CN102258529A - Compound ivermectin injection and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of veterinary anti-parasitic medicaments, particularly relates to a compound ivermectin injection and a preparation method thereof, and aims to provide an injection for treating parasitic infection of livestock, expanding an anti-parasitic spectrum and enhancing a therapeutic effect and a preparation method thereof. Every 100ml of compound ivermectin injection comprises 0.5-2g of ivermectin, 2.5-10g of albendazole sulfoxide, 5-15ml of polyethylene glycol 400 (PEG400), 1-10ml of acetic ether, 0.5-2ml of benzyl alcohol, 0.05-0.2ml of alpha-thioglycerol, 10-30ml of dimethyl sulfoxide and the balance of propylene glycol. In the injection, the ivermectin and the albendazole sulfoxide are used as anti-parasitic main components; the injection has double complementary advantages; the anti-parasitic spectrum is expanded; the drug resistance probability of parasites can be effectively reduced; and the sensitivity of the parasites is improved. The invention brings a completely new situation for safely, effectively and conveniently preventing and treating parasitic diseases in animal husbandry and aquaculture of China.

Description

A kind of compound ivermectin injection and preparation method thereof

Technical field

The present invention relates to anti-parasite medicine for animal use thing technical field, be specifically related to a kind of compound ivermectin injection and preparation method thereof.

Background technology

Ivermectin is a kind of novel Macrolide antiparasitic, with its wide spectrum, efficient (nematicide, insecticide and demodicid mite are all had efficiently killing effect), toxic and side effects is little, consumption is little, safe, the residence time characteristics such as lacks and is widely used in the herding production in animal food.

Ivermectin has only ordinary preparation at present, and each administration weak point of holding time needs multiple dosing, exists and uses inconvenience, expends shortcomings such as a large amount of manpower and materials again, presses for the new product of research, to adapt to Developing of Animal Industry.Ivermectin has the stronger effect of killing to animal body entozoa (nematicide) and vermin (Ticks, demodicid mite, louse, flea etc.); Albendazole-sulfoxide is all killed effect to nematicide, cestode, trematodiasis.In view of two kinds of medicines all have stronger anti-insect activity and have complementary action on pest-resistant spectrum, successfully developing its compound injection has its significance, has had not yet to see the correlational study report.

Summary of the invention

At the deficiencies in the prior art, the object of the present invention is to provide that a kind of preparation method is simple, cost of material is low, efficient, wide spectrum and animal compound ivermectin injection of being difficult for developing immunity to drugs and preparation method thereof.

The present invention is compound in ivermectin and albendazole-sulfoxide in the solvent in the proper ratio, and combines dexterously by compositions such as suitable stabilizing agent and antibacterial, makes stable compound preparation.On pest-resistant spectrum, have the complementary effect of double dominant thereby reach, enlarge pest-resistant spectrum, improve pest-resistant curative effect, reduce the drug resistance of polypide, improve parasitic sensitivity.

The objective of the invention is to be achieved through the following technical solutions:

A kind of compound ivermectin injection, this injection of every 100ml comprises: the propylene glycol of ivermectin 0.5～2g, albendazole-sulfoxide 2.5～10g, PEG400 (PEG400) 5～15ml, ethyl acetate 1～10ml, benzyl alcohol 0.5～2ml, α-thioglycerol 0.05～0.2ml, dimethyl sulfoxide 10～30ml and surplus.

The preparation method step of above-mentioned compound ivermectin injection is as follows:

(1) takes by weighing ivermectin and join in the ethyl acetate, stir to clarify, get solution A;

(2) take by weighing albendazole-sulfoxide and join in the dimethyl sulfoxide, stop heating immediately after heating makes it to dissolve fully, be cooled to 40 ℃, stir to clarify, get solution B;

(3) merge solution A and solution B, add PEG400, α-thioglycerol and benzyl alcohol after stirring successively, stir, treat that solution clarification back adds propylene glycol, promptly gets compound ivermectin injection.

Advantage of the present invention and beneficial effect are:

Selected ivermectin and albendazole-sulfoxide to be prepared into compound preparation among the present invention dexterously, formed dual pest-resistant advantage, had the wide spectrum pest-resistant effect, improved parasitic sensitivity according to certain ratio.In addition in this preparation because the adding of PEG400 has improved the chelating degree between medicine and solvent and the cosolvent, consequently improved the stability of this compound preparation greatly.Experiment showed, that ivermectin and albendazole-sulfoxide unite use curative effect is strengthened, clinical practice is extensive, can be widely used in the treatment of animal parasite disease, reduces parasitic infection rate, improves the economic benefit that animal husbandry is cultured.

