JP2017048174A - Orally disintegrable tablet containing chemically stable coated particles containing drug substance - Google Patents
Orally disintegrable tablet containing chemically stable coated particles containing drug substance Download PDFInfo
- Publication number
- JP2017048174A JP2017048174A JP2016166508A JP2016166508A JP2017048174A JP 2017048174 A JP2017048174 A JP 2017048174A JP 2016166508 A JP2016166508 A JP 2016166508A JP 2016166508 A JP2016166508 A JP 2016166508A JP 2017048174 A JP2017048174 A JP 2017048174A
- Authority
- JP
- Japan
- Prior art keywords
- silodosin
- tablet
- coated particles
- drug substance
- orally disintegrating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002245 particle Substances 0.000 title claims abstract description 56
- 239000008186 active pharmaceutical agent Substances 0.000 title abstract description 26
- 229940088679 drug related substance Drugs 0.000 title abstract description 26
- PNCPYILNMDWPEY-QGZVFWFLSA-N silodosin Chemical compound N([C@@H](CC=1C=C(C=2N(CCCO)CCC=2C=1)C(N)=O)C)CCOC1=CC=CC=C1OCC(F)(F)F PNCPYILNMDWPEY-QGZVFWFLSA-N 0.000 claims abstract description 53
- 229960004953 silodosin Drugs 0.000 claims abstract description 53
- 229920000642 polymer Polymers 0.000 claims abstract description 29
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 19
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 18
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 18
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 18
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims abstract description 14
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 13
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims abstract description 13
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 12
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims abstract description 9
- 229960003943 hypromellose Drugs 0.000 claims abstract description 8
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 claims abstract description 5
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims abstract 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 claims abstract description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 claims description 35
- 238000000576 coating method Methods 0.000 claims description 32
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- 238000004519 manufacturing process Methods 0.000 claims description 11
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- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 5
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 4
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 10
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- 230000000996 additive effect Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
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- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920013820 alkyl cellulose Polymers 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 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
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- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
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- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
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Abstract
Description
本発明は、原薬として１−（３−ヒドロキシプロピル）−５−［（２Ｒ）−（｛２−［２−［２−（２，２，２−トリフルオロエトキシ）フェノキシ］エチル｝アミノ）プロピル］インドリン−７−カルボキサミド、すなわちシロドシン（日本医薬品一般名称）を含有する錠剤に関する。 The present invention provides 1- (3-hydroxypropyl) -5-[(2R)-({2- [2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl} amino) as the drug substance. Propyl] indoline-7-carboxamide, that is, a tablet containing silodosin (Japanese generic name).
シロドシンは、下部尿路組織である前立腺、尿道、膀胱三角部のα１Ａ受容体サブタイプに選択的に結合し、尿道内圧の上昇を抑制する作用機構をもち、前立腺肥大に伴う排尿障害の治療薬に用いられる化合物（原薬）である（非特許文献１参照）。シロドシンと薬理学的に関連するα１遮断薬としては、プラゾシン塩酸塩、テラゾシン塩酸塩水和物、ウラジピルなどが挙げられる。 Silodosin selectively binds to α 1A receptor subtypes in the lower urinary tract tissues such as prostate, urethra, and bladder triangle, and has an action mechanism that suppresses the increase in urethral pressure, and treats dysuria associated with prostatic hypertrophy. It is a compound (drug substance) used in medicine (see Non-Patent Document 1). Examples of α 1 blockers that are pharmacologically related to silodosin include prazosin hydrochloride, terazosin hydrochloride hydrate, uradipir and the like.
現在、シロドシンはフィルムコート錠の剤形で医療現場に提供されているが、口腔内崩壊錠の剤形では医療現場にいまだ提供されていない。
口腔内崩壊錠は近年開発された剤形であり、唾液程度の少量の水で素早く崩壊する性質をもつことから、普通錠に比べて服用時の利便性が高いことが知られる。そのため、シロドシンについても患者の服用性の向上のために口腔内崩壊錠の開発は当然望まれる。しかし一般的に、口腔内崩壊錠は普通錠と技術的な相違点を有しており、原薬の化学的な安定性等の品質を保証することは困難であることが多い。
シロドシンの口腔内崩壊錠において利用可能な技術として、特許文献１ではシロドシンを含有する粒子を非腸溶性ポリマーで被覆（コーティング）することでシロドシンの苦味を改善する技術が報告されている。苦味の有る原薬において、その周囲を医薬添加物でコーティングして錠剤服用時に感じる苦味をマスキングすることは周知の技術（特許文献２、３）であり、口腔内崩壊錠の製造において重要な技術である。
Currently, silodosin is provided in the medical field in the form of a film-coated tablet, but is not yet provided in the medical field in the form of an orally disintegrating tablet.
An orally disintegrating tablet is a dosage form developed in recent years, and is known to be more convenient at the time of taking than ordinary tablets because it has the property of rapidly disintegrating with a small amount of water such as saliva. Therefore, development of an orally disintegrating tablet is naturally desired for improving the patient's dose of silodosin. In general, however, orally disintegrating tablets have technical differences from ordinary tablets, and it is often difficult to guarantee the quality of the drug substance such as chemical stability.
As a technique that can be used in an orally disintegrating tablet of silodosin, Patent Document 1 reports a technique for improving the bitter taste of silodosin by coating (coating) particles containing silodosin with a non-enteric polymer. It is a well-known technique (patent documents 2 and 3) to mask the bitter taste felt when taking tablets by coating the periphery with a pharmaceutical additive in a drug substance having a bitter taste, and an important technique in the production of orally disintegrating tablets It is.
しかし上記の特許文献１で紹介されるコーティング技術によっては、口腔内崩壊錠に含まれるシロドシンの苦味を十分に抑えることが可能でも、保存条件下での化学的な安定性を十分に改善することは困難であると本発明者は考えた。そこで本発明者は保存条件下での口腔内崩壊錠に含まれるシロドシンの安定性を向上させることを目的として、シロドシンを含有する口腔内崩壊錠の処方及び製造方法に関する検討を開始した。 However, depending on the coating technique introduced in Patent Document 1, the chemical stability under storage conditions should be sufficiently improved even though the bitter taste of silodosin contained in the orally disintegrating tablet can be sufficiently suppressed. The present inventor considered it difficult. Therefore, the present inventor has started studies on the formulation and production method of an orally disintegrating tablet containing silodosin for the purpose of improving the stability of silodosin contained in the orally disintegrating tablet under storage conditions.
