JP2020023466A - Orally disintegrating tablets with reduced bitterness of fast-dissolving drugs - Google Patents
Orally disintegrating tablets with reduced bitterness of fast-dissolving drugs Download PDFInfo
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- JP2020023466A JP2020023466A JP2018209960A JP2018209960A JP2020023466A JP 2020023466 A JP2020023466 A JP 2020023466A JP 2018209960 A JP2018209960 A JP 2018209960A JP 2018209960 A JP2018209960 A JP 2018209960A JP 2020023466 A JP2020023466 A JP 2020023466A
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- Prior art keywords
- drug
- orally disintegrating
- disintegrating tablet
- tablet
- dissolution test
- Prior art date
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Abstract
Description
本発明は、溶出速度が速い薬物（特にメマンチン塩酸塩）を含有する口腔内崩壊錠に関する。 The present invention relates to an orally disintegrating tablet containing a drug having a high dissolution rate (particularly, memantine hydrochloride).
メマンチン塩酸塩は、グルタミン酸受容体のサブタイプであるＮＭＤＡ受容体に対する拮抗作用を有し、アルツハイマー型認知症の治療薬に用いられる化合物（薬物）である（非特許文献１参照）。メマンチン塩酸塩と薬理学的に関連する化合物としては、ドネペジル塩酸塩、ガランタミン臭化水素酸塩、リバスチグミンなどが挙げられる。 Memantine hydrochloride is a compound (drug) that has an antagonistic effect on the NMDA receptor, which is a subtype of glutamate receptor, and is used as a therapeutic drug for Alzheimer-type dementia (see Non-Patent Document 1). Compounds that are pharmacologically related to memantine hydrochloride include donepezil hydrochloride, galantamine hydrobromide, rivastigmine, and the like.
現在、メマンチン塩酸塩は錠剤の剤形で医療現場に提供されている。メマンチン塩酸塩を含有する製剤の処方や製造方法は、以下の特許文献１〜３等で紹介されている。特許文献１の実施例１５、１６では流動層造粒によって得られたメマンチン塩酸塩を含む造粒物（被覆造粒物である場合を含む。）を含有する口腔内崩壊錠が記載され、特許文献２の実施例１８、１９では攪拌造粒によって得られたメマンチン塩酸塩を含む造粒物を含有する錠剤が記載され、特許文献３ではメマンチン塩酸塩を含むコーティング錠等が記載される。
しかし、メマンチン塩酸塩を含有する口腔内崩壊錠についてメマンチン塩酸塩の苦味を改善する技術は、先行文献において十分な情報が開示されていない。口腔内崩壊錠における薬物の苦味の改善は、患者による当該錠剤の服用感を改善する上で重要な課題である。
そこで本発明者は、口腔内崩壊錠中のメマンチン塩酸塩等溶出速度が速い薬物の苦味を顕著に改善することが可能な新たな技術的手段の開発を目指した。
At present, memantine hydrochloride is provided to medical sites in the form of tablets. The formulation and production method of a preparation containing memantine hydrochloride are introduced in the following Patent Documents 1 to 3. In Examples 15 and 16 of Patent Document 1, an orally disintegrating tablet containing a granulated product containing memantine hydrochloride obtained by fluidized bed granulation (including a case of a coated granulated product) is described. In Examples 18 and 19 of Document 2, tablets containing granules containing memantine hydrochloride obtained by stirring granulation are described, and Patent Document 3 describes coated tablets containing memantine hydrochloride and the like.
However, the prior art does not disclose sufficient information on the technology for improving the bitterness of memantine hydrochloride for orally disintegrating tablets containing memantine hydrochloride. Improvement of the bitter taste of a drug in an orally disintegrating tablet is an important issue in improving the feeling of taking the tablet by a patient.
Therefore, the present inventor aimed to develop a new technical means capable of remarkably improving the bitterness of a drug having a high dissolution rate such as memantine hydrochloride in an orally disintegrating tablet.
本発明が解決しようとする課題は、溶出速度が速い薬物（特にメマンチン塩酸塩）を含有する口腔内崩壊錠を服用した時に口腔内で感じる薬物の苦味を顕著に改善することである。 The problem to be solved by the present invention is to remarkably improve the bitterness of a drug felt in the oral cavity when taking an orally disintegrating tablet containing a drug with a high elution rate (particularly memantine hydrochloride).
本発明者は、口腔内崩壊錠中のメマンチン塩酸塩の苦味を改善するため、其の製剤処方や製造方法に関して鋭意検討を重ねた。その結果、メマンチン塩酸塩の初期の溶出速度を一定範囲の値に抑えることで、口腔内崩壊錠を服用した際に感じる其の苦味が有意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。 The present inventors have conducted intensive studies on the formulation and production method of memantine hydrochloride in orally disintegrating tablets in order to improve the bitter taste. As a result, they found that by suppressing the initial dissolution rate of memantine hydrochloride to a value within a certain range, the bitterness felt when taking an orally disintegrating tablet was significantly improved. Based on the knowledge, the present inventor has conducted further intensive studies and completed the following invention.
本発明は、口腔内崩壊錠が崩壊して薬物が溶出した直後の其の溶出率を或る一定範囲に調整することで薬物が口腔内に存在するときに感じるその苦味を驚くほど有意に抑えられることが可能なこと等を見出したものであり、其の好ましい構成は下記（１）〜（８）等において記述されているものである。
（１）第１７改正日本薬局方溶出試験法（パドル法）に従い、溶出試験第２液を用いて行った溶出試験の開始５分後の時点における薬物の溶出率が８０．０％以下（望ましくは４０．０％以上）である、錠剤（口腔内崩壊錠）。
溶出試験第２液：ｐＨ６．８のリン酸塩緩衝液1容量に水1容量を加えたものである日本薬局方溶出試験第二液
（２）前記溶出試験の開始５分後の時点における薬物の溶出率が７０．０％以下である、口腔内崩壊錠。
（３）薬物が、メマンチン、シタグリプチン、ソリフェナシン、プレガバリン及び前記いずれかの塩から選択される、前記（１）又は（２）に記載の口腔内崩壊錠。
（４）薬物が顆粒中に含有され、当該顆粒が酢酸セルロース、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、酢酸ビニル樹脂、アクリル酸エチル・メタクリル酸メチルコポリマーから選択される水不溶性高分子の徐放性コーティング剤によって被覆される、前記（１）〜（３）のいずれかに記載の口腔内崩壊錠。
（５）前記溶出試験の開始１０分後の時点における薬物の溶出率が７０．０％以上である、前記（１）〜（４）のいずれかに記載の口腔内崩壊錠。
（６）薬物（メマンチン塩酸塩、ソリフェナシンコハク酸塩等）が顆粒中に含有され、当該顆粒がアクリル酸エチル・メタクリル酸メチルコポリマーである水不溶性高分子及びメタクリル酸コポリマーである腸溶性高分子を含有する、口腔内崩壊錠。
（７）第１７改正日本薬局方溶出試験法（パドル法）に従い、溶出試験第１液を用いて行った溶出試験の開始５分後の時点における薬物の溶出率が５．０％以上（好ましくは１０．０〜１００．０％）を示す非腸溶性製剤である、口腔内崩壊錠。
溶出試験第１液：塩化ナトリウム２．０ｇ及び塩酸７．０ｍｌに水を加えて１０００ｍｌとしたものである日本薬局方溶出試験第１液
（７）薬物を溶解又は懸濁させたコーティング液を、流動化された核粒子に噴霧して湿式造粒（例：微粒子コーティング法）する工程を介する、前記（１）〜（６）のいずれかに記載の口腔内崩壊錠、の製造方法。
（８）腸溶性高分子を溶解したコーティング液を、流動化された薬物を含有する顆粒に噴霧して湿式造粒（例：微粒子コーティング法）する工程を介する、前記（７）に記載の口腔内崩壊錠の製造方法。
The present invention surprisingly significantly reduces the bitterness felt when a drug is present in the oral cavity by adjusting the dissolution rate of the drug immediately after the orally disintegrating tablet disintegrates and the drug elutes to a certain range. It has been found that it can be performed, and the preferred configurations are described in the following (1) to (8) and the like.
