JP5123517B2 - Ambroxol oral disintegrating tablet - Google Patents
Ambroxol oral disintegrating tablet Download PDFInfo
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- JP5123517B2 JP5123517B2 JP2006307914A JP2006307914A JP5123517B2 JP 5123517 B2 JP5123517 B2 JP 5123517B2 JP 2006307914 A JP2006307914 A JP 2006307914A JP 2006307914 A JP2006307914 A JP 2006307914A JP 5123517 B2 JP5123517 B2 JP 5123517B2
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本発明は口腔内速崩性錠剤に関する。さらに詳しくは、通常の装置で成形が可能であり、実用上問題のない硬度を有し、口腔内で口当たりよく速崩する口腔内速崩性錠剤に関する。 The present invention relates to an intraoral rapidly disintegrating tablet. More specifically, the present invention relates to an intraoral rapidly disintegrating tablet that can be molded with an ordinary apparatus, has a hardness that has no practical problem, and rapidly disintegrates in the mouth.
口腔内速崩性錠剤は口腔内で速やかに崩壊する錠剤であり、薬剤の飲みやすさを改善して患者コンプライアンス向上を図る剤形として注目されていて、種々のものが発明されている。口腔内速崩性錠剤は、口腔内での速溶性を考慮してマンニトールなどの糖アルコールを賦形剤とするものが多いが、糖アルコールは錠剤成形時に打錠障害（スティッキングなど）の要因で圧縮成形性が不良となり、実用上問題のない硬度の確保もしばしば困難となる。そのため、製造時に適当量の水分を含ませて打錠する技術が提示されている（例えば特許文献１参照）。しかしながら、この技術は、一般に特殊な装置を必要とするうえに低圧で打錠するため、硬度に限界があった。また、平均粒子径３０μｍ以下の微細な糖アルコールを用いて乾燥状態で打錠成形する技術（特許文献２参照）も開示されているが、糖アルコールを主成分とすることに変わりはないことから、上記打錠障害を防止するために滑沢剤の増量や打錠時圧力の制限を余儀なくされ、口腔内速崩性や硬度に限界があった。また、セルロース等の結合剤を添加する技術（例えば特許文献３参照）が提示されているが、結合剤の添加は口腔内崩壊時の口当たりを悪くする等の問題点があった。また、糖アルコールを含有する顆粒を崩壊剤で被覆したものを打錠成形する技術（特許文献４参照）が提示されているが、口腔内崩壊時間が長いという問題点があった。さらに、特許文献５には顆粒の内外に崩壊剤が存在する錠剤が開示されているが、顆粒が崩壊剤で被覆されているわけではなく、本発明の錠剤とは崩壊剤の分布が異なり、本件発明の効果をもたないものである。 Intraorally rapidly disintegrating tablets are tablets that disintegrate rapidly in the oral cavity, and are attracting attention as dosage forms that improve the ease of swallowing drugs and improve patient compliance, and various types have been invented. Intraorally rapidly disintegrating tablets often use sugar alcohols such as mannitol as excipients in consideration of rapid solubility in the oral cavity, but sugar alcohols are the cause of tableting troubles (such as sticking) during tablet formation. The compression moldability becomes poor, and it is often difficult to ensure hardness that is not problematic in practice. Therefore, a technique for tableting by adding an appropriate amount of moisture during production has been proposed (see, for example, Patent Document 1). However, this technique generally requires a special apparatus and is compressed at a low pressure, so that there is a limit in hardness. Moreover, although the technique (refer patent document 2) which carries out tableting molding in the dry state using the fine sugar alcohol with an average particle diameter of 30 micrometers or less is also disclosed, since it has a sugar alcohol as a main component. In order to prevent the above-mentioned tableting troubles, the amount of lubricant was increased and the pressure at the time of tableting was inevitably restricted, and there was a limit to the rapid disintegration property and hardness in the oral cavity. Moreover, although the technique (for example, refer patent document 3) of adding binders, such as a cellulose, has been shown, there existed problems, such as worsening the mouthfeel at the time of oral disintegration. Moreover, although the technique (refer patent document 4) which tablet-molds what coated the granule containing sugar alcohol with the disintegrating agent was shown, there existed a problem that oral disintegration time was long. Furthermore, Patent Document 5 discloses a tablet in which a disintegrant is present inside and outside the granule, but the granule is not coated with the disintegrant, and the distribution of the disintegrant is different from the tablet of the present invention. This does not have the effect of the present invention.
本発明の目的は、通常の装置で成形が可能であり、実用上問題のない硬度を有し、口腔内で口当たりよく速崩する口腔内速崩性錠剤を提供することである。 An object of the present invention is to provide an intraoral rapidly disintegrating tablet that can be molded with an ordinary apparatus, has a hardness that has no practical problem, and rapidly disintegrates in the mouth.
本発明者らは、錠剤を構成する顆粒内部に崩壊剤を含有し、かつ該顆粒が崩壊剤で被覆されてなる錠剤であれば、通常の装置で成形が可能であり、実用上問題のない硬度を有し、かつ口腔内で口当たりよく速崩することを見出した。
すなわち本発明は、崩壊剤で被覆された顆粒を圧縮成形してなる錠剤であって、該顆粒の内部にも崩壊剤が含まれており、該顆粒の内部および／または外部に薬物が含まれている口腔内速崩性錠剤である。
As long as the tablet contains a disintegrant inside the granule constituting the tablet and the granule is coated with the disintegrant, the present invention can be molded with an ordinary apparatus and has no practical problem. It has been found that it has hardness and quickly breaks in the mouth.
That is, the present invention is a tablet formed by compression-molding a granule coated with a disintegrant, the disintegrant being contained inside the granule, and a drug being contained inside and / or outside the granule. Orally rapidly disintegrating tablets.
かかる本発明は、少なくとも崩壊剤を含む粉末から顆粒を調製し、次にこれを崩壊剤で被覆し、さらにこれを圧縮成形してなる錠剤であって、該顆粒調製時および／または該圧縮成形時において薬剤が加えられる口腔内速崩性錠剤、と表現することもできる。
また、本発明はかかる錠剤成形に用いられる顆粒であって、その内部に崩壊剤を含んでおり、さらに薬物を含んでいてもよく、かつ崩壊剤で被覆されている顆粒である。
The present invention is a tablet prepared by preparing granules from a powder containing at least a disintegrant, then coating the granules with a disintegrant, and further compressing the granules, and at the time of preparing the granules and / or the compression molding It can also be expressed as an intraoral rapidly disintegrating tablet to which a drug is sometimes added.
In addition, the present invention is a granule used for such tableting, which contains a disintegrant inside, may further contain a drug, and is coated with the disintegrant.
本発明の錠剤は、通常の装置で成形可能であり、実用上問題のない硬度を有し、口腔内で口当たりよく速崩する効果を有する。 The tablet of the present invention can be molded with an ordinary apparatus, has a hardness that is not problematic in practice, and has an effect of rapidly breaking in the mouth.
本発明の錠剤で用いられる薬物は、塩酸アンブロキソールである。もっとも、通常の製造方法で錠剤を製造するのに特段の障害となる特性のものでない限り、他の薬物であっても本発明と同様の効果が得られる。他の薬物としては、例えば中枢神経系用薬、末梢神経系用薬、循環器官用薬、消化器官用薬、ホルモン剤、泌尿生殖器官用薬、血液・体液用薬、代謝性医薬品、痛風治療薬、腫瘍用薬、アレルギー用薬、気管支拡張剤、抗生物質、抗細菌薬、抗ウイルス薬、創傷治癒物質、鎮痙剤、抗コリン作用剤、抗ヒスタミン剤、抗炎症剤、抗コレステロール血剤、抗脂質剤、食欲抑制剤、興奮剤、凝血剤、制酸剤、化学療法剤、栄養補給剤、診断薬、麻薬・覚醒剤、鎮痛剤、鎮咳剤、喀痰剤等から選ばれる一種または二種以上の活性成分が挙げられる。 The drug used in the tablet of the present invention is ambroxol hydrochloride. However, the same effects as those of the present invention can be obtained with other drugs as long as they do not have characteristics that are particularly obstructive to the production of tablets by ordinary production methods. Other drugs include, for example, central nervous system drugs, peripheral nervous system drugs, cardiovascular drugs, gastrointestinal drugs, hormone drugs, urogenital drugs, blood and body fluid drugs, metabolic drugs, gout treatment Drugs, tumor drugs, allergy drugs, bronchodilators, antibiotics, antibacterial drugs, antiviral drugs, wound healing substances, antispasmodic drugs, anticholinergic drugs, antihistamines, anti-inflammatory drugs, anticholesterolemia drugs, antilipid drugs One or more active ingredients selected from appetite suppressants, stimulants, coagulants, antacids, chemotherapeutic agents, nutritional supplements, diagnostic agents, narcotics / stimulants, analgesics, antitussives, epilepsy, etc. Can be mentioned.
例えば、アスコルビン酸、アセトアミノフェン、エテンザミド、アレンドロネート、フェブキソスタット、塩酸クレンブテロール、イコサペント酸エチル、タカルシトール、ピコスルファート、アルファカルシドール、国際公開ＷＯ９９／２６９１８号記載の化合物、国際公開ＷＯ０１／５３２９１号記載の化合物、および国際公開ＷＯ９９／２５６８６号記載の化合物およびこれらの塩、ならびにこれらの化合物や塩の水和物からなる群から選ばれる一種または二種以上の活性成分が挙げられる。 For example, ascorbic acid, acetaminophen, etenzamide, alendronate, febuxostat, clenbuterol hydrochloride, ethyl icosapentate, tacalcitol, picosulfate, alfacalcidol, compounds described in International Publication WO99 / 26918, International Publication WO01 / The compound described in 53291, the compound described in International Publication WO99 / 25686 and salts thereof, and one or more active ingredients selected from the group consisting of hydrates of these compounds and salts.
