JP2009084236A - Bicalutamide-containing formulation - Google Patents
Bicalutamide-containing formulation Download PDFInfo
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- JP2009084236A JP2009084236A JP2007258492A JP2007258492A JP2009084236A JP 2009084236 A JP2009084236 A JP 2009084236A JP 2007258492 A JP2007258492 A JP 2007258492A JP 2007258492 A JP2007258492 A JP 2007258492A JP 2009084236 A JP2009084236 A JP 2009084236A
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- bicalutamide
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- lactose
- hydroxypropylcellulose
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- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 title claims abstract description 38
- 229960000997 bicalutamide Drugs 0.000 title claims abstract description 38
- 238000009472 formulation Methods 0.000 title abstract description 7
- 239000000203 mixture Substances 0.000 title abstract description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 30
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 28
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 21
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000004090 dissolution Methods 0.000 claims description 6
- 239000000654 additive Substances 0.000 abstract description 6
- 230000000996 additive effect Effects 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 206010060862 Prostate cancer Diseases 0.000 abstract description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 abstract description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 18
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 17
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 16
- 239000008101 lactose Substances 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 229920002472 Starch Polymers 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 235000019698 starch Nutrition 0.000 description 14
- 229910052708 sodium Inorganic materials 0.000 description 13
- 239000008107 starch Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 244000024675 Eruca sativa Species 0.000 description 10
- 235000014755 Eruca sativa Nutrition 0.000 description 10
- 235000019359 magnesium stearate Nutrition 0.000 description 9
- 239000002245 particle Substances 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 8
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 7
- 235000010980 cellulose Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000001913 cellulose Substances 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 4
- 229960003511 macrogol Drugs 0.000 description 4
- DVQHRBFGRZHMSR-UHFFFAOYSA-N sodium methyl 2,2-dimethyl-4,6-dioxo-5-(N-prop-2-enoxy-C-propylcarbonimidoyl)cyclohexane-1-carboxylate Chemical compound [Na+].C=CCON=C(CCC)[C-]1C(=O)CC(C)(C)C(C(=O)OC)C1=O DVQHRBFGRZHMSR-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 229960003943 hypromellose Drugs 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- -1 4-fluorophenylsulfonyl Chemical group 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000007962 solid dispersion Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 0 *[N+](C1=CC[C@](*=C)C=C1)[O-] Chemical compound *[N+](C1=CC[C@](*=C)C=C1)[O-] 0.000 description 1
- 241001489705 Aquarius Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000006169 McIlvaine's buffer solution Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940097647 casodex Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 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
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000009702 powder compression Methods 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、難溶性薬物であるビカルタミドの溶出性を高めた、ビカルタミド含有製剤に関する。 The present invention relates to a bicalutamide-containing preparation with improved dissolution of bicalutamide, a poorly soluble drug.
ビカルタミド（ｂｉｃａｌｕｔａｍｉｄｅ）は抗アンドロゲン活性をもつ化合物であり、前立腺癌の治療に広く用いられている。
ビカルタミドは別名４ ’ − シアノ− α ’ ， α ’ ， α ’ − トリフルオロ− ３ − （ ４ − フルオロフェニルスルホニル） − ２ − ヒドロキシ− ２ − メチルプロピオノ− ｍ − トルイジドのラセミ化合物であり、その構造は
ビカルタミドは水にほとんど溶解しない薬物のため、製剤化には溶解性の向上が不可欠である。
溶解性を向上する手段としては薬物を微粉砕することが公知であり、ＷＯ０２／１００３３９号パンフレットにはビカルタミドの好ましい平均粒子径が４μｍであることを開示している。
しかし、原薬の粉砕だけでは十分な溶解性が得られないことも多いため、更なる製剤的な工夫が必要とされる。
特開２００４−１４３１８５公報には、ビカルタミドの溶解性を高め、生物学的利用能を増加させる手段として、ビカルタミドと腸溶性ポリマーをアセトンやジクロロメタンなどの有機溶媒に溶解させた後、溶媒を除去して、固体分散体を製造する方法が開示されている。
しかし、固体分散体を製造するには、ビカルタミドよりもはるかに多くの添加剤が必要となるので、製剤が大型化してしまうという問題点と製造工程において多量の有機溶媒を使用しなければならないという問題点がある。
また、溶解性を向上する手段として界面活性剤を添加する方法も公知であるが、界面活性剤の中には毒性を示す物質もあるので、より安全な添加剤を用いて溶解性を高めることが望ましい。
ビカルタミド製剤は、商品名カソデックス錠８０ｍｇとして販売されているが、本発明者は低コストで人体への安全性に優れた添加剤を用いてビカルタミドの溶解性を改善することを検討し、本発明に至った。
Bicalutamide is a compound having antiandrogenic activity and is widely used for the treatment of prostate cancer.
