A method for preparing posaconazole oral suspension

Abstract

The application discloses a preparation method of posaconazole oral suspension, which comprises the following steps: uniformly dispersing and mixing posaconazole with a wetting agent and an antifoaming agent, adding one or more of a preservative, a pH regulator, a thickening agent, a suspending agent, an opacifying agent or a flavoring agent after heat preservation and curing, and uniformly dispersing and mixing to obtain posaconazole oral suspension. The production method is simple in process, easy and convenient to operate, low in cost, and suitable for commercial production with a scale of 50L or more. The prepared suspension is good in thermal stability, high in long-term storage stability and strong in safety.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing posaconazole oral suspension. Background Technology

[0002] Invasive fungal disease (IFD) refers to the pathological and pathophysiological process by which fungi invade human tissues and blood, grow and multiply within them, leading to tissue damage, organ dysfunction, and inflammatory responses. Immunosuppression is a major risk factor. With the development of cancer treatment and transplantation technology, the number of high-risk patients with weakened immune function is increasing, resulting in a year-on-year increase in the incidence of IFD. A prospective, multicenter epidemiological study in China showed that among hematologic malignancies receiving chemotherapy, the overall incidence of confirmed and clinically diagnosed IFD was 2.1%; among patients undergoing hematopoietic stem cell transplantation, the incidence of confirmed and clinically diagnosed IFD was 7.7%, and the suspected IFD rate was 19%. IFD is one of the leading causes of death from hematologic malignancies; the mortality rate related to IFD after hematopoietic stem cell transplantation is as high as 50%.

[0003] Early diagnosis of fungal infections (IFD) is challenging due to the lack of specific clinical signs and symptoms, the absence of specific laboratory tests, and the difficulty in obtaining specimens for histopathological examination. Evidence-based medicine suggests that early intervention can reduce mortality. Triazole antifungals are commonly used in clinical practice for the prevention and treatment of fungal infections. Posaconazole, a second-generation triazole broad-spectrum antifungal drug, has a wide range of applications in the prevention and treatment of invasive fungi.

[0004] Posaconazole has low solubility; its free base has a solubility of less than 1 μg / ml in environments with a pH of approximately 6.4 or higher. To increase the dissolution rate of posaconazole, suitable formulations (such as tablets, suspensions, microcapsules, etc.) need to be prepared. Posaconazole oral suspension was approved for marketing by the EMA in October 2005, by the US FDA in September 2006, and was approved for import into China in June 2013. The strength is 40 mg / ml, and the trade name is [Brand Name Missing]. When preparing suspensions, posaconazole needs to be micronized to a suitable particle size range to ensure its dissolution rate. However, nano-suspensions are thermodynamically unstable coarse dispersion systems. During storage, due to the extremely small particle size and large specific surface area of ​​the drug in the suspension, Ostwald ripening easily occurs, leading to particle size increase, sedimentation, aggregation, and clumping. Therefore, there are two main challenges in preparing thermally stable nano-suspensions. The first challenge is generating particles within an appropriate particle size range, and the second is maintaining the particle size within a certain range during long-term storage.

[0005] Chinese patent application CN100415234 discloses a posaconazole oral suspension and its preparation method, in which micronized posaconazole is used as the raw material to prepare a stable suspension. However, this patent has high requirements for pulverizing equipment and pulverizing parameters, and the operation is complex, making it difficult to industrialize. CN105030668A discloses a method for preparing a posaconazole oral suspension, which uses a homogenizer (pressure 30-60 MPa) to homogenize the raw material to obtain a particle size of 1500-1850 nm, avoiding the use of pulverizing equipment to micronize the raw material. CN110507609A discloses a method for preparing a posaconazole oral suspension, which subjectes the suspension to high shear treatment, and after multiple cycles, obtains posaconazole with a particle size of 1200-1600 nm, avoiding the micronization of posaconazole and solving the problem of posaconazole dissolution. The aforementioned patents employ homogenization and high-shear treatment of the suspension to avoid micronizing the raw materials using pulverizing equipment, but they do not solve the problem of thermal stability of posaconazole oral suspension after processing and during storage. CN115300460A discloses a posaconazole oral suspension and its preparation method, which adds stabilizers and co-stabilizers to give the resulting suspension good sedimentation performance and good physical stability during long-term storage; however, the patent only examines the sedimentation and content uniformity of the sample, without testing the particle size stability, a key indicator; at the same time, the formulation is too complex, and the finished product poses a risk of thermal stability issues.

[0006] CN106333925A discloses a posaconazole liquid suspension and its preparation method. The posaconazole liquid suspension prepared by using microcrystalline cellulose-sodium carboxymethyl cellulose complex as a suspending agent has a particle size D50 that increases from 1430 nm to 1860 nm after 30 days of storage. The particle size increases rapidly, but the sample stability is poor.

[0007] The technical solutions in the aforementioned patents are all laboratory-scale, complex to operate, and cannot guarantee commercial production. Summary of the Invention

[0008] This application addresses the shortcomings of existing technologies by providing a method for the commercially viable large-scale production of posaconazole oral suspension. This method is simple, easy to operate, and low-cost, suitable for commercial-scale production of 50L or more. The resulting suspension exhibits good thermal stability, high long-term storage stability, and strong safety.

[0009] This application is achieved through the following technical solution:

[0010] A method for preparing a posaconazole oral suspension, comprising the following steps:

[0011] Disperse and mix posaconazole with wetting agent and defoamer, and then allow it to mature.

