KR100557680B1 - Pellet preparations and methods for improved solubility of itraconazole - Google Patents

Abstract

The present invention relates to solubilized itraconazole pellets and a method for preparing the same, specifically, 1-50 parts by weight of itraconazole, 0.1-40 parts by weight of surfactant, 0.5-30 parts by weight of water-soluble polymer are mixed with a solvent to dissolve or disperse itraconazole, As a pharmaceutically acceptable additive, 0.1-20 parts by weight of an organic acid or an inorganic acid including succinic acid is dissolved and mixed, followed by spray drying, spray drying the spray dried on inert spherical particles having a size of 100-1500 μm and pellets of a constant size. Alternatively, the spray dried material is mixed with 0-30 parts by weight of an oil or a fatty acid thereof to prepare a milky white emulsion, and a pellet having a size of 100-1500 μm prepared by spraying the reaction solution using a dispersing apparatus and a method of preparing the same As a result, it is an efficient method for improving the stability, solubility and handleability of itraconazole.

Itraconazole, Pellets

Description

Pellet preparation for improving solubility of itraconazole and its preparation method {Pellet preparations and methods for improved solubility of itraconazole}

The present invention relates to a pellet preparation for improving the solubility of itraconazole with increased bioavailability and a method of preparing the same.

Itraconazole is a triazole-based compound having the following structural formula, despite its excellent antifungal activity, has a disadvantage of poor bioavailability when orally administered because it is poorly soluble. In fact, the solubility of itraconazole in water is less than 1 μg / ml and the pKa value is 3.7, so that it is ionized and dissolved only at very low pH. In addition, the bioavailability (absorption or blood concentration) of orally administered itraconazole is known to be greatly influenced by food and greatly influenced by individuals.

In order to increase the solubility of itraconazole in water, a method of preparing a clathrate compound with cyclodextrin has been attempted (WO 85/002767 and U.S. Patent No. 4,764,604), but this method has a solubility in water with itraconazole. It is not preferable because it requires little complicated improvement in the actual production process, and also requires several complicated steps in order to form inclusions.

Recently, a three-layered bead was developed by Janssen, coated with itraconazole and a hydrophilic polymer on a core composed of pharmaceutically inert or neutral sugar, dextrin, and starch. Commercially available (International Publication No. 94/05263, trade name; Sporanox capsules). However, this method has a lot of difficulties, such as agglomeration in the coating process by using a small core of 600 to 700 ㎛ diameter.

In addition, in order to increase the solubility of itraconazole in water to prepare a solution, it has been attempted to add itraconazole to a volatile organic acid solvent having a low molecular weight such as acetic acid and formic acid (International Publication No. 96/39835). Due to the low pH of the organic acid solvent there are disadvantages inadequate for oral administration.

On the other hand, it is increased in the bioavailability of itraconazole and hardly affected by food, which was a problem of conventional commercial formulations, water-soluble polymer mixtures such as itraconazole and hydroxypropyl methylcellulose according to the melt-extrusion method Although solid-dispersions have been developed in which melted itraconazole is dispersed in an unmelted water-soluble polymer by heating to 245 to 265 ° C. (International Publication No. 97/44014), the melt-extrusion process of itraconazole has been developed. It is difficult to manufacture the melt extrudates because it is carried out at a high temperature of 265 ℃, this melt must be dispersed very uniformly in the polymer may cause problems in the mixing process in the manufacturing process, furthermore, it is eluted while remaining unmelted itraconazole Disadvantages that it is difficult to obtain reproducible products because they can affect absorption There.

    An object of the present invention is to provide an itraconazole-containing antifungal pellets having an increased bioavailability and a method for producing the same.

    The present invention relates to a pellet prepared by the spraying method and a method for manufacturing the same, and specifically, prepared by mixing a pharmaceutically acceptable additive capable of solubilizing and stabilizing a poorly soluble substance such as itraconazole, and preparing it in a solution or emulsion state. After drying under reduced pressure or using a fluidized bed coater relates to a method for producing a microencapsulated pellet of a constant size.