Bicalutamide is a racemic compound of the alias 4′-cyano-α ′, α ′, α′-trifluoro-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methylpropiono-m-toluidide, Structure is
Since bicalutamide is a drug that hardly dissolves in water, it is essential to improve solubility for formulation.
As a means for improving the solubility, it is known to finely pulverize a drug, and WO02 / 100139 pamphlet discloses that the preferred average particle diameter of bicalutamide is 4 μm.
However, there are many cases where sufficient solubility cannot be obtained only by pulverization of the drug substance, so that further formulational measures are required.
In JP 2004-143185 A, as a means for increasing the solubility of bicalutamide and increasing bioavailability, bicalutamide and an enteric polymer are dissolved in an organic solvent such as acetone or dichloromethane, and then the solvent is removed. Thus, a method for producing a solid dispersion is disclosed.
However, in order to produce a solid dispersion, much more additives are required than bicalutamide, so the problem is that the preparation becomes large, and a large amount of organic solvent must be used in the production process. There is a problem.
In addition, a method of adding a surfactant as a means for improving the solubility is also known, but some surfactants are toxic, so use a safer additive to increase the solubility. Is desirable.
The bicalutamide preparation is marketed under the brand name Casodex Tablets 80 mg. The present inventor has studied to improve the solubility of bicalutamide by using an additive having low cost and excellent safety to the human body. It came to.
本発明は、より低コストで安全性の高い添加剤を用いた溶出性に優れるビカルタミド含有製剤の提供を目的とする。 An object of the present invention is to provide a bicalutamide-containing preparation having excellent dissolution properties using a low-cost and highly safe additive.
上記の課題を解決するため、本発明者らは安価でより安全性の高い添加剤を用いて、ビカルタミドの溶出性を鋭意検討した結果、有効成分であるビカルタミドにヒドロキシプロピルセルロースを配合することで、簡易な製法を採用しても、ビカルタミドの溶解性を高めることができることが分かり、本発明を完成するに至った。
すなわち、本発明のビカルタミド含有製剤は、ヒドロキシプロピルセルロースを含有することを特徴とする。
ヒドロキシプロピルセルロースの配合量はビカルタミド１００重量部に対して０．１〜３０重量部、好ましくは１〜２０重量部である。
ヒドロキシプロピルセルロースは粉末のままで使用することも、水やエタノールなどの溶媒に溶解させて使用することも可能である。
本発明の製剤で使用されるビカルタミドの平均粒子径は２０μｍ以下、より好ましくは１０μｍ以下である。
In order to solve the above-mentioned problems, the present inventors diligently studied the dissolution property of bicalutamide using an inexpensive and safer additive, and as a result, by combining hydroxypropyl cellulose with bicalutamide, which is an active ingredient. It has been found that the solubility of bicalutamide can be enhanced even if a simple production method is adopted, and the present invention has been completed.
That is, the bicalutamide-containing preparation of the present invention is characterized by containing hydroxypropyl cellulose.
The compounding amount of hydroxypropyl cellulose is 0.1 to 30 parts by weight, preferably 1 to 20 parts by weight with respect to 100 parts by weight of bicalutamide.
