Imidacloprid moxidectin slow-release pharmaceutical preparation for pets

Abstract

The invention belongs to the technical field of pet insecticides, and particularly relates to an imidacloprid moxidectin slow-release medicinal preparation for pets. The imidacloprid and moxidectin slow-release pharmaceutical preparation for pets comprises the following components: active components: imidacloprid and moxidectin, the mass fraction of imidacloprid is 5-20%, and the mass fraction of moxidectin is 1-10%; the slow-release carrier comprises modified lipid nanoparticles and polymer microspheres in a weight ratio of (2-3): 1, and the mass fraction of the slow-release carrier is 10%-40%; a transdermal enhancer; a stabilizer; a pH adjusting agent; the taste masking agent is selected from moringa seed oil or menthol, and the mass fraction of the taste masking agent is 0.1%-1%; and the balance of solvent ethanol. The prepared imidacloprid moxidectin slow-release medicine preparation for pets is good in slow-release effect and high in stability.

Description

Technical Field

[0001] The invention belongs to the technical field of pet insecticides, and particularly relates to a slow-release imidacloprid and moxidectin pharmaceutical preparation for pets. Background Art

[0002] With the rapid development of the pet economy, the demand for parasite control in companion animals, such as dogs and cats, is growing. Parasitic infections not only harm pet health (e.g., nutritional deprivation, tissue damage, and allergic dermatitis) but can also threaten human health through zoonotic transmission, such as heartworms and flea-borne tapeworms. Currently, chemical anthelmintics remain the mainstream treatment, but existing formulations face significant technical bottlenecks in terms of long-term efficacy, safety, and stability. There is an urgent need to develop new sustained-release formulations to meet clinical needs.

[0003] Technical limitations of existing anthelmintic preparations include: 1. A mismatch between drug release rate and duration of action. While combination formulations of imidacloprid and moxidectin (e.g., drops and pour-ons) can synergistically repel internal and external parasites (such as fleas, mites, and heartworm larvae), traditional formulations are often immediate-release. The drug diffuses rapidly across the skin surface and is rapidly metabolized, necessitating monthly repetitive dosing to maintain efficacy. Frequent medication not only increases stress in pets but can also lead to drug resistance. For example, canine Demodex infestations require continuous treatment for 2-4 months. Existing regimens significantly increase medication complexity due to their short duration of effect. 2. Inadequate transdermal efficiency and formulation stability. Imidacloprid has a low lipophilicity, making it difficult for traditional solvent systems to effectively penetrate the stratum corneum, resulting in slow onset of action and low bioavailability. Furthermore, imidacloprid easily precipitates at low temperatures, compromising the formulation's physical stability and limiting its use in cold regions. Existing technologies improve permeability by adding emulsifiers (such as Tween-80) and co-emulsifiers (such as propylene glycol), but this may introduce irritants or cause thermodynamic instability. 3. Safety risks associated with pet licking. Topical drops should be avoided to prevent licking by pets to prevent poisoning (especially in breeds sensitive to moxidectin, such as Collies).13 Traditional formulations, due to rapid drug release, may form high concentrations of residues on the skin surface, increasing the risk of accidental ingestion. Although some studies have improved pet comfort by adding taste-masking agents (such as moringa seed oil) or cooling ingredients (such as menthol), these have not fundamentally addressed the need for sustained release. 4. Environmental and operational deficiencies. Existing pour-ons and drops often use aromatic hydrocarbon solvents (such as benzyl alcohol), which pose flammability and ecotoxicity risks. Furthermore, frequent administration requires precise dosage control, requiring high levels of owner compliance, and can easily lead to treatment failure due to improper use.

[0004] Some existing studies have expanded the antiparasitic spectrum by adding ingredients like fenproxil and escitalol, but this has not addressed the issue of release rate. Existing sustained-release formulations are mostly oral or injectable (such as microspheres and nanoparticles), but pets have poor compliance with oral administration, while injectable formulations are inconvenient to administer. Transdermal sustained-release technologies (such as liposomes and polymer matrices) are rarely used in veterinary medicine, and research on their suitability for pet skin characteristics is lacking.

