An albendazole ivermectin premix and a preparation method thereof

Abstract

This invention relates to the field of pharmaceutical premixes, addressing the problem in existing technologies of simultaneously ensuring uniform dispersion of the active pharmaceutical ingredient during preparation and when the premix is ​​used with drinking water. It provides an albendazole-ivermectin premix and its preparation method, comprising the following steps: S100, dissolving ivermectin in ethanol to obtain a first solution; adding albendazole and water to the first solution to obtain a first suspension; S200, adding an adjuvant to the first suspension to obtain a second suspension; S300, mixing the second suspension with a soluble carrier, and then granulating to obtain the albendazole-ivermectin premix. This invention, by dissolving ivermectin in a mixed solvent of ethanol and water, ensures the uniformity of ivermectin in the solution system. Furthermore, when mixing the solution with a soluble carrier, it significantly improves the uniformity of ivermectin within the carrier, allowing for more precise dosage of ivermectin when using the albendazole-ivermectin premix.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical premixes, and more specifically, to an albendazole ivermectin premix and its preparation method. Background Technology

[0002] Albendazole-ivermectin premix is ​​a standard anthelmintic included in the 2017 edition of the "Veterinary Drug Quality Standards" (Chemical Drug Volume). It is used to expel internal nematodes, flukes, tapeworms, and external parasites. The dosage and administration method is to mix it with feed. However, the manufacturing process of this product has drawbacks, including uneven mixing, inconvenience in use, and poor palatability, which can lead to problems during clinical application.

[0003] Existing technologies primarily employ batch-addition mixing to address the issue of uneven mixing, but this method is cumbersome. Patent application number 201911246127.0 discloses an albendazole-ivermectin premix and its preparation method. This method involves pre-forming a suspension and adding surfactants, emulsifiers, and dispersants to ensure uniform dispersion of the active pharmaceutical ingredient within the suspension, thereby improving the uniformity of the drug components in the granulated particles and exhibiting good dispersibility when used with water. However, the aforementioned patent uses ethanol as a solvent to obtain the suspension, meaning the solvent system of the suspension contains at least ethanol. During the drying process, ethanol evaporates, resulting in the absence of ethanol in the system when the premix is ​​used with drinking water. In this case, the dispersibility of the active pharmaceutical ingredient differs from that in the suspension. Therefore, ensuring uniform dispersion of the active pharmaceutical ingredient in the premix is ​​difficult when simultaneously ensuring its dispersion effect when used with drinking water. Summary of the Invention

[0004] The purpose of this invention is to provide an albendazole ivermectin premix and its preparation method, which solves the problem that existing technologies cannot simultaneously ensure the uniform dispersion of the active pharmaceutical ingredient during the preparation process and when the premix is ​​used with drinking water.

[0005] The embodiments of the present invention are achieved through the following technical solutions:

[0006] A method for preparing an albendazole-ivermectin premix includes the following steps:

[0007] S100. Ivermectin is dissolved in ethanol to obtain a first solution; albendazole and water are added to the first solution to obtain a first suspension.

[0008] S200. After adding the adjuvant to the first suspension, a second suspension is obtained; the adjuvant is used at least to improve the suspension properties of albendazole and ivermectin.

[0009] S300. After mixing the second suspension into a soluble carrier, the albendazole ivermectin premix is ​​obtained through a granulation process.

[0010] The drying process is used to evaporate water and ethanol.

[0011] Preferably, the preparation method further includes:

[0012] Under the condition that the ratio of ivermectin, albendazole and soluble carrier is constant;

[0013] Obtain a first relationship curve between the first dosage ratio, the amount of auxiliary agent, and the stability of the second suspension; the first dosage ratio is the ratio of ethanol to water.

[0014] Obtain a second relationship curve between the second dosage ratio, the dosage of the adjuvant, and the suspension stability; the second dosage ratio is the ratio of the premix to the water, and the suspension stability is the suspension stability of ivermectin and albendazole in drinking water;

[0015] Based on the first and second relationship curves, obtain the ethanol dosage, the auxiliary agent dosage, and the ratio of the second dosage.

