Macrolide and isoxazoline medicine combined local external preparation for dogs as well as preparation method and application of macrolide and isoxazoline medicine combined local external preparation

Abstract

The invention discloses a macrolide and isoxazoline medicine combined local external preparation for dogs as well as a preparation method and application thereof, belongs to the technical field of veterinary medicines, and solves the problems that an existing preparation is limited in solvent selection, lacks a long-acting slow-release mechanism, is relatively high in medicine release speed, cannot maintain an effective concentration on the body surface of a dog for a long time, and cannot be used for a long time. The local external preparation is prepared from the following raw materials: a preparation main material, an auxiliary solvent, a synergist, a transdermal penetration enhancer, an antioxidant and a surface film-forming agent, according to the macrolide and isoxazoline medicine combined local external preparation for dogs, the solvent, the synergist and the transdermal penetration enhancer with good solubility are selected for combined use in preparation of the preparation, so that the medicine can be effectively dissolved, the permeability of the medicine in the skin of dogs is improved, the purpose of long-acting medicine release is achieved, and the curative effect of the dogs is improved. The bioavailability of the medicine is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of veterinary drugs, and specifically relates to a topical external preparation of a combination of a macrolide and an isoxazoline drug for dogs, a preparation method and application. BACKGROUND

[0002] With the improvement of people's living standards, the breeding of pet dogs is becoming more and more common. However, the problem of dog body surface parasite infection is becoming increasingly serious, which has brought many threats to the health of dogs. As a new type of highly effective insecticide, isoxazoline drugs can interfere with the signal transmission of insect nervous system by antagonizing gamma-aminobutyric acid receptors and glutamate receptor-gated chloride ion channels, thereby leading to the death of insects. This kind of drug has broad-spectrum insecticidal activity and has a significant killing effect on fleas, ticks, mites and other common parasites on the surface of dogs, so it has been widely concerned and applied in the field of veterinary drugs.

[0003] At present, the existing isoxazoline external preparation is mainly a drop for treating flea and tick infection on the surface of dogs and cats. Chinese patent CN105616406B discloses an external topical isoxazoline preparation. Specifically, the present application provides an external topical preparation containing an isoxazoline compound and a N, N-diethyl-3-methylbenzamide-containing solvent as a pharmaceutically or veterinarily acceptable liquid carrier vehicle, and an improved method for controlling and preventing parasitic invasion in animals. At the same time, Chinese patent CN111050557B discloses a novel liquid preparation for topical application to animals, which contains a fluorine-containing antiparasitic active compound and triethyl phosphate, and relates to their use for controlling and preventing animal parasites.

[0004] However, the existing preparation has some shortcomings. First, the solvent selection is limited, and there are fewer solvents for dissolving high-fat compounds. This leads to poor drug permeability, which cannot effectively penetrate the stratum corneum of dogs, affecting the dispersion and absorption of the drug on the skin surface, and thus reducing the drug efficacy; it may also cause the solvent to evaporate easily, resulting in uneven distribution of the drug on the skin surface and affecting the stability of the drug; in addition, it may also cause pet hair clumping and other problems, causing discomfort to pets and affecting their quality of life. Second, the existing preparation lacks a long-acting sustained-release mechanism, and the drug release rate is fast, which cannot maintain an effective concentration on the surface of the dog for a long time, resulting in a short drug efficacy duration and the need for frequent administration, which not only increases the drug burden of pet owners, but also may cause adverse reactions in pets due to frequent contact with the drug. In view of the above problems, we propose a topical external preparation of a combination of a macrolide and an isoxazoline drug for dogs, a preparation method and application. SUMMARY

[0005] The present application aims at solving the problems of limited solvent selection, lack of long-acting slow-release mechanism, fast drug release speed, inability to maintain effective concentration on the surface of the dog for a long time, and short drug efficacy duration of the existing preparation.

[0006] The present application is implemented as follows: the topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs comprises the following raw materials: preparation main material, auxiliary solvent, synergist, transdermal penetration enhancer, antioxidant, and surface film former.

