Dicyclanil double-layer coated microcapsule suspension and preparation method thereof

Abstract

The invention discloses dicyclanil double-layer coated microcapsule suspension. Every 100 g of the dicyclanil double-layer coated microcapsule suspension is prepared from the following components by weight: 0.01 to 2.0 g of dicyclanil, 1.0 to 4.0 g of guinea butter, 0.1 to 1.0 g of ethyl oleate, 5.0 to 10.0 g of polyoxyethylene (8) stearate, 15.0 to 35.0 g of an emulsifier OP-10, 0.5 to 1.5 g of karaya gum, 0.01 to 0.6 g of sclerotium glucan, 4.0 to 10.0 g of glycerol formal and the balance of deionized water. Meanwhile, the invention further discloses a preparation method of the microcapsule suspension, the process operability is high, after the medicine is subjected to double-layer coating treatment, the validity period is remarkably prolonged, the medicine effect is improved, the safety is better, and the market application prospect is wide.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary medicines and preparation thereof, and specifically relates to a dicyclopentyl double-layer coated microcapsule suspension and a preparation method thereof. Background Art

[0002] Fleas are one of the important parasitic pests that affect the growth of farmed animals. Their activities not only affect the rest of livestock and poultry, but also serve as a medium for many infectious diseases, leading to the spread of epidemics. More importantly, fleas have a wide range of activities and are highly active. Unlike parasites such as mites and ticks, they are not fixed in one area of ​​the body surface for a long time. They sometimes move on the surface of the animal, and sometimes detach from the surface of the animal to move in the environment, making the clinical prevention and control of the disease more difficult. It is difficult for a variety of flea control drugs to achieve ideal results in prevention and control. Commonly used flea control methods are to spray the drug on the surface of the animal, or to kill it through a full-body medicated bath, or orally, and these methods limit the drug to the animal itself. If the fleas in the environment cannot be killed, the disease will recur after a while. In addition to harming animal health, flea disease also has health effects on front-line breeders, veterinarians, breeders and other personnel.

[0003] How to effectively and permanently control flea disease has always been one of the important issues faced by many farms. In addition to maintaining hygiene in the farm and strengthening environmental disinfection, various flea control products developed with existing technologies are also important means of controlling the insects. Among these products, topical drugs are mainly pyrethroids and organophosphorus, and oral drugs are mainly avermectins. However, some of these drugs are highly toxic and can easily cause poisoning of animals and humans if used improperly. Some can only be absorbed by the body and then distributed to the subcutaneous tissue, and fleas inhale body fluids containing drugs to work. For fleas that are active and parasitic in multiple environments, the drug has a single effect and the repellent effect is not thorough. In addition, due to long-term use of these drugs, many animals have shown drug resistance.

[0004] Dicynil is a new type of insect growth regulator. It affects the normal reproduction, growth, development and metabolism of the insect body by interfering with its epidermis, and ultimately controls the population expansion of fleas. Currently, there is no drug resistance, and it is the preferred ingredient for flea control drugs. Clinical practice shows that dicynil has a high killing effect on fleas. In addition to killing fleas through the suction effect, it can also have a contact killing effect. After the drug enters the insect body, it can effectively prevent the larvae from developing normally into pupae and adults, while also reducing the amount of eggs laid by adults. It can also interfere with the hatching process of eggs, leading to the termination of reproduction. In addition, dicynil can also play a role in repelling and killing common pests such as flies and mosquitoes in farms, but it has no effect on animals that do not molt, so it is very safe for humans and animals.

[0005] Although desiril has an ideal effect in preventing and controlling fleas, it is insoluble in water due to its chemical properties. It can only be dissolved in organic solvents when preparing clinical dosage forms. When this dosage form is used with water, the drug will precipitate due to the loss of the organic environment, and it will also cause the nozzle to be blocked when spraying. At the same time, when a large amount of organic solvents are used as excipients, on the one hand, it will lead to an increase in drug costs, and on the other hand, organic solvents will also produce certain toxicity and pollution, and reduce safety. Summary of the invention

[0006] In view of the current problems faced by farms and the shortcomings of the existing technology, the present invention selects dichlorvos as the main component and prepares it into a double-layer coated microcapsule suspension. This dosage form effectively solves the problem of drug insolubility in water and drug precipitation when diluted with water. At the same time, the effective drug components are double-coated in the form of microcapsules, which can significantly reduce the number of drug applications. After spraying in the environment, it can also maintain a long-term effect, and can kill insects on the animal body surface and in the environment. The actual utilization of the drug is greatly improved, the number of drug applications and the amount of drug used are reduced, the cost of drug use is saved, and the effect of preventing and controlling flea disease in farms is more thorough.

