Liquid compositions containing posaconazole and methods of making and using the same

Abstract

This disclosure provides a liquid composition containing posaconazole, a method for preparing the same, and its uses. The liquid composition comprises posaconazole, cyclodextrin, a dilution stabilizer, an antioxidant, and an acidic pH adjuster. The dilution stabilizer comprises hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. The cyclodextrin comprises 25% to 45% of the total mass of the liquid composition. This liquid composition can improve the oral bioavailability of posaconazole, reduce the influence of food on bioavailability, and improve patient compliance.

Description

Technical Field

[0001] This disclosure pertains to the field of pharmaceutical preparations, specifically relating to liquid compositions containing posaconazole, their preparation methods, and uses. Background Technology

[0002] In vivo exposure to posaconazole oral suspension is significantly affected by food and many gastrointestinal conditions, including pH and exercise. In most patients, posaconazole plasma concentrations are extremely low, and the absorption profile is unstable. Posaconazole oral suspension requires multiple daily doses, such as 200 mg three times a day, and should be taken with a high-fat diet to ensure adequate oral absorption and systemic PK exposure. However, patients requiring antifungal prophylaxis may struggle to ensure adequate high-fat dietary intake to enhance the efficacy of posaconazole suspension due to severe nausea or vomiting caused by chemotherapy, or severe mucositis or diarrhea. These unstable absorption issues led to the subsequent development of extended-release tablets, which demonstrated higher and still unstable exposure profiles; for example, after administration of 300 mg of the upcoming posaconazole tablet, the maximum concentrations after a single dose (fasting) and steady-state administration (feeding) were 614 and 2764 ng / mL, respectively (Study P07783). The FDA recommends that tablets still be taken with food. In addition, the tablets require a loading dose on day 1 to achieve high concentrations of posaconazole more quickly. That is, the tablets are significantly affected by food intake, and the loading dose needs to be carefully controlled. Summary of the Invention

[0003] In a first aspect of this disclosure, a liquid composition is provided comprising posaconazole, cyclodextrin, a dilution stabilizer, an antioxidant, an acidic pH adjuster, and water, wherein the dilution stabilizer comprises hydroxypropyl cellulose and / or hydroxypropyl methylcellulose, and the cyclodextrin comprises 25% to 45% by mass based on the total mass of the liquid composition.

[0004] In a second aspect of this disclosure, a method for preparing the liquid composition of the first aspect of this disclosure is provided, comprising: mixing cyclodextrin with an aqueous solvent to obtain a first mixture; mixing posaconazole, an acidic pH adjuster, and an antioxidant with the first mixture to obtain a second mixture; mixing a diluent stabilizer with the second mixture to obtain a third mixture; and adding an aqueous solvent to the third mixture to make up to a final volume.

[0005] In a third aspect of this disclosure, the use of the liquid composition described in the first aspect of this disclosure or the liquid composition prepared by the method described in the second aspect of this disclosure in the preparation of a medicament for treating, improving or preventing fungal infections is provided.

[0006] In a fourth aspect of this disclosure, a method for treating, improving, or preventing fungal infections includes administering to an individual in need a liquid composition described in the first aspect of this disclosure or a liquid composition prepared using the method described in the second aspect of this disclosure. Attached Figure Description

[0007] Figure 1 This is a graph showing the change in the dissolution rate of posaconazole in the liquid compositions of Examples 1 and 2 of this disclosure as a function of dissolution time.

[0008] Figure 2 This is a graph showing the dissolution rate of posaconazole in the liquid compositions of Examples 3 to 6, Comparative Examples 2, 4 and 5 of this disclosure as a function of dissolution time.

[0009] Figure 3 This is a graph showing the dissolution rate of posaconazole in the liquid compositions of Examples 7 to 9 and Examples 13 to 15 of this disclosure as a function of dissolution time.

[0010] Figure 4 These are the XRD patterns of the dissolution extracts and posaconazole from Examples 3, 6, Comparative Examples 2, 4, and 5 of this disclosure.

[0011] Figure 5 The XRD patterns of the dissolution precipitates and posaconazole of Examples 1, 5, 7 to 14, and Comparative Example 3 of this disclosure are shown. Detailed Implementation

[0012] The present disclosure is further described below with reference to specific embodiments. It should be understood that these specific embodiments are for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0013] In a first aspect of this disclosure, a liquid composition is provided comprising posaconazole, cyclodextrin, a dilution stabilizer, an antioxidant, an acidic pH adjuster, and water, wherein the dilution stabilizer comprises hydroxypropyl cellulose and / or hydroxypropyl methylcellulose, and the cyclodextrin comprises 25% to 45% by mass based on the total mass of the liquid composition.

[0014] In this disclosure, the combined use of the diluent stabilizer and the cyclodextrin can improve the dissolution of posaconazole under different pH conditions (such as simulated intestinal pH variations) and inhibit the precipitation of posaconazole in crystalline form, so that posaconazole is in a dissolved or amorphous state in the intestine, ensuring the absorption of posaconazole in the intestine, improving the bioavailability of posaconazole, and reducing the impact of food on bioavailability.

[0015] The liquid compositions described in this disclosure may also have one or more of the following beneficial effects: minimal individual variability, no loading dose required, no organic solvents, and improved patient compliance.

[0016] In some embodiments of this disclosure, the liquid composition may be an oral formulation, such as an oral solution.

[0017] In some embodiments of this disclosure, the dilution stabilizer may comprise or be selected from hydroxypropyl cellulose and / or hydroxypropyl methylcellulose. The dilution stabilizer in the liquid composition can adjust the viscosity of the liquid composition and improve the solubility stability of the liquid composition after dilution, such as the solubility stability after clinical administration. In particular, selecting a combination of hydroxypropyl cellulose and / or hydroxypropyl methylcellulose with cyclodextrin can further improve the bioavailability of posaconazole in the liquid composition under different pH conditions and reduce the influence of food on bioavailability.

[0018] In some embodiments of this disclosure, the mass percentage of the cyclodextrin can be 25% to 45% based on the total mass of the liquid composition, for example, 25%, 26%, 27%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 40.5%, 41%, 42%, 43%, 44%, or 45%, etc. This allows the active ingredient posaconazole to have a high dissolution rate under different pH conditions, improving its bioavailability during the release phase.

