A freleana drop and a preparation method thereof

Abstract

The application relates to the Freyrelana preparation field, in particular to a Freyrelana drop. In the preparation method in the application, a Freyrelana drop with good molding property, adhesion and low volatility is provided by adding a cellulose ether and adjusting the proportion of solvents, so that the drop has better adhesion on the surface of animal skin, the stimulation of the drop on the surface of animal skin is reduced, and the drug can be better absorbed by the animal.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of fluralaner preparation, in particular to a fluralaner drop. BACKGROUND

[0002] Fluralaner is a new isoxazoline insecticide, which can effectively prevent and control agricultural pests and pet parasites by blocking the gamma-aminobutyric acid gate chloride ion channel, leading to overexcitation of the insect nervous system and death.

[0003] Fluralaner drop is a preparation developed by fluralaner, which is mainly used for external deworming of pets such as cats and dogs. The most widely used product at present is the fluralaner drop developed by Merck, which has occupied most of the market share. The main principle of the drop is to dissolve the drug and penetrate into the animal body through the animal skin, diffuse to all parts of the animal body through the blood, and then achieve the effect of systemic administration.

[0004] Since fluralaner drop is not soluble in water, it is usually used with some organic solvents (such as dimethylacetamide) as solvent, and is used with penetration agent, but in the process of use, dimethylacetamide and other materials may have strong irritation to animal skin, and at the same time, due to its strong fluidity, the adhesion performance on the skin surface is also poor. SUMMARY

[0005] Based on the above technical problems, the purpose of the present application is to improve the adhesion on the skin and reduce the irritation to the animal epidermis by adjusting the formula on the basis of the existing fluralaner drop.

[0006] Firstly, the present application provides a fluralaner drop, which comprises the following components according to mass percentage:

[0007] Fluralaner, 20-30%

[0008] Penetration agent, 10-25%

[0009] Repellent, 5-20%

[0010] Cellulose ether, 2-10%

[0011] Organic solvent is supplemented to 100%;

[0012] The organic solvent is optionally any number of amide solvents, alcohol solvents or ketone solvents.

[0013] In the above scheme, on the basis of the existing Fre Lana drops, a small amount of cellulose ether is additionally added in the system, which can adjust the overall adhesion. The cellulose ether in the system can improve the liquid surface activity, so that the drops can better adhere to the animal body surface. At the same time, the cellulose ether can also adjust the overall volatility in the system, control the volatility rate at a lower level, and improve the permeability on the body surface through long-term adhesion. At the same time, the addition of cellulose ether in the system can also reduce the irritation of the above drops, reduce the irritation to the animal body surface, and thus reduce the influence of the solvent being swallowed by the animal due to licking.

[0014] Preferably, the organic solvent comprises a combination of dimethylacetamide and acetone, and the mass ratio of dimethylacetamide to acetone is 1.5-5:1, and further preferably, the mass ratio of dimethylacetamide to acetone is 2.4-4:1.

[0015] In the above scheme, the overall low irritation and high film forming property are better, and the overall drops perform better on the body surface, so that the drug can be better absorbed by the animal. Overall, in the above scheme, a lower mass of acetone is selected, which has lower toxicity and irritation, and dimethylacetamide itself has lower irritation, and the overall volatility is slower, so that Fre Lana can better adhere to the animal body surface, and the body surface can better absorb Fre Lana under wet conditions.

[0016] Preferably, the mass of cellulose ether is 30-50% of the mass of acetone.

[0017] In the above solution system, cellulose ether overall plays a role of wrapping and stabilizing acetone, and its addition amount is related to the mass of acetone. On the above basis, good solubility and certain volatility are ensured, and irritation is reduced and adhesion is improved.

[0018] Preferably, the cellulose ether is a non-ionic cellulose ether.

[0019] The non-ionic cellulose ether has better affinity with the skin, smaller overall irritation, and better homogeneity effect on the system.

[0020] Preferably, it further comprises polyvinylpyrrolidone, and the molecular weight type of the polyvinylpyrrolidone is preferably not higher than K15, and further preferably, the addition amount of the polyvinylpyrrolidone is 1.5-3% in terms of mass percentage.