[0012] Further optimization involves dispersing and mixing posaconazole with a wetting agent and an antifoaming agent, allowing it to mature, and then adding one or more of a preservative, pH adjuster, thickener, suspending agent, opaque agent, or flavoring agent, dispersing and mixing them to obtain the finished posaconazole oral suspension.

[0013] The ripening process described in this application is heating and heat preservation.

[0014] One technical solution of this application is a method for preparing posaconazole oral suspension, which includes the following steps:

[0015] (1) Preparation of concentrated solution: water, posaconazole, some wetting agent and defoamer are dispersed and mixed to obtain a concentrated solution with the target particle size;

[0016] (2) Maturation: The concentrated solution is heated and kept at a constant temperature to achieve the target particle size;

[0017] (3) Mixing: Add the remaining wetting agent and defoamer, as well as one or more of the preservatives, pH adjusters, thickeners, suspending agents, opacifiers or flavoring agents, disperse and mix well to obtain the posaconazole oral suspension product with the target particle size.

[0018] One technical solution of the present invention is a method for preparing posaconazole oral suspension, which includes the following steps:

[0019] (1) Emulsion preparation: Water, wetting agent and defoamer are dispersed and mixed to obtain an emulsion;

[0020] (2) Preparation of concentrated solution: Part of the emulsion and posaconazole are dispersed and mixed to obtain a concentrated solution with the target particle size;

[0021] (3) Maturation: The concentrated solution is heated and kept at a constant temperature to achieve the target particle size;

[0022] (4) Total mixing: Add the remaining emulsion and one or more of the following: preservative, pH adjuster, thickener, suspending agent, opaque agent or flavoring agent, and mix thoroughly to obtain the posaconazole oral suspension product with the target particle size.

[0023] The inventors of this application made an unexpected discovery that adding a heating and warming maturation step during the preparation of posaconazole oral suspension can overcome or delay the Ostwald maturation phenomenon that occurs in the finished posaconazole oral suspension during storage. As the storage time increases, the particle size increases slowly and the particle size stability is strong.

[0024] In some embodiments, the heating and heat preservation temperature is 30–80°C, and the temperature can be selected from 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, and 80°C. Preferably, the heating and heat preservation temperature is 40–80°C.

[0025] In some embodiments, the heating and holding time is 50–300 min, and can be selected from 50 min, 60 min, 70 min, 80 min, 90 min, 100 min, 120 min, 140 min, 160 min, 180 min, 200 min, 220 min, 240 min, 260 min, 280 min, and 300 min. Experiments have shown that within the heating and holding temperature range of 40–80 °C, as the heating time increases, the particle size D50 of the final product after the concentrated solution reaches the target particle size remains consistently between 1.3 and 2.0 μm.

[0026] The inventors further discovered that a heating and curing step after dispersing and mixing posaconazole with wetting agents and defoamers resulted in better particle size stability. Even during accelerated testing at 60°C, the target particle size and dissolution rate of the posaconazole oral suspension met the requirements (D50≤2.0μm). If heating and curing are performed after mixing, the heating causes changes in the structure of the thickener (e.g., xanthan gum), directly affecting the dissolution rate and stability of the posaconazole oral suspension. In solution, xanthan gum forms a highly entangled network structure through intramolecular and intermolecular non-covalent bonds and interchain entanglement. High-intensity shearing can transform this disordered network structure into an ordered one, thus reducing viscosity and promoting dissolution. However, heating after mixing causes the ordered network structure to become disordered again, leading to an increase in viscosity. The viscosity of the finished suspension after total mixing and heating is approximately 700 mPa·s higher than that of the finished suspension without total mixing and heating, resulting in a significant decrease in the average dissolution rate of the posaconazole oral suspension. Therefore, heating and curing after total mixing is not recommended.

[0027] In some embodiments, the target particle size D50 of the concentrated solution described in this application is 0.8 to 1.5 μm, and the particle size can be 0.8 μm, 0.9 μm, 1.0 μm, 1.1 μm, 1.2 μm, 1.3 μm, 1.4 μm, or 1.5 μm; preferably, D50 is 1.0 to 1.5 μm.

[0028] In some embodiments, the target particle size D50 after ripening described in this application is 1.3 to 2.0 μm; the particle size can be 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, or 2.0 μm; preferably, D50 is 1.5 to 2.0 μm.

[0029] In some embodiments, the target particle size D50 of the posaconazole oral suspension product described in this application is 1.3 to 2.0 μm; the particle size can be 1.3 μm, 1.4 μm, 1.5 μm, 1.6 μm, 1.7 μm, 1.8 μm, 1.9 μm, or 2.0 μm; preferably, D50 is 1.5 to 2.0 μm.

[0030] In some embodiments, the dispersion and mixing described in this application includes, but is not limited to, ball milling, stirring, ultrasonic mixing, shear mixing, and homogenization. Preferably, the dispersion and mixing is shear mixing and / or homogenization. The shear mixing described in this application can be performed in any mixing or blending step, such as premixing shear mixing of wetting agents and defoamers, premixing shear mixing of posaconazole with wetting agents and defoamers, or premixing shear mixing of suspending agents and thickeners. Shear mixing can be initiated after each addition of one or more components. The homogenization mixing can be performed during the preparation of emulsions and / or concentrated solutions.