[0019] In some embodiments of this disclosure, the mass ratio of posaconazole to the diluent stabilizer can be 1:(1-7.5), for example, it can be 1 / 1, 1 / 1.25, 1 / 1.5, 1 / 1.75, 1 / 2, 1 / 2.25, 1 / 2.5, 1 / 2.75, 1 / 3, 1 / 3.25, 1 / 3.5, 1 / 3.75, 1 / 4, 1 / 4.25, 1 / 4.5, 1 / 4.75, 1 / 5, 1 / 5.25, 1 / 5.5, 1 / 5.75, 1 / 6, 1 / 6.25, 1 / 6.5, 1 / 6.75, 1 / 7, 1 / 7.25, or 1 / 7.5, etc. etc.; and / or, in the liquid composition, the mass ratio of posaconazole to cyclodextrin can be 1:(10-22.5), for example, it can be 1 / 10, 1 / 10.5, 1 / 11, 1 / 11.5, 1 / 12, 1 / 12.5, 1 / 13, 1 / 13.5, 1 / 14, 1 / 14.5, 1 / 15, 1 / 15.5, 1 / 16, 1 / 16.5, 1 / 17, 1 / 17.5, 1 / 18, 1 / 18.5, 1 / 19, 1 / 19.5, 1 / 20, 1 / 20.5, 1 / 21, 1 / 21.5, 1 / 22 or 1 / 22.5, etc. The optimal dosage of posaconazole and the diluent stabilizer within the given range further facilitates the presence of posaconazole dissolved in the liquid composition in a dissolved or amorphous state, rather than precipitating as crystals. This improves the solubility and bioavailability of posaconazole during the release phase and reduces the impact of food on bioavailability. Cyclodextrin in the liquid composition can enhance the dissolution and solubility of the active ingredient posaconazole at different pH levels. In particular, the optimal cyclodextrin content within the given range further facilitates higher solubility of posaconazole at different pH levels. Furthermore, the simultaneous fulfillment of the given ranges for the dosage of posaconazole, the diluent stabilizer, and the cyclodextrin not only improves the solubility of posaconazole at different pH levels but also ensures a supersaturated state in the liquid composition. This allows the posaconazole dissolved in the liquid composition at different pH levels to exist in a dissolved or amorphous state, maintaining high solubility and solubility stability during the release phase, further improving its bioavailability and reducing the impact of food on bioavailability. In some specific embodiments, the mass ratio of posaconazole to the diluent stabilizer can be 1:(1.5-4), or 1:(2-3). In some specific embodiments, the mass ratio of posaconazole to cyclodextrin can be 1:(11-20), or 1:(12.5-17.5).

[0020] In some embodiments of this disclosure, the cyclodextrin may comprise β-cyclodextrin and / or derivatives of β-cyclodextrin. Optionally, in some specific embodiments, the cyclodextrin may comprise one or more of hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methyl-β-cyclodextrin.

[0021] In some embodiments of this disclosure, the liquid composition may also contain water and is free of organic solvents. This allows the liquid composition to combine good posaconazole dissolution properties and absorption, improving patient compliance.

[0022] In some embodiments of this disclosure, the antioxidant may comprise one or more of methionine, sodium metabisulfite, sodium bisulfite, proline, and glycine. In some specific embodiments, the antioxidant may comprise methionine. In some specific embodiments, the antioxidant may comprise sodium metabisulfite and / or sodium bisulfite. In still other specific embodiments, the antioxidant may comprise methionine, and one or more selected from sodium metabisulfite, sodium bisulfite, proline, and glycine, such as combinations of methionine and sodium metabisulfite, methionine and sodium bisulfite, methionine and proline, and methionine and glycine. The antioxidant in the liquid composition can consume oxygen in the liquid composition, inhibit product deterioration caused by oxidation, and increase the stability of posaconazole in the liquid composition. In particular, using methionine as an antioxidant not only improves the stability of the liquid composition but is also non-toxic.

[0023] In some embodiments of this disclosure, the acidic pH adjuster may be selected from commonly used acidic pH adjusters in the pharmaceutical field, for example, the acidic pH adjuster may include, but is not limited to, one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and maleic acid. In some specific embodiments, the acidic pH adjuster may include hydrochloric acid and / or sulfuric acid. The acidic pH adjuster in the liquid composition can adjust the solubility of posaconazole in the liquid composition.

[0024] In some embodiments of this disclosure, the pH value of the liquid composition can be 1.5 to 4, for example, 1.5, 2, 2.5, 3, 3.5, or 4. This allows posaconazole to have good dissolution and solubility in the liquid composition. In some specific embodiments, the pH value of the liquid composition can be further set to 2 to 3.

[0025] In some embodiments of this disclosure, based on the total mass of the liquid composition, the mass percentage of posaconazole can be 1% to 2.7%, the mass percentage of cyclodextrin can be 25% to 45%, the mass percentage of diluent stabilizer can be 2% to 15%, the mass percentage of antioxidant can be 0.05% to 2%, and the mass percentage of acidic pH adjuster can be 1.5% to 4%. For example, the mass percentage of posaconazole can be 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, or 2.7%, etc.; the mass percentage of cyclodextrin can be 25%, 26%, 27%, 28%, 28.5%, 29%, 29.5%, 30%, 30.5%, 31%, 31.5%, 32%, 32.5%, 33%, 33.5%, 34%, 34.5%, 35%, 36%, 37%, 38%, 39%, 40%, 40.5%, 41%, 42%, 43%, 44%, or 45%. The mass percentage of the diluent stabilizer can be 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, or 15%, etc.; the mass percentage of the antioxidant can be 0.05%, 0.1%, 0.2%, 0.3%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, or 2%, etc.; the mass percentage of the acidic pH adjuster can be 1.5%, 2%, 2.5%, 3%, 3.5%, or 4%, etc. In some embodiments, the mass percentage of posaconazole, based on the total mass of the liquid composition, can be 1.5% to 2.5%, or 1.5% to 2.0%. In some embodiments, the mass percentage of cyclodextrin, based on the total mass of the liquid composition, can be 25% to 40%, or 25% to 35%. In some embodiments, the mass percentage of the diluent stabilizer, based on the total mass of the liquid composition, can be 3% to 8%, or 4% to 6%. In some embodiments, the mass percentage of the antioxidant, based on the total mass of the liquid composition, can be 0.05% to 1%, or 0.05% to 0.3%. Therefore, the liquid composition of this disclosure has at least one of the following beneficial effects: it can improve the bioavailability of posaconazole, is less affected by food bioavailability, has small individual variability, requires no loading dose, and requires no organic solvent.

