Parasite expelling drugs based on milbemycin oxime praziquantel and use thereof

Abstract

The present application provides a milbemycin oxime praziquantel-based parasitic expelling drug, which comprises the following components in parts by mass: modified milbemycin oxime 10-30 parts, nano-coated praziquantel 20-50 parts, compound synergist 5-15 parts, flavoring agent 3-8 parts, and disintegrating agent 2-5 parts. The application of the milbemycin oxime praziquantel-based parasitic expelling drug is used for preparing a preparation for preventing or treating mixed parasitic infection of dogs and cats, wherein the parasites include tapeworms, nematodes, trematodes and Demodex. Through the integrated innovation of chemical modification (succinylated milbemycin oxime), nanotechnology (HPMC-coated praziquantel) and compound synergy (non-ban Tai'er-beta cyclodextrin), the comprehensive advantages of broad-spectrum parasitic expelling, long-acting stability, safety and low toxicity are realized, and the pain points such as poor palatability, high metabolic burden and weak environmental adaptability in the prior art are solved, and the application is suitable for the prevention and treatment of mixed parasitic infection of dogs and cats.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a parasitic drug based on milbemycin oxalate and praziquantel and application thereof. BACKGROUND

[0002] Parasitic infection is a common health problem in pets (dogs, cats) and livestock, especially in hot and humid environments, the breeding of parasites such as tapeworms, nematodes, flukes, and Demodex canis can cause animal malnutrition, anemia, and even death. Existing parasiticides are mostly based on single active ingredients (such as milbemycin oxalate, praziquantel) or simple compounding (such as milbemycin oxalate + praziquantel), but still have the following defects:

[0003] 1. Limited spectrum of action: existing compound drugs have insufficient effect on mixed infections of flukes, tapeworms, nematodes, etc., especially low efficiency in killing drug-resistant worms (such as heartworm larvae).

[0004] 2. Poor stability: milbemycin oxalate is easily degraded by light and heat, resulting in a short shelf life of the drug; praziquantel has a significant first-pass effect and low bioavailability (only about 80%).

[0005] 3. Poor palatability: traditional tablets are rejected by pets due to their bitter taste, and must be forcibly administered, affecting medication compliance.

[0006] 4. Insufficient safety: sensitive breeds such as collies are prone to neurotoxicity (such as tremors, movement disorders).

[0007] Existing technologies improve palatability and parasitic spectrum by adjusting excipients (such as coating process) or compounding other parasitic ingredients (such as moxidectin). Coating processes (such as using hydroxypropyl methylcellulose or ethyl cellulose) can mask the bitter taste of the drug by physical isolation, improving palatability, but the hydrophobicity of the coating material may hinder the disintegration and dissolution of the drug in the digestive tract. For example, excessive coating can delay the release rate of active ingredients (such as milbemycin oxalate, febantel), resulting in a decrease in bioavailability of the drug at the target absorption site (such as the intestine); if the coating is too thin, the drug may be degraded prematurely due to the action of gastric acid or digestive enzymes, affecting stability. In addition, some parasiticides (such as praziquantel) are sensitive to light and heat, and existing coating techniques cannot provide sufficient protection in complex environments (such as high-temperature transportation or long-term storage), resulting in a loss of potency. Compounding broad-spectrum parasiticides such as moxidectin can expand the spectrum of action (such as covering nematodes and arthropods), but the combined use of multiple components can increase the metabolic burden on the liver and kidneys, and still cannot solve the contradiction between drug stability and bioavailability, and the compounding components may increase the metabolic burden on the liver and kidneys.

[0008] Therefore, it is necessary to design a parasitic drug based on milbemycin oxalate and praziquantel and its application. SUMMARY

[0009] To overcome the defects in the prior art, a milbemycin oxime praziquantel-based parasitic expelling drug and application thereof are provided.

[0010] To achieve the above-mentioned object, the present application provides the following technical solutions.

[0011] The milbemycin oxime praziquantel-based parasitic expelling drug comprises the following components in mass parts: modified milbemycin oxime 10-30 parts, nano-coated praziquantel 20-50 parts, compound synergist 5-15 parts, flavoring agent 3-8 parts, and disintegrating agent 2-5 parts.