[0005] In summary, the existing technology urgently needs an imidacloprid-moxidectin compound preparation that is long-lasting, stable and safe.

[0006] Sustained-release carrier design: Control the drug release rate through lipid nanoparticles, microspheres or polymer matrices to achieve continuous protection for 4-6 weeks after a single dose.

[0007] Balance of transdermal enhancement and stability: Environmentally friendly solvents (such as medium-chain triglycerides) are used in combination with low-temperature stabilizers to ensure the physical and chemical stability of the drug during storage and use.

[0008] Improved safety: Reduce the risk of licking by lowering the surface drug concentration, while adding pH-sensitive materials to prevent drug release in non-target areas.

[0009] Environmental friendliness: Abandon traditional toxic solvents and develop biodegradable carrier systems to reduce ecotoxicity.

[0010] Therefore, there is an urgent need for a slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets. Summary of the Invention

[0011] The invention aims to provide a slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets.

[0012] In order to achieve the above object, the present invention provides the following technical solutions: Imidacloprid moxidectin slow-release pharmaceutical preparation for pets, comprising the following components: Active ingredients: Imidacloprid and Moxidectin, with the mass fraction of imidacloprid being 5%-20% and that of Moxidectin being 1%-10%; Sustained-release carrier: including modified lipid nanoparticles and polymer microspheres in a weight ratio of 2-3:1, with a mass fraction of 10%-40%; Transdermal enhancer: one or more selected from medium chain triglycerides, isopropyl myristate or azone, with a mass fraction of 5%-15%; Stabilizer: one or more selected from vitamin E, butylated hydroxytoluene, and polyethylene glycol, with a mass fraction of 0.1%-5%; pH regulator: selected from citric acid-sodium citrate buffer system or phosphate buffer system, with a mass fraction of 0.5%-3%; Taste masking agent: selected from moringa seed oil or menthol, with a mass fraction of 0.1%-1%; The balance is ethanol solvent.

[0013] Furthermore, the preparation method of the modified lipid nanoparticles is: (1) Dissolve phospholipids and cholesterol in chloroform to prepare a solution, and remove the organic solvent in a rotary evaporator to form a uniform lipid film; (2) Adding aqueous phase to the lipid film to form lipid nanoparticles under ultrasonic or homogenization treatment; (3) After the lipid nanoparticles are formed, polyethylene glycol is added to graft the modifier onto the surface of the lipid nanoparticles through a chemical coupling reaction. After the reaction is completed, the unbound modifier is removed by centrifugation and washing to obtain modified lipid nanoparticles.

[0014] Furthermore, the weight ratio of phospholipid to cholesterol is 2-4:1.

[0015] Modified lipid nanoparticles, composed of phospholipids and cholesterol, have a bilayer lipid membrane structure. This allows hydrophobic drugs (such as imidacloprid) to be encapsulated in the core region, while hydrophilic drugs (such as moxidectin) are distributed in the inner aqueous core. This compartmentalized design effectively delays drug release. Surface PEGylation reduces nonspecific adsorption of the nanoparticles in the body, prolonging blood circulation time and thus achieving prolonged drug release. The lipid membrane composed of phospholipids and cholesterol effectively isolates the drug from oxygen, reducing the risk of drug oxidation, especially during long-term storage. The bilayer membrane structure of the lipid nanoparticles prevents direct contact between the drug molecules and the external environment, thus preventing drug degradation caused by humidity and temperature fluctuations.

[0016] Furthermore, the ratio of polyethylene glycol to the total weight of phospholipid and cholesterol is 1:6-7.