[0031] In some embodiments, the shear speed and homogenization pressure described in this application have a significant impact on the particle size, dissolution, and stability of the suspension. Preferably, the shear speed is 1000–10000 rpm; 1000 rpm, 2000 rpm, 3000 rpm, 4000 rpm, 5000 rpm, 6000 rpm, 7000 rpm, 8000 rpm, 9000 rpm, and 10000 rpm can be selected. The homogenization pressure is 15000–30000 psi; 15000 psi, 16000 psi, 17000 psi, 18000 psi, 19000 psi, 20000 psi, 21000 psi, 22000 psi, 23000 psi, 24000 psi, 25000 psi, 26000 psi, 27000 psi, 28000 psi, 29000 psi, and 30000 psi can be selected.

[0032] In some embodiments, the shear speed during the mixing step is greater than the shear speed during the preparation of the emulsion and / or concentrated solution. Preferably, the shear speed during mixing is 3000–5000 rpm, and the shear speed during the preparation of the emulsion or concentrated solution is 1000–3000 rpm. Using a shear speed greater in the mixing step than in the emulsion and / or concentrated solution not only ensures particle size distribution but also facilitates dissolution. Adding xanthan gum as a thickener to the mixing step serves two purposes: firstly, xanthan gum swells rapidly upon contact with water, easily forming micelles; shearing helps xanthan gum to fully contact with water, reducing micelle formation; secondly, its aqueous solution has high viscosity at low concentrations and exhibits strong pseudoplasticity. Under low shear force, the xanthan gum solution maintains high viscosity, while under high shear force, it exhibits shear-thinning characteristics. After thinning, xanthan gum is more easily dispersed evenly with other excipients, ensuring consistent dissolution properties of the suspension.

[0033] In some embodiments, the homogenization pressure during emulsion preparation is lower than the homogenization pressure during concentrated solution preparation. Preferably, the homogenization pressure during emulsion preparation is 15,000–25,000 psi, and the homogenization pressure during concentrated solution preparation is 20,000–30,000 psi.

[0034] In some implementations, it is necessary to control the temperature during the process. For example, the temperature of the drug solution in the preparation of emulsions and / or concentrated solutions is 10 to 60°C, and the temperature can be selected as 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, or 60°C.

[0035] In some embodiments, the temperature is controlled at 10–60°C, preferably 20–50°C, during the emulsion preparation process.

[0036] In some embodiments, the temperature is controlled at 15–50°C during the preparation of the concentrated solution.

[0037] In some embodiments, a method for preparing a posaconazole oral suspension includes the following steps: (1) Emulsion preparation: adding a wetting agent and an antifoaming agent to water, controlling the temperature of the liquid solution to 10-60°C, shearing and mixing, and homogenizing with a high-pressure homogenizer to obtain an emulsion; the shearing speed is 1000-3000 rpm, and the homogenization pressure is 15000-25000 psi;

[0038] (2) Preparation of concentrated solution: Take a portion of the emulsion, add posaconazole, control the temperature of the drug solution at 15-50℃, shear and mix, and homogenize using a high-pressure homogenizer to obtain a concentrated solution with a target particle size D50 of 0.8-1.5μm; the shearing speed is 1000-3000rpm, and the homogenization pressure is 20000-30000psi;

[0039] (3) Maturation: The concentrated solution is heated and kept at a temperature of 30-80℃ to achieve a target particle size D50 of 1.3-2.0μm;

[0040] (4) Mixing: Add the remaining emulsion, preservative, pH adjuster, thickener, suspending agent, opaque agent, and flavoring agent, add water to make up the volume, and shear and mix to prepare a posaconazole oral suspension with a target particle size D50 of 1.3 to 2.0 μm; the shearing speed is 3000 to 5000 rpm.

[0041] In some embodiments, a method for preparing a posaconazole oral suspension includes the following steps: (1) Concentrated solution preparation: posaconazole, a portion of wetting agent and defoamer are added to water, the temperature of the solution is controlled at 15-50°C, sheared and mixed, and homogenized by a high-pressure homogenizer to obtain a concentrated solution with a target particle size D50 of 0.8-1.5 μm; the shearing speed is 1000-3000 rpm, and the homogenization pressure is 20000-30000 psi;

[0042] (2) Maturation: The concentrated solution is heated and kept at a temperature of 30-80℃ to achieve the target particle size D50 of 1.3-2.0μm;

[0043] (3) Total mixing: Add the remaining wetting agent, defoamer, preservative, pH adjuster, thickener, suspending agent, opaque agent and flavoring agent, add water to make up the volume, shear and mix well to prepare a posaconazole oral suspension with a target particle size D50 of 1.3 to 2.0 μm. The shearing speed is 3000 to 5000 rpm.

[0044] In some embodiments, the amount of posaconazole used is 2-6% by weight of the oral posaconazole suspension, preferably 4%.

[0045] In some embodiments, the wetting agent is selected from one or more of polysorbates, poloxamer, and fatty acid esters of polyoxyethylene. The polysorbates refer to saturated / unsaturated C10-C20 esters of sorbitol, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85; most preferably, the wetting agent is polysorbate 80.

[0046] The fatty acid esters of the polyoxyethylene include polyoxygenated hydrogenated castor oil and polyoxyethylene hydrogenated castor oil.

[0047] In some embodiments, the wetting agent is used in an amount of 0.5-5% of the posaconazole oral suspension, preferably 0.5-2.5%, and most preferably 1.0%.

[0048] In some embodiments, the preservative is selected from one or more of sodium benzoate, benzalkonium chloride, methylparaben, and potassium sorbate; preferably, the preservative is sodium benzoate.

