Fluconazole dry suspension and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a fluconazole dry suspension and a preparation method thereof. The fluconazole dry suspension composition comprises the following components in parts by weight: 160 parts of fluconazole, 2100-2300 parts of a filler, 27-35 parts of a suspending aid, 2-6 parts of a lubricant and a proper amount of a pH regulator, the suspending aid is a composition of hydroxypropyl methylcellulose and glucan, and the mass ratio of the hydroxypropyl methylcellulose to the glucan is (2: 1)-(4: 1); the amount of the pH regulator enables the pH of the suspension containing 40mg of fluconazole per 1mL prepared by adding water into the dry suspension to be 3.0-4.5. The fluconazole dry suspension disclosed by the invention is slow in sedimentation in water, good in suspension property, free from caking after sedimentation and capable of being quickly redispersed after being shaken, and the prepared fluconazole dry suspension is good in flowability and good in uniformity.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a fluconazole dry suspension and a preparation method thereof. Background Art

[0002] Fluconazole is a synthetic triazole drug with antifungal activity. It mainly destroys the synthesis of fungal cell membranes by inhibiting the activity of cytochrome P450-dependent enzymes in sensitive fungi. It has a broad-spectrum antifungal effect and can be used for infections such as Blastomyces dermatitidis, Candida, Coccidioides immitis, Cryptococcus neoformans, Epidermophyton, Histoplasma capsulatum, Microsporum, and Trichophyton. Oral administration of this product is used to treat and prevent fungal infections in children, such as mucosal and skin Candida. Fluconazole has a good safety profile and is well tolerated in the pediatric population.

[0003] Dry suspension is a fine particle dosage form that has more advantages than solid dosage forms such as tablets. It has a large distribution area in the gastrointestinal tract, fast absorption, high bioavailability, and can avoid the disadvantage of tablets being difficult to swallow. It not only changes the disadvantage of ordinary tablets that are slow to be absorbed orally and are not suitable for the elderly, children, and people with dysphagia, but also uses the characteristics of easy-to-take and fast-dissolving drugs to enable them to exert their therapeutic effects faster and better in the body. Dry suspension is stored in solid form and is taken orally in the form of suspension. It is suitable for children and some adults with dysphagia, and is a dosage form worth developing.

[0004] According to the instructions for fluconazole dry suspension listed by Pfizer, the dry suspension contains the active ingredient fluconazole and the inactive ingredients: sucrose, xanthan gum, anhydrous citric acid, anhydrous sodium citrate, titanium dioxide, colloidal silicon dioxide, sodium benzoate, and orange flavor. By analyzing the listed preparation, its preparation process is a direct mixing process, which is simple and controllable, but there is a problem of low particle fluidity. Therefore, it is necessary to develop a fluconazole dry suspension with high finished product content uniformity and good fluidity and a preparation method thereof. Summary of the invention

[0005] Based on the problems existing in the prior art, the present application aims to provide a fluconazole dry suspension with high finished product content uniformity and good fluidity and a preparation method thereof. During the implementation process, the applicant conducted a lot of research and unexpectedly found that the dry suspension product prepared by using hydroxypropyl methylcellulose and dextran as suspending agents has stable quality and good fluidity, which can perfectly meet the packaging requirements.

[0006] To achieve the above objectives, this application adopts the following technical solutions:

[0007] A fluconazole dry suspension, calculated by weight of each component, comprising:

[0008] Fluconazole 160 parts

[0009] Filler 2100-2300 parts

[0010] Suspending agent 27-35 parts

[0011] 2-6 parts of lubricant

[0012] pH adjuster in appropriate amount;

[0013] The suspending agent of the present invention is a composition of hypromellose and dextran, and the mass ratio of the two is 2:1-4:1, preferably 3:1; the hypromellose is preferably hypromellose K4M, hypromellose K750, and hypromellose K1500, and more preferably hypromellose K4M.

[0014] The amount of the pH regulator of the present invention is such that the pH of the suspension containing 40 mg of fluconazole per 1 mL prepared by adding water to the dry suspension is 3.0-4.5.

[0015] The filler of the present invention is one or more of sucrose, sorbitol, mannitol, xylitol and maltitol, preferably sucrose.