本発明の主な課題は、シロドシン等の原薬を含有する口腔内崩壊錠について、保存条件下でのシロドシンの化学的な安定性を向上させ、原薬由来の分解産物（類縁体）の発生量を抑制することである。 The main object of the present invention is to improve the chemical stability of silodosin under storage conditions for the orally disintegrating tablets containing a drug substance such as silodosin, and to generate degradation products (analogues) derived from the drug substance It is to suppress the amount.
本発明者は、口腔内崩壊錠におけるシロドシンの化学的な安定性を改善するため、そのコーティングに関する処方や製造方法に関して鋭意検討を重ねた。その結果、特定種類のポリマーでコーティングされたシロドシン又はシロドシンを含有する粒子は、保存条件下でのシロドシンの化学的な安定性が向上し、原薬由来の類縁体の発生量が顕著に抑えられることを発見した。その知見に基づき、本発明者はさらに鋭意検討を重ねて下記の発明を完成させた。 In order to improve the chemical stability of silodosin in the orally disintegrating tablet, the present inventor has conducted extensive studies on the formulation and manufacturing method relating to the coating. As a result, silodosin or particles containing silodosin coated with a specific type of polymer improve the chemical stability of silodosin under storage conditions, and significantly reduce the amount of analogs derived from the drug substance. I discovered that. Based on this knowledge, the present inventor made further studies and completed the following invention.
本発明は、（Ａ）原薬、又は原薬を含有する粒子を（Ｂ）水溶性ポリマー又は腸溶性ポリマーでコーティングした粒子、を含む錠剤に関するものであり、その好ましい構成は、下記（１）〜（６）によって記述されているものである。
（１）（Ａ）シロドシン、又はシロドシンを含有する粒子を（Ｂ）水溶性ポリマー又は腸溶性ポリマーでコーティングした被覆粒子、を含む口腔内崩壊錠。
（２）水溶性ポリマーでコーティングした被覆粒子を含み、水溶性ポリマーがメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルピロリドン、カルメロースナトリウム、アルギン酸ナトリウム、マクロゴールより選ばれる、前記（１）に記載の口腔内崩壊錠。
（３）被覆粒子中に含まれる、シロドシン対水溶性ポリマーの重量比が１．０：０．５〜５．０の範囲内である、前記（２）に記載の口腔内崩壊錠。
（４）腸溶性ポリマーでコーティングした被覆粒子を含み、腸溶性ポリマーがメタクリル酸コポリマー、ヒプロメロースフタル酸エステル、ヒプロメロース酢酸エステルコハク酸エステル、カルボキシメチルエチルセルロースより選ばれる、前記（１）に記載の口腔内崩壊錠。
（５）被覆粒子中に含まれる、シロドシン対腸溶性ポリマーの重量比が１．０：０．５〜５．０の範囲内である、前記（４）に記載の口腔内崩壊錠。
（６）前記（１）〜（５）のいずれかに記載の錠剤に含まれる被覆粒子を微粒子コーティング法を介して製造する方法。
The present invention relates to a tablet comprising (A) a drug substance or particles obtained by coating a drug substance-containing drug particle with (B) a water-soluble polymer or an enteric polymer. To (6).
(1) An orally disintegrating tablet comprising (A) silodosin, or coated particles obtained by coating particles containing silodosin with (B) a water-soluble polymer or an enteric polymer.
(2) Including coated particles coated with a water-soluble polymer, the water-soluble polymer is methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl pyrrolidone, carmellose sodium Orally disintegrating tablet according to (1), selected from sodium alginate and macrogol.
(3) The orally disintegrating tablet according to (2) above, wherein the weight ratio of silodosin to the water-soluble polymer contained in the coated particles is in the range of 1.0: 0.5 to 5.0.
(4) The coated particle coated with an enteric polymer, wherein the enteric polymer is selected from a methacrylic acid copolymer, hypromellose phthalate, hypromellose acetate succinate, and carboxymethyl ethyl cellulose. Orally disintegrating tablets.
(5) The orally disintegrating tablet according to (4), wherein the weight ratio of silodosin to enteric polymer contained in the coated particles is in the range of 1.0: 0.5 to 5.0.
(6) A method for producing coated particles contained in the tablet according to any one of (1) to (5) through a fine particle coating method.
本発明によれば、シロドシン等の原薬を含有する口腔内崩壊錠について、保存条件下での原薬の化学的な安定性を向上させ、原薬由来の分解産物（類縁体）の発生量を抑制する効果が期待される。 According to the present invention, for an orally disintegrating tablet containing a drug substance such as silodosin, the chemical stability of the drug substance under storage conditions is improved, and the amount of degradation products (analogues) derived from the drug substance is generated. It is expected to suppress the
以下で本発明の錠剤の処方及び製造方法等を詳細に説明する。但し、以下の記載は本発明を説明するための例示であり、本発明をこの記載範囲にのみ限定する趣旨ではない。 Hereinafter, the formulation and production method of the tablet of the present invention will be described in detail. However, the following description is an example for explaining the present invention, and is not intended to limit the present invention to this description range.
本発明の錠剤は普通錠又は口腔内崩壊錠であるが、好ましくは口腔内崩壊錠であり、最も好ましくは素錠である口腔内崩壊錠である。 The tablet of the present invention is an ordinary tablet or an orally disintegrating tablet, preferably an orally disintegrating tablet, and most preferably an orally disintegrating tablet.
本発明の錠剤を製造するために使用される具体的な原薬としては、モンテルカスト、ミグリトール、イルベサルタン、ロスバスタチン、オルメサルタンメドキソミル、シロドシン、エゼチミブ、イミダフェナシン、ラロキシフェン、セレコキシブ、ソリフェナシンコハク酸塩、エソメプラゾール等が挙げられるが、最も好ましくはシロドシンである。原薬は錠剤全重量に対して０．０１〜２０．０重量％の範囲で含有されることが好ましい。 Specific drug substances used to produce the tablets of the present invention include montelukast, miglitol, irbesartan, rosuvastatin, olmesartan medoxomil, silodosin, ezetimibe, imidafenacin, raloxifene, celecoxib, solifenacin succinate, esomeprazole, etc. Most preferred is silodosin. The drug substance is preferably contained in the range of 0.01 to 20.0% by weight based on the total weight of the tablet.