本発明の錠剤において、薬物は錠剤を構成する顆粒の内部または崩壊剤で被覆された顆粒の外部の少なくとも一方に含まれるが、顆粒の外部のみに含まれることが速崩性を確保するうえで好ましい。
また、本発明の錠剤に用いる薬物は、フィルムコーティング剤、賦形剤、結合剤、滑沢剤等によるコーティングがなされていてもよく、可塑剤が加えられていてもよい。
In the tablet of the present invention, the drug is contained in at least one of the inside of the granule constituting the tablet or the outside of the granule coated with the disintegrant, but it can be contained only in the outside of the granule to ensure quick disintegration. preferable.
Moreover, the drug used for the tablet of the present invention may be coated with a film coating agent, an excipient, a binder, a lubricant, or the like, or may be added with a plasticizer.
本発明の錠剤で用いられる崩壊剤は、医薬製剤で用いられる崩壊剤であれば特に制限はないが、例えば、クロスポビドン、結晶セルロース、低置換度ヒドロキシプロピルセルロース、クロスカルメロースナトリウム、カルメロースカルシウム、カルボキシスターチナトリウム、カルボキシメチルスターチナトリウム、バレイショテンプン、コムギデンプン、トウモロコシデンプン、コメデンプン、部分アルファ化デンプン、ヒドロキシプロピルスターチを挙げることができる。これらを一種または二種以上使用することができる。特にクロスポビドンが好ましい。本発明において、顆粒の被覆のために用いる崩壊剤の種類は、顆粒内部に用いるものと同一であっても異なっていてもよい。 The disintegrant used in the tablet of the present invention is not particularly limited as long as it is a disintegrant used in pharmaceutical preparations. For example, crospovidone, crystalline cellulose, low-substituted hydroxypropylcellulose, croscarmellose sodium, carmellose calcium , Carboxy starch sodium, carboxymethyl starch sodium, potato starch, wheat starch, corn starch, rice starch, partially pregelatinized starch, and hydroxypropyl starch. One or more of these can be used. Crospovidone is particularly preferable. In the present invention, the type of disintegrant used for coating the granules may be the same as or different from that used inside the granules.
かかる崩壊剤は、本発明の錠剤を構成する顆粒の内部および被覆部両方に存在しなければならない。崩壊剤が顆粒の内部あるいは被覆部のどちらか一方のみに存在するだけでは、十分な口腔内速崩性は達成されない。ここでいう口腔内速崩性とは、一般的には口腔内で１分ないし３０秒以内に崩壊する性質をいう。もっとも、口腔内速崩性が目的に照らして十分であればよく、この絶対値に拘泥する必要はない。
また、崩壊剤による被覆は圧縮成形性の向上にも寄与する。すなわち、顆粒の内部および被覆部に崩壊剤が存在することが良好な圧縮成形性のために必要である。
Such a disintegrant must be present both in the interior and in the coating of the granules making up the tablet of the present invention. If the disintegrant is present only in either the inside of the granule or the coating, sufficient oral rapid disintegration cannot be achieved. The intraoral rapidly disintegrating property as used herein generally refers to the property of disintegrating in the oral cavity within 1 minute to 30 seconds. However, it is sufficient that the rapid disintegration property in the oral cavity is sufficient for the purpose, and it is not necessary to stick to this absolute value.
Further, the coating with the disintegrant contributes to the improvement of compression moldability. That is, it is necessary for good compression moldability that a disintegrant is present in the inside of the granule and in the coating part.
なお、崩壊剤が顆粒の「内部」に存在するといっても、顆粒の表面に近い部分に崩壊剤が存在しないわけではない。顆粒内部の崩壊剤は、顆粒の他の構成成分とともに顆粒内で均一に分散されていることが速崩性確保の観点から好ましい。さらに、本発明の錠剤において、崩壊剤は顆粒の内部や被覆部のほか、さらに顆粒外部に加えられていてもよい。 Note that even if the disintegrant is present “inside” the granule, it does not mean that the disintegrant is not present in a portion close to the surface of the granule. The disintegrant inside the granule is preferably dispersed uniformly in the granule together with other components of the granule from the viewpoint of ensuring quick disintegration. Furthermore, in the tablet of the present invention, the disintegrant may be added to the outside of the granule in addition to the inside of the granule and the coating part.
本発明で用いられる崩壊剤は、上述のように顆粒の内部および被覆部に存在すればよく、それらの量に特に制限はないが、一般に顆粒内部および被覆部とも、多すぎると口当たり、食感、崩壊性、圧縮成形性が悪くなり、少なすぎると崩壊性および／または圧縮成形性が悪くなる。 The disintegrant used in the present invention only needs to be present in the inside of the granule and in the coating part as described above, and the amount thereof is not particularly limited. If the amount is too small, the disintegration property and / or compression moldability will deteriorate.
かかる崩壊剤の含有量の好ましい値は、崩壊剤、後述する賦形剤あるいは結合剤を含有する場合はそれらの添加剤、あるいはそれらの粒径、製造機器の素材等の影響を受けるが、一般に顆粒内部の崩壊剤の割合が錠剤全体の４−２０重量％であり、顆粒被覆部の崩壊剤の割合が錠剤全体の４−２０重量％である。 The preferred value of the content of such disintegrants is affected by the disintegrants, excipients or binders described later, their additives, or their particle size, production equipment materials, etc. The proportion of the disintegrant inside the granule is 4-20% by weight of the whole tablet, and the proportion of the disintegrant in the granule coating is 4-20% by weight of the whole tablet.
これらを超えた場合、崩壊性の観点からは、恐らく錠剤あるいは顆粒表面が完全に崩壊剤で被覆されてしまうことで導水機構が不十分となることが崩壊性悪化の原因と推定されるが、この上限値は、後述する賦形剤とともに用いた場合、顆粒内部の賦形剤の種類およびその粒径の影響を受ける場合がある。例えば、顆粒内部の賦形剤がエリスリトールでその平均粒子径が２０μｍ程度の場合、顆粒被覆部と顆粒内部の崩壊剤の割合が全体の３０重量％を超えると崩壊性が不良となる場合があり、同じエリスリトールでもその平均粒子径が３０−３５μｍ程度の場合、顆粒被覆部と顆粒内部の崩壊剤の割合が全体の２０重量％を超えると崩壊性が不良となる場合がある。賦形剤がマンニトールの場合はその平均粒子径が５０μｍ程度の場合、顆粒被覆部と顆粒内部の崩壊剤の割合が全体の３０重量％を超えると崩壊性が不良となる場合がある。 When exceeding these, from the viewpoint of disintegration, it is presumed that the cause of deterioration of disintegration is that the water conveyance mechanism is insufficient due to the tablet or granule surface being completely covered with the disintegrant, This upper limit may be affected by the type of excipient in the granule and its particle size when used with the excipient described below. For example, if the excipient in the granule is erythritol and the average particle size is about 20 μm, the disintegration property may be poor if the ratio of the granule coating part and the disintegrant in the granule exceeds 30% by weight. Even if the same erythritol has an average particle size of about 30-35 μm, the disintegration property may be poor if the ratio of the disintegrant in the granule coating part and the granule exceeds 20% by weight. When the excipient is mannitol and the average particle size is about 50 μm, the disintegration property may be poor if the ratio of the disintegrant in the granule coating part and the granule exceeds 30% by weight.
食感を考慮したさらに好ましい値は、後述する賦形剤とともに用いた場合、顆粒内部の賦形剤の種類により異なる。賦形剤としてエリスリトールを用いる場合は、顆粒内部には錠剤全体の４−８重量％、被覆部には錠剤全体の４−８重量％存在させることが特に好ましいが、賦形剤としてマンニトールを用いる場合は、食感を考慮しても崩壊剤の含有量の好適範囲は上記の通りで変わらない。 A more preferable value considering the texture varies depending on the type of excipient in the granule when used together with the excipient described below. When erythritol is used as an excipient, it is particularly preferable that 4-8% by weight of the whole tablet is present inside the granule and 4-8% by weight of the whole tablet is present in the coating, but mannitol is used as the excipient. In that case, the preferred range of the content of the disintegrant does not change as described above even when the texture is taken into consideration.
本発明で用いられる崩壊剤の典型的な平均粒子径は１０−１００μｍ程度である。一般に、崩壊性や浸透速度の点では粒子が大きい方が有利である。一方、圧縮成形性は、粒子が小さく結合部分が多い方が有利である。また、食感の点でも粒子径が小さい方が好ましい。 The typical average particle diameter of the disintegrant used in the present invention is about 10 to 100 μm. In general, larger particles are more advantageous in terms of disintegration and penetration rate. On the other hand, the compression moldability is advantageous when the particles are small and the number of bonded portions is large. Also, from the viewpoint of texture, a smaller particle size is preferable.
本発明の錠剤は、実用上の硬度を損なわない範囲において顆粒内に空隙を有することが好ましい。このような空隙を顆粒内に保持させることにより、圧縮成形性および／または速崩性が向上する。 The tablet of the present invention preferably has voids in the granule as long as practical hardness is not impaired. By holding such voids in the granules, the compression moldability and / or the rapid collapse property are improved.
このような空隙を顆粒内に保持させるためには、例えば、水および／またはエタノールで膨潤させた崩壊剤を含む顆粒を調製し、これを崩壊剤で被覆したものを乾燥してから圧縮成形して錠剤とすればよい。なお、結合剤を添加しない場合において、流動層乾燥等の負荷の大きい乾燥法を採用すると、圧縮成形前の顆粒の構成が破壊されて錠剤の所望する機能が失われることがあるので、この場合には負荷の小さい静置乾燥を採用することが好ましい。 In order to maintain such voids in the granules, for example, a granule containing a disintegrant swollen with water and / or ethanol is prepared, and the one coated with the disintegrant is dried and then compression molded. You can use tablets. In addition, in the case where a binder is not added, if a drying method with a large load such as fluidized bed drying is adopted, the composition of the granule before compression molding may be destroyed and the desired function of the tablet may be lost. It is preferable to use stationary drying with a small load.