    Until now, the microencapsulation method has been extensively studied for the purpose of shielding effects such as taste or smell, improving fluidity and physical properties of materials, stabilization, gastrointestinal disorders and toxicity and slow release. Known microencapsulation methods are known as spray drying (spray-drying), phase separation, vapor phase suspension, solvent evaporation, pan coating and fluidized bed coating.

    Spray drying is a method that has been widely used in the pharmaceutical or other manufacturing industries in that the liquid content in the liquid form can be solidified through a single process. This method also produces the final material with fine particles, and has the advantage of changing the properties of the main component by adding other components to the liquid phase. (EP00436373A1). This method can be used at relatively low temperature that can evaporate the solvent in a short time, and even if the high temperature condition is exposed only for a very short time, it does not affect the physical properties of drugs or other excipients and spray-dried mixture In addition to minimizing the flowability of the particles and the interaction between the particles, it has the advantage that does not require an additional process such as crushing or granulating the particles made in a conventional preparation method. This method can be said to be an advanced method in terms of particle properties and process compared to the melting (extrusion) method (WO 97/44014), which is a manufacturing method of a commercially available product. In other words, the melting (extrusion) method requires careful temperature control because there is little difference between the temperature at which the drug and the polymer can be melted and mixed at the same time and the temperature at which the drug or the polymer is decomposed. In particular, the average molecular weight of the polymer to be used is increased. As the melting point increases, the area of the selectable polymer decreases by that much. Apart from this, the recrystallization of the drug is likely to occur due to the heat generated during the grinding process to obtain the formed melt as final fine powder. In addition, there arises a problem that the size of the resulting particles is significantly increased compared to the spray drying method, that is, the size of the spray drying method is 10nm ~ 100㎛, while the final particles of the melt (extrusion) method is less than 600㎛ It is common to show the size and the distribution range of the particles is also very wide, making it difficult to obtain uniform particles. This may be a problem in view of the fact that the dissolution of the drug is generally proportional to the specific surface area of the particles. On the other hand, in the case of particles which have been pulverized during the manufacturing by melting (extrusion) method, agglomeration between particles occurs due to the independent particle size, thereby reducing wettability and removing a process from the subsequent manufacturing process. The hassle of being can also be considered a problem. Therefore, in the present invention, as well as minimizing the amount of the organic solvent that is used in a large amount in the above process, there is an advantage that can be produced in a short time by developing a spray drying and pelletization process in a series of continuous processes.

It is an object of the present invention to solubilize a poorly water-soluble substance such as itraconazole, as well as to provide a preparation method in which a preparation in a pellet form with easy administration and increased bioavailability and mass production is possible.

The atlaconazole-containing pellet formulation of the present invention and a method for producing the same,

Dissolving itraconazole and a hydrophilic polymer, an organic acid or an amino acid in a co-solvent, and spraying it with a spray dryer or a fluidized bed coater to obtain a fine and uniform spray dried product, wherein the spray dried product thus obtained is sprayed onto inert spherical particles. Pellet preparation having a size of 1500㎛ and a method for manufacturing the same,

Dissolving itraconazole and a hydrophilic polymer in a co-solvent and spraying it with a spray dryer or a fluidized bed coater to obtain a fine and uniform spray dried product, wherein the spray dried product is mixed with a soluble oil or a fatty acid thereof and mixed with a hydrophilic polymer solution. After the final mixing and spraying with a reaction solution containing a divalent metal ion through a specific spraying apparatus is a pellet preparation having a size of 100 ~ 1500㎛ and a method for producing the same.

   Specifically, the present invention relates to a pellet containing 1-50 parts by weight of itraconazole, preferably 5-30 parts by weight, as a main component, and a mixed solvent of methylene chloride and ethanol, ethylene glycol which is a hydrophilic polymer, and succinic acid which is an organic acid. Completely dissolved and sprayed on inert sugar particles to provide pellets having a predetermined size.

    In addition, in the present invention, after completely dissolving itraconazole, polyethylene glycol and succinic acid in a mixed solvent of methylene chloride and ethanol, spray-drying and mixing the spray dried product with a hydrophilic sodium alginate solution to prepare a milky white liquid, Also provided are pellets prepared by mixing acceptable speed additives and stirring at high speed to produce a homogeneous mixture, and spraying into a reaction liquid through an injector.

Hereinafter, the present invention will be described in detail.

