Voriconazole dry suspension and process for its preparation

Abstract

The present application relates to a kind of triazole antifungal, especially to posaconazole dry suspension and its preparation method.Voriconazole dry suspension includes the active ingredient voriconazole, the particle size D90 of the micronized voriconazole is less than 13.0 μm.The voriconazole dry suspension of the present application solves the problem of poor solubility of voriconazole leading to low bioavailability, using micronization technology to make the particle size D90 of voriconazole less than 13.0 μm, improve its dissolution, improve the bioavailability in vivo.Using coating technology to solve the problem of poor patient compliance caused by poor taste and bitter of voriconazole.Use titanium dioxide, talc, iron oxide, calcium carbonate as sunscreen, to solve the problem of unstable voriconazole under light conditions.

Description

Technical Field

[0001] This invention relates to a triazole antifungal drug, and more particularly to voriconazole dry suspension and its preparation method. Background Technology

[0002] Voriconazole is a newly synthesized triazole drug, a second-generation synthetic fluconazole derivative. As a novel antifungal agent, it possesses a broad antibacterial spectrum and strong antifungal efficacy. Voriconazole is a white crystalline powder, odorless and tasteless, and practically insoluble in water. Due to its extremely low solubility in water (almost insoluble at pH 7, 0.2 mg / ml at pH 3), its chemical properties are unstable in solution. Voriconazole is a BCSII drug, meaning it is a low-solubility, high-permeability drug; its solubility in vivo directly affects its bioavailability. Therefore, improving the solubility of voriconazole is key to improving its bioavailability in vivo.

[0003] Voriconazole has a bitter taste, which can cause discomfort to patients when taken. Since dry suspension is a dosage form suitable for children, the taste-masking technology of voriconazole dry suspension to improve the compliance of pediatric patients is also very important.

[0004] Furthermore, voriconazole can produce unknown monoimides under light conditions, so light exposure must be avoided during formulation and use. Summary of the Invention

[0005] The purpose of this invention is to provide a voriconazole dry suspension with high bioavailability, stability, and good patient compliance; Another object of the present invention is to provide a method for preparing voriconazole dry suspension.

[0006] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: Voriconazole dry suspension, containing the active pharmaceutical ingredient voriconazole, wherein the particle size D90 of micronized voriconazole is less than 13.0 μm.

[0007] As a preferred embodiment of the present invention, the voriconazole dry suspension comprises drug-containing granules, which are composed of drug-containing pellets and a coating layer, wherein the drug-containing pellets comprise the following components: 40%~75% voriconazole, 20%~60% pregelatinized starch, 1%~3% sodium carboxymethyl cellulose, and 1%~5% opacifier.

[0008] As a preferred embodiment of the present invention, the light-blocking agent is one or a mixture of titanium dioxide, talc, iron oxide, and calcium carbonate.

[0009] As a preferred embodiment of the present invention, the coating material of the coating layer is ethyl cellulose.

[0010] This invention also discloses a method for preparing voriconazole dry suspension, comprising the following steps: 1) The voriconazole raw material is micronized so that the particle size D90 of the micronized voriconazole is less than 13.0 μm; 2) The micronized voriconazole was mixed with a light-blocking agent, pregelatinized starch and cross-linked sodium carboxymethyl cellulose, then water was added to granulate the mixture and dried to obtain drug-containing pills. (3) The drug-containing pills are coated with a fluidized bed to mask their taste; (4) Mix the obtained coated granules with the added excipients evenly to obtain the final product.

[0011] This invention relates to a voriconazole dry suspension, which solves the problem of poor bioavailability caused by the poor solubility of voriconazole. Micronization technology is used to reduce the particle size (D90) of voriconazole to less than 13.0 μm, improving its dissolution and enhancing its bioavailability in vivo. Coating technology is employed to address the issue of poor patient compliance due to the bitter taste of voriconazole. Titanium dioxide, talc, iron oxide, and calcium carbonate are used as light-blocking agents to address the instability of voriconazole under light conditions. Detailed Implementation

[0012] Example 1: Micronization of Voriconazole Voriconazole raw material was micronized using airflow milling technology.

[0013] Particle size test results The particle size D90 of the micronized voriconazole is less than 13.0 μm.

[0014] Example 2: Preparation of voriconazole pills Prescription A: Prescription B: Prescription C Prescription D Preparation method: 1) Add voriconazole, pregelatinized starch, croscarmellose sodium and opacifier to a wet mixing granulator according to the prescription, set the stirring speed to 150 rpm and run for 5 minutes; 2) Set the stirring speed to 150 rpm and the cutting speed to 1500 rpm. Add purified water after 2 minutes to granulate. Stop the machine after running for 5 minutes and discharge the material. 3) The wet granules were fed into a fluidized bed for drying, with the drying loss controlled to be less than 2.0%. The dry granules were granulated using a granulator at a speed of 300-500 rpm and a pore size of 0.8 mm. Voriconazole dry granules A, B, C, and D were obtained respectively.