[0007] Preferably, the preparation main material is an isoxazoline compound and a macrolide compound, and the auxiliary solvent comprises ethyl butylacetylaminopropionate, N,N-dimethylacetamide, acetone, ethanol, and isopropanol.

[0008] Preferably, the topical external preparation comprises the following raw materials in percentage by weight: isoxazoline compound: 25%-30%; macrolide compound: 2%-3%; ethyl butylacetylaminopropionate: 8%-12%; N,N-dimethylacetamide: 16.5%-18%; acetone: 8%-12%; synergist: 18%-22%; transdermal penetration enhancer: 8%-12%; antioxidant: 0.05%-0.2%; and surface film former: 1%-5%.

[0009] Preferably, the topical external preparation comprises the following raw materials in percentage by weight: isoxazoline compound: 26%-29%; macrolide compound: 2.1%-2.9%; ethyl butylacetylaminopropionate: 9%-11%; N,N-dimethylacetamide: 17%-17.8%; acetone: 9%-11%; synergist: 19%-21%; transdermal penetration enhancer: 9%-11%; antioxidant: 0.08%-0.15%; and surface film former: 2%-4%.

[0010] Preferably, the topical external preparation comprises the following raw materials in percentage by weight: isoxazoline compound: 27%; macrolide compound: 2.5%; ethyl butylacetylaminopropionate: 10%; N,N-dimethylacetamide: 17.4%; acetone: 10%; synergist: 20%; transdermal penetration enhancer: 10%; antioxidant: 0.1%; and surface film former: 3%.

[0011] Preferably, the isoxazoline compound is fluralaner, afoxolaner, or lotilaner, and the macrolide compound is ivermectin, moxidectin, doramectin, selamectin, or abamectin.

[0012] Preferably, the synergist is isopropyl myristate, the transdermal penetration enhancer is tetrahydrofuran polyethylene glycol ether, oleyl alcohol, propylene glycol laurate, the antioxidant is dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA).

[0013] Preferably, the surface film forming agent is one or more of povidone K17, povidone K30, sodium carboxymethylcellulose.

[0014] The application also provides a preparation method of the topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs, and the preparation method comprises the following steps: S10, a formula amount of ethyl butylacetamidopropionate, N, N-dimethylacetamide, acetone and isopropyl myristate are sequentially added into a liquid preparation tank, and stirred and mixed for 3-5 minutes; S20, a formula amount of povidone K17 is added into the liquid preparation tank, and stirred for 10 minutes to dissolve; S30, dibutylhydroxytoluene is taken and added into the liquid preparation tank, and stirred for at least 5 minutes until the dibutylhydroxytoluene is completely dissolved, and no visible undissolved substances are observed; S40, a macrolide compound is added into the liquid preparation tank and stirred for at least 10 minutes until the macrolide compound is completely dissolved; S50, an isoxazoline compound is added into the liquid preparation tank and stirred for at least 20 minutes until the isoxazoline compound is completely dissolved; S60, a transdermal penetration enhancer is added into the liquid preparation tank and stirred for 20 minutes, and after uniform mixing, the mixed drug solution in the liquid preparation tank is filtered by using a 0.45 mu m microporous membrane to prepare the topical external preparation.

[0015] The application also provides application of the topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs in preparation of a drug for treating and preventing parasitic infection in dogs.

[0016] Compared with the prior art, the application has the following beneficial effects: The topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs provided by the application uses solvents (ethyl butylacetamidopropionate (DEET), N, N-dimethylacetamide, acetone) with good solubility, a synergist / solvent (isopropyl myristate) and a transdermal penetration enhancer (tetrahydrofuran polyethylene glycol ether) in the preparation of the preparation, so that the drug can be effectively dissolved, the permeability of the drug in the skin of the dog is improved, the drug is released for a long time, and the bioavailability of the drug is improved.

