Diclazuril solution preparation capable of improving water blending stability and preparation method of diclazuril solution preparation

Abstract

The invention relates to a diclazuril solution preparation for improving water blending stability. The diclazuril solution preparation is mainly prepared from the following raw materials in percentage by mass: 0.5 to 5 percent of diclazuril; 8%-12% of polyethylene glycol (15)-hydroxy stearate; 0.3%-1.0% of hydroxypropyl methylcellulose; 0 to 0.5% of an antioxidant; the total percentage is 100%. The diclazuril solution preparation not only is stable in a stock solution state, but also can keep a medicine dissolved state for a long time after being mixed with water, so that the medicine precipitation time is prolonged. After the preparation is diluted by 100 times with water, no macroscopic crystal or precipitate is separated out after standing at room temperature for 24 hours; during the accelerated stability investigation period, the character is not obviously changed, and no crystal or precipitate is separated out.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug technology, and specifically relates to a new formulation of diclazuril solution preparation with improved water dilution stability and its preparation method. Background Technology

[0002] In the field of veterinary medicine, coccidiosis poses a significant threat to poultry farming, primarily affecting chickens aged 3-6 weeks of age, with intensive, high-density broiler chickens facing the greatest threat. Severe outbreaks can lead to decreased chicken productivity and even death, thus requiring substantial investment in drug prevention or immunization. It is estimated that by 2025, coccidiosis will cause an average annual global economic loss of $4 billion, with mortality rates in chickens reaching 20%-50% during acute outbreaks. The annual global expenditure on anticoccidial drugs exceeds $320 million.

[0003] Diclazuril, a highly effective and low-toxicity phenylacetonitrile anticoccidial drug, is widely used in livestock and poultry farming, primarily for the prevention and treatment of coccidiosis caused by Eimeria and other coccidia species. Diclazuril is extremely poorly soluble in water and almost insoluble in common organic solvents, making the preparation of aqueous solutions very difficult. During storage, the active ingredient is prone to degradation, leading to excessive levels of related substances. In user applications, dilution with well water or other waters with high mineral content can easily cause turbidity and even precipitation.

[0004] In the prior art, the following methods are typically used to prepare diclazuril into a solution.

[0005] 1) Use of highly polar organic solvents: such as large-scale use of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), etc. Although these solvents have strong dissolving power, they are often irritating, toxic or have an unpleasant odor, affecting palatability in animals and posing a risk of drug residues.

[0006] 2) Drug micronization: This method increases the specific surface area by reducing the drug particle size, thereby improving the dissolution rate. However, this method has limited effectiveness for drugs with extremely low solubility, such as diclazuril, and long-term storage can easily lead to precipitation and crystallization, resulting in inaccurate dosage and the risk of tube blockage.

[0007] Furthermore, diclazuril solutions are often administered via drinking water in clinical use. This means that after being diluted with a large amount of water, the formulation must remain dissolved for a sufficiently long time (usually at least several hours) to ensure uniform distribution of the drug in the drinking system and effective uptake by the animals. However, existing diclazuril solutions or solubilization technologies often suffer from rapid dilution of the solvent after dilution, leading to the collapse of the solubilization system, rapid drug crystallization, and problems such as inaccurate dosage, tube blockage, and uneven animal intake.

[0008] Therefore, developing a diclazuril solution formulation that is not only stable in its original state but also maintains drug solubility for an extended period after dilution with water is a technical challenge that urgently needs to be addressed in this field.

[0009] Based on this, this application was developed. Summary of the Invention

[0010] The purpose of this invention is to overcome the defects and shortcomings of existing technologies and provide a diclazuril solution formulation with improved stability after dilution. This formulation is not only stable in its undiluted state but also maintains drug solubility for an extended period after dilution, prolonging the drug precipitation time. After being diluted 100 times with water and left to stand at room temperature for 24 hours, no visible crystals or precipitates were observed. During accelerated stability testing, no significant changes in properties were observed, and no crystals or precipitates were formed.