(1) According to the 17th revised Japanese Pharmacopoeia dissolution test method (paddle method), the dissolution rate of the drug at the time of 5 minutes after the start of the dissolution test performed using the second solution of the dissolution test is 80.0% or less (desirably) Is 40.0% or more).
Dissolution test 2nd solution: Japanese Pharmacopoeia dissolution test 2nd solution which is obtained by adding 1 volume of water to 1 volume of pH 6.8 phosphate buffer (2) Drug at 5 minutes after the start of the dissolution test Orally disintegrating tablet having a dissolution rate of 70.0% or less.
(3) The orally disintegrating tablet according to (1) or (2), wherein the drug is selected from memantine, sitagliptin, solifenacin, pregabalin, and any of the above salts.
(4) A drug is contained in a granule, and the granule is a sustained-release coating agent of a water-insoluble polymer selected from cellulose acetate, ethyl cellulose, aminoalkyl methacrylate copolymer, vinyl acetate resin, ethyl acrylate / methyl methacrylate copolymer. The orally disintegrating tablet according to any one of (1) to (3), which is coated with:
(5) The orally disintegrating tablet according to any one of (1) to (4), wherein the dissolution rate of the drug at 10 minutes after the start of the dissolution test is 70.0% or more.
(6) A drug (memantine hydrochloride, solifenacin succinate, etc.) is contained in a granule, and the granule is a water-insoluble polymer that is an ethyl acrylate-methyl methacrylate copolymer and an enteric polymer that is a methacrylic acid copolymer. Orally disintegrating tablets containing.
(7) According to the 17th Revised Japanese Pharmacopoeia dissolution test method (paddle method), the dissolution rate of the drug at the point of 5 minutes after the start of the dissolution test performed using the first solution of the dissolution test is 5.0% or more (preferably) Is a non-enteric preparation showing 10.0 to 100.0%).
Dissolution test first liquid: Japanese Pharmacopoeia dissolution test first liquid (7), which is prepared by adding water to 2.0 g of sodium chloride and 7.0 ml of hydrochloric acid to make 1000 ml, a coating solution in which a drug is dissolved or suspended, The method for producing an orally disintegrating tablet according to any one of the above (1) to (6), through a step of spraying the fluidized core particles and performing wet granulation (eg, a fine particle coating method).
(8) The oral cavity according to (7), wherein the coating solution in which the enteric polymer is dissolved is sprayed onto granules containing the fluidized drug to perform wet granulation (eg, a fine particle coating method). A method for producing an internally disintegrating tablet.
本発明により、溶出速度が速い薬物（特にメマンチン塩酸塩）を含有する口腔内崩壊錠を服用した時に口腔内で感じる薬物の苦味が顕著に改善される。 According to the present invention, the bitterness of a drug felt in the oral cavity when the orally disintegrating tablet containing a drug having a high dissolution rate (particularly memantine hydrochloride) is taken is remarkably improved.
以下で本発明である溶出速度が速い薬物（特にメマンチン塩酸塩）を含有する口腔内崩壊錠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 an orally disintegrating tablet containing a drug with a high dissolution rate (particularly memantine hydrochloride) according to the present invention will be described in detail. However, the following description is an exemplification for explaining the present invention, and is not intended to limit the present invention only to this description range.
＜剤形＞
本発明の口腔内崩壊錠は、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。）であることが好ましいが、素錠にフィルムコーティング層を施すことでフィルムコーティング錠とすることも可能である。
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。口腔内での崩壊時間は、例えば、錠剤を舌の上に乗せて唾液を浸潤させた際に其の崩壊にかかる時間を測定して求めたり、口腔内崩壊錠試験機（例：ＯＤ−ｍａｔｅ／樋口商会）を用いて試験液：水（３７℃）の条件における錠剤が崩壊する時間を測定して求めてもよく、またこれ以外の本発明が属する分野の当業者が口腔内での崩壊時間を測定するために一般的に行い得る方法によって求めてもよい。本発明の口腔内崩壊錠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、本発明の口腔内崩壊錠を打錠により圧縮成形する際の打圧は、３００〜１５００ｋｇｆの範囲内にあることが好ましい。
<Dosage form>
The orally disintegrating tablet of the present invention is preferably an uncoated tablet (refers to a tablet which is not covered with a film coating layer or a sugar coating layer, and is formed as is by tableting or the like. The same applies hereinafter). It is also possible to obtain a film-coated tablet by applying a film-coating layer to the tablet.
The orally disintegrating tablet is provided as a tablet that disintegrates rapidly in the oral cavity as distinguished from ordinary tablets, and has an orally disintegrating time of less than 60 seconds, particularly preferably less than 40 seconds. The disintegration time in the oral cavity can be determined, for example, by measuring the time required for disintegrating the tablet when the tablet is placed on the tongue and infiltrating saliva, or by using an orally disintegrating tablet tester (eg: OD-mate). / Higuchi Shokai) may be used to determine the time required for the tablet to disintegrate under the conditions of test solution: water (37 ° C.), and other persons skilled in the art to which the present invention belongs may disintegrate in the oral cavity. The time may be determined by a generally available method. The shape of the orally disintegrating tablet of the present invention is not particularly limited, and may be a circular tablet {circular flat tablet (including a corner tablet, etc.), a circular R tablet (including a corner tablet, two-stage R tablet, etc.)} or a variant. Any shape such as a tablet may be used, but a circular tablet is particularly preferable. In addition, the compression pressure at the time of compression-molding the orally disintegrating tablet of the present invention by tableting is preferably in the range of 300 to 1500 kgf.
＜薬物＞
本発明の口腔内崩壊錠に含有される具体的な薬物として、メマンチン、シタグリプチン、ソリフェナシン、プレガバリン及び前記いずれかの塩等の溶出速度の早い薬物を挙げることができ、好ましくはメマンチン塩酸塩又はソリフェナシンコハク酸塩であり、特にメマンチン塩酸塩であることが好ましく、また一種類の薬物のみを含む単剤であることが好ましい。本発明の口腔内崩壊錠を製造するために使用される薬物のメディアン径（ｄ５０）は２５．０μｍ以下であることが好ましく、より好ましくは１０．０μｍ以下である。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。本発明の口腔内崩壊錠において、薬物は、素錠の全重量に対して３．０重量％以上、好ましくは５．０〜２０．０重量％、より好ましくは８．０〜１３．０重量％の範囲で素錠中に含有される。メマンチン塩酸塩は１錠中に５ｍｇ、１０ｍｇ又は２０ｍｇのいずれか含有されることが望ましく、プレガバリンは１錠中に２５ｍｇ、７５ｍｇ又は１５０ｍｇのいずれか含有されることが望ましい。
<Drug>
Specific drugs contained in the orally disintegrating tablet of the present invention include memantine, sitagliptin, solifenacin, pregabalin and a drug having a high elution rate such as any of the above salts, and preferably memantine hydrochloride or solifenacin. Succinate, particularly preferably memantine hydrochloride, and a single agent containing only one kind of drug is preferable. The median diameter (d 50 ) of the drug used for producing the orally disintegrating tablet of the present invention is preferably 25.0 μm or less, more preferably 10.0 μm or less. If necessary, dry or wet pulverization may be appropriately performed to adjust the particle size to an arbitrary value. In the orally disintegrating tablet of the present invention, the drug is at least 3.0% by weight, preferably 5.0 to 20.0% by weight, more preferably 8.0 to 13.0% by weight based on the total weight of the uncoated tablet. % In the uncoated tablet. Memantine hydrochloride is desirably contained in one tablet at 5 mg, 10 mg or 20 mg, and pregabalin is desirably contained in one tablet at 25 mg, 75 mg or 150 mg.