[0016] Preferably, a third relationship curve between the average particle size of ivermectin, the first dosage ratio, and its corresponding suspension stability is obtained to obtain the first set of pairs of numbers corresponding to the suspension stability ≥ a first set threshold; the first pair of numbers includes: the average particle size of ivermectin and the first dosage ratio;

[0017] Obtain the fourth relationship curve between the average particle size of albendazole, the first dosage ratio and its corresponding suspension stability, and obtain the second pair of numbers corresponding to the suspension stability ≥ the first set threshold; the second pair of numbers includes: the average particle size of albendazole and the first dosage ratio.

[0018] The suspension stability of albendazole and ivermectin was obtained when the first dosage ratio was the same in the first and second pairs of groups, thereby obtaining the suspension consistency.

[0019] The average particle size of albendazole and ivermectin when the suspension consistency is ≥ the second set threshold.

[0020] Preferably, the additives, by weight, comprise: 3-5 parts poloxamer 188, 0.5-1.5 parts PEG400, and 1-3 parts polysorbate 80.

[0021] Preferably, the relationship between the first dosage ratio and the solubility of ivermectin is obtained, and then the dosage of ethanol in step S100 is obtained based on the dosage of ivermectin and the minimum dosage of water in step S100.

[0022] Preferably, the amount of water in S100 is determined according to the amount of soluble carrier used and the requirements of the granulation process.

[0023] Preferred methods for determining suspension stability include:

[0024] Obtain the turbidity-time curve of the suspension at a set depth to obtain the turbidity decrease rate corresponding to the set time or the time required to reach the set turbidity difference.

[0025] Preferably, albendazole has a different color than ivermectin;

[0026] The specific methods for obtaining levitation consistency include:

[0027] Acquire images of suspensions above a set depth, and determine the first average rate of change of the area of ​​the albendazole-corresponding color patch with depth and the second average rate of change of the area of ​​the ivermectin-corresponding color patch with depth.

[0028] Suspension consistency is obtained based on the first average rate and the second average rate.

[0029] Preferably, the soluble carrier comprises polysaccharides or monosaccharides.

[0030] An albendazole ivermectin premix prepared by the aforementioned method.

[0031] The present invention has at least the following beneficial effects:

[0032] This invention ensures the homogeneity of ivermectin in the solution system by dissolving ivermectin in a mixed solvent of ethanol and water. This significantly improves the homogeneity of ivermectin within the carrier when the solution is mixed with a soluble carrier, allowing for more precise dosage when using the albendazole-ivermectin premix. When the albendazole-ivermectin premix is ​​used simultaneously with drinking water, the soluble carrier dissolves in water, forming a solution with higher density and viscosity, releasing albendazole and ivermectin. Since the adjuvant is retained in the albendazole-ivermectin premix, the dispersion uniformity and suspension stability of albendazole and ivermectin are improved with the combination of the adjuvant and the higher viscosity solution. The amount of raw material obtained through the first and second relationship curves effectively reduces the difference between the stability of the second suspension and the suspension stability of ivermectin and albendazole in drinking water, ensuring both the homogeneity of the active pharmaceutical ingredient in the premix and the suspension stability of the premix when used with drinking water. Attached Figure Description

[0033] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0034] Figure 1 This is a schematic diagram of the suspension corresponding to the premix in this invention;

[0035] Figure 2 This is a schematic diagram of the suspension corresponding to the premixed agent. Detailed Implementation

[0036] To make the objectives, methods, and advantages of the embodiments of the present invention clearer, the methods in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments.

[0037] Example 1: A method for preparing an albendazole-ivermectin premix, comprising the following steps:

[0038] S100. Ivermectin is dissolved in ethanol to obtain a first solution; albendazole and water are added to the first solution to obtain a first suspension.

[0039] S200. After adding the adjuvant to the first suspension, a second suspension is obtained; the adjuvant is used at least to improve the suspension properties of albendazole and ivermectin.

[0040] S300. After mixing the second suspension into a soluble carrier, the albendazole ivermectin premix is ​​obtained through a granulation process.

[0041] The drying process is used to evaporate water and ethanol.

[0042] In practice, due to the extremely low amount of ivermectin added to the premix, it is difficult to achieve uniform mixing in the solid system. This embodiment, by dissolving ivermectin in a mixed solvent of ethanol and water, ensures the uniformity of ivermectin in the solution system. Consequently, when mixing the solution with a soluble carrier, the uniformity of ivermectin within the carrier is significantly improved, allowing for more precise dosage when using the albendazole-ivermectin premix.

[0043] The advantage of dissolving ivermectin in ethanol first and then adding water is at least that it increases the dissolution rate of ivermectin.

