JP2004002245A - Oral administeration pharmaceutical preparation of itraconazole with improved elution characteristics - Google Patents
Oral administeration pharmaceutical preparation of itraconazole with improved elution characteristics Download PDFInfo
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- JP2004002245A JP2004002245A JP2002161163A JP2002161163A JP2004002245A JP 2004002245 A JP2004002245 A JP 2004002245A JP 2002161163 A JP2002161163 A JP 2002161163A JP 2002161163 A JP2002161163 A JP 2002161163A JP 2004002245 A JP2004002245 A JP 2004002245A
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- itraconazole
- silicon dioxide
- fine particles
- amorphous silicon
- pharmaceutical preparation
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title claims abstract description 43
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 43
- 238000010828 elution Methods 0.000 title abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 title abstract 3
- 229910021486 amorphous silicon dioxide Inorganic materials 0.000 claims abstract description 9
- 238000002156 mixing Methods 0.000 claims abstract description 8
- 239000000203 mixture Substances 0.000 claims description 24
- 235000012239 silicon dioxide Nutrition 0.000 claims description 17
- 239000010419 fine particle Substances 0.000 claims description 13
- 238000009472 formulation Methods 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 8
- 238000002844 melting Methods 0.000 claims description 7
- 230000008018 melting Effects 0.000 claims description 7
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 claims description 5
- 239000011859 microparticle Substances 0.000 abstract description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000011324 bead Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000007902 hard capsule Substances 0.000 description 2
- 229920001477 hydrophilic polymer Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229960003511 macrogol Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000010453 quartz Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229910021488 crystalline silicon dioxide Inorganic materials 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000012438 extruded product Nutrition 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- -1 sucrose fatty acid ester Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
Images
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
【０００１】
【先行技術および課題】
本発明は、溶出性の改善されたイトラコナゾール経口投与製剤に関する。
【０００２】
抗真菌剤として用いられるイトラコナゾールは親油性であるが水または希薄酸水溶液に実際上不溶なため、経口投与により消化管から殆ど吸収されない。そのためイトラコナゾールの水または希薄酸水溶液に対する溶出性を高める工夫が必要である。
【０００３】
特表平８−５０１０９２は、ノンパレルのような糖の核を芯とし、その上にイトラコナゾールと親水性ポリマーよりなる層をコーティングし、その上にポリエチレングリコールのシーリング層を順次被覆してなるイトラコナゾールの溶出性を高めたビーズを開示する。このビーズを製造するためのプロセスは多工程を含み、かつ核被覆層の形成には有機溶媒を使用しなければならない。さらにビーズはイトラコナゾールを２１〜２２％含むに過ぎず、他は糖、親水性ポリマーおよびポリエチレングリコールが占める。
