JP2019131615A - Solid preparation - Google Patents
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- JP2019131615A JP2019131615A JP2019089042A JP2019089042A JP2019131615A JP 2019131615 A JP2019131615 A JP 2019131615A JP 2019089042 A JP2019089042 A JP 2019089042A JP 2019089042 A JP2019089042 A JP 2019089042A JP 2019131615 A JP2019131615 A JP 2019131615A
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- layering
- ibuprofen
- layer
- particle
- disintegrant
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- 239000007787 solid Substances 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 12
- 239000002245 particle Substances 0.000 claims abstract description 47
- 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 36
- 229960001680 ibuprofen Drugs 0.000 claims abstract description 36
- 239000007884 disintegrant Substances 0.000 claims abstract description 21
- 239000007771 core particle Substances 0.000 claims abstract description 19
- 229920002472 Starch Polymers 0.000 claims description 17
- 235000019698 starch Nutrition 0.000 claims description 17
- 239000008107 starch Substances 0.000 claims description 17
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 15
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims description 15
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 15
- 229950008138 carmellose Drugs 0.000 claims description 15
- 239000011734 sodium Substances 0.000 claims description 15
- 229910052708 sodium Inorganic materials 0.000 claims description 15
- 229940032147 starch Drugs 0.000 claims description 14
- 230000008961 swelling Effects 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 229920000881 Modified starch Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 235000019658 bitter taste Nutrition 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- 239000010410 layer Substances 0.000 description 69
- 229940083542 sodium Drugs 0.000 description 12
- 235000015424 sodium Nutrition 0.000 description 12
- 239000000306 component Substances 0.000 description 11
- 239000003814 drug Substances 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 238000002156 mixing Methods 0.000 description 8
- 238000005096 rolling process Methods 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 238000005469 granulation Methods 0.000 description 7
- 230000003179 granulation Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 239000011248 coating agent Substances 0.000 description 5
- 238000000576 coating method Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005507 spraying Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000011361 granulated particle Substances 0.000 description 3
- 230000000873 masking effect Effects 0.000 description 3
- 238000010298 pulverizing process Methods 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- 239000002221 antipyretic Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 235000019640 taste Nutrition 0.000 description 2
- 241000834695 Auchenoglanis occidentalis Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- WJEIYVAPNMUNIU-UHFFFAOYSA-N [Na].OC(O)=O Chemical compound [Na].OC(O)=O WJEIYVAPNMUNIU-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940125715 antihistaminic agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000008358 core component Substances 0.000 description 1
- 239000012792 core layer Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229940124568 digestive agent Drugs 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000000820 nonprescription drug Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000955 prescription drug Substances 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、固形製剤の分野に関し、詳しくは、経時的に安定でかつ粒子からの薬物溶出性に優れた粒状医薬品に関する。 The present invention relates to the field of solid preparations, and in particular, to a granular pharmaceutical that is stable over time and excellent in drug dissolution from particles.
イブプロフェンは非ステロイド系消炎鎮痛剤（ＮＳＡＩＤｓ）である。イブプロフェンは全ての非選択性ＮＳＡＩＤｓの中で最も胃腸障害が少ないことが知られており、医療用医薬品だけでなく一般用医薬品の解熱鎮痛薬の有効成分として広く利用されており、素早い効き目が求められている。また、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）。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し商品性を著しく低下させる懸念があった。 Ibuprofen is a non-steroidal anti-inflammatory analgesic (NSAIDs). Ibuprofen is known to have the least gastrointestinal disturbances among all non-selective NSAIDs, and is widely used as an active ingredient in antipyretic analgesics for not only prescription drugs but also over-the-counter drugs. It has been. In addition, ibuprofen is a low melting point drug having a melting point of 75 to 77 ° C., and further has an acidic group, so that it is known to absorb moisture and form a salt under high humidity conditions when blended with an alkaline drug. 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). Interaction with other components of ibuprofen, which has a high content among the active ingredients, makes handling of the powder extremely difficult and causes adhesion and aggregation. There was a concern to make.
一般的に配合変化を生じる成分を同時配合する場合には、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配合変化を防止することが可能であった（非特許文献２参照）。また、顆粒とする場合には、配合変化を生じる成分を別の層に分けたレイヤリング粒子とすることで、前述の錠剤と同様に配合変化を防止することが可能であった（特許文献１参照）。 In general, when ingredients that cause compounding changes are blended at the same time, if they are blended into different granules, etc., and provided as double tablets or multilayer tablets, even if these ingredients are blended in the same formulation, It was possible to avoid the direct contact and prevent the change in the formulation (see Non-Patent Document 2). Moreover, when it is set as a granule, it was possible to prevent a mixing | blending change like the above-mentioned tablet by making into a layering particle | grains which divided | segmented the component which produces a mixing | blending change into another layer (patent document 1). reference).
