JP2007505103A - Itraconazole oral composition not affected by ingested food and drink and method for producing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral composition of itraconazole which has an excellent bioavailability of itraconazole and is hardly affected by ingested food and drink.
A viscous glassy composition for oral administration comprising itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and an oil.
[Selection] Figure 1

Description

  The present invention relates to an oral composition for itraconazole, which has an excellent bioavailability of itraconazole and is not affected by the intake of food and drink, and a method for producing the same.

  Itraconazole, a triazole compound, is known to have excellent antifungal activity. However, since itraconazole has a very low solubility in water of less than 1 μg / ml and a pKa value of 3.7, it exists without being ionized in gastric juice, and therefore has a very low bioavailability when administered orally. In addition, it is known that the bioavailability of itraconazole administered orally varies greatly from individual to individual, and is greatly influenced by other factors such as ingested food and drink.

  PCT International Publication No. WO 85/02767 and US Pat. No. 4,764,604 disclose methods of increasing the solubility of itraconazole using cyclodextrin compounds containing itraconazole. However, this method has the problem that it only slightly increases the solubility of itraconazole and requires a complicated manufacturing process.

  PCT International Publication No. WO 94/05263 coats a core consisting of pharmaceutically inert or neutral sucrose, dextrin, starch, etc. with a mixture of itraconazole and a hydrophilic polymer, and further on top of polyethylene glycol. Such polymer coated bead formulations are disclosed. Such coated bead formulations are marketed by Janssen Pharmaceutica (Beerse, Belgium) under the product name Sporanox® capsules. However, the manufacturing process is very complicated because the beads having an average size of 600-700 μm tend to aggregate during the manufacturing process. In addition, the bioavailability of itraconazole of this preparation varies greatly depending on whether the preparation is taken before eating or drinking or after eating or drinking.

  PCT International Publication No. WO 97/44014 describes a solid dispersion of itraconazole in a water soluble polymer produced by melt-extrusion of a mixture of itraconazole and a water soluble polymer at a temperature of 245-265 ° C. Discloses the solid dispersion. This solid dispersion is a formulation that is not affected by ingested foods and beverages, and has been described as exhibiting excellent itraconazole bioavailability, and is named Janssen Pharma under the product name Sporanox® tablets. Marketed by Sutika. However, the manufacturing process of this solid dispersion has a problem that it is difficult to adjust various process variables, and the bioavailability of itraconazole that can be achieved by the dispersion is still low.

  In addition, Sporanox solution with a pH of 2 (Jansen Pharmastica) produced by mixing itraconazole-containing hydroxypropyl-beta-cyclodextrin compound, hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin and sorbitol It also shows a high bioavailability of itraconazole even when taken on the skin, but since the concentration of itraconazole in the preparation is as low as 10 mg / ml, it must be taken in large amounts, and the active ingredient precipitates quickly when in contact with intestinal fluid Has the problem of being effective only against fungal infections of the esophagus.

  Recently, PCT International Publication No. WO 98/55148 discloses a highly viscous composition comprising a poorly water soluble drug, cyclodextrin, a water soluble acid and a water soluble organic polymer. However, since this composition has a high viscosity, a large amount of dispersant must be used during the capsule manufacturing process in order to reduce the viscosity. The composition also exhibits a very low elution rate of less than 1% under neutral or alkaline conditions at pH 6.8 or higher.

In this regard, the present inventors considered in Korean Patent Application No. 2000-83717, considering a pre-concentrated liquid of a microemulsion containing a poorly water-soluble antifungal agent, phosphoric acid, a co-surfactant, a surfactant and an oil. In addition, another microemulsion composition obtained by modifying the preconcentrated liquid has been disclosed in Korean Patent Application No. 2001-36930. However, these compositions still exhibit unsatisfactory itraconazole elution rates under neutral or alkaline conditions at pH 6.8 and above, and the bioavailability of these itraconazoles varies somewhat with food and beverage intake.
PCT International Publication No. WO85 / 02767 U.S. Pat. No. 4,764,604 PCT International Publication No. WO94 / 05263 PCT International Publication No. WO 97/44014 PCT International Publication No. WO 98/55148 Korean Patent Application No. 2000-83717 Korean Patent Application No. 2001-36930

  Therefore, the main object of the present invention is to provide an oral composition of itraconazole that has an excellent itraconazole bioavailability and is hardly affected by the food or drink taken. Another object of the present invention is to provide a method for producing the oral composition.

  In order to achieve the above object, the present invention provides a viscous glassy composition for oral administration comprising itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and an oil.

  In order to achieve the other object, the present invention comprises (a) homogeneously dissolving itraconazole in a mixture of an acidifying agent, an amphiphilic additive and a volatile solvent, and (b) a surfactant and There is provided a method for producing the composition comprising the steps of dissolving oil, and (c) removing a volatile solvent with the mixture.