本発明の錠剤で用いられる製薬学的に許容される添加剤としては、例えば賦形剤、滑沢剤、ｐＨ調整剤、矯味剤、甘味剤、酸味剤、清涼剤、発泡剤、保存剤、流動化剤、抗酸化剤、着色剤、安定化剤、界面活性剤、緩衝剤、香料、結合剤、薬物の溶解補助剤を挙げることができる。これら添加剤の具体例は、当業者であれば直ちに列挙することができよう。 Examples of the pharmaceutically acceptable additive used in the tablet of the present invention include an excipient, a lubricant, a pH adjuster, a corrigent, a sweetener, a sour agent, a refreshing agent, a foaming agent, a preservative, Examples thereof include fluidizers, antioxidants, colorants, stabilizers, surfactants, buffers, fragrances, binders, and drug solubilizers. Specific examples of these additives can be immediately listed by those skilled in the art.
これらの添加剤は本発明の効果を損なわない範囲内で、顆粒の内部、崩壊剤で被覆された顆粒の外部、崩壊剤被覆部、またはそれらのすべてに適宜配合することができるが、口腔内での口当たりを損なわないため、または崩壊性を良くするため、結合剤は添加しない方が好ましい。 These additives can be appropriately blended in the inside of the granule, the outside of the granule coated with the disintegrant, the disintegrant coating portion, or all of them within the range not impairing the effects of the present invention. It is preferable not to add a binder in order not to impair the mouthfeel in the case or to improve the disintegration.
本発明の錠剤で用いられる賦形剤としては、医薬製剤で用いられる賦形剤であれば特に制限はないが、例えばエリスリトール、マンニトール、キシリトール、ソルビトール、ラクチトール、パラチニット、パラチノース、マルチトール、マルトース、トレハロース、乳糖、白糖、ブドウ糖、オリゴ糖、果糖、麦芽糖等の糖類を挙げることができる。これらを一種または二種以上使用することができる。特にエリスリトール、マンニトールから選択される一種以上を用いることが好ましい。 The excipient used in the tablet of the present invention is not particularly limited as long as it is an excipient used in a pharmaceutical formulation. For example, erythritol, mannitol, xylitol, sorbitol, lactitol, palatinit, palatinose, maltitol, maltose, Examples include saccharides such as trehalose, lactose, sucrose, glucose, oligosaccharide, fructose and maltose. One or more of these can be used. In particular, it is preferable to use one or more selected from erythritol and mannitol.
本発明で用いられる賦形剤は、錠剤を構成する顆粒の内部および／または崩壊剤被覆部および／または崩壊剤で被覆された顆粒の外部に含まれる。なお、薬物の種類によっては圧縮成形性を確保するために賦形剤の添加を必要とする場合があるが、こうした賦形剤添加の要否は当業者の通常程度の予備検討により容易に決めることができる。 The excipient used in the present invention is contained inside the granule constituting the tablet and / or outside the granule coated with the disintegrant coating and / or the granule coated with the disintegrant. Depending on the type of drug, it may be necessary to add excipients in order to ensure compression moldability, but the necessity of such excipient addition is easily determined by ordinary preliminary studies by those skilled in the art. be able to.
また、賦形剤の粒子径に関しても、当業者であれば適宜条件検討をすることにより、好適範囲を容易に見出すことができる。典型的な崩壊剤の粒子径は２０−４０μｍ程度である。一般に、粒子径が小さい方が崩壊性や食感の点で有利であるが、賦形剤の粒子径は圧縮成形性にはほとんど影響しない。 Further, regarding the particle diameter of the excipient, those skilled in the art can easily find a suitable range by appropriately examining the conditions. The particle size of a typical disintegrant is about 20-40 μm. In general, a smaller particle size is advantageous in terms of disintegration and texture, but the particle size of the excipient has little effect on compression moldability.
本発明の錠剤で用いられる滑沢剤としては、医薬製剤で用いられる滑沢剤であれば特に制限はないが、例えば軽質無水珪酸、ステアリン酸マグネシウム、ステアリン酸、ステアリン酸カルシウム、ステアリン酸アルミニウム、モノステアリン酸アルミニウム、ショ糖脂肪酸エステル、ポリエチレングリコール、フマル酸ステアリルナトリウム、ステアリルアルコール、タルク、酸化チタン、含水二酸化ケイ素、珪酸マグネシウム、合成珪酸アルミニウム、リン酸水素カルシウム、硬化ヒマシ油、硬化ナタネ油、カルナウバロウ、ミツロウ、マイクロクリスタリンワックス、ラウリル硫酸ナトリウムを挙げることができる。これらを一種または二種以上使用することができる。なかでも軽質無水珪酸、ステアリン酸マグネシウムから選択される一種以上を用いることが好ましい。特に、軽質無水珪酸が顆粒の内部に含まれ、ステアリン酸マグネシウムが顆粒の外部に含まれる組み合わせが好ましい。 The lubricant used in the tablet of the present invention is not particularly limited as long as it is a lubricant used in pharmaceutical preparations. For example, light anhydrous silicic acid, magnesium stearate, stearic acid, calcium stearate, aluminum stearate, mono Aluminum stearate, sucrose fatty acid ester, polyethylene glycol, sodium stearyl fumarate, stearyl alcohol, talc, titanium oxide, hydrous silicon dioxide, magnesium silicate, synthetic aluminum silicate, calcium hydrogen phosphate, hydrogenated castor oil, hydrogenated rapeseed oil, carnauba wax , Beeswax, microcrystalline wax, and sodium lauryl sulfate. One or more of these can be used. Among these, it is preferable to use one or more selected from light anhydrous silicic acid and magnesium stearate. In particular, a combination in which light anhydrous silicic acid is contained inside the granule and magnesium stearate is contained outside the granule is preferable.
本発明の錠剤の形状は、通常の製造装置により、またはそれに手を加えた製造装置により困難なく製造できるものである限り特に限定されないが、一般的な錠剤の概念である、円盤状のものが典型例として例示できる。全体の大きさは特に限定されないが、例えば短径（円盤状の錠剤の場合は直径）は６−２０ｍｍの範囲内のものが適当であり、なかでも８−１２ｍｍが好ましい。厚みについても制限されないが、１−１０ｍｍが適当であり、なかでも２−８ｍｍが好ましい。 The shape of the tablet of the present invention is not particularly limited as long as it can be produced without difficulty by a normal production apparatus or a production apparatus that has been modified, but there is a disc-shaped one that is a general tablet concept. It can be illustrated as a typical example. Although the overall size is not particularly limited, for example, the short diameter (diameter in the case of a disk-shaped tablet) is suitably in the range of 6-20 mm, and 8-12 mm is particularly preferable. Although the thickness is not limited, 1-10 mm is appropriate, and 2-8 mm is particularly preferable.
本発明の錠剤は、通常の装置により、あるいはそれに手を加えた製造装置により困難なく製造することができる。例えば、崩壊剤および必要により一種類以上の製薬学的に許容される添加剤を含む顆粒を崩壊剤で被覆し、それを必要により一種類以上の製薬学的に許容される添加剤と共に圧縮成形することで製造される。 The tablet of the present invention can be produced without difficulty by an ordinary apparatus or a production apparatus in which it is modified. For example, a granule containing a disintegrant and optionally one or more pharmaceutically acceptable additives is coated with a disintegrant and optionally compressed with one or more pharmaceutically acceptable additives. It is manufactured by doing.
顆粒内部に一種類以上の製薬学的に許容される添加剤を含有させるには、顆粒調製前の崩壊剤と必要とする添加剤とを混合してから顆粒を調製すればよい。また、崩壊剤で被覆された顆粒の外部に一種類以上の製薬学的に許容される添加剤を含有させるには、崩壊剤で被覆された顆粒を圧縮成形して錠剤を製造する際に、必要とする添加剤と顆粒とを混合してから圧縮成形すればよい。 In order to contain one or more kinds of pharmaceutically acceptable additives in the granule, the granule may be prepared after mixing the disintegrant before granule preparation and the necessary additive. In order to contain one or more pharmaceutically acceptable additives outside the granules coated with the disintegrant, when the tablets coated with the disintegrant are compression-molded, What is necessary is just to compress-mold after mixing the required additive and granule.
本発明はさらに、かかる口腔内速崩性錠剤を成形するために用いられる顆粒であって、その内部に崩壊剤を含んでおり、さらに薬物を含んでいてもよく、かつ崩壊剤で被覆されている顆粒である。この顆粒には、内部に一種類以上の製薬学的に許容される添加剤を含んでいてもよい。かかる添加剤の具体例、好適例については前記したものがそのまま例示できるが、特にエリスリトールやマンニトールが好ましい。
さらに、顆粒内部に空隙を有することが好ましく、また、結合剤を含有しないことが好ましい。
顆粒内部や被覆部における崩壊剤としては、クロスポビドンが好ましい。
The present invention is further a granule used for molding such an orally rapidly disintegrating tablet, which contains a disintegrating agent, may further contain a drug, and is coated with a disintegrating agent. It is a granule. The granule may contain one or more kinds of pharmaceutically acceptable additives therein. Specific examples and preferred examples of such additives can be exemplified as they are, but erythritol and mannitol are particularly preferable.
Furthermore, it is preferable to have voids inside the granules, and it is preferable not to contain a binder.
Crospovidone is preferable as the disintegrant in the inside of the granule and in the coating part.
