JPWO2013129644A1 - Fast disintegrating tablets - Google Patents
Fast disintegrating tablets Download PDFInfo
- Publication number
- JPWO2013129644A1 JPWO2013129644A1 JP2014502409A JP2014502409A JPWO2013129644A1 JP WO2013129644 A1 JPWO2013129644 A1 JP WO2013129644A1 JP 2014502409 A JP2014502409 A JP 2014502409A JP 2014502409 A JP2014502409 A JP 2014502409A JP WO2013129644 A1 JPWO2013129644 A1 JP WO2013129644A1
- Authority
- JP
- Japan
- Prior art keywords
- carbon dioxide
- tablet
- disintegrating tablet
- pressure
- rapidly disintegrating
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
Abstract
薬物の特性に基づく所望の機能を付与した薬物含有粒子を含有する錠剤であっても、その機能に影響をもたらすことのある製剤化工程を経ても、当該機能を十分に発現する速崩壊性錠剤(特に、口腔内崩壊錠)、及びその製造方法を提供する。前記速崩壊性錠剤は、薬物、及び超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理して得られる。Even a tablet containing drug-containing particles imparted with a desired function based on the properties of the drug, or a rapidly disintegrating tablet that fully exhibits the function even after a formulation step that may affect the function (In particular, an orally disintegrating tablet) and a method for producing the same are provided. The fast-disintegrating tablet is a substance that has a function of a binder by treating with a drug, carbon dioxide in a supercritical or subcritical state, or liquid or gaseous carbon dioxide, and carbon dioxide in a supercritical or subcritical state. Alternatively, it can be obtained by treatment with liquid or gaseous carbon dioxide.
Description
本発明は、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素にて処理することにより多孔性構造を有する、速崩壊性錠剤(特に、口腔内崩壊錠)に関する。また、本発明は、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素にて処理することにより多孔性構造を有する、速崩壊性錠剤(特に、口腔内崩壊錠)の製造方法に関するものである。 The present invention relates to a rapidly disintegrating tablet (particularly an orally disintegrating tablet) having a porous structure by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide. The present invention also relates to a method for producing a rapidly disintegrating tablet (particularly an orally disintegrating tablet) having a porous structure by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide. Is.
医薬品製剤を提供する際、温度または湿度に不安定な薬物や、苦味を有する薬物、徐放性を付与することが必要な薬物等、薬物の特性によって、ある種の機能を付与した薬物含有粒子を含む医薬品製剤の開発が求められることが多々ある。 Drug-containing particles that provide certain functions depending on the characteristics of the drug, such as drugs that are unstable in temperature or humidity, drugs that have a bitter taste, or drugs that require sustained release when providing pharmaceutical preparations In many cases, it is required to develop pharmaceutical preparations containing.
医薬品製剤のなかでも錠剤は、患者の服用コンプライアンス上、最適な剤形のひとつとして、広く医療の現場に提供されている。
一方、1980年代に行われた厚生省厚生科学研究シルバーサイエンス研究によれば、「高齢者に投与最適な新規製剤及び新規包装容器の作成研究」(東京女子医大、杉原正泰氏ほか)という報告が行われている(薬事日報 平成元年8月22日発行;非特許文献1)。例えば、新規製剤として、a)口腔溶解型製剤、b)ペースト状製剤、c)ゼリー状製剤がとり上げられており、中でも口腔溶解型製剤及びペースト状製剤はその服用の容易さ、安定性より共に高齢者にとって服用が容易な製剤とされている。
口腔内崩壊錠は、嚥下の能力の低下した患者に適した剤形であり、水の摂取に制限のある疾患や、就寝前や外出時など水なしで飲むことも可能な利便性の高い剤形として広く知られている。Among pharmaceutical preparations, tablets are widely provided in the medical field as one of the optimal dosage forms for patient compliance.
On the other hand, according to the Ministry of Health and Welfare Science Silver Science Research conducted in the 1980s, a report was made that “Study on the creation of new formulations and new packaging containers optimal for elderly patients” (Tokyo Women's Medical University, Masayasu Sugihara et al.) (Pharmaceutical daily report published on August 22, 1989; Non-Patent Document 1). For example, a) oral dissolution type preparations, b) pasty preparations, and c) jelly type preparations are taken up as new preparations. Among them, oral dissolution type preparations and pasty preparations are both easier to take and more stable. It is a preparation that is easy for elderly people to take.
Orally disintegrating tablets are a dosage form suitable for patients with reduced ability to swallow, and are highly convenient agents that can be taken without water, such as diseases that restrict water intake or before going to bed or when going out. Widely known as shape.
口腔内崩壊錠に関する製剤技術としては、成形性の低い糖類を、成形性の高い糖類を結合剤として、噴霧し、被覆及び/または造粒してなる造粒物を含む口腔内崩壊錠に関する発明が報告されている(特許文献1)。
また、供給材料の流動性不良や加圧時における材料の加圧部材への付着などの障害が発生するといった製造上の不具合を改善するため、薬剤、水溶性結合剤及び水溶性賦形剤を含む乾燥状態の錠剤材料を錠剤の形態として、その形態を維持可能な硬度とするために最低必要な低圧力で加圧成形する打錠工程と、打錠工程で成形された錠剤に吸湿させるための加湿工程と、加湿工程で加湿された錠剤を乾燥させる乾燥工程と、を備えることを特徴とする速溶解性錠剤の製造方法に関する発明が報告されている(特許文献2)。
また、薬物、糖類、及びポリエチレングリコールを含有してなる組成物において、該組成物を低圧打錠後に、前記ポリエチレングリコールが溶融する温度条件下に昇温することにより、ポリエチレングリコールが薬物及び糖類との間に粒子間架橋を形成することにより、多孔性構造を有する口腔内崩壊錠に関する発明が報告されている(特許文献3)。
更に、口腔内における崩壊時間を延長させることなく、錠剤強度を高め、摩損度を改善するため、薬物、希釈剤、及び薬物と希釈剤より相対的に融点の低い糖類を含有してなり、融点の低い糖類が錠剤中に均一に配合され、薬物および/または希釈剤粒子間に、融点の低い糖類の溶融固化物による架橋を形成してなる口腔内速崩壊性錠剤に関する発明(特許文献4)、生理活性物質及びポリビニルアルコール−ポリエチレングリコールグラフトコポリマーを含有する口腔内崩壊錠に関する発明(特許文献5)、迅速な崩壊性、及び十分な錠剤強度を有する速崩壊性錠剤を製するため、(1)有効成分と、アクリルコポリマーと、少なくとも1種の薬理学的に許容される添加剤とを混合する工程、(2)(1)の工程で得られた混合物を、圧縮成形する工程、及び(3)(2)の工程で得られた圧縮成形物を50〜100℃の温度条件下で一定時間保温する工程からなることを特徴とする速崩壊性錠剤の製造方法に関する発明(特許文献6)、粉末形態の成分が、加圧液化ガスまたはガス混合物と接触され、均一化され、加圧化で成形型に導入され、減圧されることを特徴とする速崩壊性錠剤の製造方法に関する発明(特許文献7)、活性成分、添加剤、及び超臨界流体可溶性物質を含む混合物を打錠して錠剤を製造する段階と、前記錠剤を超臨界流体と接触させて超臨界流体可溶性物質を抽出し、錠剤中に微細空隙を形成させる段階とを含む方法によって製造された口腔内速崩壊錠に関する発明(特許文献8)等が報告されている。The invention relating to the orally disintegrating tablet is an invention relating to an orally disintegrating tablet comprising a granulated product obtained by spraying, coating and / or granulating a saccharide having a low moldability and a saccharide having a high moldability as a binder. Has been reported (Patent Document 1).
In addition, in order to improve manufacturing problems such as poor fluidity of the feed material and problems such as adhesion of the material to the pressure member during pressurization, drugs, water-soluble binders and water-soluble excipients are used. In order to make the tablet formed in the tableting process into a tablet form in which the tablet material in the dry state is compressed into a tablet form and press-molded at the lowest pressure necessary to maintain the form, and to absorb moisture in the tablet formed in the tableting process There has been reported an invention relating to a method for producing a fast-dissolving tablet, comprising: a humidifying step of 1) and a drying step of drying the tablet humidified in the humidifying step (Patent Document 2).
In addition, in a composition comprising a drug, a saccharide, and polyethylene glycol, the composition is heated under pressure conditions under which the polyethylene glycol melts after low-pressure tableting, so that the polyethylene glycol and the saccharide are mixed with each other. An invention relating to an orally disintegrating tablet having a porous structure has been reported by forming interparticle crosslinks between them (Patent Document 3).
Furthermore, in order to increase tablet strength and improve friability without prolonging the disintegration time in the oral cavity, it contains a drug, a diluent, and a saccharide having a melting point relatively lower than that of the drug and the diluent. Invention relating to an orally rapidly disintegrating tablet in which a low-sugar saccharide is uniformly mixed in a tablet and a cross-link is formed between drug and / or diluent particles by a melt-solidified product of a low-melting saccharide (Patent Document 4) , An invention relating to an orally disintegrating tablet containing a physiologically active substance and a polyvinyl alcohol-polyethylene glycol graft copolymer (Patent Document 5), in order to produce a rapidly disintegrating tablet having rapid disintegrating property and sufficient tablet strength, (1 ) A step of mixing an active ingredient, an acrylic copolymer and at least one pharmacologically acceptable additive; (2) compression of the mixture obtained in the step of (1) And (3) a method for producing a rapidly disintegrating tablet, comprising: a step of keeping the compression-molded product obtained in steps (3) and (2) for a certain period of time under a temperature condition of 50 to 100 ° C. The invention (Patent Document 6), a rapidly disintegrating tablet, wherein a component in powder form is brought into contact with a pressurized liquefied gas or a gas mixture, homogenized, introduced into a mold by pressurization, and decompressed (Patent Document 7) relating to the production method of the above, tableting a mixture comprising an active ingredient, an additive, and a supercritical fluid soluble substance to produce a tablet; and contacting the tablet with a supercritical fluid to make a supercritical fluid An invention (Patent Document 8) and the like relating to an intraoral quick disintegrating tablet produced by a method comprising a step of extracting a fluid-soluble substance and forming fine voids in the tablet has been reported.
しかしながら、流通工程における速崩壊性錠剤(特に、口腔内崩壊錠)の割れ欠けは依然として課題となっており、更なる技術の改善が必要である。また、機能性粒子が本来有する機能を維持した上で、製剤取扱い上十分な製剤硬度を有し、かつ速やかな崩壊性を有する錠剤(速崩壊性錠剤(特に、口腔内崩壊錠))を提供するためには、更なる技術の改善が必要である。
また、加熱処理や加湿処理は、薬物が分解する恐れがあることから、薬物の安定性に影響を与えない速崩壊性錠剤(特に、口腔内崩壊錠)の製造方法を提供するために、更なる技術の改善が必要である。However, cracking of fast disintegrating tablets (especially orally disintegrating tablets) in the distribution process still remains a problem, and further technical improvement is required. In addition, a tablet (fast disintegrating tablet (especially an orally disintegrating tablet)) having sufficient formulation hardness for handling the formulation and having rapid disintegration while maintaining the function inherent to the functional particles is provided. In order to do this, further technical improvements are necessary.
In addition, since heat treatment and humidification treatment may cause decomposition of the drug, in order to provide a method for producing a rapidly disintegrating tablet (especially an orally disintegrating tablet) that does not affect the stability of the drug. It is necessary to improve the technology.
本発明の課題は、錠剤の割れ欠けを改善した速崩壊性錠剤(特に、口腔内崩壊錠)を提供することにある。
また本発明の課題は、加湿処理や加温処理に不安定な薬物にも適用可能な速崩壊性錠剤(特に、口腔内崩壊錠)を提供することにある。更に本発明の課題は、薬物の特性に基づく所望の機能を付与した薬物含有粒子(以下、機能性粒子と略記することもある。)を含有する錠剤であっても、製剤化工程(製剤設計上、高温度や高湿度で処理される場合もあり、機能性薬物含有粒子の機能に影響をもたらすこともある)を経ても、当該機能を十分に発現する、速崩壊性錠剤(特に、口腔内崩壊錠)を提供することにある。
本発明の別の課題は、加湿処理や加温処理に不安定な薬物にも適用可能な速崩壊性錠剤(特に、口腔内崩壊錠)の製造方法を提供することにある。また、本発明の別の課題は、薬物の特性に基づく所望の機能を付与した薬物含有粒子を含有する錠剤であっても、製剤化工程(製剤設計上、高温度や高湿度で処理される場合もあり、薬物が分解する恐れ、あるいは機能性薬物含有粒子の機能に影響をもたらすこともある)を経ても、薬物自体安定な、あるいは機能性粒子の当該機能を十分に発現する、速崩壊性錠剤(特に、口腔内崩壊錠)の製造方法を提供することにある。The subject of this invention is providing the quick disintegrating tablet (especially orally disintegrating tablet) which improved the cracking chip of the tablet.
Another object of the present invention is to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) that can be applied to a drug that is unstable in humidification or heating treatment. Furthermore, an object of the present invention is to prepare a formulation step (formulation design) even for a tablet containing drug-containing particles imparted with a desired function based on drug characteristics (hereinafter sometimes abbreviated as functional particles). In addition, it may be processed at high temperature and high humidity, and may affect the function of the functional drug-containing particles. In disintegrating tablets).
Another object of the present invention is to provide a method for producing a rapidly disintegrating tablet (especially an orally disintegrating tablet) that can be applied to a drug that is unstable in humidification or heating treatment. Another object of the present invention is that a tablet containing drug-containing particles imparted with a desired function based on the characteristics of the drug is processed at a high formulation temperature (high temperature and high humidity for formulation design). In some cases, the drug may decompose or may affect the function of the functional drug-containing particles), but the drug itself is stable, or the function of the functional particles is fully expressed. It is in providing the manufacturing method of an adhesive tablet (especially orally disintegrating tablet).
係る状況下、発明者らは、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理したところ、融点またはガラス転移温度が降下する物質が存在し、当該物質が成分と成分との空隙に、所謂「粒子間」架橋を構築することにより、結合剤として機能することを知った。
また、穏和な処理条件で製造が可能であることから、かくして得られた速崩壊性錠剤(特に、口腔内崩壊錠)は、錠剤中に温度または湿度に不安定な薬物が含まれたり、或いは機能性粒子(例えば、難溶性薬物からなる固体分散体粒子、苦味マスキング粒子、徐放性粒子等)が含まれる場合、該安定性や所望の機能を十分に維持した上で、多孔性構造を有することから、製剤取扱い上十分な錠剤硬度を有し、かつ速やかな崩壊性を有する錠剤(速崩壊性錠剤(特に、口腔内崩壊錠))を提供できるものと考え、本発明を完成させるに至った。Under such circumstances, the present inventors, when treated with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state, there is a substance whose melting point or glass transition temperature falls, and the substance is divided into components and components. Has been found to function as a binder by building so-called “interparticle” crosslinks in the voids.
Further, since it can be produced under mild processing conditions, the rapidly disintegrating tablet thus obtained (particularly the orally disintegrating tablet) contains a drug unstable in temperature or humidity in the tablet, or When functional particles (for example, solid dispersion particles composed of poorly soluble drugs, bitterness masking particles, sustained-release particles, etc.) are included, the porous structure is maintained after sufficiently maintaining the stability and desired functions. Therefore, it is considered that a tablet (fast disintegrating tablet (especially orally disintegrating tablet)) having sufficient tablet hardness for handling the preparation and having rapid disintegration can be provided. It came.
すなわち、本発明は、
[1]薬物、及び超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を含有し、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理して得られる速崩壊性錠剤、
[2]超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質が、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより融点またはガラス転移温度が降下する物質である、[1]に記載の速崩壊性錠剤、
[3]超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質が、ビニルピロリドン・酢酸ビニル共重合物、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー、ポビドン、ポビドン/酢酸ビニル樹脂 プレミックス製剤、メタクリル酸コポリマーLD、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー/ポリビニルアルコール プレミックス製剤、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール、マクロゴール、ポリオキシエチレン硬化ヒマシ油(40)、アミノアルキルメタクリレートコポリマーE、メタクリル酸コポリマーL、乾燥メタクリル酸コポリマーLD、メタクリル酸コポリマーLD、メタクリル酸コポリマーS、アミノアルキルメタクリレートコポリマーRS、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、エチルセルロース、メチルメタクリレート・ジエチルアミノエチルメタクリレート共重合体、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、セラック、カーボマー、及びポリビニルアセタールジエチルアミノアセテートからなる群より選択される1種または2種以上である、[1]または[2]の速崩壊性錠剤、
[4]超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質が、錠剤の重量に対し0.1重量%以上50重量%以下である、[1]〜[3]のいずれかの速崩壊性錠剤、
[5]更に、可塑剤を含む[1]〜[4]のいずれかの速崩壊性錠剤、
[6]更に、崩壊剤を含む[1]〜[5]のいずれかの速崩壊性錠剤、
[7]錠剤硬度が20N以上である、[1]〜[6]のいずれかの速崩壊性錠剤、
[8]落下試験による破損錠数の割合が5%以下の、[1]〜[7]のいずれかの速崩壊性錠剤、
[9]速崩壊性錠剤が口腔内崩壊錠である、[1]〜[8]のいずれかの速崩壊性錠剤、
[10]口腔内崩壊時間が120秒以内である、[9]の速崩壊性錠剤、
[11]薬物が、温度もしくは湿度に不安定な薬物及び/または機能性粒子を構成する、[1]〜[10]のいずれかの速崩壊性錠剤、
[12]機能性粒子が、難溶性薬物からなる固体分散体粒子、苦味マスキング粒子、及び徐放性粒子からなる群より選択される1種または2種以上の粒子である、[11]の速崩壊性錠剤、
[13](1)薬物と、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質とを混合する工程、
(2)(1)の混合物を圧縮成形して錠剤を調製する工程、及び
(3)(2)の錠剤を、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理する工程
を含む、速崩壊性錠剤の製造方法、
[14]超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質が、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより融点またはガラス転移温度が降下する物質である、[13]の速崩壊性錠剤の製造方法、
[15]超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質が、ビニルピロリドン・酢酸ビニル共重合物、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー、ポビドン、ポビドン/酢酸ビニル樹脂 プレミックス製剤、メタクリル酸コポリマーLD、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー/ポリビニルアルコール プレミックス製剤、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール、マクロゴール、ポリオキシエチレン硬化ヒマシ油(40)、アミノアルキルメタクリレートコポリマーE、メタクリル酸コポリマーL、乾燥メタクリル酸コポリマーLD、メタクリル酸コポリマーLD、メタクリル酸コポリマーS、アミノアルキルメタクリレートコポリマーRS、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、エチルセルロース、メチルメタクリレート・ジエチルアミノエチルメタクリレート共重合体、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、セラック、及びカーボマーからなる群より選択される1種または2種以上である、[13]または[14]の速崩壊性錠剤の製造方法、
[16]超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質が、錠剤の重量に対し0.1重量%以上50重量%以下である、[13]〜[15]のいずれかの速崩壊性錠剤の製造方法、
[17]更に、可塑剤を含む[13]〜[16]のいずれかの速崩壊性錠剤の製造方法、
[18]更に、崩壊剤を含む[13]〜[17]のいずれかの速崩壊性錠剤の製造方法、
[19]錠剤硬度が20N以上である、[13]〜[18]のいずれかの速崩壊性錠剤の製造方法、
[20]速崩壊性錠剤が口腔内崩壊錠である、[13]〜[19]のいずれかの速崩壊性錠剤の製造方法、
[21]口腔内崩壊時間が120秒以内である、[20]の速崩壊性錠剤の製造方法、
[22]薬物が、温度もしくは湿度に不安定な薬物及び/または機能性粒子を構成する、[13]〜[21]のいずれかの速崩壊性錠剤の製造方法、
[23]機能性粒子が、難溶性薬物からなる固体分散体粒子、苦味マスキング粒子、及び徐放性粒子からなる群より選択される1種または2種以上の粒子である、[22]の速崩壊性錠剤の製造方法、
[24]0.1MPa以上50MPa以下、かつ−40℃以上100℃以下の二酸化炭素で処理することを含む、[13]〜[23]のいずれかの速崩壊性錠剤の製造方法、
[25]気体二酸化炭素により処理した、[13]〜[24]のいずれかの速崩壊性錠剤の製造方法
に関する。That is, the present invention
[1] Carbon dioxide or liquid in a supercritical or subcritical state containing a drug and a substance having a function of a binder by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state Or fast disintegrating tablets obtained by treatment with gaseous carbon dioxide,
[2] The substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is converted to carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state. The rapidly disintegrating tablet according to [1], which is a substance whose melting point or glass transition temperature is lowered by treatment,
[3] A substance having the function of a binder by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is a vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol. Graft copolymer, povidone, povidone / vinyl acetate resin premix formulation, methacrylic acid copolymer LD, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer / polyvinyl alcohol premix formulation, polyoxyethylene (196) polyoxypropylene (67) Glycol, macrogol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, Acrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate / diethylaminoethyl methacrylate copolymer, [1] or [2] fast disintegrating tablets, one or more selected from the group consisting of hydroxypropyl methylcellulose acetate succinate, shellac, carbomer, and polyvinyl acetal diethylaminoacetate,
[4] The substance having the function of a binder by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is 0.1% by weight or more and 50% by weight or less based on the weight of the tablet. , [1]-[3] fast disintegrating tablet,
[5] The rapidly disintegrating tablet of any one of [1] to [4], further comprising a plasticizer,
[6] The rapidly disintegrating tablet according to any one of [1] to [5], further comprising a disintegrating agent,
[7] The rapidly disintegrating tablet of any one of [1] to [6], wherein the tablet hardness is 20 N or more,
[8] The rapidly disintegrating tablet according to any one of [1] to [7], wherein the ratio of the number of broken tablets by a drop test is 5% or less,
[9] The rapidly disintegrating tablet according to any one of [1] to [8], wherein the rapidly disintegrating tablet is an orally disintegrating tablet,
[10] The rapidly disintegrating tablet according to [9], wherein the oral disintegration time is within 120 seconds,
[11] The rapidly disintegrating tablet according to any one of [1] to [10], wherein the drug constitutes a drug and / or functional particles unstable to temperature or humidity.