＜溶出率＞
本発明の口腔内崩壊錠は、第１７改正日本薬局方溶出試験法（パドル法）に従い、溶出試験第２液（ｐＨ６．８）を用いて行った溶出試験の開始５分後の時点における薬物の溶出率が８０．０％以下（望ましくは３０．０％以上、より望ましくは４０．０％以上、更により望ましくは５０．０％以上）であることが好ましく、より好ましくは７０．０％以下であり、更により好ましくは６５．０％以下である。当該溶出試験の開始１０分後の時点における薬物の溶出率は７０．０％以上（望ましくは９８．０％以下、より望ましくは９５．０％以下）、好ましくは８０．０％以上とすることが可能である。溶出試験第２液は、ｐＨ６．８のリン酸塩緩衝液1容量に水1容量を加えたものである日本薬局方溶出試験第２液のことである。当該溶出試験の詳細な条件は試験例１に記載したもの（パドル回転数：５０ｒｐｍ）に依拠することが可能である。
尚、本発明の口腔内崩壊錠は非腸溶性製剤とすることが可能であり、第１７改正日本薬局方溶出試験法（パドル法）に従い、溶出試験第１液（ｐＨ１．２）を用いて行った溶出試験の開始５分後の時点における薬物の溶出率を例えば５．０％以上（好ましくは１０．０〜１００．０％、より好ましくは２０．０〜１００．０％）とすることが可能である。溶出試験第１液は、塩化ナトリウム２．０ｇ及び塩酸７．０ｍｌに水を加えて１０００ｍｌとすることで得られる日本薬局方溶出試験第１液（ｐＨ１．２）のことである。当該溶出試験の詳細な条件は試験例３に記載したもの（パドル回転数：５０ｒｐｍ）に依拠することが可能である。
<Dissolution rate>
The orally disintegrating tablet of the present invention can be used as a drug at 5 minutes after the start of the dissolution test using the second solution (pH 6.8) in accordance with the 17th Revised Japanese Pharmacopoeia dissolution test (paddle method). Is preferably 80.0% or less (preferably 30.0% or more, more preferably 40.0% or more, and still more preferably 50.0% or more), and more preferably 70.0%. Or less, still more preferably 65.0% or less. The dissolution rate of the drug at 10 minutes after the start of the dissolution test should be 70.0% or more (preferably 98.0% or less, more preferably 95.0% or less), and preferably 80.0% or more. Is possible. The second solution of the dissolution test is the second solution of the Japanese Pharmacopoeia dissolution test obtained by adding one volume of water to one volume of a phosphate buffer having a pH of 6.8. The detailed conditions of the dissolution test can be based on those described in Test Example 1 (paddle rotation speed: 50 rpm).
The orally disintegrating tablet of the present invention can be made into a non-enteric preparation, and is prepared by using the first liquid (pH 1.2) of the dissolution test according to the 17th revised Japanese Pharmacopoeia dissolution test method (paddle method). The dissolution rate of the drug at 5 minutes after the start of the dissolution test is, for example, 5.0% or more (preferably 10.0 to 100.0%, more preferably 20.0 to 100.0%). Is possible. The first solution for dissolution test is the first solution for dissolution test (pH 1.2) obtained by adding water to 2.0 g of sodium chloride and 7.0 ml of hydrochloric acid to make 1000 ml. The detailed conditions of the dissolution test can be based on those described in Test Example 3 (paddle rotation speed: 50 rpm).
＜徐放性コーティング剤＞
本発明の口腔内崩壊錠においては、徐放性コーティング剤と薬物が同一の顆粒中に含まれていることが好ましく、徐放性コーティング剤によって薬物の周囲が被覆されていることが望ましい。徐放性コーティング剤は、素錠の全重量に対して１．０重量％以上、好ましくは２．０〜４０．０重量％、より好ましくは５．０〜１５．０重量％の範囲で素錠中に含有される。
徐放性コーティング剤として、例えば、水不溶性高分子、胃溶性高分子、腸溶性高分子等を挙げることができ、好ましくは水不溶性高分子又は腸溶性高分子であり、より好ましくは水不溶性高分子（望ましくは腸溶性高分子と共に）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。）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。
水不溶性高分子としては、例えば酢酸セルロース、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、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が挙げられ、好ましくはアクリル酸エチル・メタクリル酸メチル共重合体である。
胃溶性高分子としては、例えばポリビニルアセタールジエチルアミノアセテート、メタアクリル酸メチル・メタアクリル酸ブチル・メタアクリル酸ジメチルアミノエチル共重合体等が挙げられる。
腸溶性高分子としては、例えばヒドロキシプロピルメチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシメチルエチルセルロースフタレート、カルボキシメチルエチルセルロース、メタアクリル酸・メタアクリル酸メチル共重合体、メタクリル酸・アクリル酸エチル共重合体（メタクリル酸コポリマー）等が挙げられ、好ましくはメタクリル酸・アクリル酸エチル共重合体である。
本発明の口腔内崩壊錠において、水不溶性高分子と腸溶性高分子が含有される場合（望ましくはそれらが薬物と共に同一の顆粒の中に含有されている。）には、当該腸溶性高分子１００．０重量部に対して当該水不溶性高分子は好ましくは１２．０〜１２０．０重量部、より好ましくは１８．０〜８０．０重量部、更により好ましくは２０．０〜４８．０重量部の範囲内で素錠中に含有される。
<Sustained-release coating agent>
In the orally disintegrating tablet of the present invention, it is preferable that the sustained release coating agent and the drug are contained in the same granule, and that the drug is desirably covered with the sustained release coating agent. The sustained-release coating agent is used in an amount of 1.0% by weight or more, preferably 2.0 to 40.0% by weight, more preferably 5.0 to 15.0% by weight based on the total weight of the uncoated tablet. Included in tablets.
Examples of the sustained-release coating agent include, for example, water-insoluble polymers, gastric-soluble polymers, enteric polymers and the like, preferably water-insoluble polymers or enteric polymers, and more preferably high water-insoluble polymers. Molecules (preferably with enteric polymers). A water-insoluble polymer is substantially or not soluble in a water solvent (consisting essentially of water only) (detailed definition indicates the solubility described in the Japanese Pharmacopoeia 17th Edition) A polymer having a molecular weight of 10,000 or more characterized by "the solvent amount required to dissolve 1 g of solute is 10000 mL or more" with reference to the definition of one of the terms "almost insoluble". It is desirable that
Examples of the water-insoluble polymer include, for example, cellulose acetate, ethyl cellulose, aminoalkyl methacrylate copolymer, vinyl acetate resin, ethyl acrylate / methyl methacrylate copolymer, and preferably ethyl acrylate / methyl methacrylate copolymer. is there.
Examples of the gastric-soluble polymer include polyvinyl acetal diethylaminoacetate, methyl methacrylate / butyl methacrylate / dimethylaminoethyl methacrylate copolymer, and the like.
Examples of the enteric polymer include hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxymethylethylcellulose phthalate, carboxymethylethylcellulose, methacrylic acid / methyl methacrylate copolymer, methacrylic acid / ethyl acrylate copolymer (Methacrylic acid copolymer) and the like, and preferably a methacrylic acid / ethyl acrylate copolymer.
When the orally disintegrating tablet of the present invention contains a water-insoluble polymer and an enteric polymer (preferably, they are contained in the same granule together with the drug), the enteric polymer is used. The water-insoluble polymer is preferably 12.0 to 120.0 parts by weight, more preferably 18.0 to 80.0 parts by weight, still more preferably 20.0 to 48.0 parts by weight with respect to 100.0 parts by weight. It is contained in uncoated tablets within the range of parts by weight.