[0026] In some embodiments of this disclosure, the liquid composition may further comprise one or more of a flavoring agent, an antibacterial agent, and a chelating agent. Adding a flavoring agent can improve the taste of the liquid composition, further increasing patient compliance. Adding an antibacterial agent helps inhibit bacterial growth in the liquid composition. Adding a chelating agent can chelate metal ions in the liquid composition, further improving the stability of posaconazole in the liquid composition.

[0027] In some embodiments of this disclosure, the flavoring agent may comprise a sweetener and / or a flavoring. The flavoring agent may be selected from those commonly used in the pharmaceutical field, and may include, but is not limited to, sweeteners and / or flavorings. In some specific embodiments, the sweetener may comprise, but is not limited to, one or more of sucralose, acesulfame potassium, stevia, cyclamate, aspartame, sodium saccharin, and xylitol. In some specific embodiments, the flavoring may comprise, but is not limited to, one or more of sweet orange flavoring, banana flavoring, tangerine flavoring, strawberry flavoring, and mango flavoring.

[0028] In some embodiments of this disclosure, the antibacterial agent may comprise one or more of methylparaben, ethylparaben, and propylparaben. The antibacterial agent may be selected from antibacterial agents commonly used in the pharmaceutical field, such as, but not limited to, one or more of methylparaben, ethylparaben, and propylparaben.

[0029] In some embodiments of this disclosure, the chelating agent may comprise one or more of citric acid, malic acid, benzoic acid, edemaic acid, and sodium edema. The chelating agent may be selected from commonly used chelating agents in the pharmaceutical field, such as, but not limited to, one or more of citric acid, malic acid, benzoic acid, edemaic acid, and sodium edema.

[0030] In some embodiments of this disclosure, based on the total mass of the liquid composition, the mass percentage of the flavoring agent may be 0.1% to 10%, and / or the mass percentage of the antibacterial agent may be 0.01% to 1%, and / or the mass percentage of the chelating agent may be 0.01% to 0.1%. For example, when the liquid composition contains a flavoring agent, the mass percentage of the flavoring agent can be 0%, 0.1%, 0.2%, 0.4%, 0.5%, 0.6%, 1%, 2%, 3%, 4%, 5%, 6%, 8%, 9%, or 10%, etc.; as another example, when the liquid composition contains an antibacterial agent, the mass percentage of the antibacterial agent can be 0.01%, 0.02%, 0.05%, 0.08%, 0.1%, 0.2%, 0.5%, 0.8%, or 1%, etc.; and as yet another example, when the liquid composition contains a chelating agent, the mass percentage of the chelating agent can be 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.05%, 0.08%, or 0.1%, etc.

[0031] In some embodiments of this disclosure, the liquid composition may be an oral solution. The liquid composition may be used to treat, improve, or prevent fungal infections.

[0032] In a second aspect of this disclosure, a method for preparing the liquid composition of the first aspect of this disclosure is provided, comprising: mixing cyclodextrin with an aqueous solvent to obtain a first mixture; mixing posaconazole, an acidic pH adjuster, and an antioxidant with the first mixture to obtain a second mixture; mixing a diluent stabilizer with the second mixture to obtain a third mixture; and adding an aqueous solvent to the third mixture to make up to a final volume.

[0033] In some embodiments, the mixing operations in each step can be performed independently under stirring conditions. If necessary, the mixing operations in each step can also be performed under heating conditions to promote the dissolution of the components, such as mixing posaconazole, an acidic pH adjuster, and an antioxidant with the first mixture under heating and stirring conditions.

[0034] In some embodiments, the aqueous solvent may be water and may not contain any organic solvents.

[0035] In some embodiments of this disclosure, the liquid composition may further include one or more of a flavoring agent, an antibacterial agent, and a chelating agent. The desired dosage of the flavoring agent, antibacterial agent, chelating agent, or any combination thereof may be selectively added in at least one of the mixing steps as needed. For example, in some specific embodiments, a chelating agent and / or an antibacterial agent may be added when mixing cyclodextrin with an aqueous solvent. In some specific embodiments, the flavoring agent may be mixed with the third mixture before the addition of the aqueous solvent for volume adjustment.

[0036] In some embodiments of this disclosure, the preparation and storage of the liquid composition can be carried out under a protective atmosphere. In some specific embodiments, the protective atmosphere is a non-oxidizing atmosphere, such as a nitrogen atmosphere.

[0037] In a third aspect of this disclosure, the use of a liquid composition of the first aspect of this disclosure or a liquid composition prepared by the method of the second aspect of this disclosure in the preparation of a medicament for treating, improving or preventing fungal infections is provided.

[0038] In a fourth aspect of this disclosure, a method for treating, improving, or preventing fungal infections is provided, comprising administering to an individual in need a liquid composition of the first aspect of this disclosure or a liquid composition prepared using the method of the second aspect of this disclosure.

[0039] In some embodiments, the fungal infection is selected from one or more of the following: oropharyngeal or esophageal candidiasis; refractory oropharyngeal or esophageal candidiasis; invasive aspergillosis, candidiasis, fusarium infection, sadosporidiosis, infections caused by dimorphic fungi, zygomycosis, and invasive infections caused by rare molds and yeasts; invasive fungal infections in patients who should not or are intolerant of other therapies; candidiasis, invasive fungal infections in patients undergoing intensive chemotherapy and / or radiotherapy as part of a hematologic malignancy, bone marrow or peripheral stem cell transplantation pretreatment regimen, and in patients receiving combined immunosuppressive therapy for the treatment of acute or chronic graft-versus-host disease or for the prevention of solid organ transplant rejection; Chagas disease; and leishmaniasis.

