Voriconazole dry suspension and preparation process thereof

Abstract

The invention relates to a voriconazole dry suspension. The voriconazole dry suspension comprises the following components: 2-4 parts of voriconazole; 36 to 41 parts of isomaltitol; 1-4 parts of a microcrystalline cellulose-sodium carboxymethyl cellulose compound; 0.1 to 0.5 part of colloidal silicon dioxide; 0.2 to 1.0 part of sodium lactate; 0.05 to 0.2 part of disodium hydrogen phosphate; 0.05 to 0.5 part of essence; 0.1-0.3 part of a preservative; the dry suspension disclosed by the invention has the characteristics of high settling volume ratio, excellent stability and remarkably improved dissolution rate.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to an improved voriconazole dry suspension and a preparation process thereof. BACKGROUND

[0002] Voriconazole, a chemical name of which is (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1, 2, 4-triazol-1-yl)-2-butanol, has a chemical formula of C 16 H 14 F3N5O, is a second-generation triazole antifungal compound, and can act on severe fungal infections.

[0003] Voriconazole is a weakly basic compound, is not hygroscopic, and belongs to a low-solubility and high-permeability compound; due to poor water solubility of voriconazole, conventional preparations are prone to problems such as low dissolution, poor granule flowability and large batch difference, which greatly affect clinical efficacy. The dry suspension is convenient to carry, convenient to transport, good in stability and the like; has the advantages of liquid preparations, such as high bioavailability, convenient taking, and is suitable for children and the elderly and other patients who have difficulty in swallowing; has good patient compliance, better taste, and is more easily accepted by patients.

[0004] At present, a prescription of voriconazole generally contains voriconazole as an active ingredient, sucrose as a filler, xanthan gum as a suspending agent, colloidal silicon dioxide as a suspending agent, citric acid as a pH regulator, sodium citrate dihydrate as a pH regulator, titanium dioxide as a light shielding agent, orange flavor powder essence as a flavoring agent, and sodium benzoate as a preservative. Due to extremely low solubility of voriconazole in water, the voriconazole granules are prone to sedimentation after being washed, and since voriconazole is in a solution state after being washed, the stability of voriconazole in the solution state is poor, thereby limiting development of the voriconazole granules. The patent solves the problem of poor stability of voriconazole in the solution state by adding citric acid to prepare the voriconazole granules, but does not explain the reason, and has poor reliability. SUMMARY

[0005] Therefore, the application aims to provide a voriconazole dry suspension and a preparation process thereof. The voriconazole dry suspension prepared by the process has stable chemical properties at room temperature, can be stored at room temperature, and has great advantages in transportation, storage and use.

[0006] The present application provides a voriconazole dry suspension, comprising the following components by weight: voriconazole 2-4 parts; isomalt 36-41 parts; microcrystalline cellulose-sodium carboxymethyl cellulose complex 1-4 parts; colloidal silicon dioxide 0.1-0.5 parts; sodium lactate 0.2-1.0 parts; disodium hydrogen phosphate 0.05-0.2 parts; essence 0.05-0.5 parts; preservative 0.1-0.3 parts; light shielding agent 0.1-0.5 parts.

[0007] The voriconazole dry suspension comprises the following components by weight: voriconazole 3 parts; isomalt 38 parts; microcrystalline cellulose-sodium carboxymethyl cellulose complex 2.5 parts; colloidal silicon dioxide 0.5 parts; sodium lactate 0.3 parts; disodium hydrogen phosphate 0.1 parts; essence 0.1 parts; preservative 0.2 parts; light shielding agent 0.3 parts.

[0008] The voriconazole dry suspension, the particle size range D 90 Between 80 μm-150 μm.

[0009] The voriconazole dry suspension, wherein the preservative is sodium benzoate.

[0010] The voriconazole dry suspension, wherein the light shielding agent is titanium dioxide.

[0011] The voriconazole dry suspension, the preparation method comprising:

[0012] (1) mixing voriconazole, isomalt and sodium lactate and performing wet granulation or low shear granulation to obtain a solid dispersion;

[0013] (2) mixing the solid dispersion obtained in step (1) with microcrystalline cellulose-sodium carboxymethyl cellulose complex, disodium hydrogen phosphate, colloidal silicon dioxide, preservative, light shielding agent and essence;

[0014] (3) obtaining a uniform dry suspension powder by homogenization.