[0021] Polyvinylpyrrolidone can further improve the adhesion and film-forming property in the above system, and can further improve the adhesion of the above drop on the body surface, reduce the flow, and at the same time improve the absorption performance. Among them, the polyvinylpyrrolidone type is preferably K12 or K15, and too high molecular weight polyvinylpyrrolidone or too much addition will cause the viscosity of the system to be too large, the flow to be difficult, and the animal hair to be easily attached, thereby causing the usability to be not strong.

[0022] In the present application, the preparation method of the above Freneran drop is also included, which comprises the following steps: mixing each raw material component, then stirring and mixing uniformly, then filtering impurities, and packaging. Preferably, in the mixing step, the stirring rate is 100-500 rpm, and the stirring time is 5-30 min.

[0023] In summary, the present application provides a Freneran drop with good film-forming property, adhesion and lower volatile performance, so that the drop has better adhesion on the surface of animal skin, and at the same time reduces the irritation to the surface of animal skin, so that the drug can be better absorbed by the animal. DETAILED DESCRIPTION

[0024] The scheme in the present application is further described in the following specific embodiments.

[0025] The Freneran drop in the present application is determined by the following method:

[0026] 1. Adhesion: Fresh pig skin is used to simulate the surface of animal skin, and after depilation, 1 mL of the drop is added to the surface of the pig skin, and then the pig skin is inclined to measure the sliding angle of the drop at room temperature.

[0027] 2. Irritation: On the basis of the sliding angle not less than 45°, a drop preparation without Freneran is configured, and the irritation is determined by the back of the volunteer, and the score is 0 (no irritation, reference ethanol) -10 (tingling sensation). It is worth noting that this index is mainly used to evaluate the discomfort of the preparation on the skin surface.

[0028] 3. Stability: The drop obtained by configuration is placed at room temperature, and whether it has stratification and precipitation after 6 months is observed.

[0029] 4. Irritation: Some examples are selected, and experiments are carried out by giving drugs to healthy dogs, and the dose is 0.2 mL / kg, and the drug is given once a day, and whether the animal has skin irritation phenomenon during the period is observed.

[0030] 5. Flowability: Whether the drug can smoothly penetrate the hair layer and contact the skin surface during the administration is observed, and according to completely adhering to the hair, a large amount of adhering to the hair, and a small amount of adhering to the hair, it is respectively counted as poor, medium and good.

[0031] In the following examples, the preparation method of the drops is as follows:

[0032] S1, preparation: first weigh each raw material and add it to the liquid preparation tank, then add flucloronil, stirring speed 200 rpm, stirring for 10 min;

[0033] S2, filtration: filter the prepared liquid with a microporous filter membrane with a pore size of 0.45 μm.

[0034] S3, filling and sealing: fill the filtered liquid into aluminum plastic tubes according to the weight of each specification, then seal the tail of the aluminum plastic tube, the sealing temperature is 170-250℃. The net pattern at the sealing position is clear, the sealing performance is good, and there is no running, leaking or dripping phenomenon.

[0035] Example 1, this example mainly studies the influence of adding different types and amounts of cellulose ethers on adhesion, irritation, stability and flowability under the condition of using a fixed solvent formula. Specifically, in this example, the overall material configuration table is shown in Table 1, except for the cellulose ether.

[0036] Table 1

[0037] Material Mass percentage Freneral 25％ Tetrahydrofurfuryl alcohol polyglycol ether (penetrant) 16％ Diethyltoluamide (repellent) 12％ Polyvinylpyrrolidone K15 2％ Organic solvent Supplemented to 100%

[0038] Among them, the organic solvent is dimethylacetamide and acetone with a mass ratio of 3:1.

[0039] For this example, the specific experimental results are shown in Table 2.

[0040] Table 2

[0041]

[0042]

[0043] In the above table, the control is a commercially available preparation. By comparison, it can be seen that the scheme in this application greatly improves the sliding angle on the surface of the skin compared to the mature product on the market, significantly improves its adhesion, and helps it to remain attached to the surface of the pet for a long time.

