Imidacloprid and moxidectin compound temperature-sensitive gel as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to imidacloprid and moxidectin compound temperature-sensitive gel as well as a preparation method and application thereof. The imidacloprid and moxidectin compound temperature-sensitive gel is prepared from imidacloprid, moxidectin, poloxamer 407, poloxamer 188, a penetration enhancer, a preservative, dimethyl sulfoxide, a stabilizer and water. The imidacloprid and moxidectin compound temperature-sensitive gel is prepared from the following components in percentage by weight and volume: 10 percent of imidacloprid, 1 percent of moxidectin, 10 to 20 percent of poloxamer 407, 1.0 to 10.0 percent of poloxamer 188, 1.0 to 15.0 percent of penetration enhancer, 0.1 to 0.3 percent of preservative, 0 to 1.0 percent of stabilizer, 20.0 to 40.0 percent of dimethyl sulfoxide and the balance of water. The imidacloprid and moxidectin compound temperature-sensitive gel prepared by the preparation method disclosed by the invention not only has qualified gelling temperature, but also has an obvious slow-release effect.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound thermosensitive gel of imidacloprid and moxidectin, and a preparation method and application thereof. Background Art

[0002] Imidacloprid, with the trade name Imidacloprid, belongs to the neonicotinoid insecticides and entered the market in 1991 as an agricultural insecticide and a veterinary drug for controlling ectoparasites. The pure product of imidacloprid is a white crystal, and the technical material is a light yellow crystal. Its chemical name is 1-(6-chloropyridin-3-ylmethyl)-N-nitroimidazolidin-2-ylamine, which is an agonist of the nicotinic acetylcholine receptor and interferes with the motor nervous system of pests, causing the chemical signal transmission to fail. Its molecular formula is C 9 H 10 ClN 5 O 2 , and the chemical structural formula is as follows:

[0003]

[0004] Moxidectin, with the trade name Moxidectin, is a macrolide antibiotic and is a fermentation product with high acaricidal activity isolated from the fermentation products of Streptomyces hygroscopicus in 1967. Subsequently, in 1983, the macrolide drug nemadectin was isolated from the fermentation products of Streptomyces cyaneogriseus, and moxidectin was obtained by derivatizing it with a methoxime moiety at the C-23 position. Moxidectin is a white to light yellow amorphous powder. Its molecular formula is C 37 H 53 NO 8 , and the chemical structural formula is as follows:

[0005]

[0006] The structural formula of moxidectin contains a 16-membered macrolide ring as part of the pentacyclic framework, and is structurally similar to the drug ivermectin B1, except that there is no linked disaccharide at the C13 position, there is an olefin chain at the C25 position, and there is a methoxime moiety at the C23 position.

[0007] Moxidectin can increase the activity of the glutamate-gated chloride channels of parasites, resulting in an increase in the influx of chloride ions into neurons and the accumulation of negative membrane potential, thereby causing a slowdown in nerve drive, leading to flaccid muscle paralysis of parasites, and ultimately selectively paralyzing parasites. The first application of moxidectin preparations in the veterinary field was in 1990 when an injection preparation was launched in Argentina for the prevention and control of parasites in animals such as cattle and sheep. Subsequently, due to its good broad-spectrum anthelmintic activity, moxidectin has been prepared into various dosage forms and widely used to control ectoparasites and endoparasites in cattle, sheep, deer, dogs, and other production animals.

[0008] At present, there is only one dosage form for preparations with imidacloprid and / or moxidectin as active ingredients: drops. A relatively mature product on the market is the imidacloprid and moxidectin drops for external use produced by Bayer AG of Germany, with the Chinese trade name "Advocate". When this preparation is dropped on the skin for use, it has the characteristic of broad-spectrum insecticidal (endoparasites and ectoparasites such as nematodes and mites).

[0009] The disadvantage of the commercially available product Advocate is that it is easy to stick to the hair, with more drug loss, a large amount of organic solvent used, and great irritation to the skin. Therefore, it is necessary to find a better dosage form to reduce drug loss, improve the transdermal effect of the drug, prolong the action time of the drug, avoid or reduce the use of organic solvents, and thus improve its safety. Summary of the Invention

[0010] In order to overcome the defects of the prior art, the present invention provides a thermosensitive gel of imidacloprid and moxidectin combination, and the thermosensitive gel of imidacloprid and moxidectin combination is a preparation composed of imidacloprid and moxidectin as active ingredients, and adding a matrix, a penetration enhancer, a preservative, dimethyl sulfoxide, a stabilizer and water.