[12] The speed according to [11], wherein the functional particles are one or more particles selected from the group consisting of solid dispersion particles made of a poorly soluble drug, bitterness masking particles, and sustained-release particles. Disintegrating tablets,
[13] (1) A step of mixing a drug and a substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide,
(2) A step of preparing a tablet by compression molding the mixture of (1), and (3) a step of treating the tablet of (2) with carbon dioxide in a supercritical or subcritical state or with liquid or gaseous carbon dioxide. A method for producing a rapidly disintegrating tablet,
[14] A substance having the function of a binder by treatment with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state is carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state. A method for producing a rapidly disintegrating tablet according to [13], wherein the melting point or glass transition temperature is lowered by the treatment.
[15] A substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is a vinyl pyrrolidone / vinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol Graft copolymer, povidone, povidone / vinyl acetate resin premix formulation, methacrylic acid copolymer LD, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol / polyethylene glycol graft copolymer / polyvinyl alcohol premix formulation, polyoxyethylene (196) polyoxypropylene (67) Glycol, macrogol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, meta Rylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate / diethylaminoethyl methacrylate copolymer, [1] One or more selected from the group consisting of hydroxypropylmethylcellulose acetate succinate, shellac, and carbomer, [13] or [14]
[16] The substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide is 0.1% by weight or more and 50% by weight or less based on the weight of the tablet. , [13] to [15], a method for producing a rapidly disintegrating tablet,
[17] A method for producing a rapidly disintegrating tablet according to any one of [13] to [16], further comprising a plasticizer,
[18] A method for producing a rapidly disintegrating tablet according to any one of [13] to [17], further comprising a disintegrant,
[19] The method for producing a rapidly disintegrating tablet of any one of [13] to [18], wherein the tablet hardness is 20 N or more,
[20] The method for producing a rapidly disintegrating tablet according to any one of [13] to [19], wherein the rapidly disintegrating tablet is an orally disintegrating tablet,
[21] The method for producing a rapidly disintegrating tablet according to [20], wherein the oral disintegration time is within 120 seconds,
[22] The method for producing a rapidly disintegrating tablet according to any one of [13] to [21], wherein the drug constitutes a drug and / or functional particles unstable to temperature or humidity.
[23] The speed according to [22], wherein the functional particle is one or more particles selected from the group consisting of a solid dispersion particle composed of a poorly soluble drug, a bitter taste masking particle, and a sustained-release particle. Manufacturing method of disintegrating tablets,
[24] A method for producing a rapidly disintegrating tablet according to any one of [13] to [23], comprising treatment with carbon dioxide of 0.1 MPa to 50 MPa and −40 ° C. to 100 ° C.
[25] A method for producing a rapidly disintegrating tablet according to any one of [13] to [24], which is treated with gaseous carbon dioxide.
本発明によれば、割れ欠けを改善した耐破損性を有し、かつ口腔内で速崩壊性を有する速崩壊性錠剤(特に、口腔内崩壊錠)の提供が可能である。また、例えば、室温程度の穏和な条件での処理が可能であることから、温度または湿度に不安定な薬物や、難溶性薬物からなる固体分散体粒子、苦味マスキング粒子、徐放性粒子等が含まれる場合、該安定性や所望の機能を十分に維持した上で、速崩壊性錠剤(特に、口腔内崩壊錠)の提供が可能である。 According to the present invention, it is possible to provide a fast disintegrating tablet (particularly an orally disintegrating tablet) having breakage resistance with improved cracking and having rapid disintegration in the oral cavity. Also, for example, since treatment under mild conditions at room temperature is possible, there are drugs that are unstable in temperature or humidity, solid dispersion particles composed of poorly soluble drugs, bitterness masking particles, sustained release particles, and the like. When included, it is possible to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) while sufficiently maintaining the stability and desired functions.
以下、本発明の実施の形態について、詳細に説明する。
本明細書において、「超臨界(状態)」とは、圧力、温度ともに臨界点を超えた非凝縮性高密度流体を意味する。
また、「亜臨界(状態)」とは、圧力、温度のいずれか一方のみ臨界点を超えた状態を意味する。臨界点は、例えば、J. W. Tom およびP. G. Debenedettiによる“Particle Formation with Supercritical Fluids-A Review”,ジャーナル オブ エアロゾール サイエンス(J. Aerosol Sci.),22(5),555-584頁、1991年のFig.1に詳細に記載されたものをいう。
更に、圧力、温度ともに臨界点を超えず液化した状態を「液体」と称す。
更に、圧力、温度ともに臨界点を超えず気化した状態を「気体」と称す。
具体的には、超臨界状態にある二酸化炭素とは、臨界圧約7.38メガパスカル(MPa)、臨界温度約304.1ケルビン(K)をともに超えた状態である。具体的には、固体状態以外のものである。例えば、液体二酸化炭素、気体二酸化炭素、超臨界二酸化炭素が挙げられる。Hereinafter, embodiments of the present invention will be described in detail.
In this specification, “supercritical (state)” means a non-condensable dense fluid that exceeds the critical point in both pressure and temperature.
“Subcritical (state)” means a state in which only one of pressure and temperature exceeds the critical point. The critical point is, for example, “Particle Formation with Supercritical Fluids-A Review” by JW Tom and PG Debenedetti, Journal of Aerosol Sci., 22 (5), pp. 555-584, 1991 The one described in detail in .1.
Furthermore, the state in which both pressure and temperature do not exceed the critical point and is liquefied is referred to as “liquid”.
Furthermore, a state where both pressure and temperature are vaporized without exceeding the critical point is referred to as “gas”.
Specifically, carbon dioxide in a supercritical state is a state in which both a critical pressure of about 7.38 megapascal (MPa) and a critical temperature of about 304.1 Kelvin (K) are exceeded. Specifically, it is something other than a solid state. Examples include liquid carbon dioxide, gaseous carbon dioxide, and supercritical carbon dioxide.
本明細書において、「製剤取扱い上十分な錠剤硬度」或いは「優れた錠剤硬度」とは、錠剤が流通工程で破損しない程度であれば特に制限されないが、例えばカバーシートから製剤を押し出して取り出すことが可能な強度のめやすとして、錠剤の縦方向の硬度が挙げられる。その硬度は錠剤の大きさ、形状により異なるが、例えば直径約8.0mmで180mg錠の時20N以上、直径約8.5mmの時30N以上、直径約10.0mmの時50N以上、直径約12.0mmの時60N以上と規定する。本発明製剤は、いずれの大きさの場合にもPTP包装からの取り出しに十分耐えうる強度を有するものである。更に、ボトル包装(ガラス、プラスチック等の容器に錠剤を封入した包装)に適用可能な強度、すなわち、通常のボトル容器内において輸送搬入時に錠剤間、または錠剤と容器壁との接触に耐え得る錠剤の強度のめやすとして、30N以上が好ましい。また、別の態様として、例えばPTP包装された錠剤の落下試験による破損率が挙げられる。例えば、1枚のPTP包装シート内に錠剤を包装した状態のPTP包装シートを、錠剤収納部(ポケット)を上にして高さ150cmの高さから10枚落下させたとき、前記錠剤の破損率が5%以下、他の態様として2%以下となる強度を有することと規定する。本発明製剤は、ボトル包装における輸送または搬入に十分耐え得る強度を有するものである。 In the present specification, “tablet hardness sufficient for handling the formulation” or “excellent tablet hardness” is not particularly limited as long as the tablet is not damaged in the distribution process. For example, the formulation is extruded from the cover sheet and taken out. As an indication of the strength that can be applied, the hardness in the longitudinal direction of the tablet can be mentioned. The hardness varies depending on the size and shape of the tablet. For example, when the diameter is about 8.0 mm and a 180 mg tablet is 20 N or more, when the diameter is about 8.5 mm, it is 30 N or more, when the diameter is about 10.0 mm, 50 N or more, and the diameter is about 12 It is specified as 60N or more when 0.0mm. The preparation of the present invention has a strength sufficient to withstand removal from the PTP package in any size. Furthermore, the strength applicable to bottle packaging (packaging in which tablets are encapsulated in glass, plastic, etc.), that is, tablets that can withstand contact between tablets or between tablets and container walls when transported in a normal bottle container. As a measure of the strength, 30N or more is preferable. Further, as another aspect, for example, a breakage rate by a drop test of a PTP-packed tablet can be mentioned. For example, when 10 PTP packaging sheets in a state where tablets are packaged in one PTP packaging sheet are dropped from a height of 150 cm with the tablet storage part (pocket) facing up, the damage rate of the tablets Is 5% or less, and in another embodiment, it is defined as having a strength of 2% or less. The preparation of the present invention has sufficient strength to withstand transportation or carry-in in bottle packaging.
本明細書において、「速やかな崩壊性」を有する錠剤(速崩壊性錠剤)とは、口腔内で水を服用することなしに、だ液により実用上十分な崩壊性もしくは溶解性を有する錠剤を意味する。ここで実用上十分な崩壊性または溶解性とは、個人差もあるが、通常口腔内で1乃至300秒程度、他の態様として1乃至150秒程度、更なる態様として1乃至90秒程度、更に他の態様として1乃至60秒程度で崩壊もしくは溶解することと規定する。またトリコープテスタで測定した際には、崩壊時間が1乃至300秒以内、他の態様として1乃至120秒以内、更なる態様として1乃至90秒以内、更に他の態様として1乃至60秒以内、更に別の態様として1乃至40秒以内と規定する。また、「口腔内崩壊錠」とは、個人差もあるが、通常口腔内で1乃至120秒程度、他の態様として1乃至90秒程度、更なる態様として1乃至60秒程度で崩壊もしくは溶解する錠剤を意味する。またトリコープテスタで測定した際には、崩壊時間が1乃至120秒以内、他の態様として1乃至90秒以内、更なる態様として1乃至60秒以内、更に他の態様として1乃至40秒以内で崩壊または溶解する錠剤を意味する。 In this specification, a tablet having “rapid disintegration” (fast disintegrating tablet) refers to a tablet having practically sufficient disintegration or solubility by saliva without taking water in the oral cavity. means. Here, practically sufficient disintegration or solubility has individual differences, but usually within the oral cavity is about 1 to 300 seconds, as another aspect about 1 to 150 seconds, as a further aspect about 1 to 90 seconds, Furthermore, as another embodiment, it is defined that it disintegrates or dissolves in about 1 to 60 seconds. Moreover, when measured with a tricoop tester, the decay time is within 1 to 300 seconds, as another embodiment within 1 to 120 seconds, as a further embodiment within 1 to 90 seconds, and as another embodiment within 1 to 60 seconds. Further, it is defined as 1 to 40 seconds or less as another aspect. The “orally disintegrating tablet” varies depending on individuals, but usually disintegrates or dissolves in the oral cavity in about 1 to 120 seconds, in other embodiments in about 1 to 90 seconds, and in further embodiments in about 1 to 60 seconds. Means tablets. In addition, when measured with a tricoop tester, the decay time is within 1 to 120 seconds, as another embodiment within 1 to 90 seconds, as a further embodiment within 1 to 60 seconds, and as another embodiment within 1 to 40 seconds. Means tablets that disintegrate or dissolve.
本明細書において、「多孔性構造」とは、錠剤が口腔内で速やかに崩壊すれば特に制限されないが、例えば、空隙率が15%以上90%以下、他の態様として、25%以上70%以下、更なる態様として30%以上50%以下であると規定する。 In the present specification, the “porous structure” is not particularly limited as long as the tablet rapidly disintegrates in the oral cavity. For example, the porosity is 15% or more and 90% or less, and as another aspect, 25% or more and 70%. Hereinafter, it is specified as 30% or more and 50% or less as a further aspect.