    In the present invention, first, a solid dispersion of itraconazole, polyethylene glycol, and succinic acid is prepared. Itraconazole can achieve hydrophilic polymers and coprecipitates or solid dispersions to reduce particle size and increase solubility due to changes in physical properties. Hydrophilic polymers that can be used include hydroxypropylmethylcellulose (HPMC), Hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), sodium carboxymethyl cellulose (Na-CMC), and other cellulose derivatives, polyvinylpyrrolidone (PVP), cyclodextrins (e.g. β-CD ), Polymethylmethacrylic acid derivatives, chitin, chitosan and derivatives thereof, alginic acid and alkali or metal salts thereof, caraginaan gum, tragacanth gum, agar (agar) 1 selected from polysaccharides such as agar-agar, arabic gum, gua gum, xanthan gum, polyvinyl alcohol (PVA), polyethylene oxide (PEO), polyethylene glycol (PEG), etc. 0.5 to 30, or of two or more thereof may be mixed by weight.

    In addition, in the present invention, various inorganic and organic acids may be included to increase solubility of itraconazole and to increase stability. Hydrochloric acid and phosphoric acid belong to these inorganic acids, and 0.1-20 parts by weight of one or two or more of succinic acid, citric acid, adipic acid, lactic acid, taurocholic acid, glycocholine acid, ascorbic acid, fumaric acid, etc. Can be used mixed.

In the present invention, amino acids may be added, and one or two or more kinds of glutamic acid and aspartic acid may be used in an amount of 01 to 30 parts by weight.

    Although not listed above, many other hydrophilic polymers, inorganic and organic acids may be used as polymers and additives for solubilizing itraconazole.

    In addition, in the present invention, after dissolving or dispersing the solid dispersion of itraconazole alone or in oil and adding an emulsifier to prepare a milky white emulsion, a pharmaceutically acceptable additive is mixed and then stirred at high speed to prepare a homogeneous mixed solution. Provided are pellets produced by spraying into a reaction liquid through an injector and a method for producing the same.

   Suitable oils for the preparation of the pellets of the invention include stearyl glycyrrhetinate, tocopheryl acetate, panthenol, phosphatidylcholine; Glyceryl stearate, captylic / capric triglyceride, cetyl octanolate, isopropyl myristate, ceteatyl octanoate ), Butylene glycol dicaptylate / dicaprate, hydrogenated castor oil, mono-glycerides, diglycerides, triglycerides Esters such as beeswax, canauba wax, olive oil, jojoba oil, hybrid sunflower (Helian thus annuus) oil, and the like. Can be used, preferably mineral oil, squalene, squalane, monoglyceride, diglyceride, triglyceride, medium chain writing Ceride, myglyol, cremophor, hydrogenated castor oil, corn oil, soybean oil, sesame oil, cottonseed oil, or fat-soluble vitamins may be used, and 0-30 parts by weight of one or more of these Can be used for selection and mixing.

    The fatty acid may be linoleic acid, stearic acid, oleic acid, cetyl alcohol, stearyl alcohol, myristic acid, myristic acid, or lauric acid. acid) and the like, and preferably one or two or more thereof may be used in linolenic acid, oleic acid, or isopropyl mystic acid.

    Emulsifiers to obtain a homogeneous emulsion by mixing itraconazole and oil include sodium lauryl sulfate, hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose (HPC), and carboxymethylcellulose. ) And its sodium, calcium salt, carrageenan, alginic acid and its magnesium, sodium, calcium salt, povidone, polyvinyl alcohol, tragacanth gum, chitosan chitosan, chitin, tween, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearic acid, oleyl alcohol, lecithin, diethanolamine, cholesterol 0.1 to 40 parts by weight of one or two or more selected from esterol), poloxamer, trolamine, wax, etc. may be used.

    Other additives to keep the pellets in good shape include starch, pregelatinized starch lactose, mannitol, sorbitol, sugar, sucrose, and dextrin. , Carbomer 910, carbomer 934, carbomer 934P, carbomer 940, carbomer 941, carbomer 1342, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic ) Or one or more selected from calcium sulfate.