The specific embodiment

Below in conjunction with specific embodiment the inventive method is described in further detail.

Embodiment 1～5:

Embodiment 1～5 has all prepared a kind of compound ivermectin injection of the present invention, and the composition of raw materials of every 100ml injection of each embodiment is seen following table 1.

Table 1

Component	Embodiment 1	Embodiment 2	Embodiment 3	Embodiment 4	Embodiment 5
						Ivermectin (g)	0.5	0.5	1	1.5	2
Albendazole-sulfoxide (g)	2.5	2.5	5	7.5	10
						Ethyl acetate (ml)	1	2	5	10	10
PEG400(ml)	5	7.5	10	12	15
						Dimethyl sulfoxide (ml)	10	15	20	25	30
α-thioglycerol (ml)	0.05	0.1	0.1	0.1	0.2
						Benzyl alcohol (ml)	1	1.5	2	0.5	1.5
Propylene glycol	Surplus	Surplus	Surplus	Surplus	Surplus

It is as follows that the raw material of above-mentioned prescription makes the method step of compound ivermectin injection of the present invention:

(1) takes by weighing ivermectin and join in the ethyl acetate, stir to clarify, get solution A;

(2) take by weighing albendazole-sulfoxide and join in the dimethyl sulfoxide, stop heating immediately after heating makes it to dissolve fully, be cooled to 40 ℃, stir to clarify, get solution B;

(3) merge solution A and solution B, add PEG400, α-thioglycerol and benzyl alcohol after stirring successively, stir, treat that solution clarification back adds propylene glycol, promptly get compound ivermectin injection, testing result sees Table 2.

Each embodiment result of table 2

The result of table 2 proves that the compound ivermectin injection of the foregoing description 1～5 preparation is faint yellow supernatant liquid, (temperature is 40 ± 2 ℃ to accelerated test, relative humidity is 65 ± 5%) under the condition, the content of principal agent ivermectin, albendazole-sulfoxide is more than 98% (m/m) of labelled amount after three months, meets the requirements.

From the result, can find, the product that adds the PEG400 preparation in the test method does not add prepared test specimen and compares, has better stability (controlled trial: except not adding the PEG400, all the other components and preparation method are all with embodiment 2, the test specimen that makes after having passed through three months accelerated tests under the similarity condition, the equal not enough labelled amount of content of ivermectin and albendazole-sulfoxide 95%).PEG400 belongs to macromolecular substances, has peptizaiton and chelation preferably, can organically combine with small-molecule drug.Therefore the adding of PEG400 has improved the stability of compound ivermectin injection greatly in this compound preparation, and the content and the character of accelerated test principal agent after three months all do not have obvious variation.

The clinical trial part

1 material and method

1.1 material

1.1.1 compound ivermectin injection (containing ivermectin 0.5g, albendazole-sulfoxide 2.5g in per 100 milliliters): lot number 110125, Wuhan Hvsen Biotechnology Co., Ltd. provides, and is got by embodiment 2 preparations.

1.1.2 ivermectin injection: specification is that every 50mL contains ivermectin 0.5g, lot number 110301, and Sichuan Province elite animal pharmaceutcal corporation, Ltd produces.

1.1.3 levamisole hydrochloride injection treatment of control group group: specification is 10mL, contains levamisole 0.5g, lot number 110310, and Hebei Yuanzheng Medicine Co., Ltd produces.

1.1.4 experimental animal: the two-way cross pig of 300 4 months ages in days that the Huangshi pig farm is raised, carry out the stool examination of pig parasitic ovum, and do itemized record, select to infect 42 more serious pigs and be divided into 7 groups at random, 6 every group, carry out labelling, test.

1.2 method

1.2.1 test pig parasitic infection condition survey: before the test 6 test pig of the 7th group are butchered, carry out the inspection of distoma hepaticum, cestode, gastrointestinal nematode and other parasitic infection amounts.Determine the average infection intensity of this area pig main parasitic worm.

1.2.2 respectively organize the processing of experimental animal: press every 50kg body weight subcutaneous injection 0.5,1,1.5mL with compound ivermectin injection respectively for the 1st, 2,3 groups; The 4th group with ivermectin injection by every 50kg body weight subcutaneous injection 1mL; Use the levamisole hydrochloride injection for the 5th group, by every kg body weight intramuscular injection 0.5mL; The 6th group is matched group.In administration 7,14, respectively organize the faecal egg inspection of test pig after 21d days with the McMaster method, to observe and infect worm's ovum minimizing situation, the worm's ovum slip calculates by following formula.