[0012] The preparation method of the succinylated milbemycin oxime comprises the following steps:

[0013] a. Dissolving milbemycin oxime in acetone, adding succinic anhydride with a molar ratio of 1:1.2, and reacting at 60℃ for 4 hours;

[0014] b. Removing the solvent by distillation under reduced pressure, and recrystallizing the product with ethanol to obtain succinylated milbemycin oxime;

[0015] c. Mixing the succinylated milbemycin oxime with polyvinylpyrrolidone at a mass ratio of 1:3, and spray drying to obtain microspheres, which are modified milbemycin oxime.

[0016] The succinylated substitution degree of the modified milbemycin oxime is 0.8-1.2, and the melting point is 180-185℃.

[0017] The compound synergist is formed by inclusion of non-bantel and β-cyclodextrin, and the molar ratio of non-bantel to β-cyclodextrin is 1:2.

[0018] The coating thickness of the nano-coated praziquantel is 10-50 nm, and the encapsulation rate is ≥90%.

[0019] The particle size of the nano-coated praziquantel is 50-200 nm, and the coating material is hydroxypropyl methyl cellulose.

[0020] The flavoring agent is natural chicken powder.

[0021] The disintegrating agent is cross-linked sodium carboxymethyl cellulose.

[0022] The application of the milbemycin oxime praziquantel-based parasitic expelling drug is to prepare a preparation for preventing or treating mixed parasitic infections of dogs and cats, and the parasites include tapeworms, nematodes, flukes and Demodex.

[0023] The preparation comprises tablets, and an ethyl cellulose isolation layer with a thickness of 10-20 μm is sprayed on the surface of the tablets.

[0024] Compared with the prior art, the present application has the following advantages and beneficial effects:

[0025] 1. The present application solves the problems of narrow spectrum, drug resistance and metabolic burden of traditional anthelmintics through the organic combination of molecular modification, dosage form innovation and complex strategy, and achieves breakthroughs in palatability and environmental adaptability, providing an efficient, safe and user-friendly solution for the prevention and treatment of mixed parasitic infections in dogs and cats.

[0026] 2. Broad-spectrum anthelmintic efficacy improvement: Mirbefin is modified by succinylation to enhance its targeting effect on drug-resistant heartworm larvae. The succinyl group enhances the binding force of the drug to the glutamate chloride channel of the parasite, increasing the inhibition efficiency by 20%. It has higher killing ability for nematodes (such as hookworms, roundworms) and ectoparasites (such as Demodex, scabies) in vitro, especially for nematodes (such as hookworms, roundworms) and ectoparasites (such as Demodex, scabies) in vitro. At the same time, the complex of febantel and β-cyclodextrin not only expands the coverage of intestinal protozoa (such as coccidia, trichomonads), but also compensates for the blind area of traditional programs for whipworms and flukes through synergistic effect.

[0027] 3. Drug stability and release kinetics optimization: Nanocoating technology significantly improves the physicochemical properties of piperazine. The 10-50 nm nanocoating layer formed by hydroxypropyl methyl cellulose (HPMC) not only protects piperazine from gastric acid degradation, but also achieves intestinal targeted release, making the blood drug peak concentration (Cmax) increase by 1.5 times compared with traditional preparations, and the half-life is extended to 4-6 hours. The combination of succinylated mirbefin and polyvinylpyrrolidone (PVP) microsphere technology significantly enhances the photothermal stability of the drug at high temperatures (such as tropical storage conditions), with a degradation rate of ≤5% after 36 months of storage, and a bioavailability of ≥95%.

[0028] 4. Metabolic safety breakthrough: The present application reduces the direct stimulation of free drugs to liver metabolic enzymes (such as CYP450) by 1:2 molar complexation of febantel and β-cyclodextrin: liver and kidney burden is reduced: the liver first-pass effect of febantel is reduced by 30% after complexation, the half-life is extended to 8-12 hours, and the frequency of repeated administration is reduced. Side effect control: The molecular encapsulation of β-cyclodextrin makes febantel release at a fixed point in the intestine, reducing systemic exposure, and clinical trials show that the incidence of gastrointestinal adverse reactions such as vomiting and diarrhea is reduced by 50%.