本発明の口腔内崩壊錠を製造するために使用可能な添加物としては、上記の添加物以外に、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 orally disintegrating tablet of the present invention include, in addition to the additives described above, commonly used excipients, binders, disintegrants, lubricants, and flavoring agents. , A coating agent, a plasticizer, a light-shielding agent, a surfactant and the like.
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、バレイショデンプン、コメデンプン、コムギデンプン、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース等を挙げる事ができ、好ましくはＤ-マンニトールである。賦形剤は、素錠の全重量に対して好ましくは４０．０〜９５．０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, potato starch, rice starch, wheat starch, partial alpha Starch, low-substituted hydroxypropylcellulose and the like, and preferably D-mannitol. The excipient is contained in the uncoated tablet, preferably in the range of 40.0 to 95.0% 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、デンプン（トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン等）、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、素錠の全重量に対して好ましくは０．０１〜５．０重量％の範囲で素錠中に含有される。 Specific binders include hydroxypropylcellulose, hypromellose, methylcellulose, povidone, ethylcellulose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, starch (corn starch, potato starch, rice starch, wheat starch, etc.) ), Polyethylene glycol and the like, and preferred is hydroxypropylcellulose. The binder is contained in the uncoated tablet, preferably in the range of 0.01 to 5.0% 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好ましくは２．０〜２０．０重量％の範囲で素錠中に含有される。 Specific examples of disintegrants include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, carmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, crospovidone, agar powder, and the like, preferably crospovidone. It is. The disintegrant is preferably contained in the uncoated tablet in a range of 2.0 to 20.0% 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、好ましくはステアリン酸マグネシウムである。滑沢剤は、素錠の全重量に対して好ましくは０．１〜３．０重量％の範囲で素錠中に含有される。 Specific examples of the lubricant include light anhydrous silicic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, hydrogenated oil and the like, and preferably magnesium stearate. The lubricant is preferably contained in the uncoated tablet in a range of 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る。矯味剤は、素錠の全重量に対して好ましくは１．０〜５．０重量％の範囲で素錠中に含有される。 Specific flavoring agents include ascorbic acid, L-aspartic acid, aspartame, sucralose, acesulfame potassium, thaumatin, l-menthol, and the like. The flavoring agent is preferably contained in the uncoated tablet in a range of 1.0 to 5.0% by weight based on the total weight of the uncoated tablet.
具体的なコーティング剤としては、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、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、デンプン（トウモロコシデンプン、バレイショデンプン、コメデンプン、コムギデンプン等）、ポリエチレングリコール、タルク等の広範な種類を、上記で具体的な種類が列挙されている徐放性コーティング剤に加えて、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好ましくは２．０〜４０．０重量％の範囲で錠剤中に含有される。 Specific coating agents include hydroxypropyl cellulose, hypromellose, methyl cellulose, povidone, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, starch (corn starch, potato starch, rice starch, wheat starch, etc.), A wide variety of polyethylene glycols, talc and the like can be mentioned in addition to the sustained release coating agents whose specific types are listed above. The coating agent is contained in the tablet preferably in the range of 2.0 to 40.0% 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、好ましくはクエン酸トリエチルである。可塑剤は、素錠の全重量に対して好ましくは０．０１〜２．０重量％の範囲で素錠中に含有される。 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 butylphthalylbutylglycolate, glycerin, glycerin fatty acid ester, polyethylene glycol, propylene glycol, and stearic acid, and preferred is triethyl citrate. The plasticizer is preferably contained in the uncoated tablet in the range of 0.01 to 2.0% by weight based on the total weight of the uncoated tablet.
具体的な遮光剤としては、酸化チタン、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る。遮光剤は、素錠の全重量に対して好ましくは０．０１〜２．０重量％の範囲で錠剤中に含有される。 Specific light shielding agents include titanium oxide, yellow iron oxide, yellow iron sesquioxide, brown iron oxide, iron sesquioxide, edible yellow 4, edible yellow 5, edible yellow 4, aluminum lake, edible red 2, Edible Red No. 3, Edible Red No. 102, and the like. The light-shielding agent is contained in the tablet in an amount of preferably 0.01 to 2.0% by weight based on the total weight of the uncoated tablet.
本発明の口腔内崩壊錠は、薬物を含む顆粒の周囲がコーティング層で被覆されたもの（以下、“本発明に係る被覆顆粒”と呼ぶ。）を含有することが好ましい
当該コーティング層は徐放性コーティング剤（望ましくは可塑剤等と併せて）を含むことが好ましく、徐放性コーティング剤は、本発明に係る被覆顆粒１００.０重量部に対して、好ましくは５．０〜８０．０重量部、より好ましくは１０．０〜５０．０重量部、更により好ましくは１５．０〜３０．０重量部の範囲で本発明に係る被覆顆粒中に含有される。当該コーティング層は、本発明に係る被覆顆粒１００.０重量部に対して、好ましくは１５.０〜９０．０重量部、より好ましくは２０.０〜７０．０重量部、更により好ましくは２５．０〜５５．０重量部の範囲で本発明に係る被覆顆粒中に含まれる。
The orally disintegrating tablet of the present invention preferably contains a drug-containing granule whose periphery is coated with a coating layer (hereinafter, referred to as “coated granules according to the present invention”). It is preferable to contain a coating agent (preferably in combination with a plasticizer and the like), and the sustained-release coating agent is preferably from 5.0 to 80.0 parts by weight based on 100.0 parts by weight of the coated granules according to the present invention. It is contained in the coated granules according to the present invention in a range of 1 part by weight, more preferably 10.0 to 50.0 parts by weight, still more preferably 15.0 to 30.0 parts by weight. The coating layer is preferably 15.0 to 90.0 parts by weight, more preferably 20.0 to 70.0 parts by weight, even more preferably 25 to 100.0 parts by weight of the coated granules according to the present invention. It is contained in the coated granules according to the present invention in the range of 0.0 to 55.0 parts by weight.
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、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造粒物を製造することができる。例えば、流動層造粒機中において、核粒子となる賦形剤を流動させておき、それに薬物及び結合剤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、薬物を含む顆粒は得られる。更に、流動層造粒機中において、其の薬物を含む顆粒を流動させておき、それに徐放性コーティング剤（望ましくは可塑剤等と併せて）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は賦形剤や滑沢剤と共に混合して打錠することで本発明の口腔内崩壊錠（素錠）を製造することが可能である。 As a specific example of the method for producing granules (granules) such as coated granules according to the present invention, there is a fine particle coating method. There is no difficulty in the operation method of the above-mentioned production method, and the target granules can be easily produced according to a conventional method. For example, in a fluidized bed granulator, excipients serving as core particles are fluidized, and a coating solution containing a drug and a binder is sprayed and dried to coat (cover) the granules containing the drug. Is obtained. Further, in a fluidized bed granulator, the granules containing the drug are fluidized, and a coating solution containing a sustained-release coating agent (preferably together with a plasticizer, etc.) is sprayed and dried to form a coating ( By coating, the coated granules according to the present invention are obtained. The orally disintegrating tablet (uncoated tablet) of the present invention can be produced by mixing the coated granules according to the present invention with excipients and lubricants and tableting.
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、本発明の口腔内崩壊錠を含む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口腔内崩壊錠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。 In addition, it is possible to obtain a PTP sheet product containing the orally disintegrating tablet of the present invention by sandwiching and covering the tablet with a packaging sheet and an aluminum foil or the like, followed by heat sealing. Specific materials used for the packaging sheet include polyvinyl chloride, polypropylene, polyvinylidene chloride, polychlorotrifluoroethylene and the like. In order to improve the stability of the orally disintegrating tablet of the present invention with respect to humidity, a PTP sheet product is manufactured using a material having a drying function, the PTP sheet product is packaged in an aluminum pillow, and a desiccant is used. And a well-known method such as encapsulation in a bottle together with the tablet.
