Ordered aggregates of medicaments for automated drinking water lines in aquaculture, methods of making and using the same

Abstract

The present application discloses an ordered aggregate of a drug for aquaculture automatic drinking line and a preparation method thereof. The ordered aggregate of the drug has a two-level structure, wherein the first-level structure is a particle with an average particle size of 0.1-1 μm, and the second-level structure is a hollow or concave spherical structure or a doughnut structure with an average particle size of 10-1000 μm formed by the first-level structure. The ordered aggregate of the present application is mixed with an auxiliary material to form a composition, and the composition can be mixed with water to prepare a suspension containing a high concentration of the drug. The suspension can meet the stable drug delivery requirement of the aquaculture automatic drinking line for 6-8 hours, and the suspended particles can be quickly dissolved to form a solution for poultry to drink after entering the drinking line.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, and more specifically, relates to ordered aggregates of drugs for use in automated aquaculture drinking water lines, pharmaceutical compositions, and their preparation and application methods. Background Technology

[0002] With the booming of the livestock industry, the methods of drug administration in livestock farming have undergone revolutionary changes. The main purpose of this change is to reduce labor costs, improve efficiency, reduce human-livestock (poultry) contact, and improve biosafety. Adding drugs to automated drinking water lines, allowing livestock to receive medication through drinking water, is undoubtedly the most attractive method. This method can significantly save labor costs, reduce human-livestock (poultry) contact, and improve biosafety. Adding drugs to automated drinking water lines is usually done using a proportioning pump (or automatic proportioning pump, waterline dosing device, etc., simply called a dosing pump) powered by the water pressure in the pipeline. The dosing pump, powered by the water pressure in the pipeline, can draw concentrated drug solution into the pump according to a set ratio (generally 20–400 times, more preferably 50–300 times, and even more preferably 50–200 times). After mixing with water according to the set ratio, the drug solution is added to the automated drinking water line and delivered to various pens and stalls for drinking. This water-powered dosing method has the advantages of requiring no external power and adjustable dosing concentration. For drugs with high water solubility, or those that can be dissolved at 50-400 times the clinically recommended concentration, this dosing pump offers flexibility and convenience, significantly reducing the workload of drug preparation. For example, to prepare a concentrated solution at a 200-fold dilution, only 5 liters of solution are needed to obtain 1 ton of diluted solution for livestock drinking, greatly reducing preparation work. Currently, the biggest obstacle limiting the use of dosing pumps in automated livestock drinking lines is the solubility of the drugs themselves, especially at high concentrations. Although theoretically many drugs can form aqueous solutions at the clinically recommended concentration, suitable for livestock drinking without clogging the water line, using a dosing pump requires first preparing a high-concentration solution (e.g., 50-400 times the clinically recommended concentration) and then adding it to the automated livestock drinking line by adjusting the dosing pump's proportions. Preparing feed solutions at concentrations 50 to 400 times the clinically recommended dosage is often very difficult. This is because many drugs have low solubility. While solutions can be obtained at the clinically recommended dosage, at higher concentrations (50 to 400 times the clinically recommended dosage, then 50 to 300 times, and even further, 50 to 300 times), many drugs cannot produce homogeneous mixtures due to solubility limitations, resulting only in suspensions. Such suspensions are prone to sedimentation, leading to uneven drug concentrations. They can also clog dosing pumps. Furthermore, due to dissolution and dissolution rates, undissolved drugs added to automated aquaculture water lines may not dissolve completely, causing blockages.Therefore, for drugs that cannot be formulated into solutions due to solubility issues and can only be formulated into suspensions, the suspension needs to have good suspension properties and a fast dissolution rate when added to the water line to facilitate drug dosing using a dosing pump. This requires the suspended particles to be small, ideally at the nanometer or submicron level. This allows for a longer suspension stability time and a faster dissolution rate after dilution. However, smaller particles, especially at the micrometer and / or submicrometer levels, are prone to aggregation, resulting in poorer suspension and solubility. Therefore, simply reducing the particle diameter is not enough to solve these difficulties. Alternatively, in practical use of automated aquaculture water lines for drug administration... In this process, the solvent for the high-concentration drug solution used is not water. When this high-concentration drug solution is obtained by rapidly adding a large amount of water to achieve the clinically used concentration, the drug is directly diluted by a large amount of water, quickly bypassing the supersaturated state and directly entering the unsaturated state to obtain the drug solution corresponding to the clinically recommended dosage for use in livestock drinking. However, when the drug solution is to be added to the automated drinking water line of the livestock using a dosing pump, because it is necessary to prepare a concentrated drug solution of a certain multiple of the clinically recommended dosage, the solubility of the drug is reduced due to dilution with water under this high concentration condition. Some of the drug will precipitate out of the water due to the reduced solubility and settle, making it very difficult to add the drug solution through the dosing pump and potentially causing blockage.

[0003] Preparing drugs with low water solubility into microemulsions and then adding them to automated aquaculture water supply lines is one solution for drug administration in these lines, but its high cost hinders its large-scale application. Therefore, it is essential to obtain a new drug formulation suitable for automated aquaculture water supply lines. The drugs that this invention aims to address generally possess the following characteristics: they should be able to be dissolved at concentrations corresponding to the clinically recommended dosage, but at concentrations 20–400 times (further, 50–300 times, and even further, 50–300 times) above the clinically recommended dosage due to solubility limitations. For drugs with relatively low solubility, the solubility is generally between 0.005 and 40 g, but this is also related to the concentration corresponding to the clinically recommended dosage. For example, if a drug has very low solubility but its concentration at the clinically recommended dosage is very low, allowing it to be dissolved at concentrations 50–400 times the clinically recommended dosage, then dosing using a dosing pump is not a problem; therefore, this is not the problem this invention aims to solve. Alternatively, even if a drug has high solubility, if its clinically recommended dosage corresponds to a high concentration, it may not completely dissolve when preparing a solution at 20 to 400 times the clinically recommended dosage concentration. This is the problem that this invention aims to solve. Generally speaking, the solubility of drugs that this invention aims to address is in the range of 0.005 to 40 g, more commonly in the range of 0.01 to 20 g, and most commonly in the range of 0.01 to 10 g; even further, in the range of 0.01 to 1 g (the solubility generally refers to the solubility in water at room temperature (generally 10 to 40°C)). Drugs with even higher solubility, such that they still dissolve at 20 to 400 times the clinically recommended dosage concentration, or drugs with very low solubility, or drugs that cannot dissolve even at the clinically recommended dosage concentration, are not within the scope of this invention. Generally, the concentration corresponding to the clinically recommended dosage of a drug is between tens and thousands of ppm, mostly in the range of 20 to 1000 ppm. Therefore, the solubility of the drug in water is 0.005 to 40 g, with a further preferred solubility of 0.01 to 20 g, a further solubility of 0.01 to 10 g, and even further solubility of 0.01 to 1 g. Moreover, the drug may not dissolve at concentrations 20 to 400 times its clinically recommended dosage, especially at 50 times its clinically recommended dosage.

