KR100694667B1 - Antifungal compositions containing itraconazole with both improved bioavailability and narrow intra- and inter-individual variation of its absorption - Google Patents

Abstract

The present invention spray-dried itraconazole together with a water-soluble polymer and a solubilizer to increase the solubility of itraconazole in water and to exhibit almost uniform solubility under a wide range of acidic conditions. The present invention dissolves a variety of water-soluble polymers and solubilizers together with itraconazole in a suitable solvent system, and then spray-dried by adding pharmaceutically added excipients, salts, sugars, lubricants, etc. to show optimum solubility and to formulate pharmaceuticals simultaneously. It is composed of a method for producing the spray drying which is most efficient for the purpose. In addition to improving the in vivo absorption of itraconazole through the present invention, by removing the difference in intrinsic pH in the individual or between the individual gastric and bioavailability of the itraconazole according to food intake, it is useful to normal or hypoxic adults or AIDS patients. In addition, absorption variation by the administration time of the drug after ingestion of food can be minimized. In addition, by adopting a spray drying, which is a single process, it is possible to easily control the physical properties of the drug-containing particles and improve economics and productivity.

Itraconazole, Spray Drying

Description

Antifungal compositions containing itraconazole with both improved bioavailability and narrow intra- and inter-individual variation of its absorption}

The present invention relates to an itraconazole-containing antifungal agent and a method for preparing the same, which have an improved solubility in water and a significant difference in solubility according to pH. The present invention relates to a non-aqueous drug, itraconazole, by spray-drying with a polymer and a solubilizing agent. In addition to converting the crystal structure of the amorphous to the physical properties of the particles more hydrophilic and the solubilizer used to increase the solubilization and wetting of the drug itself. In addition, the particle size can be prepared in several micrometers by spray drying, and in this process, there is no interaction between particles, which can convert the particle properties to hydrophobicity or reduce the specific surface area. I will say. Most importantly, the solubilization of the itraconazole itself in the final spray drying and the solubilizing agent used to demonstrate the solubility of the drug result in almost uniform solubility values even at pH fluctuations that may occur in vivo, thus maximizing the absorption of the drug in vivo. The biggest feature is that it can minimize the absorption variation.

The antifungal agent itraconazole used in the present invention is a very insoluble drug in water and, despite its excellent effect, requires careful technique in formulating for in vivo administration. Itraconazole has been known to have higher solubility in aqueous solutions with lower pH, but in fact, it has a solubility of less than 1 µg / ml even under strong acidic conditions (eg pH 1.2). At least 100L is required, which means that it is no longer possible to apply in vivo, and consequently the absorption is reduced by the administration. In addition, even if the drug is poorly soluble in water, even if the formulation is designed to facilitate bioabsorption, the variation in the degree and tendency of absorption among individuals or in many cases is very severe. This may be especially true for itraconazole, which exhibits a certain degree of solubility only in the stomach, which is a strong acidic condition. The most influential factors affecting absorption deviations are intragastric pH and gastric emptying time. As is widely known, pH fluctuations in the gastrointestinal tract exist within the same individual, and in particular, the intrinsic pH fluctuations in the stomach are known to be very severe and have a pH range of 1 to 3.5. Another factor in the rate of gastric emptying also differs even in individuals, with oral tablets usually taken from fasted conditions reported as short as 10 minutes to as long as 2 hours or more. have. Therefore, in order to facilitate the absorption of itraconazole, pH in the stomach should be maintained to be strong acidity, and it is best to increase the gastric emptying time. Indeed, the administration of itraconazole-containing formulations commercially available in the fed state increased their absorption more than twofold, which is believed to be due to increased gastric acid secretion and decreased gastric emptying rate. . (Influence of concomitant food intake on the oral absorption of two triazole antifungal agents, itraconazole and fluconazole, Eur J Clin Pharmacol , 1994, 46, p147; The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects, Eur J Clin Pharmacol , 1989, 36, p.423) These results show the shortcomings of existing formulations, i.e., adopting multiple-unit dosage forms to extend the rate of gastric emptying or to reduce deviations. At the same time, even though the hydrophilic polymer was used to coat the drug on sugar spheres to increase the solubility of the drug, the difference in drug absorption due to food intake was very large. This suggests that in order to solve this problem, it is necessary to overcome the differences in gastric pH and gastric emptying time even within individuals.