[0017] Furthermore, the polymer microspheres are modified polylactic acid-glycolic acid copolymers, and the preparation method is: (1) Weigh 20 mg of polyethylene glycol and dissolve it in 1-5 ml of methanol as the modifier solution; (2) Add the modifier solution to a suspension of 200 mg of poly(lactic-co-glycolic acid) microspheres, add carbodiimide and N-hydroxysuccinimide, and stir at room temperature for 2-4 hours; (3) After the reaction is completed, the precipitate is collected by centrifugal washing and resuspended in deionized water, and the process is repeated 2-3 times to obtain a modified poly(lactic acid-glycolic acid) copolymer.

[0018] PLGA is a biodegradable polymer whose degradation rate can be controlled by adjusting the ratio of lactic acid to glycolic acid and its molecular weight. This allows the drug release rate to be precisely tailored to the needs, achieving long-term sustained release. Modified PLGA microspheres are prepared using a W / O / W double emulsion method, which uniformly encapsulates the drug within the polymer matrix, forming a stable solid dispersion system. This structure significantly delays drug release. Surface PEGylation can reduce the clearance rate of the microspheres from the body, prolonging the drug's in vivo residence time, further enhancing the sustained-release effect. PLGA itself has high chemical stability and is not susceptible to degradation or reaction with other components during storage. The dense structure of PLGA microspheres effectively isolates the drug from the external environment (such as moisture and oxygen), preventing drug degradation or deterioration.

[0019] Furthermore, the transdermal enhancer is a combination of medium-chain triglycerides and azone, with a mass ratio of 2-3:1.

[0020] Furthermore, the stabilizer is a combination of vitamin E and polyethylene glycol, with a mass ratio of 1:2-4.

[0021] Furthermore, the pH regulator is a citric acid-sodium citrate buffer system with a pH value of 5.5-6.5.

[0022] Furthermore, the preparation is an external use drop or pour-on.

[0023] Furthermore, the preparation method of the preparation includes the following steps: mixing imidacloprid, moxidectin and a sustained-release carrier to prepare a drug-carrier complex; mixing a transdermal enhancer, a stabilizer, a solvent, a pH regulator and a taste masking agent to prepare a solvent system; mixing the drug-carrier complex with the solvent system and homogenizing to obtain the final preparation.

[0024] Compared with the prior art, the advantages and beneficial effects of the present invention are: 1. Imidacloprid and moxidectin sustained-release formulations for pets need to exhibit long-lasting, stable drug release while maintaining chemical and physical stability during storage. The modified lipid nanoparticles and modified poly(lactic-co-glycolic acid) (PLGA) used as sustained-release carriers in this invention significantly enhance the sustained-release effect and storage stability of the drug.

[0025] 2. Modified lipid nanoparticles, composed of phospholipids and cholesterol, have a bilayer lipid membrane structure. This allows hydrophobic drugs (such as imidacloprid) to be encapsulated in the core region, while hydrophilic drugs (such as moxidectin) are distributed in the inner aqueous core. This compartmentalized design effectively delays drug release. Surface PEGylation reduces nonspecific adsorption of nanoparticles in the body, prolonging blood circulation time and thus achieving longer-term drug release. The lipid membrane composed of phospholipids and cholesterol effectively isolates oxygen, reducing the risk of drug oxidation, especially during long-term storage. The bilayer membrane structure of lipid nanoparticles prevents direct contact between drug molecules and the external environment, thus preventing drug degradation caused by humidity and temperature fluctuations.

[0026] 3. PLGA is a biodegradable polymer whose degradation rate can be controlled by adjusting the ratio and molecular weight of lactic acid / glycolic acid. This allows the drug release rate to be precisely controlled on demand, achieving long-term sustained release. Modified PLGA microspheres are prepared using the W / O / W double emulsion method, which uniformly encapsulates the drug within the polymer matrix to form a stable solid dispersion system. This structure can significantly delay drug release. Surface PEGylation can reduce the clearance rate of the microspheres in the body and prolong the drug's residence time, further enhancing the sustained-release effect. PLGA itself has high chemical stability and is not easily degraded or reacted with other components during storage. The dense structure of PLGA microspheres can effectively isolate the drug from the external environment (such as moisture and oxygen), preventing drug degradation or deterioration.