本発明に用いられる薬物としては、治療学的に有効な活性成分、或いは予防学的に有効な活性成分であれば特に制限されない。かかる医薬活性成分としては、例えば、催眠鎮静剤、睡眠導入剤、偏頭痛剤、抗不安剤、抗てんかん剤、抗うつ薬、抗パーキンソン剤、精神神経用剤、中枢神経系用薬、局所麻酔剤、骨格筋弛緩剤、自律神経剤、解熱鎮痛消炎剤、鎮けい剤、鎮暈剤、強心剤、不整脈用剤、利尿剤、血圧降下剤、血管収縮剤、血管拡張剤、循環器官用薬、高脂血症剤、呼吸促進剤、鎮咳剤、去たん剤、鎮咳去たん剤、気管支拡張剤、止しゃ剤、整腸剤、消化性潰瘍用剤、健胃消化剤、制酸剤、下剤、利胆剤、消化器官用薬、副腎ホルモン剤、ホルモン剤、泌尿器官用剤、ビタミン剤、止血剤、肝臓疾患用剤、痛風治療剤、糖尿病用剤、抗ヒスタミン剤、抗生物質、抗菌剤、抗悪性腫瘍剤、化学療法剤、総合感冒剤、滋養強壮保健薬、骨粗しょう症薬等が挙げられる。かかる薬物として、例えば、ソリフェナシン、トルテロジン、ミラベグロン等の過活動性膀胱治療薬、ジフェンヒドラミン、ロラゼパム、ゾルピデム等の睡眠導入薬、インドメタシン、ジクロフェナック、ジクロフェナックナトリウム、コデイン、イブプロフェン、フェニルブタゾン、オキシフェンブタゾン、メピリゾール、アスピリン、エテンザミド、アセトアミノフェン、アミノピリン、フェナセチン、臭化ブチルスコポラミン、モルヒネ、エトミドリン、ペンタゾシン、フェノプロフェンカルシウム、ナプロキセン、セレコキシブ、バルデコキシブ、トラマドール等の消炎、解熱、鎮けいまたは鎮痛薬、スマトリプタン等の偏頭痛薬、エトドラック等の抗リウマチ薬、イソニアジド、塩酸エタンブトール等の抗結核薬、硝酸イソソルビド、ニトログリセリン、ニフェジピン、塩酸バルニジピン、塩酸ニカルジピン、ジピリダモール、アムリノン、塩酸インデノロール、塩酸ヒドララジン、メチルドーパ、フロセミド、スピロノラクトン、硝酸グアネチジン、レセルピン、塩酸アモスラロール、リシノプリル、メトプロロール、ピロカルピン、テルミサルタン等の循環器官用薬、塩酸クロルプロマジン、塩酸アミトリプチリン、ネモナプリド、ハロペリドール、塩酸モペロン、ペルフェナジン、ジアゼパム、ロラゼパム、クロルジアゼポキシド、アジナゾラム、アルプラゾラム、メチルフェニデート、ミルナシプラン、ペルオキセチン、リスペリドン、バルプロ酸ナトリウム等の抗精神薬、イミプラミン等の抗うつ薬、メトクロプラミド、塩酸ラモセトロン、塩酸グラニセトロン、塩酸オンダンセトロン、塩酸アザセトロン等の制吐剤、マレイン酸クロルフェニラミン等の抗ヒスタミン薬、硝酸チアミン、酢酸トコフェノール、シコチアミン、リン酸ピリドキサール、コバマミド、アスコルビン酸、ニコチン酸アミド等のビタミン薬、アロプリノール、コルヒチン、プロベネシド等の痛風薬、レボドパ、セレギリン等のパーキンソン病薬、アモバルビタール、ブロムワレリル尿素、ミダゾラム、抱水クロラール等の催眠鎮静薬、フルオロウラシル、カルモフール、塩酸アクラルビシン、シクロホスファミド、チオテパ等の抗悪性腫瘍薬、プソイドエフェドリン、テルフェナジン等の抗アレルギー薬、アセトヘキサミド、インシュリン、トルブタミド、デスモプレッシン、グリピジド、ナテグリニド、メトホルミン、シタグリプチン、ビルダグリプチン、リナグリプチン等の糖尿病薬、ヒドロクロロチアジド、ポリチアジド、トリアムテレン等の利尿薬、アミノフィリン、フマル酸ホルモテロール、テオフィリン等の気管支拡張薬、リン酸コデイン、ノスカピン、リン酸ジメモルファン、デキストロメトルファン等の鎮咳薬、硝酸キニジン、ジキトキシン、塩酸プロパフェノン、プロカインアミド等の抗不整脈薬、アミノ安息香酸エチル、リドカイン、塩酸ジブカイン等の表面麻酔薬、フェニトイン、エトスクシミド、プリミドン等の抗てんかん薬、ヒドロコルチゾン、プレドニゾロン、トリアムシノロン、ベタメタゾン等の合成副腎皮質ステロイド類、ファモチジン、塩酸ラニチジン、シメチジン、スクラルファート、スルピリド、テプレノン、プラウノトール、5−アミノサリチル酸、スルファサラジン、オメプラゾール、ランソプラゾール等の消化管用薬、インデロキサジン、イデベノン、塩酸チアプリド、塩酸ビフェメラン、ホパテン酸カルシウム等の中枢神経系用薬、プラバスタチンナトリウム、シンバスタチン、ロバスタチン、アトルバスタチン等の高脂血症治療剤、塩酸アンピシリンフタリジル、セフォテタン、ジョサマイシン等の抗生物質、タムスロシン、メシル酸ドキサゾシン、塩酸テラゾシン等のBPH治療剤、プランルカスト、ザフィルカスト、アルブテロール、アンブロキソール、ブデソニド、レベルブテロール等の抗喘息剤、ベラプロストナトリウム等のプロスタグランジンI2誘導体の末梢循環改善剤、ミノドロン酸、アレンドロン酸等の骨粗しょう症治療剤、糖尿病の各種合併症の治療剤、皮膚潰瘍治療剤、等が挙げられる。 The drug used in the present invention is not particularly limited as long as it is a therapeutically effective active ingredient or a prophylactically effective active ingredient. Examples of such pharmaceutically active ingredients include hypnotic sedatives, sleep-inducing agents, migraine agents, anti-anxiety agents, antiepileptic agents, antidepressants, anti-Parkinson agents, psychiatric agents, central nervous system agents, local anesthetics Agent, skeletal muscle relaxant, autonomic nerve agent, antipyretic analgesic / antiinflammatory agent, antispasmodic agent, antipruritic agent, cardiotonic agent, arrhythmic agent, diuretic agent, antihypertensive agent, vasoconstrictor, vasodilator, cardiovascular agent, high Dyslipidemic agent, respiratory accelerator, antitussive agent, expectorant, antitussive agent, bronchodilator, antidiarrheal agent, intestinal adjuster, peptic ulcer agent, stomach digestive agent, antacid, laxative, antibacterial agent, Drugs for digestive organs, adrenal hormones, hormones, urinary organs, vitamins, hemostats, liver diseases, gout treatments, diabetes, antihistamines, antibiotics, antibacterials, anti-neoplastic agents, chemistry Therapeutic agents, general cold drugs, nourishing tonic health drugs, osteoporosis drugs, etc. That. Examples of such drugs include overactive bladder therapeutic agents such as solifenacin, tolterodine, mirabegron, sleep-inducing drugs such as diphenhydramine, lorazepam, zolpidem, indomethacin, diclofenac, diclofenac sodium, codeine, ibuprofen, phenylbutazone, oxyphenbutazone. , Mepyrazole, aspirin, etenzamide, acetaminophen, aminopyrine, phenacetin, butylscopolamine bromide, morphine, etomidrine, pentazocine, fenoprofen calcium, naproxen, celecoxib, valdecoxib, tramadol, etc. Migraine drugs such as sumatriptan, antirheumatic drugs such as etodolac, antituberculosis drugs such as isoniazid and ethambutol hydrochloride, isosorbide nitrate , Nitroglycerin, nifedipine, varnidipine hydrochloride, nicardipine hydrochloride, dipyridamole, amrinone, indenolol hydrochloride, hydralazine hydrochloride, methyldopa, furosemide, spironolactone, guanethidine nitrate, reserpine, amosulalol hydrochloride, lisinopril, metoprolol, pilocarpine, telmisartan, etc. Antipsychotics such as chlorpromazine hydrochloride, amitriptyline hydrochloride, nemonapride, haloperidol, moperone hydrochloride, perphenazine, diazepam, lorazepam, chlordiazepoxide, adinazolam, alprazolam, methylphenidate, milnacipran, peroxetine, risperidone, sodium valproate, etc. Antidepressant, metoclopramide, ramosetron hydrochloride, granisetro hydrochloride , Antiemetics such as ondansetron hydrochloride and azacetron hydrochloride, antihistamines such as chlorpheniramine maleate, vitamin drugs such as thiamine nitrate, tocophenol acetate, chicotiamine, pyridoxal phosphate, cobamide, ascorbic acid, nicotinamide, Goutants such as allopurinol, colchicine, probenecid, Parkinson's disease drugs such as levodopa, selegiline, hypnotic sedatives such as amobarbital, bromvaleryl urea, midazolam, chloral hydrate, fluorouracil, carmofur, aclarubicin hydrochloride, cyclophosphamide, thiotepa, etc. Antineoplastic drugs, pseudoephedrine, antiallergic drugs such as terfenadine, acetohexamide, insulin, tolbutamide, desmopressin, glipizide, nateglinide, metformin, sita Diabetes such as gliptin, vildagliptin, linagliptin, diuretics such as hydrochlorothiazide, polythiazide, triamterene, bronchodilators such as aminophylline, formoterol fumarate, theophylline, antitussives such as codeine phosphate, noscapine, dimemorphan phosphate, dextromethorphan Anti-arrhythmic drugs such as quinidine nitrate, dichitoxin, propaphenone hydrochloride, procainamide, surface anesthetics such as ethyl aminobenzoate, lidocaine, dibucaine hydrochloride, antiepileptic drugs such as phenytoin, ethosuximide, primidone, hydrocortisone, prednisolone, triamcinolone, Synthetic corticosteroids such as betamethasone, famotidine, ranitidine hydrochloride, cimetidine, sucralfate, sulpiride, teprenone, prounoto , Gastrointestinal drugs such as 5-aminosalicylic acid, sulfasalazine, omeprazole, lansoprazole, central nervous system drugs such as indeloxazine, idebenone, thioprid hydrochloride, bifemelane hydrochloride, calcium patate, pravastatin sodium, simvastatin, lovastatin, atorvastatin Antihyperlipidemic agent, antibiotics such as ampicillin phthalidyl hydrochloride, cefotetan, josamycin, BPH therapeutic agents such as tamsulosin, doxazosin mesylate, terazosin hydrochloride, pranlukast, zafirlukast, albuterol, ambroxol, budesonide, reverb Anti-asthmatic agents such as terol, peripheral circulation improving agents such as prostaglandin I2 derivatives such as beraprost sodium, osteoporosis therapeutic agents such as minodronic acid and alendronic acid, Therapeutic agent species complications, skin ulcer therapeutic agents, and the like.
または、例えばステロイド性抗炎症剤、消炎鎮痛剤、解熱鎮痛剤、抗てんかん剤、化学療法剤、合成抗菌剤、抗ウィルス剤、抗真菌剤、ホルモン剤、血管新生抑制剤、免疫抑制剤、または潰瘍性大腸炎治療剤などが挙げられる。ステロイド抗炎症剤としては、例えば酢酸コルチゾン、ベタメタゾン、プレドニゾロン、プロピオン酸フルチカゾン、デキサメタゾン、ブデソニド、プロピオン酸ベクロメタゾン、トリアムシノロン、ロトプレドノール、フルオロメトロン、ジフルプレドナード、フランカルボン酸モメタゾン、プロピオン酸クロベタゾール、酢酸ジフロラゾン、吉草酸ジフルコルトロン、フルオシノニド、アムシノニド、ハルシノニド、フルオシノロンアセトニド、トリアムシノロンアセトニド、ピバル酸フルメタゾン、または酪酸クロベタゾンなどが挙げられる。消炎鎮痛剤としては、例えばアルクロフェナク、アルミノプロフェン、イブプロフェン、インドメタシン、エピリゾール、オキサプロジン、ケトプロフェン、ジクロフェナクナトリウム、ジフルニサル、ナプロキセン、ピロキシカム、フェンブフェン、フルフェナム酸、フルルビプロフェン、フロクタフェニン、ペンタゾシン、メチアジン酸、またはメフェナム酸、モフェゾラクなどが挙げられる。解熱鎮痛剤としては、例えばアセトアミノフェン、またはスルピリンなどが挙げられる。抗てんかん剤としては、例えばアセタゾラミド、カルバマゼピン、クロナゼパム、ジアゼパム、またはニトラゼパムなどが挙げられる。化学療法剤としては、例えばサラゾスルファピリジン、スルファジメトキシン、スルファメチゾール、スルファメトキサゾール、スルファメトピラジン、またはスルファモノメトキシンなどのサルファ剤、エノキシン、オフロキサシン、シノキサシン、スパルフロキサシン、チアンフェニコール、ナリジクス酸、トシル酸トスフロキサシン、ノルフロキサシン、ピペミド酸三水和物、ピロミド酸、フレロキサシン、またはレボフロキサシンなどの合成抗菌剤、アシクロビル、ガンシクロビル、ジダノシン、ジドブジン、またはビタラビンなどの抗ウィルス剤、イトラコナゾール、ケトコナゾール、フルコナゾール、フルシトシン、ミコナゾール、またはピマリシンなどの抗真菌剤が挙げられる。ホルモン剤としては、例えばインスリン亜鉛、プロピオン酸テストステロン、または安息香酸エストラジオールなどが挙げられる。免疫抑制剤としては、例えばシクロスポリン、ラパマイシン、またはタクロリムスなどが挙げられる。潰瘍性大腸炎治療剤としてはメサラジンなどが挙げられる。 Or, for example, steroidal anti-inflammatory agents, anti-inflammatory analgesics, antipyretic analgesics, antiepileptic agents, chemotherapeutic agents, synthetic antibacterial agents, antiviral agents, antifungal agents, hormone agents, angiogenesis inhibitors, immunosuppressants, or Examples include ulcerative colitis therapeutic agents. Examples of steroidal anti-inflammatory agents include cortisone acetate, betamethasone, prednisolone, fluticasone propionate, dexamethasone, budesonide, beclomethasone propionate, triamcinolone, rotopredonol, fluorometholone, diflupredone, mometasone furanate, clobetasol propionate, diflorazone propionate, Examples include diflucortron valerate, fluocinonide, amsinonide, harsinonide, fluocinolone acetonide, triamcinolone acetonide, flumethasone pivalate, or clobetasone butyrate. Antiinflammatory analgesics include, for example, alclofenac, aluminoprofen, ibuprofen, indomethacin, epilysole, oxaprozin, ketoprofen, diclofenac sodium, diflunisal, naproxen, piroxicam, fenbufen, flufenamic acid, flurbiprofen, fructaphenine, pentazocine, methazidic acid, or Examples include mefenamic acid and mofezolac. Examples of antipyretic analgesics include acetaminophen, sulpyrine, and the like. Examples of the antiepileptic agent include acetazolamide, carbamazepine, clonazepam, diazepam, and nitrazepam. Examples of chemotherapeutic agents include sulfa drugs such as salazosulfapyridine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfamethopyrazine, or sulfamonomethoxine, enoxin, ofloxacin, synoxacin, sparfloxacin Synthetic antibacterial agents such as thiamphenicol, nalidixic acid, tosufloxacin tosylate, norfloxacin, pipemidic acid trihydrate, pyromido acid, fleloxacin, or levofloxacin, antiviral agents such as acyclovir, ganciclovir, didanosine, zidovudine, or vitarabine, And antifungal agents such as itraconazole, ketoconazole, fluconazole, flucytosine, miconazole, or pimaricin. Examples of hormone agents include insulin zinc, testosterone propionate, or estradiol benzoate. Examples of the immunosuppressive agent include cyclosporine, rapamycin, tacrolimus and the like. Examples of the therapeutic agent for ulcerative colitis include mesalazine.
また、本発明に用いられる薬物の別の態様として、温度または湿度に対して不安定な薬物が挙げられる。温度または湿度に対して不安定な薬物の医薬組成物中への配合の態様は通常製薬学的に用いられる方法であれば特に制限されない。例えば、薬物を医薬添加剤とともに造粒及び/または混合してもよいし、薬物を安定化剤等とともにセルフィア(旭化成製)等の核粒子にコーティングした後、医薬添加剤とともに造粒及び/または混合してもよい。 Another embodiment of the drug used in the present invention is a drug that is unstable with respect to temperature or humidity. There are no particular limitations on the mode of incorporation of a drug unstable to temperature or humidity into a pharmaceutical composition as long as it is a method that is usually used pharmaceutically. For example, the drug may be granulated and / or mixed with a pharmaceutical additive, or the drug may be coated on core particles such as SELPHYA (manufactured by Asahi Kasei) together with a stabilizer and the like, and then granulated and / or mixed with the pharmaceutical additive. You may mix.
また、本発明に用いられる薬物の別の態様として、機能性粒子を構成する薬物(苦味のある薬物、徐放性を付すことが必要な薬物、難溶性の薬物)が挙げられる。機能性粒子としては、例えば、苦味マスキング粒子、徐放性粒子、固体分散体粒子等が挙げられる。
また、苦味のある薬物、徐放性を付すことが必要な薬物または難溶性の薬物であり、更に、温度もしくは湿度に対して不安定な薬物を機能性粒子を構成する薬物として選択してもよい。In addition, as another embodiment of the drug used in the present invention, drugs constituting functional particles (drugs with a bitter taste, drugs that need to be sustained-released, drugs with poor solubility) can be mentioned. Examples of functional particles include bitterness masking particles, sustained release particles, solid dispersion particles, and the like.
Further, a drug having a bitter taste, a drug that needs to be sustained-released or a poorly soluble drug, and a drug that is unstable with respect to temperature or humidity may be selected as a drug constituting the functional particles. Good.
薬物は、フリー体または製薬的に許容され得る塩のいずれをも用いることができる。また、薬物は、1種または2種以上組合せて用いることもできる。またこれらの薬物は、本発明に適用できうる一例であり、限定的に解釈されるべきではない。 The drug can be used in either a free form or a pharmaceutically acceptable salt. Moreover, a drug can also be used 1 type or in combination of 2 or more types. These drugs are examples that can be applied to the present invention, and should not be interpreted in a limited manner.
その配合量については、通常薬物の種類あるいは医薬用途(適応症)により適宜選択されるが、治療学的に有効な量あるいは予防学的に有効な量であれば特に制限されない。例えば、速崩壊性錠剤(特に、口腔内崩壊錠)中に0.001〜80重量%であり、他の態様として0.01〜70重量%、更に他の態様としては0.01〜60重量%である。 The compounding amount is usually selected as appropriate depending on the type of drug or pharmaceutical use (indication), but is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. For example, it is 0.001 to 80% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 0.01 to 70% by weight as another embodiment, and 0.01 to 60% by weight as another embodiment. %.
本発明の速崩壊性錠剤(特に、口腔内崩壊錠)は、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」を、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより、錠剤中で、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」が成分(例えば、薬物の他、所望により、賦形剤、崩壊剤、安定化剤、滑沢剤等)間に架橋を形成することにより、多孔性構造を有する。 The rapidly disintegrating tablet of the present invention (especially the orally disintegrating tablet) is a supercritical or subcritical carbon dioxide or a substance having a binder function by treatment with liquid or gaseous carbon dioxide. By treating with carbon dioxide in a critical or subcritical state or with liquid or gaseous carbon dioxide, in a tablet, “by treatment with carbon dioxide in a supercritical or subcritical state or with liquid or gaseous carbon dioxide, The “substance having a function” has a porous structure by forming a cross-link between components (for example, a drug, and optionally, an excipient, a disintegrant, a stabilizer, a lubricant, etc.).
本発明に用いられる「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」としては、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理されることにより、該「物質」の融点またはガラス転移温度が降下することにより、結合剤として機能する物質であれば制限されない。他の態様として、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより、該「物質」を含む錠剤の硬度が、該「物質」を含まないものと比較して増加する物質であれば制限されない。具体的には、処理の圧力として、ある態様として、約0.1MPa〜約50MPaであり、他の態様として、約1MPa〜約20MPaである。更なる態様として、約1MPa〜15MPaである。更に他の態様として、約1MPa〜約5MPaである。また別の態様として、例えば圧力20MPaにした際の融点またはガラス転移温度が例えば5℃以上降下する物質であり、他の態様として20℃以上降下する物質である。更に別の態様として、例えば、構造式中に特に二酸化炭素と親和性をもつスチレン骨格、カルボニル基、エーテル結合、エステル結合、炭素原子間不飽和結合を有する化合物等が挙げられる。 The “substance having the function of a binder by treating with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state” used in the present invention includes carbon dioxide or liquid in a supercritical or subcritical state. Alternatively, the substance is not limited as long as it is a substance that functions as a binder by lowering the melting point or glass transition temperature of the “substance” by being treated with gaseous carbon dioxide. In another embodiment, by treating with carbon dioxide in a supercritical or subcritical state or with liquid or gaseous carbon dioxide, the hardness of the tablet containing the “substance” is compared with that not containing the “substance”. Any substance that increases can be used. Specifically, the treatment pressure is about 0.1 MPa to about 50 MPa as one aspect, and about 1 MPa to about 20 MPa as another aspect. As a further aspect, it is about 1 MPa to 15 MPa. In yet another embodiment, the pressure is about 1 MPa to about 5 MPa. In another embodiment, for example, the melting point or glass transition temperature when the pressure is 20 MPa is reduced by, for example, 5 ° C. or more, and in another embodiment, the material is decreased by 20 ° C. or more. Still another embodiment includes, for example, a compound having a styrene skeleton, a carbonyl group, an ether bond, an ester bond, an unsaturated bond between carbon atoms, etc., particularly having an affinity for carbon dioxide in the structural formula.
スチレン骨格を有する化合物としては、例えばポリスチレン樹脂およびその共重合体などである。
カルボニル基を有する化合物としては、例えばアルデヒド化合物、ケトン化合物、カルボン酸化合物、エステル化合物、アミド化合物、エノン化合物、カルボン酸塩化(ハロゲン)物、酸無水物およびその重合体、共重合体などである。
エーテル結合を有する化合物としては、例えばポリエチレングリコールやポリプロピレングリコールなどに代表されるポリエーテルである。
炭素原子間不飽和結合を有する化合物としては、例えばアルケン、エチレン、プロピレン、ベンゼンもしくはアヌレンまたはその構造を持つ重合体、共重合体である。Examples of the compound having a styrene skeleton include a polystyrene resin and a copolymer thereof.
Examples of the compound having a carbonyl group include an aldehyde compound, a ketone compound, a carboxylic acid compound, an ester compound, an amide compound, an enone compound, a carboxylic acid chloride (halogen), an acid anhydride, a polymer thereof, a copolymer, and the like. .
Examples of the compound having an ether bond include polyethers typified by polyethylene glycol and polypropylene glycol.
Examples of the compound having an unsaturated bond between carbon atoms include alkenes, ethylene, propylene, benzene, annulene, and polymers and copolymers having the structure.