[0049] In some embodiments, the amount of preservative is 0.1-0.3% of the posaconazole oral suspension by mass, preferably 0.2%.

[0050] In some embodiments, the thickener is selected from one or more of xanthan gum, tragacanth gum, guar gum, pectin, and gum arabic; preferably, the thickener is xanthan gum.

[0051] In some embodiments, the amount of the thickener is 0.1-0.5% of the posaconazole oral suspension by mass, preferably 0.2-0.4%, and most preferably 0.3%.

[0052] In some embodiments, the suspending agent is one or a combination of glycerol and syrup, which can increase the viscosity of the dispersion medium and simultaneously increase the hydrophilicity of the particles. The syrup used in this invention can be selected from one or more of liquid glucose, maltose syrup, glucose syrup, and fructose syrup. The syrup has a dual function of suspending and flavoring. Preferably, the suspending agent is a mixture of glycerol and syrup, and forms a relatively stable gel state with xanthan gum; the synergistic effect of the three makes the suspension more stable.

[0053] In some embodiments, the suspending agent is used in an amount of 25-65% of the posaconazole oral suspension, preferably 30-55%, and most preferably 45% by mass percentage. Preferably, the suspending agent is a combination of glycerol and syrup, wherein the mass ratio of glycerol to syrup is 1:2-6; most preferably, the mass ratio of glycerol to syrup is 1:3-4.

[0054] In some embodiments, the defoamer is simethicone.

[0055] In some embodiments, the amount of the defoamer is 0.2-0.4% of the posaconazole oral suspension by mass, preferably 0.3%.

[0056] In some embodiments, the pH adjuster may be selected from alkaline pH adjusters and / or acidic pH adjusters; for example, reagents suitable as pH adjusters for use as suspensions, adjusting to maintain the pH of the suspension at 4.0 to 6.0, preferably 4.2 to 4.8.

[0057] In some embodiments, the alkaline pH adjuster may be selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, triethylamine, diethanolamine, sodium citrate, sodium phosphate, or Tris (tris(hydroxymethyl)aminomethane). Preferably, the alkaline pH adjuster is sodium citrate.

[0058] In some embodiments, the acidic pH adjuster may be selected from at least one of ascorbic acid, lactic acid, malic acid, fumaric acid, citric acid, tartaric acid, succinic acid, sulfuric acid, hydrochloric acid, histidine, phosphoric acid, or acetic acid. Preferably, the acidic pH adjuster is citric acid.

[0059] In some embodiments, the pH adjuster is a buffer system of sodium citrate and citric acid, wherein the sodium citrate comprises 0.04–0.08% and the citric acid comprises 0.1–0.2% by mass percentage of the posaconazole oral suspension. Preferably, the sodium citrate comprises 0.06% and the citric acid comprises 0.15%.

[0060] In some embodiments, the light-blocking agent is titanium dioxide. The amount of the light-blocking agent is 0.2–0.6% of the posaconazole oral suspension by mass, preferably 0.4%.

[0061] In some embodiments, the flavoring agent is an edible flavoring, which is a conventional substance in the art, including but not limited to one or more of peach flavoring, grape flavoring, mint flavoring, orange flavoring, cherry flavoring, strawberry flavoring and grapefruit flavoring.

[0062] In some embodiments, the flavoring agent is used in an amount of 0.2-0.8% of the posaconazole oral suspension, preferably 0.5%.

[0063] In some embodiments, the posaconazole oral suspension comprises the following components by weight percentage: 2-6% posaconazole, 0.5-5% wetting agent, 0.1-0.3% preservative, 25-65% suspending agent, 0.2-0.4% defoamer, 0.1-0.5% thickener, 0.2-0.8% flavoring agent, 0.2-0.6% light-blocking agent, appropriate amount of water, and pH adjuster to a pH of 4.0-6.0.

[0064] In some embodiments, the pH of the posaconazole oral suspension is between 4.2 and 4.8.

[0065] In some embodiments, the posaconazole oral suspension comprises, by weight percentage:

[0066] Posaconazole 2-6%, polysorbate 80 0.5-5%, simethicone 0.2-0.4%, sodium benzoate 0.1-0.3%, sodium citrate 0.04-0.08%, citric acid 0.1-0.2%, xanthan gum 0.1-0.5%, glycerin 5-15%, liquid glucose 20-50%, edible flavoring 0.2-0.8%, titanium dioxide 0.2-0.6%, and appropriate amount of water.

[0067] Preferably, the posaconazole oral suspension comprises the following components by weight percentage:

[0068] Posaconazole 4%, polysorbate 80 1%, simethicone 0.3%, sodium benzoate 0.2%, sodium citrate 0.06%, citric acid 0.15%, xanthan gum 0.3%, glycerin 10%, liquid glucose 35%, food flavoring 0.5%, titanium dioxide 0.4%, and appropriate amount of water.

[0069] In a second aspect, this application provides a posaconazole oral suspension obtained by the preparation method described in the first aspect.

[0070] In a third aspect of this application, the use of the posaconazole oral suspension described in the second aspect above is provided for the prevention of invasive Aspergillus and Candida infections and the treatment of oropharyngeal candidiasis.

[0071] Beneficial effects

[0072] 1. The preparation method provided in this application employs a heating and aging step, resulting in a posaconazole oral suspension with high stability and good batch-to-batch reproducibility. Especially during long-term storage, the related substances increase slowly, the viscosity remains stable, and the particle size increases slowly, with a particle size D50 ≤ 2.0 μm. Compared to the unaged suspension, its particle size increase is smaller, exhibiting a more stable particle size.