本発明の錠剤を製造するために使用されるシロドシンの平均粒子径（光散乱法による測定値）は２０．０μｍ以下であることが好ましく、より好ましくは５．０〜２０．０μｍである。必要に応じて適宜乾式又は湿式粉砕を行い、任意の粒子径に調整することも可能である。本発明の錠剤において、シロドシンは錠剤全重量に対して０．５〜１０．０重量％の範囲で含有されていることが好ましく、より好ましくは１．０〜５．０重量％の範囲で含有される。シロドシンの結晶形はα、β、γ型、非晶質形態が挙げられるが、好ましくはγ型である。錠剤中においてシロドシンは、水溶性ポリマー又は腸溶性ポリマーでコーティングした被覆粒子のコーティング層よりも内側の部分（芯部）のみに含有されていることが好ましく、そのコーティング層とシロドシンは被覆粒子中で物理的に接していることがさらに好ましい。 The average particle size (measured by the light scattering method) of silodosin used for producing the tablet of the present invention is preferably 20.0 μm or less, more preferably 5.0 to 20.0 μm. If necessary, dry or wet pulverization can be appropriately performed to adjust the particle size to an arbitrary value. In the tablet of the present invention, silodosin is preferably contained in the range of 0.5 to 10.0% by weight, more preferably in the range of 1.0 to 5.0% by weight, based on the total weight of the tablet. Is done. The crystalline form of silodosin includes α, β, γ, and amorphous forms, preferably the γ form. In the tablet, silodosin is preferably contained only in the inner part (core part) of the coating layer of the coated particle coated with a water-soluble polymer or enteric polymer, and the coating layer and silodosin are contained in the coated particle. More preferably, they are in physical contact.
本発明の錠剤を製造するために使用可能な添加物としては、一般的に使用されている賦形剤、結合剤、崩壊剤、滑沢剤、矯味剤、コーティング剤等を挙げることができる。 Examples of additives that can be used for producing the tablet of the present invention include commonly used excipients, binders, disintegrants, lubricants, corrigents, and coating agents.
具体的な賦形剤としては、乳糖、結晶セルロース、Ｄ-マンニトール、エリスリトール、キシリトール、ソルビトール、イソマルト、マルチトール、白糖、ショ糖、ブドウ糖、トウモロコシデンプン、部分アルファー化デンプン等を挙げる事ができ、好ましくはＤ-マンニトール、部分アルファー化デンプン、結晶セルロース、トウモロコシデンプンから選択される。賦形剤は、錠剤全重量に対して５０．０〜９５．０重量％、好ましくは７０．０〜９０．０重量％の範囲で錠剤中に含有される。 Specific excipients include lactose, crystalline cellulose, D-mannitol, erythritol, xylitol, sorbitol, isomalt, maltitol, sucrose, sucrose, glucose, corn starch, partially pregelatinized starch, etc. Preferably, it is selected from D-mannitol, partially pregelatinized starch, crystalline cellulose and corn starch. The excipient is contained in the tablet in the range of 50.0 to 95.0% by weight, preferably 70.0 to 90.0% by weight, based on the total weight of the tablet.
具体的な結合剤としては、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、ポビドン、エチルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリエチレングリコール等を挙げる事ができ、好ましくはヒドロキシプロピルセルロースである。結合剤は、錠剤全重量に対して０．０１〜５．０重量％、好ましくは０．０５〜０．５重量％の範囲で錠剤中に含有される。 Specific examples of the binder include hydroxypropylcellulose, hypromellose, methylcellulose, povidone, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, and polyethylene glycol, preferably hydroxypropylcellulose. It is. The binder is contained in the tablet in the range of 0.01 to 5.0% by weight, preferably 0.05 to 0.5% by weight, based on the total weight of the tablet.
具体的な崩壊剤としては、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、カルメロースナトリウム、ヒドロキシプロピルスターチ、カルボキシメチルスターチナトリウム、クロスポビドン、カンテン末等を挙げる事ができ、好ましくはクロスポビドンである。崩壊剤は、錠剤全重量に対して１．０〜４０．０重量％、好ましくは２．０〜１０．０重量％の範囲で錠剤中に含有される。 Specific examples of the disintegrant include low-substituted hydroxypropyl cellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, crospovidone, and agar powder. Preferably, crospovidone is used. It is. The disintegrant is contained in the tablet in the range of 1.0 to 40.0% by weight, preferably 2.0 to 10.0% by weight, based on the total weight of the tablet.
具体的な滑沢剤としては、軽質無水ケイ酸、ステアリン酸マグネシウム、ステアリン酸カルシウム、フマル酸ステアリルナトリウム、タルク、硬化油等を挙げる事ができ、好ましくはフマル酸ステアリルナトリウム又はステアリン酸マグネシウムである。滑沢剤は、錠剤全重量に対して０．１〜１０．０重量％、好ましくは０．１〜５．０重量％の範囲で錠剤中に含有される。 Specific examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated oil, and the like, preferably sodium stearyl fumarate or magnesium stearate. The lubricant is contained in the tablet in the range of 0.1 to 10.0% by weight, preferably 0.1 to 5.0% by weight, based on the total weight of the tablet.
具体的な矯味剤としては、アスコルビン酸、Ｌ−アスパラギン酸、アスパルテーム、スクラロース、アセスルファムカリウム、ソーマチン等を挙げる事ができる。矯味剤は、錠剤全重量に対して０．５〜２．０重量％の範囲で錠剤中に含有されていることが好ましい。 Specific examples of the corrigent include ascorbic acid, L-aspartic acid, aspartame, sucralose, acesulfame potassium, thaumatin and the like. The taste-masking agent is preferably contained in the tablet in the range of 0.5 to 2.0% by weight based on the total weight of the tablet.
具体的なコーティング剤としては、ヒプロメロース，エチルセルロース，ヒドロキシメチルセルロース、ヒドロキシプロピルセルロース、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルアルコール、ポリエチレングリコール、タルク等の広範な種類を挙げる事ができ、好ましくはタルクである。コーティング剤は、錠剤全重量に対して０．５〜１０．０重量％、好ましくは１．０〜５．０重量％の範囲で錠剤中に含有される。 Specific examples of the coating agent include hypromellose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol, polyethylene glycol, talc and the like. Talc is preferred. The coating agent is contained in the tablet in the range of 0.5 to 10.0% by weight, preferably 1.0 to 5.0% by weight, based on the total weight of the tablet.
具体的な可塑剤としては、ゴマ油、ヒマシ油、綿実油・ダイズ油混合物、ジメチルポリシロキサン・二酸化ケイ素混合物、中鎖脂肪酸トリグリセリド、クエン酸トリエチル、クエン酸トリブチル、トリアセチン、フタル酸ジエチル、フタル酸ジブチル、ブチルフタリルブチルグリコレート、グリセリン、グリセリン脂肪酸エステル、ポリエチレングリコール、プロピレングリコール等を挙げる事ができ、好ましくはクエン酸トリエチルである。可塑剤は、錠剤全重量に対して０．０１〜１０．０重量％の範囲で錠剤中に含有されていることが好ましい。 Specific plasticizers include sesame oil, castor oil, cottonseed oil / soybean oil mixture, dimethylpolysiloxane / silicon dioxide mixture, medium chain fatty acid triglyceride, triethyl citrate, tributyl citrate, triacetin, diethyl phthalate, dibutyl phthalate, Examples thereof include butyl phthalyl butyl glycolate, glycerin, glycerin fatty acid ester, polyethylene glycol and propylene glycol, and triethyl citrate is preferable. The plasticizer is preferably contained in the tablet in the range of 0.01 to 10.0% by weight relative to the total weight of the tablet.