[0017] In the embodiment of the present application, firstly, the advantages of isoxazoline and macrolide components are combined, which can effectively prevent and treat various internal and external parasitic infections. Among them, fluazuron of isoxazoline can efficiently kill external parasites such as fleas, ticks, scabies mites and ear mites, and moxidectin of macrolide mainly has the effect of killing and driving internal parasites such as heartworms, hookworms and roundworms and part of external mites, the combination of fluazuron and moxidectin can play a synergistic effect, expand the spectrum of anti-parasites, and achieve the effect of internal and external driving; both fluazuron and moxidectin belong to high fat-soluble substances, by introducing liposome technology to design the prescription, adding transdermal penetration enhancer, the skin permeability is improved, and the risk of pet licking and eating drug residues is reduced; the addition of isopropyl myristate in the prescription can dissolve the wax layer on the surface of insects, destroy the protective barrier, cause the insects to die of dehydration, and play a role in quickly killing and driving external parasites. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The 24h cumulative permeation amount test results of the topical external preparation prepared in the embodiment 5 of the present application and the isoxazoline drug of reference 1 are shown.

[0019] Figure 2 The 24h cumulative permeation amount test results of the topical external preparation prepared in the embodiment 5 of the present application and the macrolide drug of reference 2 are shown.

[0020] Figure 3 The tick counting results when evaluating the efficacy on dogs infected with ticks are shown.

[0021] Figure 4 The flea counting results when evaluating the efficacy on dogs infected with fleas are shown.

[0022] Figure 5 The roundworm counting results when evaluating the efficacy on dogs infected with roundworms are shown.

[0023] Figure 6 The hookworm counting results when evaluating the efficacy on dogs infected with hookworms are shown. DETAILED DESCRIPTION

[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs; the terminology used in the description herein is for describing particular embodiments only and is not intended to be limiting of the application; the description and the drawings are to be regarded as illustrative in nature and are not intended to be limiting of the application; the terminology used in the description and the claims of the present application and the above description of drawings includes the terms specifically mentioned above, as well as their derivatives.

[0025] Reference to“an embodiment” herein means that a particular feature, structure, or characteristic described in connection with the embodiment can be included in at least one embodiment of the application. The appearances of the phrase“in an embodiment” in various places in the specification are not necessarily all referring to the same embodiment, nor are they necessarily all directed to the other embodiments. It is explicitly contemplated that embodiments described herein can be combined with each other in their individual aspects.

[0026] Embodiment 1

[0027] The embodiment of the application provides a local external preparation of a combination of a macrolide and an isoxazoline drug for dogs, and the local external preparation comprises the following raw materials: a preparation main material, an auxiliary solvent, a synergist, a transdermal penetration enhancer, an antioxidant and a surface film former, wherein the preparation main material is an isoxazoline compound and a macrolide compound, and the auxiliary solvent comprises ethyl butylacetylaminopropionate, N,N-dimethylacetamide and acetone.

[0028] The local external preparation comprises the following raw materials in percentage by weight: the isoxazoline compound is 27%; the macrolide compound is 2.3%; the ethyl butylacetylaminopropionate is 10%; the N,N-dimethylacetamide is 18%; the acetone is 11%; the synergist is 19%; the transdermal penetration enhancer is 10%; the antioxidant is 0.2%; and the surface film former is 2.5%.

[0029] The isoxazoline compound is fipronil, and the macrolide compound is moxidectin. The synergist is isopropyl myristate, wherein the isopropyl myristate is a fat-soluble solvent, can dissolve the main components fipronil and moxidectin and the like, and can make the components uniformly and stably disperse in the preparation solution, so that a more refreshing and non-greasy skin feeling is achieved. The isopropyl myristate has a certain physical killing or repelling effect on some insects (such as lice and mites), can dissolve the wax layer on the surface of the insects, destroy the protective barrier of the insects, and cause the insects to die of dehydration. The isopropyl myristate can also be used as a skin penetration enhancer, can help the insect-repelling active ingredients to better penetrate the stratum corneum, and form a uniform and durable protective film on the skin surface, so that the insect-repelling effect is improved, the effective time is prolonged, and the long-acting effect of the preparation is achieved. The transdermal penetration enhancer is tetrahydrofurfuryl alcohol polyethylene glycol ether, and is mainly used for promoting drug absorption. The antioxidant is butylated hydroxytoluene, and the antioxidant can improve the stability of the preparation. The surface film former is povidone K17, and the surface film former can improve the adhesion and sustained-release property of the drug.

