Antifungal drug capsule and preparation method thereof

Abstract

The invention provides an antifungal drug capsule and a preparation method thereof. The antifungal drug capsule is composed of a blank pellet core, an antifungal drug, a hydrophilic polymer, an enteric-coated material, a hollow capsule and the like. The preparation method comprises the following steps: dissolving an antifungal drug and a proper hydrophilic polymer in an organic solvent, spraying on a blank pellet core, drying, then wrapping a layer of enteric-coated material, and finally filling the drug-containing pellet wrapped with the enteric-coated material into a hollow capsule to obtain the antifungal drug capsule. The antifungal drug capsule prepared by the invention has excellent stability and relatively high bioavailability, and has the characteristics of low dosage, strong drug effect, small side effect and the like compared with commercially available antifungal drug capsules. In addition, the process is controllable, easy to operate and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of antifungal drugs, and in particular to a triazole derivative antifungal drug capsule and a preparation method thereof. Technical Background

[0002] Fungal infection can cause a variety of diseases, including dermatophytes, candidiasis, pulmonary mycosis, onychomycosis and fungal keratitis. Itraconazole, a commonly used antifungal drug in clinical practice, is a triazole derivative with a broad-spectrum antifungal effect. It can inhibit the synthesis of ergosterol in fungal cell membranes, thereby exerting an antifungal effect. Itraconazole has an inhibitory effect on dermatophytes (Trichophyton, Microsporum, Epidermophyton floccosum), yeasts [Cryptococcus neoformans, Pityrosporum, Candida (including Candida albicans, Candida glabrata and Candida krusei)], Aspergillus, Histoplasma, Paracoccidioides brasiliensis, Sporothrix schenckii, Chromatids, Cladosporium, Blastomyces dermatitidis and various other yeasts and fungi.

[0003] Itraconazole, chemical name is (±) 1-sec-butyl-4-[4-[4-[4-[[(2R*,4S*)2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazolyl-1-methyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-△ 2 -1,2,4-triazol-5-one; molecular formula: C 35 H 38 Cl2N8O4, molecular weight: 705.63. The chemical structure is as follows:

[0004]

[0005] Itraconazole is easily soluble in dichloromethane, slightly soluble in tetrahydrofuran, and almost insoluble in water, methanol or ethanol. Due to its low solubility physicochemical properties, its bioavailability in the body is low. At present, the common dosage forms on the market are capsules and oral solutions. The itraconazole products used clinically are mainly itraconazole capsules. However, there are many problems with itraconazole capsules sold on the domestic market, such as high dosage, low efficacy, and large side effects. It is reported that gastrointestinal discomfort, such as anorexia, nausea, abdominal pain and constipation, is common in the adverse reactions of itraconazole; most patients with important underlying pathological changes and receiving multiple drug treatments at the same time may experience symptoms such as hypokalemia, edema, hepatitis and hair loss when receiving long-term treatment with itraconazole capsules (about one month or more).

[0006] The present invention provides a novel method for preparing an antifungal drug capsule, wherein the antifungal drug capsule has the characteristics of low dosage, high efficacy and small side effects. The antifungal drug capsule of the present invention is prepared by dissolving itraconazole in dichloromethane and converting it into an amorphous state, thereby greatly improving the solubility of itraconazole; and then wrapping it with a layer of enteric material so that it is positioned in the intestine for release and absorption, thereby avoiding excessive concentration of itraconazole in the stomach after oral administration, thereby causing adverse reactions such as gastrointestinal discomfort. In addition, the antifungal drug capsule of the present invention still has higher stability and bioavailability than commercially available itraconazole capsules after reducing the dosage. Summary of the invention

[0007] The purpose of the present invention is to provide a new method for preparing antifungal drug capsules. The present invention adopts a bottom spray or side spray micro-pellet coating process, which can be completed in a Glatt fluidized bed or a Hutlin fluidized bed. The preparation method described in the present invention is to spray a solution containing itraconazole and a hydrophilic polymer on a blank pellet core, and then coat a layer of enteric material after drying, and finally put the micro-pellets into a capsule. The process of the present invention is controllable and easy to operate, and is suitable for industrial production. Compared with itraconazole capsules sold on the market, the samples prepared by the preparation method described in the present invention have excellent stability and high bioavailability, and overcome the problems of high dosage, low efficacy, and large side effects.