  The composition for oral administration of itraconazole of the present invention has excellent itraconazole bioavailability and is not affected by food or beverage intake.

A composition of the present invention comprising itraconazole as an active ingredient can be prepared using the following ingredients:
(1) Acidifying agents Representative examples of acidifying agents that can be used to dissolve itraconazole in the present invention include phosphoric acid, acetic acid, hydrochloric acid, nitric acid, sulfuric acid, citric acid, fumaric acid, maleic acid, and these. Of these, 85% phosphoric acid or a diluted solution thereof is preferable.

(2) Amphiphilic additive The amphiphilic additive used in the present invention assists in the dissolution of itraconazole and assists in adjusting the viscosity of the composition to an appropriate level for filling into capsules. Suitable amphiphilic additives for use in the present invention include transcutol (diethylene glycol monoethyl ether, Gattefosse), dimethyl isosorbide (1,4: 3,6-dianhydro-2,5-dimethyl-D-glucitol). , Glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether), propylene glycol (1,2-dihydroxypropane), propylene carbonate (4-methyl-2-oxo-1,3-dioxolane), saltol (macrogol 15 hydroxystearate) , BASF) and mixtures thereof, among which transcutol is preferred.

(3) Volatile solvents Volatile solvents that are used during the manufacturing process but are not present in the final product assist the dissolution of itraconazole by the acidifying agent. In the present invention, non-toxic organic solvents such as alcohols such as ethanol, propanol and isopropanol, which can be easily volatilized at a temperature below 100 ° C., are preferably used as such volatile solvents.

(4) Surfactant The surfactant used in the present invention assists in forming a uniform emulsion of oil and hydrophilic components, and imparts storage stability to the emulsion. Representative examples of such surfactants are as follows:
(i) Polyoxyethylene glycolated natural or hydrogenated vegetable oil, for example, polyoxyethylene glycolated natural or hydrogenated castor oil (product name: Cremophor (registered trademark) ( Cremophor (registered trademark), BASF), HCO (registered trademark) (Nikkol)),
(ii) the fatty acid is mono- or tri-lauric acid, palmitic acid, stearic acid or oleic acid, polyoxyethylene-sorbitan-fatty acid esters (product name: Tween® (Tween®, ICI)), and
(iii) Polyoxyethylene fatty acid esters, for example, polyoxyethylene stearates (product name: Myrj, ICI).

(5) Oil The oil component used in the present invention must be easily mixed with a surfactant to form a stable microemulsion in an aqueous medium. Such oils may be pharmaceutically acceptable oils such as tocopherol and derivatives thereof (eg, tocopheryl acetate, tocopheryl succinate and polyethylene glycol-1000-tocopheryl succinate (TPGS)).

  The composition of the present invention comprises (a) itraconazole dissolved in a mixture of acidifying agent, amphiphilic additive and volatile solvent, and (b) after dissolving the surfactant and oil in this solution, (C) A volatile solvent is removed from the resulting mixture to produce.

  In the step (c), the volatile solvent can be removed by a usual method. For example, it can be removed by heating to a temperature of 40 to 100 ° C., more preferably 40 to 80 ° C. under normal pressure or reduced pressure. .

  In the manufacturing process, itraconazole, acidifying agent, amphiphilic additive, volatile solvent, surfactant and oil are 1: 0.5 to 15: 0.5 to 20: 0.5 to 20: 0.5. -15: 0.5-15, preferably in an amount corresponding to a weight ratio of 1: 1 to 10: 1 to 15: 1 to 15: 1 to 10: 1 to 10.

  The final composition of the present invention from which volatile solvents have been removed comprises itraconazole, acidifying agent, amphiphilic additive, surfactant and oil from 1: 0.5 to 15: 0.5 to 20: 0.5. -15: 0.5-15, preferably in a weight ratio of 1: 1 to 10: 1 to 15: 1 to 10: 1 to 10.

  The compositions of the present invention may also contain pharmaceutically acceptable additives for oral administration such as antioxidants.

  The pharmaceutical composition of the present invention can be formulated into various pharmaceutical preparations such as powders, granules, tablets, coating preparations and liquid preparations by conventional methods. For example, active capsules and other pharmaceutical additives can be added to the pharmaceutical composition, the mixture can be processed into powder or granules, and then the powder or granules can be filled into hard gelatin capsules to produce hard capsules. In addition, after adding appropriate additives to the pharmaceutical composition, the mixture is compressed into tablets, the pharmaceutical composition is dissolved in water to form a liquid preparation, and the pharmaceutical composition solution is non-pareil (registered trademark) Each coated formulation can be manufactured by coating sugar beads such as (Non-pareil® (Edward Mendell Co., UK)).

