JP6366794B2 - Orally disintegrating tablets with improved chemical stability and dosage - Google Patents
Orally disintegrating tablets with improved chemical stability and dosage Download PDFInfo
- Publication number
- JP6366794B2 JP6366794B2 JP2017143154A JP2017143154A JP6366794B2 JP 6366794 B2 JP6366794 B2 JP 6366794B2 JP 2017143154 A JP2017143154 A JP 2017143154A JP 2017143154 A JP2017143154 A JP 2017143154A JP 6366794 B2 JP6366794 B2 JP 6366794B2
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- Prior art keywords
- weight
- silodosin
- tablet
- orally disintegrating
- coated
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- 239000006191 orally-disintegrating tablet Substances 0.000 title claims description 46
- 239000000126 substance Substances 0.000 title description 14
- 239000008187 granular material Substances 0.000 claims description 79
- 229960004953 silodosin Drugs 0.000 claims description 55
- 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 description 55
- 229920000642 polymer Polymers 0.000 claims description 36
- 239000007931 coated granule Substances 0.000 claims description 32
- 239000011248 coating agent Substances 0.000 claims description 22
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- 239000007771 core particle Substances 0.000 claims description 10
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- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical group CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 9
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- 230000002496 gastric effect Effects 0.000 claims description 7
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 12
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- 229910000021 magnesium carbonate Inorganic materials 0.000 description 9
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- 238000000034 method Methods 0.000 description 9
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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）等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 pharmaceutical generic name) and the like.
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.
シロドシンは化学的な安定性が低いことや極めて強い苦味を有することが特徴であり、口腔内崩壊錠の剤形で医療現場に提供する上ではそれらの改善が必須である。
シロドシンの口腔内崩壊錠において利用可能な先行技術は、特許文献１、２等にて紹介されている。特許文献１、２ではシロドシンを含有する粒子をシロドシン１００重量部に対して８０〜４００重量部の非腸溶性高分子等で覆うことで苦味を改善する技術が紹介されている。しかし上記の特許文献１、２では、化学的な安定性を改善する方法や、苦味以外の服用感、特にざらつき感を改善する方法については満足に示されておらず、多量の非腸溶性高分子で顆粒を覆うことは其の粒子径の増加につながるためにざらつき感を感じる原因になると考えられる。
そこで本発明者は先行技術に対して、口腔内崩壊錠に含まれるシロドシンの化学的な安定性及び苦味等の服用感（好ましくは苦味とざらつき感の両方）を共に改善す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。
Silodosin is characterized by low chemical stability and extremely strong bitterness, and these improvements are essential for providing it to the medical site in the form of orally disintegrating tablets.
Prior arts that can be used in silodosin orally disintegrating tablets are introduced in Patent Documents 1, 2 and the like. Patent Documents 1 and 2 introduce a technique for improving bitterness by covering particles containing silodosin with 80 to 400 parts by weight of a non-enteric polymer with respect to 100 parts by weight of silodosin. However, in the above Patent Documents 1 and 2, a method for improving chemical stability and a method for improving a feeling of taking other than bitterness, particularly a feeling of roughness, are not shown satisfactorily. It is considered that covering the granules with molecules leads to an increase in the particle size, which causes a feeling of roughness.
Therefore, for the purpose of improving both the chemical stability of silodosin contained in the orally disintegrating tablet and the feeling of taking such as bitterness (preferably both bitter and rough) with respect to the prior art, the present inventor, A study on the formulation and production method of orally disintegrating tablets containing silodosin was started.
本発明が解決しようとする課題は、原薬の化学的な安定性や苦味等の服用感が改善された、口腔内崩壊錠又は其の製造方法を提供することである。 The problem to be solved by the present invention is to provide an orally disintegrating tablet or a method for producing the same, in which the drug stability such as chemical stability and bitterness of the drug substance is improved.
本発明者は、口腔内崩壊錠に含まれるシロドシンの化学的な安定性及び服用時におけるシロドシンの苦味とざらつき感を共に改善するため、其の錠剤処方や製造方法に関して鋭意検討を重ねた。その結果、シロドシンを含むコーティング液を噴霧して製造した顆粒を非腸溶性高分子で覆うことでシロドシンの化学的な安定性及び苦味が共に改善され、特に低量の非腸溶性高分子で覆った場合には苦味とざらつき感が共に改善さ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 both the chemical stability of silodosin contained in the orally disintegrating tablet and the bitterness and roughness of silodosin at the time of taking, the present inventor has conducted intensive studies on the tablet formulation and production method. As a result, the chemical stability and bitterness of silodosin are improved by covering the granules produced by spraying a coating solution containing silodosin with a non-enteric polymer, especially with a low amount of non-enteric polymer. I found that both the bitterness and the feeling of roughness were improved. Based on this knowledge, the present inventor made further studies and completed the following invention.
本発明はまず、特定の原薬を含む顆粒を製造した上でそれを非腸溶性高分子で被覆することによって当該原薬の化学的な安定性や苦味等の服用感が顕著に改善可能なことを主に見出したものであり、其の好ましい構成は下記（１）〜（１０）において記述されているものである。
（１）核粒子の周囲がコーティング層で被覆されていることを特徴とする原薬を含む顆粒が、非腸溶性高分子を含むコーティング層で更に被覆されていることを特徴とする被覆顆粒、を含有する口腔内崩壊錠。
（２）原薬がシロドシンである、前記（１）に記載の口腔内崩壊錠。
（３）素錠全重量に対して２．０〜１４．０重量％の、原薬を含む顆粒が、素錠全重量に対して０．５〜２．０重量％の非腸溶性高分子で被覆されていることを特徴とする被覆顆粒を含有する、前記（１）又は（２）に記載の口腔内崩壊錠。
（４）核粒子１００.０重量部に対して原薬が２０.０〜５０．０重量部含まれた顆粒を含有する、前記（１）〜（３）のいずれかに記載の口腔内崩壊錠。
（５）素錠全重量に対して２．０〜１４．０重量％の、原薬であるシロドシンを含む顆粒が、素錠全重量に対して０．５〜２．０重量％の非腸溶性高分子で被覆されていることを特徴とする被覆顆粒、を含有する口腔内崩壊錠。
（６）非腸溶性高分子が胃溶性高分子又は水不溶性高分子である、前記（１）〜（５）のいずれかに記載の口腔内崩壊錠。
（７）非腸溶性高分子が胃溶性高分子であり、胃溶性高分子がアミノアルキルメタクリレートコポリマーＥ、メタクリル酸メチル・メタクリル酸ジエチルアミノエチル共重合体、及びポリビニルアセタールジエチルアミノアセテートから選ばれる、前記（１）〜（５）のいずれかに記載の口腔内崩壊錠。
（８）非腸溶性高分子が水不溶性高分子であり、水不溶性高分子がエチルセルロース、酢酸セルロース、アミノアルキルメタクリレートコポリマーＲＳ、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、及び酢酸ビニル樹脂から選ばれる、前記（１）〜（５）のいずれかに記載の口腔内崩壊錠。
（９）原薬及び結合剤を含有するコーティング液を賦形剤に噴霧することで原薬を含む顆粒を製造する工程を介する、前記（１）〜（８）のいずれかに記載の口腔内崩壊錠、を製造する方法。
（１０）デンプン又はデンプン誘導体を含有する造粒液を、非腸溶性高分子で被覆された被覆顆粒に噴霧して更なる顆粒を製造する工程を介する、前記（１）〜（８）のいずれかに記載の口腔内崩壊錠、を製造する方法。
In the present invention, first, a granule containing a specific drug substance is manufactured and then coated with a non-enteric polymer, whereby the chemical stability and bitterness of the drug substance can be remarkably improved. This has been mainly found, and preferred configurations thereof are those described in the following (1) to (10).
(1) A coated granule characterized in that a granule containing a drug substance characterized in that the core particles are coated with a coating layer, and further coated with a coating layer containing a non-enteric polymer, Orally disintegrating tablets.
(2) The orally disintegrating tablet according to (1), wherein the drug substance is silodosin.
(3) A non-enteric polymer in which 2.0 to 14.0% by weight of granules containing the drug substance is 0.5 to 2.0% by weight based on the total weight of the uncoated tablet The orally disintegrating tablet according to (1) or (2), comprising coated granules characterized by being coated with.
(4) The oral disintegration according to any one of (1) to (3) above, wherein the drug substance contains granules containing 20.0 to 50.0 parts by weight of the drug substance with respect to 100.0 parts by weight of the core particles. Tablets.
(5) 2.0 to 14.0% by weight of granules containing silodosin, which is the drug substance, based on the total weight of the uncoated tablet is 0.5 to 2.0% by weight based on the total weight of the uncoated tablet. An orally disintegrating tablet comprising coated granules characterized by being coated with a soluble polymer.
(6) The orally disintegrating tablet according to any one of (1) to (5), wherein the non-enteric polymer is a gastric polymer or a water-insoluble polymer.