本発明の錠剤は、原薬、又は原薬を含有する粒子（好ましくは平均粒子径が２００μｍ以下の粒子）を、水溶性ポリマー又は腸溶性ポリマーを含むコーティング液（好ましくは水溶性ポリマーを含む）を噴霧することによってコーティングした被覆粒子を含有するものである。
本発明に係る水溶性ポリマーは、任意のｐＨ値をもつ水溶媒（実質的に水のみからなる）又は水溶液溶媒に対して良好な溶解性を示すことを特徴とし、水溶媒（例えば、ｐＨが６．５〜７．５の範囲内にある）１００ｇに対する２５℃における溶解度が１．０ｇ以上の、平均分子量が１００００以上のポリマーであることが望ましい。具体的に使用可能な水溶性ポリマーとしては、アルキルセルロース（例えばメチルセルロース）、ヒドロキシアルキルセルロース（例えばヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシブチルセルロース）、ヒドロキシアルキルアルキルセルロース（例えばヒドロキシエチルメチルセルロース、ヒプロメロース）、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルピロリドン、カルメロースナトリウム、アルギン酸ナトリウム、マクロゴール等を挙げる事ができ、好ましくはメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ポリビニルピロリドン、カルメロースナトリウム、アルギン酸ナトリウム、マクロゴールから選択され、より好ましくはヒドロキシプロピルセルロースである。
本発明に係る腸溶性ポリマーは、腸内環境を想定した中性〜アルカリ性のｐＨ値をもつ水溶液溶媒に対して良好な溶解性を示すことを特徴とし、ｐＨが６．８〜１２．０の範囲内にある０．１ｍｏｌ／Ｌ以下のモル濃度をもつ水溶液溶媒（例えば、ｐＨが１０．２である０．０５ｍｏｌ／Ｌ炭酸ナトリウム緩衝液）１００ｇに対する２５℃における溶解度が１．０ｇ以上の、平均分子量が１００００以上のポリマーであることが望ましい。具体的に使用可能な腸溶性ポリマーとしては、メタクリル酸コポリマー（例えばメタクリル酸コポリマーＬ、メタクリル酸コポリマーＬＤ、メタクリル酸コポリマーＳ等）、ヒドロキシアルキルアルキルセルロースフタル酸エステル（例えばヒプロメロースフタル酸エステル）、ヒドロキシアルキルアルキルセルロース酢酸エステルコハク酸エステル（例えばヒプロメロース酢酸エステルコハク酸エステル）、カルボキシアルキルアルキルセルロース（例えばカルボキシメチルエチルセルロース）等を挙げる事ができ、好ましくはメタクリル酸コポリマー、ヒプロメロースフタル酸エステル、ヒプロメロース酢酸エステルコハク酸エステル、カルボキシメチルエチルセルロースから選択され、より好ましくはメタクリル酸コポリマーであり、さらにより好ましくはメタクリル酸コポリマーＬである。
被覆粒子中に含まれる、原薬対、水溶性ポリマー又は／及び腸溶性ポリマー、の重量比は、１：０．０５〜２０．０の範囲内であることが好ましく、より好ましくは１：０．１〜５．０の範囲内であり、さらにより好ましくは１：０．１〜３．０の範囲内である。
The tablet of the present invention is a coating liquid (preferably containing a water-soluble polymer) containing a drug substance or particles containing the drug substance (preferably particles having an average particle diameter of 200 μm or less) and a water-soluble polymer or enteric polymer. Containing coated particles coated by spraying.
The water-soluble polymer according to the present invention is characterized by exhibiting good solubility in an aqueous solvent having an arbitrary pH value (substantially only water) or an aqueous solvent, and an aqueous solvent (for example, having a pH of It is desirable that the polymer has an average molecular weight of 10,000 or more and a solubility at 25 ° C. with respect to 100 g (within a range of 6.5 to 7.5) of 1.0 g or more. Specific examples of water-soluble polymers that can be used include alkyl cellulose (eg, methyl cellulose), hydroxyalkyl cellulose (eg, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose), and hydroxyalkyl alkyl cellulose (eg, hydroxyethyl methyl cellulose, hypromellose). ), Polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinylpyrrolidone, carmellose sodium, sodium alginate, macrogol, etc., preferably methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl Alcohol, polyvinyl alcohol, acrylic · Methyl methacrylate copolymer, polyvinylpyrrolidone, croscarmellose sodium, sodium alginate, selected from macrogol, more preferably hydroxypropylcellulose.
The enteric polymer according to the present invention is characterized by exhibiting good solubility in an aqueous solution solvent having a neutral to alkaline pH value assuming an intestinal environment, and having a pH of 6.8 to 12.0. The solubility at 25 ° C. in 100 g of an aqueous solvent having a molar concentration of 0.1 mol / L or less within the range (for example, 0.05 mol / L sodium carbonate buffer having a pH of 10.2) is 1.0 g or more, A polymer having an average molecular weight of 10,000 or more is desirable. Specific examples of enteric polymers that can be used include methacrylic acid copolymers (for example, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S), and hydroxyalkylalkylcellulose phthalates (for example, hypromellose phthalate). , Hydroxyalkylalkyl cellulose acetate succinate (for example, hypromellose acetate succinate), carboxyalkyl alkyl cellulose (for example, carboxymethyl ethyl cellulose), etc., preferably methacrylic acid copolymer, hypromellose phthalate, Selected from hypromellose acetate succinate, carboxymethyl ethyl cellulose, more preferably a methacrylic acid copolymer, Preferably the al is methacrylic acid copolymer L.
The weight ratio of drug substance to water-soluble polymer or / and enteric polymer contained in the coated particles is preferably in the range of 1: 0.05 to 20.0, more preferably 1: 0. Within the range of .1 to 5.0, and even more preferably within the range of 1: 0.1 to 3.0.