[0027] 4. Modified lipid nanoparticles are suitable for rapid release of a portion of the drug to quickly reach therapeutic concentrations. Modified PLGA microspheres are responsible for slow release of the drug to maintain long-term efficacy. The combination of the two can achieve a dual release mode of "rapid-acting + long-acting," meeting the treatment needs of different stages. The antioxidant capacity and physical barrier effect of the modified lipid nanoparticles complement the chemical inertness and dense structure of the modified PLGA microspheres, jointly improving the overall stability of the drug formulation. During storage, the combination of the two carriers effectively reduces the impact of the external environment on the drug, ensuring that the formulation remains active throughout its shelf life. DETAILED DESCRIPTION

[0028] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0029] Example 1 This embodiment provides a slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets, comprising the following components: Active ingredients: Imidacloprid and Moxidectin, with the mass fraction of imidacloprid being 10% and that of Moxidectin being 5%; Sustained-release carrier: comprising modified lipid nanoparticles and polymer microspheres in a weight ratio of 3:1, with a mass fraction of 20%; Stabilizer: mass fraction is 2%; the stabilizer is a combination of vitamin E and polyethylene glycol, the mass ratio of which is 1:3.

[0030] pH regulator: selected from citric acid-sodium citrate buffer system, with a mass fraction of 1%; Taste masking agent: selected from Moringa seed oil, with a mass fraction of 0.5%; The transdermal enhancer is a combination of medium-chain triglycerides and azone, with a mass ratio of 3:1 and a mass fraction of 5%.

[0031] The balance is ethanol solvent.

[0032] The preparation method of the modified lipid nanoparticles is: (1) Dissolve phospholipids and cholesterol in chloroform to prepare a solution, and remove the organic solvent in a rotary evaporator to form a uniform lipid film; (2) Adding aqueous phase to the lipid film to form lipid nanoparticles under ultrasonic or homogenization treatment; (3) After the lipid nanoparticles are formed, polyethylene glycol is added to graft the modifier onto the surface of the lipid nanoparticles through a chemical coupling reaction. After the reaction is completed, the unbound modifier is removed by centrifugation and washing to obtain modified lipid nanoparticles.

[0033] The weight ratio of phospholipids to cholesterol is 3:1.

[0034] The ratio of polyethylene glycol to the total weight of phospholipids and cholesterol is 1:6.

[0035] The polymer microspheres are modified polylactic acid-glycolic acid copolymers, and the preparation method is as follows: (1) Weigh 20 mg of polyethylene glycol and dissolve it in 3 ml of methanol as the modifier solution; (2) Add the modifier solution to a suspension of 200 mg of poly(lactic-co-glycolic acid) microspheres, add carbodiimide and N-hydroxysuccinimide, and stir at room temperature for 3 hours. (3) After the reaction is completed, the precipitate is collected by centrifugal washing and resuspended in deionized water, and the process is repeated 2-3 times to obtain a modified poly(lactic acid-glycolic acid) copolymer.

[0036] The preparation method of the preparation comprises the following steps: mixing imidacloprid, moxidectin and a sustained-release carrier to prepare a drug-carrier complex; mixing a transdermal enhancer, a stabilizer, a solvent, a pH regulator and a taste masking agent to prepare a solvent system; mixing the drug-carrier complex with the solvent system and homogenizing them to obtain the final preparation.

[0037] Example 2 This embodiment provides a slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets, comprising the following components: Active ingredients: Imidacloprid and Moxidectin, with the mass fraction of imidacloprid being 10% and that of Moxidectin being 5%; Sustained-release carrier: comprising modified lipid nanoparticles and polymer microspheres in a weight ratio of 2:1, with a mass fraction of 20%; Stabilizer: mass fraction is 2%; the stabilizer is a combination of vitamin E and polyethylene glycol, the mass ratio of which is 1:3.