(7) The non-enteric polymer is a gastric polymer, and the gastric polymer is selected from aminoalkyl methacrylate copolymer E, methyl methacrylate / diethylaminoethyl methacrylate copolymer, and polyvinyl acetal diethylaminoacetate, The orally disintegrating tablet according to any one of 1) to (5).
(8) The non-enteric polymer is a water-insoluble polymer, and the water-insoluble polymer is selected from ethyl cellulose, cellulose acetate, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer dispersion, and vinyl acetate resin. The orally disintegrating tablet according to any one of (1) to (5).
(9) The oral cavity according to any one of the above (1) to (8), through a step of producing granules containing the drug substance by spraying a coating liquid containing the drug substance and a binder onto the excipient A method of manufacturing a disintegrating tablet.
(10) Any one of the above (1) to (8), wherein the granulated liquid containing starch or starch derivative is sprayed onto the coated granules coated with the non-enteric polymer to produce further granules. A method for producing an orally disintegrating tablet according to claim 1.
また本発明は、シロドシンの化学的な安定性を改善するという課題を解決する上では、錠剤中にて炭酸マグネシウム等の塩基性の無機酸塩をシロドシンを含む顆粒、の外に含有することが好ましいことも更に見出したものであり、其の好ましい構成は下記（１１）〜（１３）においても記述されているものである。下記（１１）〜（１３）のいずれかに記載の口腔内崩壊錠は、前記（１）〜（８）のいずれかに記載の口腔内崩壊錠であること又は前記（９）又は（１０）のいずれかに記載の製造方法によって製造されることが好ましい。
（１１）シロドシンを含む顆粒と、顆粒外の塩基性の無機酸塩を含有する口腔内崩壊錠。
（１２）塩基性の無機酸塩が炭酸、ケイ酸又は燐酸の金属塩である、前記（１１）に記載の口腔内崩壊錠。
（１３）塩基性の無機酸塩が炭酸マグネシウム、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、炭酸カルシウム又は炭酸アンモニウムである、前記（１１）又は（１２）に記載の口腔内崩壊錠。
In addition, in order to solve the problem of improving the chemical stability of silodosin, the present invention may contain a basic inorganic acid salt such as magnesium carbonate outside the granules containing silodosin in the tablet. The present invention has also been found to be preferable, and preferable configurations thereof are also described in the following (11) to (13). The orally disintegrating tablet according to any one of (11) to (13) below is the orally disintegrating tablet according to any one of (1) to (8), or (9) or (10) above. It is preferable to manufacture by the manufacturing method in any one of.
(11) An orally disintegrating tablet containing granules containing silodosin and basic inorganic acid salts outside the granules.
(12) The orally disintegrating tablet according to (11), wherein the basic inorganic acid salt is a metal salt of carbonic acid, silicic acid or phosphoric acid.
(13) The orally disintegrating tablet according to (11) or (12), wherein the basic inorganic acid salt is magnesium carbonate, sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, calcium carbonate, or ammonium carbonate. .
本発明は、口腔内崩壊錠について原薬の化学的な安定性や苦味等の服用感を顕著に改善する優れた効果を有するものである。 The present invention has an excellent effect of remarkably improving the ingestion feeling such as chemical stability and bitterness of the drug substance for the orally disintegrating tablet.
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.
本発明の錠剤の剤形は口腔内崩壊錠であることが好ましく、より好ましくは素錠（フィルムコーティング層や糖衣層等で覆われていない、打錠等により成形したままの錠剤を指す。以下同じ。）である口腔内崩壊錠である。口腔内崩壊錠は口腔内で迅速に崩壊する錠剤として普通錠と区別して提供されるもので、口腔内崩壊時間が６０秒未満のものであり、４０秒未満であるものが特に好ましい。本発明の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特に好ましい。尚、本発明の錠剤を打錠により圧縮成形する際の打圧は、４００〜８００ｋｇｆの範囲内にあることが好ましい。 The dosage form of the tablet of the present invention is preferably an orally disintegrating tablet, more preferably an uncoated tablet (a tablet that is not covered with a film coating layer, a sugar coating layer, or the like, but is formed by tableting or the like). The same)) orally disintegrating tablets. Orally disintegrating tablets are provided as distinguished from ordinary tablets as tablets that disintegrate rapidly in the oral cavity, and those having an oral disintegration time of less than 60 seconds and particularly preferably less than 40 seconds. The shape of the tablet of the present invention is not particularly limited, and may be any of round tablets {circular flat tablets (including corner locks, etc.), round R tablets (including corner locks, 2-stage R tablets, etc.)}, irregular tablets, and the like. The shape may be sufficient, but a circular tablet is particularly preferable. The compression pressure when the tablet of the present invention is compression-molded by tableting is preferably in the range of 400 to 800 kgf.
本発明の錠剤は、苦味等の不快な味を有する原薬を含むが、特にシロドシンを含むことが好ましく、また一種類の原薬のみを含む単剤であることが好ましい。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メディアン径（ｄ５０）は２０．０μｍ以下であることが好ましく、より好ましくは２．０〜１０．０μｍ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。
本明細書におけるシロドシンの粒子径分布は、例えばレーザー回析・散乱法（体積基準）によって測定されたものである。本発明の錠剤において、シロドシンは、素錠の全重量に対して好ましくは０．５〜１０．０重量％の範囲で、より好ましくは１．０〜５．０重量％の範囲で素錠中に含有される。使用可能なシロドシンの結晶形はα、β、γ型、非晶質形態等が挙げられる。錠剤中においてシロドシンは、非腸溶性高分子で周囲が覆われて存在することが好ましい。
The tablet of the present invention contains a drug substance having an unpleasant taste such as a bitter taste, but preferably contains silodosin, and is preferably a single drug containing only one kind of drug substance. Median diameter of silodosin to be used to produce the tablets of the present invention (d 50) is preferably at most 20.0 .mu.m, more preferably 2.0～10.0Myuemu. If necessary, dry or wet pulverization can be appropriately performed to adjust the particle size to an arbitrary value.
The particle size distribution of silodosin in the present specification is measured by, for example, a laser diffraction / scattering method (volume basis). In the tablet of the present invention, silodosin is preferably 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 plain tablet. Contained in Examples of crystal forms of silodosin that can be used include α, β, γ, and amorphous forms. In the tablet, it is preferable that silodosin is present in a non-enteric polymer.
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、可塑剤、遮光剤、界面活性剤等を挙げることができる。 Additives that can be used to produce the tablet of the present invention include commonly used excipients, binders, disintegrants, lubricants, flavoring agents, coating agents, plasticizers, light-shielding agents, Surfactant etc. can be mentioned.
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、素錠の全重量に対して５０．０〜９５．０重量％、好ましくは７０．０〜９０．０重量％の範囲で素錠中に含有される。 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 uncoated 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 uncoated 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、トウモロコシデンプン、ポリエチレングリコール等を挙げる事ができ、好ましくはトウモロコシデンプン、ヒドロキシプロピルセルロースから選択される。結合剤は、素錠の全重量に対して０．０１〜５．０重量％、好ましくは０．０５〜０．５重量％の範囲で素錠中に含有される。 Specific examples of the binder include hydroxypropylcellulose, hypromellose, methylcellulose, povidone, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, corn starch, and polyethylene glycol. Selected from corn starch, hydroxypropylcellulose. The binder is contained in the uncoated tablet in an amount of 0.01 to 5.0% by weight, preferably 0.05 to 0.5% by weight, based on the total weight of the uncoated 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、素錠の全重量に対して１．０〜４０．０重量％、好ましくは２．０〜１５．０重量％の範囲で素錠中に含有される。 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 uncoated tablet in an amount of 1.0 to 40.0% by weight, preferably 2.0 to 15.0% by weight, based on the total weight of the uncoated 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、ステアリン酸マグネシウムから選択される。滑沢剤は、素錠の全重量に対して０．１〜１０．０重量％、好ましくは０．１〜３．０重量％の範囲で素錠中に含有される。 Specific lubricants include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated oil, etc., preferably selected from sodium stearyl fumarate and magnesium stearate. The The lubricant is contained in the uncoated tablet in an amount of 0.1 to 10.0% by weight, preferably 0.1 to 3.0% by weight, based on the total weight of the uncoated 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、ｌ−メントール等を挙げる事ができ、好ましくはスクラロース、ｌ−メントールから選択され、最も好ましくはスクラロースである。矯味剤は、素錠の全重量に対して１．０〜５．０重量％の範囲で素錠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, l-menthol and the like, preferably selected from sucralose and l-menthol, and most preferably sucralose. It is. It is preferable that the corrigent is contained in the uncoated tablet in the range of 1.0 to 5.0% by weight with respect to the total weight of the uncoated 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、下記で具体的な種類が列挙されている非腸溶性高分子に加えて、挙げる事ができる。コーティング剤は、素錠の全重量に対して０．５〜１０．０重量％、好ましくは１．０〜５．０重量％の範囲で素錠中に含有される。 Specific coating agents include hypromellose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol, polyethylene glycol, talc, etc. In addition to the non-enteric polymers listed in various types, mention may be made. The coating agent is contained in the uncoated 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 uncoated 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、ステアリン酸等を挙げる事ができ、好ましくはステアリン酸、トリアセチンから選択される。可塑剤は、素錠の全重量に対して０．０１〜１．０重量％の範囲で素錠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, propylene glycol, stearic acid and the like, preferably selected from stearic acid and triacetin. The plasticizer is preferably contained in the uncoated tablet in the range of 0.01 to 1.0% by weight based on the total weight of the uncoated tablet.