[0073] 2. The posaconazole oral suspension prepared by the method of this application has good dissolution and can achieve a good fit with the reference formulation.

[0074] 3. The preparation method of this application does not have strict requirements on the particle size of the raw material posaconazole, and does not require micronization. Therefore, the equipment investment is low, the preparation method is easy to operate, and the reproducibility is good.

[0075] 4. In the preparation method of this application, a shearing machine and a homogenizer are used in synergistic processing, and the resulting suspension is uniformly and stably dispersed with a particle size distribution D50 of 1.3 to 2.0 μm.

[0076] Additional aspects and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description or may be learned by practice of the invention.

[0077] the term

[0078] Simethicone: a mixture of dimethicone and silica, CAS NO.8050-81-5.

[0079] D50: d(0.5)μm, refers to the particle size corresponding to the cumulative particle size distribution percentage of a sample reaching 50%, also known as the median diameter or median particle size. Its physical meaning is that particles larger than it account for 50%, and particles smaller than it also account for 50%.

[0080] Mass percentage concentration (wt%): refers to the amount of solute contained in the solution. All concentrations mentioned in this invention are mass percentage concentrations.

[0081] The formula for calculating the mass percentage concentration is: wt% = [mass of B / (mass of A + mass of B)] × 100%. The formula for calculating the particle size growth rate is: D50 particle size growth rate % = [(D50 particle size during stability period - particle size of D50 on day 0) / particle size on day 0] × 100%.

[0082] The formula for calculating particle size growth is: D50 particle size growth = D50 particle size during the stability period - particle size of D50 on day 0. Detailed Implementation

[0083] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0084] It should be noted that the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature. Furthermore, in the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0085] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0086] Example 1

[0087] Posaconazole oral suspension, batch size 100L, prescription as follows:

[0088]

[0089] The preparation method is as follows:

[0090] (1) Emulsion preparation: Add polysorbate 80 to an appropriate amount of purified water, stir to dissolve, add simethicone oil through a high shear machine, shear speed 1000 rpm, control the temperature of the drug solution 20-40℃, shear and mix, homogenize with a high pressure homogenizer at a pressure of 15000psi to obtain the emulsion.

[0091] (2) Preparation of concentrated solution: Take 50% emulsion, add posaconazole through a high shear mill, shear speed 1000 rpm, control the temperature of the drug solution 15-50℃, shear and mix, and then homogenize through a high pressure homogenizer at a pressure of 15000psi to obtain a concentrated solution, wherein the particle size D50 of the concentrated solution is 1.1-1.2μm.

[0092] (3) Maturation: The concentrated solution is kept warm and matured, with the temperature range of the solution controlled at 40-50℃, until the particle size D50 of the solution reaches 1.5-1.7μm;

[0093] (4) Total mixing: Add the remaining emulsion, sodium benzoate, sodium citrate, and citric acid, and shear and mix well; add xanthan gum, glycerin, liquid glucose, titanium dioxide, and cherry flavor, add purified water to make up to volume, and shear and mix well to prepare a posaconazole oral suspension with a target particle size D50 of 1.5-2.0 μm; the shearing speed is 3000 rpm.

[0094] Example 2

[0095] Posaconazole oral suspension, 50L batch, prescription as follows:

[0096]

[0097] The preparation method is as follows:

[0098] (1) Emulsion preparation: Add polysorbate 80 to an appropriate amount of purified water, stir to dissolve, add simethicone oil through a high shear machine, shear speed 1500 rpm, control the temperature of the drug solution 20-40℃, shear and mix, homogenize with a high pressure homogenizer at a pressure of 20000psi to obtain the emulsion.

[0099] (2) Preparation of concentrated solution: Take 50% emulsion, add posaconazole through a high shear mill, shear speed 2000 rpm, control the temperature of the drug solution 15-50℃, shear and mix, homogenize with a high pressure homogenizer, and obtain concentrated solution with a homogenization pressure of 20000psi. The particle size D50 of the concentrated solution is 1.0-1.3μm.

[0100] (3) Maturation: The concentrated solution is kept warm and matured, with the temperature range of the solution controlled at 40℃, until the particle size D50 of the solution reaches 1.6~1.8μm;

[0101] (4) Total mixing: Add the remaining emulsion, sodium benzoate, sodium citrate, and citric acid, and shear and mix well; add xanthan gum, glycerin, liquid glucose, titanium dioxide, and cherry flavor, add purified water to make up to volume, and shear and mix well to prepare a posaconazole oral suspension with a target particle size D50 of 1.5-2.0 μm; the shearing speed is 3500 rpm.

[0102] Examples 3-10

[0103] The preparation method was carried out according to Example 1, and the parameters are shown in Table 1 below.

[0104] Table 1 Parameters of Examples 3-10

[0105]

[0106] Example 11

[0107] Using the prescription from Example 1, a method for preparing a posaconazole oral suspension includes the following steps:

[0108] (1) Preparation of concentrated solution: Posaconazole and 50% polysorbate 80 were added to purified water and stirred to dissolve. 50% simethicone was added through a high-shear mill at a shear speed of 2000 rpm and the temperature of the drug solution was controlled at 15-50℃. The mixture was sheared and homogenized by a high-pressure homogenizer at a pressure of 20000 psi. A concentrated solution with a target particle size D50 of 1.1-1.2 μm was obtained.

