Cyromazine granules and preparation method thereof
By employing fluidized bed granulation and a sustained-release matrix composed of phenyl salicylate, the degradation problem of cyproheptadine formulations under light and high temperature and humidity conditions has been solved, achieving stability of cyproheptadine granules and enabling multi-purpose administration, while reducing costs.
Patent Information
- Application Number
- CN202511827929.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-05
- Publication Date
- 2026-01-23
AI Technical Summary
Cyproheptadine preparations are easily degraded under light or high temperature and humidity conditions, have a short duration of action, poor stability, and existing dosage forms cannot meet the needs of various external administration methods, increasing the number of applications and costs.
Cyproheptadine granules were prepared using fluidized bed granulation technology, combined with phenyl salicylate as a light stabilizer, and encapsulated by a sustained-release skeleton. Disintegrants, binders, fillers, suspending agents and other raw materials were added and used in an optimized combination to form a sustained-release skeleton to protect phenyl salicylate and reduce its irritation.
It significantly improves the degradation problem of cyproheptadine under strong light, prolongs the duration of action, reduces the number of applications, improves stability, is suitable for various external administration methods, and reduces costs.
Smart Images
Figure CN121370786A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a cyromazine granule and a preparation method thereof. BACKGROUND
[0002] Cyromazine belongs to insecticides and is used for controlling the reproduction of fly larvae in animal houses. Cyromazine can inhibit the molting of dipteran larvae, so that the reproduction of fly larvae is hindered. The use of cyromazine can significantly reduce the ammonia content in the chicken house, greatly improve the environment for livestock and poultry feeding, and the active ingredient of cyromazine can be decomposed in the soil, which is pollution-free to the environment and belongs to high-efficiency and environmentally friendly pesticides. With the increasingly wide use of cyromazine, drug-resistant fly larvae have appeared, so the amount of cyromazine added in feed is increasing. However, with the increase of the amount of cyromazine, the problem of increasing residual amount of melamine, a metabolic product in the animal body, occurs, and many countries have prohibited the addition of cyromazine in feed, so it is urgent to develop an external dosage form of cyromazine.
[0003] The cyromazine preparations on the market mainly include soluble powder, premix and granule. The soluble powder is easy to generate dust, the premix is generally used for mixing, and the granule cannot meet the external use. Although the granule solves the shortcomings of the other two dosage forms, the several dosage forms on the market do not have protective effect on cyromazine, and cyromazine is easy to degrade under light or high temperature and high humidity conditions, so repeated administration is often required, increasing the cost. SUMMARY
[0004] In view of the problems in the prior art, the present application provides a cyromazine granule and a preparation method thereof, which can solve the problems of easy degradation of cyromazine preparation under light or high temperature and high humidity conditions, short action time and poor stability, and can meet the requirements of various external administration modes of cyromazine granule and a preparation method thereof.
[0005] To solve the above technical problems, the technical scheme adopted by the present application is as follows: A cyromazine granule, wherein the raw materials of the cyromazine granule include cyromazine raw powder, disintegrating agent, binding agent, filling agent, light absorbing agent, suspending agent and sustained-release matrix. The disintegrating agent is sodium carboxymethyl starch, the binding agent is PVP K30, the filling agent is corn starch, the light absorbing agent is phenyl salicylate, the suspending agent is HPMC, and the sustained-release matrix is ethyl cellulose. The weight percentage of the cyromazine raw powder in the dry matter is 2%. The weight percentage of the disintegrating agent in the dry matter is 10-15%. The weight percentage of the binding agent in the dry matter is 6-10%. The filler accounts for 31-45% of the weight percentage of dry matter; The light absorber accounts for 5-8% of the weight percentage of dry matter; The suspending agent accounts for 18-25% of the weight percentage of dry matter; The slow-release skeleton accounts for 8-12% of the weight percentage of dry matter.
[0006] The preparation method of the foregoing cyromazine granules, cyromazine raw powder, disintegrating agent, filler, light absorber, suspending agent, and slow-release skeleton are mixed, and then added to a fluidized bed to make the material in a fluidized state, spray into an aqueous binder solution, granulate, dry, and obtain cyromazine granules; The concentration of the aqueous binder solution is 15-25g / 100mL; During granulation, the granulation particle size is 0.5-1mm; During granulation, the conditions of the fluidized bed are as follows: the frequency of the peristaltic pump is 20-25%, the air inlet wind speed is 50-55m 3 / h, and the air inlet temperature is 55-60℃.
