Tildipirosin suspension injection and preparation method thereof

Abstract

The invention relates to the technical field of tildipirosin suspension injections, in particular to a tildipirosin suspension injection, which comprises the following components by weight: 10-15 g of tildipirosin, 30-40 ml of a solubilizer, 4-5 g of a stabilizer, 3 g of a dispersant, a proper amount of a pH regulator, and the balance of sterile water to 100 ml. The solubilizer comprises polyethylene glycol and glycerol; the stabilizer comprises gelatin and polyvinylpyrrolidone; the dispersing agent is prepared from poloxamer 188 and polysorbate 80; the pH regulator comprises sodium citrate and a phosphate buffer solution. The particle size of the medicine particles is controlled to be 200 nm or below, the absorption speed of the medicine is remarkably increased, and it is ensured that the medicine effect is rapidly exerted. According to the multiphase blending technology, through solubilizer micro-emulsification and medicine blending, agglomeration of medicine particles is avoided, and it is ensured that the medicine is evenly distributed in a suspension. Compared with traditional mechanical stirring, the ultrahigh-pressure homogenizing technology is introduced, medicine particles are further refined and dispersed, and stability is enhanced.

Description

Technical Field

[0001] The invention relates to the technical field of tediloxine suspension injection, in particular to a tediloxine suspension injection and a preparation method thereof. Background Art

[0002] With the expansion of intensive farming, respiratory diseases, digestive diseases and other diseases of livestock and poultry are becoming more and more serious. Respiratory tract infection is an infectious disease that is difficult to control in animal husbandry, which will cause huge economic losses to animal husbandry production. Therefore, how to prevent and treat respiratory tract infections in pigs, cattle and other livestock is an important research topic for veterinarians and veterinary medicine workers. Since respiratory tract infections are generally multiple infections, there are many pathogenic factors, and there are many types of pathogens that cause diseases, including viruses, bacteria and mycoplasmas, with varying morbidity and mortality rates. Clinical manifestations include symptoms such as tearing, runny nose, coughing or sneezing, panting, and difficulty breathing. At the same time, due to the abuse of antibiotics in livestock and poultry farming, the problem of drug-resistant strains has become more and more serious, and many farms are facing the problem of no medicine to treat respiratory diseases caused by bacteria or mycoplasmas. In my country, tilmicosin and tylosin are widely used drugs for the prevention and treatment of respiratory diseases in livestock and poultry. Although these two drugs have achieved good results in production and clinical practice, with the extension of the use time, different degrees of drug-resistant strains have appeared in many areas of my country, resulting in the continuous increase in drug dosage, but the treatment effect is gradually decreasing. Therefore, the development of new drugs is an urgent problem to be solved in the chemical prevention and control of respiratory diseases;

[0003] The existing tediluoxin suspension injection usually adopts traditional processes such as high-energy mechanical grinding during the preparation process to suspend the drug in the solution, which has the following shortcomings:

[0004] Uneven particle size distribution: In the existing tediluoxin suspension, the particle size of the drug particles is relatively large, which can easily lead to drug instability and low absorption rate in the injection solution.

[0005] Poor drug stability: Drugs tend to settle during storage, resulting in uneven drug distribution.

[0006] The preparation process is complex and the cost is high: the mechanical grinding equipment used in the prior art consumes a lot of energy, is complex to operate, and has low production efficiency. Summary of the invention

[0007] The purpose of the present invention is to provide a tediluoxin suspension injection and a preparation method thereof, which improves the stability and uniformity of the drug particle size distribution and enhances the drug absorption rate by introducing nano-processing, multiphase blending technology and solubilizer optimization. The purpose is to solve the problems of uneven particle size distribution and unstable drugs in the prior art.

[0008] To achieve the above object, the present invention provides the following technical solution: a tediluoxin suspension injection, comprising the following components by weight:

[0009] Taidiluosin 10g-15g, solubilizer 30ml-40ml, stabilizer 4g-5g, dispersant 3g, pH adjuster as needed, and sterile water to make up to 100ml;

[0010] Solubilizers include polyethylene glycol and glycerol;

[0011] Stabilizers include gelatin and polyvinyl pyrrolidone;

[0012] Dispersants include poloxamer 188 and polysorbate 80;

[0013] pH adjusters include sodium citrate and phosphate buffer.

