MXPA06002239A - Oral itraconazole composition which is not affected by ingested food and process for preparing same. - Google Patents

Abstract

A viscous and glassy composition for oral administration comprising itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and an oil provides a high in vivo bioavailability of itraconazole which is little influenced by ingested food.

Description

before. the expiralion of the. lime limil for atnending the. For tH'o-letter codes and oiher abbreviations, refer to the. "Guid-claims and o be republished in the event of receiption of anee. Notes or Codes and Abbreviations" appearing at the be.gin-arnendmenls no of each regular issue. of the PCT Gazelte.

COMPOSITION OF ORAL ITRACONAZOLE WHICH IS AFFECTED FOR INGESTED FOODS AND PROCESS FOR PREPARING THE SAME FIELD OF THE INVENTION The present invention relates to an oral composition and itraconazole having improved bioavailability of itraconazole that is not affected by the ingested food, and a process for the preparation thereof.

BACKGROUND OF THE INVENTION Itraconazole, a triazole compound, is known to have excellent antifungal activity. However, the bioavailability of itraconazole administered orally is very low because it has an excessively low solubility of less than 1 μ9 / p ?? in water and remains un ionized in gastric juice due to its pKa value of 3.7. In addition, it is known that the degree of bioavailability of itraconazole administered orally varies widely among individuals and depends on other factors such as ingested food. International Publication TCP No. WO 85/02767 and U.S. Patent No. 4,764,604 teach a method for increasing the solubility of itraconazole ai 2 employing an inclusion compound of cyclodextrin from itraconazoi. However, this method has problems that the incremental increase in the solubility of itraconazoi is only marginal and several complicated preparation procedures are required. International Publication TCP No. WO94 / 05263 discloses a coated bed preparation, wherein a core made of sucrose, dextrin, starch and similar pharmaceutically inert or neutral is coated with a mixture of itraconazoi and a hydrophilic polymer and then the resulting mixture it is again coated with a polymer, for example, polyethylene glycol. Said coated bed preparation is commercially available from Janssen Pharmaceutica (Beerse, Belgium) under the trade name of Sopranos® capsules. However, the manufacturing process of the previous preparation is very complicated because the beds that have an average size of only 600 to 700 ?? They tend to experience agglomeration during the manufacturing process. In addition, the bioavailability of itraconazoi in this preparation varies widely depending on whether it is taken before or after food ingestion. International Publication TCP No. WO 97/44014 teaches a solid dispersion of itraconazoi in a water soluble polymer, which is prepared by subjecting a mixture of itraconazoi and the water-soluble polymer to a melt extrusion process at a varying temperature. from 245 ° C to 265 ° C. This solid dispersion is described to have an improved bioavailability of 3 itraconazole which is not influenced by the ingested food, and is commercially available from Janssen Pharmaceutica (Beerse, Belgium) under the trade name Sopranos® tablets. However, the manufacturing process of the solid dispersion is impeded by a number of difficulties in controlling many process variables, and the im vivo bioavailability of itraconazole that can be achieved with the above dispersion is still low. Sporanox® liquid pH 2, which is prepared by mixing an inclusion compound hydroxypropyl-P-cyclodextrin from itraconazole, hydrochloric acid, propylene glycol, purified water, sodium hydroxide, sodium saccharin and sorbitol, and is commercially available from Janssen Pharmaceutica (Beerse, Belgium), exhibits a high bioavailability of itraconazole when administered before ingestion, although it has problems since it must be taken in large quantities due to its low concentration of itraconazole of 10 mg / ml, the active ingredient is precipitated quickly when it comes in contact with the intestinal juice, and is effective only against fungal infection of the esophagus. Recently, the International Publication TCP N o.

W098 / 55148 describes a high viscosity composition comprising a drug having a very low solubility in water, cyclodextrin, water soluble acid and water soluble organic polymer. However, this composition has a high viscosity and, consequently, a large amount of dispersant is used to reduce the viscosity during the capsule manufacturing process. In addition, the composition exhibits a very low dissolution rate of less than 1% under a neural or alkaline condition of pH 6.8 or higher. In this regard, the inventors hereby suggested a micro-emulsion pre-concentrate comprising an antiviral agent having very low solubility in water, phosphoric acid, a surfactant and an oil in Korean Application No. 2000-83717, and suggested in addition another modified micro-emulsion composition based on said pre-concentrate of Korean Application No. 2001 -36930. However, these compositions still exhibit unsatisfactory dissolution rates of itraconazole under a neutral or alkaline condition of pH 6.8 or higher, and thus their bioavailabilities of itraconazole depend more or less on the food eaten.