[0007] Specifically, to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0008] The invention discloses a dicyclopentane double-layer coated microcapsule suspension. The weight composition of each 100g of the microcapsule suspension is: dicyclopentane 0.01-2.0g, lard 1.0-4.0g, ethyl oleate 0.1-1.0g, polyoxyethylene (8) stearate 5.0-10.0g, emulsifier OP-101 5.0-35.0g, karaya gum 0.5-1.5g, sclerotium glucan 0.01-0.6g, glycerol formal 4.0-10.0g, and the balance is deionized water.

[0009] Preferably, the weight composition of each 100g of the microcapsule suspension is: 0.5-1.5g of dicyandiamide, 1.5-3.5g of lard, 0.2-0.8g of ethyl oleate, 6.0-9.0g of polyoxyethylene (8) stearate, 8.0-32.0g of emulsifier OP-101, 0.6-1.4g of karaya gum, 0.1-0.5g of sclerotium glucan, 5.0-9.0g of glycerol formal, and the balance is deionized water.

[0010] More preferably, dicyandiamide 1.0 g, lard 2.5 g, ethyl oleate 0.5 g, polyoxyethylene (8) stearate 7.5 g, emulsifier OP-102 5.0 g, karaya gum 1.0 g, sclerotium glucan 0.3 g, glycerol formal 7.0 g, and deionized water 55.2 g.

[0011] The present invention further discloses a method for preparing the dicyclopentyl double-layer coated microcapsule suspension, comprising the following steps:

[0012] Mix lard and ethyl oleate, heat to 50-65°C, add dicyclopentyl and stir to dissolve, then add polyoxyethylene (8) stearate and stir evenly, then adjust the system temperature to 30-40°C, add a mixture of emulsifier OP-10 and karaya gum, and stir evenly; maintain the temperature unchanged, gradually add deionized water of the same temperature to the system, while ultrasonically stirring, until the system changes from a light yellow translucent state to a milky yellow opaque state; then add sclerotium glucan and glycerol formal respectively, stir while cooling, and after the system returns to room temperature, sterilize and package to obtain the dicyclopentyl double-layer coated microcapsule suspension of the present invention.

[0013] In the final system of the present invention, the main ingredient dicynilide is in the form of a double-layer coated microcapsule, which can significantly prolong the drug release time, and the drug efficacy can be exerted for a long time after a single use, which prolongs the medication cycle and reduces the number of medications, saving a certain amount of manpower and time costs for the farm. On the other hand, the viscosity of the drug increases significantly after double-layer coating, and compared with ordinary dosage forms, it can adhere to the surface of animal fur with high strength, and the flea killing effect is enhanced. At the same time, the safety of the drug is improved, and even if the animal licks its fur during the treatment process, it will not be poisoned, filling the market application gap of dicynilide.

[0014] In the prescription of the present invention, dichlorvos is the main component, and the others are auxiliary components. The functions of each auxiliary component are:

[0015] 1) The selection of lard and ethyl oleate as the components of the present invention is based on laboratory testing and evaluation. The combination of these two has a greater solubility for dicyclopentyl and can meet the drug loading requirements to the greatest extent. At the same time, the prepared sample has stronger stability, which can be evaluated by high and low temperature stability. In addition, these two auxiliary raw materials are easily available and have standardized and mature quality standards, which is conducive to later production transformation and large-scale promotion of products;

[0016] 2) Polyoxyethylene (8) stearate is selected as the component of the present invention because the lipophilic end of the surfactant has good compatibility with the mixture of lard and ethyl oleate, and is suitable for emulsifying the mixed phase, which is conducive to the transformation of the capsule into a spherical or quasi-spherical shape. At the same time, its solidification point is between 27 and 29°C, which is higher than the normal room temperature and lower than the solidification point of lard, which is conducive to achieving secondary encapsulation by adjusting the temperature.