[0029] 5. Palatability and medication compliance improvement: The present application uses an ethyl cellulose isolation layer (10-20 μm) spraying process to effectively block the overflow of bitter taste, making the palatability score reach 4.8 / 5 (traditional tablets are 3.2 / 5). Combined with natural chicken powder flavoring agent, it further increases the willingness of dogs and cats to eat voluntarily. In addition, cross-linked sodium carboxymethyl cellulose as a disintegrating agent ensures that the tablet disintegrates quickly in the stomach (completely dispersed within 3 minutes), avoiding the refusal to eat caused by drug retention.

[0030] 6. The application realizes the comprehensive advantages of broad-spectrum anthelmintic, long-acting and stable, safe and low toxicity through the integrated innovation of chemical modification (succinylated milbemycin oxime), nanotechnology (HPMC-coated praziquantel), and complex synergy (febantel-β-cyclodextrin), while solving the pain points of poor palatability, high metabolic burden, and weak environmental adaptability in the prior art, and is suitable for the prevention and treatment of mixed parasitic infections in dogs and cats. DETAILED DESCRIPTION

[0031] The technical solutions in the embodiments of the application will be described below in a clear and complete manner. Obviously, the described embodiments are only some of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the application.

[0032] In the application, the models of various raw materials are described as follows:

[0033] Milbemycin oxime: purchased from Hubei Weisheng Chemical Reagent Co., Ltd. (Hubei, China), model HBW-19 (export standard).

[0034] Praziquantel: purchased from Zhejiang Haizheng Pharmaceutical Co., Ltd. (Zhejiang, China), model CP2015 / USP42 (pharmaceutical grade).

[0035] Hydroxypropyl methylcellulose (HPMC): purchased from Ashland Inc. (USA), model E5 LV (low-viscosity coating material).

[0036] β-cyclodextrin (β-CD): purchased from Roquette (France), model food grade (purity ≥ 99%).

[0037] Febantel: purchased from Sigma-Aldrich (USA), model pharmaceutical grade (purity ≥ 98%).

[0038] Ethyl cellulose (EC): purchased from Dow Chemical Co. (USA), model Ethocel™ Standard 7FP (coating isolation layer).

[0039] Cross-linked sodium carboxymethylcellulose (CCMC-Na): purchased from FMC Corporation (USA), model Ac-Di-Sol® (disintegrant).

[0040] Natural chicken meal: purchased from Kerry Group (Ireland), model food-grade flavoring agent.

[0041] Polyvinylpyrrolidone (PVP): purchased from BASF, type K30.

[0042] The parasiticides based on milbemycin oxime praziquantel include the following components by mass fraction: modified milbemycin oxime 10-30 parts, nano-coated praziquantel 20-50 parts, compound synergist 5-15 parts, flavoring agent 3-8 parts, disintegrant 2-5 parts.

[0043] The preparation method of the succinylated milbemycin oxime includes the following steps:

[0044] a. Dissolve milbemycin oxime in acetone, add succinic anhydride at a molar ratio of 1:1.2, and react at 60℃ for 4 hours;

[0045] b. Remove the solvent by distillation under reduced pressure, and recrystallize the product with ethanol to obtain succinylated milbemycin oxime;

[0046] c. Mix the succinylated milbemycin oxime with polyvinylpyrrolidone at a mass ratio of 1:3, and spray dry to obtain microspheres, which are modified milbemycin oxime.

[0047] The succinylated degree of the modified milbemycin oxime is 0.8-1.2, and the melting point is 180-185℃.

[0048] The compound synergist is formed by inclusion of fibrate and β-cyclodextrin, and the molar ratio of fibrate to β-cyclodextrin is 1:2.

[0049] The coating thickness of the nano-coated praziquantel is 10-50 nm, and the encapsulation efficiency is ≥90%.

[0050] The particle size of the nano-coated praziquantel is 50-200 nm, and the coating material is hydroxypropyl methyl cellulose.

[0051] The flavoring agent is natural chicken powder.

[0052] The disintegrant is cross-linked sodium carboxymethyl cellulose.

[0053] The application of the parasiticides based on milbemycin oxime praziquantel is used for preparing a preparation for preventing or treating mixed parasitic infections of dogs and cats, and the parasites include tapeworms, nematodes, flukes and Demodex.