具体的には、ビニルピロリドン・酢酸ビニル共重合物(以下、コポリビドンと略すことがある)、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー(polyvinyl caprolactam−polyvinyl acetate−polyethylene glycol graft copolymer)、ポビドン、ポビドン/酢酸ビニル樹脂 プレミックス製剤(Polyvinyl acetate and polyvinylpyrrolidone (8:2))、メタクリル酸コポリマーLD(Methacrylic acid and ethyl acrylate copolymer)、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー(Polyvinyl alcohol and Polyethylene glycol graft copolymer (75:25))、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー/ポリビニルアルコール プレミックス製剤(Polyvinyl alcohol and Polyethylene glycol graft copolymer (75:25) and polyvinyl alcohol (60/40))、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール(Ethylene oxide and propylene oxide)、マクロゴール、ポリオキシエチレン硬化ヒマシ油(40)、アミノアルキルメタクリレートコポリマーE、メタクリル酸コポリマーL、乾燥メタクリル酸コポリマーLD、メタクリル酸コポリマーLD、メタクリル酸コポリマーS、アミノアルキルメタクリレートコポリマーRS、アクリル酸エチル・メタクリル酸メチルコポリマー分散液、エチルセルロース、メチルメタクリレート・ジエチルアミノエチルメタクリレート共重合体、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(以下、HPMCASと略すことがある)、セラック、カーボマー、ポリビニルアセタールジエチルアミノアセテート等が挙げられる。他の態様として、コポリビドン、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー、アミノアルキルメタクリレートコポリマーE、アミノアルキルメタクリレートコポリマーRS、メチルメタクリレート・ジエチルアミノエチルメタクリレート共重合体、HPMCAS、エチルセルロース、セラック、ポビドン/酢酸ビニル樹脂 プレミックス製剤、ポビドン、カーボマー、ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコールが挙げられる。更なる態様として、コポリビドン、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー、アミノアルキルメタクリレートコポリマーE、アミノアルキルメタクリレートコポリマーRS、メチルメタクリレート・ジエチルアミノエチルメタクリレート共重合体、HPMCAS、エチルセルロース、ポビドン/酢酸ビニル樹脂 プレミックス製剤が挙げられる。更に別の態様として、コポリビドン、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー、アミノアルキルメタクリレートコポリマーE、HPMCAS、エチルセルロースが挙げられる。また別の態様として、コポリビドン、アミノアルキルメタクリレートコポリマーEが挙げられる。さらに他の態様として、アミノアルキルメタクリレートコポリマーEが挙げられる。 Specifically, a vinyl pyrrolidone / vinyl acetate copolymer (hereinafter may be abbreviated as copolyvidone), a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, a polyvinylacetate-polyethylene grafol copolymer, / Vinyl acetate resin Premix formulation (Polyvinyl acetate and polypyrrolidone (8: 2)), Methacrylic acid copolymer (Ethyl acrylate copolymer), Polyvinyl alcohol / polyethylene glycol graft copolymer (Polyv) nyl alcohol and polyethylene graft polymer (75:25)), polyvinyl alcohol / polyethylene glycol graft copolymer / polyvinyl alcohol premix preparation (Polyvinyl alcohol and polyethylene graft polymer 75) Polyoxyethylene (196) polyoxypropylene (67) glycol (Ethylene oxide and polypropylene oxide), macrogol, polyoxyethylene hydrogenated castor oil (40), aminoalkyl methacrylate copolymer E, methacrylic acid copolymer L Dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate / methyl methacrylate copolymer dispersion, ethyl cellulose, methyl methacrylate / diethylaminoethyl methacrylate copolymer, hydroxypropyl methylcellulose acetate succi Nate (hereinafter sometimes abbreviated as HPMCAS), shellac, carbomer, polyvinyl acetal diethylaminoacetate and the like. Other embodiments include copolyvidone, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methyl methacrylate / diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, shellac, povidone / vinyl acetate. Resin Premix formulation, povidone, carbomer, polyoxyethylene (196) polyoxypropylene (67) glycol. Further embodiments include copolyvidone, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, methyl methacrylate / diethylaminoethyl methacrylate copolymer, HPMCAS, ethyl cellulose, povidone / vinyl acetate resin pre A mixed preparation is mentioned. Still another embodiment includes copolyvidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer E, HPMCAS, and ethyl cellulose. Another embodiment includes copolyvidone and aminoalkyl methacrylate copolymer E. Yet another embodiment includes aminoalkyl methacrylate copolymer E.
これらの化合物は、例えば、以下の商品名で市販品として入手可能である。
・コポリビドン:Kollidon VA−64(BASFジャパン)、Kollidon VA−64Fine(BASFジャパン)、プラスドンS−630(アイエスピー・ジャパン)
・ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー:Soluplus(BASFジャパン)
・ポビドン:Kollidon 12PF(BASFジャパン)、Kollidon 17PF(BASFジャパン)、Kollidon 30(BASFジャパン)、Kollidon 90F(BASFジャパン)
・ポビドン/酢酸ビニル樹脂 プレミックス製剤:Kollidon SR(BASFジャパン)
・メタクリル酸コポリマーLD:Kollicoat MAE 100P(BASFジャパン)
・ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー:Kollicoat IR(BASFジャパン)
・ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー/ポリビニルアルコール プレミックス製剤:Kollicoat Protect(BASFジャパン)
・ポリオキシエチレン(196)ポリオキシプロピレン(67)グリコール:コリフォールP407(BASFジャパン)
・マクロゴール:Lutrol E400(BASFジャパン)
・ポリオキシエチレン硬化ヒマシ油(40):Cremophor RH40(BASFジャパン)
・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E100(エボニックデグサジャパン)、オイドラギットEPO(エボニックデグサジャパン)
・メタクリル酸コポリマーL:オイドラギットL100(エボニックデグサジャパン)
・乾燥メタクリル酸コポリマーLD:オイドラギットL100−55(エボニックデグサジャパン)
・メタクリル酸コポリマーLD:オイドラギットL30D−55(エボニックデグサジャパン)
・メタクリル酸コポリマーS:オイドラギットS100(エボニックデグサジャパン)
・アミノアルキルメタクリレートコポリマーRS:オイドラギットRL100(エボニックデグサジャパン)、オイドラギットRLPO(エボニックデグサジャパン))、オイドラギットRS100(エボニックデグサジャパン)、オイドラギットRSPO(エボニックデグサジャパン)
・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NE30(エボニックデグサジャパン)、Kollicoat EMM30D(BASFジャパン)
・エチルセルロース:エトセル(ダウケミカルジャパン)
・メチルメタクリレート・ジエチルアミノエチルメタクリレート共重合体:Kollicoat Smartseal 30D(BASFジャパン)
・HPMCAS:AQOAT AS−HF、AQOAT AS−MF、 AQOAT AS−LF(信越化学工業)
・セラック:日本シェラック工業社より市販されている乾燥透明白ラック等
・カーボマー:Lubrizol社より市販されている、カーボポール(Carbopol)71G、971P、974P、980、981、5984、ETD2020、Ultrez10、934、934P、940、941、1342等やペムラン(Pemulen)TR−1、TR−2等、住友精化社から市販されているアクペック(AQUPEC)HV−501、HV501E、HV−501ER、HV−504、HV−504E、HV−505、HV−505E、HV−505ED等、和光純薬から市販されているハイビスワコー103、104、105等
・ポリビニルアセタールジエチルアミノアセテート:AEA(三菱化学フーズ)等。These compounds are available as commercial products under the following trade names, for example.
・ Copolyvidone: Kollidon VA-64 (BASF Japan), Kollidon VA-64Fine (BASF Japan), Plusdon S-630 (ASP Japan)
・ Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer: Soloplus (BASF Japan)
・ Povidone: Kollidon 12PF (BASF Japan), Kollidon 17PF (BASF Japan), Kollidon 30 (BASF Japan), Kollidon 90F (BASF Japan)
・ Povidone / vinyl acetate resin Premix formulation: Kollidon SR (BASF Japan)
・ Methacrylic acid copolymer LD: Kollicoat MAE 100P (BASF Japan)
・ Polyvinyl alcohol ・ Polyethylene glycol graft copolymer: Kollicoat IR (BASF Japan)
・ Polyvinyl alcohol ・ Polyethylene glycol graft copolymer / Polyvinyl alcohol Premix formulation: Kollicoat Protect (BASF Japan)
・ Polyoxyethylene (196) polyoxypropylene (67) glycol: Collifol P407 (BASF Japan)
・ Macro Goal: Lutrol E400 (BASF Japan)
・ Polyoxyethylene hydrogenated castor oil (40): Cremophor RH40 (BASF Japan)
Aminoalkyl methacrylate copolymer E: Eudragit E100 (Evonik Degussa Japan), Eudragit EPO (Evonik Degussa Japan)
Methacrylic acid copolymer L: Eudragit L100 (Evonik Degussa Japan)
-Dry methacrylic acid copolymer LD: Eudragit L100-55 (Evonik Degussa Japan)
・ Methacrylic acid copolymer LD: Eudragit L30D-55 (Evonik Degussa Japan)
・ Methacrylic acid copolymer S: Eudragit S100 (Evonik Degussa Japan)
Aminoalkyl methacrylate copolymers RS: Eudragit RL100 (Evonik Degussa Japan), Eudragit RLPO (Evonik Degussa Japan)), Eudragit RS100 (Evonik Degussa Japan), Eudragit RSPO (Evonik Degussa Japan)
・ Ethyl acrylate / methyl methacrylate copolymer dispersion: Eudragit NE30 (Evonik Degussa Japan), Kollicoat EMM30D (BASF Japan)
・ Ethylcellulose: Etocel (Dow Chemical Japan)
・ Methyl methacrylate / diethylaminoethyl methacrylate copolymer: Kollicoat Smartseal 30D (BASF Japan)
・ HPMCAS: AQOAT AS-HF, AQOAT AS-MF, AQOAT AS-LF (Shin-Etsu Chemical)
-Shellac: dry transparent white rack etc. marketed by Nippon Shellac Industrial Co., Ltd.-Carbomer: Carbopol 71G, 971P, 974P, 980, 981, 5984, ETD2020, Ultrez 10, 934, marketed by Lubrizol. 934P, 940, 941, 1342, etc., Pemulen TR-1, TR-2, etc., such as AQUPEC HV-501, HV501E, HV-501ER, HV-504, commercially available from Sumitomo Seika Co., Ltd. HV-504E, HV-505, HV-505E, HV-505ED, etc. Hibiswako 103, 104, 105, etc. commercially available from Wako Pure Chemicals, etc. Polyvinyl acetal diethylaminoacetate: AEA (Mitsubishi Chemical Foods), etc.
本発明の速崩壊性錠剤(特に、口腔内崩壊錠)においては、本発明に用いられる「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」として、1種または2種以上組み合わせて使用することができる。
「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」の形状は、粒状、針状等、特に制限されない。粉砕して使用することもできる。該物質の形状が粒状の場合、平均粒子径は、結合剤の機能を有する限り特に制限されないが、例えば、レーザー回折式粒度分布測定装置で測定したときの平均粒子径として、0.1〜350μmが好適である。該物質は、グレード、形状、平均粒子径等の異なるものを1種または2種以上適宜組合せて使用することができる。
その配合量は、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」としての機能を発揮する量であれば制限されない。他の態様として、速速崩壊性錠剤(特に、口腔内崩壊錠)の硬度が改善される量であれば特に制限されない。具体的には、例えば、速崩壊性錠剤(特に、口腔内崩壊錠)中に0.1〜50重量%であり、別の態様として1〜30重量%、更に別の態様としては3〜20重量%である。In the rapidly disintegrating tablet (especially orally disintegrating tablet) of the present invention, the function of the binder can be achieved by treating with “supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide used in the present invention. As the “substance having”, one kind or a combination of two or more kinds can be used.
The shape of the “substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” is not particularly limited, such as granular or needle-like. It can also be used after pulverization. When the shape of the substance is granular, the average particle size is not particularly limited as long as it has the function of a binder. For example, the average particle size when measured with a laser diffraction particle size distribution analyzer is 0.1 to 350 μm. Is preferred. These substances can be used singly or in combination of two or more kinds having different grades, shapes, average particle diameters, and the like.
The blending amount thereof is not limited as long as the amount exhibits the function as “substance having the function of a binder by being treated with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide”. In another embodiment, the amount is not particularly limited as long as the hardness of the fast disintegrating tablet (particularly the orally disintegrating tablet) is improved. Specifically, for example, it is 0.1 to 50% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 1 to 30% by weight as another aspect, and 3 to 20 as another aspect. % By weight.
本発明の速崩壊性錠剤(特に、口腔内崩壊錠)は、所望により、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」の機能を高める可塑剤を含有させることができる。
本発明に用いられる「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」の機能を高める可塑剤としては、例えばクエン酸トリエチル、カリオン83、グリセリン、グリセリン脂肪酸エステル、ゴマ油、ジメチルポリシロキサン・二酸化ケイ素混合物、D−ソルビトール、中鎖脂肪酸トリグリセリド、トウモロコシデンプン由来糖アルコール液、トリアセチン、濃グリセリン、ヒマシ油、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、プロピレングリコール、ポリオキシエチレン(105)ポリオキシプロピレン(5)グリコール、ポリソルベート80、マクロゴール400、マクロゴール600、マクロゴール1500、マクロゴール4000、マクロゴール6000、モノステアリン酸グリセリン、キシリトール等の糖類が挙げられる。他の態様として、クエン酸トリエチル、トリアセチン、マクロゴール4000、マクロゴール6000、キシリトール等の糖類が挙げられる。別の態様としては、クエン酸トリエチルが挙げられる。可塑剤は1種または2種以上組み合わせて使用することができる。可塑剤の配合量としては、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」の機能を高める量であれば特に制限されない。具体的には、例えば、速崩壊性錠剤(特に、口腔内崩壊錠)中に0.1〜20重量%であり、別の態様として0.1〜10重量%、更に別の態様としては0.1〜7重量%であり、また別の態様としては、1〜7重量%であり、また更に別の態様としては、2〜5重量%である。また、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」に対する可塑剤の配合量としては、例えば、0.5〜200重量%であり、別の態様としては、0.5〜40重量%であり、更に別の態様では10〜40重量%である。The rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention is optionally “a substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide”. The plasticizer which improves the function of can be contained.
Examples of the plasticizer that enhances the function of “substance having the function of a binder by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” used in the present invention include, for example, triethyl citrate, carion 83, glycerin, glycerin fatty acid ester, sesame oil, dimethylpolysiloxane / silicon dioxide mixture, D-sorbitol, medium chain fatty acid triglyceride, corn starch-derived sugar alcohol solution, triacetin, concentrated glycerin, castor oil, diethyl phthalate, dibutyl phthalate, Butyl phthalyl butyl glycolate, propylene glycol, polyoxyethylene (105) polyoxypropylene (5) glycol, polysorbate 80, macrogol 400, macrogol 600, macrogol 1500, macro Lumpur 4000, macrogol 6000, monostearate glycerin, sugars xylitol. Other embodiments include sugars such as triethyl citrate, triacetin, macrogol 4000, macrogol 6000, and xylitol. Another embodiment includes triethyl citrate. A plasticizer can be used 1 type or in combination of 2 or more types. The blending amount of the plasticizer is not particularly limited as long as it is an amount that enhances the function of “substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide”. Specifically, for example, it is 0.1 to 20% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet), 0.1 to 10% by weight as another aspect, and 0 as another aspect. 0.1 to 7% by weight, and in another aspect, 1 to 7% by weight, and in still another aspect, 2 to 5% by weight. In addition, the blending amount of the plasticizer with respect to “substance having a function of a binder by being treated with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” is, for example, 0.5 to 200% by weight In another embodiment, it is 0.5 to 40% by weight, and in yet another embodiment, it is 10 to 40% by weight.
本発明の速崩壊性錠剤(特に、口腔内崩壊錠)には、所望により、医薬品添加剤として通常添加される賦形剤を含有させることができる。
本発明に用いられる賦形剤としては、親水性物質或いは水溶性物質であれば制限されない。ある態様としては、糖類、セルロース誘導体、リン酸塩、硫酸塩が挙げられる。糖類としては、例えば、マンニトール、乳糖、スクロース、サッカロース、グルコース、フルクトース、ソルビトール、キシリトール、エリスリトール、トレハロース、白糖、マルチロールが挙げられる。セルロース誘導体としては、結晶セルロース等が挙げられる。リン酸塩としては、リン酸一水素カルシウム、リン酸水素カルシウム水和物、リン酸水素カルシウム造粒物、リン酸水素ナトリウム水和物、リン酸二水素カリウム、リン酸二水素ナトリウム等が挙げられる。硫酸塩としては、硫酸カルシウム等が挙げられる。The fast disintegrating tablet (especially orally disintegrating tablet) of the present invention can contain an excipient usually added as a pharmaceutical additive, if desired.
The excipient used in the present invention is not limited as long as it is a hydrophilic substance or a water-soluble substance. As a certain aspect, saccharides, a cellulose derivative, phosphate, and a sulfate are mentioned. Examples of the saccharide include mannitol, lactose, sucrose, sucrose, glucose, fructose, sorbitol, xylitol, erythritol, trehalose, sucrose, and multirole. A cellulose derivative etc. are mentioned as a cellulose derivative. Examples of the phosphate include calcium monohydrogen phosphate, calcium hydrogen phosphate hydrate, calcium hydrogen phosphate granule, sodium hydrogen phosphate hydrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate and the like. It is done. Examples of the sulfate include calcium sulfate.
本発明の速崩壊性錠剤(特に、口腔内崩壊錠)においては、賦形剤は1種または2種以上組み合わせて使用することができる。
賦形剤の配合量は、具体的には、例えば、速崩壊性錠剤(特に、口腔内崩壊錠)中に0.001〜99.99重量%であり、他の態様として1〜99.9重量%、更に他の態様としては10〜99重量%である。In the fast disintegrating tablet (especially orally disintegrating tablet) of the present invention, the excipient can be used alone or in combination of two or more.
Specifically, the blending amount of the excipient is, for example, 0.001 to 99.99% by weight in a rapidly disintegrating tablet (particularly an orally disintegrating tablet). It is 10 to 99% by weight in yet another embodiment.
本発明の速崩壊性錠剤(特に、口腔内崩壊錠)には、前記賦形剤以外にも、所望により更に各種医薬添加剤が適宜使用され、製剤化される。かかる医薬添加剤としては、製薬的に許容され、かつ薬理的に許容されるものであれば特に制限されない。例えば、結合剤、崩壊剤、酸味料、発泡剤、人工甘味料、香料、滑沢剤、着色剤、安定化剤、緩衝剤、抗酸化剤、界面活性剤などが使用される。なお、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質以外にも、以下に示すような結合剤を添加することもできる。 In addition to the excipients described above, various pharmaceutical additives are optionally used and formulated into the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention. Such a pharmaceutical additive is not particularly limited as long as it is pharmaceutically acceptable and pharmacologically acceptable. For example, binders, disintegrants, acidulants, foaming agents, artificial sweeteners, fragrances, lubricants, colorants, stabilizers, buffers, antioxidants, surfactants, and the like are used. In addition to the substance having the function of a binder by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, the following binders can also be added.
結合剤としては、例えばコポリビドン、ポビドン、ポリビニルアルコール・ポリエチレングリコールグラフトコポリマー、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、ヒドロキシプロピルメチルセルロース、アラビアゴム、アメ粉、アルギン酸ナトリウム、アルファー化デンプン、カンテン、酢酸ビニル樹脂、プルラン、デンプン、ヒドロキシプロピルセルロース、などが挙げられる。
崩壊剤としては、例えばトウモロコシデンプン、バレイショデンプン、カルメロースカルシウム、カルメロースナトリウム、クロスポビドン、アルファー化デンプン、部分アルファー化デンプン、カルメロース、結晶セルロース、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、炭酸マグネシウム、低置換度ヒドロキシプロピルセルロース、低置換度カルボキシメチルスターチナトリウム、沈降炭酸カルシウム、ゼラチン、水酸化アルミナマグネシウム、合成ケイ酸アルミニウムなどが挙げられる。他の態様として、クロスポビドン、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルメチルセルロース、カルボキシメチルスターチナトリウム、アルファー化デンプン、部分アルファー化デンプン、カルメロース、カルメロースカルシウムが挙げられる。更に別の態様として、低置換度ヒドロキシプロピルメチルセルロース、部分アルファー化デンプン、クロスカルメロースナトリウムが挙げられる。
酸味料としては、例えばクエン酸、酒石酸、リンゴ酸などが挙げられる。
発泡剤としては、例えば重曹、酒石酸、炭酸水素ナトリウム、無水クエン酸、炭酸水素ナトリウムなどが挙げられる。
人工甘味料としては、例えばサッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなどが挙げられる。
香料としては、例えばレモン、レモンライム、オレンジ、メントールなどが挙げられる。
滑沢剤としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、ショ糖脂肪酸エステル、フマル酸ステアリルナトリウム、ポリエチレングリコール、タルク、ステアリン酸などが挙げられる。
着色剤としては、例えば黄色三二酸化鉄、赤色三二酸化鉄、食用黄色4号、5号、食用赤色3号、102号、食用青色3号などが挙げられる。
安定化剤としては、例えばアスコルビン酸、アスパラギン酸、塩化ナトリウム、塩化マグネシウム、グリシン、グリセリン、軽質無水ケイ酸、グルコン酸マグネシウム、キシリトール、クエン酸カルシウム、水酸化カルシウム、水酸化ナトリウム、水酸化マグネシウム、炭酸カリウム、炭酸水素カリウム、炭酸水素ナトリウムなどが挙げられる。
緩衝剤としては、クエン酸、コハク酸、フマル酸、酒石酸、アスコルビン酸またはその塩類、グルタミン酸、グルタミン、グリシン、アスパラギン酸、アラニン、アルギニンまたはその塩類、酸化マグネシウム、酸化亜鉛、水酸化マグネシウム、リン酸、ホウ酸またはその塩類などが挙げられる。
抗酸化剤としては、例えばアスコルビン酸、ジブチルヒドロキシトルエン、没食子酸プロピルなどが挙げられる。
界面活性剤としては、例えばポリソルベート80、ラウリル硫酸ナトリウム、ポリオキシエチレン硬化ヒマシ油などが挙げられる。
医薬添加剤としては、1種または2種以上組合せて適宜適量添加することができる。
これらの各種医薬添加剤の配合量は、任意に設定できる。Examples of the binder include copolyvidone, povidone, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, hydroxypropyl methylcellulose, gum arabic, candy powder, sodium alginate, pregelatinized starch , Agar, vinyl acetate resin, pullulan, starch, hydroxypropyl cellulose, and the like.
Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, crospovidone, pregelatinized starch, partially pregelatinized starch, carmellose, crystalline cellulose, croscarmellose sodium, sodium carboxymethyl starch, magnesium carbonate, Examples include low-substituted hydroxypropyl cellulose, low-substituted sodium carboxymethyl starch, precipitated calcium carbonate, gelatin, magnesium alumina hydroxide, and synthetic aluminum silicate. Other embodiments include crospovidone, croscarmellose sodium, low-substituted hydroxypropylmethylcellulose, sodium carboxymethyl starch, pregelatinized starch, partially pregelatinized starch, carmellose, and carmellose calcium. Still another embodiment includes low-substituted hydroxypropyl methylcellulose, partially pregelatinized starch, and croscarmellose sodium.
Examples of the sour agent include citric acid, tartaric acid, malic acid and the like.
Examples of the foaming agent include sodium bicarbonate, tartaric acid, sodium hydrogen carbonate, anhydrous citric acid, sodium hydrogen carbonate and the like.
Examples of the artificial sweetener include saccharin sodium, dipotassium glycyrrhizin, aspartame, stevia and thaumatin.
Examples of the fragrances include lemon, lemon lime, orange and menthol.
Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, polyethylene glycol, talc, stearic acid and the like.
Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, and edible blue No. 3.
Examples of the stabilizer include ascorbic acid, aspartic acid, sodium chloride, magnesium chloride, glycine, glycerin, light anhydrous silicic acid, magnesium gluconate, xylitol, calcium citrate, calcium hydroxide, sodium hydroxide, magnesium hydroxide, Examples thereof include potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.
Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof.
Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.
Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.
As a pharmaceutical additive, one or a combination of two or more can be appropriately added.
The compounding quantity of these various pharmaceutical additives can be arbitrarily set.
本発明の速崩壊性錠剤は、好適には口腔内崩壊錠である。
以下に本発明の速崩壊性錠剤(特に、口腔内崩壊錠)の製造方法に関して説明する。
本発明における「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素により処理される」とは、成分と成分との間に架橋構造を構築する、所謂「結合剤」としての機能を有する物質がその「一部」乃至「完全」に溶解する処理であれば制限されない。具体的には、用いる容器の大きさや種類によって異なるが、例えば、超臨界状態もしくは亜臨界状態または液体もしくは気体状態にある約1mL〜約2000Lの二酸化炭素中に対して、打錠後の錠剤(特に、口腔内崩壊錠)を、ある態様として約0.1g〜約2000kg、他の態様として約5g〜約100kgの割合で処理する。処理の時間は、ある態様として約1分〜約50時間、別の態様として、約1分〜約24時間、他の態様として約2分〜約12時間、更に別の態様として約5分〜約2時間である。The rapidly disintegrating tablet of the present invention is preferably an orally disintegrating tablet.
The production method of the rapidly disintegrating tablet (particularly the orally disintegrating tablet) of the present invention will be described below.
In the present invention, “treated with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” has a function as a so-called “binder” that builds a crosslinked structure between components. The treatment is not limited as long as the substance has a “partial” to “complete” dissolution. Specifically, although it varies depending on the size and type of the container used, for example, about 1 mL to about 2000 L of carbon dioxide in a supercritical state, a subcritical state, or a liquid or gas state, a tablet after tableting ( In particular, orally disintegrating tablets) are treated at a rate of from about 0.1 g to about 2000 kg in one embodiment and from about 5 g to about 100 kg in another embodiment. The treatment time may range from about 1 minute to about 50 hours in one embodiment, from about 1 minute to about 24 hours in another embodiment, from about 2 minutes to about 12 hours in another embodiment, and from about 5 minutes to another embodiment. About 2 hours.
処理は、耐圧性の容器内で行うのがよい。具体的には、例えば、耐圧容器:Hシリーズ(多摩精器製)やEVシリーズ(日本分光製)またはVE−1(三菱化工機製)、CO2送液ポンプ:SCF−GETやPU−2086(日本分光製)、CO2コンプレッサー:PU−1(三菱化工機製)、温度計:白金測温抵抗体(R36S)(日本電測製)やTI−2068−01(日本分光製)、ヒーター:リボンヒーター(JK)(アズワン製)やオーブンCO−2060(日本分光製)、温度計指示制御機:E5CN(オムロン製)、圧力指示機:WGA−710B(協和電業製)、圧力計:PG−500KU(協和電業製)、自動背圧調整弁:BP−2080(日本分光製)などがシステム構成に用いられている装置である。処理の温度は、本発明の速崩壊性錠剤(特に、口腔内崩壊錠)を構成する成分の種類によって異なるが、ある態様として約−40℃〜約100℃である。例えば、「超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質」がコポリビドンの場合、約25℃〜約70℃、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマーの場合、約10℃〜約65℃、アミノアルキルメタクリレートコポリマーEの場合、約10℃〜約65℃、エチルセルロースの場合、約10℃〜約100℃である。処理の圧力は同様に、本発明の速崩壊性錠剤(特に、口腔内崩壊錠)を構成する成分の種類によって異なるが、ある態様として約0.1MPa〜約50MPaであり、他の態様として約1MPa〜約20MPaである。The treatment is preferably performed in a pressure-resistant container. Specifically, for example, pressure vessel: H series (manufactured by Tama Seiki), EV series (manufactured by JASCO) or VE-1 (manufactured by Mitsubishi Chemical Corporation), CO 2 liquid feed pump: SCF-GET or PU-2086 ( (Manufactured by JASCO), CO 2 compressor: PU-1 (manufactured by Mitsubishi Chemical Corporation), thermometer: platinum resistance thermometer (R36S) (manufactured by Nippon Denshoku) and TI-2068-01 (manufactured by JASCO), heater: ribbon Heater (JK) (manufactured by ASONE), oven CO-2060 (manufactured by JASCO), thermometer instruction controller: E5CN (manufactured by OMRON), pressure indicator: WGA-710B (manufactured by Kyowa Denki), pressure gauge: PG- 500 KU (manufactured by Kyowa Denki), automatic back pressure regulating valve: BP-2080 (manufactured by JASCO), etc. are devices used in the system configuration. Although the temperature of a process changes with kinds of component which comprises the quick disintegrating tablet (especially orally disintegrating tablet) of this invention, it is about -40 degreeC-about 100 degreeC as a certain aspect. For example, when “a substance having the function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide” is copolyvidone, about 25 ° C. to about 70 ° C., polyvinyl caprolactam-polyvinyl acetate -In the case of polyethylene glycol graft copolymer, from about 10 ° C to about 65 ° C, in the case of aminoalkyl methacrylate copolymer E, from about 10 ° C to about 65 ° C, in the case of ethyl cellulose, from about 10 ° C to about 100 ° C. Similarly, the treatment pressure varies depending on the types of components constituting the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention, but is about 0.1 MPa to about 50 MPa as one embodiment, and about 1 MPa to about 20 MPa.
処理の際には、二酸化炭素に他の溶媒を混和などして加えることができる。他の溶媒としては、例えば、水;ベンゼン、トルエン、酢酸エチル、シクロヘキサン、キシレンなどの芳香族炭化水素類;ジメチルエーテル、ジエチルエーテル、ジオキサン、ジエトキシエタン、テトラヒドロフラン、1,2−ジメトキシエタンなどのエーテル類;ジクロロメタン、クロロホルム、四塩化炭素、1,2−ジクロロエタンなどの有機塩素系有機溶剤;アセトニトリル、プロピオニトリルなどのアルキルニトリル類;ニトロメタン、ニトロエタンなどのニトロアルカン類;N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミドなどのアミド類;アセトンなどのケトン類;酢酸、無水酢酸、オレイン酸などの脂肪酸;メタノール、エタノール、プロパノールなどのアルコール類;ジメチルスルホキシド等のスルホキシド類など;またはこれらの混合溶媒などが用いられ、なかでもエタノール、アセトンなどが好ましい。他の溶媒の使用量は、通常、超臨界または亜臨界状態または液体もしくは気体状態にある二酸化炭素中に、ある態様として約0.1〜約99.9体積%、他の態様として約1〜99体積%である。
また、処理の際には、二酸化炭素に他のガスを加えることが出来る。他のガスとしては、例えば、窒素などを用いることができる。In the treatment, carbon dioxide can be mixed with another solvent. Examples of other solvents include water; aromatic hydrocarbons such as benzene, toluene, ethyl acetate, cyclohexane, and xylene; ethers such as dimethyl ether, diethyl ether, dioxane, diethoxyethane, tetrahydrofuran, and 1,2-dimethoxyethane. Organochlorine organic solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alkyl nitriles such as acetonitrile and propionitrile; nitroalkanes such as nitromethane and nitroethane; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide; Ketones such as acetone; Fatty acids such as acetic acid, acetic anhydride and oleic acid; Alcohols such as methanol, ethanol and propanol; Sulfoxides such as dimethyl sulfoxide Etc.; or and mixtures of these solvents are used, inter alia ethanol, acetone is preferred. The amount of other solvents used is usually from about 0.1 to about 99.9% by volume in carbon dioxide in a supercritical or subcritical state or in a liquid or gaseous state, and from about 1 to about 99.9% in other embodiments. 99% by volume.
In addition, other gases can be added to the carbon dioxide during the treatment. For example, nitrogen can be used as the other gas.
具体的には、例えば、以下の(0)の手順の後、以下の(1)〜(4)のいずれかの手順に従って、本発明の速崩壊性錠剤(特に、口腔内崩壊錠)を製造することができるが、以下のものに限定はされない。以後、(1)〜(4)のいずれかの手順を二酸化炭素(圧力)処理と記載することもある。 Specifically, for example, after the following procedure (0), the rapidly disintegrating tablet (especially the orally disintegrating tablet) of the present invention is produced according to any of the following procedures (1) to (4). However, it is not limited to the following. Hereinafter, any of the procedures (1) to (4) may be described as carbon dioxide (pressure) treatment.
(0)二酸化炭素処理前の速崩壊性錠剤(例えば、口腔内崩壊錠)を調製する。
具体的には、例えば、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質に薬効成分を添加した混合物を圧縮成形する方法、薬効成分を超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を含有する水溶液で造粒し、得られた造粒物を圧縮成形する方法、薬効成分と超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を水溶液で造粒し、得られた造粒物を圧縮成形する方法、薬効成分と超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を有機溶媒で造粒し、得られた造粒物を圧縮成形する方法、薬効成分と超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を用いて造粒し、得られた造粒物を圧縮成形する方法、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質とその他医薬添加剤を造粒し、得られた造粒物を薬効成分と混合した混合物を圧縮成形する方法、あるいは、薬効成分と超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質を噴霧乾燥機を用いて固体分散体を製し、得られた固体分散体とその他医薬添加剤を混合した混合物を圧縮成形する方法等が挙げられる。(0) A rapidly disintegrating tablet (for example, orally disintegrating tablet) before carbon dioxide treatment is prepared.
Specifically, for example, a method of compression molding a mixture in which a medicinal component is added to a substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, medicinal component Granulating with an aqueous solution containing a substance having the function of a binder by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide, and compression-molding the resulting granulated product, A method of granulating a substance having the function of a binder by treatment with a medicinal component and carbon dioxide in a supercritical or subcritical state or a liquid or gaseous carbon dioxide with an aqueous solution, and compression-molding the obtained granulated product, Has the function of a binder by treating with medicinal ingredients and carbon dioxide in supercritical or subcritical state or liquid or gaseous carbon dioxide A method of granulating a substance with an organic solvent and compression-molding the resulting granulated product, a function of the binder by treating with medicinal components and carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state. A method of granulating a substance having a function of a binder by treating the substance having a supercritical or subcritical carbon dioxide or liquid or gaseous carbon dioxide, and compression-molding the obtained granulated product , Granulate the substance having the function of a binder and other pharmaceutical additives by treatment with carbon dioxide in supercritical or subcritical state or liquid or gaseous carbon dioxide, and mix the resulting granulated material with medicinal ingredients By compression molding the treated mixture or by treating it with carbon dioxide or liquid or gaseous carbon dioxide in a supercritical or subcritical state with medicinal ingredients Papermaking solid dispersion material having more functional binder with a spray dryer, and a method of compression molding the resulting solid dispersion and the mixture was mixed with other pharmaceutical additives.
(1)
・耐圧性容器に速崩壊性錠剤(例えば、口腔内崩壊錠)を入れる。
・該耐圧性容器の温度を二酸化炭素の臨界点以上に保つ。
・該耐圧性容器に二酸化炭素を充填する(必要に応じて、上記溶媒または他のガスを混和する)。
・該耐圧性容器内の圧力を二酸化炭素の臨界点以上に保ち、二酸化炭素処理を行う。
・二酸化炭素で処理完了後、抜圧し、得られた速崩壊性錠剤(例えば、口腔内崩壊錠)を取り出す。(1)
-Put a rapidly disintegrating tablet (for example, orally disintegrating tablet) into a pressure-resistant container.
-Keep the temperature of the pressure-resistant container above the critical point of carbon dioxide.
Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary).
-The pressure in the pressure-resistant container is kept at a carbon dioxide critical point or higher to perform carbon dioxide treatment.
-After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
(2)
・耐圧性容器に速崩壊性錠剤(例えば、口腔内崩壊錠)を入れる。
・該耐圧性容器の温度を二酸化炭素の臨界点以上に保つ。
・該耐圧性容器に二酸化炭素を充填する(必要に応じて、上記溶媒または他のガスを混和する)。
・該耐圧性容器内の圧力を二酸化炭素の臨界点未満に保ち、二酸化炭素処理を行う。
・二酸化炭素で処理完了後、抜圧し、得られた速崩壊性錠剤(例えば、口腔内崩壊錠)を取り出す。(2)
-Put a rapidly disintegrating tablet (for example, orally disintegrating tablet) into a pressure-resistant container.
-Keep the temperature of the pressure-resistant container above the critical point of carbon dioxide.
Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary).
-The pressure in the pressure-resistant container is kept below the critical point of carbon dioxide, and carbon dioxide treatment is performed.
-After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
(3)
・耐圧性容器に速崩壊性錠剤(例えば、口腔内崩壊錠)を入れる。
・該耐圧性容器の温度を二酸化炭素の臨界点未満に保つ。
・該耐圧性容器に二酸化炭素を充填する(必要に応じて、上記溶媒または他のガスを混和する)。
・該耐圧性容器内の圧力を二酸化炭素の臨界点以上に保ち、二酸化炭素処理を行う。
・二酸化炭素で処理完了後、抜圧し、得られた速崩壊性錠剤(例えば、口腔内崩壊錠)を取り出す。(3)
-Put a rapidly disintegrating tablet (for example, orally disintegrating tablet) into a pressure-resistant container.
-Keep the temperature of the pressure vessel below the critical point of carbon dioxide.
Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary).
-The pressure in the pressure-resistant container is kept at a carbon dioxide critical point or higher to perform carbon dioxide treatment.
-After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
(4)
・耐圧性容器に速崩壊性錠剤(例えば、口腔内崩壊錠)を入れる。
・耐圧性容器の温度を二酸化炭素の臨界点未満に保つ。
・該耐圧性容器に二酸化炭素を充填する(必要に応じて、上記溶媒または他のガスを混和する)。
・該耐圧性容器内の圧力を二酸化炭素の臨界点未満に保ち、二酸化炭素処理を行う。
・二酸化炭素で処理完了後、抜圧し、得られた速崩壊性錠剤(例えば、口腔内崩壊錠)を取り出す。(4)
-Put a rapidly disintegrating tablet (for example, orally disintegrating tablet) into a pressure-resistant container.
-Keep the pressure vessel temperature below the critical point of carbon dioxide.
Fill the pressure-resistant container with carbon dioxide (mix the solvent or other gas as necessary).
-The pressure in the pressure-resistant container is kept below the critical point of carbon dioxide, and carbon dioxide treatment is performed.
-After completion of the treatment with carbon dioxide, the pressure is released, and the obtained rapidly disintegrating tablet (for example, orally disintegrating tablet) is taken out.
以下、実施例、比較例、参考例及び試験例を挙げて、本発明を更に詳細に説明するが、本発明はこれらにより限定解釈されるものではない。
なお、薬物によっては、極微量(例えば、数ngや数μg等)を配合されるものもあることから、以下の実施例は全て、薬物が極微量が含まれているとみなす。EXAMPLES Hereinafter, although an Example, a comparative example, a reference example, and a test example are given and this invention is demonstrated further in detail, this invention is not limitedly interpreted by these.
In addition, since some drugs contain a very small amount (for example, several ng, several μg, etc.), all of the following examples are considered that the drug contains a very small amount.
実施例1
D−マンニトール(Pearitol 50C、ロケットジャパン製、以下特に断りが無い場合は同様)59.0w/w%、結晶セルロース(MCC SANAQ burst、PHARMATRANS SANAQAG製)20.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)10.0w/w%、クロスポビドン(Kollidon CL、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム(Parteck LUB MST、メルク製、以下特に断りが無い場合は同様)1.0w/w%を配合し、単発打錠機(オートグラフAGS−20kNG、島津製作所製、以下特に断りのない場合は同様)を用いて打錠圧約1.0kN/杵にて1錠あたり180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は8N(n=1)であった。次にこの錠剤を耐圧性容器(耐圧セル)を用いて、二酸化炭素圧力8.0MPa、45℃で30分間処理後、減圧速度約16kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 1
D-mannitol (Pearitol 50C, manufactured by Rocket Japan, hereinafter the same unless otherwise specified) 59.0 w / w%, crystalline cellulose (MCC SANAQ burst, PHARMATRANS SANAQAG) 20.0 w / w%, copolyvidone (Kollidon VA64 Fine) , Manufactured by BASF Japan) 10.0 w / w% and crospovidone (Kollidon CL, manufactured by BASF Japan) 10.0 w / w% were mixed. This mixture is blended with magnesium stearate (Parteck LUB MST, manufactured by Merck, unless otherwise noted) 1.0 w / w%, and is a single tableting machine (Autograph AGS-20kNG, manufactured by Shimadzu Corporation, hereinafter particularly 180 mg tablets per tablet were prepared at a tableting pressure of about 1.0 kN / kg (tablet diameter 8.5 mm). Tablet hardness was 8N (n = 1). Next, this tablet was treated in a pressure-resistant container (pressure cell) at a carbon dioxide pressure of 8.0 MPa and 45 ° C. for 30 minutes, and then decompressed at a decompression rate of about 16 kPa / second to obtain the rapidly disintegrating tablet of the present invention. It was.