[0017] 3) The emulsifier OP-10 is selected as the component of the present invention because its hydrophilic-lipophilic balance (HLB) value is moderately different from that of polyoxyethylene (8) stearate, and the drug is more stable after secondary encapsulation. In addition, the sample can meet the requirements of stability evaluation and is more suitable for conversion production.

[0018] 4) Karaya gum was selected because, on the one hand, it has good inertness as a capsule material for coating dicyclopentane and does not chemically react with the active ingredient. On the other hand, when it is combined with the emulsifier OP-10, secondary coating can be achieved through the adjustment of interfacial tension by surface activity, which has lower process requirements and helps to reduce production costs.

[0019] 5) Sclerotium glucan is selected as an essential component of the present invention, mainly because it is suitable as a suspending agent in the system. After the drug is placed in layers for a long time, it can be evenly redispersed by just gently shaking, and there will be no aggregation and adhesion between drug particles (Comparative Example 1), which is conducive to clinical use.

[0020] 6) Glycerol formal is selected as the component of the present invention because glycerol formal can help maintain the stability of the double-layer coated desinir microcapsules. If it is removed, the microcapsules are prone to rupture (Comparative Example 2, Figure 2 ), the system becomes unstable and its long-term effect will be weakened or even lost after clinical use.

[0021] In the preparation process of the present invention, the mixture of lard and ethyl oleate is heated to 50-60°C for mixing, in order to promote the melting of lard and better fusion with ethyl oleate, so that the first layer coating effect is better. Then the temperature is lowered to between 30-40°C and the second layer coating is performed, in order to solidify the "drug capsule core" while the first layer coating remains in liquid state, which is conducive to the second layer coating.

[0022] Compared with the prior art, the present invention achieves the following technical effects through the improvement of formulation and process:

[0023] (1) The dicyclopentyl microcapsules of the present invention are double-layer coated and have obvious long-lasting effects in clinical use, which can significantly reduce the number of medications and improve the drug effect;

[0024] (2) The dicyclopentyl double-layer coated microcapsules of the present invention are suspensions, which fill the gap in the existing market preparations of dicyclopentyl;

[0025] (3) The particle size distribution of the drug microcapsules of the present invention is between 1.0 and 50.0 μm, and compared with conventional dosage forms, the bioavailability of the drug is higher.

[0026] (4) The present invention has stable properties, strong process operability, and is conducive to large-scale production and transformation. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a transmission electron microscope photograph of the diacetyl double-layer coated microcapsule suspension of the present invention (Example 1);

[0028] Figure 2This is an electron microscope picture of the drug microcapsule after rupture after the glycerol formal is removed in Example 1 of the present invention. DETAILED DESCRIPTION

[0029] The present invention will be further described below by means of specific examples, but these specific embodiments do not limit the protection scope of the present invention in any way.

[0030] Examples 1-10

[0031] To make the specification concise, the weight composition of the diacetyl double-layer coated microcapsule suspension of the present invention described in Examples 1-10 is given in the form of a table below, as shown in Table 1.

[0032] Table 1 Weight composition per 100g of the present invention in Examples 1-10

[0033]

[0034]

[0035] The method for preparing the dicyclopentyl double-layer coated microcapsule suspension described in Example 1 comprises the following steps:

[0036] 2.5g lard and 0.5g ethyl oleate were mixed, heated to 55°C, 1.0g desinir was added and stirred to dissolve, and then 7.5g polyoxyethylene (8) stearate was added and stirred evenly. The system temperature was then adjusted to 35°C, 25.0g emulsifier OP-10 and 1.0g karaya gum were mixed and added to the above system, stirred evenly, and the temperature was maintained constant. 55.2g of deionized water at 35°C was gradually added to the system while ultrasonic stirring was performed. At this time, the system changed from a light yellow translucent state to a milky yellow opaque state. 0.3g sclerotium glucan and 7.0g glycerol formal were added respectively, and the temperature was lowered while stirring. After the system returned to room temperature, it was sterilized and packaged to obtain the desinir double-layer coated microcapsule suspension of the present invention.