[0054] The preparation includes tablets, and an ethyl cellulose isolation layer with a thickness of 10-20 μm is sprayed on the surface of the tablets.

[0055] In practical application, the dosage of the drug of the present application is 0.5-2 mg / kg body weight, once a week, for three consecutive weeks. After storage at 25°C for 36 months, the degradation rate of milbemycin oxime is ≤5%, and the bioavailability of praziquantel is ≥95%. Compared with the free state of non-ban Tai, the liver first pass effect is reduced by 30%, and the half-life is prolonged to 8-12 hours.

[0056] The present application is further described below in combination with specific examples and analysis tests:

[0057] Example 1

[0058] The parasitic worm expelling drug based on milbemycin oxime praziquantel comprises the following components in mass parts: modified milbemycin oxime 20 parts, nano-coated praziquantel 35 parts, compounded synergist 10 parts, flavoring agent 5 parts, disintegrating agent 3 parts.

[0059] The succinyl substitution degree of the modified milbemycin oxime is 1.

[0060] The compounded synergist is formed by inclusion of non-ban Tai and β-cyclodextrin, and the molar ratio of non-ban Tai to β-cyclodextrin is 1:2.

[0061] The coating thickness of the nano-coated praziquantel is 30 nm, and the encapsulation rate is ≥90%.

[0062] The particle size of the nano-coated praziquantel is 100 nm, and the coating material is hydroxypropyl methyl cellulose.

[0063] The flavoring agent is natural chicken powder.

[0064] The disintegrating agent is cross-linked sodium carboxymethyl cellulose.

[0065] The application of the parasitic worm expelling drug based on milbemycin oxime praziquantel is used for preparing a preparation for preventing or treating mixed parasitic infection of dogs and cats, which includes tapeworms, nematodes, flukes and Demodex.

[0066] The preparation comprises tablets, and an ethyl cellulose isolation layer with a thickness of 15 μm is sprayed on the surface of the tablets.

[0067] Example 2

[0068] The parasitic worm expelling drug based on milbemycin oxime praziquantel comprises the following components in mass parts: modified milbemycin oxime 25 parts, nano-coated praziquantel 40 parts, compounded synergist 12 parts, flavoring agent 6 parts, disintegrating agent 4 parts.

[0069] The succinyl substitution degree of the modified milbemycin oxime is 1.2.

[0070] The complex synergist comprises non-bantel and β-cyclodextrin inclusion, and the molar ratio of non-bantel to β-cyclodextrin is 1:2.

[0071] The coating thickness of the nano-coated pyrantel is 30 nm, and the encapsulation rate is ≥90%.

[0072] The particle size of the nano-coated pyrantel is 100 nm, and the coating material is hydroxypropyl methyl cellulose.

[0073] The flavoring agent is natural chicken powder.

[0074] The disintegrating agent is cross-linked sodium carboxymethyl cellulose.

[0075] The application of the milbex pyrantel-based parasiticides for preparing a preparation for preventing or treating mixed parasitic infections of dogs and cats, which include tapeworms, nematodes, flukes and Demodex.

[0076] The preparation comprises tablets, and an ethyl cellulose isolation layer with a thickness of 10 μm is sprayed on the surface of the tablets.

[0077] Example 3

[0078] The milbex pyrantel-based parasiticides comprise the following components in mass parts: modified milbex 15 parts, nano-coated pyrantel 30 parts, complex synergist 8 parts, flavoring agent 4 parts, and disintegrating agent 2 parts.

[0079] The succinylation degree of the modified milbex is 0.8.

[0080] The complex synergist comprises non-bantel and β-cyclodextrin inclusion, and the molar ratio of non-bantel to β-cyclodextrin is 1:2.

[0081] The coating thickness of the nano-coated pyrantel is 30 nm, and the encapsulation rate is ≥90%.

[0082] The particle size of the nano-coated pyrantel is 100 nm, and the coating material is hydroxypropyl methyl cellulose.

[0083] The flavoring agent is natural chicken powder.

[0084] The disintegrating agent is cross-linked sodium carboxymethyl cellulose.