[0044] From the above experimental data, three types of cellulose ethers can all have surface activity effects, and increasing the sliding angle will remain stable as the amount of cellulose ether increases, and the irritation to the skin and the relationship between the addition of cellulose ether are relatively small. Overall, the irritation of carboxymethyl cellulose ether to the skin will be stronger than that of methyl cellulose ether and hydroxypropyl methyl cellulose ether. In another case, too high concentration of cellulose ether will have adverse effects on the system, the molecular chain breakage and polymerization of which can easily lead to the presence of a certain amount of precipitation in the system, and also have certain adverse effects on the flowability.

[0045] In Example 2, the mass percentages of acetone, dimethylacetamide and hydroxypropyl methylcellulose in the solvent are further adjusted on the basis of the selected methylcellulose ether, and the results are shown in Table 3.

[0046] Table 3

[0047]

[0048] In combination with Examples 1 and 2, it can be seen that when the mass of the cellulose ether is 30-50% of the mass of acetone, the system can have better adhesion, and the overall slip angle is higher. When the cellulose ether addition amount is lower, the system will have a significant increase in irritation. The selection of the solvent has a significant effect on the flowability and irritation of the system. The increase in acetone will significantly increase the skin irritation, and dimethylacetamide will cause the viscosity of the system to increase to a certain extent. In addition, when the content of acetone is too high, the system is prone to stratification and a certain amount of precipitation, which may be caused by the poor solubility of acetone.

[0049] In Example 3, the effect of the addition and type of polyvinylpyrrolidone on the overall performance of the system is mainly studied. In this example, based on Examples 1-9, polyvinylpyrrolidone K12, polyvinylpyrrolidone K15 and polyvinylpyrrolidone K17 are selected, and the specific experimental results are shown in Table 4. In Table 4, the increase and decrease of the mass of polyvinylpyrrolidone is supplemented by an organic solvent.

[0050] Table 4

[0051]

[0052] As can be seen from the above experiments, with the increase of polyvinylpyrrolidone and the increase of the molecular weight of polyvinylpyrrolidone, it will have a significant impairment effect on the flowability. After using polyvinylpyrrolidone with a higher label than K17, it is difficult to ensure both the adhesion to the skin surface and the good flowability.

[0053] In Example 4, the experimental groups 1-9 are selected for animal experiments, and are compared with commercially available The above preparations are dropped on the skin between the shoulder and the hip of the back of the dog, each kg of body weight of the dog ≥25 mg, and the mass is shown in Table 6, and the drug is administered once every 12 weeks.

[0054] Before use, open the sachet, take out the dropper, avoid direct contact with the product, hold the bottom or upper end cap of the dropper below the fixed part, keep the top end of the dropper upward, rotate the end cap clockwise or counterclockwise for a full turn, when the sealing ring is broken, the dropper is opened, the dropper cap should be retained on the dropper and cannot be removed.

[0055] Table 5 Test dog administration schedule

[0056]

[0057] Table 6 Test dog administration dose

[0058]

[0059] The number of ticks on the whole body surface of the test dogs was counted before administration (D0), D2, D28, D56, D70 and D84, and the tick reduction rate at different time points after administration of each animal was calculated. At the same time, clinical systemic examination was carried out, body temperature (rectal temperature), respiratory rate and heart rate were measured, and the local body surface itching, skin damage, red rash and other conditions of tick bite were checked and the skin damage degree was scored. During the test, the mental state, appetite, defecation, and various adverse reactions were observed and recorded every day.

[0060] In this test, the average tick reduction rate of each group of test dogs was taken as the main index of effectiveness. Specifically, referring to the Guideline on evaluation of the efficacy of substances for the treatment and prevention of tick and flea infestations in dogs and cats published by EMA in 2022, the average tick reduction rate of the two groups of test dogs at D2, D28, D56, D70 and D84 was calculated:

[0061]

[0062] Evaluation criteria for clinical efficacy test results of each group:

[0063] Effective: During the treatment period and after the end of treatment, the average tick reduction rate of the body surface is ≥90%, and there is no itching, no red rash, no dandruff or self-biting damage of the test animals in the affected area.

[0064] Ineffective: During the treatment period and after the end of treatment, the average tick reduction rate of the body surface is <90%, and there is still itching, red rash, dandruff or obvious self-biting damage of the test animals in the affected area.

[0065] The effectiveness test results of each group of experimental dogs are shown in Tables 7-9. Among them, Table 7 is the experimental results of all types of ticks, and Tables 8 and 9 are the experimental results of the above drugs against Haemaphysalis longicornis and Haemaphysalis flava, respectively.