具体的な遮光剤としては、黄酸化鉄、黄色三二酸化鉄、褐色酸化鉄、三二酸化鉄、食用黄色４号、食用黄色５号、食用黄色４号アルミニウムレーキ、食用赤色２号、食用赤色３号、食用赤色１０２号等を挙げる事ができ、好ましくは黄色三二酸化鉄、三二酸化鉄から選択される。遮光剤は、素錠の全重量に対して０．０１〜１．０重量％の範囲で素錠中に含有されていることが好ましい。 Specific examples of the light-shielding agent include yellow iron oxide, yellow ferric oxide, brown ferric oxide, ferric oxide, edible yellow No. 4, edible yellow No. 5, edible yellow No. 4 aluminum lake, edible red No. 2, edible red 3 No., Edible Red No. 102, etc., and preferably selected from yellow ferric oxide and ferric oxide. The light-shielding agent is preferably contained in the uncoated tablet in a range of 0.01 to 1.0% by weight with respect to the total weight of the uncoated tablet.
具体的な界面活性剤としては、ラウリル硫酸ナトリウム、ラウロマクロゴール、ショ糖脂肪酸エステル、セタノール、ソルビタン脂肪酸エステル、トリオレイン酸ソルビタン、ポリソルベート20、ポリソルベート60、ポリソルベート80、マクロゴール400、モノオレイン酸ソルビタン、モノステアリン酸グリセリン、モノラウリン酸ソルビタン、ポリオキシエチレン(105)ポリオキシプロピレン（5）グリコール、ポリオキシエチレン（160）ポリオキシプロピレン（30）グリコール等が挙げられるが、好ましくはラウリル硫酸ナトリウムである。界面活性剤は、素錠の全重量に対して０．０１〜１．０重量％の範囲で素錠中に含有される。本発明において界面活性剤は、水溶液に対する非腸溶性高分子の溶解を促進させることを主な目的として用いられる。 Specific surfactants include sodium lauryl sulfate, lauromacrogol, sucrose fatty acid ester, cetanol, sorbitan fatty acid ester, sorbitan trioleate, polysorbate 20, polysorbate 60, polysorbate 80, macrogol 400, sorbitan monooleate Glyceryl monostearate, sorbitan monolaurate, polyoxyethylene (105) polyoxypropylene (5) glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, etc., preferably sodium lauryl sulfate . The surfactant is contained in the uncoated tablet in the range of 0.01 to 1.0% by weight based on the total weight of the uncoated tablet. In the present invention, the surfactant is used mainly for promoting the dissolution of the non-enteric polymer in the aqueous solution.
本発明の錠剤は、原薬を含む顆粒が非腸溶性高分子を含むコーティング層で被覆されていることを特徴とする被覆顆粒（以下、“本発明に係る被覆顆粒”と呼ぶ。）を含有するものである。其の原薬を含む顆粒は、原薬である核粒子の周囲がコーティング層で被覆されていること乃至は核粒子の周囲が原薬を含むコーティング層で被覆されていることを特徴とする顆粒（以下、“本発明に係る顆粒”と呼ぶ。）であることが好ましいが、より好ましくは核粒子の周囲が原薬を含むコーティング層で被覆されていることを特徴とする顆粒である。 The tablet of the present invention contains coated granules (hereinafter referred to as “coated granules according to the present invention”), wherein the granules containing the drug substance are coated with a coating layer containing a non-enteric polymer. To do. The granule containing the drug substance is coated with a coating layer around the core particle of the drug substance, or is coated with a coating layer containing the drug substance around the core particle (Hereinafter referred to as “a granule according to the present invention”), but more preferably a granule characterized in that the core particle is coated with a coating layer containing the drug substance.
本発明に係る顆粒においては、原薬は核粒子１００.０重量部に対して１０.０重量部以上、より好ましくは２０．０〜５０．０重量部、更により好ましくは２５．０〜４０．０重量部の範囲で含まれる。核粒子は賦形剤又は原薬であり、好ましくは賦形剤であり、特に好ましくは部分アルファー化デンプンである。核粒子のメディアン径（ｄ５０）は１２０．０μｍ以下、好ましくは２０．０〜１００．０μｍ、より好ましくは４０．０〜７５．０μｍである。本発明に係る顆粒は、素錠全重量に対して好ましくは２．０〜１４．０重量％、より好ましくは６．０〜１０．０重量％の範囲で素錠中に含有される。また本発明に係る顆粒が有するコーティング層においては、コーティング剤を含むことが好ましく、コーティング剤は原薬１００.０重量部に対して２．０重量部以上、好ましくは８．０重量部以上の範囲で含有される。本発明に係る顆粒や本発明に係る被覆顆粒は表面の凹凸が少ない方が本発明においてより好ましいものとなる。 In the granule according to the present invention, the drug substance is 10.0 parts by weight or more, more preferably 20.0 to 50.0 parts by weight, still more preferably 25.0 to 40 parts by weight based on 100.0 parts by weight of the core particles. In the range of 0.0 part by weight. The core particles are excipients or drug substances, preferably excipients, particularly preferably partially pregelatinized starch. The median diameter (d 50 ) of the core particles is 120.0 μm or less, preferably 20.0 to 100.0 μm, more preferably 40.0 to 75.0 μm. The granule according to the present invention is contained in the uncoated tablet in an amount of preferably 2.0 to 14.0% by weight, more preferably 6.0 to 10.0% by weight based on the total weight of the uncoated tablet. The coating layer of the granule according to the present invention preferably contains a coating agent, and the coating agent is 2.0 parts by weight or more, preferably 8.0 parts by weight or more with respect to 100.0 parts by weight of the drug substance. Contained in a range. The granule according to the present invention and the coated granule according to the present invention are more preferable in the present invention if the surface has less irregularities.
本発明に係る被覆顆粒のメディアン径（ｄ５０）は１５０．０μｍ以下、好ましくは１２０．０μｍ以下、より好ましくは５０．０〜１００．０μｍである。更に、本発明に係る被覆顆粒については、累積１０％粒子径（ｄ１０）が１０．０μｍ以上であって好ましくは２０．０μｍ以上であり、累積９０％粒子径（ｄ９０）が４００．０μｍ以下であって好ましくは３００．０μｍ以下であることが望ましい。非腸溶性高分子は、素錠全重量に対して好ましくは０．５〜２．０重量％、より好ましくは０．８〜１．２重量％の範囲で素錠中に含有される。本発明に係る被覆顆粒中において、非腸溶性高分子はシロドシン１００.０重量部に対して２０．０重量部以上、好ましくは３０．０〜１００．０重量部、より好ましくは４０．０〜７０．０重量部の範囲内で含まれる。
本発明に係る非腸溶性高分子は、胃溶性高分子又は水不溶性高分子であることが好ましい。
胃溶性高分子とは、胃内環境を想定した酸性のｐＨ値（５．０以下）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する、分子量が１００００以上の高分子であることが望ましい。具体的に使用可能な胃溶性高分子としては、アミノアルキルメタクリレートコポリマーＥ、メタクリル酸メチル・メタクリル酸ジエチルアミノエチル共重合体、ポリビニルアセタールジエチルアミノアセテートを挙げる事ができ、好ましくはアミノアルキルメタクリレートコポリマーＥである。
水不溶性高分子とは、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ほぼ乃至は全く溶解しないこと（詳細な定義は、第十七改正日本薬局方に記載される溶解性を示す用語の一つ、“ほとんど溶けない”、の定義を参考として、「溶質１ｇを溶かすに要する溶媒量が１００００ｍＬ以上であること」、とする。）を特徴とする、分子量が１００００以上の高分子であることが望ましい。具体的に使用可能な水不溶性高分子としては、酢酸セルロース、エチルセルロース、アミノアルキルメタクリレートコポリマーＲＳ、酢酸ビニル樹脂、アクリル酸エチル・メタクリル酸メチル共重合体等を挙げる事ができ、好ましくはエチルセルロースである。
The median diameter (d 50 ) of the coated granule according to the present invention is 150.0 μm or less, preferably 120.0 μm or less, more preferably 50.0 to 100.0 μm. Furthermore, the coated granule according to the present invention has a cumulative 10% particle diameter (d 10 ) of 10.0 μm or more, preferably 20.0 μm or more, and a cumulative 90% particle diameter (d 90 ) of 400.0 μm. Or less, preferably 300.0 μm or less. The non-enteric polymer is preferably contained in the uncoated tablet in the range of 0.5 to 2.0% by weight, more preferably 0.8 to 1.2% by weight based on the total weight of the uncoated tablet. In the coated granule according to the present invention, the non-enteric polymer is 20.0 parts by weight or more, preferably 30.0 to 100.0 parts by weight, more preferably 40.0 to 4 parts by weight based on 100.0 parts by weight of silodosin. It is contained within the range of 70.0 parts by weight.