[0040] The liquid composition disclosed herein has one or more of the following beneficial effects: it can improve the dissolution of posaconazole under different pH conditions (such as simulated intestinal pH variations), inhibit the precipitation of posaconazole in crystalline form, improve the bioavailability of posaconazole, and reduce the influence of food on bioavailability; it has small individual variability; it does not require a loading dose; it does not require the use of organic solvents; it has good patient compliance; and it can provide more options for patients who cannot take enteric-coated tablets orally.

[0041] Example

[0042] The present disclosure will be further described in detail below with reference to specific embodiments. Modifications can be made to these embodiments to obtain other implementations without departing from the scope or spirit of the present disclosure. Therefore, the following embodiments are non-limiting.

[0043] Unless otherwise specified, all figures used in this specification and claims to indicate feature dimensions, quantities, and physical properties should be understood to be modified by the term "about" in all cases. Therefore, unless stated to the contrary, the numerical parameters listed in the foregoing specification and appended claims are approximations, and those skilled in the art can appropriately modify these approximations to obtain the desired characteristics using the teachings disclosed herein. The use of numerical ranges indicated by endpoints includes all numbers within that range and any range within that range; for example, 1 to 5 includes 1, 1.1, 1.3, 1.5, 2, 2.75, 3, 3.80, 4, and 5, etc.

[0044] Unless otherwise specified, all drugs or reagents used in this disclosure are commercially available products.

[0045] General detection methods:

[0046] (1) Dissolution test method:

[0047] Unless otherwise specified, the dissolution of posaconazole oral solution shall be detected using the following method:

[0048] Dissolution: Take 5 ml of this product and dissolve and release it according to the method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931, Method II), using 500 ml of 0.2 mol / L phosphate buffer (pH 6.8) as the dissolution medium, at a speed of 50 rpm and a medium temperature of 37℃. After 10 min, 30 min, 60 min, 120 min, 240 min, 360 min, and 480 min, take an appropriate amount of the solution and centrifuge (12000 rpm, 5 min). Dilute the supernatant 5 times with methanol to obtain the test solution. Separately, take an appropriate amount of posaconazole reference standard, dissolve and dilute it in methanol-hydrochloric acid (100:0.4) to prepare a solution containing approximately 0.4 mg of posaconazole per ml as a stock solution. Accurately measure 2 ml of the stock solution and place it in a 20 ml volumetric flask. Add dissolution medium and dilute to the mark to obtain the reference solution. The determination was performed according to high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512). Octadecylsilane-bonded silica gel was used as the stationary phase, with a mobile phase of phosphoric acid aqueous solution [1.5 ml of phosphoric acid was added to 640 ml of water and stirred until homogeneous]-acetonitrile (640:36), a flow rate of 1.0 ml / min, a column temperature of 30℃, and a detection wavelength of 254 nm. The theoretical plate number, calculated based on posaconazole, should be no less than 2000. The amount of posaconazole dissolved in each vial at different times was calculated using the external standard method.

[0049] (2) Content testing method:

[0050] Content: determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0051] Test solution: Weigh an appropriate amount of this product (about 1g) accurately, place it in a 100ml volumetric flask, add an appropriate amount of methanol-water-hydrochloric acid (100:100:0.2), shake to dissolve, dilute to the mark with solvent, shake well, filter, and take the filtrate.

[0052] Reference solution: Weigh an appropriate amount of posaconazole reference standard accurately, dissolve it in methanol, and dilute it to prepare a solution containing approximately 1 mg of posaconazole per 1 ml as a stock solution. Accurately measure 5 ml of the stock solution and place it in a 25 ml volumetric flask. Dilute to the mark with methanol-water-hydrochloric acid (100:100:0.2) to obtain the reference solution.

[0053] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the packing material; the mobile phase was phosphoric acid aqueous solution [1.5 ml of phosphoric acid was added to water to 640 ml and stirred to mix well]-acetonitrile (640:36); the flow rate was 1.0 ml per minute; the detection wavelength was 254 nm; the column temperature was 30 ℃; and the injection volume was 10 μl.

[0054] System applicability requirements: The number of theoretical plates calculated based on the itraconazole peak should be no less than 3000.

[0055] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results based on peak area using the external standard method.

[0056] (3) Methods for testing related substances:

[0057] Unless otherwise specified, the following high-performance liquid chromatography (HPLC) conditions shall be used to detect impurities in posaconazole:

[0058] Related substances: determined according to the high performance liquid chromatography method (General Chapter 0512) of the 2020 edition of the Chinese Pharmacopoeia, Part IV. Octadecylsilane-bonded silica gel was used as the stationary phase; gradient elution was performed using acetonitrile-0.05 mol / L ammonium acetate solution (adjusted to pH 4.0 with acetic acid) as the mobile phase at a flow rate of 1.0 mL / min.

[0059] The gradient elution procedure is shown in Table 1:

[0060] Table 1

[0061] Time (min) ％B 0.01 5.0 3.00 35.0 4.00 35.0 17.00 60.0 18.00 60.0 35.00 90.0 36.00 90.0 40.00 5.0 50.00 5.0

[0062] The detection wavelength is 262 nm. The theoretical plate number, calculated based on the posaconazole peak, should be no less than 3000, and the resolution between adjacent impurity peaks should meet the requirements. Separately, take an appropriate amount of posaconazole oral solution, dilute it with 50% acetonitrile to a solution containing 1.5 mg / ml of posaconazole, centrifuge, and inject the supernatant into the liquid chromatograph. Record the chromatogram; calculate the result as a percentage of peak area using the area normalization method.

[0063] (4) Crystal form inspection method:

[0064] Unless otherwise specified, the following method shall be used to determine the crystal form of posaconazole precipitates:

[0065] Collect the precipitates after dissolution, combine and centrifuge (12000 rpm, 5 min), take the precipitate, air dry, grind finely, and use a DX-27mini X powder diffractometer to detect its crystal form.

[0066] Source of drugs or reagents:

[0067] Unless otherwise specified, the drugs or reagents used in the following examples and comparative examples are all conventional commercially available products.