[0044] The adjuvant can make albendazole uniformly dispersed and stably suspended in the second suspension.

[0045] When albendazole-ivermectin premix is ​​used simultaneously with drinking water, the soluble carrier dissolves in the water, forming a solution with higher density and viscosity, and releasing albendazole and ivermectin. Because the adjuvants are retained in the albendazole-ivermectin premix, the combination of the adjuvants and the higher viscosity solution improves the dispersion uniformity and suspension stability of albendazole and ivermectin.

[0046] Example 2: To simultaneously ensure uniform dispersion of the solids in the second suspension and uniform dispersion of the premix when added to drinking water, improvements were made based on Example 1. In this example, the preparation method further includes:

[0047] Under the condition that the ratio of ivermectin, albendazole and soluble carrier is constant;

[0048] Obtain a first relationship curve between the first dosage ratio, the amount of auxiliary agent, and the stability of the second suspension; the first dosage ratio is the ratio of ethanol to water.

[0049] Obtain a second relationship curve between the second dosage ratio, the dosage of the adjuvant, and the suspension stability; the second dosage ratio is the ratio of the premix to the water, and the suspension stability is the suspension stability of ivermectin and albendazole in drinking water;

[0050] Based on the first and second relationship curves, obtain the ethanol dosage, the auxiliary agent dosage, and the ratio of the second dosage.

[0051] In practice, the uniform dispersion and stable suspension of albendazole in the second suspension does not necessarily mean that it will achieve uniform dispersion and stable suspension in the final drinking water system. This is because, at least, the evaporation of ethanol creates a difference in the presence or absence of ethanol in the two solutions. Ethanol, besides being a solvent for ivermectin, also contributes to improved suspension stability. For example, both albendazole and ivermectin are strongly hydrophobic drugs, making it difficult for water to effectively wet the drug particles, thus affecting the efficacy of adjuvants, such as the adsorption and unfolding of surfactants on the particle surface. Furthermore, the presence of ethanol in the solvent reduces the overall polarity of the solvent, making it easier for the hydrophobic portion of the adjuvant to approach and adsorb onto the surface of the drug particles. As can be seen from the foregoing, the evaporation of ethanol leads to a decrease in the suspension stability of ivermectin and albendazole in drinking water. Therefore, this invention employs a soluble carrier to compensate for the decrease in suspension stability caused by ethanol evaporation to a certain extent. Furthermore, the weight of water in the second suspension is much lower than that of the soluble carrier, which needs to be dissolved in drinking water. Therefore, the amount of drinking water used is much higher than the amount of water in the second suspension. This reduces the effectiveness of the adjuvant in maintaining particle suspension, meaning the stability of the second suspension may differ significantly from the stability of the premix in drinking water. The stability of the second suspension affects the uniformity of dispersion of the active pharmaceutical ingredient in the premix, while the stability of the premix in drinking water affects the drug's efficacy against biological agents. Therefore, the applicant aims to ensure suspension stability in both stages as simultaneously as possible, given a fixed ratio of ivermectin, albendazole, and the soluble carrier.

[0052] After determining the initial dosage ratio, the solubility of ivermectin in the ethanol-water mixture was essentially determined. Following the confirmation of the ivermectin dosage, the minimum dosage of the mixture was also determined. Because the amount of ivermectin is extremely small, its dissolution in the mixture has almost no effect on the suspension stability of albendazole. When the minimum dosage of the mixture is used, and the dosage of albendazole is fixed, the suspension stability of albendazole in the second suspension is related to the amount of adjuvant. After confirming the initial dosage ratio, the minimum dosage of the mixture was used to obtain data on the adjuvant dosage and its corresponding stability in the second suspension. Then, the initial dosage ratio was continuously changed, and data on the adjuvant dosage and its corresponding stability in the second suspension were obtained. Finally, the first relationship curve can be easily obtained.

[0053] The amount of adjuvant used when the stability of the second suspension meets the requirements can be obtained from the first relationship curve, thereby obtaining the proportion of adjuvant in the premix and the mixing ratio, thus ensuring the uniformity of dispersion of the active pharmaceutical ingredient in the premix.