次に、本発明を実施例を用いて説明するが、本発明はこれらによって限定されるものではない。
［評価方法］
後述する実施例、比較例においては、次の評価方法を採用した。
ａ）「硬度」は富山産業のＴＨ−２０３ＭＰ型錠剤破壊強度測定器を用いて測定した。
ｂ）「摩損度」は萱垣医科工業の摩損度試験機を用いて測定した。具体的には、錠剤５５錠を投入し、１００回転させ、（初期重量−試験後）／初期重量 を％表示した。
ｃ）「官能評価」は咀嚼せずに口腔内で崩壊に要する時間を測定した。なお、実施例／比較例におけるプラセボ製剤では成人男子１名のＮ＝６の平均値を用い、実施例におけるアクティブ３種では、成人男子３名のＮ＝３の平均値を用いた。
ｄ）「日局崩壊試験」は日局崩壊試験法によった。試験液はミリＱ水を使用した。
ｅ）「浸透時間」は青色１号で着色したミリＱ水１ｍｌをシャーレ錠に滴下し、この上に錠剤を置き、錠剤全体に水が浸透するのに要する時間を測定した。
Next, although this invention is demonstrated using an Example, this invention is not limited by these.
[Evaluation method]
In Examples and Comparative Examples described later, the following evaluation methods were adopted.
a) “Hardness” was measured using a TH-203MP type tablet breaking strength measuring instrument manufactured by Toyama Sangyo.
b) “Degree of wear” was measured using a wear degree tester manufactured by Higaki Medical School. Specifically, 55 tablets were put in, rotated 100 times, and (initial weight−after test) / initial weight was expressed in%.
c) "Sensory evaluation" measured the time required for disintegration in the oral cavity without chewing. In the placebo preparations in Examples / Comparative Examples, the average value of N = 6 for one adult male was used, and for the three active types in the Examples, the average value of N = 3 for three adult males was used.
d) The “Japanese disintegration test” was based on the Japanese disintegration test method. Milli-Q water was used as a test solution.
e) “Penetration time” was measured by dropping 1 ml of Milli-Q water colored with Blue No. 1 onto a petri dish, placing a tablet thereon, and measuring the time required for water to penetrate into the whole tablet.
［参考例１］
Ｄ−マンニトール（東和化成工業（株）、商品名；マンニットＰ（平均粒子径は５０μｍ程度）、以下の例で同じ）２６４．４ｇ、軽質無水珪酸（フロイント産業（株））１４．２ｇ、クロスポビドン（ＩＳＰ、商品名；ポリプラスドンＸＬ−１０（平均粒子径はメーカー記載値で３０μｍ）、以下の例で特に記載のない限り同じ）２０．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン１１．０ｇを膨潤させた精製水を噴霧し、顆粒を得た。この顆粒にクロスポビドン４８．８ｇを投入し、クロスポビドン１．２ｇを膨潤させた精製水で粉コーティングした。得られた崩壊剤被覆顆粒１７７．０ｇにフェブキソスタット（帝人ファーマ（株））２０．０ｇ、ステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Reference Example 1]
D-mannitol (Towa Kasei Kogyo Co., Ltd., trade name; Mannit P (average particle diameter is about 50 μm), the same in the following examples) 264.4 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 14.2 g, Crospovidone (ISP, trade name: Polyplastidone XL-10 (average particle size is 30 μm as described by the manufacturer), the same unless otherwise specified in the following examples) 20.3 g of fluidized bed granulation dryer [(stock ) Made of Paulek, LAB-1], and purified water in which 11.0 g of crospovidone was swollen was sprayed to obtain granules. The granules were charged with 48.8 g of crospovidone and powder-coated with purified water in which 1.2 g of crospovidone was swollen. After adding 200.0 g of febuxostat (Teijin Pharma Co., Ltd.) and 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 177.0 g of the obtained disintegrant-coated granules, a rotary tableting machine [(Co., Ltd. ) Compression molding using HT-AP6SS-U, manufactured by Hata Seisakusho. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［参考例２］
Ｄ−マンニトール（東和化成工業（株））２６４．４ｇ、軽質無水珪酸（フロイント産業（株））１４．２ｇ、クロスポビドン（ＩＳＰ）２０．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン１１．０ｇを膨潤させた精製水を噴霧し、顆粒を得た。この顆粒にクロスポビドン４８．８ｇを投入し、クロスポビドン１．２ｇを膨潤させた精製水で粉コーティングした。得られた崩壊剤被覆顆粒１７７．０ｇにアスコルビン酸（武田薬品工業（株））２０．０ｇ、ステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Reference Example 2]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 264.4 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 14.2 g, crospovidone (ISP) 20.3 g of fluidized bed granulator / dryer [manufactured by POWREC CO., LTD. LAB-1] and purified water swollen with 11.0 g of crospovidone was sprayed to obtain granules. The granules were charged with 48.8 g of crospovidone and powder-coated with purified water in which 1.2 g of crospovidone was swollen. After adding and mixing 27.0 g of ascorbic acid (Takeda Pharmaceutical Co., Ltd.) and 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 177.0 g of the obtained disintegrant-coated granules, rotary tableting machine [(Co., Ltd. ) Compression molding using HT-AP6SS-U, manufactured by Hata Seisakusho. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例１］
Ｄ−マンニトール（東和化成工業（株））２６４．４ｇ、軽質無水珪酸（フロイント産業（株））１４．２ｇ、クロスポビドン（ＩＳＰ）２０．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン１１．０ｇを膨潤させた精製水を噴霧し、顆粒を得た。この顆粒にクロスポビドン４８．８ｇを投入し、クロスポビドン１．２ｇを膨潤させた精製水で粉コーティングした。得られた崩壊剤被覆顆粒１７７．０に塩酸アンブロキソール（日本バルク薬品（株））２０．０ｇ、ステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
実施例１および参考例１ないし２の錠剤の評価結果を表１に示す。
[Example 1]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 264.4 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 14.2 g, crospovidone (ISP) 20.3 g of fluidized bed granulator / dryer [manufactured by POWREC CO., LTD. LAB-1] and purified water swollen with 11.0 g of crospovidone was sprayed to obtain granules. The granules were charged with 48.8 g of crospovidone and powder-coated with purified water in which 1.2 g of crospovidone was swollen. 20.0 g of ambroxol hydrochloride (Nippon Bulk Chemical Co., Ltd.) and 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) were added to the obtained disintegrant-coated granules 177.0 and mixed, and then a rotary tableting machine [ Compression molding was carried out using HT-AP6SS-U, manufactured by Hata Plant. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
Table 1 shows the evaluation results of the tablets of Example 1 and Reference Examples 1 and 2.
この結果から、本発明錠剤は硬度、圧縮成形性（摩損度）、崩壊性の評価項目すべてを満足することがわかる。また、こうした効果は、薬物の種類を問わずに達成されることがわかる。 From this result, it can be seen that the tablet of the present invention satisfies all the evaluation items of hardness, compression moldability (friability) and disintegration. Moreover, it turns out that such an effect is achieved regardless of the kind of drug.
［実施例２］
エリスリトール（日研化成（株）、グレード１００Ｍ（平均粒子径１５μｍ程度）で以下比較例１、２でも同じ）２９６．０ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２１．９ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。
得られた崩壊剤被覆造粒物１９７．１ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用い圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。
[Example 2]
Erythritol (Nikken Kasei Co., Ltd., grade 100M (average particle size of about 15 μm), the same applies to Comparative Examples 1 and 2 below) 296.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) ) 18.3 g was charged into a fluidized bed granulator / dryer [Lab-1 manufactured by POWREC Co., Ltd.] and purified water in which 9.9 g of crospovidone was swollen was sprayed to obtain a granulated product. To this granulated product, 21.9 g of crospovidone was charged and powder-coated with purified water obtained by swelling 1.1 g of crospovidone. The disintegrant-coated granulated product was left to stand in a dryer.
After adding and mixing 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.1 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Kogyo Co., Ltd., HT-AP6SS-U]. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf.
［比較例１］
エリスリトール（日研化成（株））３２５．２ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２２．０ｇを投入し、精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用い圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。この比較例は、顆粒内に崩壊剤が存在することによる成型性や速崩性に対する効果を確認するため、顆粒内に崩壊剤が存在しないものを製造したものである。
[Comparative Example 1]
Erythritol (Nikken Kasei Co., Ltd.) 325.2g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8g was charged into a fluidized bed granulator / dryer [LAW-1 manufactured by Paulec Co., Ltd.] Spraying was performed to obtain a granulated product. Crospovidone (22.0 g) was added to the granulated product and powder-coated with purified water. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf. In this comparative example, in order to confirm the effect on moldability and rapid disintegration due to the presence of the disintegrant in the granule, a product having no disintegrant in the granule was produced.
［比較例２］
エリスリトール（日研化成（株））３１０．８ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、ヒドロキシプロピルセルロース（日本曹達（株）、ＨＰＣ−Ｌ）１４．６ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２１．９ｇを投入し、精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用い圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。この比較例は、比較例１で顆粒結合力の不足から成形ができず、速崩性を検証できないため、さらに結合剤を加えて成形したものである。
実施例２、および比較例１ないし２の錠剤の評価結果を表２に示す。
[Comparative Example 2]
Erythritol (Nikken Kasei Co., Ltd.) 310.8g, Light Silicic Anhydride (Freund Sangyo Co., Ltd.) 12.8g, Hydroxypropyl Cellulose (Nippon Soda Co., Ltd., HPC-L) 14.6g in fluidized bed granulated and dried It was charged into a machine [LAB-1 manufactured by POWREC Co., Ltd.] and purified water was sprayed to obtain a granulated product. Crospovidone (21.9 g) was added to the granulated product and powder-coated with purified water. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf. Since this comparative example cannot be molded due to the lack of granule binding force in Comparative Example 1 and the rapid disintegration property cannot be verified, it is molded by further adding a binder.