実施例2
D−マンニトール54.0w/w%、結晶セルロース(MCC SANAQ burst、PHARMATRANS SANAQ AG製)20.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)15.0w/w%、クロスポビドン(Kollidon CL、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は8N(n=1)であった。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力8.0MPa、45℃で30分間処理後、減圧速度約16kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 2
D-mannitol 54.0 w / w%, crystalline cellulose (MCC SANAQ burst, PHARMATRANS SANAQ AG) 20.0 w / w%, copolyvidone (Kollidon VA64 Fine, BASF Japan) 15.0 w / w%, crospovidone (Kollidon) CL, manufactured by BASF Japan) 10.0 w / w% was mixed. To this mixture, magnesium stearate 1.0 w / w% was blended, and tablets of 180 mg per tablet were produced at a tableting pressure of about 1.0 kN / 杵 using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 8N (n = 1). Next, this tablet was treated using a pressure cell at a carbon dioxide pressure of 8.0 MPa at 45 ° C. for 30 minutes, and then decompressed at a decompression rate of about 16 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例3
D−マンニトール97.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)3.0w/w%を混合した。この混合物を単発打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり270mgの錠剤を製した(錠剤直径9.0mm)、錠剤硬度は10N(n=3)であった。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力6.0MPa、40℃で30分間処理後、なりゆきで減圧し、本発明の速崩壊性錠剤を得た。Example 3
D-mannitol 97.0 w / w% and copolyvidone (Kollidon VA64 Fine, manufactured by BASF Japan) 3.0 w / w% were mixed. This mixture was used to produce 270 mg tablets (tablet diameter: 9.0 mm) at a tableting pressure of about 1.0 kN / N using a single tableting machine, and the tablet hardness was 10 N (n = 3). Next, this tablet was treated at a carbon dioxide pressure of 6.0 MPa at 40 ° C. for 30 minutes using a pressure cell, and then decompressed gradually to obtain a rapidly disintegrating tablet of the present invention.
実施例4
D−マンニトール95.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)5.0w/w%を混合した。この混合物を単発打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり270mgの錠剤を製した(錠剤直径9.0mm)。錠剤硬度は10N(n=1)であった。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力6.0MPa、40℃で30分間処理後、なりゆきで減圧し、本発明の速崩壊性錠剤を得た。Example 4
D-mannitol 95.0 w / w% and copolyvidone (Kollidon VA64 Fine, manufactured by BASF Japan) 5.0 w / w% were mixed. Using this mixture, tablets of 270 mg per tablet were prepared at a tableting pressure of about 1.0 kN / 杵 using a single tableting machine (tablet diameter: 9.0 mm). Tablet hardness was 10N (n = 1). Next, this tablet was treated at a carbon dioxide pressure of 6.0 MPa at 40 ° C. for 30 minutes using a pressure cell, and then decompressed gradually to obtain a rapidly disintegrating tablet of the present invention.
実施例5
D−マンニトール90.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)10.0w/w%を混合した。この混合物を単発打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり270mgの錠剤を製した(錠剤直径9.0mm)。錠剤硬度は10N(n=1)であった。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力6.0MPa、40℃で30分間処理後、なりゆきで減圧し、本発明の速崩壊性錠剤を得た。Example 5
D-mannitol 90.0 w / w% and copolyvidone (Kollidon VA64 Fine, manufactured by BASF Japan) 10.0 w / w% were mixed. Using this mixture, tablets of 270 mg per tablet were prepared at a tableting pressure of about 1.0 kN / 杵 using a single tableting machine (tablet diameter: 9.0 mm). Tablet hardness was 10N (n = 1). Next, this tablet was treated at a carbon dioxide pressure of 6.0 MPa at 40 ° C. for 30 minutes using a pressure cell, and then decompressed gradually to obtain a rapidly disintegrating tablet of the present invention.
実施例6
エフメルト(富士化学製)89.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり180mgの錠剤を製した(錠剤直径8.0mm)。錠剤硬度は17N(n=3)であった。口腔内崩壊時間19秒(n=3)を示した。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力6.0MPa、40℃で30分間処理後、なりゆきで減圧し、本発明の速崩壊性錠剤を得た。Example 6
Fmelt (Fuji Chemical) 89.0 w / w% and copolyvidone (Kollidon VA64 Fine, BASF Japan) 10.0 w / w% were mixed. This mixture was blended with magnesium stearate 1.0 w / w%, and tablets of 180 mg per tablet were produced at a tableting pressure of about 1.0 kN / 杵 using a single tableting machine (tablet diameter 8.0 mm). Tablet hardness was 17N (n = 3). The oral disintegration time was 19 seconds (n = 3). Next, this tablet was treated at a carbon dioxide pressure of 6.0 MPa at 40 ° C. for 30 minutes using a pressure cell, and then decompressed gradually to obtain a rapidly disintegrating tablet of the present invention.
実施例7
エフメルト(富士化学製)89.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機(HT−EXシリーズ、畑鐵工所製、以下特に断りが無い場合は同様)を用いて打錠圧約1.0kN/杵にて1錠あたり180mgの錠剤(参考例1)を製した(錠剤直径8.0mm)。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で5分間処理後、なりゆきで減圧し、本発明の速崩壊性錠剤を得た。Example 7
Fmelt (Fuji Chemical) 89.0 w / w% and copolyvidone (Kollidon VA64 Fine, BASF Japan) 10.0 w / w% were mixed. This mixture is blended with magnesium stearate 1.0 w / w%, and a tableting pressure of about 1.0 kN using a rotary tableting machine (HT-EX series, manufactured by Hata Seiko Co., Ltd., unless otherwise specified). / Tablets (reference example 1) of 180 mg per tablet were produced with a koji (tablet diameter 8.0 mm). Next, this tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 5 minutes using a pressure cell, and then reduced in pressure to obtain a rapidly disintegrating tablet of the present invention.
実施例8
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で15分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 8
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例9
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で30分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 9
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例10
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、25℃で5分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 10
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 25 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例11
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、25℃で15分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 11
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa at 25 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例12
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、25℃で30分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 12
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 25 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例13
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、35℃で5分間で処理後、減圧し本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 13
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 35 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例14
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、35℃で15分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 14
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 35 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例15
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、35℃で30分間で処理後、減圧し本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 15
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 35 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例16
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、35℃で5分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 16
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 35 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例17
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、35℃で15分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 17
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 35 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例18
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、35℃で30分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 18
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 35 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例19
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、45℃で5分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 19
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例20
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、45℃で15分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 20
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 15 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例21
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、45℃で30分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約27kPa/秒で行った。Example 21
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 27 kPa / sec.
実施例22
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、45℃で5分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 22
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 5 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例23
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、45℃で15分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 23
The tablet of Reference Example 1 was treated using a pressure cell at a carbon dioxide pressure of 8 MPa at 45 ° C. for 15 minutes and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例24
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、45℃で30分間で処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約16kPa/秒で行った。Example 24
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 16 kPa / sec.
実施例25
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、45℃で30分間処理後、減圧速度約800kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 25
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 800 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例26
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、45℃で2400分間処理後、減圧速度約800kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 26
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 8 MPa and 45 ° C. for 2400 minutes using a pressure cell, and then decompressed at a decompression rate of about 800 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例27
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力8MPa、45℃で2400分間処理後、減圧速度約16kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 27
The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 8 MPa and 45 ° C. using a pressure cell, and then decompressed at a decompression rate of about 16 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例28
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力20MPa、45℃で30分間処理後、減圧速度約27kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 28
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 20 MPa at 45 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 27 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例29
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力20MPa、45℃で30分間処理後、減圧速度約2000kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 29
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 20 MPa and 45 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例30
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力20MPa、45℃で2400分間処理後、減圧速度約2000kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 30
The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 45 ° C. using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例31
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力20MPa、45℃で2400分間処理後、減圧速度約27kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 31
The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 45 ° C. using a pressure cell, and then the pressure was reduced at a pressure reduction rate of about 27 kPa / second to obtain a rapidly disintegrating tablet of the present invention.
実施例32
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力20MPa、40℃で30分間処理後、減圧速度約2000kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 32
The tablet of Reference Example 1 was treated at a carbon dioxide pressure of 20 MPa and 40 ° C. for 30 minutes using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例33
参考例1の錠剤を耐圧セルを用いて、二酸化炭素圧力20MPa、40℃で2400分間処理後、減圧速度約2000kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 33
The tablet of Reference Example 1 was treated for 2400 minutes at a carbon dioxide pressure of 20 MPa and 40 ° C. using a pressure cell, and then decompressed at a decompression rate of about 2000 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
実施例34
D−マンニトール54.0w/w%、結晶セルロース(PHARMATRANS SANAQ AG製)20.0w/w%、ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー(ソルプラス、BASFジャパン製)15.0w/w%、クロスポビドン(Kollidon CL、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり180mgの錠剤を製した(錠剤直径8.5mm)。次にこの錠剤を耐圧セルを用いて、二酸化炭素圧力8.0MPa、45℃で30分間処理後、減圧速度約16kPa/秒で減圧し、本発明の速崩壊性錠剤を得た。Example 34
D-mannitol 54.0 w / w%, crystalline cellulose (manufactured by PHARMATRANS SANAQ AG) 20.0 w / w%, polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer (Solplus, BASF Japan) 15.0 w / w%, cross Povidone (Kollidon CL, manufactured by BASF Japan) 10.0 w / w% was mixed. To this mixture, magnesium stearate 1.0 w / w% was blended, and tablets of 180 mg per tablet were produced at a tableting pressure of about 1.0 kN / 杵 using a single tableting machine (tablet diameter 8.5 mm). Next, this tablet was treated using a pressure cell at a carbon dioxide pressure of 8.0 MPa at 45 ° C. for 30 minutes, and then decompressed at a decompression rate of about 16 kPa / sec to obtain a rapidly disintegrating tablet of the present invention.
比較例1
エフメルト(富士化学製)89.0w/w%、コポリビドン(Kollidon VA64 Fine、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機を用いて打錠圧約2.5kN/杵にて1錠あたり180mgの錠剤を製した(錠剤直径8.0mm)。Comparative Example 1
Fmelt (Fuji Chemical) 89.0 w / w% and copolyvidone (Kollidon VA64 Fine, BASF Japan) 10.0 w / w% were mixed. This mixture was mixed with magnesium stearate 1.0 w / w%, and 180 mg tablets (tablet diameter: 8.0 mm) were prepared using a rotary tableting machine at a tableting pressure of about 2.5 kN / 杵.
試験例1
実施例1、2、34(n=1)、実施例3〜6(n=3)、実施例7〜33、比較例1(n=5)の錠剤について硬度を測定した。硬度は、錠剤硬度計(Tablet Hardness Tester、“Schleuniger”、Model 6D、Schleuniger社製)を用いて測定した。結果は表3に示す。Test example 1
Hardness was measured for the tablets of Examples 1, 2, 34 (n = 1), Examples 3-6 (n = 3), Examples 7-33, and Comparative Example 1 (n = 5). The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 3.
試験例2
参考例1、実施例1、2、6、34(n=1)、実施例7〜33、比較例1(n=3)の錠剤について口腔内崩壊時間を測定した。口腔内崩壊時間は、口腔内崩壊試験機(トリコープテスタ、岡田精工社製)を用いて測定した。結果は表3に示す。Test example 2
Oral disintegration time was measured for the tablets of Reference Example 1, Examples 1, 2, 6, 34 (n = 1), Examples 7 to 33, and Comparative Example 1 (n = 3). The oral disintegration time was measured using an oral disintegration tester (Trichop Tester, Okada Seiko Co., Ltd.). The results are shown in Table 3.
試験例3
参考例1、実施例7〜33、比較例1の錠剤について厚みを測定した(n=5)。錠剤の厚みは、デジマチックインジケータ(Mitutoyo Absolute、ミツトヨ社製)を用いて測定した。結果は表3に示す。Test example 3
The thicknesses of the tablets of Reference Example 1, Examples 7 to 33, and Comparative Example 1 were measured (n = 5). The thickness of the tablet was measured using a Digimatic Indicator (Mitutoyo Absolute, manufactured by Mitutoyo Corporation). The results are shown in Table 3.
試験例4
参考例1、実施例7〜33、比較例1の錠剤について空隙率を測定した(n=1)。空隙率は、かさ密度測定装置(アキュビック1330、GeoPycTM1360、マイクロメリティクス社製)を用いて測定した。結果は表3に示す。Test example 4
The porosity was measured for the tablets of Reference Example 1, Examples 7 to 33, and Comparative Example 1 (n = 1). The porosity was measured using a bulk density measuring device (Acubic 1330, GeoPyc ™ 1360, manufactured by Micromeritics). The results are shown in Table 3.
試験例5
二酸化炭素を用い、コポリビドン(Kollidon VA64、BASFジャパン)及びポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー(Soluplus、BASFジャパン)を処理した。処理時の二酸化炭素圧力及び各物質のガラス転移点を表1(コポリビドン)および表2(ポリビニルカプロラクタム−ポリビニル酢酸−ポリエチレングリコールグラフトコポリマー)に示す。
その結果、融点またはガラス転移温度が降下する現象がみられた(表1、表2)。当該ガラス転移温度は、耐圧セル中の各物質が目視判定にて相転移を起こす温度を確認して求めた。このように二酸化炭素を用いることにより室温付近でも超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理することにより結合剤の機能を有する物質の相変化を利用することが可能となり、粒子間架橋を形成させる多孔性構造を速崩壊性錠剤(特に、口腔内崩壊錠)に適用できた。Test Example 5
Copolyvidone (Kollidon VA64, BASF Japan) and polyvinyl caprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer (Soluplus, BASF Japan) were treated with carbon dioxide. The carbon dioxide pressure during the treatment and the glass transition point of each material are shown in Table 1 (copolyvidone) and Table 2 (polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer).
As a result, a phenomenon that the melting point or the glass transition temperature was lowered was observed (Tables 1 and 2). The glass transition temperature was determined by confirming the temperature at which each substance in the pressure cell causes a phase transition by visual judgment. By using carbon dioxide in this way, it becomes possible to utilize the phase change of a substance having a binder function by treating with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide even near room temperature. The porous structure that forms interparticle crosslinks could be applied to fast disintegrating tablets (especially orally disintegrating tablets).
参考例2
直打用マンニトール(Parteck M100、メルク製)99.0w/w%にステアリン酸マグネシウム(Parteck LUB MST、メルク製、以下特に断りが無い場合は同様)1.0w/w%を配合し、単発打錠機(オートグラフAGS−20kNG、島津製作所製、以下特に断りのない場合は同様)を用いて錠剤硬度約20N、錠剤厚みが約3.9mmとなるように打錠した(錠剤直径8.5mm)。
これらの錠剤を耐圧セルを用いて、二酸化炭素圧力10MPa、40℃で60分間処理後、減圧し、参考例2の錠剤を得た。Reference example 2
Single shot mannitol (Parteck M100, manufactured by Merck) 99.0 w / w% and magnesium stearate (Parteck LUB MST, manufactured by Merck, hereinafter the same unless otherwise specified) 1.0 w / w% Tableting was performed using a tablet machine (Autograph AGS-20kNG, manufactured by Shimadzu Corporation, hereinafter the same unless otherwise specified) so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm). ).
These tablets were treated for 60 minutes at a carbon dioxide pressure of 10 MPa and 40 ° C. using a pressure cell, and then the pressure was reduced to obtain tablets of Reference Example 2.
参考例3〜8
直打用マンニトール(Parteck M100、メルク製)79.0w/w%に表4記載の各種医薬添加剤20.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて錠剤硬度約20N、錠剤厚みが約3.9mmとなるように打錠した(錠剤直径8.5mm)。
これらの錠剤を耐圧セルを用いて、二酸化炭素圧力6MPa、25℃で45分間処理後、減圧し、参考例3〜8の錠剤を得た。Reference Examples 3-8
Various pharmaceutical additives 20.0 w / w% shown in Table 4 were mixed with 79.0 w / w% for direct hitting mannitol (Parteck M100, manufactured by Merck). This mixture was blended with magnesium stearate 1.0 w / w%, and tableted using a single tableting machine so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm).
These tablets were treated at a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain tablets of Reference Examples 3 to 8.
参考例9〜24
直打用マンニトール(Parteck M100、メルク製)79.0w/w%に表4記載の各種医薬添加剤20.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて錠剤硬度約20N、錠剤厚みが約3.9mmとなるように打錠した(錠剤直径8.5mm)。
これらの錠剤を耐圧セルを用いて、二酸化炭素圧力10MPa、40℃で60分間処理後、減圧し、参考例9〜24の錠剤を得た。Reference Examples 9-24
Various pharmaceutical additives 20.0 w / w% shown in Table 4 were mixed with 79.0 w / w% for direct hitting mannitol (Parteck M100, manufactured by Merck). This mixture was blended with magnesium stearate 1.0 w / w%, and tableted using a single tableting machine so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm).
These tablets were treated at a carbon dioxide pressure of 10 MPa and 40 ° C. for 60 minutes using a pressure cell, and then decompressed to obtain tablets of Reference Examples 9 to 24.
試験例6
参考例2〜24について二酸化炭素圧力処理前後の錠剤硬度をそれぞれ測定した。硬度は、錠剤硬度計(Tablet Hardness Tester、“Schleuniger”、Model 6D、Schleuniger社製)を用いて測定した。結果は表4に示す。Test Example 6
For Reference Examples 2 to 24, the tablet hardness before and after the carbon dioxide pressure treatment was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 4.
表4の結果より、参考例2、参考例15〜24については二酸化炭素圧力処理後も錠剤硬度の上昇が認められなかったのに対し、参考例3〜14では硬度上昇が確認された。本結果により、参考例3〜14に含有される医薬添加剤と二酸化炭素圧力処理を組み合わせることで物質の相変化を利用して錠剤硬度が高められることを確認した。よって、参考例3〜14は本発明の実施例ともなりうる。 From the results of Table 4, for Reference Example 2 and Reference Examples 15 to 24, no increase in tablet hardness was observed after carbon dioxide pressure treatment, whereas in Reference Examples 3 to 14, an increase in hardness was confirmed. From this result, it was confirmed that the tablet hardness was increased by utilizing the phase change of the substance by combining the pharmaceutical additive contained in Reference Examples 3 to 14 and the carbon dioxide pressure treatment. Therefore, Reference Examples 3 to 14 can be examples of the present invention.
参考例25
直打用マンニトール(Parteck M100、メルク製)79.0w/w%に平均粒子径10〜20μmのコポリビドン(Kollidon VA64 Fine、BASFジャパン製)20.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて錠剤硬度19N、錠剤厚みが約3.9mmの錠剤を得た(錠剤直径8.5mm)。この錠剤を耐圧セルを用いて、二酸化炭素圧力6MPa、25℃で45分間処理後、減圧し参考例25の錠剤を得た。Reference Example 25
Copolyvidone (Kollidon VA64 Fine, manufactured by BASF Japan) 20.0 w / w% having an average particle diameter of 10 to 20 μm was mixed with 79.0 w / w% for direct hitting mannitol (Parteck M100, manufactured by Merck). This mixture was mixed with magnesium stearate 1.0 w / w%, and a tablet with a tablet hardness of 19 N and a tablet thickness of about 3.9 mm was obtained using a single tableting machine (tablet diameter 8.5 mm). Using a pressure cell, the tablets were treated at a carbon dioxide pressure of 6 MPa at 25 ° C. for 45 minutes and then decompressed to obtain tablets of Reference Example 25.