    The pellet forming reaction solution used in the present invention uses a calcium aqueous solution as a material to maintain a constant shape by solidifying the membrane material that was in a liquid state by reacting with a material capable of forming a film. Sodium alginate, which is an emulsifier and film-forming substance added in the present invention, has a property of solidifying upon contact with capacitive ions. When sodium alginate comes into contact with metal divalent ions such as calcium ions, ion exchange occurs instantaneously so that two molecules of sodium and one molecule of calcium ions are replaced with each other. Therefore, the water-soluble sodium alginate is solidified in the aqueous solution as the calcium ion is substituted and converted into calcium alginate. At this time, it takes about 7 minutes, and by adjusting the reaction time and the concentration of calcium ions according to the characteristics of the product, it is possible to produce pellets having various shapes and emission patterns having a particle size of 100 ~ 1500 ㎛. .

    Hereinafter, the present invention will be described in more detail with reference to Examples.

    However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the examples.

<Example 1>

    250 grams of itraconazole, 100 grams of polyethylene glycol, and 10 grams of sodium lauryl sulfate (SLS) are added to a mixed solvent of 2500 grams of methylene chloride and 1500 grams of ethanol and completely dissolved. The solution was connected to the liquid inlet pipe of the fluidized bed coater and sprayed on the inert particles which were fluidized at an inlet air temperature of 45 ° C., a product temperature of 30 ° C., and an injection pressure of 1.2 bar. Finally, coated pellets were prepared using 50 grams of hydroxypropylmethylcellulose (HPMC) and 7 grams of polyethylene glycol (PEG) (see Table 1).

TABLE 1

<Example 2>

    250 grams of itraconazole, 250 grams of polyethylene glycol, and 10 grams of sodium lauryl sulfate (SLS) are added to a mixed solvent of 2500 grams of methylene chloride and 1500 grams of ethanol and completely dissolved. The solution was connected to the liquid inlet pipe of the fluidized bed coater and sprayed onto the fluidized sugar particles at a device inlet air temperature of 45 ° C, a product temperature of 30 ° C, and an injection pressure of 1.2 bar. It carried out similarly to Example 1 below (refer Table 2).

TABLE 2

Example 3

    The drug, 250 grams of itraconazole, 250 grams of polyethylene glycol, 10 grams of sodium lauryl sulfate (SLS), and 10 grams of succinic acid are added to a mixed solvent of 2500 grams of methylene chloride and 1500 grams of ethanol and completely dissolved. The solution was connected to the liquid inlet pipe of the fluidized bed coater and sprayed onto the fluidized sugar particles at a device inlet air temperature of 45 ° C, a product temperature of 30 ° C, and an injection pressure of 1.2 bar. It carried out similarly to Example 1 below (refer Table 3).

TABLE 3

Example 4

The drug itraconazole and polyethylene glycol solid dispersion were added to a polymer swelling solution in which 8 grams of sodium alginate and 8 grams of HPMC were dissolved, and stirred with a homogenizer for 10 minutes, followed by addition of starch and lactose, followed by stirring for 10 minutes with a homogenizer. To prepare milky emulsion. The mixed solution is sprayed into a 2-4% aqueous calcium chloride (CaCl ₂ ) solution using a nozzle designed while feeding at a constant rate using a Peristaltic pump. After spraying, it is left for about 15 minutes, filtered through 100 mesh sieve, and washed with clean water to remove calcium ions remaining in the pellet. After the water is removed, it is lyophilized to obtain pellets of about 100-1500 μm. Subsequently, the film was coated using a fluidized bed coater to obtain an itraconazole pellet having an increased dissolution rate (see Table 4).

TABLE 4

Example 5

Mix the drug itraconazole and polyethylene glycol solid dispersion with palm oil, add it to the polymer swelling solution containing 8 grams of sodium alginate and 8 grams of HPMC, and stir for 10 minutes with a homogenizer, add starch, lactose and add homo The milky emulsion is prepared by stirring for 10 minutes with a analyzer. The mixed solution is sprayed into a 2-4% aqueous calcium chloride (CaCl ₂ ) solution using a nozzle designed while feeding at a constant rate using a Peristaltic pump. After spraying, it is left for about 15 minutes, filtered through 100 mesh sieve, and washed with clean water to remove calcium ions remaining in the pellet. After the water is removed, it is lyophilized to obtain pellets of about 100-1500 μm. Subsequently, the film was coated using a fluidized bed coater to obtain an itraconazole pellet having an increased dissolution rate. (See Table 5)