Table 2 shows the evaluation results of the tablets of Example 2 and Comparative Examples 1 and 2.
この結果、比較例１の錠剤は実施例２の約２倍の打錠圧をかけても硬度が０．６ｋｇｆまでしか上がらず、非常に脆く、摩損度試験機では測定不能であった。ゆえに比較例１の錠剤は実用には不適である。この結果から、実施例２の錠剤において顆粒内に崩壊剤が存在することが成形性のために不可欠であることがわかる。 As a result, the tablet of Comparative Example 1 had a hardness of only 0.6 kgf even when a tableting pressure about twice that of Example 2 was applied, was very brittle, and was not measurable with a friability tester. Therefore, the tablet of Comparative Example 1 is not suitable for practical use. From this result, it can be seen that the presence of a disintegrant in the granules of the tablet of Example 2 is essential for moldability.
比較例１の処方に結合剤を加えて錠剤を成形した比較例２では、実施例２に比べ、結合剤が入っているにもかかわらず摩損度が高く、圧縮成型性がなお不十分であるほか、崩壊時間も約２倍となっている。このことから顆粒内に崩壊剤が存在することにより崩壊性や圧縮成形性が向上することがわかる。
なお、崩壊剤が顆粒内および被覆部の両方に存在することによる圧縮成型性向上の機構は明らかになっていない。
In Comparative Example 2 in which a binder was added to the formulation of Comparative Example 1 to form a tablet, compared to Example 2, the friability was high despite the presence of the binder, and the compression moldability was still insufficient. In addition, the decay time has also been doubled. This shows that disintegration and compression moldability are improved by the presence of the disintegrant in the granules.
It should be noted that the mechanism for improving the compression moldability due to the presence of the disintegrant both in the granules and in the coating is not clear.
［実施例３］
Ｄ−マンニトール（東和化成工業（株））３１８．０ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）９．２ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン５．０ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン１４．６ｇを投入し、クロスポビドン０．６ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 3]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 318.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, and crospovidone (ISP) 9.2 g were fluidized bed granulator / dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water swollen with 5.0 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 14.6 g of crospovidone was charged and powder-coated with purified water in which 0.6 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 2.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Plant, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例４］
Ｄ−マンニトール（東和化成工業（株））３０３．４ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン１４．６ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 4]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 303.4 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g was fluidized bed granulator / dryer [manufactured by POWREC CO., LTD. LAB-1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. The granulated product was charged with 14.6 g of crospovidone and powder-coated with purified water obtained by swelling 1.1 g of crospovidone. The disintegrant-coated granulated product was left to stand in a dryer. After adding 2.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Plant, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例５］
Ｄ−マンニトール（東和化成工業（株））２９６．１ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２１．９ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 5]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 296.1 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, and crospovidone (ISP) 18.3 g were fluidized bed granulation dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 21.9 g of crospovidone was charged and powder-coated with purified water obtained by swelling 1.1 g of crospovidone. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例６］
Ｄ−マンニトール（東和化成工業（株））２８８．８ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２９．２ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 6]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 288.8 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g were fluidized bed granulation dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 29.2 g of crospovidone was charged and powder-coated with purified water obtained by swelling 1.1 g of crospovidone. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例７］
Ｄ−マンニトール（東和化成工業（株））２８１．５ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン３６．５ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．３ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 7]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 281.5 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g were fluidized bed granulator / dryer [manufactured by POWREC Co., Ltd. LAB-1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 36.5 g of crospovidone was charged and powder-coated with purified water in which 1.1 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.3 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [manufactured by Hata Kogyo Co., Ltd., HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例８］
Ｄ−マンニトール（東和化成工業（株））２３７．５ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン８０．４ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 8]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 237.5 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g were fluidized bed granulator / dryer [manufactured by POWREC CO., LTD. LAB-1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 80.4 g of crospovidone was charged and powder-coated with purified water obtained by swelling 1.1 g of crospovidone. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［実施例９］
Ｄ−マンニトール（東和化成工業（株））３１８．０ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）９．１ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン５．０ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン１４．６ｇを投入し、クロスポビドン０．６ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を流動層造粒乾燥機内で乾燥した。得られた崩壊剤被覆造粒物１９６．９ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Example 9]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 318.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 9.1 g was fluidized bed granulator / dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water swollen with 5.0 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 14.6 g of crospovidone was charged and powder-coated with purified water in which 0.6 g of crospovidone was swollen. This disintegrant-coated granulated product was dried in a fluidized bed granulation dryer. After adding 2.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 196.9 g of the resulting disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Works, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［比較例３］
Ｄ−マンニトール（東和化成工業（株））３１８．０ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン１１．０ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物を乾燥機内で静置乾燥した。得られた造粒物１９６．８ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Comparative Example 3]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 318.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g was fluidized bed granulator / dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water swollen with 11.0 g of crospovidone was sprayed to obtain a granulated product. The granulated product was left to dry in a dryer. 1.9 g of calcium stearate (Nippon Yushi Co., Ltd.) was added to and mixed with 196.8 g of the obtained granulated product, and then a rotary tableting machine [manufactured by Hata Seiko Co., Ltd., HT-AP6SS-U] was used. And compression molded. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［比較例４］
Ｄ−マンニトール（東和化成工業（株））３１８．０ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、を流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２９．３ｇを投入し、精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
[Comparative Example 4]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 318.0 g and light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g were charged into a fluidized bed granulator / dryer [manufactured by Paulec Co., Ltd., LAB-1] Purified water was sprayed to obtain a granulated product. 29.3 g of crospovidone was added to this granulated product and powder-coated with purified water. The disintegrant-coated granulated product was left to stand in a dryer. After adding 2.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Plant, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
［比較例５］
Ｄ−マンニトール（東和化成工業（株））３３１．３ｇ、軽質無水珪酸（フロイント産業（株））１３．２ｇ、クロスポビドン（ＩＳＰ）９．５ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン５．７ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物を乾燥機内で静置乾燥した。得られた造粒物１８９．０ｇにクロスポビドン（ＩＳＰ）８．０ｇを加えて１次混合し、さらにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて２次混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。
実施例３ないし９、および比較例３ないし５の錠剤の評価結果を表３に示す。
[Comparative Example 5]
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 331.3 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 13.2 g, crospovidone (ISP) 9.5 g were fluidized bed granulator / dryer [manufactured by POWREC Co., Ltd. LAB-1] and purified water swollen with 5.7 g of crospovidone was sprayed to obtain a granulated product. The granulated product was left to dry in a dryer. Crospovidone (ISP) 8.0 g was added to the obtained granulated product 189.0 g and mixed first, and then calcium stearate (Nippon Yushi Co., Ltd.) 3.0 g was added and secondarily mixed, followed by rotary tableting. Compression molding was performed using a machine (manufactured by Hata Kogyo Co., Ltd., HT-AP6SS-U). The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch.
Table 3 shows the evaluation results of the tablets of Examples 3 to 9 and Comparative Examples 3 to 5.
実施例３ないし８は顆粒内の賦形剤としてマンニトールを用いたもので、顆粒内および被覆部における崩壊剤の割合（重量％）を変化させたものである。これらの錠剤はいずれも硬度、圧縮成形性（摩損度）、崩壊性の評価項目すべてを満足することがわかる。この結果より顆粒内及び被覆部とも、崩壊剤の割合が少なくとも４−２０重量％であればよいが被覆部の崩壊剤が２０重量％より多いと食感や崩壊性が若干低下する（実施例８）。 In Examples 3 to 8, mannitol was used as an excipient in the granules, and the ratio (% by weight) of the disintegrant in the granules and the coating part was changed. It can be seen that these tablets all satisfy the evaluation items of hardness, compression moldability (friability) and disintegration. From this result, it is sufficient that the ratio of the disintegrant in the granules and the coating part is at least 4 to 20% by weight, but when the disintegrant in the coating part is more than 20% by weight, the texture and disintegration are slightly reduced (Examples) 8).
また、乾燥方法を静置乾燥に代えて流動層乾燥としても本発明の効果を奏することは変わらないが、若干高い打錠圧を要する（実施例９）ので静置乾燥の方が望ましいことがわかる。これは、流動層乾燥により顆粒構造に何らかの変化をもたらし、その変化のひとつが顆粒内の空隙の数や大きさを静置乾燥のそれより減らすということで、主にこれにより圧縮成形性が低下すると考えられる。 Moreover, although the effect of the present invention is not changed even if the drying method is replaced with stationary drying instead of fluidized bed drying, it is preferable that stationary drying is preferable because a slightly higher tableting pressure is required (Example 9). Recognize. This is due to fluidized bed drying causing some change in the granule structure, one of which is that the number and size of voids in the granule is reduced from that of static drying, which mainly reduces compression moldability. I think that.
比較例３の錠剤は、崩壊剤による被覆がなされていないものである。この錠剤は本発明の錠剤に比較して崩壊性が劣るほか、圧縮成形性が劣り、打錠圧が実用上の限界を超えている。 The tablet of Comparative Example 3 is not coated with a disintegrant. This tablet is inferior in disintegration as compared with the tablet of the present invention, inferior in compression moldability, and the tableting pressure exceeds the practical limit.
比較例４の錠剤は、顆粒内部に崩壊剤を含まないものである。この錠剤も本発明の錠剤に比較して崩壊性が大きく劣るほか、打錠圧が実用上の限界に近いものである。 The tablet of Comparative Example 4 does not contain a disintegrant inside the granule. This tablet is also inferior in disintegration to the tablet of the present invention, and the tableting pressure is close to the practical limit.