【０００４】
特表平１１−５０９２３８は、もっと簡単な溶出性を高めたイトラコナゾールを含む粒子製剤の製造法を開示する。この粒子はイトラコナゾールとＨＰＭＣのような水溶性ポリマーのブレンドを１２０〜３００℃の温度で押出し、押出し物を粉砕することよりなる。好ましくは両者の溶融押出し物を粉砕した固体分散体であり、イトラコナゾールに対する水溶性ポリマーの割合は１：１〜１：１７である。この方法は有機溶媒を必要とせず、操作も簡単であるが、一般に水溶液ポリマーは押出し温度において熱的に安定でなく、従ってその押出し機内の滞留時間を注意深くコントロールしなければならない。また、水溶性ポリマーはイトラコナゾールと少なくとも同量またはそれ以上でなければならず、イトラコナゾール単位重量あたりの製剤の総重量および容積が増す。
【０００５】
本発明の課題は、先行技術よりも簡単な操作によって製造することができ、しかも製剤中の有効薬物の含有量の高い溶出性を高めたイトラコナゾール経口投与製剤を提供することである。
【０００６】
【課題を解決するための手段】
本発明は、溶融したイトラコナゾールを非晶質二酸化ケイ素微粒子と混合して得られる、高い溶出性を有するイトラコナゾール経口投与製剤を提供する。良く知られているように、二酸化ケイ素（シリカ）は化学的および熱的に非常に安定で、その溶融温度は非常に高い。一方イトラコナゾールの融点は１６６．２℃である。従ってイトラコナゾールと二酸化ケイ素両者の溶融混合物は得られないが、溶融状態のイトラコナゾールへ二酸化ケイ素微粒子を分散することは可能である。この混合物を冷却固化し、粉砕して得られる製剤は、含まれるイトラコナゾールの溶出性が十分に高められているので、経口投与によるバイオアベイラビリティーが満足なレベルへ上昇する。
【０００７】
【好ましい実施態様】
結晶性二酸化ケイ素は、水晶、石英などの形で天然に存在する。本発明で用いる二酸化ケイ素は非晶質二酸化ケイ素（シリカ）の微粒子、好ましくは軽質無水ケイ酸として知られる二酸化ケイ素微粒子である。このものは低いかさ密度と大きい比表面積を特徴とし、平均粒径は一般に０．１μｍ以下である。
【０００８】
イトラコナゾールに対する非晶質二酸化ケイ素微粒子の配合割合は重量比で１：０．２〜１：１で良く、イトラコナゾールより多量の二酸化ケイ素を使用する必要はない。例えばイトラコナゾール１００部に対し、二酸化ケイ素４０部の割合でよい。
【０００９】
溶融状態のイトラコナゾールへ二酸化ケイ素微粒子を分散する方法は任意である。例えば両者のドライブレンドをイトラコナゾールの融点付近の温度へ加熱し、冷却後粉砕する。しかしながら好ましい混合方法は、両者のドライブレンドをイトラコナゾールの融点付近の温度例えば２００℃で二軸スクリュー押出し機で押出し、押出し物を冷後粉砕する方法である。
【００１０】
このようにして得られた製剤は慣用の製剤補助原料と共に場合により造粒した後カプセルに充填し、または錠剤に打錠することができる。そのような製剤技術は医薬品産業の分野において周知である。
【００１１】
本発明の製剤の既知の製剤を上廻る主な利点は、製剤中のイトラコナゾールの割合が高いことばかりでなく、配合成分の二酸化ケイ素微粒子は化学的にも熱的にも非常に安定なため、製剤作業中および貯蔵中添加物に起因する品質劣化が殆ど生じないことである。また、二酸化ケイ素微粒子の高い親水性および化学的安定性は、消化管特に胃における製剤の崩壊性にとって有利である。
【００１２】
【実施例】
以下の実施例および比較例によって本発明の効果を実証する。
【００１３】
実施例１
イトラコナゾール１５０ｇと、軽質無水ケイ酸微粒子（日本アエロジル（株）製アエロジル２００を使用、以下同じ。）６０ｇをドライブレンドし、１８０℃で８時間加熱した。溶融物を冷却し、固化した塊を粉砕した。
粉砕物７０ｇと、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）８０ｇと、マクロゴール６０００ ４８ｇと、タルク２ｇとを混合し、５０％エタノールを造粒液として流動層造粒し、１カプセル当り造粒物２００ｍｇをゼラチン硬カプセルに充填してカプセル剤を得た。
【００１４】
実施例２
イトラコナゾール５０ｇと軽質無水ケイ酸微粒子２０ｇのドライブレンドを、二軸押出し機に供給し、イトラコナゾールの融点付近の温度において押出し、冷後押出し物をパワーミルで粉砕した。
この粉砕物７０ｇと、ヒドロキシプロピルメチルセルロース１０ｇと、低置換度ヒドロキシプロピルセルロース７０ｇと、しょ糖脂肪酸エステル４０ｇを混合し、１カプセルあたりこの混合物１９０ｍｇをゼラチン硬カプセルに充填し、カプセル剤を得た。
【００１５】
比較例
イトラコナゾール１５０ｇと、軽質無水ケイ酸微粒子６０ｇと、ヒドロキシプロピルメチルセルロース８０ｇと、マクロゴール６０００ ４８ｇと、タルク２ｇをドライブレンドし、５０％エタノールを造粒液として流動層造粒し、１カプセルあたり造粒物２００ｍｇを硬カプセルに充填し、カプセル剤を得た。
【００１６】
【溶出試験】
実施例および比較例のカプセルを第１４改正日本薬局方溶出試験法に従って試験した。試験液のｐＨは１．２，パドルの回転速度は１００ｒｐｍとした。結果を表１および図１に示す。
【００１７】
【表１】
表１および図１の結果が示すように、イトラコナゾールと非晶質二酸化ケイ素微粒子とをイトラコナゾールの溶融状態において混合することにより、イトラコナゾールの溶出率を大きく高めることができる。さらに実施例１と実施例２の比較により、溶出率はイトラコナゾールの融点付近の温度で押出し機を使って押出すことにより一層大きく増大する。
【図面の簡単な説明】
【図１】実施例および比較例の製剤のイトラコナゾール溶出率のグラフ。[0001]
[Prior art and problems]
The present invention relates to an oral formulation of itraconazole having improved dissolution.