[0008] To achieve the above object, the present invention provides the following technical solutions:

[0009] An antifungal drug capsule and a preparation method thereof, wherein the antifungal drug capsule is composed of antifungal drug micropills and hollow capsules, and each 1000 antifungal drug micropills are composed of the following weight ratios:

[0010] 150-250 g of blank pill core, 75-100 g of itraconazole, 100-300 g of hydrophilic polymer, and 10-30 g of enteric material.

[0011] The blank pill core is a sucrose pill core or a microcrystalline cellulose pill core;

[0012] The hydrophilic polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS);

[0013] The enteric material is hydroxypropyl methylcellulose phthalate (HPMCP) or acrylic resin (Eudragit);

[0014] The preparation method of the antifungal drug capsule comprises the following steps:

[0015] Step 1: dissolving itraconazole and a suitable hydrophilic polymer in an organic solvent to prepare a drug-containing solution; the organic solvent comprises dichloromethane and ethanol; spraying the drug-containing solution on a blank pellet core to prepare drug-containing micropellets;

[0016] Step 2: dissolving the enteric material in a solvent to obtain an enteric layer solution; the solvent is water or ethanol; spraying the obtained enteric solution on the drug-containing pellets obtained in step 1 to obtain antifungal drug pellets;

[0017] Step 3: Fill the antifungal drug pellets prepared in step 2 into hollow capsules to obtain antifungal drug capsules.

[0018] The present invention further discloses the application of the antifungal drug capsule prepared by the method in improving the bioavailability and stability of the preparation. The experimental results show that the relative bioavailability of itraconazole in the antifungal drug capsule prepared by the present invention is 44% higher than that of the commercially available itraconazole capsule of the same dose; the relative bioavailability of the antifungal drug capsule prepared by the present invention after reducing the dose to 75mg is still 22% higher than that of the commercially available preparation (specification 100mg); it can meet the requirement that the related substances do not change significantly during the 12-month storage process under accelerated conditions, and has excellent stability; and it has an excellent dissolution effect, and the dissolution rate of itraconazole in a hydrochloric acid solution can reach more than 90% in 30 minutes.

[0019] It should be noted that, in order to enable persons skilled in the art to more clearly understand the content and technical connotation of the present invention, the inventors of the present invention provide the following explanations of the professional terms, symbols, reagents, consumables and instruments involved:

[0020] “Commercially available preparation” refers to itraconazole capsules sold on the market, with a specification of 100 mg;

[0021] “Day 0”: refers to the time when sample preparation is completed;

[0022] “Accelerated conditions”: refers to a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. DETAILED DESCRIPTION

[0023] Example 1

[0024] Prescription (1000 tablets)

[0025]

[0026]

[0027] Preparation method:

[0028] 1. Add itraconazole and hydroxypropyl methylcellulose E5 to dichloromethane and anhydrous ethanol and stir for 2 hours;

[0029] 2. Place sucrose pellets in a Glatt fluidized bed equipped with a Wurster (bottom spray) baffle, introduce dry air, and spray the pre-prepared itraconazole spray solution on the sucrose pellets; spraying process control parameters: inlet air temperature 40-50°C, material temperature 30-40°C, atomization pressure 0.2-0.3MPa; after spraying, transfer to a vacuum dryer and dry at 70-80°C and 10-300mbar temperature and pressure for 50 hours.

[0030] 3. Add HP-50 phthalate to ethanol and stir for 1 hour;

[0031] 4. The pellets coated with itraconazole were loaded into a Glatt fluidized bed equipped with a Wurster (bottom spray) baffle, dry air was introduced, and the pre-prepared HP-50 spray solution of hydroxypropyl methylcellulose phthalate was sprayed on the pellets coated with itraconazole; the spraying process control parameters were: inlet air temperature 35-45°C, material temperature 25-35°C, and atomization pressure 0.2-0.3MPa; after spraying, dry for 15 minutes under the introduction of 50-55°C dry air.

[0032] 5. The prepared antifungal drug micropellets are loaded into gelatin capsules to obtain antifungal drug capsules.

