External-use selamectin drop pharmaceutical composition and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary drug preparations, and particularly relates to a selamectin external drop pharmaceutical composition and a preparation method thereof, the selamectin external drop pharmaceutical composition comprises the following components (w / v): 2%-20% of selamectin, 10%-40% of dipropylene glycol monomethyl ether, 4%-30% of povidone, 0.01%-0.1% of butylated hydroxytoluene, and 50%-80% of diethylene glycol monoethyl ether. The preparation method comprises the following steps: sequentially dissolving the butylated hydroxytoluene, the selamectin and the povidone into a mixed solution of the dipropylene glycol monomethyl ether and the diethylene glycol monoethyl ether, and sub-packaging into appropriate single-dose containers, so as to obtain the compound. The prepared selamectin external drops are simple and convenient to produce and operate, and the product quality is stable.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug formulation technology, specifically relating to a topical transdermal drop composition based on selamectin and its preparation process. In particular, this invention provides a selamectin drop pharmaceutical composition comprising a penetration enhancer, a viscosity modifier, a stabilizer, and a solvent, suitable for the prevention and treatment of internal and external parasite infections in dogs and cats, specifically relating to a selamectin topical drop pharmaceutical composition and its preparation method. Background Technology

[0002] Avermectin compounds are a group of macrolide antiparasitic drugs produced by the fermentation of Streptomyces spp. They are produced through the fermentation and metabolism of Streptomyces spp. Their unique mechanism of action, which irreversibly activates glutamate-controlled chloride ion channels leading to neuromuscular paralysis of parasites, has established an excellent spectrum of action in veterinary medicine. Selamectin (SEI) is an avermectin antibiotic produced by the fermentation of a new recombinant strain of Streptomycetes sav ermitilis. It is used as an antiparasitic drug against internal and external parasites in animals, exhibiting good lipid solubility and tissue penetration.

[0003] Current clinical data indicate that selamectin achieves an efficacy of over 98.7% against common ectoparasites in dogs and cats (including *Ctenocephalides felis*, *Ctenocephalides canis*, and *Demodex canis*) and endoparasites (such as *Toxocara canis* and *Ancylostoma caninum*) (based on FDA NADA 141-051 pharmacodynamic report). Its unique long-lasting protective properties (maintaining effective blood concentrations for 28-35 days after administration) make it widely used in the prevention of canine heartworm disease (Dirofilaria immitis). Furthermore, selamectin's good safety profile makes it irreplaceable in clinical practice for young dogs and cats.

[0004] Currently popular topical selamectin drops have several flaws and safety hazards throughout their entire lifecycle: 1) Odor: The solvents used in commercially available products are highly volatile and have a strong odor, causing distress and safety risks to both animals and owners; 2) High volatility: The solvents used in commercially available products are highly volatile and are flammable and explosive, posing a significant challenge to the production process, primarily in terms of material balance, safety, and environmental protection; 3) Skin irritation: Commercially available products cause significant skin irritation to animals, easily leading to discomfort or stress. Compared to currently popular selamectin products on the market, this drug composition has advantages such as good stability, mild properties, colorless and odorless nature, and good compliance. Summary of the Invention

[0005] The existing technical defects of selamectin drops include: (1) the solvent system is highly volatile, resulting in unstable content of active ingredients; (2) to ensure that the content of active ingredients meets the requirements during the production process, the sealing requirements of the production equipment are very strict, increasing investment; (3) skin irritation, the solvent has a burning sensation on the animal's skin, which can easily cause discomfort or stress in sensitive animals; (4) odor, due to the volatility and corrosiveness of the solvent, the solvent and packaging materials have compatibility reactions, and a pungent odor gradually appears during the product storage process, which seriously affects the consumption willingness of pet owners, etc., which are the pain points of formulation technology and clinical practice.