Hydroxypropyl cellulose can be used in the form of a powder or can be used after being dissolved in a solvent such as water or ethanol.
The average particle size of bicalutamide used in the preparation of the present invention is 20 μm or less, more preferably 10 μm or less.
本発明においては、難溶性薬物であるビカルタミドにヒドロキシプロピルセルロースを配合することで溶出性を改善することができたので市販製剤に比較して溶出性を同等以上に確保しつつ、低コストで人体により安全な製剤を得ることができる。 In the present invention, the dissolution property was improved by adding hydroxypropyl cellulose to bicalutamide, which is a poorly soluble drug. A safer formulation can be obtained.
本発明の製剤にはビカルタミド及びヒドロキシプロピルセルロース以外に、医薬品添加物として通常使用される賦形剤、結合剤、崩壊剤、滑沢剤などを適宜配合することが可能である。
本発明で使用される賦形剤としては、乳糖などの糖類、結晶セルロースなどのセルロース類、トウモロコシデンプンなどのデンプン類、リン酸水素カルシウムなどが挙げられるが、乳糖および結晶セルロースが好ましい。
結合剤としては、ヒドロキシプロピルセルロース、ヒプロメロース、メチルセルロース、ポリビニルアルコール、部分アルファー化デンプンなどが挙げられるが、ヒドロキシプロピルセルロースが好ましい。
崩壊剤としては、カルボキシメチルスターチナトリウム、低置換度ヒドロキシプロピルセルロース、カルメロース、カルメロースカルシウム、クロスカルメロースナトリウム、クロスポビドンなどが挙げられるが、カルボキシメチルスターチナトリウムおよび低置換度ヒドロキシプロピルセルロースが好ましい。
滑沢剤としては、ステアリン酸マグネシウム、ステアリン酸カルシウム、ステアリン酸、フマル酸ステアリルナトリウム、ショ糖脂肪酸エステル、硬化油などが挙げられるが、ステアリン酸マグネシウムが好ましい。
本発明の錠剤の製造方法としては、湿式顆粒圧縮法、乾式顆粒圧縮法、直接粉末圧縮法などが挙げられるが、湿式顆粒圧縮法が好ましい。
湿式顆粒圧縮法で用いられる造粒方法としては、撹拌造粒、転動流動層造粒、流動層造粒、押出し造粒、噴霧乾燥造粒などが挙げられるが、撹拌造粒および転動流動層造粒が好ましい。
また、造粒工程で使用する溶媒としては、水、エタノール、メタノール、塩化メチレンなどが挙げられるが、水またはエタノールが好ましい。
以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲は下記の実施例に限定されるものではない。
In addition to bicalutamide and hydroxypropylcellulose, excipients, binders, disintegrants, lubricants and the like that are usually used as pharmaceutical additives can be appropriately blended in the preparation of the present invention.
Examples of the excipient used in the present invention include sugars such as lactose, celluloses such as crystalline cellulose, starches such as corn starch, calcium hydrogen phosphate and the like, and lactose and crystalline cellulose are preferred.
Examples of the binder include hydroxypropylcellulose, hypromellose, methylcellulose, polyvinyl alcohol, and partially pregelatinized starch, with hydroxypropylcellulose being preferred.
Examples of the disintegrant include carboxymethyl starch sodium, low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose sodium, crospovidone, and carboxymethyl starch sodium and low-substituted hydroxypropylcellulose are preferable.
Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, sodium stearyl fumarate, sucrose fatty acid ester, and hardened oil, and magnesium stearate is preferable.
Examples of the method for producing the tablet of the present invention include a wet granule compression method, a dry granule compression method, and a direct powder compression method, and the wet granule compression method is preferable.
Examples of the granulation method used in the wet granulation method include stirring granulation, rolling fluidized bed granulation, fluidized bed granulation, extrusion granulation, spray drying granulation, and the like. Layer granulation is preferred.