しかし、従来のレイヤリング粒子は、配合変化の防止効果や味マスキング効果を有する一方で、内層に配合した成分の溶出は抑制される傾向にあることから、薬物の放出制御を目的として用いられることが多く、内層に配合した成分の溶出性を高める方法はあまり知られていなかった。 However, the conventional layering particles have the effect of preventing change in composition and the taste masking effect, while the elution of the components mixed in the inner layer tends to be suppressed, so that they can be used for drug release control purposes. However, a method for increasing the dissolution property of the components blended in the inner layer has not been well known.
本発明は、イブプロフェンの溶出性を改善したレイヤリング粒子を提供することを課題とする。 This invention makes it a subject to provide the layering particle | grains which improved the elution property of ibuprofen.
そこで、本発明者らは、このような事情を鑑み鋭意検討した結果、水溶性の核粒子に、イブプロフェン及び膨潤型の崩壊剤を含有する層（内層）を被覆し、さらに、崩壊剤を含有する層（外層）を被覆することにより、保存安定性や服用性を損なうことなく、イブプロフェンの素早い溶出性を確保したレイヤリング粒子を得られることを見出した。 Therefore, as a result of intensive studies in view of such circumstances, the present inventors coated water-soluble core particles with a layer (inner layer) containing ibuprofen and a swelling disintegrant, and further contained a disintegrant. It was found that by coating a layer (outer layer), layered particles that ensure quick dissolution of ibuprofen can be obtained without impairing storage stability and dosing properties.
かかる知見により得られた本発明の様態は次のとおりである。
（１）核粒子と該核粒子を覆う２以上の層からなるレイヤリング粒子であって、（ａ）水溶性核粒子、（ｂ）イブプロフェン及び膨潤型の崩壊剤を含有する内層、並びに（ｃ）崩壊剤を含有する外層を有することを特徴とするレイヤリング粒子。
（２）（ｃ）崩壊剤を含有する外層が２以上である前記（１）に記載のレイヤリング粒子。
（３）水溶性核粒子が白糖・デンプン球状顆粒、D-マンニトール及び白糖からなる群より選ばれる１種以上を含有する前記（１）又は（２）に記載のレイヤリング粒子。
（４）膨潤型の崩壊剤がカルボキシメチルスターチナトリウム、カルメロース、クロスカルメロースナトリウム、クロスポビドン、カルメロースカルシウム及び部分アルファー化デンプンからなる群より選ばれる１種以上である前記（１）〜（３）に記載のレイヤリング粒子。
（５）膨潤型の崩壊剤がカルボキシメチルスターチナトリウム及びカルメロースからなる群より選ばれる１種以上である（１）〜（４）に記載のレイヤリング粒子。
（６）外層に含まれる崩壊剤がカルボキシメチルスターチナトリウム及びカルメロースからなる群より選ばれる１種以上である（１）〜（５）に記載のレイヤリング粒子。
（７）（１）〜（６）に記載のレイヤリング粒子を含む固形製剤。
The aspect of the present invention obtained by such knowledge is as follows.
(1) A layering particle comprising a core particle and two or more layers covering the core particle, wherein (a) a water-soluble core particle, (b) an inner layer containing ibuprofen and a swelling disintegrant, and (c) ) Layering particles characterized by having an outer layer containing a disintegrant.
(2) (c) Layering particle | grains as described in said (1) whose outer layer containing a disintegrating agent is two or more.
(3) The layering particle according to (1) or (2), wherein the water-soluble core particle contains one or more selected from the group consisting of sucrose / starch spherical granules, D-mannitol and sucrose.
(4) The above-mentioned (1) to (3), wherein the swelling type disintegrant is at least one selected from the group consisting of sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, carmellose calcium and partially pregelatinized starch. The layering particles described in).
(5) The layering particles according to (1) to (4), wherein the swelling type disintegrant is at least one selected from the group consisting of sodium carboxymethyl starch and carmellose.
(6) The layering particles according to (1) to (5), wherein the disintegrant contained in the outer layer is one or more selected from the group consisting of sodium carboxymethyl starch and carmellose.
(7) A solid preparation containing the layering particles according to (1) to (6).