[0006] This invention innovatively screens out superior solvent systems and develops their preparation processes. By optimizing the solvent system, it achieves the following: (1) the drug is gentler and less irritating to the skin, improving animal compliance and safety; (2) no unpleasant odor, improving the medication experience and personal safety for animal owners; (3) the solvent system is essentially non-volatile, resulting in more stable drug quality; (4) the solvent system is stable and non-corrosive, allowing for a wider range of inner packaging materials that can directly contact the drug; (5) the addition of a viscosity modifier makes the drug solution viscosity more reasonable, making it more convenient to use; and (6) the solvent system is essentially non-volatile, requiring no special equipment, making large-scale commercial production more convenient.

[0007] The objective of this invention is achieved through the following technology: a selamectin drop, wherein each 100ml of the pharmaceutical composition contains: 2-20g selamectin, 10-40g dipropylene glycol methyl ether, 4-30g povidone, 0.01-0.1g butylated hydroxytoluene, and 50-80g diethylene glycol monoethyl ether.

[0008] The preparation method of the above-mentioned selamectin drops is as follows: (1) Weigh diethylene glycol monoethyl ether and dipropylene glycol methyl ether, stir and mix evenly; (2) Add dibutylhydroxytoluene and stir until dissolved; (3) Add selamectin and stir until dissolved; (4) Add povidone and stir until dissolved.

[0009] The advantages and unique effects of this invention are as follows: This invention innovatively screens out a better solvent system and develops a more stable, gentler, and safer topical selamectin drop for animals and owners. It is filled and sealed into disposable veterinary polypropylene caps according to clinical needs. The cap is designed with a disposable needle-like structure to pierce the cap and drop the drug solution onto the skin surface of the back of the neck and the front of the scapula of the animal to exert the drug effect of inhibiting and killing internal and external parasites in the animal. The advantages of the solvent system are: (1) The solvent has strong dissolving ability and will not affect the dissolution effect of selamectin due to ambient temperature. There is no risk of turbidity, precipitation, or solidification in low-temperature environments. (2) The solvent has stable physicochemical properties, is not volatile, and is not flammable or explosive, which reduces safety risks and cost inputs in the production, storage, and transportation of the drug composition. Specifically, the raw materials do not need to be stored in special warehouses as flammable and explosive materials; the production equipment does not need to be equipped with strict sealing and explosion-proof functions; and the storage and transportation of finished products do not need to formulate contingency plans to prevent liquid evaporation and explosion. (3) Thanks to the stable physicochemical properties and non-volatile nature of the solvent system, the content of active substances in the drug composition is more stable, the medication is more accurate, and the clinical effect is more guaranteed. (4) The solvent has good safety. Diethylene glycol monoethyl ether is widely used in oral, skin and gastrointestinal drug preparations, as well as as a cosmetic ingredient. The Cosmetic Ingredient Review (CIR) expert panel evaluated diethylene glycol monoethyl ether and found that it is safe when used in cosmetics at a maximum concentration of 50%. It is generally considered to be non-irritating and non-toxic, with good animal compliance and high acceptance by owners. The acute toxicity of diethylene glycol monoethyl ether in oral, intravenous, skin and respiratory inhalation has been studied and it can be considered to have very low toxicity in the studied species. (5) The solvent system is stable and non-corrosive, and the range of inner packaging materials that can directly contact the drug is wider. (6) The addition of viscosity modifiers makes the viscosity of the drug solution more reasonable and the operation more convenient.

[0010] The following embodiments are provided to illustrate the invention in a more comprehensive manner, but the embodiments are not limited to the invention, which is fully limited by the appended claims. Detailed Implementation Plan

[0011] The method of the present invention will be further described in detail below with reference to specific embodiments.

[0012] Examples 1-4:

[0013] Examples 1-4 all prepared the selamectin drops of the present invention. The formulation amounts of raw materials and excipients per 100 ml of selamectin drops in each example are shown in Table 1 below:

[0014] The steps for preparing selamectin drops from the above-mentioned raw and auxiliary materials are as follows: (1) Weigh diethylene glycol monoethyl ether and dipropylene glycol methyl ether, stir and mix evenly; (2) Add butylated hydroxytoluene and stir until dissolved; (3) Add selamectin and stir until dissolved; (4) Add povidone and stir until dissolved; (5) Fill into disposable veterinary polypropylene end caps according to the theoretical filling volume of 0.5 ml / vial and seal.