[0109] (2) Maturation: The concentrated solution is heated and kept warm, and the temperature of the solution is controlled at 40℃ to achieve the target particle size D50 of 1.5~1.7μm;

[0110] (3) Total mixing: Add the remaining 50% of polysorbate 80, the remaining 50% of simethicone, sodium benzoate, sodium citrate, and citric acid, and shear and mix well; add xanthan gum, glycerin, liquid glucose, titanium dioxide, and cherry flavor, add purified water to make up to volume, and shear and mix well to prepare a posaconazole oral suspension with a target particle size D50 of 1.5-2.0 μm; the shearing speed is 3500 rpm.

[0111] Example 12

[0112] Using the prescription from Example 1, a method for preparing a posaconazole oral suspension includes the following steps:

[0113] (1) Preparation of concentrated solution: Posaconazole and 30% polysorbate 80 were added to purified water and stirred to dissolve. 30% simethicone was added through a high-shear mill at a shear speed of 1000 rpm and the temperature of the drug solution was controlled at 15-50℃. The mixture was sheared and homogenized by a high-pressure homogenizer at a pressure of 15000 psi. A concentrated solution with a target particle size D50 of 1.1-1.2 μm was obtained.

[0114] (2) Maturation: The concentrated solution is heated and kept warm, and the temperature of the solution is controlled at 50°C to achieve the target particle size D50 of 1.5~1.7μm;

[0115] (3) Total mixing: Add the remaining polysorbate 80, the remaining simethicone, sodium benzoate, sodium citrate, and citric acid, and stir to mix well; add xanthan gum, glycerin, liquid glucose, titanium dioxide, and cherry flavor, add purified water to make up to volume, and shear to mix well to prepare a posaconazole oral suspension with a target particle size D50 of 1.5-2.0 μm; the shearing speed is 3000 rpm.

[0116] Experimental Example 1: Effect of ripening process on particle size stability

[0117] This application: Example 7

[0118] Comparative Example 1: The suspension was prepared according to Example 7, except that it did not contain the aging process of step (3).

[0119] See Table 2 for specific parameters.

[0120] Comparative Example 2: Reference preparation, strength 40 mg / ml, trade name

[0121] Table 2. Maturation Process Parameters

[0122]

[0123] Test method: Examples 7, 1 and 2 were placed at 30℃±2℃, RH65%±5% and 40℃±2℃, RH75%±5% for 3 and 6 months respectively, and their related substances and particle size distribution were tested.

[0124] The method for detecting related substances is as follows: high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition, Part IV, General Chapter 0512).

[0125] Particle size determination method: determined according to the method for determination of particle size and particle size distribution (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0982, Method III).

[0126] Experimental results: See Table 3

[0127] Table 3 Summary of results regarding material and particle size distribution

[0128]

[0129] As shown in Table 3, after being stored at 30℃ and 40℃ for 3 and 6 months respectively, the growth trend of related substances in Example 7 was similar to that of Comparative Example 2, but overall lower than that of Comparative Example 2, indicating stronger stability. The particle size D50 growth in Example 7 was slower than that in Comparative Examples 1 and 2, especially compared to Comparative Example 1, where the growth rate decreased by approximately two times after being stored at 30℃ and 40℃ for 3 and 6 months respectively. This indicates that the aging process significantly contributes to particle size stability. Example 2: Effect of Homogenized Concentrated Solutions of Different Particle Sizes on the Particle Size Stability of Suspensions

[0130] This application: Examples 4-10

[0131] Comparative Examples 4-6: Prepared according to the method of Example 7, with the following differences: step (3) aging was omitted, and the particle size of the concentrated solution after homogenization in step (2) was different. Specific parameters are shown in Table 4.

[0132] Table 4. Parameters of homogenized concentrated solutions with different particle sizes

[0133]

[0134] Test method: Examples 4-10 and Comparative Examples 4-6 were placed at 60℃ for 30 days and at 40±2℃ with RH 75%±5% for 6 months, respectively, and their particle size was tested.

[0135] Experimental Results: See Table 5. Comparative Examples 4-6 show that after homogenization of the concentrated solution, without a curing process, the finished product exhibited excessively rapid particle size increase in the stability test at 60℃. After 30 days at 60℃, the particle size D50 increased by 1.03–1.57 μm, and by the 5th day, the particle size D50 had exceeded 2.0 μm, failing to meet the standard. It was also found that the smaller the particle size of the uncooked concentrated solution, the worse its stability and the higher the particle size increase. Therefore, it can be seen that the particle size D50 of the concentrated solution before curing is in the range of 1.0–1.5 μm. Without a curing step, a particle size-stable suspension cannot be obtained. This experiment proves that the curing process is a necessary condition for obtaining a highly stable posaconazole suspension.

[0136] Table 5. Summary of the effects of homogenized concentrated solutions of different particle sizes on the particle size stability of suspensions.

[0137]

[0138] Experimental Example 3: Investigation of the effects of the order of maturation steps, maturation temperature, and concentrated solution particle size on the particle size stability of suspensions.

[0139] This application: Examples 4-10

[0140] Comparative Example 3: The prescription and preparation method are the same as in Example 7, except that step (3) of maturation is placed after step (4) of total mixing, i.e., the method is as follows:

[0141] The preparation method is as follows:

[0142] (1) Emulsion preparation: Add polysorbate 80 to an appropriate amount of purified water, stir to dissolve, add simethicone oil through a high shear machine, shear speed 2000 rpm, control the temperature of the drug solution 25-30℃, shear and mix, homogenize with a high pressure homogenizer at a pressure of 20000psi to obtain the emulsion.