[0015] Example 3: Coating of Voriconazole dry granules Process: 1. Preparation of flavor-masking coating solution: For coating solutions using Eutrapept E100 as the flavor-masking material, Eutrapept E100 should be added to 95% ethanol and stirred to disperse; for coating solutions using ethyl cellulose as the flavor-masking material, simply add purified water to the ethyl cellulose dispersion for dilution. 2. Coat the dry granules in a fluidized bed with an inlet air temperature of 30~70℃ and a liquid spraying rate of 2~15g / min; 3. After the coating solution has been completely sprayed, the flavor-masked coated granules are obtained. Formula E does not use ethyl cellulose dispersion but uses Eutech E100 as the flavor-masking material.

[0016] Example 4: Voriconazole dry suspension Take the voriconazole flavor-masking coated granules A, B, C, D and E obtained in Example 5, add the excipients according to the following formula and put them into the mixing tank. Mix at 10 rpm for 10 min to obtain the final granules. In addition, use uncrushed voriconazole to mix a batch of formula F that has not been flavor-masking coated according to the direct mixing process.

[0017] Example 5: Taste test of voriconazole dry suspension sample Prescription A Prescription B Prescription C Prescription D Prescription E Prescription F The time to feel bitterness 120s 240s 185s 225s 230s 5s Taste tests show that granules coated with a masking coating can remain in the mouth for 120-240 seconds to prevent drug dissolution, thus masking the taste. Unmasked granules quickly produce a bitter taste in the mouth, resulting in poor patient compliance.

[0018] Example 6: Dissolution test of voriconazole dry suspension Dissolution method: paddle method, 50 rpm, 0.1 NHCl medium, 900 ml; Results: The taste-masked coated granules dissolve extremely rapidly. Specifically, over 85% dissolves within 15 minutes, reducing the risk of decreased bioavailability due to low drug solubility.

[0019] Example 6: Light Illumination Experiment Light stability test Take 10 bags of each test sample, pour out the contents, add them to a 50ml stoppered graduated cylinder, add water to the mark, shake vigorously, transfer the suspension to a vial, and place it in a light stability test chamber. Take samples after 7 days and 14 days to test related substances. The specific data are as follows: Conclusion: Granulation with a mixture of opacifiers such as iron oxide, talc, calcium carbonate, and titanium dioxide and voriconazole, followed by coating of the granules, can effectively control the growth of impurities.

Claims

1. Voriconazole dry suspension, characterized in that... The product includes drug-containing granules, which consist of drug-containing pellets and a coating layer. The drug-containing pellets comprise the following components: 63.49% voriconazole, 31.75% pregelatinized starch, 1.59% croscarmellose sodium, and 3.17% opacifier. The voriconazole, after micronization, has a particle size D90 of less than 13.0 μm. The opacifier is iron oxide or calcium carbonate. The coating material of the coating layer is ethyl cellulose dispersion. Furthermore, the preparation method of the voriconazole dry suspension includes the following steps: 1) The voriconazole raw material is micronized so that the particle size D90 of the micronized voriconazole is less than 13.0 μm; 2) The micronized voriconazole was mixed with a light-blocking agent, pregelatinized starch and cross-linked sodium carboxymethyl cellulose, then water was added to granulate the mixture and dried to obtain drug-containing pills. 3) The drug-containing pills are coated with a fluidized bed to mask their flavor; 4) Mix the obtained coated granules with the added excipients until they are evenly mixed.

2. The method for preparing voriconazole dry suspension according to claim 1, characterized in that... Includes the following steps: 1) The voriconazole raw material was micronized using air jet milling technology, so that the particle size D90 of the micronized voriconazole was less than 13.0 μm; 2) Add the micronized voriconazole, opacifier, pregelatinized starch and cross-linked sodium carboxymethyl cellulose into a wet mixing granulator, set the stirring speed to 150 rpm and run for 5 minutes; 3) Set the stirring speed to 150 rpm and the cutting speed to 1500 rpm. Add purified water after 2 minutes to granulate. Stop the machine after running for 5 minutes and discharge the material. 4) The wet granules are fed into a fluidized bed for drying, and the drying loss is controlled to be less than 2.0%. The dry granules are granulated using a granulator with a speed of 300-500 rpm and a pore size of 0.8 mm to obtain drug-containing pills. 5) Dilute the ethyl cellulose dispersion containing the odor-masking material with purified water to obtain a coating solution; 6) Coat the obtained drug-containing pills in a fluidized bed with an inlet air temperature of 30-70℃ and a spray flow rate of 2-15 g / min; 7) After the coating liquid has been completely sprayed, odor-masked coated granules are obtained; 8) Add the obtained flavor-masked coated granules and the added excipients sucrose, xanthan gum and colloidal silica into the mixing tank, mix at 10 rpm for 10 min to obtain the final granules.

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