Apart from the above, there have been studies to improve the solubility of itraconazole in water to promote the absorption in the body, and in fact, it has been reported that the cyclodextrin clathrate compound of itraconazole increased the solubility in water and increased the bioavailability. It became. (WO 85/02767, US-4,764,604) In addition, bead formulations using water-soluble polymers (WO 94/05263, KR 95-702826), inclusion compounds using cyclodextrins (WO 95/08993) have been developed for oral use, and liposomes have been developed. Topical formulations used (WO 93/15719) have been proposed. Recently, the method of increasing the solubility of itraconazole using spray drying method (WO 98/57967, KR 99-1564) or increasing the bioavailability by forming molten (extruded) water with a water-soluble polymer (WO 97 / 44014).

However, the techniques for improving the solubility of itraconazole in water as described above have been a problem that the solubility of the itraconazole itself drops sharply even if the pH is slightly increased. In particular, even in the vicinity of pH 2, even 1 μg / ml does not dissolve, which may be a bigger problem in that the normal pH range of humans is about 1 to 3.5, and about 16% of adults have a gastrointestinal pH of 3 or more. In the confirmed findings, the problem is more serious. (The design and evaluation of controlled release systems for the gastro-intestinal tract-In: Advances in drug delivery systems, JM Anderson and SW Kim eds., Elsevier, Amsterdam, 1986, p27-38; Comportement pharmacocinetigue des spheroides: apport et interet en clinique -.. Proceed Symp Capsugel , Paris, 1987, pp.73-81) in general, for those who have gastric acid secretion is not enough known to the absorption of ketoconazole and itraconazole very difficult and actually facilitate gastric acid secretion case of AIDS patients It has been reported that the absorption of itraconazole is only 50% of normal people. (The pharmacokinetics of oral itraconazole in AIDS patients, J Pharm Pharmacol , 44, 1992, p 618)

Therefore, there is an urgent need for a formulation that can overcome the differences in absorption of this traconazole due to gastrointestinal physiological differences in or between individuals.

On the other hand, the spray drying method is a method that has been widely used in pharmaceutical or other manufacturing, in that it can solidify the substance content in the liquid form 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, which can volatilize the solvent in a short time. Even under high temperature conditions, the exposure time is less than 1 second, so it does not affect the physical properties of drugs and other excipients. Do not. In addition, this method has the advantage of not only minimizing the flowability of particles and the interaction between particles, but also requiring no additional process such as crushing or granulating the particles after manufacture. Compared to the melting (extrusion) method (WO 97/44014), which is a manufacturing method of a commercially available product, this method is an advanced method not only in terms of particle properties but also in terms of processes. 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㎛, whereas the final particles of the melt (extrusion) method is 600㎛ or less It shows the size and the distribution range of the particles is also very wide, it is difficult to obtain uniform particles. This is generally a problem that can be highlighted in view of the dissolution of the drug in proportion 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, independent of their size, to reduce wettability and to remove them from the subsequent manufacturing process. The hassle of being can also be considered a problem.

In the process of obtaining the itraconazole spray dried product using the advantages of the spray drying method, a method of using a pH-dependent polymer, that is, a polymer dissolved at a pH of 5 or less has been developed. (WO9933467A1) However, in the case of pH-dependent polymers used in this technique, even when acidic conditions, if the pH is slightly moved toward neutral, not only the solubility of the itraconazole itself but also the solubility of the polymer itself decreases rapidly, From the scope, it can be said that it is difficult to ensure the solubility of the drug sufficient for absorption.

The present invention relates to improving the absorption in vivo by spray-drying itraconazole with a water-soluble polymer and a solubilizing agent, which is not easily absorbed in vivo due to its low solubility in water, and in particular, in particular in the stomach of a normal person The purpose of the present invention is to provide a property capable of minimizing the difference in itraconazole absorption by minimizing the difference in solubility caused by pH variation. In addition, it is to provide the most efficient manufacturing method for producing a composition that can satisfy these properties.

