JP2014141469A - Layering particle - Google Patents
Layering particle Download PDFInfo
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- JP2014141469A JP2014141469A JP2013266198A JP2013266198A JP2014141469A JP 2014141469 A JP2014141469 A JP 2014141469A JP 2013266198 A JP2013266198 A JP 2013266198A JP 2013266198 A JP2013266198 A JP 2013266198A JP 2014141469 A JP2014141469 A JP 2014141469A
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- JP
- Japan
- Prior art keywords
- ibuprofen
- containing layer
- layer
- layering
- melting point
- 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
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- 239000002245 particle Substances 0.000 title claims abstract description 139
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims abstract description 192
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 192
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 63
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 63
- 239000008187 granular material Substances 0.000 claims abstract description 60
- 238000002844 melting Methods 0.000 claims abstract description 58
- 230000008018 melting Effects 0.000 claims abstract description 58
- 238000005469 granulation Methods 0.000 claims abstract description 54
- 230000003179 granulation Effects 0.000 claims abstract description 53
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- 239000000843 powder Substances 0.000 claims abstract description 40
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- SBNKFTQSBPKMBZ-UHFFFAOYSA-N ethenzamide Chemical compound CCOC1=CC=CC=C1C(N)=O SBNKFTQSBPKMBZ-UHFFFAOYSA-N 0.000 claims description 15
- 229960002373 loxoprofen Drugs 0.000 claims description 15
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical compound O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 claims description 15
- HOKDBMAJZXIPGC-UHFFFAOYSA-N Mequitazine Chemical compound C12=CC=CC=C2SC2=CC=CC=C2N1CC1C(CC2)CCN2C1 HOKDBMAJZXIPGC-UHFFFAOYSA-N 0.000 claims description 14
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 21
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- 239000011259 mixed solution Substances 0.000 description 14
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 12
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- 239000003814 drug Substances 0.000 description 9
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- 230000000694 effects Effects 0.000 description 3
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- 229920001218 Pullulan Polymers 0.000 description 2
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- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 2
- 230000001387 anti-histamine Effects 0.000 description 2
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- 229960004949 glycyrrhizic acid Drugs 0.000 description 2
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 2
- 235000019410 glycyrrhizin Nutrition 0.000 description 2
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- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- DBAKFASWICGISY-BTJKTKAUSA-N Chlorpheniramine maleate Chemical compound OC(=O)\C=C/C(O)=O.C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 DBAKFASWICGISY-BTJKTKAUSA-N 0.000 description 1
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- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
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- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical compound [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
本発明は、固形製剤の分野に関し、詳しくは、有効成分としてイブプロフェン及びイブプロフェンの融点降下を生じる成分を含有するレイヤリング粒子に関する。 The present invention relates to the field of solid preparations, and in particular, relates to layering particles containing ibuprofen and an ingredient that causes a melting point drop of ibuprofen as active ingredients.
頭痛薬や総合感冒薬の有効成分として汎用されているイブプロフェンは融点７５〜７７℃の低融点薬物であり、さらに酸性基を有するためアルカリ性薬物と配合すると高湿度条件下において吸湿し塩を形成することが知られている。特に抗ヒスタミン薬、解熱鎮痛薬、消化薬と配合すると色調変化や湿潤化といった変化を認めるものが多い（非特許文献１参照）。同じく頭痛薬や総合感冒薬の有効成分として知られるエテンザミドなど多くの成分と混在すると融点降下を引き起こすことが知られている（非特許文献２参照）。有効成分の中でも含有量が多いイブプロフェンの他の成分との相互作用は、粉体のハンドリングを著しく困難にし、付着や凝集を引き起こす他、製品化後に変色等の問題を招来することがあった。 Ibuprofen, which is widely used as an active ingredient in headache and general cold medicine, is a low-melting-point drug with a melting point of 75-77 ° C, and further has an acidic group, so when mixed with an alkaline drug, it absorbs moisture under high humidity conditions to form a salt. It is known. In particular, when combined with antihistamines, antipyretic analgesics, and digestives, there are many cases in which changes such as color change and wetting are recognized (see Non-Patent Document 1). Similarly, it is known to cause a melting point drop when mixed with many components such as ethenamide, which is known as an active ingredient of a headache drug or a general cold medicine (see Non-Patent Document 2). The interaction of ibuprofen, which has a high content among the active ingredients, with other ingredients makes powder handling extremely difficult, causes adhesion and aggregation, and may cause problems such as discoloration after commercialization.
そのため、有効成分としてイブプロフェン及びイブプロフェンの融点降下を生じる成分（以下、適宜に「融点降下成分」と略記する。）を配合した固形製剤では、これらを異なる顆粒等に配合し、二重錠や多層錠として提供すれば、これら成分が同一の製剤中に配合されていても、直接の接触を回避してイブプロフェンの融点降下を防止することが可能であった（非特許文献３参照）。 For this reason, in the case of solid preparations that contain ibuprofen and a component that causes a melting point drop of ibuprofen (hereinafter abbreviated as “melting point lowering component” where appropriate) as active ingredients, these are blended into different granules, etc. If provided as a tablet, even if these components were blended in the same preparation, it was possible to avoid a direct contact and prevent a melting point drop of ibuprofen (see Non-Patent Document 3).
また、イブプロフェン及び融点降下成分のほか、さらにトラネキサム酸やジメモルファンリン酸塩、クレゾールスルホン酸カリウム，グリチルリチン酸等の他の有効成分を同時配合することで変色を抑制する技術が知られている（特許文献１〜３参照）。 In addition to ibuprofen and a melting point lowering component, a technology for suppressing discoloration by simultaneously blending other active ingredients such as tranexamic acid, dimemorphan phosphate, potassium cresolsulfonate, glycyrrhizic acid is known. (See Patent Documents 1 to 3).
しかしながら、散剤、顆粒剤等を提供する場合には、単に融点降下成分を異なる顆粒等に配合しただけでは充分に接触を回避できず、イブプロフェンの融点降下を充分に抑制することができなかった。 However, in the case of providing powders, granules, etc., simply blending the melting point lowering component into different granules, etc. cannot sufficiently avoid contact, and the melting point drop of ibuprofen cannot be sufficiently suppressed.
また他の有効成分を添加する手法により安定化を図った場合には、添加した成分により所望以外の好ましくない作用が発現し、副作用を生じる恐れがある。 In addition, when stabilization is achieved by a method of adding other active ingredients, the added ingredients may cause undesirable effects other than desired, which may cause side effects.
これに対し、常套手段としてはイブプロフェン及び融点降下成分を異なる顆粒等に配合した後、少なくともその何れかをフィルムコーティングすることが考えられる（特許文献４及び５参照）。 On the other hand, as a conventional means, it is conceivable to mix ibuprofen and a melting point lowering component into different granules and then film-coat at least one of them (see Patent Documents 4 and 5).
そこで、フィルム基剤として最もポピュラーなヒプロメロース（ヒドロキシプロピルメチルセルロース）を採択し、イブプロフェン及び融点降下成分としてエテンザミドが混在する場合のイブプロフェンの融点降下について検討したところ、ヒプロメロースではイブプロフェンの融点降下を充分に抑制できないことが判明した。 Therefore, the most popular hypromellose (hydroxypropyl methylcellulose) was selected as the film base, and the melting point drop of ibuprofen when ibuprofen and ethenzamide were mixed as a melting point lowering component was investigated. Hypromellose sufficiently suppressed the melting point drop of ibuprofen. It turned out not to be possible.
本発明の課題は、有効成分であるイブプロフェンと融点降下成分を同一の顆粒等に配合する手段としてレイヤリング粒子（顆粒）を採択し、イブプロフェンと融点降下成分をレイヤリング粒子の異なる層に配するとともに、これらの層の間に他の成分を含む層（以下、適宜に「中間層」と略記する。）を配し、さらにイブプロフェンの融点降下を抑制するのに最も適した造粒溶剤を選定して、保存安定性や服用性、溶出性に優れた散剤、顆粒剤等のイブプロフェン及び融点降下成分含有固形製剤を提供することである。 The object of the present invention is to adopt layering particles (granules) as a means for blending the active ingredient ibuprofen and the melting point lowering component into the same granule, etc., and arranging ibuprofen and the melting point lowering component in different layers of the layering particles. At the same time, a layer containing other components (hereinafter abbreviated as “intermediate layer” as appropriate) is arranged between these layers, and the most suitable granulation solvent for suppressing the melting point drop of ibuprofen is selected. Thus, it is to provide a solid preparation containing ibuprofen and a melting point lowering component such as powders and granules excellent in storage stability, ingestion and dissolution.