[0014] A method for preparing a tediluoxin suspension injection comprises the following steps:

[0015] Step 1: Drug nano-processing, wet nano-grinding the tediluoxin powder, and controlling its particle size to less than 200nm by nano-processing equipment;

[0016] Step 2: Blending the solubilizer with the drug, selecting a solubilizer and blending it with the nanosized tediluosin in proportion to form a solubilized solution;

[0017] Step 3: Add stabilizers and dispersants to form a stable suspension system, and use a homogenizer to perform ultra-high pressure homogenization on the mixed liquid to further evenly distribute the drug particles in the solution and stabilize them in a suspended state;

[0018] Step 4: pH adjustment and aseptic treatment: Use a buffer to adjust the pH value of the suspension to maintain it between 5.0 and 7.0. Under aseptic conditions, use a sterile filter to filter and sterilize the suspension;

[0019] Step 5: Filling and packaging. The sterile suspension is aseptically filled in a clean workshop, and after filling, the liquid medicine is packaged through automatic packaging equipment.

[0020] Preferably, in the step 1, a particle size distribution control model is built into the drug nano-processing to control the particle size distribution by adjusting the energy input, ultrasonic and wet grinding parameters.

[0021] Preferably, during the nano-crystallization process, the particle size D is related to the grinding time t, the grinding energy E and the hardness H of the material, and the relationship can be expressed as:

[0022]

[0023] Where: D0 is the initial particle size; E is the grinding energy, unit: J; t is the grinding time; k is the grinding rate constant;

[0024] H is the hardness of the material.

[0025] Optimization strategy: By adjusting the grinding time t and energy E, the particle size of the drug is controlled within the range of 100nm-200nm. Nanoparticles in this range have a larger specific surface area, higher absorption rate, and good stability in the injection solution.

[0026] Preferably, in the step 2: in the blending of the solubilizer and the drug, a dispersion model of the nanoparticles in the solubilizer is built in to ensure uniform dispersion of the nanosized tediluosin particles in the solution and avoid particle agglomeration.

[0027] Preferably, the dispersion uniformity formula, dispersion degree D s Indicates the degree of dispersion of particles in the solution, subject to shear force F s and particle surface energy γ, expressed as:

[0028]

[0029] Among them: F s is the shear force provided by stirring or ultrasound; γ is the surface energy of the particles.

[0030] Increase F s Or reduce γ by using surfactants such as poloxamer to improve the dispersion uniformity of particles, and ensure the uniform distribution of drugs in the solution and prevent particle agglomeration by adjusting the type of solubilizer and stirring speed.

[0031] Preferably, in the step three: adding stabilizers and dispersants, ultra-high pressure homogenization technology is used to accelerate the drug solution through small holes by high pressure, thereby generating high shear force to further disperse the drug particles.

[0032] Preferably, the relationship between the shear stress τ and the homogenization pressure P, the fluid velocity v and the particle radius r during the high-pressure homogenization process is:

[0033]

[0034] Where: P is the operating pressure of the homogenizer; v is the fluid velocity; τ is the radius of the drug particle.

[0035] Optimization strategy: By increasing the working pressure P of the homogenizer, the agglomeration of drug particles can be effectively reduced and the uniformity of particles can be further improved. The goal is to increase the uniform distribution of particles to a level less than 100nm, thereby ensuring the long-term stability of the preparation.

[0036] Preferably, in the step three: adding the stabilizer and dispersant, the settling velocity of the particles in the suspension is calculated by the Stokes settling formula, and the settling velocity is reduced by controlling the particle size and the viscosity of the suspension.

[0037] Preferably, the settling velocity formula is the Stokes formula:

[0038]

[0039] Where: v is the particle settling velocity; r is the particle radius; ρ p and ρf are the densities of the particles and the suspension respectively; g is the acceleration due to gravity; η is the viscosity of the suspension.

[0040] The particle radius r is reduced through nano-technology to significantly reduce the sedimentation velocity; increasing the use of stabilizers and dispersants, increasing the viscosity η of the suspension, further reducing the sedimentation velocity v, and ensuring that the drug will not settle during storage.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] Nanoparticle processing: The particle size of drug particles is controlled below 200nm, which significantly improves the absorption rate of drugs and ensures rapid drug efficacy.