The non-enteric polymer according to the present invention is preferably a gastric polymer or a water-insoluble polymer.
The gastric soluble polymer is a polymer having a molecular weight of 10,000 or more, characterized by having good solubility in an aqueous solvent having an acidic pH value (5.0 or less) assuming the stomach environment. It is desirable to be. Specific examples of the gastric polymer that can be used include aminoalkyl methacrylate copolymer E, methyl methacrylate / diethylaminoethyl methacrylate copolymer, and polyvinyl acetal diethylaminoacetate. Aminoalkyl methacrylate copolymer E is preferable. .
A water-insoluble polymer is substantially or not soluble in an aqueous solvent (substantially only water) or an aqueous solvent (the detailed definition is the solubility described in the 17th revised Japanese Pharmacopoeia) The molecular weight is 10,000 or more, characterized by the fact that “the amount of solvent required to dissolve 1 g of solute is 10,000 mL or more” with reference to the definition of “mostly insoluble” as one of the terms indicating A polymer is desirable. Specific examples of water-insoluble polymers that can be used include cellulose acetate, ethyl cellulose, aminoalkyl methacrylate copolymer RS, vinyl acetate resin, ethyl acrylate / methyl methacrylate copolymer, and preferably ethyl cellulose. .
本発明に係る被覆顆粒等の造粒物（顆粒）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。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顆粒等の造粒物を製造することができる。例えば、流動層造粒機中のシロドシンを含む顆粒（本発明に係る顆粒であることが好ましい。）に非腸溶性高分子を含むコーティング液を噴霧・乾燥してコーティング（被覆）することで、本発明に係る被覆顆粒は得られる。本発明に係る被覆顆粒を製造する上で用いられる本発明に係る顆粒を製造する方法は、シロドシン及びコーティング剤を含有するコーティング液を賦形剤に噴霧する工程を介したものであることが好ましい。本発明の錠剤を製造する工程は、本発明に係る被覆顆粒に（望ましくは賦形剤及び崩壊剤を加えた混合物に）、結合剤（望ましくはデンプン等の多糖類又は其の誘導体）を含む造粒液を噴霧することで更なる造粒物を製造する工程を介することが好ましい。本発明に係る被覆顆粒に賦形剤及び崩壊剤を加えた混合物を含む造粒物は、当該造粒物１００.０重量部に対して、当該賦形剤を５０.０重量部以上、当該崩壊剤を４.０重量部以上含むものであって、素錠中に含有されることが望ましい。其の造粒物は、口腔内で速やかに砕けることが期待され、本発明の錠剤を服用した際に口腔内でのざらつき感を生じる原因とはならない。 Specific examples of the method for producing a granulated product (granule) such as a coated granule according to the present invention include a fluidized bed granulation method and a fine particle coating method. There is no difficulty in the operation method of the above production method, and a granulated product such as a desired coated granule can be easily produced according to a conventional method. For example, by spraying and drying a coating liquid containing a non-enteric polymer on a granule containing silodosin (preferably a granule according to the present invention) in a fluid bed granulator, The coated granules according to the invention are obtained. The method for producing a granule according to the present invention used for producing the coated granule according to the present invention is preferably via a step of spraying a coating liquid containing silodosin and a coating agent onto an excipient. . The process for producing the tablet of the present invention includes a binder (desirably a polysaccharide such as starch or a derivative thereof) in the coated granule according to the present invention (desirably in a mixture containing an excipient and a disintegrant). It is preferable to go through a step of producing a further granulated product by spraying the granulating liquid. The granulated product containing a mixture obtained by adding an excipient and a disintegrant to the coated granule according to the present invention contains 50.0 parts by weight or more of the excipient with respect to 100.0 parts by weight of the granulated product. It contains 4.0 parts by weight or more of a disintegrant and is desirably contained in an uncoated tablet. The granulated product is expected to be quickly crushed in the oral cavity, and does not cause a rough feeling in the oral cavity when the tablet of the present invention is taken.
本発明の錠剤は、シロドシンを含む顆粒（本発明に係る被覆顆粒であるものが好ましい。）と、顆粒外の塩基性の無機酸塩を含むことが好ましく、其の製造方法はシロドシンを含む顆粒と顆粒中に含有されていない（顆粒外の）塩基性の無機酸塩を混合して打錠する工程を介するものであることが好ましい。塩基性の無機酸塩は、素錠の全重量に対して０．１重量％以上、好ましくは０．５〜１０．０重量％の範囲で素錠中に含有されていることが好ましい。塩基性の無機酸塩として具体的には、炭酸、ケイ酸又は燐酸の金属塩（特にアルカリ土類金属塩が好ましい。）等から選択され、より具体的には、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、軽質無水ケイ酸等から選択され、より好ましくはケイ酸カルシウム、ケイ酸マグネシウム、炭酸マグネシウム、ケイ酸アルミン酸マグネシウムから選択され、最も好ましくは炭酸マグネシウムである。 The tablet of the present invention preferably contains a granule containing silodosin (preferably a coated granule according to the present invention) and a basic inorganic acid salt outside the granule, and the production method thereof is a granule containing silodosin. And a basic inorganic acid salt (extragranular) not contained in the granule is preferably mixed and tableted. It is preferable that the basic inorganic acid salt is contained in the uncoated tablet in an amount of 0.1% by weight or more, preferably 0.5 to 10.0% by weight, based on the total weight of the uncoated tablet. Specifically, the basic inorganic acid salt is selected from a metal salt of carbonic acid, silicic acid or phosphoric acid (especially preferred is an alkaline earth metal salt), and more specifically, 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 It is selected from silicic acid and the like, more preferably selected from calcium silicate, magnesium silicate, magnesium carbonate, magnesium aluminate silicate, and most preferably magnesium carbonate.
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.
部分アルファー化デンプン（旭化成社製：ＰＣＳ ＰＣ−１０）２９５．０ｇ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８４６．５ｇ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・乾燥して顆粒を得た。
得られた顆粒２４３．０ｇ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Ｅ３８．２５ｇ、ラウリル硫酸ナトリウム３．７５ｇ、ステアリン酸５．７０ｇ、及びタルク１３．５ｇを精製水３２１．３ｇに溶解・懸濁したコーティング液を噴霧・乾燥して被覆顆粒を得て、それを３０メッシュの篩にて篩過して整粒した。
整粒した被覆顆粒６０．８４ｇ、Ｄ−マンニトール３８４．９６ｇ、クロスポビドン３０．０ｇ及び結晶セルロース８１．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、トウモロコシデンプン１８．０ｇ、黄色三二酸化鉄０．６ｇ、及び三二酸化鉄０．６ｇを精製水５８２．０ｇに加温懸濁した液を噴霧・乾燥して顆粒を得て、それを２４メッシュの篩にて篩過して整粒した。
整粒した顆粒１９２．０ｇ、スクラロース６．０ｇ、ｌ−メントール０．１６ｇをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム２．０ｇを加えて混合して混合物を得た。得られた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２００．１６ｍｇの下記組成の口腔内崩壊錠を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・１次顆粒部
シロドシン（γ型） ４．０
部分α化デンプン １１．８
ヒドロキシプロピルセルロース ０．４
・・被覆顆粒（２次顆粒）部
アミノアルキルメタクリレートコポリマーＥ ２．５５
ラウリル硫酸ナトリウム ０．２５
ステアリン酸 ０．３８
タルク ０．９０
・・・３次顆粒部
Ｄ−マンニトール １２８．３２
クロスポビドン １０．０
結晶セルロース ２７．０
トウモロコシデンプン ６．０
黄色三二酸化鉄 ０．２
三二酸化鉄 ０．２
・外添加部
スクラロース ６．０
ｌ−メントール ０．１６
ステアリン酸マグネシウム ２．０
295.0 g of partially pregelatinized starch (Asahi Kasei Co., Ltd .: PCS PC-10) was charged into a spouted fluidized bed granulator (Powrec Co., Ltd .: MP-01-SPC type), and 10.0 g of hydroxypropylcellulose was added to purified water 846. A liquid obtained by suspending 100.0 g of silodosin (γ type) in a liquid dissolved in 0.5 g was sprayed and dried to obtain granules.