以下に実施例等により本発明を説明するが、本発明はこれらの実施例等に限定されるものではない。以下の実施例１の錠剤の製造に使用されたメマンチン塩酸塩は、事前にジェットミル粉砕の操作を行って、粒子径分布がｄ１０＝２．２、ｄ５０＝７．０、ｄ９０＝２４．３｛レーザー回析・散乱法によって測定（体積基準）｝となったものを使用した。 Hereinafter, the present invention will be described with reference to examples and the like, but the present invention is not limited to these examples and the like. The memantine hydrochloride used in the production of the tablets of Example 1 below was subjected to a jet milling operation in advance to obtain a particle size distribution of d 10 = 2.2, d 50 = 7.0, and d 90 = 24.3 {measured by laser diffraction / scattering method (volume basis)} was used.
Ｄ−マンニトール（ＰＥＡＲＬＩＴＯＬ１００ＳＤ／ロケットジャパン社製：ｄ１０＝４９．８／ｄ５０＝９７．３／ｄ９０＝１５３．３）２４０．０ｇを噴流流動層造粒機（ＭＰ−０１−ＳＰＣ型／パウレック社製）内に投入して流動化させ、これにメチルセルロース（メトローズ ＳＭ−１５／信越化学工業社製）６０．０ｇを精製水１８００ｇに溶解した液にメマンチン塩酸塩３００．０ｇを懸濁した液を噴霧・乾燥し、整粒して顆粒（核顆粒）を得た。
上記で得られた核顆粒２４０ｇを噴流流動層造粒機内にて流動化させ、これにメタクリル酸コポリマーＬＤ（オイドラギットＬ３０Ｄ５５／エボニックジャパン社製：固形分３０％）３００ｇ、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（オイドラギットＮＥ３０Ｄ／エボニックジャパン社製：固形分３０％）1００ｇ、クエン酸トリエチル（シトロフレックス２ＳＣ−６０／森村商事社製）９．０ｇ、軽質無水ケイ酸（アエロジル３００／エボニックジャパン社製）３．０ｇ、タルク（ビクトリライトＳＫ−Ｃ／勝光山鉱業所社製）６０ｇを精製水６００ｇに懸濁・分散した液を噴霧・乾燥し、３０メッシュの篩にて篩過（整粒）して顆粒（被覆顆粒）を得た。
上記で得られた被覆顆粒２１．６ｇ、ＰＥＡＲＬＩＴＯＬ ＦＬＡＳＨ（登録商標）（ロケットジャパン社製）３１．７７ｇ、クロスポビドン（コリドンＣＬ−Ｆ/ＢＡＳＦ社製）２．４ｇ、アスパルテーム（味の素社製）０．７５ｇ、ストロベリーフレーバー（小川香料社製）０．０３ｇ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（太平化学産業社製）０．４５ｇを加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／菊水製作所社製）を用いて打圧１０００ｋｇｆで圧縮成型し、１錠質量が１９０．０ｍｇ、直径８．０ｍｍ、厚さ３．４ｍｍの素錠（円形Ｒ錠）を得た。
＊ＰＥＡＲＬＩＴＯＬ Ｆｌａｓｈ（登録商標）は、マンニトールとトウモロコシデンプンから成る添加剤である。
240.0 g of D-mannitol (PEARLITOL100SD / manufactured by Rocket Japan Co., Ltd .: d 10 = 49.8 / d 50 = 97.3 / d 90 = 153.3) was spouted by a spouted fluidized bed granulator (MP-01-SPC type / (Manufactured by Powrex Co.) and fluidized, and 300.0 g of memantine hydrochloride was suspended in a solution of 60.0 g of methylcellulose (Metroze SM-15 / manufactured by Shin-Etsu Chemical Co., Ltd.) dissolved in 1800 g of purified water. The liquid was sprayed, dried and sized to obtain granules (core granules).
240 g of the core granules obtained above was fluidized in a spouted fluidized bed granulator, and 300 g of methacrylic acid copolymer LD (Eudragit L30D55 / manufactured by Evonik Japan: solid content 30%), ethyl acrylate / methyl methacrylate 100 g of copolymer dispersion (Eudragit NE30D / Evonik Japan: 30% solids), 9.0 g of triethyl citrate (Citroflex 2SC-60 / Morimura Shoji), light anhydrous silicic acid (Aerosil 300 / Evonik Japan) ) 3.0 g, 60 g of talc (Victrilite SK-C / Katsumitsu Mining Co., Ltd.) was suspended and dispersed in 600 g of purified water, sprayed and dried, and sieved with a 30-mesh sieve (sized). Thus, granules (coated granules) were obtained.
21.6 g of the coated granules obtained above, 31.77 g of PEARLITOL FLASH (registered trademark) (manufactured by Rocket Japan), 2.4 g of crospovidone (manufactured by Kollidon CL-F / BASF), and aspartame (manufactured by Ajinomoto) 0 After mixing 0.75 g and 0.03 g of strawberry flavor (manufactured by Ogawa Koran Co., Ltd.) in a polyethylene bag, 0.45 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain a mixture. This mixture was compression-molded using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 1000 kgf, and a tablet having a mass of 190.0 mg, a diameter of 8.0 mm and a thickness of 3.4 mm (circular) R tablet).
* PEARLITOL Flash® is an additive consisting of mannitol and corn starch.
[比較例１]
低置換度ヒドロキシプロピルセルロース（ＮＢＤ−０２１／信越化学工業社製：ｄ１０＝２０／ｄ５０＝４５／ｄ９０＝１００）２００．０ｇを噴流流動層造粒機（ＭＰ−０１−ＳＰＣ型／パウレック社製）内に投入して流動化させ、これにヒドロキシプロピルセルロース（ＨＰＣ−Ｌ／日本曹達社製）４０．０ｇを精製水２０００ｇに溶解した液にメマンチン塩酸塩２００．０ｇを懸濁した液を噴霧・乾燥し、整粒して顆粒（核顆粒）を得た。
上記で得られた核顆粒６．６ｇ、ＰＥＡＲＬＩＴＯＬ ＦＬＡＳＨ（登録商標）（ロケットジャパン社製）３５．９７ｇ、クロスポビドン（コリドンＣＬ−Ｆ/ＢＡＳＦ社製）１．５ｇ、アスパルテーム（味の素社製）０．６０ｇ、ストロベリーフレーバー（小川香料社製）０．０３ｇ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（太平化学産業社製）０．３０ｇを加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／菊水製作所社製）を用いて打圧１０００ｋｇｆで圧縮成型し、１錠質量が１５０．０ｍｇ、直径７．５ｍｍ、厚さ３．４ｍｍの素錠（円形Ｒ錠）を得た。
[Comparative Example 1]
200.0 g of low-substituted hydroxypropylcellulose (NBD-021 / manufactured by Shin-Etsu Chemical Co., Ltd .: d 10 = 20 / d 50 = 45 / d 90 = 100) was spouted in a fluidized bed granulator (MP-01-SPC / (Manufactured by Powrex) and fluidized, and 200.0 g of memantine hydrochloride was suspended in a solution in which 40.0 g of hydroxypropylcellulose (HPC-L / manufactured by Nippon Soda Co., Ltd.) was dissolved in 2000 g of purified water. The liquid was sprayed, dried and sized to obtain granules (core granules).
6.6 g of the nuclear granules obtained above, 35.97 g of PEARLITOL FLASH (registered trademark) (manufactured by Rocket Japan), 1.5 g of crospovidone (manufactured by Kollidon CL-F / BASF), and aspartame (manufactured by Ajinomoto) 0 After mixing 0.60 g and 0.03 g of strawberry flavor (manufactured by Ogawa Koran Co., Ltd.) in a polyethylene bag, 0.30 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain a mixture. This mixture was compression-molded using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 1000 kgf, and a tablet having a mass of 150.0 mg, a diameter of 7.5 mm and a thickness of 3.4 mm (circular) R tablet).