[0011] The present invention also provides a method for preparing the above-mentioned diclazuril solution formulation with improved water dilution stability.

[0012] To achieve the above objectives, the present invention adopts the following technical solution: A diclazuril solution formulation with improved water-dilutable stability is mainly composed of the following raw materials: diclazuril; polyethylene glycol (15)-hydroxystearate; hydroxypropyl methylcellulose; a complex solvent; and optional antioxidants.

[0013] Furthermore, the above-mentioned diclazuril solution formulation for improving water stability is mainly composed of the following raw materials in the indicated mass percentages: Diclazuril: 0.5% - 5%; Polyethylene glycol (15)-hydroxystearate: 8% - 12%; Hydroxypropyl methylcellulose: 0.3% - 1.0%; Antioxidant: 0 - 0.5%; Composite solvent: Top up to 100%.

[0014] Specifically, the composite solvent is composed of polyethylene glycol 400, ethanol and N,N-dimethylacetamide.

[0015] Furthermore, the composite solvent is composed of polyethylene glycol 400, ethanol and N,N-dimethylacetamide in a mass ratio of (8-10): (4-6): 1.

[0016] Preferably, the composite solvent is composed of polyethylene glycol 400, ethanol and N,N-dimethylacetamide in a mass ratio of 9:5:1.

[0017] Specifically, the selected antioxidants include, but are not limited to, at least one of tocopherol, propyl gallate, tert-butylhydroquinone, sodium metabisulfite, ascorbyl palmitate, tert-butylhydroxyanisole, butylated hydroxytoluene, sodium thiosulfate, etc.

[0018] As a preferred technical solution, the above-mentioned diclazuril solution formulation for improving water dilution stability is mainly composed of the following raw materials in the indicated mass percentages: Diclazuril: 1% - 5%; Polyethylene glycol (15)-hydroxystearate: 8% - 12%; Hydroxypropyl methylcellulose: 0.3% - 1.0%; Antioxidant: 0.05-0.2%; Composite solvent: 70%~85%.

[0019] More preferably, the polyethylene glycol (15)-hydroxystearate has a mass percentage of 10%, and the hydroxypropyl methylcellulose has a mass percentage of 0.5%. The polyethylene glycol (15)-hydroxystearate and hydroxypropyl methylcellulose work synergistically to form a water-stable diclazuril composite system.

[0020] This invention provides a method for preparing the above-mentioned diclazuril solution formulation with improved water stability, which includes the following steps: (a) Heat a portion of the composite solvent (a mixture of polyethylene glycol 400, ethanol and N,N-dimethylacetamide) to 50-60°C; (b) Under stirring and heat preservation conditions, polyethylene glycol (15)-hydroxystearate and hydroxypropyl methylcellulose were added to the composite solvent in step (a), and stirring was continued until completely dissolved to obtain a clear solution. (c) Add micronized diclazuril raw material (milled using a ball mill so that more than 90% of its particles have a particle size (D90) < 20 μm, preferably D90 < 10 μm, more preferably, with a median particle size (D50) of 1-10 μm) to the clear solution obtained in step (b), and stir thoroughly until completely dissolved; (d) Add the antioxidant while stirring, and stir until completely dissolved; (e) Cool to room temperature, add the remaining composite solvent (the remaining polyethylene glycol 400) to a final volume of 100%, stir well, filter through a 0.45 μm filter membrane, and fill into containers to obtain the final product.

[0021] The diclazuril solution formulation with improved water stability described in this invention shows that, after being diluted 100 times with water and left to stand at room temperature for 24 hours, no visible crystals or precipitates are formed; and it remains stable within a temperature range of 4°C to 60°C.