  The produced itraconazole composition of the present invention is transparent and non-flowable glassy, and has a high viscosity of 10,000 cps or more at 25 ° C. This can be achieved by the mixing action of the amphiphilic additive and volatile solvent used in the method of the present invention. Such a high viscosity glassy composition is less bulky than existing microemulsion compositions.

The composition of the present invention has a self-microemulsifying capability that forms microemulsion particles that are very stable and highly available in body fluids upon oral administration. Therefore, since the composition of the present invention can maintain a stable and high itraconazole elution rate even under neutral or alkaline conditions at pH 6.8 or higher, the bioavailability of this itraconazole is hardly affected by the ingested food and drink. The bioavailability before and after a meal is the same. That is, the ratio (AUC _{before meal} / _after AUC _meal ) of the area (AUC) under the itraconazole blood concentration curve before and after _meal is close to 1, preferably 0.8 or more.

〔Example〕
The following examples serve to illustrate the invention in more detail and do not limit the scope of the invention.

  Also, the percentages given below for solids in liquid mixtures, liquids in liquids, and solids in liquids are based on weight / weight, volume / volume and weight / volume, respectively, unless otherwise stated. It is.

: Manufacture of hard capsules-1)
Hard capsules were made using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 208
Ethanol 300 ^*
Transcutor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70
Cremophor (registered trademark) EL 220
dl-α-tocopherol 60
( ^* : Not included in the final composition)
Itraconazole was uniformly dissolved in a mixture of 85% phosphoric acid, transcutol and ethanol, and then other components were added thereto and dissolved. Subsequently, this mixture was heated and concentrated at 55 ° C. for 4 hours to volatilize ethanol to obtain a highly viscous transparent composition having no fluidity. This composition was filled into a hard capsule by the usual method described in the general preparation general rules of Korean medicine.

: Manufacture of soft capsules Soft capsules were manufactured using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 150
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 80
Cremophor (registered trademark) EL 200
dl-α-tocopherol 60
( ^* : Not included in the final composition)
Using the above components, the same procedure as in Example 1 was carried out to obtain a highly viscous transparent composition having no fluidity. This composition was filled into a soft capsule by a conventional method described in the general preparation general rules of Korean medicine.

: Manufacture of hard capsules-2)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 200
Cremophor (registered trademark) EL 80
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Production of hard capsules-3)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 200
Tween (registered trademark) 20 80
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Manufacture of hard capsules-4)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 150
Cremophor® EL 150
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Manufacture of hard capsules-5)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 83
Tween (registered trademark) 20 200
Cremophor (registered trademark) EL 80
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Manufacture of hard capsules-6)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 83
Tween (registered trademark) 20 150
Cremophor® EL 150
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Manufacture of hard capsules-7)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 200
Ethanol 300 ^*
Transcutor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 200
Cremophor (registered trademark) EL 80
dl-α-tocopherol 120
( ^* : Not included in the final composition)

: Manufacture of hard capsules-8)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
Hydrochloric acid 150
Ethanol 300 ^*
Transcutor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70
Cremophor (registered trademark) EL 220
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Manufacture of hard capsules-9)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 208
Ethanol 300 ^*
Dimethylisosorbide 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70
Cremophor (registered trademark) EL 220
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Production of hard capsules-10)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 208
Ethanol 300 ^*
Glycoflor 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70
Cremophor (registered trademark) EL 220
dl-α-tocopherol 60
( ^* : Not included in the final composition)

: Manufacture of hard capsules-11)
Hard capsules were prepared in the same manner as in Example 1 using the following ingredients:
Ingredient Content (mg / capsule)
Itraconazole 50
Hydrochloric acid 150
Ethanol 300 ^*
Dimethylisosorbide 83
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70
Cremophor (registered trademark) EL 220
dl-α-tocopherol 60
( ^* : Not included in the final composition)

Comparative example

: Production of hard capsule A hard capsule was produced in the same manner as in Example 1 except that transcutol as an amphiphilic additive was not used.

Ingredient Content (mg / capsule)
Itraconazole 50
85% phosphoric acid aqueous solution 208
Ethanol 300 ^*
Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70
Cremophor (registered trademark) EL 220
dl-α-tocopherol 60
( ^* : Not included in the final composition)

Test example 1

: Dissolution test For the preparation of the present invention of Example 1, the preparation of the comparative example, Sporanox (registered trademark) capsule, Sporanox (registered trademark) tablet and Sporanox (registered trademark) liquid (Jansen Korea) The dissolution amount of itraconazole was measured under the following conditions according to the dissolution test method II (Puddle method) described in General Test Methods
Dissolution test equipment: Erweka DT 80 (Erweka, Germany)
Eluent: 900ml artificial gastric fluid with pH 1.2
900 ml phosphate buffer solution with pH 6.8
Eluent temperature: 37 ± 0.5 ° C
Rotation speed: 100 ± 4rpm
Analysis method: Liquid chromatography method
Column-Cosmosil C ₁₈
(150mm × 4.6mm; Nacalai tesque, Japan)
Mobile phase-acetonitrile / phosphate buffer solution of pH 7.0 = 60: 40
Flow rate-1.2ml / min Detector-UV255nm
Injection volume-10 μl
The amount of itraconazole dissolved is shown as the cumulative amount of itraconazole eluted over 45 minutes and the results are shown in Tables 1 and 2.

