigma company；High performance liquid chromatograph, Waters, US；Sep-Pak alkalescence Aluminium oxide solid-phase extraction column, Waters, US.Cecil McMaster counting chamber, rustless steel medicine spoon, centrifuge tube, 60 mesh copper sieves, Enumerator, medical centrifuge, electronic balance, glue head straw, microscope, saturated aqueous common salt etc..

The a group of any anthelmintic drug was not used to herd breeds differentiation (Qinghai Province to 9 months before 1.2 experimental animal tests Qilian County) carry out stool examination, selecting weight range is 27.5～36kg(about 1.5 years old), infected nematicide, trematodiasis and The sheep 120 of cestode is served only for this test.

2 test methods

2.1 animals packet by 120 only for examination sheep press gastrointestinal nematode, thread lungworm (Protostrongylidae nematicide, net filaria), Distoma hepaticum, Anoplocephalidae cestodes infection conditions collocation be divided into 6 groups (guarantee every treated animal in addition to nematode infections, at least more than 5 Sheep infects simultaneously trematodiasis or cestode), often group 20, medicine the most of the present invention basic, normal, high dosage group (A group, B group, C Group), control drug 1 group (D group), control drug 2 groups (E group) and positive controls (F group).The route of administration of each group and dosage are such as Under: A group, medicine low dose group of the present invention, 0.1ml/kg dosage intramuscular administration；B group, dosage group in medicine of the present invention, 0.2ml/kg dosage intramuscular administration；C group, medicine high dose group of the present invention, 0.3ml/kg dosage intramuscular administration；D group, Ivermectin injection drug control group (Ivomec group), 0.2mg/kg injected sc is administered；E group, praziquantel tablets in healthy volunteers medicine Thing matched group, 30mg/kg dosage oral administration clothes are administered；F group, positive controls, it is not administered.

2.2 test procedure

2.2.1 before being administered, excrement inspection is administered front to each group of test sheep marking, by only gathering fresh excreta, takes back laboratory, often Part weighs 1g saturated saline floatation and checks every gram of faecal egg number (EPG), weighs 3g and separates larva, mirror by Bel's Man method Inspection counting.

2.2.2 administration processes drug test and respectively organizes sheep by only weighing, registering, A～C group sheep is by designing dosage intramuscular injection Ivermectin praziquantel suspension injection, D group sheep cervical region subcutaneous injection Ivomec injection, E group sheep oral administration takes praziquantel tablets Agent, F group sheep is not administered.

2.2.3 after after being administered, excrement inspection is administered respectively at the 7th, 14d respectively organize sheep by only gathering fresh excreta, carry out feces worm Ovum, larva check, statistics EPG and larva number.

2.2.4 after cuing open inspection administration, 16～19d start day by day from 3 test group, 2 drug control groups and positive controls Randomly draw sheep each 5 intert cut open inspection, by Si Shi method check nematicide, cestode, trematodiasis lotus amount.Microscopy taxonomic identification to belong to or Kind, add up lotus borer population.

2.3 efficacy determinations are calculated Negative rate on the egg, Redution of eggs and rough anthelminthic rate respectively by following equation:

Negative rate on the egg (%)=worm's ovum is turned out cloudy number of animals/experimental animal number × 100%

EPG × 100% before EPG/ anthelmintic after EPG-anthelmintic before Redution of eggs (%)=anthelmintic

Larva negative conversion rate (%)=larva is turned out cloudy number of animals/experimental animal number × 100%

Larva number/anthelmintic prelarva number × 100% after larva slip (%)=anthelmintic prelarva number-anthelmintic

Rough anthelminthic rate (%)=positive controls lotus borer population-anthelmintic group lotus borer population/positive controls lotus borer population × 100%