本発明者らは、上記課題を解決すべく鋭意検討した結果、レイヤリング粒子のイブプロフェン含有層と融点降下成分含有層の間に中間層を配し、さらに中間層を造粒する際に用いる造粒溶剤としてポリビニルアルコール（以下、適宜に「ＰＶＡ」と略記する。）を含む溶液を採択した場合にのみイブプロフェンの融点降下を効果的に抑制しうることを見出した。 As a result of intensive studies to solve the above problems, the present inventors have arranged an intermediate layer between the ibuprofen-containing layer and the melting point lowering component-containing layer of the layering particles, and further used the granulation used for granulating the intermediate layer. It has been found that the drop in melting point of ibuprofen can be effectively suppressed only when a solution containing polyvinyl alcohol (hereinafter abbreviated as “PVA” where appropriate) is adopted as a granular solvent.
かかる知見により得られた本発明の態様は次のとおりである。
（１）核粒子と該核粒子を覆う３以上の層からなるレイヤリング粒子であって、イブプロフェン含有層とイブプロフェンの融点降下を生じる成分含有層との間にポリビニルアルコール含有層（ただし、ポリビニルアルコールを含有するフィルム層である場合を除く。）を有することを特徴とするレイヤリング粒子。
（２）内側から順に、（ａ）核粒子、（ｂ）イブプロフェン含有層、（ｃ）ポリビニルアルコール含有層（ただし、ポリビニルアルコールを含有するフィルム層である場合を除く。）、及び（ｄ）イブプロフェンの融点降下を生じる成分含有層、をもって構成されるレイヤリング粒子。
（３）イブプロフェンの融点降下を生じる成分が、エテンザミド、ロキソプロフェン、メキタジン及びこれらの塩類から選ばれる１種又は２種以上である前記（１）又は（２）に記載のレイヤリング粒子。
（４）ポリビニルアルコール含有層がポリビニルアルコールを含む造粒溶剤で造粒された層である前記（１）〜（３）のレイヤリング粒子。
（５）散剤、顆粒剤、微粒剤又はカプセル剤である前記（１）〜（４）のレイヤリング粒子。
The embodiments of the present invention obtained from such findings are as follows.
(1) Layering particles composed of core particles and three or more layers covering the core particles, and a polyvinyl alcohol-containing layer (provided that polyvinyl alcohol is interposed between the ibuprofen-containing layer and the component-containing layer that causes a melting point drop of ibuprofen) Except for the case of a film layer containing).
(2) In order from the inside, (a) core particles, (b) an ibuprofen-containing layer, (c) a polyvinyl alcohol-containing layer (except for a film layer containing polyvinyl alcohol), and (d) ibuprofen. A layering particle comprising a component-containing layer that causes a melting point drop of.
(3) The layering particle according to (1) or (2), wherein the component that causes a melting point decrease of ibuprofen is one or more selected from etenzamide, loxoprofen, mequitazine, and salts thereof.
(4) The layering particles according to (1) to (3), wherein the polyvinyl alcohol-containing layer is a layer granulated with a granulation solvent containing polyvinyl alcohol.
(5) The layering particles according to (1) to (4), which are powders, granules, fine granules, or capsules.
本発明により、有効成分としてイブプロフェンと融点降下成分を配合した散剤、顆粒剤等の固形製剤を提供することが可能となった。また、レイヤリング粒子においてイブプロフェン含有層の外側に中間層及び融点降下成分含有層を配することでイブプロフェンに起因する昇華や苦味も抑制され、保存安定性や服用性に優れた固形製剤として提供することが可能となった。 According to the present invention, it has become possible to provide solid preparations such as powders and granules containing ibuprofen and a melting point lowering component as active ingredients. In addition, by providing an intermediate layer and a melting point lowering component-containing layer on the outside of the ibuprofen-containing layer in the layering particles, sublimation and bitterness caused by ibuprofen are suppressed, and provided as a solid preparation excellent in storage stability and ingestion It became possible.
本発明では、有効成分であるイブプロフェンと融点降下成分は同一のレイヤリング粒子中の異なる層に配するとともに、イブプロフェン含有層と融点降下成分含有層との間には必ずＰＶＡを含む造粒溶剤で造粒された中間層を設ける必要があり、この中間層は単にＰＶＡを含有するフィルム層とは異なるものである。 In the present invention, the active ingredient ibuprofen and the melting point lowering component are arranged in different layers in the same layering particle, and a granulating solvent containing PVA is always used between the ibuprofen containing layer and the melting point lowering component containing layer. It is necessary to provide a granulated intermediate layer, which is different from a film layer that simply contains PVA.
「イブプロフェンの融点降下を生じる成分（融点降下成分）」とは、イブプロフェンと混在することによりイブプロフェンの融点降下を引き起こす成分であり、例えば、エテンザミドやロキソプロフェンナトリウム水和物等の解熱鎮痛成分やカルビノキサミンマレイン酸塩やクロルフェニラミンマレイン酸塩、メキタジン等の抗ヒスタミン成分、デキストロメトルファン臭化水素酸塩やノスカピン等の鎮咳去痰成分の他、ビスイブチアミン等のビタミン類が挙げられる。 “Components that cause melting point depression of ibuprofen (melting point depression component)” are components that cause melting point depression of ibuprofen when mixed with ibuprofen, such as antipyretic analgesic components such as ethenamide and loxoprofen sodium hydrate, and carbinoxyl. In addition to antihistamine components such as samine maleate, chlorpheniramine maleate and mequitazine, antitussive expectorant components such as dextromethorphan hydrobromide and noscapine, and vitamins such as bisibuthiamine.
「レイヤリング粒子」とは、「核粒子（医薬品に適用可能な基剤からなる核）」に有効成分の他に賦形剤等を配合した粉体を遠心転動造粒等の湿式造粒を経て被覆し調製された幾何平均粒子径２００〜８５０μｍの固形の製剤粒子である。 "Layering particles" refers to wet granulation such as centrifugal rolling granulation of powders containing excipients in addition to active ingredients in "nuclear particles (cores consisting of bases applicable to pharmaceuticals)" It is a solid preparation particle having a geometric average particle diameter of 200 to 850 μm prepared by coating via
本発明では、イブプロフェンと融点降下成分は同一のレイヤリング粒子中の異なる層に配するとともに、イブプロフェン含有層と融点降下成分含有層との間には必ずＰＶＡを含む造粒溶剤で造粒された中間層を設ける必要があるので、レイヤリング粒子としては、核粒子の外殻に少なくとも３層以上のレイヤリング層を有することになる。 In the present invention, the ibuprofen and the melting point lowering component are arranged in different layers in the same layering particle, and the ibuprofen-containing layer and the melting point lowering component-containing layer are always granulated with a granulating solvent containing PVA. Since it is necessary to provide an intermediate layer, the layering particles have at least three or more layering layers on the outer shell of the core particles.
レイヤリング粒子は、内側から順に、核粒子と３層以上のレイヤリング層をもって構成され、イブプロフェンと融点降下成分を異なるレイヤリング層に配する他、両層の間には単なるフィルム層とは異なるＰＶＡを造粒溶剤として造粒されたＰＶＡ含有層を有するのが特徴である。もっとも、イブプロフェン含有層を外殻に配するとイブプロフェンに起因する昇華を抑え、刺激のある苦味をマスキングするためにさらにその外側にフィルム層等を設ける必要があるので、レイヤリング粒子をできうる限り小さくし、安価に、効率よく調製するには、内側から順に、（ａ）核粒子、（ｂ）イブプロフェン含有層、（ｃ）ポリビニルアルコール含有層（ただし、ポリビニルアルコールを含有するフィルム層である場合を除く。）、及び（ｄ）融点降下成分含有層、をもって構成されるのがもっとも好ましい態様である。 The layering particles are composed of core particles and three or more layering layers in order from the inside. In addition to arranging ibuprofen and a melting point lowering component in different layering layers, the layers are different from simple film layers. It is characterized by having a PVA-containing layer granulated using PVA as a granulating solvent. However, if the ibuprofen-containing layer is placed in the outer shell, it is necessary to provide a film layer etc. on the outside to suppress sublimation caused by ibuprofen and mask the bitterness with irritation. In order to prepare efficiently at low cost, (a) core particles, (b) ibuprofen-containing layer, (c) polyvinyl alcohol-containing layer (however, a film layer containing polyvinyl alcohol) And (d) a melting point lowering component-containing layer is the most preferred embodiment.