[0004] In addition, Mycoplasma synoviae (MS) has been a persistent problem in the production of broilers, laying hens, and even breeding chickens in my country for many years. Chlortetracycline hydrochloride, as an effective drug against mycoplasma, is widely used in MS control. Chlortetracycline hydrochloride is generally in the form of crystalline flakes, and its solubility is relatively low and its dissolution rate is slow. In practical use, it is usually formulated into a soluble powder with various excipients. Because chlortetracycline hydrochloride has low solubility, it is feasible to prepare a solution at the clinically recommended concentration, such as 0.2–0.4 g / L in water, in practical use. However, when used in automated aquaculture water lines for dosing via a dosing device, it needs to be prepared into a solution with a concentration 50–200 times that of the automated aquaculture water line (i.e., the concentration corresponding to the clinically recommended dosage), i.e., a concentration of 10 g / L–80 g / L. This concentration greatly exceeds the solubility of chlortetracycline hydrochloride in room temperature water (approximately 0.86 g, with a concentration of about 8.6 g / L), making it impossible to directly use the existing chlortetracycline hydrochloride in automated aquaculture water lines for dosing via a dosing device.

[0005] Therefore, there is a need for a drug formulation that can be prepared into a stable, uniform, high-concentration (relative to the concentration corresponding to the clinically recommended dosage) suspension, which can maintain high suspension stability and be added to the automated aquaculture water line through a dosing device without causing blockage. Furthermore, it can quickly form a uniform solution with the diluted water after entering the automated aquaculture water line through the dosing device. Summary of the Invention

[0006] One objective of this invention is to provide an ordered aggregate of a drug for use in an automated aquaculture water supply line. The ordered aggregate of the drug has a two-level structure, wherein the primary structure is particles with an average particle size of 0.1 to 1 μm, and the secondary structure is a hollow or concave spherical structure or a donut structure with an average particle size of 10 to 1000 μm formed from the primary structure.

[0007] More preferably, the average particle size of the primary structure is 0.1 to 0.5 μm; even more preferably, the average particle size of the primary structure is 0.2 to 0.4 μm.

[0008] More preferably, the average particle size of the secondary structure is 15–500 μm; even more preferably, the average particle size of the secondary structure is 20–100 μm.

[0009] The drug used to prepare the ordered aggregates of the present invention has a solubility in water of 0.05 to 40 g, more preferably 0.1 to 20 g, and even more preferably 0.1 to 10 g, at a temperature of 10 to 40 °C.

[0010] The drug may be selected from one or more of the following: chlortetracycline hydrochloride, florfenicol, fenbendazole, albendazole, trimethoprim, dimetridazole, sulfamethoxazole, sulfamethoxazole, flunixin meglumine, tiamulin fumarate, diclazuril, toltrazuril, ivermectin, doxycycline hydrochloride, sulfonamides, fluoroquinolones, amoxicillin, ampicillin, gentamicin, neomycin sulfate, apramycin, doxycycline, oxytetracycline, lincomycin, spectinomycin, tylosin tartrate, tilmicosin, tiamulin, colistin sulfate, ofloxacin, and chlortetracycline.

[0011] In some specific embodiments of the present invention, the drug is selected from chlortetracycline hydrochloride, florfenicol, demetridazole, or combinations thereof.

[0012] The ordered aggregates of the present invention can be formulated into an aqueous solution at the concentration of a clinically used drug, but cannot be completely dissolved in water at concentrations of 20 to 400 times the clinically recommended dosage, further at concentrations of 50 to 300 times, and even further at concentrations of 50 to 200 times.

[0013] Preferably, the ordered aggregates of the drug further include a surfactant.

[0014] Preferably, the surfactant is selected from nonionic surfactants, more preferably Span and Tween, and even more preferably Span 20, 40, 60, 80; Tween 20, 40, 60, 80.

[0015] Preferably, the amount of the surfactant is 0.01-1%, more preferably 0.05-0.5%.

[0016] Preferably, the ordered aggregates of the drug further include a thickener.

[0017] Preferably, the thickener is selected from one or a combination of xanthan gum, guar gum, pectin, polyethylene glycol, polyoxyethylene, and carboxymethyl cellulose.

[0018] Preferably, the polyethylene glycol has a molecular weight of 1,000 to 20,000, and more preferably 2,000 to 10,000.

[0019] Preferably, the amount of the thickener is 0.01-1%, more preferably 0.05-0.5%.

[0020] Another aspect of the present invention provides a method for preparing ordered aggregates of drugs for use in automated aquaculture water supply lines, the method comprising the following steps:

[0021] (1) Obtain a slurry containing the primary structure and its poor solvent.

[0022] (2) The slurry is spray-dried to obtain ordered aggregates of the drug.

[0023] Preferably, the method for obtaining the slurry includes the following steps (1-1):

[0024] Drug particles with a particle size of 0.1–1 μm are obtained, and then they are mixed with a poor solvent, or

[0025] The mixture of the grinding drug and its unsuitable solvent is ground until the particle size of the drug particles therein is 0.1–1 μm, or

[0026] Adding a poor solvent to a solution containing the drug results in the precipitation of drug particles with a particle size of 0.1–1 μm. After filtration, the drug particles are mixed with the poor solvent, or...

[0027] Add a poor solvent to a solution containing the drug to precipitate the drug particles, while simultaneously grinding the solution and filtering to obtain a mixture of the drug particles and the poor solvent.

[0028] Preferably, the method for obtaining the slurry further includes the following steps (1-2):

[0029] Surfactants and / or thickeners are added during the process of obtaining a slurry containing the primary structure and its undesirable solvent to obtain a uniformly dispersed slurry.

[0030] Preferably, the unsuitable solvent is selected from water.

[0031] Preferably, the mass ratio of the primary structure to the poor solvent in the slurry is 1:1 to 1:100, more preferably 1:1 to 1:80, and even more preferably 1:1 to 1:60.

[0032] In another aspect, the present invention provides a pharmaceutical composition comprising an ordered aggregate of the aforementioned drug and an excipient, wherein the excipient has a solubility in water of 10-200 g at 10-40°C, more preferably 40-180 g, and even more preferably 50-150 g.

[0033] Preferably, the ordered aggregates of the drug in the pharmaceutical composition constitute 40-95% by weight, more preferably 60-90%, and even more preferably 70-80%.

[0034] Preferably, the excipients are selected from glucose, sucrose, fructooligosaccharides, soluble starch, sodium sulfate, magnesium sulfate, potassium sulfate, ammonium sulfate, sodium chloride, potassium chloride, ammonium chloride, or combinations thereof, more preferably glucose and / or sodium sulfate; most preferably glucose.