[0143] (2) Preparation of concentrated solution: Take 50% emulsion, add posaconazole through a high shear mill, shear speed 2500 rpm, control the temperature of the drug solution 15-50℃, shear dispersion, homogenize and mix with a high pressure homogenizer at a pressure of 25000 psi to obtain a concentrated solution of the target particle size.

[0144] (3) Total mixing: Add the remaining emulsion, sodium benzoate, sodium citrate, and citric acid, and shear mix; add xanthan gum, glycerin, liquid glucose, titanium dioxide, and cherry flavor, add purified water to make up to volume, shear mix, and prepare a suspension with the target particle size; the shearing speed is 5000 rpm;

[0145] (4) Maturation: The mixed suspension is heated and kept warm to mature the drug solution at 60°C until the target particle size is reached.

[0146] Comparative Example 7: Prepared according to Example 7, except that the particle size (after homogenization of the concentrated solution) D50 before aging was greater than 1.5 μm.

[0147] Comparative Example 8: Prepared according to Example 7, except that the curing temperature was 25°C.

[0148] Experimental method: Examples 4-10, Comparative Examples 3 and 7-8 were placed at 60°C for 30 days and at 40°C for 6 months, respectively, and their particle size was tested.

[0149] Experimental Results: See Table 6. As can be seen from Examples 4-10, after homogenization of the concentrated solution, regardless of whether the aging period was 40℃ for 6 months or 60℃ for 30 days, the final particle size D50 remained within 2.0 μm. Furthermore, the particle size increase was within +0.4 μm at 60℃ for 30 days and within +0.18 μm at 40℃ for 6 months, indicating stable quality. Examples 4-10 also show that as the aging temperature increases, the time required to reach the target particle size gradually shortens, but there is no significant difference in aging time between 60℃ and 70℃. While 80℃ shortens the aging time, which is beneficial for improving production efficiency, the short time makes timely particle size monitoring and judgment difficult. Therefore, the preferred aging temperature is 40–70℃.

[0150] Comparative Example 3: After total mixing, the particles were heated and matured. After being placed at 60℃ for 5 days, the particle size D50 exceeded 2.0μm, which did not meet the quality standard (D50≤2.0μm). At the same time, the particle size increased by 0.42μm after 60℃ for 30 days. It can be seen that placing the maturity step last makes the particle size of the finished product slightly unstable. With the extension of the maturity time, the particle size increase may be even higher.

[0151] Comparative Example 8: The particle size D50 before maturation was 1.33 μm, which decreased to 1.54 μm after being placed at room temperature (25℃). After being stored at 60℃ for 30 days, the particle size increased by 0.74 μm. This shows that after homogenization of the concentrated solution, placement at room temperature for a period of time, or maintaining room temperature (25℃) for a period of time before final mixing, resulted in a faster increase in the final particle size. The increase was significant after 60℃ for 30 days, exceeding 2.0 μm by day 5. This also demonstrates that the suspension is extremely unstable under room temperature storage conditions.

[0152] In Comparative Example 7, to quickly achieve the target particle size D50 of 1.5–2.0 μm, the concentrated solution was homogenized until the larger particle size D50 was above 1.5 μm. After heating and aging, the finished product particle size D50 reached approximately 1.70 μm. However, during routine storage, the particle size itself undergoes a growth equilibrium process, which can easily cause it to exceed the standard (D50 ≤ 2.0 μm). Therefore, it is preferable that the particle size D50 before aging is controlled at 1.0–1.5 μm, which can meet the quality standard requirements.

[0153] Table 6. Summary of the effects of the order of maturation steps, maturation temperature, and concentrated solution particle size on the particle size stability of the suspension.

[0154]

Claims

1. A method for preparing a posaconazole oral suspension, characterized in that, Includes the following steps: Posaconazole is dispersed and mixed with wetting agent and defoamer, and then aged; the aging process involves heating and heat preservation. Preferably, the method includes the following steps: dispersing and mixing posaconazole with a wetting agent and an antifoaming agent, aging it, and then adding one or more of a preservative, pH adjuster, thickener, suspending agent, opaque agent, or flavoring agent, dispersing and mixing it to obtain the finished posaconazole oral suspension, wherein the aging is performed by heating and keeping warm.

2. The preparation method according to claim 1, wherein, Includes the following steps: (1) Preparation of concentrated solution: water, posaconazole, some wetting agent and defoamer are dispersed and mixed to obtain a concentrated solution with the target particle size; (2) Maturation: The concentrated solution is heated and kept at a constant temperature to achieve the target particle size; (3) Mixing: Add the remaining wetting agent and defoamer, as well as one or more of the preservatives, pH adjusters, thickeners, suspending agents, opacifiers or flavoring agents, disperse and mix well to obtain the posaconazole oral suspension product with the target particle size. or Includes the following steps: (1) Emulsion preparation: Water, wetting agent and defoamer are dispersed and mixed to obtain an emulsion; (2) Preparation of concentrated solution: Disperse and mix part of the emulsion and posaconazole to obtain a concentrated solution with the target particle size; (3) Maturation: The concentrated solution is heated and kept at a constant temperature to achieve the target particle size; (4) Total mixing: Add the remaining emulsion and one or more of the following: preservative, pH adjuster, thickener, suspending agent, opaque agent or flavoring agent, and mix thoroughly to obtain the posaconazole oral suspension product with the target particle size.