BRIEF DESCRIPTION OF THE NORTH ION Therefore, it is a principal object of the present invention to provide an itraconazole oral composition having an improved itraconazole bioavailability that is poorly influenced by ingested foods. It is a further object of the present invention to provide a process for preparing said oral composition. In accordance with one aspect of the present invention, a viscous glassy composition for oral administration comprising itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and an oil is provided. According to another aspect of the present invention, there is provided a method for the preparation of said composition comprising the steps of: (a) dissolving itraconazole uniformly in a mixture of the acidifying agent, the amphiphilic additive and a volatile solvent, (b) ) dissolving the surfactant and oil in the resulting solution, and (c) removing the volatile solvent therefrom.

BRIEF DESCRIPTION OF THE DRAWINGS The above and other objects and features of the present invention will become apparent from the following description of the invention, when taken in conjunction with the accompanying drawing, Figure 1, which shows the respective bioavailability of itraconazole of the preparations made in Example 1 and the Comparative Example before and after the ingestion of food.

DETAILED DESCRIPTION OF THE INVENTION The composition of the invention comprising itraconazole as an active ingredient can be prepared using the following components: 6 (1) Acidification agent Representative examples of the acidifying agent that can be used in the present invention to dissolve itraconazole include phosphoric acid, acetic acid, hydrochloric acid, nitric acid, sulfuric acid, citric acid, fumaric acid, maleic acid, and an aqueous solution thereof, wherein 85% phosphoric acid or a diluted solution thereof is preferred. (2) Amphiphilic additive The amphiphilic additive used in the present invention serves to dissolve the itraconazole and adjust the viscosity of the composition to an extent suitable for filling into a capsule. Suitable amphiphilic additives that can be used in the present invention include transcutoi (diethylene glycol monoethyl ether, Gattefosse), dimethy isosorbide (1,4: 3,6-dianhydro-2,5-dimethyl-D-glucitol), glycofurol (alkoxy), tetrahydrofurfuryl ether of polyethylene glycol), propylene glycol (1,2-dydroxypropane), propylene carbonate (4-metii-2-oxo-1,3-dioxolan), solute! (macrogol 15 hydroxystearate, BASF) and a mixture thereof, where transcutoi is preferred. 7 (3) Volatile solvent The volatile solvent used during the manufacturing process, although not present in the final product, aids in the dissolution of itraconazole by means of the action of the acidifying agent. In the present invention, a non-toxic organic solvent such as an alcohol, for example, ethanol, propanol and isopropanol, which can easily be volatilized at a temperature of less than 100 ° C, is preferably used as the volatile solvent. (4) Surfactant The surfactant used in the present invention assists in the formulation of a uniform emulsion of an oil and hydroftlic components, and keeps the emulsion stable during storage. Representative examples of the surfactant include: (1) polyoxyethylene glycolized natural or hydrogenated vegetable oils such as natural or hydrogenated polyoxyethylene glycollate castor oil (Cremophor®, BASF, HCO®, Nikkol), (2) esters of polyoxyethylene fatty acid sorbitan where the fatty acid is mono- or tri-lauric, palmitic, stearic or oleic acid (Tween®, ICI), and (3) polyoxyethylene-fatty acid esters such as polyoxyethylene stearic acid ester (Myrj, CI) . 