なお、服用性等を考慮し、レイヤリング粒子の最外殻に水溶性高分子等を含有するフィルム層を設けることは差し支えない。 In consideration of ingestion and the like, a film layer containing a water-soluble polymer or the like may be provided on the outermost shell of the layering particles.
「核粒子」としては粒度の揃ったものが好ましく、例えばセルフィア（商品名：旭化成ケミカルズ製）やノンパレル（商品名：フロイント産業製）など、結晶セルロースや糖類を基剤として調製された球形粒子の他、精製白糖等の糖類からなる微細な結晶が挙げられる。これらの核粒子の大きさは、造粒性と服用性の観点から、１００μｍ〜１ｍｍであり、１００μｍ〜８５０μｍが好ましい。 “Nucleic particles” preferably have a uniform particle size. For example, spherical particles prepared based on crystalline cellulose or saccharides such as SELPHYA (trade name: manufactured by Asahi Kasei Chemicals) and non-parrel (trade name: manufactured by Freund Industries). In addition, there are fine crystals composed of sugars such as purified white sugar. The size of these core particles is 100 μm to 1 mm, preferably 100 μm to 850 μm, from the viewpoints of granulation properties and ingestibility.
核粒子に有効成分等を付着させ、レイヤリング層を設ける方法としては、遠心転動造粒機（商品名：ＣＦ−３６０；フロイント産業製）、転動流動層造粒機（商品名：ＭＰ−０１；パウレック製）またはワースターコラム型の流動層コーティング機（商品名：ＧＰＣＧ−１；グラット製）などを用いた湿式造粒法が挙げられるが、好ましいのは遠心転動造粒機を用いた遠心転動造粒法である。 As a method of attaching an active ingredient or the like to the core particles and providing a layering layer, a centrifugal rolling granulator (trade name: CF-360; manufactured by Freund Sangyo), a rolling fluidized bed granulator (trade name: MP) -01; manufactured by Paulek) or a Wurster column type fluidized bed coating machine (trade name: GPCG-1; manufactured by Glatt). It is the centrifugal rolling granulation method used.
「イブプロフェン含有層」とは、イブプロフェンの他、イブプロフェンとの相互作用が軽微な各種有効成分や医薬品に適用可能な賦形剤を混合した粉体を、結合溶剤を噴霧しながら被覆し形成した薬物含有レイヤリング層であり、イブプロフェン含有層における有効成分の含有率は５０〜８０質量％が好ましい。イブプロフェン含有層の造粒に用いられる結合剤としては、イブプロフェンとの相互作用や溶出性への影響が軽微であるヒプロメロース（ＨＰＭＣ）やＰＶＡ，プルランが好ましく、造粒溶剤の濃度は通常１〜２０ｗ/ｗ％である。また、造粒溶剤は水性溶液であればよく、水の他、必要に応じて水と混和するアルコール等を加えてもよい。 "Ibuprofen-containing layer" is a drug formed by coating powders mixed with various active ingredients that have little interaction with ibuprofen and excipients applicable to pharmaceuticals while spraying a binding solvent. The content of the active ingredient in the ibuprofen-containing layer is preferably 50 to 80% by mass. The binder used for granulation of the ibuprofen-containing layer is preferably hypromellose (HPMC), PVA, or pullulan, which has a slight effect on the interaction and dissolution properties with ibuprofen, and the concentration of the granulating solvent is usually 1 to 20 w. / w%. Moreover, the granulation solvent should just be an aqueous solution, You may add alcohol etc. which are miscible with water other than water as needed.
「イブプロフェンの融点降下を生じる成分（融点降下成分）含有層」とは、エテンザミドの他、イブプロフェンの融点降下を生じる有効成分や医薬品に適用可能な賦形剤を混合した粉体を、結合溶剤を噴霧しながら被覆し形成した薬物含有レイヤリング層であり、融点降下成分含有層における有効成分の含有率は４０〜８０質量％が好ましい。また、味のマスキングのため甘味料や酸味料等の各種矯味剤、香料を配合することが可能である。融点降下成分含有層の造粒に用いられる結合剤としては、ヒドロキシプロピルメチルセルロース（ＨＰＭＣ）、ヒドロキシプロピルセルロース（ＨＰＣ）、メチルセルロース（ＭＣ）、ポリビニルピロリドン（ＰＶＰ）、ポリビニルアルコール（ＰＶＡ）、プルラン，でんぷん糊が挙げられ、造粒溶剤の濃度は通常１〜２０ｗ/ｗ％である。また、造粒溶剤は水性溶液であればよく、水の他、必要に応じて水と混和するアルコール等を加えてもよい。 “Ibuprofen-containing component that lowers the melting point of the ibuprofen (melting point-decreasing component)” refers to a powder that contains ethenamide, an active ingredient that lowers the melting point of ibuprofen, and an excipient that can be applied to pharmaceuticals. It is a drug-containing layering layer formed by coating while spraying, and the content of the active ingredient in the melting point lowering component-containing layer is preferably 40 to 80% by mass. Moreover, it is possible to mix | blend various flavoring agents, such as a sweetener and a sour agent, and a fragrance | flavor for taste masking. As binders used for granulation of the melting point lowering component-containing layer, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose (MC), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), pullulan, starch Paste is mentioned, and the concentration of the granulating solvent is usually 1 to 20 w / w%. Moreover, the granulation solvent should just be an aqueous solution, You may add alcohol etc. which are miscible with water other than water as needed.
「ポリビニルアルコール（ＰＶＡ）含有層」は、イブプロフェン含有層と融点降下成分含有層の間に配され、イブプロフェン及び融点降下成分を除く有効成分や賦形剤を含む混合粉体を、ＰＶＡを含む造粒溶剤で造粒したレイヤリング層であり、これは単にＰＶＡを含むフィルムコーティング液で被覆されたフィルム層とは異なるものである。 “Polyvinyl alcohol (PVA) -containing layer” is a layer that is placed between an ibuprofen-containing layer and a melting point-lowering component-containing layer, and a mixed powder containing active ingredients and excipients excluding ibuprofen and a melting-point-lowering component is produced by using PVA. It is a layering layer granulated with a granular solvent, which is different from a film layer that is simply coated with a film coating solution containing PVA.
ポリビニルアルコール（ＰＶＡ）含有層の造粒に用いられる結合剤には、イブプロフェンと融点降下成分の接触を防止し保存安定性を高めるためにポリビニルアルコール（ＰＶＡ）を用いる必要があり、それ以外にプルランやＰＶＡコポリマー等の他の結合剤を含有させてもよい。ＰＶＡを含む造粒溶剤の濃度は１〜２０ｗ/ｗ％が好ましい。また、造粒溶剤は水性溶液であれば良く、水の他、必要に応じて水と混和するアルコール等を加えても良い。 As a binder used for granulation of a polyvinyl alcohol (PVA) -containing layer, it is necessary to use polyvinyl alcohol (PVA) in order to prevent contact between ibuprofen and a melting point lowering component and enhance storage stability. Or other binders such as PVA copolymers. The concentration of the granulating solvent containing PVA is preferably 1 to 20 w / w%. Moreover, the granulation solvent should just be an aqueous solution, and you may add alcohol etc. which are miscible with water other than water as needed.
「ポリビニルアルコール（ＰＶＡ）」とは、ポリ酢酸ビニルをけん化して得た重合物で、白色若しくは微黄白色の粉末である。ここで本発明において使用するＰＶＡは、その種類が特に制限されるものではないが、付着力と溶解性を考慮すれば部分けん化物を使用することが好ましく、好ましいけん化度は８５〜９０モル％品である。 “Polyvinyl alcohol (PVA)” is a polymer obtained by saponifying polyvinyl acetate, and is a white or slightly yellowish white powder. Here, the type of PVA used in the present invention is not particularly limited, but it is preferable to use a partially saponified material in consideration of adhesion and solubility, and a preferable degree of saponification is 85 to 90 mol%. It is a product.
「イブプロフェン及び融点降下成分含有レイヤリング粒子」は、イブプロフェン含有層、融点降下成分含有層及びＰＶＡ含有層の他、必要に応じて、イブプロフェンや融点降下成分と配合禁忌の有効成分を含有する層を有し、最外殻をフィルム層で被覆し、散剤、顆粒剤、微粒剤、カプセル剤等として提供されうる。 In addition to the ibuprofen-containing layer, the melting point-decreasing component-containing layer, and the PVA-containing layer, the “ibuprofen and the melting-point-decreasing component-containing layering particle” includes a layer containing ibuprofen, a melting point-lowering component, and an incompatible ingredient as necessary. The outermost shell is coated with a film layer, and can be provided as a powder, granule, fine granule, capsule or the like.