TABLE 5

Example 6

The drug itraconazole and polyethylene glycol solid dispersion are mixed with medium-chain fatty acid, and the mixture is added to a polymer swelling solution in which 8 grams of sodium alginate and 8 grams of HPMC are dissolved, followed by stirring for 10 minutes with a homogenizer. The milky emulsion is prepared by stirring for 10 minutes with a niger. The mixed solution is sprayed into a 2-4% aqueous calcium chloride (CaCl ₂ ) solution using a nozzle designed while feeding at a constant rate using a Peristaltic pump. After spraying, it is left for about 15 minutes, filtered through 100 mesh sieve, and washed with clean water to remove calcium ions remaining in the pellet. After the water is removed, it is lyophilized to obtain pellets of about 100-1500 μm. Subsequently, the film was coated using a fluidized bed coater to obtain an itraconazole pellet having an increased dissolution rate (see Table 6).

TABLE 6

Example 7

    The drug itraconazole and polyethylene glycol solid dispersion are mixed with medium-chain fatty acid, and added to a polymer swelling solution containing 8 grams of sodium alginate, 4 grams of HPMC, and 4 grams of chitosan, and stirred with a homogenizer for 10 minutes, followed by addition of starch and lactose. Put it in the mixture and stir for 10 minutes with a homogenizer to prepare a milky emulsion. The mixed solution is sprayed into a 2-4% aqueous solution of calcium chloride using a nozzle designed while feeding at a constant rate using a Peristaltic pump. After spraying, it is left for about 15 minutes, filtered through 100 mesh sieve and washed with clean water to remove calcium ions remaining in the pellet. After the water is removed, it is lyophilized to obtain pellets of about 100-1500 μm. Subsequently, the film was coated using a fluidized bed coater to obtain an itraconazole pellet having an increased dissolution rate (see Table 7).

TABLE 7

Example 8

    The drug itraconazole and polyethylene glycol solid dispersion are mixed with medium-chain fatty acid, and added to a polymer swelling solution containing 8 grams of sodium alginate, 4 grams of PVP, and 4 grams of chitosan, and stirred with a homogenizer for 10 minutes, followed by addition of starch and lactose. Put it in the mixture and stir for 10 minutes with a homogenizer to prepare a milky emulsion. The mixed solution is sprayed into a 2-4% aqueous solution of calcium chloride using a nozzle designed while feeding at a constant rate using a Peristaltic pump. After spraying, it is left for about 15 minutes, filtered through 100 mesh sieve, and washed with clean water to remove calcium ions remaining in the pellet. After the water is removed, it is lyophilized to obtain pellets of about 100-1500 μm. Subsequently, the film was coated using a fluidized bed coater to obtain an itraconazole pellet having an increased dissolution rate (see Table 8).

TABLE 8

Example 9 Preparation Time of Pellets

    The composition of the pellet was carried out in the same manner as in Example 4, and the reaction time in the calcium chloride solution was extended to 30 minutes to increase the strength of the pellet, minimizing the breakage of the pellet during film coating.

Example 10 Preparation Time of Pellets

    The composition of the pellet was carried out in the same manner as in Example 5, and the reaction time in the calcium chloride solution was extended to 30 minutes to increase the strength of the pellet, minimizing the breakage of the pellet during film coating.

Example 11 Preparation Time of Pellets

    The composition of the pellet was carried out in the same manner as in Example 6, the reaction time in the calcium chloride solution was extended to 30 minutes to increase the strength of the pellet, minimizing the breakage of the pellet during film coating.

Example 12 Preparation Time of Pellets

    The composition of the pellet was carried out in the same manner as in Example 7, the reaction time in the calcium chloride solution was extended to 30 minutes to increase the strength of the pellet, minimizing the breakage of the pellet during film coating.

Example 13 Production Time of Pellets

    The composition of the pellet was carried out in the same manner as in Example 8, the reaction time in the calcium chloride solution was extended to 30 minutes to increase the strength of the pellet, minimizing the breakage of the pellet during film coating.