[0030] The preparation method of the topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs in the embodiment of the present application specifically comprises the following steps: S10, a formula amount of butyl acetyl amino propyl acid ethyl ester, N, N-dimethyl acetamide, acetone and isopropyl myristate is sequentially added into a liquid preparation tank, and stirred and mixed for 3-5 minutes; S20, a formula amount of povidone K17 is added into the liquid preparation tank, and stirred for 10 minutes to dissolve; S30, dibutyl hydroxytoluene is taken and added into the liquid preparation tank, and stirred for at least 5 minutes until the dibutyl hydroxytoluene is completely dissolved, and no visible undissolved substances are observed; S40, a macrolide compound is added into the liquid preparation tank and stirred for at least 10 minutes until the macrolide compound is completely dissolved, and no visible undissolved substances are observed; S50, an isoxazoline compound is added into the liquid preparation tank and stirred for at least 20 minutes until the isoxazoline compound is completely dissolved, and no visible undissolved substances are observed; S60, a transdermal penetration enhancer is added into the liquid preparation tank and stirred for 20 minutes, and after the mixture is uniformly mixed, the mixed liquid in the liquid preparation tank is filtered by using a 0.45 μm microporous membrane to prepare a topical external preparation, and the topical external preparation is canned to obtain a final preparation, and the final preparation can be a drop, a spray, a liniment or a pouring agent, and is suitable for topical external use on a dog body surface.

[0031] The topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs provided in the present application uses solvents (butyl acetyl amino propyl acid ethyl ester (DEET), N, N-dimethyl acetamide, acetone) with good solubility, synergists / solvents (isopropyl myristate) and transdermal penetration enhancers (tetrahydrofuran polyethylene glycol ether) in combination during preparation of the preparation, so that the drugs can be effectively dissolved, the permeability of the drugs in the skin of a dog is improved, long-acting release of the drugs is achieved, and the bioavailability of the drugs is improved.

[0032] Example 2

[0033] The embodiment of the present application provides a topical external preparation of the combination of the macrolide and the isoxazoline drug for dogs, and the topical external preparation comprises the following raw materials: a preparation main material, an auxiliary solvent, a synergist, a transdermal penetration enhancer, an antioxidant and a surface film former.

[0034] The topical external preparation includes the following raw materials in percentage by weight: isoxazoline compound: 27.5%; macrolide compound: 2.7%; ethyl butylacetylaminopropionate: 10.3%; N, N-dimethylacetamide: 17.6%; acetone: 10.4%; synergist: 19%; transdermal penetration enhancer: 8.5%; antioxidant: 0.05%; surface film forming agent: 3.95%.

[0035] The isoxazoline compound is fluralaner, and the macrolide compound is moxidectin. The synergist is isopropyl myristate, the transdermal penetration enhancer is tetrahydrofuran polyethylene glycol ether, and the antioxidant is dibutylhydroxytoluene. The surface film forming agent is sodium carboxymethyl cellulose.

[0036] Example 3

[0037] The embodiment of the present application provides a topical external preparation of a macrolide and an isoxazoline drug combination for dogs, which includes the following raw materials: preparation main material, auxiliary solvent, synergist, transdermal penetration enhancer, antioxidant, surface film forming agent, wherein the preparation main material is an isoxazoline compound and a macrolide compound, and the auxiliary solvent includes ethyl butylacetylaminopropionate, N, N-dimethylacetamide, and acetone.

[0038] The topical external preparation includes the following raw materials in percentage by weight: isoxazoline compound: 28.5%; macrolide compound: 2.4%; ethyl butylacetylaminopropionate: 9.2%; N, N-dimethylacetamide: 17.4%; acetone: 10.5%; synergist: 19.2%; transdermal penetration enhancer: 9.5%; antioxidant: 0.1%; surface film forming agent: 3.2%.