以下に、実施例、比較例及び試験例を挙げ、本発明をさらに詳細に説明する。 Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
実施例１
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
精製白糖（核粒子）１９８０ｇ及び軽質無水ケイ酸２．０ｇを転動造粒機（商品名：ＣＦ−３６０；フロイント産業製）に投入し、ヒプロメロース６５ｇを精製水６２ｇと９５％エタノール（以下、単に「エタノール」と称する。）５５８ｇの混液に溶解させた造粒溶剤を噴霧しながらイブプロフェン６４８ｇ、Ｄ−マンニトール９０ｇ、軽質無水ケイ酸２２.５ｇ及びメタケイ酸アルミン酸マグネシウム２２.５ｇを混合し粉砕した粉体（以下、「粉体Ａ」と略記する。）７８３ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュ（目開き８５０μｍ）の篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Example 1
(1) Preparation of layering particles coated with ibuprofen-containing layer 1980 g of purified sucrose (nuclear particles) and 2.0 g of light anhydrous silicic acid are introduced into a rolling granulator (trade name: CF-360; manufactured by Freund Sangyo) Then, 648 g of ibuprofen, 90 g of D-mannitol, light anhydrous silicic acid 22 were sprayed with a granulating solvent in which 65 g of hypromellose was dissolved in a mixed solution of 62 g of purified water and 558 g of 95% ethanol (hereinafter simply referred to as “ethanol”). 0.53 g and 22.5 g of magnesium aluminate metasilicate mixed and pulverized 783 g of powder (hereinafter abbreviated as “powder A”) were gradually added for granulation. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, they were classified with an 18 mesh (mesh 850 μm) sieve to produce layered particles coated with an ibuprofen-containing layer.
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１８８４ｇを転動造粒機に投入し、ポリビニルアルコール７２ｇを精製水１６８ｇ及びエタノール１２０ｇの混液に溶解させた造粒溶剤を噴霧しながら、ブロモバレリル尿素３００ｇ、無水カフェイン１５０ｇ、Ｄ−マンニトール４０ｇ及び軽質無水ケイ酸１５ｇを混合し粉砕した粉体（以下、「粉体Ｂ」と略記する。）５０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1884 g of layering particles coated with ibuprofen-containing layer were put into a rolling granulator, 72 g of polyvinyl alcohol was added to 168 g of purified water and 120 g of ethanol. While spraying the granulation solvent dissolved in the mixed solution, 300 g of bromovaleryl urea, 150 g of anhydrous caffeine, 40 g of D-mannitol and 15 g of light anhydrous silicic acid were mixed and pulverized (hereinafter abbreviated as “powder B”). ) Gradually added 505 g. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer and an intermediate layer.
（３）イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子１８０１ｇを転動造粒機に投入し、ＰＶＡ７４ｇを精製水１７２ｇ及びエタノール１２３ｇの混液に溶解させた造粒溶剤を噴霧しながらエテンザミド１８０ｇ、ブロモバレリル尿素２１３ｇ、Ｄ−マンニトール３２ｇ及び軽質無水ケイ酸１１ｇを混合し粉砕した粉体（以下、「粉体Ｃ」と略記する。）４３６ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径６２３μｍのイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer 1801 g of layering particles coated with ibuprofen-containing layer and intermediate layer were put into a rolling granulator, and 74 g of PVA was purified water. While spraying a granulation solvent dissolved in a mixture of 172 g and ethanol 123 g, 180 g of etenzaamide, 213 g of bromovaleryl urea, 32 g of D-mannitol and 11 g of light anhydrous silicic acid were mixed and pulverized (hereinafter referred to as “powder C”) (Abbreviated) 436 g was gradually added and granulated. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer, an intermediate layer, and an ethenamide-containing layer having an average particle size of 623 μm. .
（４）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子９５ｇにメタケイ酸アルミン酸マグネシウム０．９ｇ、クエン酸０．７２ｇ、グリチルリチン酸二カリウム１．１７ｇ、ｌ−メントール０．０７ｇ及び香料０．０９ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(4) Preparation of ibuprofen and etenzamide-containing granules 95 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer and ethenamide-containing layer were added to 0.9 g of magnesium aluminate metasilicate, 0.72 g of citric acid, diglycyrrhizinate 1.17 g of potassium, 0.07 g of 1-menthol and 0.09 g of fragrance were added and mixed to obtain granules containing ibuprofen and ethenzamide.
実施例２
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
精製白糖（核粒子）１９８０ｇ及び軽質無水ケイ酸９．０ｇを転動造粒機に投入し、ヒプロメロース７２ｇを精製水６８ｇ及びエタノール６１６ｇの混液に溶解させた造粒溶剤を噴霧しながらイブプロフェン６４８ｇ、Ｄ−マンニトール９０ｇ、結晶セルロース１８ｇ、軽質無水ケイ酸９ｇ及びメタケイ酸アルミン酸マグネシウム９ｇを混合し粉砕した粉体（以下、「粉体Ｄ」と略記する。）７７４ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Example 2
(1) Preparation of layering particles coated with ibuprofen-containing layer 1980 g of purified sucrose (nuclear particles) and 9.0 g of light anhydrous silicic acid were put into a tumbling granulator, and 72 g of hypromellose was added with 68 g of purified water and 616 g of ethanol. While spraying the granulated solvent dissolved in the mixed solution, 648 g of ibuprofen, 90 g of D-mannitol, 18 g of crystalline cellulose, 9 g of light anhydrous silicic acid and 9 g of magnesium aluminate metasilicate (hereinafter referred to as “powder D” Abbreviated as “.) 774 g was gradually added and granulated. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer were produced.
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１８９０ｇ及び軽質無水ケイ酸４．５ｇを転動造粒機に投入し、ポリビニルアルコール７２ｇを精製水１６８ｇ及びエタノール１６８ｇの混液に溶解させた造粒溶剤を噴霧しながらブロモバレリル尿素３９２ｇ、無水カフェイン１４７ｇ、Ｄ−マンニトール４４ｇ及び軽質無水ケイ酸２２ｇを混合し粉砕した粉体（以下、「粉体Ｅ」と略記する。）６０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1890 g of layering particles coated with ibuprofen-containing layer and 4.5 g of light anhydrous silicic acid were charged into a rolling granulator, and 72 g of polyvinyl alcohol was added. Powder crushed by mixing 392 g of bromovaleryl urea, 147 g of anhydrous caffeine, 44 g of D-mannitol and 22 g of light anhydrous silicic acid while spraying a granulation solvent in which 168 g of purified water was dissolved in a mixed solution of 168 g of purified water (hereinafter “ Abbreviated as “powder E”.) 605 g was gradually added and granulated. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer and an intermediate layer.
（３）イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子１７２３ｇ及び軽質無水ケイ酸４．１ｇを転動造粒機に投入し、ヒドロキシプロピルセルロース３２ｇをエタノール３０５ｇに溶解させた造粒溶剤を噴霧しながらエテンザミド１６７ｇ、ブロモバレリル尿素１３２ｇ、Ｄ−マンニトール３０ｇ、グリチルリチン酸二カリウム１２ｇ及び軽質無水ケイ酸１２ｇを混合し粉砕した粉体（以下、「粉体Ｆ」と略記する。）３５３ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径６１９μｍのイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer Rolling granulator with 1723 g of layering particles coated with ibuprofen-containing layer and intermediate layer and 4.1 g of light anhydrous silicic acid The mixture was pulverized by mixing 167 g of etenzamide, 132 g of bromovaleryl urea, 30 g of D-mannitol, 12 g of dipotassium glycyrrhizinate and 12 g of light anhydrous silicic acid while spraying a granulation solvent in which 32 g of hydroxypropylcellulose was dissolved in 305 g of ethanol. 353 g of powder (hereinafter abbreviated as “powder F”) was gradually added and granulated. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18 mesh sieve to produce layered particles coated with an ibuprofen-containing layer, an intermediate layer and an ethenamide-containing layer having an average particle size of 619 μm. .
（４）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子１１０ｇにメタケイ酸アルミン酸マグネシウム１．０５ｇ、クエン酸０．８４ｇ、グリチルリチン酸二カリウム０．７ｇ、ｌ−メントール０．０４２ｇ及び香料０．１０５ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(4) Preparation of ibuprofen and etenzamide-containing granules 110 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer, and ethenamide-containing layer were added to 1.05 g of magnesium aluminate metasilicate, 0.84 g of citric acid, diglycyrrhizinate Potassium 0.7g, l-menthol 0.042g, and fragrance 0.105g were added and mixed to obtain granules containing ibuprofen and etenzaamide.