[0035] In another aspect, the present invention provides an ordered aggregate of chlortetracycline hydrochloride for use in automated aquaculture drinking water lines. The ordered aggregate of chlortetracycline hydrochloride has a two-level structure, wherein the primary structure is particles with an average particle size of 0.1 to 1 μm, and the secondary structure is a hollow or concave spherical structure or a donut structure with an average particle size of 10 to 1000 μm formed from the primary structure.

[0036] In some preferred embodiments of the present invention, the average particle size of the primary structure is 0.1 to 0.5 μm; in some more preferred embodiments of the present invention, the average particle size of the primary structure is 0.2 to 0.4 μm.

[0037] In some preferred embodiments of the present invention, the average particle size of the secondary structure is 15-500 μm; in some more preferred embodiments of the present invention, the average particle size of the secondary structure is 15-100 μm; and most preferably, the average particle size of the secondary structure is 20-50 μm.

[0038] In another aspect, the present invention provides a composition comprising the ordered aggregates of the above-mentioned chlortetracycline hydrochloride and glucose, wherein the glucose content is 60-90% by mass.

[0039] In some preferred embodiments of the present invention, the glucose content is 70-80% by mass.

[0040] In another aspect, the present invention provides a method for administering drugs through an automated aquaculture water line, the method comprising preparing the above composition into a suspension using water, and then adding it to the automated aquaculture water line to obtain a solution, wherein the drug concentration in the suspension is 20 to 400 times, more preferably 50 to 300 times, and even more preferably 50 to 200 times, the drug concentration in the automated aquaculture water line.

[0041] The preferred method for adding the suspension to the automated drinking water line for livestock is to use a water line dosing device (proportional pump dosing device). The dilution ratio is adjusted to match the concentration of the prepared suspension and the clinical usage concentration (e.g., the clinical usage concentration of chlortetracycline hydrochloride is 0.2–0.4 g / L. If the planned dosage is 0.2 g / L of the ordered aggregate chlortetracycline hydrochloride described in this application, a concentrated solution prepared at 200 times its concentration would be 40 g / L, which is an incompletely soluble suspension. Therefore, to obtain a 0.2 g / L solution at the water line, the dilution ratio of the proportional pump dosing device needs to be adjusted to 200, and the concentrated solution can be drawn into the water line to dilute it 200 times to obtain the required 0.2 g / L solution). The solution obtained by rapidly diluting and dissolving the drug added to the drinking water line through the water line dosing device can be transported to various pens and stalls for livestock to drink. Attached Figure Description

[0042] Figure 1 The scanning electron microscope image of the ordered aggregates of chlortetracycline hydrochloride prepared in this invention, at a magnification of 2500, shows that the secondary structure of the ordered aggregates is a hollow or concave spherical structure or a donut structure.

[0043] Figure 2 The image is a scanning electron microscope (SEM) image of the ordered aggregates of chlortetracycline hydrochloride prepared according to the present invention, with a magnification of 5000, showing that the secondary structure of the ordered aggregates is a concave spherical structure.

[0044] Figure 3 The image is a scanning electron microscope (SEM) image of the ordered aggregates of chlortetracycline hydrochloride prepared according to the present invention, with a magnification of 10,000, showing that the secondary structure of the ordered aggregates is a donut structure.

[0045] Figure 4 The image is a scanning electron microscope (SEM) image of the ordered aggregates of chlortetracycline hydrochloride prepared according to the present invention, with a magnification of 10,000. It shows the primary structure exposed after the ordered aggregates are truncated, and the wall thickness of the ordered aggregates is approximately 6 μm.

[0046] Figure 5 The image is a scanning electron microscope (SEM) image of the ordered aggregates of chlortetracycline hydrochloride prepared according to the present invention, with a magnification of 20,000, showing the primary structure exposed after the ordered aggregates are truncated.

[0047] Figure 6 Microscopic images of ordinary chlortetracycline hydrochloride flakes are shown.

[0048] Figure 7 The solution containing the drug concentration from the automated aquaculture water supply line is shown to be a transparent solution.

[0049] Figure 8 The invention shows a suspension of ordered aggregates of chlortetracycline hydrochloride prepared according to the present invention, wherein the concentration of chlortetracycline hydrochloride is 200 times that in automated aquaculture water lines.

[0050] Figure 9 The image shows a field photograph of a suspension of a drug composition containing 20% ​​by mass of ordered aggregates of chlortetracycline hydrochloride. The suspension concentration used was 40 g / L, which is 100 times the clinically recommended concentration of 0.4 g / L.

[0051] Figure 10 This is a schematic diagram of the structure of a dosing tank with a pressure balance pipe that can be used in this invention, wherein 1—tank body, 2—dosing inlet pipe connected to the dosing pump, 3—air inlet pipe, and 4—filter. Detailed Implementation

[0052] Addressing the problem in existing technologies that some drugs are difficult to prepare into high-concentration, stable, and homogeneous liquids (suspensions) for rapid addition to automated aquaculture water lines via dosing devices to achieve a uniform solution, the inventors of this application, through in-depth research, discovered that preparing such drugs into ordered aggregates and then mixing them with excipients to form a composition allows for the preparation of a high-concentration, stable, and homogeneous liquid using water. When this slurry is added to the automated aquaculture water line via a dosing device, it can quickly disperse or dissolve in water to obtain a homogeneous solution without causing blockages in the automated aquaculture water line. Based on this, the present invention was completed.

[0053] The drugs targeted by this invention can produce a homogeneous aqueous solution at the concentration corresponding to the clinically recommended dosage for administration in automated aquaculture drinking water lines. However, at concentrations 50 to 200 times the clinically recommended dosage, their solubility in water is insufficient to produce a homogeneous aqueous solution. For example, chlortetracycline hydrochloride has a solubility of approximately 0.86 g (8.6 g / L) in water at room temperature, while the concentration corresponding to the clinically recommended dosage is 0.2 to 0.4 g / L, which is less than its maximum solubility. Therefore, it can form a homogeneous aqueous solution in automated aquaculture drinking water lines for administration. However, when prepared into a solution with a concentration of 10 to 80 g / L at concentrations 20 to 400 times (further, 50 to 300 times, and even further, 50 to 200 times) of its clinically recommended dosage, only a solid-liquid mixture with obvious precipitation can be obtained because this concentration is much greater than its solubility. This unevenly mixed solid-liquid mixture cannot be used by the dosing device to uniformly add the drug to the automated aquaculture drinking water line to form drinking water with a consistent drug concentration. For drugs with very low solubility in water, which cannot completely dissolve to obtain a homogeneous solution even at the clinically recommended dosage concentration, administration via automated aquaculture water lines may cause blockages. Therefore, such drugs are not suitable for this invention. They can be administered by mixing with feed, rather than through automated aquaculture water lines. The drugs used in this invention need to have a certain solubility at room temperature, for example, 0.05–40 g in water at 10–40°C, further 0.1–30 g, and even further 0.5–20 g, and this solubility is also related to the actual clinical concentration used. This invention prepares the drug into ordered aggregates, allowing it to be formulated into a homogeneous and stable suspension at 20–400 times (further, 50–300 times, and even further, 50–200 times) the clinically recommended dosage concentration. When this suspension is added to the automated aquaculture water line using a dosing device, the drug can quickly dissolve in water, obtaining a homogeneous aqueous solution.