8 (5) Oil The oil component used in the present invention will be compatible with the surfactant and capable of forming a stable microemulsion in an aqueous medium. It may be one of the pharmaceutically acceptable oils such as tocopherols and derivatives thereof including tocopheryl acetate, tocopheryl succinate, and polyethyleneglycol-1000-tocopheryl succinate (TPGS). The composition of the invention is prepared by (a) dissolving itraconazole in a mixture of the acidifying agent, the amphiphilic additive and the volatile solvent, (b) dissolving the surfactant and the oil in the resulting solution, and (c) Removal of the volatile solvent from the resulting mixed solution. In step (c), the volatile solvent can be removed by the conventional method, for example, by heating under ambient pressure or a vacuum, preferably at a temperature ranging from 40 to 100 ° C, more preferably at a temperature that varies from 40 to 80 ° C. In the above manufacturing process, itraconazole, the acidifying agent, the amphiphilic additive, the volatile solvent, the surfactant and the oil are used in amounts corresponding to a weight ratio in the range of 1: 0.5 ~ 1 5 : 0.5-20: 0.5-20: 0.5-15: 0.5-15, preferably 1: 1 -10: 1 -15: 1 -1 5: 1 -10: 1 -10. The final composition of the present invention in the absence of the volatile solvent comprises itraconazole, the acidifying agent, the amphiphilic additive, the surfactant and the in a weight ratio in the range of 1: 0.5-15: 0.5-20: 0.5. ~ 15: 0.5-15, preferably 1: 1 -1 0: 1 -15: 1-10: 1 ~ 10. In addition, the composition of the invention may comprise pharmaceutically acceptable additives for oral administration such as anti-oxidants. The pharmaceutical composition of the present invention can be formulated to obtain various pharmaceutical preparations, for example, a powder, granule, tablet, coated preparation or liquid preparation, according to any of the conventional procedures. For example, a hard capsule can be prepared by adding a lubricant and other pharmaceutical additives to the pharmaceutical composition, processing the mixture into a powder or granule and filling the powder or granule into a hard gelatin capsule; a tablet, through the addition of a suitable additive to the pharmaceutical composition and tabletting the mixture; a liquid preparation, by dissolving the pharmaceutical composition in water; and a coated preparation, by coating a solution of the pharmaceutical composition on a sugar bed such as Non-pareil® (Edward Mendell Ce, U). The itraconazole composition of the prepared invention is transparent and glassy, ie it has no fluidity, and has a high viscosity of at least 10,000 cps at 25 ° C. This can be achieved through the combined action of the amphiphilic additive and the volatile solvent used in the method of the invention. The high viscosity glassy composition is much more compact compared to a conventional microemuisin composition. The composition of the invention has self-microemulsifying ability to form microemuission particles of high stability and availability when administered orally in the body fluid. Therefore, since the composition of the invention could maintain a high and stable level of dissolution rate of itraconazole even under a neutral or alkaline condition of pH 6.8 or higher, the bioavailability of itraconazole thereof is little influenced by food ingested; the itaconazole blockabilities of the composition of the invention before and after the ingestion are the same, the ratio of AUCanies of ingestion and Aucdespu es of ingestion are close to 1 (AUC: area under the blood concentration curve), preferable way 0.8 or higher. The following Examples are intended to illustrate the present invention without limiting its scope. In addition, the percentages given below for solid in solid, liquid in liquid, and solid in liquid are on a weight / weight basis, vol / vol and weight / vol, respectively, unless specifically indicated otherwise. .