[0038] pH regulator: selected from citric acid-sodium citrate buffer system, with a mass fraction of 1%; Taste masking agent: selected from Moringa seed oil, with a mass fraction of 0.5%; The transdermal enhancer is a combination of medium-chain triglycerides and azone, with a mass ratio of 3:1 and a mass fraction of 5%.

[0039] The balance is ethanol solvent.

[0040] The preparation method of the modified lipid nanoparticles is: (1) Dissolve phospholipids and cholesterol in chloroform to prepare a solution, and remove the organic solvent in a rotary evaporator to form a uniform lipid film; (2) Adding aqueous phase to the lipid film to form lipid nanoparticles under ultrasonic or homogenization treatment; (3) After the lipid nanoparticles are formed, polyethylene glycol is added to graft the modifier onto the surface of the lipid nanoparticles through a chemical coupling reaction. After the reaction is completed, the unbound modifier is removed by centrifugation and washing to obtain modified lipid nanoparticles.

[0041] The weight ratio of phospholipids to cholesterol is 3:1.

[0042] The ratio of polyethylene glycol to the total weight of phospholipids and cholesterol is 1:6.

[0043] The polymer microspheres are modified polylactic acid-glycolic acid copolymers, and the preparation method is as follows: (1) Weigh 20 mg of polyethylene glycol and dissolve it in 3 ml of methanol as the modifier solution; (2) Add the modifier solution to a suspension of 200 mg of poly(lactic-co-glycolic acid) microspheres, add carbodiimide and N-hydroxysuccinimide, and stir at room temperature for 3 hours; (3) After the reaction is completed, the precipitate is collected by centrifugal washing and resuspended in deionized water, and the process is repeated 2-3 times to obtain a modified poly(lactic acid-glycolic acid) copolymer.

[0044] The preparation method of the preparation comprises the following steps: mixing imidacloprid, moxidectin and a sustained-release carrier to prepare a drug-carrier complex; mixing a transdermal enhancer, a stabilizer, a solvent, a pH regulator and a taste masking agent to prepare a solvent system; mixing the drug-carrier complex with the solvent system and homogenizing them to obtain the final preparation.

[0045] Comparative Example 1 The difference between this comparative example and Example 1 is that the sustained-release carrier comprises modified lipid nanoparticles and polymer microspheres in a weight ratio of 1:1.

[0046] Comparative Example 2 The difference between this comparative example and Example 1 is that the modified lipid nanoparticles are not modified. Specifically: (1) Dissolve phospholipids and cholesterol in chloroform to prepare a solution, and remove the organic solvent in a rotary evaporator to form a uniform lipid film; (2) Aqueous phase is added to the lipid film to form lipid nanoparticles under ultrasonic or homogenization treatment.

[0047] Comparative Example 3 The difference between this comparative example and Example 1 is that the modified polylactic acid-glycolic acid copolymer is replaced by polylactic acid-glycolic acid copolymer microspheres.

[0048] Comparative Example 4 The difference between this comparative example and Example 1 is that the weight ratio of phospholipid to cholesterol is 1:3.

[0049] Performance Testing 1. Drug release performance test In vitro release testing (Franz diffusion cell method) was performed to simulate the pet skin environment (pH 6, temperature 37°C). Drug release at different time points (24 hours, 7 days, and 28 days) was measured.

[0050] Evaluation criteria: 24-hour release ≤30%; 7-day release ≤70%; The release amount in 28 days is ≥90%.

[0051] 2. Stability test Long-term stability test: The preparation was stored at 25°C and 60% relative humidity for 6 months to determine whether stratification and precipitation occurred.

[0052] Table 1 Drug release performance test results

[0053] As can be seen from Table 1, the slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets of the present invention has excellent sustained-release effect and stability.

[0054] In Comparative Example 1, the sustained-release carrier includes modified lipid nanoparticles and polymer microspheres in a weight ratio of 1:1. It can be found that the sustained-release effect of the preparation is too fast.