試験例7
参考例25の錠剤について、打錠品および二酸化炭素処理したものの硬度をそれぞれ測定した。硬度は、錠剤硬度計(Tablet Hardness Tester、“Schleuniger”、Model 6D、Schleuniger社製)を用いて測定した。結果は表5に示す。Test Example 7
About the tablet of Reference Example 25, the hardness of the tableted product and the one treated with carbon dioxide was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 5.
表5の結果に示すように、参考例8と参考例25の錠剤硬度を比較した結果、二酸化炭素圧力処理により結合剤の機能を有する物質について同一成分を使用した場合でも、粒径をより小さく制御することで二酸化炭素圧力処理によって相変化を誘導した際により効果的に錠剤硬度を高められることが分かった。これは相変化する成分の粒子径を小さく制御することで表面積が増大し、粒子間架橋がより効率的に進行するためと考えられた。よって、参考例25は本発明の実施例ともなりうる。 As shown in the results of Table 5, as a result of comparing the tablet hardness of Reference Example 8 and Reference Example 25, even when the same component was used for the substance having the function of a binder by carbon dioxide pressure treatment, the particle size was made smaller. It was found that the tablet hardness can be increased more effectively when the phase change is induced by carbon dioxide pressure treatment. This was considered to be because the surface area was increased by controlling the particle diameter of the phase-changing component to be small, and the interparticle crosslinking proceeded more efficiently. Therefore, Reference Example 25 can be an example of the present invention.
参考例26
直打用マンニトール(Parteck M100、メルク製)79.0w/w%にエチルセルロース(Ethocel standard 7 FP Premium、ダウケミカル製)20.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて錠剤硬度約20N、錠剤厚みが約3.9mmとなるように打錠した(錠剤直径8.5mm)。これらの錠剤を耐圧セルを用いて、二酸化炭素圧力6MPa、25℃で45分間処理後、減圧し、参考例26の錠剤を得た。Reference Example 26
Ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) 20.0 w / w% was mixed with 79.0 w / w% of mannitol for direct hitting (Parteck M100, manufactured by Merck). This mixture was blended with magnesium stearate 1.0 w / w%, and tableted using a single tableting machine so that the tablet hardness was about 20 N and the tablet thickness was about 3.9 mm (tablet diameter 8.5 mm). These tablets were treated for 45 minutes at a carbon dioxide pressure of 6 MPa and 25 ° C. using a pressure cell, and then the pressure was reduced to obtain tablets of Reference Example 26.
参考例27
エチルセルロース(Ethocel standard 7 FP Premium、ダウケミカル製)13.5gとクエン酸トリエチル(Triethyl Citrate、東京化成製)1.5gをエタノール(エタノール99.5%、関東化学製)150gに溶解させ、スプレードライヤー(ミニスプレードライヤー B−290、ビュッヒ製、以下特に断りのない場合は同様)にて噴霧乾燥することでエチルセルロース/クエン酸トリエチル(9/1)噴霧乾燥品を得た。
直打用マンニトール(Parteck M100、メルク製)79.0w/w%にエチルセルロース/クエン酸トリエチル(9/1)噴霧乾燥品20.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて錠剤硬度22N、錠剤厚みが約3.9mmの錠剤を得た(錠剤直径8.5mm)。この錠剤を耐圧セルを用いて、二酸化炭素圧力6MPa、25℃で45分間処理後、減圧し参考例27の錠剤を得た。Reference Example 27
13.5 g of ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) and 1.5 g of triethyl citrate (Triethyl Citrate, manufactured by Tokyo Chemical Industry) are dissolved in 150 g of ethanol (ethanol 99.5%, manufactured by Kanto Chemical) and spray dryer. By spray-drying (mini spray dryer B-290, manufactured by Büch, hereinafter the same unless otherwise specified), an ethylcellulose / triethyl citrate (9/1) spray-dried product was obtained.
Ethyl cellulose / triethyl citrate (9/1) spray-dried product 20.0 w / w% was mixed with mannitol for direct hitting (Parteck M100, manufactured by Merck) 79.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and a tablet with a tablet hardness of 22 N and a tablet thickness of about 3.9 mm was obtained using a single tableting machine (tablet diameter 8.5 mm). This tablet was treated at a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a tablet of Reference Example 27.
参考例28
エチルセルロース(Ethocel standard 7 FP Premium、ダウケミカル製)11.25gとクエン酸トリエチル(Triethyl Citrate、東京化成製)3.75gをエタノール(エタノール99.5%、関東化学製)150gに溶解させ、スプレードライヤーにて噴霧乾燥することでエチルセルロース/クエン酸トリエチル(7.5/2.5)噴霧乾燥品を得た。
直打用マンニトール(Parteck M100、メルク製)79.0w/w%にエチルセルロース/クエン酸トリエチル(7.5/2.5)噴霧乾燥品20.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて錠剤硬度20N、錠剤厚みが約3.9mmの錠剤を得た(錠剤直径8.5mm)。この錠剤を耐圧セルを用いて、二酸化炭素圧力6MPa、25℃で45分間処理後、減圧し参考例28の錠剤を得た。Reference Example 28
11.25 g of ethylcellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) and 3.75 g of triethyl citrate (manufactured by Tokyo Chemical Industry) are dissolved in 150 g of ethanol (ethanol 99.5%, manufactured by Kanto Chemical) and spray dryer Spray dried product of ethyl cellulose / triethyl citrate (7.5 / 2.5) was obtained.
Ethylcellulose / triethyl citrate (7.5 / 2.5) spray-dried product 20.0 w / w% was mixed with mannitol for direct hitting (Parteck M100, manufactured by Merck) 79.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and a tablet having a tablet hardness of 20 N and a tablet thickness of about 3.9 mm was obtained using a single tableting machine (tablet diameter 8.5 mm). This tablet was treated at a carbon dioxide pressure of 6 MPa and 25 ° C. for 45 minutes using a pressure cell, and then the pressure was reduced to obtain a tablet of Reference Example 28.
試験例8
参考例26〜28の錠剤について、二酸化炭素処理前後の硬度をそれぞれ測定した。硬度は、錠剤硬度計(Tablet Hardness Tester、“Schleuniger”、Model 6D、Schleuniger社製)を用いて測定した。結果は表6に示す。Test Example 8
For the tablets of Reference Examples 26 to 28, the hardness before and after the carbon dioxide treatment was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 6.
表6の結果から、エチルセルロースに可塑剤を含有するスプレードライ品を使用した参考例27および28の錠剤においては、エチルセルロースのみの使用による効果よりも、より顕著な錠剤硬度の上昇が得られることを確認した。よって、参考例26〜28は本発明の実施例ともなりうる。 From the results of Table 6, it can be seen that in the tablets of Reference Examples 27 and 28 using a spray-dried product containing a plasticizer in ethyl cellulose, a more significant increase in tablet hardness can be obtained than the effect of using ethyl cellulose alone. confirmed. Therefore, Reference Examples 26 to 28 can be examples of the present invention.
実施例35
D−マンニトール(Pearitol 50C、ロケットジャパン製、以下特に断りが無い場合は同様)410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機(フローコーター FLO−1、フロイント産業/大河原製作所製、以下特に断りのない場合は同様)を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE(Eudragit EPO、エボニックデグサジャパン製、以後特に断りがなければ同様)10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機(HT−EXシリーズ、畑鐵工所製、以下特に断りが無い場合は同様)を用いて打錠圧約1kN/杵にて1錠あたり約170mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は11N(n=10)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力5MPa、25℃で5分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 35
D-mannitol (Pearitol 50C, manufactured by Rocket Japan, hereinafter the same unless otherwise specified) 410 g of copolyvidone (Kollidon VA64, manufactured by BASF Japan) 100 g of aqueous solution (10.0 w / w%) as a binder fluid bed granulator (Flow coater FLO-1, manufactured by Freund Sangyo / Okawara Seisakusho, the same applies hereinafter unless otherwise specified). A part of this granulated product is aminoalkyl methacrylate copolymer E (Eudragit EPO, manufactured by Evonik Degussa Japan, unless otherwise specified) 10.0 w / w%, crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5 0.0 w / w% was mixed. This mixture is mixed with magnesium stearate 1.0 w / w%, and a tableting pressure of about 1 kN / kg using a rotary tableting machine (HT-EX series, manufactured by Hata Seiko Co., Ltd., unless otherwise specified). Produced tablets of about 170 mg per tablet (tablet diameter 8.5 mm). The tablet hardness was 11 N (n = 10). The tablet was treated for 5 minutes at a carbon dioxide pressure of 5 MPa and 25 ° C. using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例36
実施例35の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で60分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 36
The tablet of Example 35 was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 60 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例37
実施例35の錠剤を耐圧セルを用いて、二酸化炭素圧力3MPa、25℃で840分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 37
The tablet of Example 35 was treated at a carbon dioxide pressure of 3 MPa and 25 ° C. for 840 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例38
実施例35の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、15℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 38
The tablet of Example 35 was treated at a carbon dioxide pressure of 4 MPa and 15 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例39
実施例35の錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、45℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 39
The tablet of Example 35 was treated at a carbon dioxide pressure of 4 MPa and 45 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例40
実施例35の錠剤を耐圧セルを用いて、二酸化炭素圧力3MPa、60℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 40
The tablet of Example 35 was treated at a carbon dioxide pressure of 3 MPa and 60 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例41
エフメルト(富士化学製)89.0w/w%、アミノアルキルメタクリレートコポリマーE1.0w/w%、コポリビドン(Kollidon VA64、BASFジャパン製)9.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1.5kN/杵にて1錠あたり170mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力3MPa、45℃で120分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 41
Fmelt (Fuji Chemical) 89.0 w / w%, aminoalkyl methacrylate copolymer E1.0 w / w%, and copolyvidone (Kollidon VA64, BASF Japan) 9.0 w / w% were mixed. This mixture was blended with magnesium stearate 1.0 w / w%, and a single tableting machine was used to produce 170 mg tablets (tablet diameter 8.5 mm) per tablet at a tableting pressure of about 1.5 kN / 杵. Tablet hardness was 12N (n = 3). The tablet was treated at a carbon dioxide pressure of 3 MPa and 45 ° C. for 120 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例42
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE7.5w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約2.5kN/杵にて1錠あたり約190mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は27N(n=2)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力3MPa、45℃で120分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 42
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E7.5 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 10.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 190 mg per tablet were produced at a tableting pressure of about 2.5 kN / kg using a single tableting machine (tablet diameter 8.5 mm). . Tablet hardness was 27N (n = 2). The tablet was treated at a carbon dioxide pressure of 3 MPa and 45 ° C. for 120 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例43
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE20.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)10.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約2.0kN/杵にて1錠あたり約176mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は37N(n=2)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力1MPa、35℃で840分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 43
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E20.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 10.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and a tablet of about 176 mg per tablet was produced at a tableting pressure of about 2.0 kN / kg using a single tableting machine (tablet diameter 8.5 mm). . Tablet hardness was 37N (n = 2). The tablets were treated using a pressure-resistant cell at a carbon dioxide pressure of 1 MPa and 35 ° C. for 840 minutes, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例44
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(5.0w/w%)50gとポビドン(Kollidon K30、BASFジャパン製)水溶液(5.0w/w%)50gの混液を結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機を用いて打錠圧約1.0kN/杵にて1錠あたり約171mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=10)であった。錠剤を耐圧セルを用いて、窒素圧力10MPaを加えた後、更に二酸化炭素圧力5.0MPa、25℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 44
D-mannitol (410 g) was mixed with 50 g of copolyvidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (5.0 w / w%) and povidone (Kollidon K30, manufactured by BASF Japan) 50 g (5.0 w / w%) as a combined solution. Granulated using a fluid bed granulator. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 171 mg per tablet were produced at a tableting pressure of about 1.0 kN / 杵 using a rotary tableting machine (tablet diameter 8.5 mm). . Tablet hardness was 12N (n = 10). The tablet was subjected to a nitrogen pressure of 10 MPa using a pressure cell, further treated with carbon dioxide pressure of 5.0 MPa and 25 ° C. for 45 minutes, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例45
実施例44の錠剤を耐圧セルを用いて、二酸化炭素圧力5.0MPaを加えた後、更に窒素圧力5.0MPaを加え、25℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 45
The tablet of Example 44 was added with a carbon dioxide pressure of 5.0 MPa using a pressure cell, further added with a nitrogen pressure of 5.0 MPa, treated at 25 ° C. for 45 minutes, and then decompressed to quickly disintegrate the tablet of the present invention. Got. The decompression speed condition was about 1 MPa / min.
実施例46
D−マンニトール410gをポビドン(Kollidon K30、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機を用いて打錠圧約1kN/杵にて1錠あたり約170mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は13N(n=10)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で30分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 46
410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. To this mixture, 1.0 w / w% magnesium stearate was blended, and tablets of about 170 mg per tablet were produced at a tableting pressure of about 1 kN / 杵 using a rotary tableting machine (tablet diameter 8.5 mm). Tablet hardness was 13N (n = 10). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 30 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例47
D−マンニトール320gを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(POVACOAT Type F、大同化成工業製)水溶液(5.0w/w%)80gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は16N(n=2)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で35分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 47
Using a fluidized bed granulator, 320 g of D-mannitol was combined with 80 g of an aqueous solution (5.0 w / w%) of polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer (POVACOAT Type F, manufactured by Daido Kasei Kogyo Co., Ltd.). Grained. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 180 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 16N (n = 2). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例48
D−マンニトール320gをヒドロキシプロピルセルロース(HPC−SSL、日本曹達製)水溶液(5.0w/w%)80gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=2)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 48
320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of an aqueous solution (5.0 w / w%) of hydroxypropylcellulose (HPC-SSL, manufactured by Nippon Soda) as a binder. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 180 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 12N (n = 2). The tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 45 minutes using a pressure cell and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例49
D−マンニトール320gをヒプロメロース(TC−5E、信越化学工業製)水溶液(5.0w/w%)80gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=2)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 49
320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of an aqueous solution of hypromellose (TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) (5.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 180 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 12N (n = 2). The tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 45 minutes using a pressure cell and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例50
D−マンニトール320gをポリビニルアルコール・ポリエチレングリコールグラフトコポリマー(Kollicoat IR、BASFジャパン製)水溶液(5.0w/w%)80gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=2)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 50
320 g of D-mannitol was granulated using a fluidized bed granulator using 80 g of an aqueous solution (5.0 w / w%) of polyvinyl alcohol / polyethylene glycol graft copolymer (Kollicoat IR, manufactured by BASF Japan) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 180 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 12N (n = 2). The tablet was treated at a carbon dioxide pressure of 4 MPa at 25 ° C. for 45 minutes using a pressure cell and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例51
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE9.0w/w%、低置換度ヒドロキシプロピルセルロース(L−HPC NBD−022、信越化学工業製)9.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約185mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は13N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で35分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 51
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. Aminoalkyl methacrylate copolymer E 9.0 w / w% and low-substituted hydroxypropyl cellulose (L-HPC NBD-022, manufactured by Shin-Etsu Chemical Co., Ltd.) 9.0 w / w% were mixed with a part of this granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 185 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 13N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例52
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスカルメロースナトリウム(Kiccolate ND−2HS、旭化成ケミカルズ製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で10分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 52
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and croscarmellose sodium (Kiccolate ND-2HS, manufactured by Asahi Kasei Chemicals) 5.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 180 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 12N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例53
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE9.0w/w%、部分アルファー化デンプン(PCS、旭化成ケミカルズ製)9.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は9N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で35分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 53
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. Aminoalkyl methacrylate copolymer E 9.0 w / w% and partially pregelatinized starch (PCS, manufactured by Asahi Kasei Chemicals) 9.0 w / w% were mixed with a part of this granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 180 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 9N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例54
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE9.0w/w%、カルボキシメチルスターチナトリウム(Primojel、DMV−Fonterra Excipients製)9.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約185mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は8N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で10分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 54
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. Aminoalkyl methacrylate copolymer E 9.0 w / w% and sodium carboxymethyl starch (Primojel, manufactured by DMV-Fonterra Experts) 9.0 w / w% were mixed with a part of the granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 185 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 8N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例55
D−マンニトール410gをコポリビドン(Kolidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、カルメロースカルシウム(ECG−505、五徳薬品製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約181mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は10N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で10分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 55
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kolidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and carmellose calcium (ECG-505, manufactured by Gotoku Pharmaceutical) 5.0 w / w%. To this mixture, magnesium stearate 1.0 w / w% was blended, and tablets of about 181 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 10N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例56
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE9.0w/w%、アルファー化デンプン(SWELSTAR PD−1、旭化成ケミカルズ製)9.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約184mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は8N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で35分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 56
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. Aminoalkyl methacrylate copolymer E 9.0 w / w% and pregelatinized starch (SWELSTAR PD-1, manufactured by Asahi Kasei Chemicals) 9.0 w / w% were mixed with a part of this granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 184 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 8N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 35 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例57
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE9.0w/w%、カルメロース(NS−300、五徳薬品製)9.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約181mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は11N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で10分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 57
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E 9.0 w / w% and carmellose (NS-300, manufactured by Gotoku Pharmaceutical) 9.0 w / w%. To this mixture, magnesium stearate 1.0 w / w% was blended, and tablets of about 181 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 11N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 10 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例58
D−マンニトール410gをポビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物7.59gにアセトアミノフェン(山本化学工業製)0.56g、アミノアルキルメタクリレートコポリマーE1.0g、クロスポビドン(Kollidon CL−F、BASFジャパン製)0.75gを混合した。この混合物にステアリン酸マグネシウム0.10gを配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は12N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で25分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 58
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of povidone (Kollidon VA64, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. Acetaminophen (manufactured by Yamamoto Chemical Co., Ltd.) 0.56 g, aminoalkyl methacrylate copolymer E 1.0 g, and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 0.75 g were mixed with 7.59 g of this granulated product. To this mixture, 0.10 g of magnesium stearate was blended, and tablets of about 180 mg per tablet were produced using a single tableting machine at a tableting pressure of about 1 kN / kg (tablet diameter 8.5 mm). Tablet hardness was 12N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例59
D−マンニトール410gをポビドン(Kollidon K30、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物7.04gにファモチジン(アステラス製薬製)1.11g、アミノアルキルメタクリレートコポリマーE1.0g、クロスポビドン(Kollidon CL−F、BASFジャパン製)0.75gを混合した。この混合物にステアリン酸マグネシウム0.10gを配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は16N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で25分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 59
410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. 7.01 g of this granulated product was mixed with 1.11 g of famotidine (manufactured by Astellas Pharma), 1.0 g of aminoalkyl methacrylate copolymer E, and 0.75 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan). To this mixture, 0.10 g of magnesium stearate was blended, and tablets of about 180 mg per tablet were produced using a single tableting machine at a tableting pressure of about 1 kN / kg (tablet diameter 8.5 mm). Tablet hardness was 16N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例60
D−マンニトール410gをポビドン(Kollidon K30、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物8.09gにタムスロシン塩酸塩(アステラス製薬製)0.056g、アミノアルキルメタクリレートコポリマーE1.0g、クロスポビドン(Kollidon CL−F、BASFジャパン製)0.75gを混合した。この混合物にステアリン酸マグネシウム0.10gを配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約180mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は17N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で25分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 60
410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. To this granulated product (8.99 g), 0.056 g of tamsulosin hydrochloride (manufactured by Astellas Pharma Inc.), 1.0 g of aminoalkyl methacrylate copolymer E, and 0.75 g of crospovidone (Kollidon CL-F, manufactured by BASF Japan) were mixed. To this mixture, 0.10 g of magnesium stearate was blended, and tablets of about 180 mg per tablet were produced using a single tableting machine at a tableting pressure of about 1 kN / kg (tablet diameter 8.5 mm). Tablet hardness was 17N (n = 3). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 25 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例61
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にHPMCAS(AQOAT AS−HF、信越化学工業製)20.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約176mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は25N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力5MPa、25℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 61
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. HPMCAS (AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) 20.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w% were mixed with a part of this granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 176 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 25N (n = 3). The tablet was treated at a carbon dioxide pressure of 5 MPa and 25 ° C. for 45 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例62
D−マンニトール410gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にHPMCAS(AQOAT AS−HF、信越化学工業製)15.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約176mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は25N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力5MPa、45℃で840分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 62
410 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of an aqueous solution of copolyvidone (Kollidon VA64, manufactured by BASF Japan) (10.0 w / w%) as a binding liquid. HPMCAS (AQOAT AS-HF, manufactured by Shin-Etsu Chemical Co., Ltd.) 15.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w% were mixed with a part of this granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 176 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). Tablet hardness was 25N (n = 3). The tablet was treated using a pressure cell at 540 minutes at a carbon dioxide pressure of 5 MPa and 45 ° C. and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例63
実施例62の錠剤を耐圧セルを用いて、二酸化炭素圧力5MPa、60℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 63
The tablet of Example 62 was treated at a carbon dioxide pressure of 5 MPa and 60 ° C. for 45 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例64
D−マンニトール410gをポビドン(Kollidon K30、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にエチルセルロース(Ethocel standard 7 FP Premium、ダウケミカル製)15.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)8.0w/w%、l-メントール(関東化学製)1.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約171mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は21N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力5MPa、60℃で45分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 64
410 g of D-mannitol was granulated using a fluidized bed granulator with 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. Part of this granulated product was ethyl cellulose (Ethocel standard 7 FP Premium, manufactured by Dow Chemical) 15.0 w / w%, crospovidone (Kollidon CL-F, manufactured by BASF Japan) 8.0 w / w%, l-menthol ( Manufactured by Kanto Chemical Co., Ltd.) 1.0 w / w% was mixed. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 171 mg per tablet were produced at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet diameter 8.5 mm). The tablet hardness was 21 N (n = 3). The tablet was treated at a carbon dioxide pressure of 5 MPa and 60 ° C. for 45 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例65
実施例35の錠剤を耐圧セルを用いて、二酸化炭素圧力3.5MPa、25℃で120分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 65
The tablet of Example 35 was treated for 120 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例66
実施例46の錠剤を耐圧セルを用いて、二酸化炭素圧力3.5MPa、25℃で120分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 66
The tablet of Example 46 was treated for 120 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例67
実施例44の錠剤を耐圧セルを用いて、二酸化炭素圧力3.5MPa、25℃で120分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 67
The tablet of Example 44 was treated at a carbon dioxide pressure of 3.5 MPa at 25 ° C. for 120 minutes using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例68
D−マンニトール415gをポビドン(Kollidon K30、BASFジャパン製)水溶液(5.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機を用いて打錠圧約1kN/杵にて1錠あたり約171mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は10N(n=10)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力4MPa、25℃で40分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 68
415 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (5.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. To this mixture, magnesium stearate 1.0 w / w% was blended, and tablets of about 171 mg per tablet were produced at a tableting pressure of about 1 kN / 杵 using a rotary tableting machine (tablet diameter 8.5 mm). Tablet hardness was 10N (n = 10). The tablet was treated at a carbon dioxide pressure of 4 MPa and 25 ° C. for 40 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
実施例69
D−マンニトール415gをポビドン(Kollidon K30、BASFジャパン製)水溶液(5.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物の一部にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、ロータリー打錠機を用いて打錠圧約1.8kN/杵にて1錠あたり約186mgの錠剤を製した(錠剤直径8.5mm)。錠剤硬度は19N(n=10)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力3.5MPa、25℃で90分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 69
415 g of D-mannitol was granulated using a fluidized bed granulator using 100 g of povidone (Kollidon K30, manufactured by BASF Japan) aqueous solution (5.0 w / w%) as a binding liquid. A part of this granulated product was mixed with aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w%. This mixture was mixed with magnesium stearate 1.0 w / w%, and tablets of about 186 mg per tablet were produced at a tableting pressure of about 1.8 kN / 約 using a rotary tableting machine (tablet diameter 8.5 mm). . Tablet hardness was 19N (n = 10). The tablet was treated for 90 minutes at a carbon dioxide pressure of 3.5 MPa and 25 ° C. using a pressure cell, and then decompressed to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
比較例2
実施例35の錠剤を大気下で、60℃で45分間の処理後、比較例2の錠剤を得た。Comparative Example 2
After treating the tablet of Example 35 under atmospheric pressure at 60 ° C. for 45 minutes, the tablet of Comparative Example 2 was obtained.