<Comparative Example>

    Dissolve 100 grams of itraconazole, 8 grams of sodium alginate and 8 grams of HPMC, in 600 grams of purified water, add to a solution left overnight, and stir for 10 minutes with a homogenizer. Add 192 grams of starch and 192 grams of lactose. The milky emulsion is prepared by stirring for 10 minutes with a analyzer. The following pellet manufacturing process is performed similarly to Example 1 (refer Table 9).

TABLE 9

Experimental Example 1

    Using the itraconazole pellets prepared as described above was compared and analyzed for each dissolution rate. The dissolution was tested in accordance with the 2nd method of the Korean Pharmacopoeia General Test Method and 900 ml of the first solution (pH1.2) was used as the test solution. The rotational speed of the paddle was 100 rpm, and 5 ml of eluate was taken every time, and the solution filtered through a membrane filter was used as the sample solution. HPLC analysis was performed using HPLC. The mobile phase was mixed with water: ACN: diethylamine in a ratio of 420: 580: 0.005, the flow rate was 1.5ml / min, the column was ODS column (C18), and the UV detector was used. Experiment at 262 nm. The dissolution rate was calculated using the following formula (see Table 10).

                 SPA STW

      Dissolution rate = ------ X ------ X 100

                STA 55.56

      SPA: Peak height of itraconazole in the sample solution

         STA: peak height of itraconazole in the standard solution

         STW: Collection amount of itraconazole standard (mg)

      ※ Preparation of Itraconazole Standard Solution

         Approximately 55.56 mg of itraconazole standard is precisely taken into a 500 ml flask and about 60 ml of methanol is dissolved completely, followed by marking with methanol. Take 5 ml of this solution into a 50 ml volumetric flask and mark it as a mobile phase.

Table 10: Content test results according to stability test of itraconazole pellets

Experimental Example 2

    It is the result of the stability test for the content and dissolution of itraconazole pellet formulation. The stability test was carried out for 6 months under accelerated conditions (40 ° C. RH 75%) and room temperature conditions. The test results are shown in Table 11. The test method was performed in the same manner as in Experiment 1.

 Table 11 Contents Test Results According to Stability Test of Itraconazole Pellets

Itraconazole is a very poorly water-soluble antifungal agent, and its therapeutic effect is very good. However, as the present invention was completed, a more effective and stable nitraconazole-containing preparation was developed, and in the future, when the formulation technology devised in the present invention is used to formulate a similar poorly soluble drug, it is thought that the development of a very useful and excellent formulation is possible.

Claims (18)