尚、本発明に係る上記被覆粒子の製造工程においては、腸溶性ポリマーはｐＨ調節剤と共にコーティング液中に溶解・中和されて噴霧されることが好ましい。其の本発明に係るｐＨ調節剤として具体的には水酸化カリウム、水酸化カルシウム、水酸化ナトリウム、水酸化マグネシウム、Ｌ−アルギニン、Ｌ−リジン、メグルミン、トリエタノールアミン、モノエタノールアミン、ジイソプロパノールアミン、炭酸マグネシウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸水素カリウム、炭酸カリウム、炭酸カルシウム、炭酸アンモニウム、無水リン酸水素カルシウム、リン酸水素二カリウム、ケイ酸カルシウム、ケイ酸マグネシウム、ケイ酸アルミン酸マグネシウム、メタケイ酸アルミン酸マグネシウム、軽質無水ケイ酸、リン酸二水素ナトリウム、リン酸水素二ナトリウム、リン酸水素二カリウム、リン酸二水素カリウム、クエン酸カルシウム、クエン酸二ナトリウム、酢酸カリウム等を挙げる事ができ、好ましくは水酸化ナトリウムである。本発明に係るｐＨ調節剤は、酸性の水溶液中に適当な量を溶解することによってｐＨを７．０〜１２．０の範囲内に中和することが可能であるものが好ましい。さらに、腸溶性ポリマーは可塑剤と共にコーティング液中に溶解されていることが好ましく、それら腸溶性ポリマー対可塑剤の重量比は１：０．０５〜０．５の範囲内であることが好ましい。 In the production process of the coated particle according to the present invention, it is preferable that the enteric polymer is dissolved and neutralized in the coating solution together with the pH adjuster and sprayed. Specific examples of the pH regulator according to the present invention include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, L-arginine, L-lysine, meglumine, triethanolamine, monoethanolamine, diisopropanol. Amine, magnesium carbonate, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium carbonate, ammonium carbonate, anhydrous calcium hydrogen phosphate, dipotassium hydrogen phosphate, calcium silicate, magnesium silicate, magnesium aluminate silicate , Magnesium aluminate metasilicate, light anhydrous silicic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, calcium citrate, disodium citrate, potassium acetate, etc. It can be, preferably sodium hydroxide. The pH adjuster according to the present invention is preferably one that can neutralize the pH within a range of 7.0 to 12.0 by dissolving an appropriate amount in an acidic aqueous solution. Further, the enteric polymer is preferably dissolved in the coating solution together with the plasticizer, and the weight ratio of the enteric polymer to the plasticizer is preferably in the range of 1: 0.05 to 0.5.
本発明に係る被覆粒子の製造方法の具体的な例として、流動層造粒法、微粒子コーティング法が挙げられるが、好ましくは微粒子コーティング法である。前記の製造方法の操作法に困難はなく、常法にしたがって容易に目的の被覆粒子を製造することができる。例えば微粒子コーティング法では、流動層造粒機中の原薬又は原薬を含む粒子にコーティング液を噴霧・乾燥してコーティングする、一般的な方法で行われる。上記製造方法によって得られた本発明に係る被覆粒子を、他の適当な医薬添加物と共に混合・打錠することで本発明の錠剤を製造することが可能である。また、本発明に係る錠剤の形状は特に限定されず、円形錠｛円形平錠（隅角錠等含む）、円形Ｒ錠（隅角錠、２段Ｒ錠等含む）等｝や異形錠等のいずれの形状でもよいが、円形錠であることが好ましい。 Specific examples of the method for producing coated particles according to the present invention include a fluidized bed granulation method and a fine particle coating method, and a fine particle coating method is preferred. There is no difficulty in the operation method of the said manufacturing method, The target coated particle can be manufactured easily according to a conventional method. For example, the fine particle coating method is performed by a general method in which a drug substance or particles containing a drug substance in a fluid bed granulator are coated by spraying and drying a coating liquid. It is possible to produce the tablet of the present invention by mixing and tableting the coated particles according to the present invention obtained by the above production method together with other appropriate pharmaceutical additives. In addition, the shape of the tablet according to the present invention is not particularly limited, and circular tablets {circular flat tablets (including corner locks, etc.), round R tablets (including corner locks, two-stage R locks, etc.)}, irregular tablets, etc. However, it is preferably a circular tablet.
また、包装用シートとアルミ箔等で錠剤を挟んで覆い、加熱シールすることで、本発明の錠剤を含むＰＴＰシート製品を得ることは可能である。其の包装用シートに使用される具体的な素材としては、ポリ塩化ビニル、ポリプロピレン、ポリ塩化ビニリデン、ポリクロロトリフルオロエチレン等が挙げられる。尚、湿度に対する本発明の錠剤の安定性を改善するためには、乾燥機能を有した素材を用いてＰＴＰシート製品を製造したり、ＰＴＰシート製品をアルミピロー包装したり、乾燥剤を錠剤と共に瓶に封入する等の周知の方法を行うことが可能である。 Further, it is possible to obtain a PTP sheet product including the tablet of the present invention by covering the tablet with a packaging sheet and aluminum foil or the like, and heat-sealing. Specific materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like. In addition, in order to improve the stability of the tablet of the present invention against humidity, a PTP sheet product is manufactured using a material having a drying function, the PTP sheet product is packaged in an aluminum pillow, or a desiccant is combined with the tablet. It is possible to perform a known method such as sealing in a bottle.
部分アルファ化デンプン３２０．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１−ＳＰＣ型）に投入し、ヒドロキシプロピルセルロース３．０ｇを精製水３６９．０ｇに溶解した液にシロドシン（γ型）１００．０ｇを懸濁した液を噴霧し、シロドシンを含有するコーティング粒子を得た。さらにヒドロキシプロピルセルロース１６．０ｇ及びタルク１４４．０ｇを精製水１０７０．０ｇに溶解懸濁したコーティング液を噴霧しコーティング粒子を得た。得られたコーティング粒子１１６．６ｇにＤ−マンニトール６０５．０ｇ、クロスポビドン５５．０ｇ及び結晶セルロース１３０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、トウモロコシデンプン７４．０ｇ及びフマル酸ステアリルナトリウム２０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、この混合物を卓上型単発式打錠機を用いて直径８．０ｍｍに打圧５００ｋｇｆで圧縮成型し、１錠質量が２００．１２ｍｇの下記組成の口腔内崩壊錠（円形平錠）を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・コーティング粒子部
シロドシン（γ型） ４．０
部分α化デンプン １２．８
ヒドロキシプロピルセルロース ０．７６
タルク ５．７６
・外添加部
Ｄ−マンニトール １２１．０
クロスポビドン １１．０
結晶セルロース ２６．０
トウモロコシデンプン １４．８
フマル酸ステアリルナトリウム ４．０
320.0 g of partially pregelatinized starch was charged into a spouted fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01-SPC), and 3.0 g of hydroxypropylcellulose was dissolved in 369.0 g of purified water. The liquid in which 100.0 g of the mold was suspended was sprayed to obtain coated particles containing silodosin. Further, a coating solution in which 16.0 g of hydroxypropyl cellulose and 144.0 g of talc were dissolved and suspended in 1070.0 g of purified water was sprayed to obtain coated particles. D-mannitol 605.0 g, crospovidone 55.0 g, and crystalline cellulose 130.0 g were added to 116.6 g of the obtained coating particles, and mixed in a polyethylene bag. Next, 74.0 g of corn starch and 20.0 g of sodium stearyl fumarate were added and mixed in a polyethylene bag. Subsequently, this mixture was compression-molded to a diameter of 8.0 mm with a punching pressure of 500 kgf using a tabletop single-type tableting machine to obtain an orally disintegrating tablet (round flat tablet) having the following composition with a tablet mass of 200.12 mg. It was.