Examples of the solvent used in the granulation step include water, ethanol, methanol, methylene chloride, and the like, but water or ethanol is preferable.
EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example.
ビカルタミド（平均粒子径：３．０μｍ）８０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）１０４．０ｇ、ヒドロキシプロピルセルロース（商品名：ＨＰＣ、日本曹達）４．０ｇ、カルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）７．０ｇを攪拌造粒機（ＶＧ−０１、パウレック製）に入れ、混合後、水３４．０ｇを添加して造粒した。
造粒物を流動層乾燥機（フローコーターミニ、フロイント産業製）で乾燥し、２２メッシュ篩で整粒した。
整粒品１８４．６ｇに対してカルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）６．６ｇ、ステアリン酸マグネシウム（日本油脂製）２．８ｇを加えて混合し、ロータリー打錠機（ＰＩＣＣＯＬＡ、奈良機械製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
Bicalutamide (average particle size: 3.0 μm) 80.0 g, lactose (trade name: lactose 200M, manufactured by DMV) 104.0 g, hydroxypropylcellulose (trade name: HPC, Nippon Soda) 4.0 g, sodium carboxymethyl starch ( Product name: Glycoris, manufactured by ROQUETTE (7.0 g) was placed in a stirring granulator (VG-01, manufactured by Paulek), mixed, and then granulated by adding 34.0 g of water.
The granulated product was dried with a fluidized bed dryer (Flow coater mini, manufactured by Freund Corporation) and sized with a 22 mesh sieve.
6.6 g of sodium carboxymethyl starch (trade name: Glycoris, manufactured by ROQUETTE) and 2.8 g of magnesium stearate (manufactured by NOF Corporation) are added to and mixed with 184.6 g of the sized product, and a rotary tableting machine (PICCOLA, Manufactured by Nara Machinery Co., Ltd.), tablets with a diameter of 7.5 mm and a weight of 205 mg were obtained.
ビカルタミド（平均粒子径：３．０μｍ）８０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）６４．０ｇ、結晶セルロース（商品名：セオラスＫＧ８０２、旭化成製）４０．０ｇ、ヒドロキシプロピルセルロース（商品名：ＨＰＣ、日本曹達）４．０ｇ、カルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）７．０ｇを攪拌造粒機（ＶＧ−０１、パウレック製）に入れ、混合後、水６０．０ｇを添加して造粒した。
造粒物を流動層乾燥機（フローコーターミニ、フロイント産業製）で乾燥し、２２メッシュ篩で整粒した。
整粒品１８７．２ｇに対してカルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）６．７ｇ、ステアリン酸マグネシウム（日本油脂製）２．９ｇを加えて混合し、ロータリー打錠機（ＰＩＣＣＯＬＡ、奈良機械製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
Bicalutamide (average particle size: 3.0 μm) 80.0 g, lactose (trade name: lactose 200M, manufactured by DMV) 64.0 g, crystalline cellulose (trade name: Theolas KG802, manufactured by Asahi Kasei) 40.0 g, hydroxypropyl cellulose (product) Name: HPC, Nippon Soda Co., Ltd.) 4.0 g, sodium carboxymethyl starch (trade name: Glycoris, manufactured by ROQUETTE) 7.0 g was added to an agitating granulator (VG-01, manufactured by Pauleck), mixed, and then water 60.0 g And granulated.
The granulated product was dried with a fluidized bed dryer (Flow coater mini, manufactured by Freund Corporation) and sized with a 22 mesh sieve.
6.7 g of sodium carboxymethyl starch (trade name: Glycoris, manufactured by ROQUETTE) and 2.9 g of magnesium stearate (manufactured by NOF Corporation) are added to and mixed with 187.2 g of the sized product, and a rotary tableting machine (PICCOLA, Manufactured by Nara Machinery Co., Ltd.), tablets with a diameter of 7.5 mm and a weight of 205 mg were obtained.