[0016] The lubricant of the present invention is one or more of colloidal silicon dioxide, magnesium stearate and talc.

[0017] The particle size of the fluconazole of the present invention is D90≤50μm and D50≤10μm.

[0018] Preferably, the pH regulator is anhydrous citric acid and anhydrous sodium citrate, and calculated by weight, the anhydrous citric acid is 16-52 parts, and the anhydrous sodium citrate is 13-24 parts.

[0019] Preferably, calculated based on the weight of each component, the dry suspension of the present invention further comprises: 2-6 parts of a sunscreen, 8-11 parts of a preservative, and 30-50 parts of a taste masking agent.

[0020] Preferably, the sunscreen is titanium dioxide.

[0021] Preferably, the preservative is selected from one or more of sodium benzoate, benzoic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sorbic acid, potassium sorbate, and calcium sorbate.

[0022] Preferably, the taste masking agent is selected from one or more of orange powder flavor, peach flavor, apple flavor, pineapple flavor, and banana flavor.

[0023] Preferably, the fluconazole dry suspension comprises, calculated by weight of each component, 160 parts of fluconazole, 2100-2300 parts of sucrose, 27-35 parts of suspending agent, 16-52 parts of anhydrous citric acid, 12-24 parts of anhydrous sodium citrate, 2-6 parts of titanium dioxide, 2-6 parts of colloidal silicon dioxide, 8-11 parts of sodium benzoate, and 30-50 parts of orange powder flavor; wherein the suspending agent is a combination of hypromellose and dextran, and the mass ratio of the two is 2:1-4:1.

[0024] Further preferably, the fluconazole dry suspension, calculated by the weight of each component, includes: 160 parts of fluconazole, 2185.1 parts of sucrose, 30.7 parts of suspending agent, 16.8 parts of anhydrous citric acid, 12.7 parts of anhydrous sodium citrate, 3.9 parts of titanium dioxide, 3.9 parts of colloidal silicon dioxide, 9.5 parts of sodium benzoate, and 40 parts of orange powder flavor; the suspending agent is a combination of hypromellose and dextran, and the mass ratio of the two is 3:1.

[0025] The present invention also provides a method for preparing the fluconazole dry suspension, comprising the following steps:

[0026] (1) Pretreatment: micronize fluconazole to a particle size of D90≤50 μm and D50≤10 μm; grind the raw and auxiliary materials separately and pass through an 80-mesh sieve for later use;

[0027] (2) Premixing: Premixing the prescribed amount and the crushed auxiliary materials. After the premixing is completed, the mixture is sieved through an 80-mesh sieve to obtain a first mixture.

[0028] (3) Total mixing: uniformly mixing the prescribed amount of crushed fluconazole with the first mixture to obtain a fluconazole dry suspension.

[0029] Compared with the prior art, the beneficial effects of the present application are as follows: the present invention adopts hydroxypropyl methylcellulose and dextran as fluconazole dry suspension, the prepared fluconazole dry suspension settles slowly in water, has good suspension property, does not form lumps after settling, can be quickly redispersed after shaking, and the prepared fluconazole dry suspension has good fluidity and good uniformity. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The dissolution curves of Examples 1, 2, 3 and Comparative Example 8 (0.1 mol / L hydrochloric acid dissolution medium) are shown. DETAILED DESCRIPTION

[0031] In order to better understand the technical solution of the present invention, the technical solution of the present invention is further described below in conjunction with specific embodiments. The embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0032] Example 1

[0033] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, hypromellose K4M 23g, dextran 7.7g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0034] Preparation method:

[0035] (1) micronizing fluconazole to a particle size of D90≤50 μm and D50≤10 μm; pulverizing sucrose, hydroxypropyl methylcellulose K4M, dextran, anhydrous citric acid, anhydrous sodium citrate, titanium dioxide, colloidal silicon dioxide, sodium benzoate, and orange powder flavor in a pulverizer, respectively, and filtering through an 80-mesh sieve for later use;

[0036] (2) Add sucrose, hypromellose K4M, dextran, anhydrous citric acid, anhydrous sodium citrate, titanium dioxide, colloidal silicon dioxide, sodium benzoate, and orange powder flavor according to the above prescription into a mixer, set the mixer speed to 400 rpm, and mix for 5 minutes.