[0015] Beneficial effects: the present application introduces isomalt as the main filler, uses Avicel RC591 (microcrystalline cellulose-sodium carboxymethyl cellulose) complex suspension system to construct gel structure, and replaces the traditional citric acid / sodium citrate system with sodium lactate to form a weak salt type stable environment, thereby improving the dissolution, resuspension, suspension stability and chemical stability of voriconazole from two dimensions of prescription system and microstructure. The combination of the above-mentioned excipients in the present application is not a simple splicing, but a new stable system different from the existing voriconazole dry suspension is constructed through multiple synergistic mechanisms, and the comprehensive effect is significantly better than the prior art. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 The impurity content of the sample of the present application under the condition of 60℃ is compared;

[0017] Figure 2 The dissolution rate of the present application in a medium with pH=1.0 is compared. DETAILED DESCRIPTION

[0018] In order to make the purpose, technical scheme and advantages of the embodiments of the present application clearer, the technical scheme in the embodiments will be clearly and completely described below in combination with the embodiments of the present application. The following embodiments are used to illustrate the present application but not to limit the scope of the present application.

[0019] Embodiment 1

[0020] Take voriconazole (particle size range D 90 between 80 μm-150 μm) 30 g; isomalt 380 g; microcrystalline cellulose-sodium carboxymethyl cellulose complex 25 g; colloidal silicon dioxide 5 g; sodium lactate 3 g; disodium hydrogen phosphate 1 g; peach flavor 1 g; sodium benzoate 2 g; titanium dioxide 3 g, the preparation method comprising:

[0021] (1) Mix voriconazole with isomalt, and wet granulation with sodium lactate aqueous solution, low-temperature drying to obtain a solid dispersion;

[0022] (2) Mix the solid dispersion obtained in step (1) with microcrystalline cellulose-sodium carboxymethyl cellulose complex, disodium hydrogen phosphate, colloidal silicon dioxide, sodium benzoate, titanium dioxide and flavor;

[0023] (3) Homogeneous mixing to obtain uniform dry suspension powder.

[0024] Embodiment 2

[0025] Take voriconazole (particle size range D 90 between 80 μm-150 μm) 20 g; isomalt 410 g; microcrystalline cellulose-sodium carboxymethyl cellulose complex 10 g; colloidal silicon dioxide 5 g; sodium lactate 2 g; disodium hydrogen phosphate 2 g; orange flavor 0.5 g; sodium benzoate 3 g; titanium dioxide 1 g, the preparation method comprising:

[0026] (1) Mix voriconazole with isomalt, and wet granulation with sodium lactate aqueous solution, low-temperature drying to obtain a solid dispersion;

[0027] (2) Mix the solid dispersion obtained in step (1) with microcrystalline cellulose-sodium carboxymethyl cellulose complex, disodium hydrogen phosphate, colloidal silicon dioxide, sodium benzoate, titanium dioxide and flavor;

[0028] (3) Homogeneous mixing to obtain uniform dry suspension powder.

[0029] Example 3

[0030] Voriconazole (particle size range D 90 between 80 μm-150 μm) 40 g; isomalt 360 g; microcrystalline cellulose-sodium carboxymethyl cellulose complex 40 g; colloidal silicon dioxide 1 g; sodium lactate 10 g; disodium hydrogen phosphate 0.5 g; apple flavor 5 g; sodium benzoate 1 g; titanium dioxide 5 g, the preparation method comprising:

[0031] (1) Voriconazole is mixed with isomalt, and an aqueous solution of sodium lactate is wet granulated, dried at low temperature, to obtain a solid dispersion;

[0032] (2) The solid dispersion obtained in step (1) is mixed with microcrystalline cellulose-sodium carboxymethyl cellulose complex, disodium hydrogen phosphate, colloidal silicon dioxide, sodium benzoate, titanium dioxide, and flavor;

[0033] (3) A uniform dry suspension powder is obtained by homogenization.

[0034] Comparative Example 1

[0035] Voriconazole (particle size D 90 between 80 μm-150 μm) 33 g, citric acid 1 g, sucrose 400 g, pregelatinized starch 166 g, croscarmellose sodium 50 g, povidone K30 40 g, magnesium stearate 10 g, the preparation method comprising:

[0036] 1) Voriconazole is micronized to control the particle size D90 within the range of 80 μm-150 μm;

[0037] 2) The micronized voriconazole, sucrose, pregelatinized starch, citric acid, and croscarmellose sodium are mixed uniformly according to the prescription amount, and a soft material is prepared by adding an aqueous solution of povidone K30, sieved and granulated to obtain wet granules;

[0038] 3) The above granules are dried to obtain dry granules;

[0039] 4) The dry granules are sieved and granulated, magnesium stearate is added and mixed uniformly, and after quality inspection, the product is packaged to obtain the voriconazole granules.