ビカルタミド（平均粒子径：３．０μｍ）８０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）６４．０ｇ、結晶セルロース（商品名：セオラスＫＧ８０２、旭化成製）４０．０ｇ、ヒドロキシプロピルセルロース（商品名：ＨＰＣ、日本曹達）４．０ｇ、低置換度ヒドロキシプロピルセルロース（商品名：Ｌ−ＨＰＣ、信越化学製）７．０ｇを攪拌造粒機（ＶＧ−０１、パウレック製）に入れ、混合後、水５５．０ｇを添加して造粒した。
造粒物を流動層乾燥機（フローコーターミニ、フロイント産業製）で乾燥し、２２メッシュ篩で整粒した。
整粒品１７９．１ｇに対して低置換度ヒドロキシプロピルセルロース（商品名：Ｌ−ＨＰＣ、信越化学製）６．４ｇ、ステアリン酸マグネシウム（日本油脂製）２．８ｇを加えて混合し、ロータリー打錠機（ＰＩＣＣＯＬＡ、奈良機械製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
Bicalutamide (average particle size: 3.0 μm) 80.0 g, lactose (trade name: lactose 200M, manufactured by DMV) 64.0 g, crystalline cellulose (trade name: Theolas KG802, manufactured by Asahi Kasei) 40.0 g, hydroxypropyl cellulose (product) Name: HPC, Nippon Soda) 4.0 g, low substituted hydroxypropylcellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical) 7.0 g was added to a stirring granulator (VG-01, manufactured by Pou Lec) and mixed. Then, 55.0 g of water was added and granulated.
The granulated product was dried with a fluidized bed dryer (Flow coater mini, manufactured by Freund Corporation) and sized with a 22 mesh sieve.
7.4 g of low-substituted hydroxypropyl cellulose (trade name: L-HPC, manufactured by Shin-Etsu Chemical Co., Ltd.) and 2.8 g of magnesium stearate (manufactured by Nippon Oil & Fats) were added to and mixed with 179.1 g of the sized product. A tablet with a diameter of 7.5 mm and a weight of 205 mg was obtained with a tablet machine (PICCOLA, manufactured by Nara Machinery Co., Ltd.).
ビカルタミド（平均粒子径：３．０μｍ）８０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）６０．０ｇ、結晶セルロース（商品名：セオラスＫＧ８０２、旭化成製）４０．０ｇ、ヒドロキシプロピルセルロース（商品名：ＨＰＣ、日本曹達）８．０ｇ、カルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）１４．０ｇを攪拌造粒機（ＶＧ−０１、パウレック製）に入れ、混合後、水６８．０ｇを添加して造粒した。
造粒物を流動層乾燥機（フローコーターミニ、フロイント産業製）で乾燥し、２２メッシュ篩で整粒した。
整粒品１９５．８ｇに対してステアリン酸マグネシウム（日本油脂製）２．９ｇを加えて混合し、ロータリー打錠機（ＰＩＣＣＯＬＡ、奈良機械製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
Bicalutamide (average particle size: 3.0 μm) 80.0 g, lactose (trade name: lactose 200M, manufactured by DMV) 60.0 g, crystalline cellulose (trade name: Theolas KG802, manufactured by Asahi Kasei) 40.0 g, hydroxypropyl cellulose (product) Name: HPC, Nippon Soda) 8.0 g, sodium carboxymethyl starch (trade name: Glycolis, manufactured by ROQUETTE) 14.0 g was added to a stirring granulator (VG-01, manufactured by Paulek), and after mixing, 68.0 g of water. And granulated.
The granulated product was dried with a fluidized bed dryer (Flow coater mini, manufactured by Freund Corporation) and sized with a 22 mesh sieve.
1.9 g of magnesium stearate (manufactured by NOF Corporation) was added to and mixed with 195.8 g of the sized product, and a tablet with a diameter of 7.5 mm and a weight of 205 mg was used on a rotary tableting machine (PICCOLA, Nara Machinery Co., Ltd.). Got.