[0068] in:

[0069] Posaconazole: Purchased from Wuhan Ruisheng Pharmaceutical Co., Ltd., batch number: C046-2307001;

[0070] Hydroxypropyl-β-cyclodextrin: purchased from Shandong Binzhou Zhiyuan Biotechnology Co., Ltd., batch number: HP20240315;

[0071] Sulfobutyl ether-β-cyclodextrin: provided by Luofu Pharmaceutical Technology (Shanghai) Co., Ltd., manufacturer: CyclolabCyclodextrin Research & Development Laboratory Ltd., batch number: 47K150521;

[0072] Hydroxypropyl methylcellulose: purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd., batch number: 240203;

[0073] Hydroxypropyl cellulose: purchased from Shanghai Junsen Chemical Preparations & Excipients Co., Ltd., batch number: 64328.

[0074] Comparative Example 1

[0075]

[0076]

[0077] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole and 10% sulfuric acid aqueous solution, and stir in a 60°C water bath to dissolve the components. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water and determine the final weight.

[0078] Comparative Example 2

[0079]

[0080] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite, and hydrochloric acid (commercially available hydrochloric acid, concentration 36%–38%) and place in a 60°C water bath with stirring until the components dissolve. Cool, add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0081] Comparative Example 3

[0082]

[0083] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite, ascorbic acid and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl cellulose and stir to dissolve. Adjust the pH to 4.0 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0084] Comparative Example 4

[0085]

[0086] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite, and hydrochloric acid (same as in Comparative Example 2). Place in a 60°C water bath and stir to dissolve the components. Cool, add povidone K30 and stir to dissolve. Add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0087] Comparative Example 5

[0088]

[0089] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite, and hydrochloric acid (same as in Comparative Example 2). Place in a 60°C water bath and stir to dissolve the components. Cool, add polyethylene glycol 4000 and stir to dissolve. Add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0090] Example 1

[0091]

[0092]

[0093] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl cellulose and stir to dissolve. Adjust the pH to 1.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0094] Example 2

[0095]

[0096] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl cellulose and stir to dissolve. Adjust the pH to 4 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0097] Example 3

[0098]

[0099] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0100] Example 4

[0101]

[0102] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0103] Example 5

[0104]

[0105] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0106] Example 6

[0107]

[0108]

[0109] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.3 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0110] Example 7

[0111]

[0112] Preparation: Weigh hydroxypropyl-β-cyclodextrin and malic acid, add water and stir to dissolve. Then add posaconazole, methionine, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and sweet orange flavor, and stir to dissolve. Adjust the pH to 3.0 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0113] Example 8

[0114]

[0115] Preparation: Weigh hydroxypropyl-β-cyclodextrin and citric acid, add water and stir to dissolve. Then add posaconazole, methionine, and phosphoric acid (commercially available phosphoric acid, concentration ≥85%) and place in a 60℃ water bath with stirring to dissolve the components. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add propylparaben, aspartame, and peach flavoring, and stir to dissolve. Adjust the pH to 3.5 with 1% phosphoric acid, add water, and determine the final weight.

[0116] Example 9

[0117]

[0118] Preparation: Weigh sulfobutyl ether-β-cyclodextrin and benzoic acid, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl cellulose and stir to dissolve. Cool, add cyclamate and banana flavoring, and stir to dissolve. Adjust the pH to 3.0 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0119] Example 10

[0120]

[0121] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, methionine, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0122] Example 11

[0123]

[0124] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, methionine, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0125] Example 12

[0126]

[0127] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, methionine, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0128] Example 13

[0129]

[0130]

[0131] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium bisulfite, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0132] Example 14

[0133]

[0134] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium bisulfite, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add cyclamate and cherry flavor, and stir to dissolve. Adjust the pH to 2.0 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0135] Example 15

[0136]

[0137]

[0138] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, sodium metabisulfite and hydrochloric acid (same as in Comparative Example 2), and place in a 60°C water bath with stirring to dissolve the components. Add hydroxypropyl cellulose and stir to dissolve. Cool, add sucralose and cherry flavoring, and stir to dissolve. Adjust the pH to 2.5 with dilute hydrochloric acid or 1 mol / L NaOH, add water and determine the final weight.

[0139] Example 16

[0140]

[0141] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, ascorbic acid, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0142] Example 17

[0143]

[0144] Preparation: Weigh hydroxypropyl-β-cyclodextrin and disodium edetate, add water and stir to dissolve. Then add posaconazole, thioglycerol, and a 10% sulfuric acid aqueous solution, and place in a 60°C water bath with stirring until the components dissolve. Add hydroxypropyl methylcellulose and stir to dissolve. Cool, add acesulfame potassium and orange flavoring, and stir to dissolve. Adjust the pH to 2.5 with 1% sulfuric acid or 1 mol / L NaOH, add water, and determine the final weight.

[0145] Test Implementation Examples

[0146] 1. Solubility test of posaconazole

[0147] Refer to the "Content Testing Method" in the above general testing methods.

[0148] 1) Solubility test of posaconazole in aqueous solutions of different concentrations of hydroxypropyl-β-cyclodextrin and different pH values

[0149] Hydroxypropyl-β-cyclodextrin was used to prepare aqueous solutions of 20%, 25%, 30%, 35%, and 40%, respectively. Excess posaconazole was added to form suspensions, and the pH values ​​were adjusted to 2.0, 3.0, and 4.0 with 1% sulfuric acid solution, respectively. The suspensions were then heated and stirred in a 60°C water bath to dissolve the suspensions. After cooling to room temperature and standing for 48 hours, the suspensions were centrifuged (12000 rpm, 5 min) and the supernatant was collected. The supernatant was diluted 100 times with methanol-water-hydrochloric acid (100:100:0.2). The concentration of the samples was tested according to the above-mentioned content testing method. The saturated solubility of posaconazole under different concentrations of hydroxypropyl-β-cyclodextrin and different pH conditions was calculated. The calculation results are shown in Table 2.

[0150] Table 2

[0151]

[0152] Conclusion: Based on the saturated solubility of posaconazole in aqueous solutions of hydroxypropyl-β-cyclodextrin at different concentrations and pH values, it can be seen that the higher the concentration of hydroxypropyl-β-cyclodextrin, the greater the saturated solubility of posaconazole, and the lower the saturated solubility of posaconazole at higher pH values. This indicates that hydroxypropyl-β-cyclodextrin can significantly improve the solubility of posaconazole, and that posaconazole can increase its solubility by forming salts under strong acid conditions.