[0022] The innovation and core features of the diclazuril solution formulation with improved water stability described in this invention are mainly as follows: 1) This invention constructs a ternary composite solvent system: A ternary composite solvent is constructed using polyethylene glycol 400, ethanol, and N,N-dimethylacetamide. This system, through the synergistic effect of hydrogen bonding and dipole interactions, solves the initial dissolution problem of diclazuril at the molecular level, laying a solid foundation for high drug loading and high stability of the entire formulation. This solvent system enables the drug to maintain a molecular-level dispersion state within a wide temperature range of 4℃-60℃. 2) By adding polyethylene glycol (15)-hydroxystearate and hydroxypropyl methylcellulose, polyethylene glycol (15)-hydroxystearate can form micelles to encapsulate drug molecules, improving the solubility of diclazuril in water. Simultaneously, to prevent the micelle structure from being damaged and leading to drug precipitation after prolonged storage following dilution, hydroxypropyl methylcellulose is added. This excipient can adsorb onto the micelle surface, forming a spatial barrier to prevent the micelle structure from being destroyed and prolonging the drug precipitation time.

[0023] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows: 1) Composite Solvent System: A ternary composite solvent composed of polyethylene glycol 400, ethanol, and N,N-dimethylacetamide was selected. This specific ratio of ternary solvent works synergistically through the following mechanism: it effectively dissociates the crystalline state and stabilizes it in the solvent, thereby ensuring the initial stability of the formulation over a wide temperature range of 4°C to 60°C. The preferred mass percentage of polyethylene glycol 400 in the composite solvent is 45%-55%, which is the foundation and main component of the composite solvent system, and its concentration is crucial for maintaining the system's hydrogen bonding ability and viscosity. Furthermore, the specific proportion of ethanol in the composite solvent not only acts as a dipole in the solvent system but also reduces the local irritation of the solution and improves animal compliance after administration.

[0024] 2) This invention discovers and utilizes a specific combination of polyethylene glycol (15)-hydroxystearate and hydroxypropyl methylcellulose to achieve not only extraordinary solubilization of micronized diclazuril but also to form a unique "stereo-micelle" composite stable structure, thereby solving the technical bottleneck of diclazuril's tendency to crystallize and precipitate during storage. Furthermore, after dilution with water, it significantly delays the precipitation time of diclazuril, keeping the diluted solution clear and transparent for at least 24 hours, without visible crystals or precipitation, thus ensuring the accuracy and effectiveness of oral administration. In addition, the formulation showed no significant changes in properties during accelerated stability testing, with no crystallization or precipitation. Attached Figure Description

[0025] Figure 1 The results of water stability testing for products from different embodiments (diluted 100 times with water). Detailed Implementation

[0026] The technical solution of the present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto.

[0027] In the following examples, all raw materials used are common commercially available products that can be purchased directly, or can be prepared using conventional techniques in the art.

[0028] In the following examples, the diclazuril active pharmaceutical ingredient was pre-micronized, specifically by grinding it with a ball mill so that more than 90% of the particles had a particle size (D90) < 10 μm.

[0029] Room temperature refers to 25±5℃. Example 1

[0030] A diclazuril solution formulation with improved water-dilubility is prepared according to the following formula and steps: 1) Take 45g of polyethylene glycol 400, 25g of ethanol, and 5g of N,N-dimethylacetamide, mix them evenly, and heat to 55℃; 2) Under stirring and heat preservation conditions, add 10g of polyethylene glycol (15)-hydroxystearate and 0.5g of hydroxypropyl methylcellulose, and continue stirring at 55°C until completely dissolved to obtain a clear solution; 3) Add 0.5g of diclazuril raw material and stir thoroughly until completely dissolved; 4) Add 0.2g of antioxidant butylated hydroxytoluene while stirring, and stir until completely dissolved; 5) Cool to room temperature, add polyethylene glycol 400 to make up to 100g of total mass, and stir well; 6) Pass the filter through a 0.45μm polyethersulfone filter and fill it into a brown glass bottle to obtain the final product. Example 2