ビカルタミド（平均粒子径：３．２μｍ）２４０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）１９２．０ｇ、結晶セルロース（商品名：セオラスＫＧ８０２、旭化成製）１２０．０ｇ、ヒドロキシプロピルセルロース（商品名：ＨＰＣ、日本曹達）１２．０ｇ、カルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）４２．０ｇを攪拌造粒機（ＶＧ−０５、パウレック製）に入れ、混合後、水２１６．０ｇを添加して造粒した。
造粒物を流動層乾燥機（ＭＰ−０１、パウレック製）で乾燥し、２２メッシュ篩で整粒した。
整粒品５６５．６ｇに対してステアリン酸マグネシウム（日本油脂製）８．４ｇを加えて混合し、ロータリー打錠機（アクエリアス、菊水製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
精製水１２９．６８ｇ、ヒプロメロース（商品名：ＴＣ−５ＲＷ、信越化学製）６．８３ｇ、マクロゴール６０００（商品名：マクロゴール６０００Ｐ、日本油脂製）１．０５ｇ、酸化チタン（商品名：ＴＩＰＡＱＵＥ、石原産業製）１．５８ｇ、タルク（商品名：タルカンハヤシ、林化成製）１．０５ｇを溶解、分散させたコーティング液を調製し、先に得た錠剤３０７．５を錠剤コーティング機（ＨＣ−ＬＡＢＯ：フロイント産業製）に入れ、１錠の重量が２１０ｍｇになるまでコーティング液をスプレーして、フィルムコーティング錠を得た。
以上の実施例１〜５の処方を図１の表に一錠当りの配合成分量として表した。
表中、ＨＰＣはヒドロキシプロピルセルロースを示し、ＣＭＳ−Ｎａはカルボキシメチルスターチナトリウムを示す。
240.0 g of bicalutamide (average particle size: 3.2 μm), 192.0 g of lactose (trade name: lactose 200M, manufactured by DMV), 120.0 g of crystalline cellulose (trade name: Theolas KG802, manufactured by Asahi Kasei), hydroxypropyl cellulose (product) Name: HPC, Nippon Soda) 12.0 g, Carboxymethyl starch sodium (trade name: Glycoris, manufactured by ROQUETTE) 42.0 g was added to a stirring granulator (VG-05, manufactured by Pauleck), mixed, and 216.0 g of water. And granulated.
The granulated product was dried with a fluidized bed dryer (MP-01, manufactured by Paulek) and sized with a 22 mesh sieve.
8.4 g of magnesium stearate (manufactured by NOF Corporation) is added to and mixed with 565.6 g of the sized product, and a tablet with a diameter of 7.5 mm and a weight of 205 mg is prepared using a rotary tableting machine (Aquarius, manufactured by Kikusui Seisakusho). Obtained.
129.68 g of purified water, hypromellose (trade name: TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.) 6.83 g, macrogol 6000 (trade name: Macrogol 6000P, manufactured by Nippon Oil & Fats) 1.05 g, titanium oxide (trade name: TIPAQUE, Ishihara Sangyo Co., Ltd. (1.58 g) and talc (trade name: Talkan Hayashi Co., Ltd., Hayashi Kasei Co., Ltd.) 1.05 g are dissolved and dispersed to prepare a coating solution. LABO (manufactured by Freund Corporation) was sprayed with the coating solution until the weight of one tablet was 210 mg to obtain film-coated tablets.
The formulations of Examples 1 to 5 described above are shown in the table of FIG.
In the table, HPC represents hydroxypropylcellulose, and CMS-Na represents sodium carboxymethyl starch.