実施例３
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
精製白糖（核粒子）１９８０ｇ及び軽質無水ケイ酸９．０ｇを転動造粒機に投入し、ポリビニルアルコール８１ｇを精製水１９４ｇとエタノール１３０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｄ」７７４ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Example 3
(1) Preparation of layering particles coated with ibuprofen-containing layer 1980 g of purified sucrose (nuclear particles) and 9.0 g of light silicic anhydride were put into a rolling granulator, 81 g of polyvinyl alcohol was added to 194 g of purified water and 130 g of ethanol. While spraying the granulation solvent dissolved in the mixed solution, 774 g of “Powder D” was gradually added for granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer were produced.
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１８９０ｇ及び軽質無水ケイ酸４．５ｇを転動造粒機に投入し、ポリビニルアルコール７２ｇを精製水１６８ｇ及びエタノール１６８ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｅ」６０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1890 g of layering particles coated with ibuprofen-containing layer and 4.5 g of light anhydrous silicic acid were charged into a rolling granulator, and 72 g of polyvinyl alcohol was added. 605 g of “Powder E” was gradually added while spraying a granulation solvent in which 168 g of purified water was dissolved in a mixed solution of 168 g of purified water and 168 g of ethanol, and granulation was performed. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer and an intermediate layer.
（３）イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子１７２２．５ｇ及び軽質無水ケイ酸４．１ｇを転動造粒機に投入し、ヒドロキシプロピルセルロース３２ｇをエタノール３０５ｇに溶解させた造粒溶剤を噴霧しながら「粉体Ｆ」３５３ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径７００μｍのイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer 1722.5 g of layering particles coated with ibuprofen-containing layer and intermediate layer and 4.1 g of light anhydrous silicic acid were rolled. The mixture was put into a granulator, and 353 g of “Powder F” was gradually added while spraying a granulating solvent in which 32 g of hydroxypropylcellulose was dissolved in 305 g of ethanol to perform granulation. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer, an intermediate layer, and an ethenamide-containing layer having an average particle diameter of 700 μm. .
（４）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子１１０ｇにメタケイ酸アルミン酸マグネシウム１．０５ｇ、クエン酸０．８４ｇ、グリチルリチン酸二カリウム０．７ｇ、ｌ−メントール０．０４２ｇ及び香料０．１０５ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(4) Preparation of ibuprofen and etenzamide-containing granules 110 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer, and ethenamide-containing layer were added to 1.05 g of magnesium aluminate metasilicate, 0.84 g of citric acid, diglycyrrhizinate Potassium 0.7g, l-menthol 0.042g, and fragrance 0.105g were added and mixed to obtain granules containing ibuprofen and etenzaamide.
実施例４
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
精製白糖（核粒子）１８９０ｇ及びトウモロコシデンプン３３ｇを転動造粒機（商品名：ＣＦ−３６０；フロイント産業製）に投入し、ポリビニルアルコール３１.５ｇを精製水１５６ｇとエタノール２３４ｇの混液に溶解させた造粒溶剤を噴霧しながらイブプロフェン６５２ｇ、Ｄ−マンニトール９０ｇ、デンプングリコール酸ナトリウム４５ｇ、軽質無水ケイ酸９ｇ及びメタケイ酸アルミン酸マグネシウム９ｇを混合し粉砕した粉体（以下、「粉体Ｇ」と略記する。）８０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後メタケイ酸アルミン酸マグネシウム３ｇを添加した後１８メッシュ（目開き８５０μｍ）の篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子（以下、「レイヤリング粒子Ａ」と略記する。）を製造した。
Example 4
(1) Preparation of layering particles coated with ibuprofen-containing layer 1890 g of refined sucrose (core particles) and 33 g of corn starch were introduced into a tumbling granulator (trade name: CF-360; manufactured by Freund Sangyo) and polyvinyl alcohol While spraying a granulation solvent in which 31.5 g was dissolved in a mixture of 156 g of purified water and 234 g of ethanol, 652 g of ibuprofen, 90 g of D-mannitol, 45 g of sodium starch glycolate, 9 g of light anhydrous silicic acid and 9 g of magnesium aluminate metasilicate 805 g of mixed and pulverized powder (hereinafter abbreviated as “powder G”) was gradually added to perform granulation. The obtained granulated particles are dried with a fluidized bed dryer, and after drying, 3 g of magnesium aluminate metasilicate is added, and then classified with an 18 mesh (mesh 850 μm) sieve, and layered particles coated with an ibuprofen-containing layer (Hereinafter abbreviated as “layering particle A”).
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆された「レイヤリング粒子Ａ」１２８７ｇを転動造粒機に投入し、ポリビニルアルコール２１ｇを精製水１０１ｇ及びエタノール１５１ｇの混液に溶解させた造粒溶剤を噴霧しながら、無水カフェイン２４０ｇ、Ｄ−マンニトール４８０ｇ、トウモロコシデンプン２４ｇ及び軽質無水ケイ酸１６ｇを混合し粉砕した粉体（以下、「粉体Ｈ」と略記する。）３３０ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子（以下、「レイヤリング粒子Ｂ」と略記する。）を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1287 g of “layering particles A” coated with ibuprofen-containing layer was put into a rolling granulator, and 21 g of polyvinyl alcohol was added to 101 g of purified water and While spraying a granulation solvent dissolved in a mixed solution of ethanol 151 g, 240 g of anhydrous caffeine, 480 g of D-mannitol, 24 g of corn starch and 16 g of light anhydrous silicic acid were mixed and pulverized (hereinafter referred to as “powder H”) The agglomeration was performed by gradually adding 330 g. The obtained granulated particles are dried with a fluidized bed dryer, and after drying, classified with an 18 mesh sieve, layered particles (hereinafter abbreviated as “layered particles B”) coated with an ibuprofen-containing layer and an intermediate layer. .) Was manufactured.
（３）イブプロフェン含有層、中間層及びメキタジン含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆された「レイヤリング粒子Ｂ」７００ｇを転動造粒機に投入し、ＨＰＣ-Ｌ５ｇを精製水４８ｇ及びエタノール４８ｇの混液に溶解させた造粒溶剤を噴霧しながらメキタジン１５ｇ、Ｄ−マンニトール２４９ｇ、トウモロコシデンプン９ｇ、リボフラビン１ｇ及び軽質無水ケイ酸６ｇを混合し粉砕した粉体（以下、「粉体Ｉ」と略記する。）８４ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層、中間層及びメキタジン含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and mequitazine-containing layer 700 g of “layering particle B” coated with ibuprofen-containing layer and intermediate layer was put into a rolling granulator, and HPC -Powder obtained by mixing 15 g of mequitazine, 249 g of D-mannitol, 9 g of corn starch, 1 g of riboflavin and 6 g of light anhydrous silicic acid while spraying a granulation solvent in which 5 g of L was dissolved in 48 g of purified water and 48 g of ethanol Hereinafter, abbreviated as “powder I”.) 84 g was gradually added to perform granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer, an intermediate layer and a mequitazine-containing layer were produced.
（４）イブプロフェン及びメキタジン含有顆粒の調製
得られたイブプロフェン含有層、中間層及びメキタジン含有層で被覆されたレイヤリング粒子１３０ｇに軽質無水ケイ酸１.２ｇを添加・混合しイブプロフェン及びメキタジン含有顆粒を得た。
(4) Preparation of Ibuprofen and Mequitazine-Containing Granules 1.2 g of light anhydrous silicic acid was added to and mixed with 130 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer and mequitazine-containing layer to obtain ibuprofen and mequitazine-containing granules. Obtained.
実施例５
（１）イブプロフェン含有層、中間層及びロキソプロフェンナトリウム含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆された「レイヤリング粒子Ｂ」７００ｇを転動造粒機に投入し、ＨＰＣ-Ｌ３.３ｇを精製水３１ｇ及びエタノール３１ｇの混液に溶解させた造粒溶剤を噴霧しながらロキソプロフェンナトリウム水和物２０４ｇ、Ｄ−マンニトール６０ｇ、トウモロコシデンプン９ｇ、リボフラビン１ｇ及び軽質無水ケイ酸６ｇを混合し粉砕した粉体（以下、「粉体Ｊ」と略記する。）８４ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層、中間層及びロキソプロフェンナトリウム含有層で被覆されたレイヤリング粒子を製造した。
Example 5
(1) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and loxoprofen sodium-containing layer 700 g of “layering particle B” coated with ibuprofen-containing layer and intermediate layer was charged into a rolling granulator, While spraying a granulation solvent in which 3.3 g of HPC-L was dissolved in 31 g of purified water and 31 g of ethanol, 204 g of loxoprofen sodium hydrate, 60 g of D-mannitol, 9 g of corn starch, 1 g of riboflavin and 6 g of light anhydrous silicic acid were added. 84 g of the mixed and pulverized powder (hereinafter abbreviated as “powder J”) was gradually added and granulated. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer, an intermediate layer, and a loxoprofen sodium-containing layer were produced.