3. result of the test

3.1 faecal eggs check result each test group sheep be administered after the 7th day and the 14th day excrement examine statistical result and be shown in Table 3 With table 4.From table 3 and table 4, each test group turns out cloudy data it can be seen that A group, B group, C group, the Negative rate on the egg (present invention of D group Medicine basic, normal, high dosage group and Ivomec group) significant difference is all there is with F group (positive controls), and A group, B group, C group, D Organize between four groups without significant difference, show the angle from Negative rate on the egg, medicine of the present invention basic, normal, high dosage group and Ivomec group All there is an obvious anthelminthic effect, and E group (praziquantel tablets in healthy volunteers group) effect extreme difference, its reason is that the test that this test is selected is equal with sheep Have and infect various nematicides and only part sheep infects trematodiasis or cestode, and praziquantel is undesirable to the anthelminthic effect of nematicide.This Outward, from table 3 and table 4 each test group worm's ovum reduce data it is also seen that A group, B group, C group, D group Negative rate on the egg all with There is significant difference in F group, shows that medicine of the present invention basic, normal, high dosage group and Ivomec group all have an obvious anthelminthic effect, but A group And also there is significant difference between B group, C group, D group, and between B group, C group, D group, the most there is not significant difference, show medicine of the present invention The anthelminthic effect of low dose group is not so good as medicine of the present invention middle and high dosage group and Ivomec group.

Table 3 is administered latter 7 days each test group Negative rate on the eggs and slip

Note: 1, the dosage of medicine senior middle school of the present invention low dose group (A group, B group, C group) is respectively 0.1ml kg^-1、 0.2ml·kg^-1、0.3ml·kg^-1, wherein 0.1ml medicine of the present invention 0.1mg Han ivermectin, containing praziquantel 15mg；Yi Wei bacterium Element control drug group (D group) dosage is 0.2mg kg^-1, praziquantel control drug group (E group) dosage is 30mg kg^-1, F group is positive controls；

2, same column shoulder mark^{(a, b, c)}Identical group of difference is not notable (P ＞ 0.05)；Same column shoulder mark^{(a, b, c)}Different group significant difference (P ＜ 0.05)；

3, EPG is every gram of faecal egg number, is the average of 20 sheep.

Table 4 is administered latter 14 days each test group Negative rate on the eggs and slip

3, EPG is every gram of faecal egg number, is the average of 20 sheep.

3.2 feces larvas check result

After each test group sheep is administered, the 7th day and the 14th day excrement are examined statistical result and are shown in Table 5 and table 6.

Table 5 is administered latter 7 days each test group larva negative conversion rates and slip

3, the larva number before being administered and after administration is the average of each group of sheep.

From table 5 and table 6 each test group turn out cloudy data it can be seen that A group, B group, C group, D group sheep be administered after the 7th day Larva negative conversion rate and larva slip all below 80%, and sheep be administered after after the 14th day all more than 80%, show A group, B group, C group, D group, medicine the most of the present invention basic, normal, high dosage group and Ivomec matched group are all not up to anthelmintic in being administered one week after Effect, and two Zhou Houjun can reach good anthelminthic effect.As can also be seen from Table 6, A group, B group, C group, D group larva negative conversion rate equal Have between significant difference, and A group, B group, C group, D group four groups without significant difference with F group (positive controls), show to turn from larva From the perspective of cloudy rate, medicine of the present invention basic, normal, high dosage group and Ivomec group all have an obvious anthelminthic effect, and E group (pyrrole quinoline Ketone tablet group) effect is poor.Additionally, the larva of each test group reduces data it is also seen that A group, B group, C group, D group from table 6 Larva negative conversion rate all with F group, there is significant difference, show that medicine of the present invention basic, normal, high dosage group and Ivomec group all have bright Aobvious anthelminthic effect, but also there is significant difference between A group and B group, C group, D group, and the most there is not significance difference between B group, C group, D group Different, show that the anthelminthic effect of medicine low dose group of the present invention is not so good as medicine of the present invention middle and high dosage group and Ivomec group, this knot Fruit is consistent with faecal egg testing result.

Table 6 is administered latter 14 days each test group larva negative conversion rates and slip

3.3 cut open inspection result

After administration 16～19d start day by day from each test group randomly draw sheep each 5 intert cut open inspection, by Si Shi method check Nematicide, cestode, trematodiasis lotus amount, microscopy taxonomic identification is to belonging to or planting, and statistics lotus borer population also calculates deworming rates, the lotus of all kinds of parasites Borer population and deworming rates result are shown in Table 7 and table 8 respectively, wherein the deworming rates of table 8 by table 7 data according to " rough anthelminthic rate " in 1.5 Formula calculate and obtain.