[0031] A diclazuril solution preparation is obtained according to the following formulation and steps: 1) Take 45g of polyethylene glycol 400, 25g of ethanol, and 5g of N,N-dimethylacetamide, mix them evenly, and heat to 55℃; 2) Under stirring and heat preservation conditions, add 10g of polyethylene glycol (15)-hydroxy stearate, and continue stirring at 55°C until completely dissolved to obtain a clear solution; 3) Add 0.5g of diclazuril raw material and stir thoroughly until completely dissolved; 4) Add 0.2g of antioxidant butylated hydroxytoluene while stirring, and stir until completely dissolved; 5) Cool to room temperature, add polyethylene glycol 400 to make up to 100g of total mass, and stir well; 6) Pass the filter through a 0.45μm polyethersulfone filter and fill it into a brown glass bottle to obtain the final product.

[0032] The difference between this embodiment and Embodiment 1 is that 0.5g of hydroxypropyl methylcellulose was not added. Example 3

[0033] A diclazuril solution preparation is obtained according to the following formulation and steps: 1) Take 45g of polyethylene glycol 400, 25g of ethanol, and 5g of N,N-dimethylacetamide, mix them evenly, and heat to 55℃; 2) Under stirring and heat preservation conditions, add 0.5g of hydroxypropyl methylcellulose and stir continuously at 55℃ until completely dissolved to obtain a clear solution; 3) Add 0.5g of diclazuril raw material and stir thoroughly until completely dissolved; 4) Add 0.2g of antioxidant butylated hydroxytoluene while stirring, and stir until completely dissolved; 5) Cool to room temperature, add polyethylene glycol 400 to make up to 100g of total mass, and stir well; 6) Pass the filter through a 0.45μm polyethersulfone filter and fill it into a brown glass bottle to obtain the final product.

[0034] The difference between this embodiment and Example 1 is that 10g of polyethylene glycol (15)-hydroxystearate was not added. Example 4

[0035] The difference between the formulation in this embodiment and that in Example 1 is that the antioxidant is tocopherol. The preparation method is the same as in Example 1. Example 5

[0036] The difference between the formulation in this embodiment and that in Example 1 is that the antioxidant is propyl gallate. The preparation method is the same as in Example 1. Example 6

[0037] The formulation in this embodiment differs from that in Example 1 in that the antioxidant is ascorbate palmitate. The preparation method is the same as in Example 1. Example 7

[0038] The difference between the formulation in this embodiment and that in Example 1 is that the antioxidant is tert-butylhydroquinone. The preparation method is the same as in Example 1. Example 8

[0039] The difference between the formulation in this embodiment and that in Example 1 is that the antioxidant is tert-butylhydroxyanisole. The preparation method is the same as in Example 1. Example 9

[0040] The difference between the formulation in this embodiment and that in Example 1 is that the antioxidant is sodium metabisulfite. The preparation method is the same as in Example 1.

[0041] The diclazuril solution preparations obtained in Examples 1 to 3 above were subjected to accelerated stability tests (40°C, 75%RH, 6 months), and the results are shown in Table 1 below.

[0042] Table 1: Accelerated stability results

[0043] Table 1 shows that the appearance, content, and impurities of the present invention (Example 1, complete formulation) are all at optimal levels. Comparative Example 1 (Example 2, without hydroxypropyl methylcellulose) showed complete stability failure (crystallization in the 4th month, impurities increased to 5.24%), proving that hydroxypropyl methylcellulose is indispensable for preventing crystallization and degradation. Comparative Example 2 (Example 3, without polyethylene glycol (15)-hydroxystearate) did not crystallize, but the increase in impurity content (1.22%) was significantly higher than that of the present invention (0.01%), proving that changing or omitting any key component alone cannot achieve the synergistic stabilizing effect of the present invention. Conclusion: Polyethylene glycol (15)-hydroxystearate and hydroxypropyl methylcellulose exhibit an unexpected synergistic effect in the specific system of the present invention; both are indispensable, jointly achieving a dual breakthrough in the physical and chemical stability of diclazuril solution.