[0054] The ordered drug aggregates of the present invention have at least two levels of structure; the first level structure consists of nano- and / or micro-sized particles with an average diameter of less than 1 μm; the second level structure is an ordered aggregate macrostructure (hollow or concave spherical structure, or donut structure) with an average particle size greater than 10 μm. The particle size of the particles, as the primary structure, is one of the key factors in achieving the objectives of this application, because the particle size plays a crucial role in the stability of high-concentration drug suspensions and the rapid dissolution of such suspensions upon dilution with water to obtain a solution state. Particle sedimentation follows the Stokes equation, and the limiting velocity of particle sedimentation can be expressed by the following formula:

[0055]

[0056] Where u t ρ' represents the descent velocity of a particle under ideal conditions as time approaches infinity. Before reaching this velocity, the particle's settling velocity should be lower than this value. For particles with smaller diameters, the particle can quickly approach or reach its settling limit velocity. Therefore, when calculating the settling time, the time to reach the limit velocity and the sinking distance in that stage can be ignored, simplifying the calculation to use only the limit velocity to calculate the time required for the particle to sink; ρ' is the particle density; ρ is the density of the medium; μ is the viscosity of the medium; g is the gravitational acceleration; α represents half the equivalent diameter (equivalent radius) of the particle.

[0057] As can be seen from the above formula, if, under otherwise unchanged conditions, the equivalent radius of the particle doubles, its final stable descent rate quadruples, and vice versa. When the particle diameter of the drug decreases from 30 μm to 0.3 μm, it is equivalent to the equivalent radius becoming one-hundredth of its original value, and under ideal conditions, the particle descent rate becomes one ten-thousandth of its original value. Taking 0.3 μm chlortetracycline particles in an aqueous medium as an example, their density is 1.1770 g / cm³. 3 The viscosity of water is calculated to be 2.98 × 10⁻⁶. -3Pas. Calculations show that the ultimate descent speed is 0.0029 μm / s, a value calculated for a single spherical particle under ideal conditions. In reality, particle diameters are not exactly the same, and the actual calculation result will deviate slightly from this result, but both are still of the same order of magnitude. Using this speed, for a feed solution in a 10cm high dosing tank, it would take 344,828 seconds (approximately 96 hours) for the topmost chlortetracycline particle to descend 10cm. This time is significantly longer than the 6-hour dosing time required to add the drug to an automated aquaculture watering line using a dosing device. For drug particles smaller than 1μm, the settling time in a conventional dosing tank, calculated using the above formula, exceeds 10 hours, which is sufficient for the total dosing time (6-8 hours) of a typical automated aquaculture watering line. Furthermore, the dosing process generates some disturbance (due to the negative pressure created by the dosing tank), further prolonging the settling time. For example, drug particles with a diameter of 0.5 μm settle approximately four times faster than those with a diameter of 1 μm. According to the formula above, the settling time is 40 hours. This demonstrates that a particle size of 0.5 μm ensures that drug particles remain suspended in a high-concentration suspension for a sufficiently long time, and this suspension exhibits good fluidity, making it easy to add to automated aquaculture water lines using a dosing device.

[0058] Materials with a particle size of less than 0.1 μm (i.e., 100 nm) are called nanomaterials. Many current studies have shown that nanomaterials are harmful to living organisms; for example, nanomaterials have been shown to cause lung damage, including inflammation, fibrosis, and tumor formation. Due to concerns about the safety of nanomaterials, this invention preferably uses drug particles with a particle size greater than 0.1 μm.

[0059] In terms of solubility, when a suspension containing the primary structure of ordered aggregates of drugs (i.e., drug particles) is added to a large amount of water (added to the automated aquaculture water line via a dosing device), it can instantly reach a state below the drug saturation concentration. Moreover, during the process of drug particles entering the automated aquaculture water line, the disturbance and / or stirring generated by the dosing device further promotes their dissolution in a very short time, avoiding blockage of the water line.

[0060] According to the above formula, the smaller the particle size of the drug particles, the longer their settling time. However, smaller is not always better. From a preparation perspective, smaller particle sizes require more energy to overcome, resulting in higher energy consumption and costs. In the actual preparation process, obtaining particles with a diameter greater than 0.1 μm is relatively easy. Obtaining particles smaller than 0.1 μm through grinding is difficult. Furthermore, from a practical application perspective, excessively small particle sizes are unnecessary for adding drugs to automated aquaculture water lines via dosing devices. Therefore, the particle size of the primary structure particles in this invention is 0.1–1 μm, more preferably 0.1–0.5 μm, and most preferably 0.2–0.4 μm, for example, 0.20 μm, 0.25 μm, 0.30 μm, 0.35 μm, 0.40 μm, etc.

[0061] Smaller particle sizes are advantageous for achieving high-concentration suspensions, but they also have drawbacks. Due to their relatively large specific surface area and surface energy, particles easily agglomerate to reduce surface energy and improve stability. These agglomerated aggregates affect the dissolution rate and suspension stability of the drug particles in water. Therefore, to address this issue, this invention prepares drugs with the aforementioned primary structure into ordered aggregates, i.e., secondary structures. These secondary structures are formed by arranging the primary structures in a specific manner. These primary structures (i.e., smaller particle sizes) can reduce their surface energy and eliminate agglomeration behavior by forming secondary structures. The average particle size of the ordered aggregates of the secondary structure is preferably 10 μm or larger, so as not to generate significant dust during use. Excessively large particle sizes would prevent the primary structure from rapidly disintegrating upon contact with water to achieve a good suspension. Therefore, this invention preferably uses secondary structure particles with a particle size of less than 1000 μm. That is, the particle size of the secondary structure of the present invention is preferably 10 μm to 1000 μm, more preferably 15 to 500 μm, even more preferably 20 to 200 μm, and even more preferably 20 to 100 μm. For example, 20 μm, 25 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, etc.

[0062] When particles, as the primary structure, are orderly packed into a secondary structure with a macroscopic surface, the surface area of ​​the particles is reduced, significantly decreasing the area in contact with the outside world; on the other hand, the possibility of clumping is reduced. Upon contact with water, the supporting forces between the primary structure particles in the secondary structure rapidly disappear, and the secondary structure quickly collapses back into the primary structure. Because the particle size is small, the dissolution rate is very fast; before reaching the drug saturation concentration, it dissolves rapidly, which is the desired state for clinical use. When the drug concentration exceeds its saturation solubility, the particles remain suspended in the aqueous medium in the primary structure form. This is the desired state of the prepared high-concentration drug solution in the container before adding the drug to the drinking water line using a dosing device. When a liquid containing a high concentration of drug (mainly a suspension of drug particles) is drawn into the drinking water line, the stirring and mixing effect generated by the turbulence of the water allows the smaller-diameter drug particles to dissolve in the drinking water of the line in a very short time, obtaining a uniform drug aqueous solution.