[0037] The double-layer coated microcapsules of dichlorvos prepared in Example 1 were observed by electron microscope. Figure 1 It can be seen that the drug particles are coated by two layers. The particle size distribution of the drug particles is between 12.5 and 40.2 μm as measured by Malvern laser particle size analyzer.

[0038] The preparation methods of the dicyclopentane double-layer coated microcapsule suspensions described in Examples 2 to 10 are the same as those in Example 1.

[0039] Comparative experiment

[0040] Comparative Example 1: Effect of Sclerotium Glucan Components on the Present Invention

[0041] Sclerotium glucan plays a suspending effect in the present invention. If it is removed or replaced with other kinds of suspending agents, the system properties will change. After long-term layered precipitation, its redispersion effect will decline. In order to verify its effect, the inventor prepared 4 groups of samples with reference to the prescription and process of Example 1. Wherein the 1st group is Example 1 sample of the present invention, the 2nd group is to obtain the sample after removing the sclerotium glucan, the 3rd group is to replace the sclerotium glucan with the suspending agent sodium carboxymethyl cellulose, and the 4th group is to replace the sclerotium glucan with the suspending agent xanthan gum. The 4 groups of samples are placed at room temperature for observation, and inverted at 15d, 30d, 60d, 90d, 180d and 360d to observe the dispersion of the drug in the system, and the results are shown in the table below.

[0042] Table 2 Comparative test results of the effect of sclerotium glucan on the present invention

[0043]

[0044] The results show that the sclerotium glucan has a good suspending effect on the system of the present invention, can help to redisperse the drug solution that has been layered for a long time, and the drug particles will not aggregate and adhere, which is conducive to uniform clinical drug administration.

[0045] Comparative Example 2: Effect of glycerol formal on the stability of the system of the present invention

[0046] Glycerol formal mainly plays the role of stabilizer in the system of the present invention. If it is removed, the dichlorvos microcapsule particles are prone to rupture. This experiment is compared with the formulation and process of Example 1 as a reference. Group A is the sample obtained in Example 1, and Group B is the sample obtained after removing glycerol formal (the remainder is supplemented with deionized water). The two groups of samples are placed in a constant temperature environment at a temperature of 40°C and a relative humidity of 70%. At the same time, samples are taken for electron microscopy observation at 7d, 15d, 30d, 60d, 90d and 180d after the start of the experiment, and whether there is rupture of the capsule in the field of view is recorded.

[0047] Table 3 Effect of removing glycerol formal on the system of the present invention

[0048]

[0049] The results showed that in the accelerated stability test of the drug in a high temperature and high humidity environment, the sample without glycerol formal had completely broken the encapsulated drug after the end of the test period (such as Figure 2 ), the shapes are irregular, the sizes are different, they are sticky, and the system behaves unstable.

[0050] The results showed that glycerol formal played an important role in maintaining the shape of drug microcapsules, and its removal could lead to rupture of the capsules and cause system instability.

[0051] Test example

[0052] Test Example 1 Stability Test

[0053] The samples of the double-layer coated microcapsule suspension of dichlorvos prepared in Examples 1-10 were examined according to the requirements of pharmaceutical stability evaluation. In order to reduce the error, the number of samples examined in each example was 20, and after being packaged in transparent ampoules, they were placed in -20°C, 4°C, 25°C and 40°C environments for high and low temperature stability examinations. The day after the test started was the first day, and samples were taken on the 15th day, 30th day, 60th day, 90th day and 180th day to see if there were any unstable conditions such as drug precipitation, discoloration, coagulation or capsule rupture.

[0054] Test results: The samples stored at 4℃, 25℃ and 40℃ had a stable appearance during the test, no drug precipitation, and no change in properties. No capsule rupture was observed under the microscope. The samples stored at -20℃ were frozen after being taken out. After returning to room temperature and shaking, the appearance of the system was the same as before, with no unstable phenomena such as drug precipitation, discoloration, coagulation, etc., and no capsule rupture was observed under the microscope.