[0054] The ratio of drinking water, excipients, and soluble carriers affects the suspension stability of ivermectin and albendazole in the solution system. Based on the first relationship curve, the range of excipient proportions in the premix can be obtained. After determining the second dosage ratio based on this range, the dosage of excipients in the premix and their corresponding suspension stability can be obtained. This allows for determining the appropriate excipient dosage in the premix when the suspension stability of the active pharmaceutical ingredient in drinking water meets the requirements, further narrowing the range of excipient proportions in the premix so that the excipient proportion simultaneously satisfies both the second requirement for suspension stability and the suspension stability of drug particles in drinking water. Furthermore, the dosage of drinking water can be determined based on the second dosage ratio to guide the use of the premix.

[0055] The second type of suspension stability, as well as the suspension stability of ivermectin and albendazole in drinking water, can be characterized by particle settling velocity or time to complete settling, or by the ratio of settling volumes over a specified time.

[0056] Example 3: Since ivermectin in the second suspension is in a dissolved state, but will disperse in the premix as a solid state after drying, its suspension properties in drinking water in the solid state may differ significantly from those of albendazole. This could even lead to the two drug components gradually separating during storage, affecting the overall efficacy of the drug. Furthermore, it would increase the amount of data required to obtain the second relationship curve, resulting in a smaller range of adjuvant dosages. Therefore, the applicant improved upon Example 2. In this example, the method further includes:

[0057] Obtain the third relationship curve between the average particle size of ivermectin, the first dosage ratio and its corresponding suspension stability, and obtain the first set of numbers corresponding to the suspension stability ≥ the first set threshold; the first set of numbers includes: the average particle size of ivermectin and the first dosage ratio.

[0058] Obtain the fourth relationship curve between the average particle size of albendazole, the first dosage ratio and its corresponding suspension stability, and obtain the second pair of numbers corresponding to the suspension stability ≥ the first set threshold; the second pair of numbers includes: the average particle size of albendazole and the first dosage ratio.

[0059] The suspension stability of albendazole and ivermectin was obtained when the first dosage ratio was the same in the first and second pairs of groups, thereby obtaining the suspension consistency.

[0060] The average particle size of albendazole and ivermectin when the suspension consistency is ≥ the second set threshold.

[0061] In practice, the first threshold can be set according to actual needs. For example, when suspension stability is characterized by the time to complete settling, the first threshold can be set as the minimum time required for complete settling. The larger the aforementioned time value, the higher the required suspension stability.

[0062] A common first dosage ratio is selected from the first and second pairs of groups, and the average particle size of albendazole and ivermectin corresponding to the aforementioned common first dosage ratio is obtained. The suspension stability corresponding to the aforementioned average particle size can then be obtained, and finally, the suspension consistency is calculated. As an example, suspension consistency = |1 - suspension stability of ivermectin / suspension stability of albendazole|. The closer the suspension consistency is to 0, the higher the consistency.

[0063] The second threshold can be set according to actual needs. The closer the value is to 0, the higher the requirement for suspension consistency. As an example, the second threshold is set to 0.1.

[0064] Suspension stability refers to the suspension stability of the drug in a mixture of ethanol and water at the first dosage ratio.

[0065] After obtaining the average particle size of albendazole and ivermectin when the suspension consistency is ≥ the second set threshold, the first relationship curve and the second relationship curve are then obtained.

[0066] Example 4: Since only a mixture of ethanol and water was used to obtain the average particle size of albendazole and ivermectin without adding any adjuvants, in order to minimize the difference in the effect of the adjuvants on the suspension of the two particles, thereby further reducing the amount of data, while increasing the range of applicable parameters obtained in the end and further improving the selectivity of process parameters, an improvement was made based on Example 3. In this example, the adjuvants, by weight, include: 3-5 parts poloxamer 188, 0.5-1.5 parts PEG400 and 1-3 parts polysorbate 80.

[0067] In practice, when both drug particles are hydrophobic, have a fixed particle size, and are located in the same solution system, the factors affecting the difference in suspension stability of the two drug particles are mainly the wetting and binding effects of the adjuvants on the surface of the drug particles. Therefore, this embodiment limits the selection of adjuvants to ensure that the surface properties of the two drug particles are as similar as possible. Poloxamer 188 is a nonionic block copolymer with excellent biocompatibility, non-toxicity, and non-irritation. It not only reduces interfacial tension and promotes wetting but also forms a strong steric stabilizing effect through its long chains, exhibiting stable performance in high-sugar environments. Furthermore, poloxamer 188 can promote drug absorption and improve bioavailability. PEG400 has good wettability and can promote the contact, spreading, and encapsulation of poloxamer 188 and polysorbate 80 on the surface of the drug particles. The monooleate chains in polysorbate 80 can be anchored to the drug particles through hydrophobic interactions, while the large hydrophilic chains provide strong steric hindrance and stereostrate stability, preventing particle aggregation. The drug surface, the PPO segments of poloxamer, and the monooleate chain of polysorbate 80 can be tightly bonded together through extremely strong hydrophobic interactions to form a strong composite anchoring layer.