[0037] (3) The prescribed amount of crushed fluconazole was added into a mixer, the mixer speed was set to 400 rpm, and the mixture was mixed for 15 minutes to obtain a fluconazole dry suspension.

[0038] Example 2

[0039] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, hypromellose K4M 20.5g, dextran 10.2g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0040] Preparation method: except that the suspending agent is adjusted to 20.5 g of hypromellose K4M and 10.2 g of dextran, the rest of the process is the same as Example 1.

[0041] Example 3

[0042] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, hypromellose K4M 24.6g, dextran 6.1g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0043] Preparation method: except that the suspending agent is adjusted to 24.6 g of hypromellose K4M and 6.1 g of dextran, the rest of the process is the same as Example 1.

[0044] Comparative Example 1

[0045] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, hypromellose K4M 30.7g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0046] Preparation method: except that the suspending agent is adjusted to 30.7 g of hypromellose K4M, the rest of the process is the same as Example 1.

[0047] Comparative Example 2

[0048] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, dextran 30.7g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0049] Preparation method: except that the suspending agent is adjusted to 30.7 g of dextran, the rest of the process is the same as Example 1.

[0050] Comparative Example 3

[0051] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, hypromellose K4M 15.4g, dextran 15.4g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0052] Preparation method: except that the suspending agent is adjusted to 15.4 g of hypromellose K4M and 15.4 g of dextran, the rest of the process is the same as Example 1.

[0053] Comparative Example 4

[0054] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, hypromellose K4M 25.6g, dextran 5.1g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0055] Preparation method: except that the suspending agent is adjusted to 25.6 g of hypromellose K4M and 5.1 g of dextran, the rest of the process is the same as Example 1.

[0056] Comparative Example 5

[0057] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, methylcellulose 20.5g, dextran 10.2g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0058] Preparation method: except that the suspending agent is adjusted to 20.5 g of methyl cellulose and 10.2 g of dextran, the rest of the process is the same as Example 1.

[0059] Comparative Example 6

[0060] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, methylcellulose 23g, dextran 7.7g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0061] Preparation method: except that the suspending agent is adjusted to 23 g of methyl cellulose and 7.7 g of dextran, the rest of the process is the same as Example 1.

[0062] Comparative Example 7

[0063] Prescription composition (100 bottles, 1.6g / bottle): Fluconazole 160g, sucrose 2185.1g, methylcellulose 24.6g, dextran 6.1g, anhydrous citric acid 16.8g, anhydrous sodium citrate 12.7g, titanium dioxide 3.9g, colloidal silicon dioxide 3.9g, sodium benzoate 9.5g, orange powder flavor 40g.

[0064] Preparation method: except that the suspending agent is adjusted to 24.6 g of methyl cellulose and 6.1 g of dextran, the rest of the process is the same as Example 1.

[0065] Comparative Example 8

[0066] The original fluconazole dry suspension (200 mg / 5 mL) was compared with the fluconazole suspension of the present invention.

[0067] Product quality testing methods:

[0068] 1. The dry suspension content detection method described in the present invention: refer to the Chinese Pharmacopoeia 2020 edition, high performance liquid chromatography (General Rule 0512) determination; wavelength: 261nm; chromatographic column: octadecylsilane bonded silica gel chromatographic column; methanol-phosphate buffer (pH7.0) (45:55) as the mobile phase;

[0069] 2. Fluconazole content uniformity detection method of the dry suspension of the present invention: Determine the content of each point, and the content range of 95%-105% basically meets the requirements; calculate the content uniformity and evaluate it with RSD, RSD≤5.0%, which basically meets the requirements;

[0070] 3. Sedimentation ratio detection method of the dry suspension described in the present invention: refer to the 2020 edition of the Chinese Pharmacopoeia, and operate as follows: take the test sample, shake it vigorously to make the suspension evenly dispersed, quickly measure 50mL with a stoppered measuring cylinder, stopper it, and let it stand for 3h. At the same time, record the liquid level height H0 of the suspension and the final height H of the suspension. The sedimentation volume ratio = H / H0.