（２）イブプロフェン及びロキソプロフェンナトリウム含有顆粒の調製
得られたイブプロフェン含有層、中間層及びロキソプロフェンナトリウム含有層で被覆されたレイヤリング粒子１３０ｇに軽質無水ケイ酸１.２ｇを添加・混合しイブプロフェン及びロキソプロフェンナトリウム含有顆粒を得た。
(2) Preparation of ibuprofen and loxoprofen sodium-containing granules 1.2 g of light anhydrous silicic acid was added to and mixed with 130 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer and loxoprofen sodium-containing layer, and ibuprofen and loxoprofen sodium Containing granules were obtained.
比較例１
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
核粒子としてセルフィア（商品名：旭化成ケミカルズ製）１９８０ｇを転動造粒機に投入し、ヒドロキシプロピルセルロース６３ｇをエタノール６００ｇに溶解させた造粒造剤を噴霧しながら「粉体Ａ」７８３ｇを徐々に投入した後、タルク２７ｇを投入して造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Comparative Example 1
(1) Preparation of layering particles coated with ibuprofen-containing layer 1980 g of SELPHYR (trade name: manufactured by Asahi Kasei Chemicals) as a core particle was put into a rolling granulator, and 63 g of hydroxypropyl cellulose was dissolved in 600 g of ethanol. While spraying the granulating agent, 783 g of “Powder A” was gradually added, and then 27 g of talc was added for granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer were produced.
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１９０２ｇを転動造粒機に投入し、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ）４２ｇを精製水１５０ｇ及びエタノール２５０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｂ」５０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1902 g of layering particles coated with ibuprofen-containing layer was put into a tumbling granulator, and 42 g of hydroxypropylcellulose (HPC-L) was purified. While spraying a granulation solvent dissolved in a mixed solution of 150 g of water and 250 g of ethanol, 505 g of “Powder B” was gradually added for granulation. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer and an intermediate layer.
（３）イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子１９５９．２ｇを転動造粒機に投入し、ヒドロキシプロピルセルロース（ＨＰＣ−Ｌ）３４ｇを精製水１２０ｇ及びエタノール２００ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｃ」４８９．６ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径５６４μｍのイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer 1959.2 g of layering particles coated with ibuprofen-containing layer and intermediate layer were put into a tumbling granulator, and hydroxypropyl While spraying a granulation solvent in which 34 g of cellulose (HPC-L) was dissolved in a mixture of 120 g of purified water and 200 g of ethanol, 489.6 g of “Powder C” was gradually added to perform granulation. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer, an intermediate layer and an ethenamide-containing layer having an average particle size of 564 μm. .
（４）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子３１０ｇにメタケイ酸アルミン酸マグネシウム３ｇ、クエン酸４．８ｇ、グリチルリチン酸二カリウム３．９ｇ、ｌ−メントール０．３ｇ及び香料０．３ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(4) Preparation of ibuprofen and etenzamide-containing granule 3 g of magnesium aluminate metasilicate, 4.8 g of citric acid, dipotassium glycyrrhizinate 3 to 310 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer, and ethenamide-containing layer .9 g, 0.3 g of l-menthol and 0.3 g of fragrance were added and mixed to obtain granules containing ibuprofen and etenzaamide.
比較例２
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
核粒子として精製白糖１９８０gを転動造粒機に投入し、ヒプロメロース６３ｇを精製水６０ｇ及びエタノール５４０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ａ」７８３ｇを徐々に投入して造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Comparative Example 2
(1) Preparation of layering particles coated with ibuprofen-containing layer A granulated solvent in which 1980 g of purified sucrose as core particles was put into a tumbling granulator, and 63 g of hypromellose was dissolved in a mixture of 60 g of purified water and 540 g of ethanol. While spraying, 783 g of “Powder A” was gradually added to perform granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer were produced.
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１８８４ｇを転動造粒機に投入し、ヒプロメロース４２ｇを精製水４０ｇ及びエタノール３６０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｂ」５０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1884 g of layering particles coated with ibuprofen-containing layer were put into a rolling granulator, and 42 g of hypromellose was mixed with 40 g of purified water and 360 g of ethanol. 505 g of “Powder B” was gradually added while spraying the granulation solvent dissolved in the solution, and granulation was performed. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer and an intermediate layer.
（３）イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子１８２３ｇを転動造粒機に投入し、ヒプロメロース３２ｇを精製水３０ｇ及びエタノール２７０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｃ」４５９ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径５６３μｍのイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer Layered particles 1823g coated with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer were charged into a rolling granulator, While spraying a granulation solvent in which 32 g of hypromellose was dissolved in a mixed solution of 30 g of purified water and 270 g of ethanol, 459 g of “Powder C” was gradually added for granulation. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18 mesh sieve to produce layered particles coated with an ibuprofen-containing layer, an intermediate layer, and an ethenamide-containing layer having an average particle size of 563 μm. .
（４）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子９２．５ｇにメタケイ酸アルミン酸マグネシウム０．９ｇ、クエン酸０．７２ｇ、グリチルリチン酸二カリウム１．１７ｇ、ｌ−メントール０．０７２ｇ及び香料０．０９ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(4) Preparation of ibuprofen and etenzamide-containing granules 92.5 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer, and ethenamide-containing layer were added to 0.9 g of magnesium aluminate metasilicate, 0.72 g of citric acid, and glycyrrhizin 1.17 g of dipotassium acid, 0.072 g of 1-menthol and 0.09 g of a fragrance were added and mixed to obtain granules containing ibuprofen and ethenzamide.
比較例３
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
核粒子として精製白糖１９８０gを転動造粒機に投入し、ヒプロメロース６３ｇを精製水６０ｇ及びエタノール５４０ｇの混液に溶解させた造粒溶剤を噴霧しながらイブプロフェン６４８ｇ、結晶セルロース９０ｇ、軽質無水ケイ酸２２．５ｇ及びメタケイ酸アルミン酸マグネシウム２２．５ｇを混合し粉砕した粉体（以下、「粉体Ｋ」と略記する。）７８３ｇを徐々に投入して造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Comparative Example 3
(1) Preparation of layering particles coated with ibuprofen-containing layer A granulated solvent in which 1980 g of purified sucrose as core particles was put into a tumbling granulator, and 63 g of hypromellose was dissolved in a mixture of 60 g of purified water and 540 g of ethanol. While spraying, 648 g of ibuprofen, 90 g of crystalline cellulose, 22.5 g of light anhydrous silicic acid and 22.5 g of magnesium aluminate metasilicate were mixed and pulverized 783 g of powder (hereinafter abbreviated as “powder K”) gradually. The mixture was granulated. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer were produced.
（２）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１８８４ｇを転動造粒機に投入し、ヒプロメロース４２ｇを精製水４０ｇ及びエタノール３６０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｂ」５０５ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し中間層被覆粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1884 g of layering particles coated with ibuprofen-containing layer were put into a rolling granulator, and 42 g of hypromellose was mixed with 40 g of purified water and 360 g of ethanol. 505 g of “Powder B” was gradually added while spraying the granulation solvent dissolved in the solution, and granulation was performed. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18 mesh sieve to produce intermediate layer coated particles.
（３）イブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子１８２３ｇを転動造粒機に投入し、ヒプロメロース３２ｇを精製水３０ｇ及びエタノール２７０ｇの混液に溶解させた造粒剤を噴霧しながら「粉体Ｃ」４５９ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径５５２μｍのイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles covered with ibuprofen-containing layer, intermediate layer and ethenamide-containing layer 1823 g of layering particles covered with ibuprofen-containing layer and intermediate layer were put into a tumbling granulator and purified 32 g of hypromellose. While spraying a granulating agent dissolved in a mixed solution of 30 g of water and 270 g of ethanol, 459 g of “Powder C” was gradually added to perform granulation. The obtained granulated particles were dried with a fluidized bed dryer, and after drying, classified with an 18-mesh sieve to produce layered particles coated with an ibuprofen-containing layer, an intermediate layer, and an ethenamide-containing layer having an average particle diameter of 552 μm. .