[0011] Specifically, the thermosensitive gel of imidacloprid and moxidectin combination contains imidacloprid, moxidectin, poloxamer 407, poloxamer 188, a penetration enhancer, a preservative, dimethyl sulfoxide, a stabilizer, water; the weight / volume percentages of each component in the thermosensitive gel of imidacloprid and moxidectin combination are: imidacloprid 10%, moxidectin 1%, poloxamer 407 is 10 - 20%, poloxamer 188 is 1.0 - 10.0%, the penetration enhancer is 1.0 - 15.0%, the preservative is 0.1 - 0.3%, the stabilizer is 0 - 1.0%, dimethyl sulfoxide is 20.0 - 40.0%, and the balance is water.

[0012] The penetration enhancer is one, two or a combination of three of 1,2 - propylene glycol, polyethylene glycol 400, azone, absolute ethanol, peppermint oil, and crotamiton.

[0013] Preferably, the penetration enhancer is 1,2 - propylene glycol, a combination of 1,2 - propylene glycol and absolute ethanol, or a combination of 1,2 - propylene glycol and polyethylene glycol 400.

[0014] The stabilizer is HPMC E5, HPMC E50.

[0015] The preservative is ethylparaben.

[0016] Further, the present invention preferably provides the following imidacloprid and moxidectin compound thermosensitive gel, wherein the weight - volume percentages of each component in the imidacloprid and moxidectin compound thermosensitive gel are as follows: imidacloprid 10%, moxidectin 1%, poloxamer 407 10.0 - 15.0%, poloxamer 188 2.0 - 5.0%, penetration enhancer 4.0 - 15.0%, preservative 0.1 - 0.3%, stabilizer 0.1 - 0.6%, dimethyl sulfoxide 22.0 - 36.0%, and the balance is water.

[0017] Preferably, the penetration enhancer is 1,2 - propylene glycol.

[0018] Further, the present invention preferably provides the following imidacloprid and moxidectin compound thermosensitive gel, wherein the weight - volume percentages of each component in the thermosensitive gel are as follows: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0 - 13.0%, poloxamer 188 2.5 - 4.5%, penetration enhancer 1,2 - propylene glycol 7.0 - 12.0%, preservative ethyl paraben 0.1 - 0.3%, stabilizer 0.1 - 0.6%, dimethyl sulfoxide 22 - 36.0%, and the balance is water.

[0019] Preferably, the weight - volume percentages of each component in the thermosensitive gel are: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0 - 13.0%, poloxamer 188 2.5 - 4.5%, penetration enhancer 1,2 - propylene glycol 8.0 - 9.0%, preservative ethyl paraben 0.1 - 0.3%, stabilizer 0.1 - 0.6%, dimethyl sulfoxide 34.0 - 36.0%, and the balance is water;

[0020] Or the weight - volume percentages of each component in the thermosensitive gel are: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0 - 13.0%, poloxamer 188 2.5 - 4.5%, penetration enhancer 1,2 - propylene glycol 8.0 - 9.0%, preservative ethyl paraben 0.1 - 0.3%, dimethyl sulfoxide 34.0 - 36.0%, and the balance is water.

[0021] Further, the present invention preferably provides the following thermosensitive gel, wherein the weight - volume percentages of each component in the thermosensitive gel are as follows: imidacloprid 10%, moxidectin 1%, poloxamer 407 12.0%, poloxamer 188 3.5%, penetration enhancer 1,2 - propylene glycol 8.0 - 9.0%, preservative ethyl paraben 0.1 - 0.3%, stabilizer HPMC E50 0.2% or HPMC E50.5%, dimethyl sulfoxide 34.0 - 36.0%, and the balance is water;

[0022] Or the weight - volume percentage of each component in the thermosensitive gel is as follows: imidacloprid 10%, moxidectin 1%, poloxamer 407 12.0%, poloxamer 188 3.5%, penetration enhancer 1,2 - propanediol 8.0 - 9.0%, preservative ethylparaben 0.1 - 0.3%, dimethyl sulfoxide 34.0 - 36.0%, and the balance is water;

[0023] Preferably,

[0024] Furthermore,

[0025] The mass ratio of dimethyl sulfoxide to 1,2 - propanediol is 2.1 - 4.1:1.