243.0 g of the obtained granules were put into a spouted fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01-SPC type), 38.25 g aminoalkyl methacrylate copolymer E, 3.75 g sodium lauryl sulfate, 5.70 g stearic acid. A coating solution obtained by dissolving and suspending 13.5 g of talc in 321.3 g of purified water was sprayed and dried to obtain coated granules, which were sieved with a 30-mesh sieve and sized.
Corned starch was charged into 60.84 g of the sized granules, 384.96 g of D-mannitol, 30.0 g of crospovidone, and 81.0 g of crystalline cellulose in a spouted fluidized bed granulator (manufactured by Paulek: MP-01 type). 18.0 g, 0.6 g of yellow iron sesquioxide and 0.6 g of iron sesquioxide heated in 582.0 g of purified water are sprayed and dried to obtain granules, which are then passed through a 24-mesh sieve. And sieved.
After mixing 192.0 g of the sized granules, 6.0 g of sucralose, and 0.16 g of 1-menthol in a polyethylene bag, 2.0 g of magnesium stearate was further added and mixed to obtain a mixture. The obtained 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 having the following composition having a mass of 200.16 mg per tablet.
[Components] [Weight per tablet (mg)]
・ Primary granule silodosin (γ type) 4.0
Partially pregelatinized starch 11.8
Hydroxypropyl cellulose 0.4
..Coated granules (secondary granules) part aminoalkyl methacrylate copolymer E 2.55
Sodium lauryl sulfate 0.25
Stearic acid 0.38
Talc 0.90
... Tertiary granule part D-mannitol 128.32
Crospovidone 10.0
Crystalline cellulose 27.0
Corn starch 6.0
Yellow ferric oxide 0.2
Iron trioxide 0.2
・ External additive part
Sucralose 6.0
l-Menthol 0.16
Magnesium stearate 2.0
部分アルファー化デンプン（旭化成社製：ＰＣＳ ＰＣ−１０）２９５．０ｇ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８４６．５ｇ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・乾燥して顆粒を得た。
得られた顆粒２４３．０ｇ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Ｅ３０．００ｇ、ラウリル硫酸ナトリウム２．９４ｇ、ステアリン酸４．４７ｇ、及びタルク１０．５９ｇを精製水２５２．０ｇに溶解・懸濁したコーティング液を噴霧して被覆顆粒を得て、それを３０メッシュの篩にて篩過して整粒した。
整粒した被覆顆粒５８．２０ｇ、Ｄ−マンニトール３８７．６ｇ、クロスポビドン３０．０ｇ及び結晶セルロース８１．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、トウモロコシデンプン１８．０ｇ、黄色三二酸化鉄０．６ｇ及び三二酸化鉄０．６ｇを精製水５８２．０ｇに加温懸濁した液を噴霧・乾燥して顆粒を得て、２４メッシュの篩にて篩過して整粒した。
整粒した顆粒１９２．０ｇ、スクラロース６．０ｇ、ｌ−メントール０．１６ｇをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム２．０ｇを加えて混合して混合物を得た。得られた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２００．１６ｍｇの下記組成の口腔内崩壊錠を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・１次顆粒部
シロドシン（γ型） ４．０
部分α化デンプン １１．８
ヒドロキシプロピルセルロース ０．４
・・被覆顆粒（２次顆粒）部
アミノアルキルメタクリレートコポリマーＥ ２．００
ラウリル硫酸ナトリウム ０．１９６
ステアリン酸 ０．２９８
タルク ０．７０６
・・・３次顆粒部
Ｄ−マンニトール １２９．２
クロスポビドン １０．０
結晶セルロース ２７．０
トウモロコシデンプン ６．０
黄色三二酸化鉄 ０．２
三二酸化鉄 ０．２
・外添加部
スクラロース ６．０
ｌ−メントール ０．１６
ステアリン酸マグネシウム ２．０
295.0 g of partially pregelatinized starch (Asahi Kasei Co., Ltd .: PCS PC-10) was charged into a spouted fluidized bed granulator (Powrec Co., Ltd .: MP-01-SPC type), and 10.0 g of hydroxypropylcellulose was added to purified water 846. A liquid obtained by suspending 100.0 g of silodosin (γ type) in a liquid dissolved in 0.5 g was sprayed and dried to obtain granules.
243.0 g of the obtained granule was put into a spouted fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01-SPC type), aminoalkyl methacrylate copolymer E30.00 g, sodium lauryl sulfate 2.94 g, stearic acid 4.47 g. A coating solution obtained by dissolving and suspending 10.59 g of talc in 252.0 g of purified water was sprayed to obtain coated granules, which were sieved with a 30-mesh sieve and sized.
Corn granulated starch (58.20 g), D-mannitol (387.6 g), crospovidone (30.0 g) and crystalline cellulose (81.0 g) were charged into a spouted fluidized bed granulator (manufactured by Paulek: MP-01 type). 18.0 g, 0.6 g of yellow iron sesquioxide and 0.6 g of iron sesquioxide heated and suspended in 582.0 g of purified water are sprayed and dried to obtain granules, which are sieved with a 24 mesh sieve. And sized.
After mixing 192.0 g of the sized granules, 6.0 g of sucralose, and 0.16 g of 1-menthol in a polyethylene bag, 2.0 g of magnesium stearate was further added and mixed to obtain a mixture. The obtained 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 having the following composition having a mass of 200.16 mg per tablet.
[Components] [Weight per tablet (mg)]
・ Primary granule silodosin (γ type) 4.0
Partially pregelatinized starch 11.8
Hydroxypropyl cellulose 0.4
..Coated granules (secondary granules)
Aminoalkyl methacrylate copolymer E 2.00
Sodium lauryl sulfate 0.196
Stearic acid 0.298
Talc 0.706
... Tertiary granule part
D-mannitol 129.2
Crospovidone 10.0
Crystalline cellulose 27.0
Corn starch 6.0
Yellow ferric oxide 0.2
Iron trioxide 0.2
・ External additive part
Sucralose 6.0
l-Menthol 0.16
Magnesium stearate 2.0
部分アルファー化デンプン（旭化成社製：ＰＣＳ ＰＣ−１０）２９５．０ｇ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８４６．５ｇ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・乾燥して顆粒を得た。
得られた顆粒２４３．０ｇ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Ｅ１８．００ｇ、ラウリル硫酸ナトリウム１．８０ｇ、ステアリン酸２．７０ｇ、及びタルク６．０ｇを精製水２１９．０ｇに溶解・懸濁したコーティング液を噴霧して被覆顆粒を得て、それを３０メッシュの篩にて篩過して整粒した。
整粒した被覆顆粒５４．３０ｇ、Ｄ−マンニトール３９１．５０ｇ、クロスポビドン３０．０ｇ及び結晶セルロース８１．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、トウモロコシデンプン１８．０ｇ、黄色三二酸化鉄０．６ｇ及び三二酸化鉄０．６ｇを精製水５８２．０ｇに加温懸濁した液を噴霧・乾燥して顆粒を得て、２４メッシュの篩にて篩過して整粒した。
整粒した顆粒１９２．０ｇ、スクラロース６．０ｇ、ｌ−メントール０．１６ｇをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム２．０ｇを加えて混合して混合物を得た。得られた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２００．１６ｍｇの下記組成の口腔内崩壊錠を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・１次顆粒部
シロドシン（γ型） ４．０
部分α化デンプン １１．８
ヒドロキシプロピルセルロース ０．４
・・被覆顆粒（２次顆粒）部
アミノアルキルメタクリレートコポリマーＥ １．２０
ラウリル硫酸ナトリウム ０．１２
ステアリン酸 ０．１８
タルク ０．４０
・・・３次顆粒部
Ｄ−マンニトール １３０．５
クロスポビドン １０．０
結晶セルロース ２７．０
トウモロコシデンプン ６．０
黄色三二酸化鉄 ０．２
三二酸化鉄 ０．２
・外添加部
スクラロース ６．０
ｌ−メントール ０．１６
ステアリン酸マグネシウム ２．０
295.0 g of partially pregelatinized starch (Asahi Kasei Co., Ltd .: PCS PC-10) was charged into a spouted fluidized bed granulator (Powrec Co., Ltd .: MP-01-SPC type), and 10.0 g of hydroxypropylcellulose was added to purified water 846. A liquid obtained by suspending 100.0 g of silodosin (γ type) in a liquid dissolved in 0.5 g was sprayed and dried to obtain granules.
243.0 g of the obtained granule was put into a spouted fluidized bed granulator (manufactured by Paulec Co., Ltd .: MP-01-SPC type), aminoalkyl methacrylate copolymer E 18.00 g, sodium lauryl sulfate 1.80 g, stearic acid 2.70 g. A coating solution obtained by dissolving and suspending 6.0 g of talc in 219.0 g of purified water was sprayed to obtain coated granules, which were sieved with a 30-mesh sieve and sized.