[比較例２]
比較例１で得られた核顆粒１６５ｇを噴流流動層造粒機内にて流動化させ、これにヒドロキシプロピルメチルセルロースアセテートサクシネート（Ｓｈｉｎ−Ｅｔｓｕ ＡＱＯＡＴ ＡＳ−ＬＧ（登録商標）／信越化学工業社製）８９．１ｇ、メチルセルロース（ＳＭ−４／信越化学工業社製）９．９ｇ、タルク（ビクトリライトＳＫ−Ｃ／勝光山鉱業所社製）３３ｇおよび１０％アンモニア水２４ｇを精製水１５００ｇに懸濁・分散した液を噴霧・乾燥し、３０メッシュの篩にて篩過（整粒）して顆粒（被覆顆粒）を得た。
上記で得られた被覆顆粒１１．８８ｇ、ＰＥＡＲＬＩＴＯＬ ＦＬＡＳＨ（登録商標）（ロケットジャパン社製）３０．６９ｇ、クロスポビドン（コリドンＣＬ−Ｆ/ＢＡＳＦ社製）１．５ｇ、アスパルテーム（味の素社製）０．６０ｇ、ストロベリーフレーバー（小川香料社製）０．０３ｇ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（太平化学産業社製）０．３０ｇを加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／菊水製作所社製）を用いて打圧１０００ｋｇｆで圧縮成型し、１錠質量が１５０．０ｍｇ、直径７．５ｍｍ、厚さ３．４ｍｍの素錠（円形Ｒ錠）を得た。
[Comparative Example 2]
165 g of the core granules obtained in Comparative Example 1 was fluidized in a spouted fluidized bed granulator, and hydroxypropyl methylcellulose acetate succinate (Shin-Etsu AQOAT AS-LG (registered trademark) / Shin-Etsu Chemical Co., Ltd.) was added thereto. 89.1 g, 9.9 g of methylcellulose (SM-4 / Shin-Etsu Chemical Co., Ltd.), 33 g of talc (Victrilite SK-C / Katsumitsu Mining Co., Ltd.) and 24 g of 10% ammonia water were suspended in 1500 g of purified water. The dispersed liquid was sprayed and dried, and sieved (granulated) with a 30-mesh sieve to obtain granules (coated granules).
11.88 g of the coated granules obtained above, 30.69 g of PEARLITOL FLASH (registered trademark) (manufactured by Rocket Japan), 1.5 g of crospovidone (manufactured by Kollidon CL-F / BASF), and 0 aspartame (manufactured by Ajinomoto) After mixing 0.60 g and 0.03 g of strawberry flavor (manufactured by Ogawa Koran Co., Ltd.) in a polyethylene bag, 0.30 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain a mixture. This mixture was compression-molded using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 1000 kgf, and a tablet having a mass of 150.0 mg, a diameter of 7.5 mm and a thickness of 3.4 mm (circular) R tablet).
[比較例３]
比較例１で得られた核顆粒１６５ｇを噴流流動層造粒機内にて流動化させ、これに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／エボニックジャパン社製）８２．５ｇ、ラウリル硫酸ナトリウム８．２５ｇ、ステアリン酸（メルク社製）１２．３８ｇ、タルク（ビクトリライトＳＫ−Ｃ／勝光山鉱業所社製）２８．８８ｇを精製水７５０ｇに懸濁・分散した液を噴霧・乾燥し、３０メッシュの篩にて篩過（整粒）して顆粒（被覆顆粒）を得た。
上記で得られた被覆顆粒１１．８８ｇ、ＰＥＡＲＬＩＴＯＬ ＦＬＡＳＨ（登録商標）（ロケットジャパン社製）３０．６９ｇ、クロスポビドン（コリドンＣＬ−Ｆ/ＢＡＳＦ社製）１．５ｇ、アスパルテーム（味の素社製）０．６０ｇ、ストロベリーフレーバー（小川香料社製）０．０３ｇ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（太平化学産業社製）０．３０ｇを加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／菊水製作所社製）を用いて打圧１０００ｋｇｆで圧縮成型し、１錠質量が１５０．０ｍｇ、直径７．５ｍｍ、厚さ３．４ｍｍの素錠（円形Ｒ錠）を得た。
[Comparative Example 3]
165 g of the core granules obtained in Comparative Example 1 were fluidized in a spouted fluidized bed granulator, and 82.5 g of aminoalkyl methacrylate copolymer E (Eudragit EPO / Evonik Japan), 8.25 g of sodium lauryl sulfate, A liquid obtained by suspending and dispersing 12.38 g of stearic acid (Merck) and 28.88 g of talc (Victrilite SK-C / Katsumitsu Mining Co., Ltd.) in 750 g of purified water is sprayed and dried, and a 30-mesh sieve. To obtain granules (coated granules).
11.88 g of the coated granules obtained above, 30.69 g of PEARLITOL FLASH (registered trademark) (manufactured by Rocket Japan), 1.5 g of crospovidone (manufactured by Kollidon CL-F / BASF), and 0 aspartame (manufactured by Ajinomoto) After mixing 0.60 g and 0.03 g of strawberry flavor (manufactured by Ogawa Koran Co., Ltd.) in a polyethylene bag, 0.30 g of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) was added and mixed to obtain a mixture. This mixture was compression-molded using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho Co., Ltd.) at a compression pressure of 1000 kgf, and a tablet having a mass of 150.0 mg, a diameter of 7.5 mm and a thickness of 3.4 mm (circular) R tablet).
実施例１及び比較例１〜３で得られる錠剤の処方を下記の表１に一覧して示す（数値単位はｍｇ）。 The formulations of the tablets obtained in Example 1 and Comparative Examples 1 to 3 are listed and shown in Table 1 below (numerical units are mg).
[表１]
［試験例１］徐放性コート薬物の溶出試験
実施例１及び比較例２、３で製造した錠剤（薬物顆粒が徐放性コーティング剤でコートされたもの）について其々、第１７改正日本薬局方・一般試験法の溶出試験法（パドル法）により試験開始５、１０分後のメマンチンの溶出率（％）を求め（ＬＣ／ＭＳ使用）、結果（ｎ＝３）を下記の表２に示した。溶出試験の詳細な条件は下記に記載する。
＜測定条件＞
・試験液：日局「溶出試験第２液」（ｐＨ６．８）
・試験液量：９００ｍＬ
・パドル回転数：５０ｒｐｍ
・液温：３７℃
[Test Example 1] Dissolution test of sustained-release coated drug The tablets (drug granules coated with a sustained-release coating agent) manufactured in Example 1 and Comparative Examples 2 and 3 were each revised 17th Japan Pharmacy The dissolution rate (%) of memantine at 5 and 10 minutes after the start of the test was determined (using LC / MS) according to the dissolution test method (paddle method) of the general test method. Indicated. Detailed conditions of the dissolution test are described below.
<Measurement conditions>
・ Test solution: Japanese Pharmacopoeia “Dissolution test second solution” (pH 6.8)
・ Test liquid volume: 900mL
・ Paddle rotation speed: 50 rpm
・ Liquid temperature: 37 ° C
［試験例２］口腔内崩壊錠の官能試験
成人男性である被験者３名其々に、実施例１及び比較例１、２，３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、其の評価結果の平均値を下記の表１に示した。各被験者による前記評価は、苦味について、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 2] Sensory test of orally disintegrating tablet Each of three orally-disintegrating tablets described in Example 1 and Comparative Examples 1, 2 and 3 was subjected to 1 We asked them to disintegrate in the mouth while moving the tongue lightly with only the tablets included. Each subject evaluated the bitterness of each orally disintegrating tablet felt in the oral cavity at that time, and the average of the evaluation results is shown in Table 1 below. The evaluation by each subject is performed by asking the subject to select the most appropriate one of the numerical items of bitterness: 0: not bitter, 1: slightly bitter, 2: bitter, 3: very bitter. went.