本発明により、素早い溶出性を有したイブプロフェン配合レイヤリング粒子を含む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 a solid preparation such as a granule containing ibuprofen-containing layering particles having quick dissolution properties. Further, by providing a layer outside the ibuprofen-containing layer in the layering particles, sublimation and bitterness caused by ibuprofen are suppressed, and it has become possible to provide a solid preparation excellent in storage stability and ingestibility.
本発明のレイヤリング粒子とは、（ａ）水溶性核粒子に少なくとも（ｂ）内層を構成する成分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、さらに（ｃ）外層を構成する成分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。 The layering particles of the present invention are obtained by coating (a) water-soluble core particles with at least (b) a component constituting the inner layer through wet granulation such as centrifugal rolling granulation, and (c) ) Solid preparation particles having a geometric average particle diameter of 200 to 850 μm prepared by coating a powder containing the components constituting the outer layer through wet granulation such as centrifugal rolling granulation.
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、好ましく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 providing a layering layer, a centrifugal tumbling granulator (trade name: CF-360; manufactured by Freund Industries), a rolling fluidized bed granulator (trade name: MP-01; manufactured by POWREC), or a Wurster column. A wet granulation method using a fluidized bed coating machine (trade name: GPCG-1; manufactured by Glatt) or the like is used, and a centrifugal rolling granulation method using a centrifugal rolling granulator is preferable.
本発明のレイヤリング粒子で使用する（ａ）水溶性核粒子とは、医薬品に適用可能な基剤からなる水溶性の核であり、粒度の揃ったものが好ましく、白糖・デンプン球状顆粒（商品名：ノンパレル−１０１；フロイント産業製）及びD-マンニトール（商品名：ノンパレル−１０８；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等が挙げられる。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、１５０μｍ〜８５０μｍが好ましい。 The (a) water-soluble core particles used in the layering particles of the present invention are water-soluble nuclei composed of a base applicable to pharmaceuticals, and those having a uniform particle size are preferable. Name: Nonparel-101; manufactured by Freund Sangyo) and D-mannitol (trade name: Nonparel-108; manufactured by Freund Sangyo) and other spherical particles prepared based on crystalline cellulose and saccharides, as well as sugars such as purified white sugar For example, a fine crystal. The size of these core particles is 100 μm to 1 mm, preferably 150 μm to 850 μm, from the viewpoints of granulation properties and ingestibility.
本発明の（ｂ）内層は、イブプロフェン及び膨潤型の崩壊剤の他、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水溶性核粒子に被覆し形成した薬物含有レイヤリング層であり、内層における有効成分の含有率は５０〜８０質量％が好ましい。内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。 The inner layer (b) of the present invention is prepared by spraying a binder with a powder mixed with ibuprofen and a swelling disintegrant, as well as various active ingredients with slight interaction with ibuprofen and excipients applicable to pharmaceuticals. However, it is a drug-containing layering layer formed by coating with water-soluble core particles, and the content of the active ingredient in the inner layer is preferably 50 to 80% by mass. As the binder used for granulation of the inner layer, hypromellose (HPMC), PVA, and pullulan, which have a slight effect on the interaction with ibuprofen and elution, are preferable. %. 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.
本発明の膨潤型の崩壊剤としては、カルボキシメチルスターチナトリウム、カルメロース、クロスカルメロースナトリウム、クロスポビドン、カルメロースカルシウム、部分アルファー化デンプン等が挙げられる。このうち、特にカルボキシメチルスターチナトリウムが好ましい。
本発明の（ｃ）外層は、イブプロフェンと相互作用を生じる成分及び崩壊剤を含有し、内層と同様に、内層に被覆し形成した薬物含有レイヤリング層である。また、外層にさらに被覆し形成したレイヤリング層も本発明の外層に含まれる。
Examples of the swelling disintegrant of the present invention include sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, carmellose calcium, and partially pregelatinized starch. Of these, sodium carboxymethyl starch is particularly preferable.
The outer layer (c) of the present invention is a drug-containing layering layer formed by covering and forming the inner layer, similar to the inner layer, containing a component that interacts with ibuprofen and a disintegrant. A layering layer formed by further covering the outer layer is also included in the outer layer of the present invention.
本発明の外層は１層であっても効果を有するが、イブプロフェンの苦味マスキング効果及びイブプロフェンと他の薬物との相互作用抑制効果の面から２層以上であることが好ましい。 The outer layer of the present invention is effective even if it is a single layer, but it is preferably two or more layers from the viewpoint of the bitter taste masking effect of ibuprofen and the effect of suppressing the interaction between ibuprofen and other drugs.