Table 7 each test group sheep lotus borer population (bar)

Note: the dosage of medicine senior middle school of the present invention low dose group (A group, B group, C group) is respectively 0.1ml kg^-1、 0.2ml·kg^-1、0.3ml·kg^-1, wherein 0.1ml medicine of the present invention 0.1mg Han ivermectin, containing praziquantel 15mg；Yi Wei bacterium Element control drug group (D group) dosage is 0.2mg kg^-1, praziquantel control drug group (E group) dosage is 30mg kg^-1, F group is positive controls.

It can be seen that be administered 16 days, A group, B group, C group, total deworming rates of D group all exist each group data from table 8 later More than 90%, show that A group, B group, C group, D group, medicine the most of the present invention basic, normal, high dosage group and Ivomec matched group are administered at this Test is respectively provided with fabulous anthelminthic effect, and the anthelminthic effect extreme difference of E group (praziquantel tablets in healthy volunteers group), its reason is this test institute The test sheep selected and the test trematodiasis that checks of sheep analysed and cestode number less extremely, this result is further Confirm ivermectin and nematicide has been had good repelling and killing efficacy (invalid to trematodiasis and cestode), and trematodiasis and cestode have been had by praziquantel There is good repelling and killing efficacy (to nematicide without nearly unavailable).Additionally, due to low dosage medicine of the present invention group (A group) is to trematodiasis and cestode Repelling and killing efficacy the most not ideal enough (deworming rates is respectively 66.670% and 64.52%, respectively less than 70%), and in (B group), high (C Group) dosage group medicine of the present invention all has good repelling and killing efficacy (deworming rates is above 90%), and both to nematicide, trematodiasis and cestode Without significant difference.Therefore, this medicine is used for treating the mixed infection of the nematicide of sheep, trematodiasis and cestode clinically is should be with middle dosage It is advisable.

Table 8 each test group sheep deworming rates (%)

4. conclusion (of pressure testing)

Medicine of the present invention all has good repelling and killing efficacy to sheep nematicide, trematodiasis and cestode, can be clinically used for the line of sheep The mixed infection of worm, trematodiasis and cestode, advises that when Clinical practice using dosage is middle dosage, and i.e. every kg body weight intramuscular is noted Penetrate medicine ivermectin praziquantel suspension injection 0.2mL (being equivalent to ivermectin 0.2mg and praziquantel 30mg) of the present invention.

Claims

1. containing ivermectin and an animal compound suspension injection for praziquantel, be with ivermectin with praziquantel for effectively becoming The animal compound suspension injection divided, it is characterised in that: in described animal compound suspension injection, the content of each effective ingredient is, By weight/concentration of volume percent meter, g/100mL: ivermectin 0.05-2%, praziquantel 10-50%；

Described animal compound suspension injection also includes following excipient substance: dispersion matchmaker, suspending agent, wetting agent, antioxidant and Preservative；Described dispersion matchmaker is in glyceryl triacetate, ethyl oleate, medium chain triglyceride, injection soybean oil and Oleum Ricini Two kinds；Described antioxidant is one or both in vitamin E and ascorbic acid.

Animal compound suspension injection the most according to claim 1, it is characterised in that: described animal compound suspension injection In the content of each effective ingredient be, by weight/concentration of volume percent meter, g/100mL: ivermectin 0.1-0.5%, praziquantel 15-25%.

Animal compound suspension injection the most according to claim 1, it is characterised in that: described dispersion matchmaker be ethyl oleate and The composite diffusion matchmaker of injection soybean oil, compositely proportional is unrestricted.

Animal compound suspension injection the most according to claim 3, it is characterised in that: ethyl oleate and injection soybean oil 5:3-4 is combined by volume.

Animal compound suspension injection the most according to claim 1, it is characterised in that: described suspending agent is vaseline, gathers One or both in vinylpyrrolidone, aluminium stearate, lecithin, cholesterol, sodium carboxymethyl cellulose and castor oil hydrogenated.