[0007] Phenyl salicylate is a common light stabilizer in plastics, which can resist the damage of light to substances. Considering that the application scene of cyromazine preparation is mainly in the environment of strong light, high temperature and high humidity in summer, and cyromazine itself is sensitive to light, but the cost of the common light stabilizer in general preparation is high, and the yield is small, which is not suitable for large-scale use of veterinary drugs. Therefore, phenyl salicylate is used as the light stabilizer of cyromazine granules in the present application, and the cost of phenyl salicylate is low and the yield is large, which can protect cyromazine from being decomposed by light and prolong the action time when added to the preparation. In addition, in order to avoid the problem that the decomposition product of phenyl salicylate used as a light stabilizer of the preparation has irritation, the present application uses the fluidized bed granulation technology and adds a slow-release skeleton in the preparation process, which can wrap the phenyl salicylate, ensure its slow release, reduce its local concentration, and at the same time form a physical barrier to reduce the irritation of phenyl salicylate.
[0008] Compared with the prior art, the present application has the following beneficial effects: (1) The preparation method of the cyromazine granules of the present application, compared with the prior art, utilizes fluidized bed granulation, the prepared granules have good flowability and less fine powder, the addition of phenyl salicylate in the formula can obviously improve the problem that cyromazine is easily degraded under strong light, prolongs the action time, reduces the administration frequency, and lowers the cost, the use of HPMC as a suspending agent can make cyromazine uniformly dispersed in water, which can be used for drinking water administration and also for mixing with feed, and can also be used for spraying and dry scattering, in addition, through the combination use of various raw materials and the optimization of the amount of each raw material, a sustained-release matrix of phenyl salicylate is formed in the prepared cyromazine granules, which can both wrap phenyl salicylate to ensure its slow release and form a physical barrier to phenyl salicylate to reduce the irritability of phenyl salicylate.
[0009] (2) The preparation method of the cyromazine granules of the present application can solve the problems that cyromazine preparations are easily degraded under light or high temperature and high humidity conditions, have short action time, and poor stability, after the cyromazine granules prepared by the present application are dispersed in water, the state in water is white and slightly viscous, after standing for 3 h, the sedimentation volume ratio is 0.96-1.00, and the cyromazine content retention rate in the upper solution is 96.98%-97.94%; after the cyromazine granules prepared by the present application are irradiated in a light box with an illuminance of 4500 lx for 1 day, the cyromazine content retention rate in the cyromazine granules is 99.12-99.67%, after irradiation for 2 days, the cyromazine content retention rate in the cyromazine granules is 98.82-99.23%, after irradiation for 5 days, the cyromazine content retention rate in the cyromazine granules is 97.39-98.66%, after irradiation for 8 days, the cyromazine content retention rate in the cyromazine granules is 96.82-97.71%, and after irradiation for 10 days, the cyromazine content retention rate in the cyromazine granules is 96.45-97.08%.
[0010] (3) The cyromazine granules prepared by the present application can meet various external administration modes and have wide application range. BRIEF DESCRIPTION OF DRAWINGS
[0011] Figure 1 The liquid chromatogram of the cyromazine granules prepared in Example 2 in Test Example 2 after strong light experiment for 1 day; Figure 2 The liquid chromatogram of the cyromazine granules prepared in Example 2 in Test Example 2 after strong light experiment for 5 days; Figure 3 The liquid chromatogram of the cyromazine granules prepared in Example 2 in Test Example 2 after strong light experiment for 10 days; Figure 4 The liquid chromatogram of the cyromazine granules prepared in Comparative Example 3 in Test Example 2 after strong light experiment for 1 day; Figure 5 The liquid chromatogram of the cyclopropamine granules prepared in Comparative Example 3 of Test Example 2 after 5 days of intense light experiment; Figure 6 The liquid chromatogram of the cyclopropamine granules prepared in Comparative Example 3 of Test Example 2 after 10 days of intense light experiment. Detailed Implementation
[0012] To provide a clearer understanding of the technical features, objectives, and effects of the present invention, specific embodiments of the present invention are now described.