[0066] Table 7 Statistical results of tick count of each group of test dogs (number)

[0067]

[0068] Table 8 Statistical results of tick count of each group of test dogs infected with Haemaphysalis flava (number)

[0069]

[0070] Table 9 Statistical results of the number of ticks on the test dogs infected with Haemaphysalis longicornis

[0071]

[0072] At 48 h after administration (D2), all the ticks on 78.13% (50 / 64) of the test dogs in Group I and 83.08% (54 / 65) of the test dogs in Group II died, and most of the dead ticks were automatically shed from the skin. Dry and dull tick corpses were found on the ground, and some of the dead ticks were also found in the hair of the test dogs. Most of the ticks on the remaining test dogs were also poisoned to death, and some of the surviving ticks showed reduced activity. The average reduction rates of the ticks on the test dogs in Group I and Group II were 94.10% and 94.78%, respectively, at D2, which met the effective standard (90%). Further analysis of the average reduction rates of the different tick species showed that the average reduction rates of the Rhipicephalus sanguineus ticks in Group I and Group II were 94.90% and 95.44%, respectively, and the average reduction rates of the Haemaphysalis longicornis ticks in Group I and Group II were 93.54% and 94.34%, respectively, which met the effective standard (90%).

[0073] At 28 days after administration (D28), the ticks on the test dogs in Group I and Group II had basically all died and fallen off, and only a few dead ticks were occasionally found in the hair of the test dogs. Only 7.81% (5 / 64) of the test dogs in Group I and 6.15% (4 / 65) of the test dogs in Group II had a small number of live ticks. The average reduction rates of the ticks on the test dogs in the two groups were 99.75% and 99.77%, respectively, which met the effective standard (90%). At D56, D70, and D84 after administration, the efficacy of the tick-killing treatment in Group I and Group II decreased, but was still above the effective standard (90%). Further analysis showed that the average reduction rates of the Rhipicephalus sanguineus ticks and the Haemaphysalis longicornis ticks in Group I and Group II were above the effective standard at D28, D56, D70, and D84.

[0074] The above results showed that the average reduction rates of the ticks in Group I and Group II met the effective standard (90%) at D2 and were maintained until D84.

[0075] The tick count of the group I and group II at different time points was not significantly different (P=0.971>0.05) by the intergroup comparison. Since there was no interaction between the group and time (P=0.9.4>0.05), the analysis of each group at each time point was not performed. Further analysis and comparison of each tick species showed that the Haemaphysalis flava count of the group I and group II at different time points was not significantly different (P=0.696>0.05), and since there was no interaction between the group and time (P=0.340>0.05), the analysis of each group at each time point was not performed; the Haemaphysalis longicornis count of the group I and group II at different time points was not significantly different (P=0.703>0.05), and since there was no interaction between the group and time (P=0.841>0.05), the analysis of each group at each time point was not performed.

[0076] The specific embodiments are only an explanation of the present application, which is not a limitation of the present application. Those skilled in the art can make modifications to the embodiments without creative contribution after reading the specification, and the modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A Fremanae drop, characterized in that, comprising the following components by mass percentage: Ferlana, 20-30% penetrant, 10-25% repellent, 5-20% cellulose ether, 2-10% organic solvent to 100%; said organic solvent comprising at least a combination of dimethylacetamide and acetone in a mass ratio of 2.4-4:1; said cellulose ether having a mass of 30-50% of the mass of acetone; said cellulose ether being methyl cellulose ether, hydroxypropyl methyl cellulose ether or carboxymethyl cellulose ether; said penetrant being tetrahydrofuran polyethylene glycol ether; said repellent being diethyltoluamide; further comprising polyvinylpyrrolidone, the molecular weight of which is not higher than K15, the addition amount of which is 1.5-3% by mass percentage.

2. A process for the preparation of Freleana drops as claimed in claim 1, wherein, comprising the following steps: mixing the raw material components, then stirring sufficiently and mixing uniformly, followed by filtering out impurities and packaging.

3. A process for the preparation of Fralana drops as claimed in claim 2, wherein, in the mixing step, the stirring rate is 100-500 rpm and the stirring time is 5-30 min.

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