[0063] Drugs that can be prepared into ordered aggregates as described in this invention include, but are not limited to, chlortetracycline hydrochloride, florfenicol, fenbendazole, albendazole, trimethoprim, dimetridazole, sulfamethoxypyrimidine, sulfamethoxypyrimidine sodium, flunixin meglumine, tiamulin fumarate, diclazuril, toltrazuril, ivermectin, doxycycline hydrochloride, sulfonamides, fluoroquinolones, amoxicillin, ampicillin, gentamicin, neomycin sulfate, apramycin, doxycycline, oxytetracycline, lincomycin, spectinomycin, tylosin tartrate, tilmicosin, tiamulin, colistin sulfate, ofloxacin, and chlortetracycline.

[0064] The method for preparing ordered aggregates of drugs for use in automated aquaculture water supply lines according to the present invention includes the following steps:

[0065] (1) Obtain a slurry containing the primary structure and its poor solvent.

[0066] (2) The slurry is spray-dried to obtain ordered aggregates of the drug.

[0067] The steps for obtaining a slurry containing the primary structure and its unsuitable solvent can be as follows: grinding the drug to a particle size of 0.1–1 μm, then mixing it with the unsuitable solvent; or grinding the mixture of the drug and its unsuitable solvent to a particle size of 0.1–1 μm; or adding the unsuitable solvent to a solution containing the drug to precipitate the drug particles, grinding the slurry, filtering to obtain a mixture of the drug particles and the unsuitable solvent. The grinding equipment can be existing equipment such as a colloid mill, ball mill, or homogenizer, and a particle size analyzer can be used to measure whether the desired particle size is obtained. Surfactants and / or thickeners can be added during the grinding process to promote the grinding process. Surfactants prevent particles from agglomerating (i.e., agglomerating) during grinding, resulting in uniform particle dispersion and maintaining the spherical shape of the subsequently formed ordered aggregates of the drug. Thickeners prevent particle sedimentation during grinding and generate additional adhesive forces during the subsequent spray drying process when the primary structure forms the secondary structure, resulting in ordered aggregates with stronger mechanical strength. Furthermore, when formulating ordered aggregates of drugs into high-concentration drug suspensions, both surfactants and thickeners contribute to the uniformity and stability of the suspension. The amounts of surfactants and thickeners used are each preferably 0.01–1%, more preferably 0.05–0.5%. For example, if the content of a thickener is too high, the viscosity of the prepared high-concentration drug suspension will be too great to be easily added to automated aquaculture water lines using a dosing device.

[0068] Drug particles of the target size can also be obtained in the following ways:

[0069] (1) Add a poor solvent to the solution containing the drug and control the particle size of the precipitated crystal particles. This can be controlled by controlling the amount of poor solvent added and the stirring speed. If necessary, a certain amount of surfactant can be added to inhibit the increase of the particle size of the crystal particles in order to obtain particles of the target particle size.

[0070] (2) Particles of the target particle size are obtained by lowering the temperature of the saturated solution containing the drug. Preferably, the particle size of the precipitated particles is controlled by stirring during the cooling process. In this process, an appropriate surfactant may also be added to further control the particle size of the precipitated particles.

[0071] Alternatively, a reasonable combination of two or more of the above methods can be used to obtain the desired particle size of the drug particles.

[0072] The ordered aggregates of the drug of the present invention are hollow or concave spherical or donut-shaped structures, which are produced by the preparation process. This application preferably uses spray drying to obtain ordered aggregates of the drug for use in automated aquaculture watering lines.

[0073] Spray drying comprises two interconnected stages: the first stage is droplet formation; the second stage is removing the solvent from the formed droplets to obtain ordered aggregates of the drug. Specifically, droplets are obtained under high pressure, high-speed centrifugation, or high-speed collision conditions, followed by solvent evaporation and drying at a specific temperature and pressure. For drugs that decompose under prolonged high temperatures, the inlet and outlet temperatures of the nozzle must be considered during spray drying. Vacuum conditions are advantageous for lowering the system temperature and accelerating liquid evaporation.

[0074] To obtain the secondary structure, the generated droplets need to remove the solvent within a short time and form ordered aggregates of the drug by means of surface tension and capillary forces.

[0075] Hollow secondary structures dissolve faster than solid secondary structures when preparing high-concentration drug suspensions. Therefore, to obtain hollow secondary structures, this invention preferably performs spray drying at relatively high vacuum and / or relatively high temperatures, because under such conditions, the solvent (i.e., water) of the atomized droplets evaporates rapidly, which is advantageous for obtaining hollow structures. During the drying process, the atomized droplets initially shrink into spherical or near-spherical shapes due to surface tension, and the presence of surfactants in the system further facilitates this process. Larger droplets may deviate from a spherical shape, but for this invention, most droplets have micron or submicron diameters, for example, less than 1000 microns or less than 500 microns. Droplets of this size are more likely to form spherical shapes under surface tension, and even in the presence of other external factors (such as high-speed centrifugation, wind, collision forces, etc.), the droplets will rapidly form spherical or near-spherical shapes. Furthermore, the primary structures contained in the droplets are distributed substantially uniformly within the droplets. Under high vacuum and relatively high temperatures, due to the high specific surface area of ​​the droplets, the solvent (e.g., water) can evaporate rapidly. As the surface water evaporates, the droplet diameter decreases, and the drug particles, which were originally uniformly dispersed in the droplet, tend to move towards the center of the liquid sphere. Thus, particles that were initially dispersed within the droplet with little or no contact with each other gradually move towards the center to maintain their position on the surface of the reduced droplet. As the droplet diameter further decreases, the drug particles in the droplet come into contact with each other, forming a spherical or near-spherical shape. As the water on the droplet surface evaporates further, the drug dissolved in the solvent precipitates and further fills the formed spherical shell. Then, the solvent inside the shell diffuses along the gaps in the shell formed by the surface particles, which also causes the internal solvent to carry the particles within it to move towards the surface of the formed shell, further increasing the thickness of the particle accumulation in the shell. Once the solvent has completely evaporated, an ordered aggregate of drug particles (i.e., secondary structure) is formed. This secondary structure is a relatively smooth, spherical structure with a certain shell thickness and a central cavity. This structure allows the secondary structure to quickly collapse back into the primary structure during subsequent use. The primary structure dissolves rapidly in low-concentration aqueous solutions and forms a suspension with good suspension properties in high-concentration aqueous solutions. If the droplet size is large and / or the drug particle content in the solution is low and / or the solvent evaporation rate is too fast due to excessively high temperature and / or excessively high vacuum, the initial spherical shell will collapse due to the rapid evaporation of the solvent inside, creating a vacuum. At some stage of liquid evaporation, due to the pressure difference between the inside and outside, parts of the shell will collapse. This collapse can occur at one end or simultaneously at both symmetrical ends. When collapse occurs at one end of the shell, a concave spherical structure is formed; when collapse occurs simultaneously at both symmetrical ends, a donut structure is formed.In another scenario, when the particle size is large and / or the evaporation rate is slow, the shell has already formed while the interior is still in liquid form, which can cause cracking and result in a concave spherical shape.