[Components] [Weight per tablet (mg)]
・ Coating particle part
Silodosin (γ type) 4.0
Partially pregelatinized starch 12.8
Hydroxypropyl cellulose 0.76
Talc 5.76
・ External additive part
D-mannitol 121.0
Crospovidone 11.0
Crystalline cellulose 26.0
Corn starch 14.8
Sodium stearyl fumarate 4.0
部分アルファ化デンプン２９０．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１−ＳＰＣ型）に投入し、ヒドロキシプロピルセルロース１０．０ｇを精製水４９０．０ｇに溶解した液にシロドシン（γ型）１００．０ｇを懸濁した液を噴霧し、シロドシンを含有するコーティング粒子を得た。さらにメタクリル酸コポリマーＬＤ３０％懸濁液（オイドラギットＬ３０−Ｄ５５）３２０．０ｇ（固形分９６．０ｇ）、Ｄ−マンニトール２７．０ｇ、タルク８０．２５ｇ、クエン酸トリエチル１０．０ｇ及び水酸化ナトリウム２４．０ｇを精製水８４６．０ｇに溶解懸濁したコーティング液を噴霧しコーティング粒子を得た。得られたコーティング粒子１２７．４５ｇにＤ−マンニトール６００．０ｇ、クロスポビドン５０．０ｇ及び結晶セルロース１３０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、トウモロコシデンプン７３．０ｇ及びフマル酸ステアリルナトリウム２０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、この混合物を卓上型単発式打錠機を用いて直径８．０ｍｍに打圧５００ｋｇｆで圧縮成型し、１錠質量が２００．０９ｍｇの下記組成の口腔内崩壊錠（円形平錠）を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・コーティング粒子部
シロドシン（γ型） ４．０
部分α化デンプン １１．６
ヒドロキシプロピルセルロース ０．４
Ｄ−マンニトール １．０８
メタクリル酸コポリマーＬＤ（固形分） ３．８４
タルク ３．２１
クエン酸トリエチル ０．４
水酸化ナトリウム ０．９６
・外添加部
Ｄ−マンニトール １２０．０
クロスポビドン １０．０
結晶セルロース ２６．０
トウモロコシデンプン １４．６
フマル酸ステアリルナトリウム ４．０
290.0 g of partially pregelatinized starch was put into a spouted fluidized bed granulator (manufactured by Paulec: MP-01-SPC type), and silodosin (γ was dissolved in a solution obtained by dissolving 10.0 g of hydroxypropyl cellulose in 490.0 g of purified water. The liquid in which 100.0 g of the mold was suspended was sprayed to obtain coated particles containing silodosin. Furthermore, 320.0 g of methacrylic acid copolymer LD 30% suspension (Eudragit L30-D55) (solid content 96.0 g), 27.0 g of D-mannitol, 80.25 g of talc, 10.0 g of triethyl citrate and 24. Coating particles in which 0 g was dissolved and suspended in 846.0 g of purified water were sprayed to obtain coating particles. D-mannitol 600.0 g, crospovidone 50.0 g and crystalline cellulose 130.0 g were added to 127.45 g of the obtained coating particles, and mixed in a polyethylene bag. Next, 73.0 g of corn starch and 20.0 g of sodium stearyl fumarate were added and mixed in a polyethylene bag. Next, this mixture was compression-molded to a diameter of 8.0 mm with a punching pressure of 500 kgf using a tabletop single-type tableting machine to obtain an orally disintegrating tablet (round flat tablet) having the following composition having a mass of 200.09 mg. It was.
[Components] [Weight per tablet (mg)]
・ Coating particle part
Silodosin (γ type) 4.0
Partially pregelatinized starch 11.6
Hydroxypropyl cellulose 0.4
D-mannitol 1.08
Methacrylic acid copolymer LD (solid content) 3.84
Talc 3.21
Triethyl citrate 0.4
Sodium hydroxide 0.96
・ External additive part
D-mannitol 120.0
Crospovidone 10.0
Crystalline cellulose 26.0
Corn starch 14.6
Sodium stearyl fumarate 4.0
〔比較例１〕
シロドシン（γ型）１６０．０ｇ、部分α化デンプン５８８．８ｇ及びタルク４０．０ｇを流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、ヒドロキシプロピルセルロース１１．２ｇを精製水２１２．８ｇに溶解した液を噴霧、造粒して、シロドシンを含有する造粒物を得た。得られた造粒物を乾燥し、３０メッシュの篩にて篩過して整粒品を得た。
次いで整粒品２００．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１−ＳＰＣ型）に投入し、アミノアルキルメタクリレートコポリマーＥ（オイドラギットＥＰＯ）７０．０ｇ、ラウリル硫酸ナトリウム７．０ｇ、ステアリン酸１０．５ｇ及びタルク２４．５ｇを精製水５８８．０ｇに溶解懸濁したコーティング液を噴霧しコーティング粒子を得た。得られたコーティング粒子１５６．０ｇにＤ−マンニトール５８４．１ｇ、クロスポビドン５０．０ｇ及び結晶セルロース１２０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、トウモロコシデンプン７０．０ｇ及びフマル酸ステアリルナトリウム２０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、この混合物を卓上型単発式打錠機を用いて打圧５００ｋｇｆで直径８．０ｍｍに圧縮成型し、１錠質量が２００．０２ｍｇの下記組成の口腔内崩壊錠（円形平錠）を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・造粒部
シロドシン（γ型） ４．０
部分α化デンプン １４．７２
タルク １．０
ヒドロキシプロピルセルロース ０．２８
・コーティング粒子部
アミノアルキルメタクリレートコポリマーＥ ７．０
ラウリル硫酸ナトリウム ０．７
ステアリン酸 １．０５
タルク ２．４５
・外添加部
Ｄ−マンニトール １１６．８２
クロスポビドン １０．０
結晶セルロース ２４．０
トウモロコシデンプン １４．０
フマル酸ステアリルナトリウム ４．０
[Comparative Example 1]
160.0 g of silodosin (γ type), 588.8 g of partially pregelatinized starch and 40.0 g of talc were charged into a fluidized bed granulator (manufactured by Paulek: MP-01 type), and 11.2 g of hydroxypropylcellulose was purified water. The liquid dissolved in 212.8 g was sprayed and granulated to obtain a granulated product containing silodosin. The obtained granulated product was dried and sieved with a 30-mesh sieve to obtain a sized product.