[0153] 2) Effect of hydroxypropyl-β-cyclodextrin concentration in liquid composition on the dissolution rate of posaconazole

[0154] The dissolution rate of posaconazole in the liquid compositions of Examples 1 and 2 was tested at different dissolution times, and the test results are shown in [Figure number missing]. Figure 1 .

[0155] Conclusion: Combining Figure 1 It is known that the higher the amount of hydroxypropyl-β-cyclodextrin used in the liquid composition, the higher the concentration of posaconazole released in the dissolution medium after dilution in a near-neutral dissolution medium.

[0156] 3) Effect of diluent stabilizer in liquid composition on the dissolution rate of posaconazole

[0157] The dissolution rate of posaconazole in the liquid compositions of each embodiment and comparative embodiment at different dissolution times was tested.

[0158] The dissolution test results of posaconazole at different dissolution times in the liquid compositions of Examples 3 to 6, Comparative Examples 2, 4, and 5 are shown in the figure. Figure 2 The dissolution test results of posaconazole in the liquid composition of Example 15 at different dissolution times are shown in the figure. Figure 3 .

[0159] Conclusion: Combining Figure 2 and Figure 3 It is known that without the addition of diluents or other common crystallization inhibitors (such as povidone K30 or polyethylene glycol 4000), the posaconazole liquid composition rapidly precipitates in a medium simulating intestinal pH, and the concentration of posaconazole in the dissolved state in the solution is significantly low.

[0160] Overall, when hydroxypropyl methylcellulose or hydroxypropyl cellulose is used as a diluent and stabilizer, the posaconazole liquid composition can maintain a high concentration of posaconazole in a medium simulating intestinal pH and increase the duration of the dissolved state. The more hydroxypropyl methylcellulose used, the less posaconazole is released in the medium during the initial release, possibly because the higher the amount of hydroxypropyl methylcellulose used as a diluent and stabilizer, the higher the viscosity of the liquid composition and the slower the dispersion of the liquid composition. In the later release, the diluent and stabilizer hydroxypropyl methylcellulose can inhibit the precipitation of posaconazole and prolong the supersaturation time of the solution.

[0161] In addition, the dissolution test results of posaconazole at different dissolution times in the liquid compositions of Examples 7 to 9 and Examples 13 to 14 are shown in the figure. Figure 3 .

[0162] Conclusion: Combining Figures 1-3 It is understood that the liquid compositions in the above embodiments of this disclosure can maintain a high concentration of posaconazole in a medium simulating intestinal pH.

[0163] 2. Stability Test

[0164] Refer to the "Content Testing Method" and "Related Substances Testing Method" in the above general testing methods.

[0165] The contents of posaconazole and related substances in each liquid composition and in the posaconazole raw material were tested separately. The test results for the contents of posaconazole and related substances in the liquid compositions of Examples 9 to 12, Comparative Examples 1, 4, and 5, and in the posaconazole raw material are shown in Table 3.

[0166] Table 3 Sample stability data

[0167]

[0168]

[0169] Conclusion: As shown in Table 3, compared with Comparative Example 1 (without antioxidant) and Examples 16 and 17 (with ascorbic acid or thioglycerol as antioxidants), the liquid compositions of Examples 9-12 of this disclosure exhibit better relative stability under both room temperature and accelerated storage conditions. In particular, the liquid compositions containing methionine as an antioxidant show better stability and lower maximum single impurity and / or total impurity content under both accelerated and room temperature storage conditions.

[0170] 3. Crystal form testing

[0171] According to the "Crystal Form Examination Method" in the above general detection method, after the dissolution is completed (i.e., 480 min later), collect the precipitates after the dissolution is completed, combine and centrifuge (12000 rpm, 5 min), take the precipitate, dry it, grind it into a fine powder, and use a DX-27mini X powder diffractometer to detect its crystal form.

[0172] Test results are available Figure 4 and Figure 5 .

[0173] Conclusion: Combining Figure 4 and Figure 5 It can be seen that, compared with Comparative Examples 2, 4-5 and posaconazole, in the XRD patterns of the precipitates after dissolution tests of the liquid compositions of Examples 1-2 and 5-14 of this disclosure, the diffraction peak intensity corresponding to posaconazole is weaker or there is no diffraction peak corresponding to posaconazole. This indicates that the amount of posaconazole crystallized in the liquid composition is low or there is no crystallization. In other words, most of the dissolved posaconazole exists in a dissolved or amorphous state, and rarely precipitates in a crystalline form or not in a crystalline form.

[0174] 4. Pharmacokinetic testing

[0175] In the pharmacokinetic studies described below, the doses administered to Beagle dogs are based on the amount of posaconazole contained in the formulation. For example, an intravenous infusion of 3 mg / kg of posaconazole injection means an intravenous infusion of posaconazole injection at a dose of 3 mg posaconazole / kg of animal body weight; similarly, an oral administration of 6 mg / kg of HYPS-04 means an oral administration of HYPS-04 at a dose of 6 mg posaconazole / kg of animal body weight; and similarly, an oral administration of 10 mg / kg of posaconazole enteric-coated tablets means an oral administration of posaconazole enteric-coated tablets at a dose of 10 mg posaconazole / kg of animal body weight.

[0176] 4.1) Pharmacokinetic studies of Beagle dogs after oral administration of HYPS-04 and intravenous administration of posaconazole injection.

[0177] Sources of samples and reference standards:

[0178]

[0179] Objective: To study the pharmacokinetic parameters of HYPS-04 in Beagle dogs after oral administration and to compare them with those of the marketed posaconazole injection.

[0180] Methods: Nine female Beagle dogs were divided into two groups. Group 1 (n=3 animals) received intravenous infusion of 3 mg / kg posaconazole injection. Blood samples were collected at 0 h before administration, 1 min after administration, 3 min after administration, and at 0 h, 0.083 h (approximately 5 min after administration), 0.25 h, 0.5 h, 1 h, 1.5 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 24 h, 36 h, 48 h, 72 h, and 96 h after administration. Group 2... Six animals were orally administered 6 mg / kg of HYPS-04 (i.e., the content of posaconazole active ingredient in the orally administered HYPS-04 was twice that in the injected posaconazole injection). Blood samples were collected at 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 14 h, 16 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, and 144 h after administration. Whole blood was centrifuged to obtain plasma samples, and the samples were analyzed to determine drug concentrations. Pharmacokinetic parameters were fitted using a DAS non-compartmental model.