本発明の外層に含まれる崩壊剤としては、カルボキシメチルスターチナトリウム、カルメロース、クロスカルメロースナトリウム、クロスポビドン、カルメロースカルシウム、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロース、結晶セルロース、トウモロコシデンプン、炭酸水素ナトリウム等が挙げられるが、溶出改善の点から好ましくは、カルボキシメチルスターチナトリウム及びカルメロースである。 Disintegrants included in the outer layer of the present invention include sodium carboxymethyl starch, carmellose, croscarmellose sodium, crospovidone, carmellose calcium, partially pregelatinized starch, low-substituted hydroxypropylcellulose, crystalline cellulose, corn starch, carbonic acid Sodium hydrogen and the like can be mentioned, and sodium carboxymethyl starch and carmellose are preferable from the viewpoint of improving elution.
各層における崩壊剤の含有率は１〜４０質量％が好ましく，５〜２０質量％が特に好ましい。 1-40 mass% is preferable and, as for the content rate of the disintegrating agent in each layer, 5-20 mass% is especially preferable.
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.
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、香料を各層に配合することが可能である。 Moreover, it is possible to mix | blend various flavoring agents, such as a sweetener and a sour agent, and a fragrance | flavor in each layer for masking of taste.
また、本発明のレイヤリング粒子で使用するカルボキシメチルスターチナトリウムには、Ｐｒｉｍｏｊｅｌ（商品名、ＤＭＶ製）やエキスプロタブ（商品名、木村産業製）などが挙げられる。本発明のレイヤリング粒子で使用するカルメロースには、ＮＳ-３００（商品名、五徳薬品製）などがあげられる。 Examples of the carboxymethyl starch sodium used in the layering particles of the present invention include Primojel (trade name, manufactured by DMV) and Exprotab (trade name, manufactured by Kimura Sangyo). Examples of carmellose used in the layering particles of the present invention include NS-300 (trade name, manufactured by Gotoku Pharmaceutical).
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。
実施例１〜２、比較例１〜５
（１）内層（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
表１に記載した核粒子及びA成分を転動造粒機（商品名：ＣＦ−３６０；フロイント産業製）に投入し、内層の溶液ａを噴霧しながらB成分を混合し粉砕した粉体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、内層で被覆されたレイヤリング粒子を製造した。
Hereinafter, the present invention will be described in more detail with reference to Examples, Comparative Examples and Test Examples.
Examples 1-2 and Comparative Examples 1-5
(1) Preparation of layering particles coated with inner layer (ibuprofen-containing layer) The core particles and component A described in Table 1 were put into a rolling granulator (trade name: CF-360; manufactured by Freund Sangyo). While spraying the solution a in the inner layer, the powder obtained by mixing and pulverizing the component B was gradually added and granulated. 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 covered with an inner layer.
（２）内層及び外層（第２層）で被覆されたレイヤリング粒子の調製
（１）で製造したレイヤリング粒子を転動造粒機に投入し、表２記載の外層（第２層）の溶液ｂを噴霧しながら、C成分を混合し粉砕した粉体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、内層及び外層（第２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 inner layer and outer layer (second layer) The layering particles produced in (1) were put into a rolling granulator, and the outer layer (second layer) described in Table 2 While spraying the solution b, the powder obtained by mixing and pulverizing the C component 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 inner layer and an outer layer (second layer) were produced.
（３）内層、外層（第２層）及び外層（第３層）で被覆されたレイヤリング粒子の調製
（２）で内層及び外層（第２層）で被覆されたレイヤリング粒子を転動造粒機に投入し、表３に記載した溶液ｃを噴霧しながらD成分を混合し粉砕した粉体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、内層、外層（第２層）及び外層（第３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 inner layer, outer layer (second layer) and outer layer (third layer) Rolling structure of layering particles coated with inner layer and outer layer (second layer) in (2) The mixture was put into a granulator, and the powder obtained by mixing and pulverizing the D component while spraying the solution c shown in Table 3 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 the inner layer, outer layer (second layer) and outer layer (third layer). .
（４）イブプロフェン含有製剤の調製
（１）〜（３）で得られたレイヤリング粒子に表４に記載した成分を添加・混合し、イブプロフェン含有製剤を得た。
(4) Preparation of ibuprofen-containing preparation The components listed in Table 4 were added to and mixed with the layering particles obtained in (1) to (3) to obtain an ibuprofen-containing preparation.