Animal compound suspension injection the most according to claim 1, it is characterised in that: described wetting agent is tween 80, department One or both in dish-60, Arlacel-80 and oxireme-40-castor oil hydrogenated.

Animal compound suspension injection the most according to claim 1, it is characterised in that: described preservative is benzyl alcohol, Buddhist nun Pool tortoise beetle ester and propylparaben in one or both.

8. according to the animal compound suspension injection described in any one of claim 1-7, it is characterised in that: described animal compound mixes In outstanding injection, the content of each composition is: ivermectin 0.05-2%, praziquantel 10-50%, suspending agent 0.1-2%, wetting agent 0.5-1.5%, antioxidant 0.01-0.5%, preservative 0.005-1%, remaining is dispersion matchmaker；Wherein, ivermectin, praziquantel, The content of suspending agent, antioxidant and preservative by weight/concentration of volume percent meter, g/100mL, wetting agent by volume percentage ratio Densitometer, mL/100mL.

Animal compound suspension injection the most according to claim 8, it is characterised in that: described animal compound suspension injection In the content of each composition be: ivermectin 0.1-0.25%, praziquantel 15-40%, suspending agent 0.1-2%, wetting agent 0.5- 1.5%, antioxidant 0.01-0.5%, preservative 0.005-0.5%, remaining is dispersion matchmaker；Wherein, ivermectin, praziquantel, help The content of suspension, antioxidant and preservative by weight/concentration of volume percent meter, g/100mL, wetting agent by volume percentage ratio is dense Degree meter, mL/100mL.

Animal compound suspension injection the most according to claim 9, it is characterised in that: described animal compound suspendible is injected In liquid, the content of each composition is: ivermectin 0.1-0.25%；Praziquantel 15-25%；Suspending agent 0.1-0.5%, suspending agent is Lecithin or aluminium stearate and the mixing of cholesterol；Wetting agent 0.5-1.0%, wetting agent is oxireme-40-hydrogenated castor Oil；Antioxidant 0.01-0.05%；Preservative 0.01-0.02%, preservative is methyl hydroxybenzoate；Remaining is dispersion matchmaker, disperses matchmaker For the composite diffusion matchmaker of ethyl oleate Yu injection soybean oil, wherein the 50% of suspension injection cumulative volume is ethyl oleate, remaining Amount is injection soybean oil；Wherein, the content of ivermectin, praziquantel, suspending agent, antioxidant and preservative by weight/volume Percent concentration meter, g/100mL, wetting agent by volume percent concentration meter, mL/100mL.

The injection of the animal compound suspendible containing ivermectin and praziquantel that 11. 1 kinds are prepared described in any one of claim 1-10 The method of liquid, comprises the following steps:

1) take suspending agent, antioxidant and preservative to be dissolved or dispersed in the dissipation of heat matchmaker of formula ratio 3-20%, obtain A liquid；

2) the dispersion matchmaker taking formula ratio 30-90% pours in colloid mill, starts colloid mill, is then slowly added into above-mentioned A liquid, treats complete Portion adds completely, adds wetting agent while stirring；

3) treat that whole supplementary material adds completely, be sequentially added into ivermectin and praziquantel, then use circular grinding and acyclic grind The mode that mill alternates is ground；

4) check fineness of the particles, stop after meeting the requirements grinding, add surplus and disperse matchmaker to formula ratio, mixing, fill, seal, go out Bacterium, obtains the animal compound suspension injection containing ivermectin and praziquantel；

When using composite diffusion matchmaker, a kind of consumption in two kinds of dispersion matchmakers is fixed, and another kind of consumption floats, in operation, in institute State step 1) first disperse matchmaker suspending agent, antioxidant, preservative to be dissolved by the one of which of total formula ratio 3%；In step 2) in First using that dispersion matchmaker that consumption is fixing, re-use that dispersion matchmaker that consumption floats to step 2) the dispersion matchmaker that sets uses Amount, the 47-60% of i.e. total formula ratio；Last in step 4) in use consumption to float the surplus of that dispersion matchmaker be settled to always join Fang Liang.