Corned starch was charged into 54.30 g of the sized coated granules, 391.50 g of D-mannitol, 30.0 g of crospovidone, and 81.0 g of crystalline cellulose in a spouted fluidized bed granulator (manufactured by Paulek: MP-01 type). 18.0 g, 0.6 g of yellow iron sesquioxide and 0.6 g of iron sesquioxide heated and suspended in 582.0 g of purified water are sprayed and dried to obtain granules, which are sieved with a 24 mesh sieve. And sized.
After mixing 192.0 g of the sized granules, 6.0 g of sucralose, and 0.16 g of 1-menthol in a polyethylene bag, 2.0 g of magnesium stearate was further added and mixed to obtain a mixture. The obtained 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 having the following composition having a mass of 200.16 mg per tablet.
[Components] [Weight per tablet (mg)]
・ Primary granule
Silodosin (γ type) 4.0
Partially pregelatinized starch 11.8
Hydroxypropyl cellulose 0.4
..Coated granules (secondary granules) part aminoalkyl methacrylate copolymer E 1.20
Sodium lauryl sulfate 0.12
Stearic acid 0.18
Talc 0.40
... Tertiary granule part D-mannitol 130.5
Crospovidone 10.0
Crystalline cellulose 27.0
Corn starch 6.0
Yellow ferric oxide 0.2
Iron trioxide 0.2
・ External additive part
Sucralose 6.0
l-Menthol 0.16
Magnesium stearate 2.0
部分アルファー化デンプン（旭化成社製：ＰＣＳ ＰＣ−１０）２９５．０ｇ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８４６．５ｇ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・乾燥して顆粒を得た。
得られた顆粒２４３．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１−ＳＰＣ型）に投入し、エチルセルロース水分散液（固形分：３０％）１２７．５０ｇ、トリアセチン１０．５ｇ、及びＤ−マンニトール１０．５ｇを精製水２３７．０ｇに溶解・懸濁したコーティング液を噴霧して被覆顆粒を得て、それを３０メッシュの篩にて篩過して整粒した。
整粒した被覆顆粒６０．４５ｇ、Ｄ−マンニトール３８５．３５ｇ、クロスポビドン３０．０ｇ及び結晶セルロース８１．０ｇを噴流流動層造粒機（パウレック社製：ＭＰ−０１型）に投入し、トウモロコシデンプン１８．０ｇ、黄色三二酸化鉄０．６ｇ及び三二酸化鉄０．６ｇを精製水５８２．０ｇに加温懸濁した液を噴霧・乾燥して顆粒を得て、２４メッシュの篩にて篩過して整粒した。
整粒した顆粒１９２．０ｇ、スクラロース６．０ｇ、ｌ−メントール０．１６ｇをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム２．０ｇを加えて混合して混合物を得た。得られた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２００．１６ｍｇの下記組成の口腔内崩壊錠を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・１次顆粒部
シロドシン（γ型） ４．０
部分α化デンプン １１．８
ヒドロキシプロピルセルロース ０．４
・・被覆顆粒（２次顆粒）部
エチルセルロース ２．５５
トリアセチン ０．７
Ｄ−マンニトール ０．７
・・・３次顆粒部
Ｄ−マンニトール １２８．４５
クロスポビドン １０．０
結晶セルロース ２７．０
トウモロコシデンプン ６．０
黄色三二酸化鉄 ０．２
三二酸化鉄 ０．２
・外添加部
スクラロース ６．０
ｌ−メントール ０．１６
ステアリン酸マグネシウム ２．０
295.0 g of partially pregelatinized starch (Asahi Kasei Co., Ltd .: PCS PC-10) was charged into a spouted fluidized bed granulator (Powrec Co., Ltd .: MP-01-SPC type), and 10.0 g of hydroxypropylcellulose was added to purified water 846. A liquid obtained by suspending 100.0 g of silodosin (γ type) in a liquid dissolved in 0.5 g was sprayed and dried to obtain granules.
243.0 g of the obtained granule was put into a spouted fluidized bed granulator (manufactured by Paulek: MP-01-SPC type), and 127.50 g of ethyl cellulose aqueous dispersion (solid content: 30%), 10.5 g of triacetin, And the coating liquid which melt | dissolved and suspended 10.5g of D-mannitol in 237.0g of purified water was sprayed, and the coated granule was obtained, and it sieved with the 30 mesh sieve, and sized.
Corned starch was charged into 60.45 g of the sized granules, 385.35 g of D-mannitol, 30.0 g of crospovidone and 81.0 g of crystalline cellulose in a spouted fluidized bed granulator (manufactured by Paulek: MP-01 type). 18.0 g, 0.6 g of yellow iron sesquioxide and 0.6 g of iron sesquioxide heated and suspended in 582.0 g of purified water are sprayed and dried to obtain granules, which are sieved with a 24 mesh sieve. And sized.
After mixing 192.0 g of the sized granules, 6.0 g of sucralose, and 0.16 g of 1-menthol in a polyethylene bag, 2.0 g of magnesium stearate was further added and mixed to obtain a mixture. The obtained 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 having the following composition having a mass of 200.16 mg per tablet.
[Components] [Weight per tablet (mg)]
・ Primary granule
Silodosin (γ type) 4.0
Partially pregelatinized starch 11.8
Hydroxypropyl cellulose 0.4
..Coated granules (secondary granules)
Ethylcellulose 2.55
Triacetin 0.7
D-mannitol 0.7
... Third granule part D-mannitol 128.45
Crospovidone 10.0
Crystalline cellulose 27.0
Corn starch 6.0
Yellow ferric oxide 0.2
Iron trioxide 0.2
・ External additive part
Sucralose 6.0
l-Menthol 0.16
Magnesium stearate 2.0
部分アルファー化デンプン（旭化成社製：ＰＣＳ ＰＣ−１０）３５４．０ｇ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１２．０ｇを精製水８４５．０ｇに溶解した液にシロドシン（β型）１２０．０ｇを懸濁した液を噴霧・乾燥して顆粒を得た。
続いて、アミノアルキルメタクリレートコポリマーＥ６０．００ｇ、ラウリル硫酸ナトリウム６．０ｇ、ステアリン酸９．０ｇ、及びタルク２１．０ｇを精製水５０４．０ｇに溶解・懸濁したコーティング液を噴霧・乾燥して被覆顆粒を得て、それを３０メッシュの篩にて篩過して整粒した。
整粒した被覆顆粒５８２．０ｇ、Ｄ−マンニトール４１４８．４ｇ、クロスポビドン３００．０ｇ及び結晶セルロース８１０．０ｇを噴流流動層造粒機（パウレック社製：ＧＰＣＧ‐５型）に投入し、トウモロコシデンプン１８０．０ｇ、黄色三二酸化鉄６．０ｇ、及び三二酸化鉄４．５ｇを精製水２４００．０ｇに加温懸濁した液を噴霧・乾燥して顆粒を得て、それを２４メッシュの篩にて篩過して整粒した。
整粒した顆粒６０３０．９ｇ、スクラロース１８０．０ｇ、ｌ−メントール４．８ｇ及び結晶セルロース９．６ｇをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム９０．０ｇを加えて混合して混合物を得た。得られた混合物をロータリー打錠機を用いて直径８．０ｍｍに打圧６００ｋｇｆで圧縮成型し、１錠質量が２１０．５１ｍｇの下記組成の口腔内崩壊錠を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・１次顆粒部
シロドシン（β型） ４．０
部分α化デンプン １１．８
ヒドロキシプロピルセルロース ０．４
・・被覆顆粒（２次顆粒）部
アミノアルキルメタクリレートコポリマーＥ ２．００
ラウリル硫酸ナトリウム ０．２０
ステアリン酸 ０．３０
タルク ０．７０
・・・３次顆粒部
Ｄ−マンニトール １３８．２８
クロスポビドン １０．０
結晶セルロース ２７．０
トウモロコシデンプン ６．０
黄色三二酸化鉄 ０．２
三二酸化鉄 ０．１５
・外添加部
スクラロース ６．０
ｌ−メントール ０．１６
結晶セルロース ０．３２
ステアリン酸マグネシウム ３．０
354.0 g of partially pregelatinized starch (Asahi Kasei Co., Ltd .: PCS PC-10) was charged into a spouted fluidized bed granulator (Powrec Co., Ltd .: MP-01-SPC type), and 12.0 g of hydroxypropylcellulose was added to purified water 845. A liquid obtained by suspending 120.0 g of silodosin (β-type) in a liquid dissolved in 0.0 g was sprayed and dried to obtain granules.
Subsequently, a coating solution prepared by dissolving and suspending 60.00 g of aminoalkyl methacrylate copolymer E, 6.0 g of sodium lauryl sulfate, 9.0 g of stearic acid, and 21.0 g of talc in 504.0 g of purified water was sprayed and dried to cover the coating solution. Granules were obtained and sieved through a 30-mesh sieve and sized.
Corned starch was charged with 582.0 g of the sized granules, 4188.4 g of D-mannitol, 300.0 g of crospovidone, and 810.0 g of crystalline cellulose into a spouted fluidized bed granulator (Pauleck, Inc .: GPCG-5 type). 180.0 g, yellow iron sesquioxide 6.0 g, and iron sesquioxide 4.5 g heated and suspended in 2400.0 g purified water are sprayed and dried to obtain granules, which are then passed through a 24 mesh sieve. And sieved.