[0015] The test results of the products prepared in each embodiment are shown in Table 2:

[0016] The selamectin drops prepared in Examples 1 to 4 above were all pale yellow clear liquids. After 3 months of accelerated testing (40±2℃, RH65±5%), the selamectin content was stable and the properties did not change significantly.

[0017] Experimental Examples 1-4: Simulated Drug Administration Trials

[0018] 1. Test samples: Prepare samples according to Examples 1-4;

[0019] 2. Experimental method: Take 10 samples for each group of samples and record the weight of each sample; simulate an animal owner administering medication to an animal, open the sealed end tube with the cap, squeeze the sealed end tube 7 times in a row to release the liquid, and record the weight of each sample; wash the sealed end tube with ethanol, dry it, and record the weight of the empty tube.

[0020] The residual amount of drug solution and net filling amount of each sample can be calculated, and then the residual ratio of each sample can be calculated; the average residual amount and RSD of each group of 10 samples can be calculated.

[0021] 3. The results of the simulated drug administration test are shown in Table 3:

[0022] As can be seen from the data in Table 3, in Examples 2-4 of this invention, the viscosity of the selamectin drops increased with increasing povidone concentration, leading to a higher residual amount in the tube. However, Example 1 was an exception because the surface tension of the drug solution was relatively low, making it easier for residual drug to spread at the outlet of the sealing tube, resulting in a higher residual amount and a larger variation (higher RSD value) in Example 1. In this invention, Example 2 showed low residual amount and small variation, which is most conducive to accurate drug administration.

[0023] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any modifications made to the above embodiments by those skilled in the art without departing from the spirit and scope of the present invention are not permitted. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the technical concept provided by the present invention are still covered by the claims of the present invention.

Claims

1. A topical drop containing selamectin, characterized in that, The pharmaceutical composition comprises selamectin, a penetration enhancer, a solvent, a stabilizer, a viscosity modifier, etc., with the following proportions (w / v): selamectin 2%–20%, penetration enhancer 10%–40%, and viscosity modifier 4%–30%.

2. The selamectin drops as described in claim 1, characterized in that, The penetration enhancer is one or more of the following: dipropylene glycol methyl ether, isopropanol, oleyl alcohol, octanoic acid caprylic acid glyceride, monolinoleic acid glyceride, polyglycerol oleate, propylene glycol laurate, oleyl polyoxyethylene glyceride, and polyoxyethylene stearate.

3. The selamectin drops as described in claim 1, characterized in that, The solvent is a mixed solution of dipropylene glycol methyl ether and diethylene glycol monoethyl ether, and the solvent accounts for 50% to 80% of the weight of selamectin drops.

4. The selamectin drops as described in claim 1, characterized in that, The stabilizer is one or more of butylated hydroxyanisole, butylated hydroxytoluene, lecithin, vitamin E, vitamin A, and ascorbyl palmitate.

5. The method for preparing selamectin drops as described in claim 1, characterized in that, Includes the following steps: (1) Weigh out diethylene glycol monoethyl ether and dipropylene glycol methyl ether, stir and mix evenly; (2) Add dibutylhydroxytoluene and stir until dissolved; (3) Add selamectin and stir until dissolved; (4) Add povidone and stir until dissolved.

6. The selamectin drops according to any one of claims 1-5 are used in the preparation of drugs for inhibiting and killing internal and external parasites in animals, and the administration method is to drop the drug solution onto the skin surface of the back of the neck and the front of the scapula of the animal.

7. The application as described in claim 6, characterized in that, The parasites mentioned are fleas, lice, mites, roundworms, hookworms, or heartworms.

8. The application as described in claims 6-7, characterized in that, The animals mentioned are dogs and cats.

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