When itraconazole is spray dried, the water-soluble polymer and the solubilizer are dissolved in a suitable solvent at a ratio of 10 to 1000% and 0.1 to 100%, respectively, and then spray-dried by adding an appropriate additive to improve the characteristics of the spray dried product. Get the final product.

The water-soluble polymer used at this time is used in combination with one or the following.

Cellulose derivative

Yes. Methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose, etc.

Polyvinyl alcohol

Polyvinylacetate

Polyvinylpyrrolidone or polymer comprising the same

Polyalkene oxide or polyalkeneglycol and polymer comprising the same

By using the above-listed polymers alone or in combination, it is possible not only to amorphize the itraconazole, but also to convert the drug molecule or particles around into hydrophilic. However, in order to overcome the difference in solubility in the intrinsic pH fluctuation range of the stomach, the value of the solubility itself is lower than expected, and it is necessary to increase the polymer to improve it. Correlation with solubility should be established when the polymer is increased, but the solubility of the present drug does not increase the solubility anymore when the polymer is contained to a certain degree, and it is not easy to formulate. In other words, due to the increase in the polymer content, the overall hardness of the formulation was increased, and when exposed to the eluent, the polymer swelled excessively to form a membrane around the formulation. Therefore, it was necessary to select a polymer content of a degree that is not difficult to formulate.

The biggest feature of the above formulation design is to surround the itraconazole molecule with a water-soluble polymer and to reduce the crystallinity and hydrophilicity of the itraconazole. However, the difference in solubility in the gastric intrinsic pH range (pH 1 ~ 3.5) is very large in the spray dried product thus prepared, which is inadequate to reduce the deviation of drug absorption. These findings can be attributed to the fact that the spray drying still contains itraconazole intrinsic crystallinity, i.e., when a drug coexists in crystalline and amorphous form, the maximum solubility and maximum dissolution rate of the drug is generally amorphous. It is largely dominated by this share. (The effects of disordered structure on the solubility and dissolution rates of some hydrophilic, sparingly soluble drugs, Int J Pharm 177, 1999, p 29) In addition, since the limit is bound to be reached, if the solubility is to be maximized, the physical properties of the crystalline drug must be changed.

To this end, in the present invention, a surfactant and an amphophile, which are generally widely used for the purpose of solvolyzing a crystalline drug, are added. Surfactants and affinity materials used were as follows.

Anionic surfactant

Docusate Sodium Chloride,

Sodium Lauryl Sulfate, etc.

Cationic surfactant

Benzalkonium Chloride

Benzethonium Chloride

Cetrimide, etc.

Nonionic surfactant

Glyceryl Monooleate

Polyoxyethylene Sorbitan Fatty Acid Esters,

Sorbitan esters, etc.

Positive Affinity Polymer

Polyethylene-Polypropylene Polymers and Polyoxyethylene-Polyoxypropylene Polymers (Poloxamers)

Etc

Gelucire ^TM

Monocaprylic Acid Glycol Monocaprylate

      (Propylene Glycol Monocaprylate)

Oleoyl Macrogol-6 Glyceride

Linoleoyl Macrogol-6-Glyceride

Caprylocaproyl macrogol-8 Glyceride

Propylene Glycol Monolaurate

Polyglyceryl-6 Dioleate, etc.

The addition of these substances is known to enable solubilization with improved wettability of poorly soluble materials, and has been reported to mainly promote solubilization rather than to improve wettability. Therefore, the addition of these materials can promote the solubilization of amorphous and crystalline itraconazole. Of these, cationic surfactants and poloxamers showed the best results, with the addition of these two substances being 1.1 to 3 times higher at pH 1.6 and 2.5 to 12 times higher at pH 2.4 than before addition. Improvements could reduce the solubility ratio (pH 1.6 / pH 2.4) between the two pHs up to 1.4. This figure was markedly reduced in view of the fact that the solubility ratio between the two pHs of the already available Sporanox ^TM capsules was 5.3, which was due to the intrinsic and intragastric intrinsic pH fluctuations, as well as the food and food intake time difference after ingestion. It can be said that the variation in the bioavailability of itraconazole can be greatly alleviated.