比較例3
実施例69の錠剤を大気下で、70℃で840分間の処理後、比較例3の錠剤を得た。Comparative Example 3
After the tablet of Example 69 was treated at 70 ° C. for 840 minutes in the air, the tablet of Comparative Example 3 was obtained.
比較例4
実施例70の錠剤を大気下で、70℃で840分間の処理後、比較例4の錠剤を得た。Comparative Example 4
After the tablet of Example 70 was treated at 70 ° C. for 840 minutes in the air, the tablet of Comparative Example 4 was obtained.
試験例9
実施例35〜69、比較例2〜4の錠剤について、硬度をそれぞれ測定した。硬度は、錠剤硬度計(Tablet Hardness Tester、“Schleuniger”、Model 6D、Schleuniger社製)を用いて測定した。結果は表7に示す。Test Example 9
Hardness was measured about the tablet of Examples 35-69 and Comparative Examples 2-4, respectively. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 7.
試験例10
実施例35〜69、比較例2〜4の錠剤について口腔内崩壊時間を測定した。口腔内崩壊時間は、口腔内崩壊試験機(トリコープテスタ、岡田精工社製)を用いて測定した。結果は表7に示す。Test Example 10
The oral disintegration time was measured for the tablets of Examples 35 to 69 and Comparative Examples 2 to 4. The oral disintegration time was measured using an oral disintegration tester (Trichop Tester, Okada Seiko Co., Ltd.). The results are shown in Table 7.
試験例11
実施例35〜69、比較例2〜4の錠剤について厚みを測定した(n=5)。錠剤の厚みは、デジマチックインジケータ(Mitutoyo Absolute、ミツトヨ社製)を用いて測定した。結果は表7に示す。Test Example 11
The thicknesses of the tablets of Examples 35 to 69 and Comparative Examples 2 to 4 were measured (n = 5). The thickness of the tablet was measured using a Digimatic Indicator (Mitutoyo Absolute, manufactured by Mitutoyo Corporation). The results are shown in Table 7.
試験例12
実施例65〜69、比較例3〜4の速崩壊性錠剤をPTPシート(34×111mm、7錠×2列/枚)に包装し、以下の条件で落下試験を行った。
・落下高さ:150cm
・落下繰り返し回数:10回
・試験を行うPTPシート数:10枚
・PTPシートの向き:薬剤収納部(ポケット)を上とする
・破損率:(割れ及び/または欠けが発生した速崩壊性錠剤数)/140×100
結果は表7に示す。Test Example 12
The rapidly disintegrating tablets of Examples 65 to 69 and Comparative Examples 3 to 4 were packaged in PTP sheets (34 × 111 mm, 7 tablets × 2 rows / sheet), and a drop test was performed under the following conditions.
-Drop height: 150cm
・ Number of repeated drops: 10 times ・ Number of PTP sheets to be tested: 10 sheets ・ PTP sheet orientation: drug storage part (pocket) on top ・ Fracture rate: (Fast disintegrating tablets with cracks and / or chips) Number) / 140 × 100
The results are shown in Table 7.
表7の結果より、二酸化炭素圧力処理によるアミノアルキルメタクリレートコポリマーEやHPMCASおよびエチルセルロースの相変化による架橋を利用することで、錠剤硬度を高めた本発明の速崩壊性錠剤を得ることができた。
詳細には実施例35〜43においては、アミノアルキルメタクリレートコポリマーEの添加量、二酸化炭素処理圧力、処理温度、処理時間を適切に組み合わせることで本発明の速崩壊性錠剤が得られることを確認した。比較例2においては大気下で60℃45分加熱処理を施したが、錠剤硬度の上昇は認められていなかった。その一方で、実施例35においては二酸化炭素圧力5MPa下で25℃5分の処理をすることで顕著な錠剤硬度の上昇を確認したことから、室温付近のマイルドな温度環境下でも錠剤硬度上昇が達成されることが確認できた。
実施例44〜45においては、二酸化炭素を窒素と併用することで同様に錠剤硬度の上昇を誘導できることが確認された。本結果から、本発明には二酸化炭素に加えてその他のガスも利用できる可能性が示された。
実施例46〜50においては造粒工程に使用される結合剤としてポビドンや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といった各種汎用結合剤が使用可能であることが示された。
実施例51〜57においては、崩壊剤として低置換度ヒドロキシルプロピセルロース、クロスカルメロースナトリウムや部分アルファー化デンプンといった各種汎用崩壊剤を利用することで本発明の速崩壊性錠剤を得られることが示された。
実施例58〜60においては、モデル薬物を含有する製剤においても同様の性能を有する速崩壊性錠剤を得られることが確認された。
実施例61〜64においては、HPMCASあるいはエチルセルロースと二酸化炭素圧力処理を組み合わせることでもアミノアルキルメタクリレートコポリマーE同様に錠剤硬度を高めることができ、本発明の速崩壊性錠剤が得られることが示された。このことから、参考例で二酸化炭素圧力によって錠剤硬度を高める機能を有した成分に代表される添加剤群についても、適切な処方設計をすることで本発明の速崩壊性錠剤が得られる可能性が示された。
実施例65〜69については落下試験における破損率を評価したがいずれも0〜0.7%の非常に低い破損率を確認した。その一方で、実施例68、69と同一処方の速崩壊性錠剤を二酸化炭素ではなく加熱処理によって同程度の錠剤硬度に高めた比較例3、4については、2.1〜5%と相対的に高い破損率を示した。本発明の速崩壊性錠剤は耐破損性にも優れることが明らかとなった。From the results shown in Table 7, the rapidly disintegrating tablet of the present invention with increased tablet hardness could be obtained by utilizing cross-linking by phase change of aminoalkyl methacrylate copolymer E, HPMCAS and ethyl cellulose by carbon dioxide pressure treatment.
Specifically, in Examples 35 to 43, it was confirmed that the rapidly disintegrating tablet of the present invention was obtained by appropriately combining the addition amount of the aminoalkyl methacrylate copolymer E, the carbon dioxide treatment pressure, the treatment temperature, and the treatment time. . In Comparative Example 2, heat treatment was performed at 60 ° C. for 45 minutes in the atmosphere, but no increase in tablet hardness was observed. On the other hand, in Example 35, a significant increase in tablet hardness was confirmed by treatment at 25 ° C. for 5 minutes under a carbon dioxide pressure of 5 MPa. Therefore, the tablet hardness increased even in a mild temperature environment near room temperature. It was confirmed that it was achieved.
In Examples 44 to 45, it was confirmed that an increase in tablet hardness could be similarly induced by using carbon dioxide in combination with nitrogen. From this result, it was shown that the present invention may use other gases in addition to carbon dioxide.
In Examples 46 to 50, it was shown that various general-purpose binders such as povidone and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer can be used as the binder used in the granulation step.
In Examples 51-57, it is shown that the rapidly disintegrating tablet of the present invention can be obtained by using various general-purpose disintegrating agents such as low-substituted hydroxylpropycellulose, croscarmellose sodium and partially pregelatinized starch as disintegrating agents. It was done.
In Examples 58 to 60, it was confirmed that a rapidly disintegrating tablet having the same performance can be obtained even in a preparation containing a model drug.
In Examples 61 to 64, it was shown that tablet hardness can be increased similarly to aminoalkyl methacrylate copolymer E by combining HPMCAS or ethyl cellulose with carbon dioxide pressure treatment, and the fast disintegrating tablet of the present invention can be obtained. . From this, it is possible that the rapidly disintegrating tablet of the present invention can be obtained by appropriately designing the additive group represented by the component having the function of increasing the tablet hardness by the carbon dioxide pressure in the reference example. It has been shown.
About Examples 65-69, although the breakage rate in the drop test was evaluated, all confirmed a very low breakage rate of 0-0.7%. On the other hand, in Comparative Examples 3 and 4 in which fast disintegrating tablets having the same formulation as in Examples 68 and 69 were increased to the same degree of tablet hardness by heat treatment instead of carbon dioxide, relative to 2.1 to 5% Showed a high damage rate. It was revealed that the fast disintegrating tablet of the present invention is excellent in breakage resistance.
実施例70
コハク酸ソリフェナシン(アステラス製薬製)を含有し、苦みマスキング機能を有する微粒子80.7gをコポリビドン(Kollidon VA64、BASFジャパン製)水溶液(10.0w/w%)100gを結合液として流動層造粒機を用いて造粒した。この造粒物にアミノアルキルメタクリレートコポリマーE10.0w/w%、クロスポビドン(Kollidon CL−F、BASFジャパン製)5.0w/w%を混合した。この混合物にステアリン酸マグネシウム1.0w/w%を配合し、単発打錠機を用いて打錠圧約1kN/杵にて1錠あたり約150mgの錠剤(コハク酸ソリフェナシン含量5mg)を製した(錠剤直径7.5mm)。錠剤硬度は10N(n=3)であった。錠剤を耐圧セルを用いて、二酸化炭素圧力5MPa、35℃で30分間処理後、減圧し、本発明の速崩壊性錠剤を得た。なお減圧速度条件は、約1MPa/分で行った。Example 70
Fluidized bed granulator containing solifenacin succinate (manufactured by Astellas Pharma Inc.), 80.7 g of fine particles having a bitter masking function and 100 g of copolyvidone (Kollidon VA64, BASF Japan) aqueous solution (10.0 w / w%) as a binding liquid. Was granulated. Aminoalkyl methacrylate copolymer E10.0 w / w% and crospovidone (Kollidon CL-F, manufactured by BASF Japan) 5.0 w / w% were mixed with this granulated product. This mixture was mixed with magnesium stearate 1.0 w / w%, and about 150 mg tablets (solifenacin succinate content 5 mg) per tablet were prepared at a tableting pressure of about 1 kN / kg using a single tableting machine (tablet Diameter 7.5 mm). Tablet hardness was 10N (n = 3). The tablet was treated at a carbon dioxide pressure of 5 MPa and 35 ° C. for 30 minutes using a pressure cell, and then the pressure was reduced to obtain a rapidly disintegrating tablet of the present invention. The decompression speed condition was about 1 MPa / min.
比較例5
実施例70の錠剤を大気下で、70℃で840分間加熱処理を施して比較例5の錠剤を得た。Comparative Example 5
The tablet of Example 70 was heat-treated at 70 ° C. for 840 minutes in the air to obtain the tablet of Comparative Example 5.
試験例13
実施例70の速崩壊性錠剤および比較例5の錠剤について、硬度をそれぞれ測定した。硬度は、錠剤硬度計(Tablet Hardness Tester、“Schleuniger”、Model 6D、Schleuniger社製)を用いて測定した。結果は表8に示す。Test Example 13
The hardness of each of the rapidly disintegrating tablet of Example 70 and the tablet of Comparative Example 5 was measured. The hardness was measured using a tablet hardness tester (Table Hardness Tester, “Schleuniger”, Model 6D, manufactured by Schleuniger). The results are shown in Table 8.
試験例14
実施例70で使用した苦みマスキング粒子、実施例70の速崩壊性錠剤、および比較例5の錠剤について溶出試験を行った。溶出試験装置はDissolution tester NTR−6100A(富山化学製)を使用し、コハク酸ソリフェナシンの溶出率については液体クロマトグラフィー(島津製作所製)を用いて測定した。試験条件を下記に示す。
・パドル法 50rpm
・試験液:日局崩壊試験第2液(pH6.8) 900mL
・試験液温度:37℃±0.5℃
・サンプリングタイム:2分、30分
結果は表8に示す。Test Example 14
The bitter masking particles used in Example 70, the fast disintegrating tablet of Example 70, and the tablet of Comparative Example 5 were subjected to a dissolution test. Dissolution tester NTR-6100A (manufactured by Toyama Chemical) was used as the dissolution test apparatus, and the dissolution rate of solifenacin succinate was measured using liquid chromatography (manufactured by Shimadzu Corporation). Test conditions are shown below.
・ Paddle method 50rpm
Test liquid: JP disintegration test second liquid (pH 6.8) 900 mL
・ Test solution temperature: 37 ℃ ± 0.5 ℃
Sampling time: 2 minutes and 30 minutes are shown in Table 8.
試験例15
実施例70で使用した苦みマスキング粒子、実施例70の速崩壊性錠剤、および比較例5の錠剤について、コハク酸ソリフェナシン及びその分解物の総量に対する、最も量が多い分解物の生成量(以下、主分解物の生成量と略すことがある)、及びコハク酸ソリフェナシン及びその分解物の総量に対する総分解物量(以下、分解物総量と略すことがある)を測定した。結果は表8に示す。Test Example 15
About the bitterness masking particles used in Example 70, the fast disintegrating tablet of Example 70, and the tablet of Comparative Example 5, the amount of the most decomposed product (hereinafter referred to as “solifenacin succinate” and its decomposed product) The amount of the main decomposition product may be abbreviated), and the total amount of decomposition product relative to the total amount of solifenacin succinate and its decomposition product (hereinafter sometimes abbreviated as total decomposition product) was measured. The results are shown in Table 8.
表8より、実施例70の速崩壊性錠剤は、苦みマスキング粒子と同程度の主分解物の生成量、及び分解物総量であったのに対し、比較例5の錠剤は、顕著な増加が認められた。 From Table 8, the rapidly disintegrating tablet of Example 70 had the same amount of main degradation products as the bitterness masking particles and the total amount of degradation products, whereas the tablet of Comparative Example 5 showed a significant increase. Admitted.
本発明は、流通工程で発生する錠剤の割れ欠けを改善し、温度または湿度に不安定な薬物や、難溶性薬物からなる固体分散体粒子、苦味マスキング粒子、徐放性粒子等の薬物の特性に基づく所望の機能を付与した機能性粒子に付与された各種機能を十分に維持したうえで、速崩壊性錠剤(特に、口腔内崩壊錠)の提供が可能である。
以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。The present invention improves the tablet chipping that occurs in the distribution process, and is characterized by drugs such as drugs that are unstable in temperature or humidity, solid dispersion particles consisting of poorly soluble drugs, bitterness masking particles, sustained release particles, etc. It is possible to provide a rapidly disintegrating tablet (particularly an orally disintegrating tablet) while sufficiently maintaining various functions imparted to the functional particles imparted with a desired function based on the above.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.
Claims (25)
(2)(1)の混合物を圧縮成形して錠剤を調製する工程、及び
(3)(2)の錠剤を、超臨界もしくは亜臨界状態にある二酸化炭素または液体もしくは気体二酸化炭素で処理する工程
を含む、速崩壊性錠剤の製造方法。(1) A step of mixing a drug with a substance having a function of a binder by treatment with carbon dioxide in a supercritical or subcritical state or liquid or gaseous carbon dioxide,
(2) A step of preparing a tablet by compression molding the mixture of (1), and (3) a step of treating the tablet of (2) with carbon dioxide in a supercritical or subcritical state or with liquid or gaseous carbon dioxide. A method for producing a rapidly disintegrating tablet.
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