Next, 200.0 g of the sized product was put into a spouted fluidized bed granulator (manufactured by Paulek: MP-01-SPC type), 70.0 g of aminoalkyl methacrylate copolymer E (Eudragit EPO), 7.0 g of sodium lauryl sulfate, A coating solution in which 10.5 g of stearic acid and 24.5 g of talc were dissolved and suspended in 588.0 g of purified water was sprayed to obtain coated particles. To 156.0 g of the obtained coating particles, 584.1 g of D-mannitol, 50.0 g of crospovidone and 120.0 g of crystalline cellulose were added and mixed in a polyethylene bag. Next, 70.0 g of corn starch and 20.0 g of sodium stearyl fumarate were added and mixed in a polyethylene bag. Next, this mixture was compression-molded to a diameter of 8.0 mm with a punching pressure of 500 kgf using a table type single-punch tableting machine to obtain an orally disintegrating tablet (round flat tablet) having the following composition having a mass of 200.02 mg. It was.
[Components] [Weight per tablet (mg)]
・ Granulation part
Silodosin (γ type) 4.0
Partially pregelatinized starch 14.72
Talc 1.0
Hydroxypropylcellulose 0.28
・ Coating particle part
Aminoalkyl methacrylate copolymer E 7.0
Sodium lauryl sulfate 0.7
Stearic acid 1.05
Talc 2.45
・ External additive part
D-mannitol 116.82
Crospovidone 10.0
Crystalline cellulose 24.0
Corn starch 14.0
Sodium stearyl fumarate 4.0
〔比較例２〕
部分アルファ化デンプン２８０．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１−ＳＰＣ型）に投入し、ヒドロキシプロピルセルロース２０．０ｇを精製水４９０．０ｇに溶解した液にシロドシン（γ型）１００．０ｇを懸濁した液を噴霧し、シロドシンを含有するコーティング粒子を得た。さらにメタクリル酸コポリマーＬＤ３０％懸濁液（オイドラギットＬ３０−Ｄ５５）約４８０．８ｇ（固形分１４４．２５ｇ）、Ｄ−マンニトール４０．５ｇ、タルク４０．５ｇ及びクエン酸トリエチル１５．０ｇを精製水５１５．０ｇに溶解懸濁したコーティング液を噴霧しコーティング粒子を得た。得られたコーティング粒子１２８．０８ｇにＤ−マンニトール６００．０ｇ、クロスポビドン５０．０ｇ及び結晶セルロース１２７．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、トウモロコシデンプン７５．０ｇ及びフマル酸ステアリルナトリウム２０．０ｇを加え、ポリエチレン製の袋にて混合した。次いで、この混合物を卓上型単発式打錠機を用いて直径８．０ｍｍに打圧５００ｋｇｆで圧縮成型し、１錠質量が２００．０１ｍｇの下記組成の口腔内崩壊錠（円形平錠）を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・コーティング粒子部
シロドシン（γ型） ４．０
部分α化デンプン １１．２
ヒドロキシプロピルセルロース ０．８
Ｄ−マンニトール １．６２
メタクリル酸コポリマーＬＤ（固形分） ５．７７
タルク １．６２
クエン酸トリエチル ０．６
・外添加部
Ｄ−マンニトール １２０．０
クロスポビドン １０．０
結晶セルロース ２５．４
トウモロコシデンプン １５．０
フマル酸ステアリルナトリウム ４．０
[Comparative Example 2]
280.0 g of partially pregelatinized starch was charged into a spouted fluidized bed granulator (manufactured by Paulec: MP-01-SPC type), and silodosin (γ was dissolved in a solution of 20.0 g of hydroxypropylcellulose in 490.0 g of purified water. The liquid in which 100.0 g of the mold was suspended was sprayed to obtain coated particles containing silodosin. Further, about 480.8 g (solid content 144.25 g) of a methacrylic acid copolymer LD 30% suspension (Eudragit L30-D55), 40.5 g of D-mannitol, 40.5 g of talc, and 15.0 g of triethyl citrate were added to purified water 515. The coating liquid dissolved and suspended in 0 g was sprayed to obtain coating particles. D-mannitol 600.0 g, crospovidone 50.0 g and crystalline cellulose 127.0 g were added to 128.08 g of the obtained coating particles, and mixed in a polyethylene bag. Next, 75.0 g of corn starch and 20.0 g of sodium stearyl fumarate were added and mixed in a polyethylene bag. Subsequently, this mixture was compression-molded to a diameter of 8.0 mm with a punching pressure of 500 kgf using a tabletop single-type tableting machine to obtain an orally disintegrating tablet (round flat tablet) having the following composition with a mass of 200.01 mg. It was.
[Components] [Weight per tablet (mg)]
・ Coating particle part
Silodosin (γ type) 4.0
Partially pregelatinized starch 11.2
Hydroxypropylcellulose 0.8
D-mannitol 1.62
Methacrylic acid copolymer LD (solid content) 5.77
Talc 1.62
Triethyl citrate 0.6
・ External additive part
D-mannitol 120.0
Crospovidone 10.0
Crystalline cellulose 25.4
Corn starch 15.0
Sodium stearyl fumarate 4.0
〔試験例〕
実施例１及び２並びに比較例１及び２で得られた各々の錠剤について、製造直後及び、バイアル瓶中に密栓又は開栓した状態で温度６０℃相対湿度７５％の環境下において１週間保存後に、シロドシンの総類縁物質量をＨＰＬＣ法で測定した。其の測定結果は下記の表１に示す。尚、密栓条件は主に温度条件による原薬への影響を評価することに適し、開栓条件は主に温度及び湿度条件による原薬への影響を評価することに適している。
[Test example]
About each tablet obtained in Examples 1 and 2 and Comparative Examples 1 and 2, immediately after production and after storage for 1 week in an environment with a temperature of 60 ° C. and a relative humidity of 75% in a sealed state or opened in a vial The total amount of silodosin related substances was measured by the HPLC method. The measurement results are shown in Table 1 below. The sealing condition is mainly suitable for evaluating the influence of the temperature condition on the drug substance, and the opening condition is mainly suitable for evaluating the influence of the temperature and humidity condition on the drug substance.