[0055] The results show that the dicyclopentyl double-layer coated microcapsule suspension of the present invention has good stability.

[0056] Test Example 2 Safety Test

[0057] Safety is the prerequisite guarantee for the smooth promotion of products in the market. In order to verify the safety of clinical use of the present invention, the inventors selected Hy-Line brown laying hens in the laying period as test subjects to obtain clinical safety data. 4,000 healthy Hy-Line brown laying hens aged 312 days raised in the same chicken house were randomly divided into 4 groups, with 1,000 hens in each group. Group 1 was the control group, which was fed normally without the use of any drugs. Groups 2, 3, and 4 were the low-, medium-, and high-dose test groups of the present invention (tested with samples prepared in Example 1), respectively, at 10 ml / m 3 , 50ml / m 3 and 100ml / m 3 The environment of each experimental house was sprayed with chickens at a dosage of the drug. The droplets containing the drug could adhere to the feathers on the chickens' bodies, as well as to feeding utensils, walls, floors and other environments. The drug was applied once in the morning and afternoon each day for one week.

[0058] In order to avoid mutual interference between groups and reduce experimental errors, chickens in different groups were separated by partitions to ensure that the medication process did not affect each other. At the same time, the chickens in each group were managed by the same breeder, and there was no difference in feed and drinking water. During the experiment, the mortality rate, egg production rate, average feed intake, feed-egg ratio and poisoning behavior of each group of chickens were observed.

[0059] Table 4 Safety evaluation of dichlorvos double-layer coated microcapsule suspension of the present invention

[0060]

[0061] The results show that the present invention is clinically safe for laying hens, will not cause animal poisoning or death, will not affect production performance, and has no effect on feeding.

[0062] Test Example 3: Efficacy Test

[0063] The inventor conducted experiments at a stray dog ​​shelter in Zhengzhou, Henan. The base houses a total of 276 dogs of all sizes. Due to the poor hygiene of the breeding environment, the management personnel have long been troubled by flea disease. They have used a variety of drugs to kill fleas, but either the efficacy was unsatisfactory or the fleas relapsed within a short period of time after use. In order to reduce the experimental error, the inventor randomly divided the 276 dogs into 6 groups, with 46 dogs in each group. Group 1 was the control group and no drugs were used, and they were raised normally. Groups 2 to 6 were the experimental groups, which used environmental spraying, oral administration, injection, pouring and other methods to kill fleas. Group 2 was given 50ml / m 3 The sample prepared in Example 1 of the present invention was sprayed in the environment. The third group was sprayed at 50 ml / m 3 The environment was sprayed with highly effective cypermethrin solution, the fourth group took avermectin tablets at 0.1 mg / kg body weight orally, the fifth group took ivermectin at 0.3 mg / kg body weight intramuscularly, and the sixth group used phoxim solution diluted 1:2000 times and then poured on the dog's body surface for the purpose of flea control. After the first day of medication, the same method was used for medication again one week after the first day of medication, and then waited for another 2 weeks. During this period, the fleas on the animal's body surface were manually turned over every day to determine whether they had been completely expelled or whether the recovered dogs that had been completely expelled had relapsed, so as to evaluate the flea control effect.

[0064] In order to reduce the experimental error and avoid mutual interference between groups, each group of animals is managed in a separate closed manner, but the feeding environment, feed, drinking water, lighting and other conditions are the same. During the experiment, patrols were conducted once a day in the morning, noon, evening and night to observe the behavior of each group of dogs, including observation of behaviors such as scratching, resting, drinking water, eating, and inspection of body hair loss. If a dog is found dead, an on-site autopsy will be performed to determine whether it is drug poisoning, and records will be kept. After the experiment, the following standards can be used to evaluate the flea control effect of each group.