[0026] The mass ratio of poloxamer 407 to poloxamer 188 is 3.3 - 3.5:1.

[0027] The mass ratio of the sum of poloxamer 407 and poloxamer 188 to 1,2 - propanediol is 1.4 - 2.1:1;

[0028] The preparation process of the thermosensitive gel described in the present invention is as follows:

[0029] (1) Add poloxamer 407 and poloxamer 188 to distilled water, with or without a stabilizer, and swell in a 4°C refrigerator for 24 h to obtain an aqueous solution of poloxamer 407 and poloxamer 188;

[0030] (2) Add the preservative and the penetration enhancer to the aqueous solution of poloxamer 407 and poloxamer 188, stir evenly, seal, and let stand at room temperature for 0.5 - 1 hour to obtain a matrix solution;

[0031] (3) Place imidacloprid, moxidectin, and dimethyl sulfoxide in an EP tube, ultrasonicate for 30 - 60 minutes to dissolve, add to the above - mentioned matrix solution, stir evenly, continue to ultrasonically dissolve in an ice bath for 2 - 4 h, seal, and let stand;

[0032] (4) Make up the volume to a certain amount with distilled water, stir evenly, and dispense to obtain the product.

[0033] The specification of the prepared thermosensitive gel is 0.40 ml, and each 0.40 ml contains 40 mg of imidacloprid and 4 mg of moxidectin. This preparation is a milky - white solution at room temperature (not higher than 25°C). This product is stored sealed at room temperature (not higher than 25°C).

[0034] The present invention takes the gelling temperature, gelling time, and transdermal duration as evaluation indexes to investigate the gelling temperature of the prepared thermosensitive gel and the transdermal experimental effect on rats.

[0035] When the imidacloprid and moxidectin compound thermosensitive gel prepared by the present invention is in an environment simulating skin temperature and without adding a stabilizer, the gelation time of 0.40 ml of the preparation is 13 s. And the transdermal sustained release duration is 3 - 5 times that of the commercially available product. When adding a stabilizer, the gelation time of 0.40 ml of the preparation is 26 s. And the transdermal sustained release duration is 3 - 5 times that of the commercially available product. Description of the Drawings

[0036] Figure 1 It is the graph of the cumulative permeation amount of imidacloprid drug over time for the commercially available product Advantage Multi and Examples 1, 8, 23, 12, 13.

[0037] Figure 2 It is the graph of the cumulative permeation amount of imidacloprid drug over time for the commercially available product Advantage Multi and Examples 13, 34.

[0038] Figure 3 It is the graph of the cumulative permeation amount of imidacloprid drug over time for the commercially available product Advantage Multi and Examples 34 - 38.

[0039] Figure 4 It is the graph of the cumulative permeation amount of imidacloprid drug over time for Examples 34 - 38.

[0040] Figure 5 It is the graph of the cumulative permeation amount of moxidectin drug over time for the commercially available product Advantage Multi and Examples 1, 8, 23, 12, 13.

[0041] Figure 6 It is the graph of the cumulative permeation amount of moxidectin drug over time for the commercially available product Advantage Multi and Examples 13, 34.

[0042] Figure 7 It is the graph of the cumulative permeation amount of moxidectin drug over time for the commercially available product Advantage Multi and Examples 34 - 38.

[0043] Figure 8 It is the graph of the cumulative permeation amount of moxidectin drug over time for Examples 34 - 38. Detailed Embodiments

[0044] The present invention will be further illustrated by the following examples, but the present invention is not limited to the following examples. Without departing from the above technical premise of the present invention, the corresponding replacement or modification made according to the common general knowledge and conventional means in the art is included in the scope of the present invention.

[0045] Example 1:

[0046] The formulation is shown in Table 1.

[0047] Preparation method:

[0048] (1) Weigh 4.8 g of poloxamer 407 and 1.4 g of poloxamer 188. Add poloxamer 407 and poloxamer 188 to 20.0 ml of distilled water to prepare an aqueous solution of poloxamer 407 and poloxamer 188.