表３より、溶出試験開始５分時点での溶出率がより高い比較例２、３よりも、溶出試験開始５分時点での溶出率がより低い実施例１の方が顕著に苦味が低減されていることが示された。
よって本発明の口腔内崩壊錠は、薬物が口腔内に存在するときに感じるその苦味を驚くほど有意に抑えられるものであることが示唆される。
As shown in Table 3, the bitterness is significantly reduced in Example 1 in which the dissolution rate at 5 minutes after the start of the dissolution test is lower than in Comparative Examples 2 and 3 in which the dissolution rate at 5 minutes after the start of the dissolution test is higher. It was shown that.
Therefore, it is suggested that the orally disintegrating tablet of the present invention can surprisingly and significantly suppress the bitterness felt when a drug is present in the oral cavity.
（Ａ）Ｄ−マンニトール（ＰＥＡＲＬＩＴＯＬ１００ＳＤ／ロケットジャパン社製）を噴流流動層造粒機（ＭＰ−０１−ＳＰＣ型／パウレック社製）内に投入して流動化させ、これにメチルセルロース（メトローズ ＳＭ−１５／信越化学工業社製）を精製水に溶解した液にメマンチン塩酸塩を懸濁した液を噴霧・乾燥し、整粒して顆粒αを得た。
（Ｂ）上記で得られた顆粒αを噴流流動層造粒機内にて流動化させ、これにメタクリル酸コポリマーＬＤ（オイドラギットＬ３０Ｄ５５／エボニックジャパン社製：固形分３０％）、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（オイドラギットＮＥ３０Ｄ／エボニックジャパン社製：固形分３０％）、クエン酸トリエチル（シトロフレックス２ＳＣ−６０／森村商事社製）、タルク（ビクトリライトＳＫ−Ｃ／勝光山鉱業所社製）を精製水に懸濁・分散した液を噴霧・乾燥して顆粒βを得た。
（Ｃ）上記で得られた顆粒βをＤ−マンニトール（マンニットＱ／三菱商事フードテック社製）と共に噴流流動層造粒機内にて流動化させ、これにスクラロース（スクラロースＰ／三栄源エフ・エフ・アイ社製）を精製水に溶解した液を噴霧・乾燥して顆粒γを得た。
（Ｄ）上記で得られた顆粒γとクロスポビドン（コリドンＣＬ−Ｆ/ＢＡＳＦ社製）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（太平化学産業社製）を加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／菊水製作所社製）を用いて打圧８００ｋｇｆで圧縮成型し、１錠質量が１７０．０ｍｇ、直径８．０ｍｍ、厚さ４．０ｍｍの口腔内崩壊錠（素錠、円形Ｒ錠）を得た。
尚、上記の原薬並びに各添加剤は、下記表４に示す錠剤の処方となるような量で上記の製造に用いた。
(A) D-mannitol (PEARLITOL100SD / Rocket Japan) is charged into a spouted fluidized bed granulator (MP-01-SPC type / Powrex) to fluidize, and methylcellulose (Metroze SM-15) is added thereto. (Manufactured by Shin-Etsu Chemical Co., Ltd.) in purified water was sprayed and dried with a liquid in which memantine hydrochloride was suspended, and sized to obtain granules α.
(B) The granules α obtained above are fluidized in a spouted fluidized bed granulator, and methacrylic acid copolymer LD (Eudragit L30D55 / Evonik Japan: solid content 30%), ethyl acrylate / methacrylic acid Methyl copolymer dispersion (Eudragit NE30D / Evonik Japan: 30% solids), triethyl citrate (Citroflex 2SC-60 / Morimura Shoji), talc (Victrilite SK-C / Katsumitsuyama Co., Ltd.) Was sprayed and dried to obtain granules β.
(C) The granules β obtained above are fluidized in a spouted fluidized bed granulator together with D-mannitol (Mannit Q / manufactured by Mitsubishi Corp. Foodtech), and sucralose (Sucralose P / San-Eigen F. A solution of F.I. in purified water was sprayed and dried to obtain granules γ.
(D) The granules γ obtained above and crospovidone (Kolidone CL-F / BASF) are mixed in a polyethylene bag, and then magnesium stearate (Taira Chemical Industry Co., Ltd.) is added and mixed. To obtain a mixture. This mixture was compression-molded using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho) at a compression pressure of 800 kgf, and the mass of one tablet was 170.0 mg, the diameter was 8.0 mm, and the thickness was 4.0 mm. (Uncoated tablet, round R tablet) was obtained.
In addition, the above-mentioned drug substance and each additive were used in the above-mentioned production in such an amount as to give a tablet formulation shown in Table 4 below.
（Ａ）流動層造粒乾燥コーティング機（ＭＰ０１型／パウレック社製）に投入して流動化させた含水二酸化ケイ素に、トコフェロールをエタノールに溶解した溶液を噴霧・乾燥し、次いで、ソリフェナシンコハク酸塩及びメチルセルロースを水に溶解した水溶液に軽質無水ケイ酸を懸濁した懸濁液を噴霧・乾燥し、非晶質体のソリフェナシンコハク酸塩を含む被覆顆粒Ａを得た。
（Ｂ）上記で得られた被覆顆粒Ａを流動層造粒乾燥コーティング機に投入して流動化させ、エチルセルロース水分散液（固形分：３０％）、クエン酸トリエチル、及びＤ−マンニトールを精製水に溶解・懸濁したコーティング液を噴霧・乾燥して被覆顆粒Ｂを得た。
（Ｃ）上記で得られた被覆顆粒Ｂを流動層造粒乾燥コーティング機に投入して流動化させ、これにメタクリル酸コポリマーＬＤ（オイドラギットＬ３０Ｄ５５／エボニックジャパン社製：固形分３０％）、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（オイドラギットＮＥ３０Ｄ／エボニックジャパン社製：固形分３０％）、クエン酸トリエチル、モノステアリン酸グリセリン、及びポリソルベート８０を精製水に懸濁・分散した液を噴霧・乾燥して被覆顆粒Ｃを得た。
（Ｄ）上記で得られた被覆顆粒ＣをＤ−マンニトール（マンニットＱ／三菱商事フードテック社製）と共に噴流流動層造粒機内にて流動化させ、これにスクラロース（スクラロースＰ／三栄源エフ・エフ・アイ社製）を精製水に溶解した液を噴霧・乾燥して顆粒Ｄを得た。
（Ｅ）上記で得られた顆粒αとクロスポビドン（コリドンＣＬ−Ｆ/ＢＡＳＦ社製）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（太平化学産業社製）を加えて混合して混合物を得た。この混合物をロータリー式打錠機（Ｖｅｒａ５／菊水製作所社製）を用いて打圧７５０ｋｇｆで圧縮成型し、１錠質量が１５０．０ｍｇ、直径７．５ｍｍ、厚さ３．９ｍｍの口腔内崩壊錠（素錠、円形Ｒ錠）を得た。
(A) A solution obtained by dissolving tocopherol in ethanol is sprayed and dried on hydrous silicon dioxide which has been fluidized by being introduced into a fluidized bed granulation drying coating machine (MP01 type / manufactured by Powrex), and then solifenacin succinate A suspension of light anhydrous silicic acid in an aqueous solution of methylcellulose dissolved in water was sprayed and dried to obtain coated granules A containing amorphous solifenacin succinate.