[0039] The isoxazoline compound is fluralaner, and the macrolide compound is moxidectin. The synergist is isopropyl myristate, the transdermal penetration enhancer is tetrahydrofuran polyethylene glycol ether, and the antioxidant is dibutylhydroxytoluene. The surface film forming agent is sodium carboxymethyl cellulose.

[0040] Example 4

[0041] The embodiment of the present application provides a topical external preparation of a macrolide and an isoxazoline drug combination for dogs, which includes the following raw materials: preparation main material, auxiliary solvent, synergist, transdermal penetration enhancer, antioxidant, surface film forming agent, wherein the preparation main material is an isoxazoline compound and a macrolide compound, and the auxiliary solvent includes ethyl butylacetylaminopropionate, N, N-dimethylacetamide, and acetone.

[0042] The topical preparation includes the following raw materials in percentage by weight: isoxazoline compound: 28.7%; macrolide compound: 2.3%; ethyl butylacetylaminopropionate: 10%; N, N-dimethylacetamide: 17.5%; acetone: 10.5%; synergist: 19%; transdermal penetration enhancer: 9%; antioxidant: 0.1%; surface film forming agent: 2.9%.

[0043] The isoxazoline compound is fluralaner, and the macrolide compound is moxidectin. The synergist is isopropyl myristate, the transdermal penetration enhancer is tetrahydrofuran polyethylene glycol ether, and the antioxidant is dibutylhydroxytoluene. The surface film forming agent is a mixture of povidone K17 and povidone K30.

[0044] Example 5

[0045] The embodiment of the present application provides a topical preparation of a combination of macrolide and isoxazoline drugs for dogs, which includes the following raw materials: preparation main material, auxiliary solvent, synergist, transdermal penetration enhancer, antioxidant, surface film forming agent, wherein the preparation main material is an isoxazoline compound and a macrolide compound, and the auxiliary solvent includes ethyl butylacetylaminopropionate, N, N-dimethylacetamide, and acetone.

[0046] The topical preparation includes the following raw materials in percentage by weight: isoxazoline compound: 27%; macrolide compound: 2.5%; ethyl butylacetylaminopropionate: 10%; N, N-dimethylacetamide: 17.4%; acetone: 10%; synergist: 20%; transdermal penetration enhancer: 10%; antioxidant: 0.1%; surface film forming agent: 3%.

[0047] The isoxazoline compound is fluralaner, and the macrolide compound is moxidectin. The synergist is isopropyl myristate, the transdermal penetration enhancer is tetrahydrofuran polyethylene glycol ether, and the antioxidant is dibutylhydroxytoluene. The surface film forming agent is povidone K17.

[0048] Comparative Example 1 A commercially available preparation of the same type for dogs was selected as Reference 1.

[0049] Comparative Example 2 A commercially available preparation of the same type for dogs was selected as Reference 2.

[0050] Performance test: According to the requirements of the in vitro transdermal (IVPT) in the "Guidelines for in vitro release test (IVRT) and in vitro permeation test (IVPT) of topically acting chemical generic drugs", artificial biological membrane is selected as the skin for the in vitro transdermal test of the preparation of the present application to confirm whether the topical preparation of the present application has a transdermal effect, and the commercially available canine preparation of the same component, Comparative Example 1 (Reference 1) and Comparative Example 2 (Reference 2) are selected for comparison. The in vitro transdermal test results are shown in Table 1, wherein, Figures 1-2 Figure 1 The cumulative penetration amount test results of the topical preparation prepared in Example 5 of the present application and Reference 1 for isoxazoline drugs for 24 hours are shown. Figure 2 The cumulative penetration amount test results of the topical preparation prepared in Example 5 of the present application and Reference 2 for macrolide drugs for 24 hours are shown, and the test results show that the preparation of the present application has better advantages compared with the commercially available preparation of the same kind for dogs.