（比較例１）
ビカルタミド（平均粒子径：３．０μｍ）８０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）１０４．０ｇ、ポリビニルピロリドンＫ３０（商品名：コリドン３０、ＢＡＳＦ）４．０ｇ、カルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）７．０ｇを攪拌造粒機（ＶＧ−０１、パウレック製）に入れ、混合後、水３４．０ｇを添加して造粒した。
造粒物を流動層乾燥機（フローコーターミニ、フロイント産業製）で乾燥し、２２メッシュ篩で整粒した。
整粒品１８４．６ｇに対してカルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）６．６ｇ、ステアリン酸マグネシウム（日本油脂製）２．８ｇを加えて混合し、ロータリー打錠機（ＰＩＣＣＯＬＡ、奈良機械製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
(Comparative Example 1)
Bicalutamide (average particle size: 3.0 μm) 80.0 g, lactose (trade name: lactose 200M, manufactured by DMV) 104.0 g, polyvinylpyrrolidone K30 (trade name: Kollidon 30, BASF) 4.0 g, sodium carboxymethyl starch ( Product name: Glycoris, manufactured by ROQUETTE (7.0 g) was placed in a stirring granulator (VG-01, manufactured by Paulek), mixed, and then granulated by adding 34.0 g of water.
The granulated product was dried with a fluidized bed dryer (Flow coater mini, manufactured by Freund Corporation) and sized with a 22 mesh sieve.
6.6 g of sodium carboxymethyl starch (trade name: Glycoris, manufactured by ROQUETTE) and 2.8 g of magnesium stearate (manufactured by NOF Corporation) are added to and mixed with 184.6 g of the sized product, and a rotary tableting machine (PICCOLA, Manufactured by Nara Machinery Co., Ltd.), tablets with a diameter of 7.5 mm and a weight of 205 mg were obtained.
（比較例２）
精製水１４９．７２ｇ、ヒプロメロース（商品名：ＴＣ−５ＲＷ、信越化学製）７．８８ｇ、マクロゴール３００（商品名：マクロゴール３００、三洋化成製）１．０５ｇ、酸化チタン（商品名：ＴＩＰＡＱＵＥ、石原産業製）１．５８ｇを溶解、分散させたコーティング液を調製し、比較例１で得た錠剤および希釈錠合計３０７．５を錠剤コーティング機（ＨＣ−ＬＡＢＯ：フロイント産業製）に入れ、１錠の重量が２１０ｍｇになるまでコーティング液をスプレーして、フィルムコーティング錠を得た。
(Comparative Example 2)
149.72 g of purified water, 7.88 g of hypromellose (trade name: TC-5RW, manufactured by Shin-Etsu Chemical Co., Ltd.), 1.05 g of Macrogol 300 (trade name: Macrogol 300, manufactured by Sanyo Kasei), titanium oxide (trade name: TIPAQUE, Ishihara Sangyo Co., Ltd.) A coating solution in which 1.58 g was dissolved and dispersed was prepared, and a total of 307.5 tablets and diluted tablets obtained in Comparative Example 1 were placed in a tablet coating machine (HC-LABO: Freund Sangyo). The coating solution was sprayed until the weight of the tablet was 210 mg to obtain a film-coated tablet.
（比較例３）
ビカルタミド（平均粒子径：３．０μｍ）８０．０ｇ、乳糖（商品名：乳糖２００Ｍ、ＤＭＶ製）１００．０ｇ、ポリビニルピロリドンＫ３０（商品名：コリドン３０、ＢＡＳＦ）８．０ｇ、カルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）７．０ｇを攪拌造粒機（ＶＧ−０１、パウレック製）に入れ、混合後、水３２．０ｇを添加して造粒した。
造粒物を流動層乾燥機（フローコーターミニ、フロイント産業製）で乾燥し、２２メッシュ篩で整粒した。
整粒品１８４．６ｇに対してカルボキシメチルスターチナトリウム（商品名：グリコリス、ＲＯＱＵＥＴＴＥ製）６．６ｇ、ステアリン酸マグネシウム（日本油脂製）２．８ｇを加えて混合し、ロータリー打錠機（ＰＩＣＣＯＬＡ、奈良機械製作所製）にて、直径７．５ｍｍ、重量２０５ｍｇの錠剤を得た。
以上の比較例１〜３の処方を図２の表に一錠当りの配合成分量として表した。
表中、ＰＶＰはポリビニルピロリドンを示す。
(Comparative Example 3)
Bicalutamide (average particle size: 3.0 μm) 80.0 g, lactose (trade name: lactose 200M, manufactured by DMV) 100.0 g, polyvinylpyrrolidone K30 (trade name: Kollidon 30, BASF) 8.0 g, sodium carboxymethyl starch ( Product name: Glycoris, manufactured by ROQUETTE (7.0 g) was placed in a stirring granulator (VG-01, manufactured by Paulek), and after mixing, 32.0 g of water was added and granulated.