[0043] Multiphase blending technology: By microemulsifying the solubilizer and blending it with the drug, the agglomeration of drug particles is avoided and the uniform distribution of the drug in the suspension is ensured.

[0044] Ultra-high pressure homogenization technology: Compared with traditional mechanical stirring, the present invention introduces ultra-high pressure homogenization technology to further refine and disperse drug particles and enhance stability.

[0045] Low temperature sterilization process: Double-layer filter membrane technology is used for low temperature sterilization to avoid loss of drug activity due to high temperature treatment.

[0046] Improved stability: Through nano-processing and ultra-high pressure homogenization technology, the stability of drug particles in the injection solution is significantly improved, and there is no sedimentation or stratification during long-term storage.

[0047] Rapid absorption: Drug particles with a particle size of less than 200nm have a larger specific surface area, which significantly accelerates the absorption rate of the drug in the body.

[0048] Cost reduction: The introduction of new ultrasonic-assisted grinding and low-temperature sterilization processes reduces the use of high-energy equipment and reduces preparation costs, while simplifying the production process and improving production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0050] Figure 1 The present invention is a flow chart of the preparation method of the tediluoxin suspension injection;

[0051] Figure 2 This is a reference table comparing Example 1 and Example 2 of the present invention. DETAILED DESCRIPTION

[0052] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0053] See also Figure 1-Figure 2 , the present invention provides a technical solution:

[0054] A tediluoxin suspension injection, comprising the following components by weight:

[0055] Taidiluosin 10g-15g, solubilizer 30ml-40ml, stabilizer 4g-5g, dispersant 3g, pH adjuster as needed, and sterile water to make up to 100ml;

[0056] Solubilizers include polyethylene glycol and glycerol;

[0057] Stabilizers include gelatin and polyvinyl pyrrolidone;

[0058] Dispersants include poloxamer 188 and polysorbate 80;

[0059] pH adjusters include sodium citrate and phosphate buffer.

[0060] A method for preparing a tediluoxin suspension injection comprises the following steps:

[0061] Step 1: Drug nano-processing, wet nano-grinding the tediluoxin powder, and controlling its particle size to less than 200nm by nano-processing equipment;

[0062] Step 2: Blending the solubilizer with the drug, selecting a solubilizer and blending it with the nanosized tediluosin in proportion to form a solubilized solution;

[0063] Step 3: Add stabilizers and dispersants to form a stable suspension system, and use a homogenizer to perform ultra-high pressure homogenization on the mixed liquid to further evenly distribute the drug particles in the solution and stabilize them in a suspended state;

[0064] Step 4: pH adjustment and aseptic treatment: Use a buffer to adjust the pH value of the suspension to maintain it between 5.0 and 7.0. Under aseptic conditions, use a sterile filter to filter and sterilize the suspension;

[0065] Step 5: Filling and packaging. The sterile suspension is aseptically filled in a clean workshop, and after filling, the liquid medicine is packaged through automatic packaging equipment.

[0066] Specifically, in the step 1, a particle size distribution control model is built into the drug nano-processing to control the particle size distribution by adjusting the energy input, ultrasonic and wet grinding parameters.

[0067] Specifically, in the nano-crystallization process, the particle size D is related to the grinding time t, the grinding energy E and the hardness H of the material, and the relationship can be expressed as:

[0068]

[0069] Where: D0 is the initial particle size; E is the grinding energy, unit: J; t is the grinding time; k is the grinding rate constant;

[0070] H is the hardness of the material.

[0071] Optimization strategy: By adjusting the grinding time t and energy E, the particle size of the drug is controlled within the range of 100nm-200nm. Nanoparticles in this range have a larger specific surface area, higher absorption rate, and good stability in the injection solution.

[0072] Specifically, in the step 2, when the solubilizer and the drug are blended, a dispersion model of nanoparticles in the solubilizer is built in to ensure uniform dispersion of the nanosized tediluosin particles in the solution and avoid particle agglomeration.

[0073] Specifically, the dispersion uniformity formula, dispersion degree D s Indicates the degree of dispersion of particles in the solution, subject to shear force F s and particle surface energy γ, expressed as:

[0074]

[0075] Among them: F s is the shear force provided by stirring or ultrasound; γ is the surface energy of the particles.