1.2.3 the average infection intensity of each experimental animal changes before and after the test: the Total Test pig send the slaughterhouse to butcher after the off-test, and collects the inspection that internal organs are done distoma hepaticum, cestode, gastrointestinal nematode and other parasitic infection amounts.Determine the test front and back and respectively organize the situation of change of average infection intensity, deworming rates is calculated by following formula.

2 result of the tests

Result of the test sees Table 1, table 2, table 3, table 4, table 5.

Table 1 test pig farm pig parasitic infection intensity statistics

Parasite species	Infection rate (%)	Infective dose (bar/only)	Average infection intensity (bar/only)
				Distoma hepaticum	50	10～25	20
Cestode	60	5～30	26
				The Strongyloides ransomi disease	100	20～200	112
The stomach strongylasis	100	30～60	40
				Whipworm	20	50～150	85
The total infectiosity of mean parasitized worm			283

Table 2 faecal egg infective dose digestive tract worm's ovum number reduces test

Average infection intensity situation of change before and after the test of table 3 distoma hepaticum

Group	Before the test (bar/only)	The test back (bar/only)	Kill rate (%)
				1	20	12	44.4
2	20	5	81.5
				3	20	1	92.6
4	20	22	0
				5	20	21	0
6	20	28	0

Average infection intensity situation of change before and after the test of table 4 cestode

Group	Before the test (bar/only)	The test back (bar/only)	Kill rate (%)
				1	26	9	65.4
2	26	2	92.3
				3	26	0	100
4	26	27	0
				5	26	27	0
6	26	30	0

Average infection intensity situation of change before and after the test of table 5 gastrointestinal tract nematicide

Group	Before the test (bar/only)	The test back (bar/only)	Kill rate (%)
				1	79	15	81.1
2	79	5	93.7
				3	79	2	97.5
4	79	17	78.5
				5	79	12	84.8
6	79	98	0

The overall anthelminthic effect of table 6

Group	Before the test (bar/only)	The test back (bar/only)	Kill rate (%)
				1	283	94	66.8
2	283	23	90.9
				3	283	12	95.8
4	283	119	58.0
				5	283	103	63.6
6	283	298	0

3 discuss

3.1, prove that compound ivermectin injection of the present invention has the extraordinary effectiveness of killing to pork liver plate trematodiasis, cestode, gastrointestinal tract nematicide by clinical trial.Test data shows that by every 50kg body weight subcutaneous injection 1mL, the worm's ovum negative conversion rate reaches 100% behind the 14d, and deworming rates reaches 93.7%.This test proves that fully the compound ivermectin injection prescription is scientific and reasonable, can enlarge the pest-resistant spectrum and the anthelmintic efficiency of compound preparation.

3.2 people use its derivant of avilamycin to produce serious Drug resistance in a large number disorderly over many years.This test has also proved this point, and the problem that clinical application effect reduces, drug residue increases is appeared suddenly day by day.Compound Synergistic, expansion anthelmintic spectrum, the polyenergic purpose of a medicine of reaching by two medicines can address the above problem preferably.

3.3 according to the data introduction, ivermectin is to distoma hepaticum and cestode poor effect, but compound ivermectin group deworming rates shows that all it has powerful anthelminthic effect (92.6% and 100%) to pork liver plate trematodiasis and cestode in this test, with point out that albendazole-sulfoxide is consistent to the result that cestode, trematodiasis have very strong repelling and killing efficacy, has proved the potentiation of compound preparation in the pertinent literature report.

3.4 this evidence 2 kinds of broad-spectrum de-worming medicines have obvious synergistic effect after compound, produced double dominant.

Claims (2)

1. a compound ivermectin injection is characterized in that every 100ml injection comprises: the propylene glycol of ivermectin 0.5～2g, albendazole-sulfoxide 2.5～10g, PEG400 5～15 ml, ethyl acetate 1～10ml, benzyl alcohol 0.5～2ml, α-thioglycerol 0.05～0.2ml, dimethyl sulfoxide 10～30ml and surplus.

2. the preparation method of the described a kind of compound ivermectin injection of claim 1, its step is as follows:

(1) takes by weighing ivermectin and join in the ethyl acetate, stir to clarify, get solution A;

(2) take by weighing albendazole-sulfoxide and join in the dimethyl sulfoxide, stop heating immediately after heating makes it to dissolve fully, be cooled to 40 ℃, stir to clarify, get solution B;

(3) merge solution A and solution B, add PEG400, α-thioglycerol and benzyl alcohol after stirring successively, stir, treat that solution clarification back adds propylene glycol, promptly gets compound ivermectin injection.