[0049] (2) Weigh accurately 4.16 g of the prescription amount of 1,2 - propanediol and add it to the above solution. Stir evenly, seal it, and let it stand in a 4°C refrigerator for 24 hours to obtain a gel matrix.

[0050] (3) Weigh accurately 4 g of imidacloprid, 0.4 g of moxidectin, and 8.8 g of dimethyl sulfoxide in the prescription amount, and add them to the gel matrix prepared in step (2). Ultrasonic in a low - temperature ultrasonic instrument until the drug is completely dissolved, then seal it and let it stand in a 4°C refrigerator for 24 hours. After taking it out, make up to 40 ml with distilled water, stir evenly, and divide into portions.

[0051] The prepared preparation is 40 ml in total, and the volume of each preparation is 0.4 ml, containing 40 mg of imidacloprid and 4 mg of moxidectin.

[0052] Determination of the gelation temperature of the thermosensitive gel: Take 0.40 ml of the gel of the example into an EP tube at room temperature. At this time, the preparation is in a sol state. Place the EP tube in a water - bath pot and observe the temperature at which the sol turns into a gel under different temperature conditions. This temperature is the gelation temperature. Each example is measured three times and the average value is calculated.

[0053] Determination of the gelation time of the thermosensitive gel: Take 0.40 ml of the gel of the example into an EP tube at room temperature. At this time, the preparation is in a sol state. Place the EP tube in a water - bath pot at 32°C, start timing, and invert the EP tube from time to time to observe the gelation time of the sol, which is the gelation time of the thermosensitive gel. Each example is measured three times and the average value is calculated.

[0054] Transdermal test of the thermosensitive gel

[0055] Transdermal test on rats

[0056] Use a vertical diffusion cell to fix the rat skin between the dosing chamber and the receiving chamber, with the stratum corneum facing the supply chamber and the dermis facing the receiving chamber. The effective diffusion area is 1.54 cm 2 . Respectively take the commercially available "Advocate" drops and the thermosensitive gel of the example and add them to the dosing chamber, and evenly apply them on the rat skin. In addition, add 4 ml of 30% anhydrous ethanol physiological saline to the receiving chamber, remove the bubbles, and make the rat skin contact with the liquid surface. Stir continuously at 32°C and 500 (r / min). At different time points after dosing, draw 4 ml of the receiving solution and supplement the same volume of fresh receiving solution at the same temperature. Filter the drawn receiving solution through a 0.45 - μm filter membrane to obtain a filtrate, measure the ultraviolet absorbance, and calculate the cumulative permeation amount Q.

[0057]

[0058] ρ n is the mass concentration (μg·mL －1 ) at the nth sampling point, V is the sampling volume, and A is the permeation area.

[0059] Example 2-38:

[0060] The formulation of Example 2-38 is shown in Table 1, and the preparation method and detection method are the same as those of Example 1.

[0061] The formulations of each example are shown in Table 1:

[0062] Table 1 Formulations of Examples 1-38

[0063]

[0064]

[0065]

[0066] The states and gelling temperatures of the formulations of Examples 1-38 are shown in Table 2.

[0067] Table 2 States and gelling temperatures of the formulations of Examples 1-38

[0068]

[0069]

[0070] Examples 1-7 investigated the effects of different penetration enhancers on the gelling temperature of the gel. The results showed that: when the components and dosages of each component in the formulation except the penetration enhancer were the same, by changing the type of penetration enhancer and keeping the dosage of the penetration enhancer within the range of 7-12% of the total volume, the gelling temperatures of the drugs were different, and different penetration enhancers could affect the gelling temperature of the drug to varying degrees.

[0071] When the penetration enhancer was 1,2-propanediol, the combination of 1,2-propanediol and absolute ethanol, or the combination of 1,2-propanediol and PEG400, the preparation gelled at 30-32 °C. Especially when 1,2-propanediol was used as the penetration enhancer, the gel gelled rapidly at body temperature (32 °C). However, for the formulations using polyethylene glycol 400, absolute ethanol, the combination of 1,2-propanediol and absolute ethanol, or absolute ethanol alone as the penetration enhancer, the gelling temperature of 32 °C could not be obtained. Based on the gelling temperature results of Examples 1-7, the present invention preliminarily selected 1,2-propanediol as the penetration enhancer to prepare the thermosensitive gel.