[0076] Based on current requirements for drug delivery using dosing devices, a primary structure particle size of 0.1–1 μm satisfies the requirements for dissolution rate and suspension stability; a secondary structure particle size of 10 μm–1000 μm satisfies both the relative strength of the secondary structure and allows for relatively rapid solvent evaporation and formation of ordered aggregates during preparation. During atomization drying, the drug dissolved in the solvent rapidly precipitates out as the solvent evaporates, becoming part of the primary structure. If the slurry used to form the secondary structure also contains surfactants and / or thickeners, these will also become part of the secondary structure during the aforementioned drying process.

[0077] For secondary structures, if high-speed centrifugal spraying is used, the speed can be adjusted according to the viscosity of the liquid, generally at 300–3000 rpm / min. If pressure spraying is used, the liquid pressure should be between 1 MPa and 20 MPa; preferably between 2 MPa and 10 MPa; or a combination of methods can be used.

[0078] The ordered aggregates of the drug of the present invention are preferably prepared into a composition by mixing with excipients, and then the composition is mixed with water to prepare a suspension containing a high concentration of the drug. That is, the drug of the present invention is preferably provided in the form of a composition. Excipients that can be used in the present invention include, but are not limited to, glucose, sucrose, fructooligosaccharides, soluble starch, sodium sulfate, magnesium sulfate, potassium sulfate, ammonium sulfate, sodium chloride, potassium chloride, ammonium chloride, or combinations thereof. The role of excipients is to dilute the drug to a certain extent, improve the safety of use, and meet the legal and regulatory requirements for pharmaceutical preparations. For example, if chlortetracycline hydrochloride has a 20% effective content of soluble powder, the remaining 80% needs to be supplemented by excipients.

[0079] The aforementioned excipients have good water solubility and can dissolve in water, whether in suspensions containing high concentrations of drugs or in automatic water supply lines, without affecting the dosing process. Furthermore, these excipients will not increase the viscosity of the suspension system, thus not affecting its addition to the water line via the dosing device.

[0080] In addition, if only particles of 0.1 to 1 μm are used to directly prepare high-concentration suspensions, the suspension performance of small-diameter particles can generally be obtained. However, particles of this size have high surface energy and are prone to agglomeration during storage and transportation. In actual use, the possible agglomeration may make it difficult to obtain a uniform suspension.

[0081] In this invention, the viscosity of the suspension containing a high concentration of the drug is preferably no more than 10 times the viscosity of the drug solution in an automatic drinking water line, and more preferably no more than 5 times. A lower viscosity allows the suspension to easily pass through the dosing device into the water line; if the viscosity is too high, especially when preparing a high-concentration solution, it becomes difficult to add the suspension through the dosing device into the water line.

[0082] This application also provides a method for administering the above-mentioned composition using a dosing device, comprising preparing a suspension of the composition with water and then adding it to an automated aquaculture water supply line, wherein the drug concentration of the suspension is 20 to 400 times, more preferably 50 to 300 times, and even more preferably 50 to 200 times, the drug concentration in the automated aquaculture water supply line, which is generally adapted to the dosing dilution ratio of the dosing device used. For example, specifically: based on the concentration corresponding to the clinically recommended dosage of the drug and the dosing dilution ratio of the dosing device, a suspension with a drug concentration of 50 to 200 times the concentration corresponding to the clinically recommended dosage is prepared; the suspension is added to a dosing tank and then added to the automated aquaculture water supply line by a dosing pump. The preferred method for adding medication to the automated drinking water line is to use a water line dosing device (proportional pump dosing device). The dilution ratio is adjusted to match the concentration of the prepared suspension and the clinical usage concentration (e.g., the clinical usage concentration of chlortetracycline hydrochloride is 0.2–0.4 g / L. If the planned dosage is 0.2 g / L of the ordered aggregate chlortetracycline hydrochloride described in this application, a concentrated solution prepared at 200 times its concentration would be 40 g / L, which is an incompletely soluble suspension. Therefore, to obtain the 0.2 g / L solution at the water line, the dilution ratio of the proportional pump dosing device needs to be adjusted to 200. The concentrated solution is then drawn into the water line to dilute it 200 times to obtain the required 0.2 g / L solution). The solution obtained by rapidly diluting and dissolving the medication added to the drinking water line via the water line dosing device can be transported to various pens and stalls for livestock to drink. The dosing tank can be a closed tank with a pressure balancing pipe. It relies on the negative pressure generated by the dosing device to draw in air through the balancing pipe extending to the bottom of the tank. This further agitates the suspension, reducing sedimentation, although suspensions prepared using the ordered aggregates of this invention generally meet the suspension requirements. The suspension can be added to the water line using methods such as... Figure 9 The dosing pump shown (non-powered dosing method) can also be a dosing device equipped with a power unit. The preferred dosing method of the dosing device in this invention is as follows: Figure 9 The dosing pump shown uses the water pressure of the water line itself to draw in the drug, so that no additional power device is needed, and the drug can be added automatically according to the adjusted ratio.

[0083] As described above, the suspension properties of the ordered aggregates of the drug of the present invention generally meet the medication requirements for 6-8 hours. However, to further reduce the possibility of sedimentation, it is preferable that the dosing tank has a closed structure with a pressure balancing pipe, i.e., it consists of a tank body and a tank lid. The tank lid, except for the suction pipe and the dosing pump suction pipe, is sealed to the rest of the dosing tank. Furthermore, the inlet of the suction pipe is inserted into the bottom of the dosing tank. Thus, during dosing, because the dosing pump draws the liquid drug away through the suction port, creating negative pressure, gas is drawn into the dosing tank, causing disturbance to the drug in the dosing tank, further reducing the unevenness caused by the sedimentation of high-concentration drugs. A schematic diagram of such a dosing tank can be found in [reference needed]. Figure 10 .

[0084] After medication is added, it is preferable to rinse the dosing tank and dosing device with a small amount of water, and then add the rinsing solution to the automated aquaculture water line. Although the suspension prepared by this invention, containing a drug concentration of 20 to 400 times the clinically recommended dosage, has sufficient suspension stability to maintain a stable concentration for at least six hours, prolonged dosing is not recommended, as some drugs, such as chlortetracycline hydrochloride, may have their efficacy affected by prolonged storage.

[0085] In addition, after verification, the prepared suspension can also be combined with other materials, especially soluble materials, for drug addition.