[0002]
Itraconazole, used as an antifungal agent, is lipophilic, but is practically insoluble in water or dilute aqueous acid solutions, so that it is hardly absorbed from the gastrointestinal tract by oral administration. Therefore, it is necessary to improve the dissolution of itraconazole in water or a dilute acid aqueous solution.
[0003]
Japanese Unexamined Patent Publication No. Hei 8-501092 discloses an itraconazole obtained by coating a layer of itraconazole and a hydrophilic polymer on a nucleus of a sugar such as non-pareil as a core, and sequentially coating a sealing layer of polyethylene glycol thereon. Disclosed are beads with enhanced dissolution. The process for producing the beads involves multiple steps and the use of an organic solvent must be used to form the core coating. In addition, the beads contain only 21-22% itraconazole, the others being occupied by sugars, hydrophilic polymers and polyethylene glycol.
[0004]
Japanese Patent Application Publication No. 11-509238 discloses a method for producing a particle preparation containing itraconazole with improved dissolution properties which is easier. The particles consist of extruding a blend of itraconazole and a water-soluble polymer such as HPMC at a temperature of 120-300 ° C and grinding the extrudate. It is preferably a solid dispersion obtained by grinding both melt extrudates, and the ratio of the water-soluble polymer to itraconazole is from 1: 1 to 1:17. Although this method does not require organic solvents and is simple to operate, aqueous polymers are generally not thermally stable at the extrusion temperature and therefore the residence time in the extruder must be carefully controlled. Also, the water-soluble polymer must be at least as much or more than itraconazole, which increases the total weight and volume of the formulation per unit weight of itraconazole.
[0005]
An object of the present invention is to provide an oral administration preparation of itraconazole which can be produced by a simpler operation than the prior art and has a high active drug content in the preparation and improved dissolution.
[0006]
[Means for Solving the Problems]
The present invention provides a highly dissolvable itraconazole oral administration preparation obtained by mixing molten itraconazole with amorphous silicon dioxide fine particles. As is well known, silicon dioxide (silica) is very chemically and thermally stable and its melting temperature is very high. On the other hand, the melting point of itraconazole is 166.2 ° C. Therefore, although a molten mixture of both itraconazole and silicon dioxide cannot be obtained, it is possible to disperse silicon dioxide fine particles in itraconazole in a molten state. The preparation obtained by cooling and solidifying the mixture and pulverizing the mixture has a sufficiently high dissolution property of the contained itraconazole, so that the bioavailability by oral administration increases to a satisfactory level.
[0007]
[Preferred embodiment]
Crystalline silicon dioxide exists naturally in the form of quartz, quartz, and the like. The silicon dioxide used in the present invention is fine particles of amorphous silicon dioxide (silica), preferably fine particles of silicon dioxide known as light anhydrous silicic acid. It is characterized by a low bulk density and a large specific surface area, and the average particle size is generally less than 0.1 μm.
[0008]
The mixing ratio of the amorphous silicon dioxide fine particles to itraconazole may be 1: 0.2 to 1: 1 by weight ratio, and it is not necessary to use a larger amount of silicon dioxide than itraconazole. For example, a ratio of 40 parts of silicon dioxide to 100 parts of itraconazole may be used.
[0009]
The method of dispersing the silicon dioxide fine particles in the itraconazole in a molten state is optional. For example, both dry blends are heated to a temperature near the melting point of itraconazole, cooled, and ground. However, a preferred mixing method is a method in which the dry blend of the two is extruded at a temperature near the melting point of itraconazole, for example, 200 ° C. by a twin screw extruder, and the extrudate is cooled and then pulverized.