[0033] Example 2

[0034] Prescription (1000 tablets)

[0035]

[0036] Preparation method:

[0037] 1. Add itraconazole and hydroxypropyl methylcellulose acetate succinate to dichloromethane and anhydrous ethanol and stir for 2 hours;

[0038] 2. Place microcrystalline cellulose pellets in a Glatt fluidized bed equipped with a Wurster (bottom spray) baffle, introduce dry air, and spray the pre-prepared itraconazole spray solution on the sucrose pellets; spraying process control parameters: inlet air temperature 40-50°C, material temperature 30-40°C, atomization pressure 0.2-0.3MPa; after spraying, transfer to a vacuum dryer and dry at 70-80°C and 10-300mbar temperature and pressure for 40 hours.

[0039] 3. Add acrylic resin to purified water and stir for 1 hour;

[0040] 4. The micropellets coated with itraconazole were loaded into a Glatt fluidized bed equipped with a Wurster (bottom spray) baffle, dry air was introduced, and the pre-prepared acrylic resin spray solution was sprayed on the micropellets coated with itraconazole; the spraying process control parameters were: inlet air temperature 35-45°C, material temperature 25-35°C, and atomization pressure 0.2-0.3MPa; after spraying, dry for 20 minutes under the introduction of 50-55°C dry air.

[0041] 5. The prepared antifungal drug micropellets are loaded into gelatin capsules to obtain antifungal drug capsules.

[0042] Example 3

[0043] Prescription (1000 tablets)

[0044]

[0045] Preparation method:

[0046] 1. Add itraconazole and hydroxypropyl methylcellulose E5 to dichloromethane and anhydrous ethanol and stir for 2 hours;

[0047] 2. Place sucrose pellets in a Glatt fluidized bed equipped with a Wurster (bottom spray) baffle, introduce dry air, and spray the pre-prepared itraconazole spray solution on the sucrose pellets; spraying process control parameters: inlet air temperature 40-50°C, material temperature 30-40°C, atomization pressure 0.2-0.3MPa; after spraying, transfer to a vacuum dryer and dry at 70-80°C and 10-300mbar temperature and pressure for 40 hours.

[0048] 3. Add Hydroxypropyl Methylcellulose Phthalate HP-50 into water and stir for 1 hour;

[0049] 4. The pellets coated with itraconazole were loaded into a Glatt fluidized bed equipped with a Wurster (bottom spray) baffle, dry air was introduced, and the pre-prepared HP-50 spray solution of hydroxypropyl methylcellulose phthalate was sprayed on the pellets coated with itraconazole; the spraying process control parameters were: inlet air temperature 35-45°C, material temperature 25-35°C, and atomization pressure 0.2-0.3MPa; after spraying, dry for 10 minutes under the introduction of 50-55°C dry air.

[0050] 5. The prepared antifungal drug micropellets are loaded into gelatin capsules to obtain antifungal drug capsules.

[0051] Test Example 1

[0052] Dissolution test:

[0053] Samples of Examples 1-3 and commercially available preparations were taken for dissolution testing, and the results were as follows:

[0054]

[0055] As can be seen from the above table, the antifungal drug capsules obtained in Examples 1-3 of the present invention have an itraconazole dissolution rate of more than 90% in a hydrochloric acid solution within 30 minutes, and the dissolution performance is better than that of commercially available preparations.

[0056] Test Example 2

[0057] Stability test:

[0058] The samples of Examples 1-3 were packaged in commercial packaging and placed under accelerated conditions with commercial preparations. The samples were taken out at 0, 6, and 12 months to test the content, solubility, and related substances, etc. to investigate the stability of the samples. The results are as follows:

[0059]

[0060]

[0061] The inspection results in the above table show that the content and dissolution of the samples prepared in Examples 1-3 after being placed under accelerated conditions for 12 months are basically the same as those on day 0; the related substances have increased slightly, but the maximum increase is 0.09%; and the maximum single impurities and total impurities in the related substances of the commercially available preparations after 12 months of acceleration are close to the limit requirements of the 2020 edition of the Chinese Pharmacopoeia [maximum single impurity (0.5%), total impurities (1.5%)]. This shows that the preparation method in this patent can meet the requirement that the related substances of the samples do not change significantly during the 12-month placement under accelerated conditions, and have excellent stability.