[0076] Increase Fs Or reduce γ by using surfactants such as poloxamer to improve the dispersion uniformity of particles, and ensure the uniform distribution of drugs in the solution and prevent particle agglomeration by adjusting the type of solubilizer and stirring speed.

[0077] Specifically, in the step three, when adding stabilizers and dispersants, ultra-high pressure homogenization technology is used to accelerate the drug solution through small holes through high pressure, thereby generating high shear force to further disperse the drug particles.

[0078] Specifically, the relationship between the shear stress τ and the homogenization pressure P, the fluid velocity v and the particle radius r during the high-pressure homogenization process is:

[0079]

[0080] Where: P is the operating pressure of the homogenizer; v is the fluid velocity; τ is the radius of the drug particle.

[0081] Optimization strategy: By increasing the working pressure P of the homogenizer, the agglomeration of drug particles can be effectively reduced and the uniformity of particles can be further improved. The goal is to increase the uniform distribution of particles to a level less than 100nm, thereby ensuring the long-term stability of the preparation.

[0082] Specifically, in the step three: adding stabilizers and dispersants, the settling velocity of particles in the suspension is calculated by the Stokes settling formula, and the settling velocity is reduced by controlling the particle size and the viscosity of the suspension.

[0083] Specifically, the settling velocity formula is the Stokes formula:

[0084]

[0085] Where: v is the particle settling velocity; r is the particle radius; ρ p and ρ f are the densities of particles and suspension respectively; g is the acceleration due to gravity; η is the viscosity of the suspension.

[0086] The particle radius r is reduced through nano-technology to significantly reduce the sedimentation velocity; increasing the use of stabilizers and dispersants, increasing the viscosity η of the suspension, further reducing the sedimentation velocity v, and ensuring that the drug will not settle during storage.

[0087] Optimal selection of solubilizer:

[0088] Optimize the selection of solubilizers according to the properties of the drug to ensure the solubility and stability of the drug in the injection solution.

[0089] Solubility parameter formula (Hildebrand solubility parameter method):

[0090]

[0091] Where: δ is the solubility parameter; ΔH is the enthalpy change of the mixture; R is the gas constant; T is the temperature; V m is the molar volume of the solvent.

[0092] By adjusting the solubility parameter δ and selecting a suitable solubilizer (such as PEG 400, glycerol, etc.), the stability of tediloxine in the solution is ensured and the precipitation of drug crystals is prevented.

[0093] Optimization of drug absorption rate:

[0094] By reducing the drug particle size and increasing the specific surface area, the drug absorption rate will be significantly improved. According to the Noyes-Whitney equation, the drug dissolution rate is proportional to its specific surface area:

[0095] Dissolution rate formula:

[0096]

[0097] in: is the dissolution rate; D is the diffusion coefficient; A is the specific surface area of ​​the drug; C s is the saturated solubility of the drug in the solvent; C is the concentration of the drug in the solution; h is the thickness of the diffusion layer.

[0098] Optimization strategy: By reducing the drug particle size and increasing the specific surface area A, the drug dissolution rate and absorption efficiency can be improved.

[0099] Embodiment 1:

[0100] raw material:

[0101] Tediroxine: 10g

[0102] PEG 400: 30 mL

[0103] PVP: 5g

[0104] Poloxamer 188: 3g

[0105] pH buffer (phosphate): appropriate amount

[0106] Sterile water: make up to 100mL

[0107] Preparation steps:

[0108] 1. 10 g of tediloxine powder was subjected to ultrasonic-assisted wet grinding to control the particle size below 200 nm.

[0109] 2. Add PEG 400 and perform high-speed shear emulsification with the drug to make the drug particles evenly distributed.

[0110] 3. Add PVP and poloxamer 188 and use ultra-high pressure homogenization equipment to further disperse them evenly.

[0111] 4. Adjust the pH to 6.5 using phosphate buffer.

[0112] 5. Perform double-layer filter membrane aseptic filtration to finally obtain sterile tediluoxin suspension injection.

[0113] Embodiment 2:

[0114] raw material:

[0115] Tedirox: 15g

[0116] Glycerol: 40mL

[0117] Gelatin: 4g

[0118] Phosphate buffer: appropriate amount

[0119] Sterile water: make up to 100mL

[0120] Preparation steps:

[0121] 1. Wet-grind 15 g of tediluoxin powder and treat with ultrasound.