比較例５の錠剤は、顆粒内部のほか顆粒外部にも崩壊剤が含まれているが、顆粒は崩壊剤により被覆されていないものである。この錠剤も本発明の錠剤と比較して、高い打錠圧を要するものであり、圧縮成形性が劣る。すなわち、顆粒内部のほか、単に顆粒外部にも崩壊剤が含まれていればよいのではなく、崩壊剤による被覆が必要であることが確認された。 The tablet of Comparative Example 5 contains a disintegrating agent inside and outside the granule, but the granule is not coated with the disintegrating agent. This tablet also requires a high tableting pressure as compared with the tablet of the present invention, and is inferior in compression moldability. That is, in addition to the inside of the granule, it is not necessary that the disintegrating agent is simply contained outside the granule, and it was confirmed that a coating with the disintegrating agent is necessary.
したがって、顆粒内の崩壊剤および顆粒被覆部の崩壊剤の存在が良好な圧縮成形性、崩壊性、十分な硬度のために不可欠であることがわかる。また、全体としては同じ崩壊剤含有量の錠剤（表３の実施例３、比較例３−５）でも、本発明の錠剤（表３の実施例３）に限り、良好な圧縮成形性、崩壊性、十分な硬度を有しており、このことは、本発明により、より少ない崩壊剤の量でこれら速崩錠剤として必要な性質が達成されるという利点を有することを意味する。 Therefore, it can be seen that the presence of a disintegrant in the granule and a disintegrant in the granule coating is essential for good compression moldability, disintegration, and sufficient hardness. Moreover, as a whole, even with tablets having the same disintegrant content (Example 3 in Table 3 and Comparative Example 3-5), only the tablet of the present invention (Example 3 in Table 3) has good compression moldability and disintegration. This means that the present invention has the advantage that the properties required for these rapidly disintegrating tablets can be achieved with a smaller amount of disintegrant.
[実施例１０]
エリスリトール（日研化成（株）、グレード５０Ｍ（平均粒子径３５μｍ程度）で以下実施例例１１−１４でも同じ）３１８．０ｇ、軽質無水珪酸（フロイント産業（株））１２．７ｇ、クロスポビドン（ＩＳＰ）９．１ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン５．０ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン１４．６ｇを投入し、クロスポビドン０．６ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９６．９ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。評価は、密閉容器中、室温条件下にて３日間保存し、硬度・摩損度が安定した後実施した。
[Example 10]
Erythritol (Niken Kasei Co., Ltd., grade 50M (average particle diameter of about 35 μm), the same applies to Examples 11-14 below) 318.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.7 g, crospovidone ( (ISP) 9.1 g was charged into a fluidized bed granulator / dryer [manufactured by Paulec Co., Ltd., LAB-1], and purified water in which 5.0 g of crospovidone was swollen was sprayed to obtain a granulated product. To this granulated product, 14.6 g of crospovidone was charged and powder-coated with purified water in which 0.6 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 2.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 196.9 g of the resulting disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Works, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch. The evaluation was carried out after storage for 3 days in a sealed container at room temperature and after the hardness and friability were stabilized.
[実施例１１]
エリスリトール（日研化成（株））３０３．４ｇ、軽質無水珪酸（フロイント産業（株））１２．９ｇ、クロスポビドン（ＩＳＰ）１３．７ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン７．４ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２１．９ｇを投入し、クロスポビドン０．８ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．２ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。評価は、密閉容器中、室温条件下にて３日間保存し、硬度・摩損度が安定した後実施した。
[Example 11]
Erythritol (Niken Kasei Co., Ltd.) 303.4 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.9 g, crospovidone (ISP) 13.7 g were fluidized bed granulator dryer [manufactured by POWREC, LAB -1] and purified water swollen with 7.4 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 21.9 g of crospovidone was charged and powder-coated with purified water in which 0.8 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 2.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.2 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Plant, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch. The evaluation was carried out after storage for 3 days in a sealed container at room temperature and after the hardness and friability were stabilized.
[実施例１２]
エリスリトール（日研化成（株））２８８．７ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２９．１ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．１ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。評価は、密閉容器中、室温条件下にて３日間保存し、硬度・摩損度が安定した後実施した。
[Example 12]
Erythritol (Nikken Kasei Co., Ltd.) 288.7 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g was fluidized bed granulation dryer [manufactured by POWREC, LAB -1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. 29.1 g of crospovidone was added to this granulated product, and powder-coated with purified water in which 1.1 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 1.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.1 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Plant, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch. The evaluation was carried out after storage for 3 days in a sealed container at room temperature and after the hardness and friability were stabilized.
[実施例１３]
エリスリトール（日研化成（株））２７４．１ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン４３．８ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．１ｇにステアリン酸カルシウム（日本油脂（株））２．９ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。評価は、密閉容器中、室温条件下にて３日間保存し、硬度・摩損度が安定した後実施した。
[Example 13]
Erythritol (Nikken Kasei Co., Ltd.) 274.1 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g were mixed in a fluidized bed granulator / dryer [manufactured by POWREC, LAB -1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 43.8 g of crospovidone was charged and powder-coated with purified water in which 1.1 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 1.9 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.1 g of the obtained disintegrant-coated granulated product, a rotary tableting machine [manufactured by Hata Plant, HT-AP6SS-U ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch. The evaluation was carried out after storage for 3 days in a sealed container at room temperature and after the hardness and friability were stabilized.
[実施例１４]
エリスリトール（日研化成（株））２３７．５ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）６９．６ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン２９．３ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．２ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量１２０ｍｇ、Φ８ｍｍ割線平フチ丸の杵で硬度約５ｋｇｆとなるよう打錠した。評価は、密閉容器中、室温条件下にて３日間保存し、硬度・摩損度が安定した後実施した。
実施例１０−１４の錠剤の評価結果を表４に示す。
[Example 14]
Erythritol (Nikken Kasei Co., Ltd.) 237.5 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 69.6 g was fluidized bed granulator / dryer [manufactured by POWREC, LAB -1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 29.3 g of crospovidone was charged and powder-coated with purified water in which 1.1 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.2 g of the resulting disintegrant-coated granulated product, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd.] ] Was used for compression molding. The molding conditions were such that the tablet weight was 120 mg, and the hardness was about 5 kgf with a Φ8 mm secant flat edged round punch. The evaluation was carried out after storage for 3 days in a sealed container at room temperature and after the hardness and friability were stabilized.
Table 4 shows the evaluation results of the tablets of Examples 10-14.
実施例１０ないし１４は顆粒内の賦形剤としてエリスリトールを用いたもので、顆粒内および被覆部における崩壊剤の割合（重量％）を変化させたものである。これらの錠剤はいずれも硬度、圧縮成形性（摩損度）、崩壊性は許容範囲であるが、表３の結果と比較すると、その範囲はマンニトールと比較して狭い傾向が認められる。すなわち、エリスリトールの場合、顆粒内及び被覆部とも、崩壊剤の割合が少なくとも４−８重量％であればよいが顆粒内部の崩壊剤が８重量％以上で食感や崩壊性が若干低下し（実施例１２−１３）、２０重量％を超えると崩壊性が特に低下する（実施例１４）。 In Examples 10 to 14, erythritol was used as an excipient in the granules, and the ratio (% by weight) of the disintegrant in the granules and the coating part was changed. All of these tablets have acceptable ranges in hardness, compression moldability (friability), and disintegration, but when compared with the results in Table 3, the ranges tend to be narrower than mannitol. That is, in the case of erythritol, the ratio of the disintegrant in both the granule and the coating part may be at least 4-8% by weight, but when the disintegrant in the granule is 8% by weight or more, the texture and disintegration are slightly reduced ( Examples 12-13) When it exceeds 20% by weight, the disintegration particularly decreases (Example 14).
また、いずれの錠剤でも、硬度につき製造時よりも３日後で向上しており、このことは少なくともエリスリトールでは、製造後に時間をおくことにより、何らかの機構で硬度が増すことがわかった。 Moreover, in any tablet, the hardness was improved after 3 days from the time of manufacture, and it was found that at least for erythritol, the hardness was increased by some mechanism by taking time after the manufacture.
[参考例３]
アスコルビン酸（武田薬品工業（株）：８０メッシュ）３６．６ｇ、Ｄ−マンニトール（東和化成工業（株）：マンニットＰ）２０１．０ｇ、軽質無水珪酸（フロイント産業（株）：アドソリダー１０１）１２．８ｇ、クロスポビドン（ＩＳＰ：ポリプラスドンＸＬ−１０）５４．８ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン（ＸＬ−１０）９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン（ＸＬ−１０）４３．９ｇを投入し、クロスポビドン（ＸＬ−１０）１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。
[Reference Example 3]
Ascorbic acid (Takeda Pharmaceutical Co., Ltd .: 80 mesh) 36.6 g, D-mannitol (Towa Kasei Kogyo Co., Ltd .: Mannit P) 201.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd .: Adsolider 101) 12 8 g, 54.8 g of crospovidone (ISP: polyplastidone XL-10) was charged into a fluidized bed granulator / dryer [LAB-1 manufactured by POWREC Co., Ltd.], and 9.9 g of crospovidone (XL-10) was charged. The swollen purified water was sprayed to obtain a granulated product. To this granulated product, 43.9 g of crospovidone (XL-10) was added and powder-coated with purified water in which 1.1 g of crospovidone (XL-10) was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf.