[0068] The amount of additives used is the total amount of poloxamer 188, PEG400 and polysorbate 80.

[0069] The experiment showed that, when using the adjuvant components and proportions provided in this embodiment, the use of the adjuvant had minimal impact on the suspension differences of ivermectin and albendazole when using the average particle size obtained in Example 3.

[0070] Example 5: To ensure that ivermectin dissolves in the second suspension, an improvement was made based on Example 2. In this example, the preparation method includes:

[0071] Obtain the relationship between the first dosage ratio and the solubility of ivermectin, and then, based on the dosage of ivermectin and the minimum amount of water in step S100, obtain the amount of ethanol used in step S100.

[0072] In the specific implementation process, since the amount of ivermectin used in this embodiment is extremely small, the use of a mixture of ethanol and water can easily satisfy the requirement of sufficient dissolution of ivermectin.

[0073] As an example, in order to minimize the amount of ethanol used so that the soluble carrier in the premix can better compensate for the loss of suspension stability of drug particles after ethanol loss, the minimum first dosage ratio required to meet the dissolution requirements of ivermectin can be used, and then the amount of ethanol can be easily obtained based on the amount of water used in S100.

[0074] Example 6: The amount of water used in S100 was determined according to the amount of soluble carrier used and the requirements of the granulation process.

[0075] In the specific implementation process, the granulation process can adopt spray drying. Since spray drying has certain requirements on the system viscosity, if the viscosity is too high, the system fluidity will be poor. It usually needs to be controlled below 1000 cP to ensure smooth atomization and pumping. Therefore, the minimum amount of water can be obtained based on the amount of soluble carrier and the viscosity requirements of spray drying. The amount of water in S100 is greater than or equal to the aforementioned minimum amount.

[0076] The granulation process can also employ existing wet granulation methods. The soluble carrier and the second suspension are mixed using a granulator to form a moistened, lumpy soft mass, which is then extruded to obtain wet granules. These wet granules are then dried to obtain the albendazole ivermectin premix. In S100, the amount of water used needs to ensure the structural stability of the lumpy soft mass and wet granules during wet granulation to ensure proper molding. The range of water usage can be easily determined through experimentation, and the maximum value within that range can be selected.

[0077] Example 7: Based on Examples 2-6, this example provides a method for determining suspension stability, including:

[0078] Obtain the turbidity-time curve of the suspension at a set depth to obtain the turbidity difference corresponding to the set time or the time required to reach the set turbidity difference.

[0079] In practice, the stability of the second suspension and the suspension stability in the second relationship curve can both be measured using the method provided in this embodiment. The larger the turbidity difference corresponding to the set time, the worse the suspension stability. The longer the time required to reach the set turbidity difference, the better the suspension stability.

[0080] Turbidity can be detected using existing turbidimeters. The core mechanism is based on the interaction between light and suspended particles, primarily calculating the suspended matter concentration by measuring changes in scattered or transmitted light. As an example, the incident light is horizontally incident, and a photodetector receives the scattered light at a 90° angle to the incident light. This is converted into an electrical signal, which is then calibrated to calculate the turbidity value. The set depth is the depth of the incident light relative to the suspension surface, and can be selected according to actual conditions, such as setting the depth to 50% of the suspension height. The set time can also be set according to actual conditions, such as 6 hours. Turbidity reduction rate = 100% * (initial turbidity - current turbidity) / initial turbidity. The set turbidity difference can also be set according to actual conditions, such as setting it to 50% of the initial turbidity value.

[0081] When suspension stability is characterized by the rate of turbidity decrease, the first set threshold is a percentage.

[0082] When suspension stability is characterized by time, the first set threshold is the length of time.

[0083] Example 8: To better characterize suspension stability, improvements were made based on Example 7. In this example, albendazole and ivermectin have different colors. The method for obtaining suspension consistency specifically includes: acquiring images of suspensions above a set depth; obtaining the first average rate of change of the area of ​​the albendazole-corresponding color patch with depth and the second average rate of change of the area of ​​the ivermectin-corresponding color patch with depth based on the first average rate and the second average rate; and obtaining the suspension consistency based on the first average rate and the second average rate.