（４）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子１５４ｇにメタケイ酸アルミン酸マグネシウム１．５ｇ、クエン酸１．２ｇ、グリチルリチン酸二カリウム１．９５ｇ、ｌ−メントール０．１２ｇ及び香料０．１５ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(4) Preparation of ibuprofen and etenzamide-containing granule 1.5 g of magnesium aluminate metasilicate, 1.2 g of citric acid, diglycyrrhizin diacid 154 g coated with the obtained ibuprofen-containing layer, intermediate layer and ethenamide-containing layer 1.95 g of potassium, 0.12 g of l-menthol and 0.15 g of fragrance were added and mixed to obtain granules containing ibuprofen and ethenzamide.
比較例４
（１）イブプロフェン含有層で被覆されたレイヤリング粒子の調製
核粒子として精製白糖１９８０gを転動造粒機に投入し、ヒプロメロース６３ｇを精製水６０ｇ及びエタノール５４０ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ａ」７８３ｇを徐々に投入して造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層で被覆されたレイヤリング粒子を製造した。
Comparative Example 4
(1) Preparation of layering particles coated with ibuprofen-containing layer A granulated solvent in which 1980 g of purified sucrose as core particles was put into a tumbling granulator, and 63 g of hypromellose was dissolved in a mixture of 60 g of purified water and 540 g of ethanol. While spraying, 783 g of “Powder A” was gradually added to perform granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer were produced.
（２）イブプロフェン含有層及びＰＶＡ含有フィルム層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆されたレイヤリング粒子１６０１ｇを転動造粒機に投入し、ヒプロメロース２４ｇ、ＰＶＡ２４ｇ、パラフィン６．４ｇ、カルナウバロウ６．４ｇ、ショ糖脂肪酸エステル１．６ｇ、ポリソルベート−８０ １．６ｇ及び酸化チタン１６ｇを精製水４８０ｇに溶解・分散させたコーティング液を噴霧し、フィルムコーティングを行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及びＰＶＡ含有フィルム層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer and PVA-containing film layer 1601 g of layering particles coated with ibuprofen-containing layer was put into a rolling granulator, and 24 g of hypromellose, 24 g of PVA, and 6.4 g of paraffin. Film coating was performed by spraying a coating solution in which 6.4 g of carnauba wax, 1.6 g of sucrose fatty acid ester, 1.6 g of polysorbate-80 and 16 g of titanium oxide were dissolved and dispersed in 480 g of purified water. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer and a PVA-containing film layer were produced.
（３）イブプロフェン含有層、ＰＶＡ含有フィルム層及び中間層で被覆されたレイヤリング粒子の調製
その後、イブプロフェン含有層及びＰＶＡ含有フィルム層で被覆されたレイヤリング粒子１４００ｇを転動造粒機に投入し、ヒプロメロース３０ｇを精製水２８ｇ及びエタノール２５５ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｂ」３５７ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層、ＰＶＡ含有フィルム層及び中間層で被覆されたレイヤリング粒子を製造した。
(3) Preparation of layering particles covered with ibuprofen-containing layer, PVA-containing film layer and intermediate layer Thereafter, 1400 g of layering particles covered with ibuprofen-containing layer and PVA-containing film layer were put into a rolling granulator. Then, 357 g of “Powder B” was gradually added while spraying a granulation solvent in which 30 g of hypromellose was dissolved in a mixed solution of 28 g of purified water and 255 g of ethanol to perform granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer, a PVA-containing film layer, and an intermediate layer were produced.
（４）イブプロフェン含有層、ＰＶＡ含有フィルム層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層、ＰＶＡ含有フィルム層及び中間層で被覆されたレイヤリング粒子１４０１ｇを転動造粒機に投入し、ヒプロメロース２３ｇを精製水２２ｇ及びエタノール２００ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｃ」３４０ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、平均粒子径５６３μｍのイブプロフェン含有層、ＰＶＡ含有フィルム層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子を製造した。
(4) Preparation of layering particles coated with ibuprofen-containing layer, PVA-containing film layer, intermediate layer and ethenamide-containing layer Rolling and forming 1401 g of layering particles coated with ibuprofen-containing layer, PVA-containing film layer and intermediate layer The mixture was put into a granulator, and granulated by gradually adding 340 g of “Powder C” while spraying a granulation solvent in which 23 g of hypromellose was dissolved in a mixed solution of 22 g of purified water and 200 g of ethanol. The obtained granulated particles were dried with a fluidized bed dryer, classified after drying with an 18 mesh sieve, and coated with an ibuprofen-containing layer, a PVA-containing film layer, an intermediate layer, and an ethenamide-containing layer having an average particle diameter of 563 μm Ring particles were produced.
（５）イブプロフェン及びエテンザミド含有顆粒の調製
得られたイブプロフェン含有層、ＰＶＡ含有フィルム層、中間層及びエテンザミド含有層で被覆されたレイヤリング粒子１５９ｇにメタケイ酸アルミン酸マグネシウム１．５ｇ、クエン酸１．２ｇ、グリチルリチン酸二カリウム２．０ｇ、ｌ−メントール０．１２ｇ及び香料０．１５ｇを添加・混合し、イブプロフェン及びエテンザミド含有顆粒を得た。
(5) Preparation of ibuprofen and etenzamide-containing granules 1.5 g of magnesium aluminate metasilicate and 1.5 g of citric acid were added to 159 g of layering particles coated with the obtained ibuprofen-containing layer, PVA-containing film layer, intermediate layer, and ethenamide-containing layer. 2 g, 2.0 g of dipotassium glycyrrhizinate, 0.12 g of 1-menthol, and 0.15 g of a fragrance were added and mixed to obtain granules containing ibuprofen and ethenamide.
比較例５
（１）イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層で被覆された「レイヤリング粒子Ａ」１２８７ｇを転動造粒機に投入し、ＨＰＣ−Ｌ１２ｇを精製水１１３ｇ及びエタノール１１３ｇの混液に溶解させた造粒溶剤を噴霧しながら、「粉体Ｈ」３３０ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層及び中間層で被覆されたレイヤリング粒子（以下、「レイヤリング粒子Ｃ」と略記する。）を製造した。
Comparative Example 5
(1) Preparation of layering particles coated with ibuprofen-containing layer and intermediate layer 1287 g of “layering particles A” coated with ibuprofen-containing layer was put into a rolling granulator, and HPC-L12 g was added to 113 g of purified water and While spraying a granulation solvent dissolved in a mixed liquid of 113 g of ethanol, 330 g of “powder H” was gradually added to perform granulation. The obtained granulated particles are dried with a fluidized bed dryer, classified after drying with an 18 mesh sieve, and layered particles (hereinafter abbreviated as “layering particles C”) coated with an ibuprofen-containing layer and an intermediate layer. .) Was manufactured.
（２）イブプロフェン含有層、中間層及びメキタジン含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆された「レイヤリング粒子Ｃ」７００ｇを転動造粒機に投入し、ＨＰＣ-Ｌ５ｇを精製水４８ｇ及びエタノール４８ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｉ」８４ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層、中間層及びメキタジン含有層で被覆されたレイヤリング粒子を製造した。
(2) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and mequitazine-containing layer 700 g of “layering particle C” coated with ibuprofen-containing layer and intermediate layer was put into a rolling granulator, and HPC -Granulation was performed by gradually adding 84 g of "Powder I" while spraying a granulating solvent in which 5 g of L was dissolved in a mixed solution of 48 g of purified water and 48 g of ethanol. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer, an intermediate layer and a mequitazine-containing layer were produced.
（３）イブプロフェン及びメキタジン含有顆粒の調製
得られたイブプロフェン含有層、中間層及びメキタジン含有層で被覆されたレイヤリング粒子１３０ｇに軽質無水ケイ酸１.２ｇを添加・混合しイブプロフェン及びメキタジン含有顆粒を得た。
(3) Preparation of ibuprofen and mequitazine-containing granules 1.2 g of light anhydrous silicic acid was added to and mixed with 130 g of layered particles coated with the obtained ibuprofen-containing layer, intermediate layer and mequitazine-containing layer to obtain ibuprofen and mequitazine-containing granules. Obtained.