[0044] Figure 1 The results of water stability tests (100-fold dilution) of different embodiments of the product are presented. The figures show that: Example 1: The drug content remained stable within 24 hours after dilution, with a very small decrease. This proves that the composite stabilizing system of the formulation of this invention can effectively maintain the dissolution state of diclazuril after dilution, ensuring the accuracy and uniformity of dosage during animal drinking water administration. Example 2: The drug content decreased rapidly after dilution, indicating that without the steric hindrance protection provided by hydroxypropyl methylcellulose, the drug, which relies solely on micelle solubilization, is prone to precipitation after dilution, failing to meet the basic requirements for administration via drinking water. Example 3: The rate of decrease and the final loss of drug content were significantly higher than in Example 1. This indicates that without the initial "micelle encapsulation" formed by polyethylene glycol (15)-hydroxystearate, the drug's dissolution basis is weak, and even with HPMC, it is difficult to maintain its dispersion state for a long time.

Claims

1. A formulation of diclazuril solution for improved water dilution stability, characterized in that, consists essentially of the following ingredients in the following amounts by weight: Diclazuril: 1% - 5%; Polyethylene glycol (15)-hydroxystearate: 8% - 12%; Hydroxypropyl methylcellulose: 0.3% - 1.0%; Antioxidant: 0.05 - 0.2%; Complex solvent: 70% ~ 85%.

2. The solution formulation of diclazuril for improving water stability according to claim 1, wherein The complex solvent consists of polyethylene glycol 400, ethanol and N,N-dimethylacetamide mixed in a mass ratio of (8-10) : (4-6) :

1.

3. The solution formulation of dechochlorinated gliclazide for improving water stability according to claim 2, wherein The complex solvent consists of polyethylene glycol 400, ethanol and N,N-dimethylacetamide mixed in a mass ratio of (8-10) : (4-6) :

1.

4. The solution formulation of dechochlorinated gliclazide of claim 2, wherein, The complex solvent consists of polyethylene glycol 400, ethanol and N,N-dimethylacetamide mixed in a mass ratio of 9 : 5 :

1.

5. The solution formulation of dechochlorinated gliclazide of claim 1, wherein, The selected antioxidant is at least one of tocopherol, propyl gallate, tert-butyl hydroquinone, sodium pyrosulfite, ascorbic acid palmitate, tert-butyl hydroxyanisole, dibutyl hydroxytoluene, and sodium thiosulfate.

6. The solution formulation of diclazuril for improving water stability according to claim 1, wherein consists essentially of the following ingredients in the following amounts by weight: Diclazuril: 1% - 5%; Polyethylene glycol (15)-hydroxystearate: 8% - 12%; Hydroxypropyl methylcellulose: 0.3% - 1.0%; Antioxidant: 0.05 - 0.2%; Complex solvent: 70% ~ 85%.

7. The solution formulation of diclazuril for improving water stability according to claim 1, wherein The mass percentage of polyethylene glycol (15)-hydroxystearate is 10%, and the mass percentage of hydroxypropyl methylcellulose is 0.5%.

8. Process for the preparation of a solution formulation of decoquinate to improve water stability according to any one of claims 1 to 7, characterized in that, The method comprises the following steps: (a) warming part of the complex solvent to 50-60°C; (b) adding polyethylene glycol (15)-hydroxystearate and hydroxypropyl methylcellulose to the complex solvent of step (a) under stirring, dissolving completely to obtain a clear solution; (c) adding diclazuril to the clear solution obtained in step (b) and stirring until completely dissolved; (d) adding an antioxidant and stirring until dissolved; (e) cooling, constant volume with the remaining complex solvent, filtering, and filling to obtain the product.

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