[0085] The application of the milbex pyrantel-based parasiticides for preparing a preparation for preventing or treating mixed parasitic infections of dogs and cats, which include tapeworms, nematodes, flukes and Demodex.

[0086] The preparation comprises tablets, and an ethyl cellulose isolation layer with a thickness of 20 μm is sprayed on the surface of the tablets.

[0087] Comparative Example 1

[0088] In the present comparative example, the same as Example 1 is not repeated, and the differences are as follows:

[0089] The ordinary milbemycin oxime is used instead of the modified milbemycin oxime. The ordinary piperazine without coating is used instead of the nano-coated piperazine. No complex synergist is contained.

[0090] Comparative Example 2

[0091] In the present comparative example, the same as Example 1 is not repeated, and the differences are as follows:

[0092] The non-ban Tai and β-cyclodextrin are not included. The piperazine is coated with ordinary ethyl cellulose coating (50 μm).

[0093] Comparative Example 3

[0094] In the present comparative example, the same as Example 1 is not repeated, and the differences are as follows:

[0095] Gelatin is used instead of HPMC for piperazine coating.

[0096] Comparative Example 4

[0097] In the present comparative example, the same as Example 1 is not repeated, and the differences are as follows:

[0098] The non-ban Tai / β-cyclodextrin in the complex synergist is 1:1.

[0099] Comparative Example 5

[0100] In the present comparative example, the same as Example 1 is not repeated, and the differences are as follows:

[0101] There is no ethyl cellulose isolation layer, and chicken powder flavoring agent is directly added.

[0102] Test method and result analysis

[0103] The following 5 indicators are tested for the above groups:

[0104] 1. Repellent efficiency (in vitro culture experiment)

[0105] Method: Select canine heartworm (drug-resistant strain L3 larvae), dog hookworm (adult), cat tapeworm (pregnant section), and canine Demodex (adult) to establish an in vitro culture model, and add culture medium containing drugs of each example / comparative example (concentration 0.1 mg / mL) respectively. Calculate the mortality rate after 24 hours. The specific data are shown in Table 1.

[0106] As can be seen from Table 1, the killing efficiency of the drug-resistant heartworm larvae of the three example groups is significantly higher than that of the comparative examples (the comparative example 1 is not modified, resulting in insufficient binding force).

[0107] The synergistic effect of the comparative example 2 is reduced due to the non-inclusion of the synergistic agent, and the release of praziquantel is too fast, resulting in a death rate of only 78.4% of the tapeworm; and the comparative example 3 uses gelatin-coated praziquantel, which is severely degraded by gastric acid, resulting in a decrease of more than 15% in the efficacy of the drug.

[0108] Table 1: Efficacy of the drug

[0109]

[0110] 2. High humidity stability (accelerated experiment)

[0111] Method: The samples were placed in a 40°C / 75%RH environment for 6 months, and the residual rate of milbemycin oxime and praziquantel was detected (HPLC method). The specific results are shown in Table 2.

[0112] Table 2: Results of high humidity stability

[0113]

[0114] As can be seen from Table 2, the HPMC nanocoating layer of the example group effectively blocks the degradation of praziquantel in a humid environment (residual rate > 95%), while the gelatin coating of the comparative example 3 has a high hygroscopicity, resulting in a degradation of praziquantel of 34.6%. Comparative example 5 does not use an ethyl cellulose isolation layer, and milbemycin oxime is partially degraded by light (residual rate 93.6%), which is lower than that of the example group.

[0115] 3. Bioavailability (dog plasma pharmacokinetics)

[0116] Method: Beagle dogs were orally administered 20mg / kg once, and the blood drug concentration (LC-MS / MS) was detected to calculate Cmax (peak concentration) and T1 / 2 (half-life).

[0117] Table 3: Results of bioavailability test

[0118]

[0119] As can be seen from Table 3, the succinylated milbemycin oxime combined with the PVP microsphere process of example 1 makes the Cmax increase to 1.7 times that of the traditional preparation (comparative example 1), and the half-life is prolonged by nearly 2 times. The Cmax of the comparative example 3 is reduced by 45% due to the premature release of the gelatin-coated praziquantel in gastric acid.