[0086] In the description of this invention, for secondary structures (i.e., hollow or concave spherical structures, or donut structures), the average particle size is simply the maximum diameter of the maximum cross section of the structure.

[0087] the term

[0088] In the description of this invention, "primary structure" refers to particles with an average particle size of 0.1 to 1 μm. Therefore, "primary structure" and "drug particles" or "particles" refer to the same substance.

[0089] In the description of this invention, "ordered aggregate" and "secondary structure" both refer to the hollow or concave spherical structure or donut structure formed by drug particles. Therefore, "ordered aggregate", "secondary structure" and "hollow concave spherical structure", "concave spherical structure" and "donut structure" refer to the same substance. Detailed Implementation

[0091] The structure of chlortetracycline hydrochloride powder with ordered aggregates

[0092] The particles with a diameter of approximately 0.2–0.7 μm are primary particles of ordered aggregates of chlortetracycline hydrochloride, mainly obtained from the feed solution before spraying.

[0093] Preparation of chlortetracycline hydrochloride powder with an ordered aggregate structure, including its primary structure, secondary structure, and hollow structure, as shown in the attached figure. Figure 1-5 As shown.

[0094] The waterline dosing devices mentioned in the following examples are commonly used in aquaculture, such as the Shewuyou SWY-JYQ waterline dosing device, which is an existing product on the market or a similar product, and is similar in form. Figure 9 The dosing device and its installation method.

[0095] Example 1

[0096] A high-speed homogenizer was used to obtain primary granular slurry of chlortetracycline hydrochloride.

[0097] 100g of refined chlortetracycline hydrochloride powder (flaky crystals, average particle size 50 μm) was added to 1000mL of water to prepare a slurry. 1g of Tween 20 was added, and the mixture was first ground using a colloid mill for 20 minutes, followed by homogenization at high speed (20,000 rpm) for 30 minutes. During the grinding process, the system was maintained at a low temperature below 10°C. The particle size of the drug particles was measured using a particle size analyzer. If 90% of the drug particles had a particle size greater than 0.3 μm, the high-speed homogenization process was repeated. If 90% of the drug particles had a particle size of approximately 0.1–0.3 μm, the operation was terminated, yielding a slurry with the desired particle size.

[0098] Regarding the particle size of the original chlortetracycline powder, generally, performing the above homogenization operation 2 to 4 times will yield a slurry with 90% of the drug particles having a particle size of less than 1 μm; performing the homogenization operation 4 to 6 times will yield a slurry with 90% of the drug particles having a particle size of less than 0.5 μm; and performing the homogenization operation about 7 to 10 times will yield a slurry with 90% of the drug particles having a particle size of about 0.1 to 0.3 μm. The specific particle size can be adjusted according to the actual operation.

[0099] Example 2

[0100] A ball mill was used to obtain primary granular slurry of chlortetracycline hydrochloride.

[0101] 500g of refined chlortetracycline hydrochloride powder (flaky crystals, average particle size 40 μm) was added to 5L of water to prepare a slurry. The slurry was then premixed using a stirring device to obtain a liquid. 100g each of 1mm and 0.5mm zirconium beads were then used as grinding media, and the slurry was ground in a ball mill. The mill was cooled using a cooling device to maintain the liquid outlet temperature below 10°C. The grinding of all the liquid constituted one cycle, which was repeated 10 times. The particle size of the drug particles was measured using a particle size analyzer. 90% of the drug particles had a particle size of 0.1–0.5 μm.

[0102] Example 3

[0103] A ball mill was used to obtain florfenicol primary particle slurry.

[0104] Add 500g of florfenicol powder to 6L of water to prepare a solution, and then premix it using a stirring device to obtain the solution.

[0105] Using 200g of 0.5mm zirconium beads as the grinding medium, the above slurry was ground in a ball mill. The mill was cooled by a cooling device to keep the liquid outlet at a low temperature of less than 10°C. One cycle was completed when all the liquid was ground. The cycle was repeated 11 times. The particle size of the drug particles in the liquid was measured using a particle size analyzer. 90% of the drug particles had a particle size of 0.2-0.4μm.

[0106] Example 4

[0107] Spray drying yields ordered aggregates of chlortetracycline hydrochloride.

[0108] The slurry obtained in Example 1, with 90% of the drug particles having a particle size of about 0.1 to 0.3 μm, was atomized into droplets through a high-pressure nozzle under vigorous mixing. The droplet diameter was about 500 μm (estimated). The droplets were then rapidly dried by solvent evaporation under vacuum at an inlet temperature of 120°C. The dried powder was then cooled and collected to obtain ordered aggregates of aureomyces hydrochloride. The drug particles, which form the primary structure, are hollow particles with a particle size of about 0.1 to 0.3 μm and an average secondary structure size of 40 μm. Some particles are spherical, some are spherical with concave ends, and some are donut-shaped.

[0109] Example 5

[0110] Centrifugation and drying yielded ordered aggregates of chlortetracycline hydrochloride.

[0111] The slurry obtained in Example 2, with 90% of the drug particles having a particle size of 0.1–0.5 μm, was centrifuged at 3000 rpm to obtain droplets. The ejected droplets were rapidly centrifuged at 90°C under vacuum to evaporate the solvent. The particles were then cooled and collected to obtain ordered aggregates of chlortetracycline hydrochloride. Figure 1-5 As shown, most of the primary structures have a particle size of less than 1 μm, while the secondary structures have a particle size of less than 40 μm. Some secondary structures are spherical, some are spherical with concave ends, and some are donut-shaped. Some secondary structures appear to be hollow.

[0112] Example 6

[0113] By spray drying the liquid from Example 3 using a method similar to that of Example 4, ordered aggregates of florfenicol can be obtained. The average particle size of the secondary structure is about 30 μm, and the particle size of 90% of the secondary structure is 0.2 to 0.4 μm.

[0114] Example 7

[0115] The ordered aggregates of chlortetracycline hydrochloride obtained in Example 6 were mixed with glucose (as an excipient) at a weight ratio of 20:80 to obtain a composition containing 20% ​​chlortetracycline hydrochloride. Adding 2g of the above composition to 1 liter of water yielded the concentration corresponding to the recommended dose of chlortetracycline hydrochloride, with a water dissolution time of less than 10 seconds, resulting in a pale yellow, clear solution (see [link to original text]). Figure 7 When preparing a suspension at a drug concentration 100 times that corresponding to the recommended dose, this is equivalent to adding 200g of the above-mentioned soluble powder to 1 liter of water (far exceeding its literature solubility of 8.6g / L in water), resulting in a uniform, pale yellow emulsion suspension (see [link to relevant documentation]). Figure 8 The solution exhibits good stability; no sedimentation was observed at the bottom after 6 hours of standing. A small amount of sedimentation occurred after 18 hours of standing, but it was easily dispersed evenly by stirring. The suspension was added to the dosing tank, connected to the waterline dosing pump, and diluted 100 times. The negative pressure generated by the waterline flow was used to evenly add the solution. Random samples were taken at the outlet for concentration measurement, all of which were within 90-110% of the recommended clinical dosage. No blockage was observed during use. Any remaining solution in the dosing tank was diluted with water to a clear solution before being drawn into the waterline; this significantly reduced drug waste.