Example 1: Preparation of Dura-1 Capsule) Prepare a hard capsule using the following 1 1 ingredients: Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 208 Ethanol 300 * Transcutol 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70 Cremophor®EL 220 dl-a-tocopherol 60 (* not present in the final composition) Itraconazole was uniformly dissolved in a mixture of 85% phosphoric acid, transcutol and ethanol, and other ingredients were added thereto and dissolved. Then the resulting mixture was concentrated during heating at 55 ° C for 4 hours to volatilize the ethanol therefrom to obtain a viscous and transparent composition that is not fluid. The composition was co-housed within a hard capsule through the conventional method described in the General Preparation Rule of Korea Pharmacopoeia.

Example 2: Preparation of Soft Capsule A soft capsule was prepared using the following 12 ingredients: Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 150 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 80 Cremophor® EL 200 dl-cc -tocoferoi 60 (* not present in the final composition) The procedure of Example 1 was repeated using the above ingredients to obtain a viscous and transparent composition that is not fluid. The composition was placed in a soft capsule through the conventional method described in the General Preparation Rule of Korea Pharmacopoeia.

Example 3: Preparation of Dura-2 Capsule) A hard capsule is prepared through the procedure of Example 1 using the following ingredients: 1 3 Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 200 Cremophor® EL 80 dl-a-tocopheri 60 (* not present in the final composition) Example. Preparation of hard capsule-3) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 200 Tween®20 80 14 dl-a-tocopherol 60 (* not present in the final composition) Example 5: Hard Capsule Preparation-4) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Quantity (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 1 50 Cremophor® EL 1 50 dl-a-tocopherol 60 (* not present in the final composition) Example 6: Preparation of Hard-5 Capsule) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: 15 Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 83 Tween® 20 200 Cremophor EL 80 dl-a-tocopherol 60 ( * not present in the final composition) Example 7: Preparation of Hard-6 Capsule) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 83 Tween® 20 150 Cremophor® EL 50 dl-a-tocopherol 60 (* not present in the final composition) 16 Example 8: Preparation of Hard capsule -7) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Amount (mg / capsule) Itraconazole 50 Phosphoric acid 85% 200 Ethanol 300 * Transcutol 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 200 Cremophor® EL 80 dl-cc-tocopherol 120 (* not present in the final composition ) Example 9: Preparation of Hard-8 Capsule) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Quantity (mg / capsule) Itraconazole 50 Phosphoric acid 85% 50 17 Ethanol 300 * Transcutol 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70 Cremophor® EL 220 dl-a-tocopherol 60 (* not present in the final composition) Example 1 0: Preparation of Hard-9 Capsule) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Quantity (mg-capsule) Itraconazole 50 Phosphoric acid 85% 208 Ethanol 300 * Dimethylisosorbide 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70 Cremophor® EL 220 dl-a-tocopherol 60 (* not present in the final composition) 1 8 emplo 1 1 : Preparation of Hard Capsule- 0) A hard capsule was prepared through the procedure of emplo 1 using the following ingredients: Quantity (mg / capsule) Itraconazole 50 Phosphoric acid 85% 208 Ethanol 300 * Glycofurol 83 Polyoxyethylene-50 -rerogenated castor oil (HCO® 50) 70 Cremophor® EL 220 dl- oc-tocopherol 60 (* not present in the final composition) Example 12: Preparation of Hard Capsule - 1 1) A hard capsule was prepared through the procedure of Example 1 using the following ingredients: Quantity (mg / capsule) Itraconazole 50 19 Hydrochloric acid 1 50 Ethanol 300 * Dimethylisosorbide 83 Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70 Cremophor # EL 220 dl-a-tocopherol 60 (* not present in the final composition) Comparative Example: Preparation of hard capsule A hard capsule was prepared through the procedure of Example 1, except that the amphiphilic additive, transcutol, was not used, using the following ingredients: Quantity (mg / capsule) Itraconazole 50 Phosphoric acid 85% 208 Ethanol 300 * Polyoxyethylene-50-hydrogenated castor oil (HCO® 50) 70 Cremophor® EL 220 dl-a-tocopherol 60 (* not present in the final composition) 20 Test Example 1: Test of Dissolution The dissolution rates of itraconazole were determined for the preparation of the invention of Example 1; the preparation of the Comparative Example; Sporanox® capsule; Sopranos® tablet; and liquid sopranos® (Janssen Korea), according to dissolution test method ii (pallet method) described in the General Tests chapter of Koreart Pharmacopoeia under the conditions listed below: Test apparatus: Erweka DT80 (Erweka, Germany) Test solutions: 900 ml of artificial gastric juice (p H 1 .2) 900 ml of phosphate pH regulator (pH 6.8) Temperature of test solutions: 37 + 0.5 Rotation speed: 100 ± 4 rpm Method analytical: liquid chromatography column: Cosmoil C1 8 (150 mm x 4.6 mm; N acalai tesque, Japan) mobile phase: acetonitrile / phosphate pH regulator (pH 7.0) = 60:40 flow rate: 1.2 ml / min. detector: UV 255 nm injection volume: 0 μ? The amount of intraconazole dissolved is represented by the cumulative amount of itraconazole eluted in 45 minutes and the results are shown in Tables 1 and 2.

Table 1 Dissolution rates in artificial gastric juice (pH 1.2) Table 2 Dissolution rates in phosphate pH regulator (pH 6.8) As can be seen in Tables 1 and 2, the preparation of Example 1 exhibits higher amounts of dissolved itraconazole than those of the Comparative Example and commercially available preparations at pH 1.2 or 6.8. In particular, the result shows that, at pH 6.8, the dissolution rate of itraconazole from the preparation of Example 1 is markedly improved compared to commercially available preparations.