[0062] Test Example 3

[0063] Beagle dogs were selected as test animals to study the bioavailability of Example 1 of the present invention and the commercially available preparations. It should be noted in advance that during the implementation of the following test scheme, the Beagle dogs were fed with the same standardized diet throughout the entire period to eliminate the possible adverse effects of food on the results.

[0064] Selection and grouping of experimental animals: Female, healthy, same-age Beagle dogs with a body weight within the range of 10 ± 1.0 kg were selected, a total of 18 dogs were randomly divided into 3 groups, 6 dogs in each group;

[0065] Experimental plan: 1) No drugs were administered 21 days before the experiment; 2) 7 days before the experiment, 0.5 mg itraconazole / kg body weight was administered daily to pre-saturate the background of each test animal, so that the background itraconazole concentration of each test animal reached a steady-state level; 3) The test animals in each group began to fast at 20:00 one day before the experiment, and 1.6 mg itraconazole / kg body weight was administered on an empty stomach at 7:00 on the day of the experiment, and the samples were collected at each sampling time point (0 o'clock, 15 minutes, 30 minutes, 45 minutes, 1.0 hours, 1.5 hours, 2.0 hours, 4.0 hours, 6.0 hours). , 8.0 hours, 12.0 hours, 24.0 hours, and 48.0 hours), and 2 mL of blood was drawn from the median vein of the forelimb for sampling; 4) the samples of each test group of animals at each sampling time point were tested for itraconazole content using a Beagle dog itraconazole ELISA kit, and the mean of each evaluation item of the three Beagle dogs in each test group was calculated. It should be pointed out here that before the sample analysis and detection, the inventors of the present invention conducted a systematic methodological verification of the precision, recovery rate, specificity, detection limit, etc. of the method, and the results showed that the analysis method was scientific and feasible.

[0066] The results of the Beagle dog bioavailability study conducted using the test examples of the present invention are shown in the following table:

[0067]

[0068] According to the results in the above table, the relative bioavailability of itraconazole in the antifungal drug capsule of Example 3 obtained by the antifungal drug capsule of the present invention and the preparation method thereof is higher than that of the commercially available preparation by (1421-990) / 990=44%; the relative bioavailability of itraconazole in the antifungal drug capsule of Example 1 is higher than that of the commercially available preparation by (1207-990) / 990=22%. The antifungal drug capsule of the present invention has a higher bioavailability in vivo than the commercially available itraconazole capsule (dosage of 100 mg) after the dose is reduced to 75 mg.

[0069] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. An antifungal drug capsule, characterized in that: The antifungal drug capsules are composed of antifungal drug pellets and hollow capsules. Every 1000 capsules of the antifungal drug pellets are composed of the following weight ratios: 150-250 g of blank pill core, 75-100 g of antifungal drug, 100-300 g of hydrophilic polymer, and 10-30 g of enteric material; The blank pill core is a sucrose pill core or a microcrystalline cellulose pill core; The antifungal drug is (±)1-sec-butyl-4-[4-[4-[4-[[(2R*,4S*)2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazolyl-1-methyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-△ 2 -1,2,4-triazol-5-one; The hydrophilic polymer is hydroxypropyl methylcellulose (HPMC) or hydroxypropyl methylcellulose acetate succinate (HPMCAS); The enteric material is hydroxypropyl methylcellulose phthalate (HPMCP) or acrylic resin (Eudragit).

2. The method for preparing the antifungal drug capsule according to claim 1, characterized in that: Here are the steps: Step 1: dissolving the antifungal drug and a suitable hydrophilic polymer in an organic solvent to prepare a drug-containing solution; the organic solvent comprises dichloromethane and ethanol; spraying the drug-containing solution on a blank pellet core to prepare a drug-containing micropellet; Step 2: dissolving the enteric material in a solvent to obtain an enteric layer solution; the solvent is water or ethanol; spraying the obtained enteric solution on the drug-containing pellets obtained in step 1 to obtain antifungal drug pellets; Step 3: Fill the antifungal drug pellets prepared in step 2 into hollow capsules to obtain antifungal drug capsules.

3. Use of the antifungal drug capsule prepared by the method of claim 2 in improving the stability of the preparation.

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