[0010]
The preparations obtained in this way can optionally be granulated together with conventional auxiliary ingredients and then filled into capsules or compressed into tablets. Such formulation techniques are well-known in the pharmaceutical industry.
[0011]
The main advantages of the formulation of the present invention over the known formulations are not only the high ratio of itraconazole in the formulation, but also the fact that the silicon dioxide microparticles of the formulation are very stable both chemically and thermally, There is little quality degradation due to additives during the formulation operation and during storage. Also, the high hydrophilicity and chemical stability of the silicon dioxide microparticles are advantageous for the disintegration of the preparation in the digestive tract, particularly in the stomach.
[0012]
【Example】
The effects of the present invention are demonstrated by the following Examples and Comparative Examples.
[0013]
Example 1
150 g of itraconazole and 60 g of light anhydrous silicic acid fine particles (using Aerosil 200 manufactured by Nippon Aerosil Co., Ltd .; the same applies hereinafter) were dry-blended and heated at 180 ° C. for 8 hours. The melt was cooled and the solidified mass was crushed.
70 g of the pulverized product, 80 g of hydroxypropylmethylcellulose (HPMC), 48 g of Macrogol 6000 and 2 g of talc were mixed, and the mixture was granulated in a fluidized bed using 50% ethanol as a granulating liquid. Hard capsules were filled to obtain capsules.
[0014]
Example 2
A dry blend of 50 g of itraconazole and 20 g of light anhydrous silicic acid microparticles was supplied to a twin screw extruder, extruded at a temperature near the melting point of itraconazole, and after cooling, the extruded product was pulverized with a power mill.
70 g of this pulverized product, 10 g of hydroxypropylmethylcellulose, 70 g of low-substituted hydroxypropylcellulose, and 40 g of sucrose fatty acid ester were mixed, and 190 mg of this mixture per capsule was filled into hard gelatin capsules to obtain capsules.
[0015]
Comparative Example 150 g of itraconazole, 60 g of light anhydrous silicic acid microparticles, 80 g of hydroxypropyl methylcellulose, 48 g of macrogol 6000, and 2 g of talc were dry-blended, and fluidized-bed granulation was performed using 50% ethanol as a granulating liquid. Hard capsules were filled with 200 mg of the granules to obtain capsules.
[0016]
[Dissolution test]
The capsules of the examples and the comparative examples were tested according to the 14th revision Japanese Pharmacopoeia dissolution test method. The pH of the test solution was 1.2, and the rotation speed of the paddle was 100 rpm. The results are shown in Table 1 and FIG.
[0017]
[Table 1]
As shown in the results of Table 1 and FIG. 1, by mixing itraconazole and amorphous silicon dioxide fine particles in the molten state of itraconazole, the elution rate of itraconazole can be greatly increased. Further, by comparing Example 1 and Example 2, the dissolution rate is further increased by extruding with an extruder at a temperature near the melting point of itraconazole.
[Brief description of the drawings]
FIG. 1 is a graph showing the dissolution rate of itraconazole from the preparations of Examples and Comparative Examples.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002161163A JP2004002245A (en) | 2002-06-03 | 2002-06-03 | Oral administeration pharmaceutical preparation of itraconazole with improved elution characteristics |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002161163A JP2004002245A (en) | 2002-06-03 | 2002-06-03 | Oral administeration pharmaceutical preparation of itraconazole with improved elution characteristics |
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| Publication Number | Publication Date |
|---|---|
| JP2004002245A true JP2004002245A (en) | 2004-01-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2002161163A Pending JP2004002245A (en) | 2002-06-03 | 2002-06-03 | Oral administeration pharmaceutical preparation of itraconazole with improved elution characteristics |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015188927A1 (en) * | 2014-06-12 | 2015-12-17 | Pharmathen S.A. | Pharmaceutical composition comprising a triazole antifungal agent and method for preparation thereof |
-
2002
- 2002-06-03 JP JP2002161163A patent/JP2004002245A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015188927A1 (en) * | 2014-06-12 | 2015-12-17 | Pharmathen S.A. | Pharmaceutical composition comprising a triazole antifungal agent and method for preparation thereof |
| US10328076B2 (en) * | 2014-06-12 | 2019-06-25 | Pharmathen S.A. | Pharmaceutical composition comprising a triazole antifungal agent and method for preparation thereof |
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