On the other hand, the addition of these materials to the itraconazole alone before spray drying showed a slightly synergistic effect, but very low compared to the case of applying to the spray drying. This is considered to be because the solvation effect of the added substance is difficult to lower the crystallization energy of the itraconazole drug itself. Therefore, the solubility synergistic effect by the addition of such an affinity substance should be accompanied by a method that can basically lose the crystallinity of itraconazole itself.

On the other hand, when spray-drying the above water-soluble polymers and surfactants or affinity materials with itraconazole is necessary to study to have the most suitable conditions for spray drying conditions. That is, the viscosity and solids content of the spray drying solution, the appearance and flowability of the spray drying, the particle size and particle size distribution of the spray drying should be taken into consideration. Also, when the final spray drying is formulated with tablets or capsules, disintegration and dissolution of the preparation itself, etc. It should have physical properties to satisfy the pharmaceutical properties of. Above all, it is important to ensure that the final spray dryer meets the above mentioned conditions while at the same time ensuring that the spray drying inherent properties are not lost during the formulation process. In other words, even spray dried products that exhibit the highest solubility can be said to be very difficult to actualize if they have the pharmaceutical properties that can inhibit absorption when formulated and administered to a living body. Therefore, the present patent is to propose a method for optimizing the spray drying conditions and other conditions to increase the solubility of itraconazole and at the same time have a pharmaceutically acceptable properties.

In spray drying, the properties of the spray drying are greatly influenced by the air injection temperature and discharge temperature, the injection speed and spray pressure of the spray liquid. The injection temperature should be set within a range that does not cause any physical or chemical changes to the itraconazole and the polymers and solubilizers used. The injection speed and injection pressure of the spray solution should be taken into consideration in consideration of the drying capacity of the spray dryer. In particular, the exhaust temperature is most closely related to the optimization of the whole process and needs to be carefully controlled. After optimizing the above factors in detail and spray drying, the average particle size of the spray dried product could be prepared in the size of several tens of nm to several tens of micrometers. The higher the spray pressure, the lower the solids content of the spray drying solution, the smaller the particle size of the spray dried product. The higher the intake and exhaust temperatures, the higher the fluidity of the particles, but the higher the bulk density. . In addition, in general, the dissolution rate or solubility is increased due to the increase of specific surface area as the particle size decreases. However, in this study, the spray-drying material containing a large amount of fine particles of several nm is caused by the agglomeration or aggregation between particles. Rather, the solubility was lowered.

Hereinafter will be described in more detail the configuration of the present invention through the preferred embodiment of the present invention. These examples are only for illustrating the present invention in more detail, and the scope of the present invention is not limited by these examples, and various modifications are possible within the spirit and scope of the present invention.

Example 1:

Composition ratio of spray drying liquid

Furtherance A B C D E F G H ingredient amount Itraconazole 100 100 100 100 100 100 100 100 Methyl Cellulose 100 Hydroxypropyl Methyl Cellulose 100 150 Polyvinylpyrrolidone 100 Polyvinyl alcohol 100 Polyvinylacetate 100 Polyethylene Oxide 100 Hydroxypropyl cellulose 100

Itraconazole and the polymer combination are dissolved in a suitable single or mixed solvent system such as dichloromethane, chloroform, ethanol and methanol, and then salts such as sodium chloride, sugars such as white sugar and lactose or microcrystalline cellulose, calcium dihydrogen phosphate, starch and mannitol. Excipients were added from 0 to 100% compared to itraconazole, and then lubricants such as magnesium stearate, talc, and glyceryl behenate were added to 0 to 50% compared to itraconazole, and then dispersed well to obtain a spray drying solution.

Example 2:

Optimization of Spray Drying Conditions

Spray Dry Liquid Injection 40 to 700ml / min Spray Drying Pressure 0.5 to 7㎏ / ㎠ Spray Dry Intake Temperature 90 to 250 ℃ Spray Dry Exhaust Temperature 40 to 150 ℃ Solid content of spray drying liquid 0.5 to 20.0%

The various conditions were appropriately changed to optimize the spray drying conditions.

Example 3:

Effect of Solubilizer Added in Spray Drying 1

Based on the composition B of Example 1, it was intended to evaluate the effect on the solubility of itraconazole by adding various surfactants and affinity substances.