[0065] Evaluation criteria:

[0066] Death: If a dog dies during the test, -1 point;

[0067] Invalid: If a large number of fleas still parasitize on the dog's body during the test, or if fleas re-parasitize on the dog's body within 2 weeks after the end of the test, and the disease relapses, 0 points;

[0068] Effective: After the test, the symptoms of the infected dogs were alleviated, and the number of fleas parasitic on the body surface was significantly reduced, but there was no effect on the daily behavior, 1 point;

[0069] Cured: After the test, there are no live fleas on the dog's body and in the breeding house environment, and there is no recurrence within 2 weeks, 2 points;

[0070] Table 5 Clinical efficacy test of dicyclopentyl double-layer coated microcapsule suspension

[0071]

[0072] Result analysis:

[0073] 1) In Group 1, without any medication, the infected dogs continued to show symptoms related to flea infestation, such as constant itching, hair loss, and difficulty eating and drinking. There were continuous flea infestations on the skin surface.

[0074] 2) Group 2 was treated with the dichlorvos double-layer coated microcapsule suspension of the present invention. On the third day after medication, all flea infestation-related symptoms disappeared, feeding and drinking resumed, and no live fleas were found on the hair on the body surface. At the same time, the disease did not recur 2 weeks after the end of the medication.

[0075] 3) Groups 3 to 6 are the control groups of existing competitive products on the market, which are also the mainstream flea control methods commonly used in farms. Compared with Group 2, these drugs either did not kill the fleas completely, or the effect only lasted for a few days after use, and then relapsed again. The scores and cure rates were quite different from those of Group 2. In addition, one dog in Group 6 died of organophosphorus poisoning, indicating that the safety was not as good as the present invention.

[0076] The results show that the dicynilide double-layer coated microcapsule suspension of the present invention has an ideal control effect on flea disease, not only can the treatment be thorough, but also the recurrence is not easy in the later stage.

Claims

1. A dicyclopentane double-layer coated microcapsule suspension, characterized in that: The weight composition of each 100g of the microcapsule suspension is: 0.01-2.0g of dicyandiamide, 1.0-4.0g of lard, 0.1-1.0g of ethyl oleate, 5.0-10.0g of polyoxyethylene (8) stearate, 5.0-35.0g of emulsifier OP-101, 0.5-1.5g of karaya gum, 0.01-0.6g of sclerotium glucan, 4.0-10.0g of glycerol formal, and the balance is deionized water.

2. The diacetyl double-layer coated microcapsule suspension according to claim 1, characterized in that: The weight composition of each 100g of the microcapsule suspension is: 0.5-1.5g of dicyandiamide, 1.5-3.5g of lard, 0.2-0.8g of ethyl oleate, 6.0-9.0g of polyoxyethylene (8) stearate, 8.0-32.0g of emulsifier OP-101, 0.6-1.4g of karaya gum, 0.1-0.5g of sclerotium glucan, 5.0-9.0g of glycerol formal, and the balance is deionized water.

3. The dicyclopentane double-layer coated microcapsule suspension according to claim 2, characterized in that: The weight composition of each 100g of the microcapsule suspension is: 1.0g of dicyandiamide, 2.5g of lard, 0.5g of ethyl oleate, 7.5g of polyoxyethylene (8) stearate, 5.0g of emulsifier OP-102, 1.0g of karaya gum, 0.3g of sclerotium glucan, 7.0g of glycerol formal, and 55.2g of deionized water.

4. The dicyclopentane double-layer coated microcapsule suspension according to any one of claims 1 to 3, characterized in that: The particle size distribution of the microcapsule medicine is between 1.0 and 50.0 μm.

5. The method for preparing the dicyandiamide double-layer coated microcapsule suspension according to any one of claims 1 to 3, characterized in that: The following steps are involved: Mix lard and ethyl oleate, heat to 50-65°C, add dicyclopentyl and stir to dissolve, then add polyoxyethylene (8) stearate and stir evenly, then adjust the system temperature to 30-40°C, add a mixture of emulsifier OP-10 and karaya gum, and stir evenly; maintain the temperature unchanged, gradually add the remaining amount of deionized water at the same temperature to the system, while ultrasonically stirring, until the system changes from a light yellow translucent state to a milky yellow opaque state; then add sclerotium glucan and glycerol formal respectively, stir and cool, and after the system returns to room temperature, sterilize and package to obtain the dicyclopentyl double-layer coated microcapsule suspension of the present invention.

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