[0072] Furthermore, the ratio of dimethyl sulfoxide to 1,2-propanediol was changed to investigate the effect of the ratio between the two on the gelation temperature of the gel. The experimental formulations and results are shown in Examples 1, 8 - 13 in Table 1.

[0073] The results showed that Examples 1, 8 - 13 of the imidacloprid and moxidectin compound thermosensitive gel of the present invention did not gel at room temperature (not higher than 25°C). When the mass ratio of dimethyl sulfoxide to 1,2-propanediol was 2.1 - 4.1, the gelation temperature was 32°C, which was the optimal gelation temperature. However, increasing or decreasing the ratio could not obtain a suitable gelation temperature. Therefore, the mass ratio of dimethyl sulfoxide to 1,2-propanediol plays an important role in the formation of the gel, and the best gelation temperature cannot be obtained whether the ratio of dimethyl sulfoxide to 1,2-propanediol is increased or decreased.

[0074] Furthermore, taking the formulation of Example 1 as the basic formulation, by changing the mass ratio of poloxamer 407 and poloxamer 188, and adding laurocapram and peppermint oil to the penetration enhancer while changing the ratio of the two, the effect on the gelation temperature was investigated. The experimental formulations and results are shown in Examples 14 - 16 in Table 1. The prepared gel gelled at room temperature (25°C). It can be seen that simultaneously changing the type of penetration enhancer and the mass ratio of the two poloxamers cannot obtain a qualified gel product.

[0075] Next, taking Example 1 as the basic formulation, the amount of poloxamer 188 was increased and fixed, and the amount of poloxamer 407 was changed to obtain formulations with different ratios of poloxamer 407 to poloxamer 188, and thermosensitive gels with good gelation temperature could not be obtained. The formulations are shown in Examples 17 - 22.

[0076] In summary, Examples 1, 8, 12, and 13 did not gel at room temperature (not higher than 25°C) and gelled at body temperature (32°C). Therefore, the weight - volume percentage of each component in the thermosensitive gel is: poloxamer 407 is 11.0 - 13.0%, poloxamer 188 is 2.5 - 4.5%, penetration enhancer 1,2 - propanediol is 7.0 - 12.0%, dimethyl sulfoxide is 22.0 - 36.0%, preservative is 0.1 - 0.3%, imidacloprid is 10%, and moxidectin is 1%.

[0077] The mass ratio of dimethyl sulfoxide to 1,2 - propanediol is: 2.1 - 4.1:1.

[0078] The mass ratio of poloxamer 407:poloxamer 188 is 3.3 - 3.5:1.

[0079] The mass ratio of the sum of poloxamer 407 and poloxamer 188 to 1,2 - propanediol is 1.4 - 2.1:1. Under the above conditions, a thermosensitive gel with a qualified gelation temperature can be obtained.

[0080] Further, taking Example 8 as the basic formulation, different amounts of HPMC E5 or HPMC E50 were added on the basis of this formulation. At the same time, the formulation without the penetration enhancer was used as a control to investigate the effect of the addition of HMPC on the gelling temperature of the gel. The formulations are shown in Examples 23-34 in Table 1.

[0081] The experimental results show that when the weight / volume percentage of HPMC E50 is 0.1%-0.3%, Example 28 of the imidacloprid and moxidectin compound thermosensitive gel of the present invention does not gel at room temperature (not higher than 25°C) and gels at body temperature (32°C). When the weight / volume percentage of HPMC E5 is 0.4%-0.6%, the prepared thermosensitive gel has a better gelling temperature.

[0082] The results of the in-vivo percutaneous absorption test of rats over time are shown in Table 3.

[0083] Table 3 Results of the in-vivo percutaneous absorption test of rats over time

[0084]

[0085] The above results show that the cumulative drug percutaneous penetration amount of Example 23 is less than that of imidacloprid and moxidectin in other examples. Among them, the cumulative drug penetration amounts of Examples 1, 8, 12, 13 and 34 with different mass ratios of dimethyl sulfoxide and 1,2-propanediol are significantly different, and the sustained-release durations of the drugs are also different, indicating that adding a penetration enhancer to the formulation can significantly increase the cumulative penetration amount of the drug, and the action time of the drug with different amounts of the penetration enhancer is also different.