1) itraconazole, 2) hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and other cellulose derivatives, poly Vinylpyrrolidone (PVP), cyclodextrin, polymethylmethacrylic acid derivatives, chitin, chitosan and its derivatives, alginic acid and its alkali metal salts, caraginaan gum, tragacanth gum Polysaccharides such as (Tragacanth gum), Agar-agar, Arabic gum, Gua gum, Xanthan gum, Polyvinyl alcohol (PVA), Polyethylene oxide (PEO), Polyethylene 0.5 to 30 parts by weight of one or two or more hydrophilic polymer compounds selected from glycol (PEG), 3) one or more selected from succinic acid, citric acid, adipic acid, lactic acid, taurocholine acid, glycocholine acid, and ascorbic acid 2 or more organic 0.1 to 20 parts by weight, or 0.1 to 30 parts by weight of one or two amino acids in glutamic acid and aspartic acid, 4) dissolved in a mixed solvent of methylene chloride and ethanol as co-solvents, and sprayed with a spray dryer or a fluidized bed coater 5) A method of preparing a pellet formulation containing itraconazole having a size of 100-1500 μm by spraying the spray dried product obtained onto inert spherical particles and adding a formulation forming additive. delete delete delete delete The method of claim 1, wherein the emulsifier to promote dissolution is sodium laurylsulfate, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose and its sodium , Calcium salt, carrageenan, alginic acid and its magnesium, sodium, calcium salt, povidone, polyvinyl alcohol, tragacanth gum, chitosan, Chitin, Tween, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, poly Polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, oleyl alcohol, lecithin, diethanolamine, cholesterol, poloxamer (poloxamer), troll Min (Trolamine), and wax (wax) used alone or in combination of two or more of 0.1 to 40 parts by weight of a mixture selected from the method for producing a pellet formulation.  The method of claim 1, wherein the additive for maintaining the form of the pellets is starch, pregelatinized starch lactose, mannitol, sorbitol, sugar, sucrose, dextrin ( dextrin), carbomer 910, carbomer 934, carbomer 934P, carbomer 940, carbomer 941, carbomer 1342, calcium carbonate, calcium phosphate dibasic, tribasic calcium phosphate Method for preparing a pellet formulation using a mixture of one or two or more selected from phosphate tribasic), calcium sulfate. A pellet preparation containing 5 to 30% by weight of itraconazole prepared according to the method according to any one of claims 1, 6 and 7. 1) itraconazole, 2) hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (Na-CMC), and other cellulose derivatives, poly Vinylpyrrolidone (PVP), cyclodextrin, polymethylmethacrylic acid derivatives, chitin, chitosan and its derivatives, alginic acid and its alkali metal salts, caraginaan gum, tragacanth gum Polysaccharides such as (Tragacanth gum), Agar-agar, Arabic gum, Gua gum, Xanthan gum, Polyvinyl alcohol (PVA), Polyethylene oxide (PEO) 0.5-30 parts by weight of one or two or more hydrophilic polymer compounds selected from polyethylene glycol (PEG), 3) succinic acid, citric acid, adipic acid, lactic acid, taurocholine acid, glycocholine acid, and ascorbic acid Species or two or more organic acids 0.1 to 20 parts by weight, or 0.1 to 30 parts by weight of one or two amino acids in glutamic acid and aspartic acid, 4) dissolved in a mixed solvent of methylene chloride and ethanol as co-solvents, and sprayed with a spray dryer or a fluidized bed coater 5) The obtained spray dried product was obtained by stearyl glycyrrhetinate, tocopheryl acetate, panthenol and phosphatidylcholine; Glyceryl stearate, captylic / capric triglyceride, cetyl octanolate, isopropyl myristate, ceteatyl octanoate ), Butylene glycol dicaptylate / dicaprate, hydrogenated castor oil, mono-glycerides, diglycerides, triglycerides Esters such as these; Plants such as beeswax, canauba wax, olive oil, jojoba oil, hybrid sunflower (Helian thus annuus) oil and the like; Mineral oil, squalene, squalane, monoglyceride, diglyceride, triglyceride, medium chain glyceride, myglyol, cremophor, hydrogenated castor oil, corn oil, soybean oil , One or two or more oils selected from sesame oil, cottonseed oil or fat-soluble vitamins, or linoleic acid, stearic acid, oleic acid, cetyl alcohol, stearyl alcohol And dissolve by mixing 0 to 30 parts by weight of one or two fatty acids from myritic acid, lauric acid or isopropyl mystic acid, and 6) sodium alginate or sodium alginate And a solution of a mixture of the hydrophilic polymer compound and sprayed with aqueous calcium chloride solution through a spraying device to prepare a pellet preparation containing itraconazole having a size of 100-1500 μm. Joe method. delete delete delete delete delete delete 10. The method according to claim 9, wherein sodium laurylsulfate, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), carboxymethyl cellulose and its Sodium, calcium salt, carrageenan, alginic acid and its magnesium, sodium, calcium salt, povidone, polyvinyl alcohol, tragacanth gum, chitosan Chitin, tween, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, Polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, oleyl alcohol, lecithin, diethanolamine, cholesterol, poloxol Poloxamer ), A method for producing a pellet formulation by using a mixture of 0.1 to 40 parts by weight of one or two or more selected from trolamine, wax. 10. The method of claim 9, wherein the additive for maintaining the form of the pellets is starch, pregelatinized starch lactose, mannitol, sorbitol, sugar, sucrose, dextrin ( dextrin, carbomer 910, carbomer 934, carbomer 934P, carbomer 940, carbomer 941, carbomer 1342, calcium carbonate, dibasic calcium phosphate dibasic, tribasic calcium phosphate Method for preparing a pellet formulation using a mixture of one or two or more selected from phosphate tribasic, calcium sulfate. A pellet preparation containing 5-30% by weight of itraconazole prepared according to the method according to any one of claims 9, 16 and 17.