[0013] Example 1 A method for preparing cyproheptadine granules, specifically comprising: 1. Take 10g of cyproheptadine raw powder, 75g of sodium carboxymethyl starch, 210g of corn starch, 40g of phenyl salicylate, 95g of HPMC, and 40g of ethyl cellulose. Mix the above components using a three-dimensional mixer and then add them to a fluidized bed.
[0014] 2. Dissolve 30g of PVP K30 in 200mL of water and stir well. Use this as a binder. Turn on the fluidized bed and after the material is in a fluidized state, spray the binder into the fluidized bed to granulate the material to a particle size of 1mm.
[0015] 3. After granulation, dry the product, discharge it, weigh it, and obtain ciprofloxacin granules.
[0016] This embodiment also provides a cyclopropamine granule prepared by the aforementioned preparation method.
[0017] Example 2 A method for preparing cyproheptadine granules, specifically comprising: 1. Take 10g of cyproheptadine raw powder, 50g of sodium carboxymethyl starch, 225g of corn starch, 35g of phenyl salicylate, 90g of HPMC, and 50g of ethyl cellulose. Mix the above components evenly with a three-dimensional mixer and then add them to a fluidized bed.
[0018] 2. Dissolve 40g of PVP K30 in 200mL of water and stir well. Use this as a binder. Turn on the fluidized bed and after the material is in a fluidized state, spray the binder into the fluidized bed to granulate the material to a particle size of 1mm.
[0019] 3. After granulation, dry the product, discharge it, weigh it, and obtain ciprofloxacin granules.
[0020] This embodiment also provides a cyclopropamine granule prepared by the aforementioned preparation method.
[0021] Example 3 A method for preparing cyproheptadine granules, specifically comprising: 1. 10 g of cypendazole, 65 g of sodium carboxymethyl starch, 195 g of corn starch, 25 g of phenyl salicylate, 110 g of HPMC, 45 g of ethyl cellulose, and the above components are mixed by a three-dimensional mixer and then added to a fluidized bed.
[0022] 2. 50 g of PVP K30 is dissolved in 200 mL of water, stirred uniformly as a binder, and then sprayed into the fluidized bed to perform granulation after the material is in a fluidized state, and the particle size is 1 mm.
[0023] 3. After the granulation is completed, drying, discharging, and weighing are performed to obtain cypendazole granules.
[0024] The embodiment also provides cypendazole granules prepared by the above preparation method.
[0025] Example 4 A preparation method of cypendazole granules, specifically comprising: 1. 10 g of cypendazole, 75 g of sodium carboxymethyl starch, 155 g of corn starch, 30 g of phenyl salicylate, 125 g of HPMC, and 60 g of ethyl cellulose are mixed by a three-dimensional mixer and then added to a fluidized bed.
[0026] 2. 45 g of PVP K30 is dissolved in 200 mL of water, stirred uniformly as a binder, and then sprayed into the fluidized bed to perform granulation after the material is in a fluidized state, and the particle size is 1 mm.
[0027] 3. After the granulation is completed, drying, discharging, and weighing are performed to obtain cypendazole granules.
[0028] The embodiment also provides cypendazole granules prepared by the above preparation method.
[0029] Comparative Example 1: Reducing the amount of light absorber A preparation method of cypendazole granules, specifically comprising: 1. 10 g of cypendazole, 75 g of sodium carboxymethyl starch, 155 g of corn starch, 30 g of phenyl salicylate, 125 g of HPMC, and 60 g of ethyl cellulose are mixed by a three-dimensional mixer and then added to a fluidized bed.
[0030] 2. 45 g of PVP K30 is dissolved in 200 mL of water, stirred uniformly as a binder, and then sprayed into the fluidized bed to perform granulation after the material is in a fluidized state, and the particle size is 1 mm.
[0031] 3. After the granulation is completed, drying, discharging, and weighing are performed to obtain cypendazole granules.
[0032] The comparative example also provides a cyromazine granule prepared by the aforementioned preparation method.