[0084] In practice, drugs produced by different manufacturers vary in color. Albendazole and ivermectin are primarily white or pale yellow. If the raw materials are similar in color and difficult to distinguish, an edible pigment insoluble in water, such as lutein, can be coated onto the surface of albendazole. Due to sedimentation, drug particles tend to aggregate at the bottom of the image. Therefore, the image can be divided into equal-width patches from top to bottom. The area of ​​the corresponding color patch for albendazole within each patch can then be obtained, leading to the first average velocity of the area change with depth.

[0085] The suspension consistency in Example 3 is used to obtain the average particle size of albendazole and ivermectin, which can ensure the suspension consistency of the premix in drinking water as much as possible. However, due to the addition of adjuvants, the suspension consistency during actual use will inevitably be affected. Therefore, the suspension consistency measurement in this example is needed to further confirm the effectiveness of the process parameters.

[0086] As an example, the first average speed = (area of ​​the bottom tile - area of ​​the top tile) / distance between the two tiles. The second average speed can be easily obtained by referring to the previous example.

[0087] As an example, by fitting a finite relationship curve to area and depth, a functional relationship is obtained: First average velocity = (Area under the curve) / Depth difference. The area under the curve can be easily obtained through integration. Depth is the distance between the horizontal central axis of the patch and the surface of the suspension.

[0088] As an example, when the first average speed is less than the second average speed, the suspension consistency = first average speed / second average speed; when the first average speed is greater than the second average speed, the suspension consistency = second average speed / first average speed. The closer the suspension consistency is to 1, the better the suspension effect.

[0089] Example 9: In order to increase the palatability of the premix, an improvement was made based on Example 7. In this example, the soluble carrier includes polysaccharides or monosaccharides.

[0090] In practice, soluble carriers such as sucrose or glucose can be used. Soluble carriers not only adjust the viscosity of the solution to a certain extent but also facilitate granulation. Furthermore, the sweetness of polysaccharides or monosaccharides can mask the unpleasant odor of the drug.

[0091] Application Example: Albendazole: 60g, Ivermectin: 2.5g, Sucrose: 350g, Maltodextrin: 350g, Anhydrous Ethanol: 150g, Water from S100: 80g, Poloxamer 188: 15g, PEG400: 4.5g, Polysorbate 80: 8g. Albendazole passes through a 120-mesh sieve, and ivermectin passes through a 150-mesh sieve. The albendazole-ivermectin premix is ​​prepared according to the aforementioned formula and the preparation method provided by this invention.

[0092] Comparative example: Using traditional processes, albendazole and ivermectin premix were obtained by physical blending according to the formula: 60g albendazole, 2.5g ivermectin, and 700g calcium carbonate.

[0093] Experiment 1: The content uniformity test method in the appendix of the Chinese Veterinary Pharmacopoeia was used to determine the content of albendazole and ivermectin in 10 individually packaged samples. The A+2.2S value was calculated and the test results are shown in Table 1.

[0094] Table 1

[0095] Albendazole Ivermectin Application examples 8.2 5.6 Comparative Example 18.6 21.3

[0096] As can be seen from Table 1, the uniformity of the active pharmaceutical ingredients in the albendazole ivermectin premix prepared by the method provided in this invention is much higher than that of products prepared by traditional processes.

[0097] Experiment 2: 5g of albendazole ivermectin premix prepared according to the application example and comparative example were added to pure water to prepare 50ml of suspension. The suspension was placed in a 100ml graduated cylinder, stirred for 1 minute and then allowed to stand. The sedimentation volume ratio was recorded at different time points. The test results are shown in Table 2.

[0098] Table 2

[0099] time 0.5h 2h 6h 12h 24h Application examples 100% 98% 95% 92% 88% Comparative Example 85% 65% 42% 30% 18%

[0100] As can be seen from Table 2, the suspension stability of the albendazole ivermectin premix prepared by the preparation method provided by the present invention is much higher than that of products prepared by traditional processes.