Furtherance Solubilizer I Sodium Lauryl Sulfate J Benzalkonium Chloride K Polyoxyethylene Sorbitan Fatty Acid Ester L Sorbitan Ester M Poloxamer N Gelucire ^TM O Propylene Glycol Monolaurate

Example 4:

Effect of Solubilizer Added during Spray Drying 2

Among the materials used in Example 3, sodium lauryl sulfate and poloxamer were evaluated for the effect on the solubility of itraconazole when the ratio was changed. Based on composition B of Example 1 and for the additives the relative amounts to itraconazole are indicated.

Furtherance additive Sodium Lauryl Sulfate Poloxamer P 3% Q 7% R 10% S 20% T 3% U 7% V 10% W 20%

Example 5:

Solubility of Spray Dry

* In case of Eudragit ^TM E, spray drying was performed by adding 150% of itraconazole.

As shown in the above results, solubility was significantly increased compared to itraconazole alone (1 μg / ml or less), and cellulose derivatives showed more improved results than other polymers. That is, the solubility of itraconazole itself was not only higher than that of other polymers in the two pH ranges, but also the solubility difference between both pHs was significantly reduced.

The solubility of solubilization and wettability in the composition I to O added surfactants and affinity substances showed a sharp increase in solubility compared to composition B. Particularly, pH 2.4 to 2.5 to 7 times of itraconazole Solubility increased. From this, it can be seen that the solubilizer used has a better effect as the pH is moved to a relatively high region, and consequently, it can supplement the intrinsic pH fluctuations in the stomach of a normal adult.

In addition, the solubilization of sodium lauryl sulfate and poloxamer, which were the most effective solubilizers, was gradually increased, but the solubility of itraconazole increased up to a certain amount. It has been shown that it is necessary to adjust the amount of solubilizer appropriately. It should be noted that, for Composition U, an increase of about 3 times at pH 1.4 and about 12 times at pH 2.4 increased the role of the solubilizer in the relatively high pH region, as already mentioned. have.

On the other hand, even when using Eudragit ^TM E, a pH-dependent polymer used in the existing patent, the solubility was reduced to about a quarter compared to pH 1.6, even if the pH was increased to 2.4, as expected. In addition, it is still insufficient to overcome the variation caused by intrinsic pH variation between individuals. Also, in the case of commercially available Sporanox ^™ tablets and capsules, the solubility difference between the two pHs is more than two times, especially in the case of capsules. By showing the difference, it is reflected that the difference in absorption of itraconazole in and between individuals.

Example 6:

Elution of Spray Dried

The dissolution test was performed in the spray dried product by selecting an appropriate excipient to prevent disintegration, and the dissolution rate was over 90% after 30 minutes in the total composition.

Example 7:

Relative Bioavailability Assessment of Itraconazole-Containing Spray Dry 1

To evaluate the relative bioavailability in fasted state using Composition U as a comparative formulation, commercially available Sporanox ^™ capsules were compared to 10 healthy adults. Each group was administered in a cross-over assay using a formulation containing 100 mg as itraconazole for Sporanox ^™ capsules and 50 mg as itraconazole for composition U. Got it.

Hours (hr) Blood concentration (ng / ml) Composition U (50 mg as itraconazole) Seuporanokseu ^TM capsule (100㎎ as itraconazole) 0.5 33 (36) * 11 (17) One 91 (81) 42 (63) 2 91 (42) 82 (83) 3 81 (40) 101 (83) 4 68 (32) 98 (66) 5 46 (21) 78 (51) 6 40 (18) 65 (45) 8 33 (19) 53 (38) Average Cmax 114 (67) 109 (83) Average AUC 521 (242) 547 (426)

       * () Is the standard deviation

As shown in the above results, Composition U containing 50 mg of itraconazole and Spiranox ^TM capsules containing 100 mg of itraconazole, prepared based on patent WO 94/05263, were used for the area under the curve (AUC) and Cmax (maximum blood Almost identical values in concentrations) indicate that the current composition can be lowered in half compared to the comparative formulation. In particular, it can be seen that the individual deviation is significantly lower than that of the comparative preparation, which, as mentioned above, minimizes the difference in solubility between the pH of itraconazole, thereby reducing the difference in absorption of the drug due to the intrinsic pH variation in the individual and between the stomach. It could be said that it was possible.