[0181] result:

[0182]

[0183] Conclusion: The bioavailability of HYPS-04 administered orally to Beagle dogs was 114.51%.

[0184] 4.2) Pharmacokinetic studies of Beagle dogs after oral administration of HYPS-04 and oral administration of posaconazole enteric-coated tablets

[0185] Sources of samples and reference standards:

[0186]

[0187] Objective: To investigate the time-dependent plasma concentrations of posaconazole in Beagle dogs after oral administration of enteric-coated posaconazole tablets and gavage administration of HYPS-04, and to calculate the corresponding pharmacokinetic parameters.

[0188] Methods: Twenty-four Beagle dogs were randomly divided into four groups of six (half male and half female). Group 1 received oral posaconazole enteric-coated tablets; Group 2 received oral HYPS-04 (Example 5); Group 3 received oral HYPS-04 (Example 2); and Group 4 received oral HYPS-04 (Comparative Example 3). (Feeding method: delayed feeding on the day of administration: 1 / 3 of the normal feed was given before administration, and the drug was administered within 20 minutes after the first feeding, followed by normal feeding 4 hours after administration). Blood samples were collected at 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 96h, 120h, and 144h after administration. Plasma samples were analyzed to determine the drug concentration, and the concentration of posaconazole in the plasma samples was determined by LC-MS / MS.

[0189] Results: Following oral administration of 10 mg / kg posaconazole enteric-coated tablets to Beagle dogs, the AUC of posaconazole in the plasma of male dogs was [data missing]. 0-144h The value is 108000 ng / mL*h, C max The concentration was 2900 ng / mL, with a half-life of 23.30 h, and T... max The AUC of posaconazole in the plasma of female dogs was 4.00 h. 0-144h The value is 109000 ng / mL*h, C max The concentration was 2170 ng / mL, with a half-life of 29.70 h, and T... max It takes 6.67 hours;

[0190] Following oral administration of 10 mg / kg HYPS-04 to Beagle dogs (Example 5), the AUC of posaconazole in the plasma of male dogs was... 0-144h The concentration is 118600 ng / mL*h, C max The concentration was 2570 ng / mL, with a half-life of 25.30 h, and T... max The AUC of posaconazole in the plasma of female dogs was 4.00 h. 0-144h The concentration is 125000 ng / mL*h, C max The concentration was 3050 ng / mL, with a half-life of 29.10 h, and T... max It takes 1.50 hours;

[0191] Following oral administration of 10 mg / kg HYPS-04 to Beagle dogs (Example 2), the AUC of posaconazole in the plasma of male dogs was... 0-144h The concentration is 97650 ng / mL*h, C max The concentration was 2260 ng / mL, with a half-life of 20.50 h, and T... max The AUC of posaconazole in female dog plasma was 3.50 h. 0-144h The concentration is 97600 ng / mL*h, C maxThe concentration was 2117 ng / mL, with a half-life of 22.66 h, and T... max It takes 2.50 hours;

[0192] Following oral administration of 10 mg / kg HYPS-04 to Beagle dogs (Comparative Example 3), the AUC of posaconazole in the plasma of male dogs was... 0-144h The concentration was 64363 ng / mL*h, C max The concentration was 1321 ng / mL, with a half-life of 19.87 h, and T... max The AUC of posaconazole in the plasma of female dogs was 2.00 h. 0-144h The concentration was 70123 ng / mL*h, C max The concentration was 1223 ng / mL, with a half-life of 22.12 h, and T... max It takes 2.50 hours.

[0193] Conclusions: Based on the intravenous results of 2024-PK-002, the bioavailability of enteric-coated tablets after oral administration in group 1 was 59.4% (male) and 60.0% (female); the bioavailability of HYPS-04 (Example 5) after oral administration in group 2 was 65.3% (male) and 68.8% (female); the bioavailability of HYPS-04 (Example 2) after oral administration in group 3 was 53.7% (male) and 53.7% (female); and the bioavailability of HYPS-04 (Comparative Example 3) after oral administration in group 4 was 35.4% (male) and 38.6% (female). The relative bioavailability of enteric-coated tablets was 103.37% (male) and 114.7% (female) in group 2 animals; 90.42% (male) and 89.50% (female) in group 3 animals; and 59.6% (male) and 64.33% (female) in group 4 animals.

[0194] 4.3) Pharmacokinetic studies of Beagle dogs after administration of HYPS-04 by gavage and posaconazole enteric-coated tablets via oral administration, both on an empty stomach and on an empty stomach.

[0195] Sources of samples and reference standards:

[0196]

[0197] Objective: To investigate the time-dependent plasma concentrations of posaconazole in Beagle dogs after oral administration of enteric-coated posaconazole tablets and oral administration of HYPS-04 via gavage, and to calculate the corresponding pharmacokinetic parameters and compare the differences in exposure.

[0198] Methods: Nine healthy and suitable male dogs were selected and divided into three groups of three. Each group was given posaconazole enteric-coated tablets, HYPS-04 (Example 5), and HYPS-04 (Example 2), respectively. Cycle I: Fasting (fasting means feeding the night before administration, followed by administration 12 hours later, and then normal feeding 12 hours after administration; cycle from the start of administration to the end of blood collection 144 hours later). Group 1 received posaconazole enteric-coated tablets, Group 2 received HYPS-04 (Example 5), and Group 3 received HYPS-04 (Example 2). Cycle II: Normal feeding (feeding before administration, followed by administration within 20 minutes after the feeding, cycle from the start of administration to the end of blood collection 144 hours later). Group 1 received posaconazole enteric-coated tablets, Group 2 received HYPS-04 (Example 5), and Group 3 received HYPS-04 (Example 2). Cycle III: Fasting (cycle from the start of administration to the end of blood collection 144 hours later). Group 1 received HYPS-04 (Example 5), and Group 2 received posaconazole enteric-coated tablets. Cycle IV: Normal feeding (cycle from the start of administration to the end of blood collection 144 hours later). Group 1 received HYPS-04 (Example 5), and Group 2 received posaconazole enteric-coated tablets. A one-week withdrawal period was observed between each cycle. Blood samples were collected at 0.25h, 0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 48h, 72h, 96h, 120h, and 144h after drug administration. Plasma samples were analyzed to determine the drug concentration, and the concentration of posaconazole in the plasma samples was determined by LC-MS / MS.