[参考例４]
アスコルビン酸（武田薬品工業（株）：８０メッシュ）３６．５ｇ、Ｄ−マンニトール（東和化成工業（株）：マンニットＰ）２０１．０ｇ、軽質無水珪酸（フロイント産業（株）：アドソリダー１０１）１２．８ｇ、クロスポビドン（ＩＳＰ：ポリプラスドンＩＮＦ−１０（平均粒子径はメーカー記載値で１１μｍ））５４．８ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン（ＩＮＦ−１０）９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン（ＩＮＦ−１０）４３．９ｇを投入し、クロスポビドン（ＩＮＦ−１０）１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。
[Reference Example 4]
Ascorbic acid (Takeda Pharmaceutical Co., Ltd .: 80 mesh) 36.5 g, D-mannitol (Towa Kasei Kogyo Co., Ltd .: Mannit P) 201.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd .: Adsolider 101) 12 .8 g, crospovidone (ISP: polyplastidone INF-10 (average particle diameter is 11 μm as described by the manufacturer)) was charged in a fluidized bed granulator / dryer [manufactured by POWREC, LAB-1], Purified water in which 9.9 g of crospovidone (INF-10) was swollen was sprayed to obtain a granulated product. To this granulated product, 43.9 g of crospovidone (INF-10) was added and powder-coated with purified water in which 1.1 g of crospovidone (INF-10) was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf.
[参考例５]
アスコルビン酸（武田薬品工業（株）：８０メッシュ）３６．６ｇ、Ｄ−マンニトール（東和化成工業（株）：マンニットＰ）２０１．０ｇ、軽質無水珪酸（フロイント産業（株）：アドソリダー１０１）１２．８ｇ、クロスポビドン（ＩＳＰ：ポリプラスドンＩＮＦ−１０）５４．８ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン（ＩＮＦ−１０）９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン（ＸＬ−１０）４３．９ｇを投入し、クロスポビドン（ＩＮＦ−１０）１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。
[Reference Example 5]
Ascorbic acid (Takeda Pharmaceutical Co., Ltd .: 80 mesh) 36.6 g, D-mannitol (Towa Kasei Kogyo Co., Ltd .: Mannit P) 201.0 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd .: Adsolider 101) 12 8 g, 54.8 g of crospovidone (ISP: polyplastidone INF-10) was charged into a fluidized bed granulator / dryer [LAB-1 manufactured by POWREC Co., Ltd.], and 9.9 g of crospovidone (INF-10) was added. The swollen purified water was sprayed to obtain a granulated product. To this granulated product, 43.9 g of crospovidone (XL-10) was added and powder-coated with purified water in which 1.1 g of crospovidone (INF-10) was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf.
[参考例６]
アスコルビン酸（武田薬品工業（株）：８０メッシュ）３６．５ｇ、Ｄ−マンニトール（東和化成工業（株）：マンニットＰ）２０１．１ｇ、軽質無水珪酸（フロイント産業（株）：アドソリダー１０１）１２．８ｇ、クロスポビドン（ＩＳＰ：ポリプラスドンＩＮＦ−１０）５４．８ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン（ＩＮＦ−１０）９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン（ＸＬ（平均粒子径はメーカー記載値で１００μｍ））４３．９ｇを投入し、クロスポビドン（ＩＮＦ−１０）１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。得られた崩壊剤被覆造粒物１９７．０ｇにステアリン酸カルシウム（日本油脂（株））３．０ｇを加えて混合後、ロータリー打錠機〔（株）畑鐵工所製、ＨＴ−ＡＰ６ＳＳ−Ｕ〕を用いて圧縮成形した。成形条件は、錠剤重量２００ｍｇ、Φ１０ｍｍ割線平フチ丸の杵で硬度約３ｋｇｆとなるよう打錠した。
参考例３−６の錠剤の評価結果を表５に示す。なお、表５で崩壊剤（％）の項目の括弧内の数字は用いた崩壊剤のメーカー記載の平均粒子径である。
[Reference Example 6]
Ascorbic acid (Takeda Pharmaceutical Co., Ltd .: 80 mesh) 36.5 g, D-mannitol (Towa Kasei Kogyo Co., Ltd .: Mannit P) 201.1 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd .: Adsolider 101) 12 8 g, 54.8 g of crospovidone (ISP: polyplastidone INF-10) was charged into a fluidized bed granulator / dryer [LAB-1 manufactured by POWREC Co., Ltd.], and 9.9 g of crospovidone (INF-10) was added. The swollen purified water was sprayed to obtain a granulated product. To this granulated product, 43.9 g of crospovidone (XL (average particle size is 100 μm as described by the manufacturer)) was added, and powder-coated with purified water in which 1.1 g of crospovidone (INF-10) was swollen. The disintegrant-coated granulated product was left to stand in a dryer. After adding 3.0 g of calcium stearate (Nippon Yushi Co., Ltd.) to 197.0 g of the obtained disintegrant-coated granulated product and mixing, a rotary tableting machine [HT-AP6SS-U, manufactured by Hata Kogyo Co., Ltd. ] Was used for compression molding. The molding condition was tableting with a tablet weight of 200 mg and a Φ10 mm scored line flat round punch having a hardness of about 3 kgf.
Table 5 shows the evaluation results of the tablets of Reference Example 3-6. In Table 5, the number in parentheses in the item of disintegrant (%) is the average particle diameter described in the manufacturer of the disintegrant used.
参考例３ないし６は、顆粒内および被覆部における崩壊剤の割合（重量％）を同じとし、用いる崩壊剤の平均粒子径を変化させたものである。顆粒内および被覆部とも崩壊剤の平均粒子径１１μｍのものを用いた場合（参考例４）、崩壊時間および浸透時間が、それらが３１μｍの場合（参考例３）に比較して若干遅延した。顆粒内を１１μｍ、被覆部を３１μｍとした場合（参考例５）は、それらが１１μｍの場合（参考例４）に比較して、成型性、崩壊時間、浸透時間とも優れていた。顆粒内を１１μｍ、被覆部を１００μｍとした場合（参考例６）は、３１μｍの粒子での被覆錠剤（参考例５）に比べると崩壊時間、浸透時間ともに速くなっている。以上のことから次のことがいえる。崩壊剤の粒子の大きさについて、崩壊性や浸透時間は、その粒子が大きい方が有利である。成形性は、粒子が小さい方が有利である。ただし、顆粒表面にクロスポビドンの微粒子が過剰になりすぎるとスティッキング（くもり）の原因となる。 In Reference Examples 3 to 6, the ratio (% by weight) of the disintegrant in the granule and in the coating part is the same, and the average particle size of the disintegrant used is changed. In the case of using a disintegrant having an average particle diameter of 11 μm in both the granule and the coating part (Reference Example 4), the disintegration time and the permeation time were slightly delayed as compared with the case of 31 μm (Reference Example 3). When the inside of the granule was 11 μm and the covering part was 31 μm (Reference Example 5), the moldability, disintegration time, and infiltration time were superior compared to the case of 11 μm (Reference Example 4). When the inside of the granule is 11 μm and the coating part is 100 μm (Reference Example 6), both the disintegration time and the permeation time are faster than those of the coated tablet with 31 μm particles (Reference Example 5). From the above, the following can be said. With regard to the size of the disintegrant particles, it is advantageous that the disintegration property and penetration time are larger. For the moldability, smaller particles are advantageous. However, if the fine particles of crospovidone are excessive on the surface of the granules, sticking (clouding) may occur.
［実施例１５］Ｘ線光電子分光分析装置（ＸＰＳ、ＥＳＣＡ）による顆粒表面分析
顆粒を調製した段階のもの、およびそれに崩壊剤による被覆を施したものの表面の窒素量をＥＳＣＡで測定することにより、上述した崩壊剤被覆操作でクロスポビドン被覆がなされていることを確認した。この測定は、株式会社日東分析センターに依頼して実施した。
[Example 15] Granule surface analysis by X-ray photoelectron spectrometer (XPS, ESCA) By measuring the amount of nitrogen on the surface of the granule prepared and coated with a disintegrant with ESCA, It was confirmed that crospovidone was coated by the disintegrant coating operation described above. This measurement was carried out at the request of Nitto Analysis Center.
ここで、ＥＳＣＡは代表的な表面分析装置の一つで、固体の表面から数ｎｍの深さ領域に関する元素および化学結合状態の分析に用いられる。すなわち、高真空中で固体試料表面に特定エネルギーの軟Ｘ線を照射すると、光電効果により試料から光電子が放出される。これをアナライザーに導き、電子の運動エネルギーで分けてスペクトルとして検出する。非弾性散乱せずに試料表面から脱出した数ｎｍの深さ領域の光電子のみがピークとして検出され、分析に用いられる。結合エネルギーは、照射した軟Ｘ線のエネルギーから光電子の運動エネルギーを引いた差として求められる。各種原子の内殻電子は固有の結合エネルギーをもっているので、検出された電子の結合エネルギーから元素の種類を、シグナル強度から元素の比率を求めることができる。ここでは、クロスポビドンに特有の窒素原子等について測定した。 Here, ESCA is one of typical surface analyzers, and is used for analysis of elements and chemical bonding states in a depth region of several nm from the surface of a solid. That is, when the surface of a solid sample is irradiated with soft X-rays having a specific energy in a high vacuum, photoelectrons are emitted from the sample by the photoelectric effect. This is guided to an analyzer, and is detected as a spectrum divided by the kinetic energy of electrons. Only the photoelectrons in the depth region of several nm that escape from the sample surface without inelastic scattering are detected as peaks and used for analysis. The binding energy is obtained as a difference obtained by subtracting the kinetic energy of photoelectrons from the energy of irradiated soft X-rays. Since the inner shell electrons of various atoms have inherent binding energies, the type of element can be determined from the detected binding energy of the electrons, and the element ratio can be determined from the signal intensity. Here, measurement was performed on nitrogen atoms and the like peculiar to crospovidone.
試料１の調製：
Ｄ−マンニトール（東和化成工業（株））２７４．１ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）１８．３ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、クロスポビドン９．９ｇを膨潤させた精製水を噴霧し、造粒物を得た。この造粒物にクロスポビドン４３．８ｇを投入し、クロスポビドン１．１ｇを膨潤させた精製水で粉コーティングした。この崩壊剤被覆造粒物を乾燥機内で静置乾燥した。
Sample 1 preparation:
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 274.1 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 18.3 g were fluidized bed granulator / dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water swollen with 9.9 g of crospovidone was sprayed to obtain a granulated product. To this granulated product, 43.8 g of crospovidone was charged and powder-coated with purified water in which 1.1 g of crospovidone was swollen. The disintegrant-coated granulated product was left to stand in a dryer.