[0051] Field test for efficacy evaluation on dogs infected with ticks: case confirmation was performed on the 0th day of the test for each dog, and physical examination and tick counting were performed on the 0th day, the 7±2nd day, the 14±2nd day, the 28±2nd day, the 60±2nd day and the 90±2nd day of the test; weighing and administration were performed on the 0th day, wherein the liquid medicine was the topical preparation prepared in Example 1 of the present application; blood routine and blood biochemical tests were performed on the 0th day and the 90±2nd day. The specific test process is shown in Table 1.

[0052] Table 1

[0053] Figure 3 The tick counting results during the efficacy evaluation on dogs infected with ticks are shown, and it can be seen from Table 1 that on the 10th day after administration, the number of ticks has decreased sharply from the initial 55 to nearly 0. This indicates that the topical preparation of the combination of canine macrolide and isoxazoline drugs of the present application has the characteristics of rapid onset, and can significantly reduce the number of ticks on the body surface of dogs in a short period of time. The topical preparation of the combination of canine macrolide and isoxazoline drugs of the present application has the advantages of rapid onset, long-acting sustained release, high safety, broad-spectrum insect resistance and convenient administration in treating dogs infected with ticks, and is an effective anti-parasitic drug for dogs. Figure 3

[0054] Field test for efficacy evaluation on dogs infected with ticks: case confirmation was performed on the 0th day of the test for each dog, and physical examination and tick counting were performed on the 0th day, the 7±2nd day, the 14±2nd day, the 28±2nd day, the 60±2nd day and the 90±2nd day of the test; weighing and administration were performed on the 0th day, wherein the liquid medicine was the topical preparation prepared in Example 1 of the present application; blood routine and blood biochemical tests were performed on the 0th day and the 90±2nd day. The specific test process is shown in Table 1.

[0054] Field test for efficacy evaluation on dogs infected with fleas: the test lasted for 90 days, case confirmation and administration were performed on the 0th day; wherein the liquid medicine was the topical preparation prepared in Example 1 of the present application; physical examination and flea and flea feces counting were performed on the 0th day, the 7±2nd day, the 14±2nd day, the 28±2nd day, the 60±2nd day and the 90±2nd day; blood routine and blood biochemical tests were performed on the 0th day (before administration) and the 90±2nd day. The specific test process is shown in Table 2.

[0055] Table 2

[0056] in, Figure 4 The table shows the flea statistics during the efficacy evaluation of the drug for flea infestation in dogs, from... Figure 4 As can be seen, from day 10 onwards, the flea population remained at a very low level, close to zero, and this state persisted throughout the entire 90-day trial period. This demonstrates that the formulation of the present invention not only has a rapid onset of action but also provides long-term control, effectively maintaining the flea population in dogs at a low level. Since the flea population remained at a low level for up to 90 days, this indicates that the formulation has long-acting sustained-release properties, continuously releasing the active ingredient, thereby reducing the frequency of administration and improving convenience for pet owners.

[0057] Field trial evaluating the efficacy of the drug against canine roundworm infection: This trial lasted for 60 days. Case confirmation and drug administration were conducted on day 0; physical examinations and roundworm egg counts were performed on days 0, 7±2, 15±2, 30±2, and 60±2; complete blood count and blood biochemistry tests were performed on day 0 (before drug administration) and day 60±2. The specific experimental procedure is shown in Table 3.

[0058] Table 3

[0059] in, Figure 5 The results of ascarid worm statistics are shown during the efficacy evaluation of drugs for canine ascariasis. Figure 5 As can be seen, in the initial stage of the experiment (day 0), the number of roundworm eggs was at a relatively high level, approximately 145, indicating that the roundworm infection in the experimental dogs was quite severe and the number of eggs was large before drug administration. However, around day 7±2, the number of roundworm eggs dropped sharply, reaching a low level close to zero in just about a week. This clearly demonstrates that the drug exerted a significant effect in a short period of time, rapidly inhibiting the reproduction of roundworms or promoting their expulsion, thereby significantly reducing the number of eggs. Therefore, the drug exhibits excellent characteristics of rapid onset and long-lasting efficacy in treating roundworm infection in dogs, and is significantly effective in controlling and eliminating roundworm infection in dogs.