[0033] Comparative Example 2 Reducing the amount of suspending agent A preparation method of a cyromazine granule, specifically: 1. 10 g of cyromazine raw powder, 75 g of carboxymethyl starch sodium, 280 g of corn starch, 40 g of phenyl salicylate, 25 g of HPMC, and 40 g of ethyl cellulose are mixed using a three-dimensional mixer, and then added to a fluidized bed.
[0034] 2. 30 g of PVP K30 is dissolved in 200 mL of water, and stirred uniformly as a binder. The fluidized bed is opened, and the material is in a fluidized state. The binder is sprayed to prepare granules with a particle size of 1 mm.
[0035] 3. After the granulation is completed, drying, discharging, and weighing are performed to prepare a cyromazine granule.
[0036] The comparative example also provides a cyromazine granule prepared by the aforementioned preparation method.
[0037] Comparative Example 3 A commercially available cyromazine premix, in which the mass content of cyromazine is 2%.
[0038] Comparative Example 4 A commercially available cyromazine soluble powder, in which the mass content of cyromazine is 2%.
[0039] In the preparation of the cyromazine granule according to the preparation methods of Examples 1-4 and Comparative Examples 1-2, 500 g of raw materials (i.e., the total amount of cyromazine raw powder, carboxymethyl starch sodium, corn starch, phenyl salicylate, HPMC, ethyl cellulose, and PVP K30 is 500 g) is used for feeding. In the granulation in the fluidized bed, the conditions of the fluidized bed are uniformly controlled as follows: the frequency of the peristaltic pump is 20%, the air inlet speed is 50 m 3 / h, and the air inlet temperature is 55℃.
[0040] Test Example 1 Determination of the state in water and the sedimentation volume ratio Take 3 g of cyromazine granules of Example 1-4 and Comparative Example 1-4 or commercially available preparation in a beaker, then add 50 mL of purified water, stir until evenly dispersed, transfer to a 50 mL graduated cylinder with a stopper, record the initial height H0 of the suspension, stand for 3 h, record the height H of the suspension again, calculate the sedimentation volume ratio F value of the suspension (F value = H / H0), the F value should be between 0-1, the larger the F value, the more stable the granules in water, and take the upper solution to detect the cyromazine content retention rate, the higher the cyromazine content retention rate, the more stable the granules in water (since the cyromazine granules are water-insoluble, after dispersing the cyromazine granules in water, the initial cyromazine granules can be evenly dispersed in water without settling, but after standing for 3 h, if the stability of the cyromazine granules in water is poor, settling will occur, by detecting the cyromazine content retention rate in the upper solution, i.e. the retention rate of the cyromazine granules that are still evenly dispersed in water after standing for 3 h, the stability of the prepared cyromazine granules in water can be characterized), the test results are shown in Table 1.
[0041] Table 1
[0042] The above results show that the cyromazine granules of Example 1-4 and Comparative Example 1 have excellent stability and basically do not settle. In Comparative Example 2, after reducing the amount of suspending agent, the sedimentation volume ratio of the prepared cyromazine granules is significantly smaller, indicating that after reducing the amount of suspending agent, the granules cannot be completely suspended, resulting in instability of the prepared cyromazine granules, thus more settling occurs after standing, further indicating that the cyromazine granules prepared in Example 1-4 have excellent stability in water and can meet the requirements of spray and dry application.
[0043] Test Example 2: Light Stability Test Take 100 g of cyromazine granules of Example 1-4 and Comparative Example 1-4 or commercially available preparation, respectively, and place them in a light box with a daylight lamp for light experiment, the illumination condition is 4500 lx, take samples after 1 day, 2 days, 5 days, 8 days, and 10 days of light experiment, respectively, perform liquid chromatography detection, calculate the cyromazine content by external standard method, and calculate the cyromazine content retention rate, the results are shown in Table 2.
[0044] Table 2
[0045] The liquid chromatograms of the cyromazine granules prepared in Example 2 after 1 day of light experiment, 5 days of light experiment, and 10 days of light experiment are shown in Figure 1 , Figure 2 , Figure 3The liquid chromatogram of the cyromazine preparation of Comparative Example 3 after 1 day of the strong light experiment, 5 days of the strong light experiment, and 10 days of the strong light experiment is shown in FIG. 1, FIG. 2, and FIG. 3, respectively. Figure 4 , Figure 5 , Figure 6 .