[0086] From the above percutaneous experiment results, it can be seen that when no HPMC is added to the preparation, the cumulative penetration amounts of imidacloprid and moxidectin in Example 13 can reach about 10% of the commercially available Advantage Multi drug. Moreover, the sustained-release duration of imidacloprid is 3.58 times that of the commercially available product Advantage Multi, and the sustained-release duration of moxidectin is 4.14 times that of the commercially available product Advantage Multi. It is thus inferred that the sustained-release duration of the imidacloprid and moxidectin compound thermosensitive gel preparation of the present invention is 3.58 times that of the commercially available product Advantage Multi.

[0087] When HPMC is added to the preparation, in Example 34, the cumulative drug percutaneous penetration amount and the drug sustained-release duration are greater than or equivalent to those of the example without HPMC. The sustained-release duration of imidacloprid is 3.55 times that of the commercially available product Advantage Multi, and the sustained-release duration of moxidectin is 3.92 times that of the commercially available product Advantage Multi.

[0088] It can be seen that the thermosensitive gel prepared by the present invention not only avoids the use of a large amount of organic solvents, but also enables the drug to achieve a sustained-release effect by adding specific matrices and penetration enhancers. It not only has a mild effect, but also has a long-lasting effect.

[0089] In summary, if the preparation does not contain HPMC, the imidacloprid and moxidectin compound thermosensitive gel prepared according to the prescription of Example 13 has a long sustained-release time, which can extend the duration of the anthelmintic effect. The commercially available product Advocate needs to be administered once a month, while this preparation product is expected to be administered at least once every 3 to 4 months. It is convenient to use and can effectively solve the problem of loss during the use of drops.

[0090] If the preparation contains HPMC, the imidacloprid and moxidectin compound thermosensitive gel prepared according to the prescription of Example 34 has a long sustained-release time, which can extend the duration of the anthelmintic effect. The commercially available product Advocate needs to be administered once a month, while this preparation product is expected to be administered at least once every 3 to 4 months. It is convenient to use and can effectively solve the problem of loss during the use of drops.

[0091] Crotamiton is a new type of transdermal penetration enhancer. Further, on the basis of the formulation of Example 34, by adding crotamiton, it was investigated whether it could affect the gelation temperature and transdermal permeability of the gel. The formulations are shown in Examples 35 - 38 in Table 1. The results showed that after standing, Examples 35 - 38 did not separate layers, and had poor fluidity at room temperature (not higher than 25°C), indicating that the addition of crotamiton could improve the layering phenomenon and significantly increase the penetration amount of the drug. However, the action time of the drug was significantly reduced, especially the action time of moxidectin was significantly shortened, and a satisfactory gelation temperature could not be obtained. It can be seen that different penetration enhancers and different prescription compositions have varying degrees of influence on the gelation temperature, cumulative drug penetration amount, and sustained-release duration of the drug. In Examples 13 and 34, when 1,2 - propanediol was used as the penetration enhancer, the cumulative penetration amount of the two drugs could reach about 10%, and the action time of the drug could be significantly extended, which was significantly better than the formulations under other conditions. When crotamone was used as the penetration enhancer, although the cumulative penetration amount of the drug could be significantly increased, its release was fast, the action time was shortened, and its gelation temperature could not meet the qualified standard. Therefore, the formulation of the present invention using 1,2 - propanediol as the penetration enhancer has the best gelation temperature, the best sustained-release transdermal penetration amount, and the drug action time.

[0092] The imidacloprid and moxidectin compound thermosensitive gel preparation prepared by the present invention is used for the prevention and treatment of internal and external parasites, and the parasites are fleas, young fleas, Trichuris vulpis, hookworms, roundworms, Angiostrongylus vasorum, ear mites, heartworms, sarcoptic mites, demodex mites, lice, microfilariae.