[0060] Field trial evaluating the efficacy of hookworm treatment in dogs: This trial lasted 60 days. Case confirmation and drug administration were conducted on day 0. Physical examinations, egg counts, and dermatitis scores were performed on days 0, 7±2, 15±2, 30±2, and 60±2. Complete blood counts and blood biochemistry tests were performed on day 0 (before drug administration) and day 60±2. The specific experimental procedure is shown in Table 4.

[0061] Table 4

[0062] wherein, Figure 6 The statistical results of hookworms in the efficacy evaluation of dogs infected with hookworms are shown, from Figure 6 As can be seen from the above table, the number of hookworm eggs rapidly decreased from 115 to 0 in the first few days after administration, which indicates that the preparation can quickly take effect and effectively reduce the number of hookworm eggs in the body of the dog. The number of hookworm eggs remained at a very low level from the 10th day, and this state lasted throughout the observation period. This shows that the preparation has a long-term control effect and can effectively maintain the number of hookworm eggs in the body of the dog at a low level. Since the number of hookworm eggs remained at a low level for up to 60 days, it indicates that the preparation has the characteristics of long-acting sustained release, can continuously release the active ingredients, reduce the frequency of administration, and improve the convenience of pet owners.

[0063] In summary, the preparation of the present application is evaluated by IVPT test, and the AMT (cumulative penetration amount) of fluorouracil is as high as 680 μg / cm 2 , and the AMT (cumulative penetration amount) of moxidectin is as high as 150 μg / cm 2 , which can effectively improve the bioavailability and make the drug effect last for 12 weeks, reduce the frequent use of pets, and provide a "one-stop" deworming solution for pet owners. The preparation of the present application is combined with the properties of two compounds, and the preparation is prepared into a topical preparation, which is convenient for pet owners to administer and avoids the palatability problem of oral administration.

[0064] In summary, the present application provides a topical external preparation of a combination of macrolides and isoxazoline drugs for dogs, a preparation method and application. The topical external preparation of a combination of macrolides and isoxazoline drugs for dogs provided by the present application uses solvents with good solubility (butyl acetyl amino propyl acid ethyl ester (DEET), N, N-dimethylacetamide, acetone), synergists / solvents (isopropyl myristate), and transdermal penetration enhancers (tetrahydrofuran polyethylene glycol ether) in combination during preparation, which can effectively dissolve the drugs and improve the permeability of the drugs in the skin of the dog, so as to achieve long-acting release of the drugs and improve the bioavailability of the drugs.

[0065] In the embodiment of the present application, firstly, the advantages of isoxazoline and macrolide components are combined, which can effectively prevent and treat various internal and external parasitic infections. Among them, the isoxazoline fluazuron can effectively kill fleas, ticks, scabies, ear mites and other external parasites, and the macrolide moxidectin is mainly used for killing and driving internal parasites such as heartworms, hookworms, roundworms and some external mites, the combination of fluazuron and moxidectin can have synergistic effect, expand the spectrum of anti-parasites, and achieve the effect of internal and external driving; Fluazuron and moxidectin belong to high fat-soluble substances, by introducing liposome technology to design the prescription, adding transdermal penetration enhancer, the skin permeability is improved, and the risk of pet licking and eating drug residues is reduced; Isopropyl myristate is added in the prescription, which can dissolve the wax layer on the surface of insects, destroy the protective barrier, cause the insects to die of dehydration, and have the effect of quickly killing and driving external parasites.

[0066] It should be noted that for the foregoing embodiments, for the sake of simple description, they are all expressed as a series of action combinations, but those skilled in the art should know that the present application is not limited by the order of the described actions, because according to the present application, certain steps can be performed in other order or simultaneously. Secondly, those skilled in the art should know that the embodiments described in the specification all belong to preferred embodiments, and the actions and modules involved are not necessarily necessary for the present application.

Claims

1. A topical formulation for dogs combining macrolides and isoxazoline drugs, characterized in that, The topical preparation comprises the following ingredients: main ingredients, auxiliary solvents, synergists, transdermal penetration enhancers, antioxidants, and surface film-forming agents.