[0199] Results: Following oral administration of 10 mg / kg posaconazole enteric-coated tablets to Beagle dogs, the AUC of posaconazole in plasma of fasted dogs was significantly increased. 0-144h The concentration is 70200 ng / mL*h, C max The concentration was 1290 ng / mL, with a half-life of 31.60 h, and T... max The AUC of posaconazole in the plasma of dogs administered the drug was 6.00 h. 0-144h The concentration is 141000 ng / mL*h, C max The concentration was 2270 ng / mL, with a half-life of 33.90 h, and T... max It is 8.00h;

[0200] Following gavage administration of 10 mg / kg HYPS-04 to Beagle dogs (Example 5), the AUC of posaconazole in the plasma of fasted dogs was measured. 0-144h The concentration is 128400 ng / mL*h, C max The concentration was 2130 ng / mL, with a half-life of 31.80 h, and T... max The AUC of posaconazole in the plasma of dogs administered the drug was 8.00 h. 0-144h The concentration is 127000 ng / mL*h, C max The concentration was 2260 ng / mL, with a half-life of 31.30 h, and T... max It takes 8.67 hours;

[0201] Following gavage administration of 10 mg / kg HYPS-04 to Beagle dogs (Example 2), the AUC of posaconazole in the plasma of fasted dogs was measured. 0-144h The concentration is 95620 ng / mL*h, C max The concentration was 2010 ng / mL, with a half-life of 25.90 h, and T... max The AUC of posaconazole in the plasma of dogs administered the drug was 6.00 h. 0-144h The concentration is 97000 ng / mL*h, C max The concentration was 2060 ng / mL, with a half-life of 30.60 h, and T... max It is 8.00h.

[0202] Conclusion: Based on the intravenous results of 2024-PK-002, the bioavailability of enteric-coated tablets administered orally to dogs that had been fasting was 34.6%; the bioavailability of HYPS-04 administered by gavage to dogs that had been fasting was 70.6%; the bioavailability of HYPS-04 administered by gavage to dogs that had been fasting was 52.6%; the bioavailability of enteric-coated tablets administered orally to dogs that had been fed was 77.6%; the bioavailability of HYPS-04 administered by gavage to dogs that had been fed was 69.9%; and the bioavailability of HYPS-04 administered by gavage to dogs that had been fed was 53.4%. That is, the bioavailability of the posaconazole liquid compositions in Examples 2 and 5 was not affected by food, while the bioavailability of the enteric-coated tablets administered orally was significantly affected by food.

Claims

1. A liquid composition comprising posaconazole, cyclodextrin, a dilution stabilizer, an antioxidant, an acidic pH adjuster, and water, wherein the dilution stabilizer comprises hydroxypropyl cellulose and / or hydroxypropyl methylcellulose, and the cyclodextrin comprises 25% to 45% by mass based on the total mass of the liquid composition.

2. The liquid composition according to claim 1, wherein the mass ratio of posaconazole to the diluent stabilizer is 1:(1-7.5), or 1:(1.5-4), or 1:(2-3); and / or The mass ratio of posaconazole to cyclodextrin is 1:(10-22.5), or 1:(11-20), or 1:(12.5-17.5).

3. The liquid composition according to claim 1 or 2, wherein the antioxidant comprises one or more of methionine, sodium metabisulfite, sodium bisulfite, proline, and glycine; or, The antioxidant contains methionine; or... The antioxidant contains methionine, and one or more selected from sodium metabisulfite, sodium bisulfite, proline, and glycine.

4. The liquid composition according to any one of claims 1 to 3, wherein the cyclodextrin comprises β-cyclodextrin and / or a derivative of β-cyclodextrin; or, The cyclodextrin comprises one or more of hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methyl-β-cyclodextrin.

5. The liquid composition according to any one of claims 1 to 4, wherein the acidic pH adjuster comprises one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and maleic acid; or, The acidic pH adjuster comprises hydrochloric acid and / or sulfuric acid; and / or The pH value of the liquid composition is 1.5 to 4 or 2 to 3.

6. The liquid composition according to any one of claims 1 to 5, wherein, based on the total mass of the liquid composition, the posaconazole comprises 1% to 2.7%, 1.5% to 2.5%, or 1.5% to 2.0% by mass, the cyclodextrin comprises 25% to 45%, 25% to 40%, or 25% to 35% by mass, the dilution stabilizer comprises 2% to 15%, 3% to 8%, or 4% to 6% by mass, the antioxidant comprises 0.05% to 2% by mass, and the acidic pH adjuster comprises 1.5% to 4% by mass.

7. The liquid composition according to any one of claims 1 to 6, further comprising one or more of a flavoring agent, an antibacterial agent, and a chelating agent.

8. The liquid composition according to claim 7, wherein, The flavoring agent comprises sweeteners and / or flavorings; and / or The antibacterial agent comprises one or more of methylparaben, ethylparaben, and propylparaben; and / or The chelating agent comprises one or more of citric acid, malic acid, benzoic acid, edetate, and sodium edetate; and / or Based on the total mass of the liquid composition: the flavoring agent accounts for 0.1-10% of the total mass, and / or the antibacterial agent accounts for 0.01-1% of the total mass, and / or the chelating agent accounts for 0.01-0.1% of the total mass.

9. A method for preparing the liquid composition according to any one of claims 1 to 8, comprising: Cyclodextrin was mixed with an aqueous solvent to obtain the first mixture; Posaconazole, an acidic pH adjuster, and an antioxidant are mixed with the first mixture to obtain a second mixture; The diluent stabilizer is mixed with the second mixture to obtain the third mixture; The third mixture was then diluted with an aqueous solvent to bring the volume to a final level.

10. Use of the liquid composition of any one of claims 1 to 8 or the liquid composition prepared by the method of claim 9 in the preparation of a medicament for treating, improving or preventing fungal infections.

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