Claims

1. A thermosensitive gel of imidacloprid and moxidectin, characterized in that: The invention adopts imidacloprid and moxidectin as active ingredients, and is added with a matrix, a penetration enhancer, a preservative, dimethyl sulfoxide, a stabilizer and water. The weight volume percentage of each component in the imidacloprid and moxidectin compound thermosensitive gel is as follows: 10% imidacloprid, 1% moxidectin, 10-20% poloxamer 407, 1.0-10.0% poloxamer 188, 1.0-15.0% penetration enhancer, 0.1-0.3% preservative, 0-1.0% stabilizer, 20.0-40.0% dimethyl sulfoxide and the balance water.

2. The imidacloprid and moxidectin composite thermosensitive gel according to claim 1, characterized in that: The penetration enhancer is 1,2-propylene glycol, a combination of 1,2-propylene glycol and anhydrous ethanol, and a combination of 1,2-propylene glycol and polyethylene glycol 400.

3. The imidacloprid and moxidectin composite thermosensitive gel according to claim 1, characterized in that: The weight volume percentage of each component in the thermosensitive gel is: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0-13.0%, poloxamer 188 2.5-4.5%, penetration enhancer 1,2-propylene glycol 7.0-12.0%, preservative ethyl paraben 0.1-0.3%, dimethyl sulfoxide 22-36.0%, and the balance is water; Or the weight volume percentage of each component in the thermosensitive gel is: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0-13.0%, poloxamer 188 2.5-4.5%, penetration enhancer 1,2-propylene glycol 7.0-12.0%, preservative ethyl paraben 0.1-0.3%, stabilizer 0.1-0.6%, dimethyl sulfoxide 22-36.0%, and water as the balance.

4. The imidacloprid and moxidectin composite thermosensitive gel according to claim 1, characterized in that: The weight volume percentage of each component in the thermosensitive gel is: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0-13.0%, poloxamer 188 2.5-4.5%, penetration enhancer 1,2-propylene glycol 8.0-9.0%, preservative ethyl paraben 0.1-0.3%, dimethyl sulfoxide 34-36.0%, and water as the balance; Or the weight volume percentage of each component in the thermosensitive gel is: imidacloprid 10%, moxidectin 1%, poloxamer 407 11.0-13.0%, poloxamer 188 2.5-4.5%, penetration enhancer 1,2-propylene glycol 8.0-9.0%, preservative ethyl paraben 0.1-0.3%, stabilizer 0.1-0.6%, dimethyl sulfoxide 34-36.0%, and water as the balance.

5. The imidacloprid and moxidectin composite thermosensitive gel according to any one of claims 1 to 4, characterized in that: The mass ratio of dimethyl sulfoxide to 1,2-propylene glycol is 2.1-4.1:

1.

6. The imidacloprid and moxidectin composite thermosensitive gel according to any one of claims 1 to 5, characterized in that: The mass ratio of poloxamer 407:poloxamer 188 is 3.3-3.5:

1.

7. The imidacloprid and moxidectin composite thermosensitive gel according to any one of claims 1 to 6, characterized in that: The mass ratio of the sum of poloxamer 407 and poloxamer 188 to 1,2-propylene glycol is 1.4-2.1:

1.

8. The method for preparing the thermosensitive gel of imidacloprid and moxidectin according to any one of claims 1 to 7, characterized in that: (1) Add poloxamer 407 and poloxamer 188 to distilled water, with or without a stabilizer, and swell in a refrigerator at 4° C. for 24 hours to obtain an aqueous solution of poloxamer 407 and poloxamer 188; (2) adding a preservative and a penetration enhancer to the aqueous solution of poloxamer 407 and poloxamer 188, stirring evenly, sealing, and standing at room temperature for 0.5-1 hour to obtain a matrix solution; (3) Place imidacloprid, moxidectin and dimethyl sulfoxide in an EP tube and ultrasonicate for 30-60 minutes to dissolve, add them to the above matrix solution, stir evenly, continue to ultrasonicate in an ice bath for 2-4 hours, seal and let stand; (4) Add distilled water to a certain volume, stir evenly, and divide into portions.

9. Use of the imidacloprid and moxidectin compound thermosensitive gel according to any one of claims 1 to 7 in insecticides.

10. Use of the imidacloprid and moxidectin compound thermosensitive gel according to any one of claims 1 to 7 in the preparation of a sustained-release insecticide.

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