[0055] In Comparative Example 2, the modified lipid nanoparticles were not modified, and in Comparative Example 3, the modified poly(lactic-co-glycolic acid) copolymer was replaced with poly(lactic-co-glycolic acid) copolymer microspheres. It was found that the sustained release effect of the preparation was too fast.

[0056] In Comparative Example 4, the weight ratio of phospholipid to cholesterol was 1:3. It was found that the sustained-release effect of the preparation was too slow.

[0057] This indicates that only by using the raw materials of the present invention can good sustained-release effect and stability be maintained through synergistic effect.

[0058] The above is a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets, characterized in that: The invention comprises the following components: active ingredients: imidacloprid and moxidectin, wherein the mass fraction of imidacloprid is 5%-20%, and the mass fraction of moxidectin is 1%-10%; a sustained-release carrier: comprising modified lipid nanoparticles and polymer microspheres in a weight ratio of 2-3:1, and the mass fraction thereof is 10%-40%; a transdermal enhancer: one or more selected from medium-chain triglycerides, isopropyl myristate or azone, and the mass fraction thereof is 5%-15%; a stabilizer: one or more selected from vitamin E, butylated hydroxytoluene, and polyethylene glycol, and the mass fraction thereof is 0.1%-5%; a pH adjuster: selected from a citric acid-sodium citrate buffer system or a phosphate buffer system, and the mass fraction thereof is 0.5%-3%; a taste masking agent: selected from moringa seed oil or menthol, and the mass fraction thereof is 0.1%-1%; and the balance is solvent ethanol.

2. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The preparation method of the modified lipid nanoparticles is: (1) Dissolve phospholipids and cholesterol in chloroform to prepare a solution, and remove the organic solvent in a rotary evaporator to form a uniform lipid film; (2) Adding aqueous phase to the lipid film to form lipid nanoparticles under ultrasonic or homogenization treatment; (3) After the lipid nanoparticles are formed, polyethylene glycol is added to graft the modifier onto the surface of the lipid nanoparticles through a chemical coupling reaction. After the reaction is completed, the unbound modifier is removed by centrifugation and washing to obtain modified lipid nanoparticles.

3. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 2, characterized in that: The weight ratio of phospholipids to cholesterol is 2-4:

1.

4. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 3, characterized in that: The ratio of polyethylene glycol to the total weight of phospholipids and cholesterol is 1:6-7.

5. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The polymer microspheres are modified polylactic acid-glycolic acid copolymers, and the preparation method is as follows: (1) Weigh 20 mg of polyethylene glycol and dissolve it in 1-5 ml of methanol as the modifier solution; (2) Add the modifier solution to a suspension of 200 mg of poly(lactic-co-glycolic acid) microspheres, add carbodiimide and N-hydroxysuccinimide, and stir at room temperature for 2-4 hours; (3) After the reaction is completed, the precipitate is collected by centrifugal washing and resuspended in deionized water, and the process is repeated 2-3 times to obtain a modified poly(lactic acid-glycolic acid) copolymer.

6. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The transdermal enhancer is a combination of medium-chain triglycerides and azone, with a mass ratio of 2-3:

1.

7. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The stabilizer is a combination of vitamin E and polyethylene glycol, with a mass ratio of 1:2-4.

8. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The pH regulator is a citric acid-sodium citrate buffer system with a pH value of 5.5-6.

5.

9. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The preparation is an external-use drop or pour-on preparation.

10. The slow-release pharmaceutical preparation of imidacloprid and moxidectin for pets according to claim 1, characterized in that: The preparation method of the preparation comprises the following steps: mixing imidacloprid, moxidectin and a sustained-release carrier to prepare a drug-carrier complex; mixing a transdermal enhancer, a stabilizer, a solvent, a pH regulator and a taste masking agent to prepare a solvent system; mixing the drug-carrier complex with the solvent system and homogenizing them to obtain the final preparation.

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