[0101] Since visual color can stimulate an animal's appetite, the present invention provides a formulation in which water-soluble lemon yellow can be added. That is, the mixture is prepared by water, ethanol and lemon yellow, and the amount of lemon yellow accounts for 0.1‰ of the soluble carrier. Of course, since the amount of colorant is small, its impact on the properties of the mixture is small. Therefore, the mixture can be prepared by water and ethanol first, and after obtaining the optimal process parameters, the colorant corresponding to the desired color can be selectively added.

[0102] Application example: The suspension after adding lemon yellow to the corresponding premix, after standing for 24 hours, is as follows... Figure 1 As shown. The suspension corresponding to the premix in the comparative example, after standing for 24 hours, is as follows. Figure 2 As shown in the figure, the comparative example shows obvious stratification with a large amount of sediment at the bottom, and a sedimentation volume ratio of about 45%. In contrast, the suspension in the application example remains basically uniformly suspended with only a small amount of sediment at the bottom, and a sedimentation volume ratio of about 88%.

[0103] The above are merely preferred embodiments of the present invention and are not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing an albendazole-ivermectin premix, characterized in that, Includes the following steps: S100. Ivermectin is dissolved in ethanol to obtain the first solution; After adding albendazole and water to the first solution, a first suspension was obtained; S200. After adding the additive to the first suspension, a second suspension is obtained; The adjuvant is used at least to improve the suspension properties of albendazole and ivermectin; S300. After mixing the second suspension into a soluble carrier, the albendazole ivermectin premix is ​​obtained through a granulation process. The drying process is used to evaporate water and ethanol.

2. The preparation method according to claim 1, characterized in that, The preparation method also includes: Under the condition that the ratio of ivermectin, albendazole and soluble carrier is constant; Obtain a first relationship curve between the first dosage ratio, the amount of auxiliary agent, and the stability of the second suspension; the first dosage ratio is the ratio of ethanol to water. Obtain a second relationship curve between the second dosage ratio, the dosage of the adjuvant, and the suspension stability; the second dosage ratio is the ratio of the premix to the water, and the suspension stability is the suspension stability of ivermectin and albendazole in drinking water; Based on the first and second relationship curves, obtain the ethanol dosage, the auxiliary agent dosage, and the ratio of the second dosage.

3. The preparation method according to claim 2, characterized in that, Obtain the third relationship curve between the average particle size of ivermectin, the first dosage ratio and its corresponding suspension stability, and obtain the first set of numbers corresponding to the suspension stability ≥ the first set threshold; the first set of numbers includes: the average particle size of ivermectin and the first dosage ratio. Obtain the fourth relationship curve between the average particle size of albendazole, the first dosage ratio and its corresponding suspension stability, and obtain the second set of numbers corresponding to the suspension stability ≥ the first set threshold; the second set of numbers includes: the average particle size of albendazole and the first dosage ratio. The suspension stability of albendazole and ivermectin was obtained when the first dosage ratio was the same in the first and second pairs of groups, thereby obtaining the suspension consistency. The average particle size of albendazole and ivermectin when the suspension consistency is greater than or equal to the second set threshold.

4. The preparation method according to claim 3, characterized in that, The additives, by weight, comprise: 3-5 parts poloxamer 188, 0.5-1.5 parts PEG400, and 1-3 parts polysorbate 80.

5. The preparation method according to claim 1, characterized in that, Obtain the relationship between the first dosage ratio and the solubility of ivermectin, and then, based on the dosage of ivermectin and the minimum amount of water in step S100, obtain the amount of ethanol used in step S100.

6. The preparation method according to claim 1, characterized in that, The amount of water used in S100 is determined based on the amount of soluble carrier used and the requirements of the granulation process.

7. The preparation method according to any one of claims 3-6, characterized in that, Methods for determining suspension stability include: Obtain the turbidity-time curve of the suspension at a set depth to obtain the turbidity decrease rate corresponding to the set time or the time required to reach the set turbidity difference.

8. The preparation method according to claim 7, characterized in that, Albendazole and ivermectin have different colors; The specific methods for obtaining levitation consistency include: Acquire images of suspensions above a set depth, and determine the first average rate of change of the area of ​​the albendazole-corresponding color patch with depth and the second average rate of change of the area of ​​the ivermectin-corresponding color patch with depth in the image. Suspension consistency is obtained based on the first average rate and the second average rate.

9. The preparation method according to claim 7, characterized in that, The soluble carrier includes polysaccharides or monosaccharides.

10. An albendazole ivermectin premix prepared by the preparation method according to any one of claims 1-9.

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