(B) The coated granules A obtained above are put into a fluidized bed granulating and drying coating machine to be fluidized, and an aqueous dispersion of ethyl cellulose (solid content: 30%), triethyl citrate, and D-mannitol are purified water. The coating solution dissolved and suspended in the mixture was sprayed and dried to obtain coated granules B.
(C) The coated granules B obtained above are put into a fluidized bed granulating and drying coating machine to be fluidized, and methacrylic acid copolymer LD (Eudragit L30D55 / Evonik Japan: solid content 30%), acrylic acid Ethyl / methyl methacrylate copolymer dispersion (Eudragit NE30D / Evonik Japan: 30% solids), triethyl citrate, glyceryl monostearate, and polysorbate 80 suspended and dispersed in purified water are sprayed and dried. Thus, coated granules C were obtained.
(D) The coated granules C obtained above were fluidized together with D-mannitol (Mannit Q / manufactured by Mitsubishi Corporation Foodtech) in a spouted fluidized bed granulator, and sucralose (Sucralose P / San-Eigen F) was added thereto. A solution prepared by dissolving F.I. in purified water was sprayed and dried to obtain granules D.
(E) The granules α obtained above and crospovidone (Kolidone CL-F / BASF) are mixed in a polyethylene bag, and then magnesium stearate (Taira Chemical Industry Co., Ltd.) is added and mixed. To obtain a mixture. This mixture was compression-molded using a rotary tableting machine (Vera5 / manufactured by Kikusui Seisakusho) at a compression pressure of 750 kgf, and the mass of one tablet was 150.0 mg, the diameter was 7.5 mm, and the thickness was 3.9 mm. (Uncoated tablet, round R tablet) was obtained.
実施例２（薬物：メマンチン塩酸塩）及び実施例３（薬物：ソリフェナシンコハク酸塩）の錠剤を其々、試験例２と同様の方法で被験者１名が口腔内で崩壊させたところ、実施例２の錠剤は苦味をほとんど感じず、実施例３の錠剤は苦みをわずかに感じる程度であった。そのため両錠剤ともに薬物の非常に強い苦味が有意に改善されていることが分かった。 Each of the tablets of Example 2 (drug: memantine hydrochloride) and Example 3 (drug: solifenacin succinate) was disintegrated in the oral cavity by one subject in the same manner as in Test Example 2. The tablet of No. 2 hardly felt bitterness, and the tablet of Example 3 was slightly bitter. Therefore, it was found that both tablets significantly improved the extremely strong bitterness of the drug.
［試験例３］徐放性コート薬物の溶出試験（２）
実施例２、３で製造した錠剤について其々、第１７改正日本薬局方・一般試験法の溶出試験法（パドル法）により試験開始５、１０分後（測定条件Ｂは試験開始５分後まで）の薬物（メマンチン、ソリフェナシン）の溶出率（％）を求め、結果（ｎ＝３）を下記の表６に示した。溶出試験は下記に記載するいずれかの条件で行なった。
＜測定条件Ａ＞
・試験液：日局「溶出試験第２液」（ｐＨ６．８）
・試験液量：９００ｍＬ
・パドル回転数：５０ｒｐｍ
・液温：３７℃
＜測定条件Ｂ＞
・試験液：日局「溶出試験第１液」（ｐＨ１．２）
・試験液量：９００ｍＬ
・パドル回転数：５０ｒｐｍ
・液温：３７℃
[Test Example 3] Dissolution test of sustained release coated drug (2)
Each of the tablets produced in Examples 2 and 3 was subjected to the dissolution test (paddle method) of the 17th Revised Japanese Pharmacopoeia / General Test Method after the start of the test, and after 5 and 10 minutes (measurement condition B was until 5 minutes after the start of the test) )) (Memantine, solifenacin) elution rate (%) was determined, and the results (n = 3) are shown in Table 6 below. The dissolution test was performed under any of the conditions described below.
<Measurement condition A>
・ Test solution: Japanese Pharmacopoeia “Dissolution test second solution” (pH 6.8)
・ Test liquid volume: 900mL
・ Paddle rotation speed: 50 rpm
・ Liquid temperature: 37 ° C
<Measurement condition B>
・ Test solution: JP “Dissolution test first solution” (pH 1.2)
・ Test liquid volume: 900mL
・ Paddle rotation speed: 50 rpm
・ Liquid temperature: 37 ° C
表６より、薬物の苦味が顕著に改善された実施例２及び３の錠剤は溶出試験（試験液：日局「溶出試験第２液」）開始５分時点等での溶出率が低いことが確認された。
また、実施例２及び３の錠剤は溶出試験（試験液：日局「溶出試験第１液」）において、５％以上の溶出性を示すことが確認された。そのため本発明の錠剤は非腸溶性製剤であることが示される。
From Table 6, it can be seen that the tablets of Examples 2 and 3, in which the bitterness of the drug was remarkably improved, had a low dissolution rate at 5 minutes after the start of the dissolution test (test solution: Japanese Pharmacopoeia, "Dissolution test 2nd solution"). confirmed.
Further, it was confirmed that the tablets of Examples 2 and 3 exhibited a dissolution property of 5% or more in a dissolution test (test solution: "Dissolution Test No. 1 Liquid" in Japan). This indicates that the tablet of the present invention is a non-enteric preparation.
本発明により、服用した時に口腔内で感じる薬物の苦味が顕著に改善された、溶出速度が速い薬物（特にメマンチン塩酸塩）を含有する口腔内崩壊錠を製造して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 produce orally disintegrating tablets containing a drug (especially memantine hydrochloride) containing a drug with a high dissolution rate (particularly memantine hydrochloride) in which the bitterness of the drug felt in the oral cavity when taken is remarkably improved. It becomes possible.
Claims (7)
第１７改正日本薬局方溶出試験法（パドル法）に従い、下記の溶出試験第２液を用いて行った溶出試験の開始５分後の時点における薬物の溶出率が７０．０％以下であることを特徴とする、口腔内崩壊錠。
溶出試験第２液：ｐＨ６．８のリン酸塩緩衝液1容量に水1容量を加えたもの。 An orally disintegrating tablet containing a drug,
According to the 17th Revised Japanese Pharmacopoeia Dissolution Test Method (Paddle Method), the dissolution rate of the drug at the time of 5 minutes after the start of the dissolution test performed using the following dissolution test solution 2 is 70.0% or less. An orally disintegrating tablet, characterized in that:
Second solution for dissolution test: One solution obtained by adding 1 volume of water to 1 volume of a phosphate buffer having a pH of 6.8.
A method for producing the orally disintegrating tablet according to any one of claims 1 to 6, wherein the coating liquid in which the drug is dissolved or suspended is sprayed onto the fluidized core particles to perform wet granulation. .
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005105045A1 (en) * | 2004-04-30 | 2005-11-10 | Astellas Pharma Inc. | Time-limited release type granular pharmaceutical composition for oral administration and intraoral rapid disintegration tablet containing the composition |
| US20170172942A1 (en) * | 2006-07-06 | 2017-06-22 | Forest Laboratories Holdings Limited | Orally dissolving formulations of memantine |
| JP2018065776A (en) * | 2016-10-21 | 2018-04-26 | ニプロ株式会社 | Pharmaceutical composition particle and orally disintegrable preparation containing the same, and method for producing pharmaceutical composition particle |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005105045A1 (en) * | 2004-04-30 | 2005-11-10 | Astellas Pharma Inc. | Time-limited release type granular pharmaceutical composition for oral administration and intraoral rapid disintegration tablet containing the composition |
| US20170172942A1 (en) * | 2006-07-06 | 2017-06-22 | Forest Laboratories Holdings Limited | Orally dissolving formulations of memantine |
| JP2018065776A (en) * | 2016-10-21 | 2018-04-26 | ニプロ株式会社 | Pharmaceutical composition particle and orally disintegrable preparation containing the same, and method for producing pharmaceutical composition particle |
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