比較例６
（１）イブプロフェン含有層、中間層及びロキソプロフェンナトリウム含有層で被覆されたレイヤリング粒子の調製
イブプロフェン含有層及び中間層で被覆された「レイヤリング粒子Ｃ」７００ｇを転動造粒機に投入し、ＨＰＣ-Ｌ２.４ｇを精製水２３ｇ及びエタノール２３ｇの混液に溶解させた造粒溶剤を噴霧しながら「粉体Ｊ」８４ｇを徐々に投入し造粒を行った。得られた造粒粒子を流動層乾燥機で乾燥し、乾燥後１８メッシュの篩で分級し、イブプロフェン含有層、中間層及びロキソプロフェンナトリウム含有層で被覆されたレイヤリング粒子を製造した。
Comparative Example 6
(1) Preparation of layering particles coated with ibuprofen-containing layer, intermediate layer and loxoprofen sodium-containing layer 700 g of “layering particles C” coated with ibuprofen-containing layer and intermediate layer were charged into a rolling granulator, While spraying a granulation solvent in which 2.4 g of HPC-L was dissolved in a mixed solution of 23 g of purified water and 23 g of ethanol, 84 g of “Powder J” was gradually added for granulation. The obtained granulated particles were dried with a fluidized bed drier, classified after drying with an 18-mesh sieve, and layered particles coated with an ibuprofen-containing layer, an intermediate layer, and a loxoprofen sodium-containing layer were produced.
（２）イブプロフェン及びロキソプロフェンナトリウム含有顆粒の調製
得られたイブプロフェン含有層、中間層及びロキソプロフェンナトリウム含有層で被覆されたレイヤリング粒子１３０ｇに軽質無水ケイ酸１.２ｇを添加・混合しイブプロフェン及びロキソプロフェンナトリウム含有顆粒を得た。
(2) Preparation of ibuprofen and loxoprofen sodium-containing granules 1.2 g of light anhydrous silicic acid was added to and mixed with 130 g of layering particles coated with the obtained ibuprofen-containing layer, intermediate layer and loxoprofen sodium-containing layer, and ibuprofen and loxoprofen sodium Containing granules were obtained.
［評価方法］
試験例１
実施例１〜３並びに比較例１〜４で調製した各顆粒を分包し、５０℃下に３時間保存した後、開封し、各顆粒を取り出して日本薬局方一般試験法粒度試験法に基づき篩分けし、保存前後での１８メッシュ（目開き８５０μｍ）のふるいを通過しない粗顆粒の割合を比較した．また目視観察により各顆粒の固結・凝集の状態を評価した。
試験例２
実施例４並びに比較例５で調製した各顆粒を分包し、５０℃下に３時間保存した後、開封し、目視観察により各顆粒の固結・凝集の状態を評価した。
試験例３
実施例５並びに比較例６で調製した各顆粒を分包し、６５℃下に２日間保存した後、開封し、目視観察により各顆粒の固結・凝集の状態を評価した。
[Evaluation method]
Test example 1
Each granule prepared in Examples 1 to 3 and Comparative Examples 1 to 4 is packaged and stored at 50 ° C. for 3 hours, then opened, each granule is taken out and based on the Japanese Pharmacopoeia General Test Method Particle Size Test Method The ratio of coarse granules that did not pass through a 18-mesh (mesh 850 μm) sieve before and after storage was compared. Further, the state of consolidation / aggregation of each granule was evaluated by visual observation.
Test example 2
Each granule prepared in Example 4 and Comparative Example 5 was packaged, stored at 50 ° C. for 3 hours, then opened, and the state of consolidation / aggregation of each granule was evaluated by visual observation.
Test example 3
Each granule prepared in Example 5 and Comparative Example 6 was packaged, stored at 65 ° C. for 2 days, then opened, and the state of solidification / aggregation of each granule was evaluated by visual observation.
［結果］
試験例１
結果を表１に示す。
[result]
Test example 1
The results are shown in Table 1.
試験例２
結果を図２及び図３に示す。
Test example 2
The results are shown in FIGS.
試験例３
結果を図４及び図５に示す。
Test example 3
The results are shown in FIGS.
表１から明らかな通り、ＰＶＡ以外の結合剤を含有する造粒溶剤で造粒した中間層を有する顆粒（比較例1〜３）では５０℃保存後に顆粒同士が凝集し、１８メッシュの篩を通過しない粗顆粒が多数発生した。 As is clear from Table 1, in the granules having the intermediate layer granulated with a granulating solvent containing a binder other than PVA (Comparative Examples 1 to 3), the granules aggregated after storage at 50 ° C., and an 18 mesh sieve was obtained. Many coarse granules that did not pass through were generated.
また、イブプロフェン含有層と中間層の間にＰＶＡ含有フィルム層を有する顆粒（比較例４）でも同様の粗顆粒の発生が認められた。 The same coarse granules were also observed in the granule (Comparative Example 4) having a PVA-containing film layer between the ibuprofen-containing layer and the intermediate layer.
一方、イブプロフェン含有層及びエテンザミド含有層をいかなる結合剤を含有する造粒溶剤で造粒したかにかかわらず、ＰＶＡを含有する造粒溶剤で造粒した場合（実施例１〜３）には、５０℃保存後にも付着・凝集等の変化は認められなかった。 On the other hand, regardless of whether the ibuprofen-containing layer and the etenzamide-containing layer were granulated with a granulating solvent containing any binder, when granulated with a granulating solvent containing PVA (Examples 1 to 3), Even after storage at 50 ° C., changes such as adhesion and aggregation were not observed.
さらに、図２及び図３から明らかな通り、融点降下成分を抗ヒスタミン薬のメキタジンに置換えた場合にも、ＨＰＣ−Ｌを含有する造粒溶剤で中間層を造粒した顆粒（比較例５）では、６５℃保存後に多数の凝集が発生したのに対し、ＰＶＡを含有する造粒溶剤で中間層を造粒した顆粒（実施例４）には、エテンザミドと同様に高温保存後に付着・凝集等の変化は認められなかった。 Further, as is apparent from FIGS. 2 and 3, even when the melting point lowering component was replaced with the antihistamine mequitazine, the granule obtained by granulating the intermediate layer with a granulating solvent containing HPC-L (Comparative Example 5) In contrast, a large number of agglomerates occurred after storage at 65 ° C., whereas granules (Example 4) obtained by granulating the intermediate layer with a PVA-containing granulation solvent adhered and agglomerated after high-temperature storage as in the case of etenzaamide. No change was observed.
加えて，図４及び図５からも、融点降下成分を塩基性の解熱鎮痛薬であるロキソプロフェンナトリウムに置換えた場合にも、ＨＰＣ−Ｌを含有する造粒溶剤で中間層を造粒した顆粒（比較例６）では、５０℃保存後に全体的に固結し大きな凝集塊となったのに対し、ＰＶＡを含有する造粒溶剤で中間層を造粒した顆粒（実施例５）には、付着・凝集等の変化は認められなかった。 In addition, from FIG. 4 and FIG. 5, even when loxoprofen sodium, a basic antipyretic analgesic, is substituted for the melting point lowering component, granules obtained by granulating the intermediate layer with a granulating solvent containing HPC-L ( In Comparative Example 6), the whole solidified after storage at 50 ° C. to form a large agglomerate, whereas the granules (Example 5) adhered to the granulate obtained by granulating the intermediate layer with a granulation solvent containing PVA.・ Changes such as aggregation were not observed.
本発明により、イブプロフェン及びイブプロフェンの融点降下を生じる成分を同時配合した際に懸念されるイブプロフェンの融点降下を防止し、イブプロフェンの融解に起因する付着・凝集を抑制する手法が見出された。これにより、イブプロフェン及びイブプロフェンの融点降下を生じる成分を同時配合した製剤をレイヤリング粒子という態様を通じて、散剤や顆粒剤等の固形製剤として提供することが可能となった。よって、イブプロフェン及びイブプロフェンの融点降下を生じる成分を配合した固形製剤としては従来の二重錠や多層錠に加えてバリエーションが増え、消費者（患者）のニーズにより的確に対応できるようになった。 According to the present invention, a technique has been found to prevent ibuprofen and a component that causes a melting point drop of ibuprofen from being melted simultaneously, thereby preventing the melting point drop of ibuprofen and suppressing adhesion / aggregation due to melting of ibuprofen. As a result, it has become possible to provide a preparation in which ibuprofen and a component that causes a melting point drop of ibuprofen are blended at the same time as a solid preparation such as a powder or a granule through an aspect of layering particles. Therefore, as a solid preparation containing ibuprofen and a component that causes a melting point lowering of ibuprofen, variations have been increased in addition to conventional double tablets and multilayer tablets, and it has become possible to respond more accurately to the needs of consumers (patients).
（ａ）核粒子
（ｂ）イブプロフェン含有層
（ｃ）ポリビニルアルコール含有層
（ｄ）融点降下成分含有層
(A) Core particles (b) Ibuprofen-containing layer (c) Polyvinyl alcohol-containing layer (d) Melting point lowering component-containing layer
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| JP2016124800A (en) * | 2014-12-26 | 2016-07-11 | 大原薬品工業株式会社 | Bioactive substance-containing granules and production method thereof |
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| JP6307874B2 (en) | 2018-04-11 |
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