  As can be seen from Tables 1 and 2, the formulation of Example 1 exhibits a higher itraconazole elution rate than the comparative and commercially available formulations at pH 1.2 or pH 6.8. In particular, at pH 6.8, the itraconazole elution rate of the preparation of Example 1 appeared significantly higher than the commercially available preparation.

Test example 2

: Bioabsorption test In order to evaluate the bioavailability of itraconazole contained in the preparation of the present invention, a bioabsorption test was performed as follows.

  Twenty 14-15 week old Sprague-Dawley male rats, each weighing about 300 g, were fasted for 48 hours or more with free access to water, and then divided into two groups of 10 rats. During the postprandial experiment, two groups of rats were continuously supplied with normal solid feed and water.

  Each of two groups of rats was orally administered with the formulation of the invention of Example 1 and the formulation of the comparative example at a dose of 20 mg itraconazole per kg body weight of the rat. Blood samples were collected directly from the heart of each rat to separate plasma samples before dosing and 1, 2, 3, 4, 5, 7 and 24 hours after dosing.

50 μl of internal standard solution (methanol solution containing 500 μg / ml econazole nitrate) and 200 μl of 1M carbonate buffer (pH 10) were added to 500 μl of plasma sample. To this, 7 ml of an extraction solvent (n-heptane: isoamyl alcohol = 9: 1) was added, and the resulting mixture was shaken at 80 rpm for 5 minutes to obtain an extract. The extract was centrifuged at 3,000 rpm for 10 minutes, and then the solvent was evaporated at 50 ° C. in a nitrogen atmosphere. 200 μl of 65% acetonitrile aqueous solution containing 0.05% triethylamine was added to the resulting residue, and the mixture was analyzed by HPLC under the following conditions. The observed results are shown in Table 3 below and FIG.
Column: Inertosyl ODS2 (250 × 4.6mm, 5μm; GL Science, Japan)
Mobile phase: 65% acetonitrile aqueous solution containing 0.05% triethylamine Detector: UV258nm
Flow rate: 1.2 ml / min Injection volume: 100 μl

  The results shown in Table 3 and FIG. 1 show that the bioavailability of itraconazole according to the preparation of the present invention is hardly affected by the food or drink ingested compared to the comparative example.

The foregoing and other objects and features of the invention will become apparent from the detailed description of the invention which follows the following drawings.
The bioavailability of itraconazole before and after a meal of each of the preparations produced in Example 1 and Comparative Example of the present invention is shown.

Claims (11)

A viscous glassy composition for oral administration comprising itraconazole, acidifying agent, amphiphilic additive, surfactant and oil. The composition according to claim 1, wherein the ratio of bioavailability of itraconazole before and after eating and drinking is 0.8 or more. The composition according to claim 1, wherein the viscosity measured at 25 ° C is 10,000 cps or more. The composition of claim 1 having a self-microemulsifying capability that forms microemulsion particles in body fluids upon oral administration. The weight ratio of the itraconazole, acidifying agent, amphiphilic additive, surfactant and oil ranges from 1: 0.5 to 15: 0.5 to 20: 0.5 to 15: 0.5 to 15. The composition according to claim 1. The composition according to claim 1, wherein the acidifying agent is selected from the group consisting of phosphoric acid, hydrochloric acid, and aqueous solutions thereof. The composition of claim 1, wherein the amphiphilic additive is selected from the group consisting of transcutol, dimethylisosorbide, glycofurol, propylene glycol, propylene carbonate, solutol, and mixtures thereof. The surfactant is selected from the group consisting of polyoxyethylene glycolated natural or hydrogenated vegetable oils, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene fatty acid esters, and mixtures thereof. The composition as described. The composition of claim 1, wherein the oil is selected from the group consisting of tocopherols, derivatives thereof and mixtures thereof. (A) homogeneously dissolving itraconazole in a mixture of acidifying agent, amphiphilic additive and volatile solvent; (b) dissolving a surfactant and oil in the solution; and (c) this mixture. The method for producing a composition according to claim 1, comprising removing a volatile solvent from the composition. The method according to claim 10, wherein the volatile solvent is an alcohol having 2 or 3 carbon atoms.

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