[0120] 4. Palatability test (self-feeding rate)

[0121] Method: 100 dogs / cats were randomly divided into groups, and drug-containing food was provided. The first self-feeding rate (within 10 minutes) was recorded. The test results of the self-feeding rate are shown in Table 4.

[0122] Table 4 Test results of self-feeding rate

[0123]

[0124] As can be seen from Table 4, the ethyl cellulose isolation layer (15 μm) of Example 1 effectively masks the bitter taste, and the self-feeding rate of dogs reaches 94% with natural chicken powder. The uncoated Comparative Example 1 results in poor palatability (feeding rate of only 62%).

[0125] 5. Safety (adverse reaction rate)

[0126] Method: Clinical trials (200 infected dogs) were recorded for the incidence of vomiting, diarrhea, and neurological symptoms. The test results of the adverse reaction rate are shown in Table 5.

[0127] Table 5 Test results of adverse reaction rate

[0128]

[0129] As can be seen from Table 5, the non-Ban Tai-β-cyclodextrin inclusion complex (1:2) of Example 1 reduces gastrointestinal irritation of free drugs, and the vomiting rate is reduced by 75% compared with Comparative Example 2. Comparative Example 4 has an improper inclusion ratio (1:1), and the insufficient release of non-Ban Tai leads to an increase in adverse reactions.

[0130] Through the comparison test of the examples and comparative examples, the technical scheme of the present application is significantly superior to the traditional process in terms of parasite killing spectrum, stability, bioavailability, and safety. Especially for the killing efficiency of drug-resistant parasites, it is increased by more than 20%, the high-temperature storage stability breaks through the industry standard (degradation rate <5%), and the palatability is improved to make the self-feeding rate of pets exceed 90%. This application provides an efficient, safe, and user-friendly solution for mixed parasite infections in dogs and cats.

[0131] The above is the preferred embodiment of the present application. It should be noted that for ordinary skilled persons in the technical field, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered within the scope of protection of the present application.

Claims

1. A parasiticidal drug based on milbemycin oxime praziquantel, characterized in that, The medicine comprises the following components in parts by mass: modified milbemycin oxime 10-30 parts, nano-coated pyrantel 20-50 parts, compound synergist 5-15 parts, flavoring agent 3-8 parts, disintegrating agent 2-5 parts; The preparation method of the modified milbemycin oxime comprises the following steps: a. Dissolving milbemycin oxime in acetone, adding succinic anhydride at a molar ratio of 1:1.2, and reacting at 60℃ for 4 hours; b. Removing the solvent by distillation under reduced pressure, and recrystallizing the product with ethanol to obtain succinylated milbemycin oxime; c. Mixing the succinylated milbemycin oxime with polyvinylpyrrolidone at a mass ratio of 1:3, and spray drying to obtain microspheres, which are the modified milbemycin oxime; The compound synergist is formed by non-bantai and β-cyclodextrin inclusion, and the molar ratio of non-bantai to β-cyclodextrin is 1:2; the coating thickness of the nano-coated pyrantel is 10-50 nm, and the encapsulation rate is ≥90%; the particle size of the nano-coated pyrantel is 50-200 nm, and the coating material is hydroxypropyl methyl cellulose.

2. The milbemycin oxime praziquantel-based parasiticides according to claim 1, characterized by the fact that: The succinylated degree of the modified milbemycin oxime is 0.8-1.2, and the melting point is 180-185℃.

3. The milbemycin oxalate-based parasiticides according to claim 1, characterized in that: The flavoring agent is natural chicken powder.

4. The milbemycin oxalate-based parasiticides according to claim 1, characterized in that: The disintegrating agent is cross-linked sodium carboxymethyl cellulose.

5. Use of a milbemycin oxime praziquantel-based parasiticidal agent according to any one of claims 1 to 4, characterized in that: The medicine is used for preparing a preparation for preventing or treating mixed parasitic infections of dogs and cats, and the parasites include tapeworms, nematodes, flukes and Demodex.

6. Use of a milbemycin oxime praziquantel-based parasiticides according to claim 5, characterized in that: The preparation comprises tablets, and an ethyl cellulose isolation layer with a thickness of 10-20 μm is sprayed on the surface of the tablets.

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