[0122] 2. Blend with glycerin, add gelatin, and process using ultra-high pressure homogenization equipment.

[0123] 3. Use buffer to adjust the pH value to 6.8 and sterilize by low temperature filtration using a double-layer filter membrane.

[0124] 4. Finally, a highly stable tediluoxin suspension injection is obtained.

[0125] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A tediluoxin suspension injection, characterized in that: It consists of the following components by weight: Taidiluosin 10g-15g, solubilizer 30ml-40ml, stabilizer 4g-5g, dispersant 3g, pH adjuster as needed, and sterile water to make up to 100ml; Solubilizers include polyethylene glycol and glycerol; Stabilizers include gelatin and polyvinyl pyrrolidone; Dispersants include poloxamer 188 and polysorbate 80; pH adjusters include sodium citrate and phosphate buffer.

2. A method for preparing a tediluoxin suspension injection according to claim 1, characterized in that: The steps include: Step 1: Drug nano-processing, wet nano-grinding the tediluoxin powder, and controlling its particle size to less than 200nm by nano-processing equipment; Step 2: Blending the solubilizer with the drug, selecting a solubilizer and blending it with the nanosized tediluosin in proportion to form a solubilized solution; Step 3: Add stabilizers and dispersants to form a stable suspension system, and use a homogenizer to perform ultra-high pressure homogenization on the mixed liquid to further evenly distribute the drug particles in the solution and stabilize them in a suspended state; Step 4: pH adjustment and aseptic treatment: Use a buffer to adjust the pH value of the suspension to maintain it between 5.0 and 7.

0. Under aseptic conditions, use a sterile filter to filter and sterilize the suspension; Step 5: Filling and packaging. The sterile suspension is aseptically filled in a clean workshop, and after filling, the liquid medicine is packaged through automatic packaging equipment.

3. A method for preparing a tediluoxin suspension injection according to claim 2, characterized in that: The step 1: a particle size distribution control model is built into the drug nano-processing to control the particle size distribution by adjusting the energy input, ultrasonic and wet grinding parameters.

4. The method for preparing a tediluoxin suspension injection according to claim 3, characterized in that: In the nano-crystallization process, the particle size D is related to the grinding time t, the grinding energy E and the hardness H of the material, and the relationship can be expressed as: Where: D0 is the initial particle size; E is the grinding energy, unit: J; t is the grinding time; k is the grinding rate constant; H is the hardness of the material.

5. The method for preparing a tediluoxin suspension injection according to claim 2, characterized in that: The step 2: when the solubilizer and the drug are blended, a dispersion model of the nanoparticles in the solubilizer is built in to ensure uniform dispersion of the nanosized tediluoxin particles in the solution and avoid particle agglomeration.

6. The method for preparing a tediluoxin suspension injection according to claim 5, characterized in that: The dispersion uniformity formula, dispersion degree D s Indicates the degree of dispersion of particles in the solution, subject to shear force F s and particle surface energy γ, expressed as: Among them: F s is the shear force provided by stirring or ultrasound; γ is the surface energy of the particles.

7. The method for preparing a tediluoxin suspension injection according to claim 2, characterized in that: In the step three, when adding stabilizers and dispersants, ultra-high pressure homogenization technology is used to accelerate the drug solution through small holes through high pressure, thereby generating high shear force to further disperse the drug particles.

8. The method for preparing a tediluoxin suspension injection according to claim 7, characterized in that: The relationship between the shear stress τ and the homogenization pressure P, the fluid velocity v and the particle radius r during the high-pressure homogenization process is: Where: P is the operating pressure of the homogenizer; v is the fluid velocity; τ is the radius of the drug particle.

9. The method for preparing a tediluoxin suspension injection according to claim 2, characterized in that: In the step three, when adding the stabilizer and dispersant, the settling velocity of the particles in the suspension is calculated by the Stokes settling formula, and the settling velocity is reduced by controlling the particle size and the viscosity of the suspension.

10. The method for preparing a tediluoxin suspension injection according to claim 9, characterized in that: The settling velocity formula is Stokes formula: Where: v is the particle settling velocity; r is the particle radius; ρ p and ρ f are the densities of particles and suspension respectively; g is the acceleration due to gravity; η is the viscosity of the suspension.

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