After mixing 6030.9g of granulated granules, 180.0g of sucralose, 4.8g of l-menthol and 9.6g of crystalline cellulose, 90.0g of magnesium stearate was further added and mixed. Got. The obtained mixture was compression-molded to a diameter of 8.0 mm with a pressing force of 600 kgf using a rotary tableting machine to obtain an orally disintegrating tablet having the following composition and having a tablet mass of 210.51 mg.
[Components] [Weight per tablet (mg)]
・ Primary granule silodosin (β type) 4.0
Partially pregelatinized starch 11.8
Hydroxypropyl cellulose 0.4
..Coated granules (secondary granules) part aminoalkyl methacrylate copolymer E 2.00
Sodium lauryl sulfate 0.20
Stearic acid 0.30
Talc 0.70
... Third granule part D-mannitol 138.28
Crospovidone 10.0
Crystalline cellulose 27.0
Corn starch 6.0
Yellow ferric oxide 0.2
Iron sesquioxide 0.15
・ External additive part
Sucralose 6.0
l-Menthol 0.16
Crystalline cellulose 0.32
Magnesium stearate 3.0
部分アルファー化デンプン（旭化成社製：ＰＣＳ ＰＣ−１０）３５４．０ｇ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１２．０ｇを精製水８４５．０ｇに溶解した液にシロドシン（β型）１２０．０ｇを懸濁した液を噴霧・乾燥して顆粒を得た。
続いて、アミノアルキルメタクリレートコポリマーＥ６０．００ｇ、ラウリル硫酸ナトリウム６．０ｇ、ステアリン酸９．０ｇ、及びタルク２１．０ｇを精製水５０４．０ｇに溶解・懸濁したコーティング液を噴霧・乾燥して被覆顆粒を得て、それを３０メッシュの篩にて篩過して整粒した。
整粒した被覆顆粒５８２．０ｇ、Ｄ−マンニトール３８４８．０ｇ、クロスポビドン３００．０ｇ及び結晶セルロース８１０．０ｇを噴流流動層造粒機（パウレック社製：ＧＰＣＧ‐５型）に投入し、トウモロコシデンプン１８０．０ｇ、黄色三二酸化鉄６．０ｇ、及び三二酸化鉄４．５ｇを精製水２４００．０ｇに加温懸濁した液を噴霧・乾燥して顆粒を得て、それを２４メッシュの篩にて篩過して整粒した。
整粒した顆粒５７３０．９ｇ、炭酸マグネシウム３００．０ｇ、スクラロース１８０．０ｇ、ｌ−メントール４．８ｇ及び結晶セルロース９．６ｇをポリエチレン製の袋にて混合した後、更にステアリン酸マグネシウム９０．０ｇを加えて混合して混合物を得た。得られた混合物をロータリー打錠機を用いて直径８．０ｍｍに打圧６００ｋｇｆで圧縮成型し、１錠質量が２１０．５１ｍｇの下記組成の口腔内崩壊錠を得た。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・核顆粒（１次顆粒）部
シロドシン（β型） ４．０
部分α化デンプン １１．８
ヒドロキシプロピルセルロース ０．４
・・被覆顆粒（２次顆粒）部
アミノアルキルメタクリレートコポリマーＥ ２．００
ラウリル硫酸ナトリウム ０．２０
ステアリン酸 ０．３０
タルク ０．７０
・・・３次顆粒部
Ｄ−マンニトール １２８．２８
クロスポビドン １０．０
結晶セルロース ２７．０
トウモロコシデンプン ６．０
黄色三二酸化鉄 ０．２
三二酸化鉄 ０．１５
・外添加部
スクラロース ６．０
炭酸マグネシウム １０．０
ｌ−メントール ０．１６
結晶セルロース ０．３２
ステアリン酸マグネシウム ３．０
354.0 g of partially pregelatinized starch (Asahi Kasei Co., Ltd .: PCS PC-10) was charged into a spouted fluidized bed granulator (Powrec Co., Ltd .: MP-01-SPC type), and 12.0 g of hydroxypropylcellulose was added to purified water 845. A liquid obtained by suspending 120.0 g of silodosin (β-type) in a liquid dissolved in 0.0 g was sprayed and dried to obtain granules.
Subsequently, a coating solution prepared by dissolving and suspending 60.00 g of aminoalkyl methacrylate copolymer E, 6.0 g of sodium lauryl sulfate, 9.0 g of stearic acid, and 21.0 g of talc in 504.0 g of purified water was sprayed and dried to cover the coating solution. Granules were obtained and sieved through a 30-mesh sieve and sized.
Corned starch was charged with 582.0 g of the sized granules, 3848.0 g of D-mannitol, 300.0 g of crospovidone and 810.0 g of crystalline cellulose into a spouted fluidized bed granulator (manufactured by Paulek: GPCG-5). 180.0 g, yellow iron sesquioxide 6.0 g, and iron sesquioxide 4.5 g heated and suspended in 2400.0 g purified water are sprayed and dried to obtain granules, which are then passed through a 24 mesh sieve. And sieved.
After 5730.9 g of the granulated granules, 300.0 g of magnesium carbonate, 180.0 g of sucralose, 4.8 g of 1-menthol and 9.6 g of crystalline cellulose were mixed in a polyethylene bag, 90.0 g of magnesium stearate was further added. In addition, mixing was performed to obtain a mixture. The obtained mixture was compression-molded to a diameter of 8.0 mm with a pressing force of 600 kgf using a rotary tableting machine to obtain an orally disintegrating tablet having the following composition and having a tablet mass of 210.51 mg.
[Components] [Weight per tablet (mg)]
-Nuclear granule (primary granule) part silodosin (β type) 4.0
Partially pregelatinized starch 11.8
Hydroxypropyl cellulose 0.4
..Coated granules (secondary granules) part aminoalkyl methacrylate copolymer E 2.00
Sodium lauryl sulfate 0.20
Stearic acid 0.30
Talc 0.70
... Third granule part D-mannitol 128.28
Crospovidone 10.0
Crystalline cellulose 27.0
Corn starch 6.0
Yellow ferric oxide 0.2
Iron sesquioxide 0.15
・ External additive part
Sucralose 6.0
Magnesium carbonate 10.0
l-Menthol 0.16
Crystalline cellulose 0.32
Magnesium stearate 3.0
［試験例１］
成人男性である被験者３名其々に、実施例１〜４に記載の口腔内崩壊錠の其々について、口腔内に１錠のみ含んでもらって舌を軽く動かしながら口腔内で崩壊させることを行ってもらった。その際に口腔内で感じた、各口腔内崩壊錠のざらつき感と苦味について上記の各被験者に評価してもらい、其の評価結果の概要を下記の表１に示した。各被験者による前記評価は、ざらつき感については、有：ざらつき感が目立って感じられる、無：ざらつき感が目立って感じられない、のいずれかの項目から、苦味については、０：苦くない、１：少し苦い、２：苦い、３：非常に苦い、のいずれかの数値項目から最も適当なものを被験者に選択してもらうことで行った。
[Test Example 1]
For each of the three adult male subjects, each of the orally disintegrating tablets described in Examples 1 to 4 is allowed to disintegrate in the oral cavity while gently moving the tongue, including only one tablet in the oral cavity. I got it. At that time, each subject mentioned above evaluated the rough feeling and bitterness of each orally disintegrating tablet felt in the oral cavity, and the summary of the evaluation results is shown in Table 1 below. The evaluation by each subject is that the bitterness is 0: not bitter from one of the items: Yes: the feeling of roughness is noticeable, No: The feeling of roughness is not noticeable, 1 : Slightly bitter, 2: Bitter, 3: Very bitter, by having the subject select the most appropriate one from the numerical items.
[表１]
苦味：各実施例において、被験者全員の苦味の評価（数値）を基に算出した平均の数値を表１に示した。
[Table 1]
Bitterness: Table 1 shows the average numerical values calculated based on the bitterness evaluation (numerical values) of all subjects in each Example.
表１において、実施例１〜４の口腔内崩壊錠は、いずれもざらつき感を目立って感じることがなく、苦味においても服用に問題ない程度まで顕著に低減されたものであることが示された。すなわち、シロドシンを含む顆粒（本発明に係る顆粒であることが好ましい。）を低量の非腸溶性高分子で被覆することで、其の粒子径を低く保ってざらつき感をほぼ乃至は全く感じない程度まで低減することが可能であって、更に苦味も、シロドシンが極めて強い苦味を有するにも関わらず、驚くべき程度まで低減することが可能であることが示唆された。よって本発明により得られる、シロドシンを含有する口腔内崩壊錠はざらつき感や苦味が共に顕著に低減され、服用感が改善された優れた製剤であることが示された。 In Table 1, it was shown that the orally disintegrating tablets of Examples 1 to 4 did not have a noticeable feeling of roughness, and were significantly reduced to the extent that there was no problem in taking even bitterness. . That is, a granule containing silodosin (preferably a granule according to the present invention) is coated with a low amount of a non-enteric polymer so that the particle size is kept low and a rough feeling is almost or completely felt. It was suggested that the bitterness can be reduced to a surprising level even though silodosin has a very strong bitterness. Therefore, it was shown that the orally disintegrating tablet containing silodosin obtained by the present invention is an excellent preparation having both a rough feeling and a bitter taste remarkably reduced and a feeling of taking improved.