3. The preparation method according to claim 1 or 2, wherein, The heating and heat preservation temperature is 30-80℃; preferably, the heating and heat preservation temperature is 40-80℃. Preferably, the heating and heat preservation time is 50 to 300 minutes.

4. The preparation method according to any one of claims 2-3, wherein, The target particle size D50 of the concentrated solution is 0.8–1.5 μm; Preferably, the target particle size D50 after the ripening step is 1.3–2.0 μm; Preferably, the target particle size D50 of the posaconazole oral suspension is 1.3 to 2.0 μm.

5. The preparation method according to any one of claims 1-4, wherein, The dispersion and mixing includes one or more of ball milling, stirring, ultrasonic mixing, shearing, and homogenization. Preferably, the dispersion mixing is shear mixing and / or homogenization mixing; Preferably, the shearing speed is 1000-10000 rpm and the homogenization pressure is 15000-30000 psi; Preferably, the shear speed during the preparation of the total mixture is greater than the shear speed during the preparation of the emulsion and / or concentrated solution; Preferably, the shear speed during the preparation of the total mixture is 3000-5000 rpm, and the shear speed during the preparation of the emulsion or concentrated solution is 1000-3000 rpm; Preferably, the homogenization pressure during emulsion preparation is lower than the homogenization pressure during concentrated solution preparation; Preferably, the homogenization pressure in the emulsion preparation is 15,000 to 25,000 psi, and the homogenization pressure in the concentrated solution preparation is 20,000 to 30,000 psi.

6. The preparation method according to any one of claims 1-5, wherein, Includes the following steps: (1) Emulsion preparation: Wetting agent and defoamer are added to water, the temperature of the liquid is controlled at 10-60℃, sheared and mixed, and homogenized by high pressure homogenizer to obtain emulsion; the shearing speed is 1000-3000 rpm, and the homogenization pressure is 15000-25000 psi. (2) Preparation of concentrated solution: Take a portion of the emulsion, add posaconazole, control the temperature of the solution at 15-50℃, shear and mix, and homogenize using a high-pressure homogenizer to obtain a concentrated solution with a target particle size D50 of 0.8-1.5μm; the shearing speed is 1000-3000rpm, and the homogenization pressure is 20000-30000psi; (3) Maturation: The concentrated solution is heated and kept at a temperature of 30-80℃ to achieve a target particle size D50 of 1.3-2.0μm; (4) Total mixing: Add the remaining emulsion, preservative, pH adjuster, thickener, suspending agent, opaque agent, and flavoring agent, add water to make up the volume, and shear and mix to prepare a posaconazole oral suspension with a target particle size D50 of 1.3 to 2.0 μm; the shearing speed is 3000 to 5000 rpm. Alternatively, the preparation method may include the following steps: (1) Preparation of concentrated solution: Posaconazole, some wetting agent and defoamer are added to water, the temperature of the drug solution is controlled at 15-50℃, sheared and mixed, and homogenized by high pressure homogenizer to obtain a concentrated solution with a target particle size D50 of 0.8-1.5μm; the shearing speed is 1000-3000rpm, and the homogenization pressure is 20000-30000psi; (2) Maturation: The concentrated solution is heated and kept at a temperature of 30-80℃ to achieve the target particle size D50 of 1.3-2.0μm; (3) Total mixing: Add the remaining wetting agent, defoamer, preservative, pH adjuster, thickener, suspending agent, opaque agent and flavoring agent, add water to make up the volume, shear and mix well to prepare a posaconazole oral suspension with a target particle size D50 of 1.3 to 2.0 μm. The shearing speed is 3000 to 5000 rpm.

7. The preparation method according to any one of claims 1-6, wherein, The posaconazole oral suspension comprises the following components by weight percentage: 2-6% posaconazole, 0.5-5% wetting agent, 0.1-0.3% preservative, 25-65% suspending agent, 0.2-0.4% defoamer, 0.1-0.5% thickener, 0.2-0.8% flavoring agent, 0.2-0.6% light-blocking agent, appropriate amount of water, and pH adjuster to pH 4.0-6.

0.

8. The preparation method according to any one of claims 1-7, wherein, The suspending agent is a combination of glycerol and syrup, wherein the mass ratio of glycerol to syrup is 1:2 to 6; preferably, the mass ratio of glycerol to syrup is 1:3 to 4.

9. The preparation method according to any one of claims 1-8, wherein, The posaconazole oral suspension comprises the following components by weight percentage: posaconazole 2-6%, polysorbate 80 0.5-5%, simethicone 0.2-0.4%, sodium benzoate 0.1-0.3%, sodium citrate 0.04-0.08%, citric acid 0.1-0.2%, xanthan gum 0.1-0.5%, glycerin 5-15%, liquid glucose 20-50%, edible flavoring 0.2-0.8%, titanium dioxide 0.2-0.6%, and appropriate amount of water; Preferably, the composition comprises 4% posaconazole, 1% polysorbate 80, 0.3% simethicone, 0.2% sodium benzoate, 0.06% sodium citrate, 0.15% citric acid, 0.3% xanthan gum, 10% glycerin, 35% liquid glucose, 0.5% food flavoring, 0.4% titanium dioxide, and an appropriate amount of water.

10. The posaconazole oral suspension prepared by the preparation method according to any one of claims 1-9.

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