試料２の調製：
Ｄ−マンニトール（東和化成工業（株））２７４．１ｇ、軽質無水珪酸（フロイント産業（株））１２．８ｇ、クロスポビドン（ＩＳＰ）７３．１ｇを流動層造粒乾燥機〔（株）パウレック製、ＬＡＢ−１〕に仕込み、精製水を噴霧し造粒物を得た。この造粒物を流動層造粒乾燥機内で乾燥した。
Sample 2 preparation:
D-mannitol (Towa Kasei Kogyo Co., Ltd.) 274.1 g, light anhydrous silicic acid (Freund Sangyo Co., Ltd.) 12.8 g, crospovidone (ISP) 73.1 g was fluidized bed granulator and dryer [manufactured by POWREC Co., Ltd.] LAB-1] and purified water was sprayed to obtain a granulated product. The granulated product was dried in a fluidized bed granulator / dryer.
試料２は顆粒を調製した段階のもの、試料１はそれにクロスポビドン被覆を施したものである。それぞれ任意の５サンプルについて測定しており、“ｎ”はそのサンプル番号である。測定条件は、次の通り。
ＥＳＣＡ；アルバック・ファイ社製Ｑｕａｎｔｕｍ２０００
Ｘｒａｙ Ｓｅｔｔｉｎｇ；１００μｍφ［２５Ｗ（１５ｋＶ）］のポイント分析
Ｘ線源；モノクロＡｌＫα
光電子取出し角；４５゜
中和条件；中和銃とイオン銃（中和モード）の併用
測定結果は表６のとおり。
Sample 2 is a granule-prepared stage, and sample 1 is crospovidone-coated. Each sample is measured for 5 samples, and “n” is the sample number. The measurement conditions are as follows.
ESCA; Quantum 2000 manufactured by ULVAC-PHI
Xray Setting; 100 μmφ [25 W (15 kV)] point analysis X-ray source; Monochrome AlK α
Photoelectron extraction angle: 45 ° neutralization condition; combined use of neutralization gun and ion gun (neutralization mode) Table 6 shows the measurement results.
この結果から、試料１、試料２に共通してＣ、Ｎ、Ｏ、Ｓｉの４元素が検出され、Ｎ、Ｓｉからそれぞれクロスポビドン、ケイ酸成分の存在が示された。そして、試料２の窒素の元素比率はいずれも０．５％未満であったのに対し、試料１の窒素の元素比率は０．７％から２．９％の範囲であった。よって、試料１のほうが表面窒素量は多く、クロスポビドン被覆操作により、実際にクロスポビドンが被覆されていることが確認された。 From these results, four elements of C, N, O, and Si were detected in common with Sample 1 and Sample 2, and the presence of crospovidone and silicic acid components were shown from N and Si, respectively. The element ratio of nitrogen in Sample 2 was less than 0.5%, whereas the element ratio of nitrogen in Sample 1 was in the range of 0.7% to 2.9%. Therefore, it was confirmed that Sample 1 had a larger amount of surface nitrogen and was actually coated with crospovidone by the crospovidone coating operation.
［実施例１６］飛行時間型二次イオン質量分析装置（ＴＯＦ−ＳＩＭＳ）による表面分析
実施例１５と同様な検討を飛行時間型二次イオン質量分析装置（ＴＯＦ−ＳＩＭＳ）を用いて行なった。すなわち、上述した崩壊剤被覆操作でクロスポビドン被覆がなされていることを確認した。この測定は、株式会社日東分析センターに依頼して実施した。
[Example 16] Surface analysis by time-of-flight secondary ion mass spectrometer (TOF-SIMS) The same examination as in Example 15 was performed using a time-of-flight secondary ion mass spectrometer (TOF-SIMS). That is, it was confirmed that crospovidone was coated by the disintegrant coating operation described above. This measurement was carried out at the request of Nitto Analysis Center.
ＴＯＦ−ＳＩＭＳとは、固体試料の最表面にどのような成分（原子、分子）が存在するかを調べるための装置である。ｐｐｍオーダーの極微量成分を検出することができ、有機物・無機物に適用できる。すなわち、高真空中で、高速のイオンビーム（１次イオン）を固体試料表面にぶつけると、スパッタリング現象によって表面の構成成分がはじき飛ばされる。このとき発生する正または負の電荷を帯びたイオン（２次イオン）を電場によって一方向に飛ばして、一定距離離れた位置で検出する。スパッタの際には、試料表面の組成に応じて様々な質量をもった２次イオンが発生するが、軽いイオンほど早く、反対に重いイオンほど遅い速度で飛んでいくので、２次イオンが発生してから検出されるまでの飛行時間を測定すれば発生した２次イオンの質量を計算することができる。ＴＯＦ−ＳＩＭＳでは１次イオン照射量が著しく少ないため、有機化合物は化学構造を保った状態でイオン化され、質量スペクトルから有機化合物の構造を知ることができる。固体試料表面の最も外側で発生した２次イオンのみが真空中へ飛び出すことができるので、試料の最表面（深さ数Å程度）の情報を得ることができる。さらに、１次イオンビームを走査することによって、試料表面のイオン像（マッピング）を測定することができる。 TOF-SIMS is an apparatus for examining what components (atoms and molecules) exist on the outermost surface of a solid sample. It is possible to detect trace components on the order of ppm, and it can be applied to organic and inorganic substances. That is, when a high-speed ion beam (primary ions) is struck against the surface of a solid sample in a high vacuum, the surface components are repelled by the sputtering phenomenon. The positively or negatively charged ions (secondary ions) generated at this time are scattered in one direction by an electric field and detected at a position separated by a certain distance. During sputtering, secondary ions with various masses are generated depending on the composition of the sample surface, but light ions fly faster and heavier ions fly faster, so secondary ions are generated. Then, if the time of flight from detection to detection is measured, the mass of the generated secondary ions can be calculated. In TOF-SIMS, since the amount of primary ion irradiation is extremely small, the organic compound is ionized while maintaining its chemical structure, and the structure of the organic compound can be known from the mass spectrum. Since only the secondary ions generated on the outermost surface of the solid sample surface can jump out into the vacuum, information on the outermost surface of the sample (depth of about several millimeters) can be obtained. Furthermore, the ion image (mapping) of the sample surface can be measured by scanning the primary ion beam.
試料１および試料２は、粘着テープ上に保持し、ＴＯＦ−ＳＩＭＳ測定用ホルダーに固定して測定した。測定条件は次の通り。
ＴＯＦ−ＳＩＭＳ；ＵＬＶＡＣ−ＰＨＩ社製ＴＲＩＦＴ２
１次イオン；６９Ｇａ＋（加速電圧１５ｋＶ）
Samples 1 and 2 were measured by being held on an adhesive tape and fixed to a TOF-SIMS measurement holder. The measurement conditions are as follows.
TOF-SIMS; TRIFT2 manufactured by ULVAC-PHI
Primary ion; 69 Ga + (acceleration voltage 15 kV)
これにより、試料１および試料２の表面の正および負２次イオン質量スペクトル、ならびに正・負イオン像が得られた。そして、各試料からクロスポビドン、ケイ酸成分、マンニトールが検出された。クロスポビドンに特徴的なイオンは、Ｃ６Ｈ１０ＮＯ＋、ＣＮ−、ＣＮＯ−等である。クロスポビドンは試料２と比べて試料１の表面に多く、上述の被覆操作でたしかにクロスポビドン被覆がなされていることがわかった。また、試料１におけるクロスポビドンの分散状態は、顆粒表面全体に存在していることから、均一にクロスポビドン被覆がなされていることが確認できた。 As a result, positive and negative secondary ion mass spectra and positive / negative ion images of the surfaces of Sample 1 and Sample 2 were obtained. And crospovidone, a silicic acid component, and mannitol were detected from each sample. The characteristic ions of crospovidone are C 6 H 10 NO + , CN − , CNO − and the like. The amount of crospovidone was larger on the surface of the sample 1 than that of the sample 2, and it was found that the crospovidone was certainly coated by the above-described coating operation. Moreover, since the dispersion state of the crospovidone in the sample 1 exists on the whole granule surface, it was confirmed that the crospovidone was uniformly coated.
本発明は、医薬品製造のために利用される。 The present invention is used for pharmaceutical manufacture.
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| JP6073543B2 (en) * | 2010-07-08 | 2017-02-01 | 沢井製薬株式会社 | Method for producing loratadine-containing orally disintegrating tablet |
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| KR102114487B1 (en) | 2012-09-20 | 2020-05-22 | 주식회사 다이셀 | Disintegrating particle composition containing acid-type carboxymethylcellulose and crystalline cellulose, and orally disintegrating tablet containing said composition |
| JP5919173B2 (en) * | 2012-11-22 | 2016-05-18 | 全星薬品工業株式会社 | Sustained release ambroxol hydrochloride orally disintegrating tablets |
| US20160136097A1 (en) * | 2013-07-06 | 2016-05-19 | Daicel Corporation | Ultrafast-disintegrating tablet and method for manufacturing same |
| WO2015046223A1 (en) * | 2013-09-27 | 2015-04-02 | 株式会社ダイセル | Disintegrating particle composition produced by two-stage wet granulation process, and intraorally disintegrating tablet containing same composition |
| CN106255512B (en) | 2014-04-21 | 2021-01-01 | 株式会社大赛璐 | Disintegrating granule composition containing microfibrous cellulose |
| WO2016061486A1 (en) | 2014-10-16 | 2016-04-21 | Cargill, Incorporated | Process for preparing a directly compressible erythritol & uses thereof |
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