Example 8:

Relative Bioavailability Assessment of Itraconazole-Containing Spray Dryings 2

To evaluate the relative bioavailability in fasted state using Composition U using commercially available Sporanox tablets as a comparative formulation in 10 healthy adults. In each group, Sporanox ^™ tablets and Composition U corresponding to 100 mg as itraconazole were administered and tested in a cross-over assay to obtain the following blood levels.

Hours (hr) Blood concentration (ng / ml) Fasted state Composition U Seuporanokseu ^TM tablets 0.5 16 (6) 20 (16) One 60 (35) 41 (27) 2 174 (71) 56 (21) 3 174 (40) 74 (34) 4 147 (29) 84 (36) 5 115 (27) 68 (35) 6 92 (27) 64 (35) 8 80 (26) 46 (25) Average Cmax 193 (50) 90 (34) Average AUC 880 (247) 466 (194)

As shown in the results, the composition U containing 100 mg of itraconazole shows about 2 times the bioavailability improvement effect in the fasted state compared to the Sporanox ^™ tablet containing the same amount of itraconazole. This is the current composition U containing the view point, itraconazole 100㎎ light of the existing patent (WO 97/44014) that the information in the fasting state seuporanokseu ^TM tablet seuporanokseu ^TM capsules vivo use rate is doubling compared to seuporanokseu ^TM tablets Of course, it shows an excellent effect compared to the commercially available Sporanox ^™ capsules.

The present invention is meaningful to provide a method of spray-drying poorly soluble itraconazole in water simultaneously with a water-soluble polymer and a solubilizer to further improve the solubility of the itraconazole and consequently to improve absorption in the body. More specifically, it may be useful not only to normal people but also to adults or AIDS patients who show hypoacidity by eliminating the difference in the intrinsic pH of the stomach and the intake of itraconazole according to food intake. Absorption variation with time can also be minimized. In addition, spray drying, which is a single process, is used to facilitate industrialization and to control the particle properties of the drug to meet the best requirements for biological applications.

Claims (9)

Cellulose derivatives selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose and hydroxypropyl cellulose; Polyvinyl alcohol; Polyvinylpyrrolidone or a polymer comprising the same; Polyvinylacetate; And one water-soluble polymer selected from the group consisting of polyalkene oxides and sodium lauryl sulfate as an anionic surfactant; Benzalkonium chloride which is a cationic surfactant; Polyoxyethylene sorbitan fatty acid esters or sorbitan esters which are nonionic surfactants; Polyethylene-polypropylene polymers and polyoxyethylene-polyoxypropylene polymers (poloxamers) which are positive affinity polymers; Gelassier monocaprylic acid glycol monocaprylate or oleoyl macrogol-6-glycerides; And spray drying with one solubilizer selected from the group consisting of monolauric acid propylene glycol. delete delete 2. The itraconazole-containing composition according to claim 1, wherein the water-soluble polymer has a content in the range of 10 to 1000% of the itraconazole. 2. The itraconazole-containing composition according to claim 1, wherein the solubilizer has a content in the range of 0.1 to 100% of the content of itraconazole. Salts such as sodium chloride according to claim 1; Sugars such as white sugar and lactose; Excipients such as microcrystalline cellulose, calcium dihydrogen phosphate, starch and mannitol; And one selected from the group consisting of lubricants such as magnesium stearate, talc, glyceryl behenate, and the like. The method of claim 1, wherein the spray drying conditions      Spray drying liquid injection amount: 40 ~ 700ml / min,      Spray Drying Pressure: 0.5 ~ 7㎏ / ㎠,      Spray drying intake temperature: 90-250 degreeC,      Spray drying exhaust temperature: 40-150 degreeC,      Solid content of the spray drying liquid: 0.5 to 20.0% Itraconazole-containing composition, characterized in that it was prepared as. The itraconazole-containing composition of claim 1, wherein the spray dried particles have a size from 10 nm to 1000 μm. The itraconazole-containing composition of claim 1 is formulated into a formulation selected from the group consisting of tablets, tablets, hard capsules, soft capsules, suspensions, suspension syrups, dry syrups, pastas, external solutions and sprays. Pharmaceutical preparations.