Test Example 2: In Vivo Absorption Test To investigate the bioavailability of itraconazole contained in the preparations of the invention, in vivo absorption tests were carried out as follows. Twenty male Sprague-Dawly rats from 14 to 15 weeks of age weighing approximately 300 g each were placed on a fast while free access to water was allowed, and then divided into two groups of ten rats each. Subsequently, for the test after ingestion of feed, solid food and water were continuously supplied to the two groups of rats. The preparation of the invention of Example 1 and the preparation of the Comparative Example were orally administered to the two groups of rats., respectively, at a dose of 20 mg itraconazole / kg of body weight of the rat. The blood samples were taken directly from the hearts of the rats before administration and after 1, 2, 3, 4, 5, 7 and 24 hours after administration, and the serum was separated therefrom. At 500 μ? from each of the serum samples were added 50 μ? of an internal standard solution (methanol solution containing 500 pglml of econazole nitrate) and 200 μ? of 1 carbonate pH regulator (pH 10.0). 7 ml of an extraction solvent (n-heptane: isoamy! AlchoJ = 9: 1) were added thereto and the resulting mixture was stirred at 80 rpm for 5 min. To obtain an extract. The extract was centrifuged at 3,000 rpm for 10 min. and the solvent was evaporated at 50 ° C under a nitrogen atmosphere. To the resulting residue, 200 μ? of 0.05% aqueous 65% acetonitrile triethylamine solution and the mixture was subjected to H PLC under the following conditions. The observed results are shown in Table 3 and Figure 1: - column: Inertsil ODS2 (250 x 4.6 mm, 5 μp?; GL science, Japan) - mobile phase: 65% aqueous acetonitrile solution containing 0.05% triethylamine - detector: W 258 nm - flow rate: 1.2 ml / min. - injection volume: 1 00 μ? Table 3 * 1 Area under the blood concentration curve up to 48 hours * 2 Maximum blood concentration * 3 Time at maximum blood concentration The results in Table 3 and Figure 1 show that the bioavailability of itraconazoi observed for the preparation of the invention is much less influenced by the ingested foods compared to that of the Comparative Example. While the present invention has been described with respect to the above specific embodiments, it will be recognized that those skilled in the art can make various changes and modifications to the invention that are also within the scope of the invention as defined by the invention. The attached claims.

Claims (10)

25 CLAIMS

1 . A viscous, glassy composition for oral administration comprising itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and an oil.

2. The composition according to claim 1, characterized in that the bioavailability ratio of itracon azole before and after the ingestion of food is 0.8 or higher.

3. The composition according to claim 1, characterized in that the viscosity measured at 25 ° C is at least 1 000 cps.

4. The composition according to claim 1, characterized in that it has the capacity of self-microemulsification to form microemulsion particles when it is administered orally in the body fluid.

5. The composition according to claim 1, characterized in that the ratio itraconazole: acidifying agent: amphiphilic additive: surfactant: oil by weight is on a scale of 1: 0.5-15: 0.5-20: 0.5-15 : 0.5-15

6. The composition according to claim 1, characterized in that the acidifying agent is selected from the group comprising phosphoric acid, hydrochloric acid and an aqueous solution thereof. The composition according to claim 1, characterized in that the amphiphile is selected from the group 26 comprising transcutol, dimethyl isosorbide, glycofurol, propylene glycol, propylene carbonate, soiutol and a mixture thereof. 8. The composition according to claim 1, characterized in that the surfactant agent is selected from the group comprising potassium hydroxylated natural or hydrogenated glycoiate oils, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters and a mixture thereof. The composition according to claim 1, characterized in that the oil is selected from the group comprising tocopherol, a derivative thereof and a mixture thereof. A method for preparing the composition according to claim 1 which comprises the steps of: (a) dissolving itraconazole uniformly in a mixture of the acidifying agent, the amphiphilic additive and a volatile solvent, (b) further dissolving the agent surfactant and the oil in the resulting solution, and (c) remove the volatile solvent therefrom. eleven . The method according to claim 10, characterized in that the volatile solvent is a C2 or C3 alcohol. 27 RESUMEN OF THE INVENTION A viscous, glassy composition for oral administration comprising itraconazole, an acidifying agent, an amphiphilic additive, a surfactant and an oil provides a high bioavailability of itraconazole which is poorly influenced by the ingested food.