[0046] The above results show that the stability of cyromazine in the cyromazine granules of Examples 1-4 and Comparative Example 2 is much better than that of the commercial preparation product, and comparing Examples 1-4 with Comparative Example 1, it can be found that the stability of the cyromazine granules of Examples 1-4 is higher than that of the product of Comparative Example 1, thus adding the light absorber and controlling the amount of the light absorber added can protect cyromazine and increase the stability of the prepared cyromazine granules under strong light.
[0047] Test Example 3: Fly control effect determination 240 growing and finishing pigs with a body weight of 30 kg ± 2 kg were selected and evenly divided into 8 groups, and the same daily feed was used for each group. The cyromazine preparations of Examples 1-4 and Comparative Examples 1-4 were diluted with water to a cyromazine concentration of 1000 ppm, then stirred to a uniform state, and the cyromazine solutions were sprayed onto the feces of the growing and finishing pigs in groups 1-8, respectively.
[0048] Fly control effect determination: 500 g of fecal samples were collected from each group 1 day before spraying, and on the 1st, 3rd, 5th, 8th, 10th, and 15th days after spraying. During collection, 100 g of samples were taken from 5 different positions of the feces of each group of growing and finishing pigs, mixed uniformly, and then 100 g of the 500 g of fecal samples were taken. After 3 weeks of further incubation in an environment with a temperature of 25°C and a humidity of 60%, the number of live and dead fly larvae that appeared during the incubation period was counted and recorded, and the mortality rate of fly larvae was calculated. The results are shown in Table 3.
[0049] Table 3
[0050] The above results show that the fly control effect of the cyromazine granules prepared in Examples 1-4 is significantly higher than that of the commercial cyromazine preparations in Comparative Examples 3 and 4 in the later period, mainly because cyromazine is easily degraded in a strong light environment. The commercial cyromazine preparations have no protective measures, so the cyromazine in the cyromazine preparations is directly exposed to strong light. Due to the poor stability of cyromazine, the action time of the commercial cyromazine preparations in Comparative Examples 3 and 4 is short, and repeated application is required to ensure the fly control effect. The addition of phenyl salicylate in Examples 1-4 can well protect cyromazine, prolong the action time of cyromazine, and reduce costs.
Claims
1. A granule of cycloaminodiazine, characterized in that, The raw materials of the cyclopropy aminezine granules include cyclopropy aminezine raw powder, disintegrant, binder, filler, light absorber, suspending agent, sustained-release matrix; The disintegrant is sodium carboxymethyl starch, the binder is PVP K30, the filler is corn starch, the light absorber is phenyl salicylate, the suspending agent is HPMC, and the sustained-release matrix is ethyl cellulose; The light absorber accounts for 5-8% of the weight percentage of dry matter; The suspending agent accounts for 18-25% of the weight percentage of dry matter.
2. The cyromazine granules according to claim 1, characterized in that, The cyclopropy aminezine raw powder accounts for 2% of the weight percentage of dry matter; The disintegrant accounts for 10-15% of the weight percentage of dry matter; The binder accounts for 6-10% of the weight percentage of dry matter; The filler accounts for 31-45% of the weight percentage of dry matter; The sustained-release matrix accounts for 8-12% of the weight percentage of dry matter.
3. A process for the preparation of a cypendazole granule as claimed in any one of claims 1-2, characterized in that, After mixing the cyclopropy aminezine raw powder, disintegrant, filler, light absorber, suspending agent, and sustained-release matrix, adding them into the fluidized bed until the materials are in a fluidized state, spraying the binder aqueous solution, granulating, drying, and obtaining the cyclopropy aminezine granules.
4. The process for the preparation of the cyromazine granules according to claim 3, characterized in that, The concentration of the binder aqueous solution is 15-25 g / 100 mL.
5. The method of claim 3, wherein the cyp halogenated pyrimidine particles are prepared by, During granulation, the granulation particle size is 0.5-1 mm; The conditions of fluidized bed during granulation were as follows: the frequency of peristaltic pump was 20-25%, the air inlet velocity was 50-55 m / s, and the air inlet temperature was 55-60°C. 3 The conditions of fluidized bed during granulation were as follows: the frequency of peristaltic pump was 20-25%, the air inlet velocity was 50-55 m / s, and the air inlet temperature was