2. The topical formulation for dogs combining macrolides and isoxazoline drugs as described in claim 1, characterized in that: The main ingredients of the formulation are isoxazoline compounds and macrolide compounds, and the auxiliary solvents include ethyl butyl acetylaminopropionate, N,N-dimethylacetamide, and acetone.

3. The topical formulation of canine macrolide and isoxazoline combination drugs as described in claim 2, characterized in that: The topical formulation comprises the following raw materials in weight percentages: isoxazoline compounds: 25%-30%; macrolide compounds: 2%-3%; ethyl butyl acetylaminopropionate: 8%-12%; N,N-dimethylacetamide: 16.5%-18%; acetone: 8%-12%. Synergist: 18%-22%; Transdermal penetration enhancer: 8%-12%; Antioxidant: 0.05%-0.2%; Surface film-forming agent: 1%-5%.

4. The topical formulation for dogs combining macrolides and isoxazoline drugs as described in claim 3, characterized in that: The topical formulation comprises the following raw materials in weight percentages: isoxazoline compounds: 26%-29%; macrolide compounds: 2.1%-2.9%; ethyl butyl acetaminopropionate: 9%-11%; N,N-dimethylacetamide: 17%-17.8%; acetone: 9%-11%; synergist: 19%-21%; transdermal penetration enhancer: 9%-11%. Antioxidant: 0.08%-0.15%; Surface film-forming agent: 2%-4%.

5. The topical formulation for dogs combining macrolides and isoxazoline drugs as described in claim 4, characterized in that: The topical formulation comprises the following raw materials in weight percentages: isoxazoline compounds: 27%; macrolide compounds: 2.5%; Ethyl butylacetylaminopropionate: 10%; N,N-dimethylacetamide: 17.4%; acetone: 10%; synergist: 20%; transdermal penetration enhancer: 10%; antioxidant: 0.1%; surface film forming agent: 3%.

6. The topical formulation of a combination of macrolide and isoxazoline drugs for dogs as described in claim 3, characterized in that: The isoxazoline compound is fleranal, and the macrolide compound is moxicritin.

7. The topical formulation of a combination of macrolide and isoxazoline drugs for dogs as described in claim 6, characterized in that: The synergist is isopropyl tetradecanoate, the transdermal penetration enhancer is tetrahydrofuran polyethylene glycol ether, and the antioxidant is butylated hydroxytoluene.

8. The topical formulation for dogs combining macrolides and isoxazoline drugs as described in claim 7, characterized in that: The surface film-forming agent is one or more of polyvinylpyrrolidone K17, polyvinylpyrrolidone K30, and sodium carboxymethyl cellulose.

9. A method for preparing a topical formulation of a combination of macrolides and isoxazoline drugs for dogs, used to prepare the topical formulation of a combination of macrolides and isoxazoline drugs for dogs as described in any one of claims 1-8, characterized in that: The preparation method includes: S10, add the formulated amounts of ethyl butyl acetylaminopropionate, N,N-dimethylacetamide, acetone and isopropyl tetradecanoate to the mixing tank in sequence, and stir for 3-5 minutes; S20, add the prescribed amount of povidone K17 to the mixing tank and stir for 10 minutes to dissolve; S30, add butylated hydroxytoluene to the mixing tank and stir for at least 5 minutes until the butylated hydroxytoluene is completely dissolved and no insoluble matter is visible. S40, add the macrolide compound to the mixing tank and stir for at least 10 minutes until the macrolide compound is completely dissolved; S50, add the isoxazoline compound to the mixing tank and stir for at least 20 minutes until the isoxazoline compound is completely dissolved; S60, add the transdermal penetration enhancer to the mixing tank and stir for 20 minutes. After mixing evenly, take the mixed drug solution from the mixing tank and filter the mixed drug solution through a 0.45μm microporous membrane to obtain a topical preparation. Bottle the topical preparation to obtain the product.

10. The use of the topical formulation of a combination of canine macrolide and isoxazoline drugs as described in any one of claims 1-8 in the preparation of a drug for the treatment and prevention of canine internal parasite infections.

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