[0071] 4. Redispersibility test method of the dry suspension of the present invention: Place the sedimentation suspension that has been placed for 3 days in a 100mL measuring cylinder, rotate the measuring cylinder upside down at 180°C, turn it upside down once, and stay for 5S, which is counted as shaking once. Record the number of rotations required for redispersion and evaluate it with "good", "good", "average", and "poor"; among them, "good" is required for uniform dispersion within no more than 12 times, "good" is required for uniform dispersion of 12-60 times, "average" is required for more than 60 times but still uniformly dispersed, and "poor" is required for non-uniform dispersion.

[0072] 5. The angle of repose of the dry suspension of the present invention is mainly used to evaluate fluidity. The determination method is: slowly add the powder from the top of the funnel, and the inclination angle of the conical accumulation formed by the material leaking from the bottom of the funnel on the horizontal plane is the angle of repose. The judgment limit is that the angle of repose below 30° indicates that the fluidity meets the requirements, and above indicates that the fluidity is poor. The smaller the angle of repose, the better the fluidity.

[0073] 6. The dissolution detection method of the dry suspension described in the present invention: refer to the 2020 edition of the Chinese Pharmacopoeia, dissolution and release determination method (0931 General Rules Second Method): 900 mL of dissolution medium was measured, the speed was 50 revolutions per minute, and the operation was carried out according to the law. After 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, and 90 min, 10 mL of solution was taken respectively, and the dissolution medium of the same temperature and volume was supplemented at the same time, filtered, and an appropriate amount of the subsequent filtrate was accurately measured, and the dissolution medium was added and quantitatively diluted to prepare a solution containing about 1 mg of fluconazole per 1 mL, and the solution was determined according to the high performance liquid chromatography method (0512); another appropriate amount of fluconazole reference substance was accurately weighed, dissolved in the mobile phase and quantitatively diluted to prepare a solution containing about 1 mg per 1 mL, and the solution was determined by the same method to calculate the dissolution amount of the dry suspension at different time points.

[0074] Test Example 1

[0075] The finished products obtained after filling of Examples 1-3, Comparative Examples 1-7, and the original reference preparation of Comparative Example 8 were tested for content uniformity of 6 unit doses of fluconazole and the content of fluconazole was calculated. The test data results are shown in Table 1:

[0076] Table 1

[0077] Measured content (%) RSD(%) Example 1 99.96 0.39 Example 2 99.42 0.90 Example 3 99.66 0.81 Comparative Example 1 98.57 3.22 Comparative Example 2 96.64 3.78 Comparative Example 3 97.24 2.86 Comparative Example 4 98.67 3.12 Comparative Example 5 98.79 3.61 Comparative Example 6 97.95 4.21 Comparative Example 7 98.53 4.73 Comparative Example 8 99.91 0.95

[0078] From the results in Table 1, it can be seen that the content and uniformity of the finished dry suspension obtained in Examples 1-3 and Comparative Examples 1-8 can meet the requirements. In contrast, the content uniformity of the finished dry suspension obtained in Example 1 is better.

[0079] Test Example 2

[0080] Water was added to Examples 1-3 and Comparative Examples 1-8 to prepare suspensions, each 1 mL of the suspension containing 40 mg of fluconazole. The pH value and suspension performance of the suspensions were tested. The test data results are shown in Table 2:

[0081] Table 2

[0082]

[0083] From the results in Table 2, it can be seen that the fluconazole dry suspension prepared with the combination of hydroxypropyl methylcellulose and dextran as suspending agents has a good suspending effect, especially with the combination of hydroxypropyl methylcellulose and dextran in a mass ratio of 3:1 as suspending agents, the suspending effect of the fluconazole dry suspension prepared is consistent with that of the original preparation.

[0084] Test Example 3

[0085] The angle of repose of Examples 1-3 and Comparative Examples 3-6 and 8 was measured and the angle of repose was calculated. The results are shown in Table 3:

[0086] Table 3

[0087]

[0088] From the results in Table 3, it can be seen that the dry suspensions prepared in Comparative Examples 3-6 have poor fluidity, and the fluidity of the dry suspensions prepared in Examples 1-3 is better than that of Comparative Example 8, especially the fluidity of the dry suspension prepared in Example 1 is better.