The granulated product was dried with a fluidized bed dryer (Flow coater mini, manufactured by Freund Corporation) and sized with a 22 mesh sieve.
6.6 g of sodium carboxymethyl starch (trade name: Glycoris, manufactured by ROQUETTE) and 2.8 g of magnesium stearate (manufactured by NOF Corporation) are added to and mixed with 184.6 g of the sized product, and a rotary tableting machine (PICCOLA, Manufactured by Nara Machinery Co., Ltd.), tablets with a diameter of 7.5 mm and a weight of 205 mg were obtained.
The prescriptions of Comparative Examples 1 to 3 are shown in the table of FIG.
In the table, PVP represents polyvinylpyrrolidone.
（試験）
各種錠剤の溶出性を確認するために、実施例１〜５及び比較例１〜３の錠剤の溶出試験を、装置：パドル法、試験液：１％ポリソルベート８０を添加したＭｃＩｌｖａｉｎｅ緩衝液（ｐＨ４．０）、試験液量：９００ｍＬ、試験液温度：３７±０．５℃、パドル回転数：５０ｒｐｍの条件で実施した。
その結果を図３の表に示す。
ヒドロキシプロピルセルロースを配合した実施例１〜５は１２０分の溶出率が９０％前後を示すが、ヒドロキシプロピルセルロースを配合していない比較例１〜３は１２０分の溶出率が７０％程度であり、溶出率に差が見られた。
有効成分であるビカルタミドにヒドロキシプロピルセルロースを配合することで、簡易な製法を採用しても、ビカルタミドの溶解性を高めることができることが明らかとなった。
(test)
In order to confirm the dissolution properties of various tablets, the dissolution tests of the tablets of Examples 1 to 5 and Comparative Examples 1 to 3 were carried out using the device: paddle method, test solution: McIlvaine buffer solution (pH 4. 0), test solution volume: 900 mL, test solution temperature: 37 ± 0.5 ° C., paddle rotation speed: 50 rpm.
The results are shown in the table of FIG.
In Examples 1 to 5 containing hydroxypropyl cellulose, the elution rate for 120 minutes is around 90%, but in Comparative Examples 1 to 3 not containing hydroxypropyl cellulose, the elution rate for 120 minutes is about 70%. There was a difference in elution rate.
It became clear that the solubility of bicalutamide can be enhanced by blending hydroxypropyl cellulose with bicalutamide, which is an active ingredient, even if a simple production method is adopted.
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004143185A (en) * | 2001-02-27 | 2004-05-20 | Astrazeneca Ab | Pharmaceutical formulation |
| WO2002100339A2 (en) * | 2001-06-13 | 2002-12-19 | Biogal Gyogyszergyar Rt. | Novel process for preparing rac-bicalutamide and its intermediates |
| JP2004175795A (en) * | 2002-11-13 | 2004-06-24 | Takeda Chem Ind Ltd | Medicinal composition excellent in releasability of medicament |
| WO2006069098A1 (en) * | 2004-12-22 | 2006-06-29 | Elan Pharma International Ltd. | Nanoparticulate bicalutamide formulations |
| JP2008540644A (en) * | 2005-07-15 | 2008-11-20 | テバ ファーマシューティカル インダストリーズ リミティド | New granulation method and granulated material produced therefrom |
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