[0116] Example 8

[0117] The ordered aggregates of florfenicol obtained in Example 6 were mixed with glucose to obtain a composition containing 30% florfenicol. This composition was then mixed with water to prepare a suspension (the clinical dosage of florfenicol generally corresponds to a concentration of 1g florfenicol to 10kg of water, while the solubility of florfenicol in water is approximately 0.2g. Therefore, to prepare a 200-fold dilution of the drug according to the above clinical dosage, a solution of 2g / 100g would be required, which clearly exceeds its maximum solubility). The drug concentration in the suspension was 20g florfenicol per liter of water. The suspension was added to an automatic drinking water line using a dosing device. No significant sedimentation was observed during the 8-hour dosing process, and the drug was added evenly to the water line without any blockage.

[0118] Example 9

[0119] The ordered aggregates of florfenicol obtained in Example 6 were mixed with glucose to obtain a composition containing 30% florfenicol. This composition was then mixed with water to prepare a suspension, wherein the drug concentration in the suspension was 10g florfenicol per liter of water (100 times the clinically recommended concentration). The suspension was added to an automatic drinking water line using a dosing device. No significant sedimentation was observed during the 8-hour dosing process, and the drug was added evenly to the water line without any blockage.

[0120] Example 10

[0121] The ordered aggregates of florfenicol obtained in Example 6 were mixed with glucose to obtain a composition containing 30% florfenicol. This composition was then mixed with water to prepare a suspension, wherein the drug concentration in the suspension was 5g florfenicol per liter of water (50 times the clinically recommended concentration). The suspension was added to an automatic drinking water line using a dosing device. No significant sedimentation was observed during the 8-hour dosing process, and the drug was added evenly to the water line without any blockage.

[0122] The above description is merely a preferred embodiment of the present invention and is not intended to limit the scope of the invention. Various variations can be made to the above embodiments of the present invention. That is, all simple and equivalent changes and modifications made based on the claims and description of this application fall within the protection scope of the claims of this patent. All aspects not described in detail in this invention are conventional technical content.

Claims

1. A pharmaceutical composition for use in automated aquaculture drinking water lines, characterized in that, It comprises ordered aggregates of drugs and excipients. The ordered aggregates of the drug have a two-level structure, wherein the primary structure consists of drug particles with an average particle size of 0.1 to 1 μm, and the secondary structure consists of hollow or concave spherical structures, or donut structures, with an average particle size of 10 to 1000 μm formed from the primary structure. The drug is selected from one or more combinations of chlortetracycline hydrochloride, florfenicol, fenbendazole, albendazole, trimethoprim, dimetridazole, sulfamethoxazole, sulfamethoxazole sodium, flunixin meglumine, tiamulin fumarate, diclazuril, toltrazuril, ivermectin, doxycycline hydrochloride, fluoroquinolones, amoxicillin, ampicillin, gentamicin, neomycin sulfate, apramycin, doxycycline, oxytetracycline, lincomycin, spectinomycin, tylosin tartrate, tilmicosin, tiamulin, colistin sulfate, ofloxacin, and chlortetracycline. The excipient has a solubility of 10-200g in water at 10-40℃, and the excipient is selected from glucose, sucrose, fructooligosaccharides, soluble starch, sodium sulfate, magnesium sulfate, potassium sulfate, ammonium sulfate, sodium chloride, potassium chloride, ammonium chloride, or combinations thereof. The excipients in the pharmaceutical composition constitute 40-95% by weight. In use, the drug composition is prepared into a suspension using water, wherein the drug concentration in the suspension is 20 to 400 times that in automated aquaculture water supply lines. The method for preparing the ordered aggregates of the drug includes the following steps: (1) Obtain a slurry containing the primary structure and its unsuitable solvent, wherein the primary structure is drug particles with an average particle size of 0.1~1μm. (2) The slurry is spray-dried to obtain ordered aggregates of the drug.

2. The pharmaceutical composition according to claim 1, characterized in that, The excipients in the pharmaceutical composition account for 60-90% by weight.

3. The pharmaceutical composition according to claim 1, characterized in that, The excipients are selected from glucose and / or sodium sulfate.

4. The pharmaceutical composition according to claim 1, characterized in that, The concentration of the drug in the suspension is 50 to 300 times that of the drug concentration in automated aquaculture water supply lines.

5. The pharmaceutical composition according to claim 1, characterized in that, The average particle size of the primary structure is 0.1~0.5μm, and / or The average particle size of the secondary structure is 15~500μm.

6. The pharmaceutical composition according to claim 1, characterized in that, The average particle size of the primary structure is 0.2~0.4 μm, and / or The average particle size of the secondary structure is 20~100μm.

7. The pharmaceutical composition according to claim 1, characterized in that, The drug is selected from chlortetracycline hydrochloride and / or florfenicol and / or dimetridazole.

8. The pharmaceutical composition according to claim 1, characterized in that, The ordered aggregates of the drug also include surfactants and / or thickeners.

9. The pharmaceutical composition according to claim 8, characterized in that, The surface activity is selected from nonionic surfactants, and / or The amount of the surface active agent used is 0.01~1%.

10. The pharmaceutical composition according to claim 9, characterized in that, The surface activity is selected from Span or Tween.

11. The pharmaceutical composition according to claim 8, characterized in that, The thickener is selected from one or more combinations of xanthan gum, guar gum, pectin, polyethylene glycol, polyoxyethylene, and carboxymethyl cellulose, and / or The amount of the thickener used is 0.01~1%.

12. The pharmaceutical composition according to claim 1, characterized in that, The method for obtaining the slurry includes the following steps (1-1): Drug particles with a particle size of 0.1~1μm are obtained, and then they are mixed with a poor solvent, or The mixture of the grinding drug and its unsuitable solvent is ground until the particle size of the drug particles therein is 0.1~1μm, or Add a poor solvent to a solution containing the drug to precipitate drug particles with a particle size of 0.1~1μm. After filtering to obtain the drug particles, mix them with the poor solvent, or... Add a poor solvent to the solution containing the drug to precipitate the drug particles, while simultaneously grinding the solution and filtering to obtain drug particles of 0.1~1μm, which are then mixed with the poor solvent.

13. The pharmaceutical composition according to claim 12, characterized in that, The method for obtaining the slurry further includes the following steps (1-2): Surfactants and / or thickeners are added during the process of obtaining a slurry containing the primary structure and its undesirable solvent to obtain a uniformly dispersed slurry.

14. The pharmaceutical composition according to claim 1, characterized in that, The unsuitable solvent is selected from water, and / or, The mass ratio of the primary structure to the poor solvent in the slurry is 1:1 to 1:100.

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