[0089] Test Example 4

[0090] The dissolution test of Examples 1-3 and Comparative Example 8 was performed, and the results are shown in Table 4:

[0091] Table 4

[0092]

[0093] From the results in Table 4, it can be seen that the dissolution rates of the dry suspensions prepared in Examples 1-3 are not significantly different from those in Comparative Example 8.

[0094] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A fluconazole dry suspension, characterized in that: Calculated by weight of each component, including: Fluconazole 160 parts Filler 2100-2300 parts Suspending agent 27-35 parts 2-6 parts of lubricant pH adjuster in appropriate amount; The suspending agent is a combination of hypromellose and dextran, and the mass ratio of the two is 2:1-4:1; The amount of the pH regulator is such that the pH of the suspension containing 40 mg of fluconazole per 1 mL of the dry suspension is 3.0-4.

5.

2. The dry suspension according to claim 1, characterized in that The filler is one or more of sucrose, sorbitol, mannitol, xylitol, and maltitol; The lubricant is one or more of colloidal silicon dioxide, magnesium stearate and talc.

3. The dry suspension according to claim 1, characterized in that The mass ratio of the suspending agent hypromellose to dextran is 3:

1.

4. The dry suspension according to claim 1, characterized in that The particle size of the fluconazole is D90≤50μm and D50≤10μm.

5. The dry suspension according to claim 1, characterized in that The pH regulator is anhydrous citric acid and anhydrous sodium citrate. Calculated by weight, the anhydrous citric acid is 16-52 parts, and the anhydrous sodium citrate is 13-24 parts.

6. The dry suspension according to claim 5, characterized in that Calculated by weight of each component, the invention further comprises: 2-6 parts of sunscreen agent, 8-11 parts of preservative, and 30-50 parts of taste masking agent.

7. The dry suspension according to claim 6, characterized in that The sunscreen is titanium dioxide; The preservative is selected from one or more of sodium benzoate, benzoic acid, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, butyl parahydroxybenzoate, sorbic acid, potassium sorbate, and calcium sorbate; The taste masking agent is selected from one or more of orange powder flavor, peach flavor, apple flavor, pineapple flavor, and banana flavor.

8. The dry suspension according to claim 6, characterized in that Calculated by weight of each component, it includes: 160 parts of fluconazole, 2100-2300 parts of sucrose, 27-35 parts of suspending agent, 16-52 parts of anhydrous citric acid, 12-24 parts of anhydrous sodium citrate, 2-6 parts of titanium dioxide, 2-6 parts of colloidal silicon dioxide, 8-11 parts of sodium benzoate, and 30-50 parts of orange powder flavor; The suspending agent is a composition of hypromellose and dextran, and the mass ratio of the two is 2:1-4:

1.

9. The dry suspension according to claim 8, characterized in that Calculated by weight of each component, it includes: 160 parts of fluconazole, 2185.1 parts of sucrose, 30.7 parts of suspending agent, 16.8 parts of anhydrous citric acid, 12.7 parts of anhydrous sodium citrate, 3.9 parts of titanium dioxide, 3.9 parts of colloidal silicon dioxide, 9.5 parts of sodium benzoate, and 40 parts of orange powder flavor; The suspending agent is a composition of hypromellose and dextran, and the mass ratio of the two is 3:

1.

10. A method for preparing the dry suspension according to any one of claims 1 to 9, characterized in that: The following steps are involved: (1) Pretreatment: micronize fluconazole to a particle size of D90≤50 μm and D50≤10 μm; grind the raw and auxiliary materials separately and pass through an 80-mesh sieve for later use; (2) Premixing: Premixing the prescribed amount and the crushed auxiliary materials. After the premixing is completed, the mixture is sieved through an 80-mesh sieve to obtain a first mixture. (3) Total mixing: uniformly mix the prescribed amount of the crushed fluconazole with the first mixture to obtain a fluconazole dry suspension.

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