[表１]
表１において、本発明に係る水溶性ポリマー又は腸溶性ポリマーを含む被覆粒子を含む実施例１及び２の口腔内崩壊錠は密栓・開栓保存後のシロドシン由来の総類縁体の増加量が顕著に低いことが観察されたが、非腸溶性ポリマー（腸内環境を想定した中性〜アルカリ性のｐＨ値をもつ水溶液溶媒に対して不良な溶解性を示すことを特徴とするポリマー。例：アミノアルキルメタクリレートコポリマーＥ）でコーティングされた被覆粒子を含む比較例１の口腔内崩壊錠は密栓・開栓保存後のシロドシン由来の総類縁体の増加量が顕著に高かった。また、塩基性のｐＨ調節剤（例：水酸化ナトリウム）を含まないで腸溶性ポリマーを含む被覆粒子を含む比較例２の口腔内崩壊錠では、シロドシン由来の総類縁体の増加量が密栓保存後では有意に低かったが、開栓保存後は顕著に大きいことが観察された。そのため、塩基性のｐＨ調節剤を含まないで腸溶性ポリマーを含む被覆粒子を含む口腔内崩壊錠では、湿度に対する製剤・包装上の工夫が必要であることが考えられる。
以上の結果をまとめると、シロドシンの周囲を水溶性ポリマー又は、腸溶性ポリマー（好ましくは塩基性のｐＨ調節剤と共に）でコーティングした、粒子を含む、口腔内崩壊錠は、シロドシンの苦味がその周囲のコーティングによって抑えられることに併せて、さらに保存条件下でのシロドシンの化学的な安定性が顕著に優れたものであることが判明した。
In Table 1, in the orally disintegrating tablets of Examples 1 and 2 containing coated particles containing a water-soluble polymer or enteric polymer according to the present invention, the increase in total analogues derived from silodosin after storage by sealing and opening is remarkable. However, non-enteric polymers (polymers characterized by poor solubility in aqueous solvents having neutral to alkaline pH values assuming the intestinal environment, eg amino The orally disintegrating tablet of Comparative Example 1 containing coated particles coated with the alkyl methacrylate copolymer E) had a markedly high increase in the total analogues derived from silodosin after being sealed and opened. Further, in the orally disintegrating tablet of Comparative Example 2 containing coated particles containing an enteric polymer without containing a basic pH regulator (eg, sodium hydroxide), the increased amount of the total analogue derived from silodosin is preserved in a sealed plug. It was significantly lower afterwards, but was observed to be significantly larger after open storage. Therefore, it is considered that an orally disintegrating tablet containing coated particles containing an enteric polymer without containing a basic pH adjusting agent needs to be devised in preparation and packaging with respect to humidity.
To summarize the above results, an orally disintegrating tablet containing particles coated with a water-soluble polymer or an enteric polymer (preferably with a basic pH adjusting agent) around silodosin has a bitter taste of silodosin around it. In addition to being suppressed by the coating, it has been found that the chemical stability of silodosin under storage conditions is remarkably excellent.
本発明によれば、保存条件下での原薬（シロドシン等）の化学的な安定性を向上させ、其の分解産物（類縁体）の発生量が抑制された錠剤を医療現場に提供することが可能となる。
According to the present invention, it is possible to improve the chemical stability of an active pharmaceutical ingredient (such as silodosin) under storage conditions and to provide a medical site with a tablet in which the generation amount of the degradation product (analogue) is suppressed. Is possible.
Claims (6)
A method for producing coated particles contained in the orally disintegrating tablet according to claim 1 through a fine particle coating method.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2018150287A (en) * | 2017-03-15 | 2018-09-27 | 武田テバファーマ株式会社 | Oral pharmaceutical composition with discomfort taste masked |
| CN108685867A (en) * | 2017-04-06 | 2018-10-23 | 昆明积大制药股份有限公司 | A kind of Silodosin Film coated tablets and preparation method thereof |
| JP2019014666A (en) * | 2017-07-05 | 2019-01-31 | 日本ケミファ株式会社 | Orally disintegrating tablet, and method for producing the same |
| CN112933084A (en) * | 2019-12-10 | 2021-06-11 | 广东东阳光药业有限公司 | Silodosin composition |
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| JP2004339071A (en) * | 2003-05-13 | 2004-12-02 | Towa Yakuhin Kk | Disintegrating tablet in oral cavity with reduced bitterness |
| WO2012005359A1 (en) * | 2010-07-09 | 2012-01-12 | 帝人ファーマ株式会社 | Orally disintegrating tablet |
| WO2014157137A1 (en) * | 2013-03-26 | 2014-10-02 | キッセイ薬品工業株式会社 | Oral administration preparation with masked bitterness of silodosin |
| WO2016051782A1 (en) * | 2014-09-30 | 2016-04-07 | キッセイ薬品工業株式会社 | Oral preparation in which bitter taste of bitter-tasting drug is masked |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2004339071A (en) * | 2003-05-13 | 2004-12-02 | Towa Yakuhin Kk | Disintegrating tablet in oral cavity with reduced bitterness |
| WO2012005359A1 (en) * | 2010-07-09 | 2012-01-12 | 帝人ファーマ株式会社 | Orally disintegrating tablet |
| WO2014157137A1 (en) * | 2013-03-26 | 2014-10-02 | キッセイ薬品工業株式会社 | Oral administration preparation with masked bitterness of silodosin |
| WO2016051782A1 (en) * | 2014-09-30 | 2016-04-07 | キッセイ薬品工業株式会社 | Oral preparation in which bitter taste of bitter-tasting drug is masked |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2018150287A (en) * | 2017-03-15 | 2018-09-27 | 武田テバファーマ株式会社 | Oral pharmaceutical composition with discomfort taste masked |
| JP7062368B2 (en) | 2017-03-15 | 2022-05-06 | 武田テバファーマ株式会社 | Oral pharmaceutical composition masked with unpleasant taste |
| CN108685867A (en) * | 2017-04-06 | 2018-10-23 | 昆明积大制药股份有限公司 | A kind of Silodosin Film coated tablets and preparation method thereof |
| JP2019014666A (en) * | 2017-07-05 | 2019-01-31 | 日本ケミファ株式会社 | Orally disintegrating tablet, and method for producing the same |
| JP7182356B2 (en) | 2017-07-05 | 2022-12-02 | 日本ケミファ株式会社 | Orally disintegrating tablet and manufacturing method thereof |
| CN112933084A (en) * | 2019-12-10 | 2021-06-11 | 广东东阳光药业有限公司 | Silodosin composition |
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