[0040] Comparative Example 2

[0041] Voriconazole (particle size range D 90 between 80 μm-150 μm) 30 g; isomalt 380 g; colloidal silicon dioxide 5 g; sodium lactate 3 g; disodium hydrogen phosphate 1 g; peach flavor 1 g; sodium benzoate 2 g; titanium dioxide 3 g, the preparation method comprising:

[0042] (1) Mix voriconazole and isomalt, wet granulation with sodium lactate solution, low temperature drying, to obtain a solid dispersion;

[0043] (2) Mix the solid dispersion obtained in step (1) with disodium hydrogen phosphate, colloidal silicon dioxide, sodium benzoate, titanium dioxide and essence;

[0044] (3) Homogeneous mixing to obtain a uniform dry suspension powder.

[0045] Comparative Example 3

[0046] Take voriconazole (particle size range D 90 30g; isomalt 380g; microcrystalline cellulose-sodium carboxymethyl cellulose complex 25g; colloidal silicon dioxide 5g; disodium hydrogen phosphate 1g; peach essence 1g; sodium benzoate 2g; titanium dioxide 3g, the preparation method comprises:

[0047] (1) Mix voriconazole and isomalt, wet granulation with water, low temperature drying, to obtain a solid dispersion;

[0048] (2) Mix the solid dispersion obtained in step (1) with microcrystalline cellulose-sodium carboxymethyl cellulose complex, disodium hydrogen phosphate, colloidal silicon dioxide, sodium benzoate, titanium dioxide and essence;

[0049] (3) Homogeneous mixing to obtain a uniform dry suspension powder.

[0050] Example 4: Dry suspension in water, palatability and sedimentation volume ratio determination

[0051] According to the "People's Republic of China Pharmacopoeia" 2020 edition, take an appropriate amount of dry suspension prepared in the above examples 1-3 and comparative example 1 in a beaker, add 50ml purified water, stir until uniform, transfer to 50ml cylinder with stopper. Record the initial height H0 of the suspension, stand for 3h, record the height H of the suspension again, calculate the sedimentation volume ratio (H / H0) of the suspension, F value should be between 0-1, the larger the F value, the more stable the suspension. The results are shown in Table 1.

[0052] Table 1 Dry suspension in water, palatability and sedimentation volume ratio determination

[0053]

[0054] From the test results in Table 1, it can be seen that the voriconazole dry suspensions prepared in Examples 1-3 of the present application all have excellent stability and basically do not produce sedimentation. Compared with Examples 1-3, the voriconazole dry suspension prepared in Comparative Example 1 without adding isomalt, microcrystalline cellulose-sodium carboxymethyl cellulose complex and colloidal silicon dioxide has a significantly smaller sedimentation volume ratio, is unstable and produces more sedimentation, mainly because isomalt as a suspending agent is not added, which cannot ensure complete suspension of the sample, thereby affecting the stability thereof; Comparative Example 2 does not add microcrystalline cellulose-sodium carboxymethyl cellulose complex, which cannot form a stable network system and cannot ensure complete suspension of the sample; Comparative Example 3 does not add sodium lactate, which cannot construct a weak salt type stable microenvironment to inhibit the sedimentation of voriconazole.

[0055] Voriconazole belongs to hydrophobic triazole compounds and is easy to recrystallize in the process of wet granulation and storage. Isomalt has a high glass transition temperature and low hygroscopicity, can form a solid-state hydrogen bond polysaccharide alcohol network in the preparation process, and makes voriconazole molecules embedded and fixed in a solid matrix with a high glass transition temperature Tg, thereby significantly inhibiting the molecular migration dynamics and making the amorphous state more stable.

[0056] The voriconazole dry suspension samples prepared in Examples 1-3 of the present application do not have obvious irritating odor after being dispersed in water, mainly because the microcrystalline cellulose-sodium carboxymethyl cellulose complex forms a gel to mask the odor, and the addition of sucrose in Comparative Example 1 group is too sweet. In summary, the voriconazole dry suspension prepared in the present application has excellent stability and good odor masking effect. After the dissolution of the sucrose filler, the local solution concentration is rapidly increased, which makes voriconazole enter a transient supersaturated state and induce the generation of crystal nuclei. The isomalt used in the present application has a low dissolution release rate and limited improvement of the solubility of voriconazole, so that the supersaturation peak value is avoided, and the instantaneous nucleation and growth are inhibited from the physical and chemical mechanism.