［試験例２]
実施例５、６の錠剤並びに比較対象として適当な市販錠剤を、保存開始時及び、温度６０℃の密封条件下又は温度６０℃相対湿度７５％の開放条件下で７日間保存した後に、原薬由来の総類縁体の生成量を測定した。其の測定は高速液体クロマトグラフィー法（定量方法は面積百分率法を使用した。）によって行った。上記の測定結果は下記の表２に示す。
[Test Example 2]
The tablets of Examples 5 and 6 and commercially available tablets suitable for comparison were stored at the start of storage and after storage for 7 days under sealed conditions at a temperature of 60 ° C. or open conditions at a temperature of 60 ° C. and a relative humidity of 75%. The amount of total analogs derived was measured. The measurement was performed by the high performance liquid chromatography method (quantitative method used area percentage method). The measurement results are shown in Table 2 below.
[表２]
表２において、実施例５、６の口腔内崩壊錠はいずれも、比較対象として適当な市販錠剤と比べて、化学的な安定性がより有意に優れていることが示された。また開放条件下で保存した場合においては、炭酸マグネシウムを含む実施例６は炭酸マグネシウムを含まない実施例５に比べて化学的な安定性が有意に優れていることが示された。よって本発明により得られる、シロドシンを含有する口腔内崩壊錠は化学的な安定性が顕著に改善された製剤であることが示された。 In Table 2, it was shown that the orally disintegrating tablets of Examples 5 and 6 are significantly more excellent in chemical stability than commercially available tablets suitable for comparison. In addition, when stored under open conditions, Example 6 containing magnesium carbonate was shown to have significantly better chemical stability than Example 5 containing no magnesium carbonate. Therefore, it was shown that the orally disintegrating tablet containing silodosin obtained by the present invention is a preparation with significantly improved chemical stability.
［参考例１］
シロドシン１２０．０ｇ、Ｄ−マンニトール４８６０．０ｇ及び部分α化デンプン６００．０ｇを流動層造粒機（パウレック社製：ＧＰＣＧ−５型）に投入し、ヒドロキシプロピルセルロース２４０．０ｇを精製水２１６０ｇ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、２４メッシュの篩にて篩過して整粒品を得た。得られた整粒品５８２０ｇにタルク６０．０ｇ及びステアリン酸マグネシウム６０．０ｇを加え、混合した。次いで、この混合物をロータリー式打錠機（菊水製作所製：ＶＩＲＧＯ型）を用いて長径１１ｍｍ、短径６ｍｍに圧縮成型し、１錠質量が１９８．０ｍｇの素錠を得た。
得られた錠剤をコーティング機（パウレック社製：ＰＲＣ−１５型）に投入し、これに予めヒプロメロース１０２．０ｇ、酸化チタン４８．０ｇ及びタルク３０．０ｇを精製水２．７０ｋｇに加え、均一分散させた液を噴霧・乾燥し、１錠質量２０４．０ｍｇになるまでコーティングして１層フィルムコーティング錠を得た。得られた其の１層コーティング錠に、予めヒプロメロース８４．０ｇ、酸化チタン９．００ｇ及びタルク２７．０ｇを精製水１．８０ｋｇに加え、均一分散させた液を噴霧・乾燥し、１錠質量２０８．０ｍｇになるまでコーティングして下記の２層フィルムコーティング錠（普通錠）を得た。得られた２層フィルムコーティング錠はレーザー印字に適しており、良好な品質を有するものである。
［成 分］ ［１錠当たりの重量（ｍｇ）］
・素錠
シロドシン ４．０
Ｄ−マンニトール １６２．０
部分α化デンプン ２０．０
ヒドロキシプロピルセルロース ８．０
タルク ２．０
ステアリン酸マグネシウム ２．０
・フィルムコーティング層１
ヒプロメロース ３．４
酸化チタン １．６
タルク １．０
・フィルムコーティング層２
ヒプロメロース ２．８
酸化チタン ０．３
タルク ０．９
上記の製造方法で示された様に普通錠を製造する場合においては、本発明を用いずとも良好な品質の製剤を製造することが充分に可能である。但し普通錠（特にフィルムコーティング錠）は、口腔内崩壊錠のような口腔内での迅速な崩壊性をもたないため、嚥下を困難とする患者には望まれない可能性がある。本発明は医療現場に必要とされる口腔内崩壊錠を製造する上で特に必要とされるものである。
[Reference Example 1]
120.0 g of silodosin, 4860.0 g of D-mannitol and 600.0 g of partially pregelatinized starch were charged into a fluidized bed granulator (manufactured by Paulek: GPCG-5 type), and 240.0 g of hydroxypropylcellulose was added to 2160 g of purified water. The dissolved liquid was sprayed and granulated to obtain a granulated product containing silodosin. The obtained granulated product was dried and sieved with a 24 mesh sieve to obtain a sized product. 60.0 g of talc and 60.0 g of magnesium stearate were added to 5820 g of the obtained sized product and mixed. Next, this mixture was compression-molded into a major axis of 11 mm and a minor axis of 6 mm using a rotary tableting machine (manufactured by Kikusui Seisakusho: VIRGO type) to obtain an uncoated tablet having a tablet mass of 198.0 mg.
The obtained tablet was put into a coating machine (Powrec Co., Ltd. model: PRC-15), and 102.0 g of hypromellose, 48.0 g of titanium oxide and 30.0 g of talc were added to 2.70 kg of purified water in advance and uniformly dispersed. The liquid thus prepared was sprayed and dried, and coated to a mass of 204.0 mg per tablet to obtain a single-layer film-coated tablet. To the obtained one-layer coated tablet, 84.0 g of hypromellose, 9.00 g of titanium oxide, and 27.0 g of talc were added in advance to 1.80 kg of purified water, and the uniformly dispersed liquid was sprayed and dried, and 1 tablet weight Coating was carried out to 208.0 mg to obtain the following two-layer film-coated tablets (ordinary tablets). The obtained two-layer film-coated tablet is suitable for laser printing and has good quality.
[Components] [Weight per tablet (mg)]
・ Uncoated tablets
Silodosin 4.0
D-mannitol 162.0
Partially pregelatinized starch 20.0
Hydroxypropyl cellulose 8.0
Talc 2.0
Magnesium stearate 2.0
・ Film coating layer 1
Hypromellose 3.4
Titanium oxide 1.6
Talc 1.0
・ Film coating layer 2
Hypromellose 2.8
Titanium oxide 0.3
Talc 0.9
In the case of producing ordinary tablets as shown in the above production method, it is possible to produce a good quality preparation without using the present invention. However, ordinary tablets (especially film-coated tablets) do not have rapid disintegration in the oral cavity like orally disintegrating tablets, and may not be desirable for patients who have difficulty in swallowing. The present invention is particularly required for producing an orally disintegrating tablet required in the medical field.
本発明によれば、原薬の化学的な安定性や苦味等の服用感が顕著に改善された効果を有する口腔内崩壊錠が得られ、医療現場に高品質な錠剤を提供することが可能となる。
According to the present invention, it is possible to obtain an orally disintegrating tablet having an effect of significantly improving the feeling of administration such as chemical stability and bitterness of the drug substance, and to provide a high-quality tablet in the medical field It becomes.
Claims (6)
アミノアルキルメタクリレートコポリマーＥ又はエチルセルロースである非腸溶性高分子を含むコーティング層で更に被覆されていることを特徴とする被覆顆粒、を含有する口腔内崩壊錠であって、
前記シロドシン１００.０重量部に対して前記コーティング剤が８．０重量部以上の範囲内で含まれ、
前記シロドシン１００.０重量部に対して前記非腸溶性高分子が３０．０〜１００．０重量部の範囲内で含まれる、口腔内崩壊錠。
Granules characterized in that the core particles are coated with a coating layer containing a coating agent that is silodosin and hydroxypropylcellulose ,
An orally disintegrating tablet comprising coated granules, further coated with a coating layer comprising a non-enteric polymer that is aminoalkyl methacrylate copolymer E or ethyl cellulose ,
The coating agent is included in a range of 8.0 parts by weight or more with respect to 100.0 parts by weight of the silodosin,
An orally disintegrating tablet comprising the non-enteric polymer in an amount of 30.0 to 100.0 parts by weight per 100.0 parts by weight of silodosin.
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