[0057] Example 5: Stability investigation

[0058] The samples obtained in Examples 1-3 and Comparative Examples 1-3 above were all sampled and placed at a high temperature of 60℃ for investigation, and samples were taken at 0, 5, 10 and 30 days for investigation of the stability of the samples, as a comparative study, and the specific results are shown in Table 2 and Figure 1

[0059] Table 2 Comparison of impurities of samples of the present application under the condition of 60℃ (total impurities%)

[0060]

[0061] Compared with Comparative Example 1, * P<0.05, ** P<0.01​

[0062] By Table 2 and Figure 1 It can be seen that, compared with Comparative Example 1, the stability of Examples 1-3 is better under the harsh condition of 60℃, and the impurity levels are significantly reduced, which shows that the voriconazole dry suspension prepared by adding isomalt, microcrystalline cellulose-sodium carboxymethyl cellulose complex and colloidal silicon dioxide has better stability. Comparative Example 1 only uses citric acid, which cannot inhibit the degradation of voriconazole. Comparative Example 2 does not add microcrystalline cellulose-sodium carboxymethyl cellulose complex, which cannot form a stable network system and cannot inhibit the degradation of voriconazole. Comparative Example 3 does not add sodium lactate, which cannot construct a weak salt type stable microenvironment and cannot inhibit the generation of voriconazole degradation impurities.

[0063] Example 6: Dissolution rate investigation

[0064] The samples 3g obtained in Examples 1-3 and Comparative Examples 1-3 above were dissolved in 900mL of pH=1.0 medium, and the dissolution rate was calculated. The specific results are shown in Table 3 and Figure 2

[0065] Table 3 Dissolution rate of the present application in pH=1.0 medium (paddle method, 50rpm)

[0066]

[0067] Compared with Comparative Example 1, * P<0.05, ** P<0.01

[0068] By Table 3 and Figure 2 It can be seen that the dissolution rates of Examples 1-3 all reach more than 97% at 60min, while the dissolution rates of Comparative Examples 1-3 are less than 90% at 60min, which shows that the excipients have a great influence on the dissolution rate of voriconazole dry suspension. The voriconazole dry suspension prepared by adding isomalt, microcrystalline cellulose-sodium carboxymethyl cellulose complex and colloidal silicon dioxide has better dissolution rate.

[0069] The above only describes the preferred embodiments of the present application and does not limit the present application in any form. Although the present application has been disclosed as the above preferred embodiments, it is not intended to limit the present application. Any skilled person in the art can make some changes or modifications to the above-mentioned technical content without departing from the scope of the technical solution of the present application, and any simple modification, equivalent change and modification of the above embodiments based on the technical essence of the present application are still within the scope of the present application.​

Claims

1. A voriconazole dry suspension, characterized in that, By weight, it comprises the following components: voriconazole 2-4 parts; isomaltitol 36-41 parts; microcrystalline cellulose-sodium carboxymethyl cellulose complex 1-4 parts; colloidal silica 0.1-0.5 parts; sodium lactate 0.2-1.0 parts; disodium hydrogen phosphate 0.05-0.2 parts; fragrance 0.05-0.5 parts; preservative 0.1-0.3 parts; and opacifier 0.1-0.5 parts.

2. The voriconazole dry suspension according to claim 1, characterized in that, By weight, it comprises the following components: 3 parts voriconazole; 38 parts isomaltitol; 2.5 parts microcrystalline cellulose-sodium carboxymethyl cellulose complex; 0.5 parts colloidal silica; 0.3 parts sodium lactate; 0.1 parts disodium hydrogen phosphate; 0.1 parts fragrance; 0.2 parts preservative; and 0.3 parts opacifier.

3. The voriconazole dry suspension according to claim 1, characterized in that, The particle size range of voriconazole D 90 Between 80μm and 150μm.

4. The voriconazole dry suspension according to claim 1, characterized in that, The preservative mentioned therein is sodium benzoate.

5. The voriconazole dry suspension according to claim 1, characterized in that, The light-blocking agent mentioned above is titanium dioxide.

6. The voriconazole dry suspension according to claim 1, characterized in that, Preparation methods include: (1) Voriconazole, isomaltitol and sodium lactate are mixed and wet granulated or low-shear granulated to obtain a solid dispersion. (2) The solid dispersion obtained in step (1) is mixed with microcrystalline cellulose-sodium carboxymethyl cellulose complex, disodium hydrogen phosphate, colloidal silica, preservative, opacifier and fragrance; (3) A uniform dry suspension powder is obtained by homogenization.

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