試験例
実施例１〜２及び比較例１〜５で得られたレイヤリング粒子についてｐＨ５．５のリン酸水素二ナトリウム・クエン酸緩衝液を用い、イブプロフェンの公的溶出試験法「イブプロフェン200 mg/g顆粒」（オレンジブック総合版ホームページ、薬効番号114 イブプロフェン、http://www2.jp-orangebook.gr.jp/data/04/04_01/04_01_Ibuprofen.pdf）に準拠し、溶出試験を実施した。試験開始１５分後の試験結果を表５に示した。公的溶出試験法の溶出規格である１５分間の溶出率が８５％以上のものについては判定を○とし、下回ったものについては判定を×と記した。
Test Example About the layered particles obtained in Examples 1 and 2 and Comparative Examples 1 to 5, using a disodium hydrogen phosphate / citrate buffer solution having a pH of 5.5, an official dissolution test method for ibuprofen “200 mg / bubu of ibuprofen” The dissolution test was carried out according to “G Granules” (Orange Book Comprehensive Website, Medicinal Number 114 Ibuprofen, http://www2.jp-orangebook.gr.jp/data/04/04_01/04_01_Ibuprofen.pdf). The test results 15 minutes after the start of the test are shown in Table 5. Judgment was marked with ○ when the elution rate for 15 minutes, which is the elution standard of the official dissolution test method, was 85% or more, and marked with x when the elution rate was lower than that.
なお、表５には、各実施例及び比較例の核粒子及び層に含まれる崩壊剤の説明を併記した。 In Table 5, descriptions of the disintegrants contained in the core particles and layers of the examples and comparative examples are also shown.
表５から明らかな通り、比較例１のように不溶性の核粒子を用いた場合は、カルボキシメチルスターチナトリウムを内層及び外層に配合しても、イブプロフェンの溶出は十分でなかった。また、比較例２〜５のように水溶性の核粒子を用いた場合でも、内層に、結晶セルロース、低置換度ヒドロキシプロピルセルロース及び炭酸水素ナトリウムといった崩壊剤を配合した場合は、外層に崩壊剤を配合してもイブプロフェンの溶出は十分でなかった。これは比較例３及び４のように外層が１層のみの場合であっても同様であった。一方、実施例１及び２は、公的溶出試験法の溶出規格である１５分間の溶出率８５％以上を満たしており、イブプロフェンの十分な溶出改善効果が見られた。これにより、水溶性の核粒子を用い、内層にカルボキシメチルスターチナトリウムを含有し、外層に崩壊剤としてカルボキシメチルスターチナトリウム及び／又はカルメロースを含有するレイヤリング粒子とすることにより、内層に配合したイブプロフェンの溶出性を改善できると言える。内層に配合するカルボキシメチルスターチナトリウムは、その他の膨潤型の崩壊剤に置き換えた場合においても同様の効果が期待できる。 As is apparent from Table 5, when insoluble core particles were used as in Comparative Example 1, the elution of ibuprofen was not sufficient even when carboxymethyl starch sodium was added to the inner layer and the outer layer. Further, even when water-soluble core particles are used as in Comparative Examples 2 to 5, when the disintegrating agent such as crystalline cellulose, low-substituted hydroxypropyl cellulose and sodium hydrogen carbonate is blended in the inner layer, the disintegrating agent is added to the outer layer. However, the elution of ibuprofen was not sufficient. This was the same even when the outer layer was only one layer as in Comparative Examples 3 and 4. On the other hand, Examples 1 and 2 satisfied the dissolution rate of 85% or more for 15 minutes, which is the dissolution standard of the official dissolution test method, and a sufficient dissolution improvement effect of ibuprofen was observed. As a result, using water-soluble core particles, the inner layer contains carboxymethyl starch sodium, and the outer layer contains layered particles containing sodium carboxymethyl starch and / or carmellose as a disintegrant, thereby blending ibuprofen in the inner layer. It can be said that the dissolution property of can be improved. The same effect can be expected when sodium carboxymethyl starch blended in the inner layer is replaced with other swelling type disintegrants.
本発明により、素早い溶出性を確保したイブプロフェン含有レイヤリング粒子の調製が可能となり、生活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, it is possible to prepare ibuprofen-containing layering particles that ensure quick dissolution, and more accurately meet the needs of consumers.
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| JPH04273816A (en) * | 1991-02-26 | 1992-09-30 | Tanabe Seiyaku Co Ltd | Pulse-releasing nucleated tablet |
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| JP2006016329A (en) * | 2004-06-30 | 2006-01-19 | Lion Corp | Granular medicine |
| JP2008037863A (en) * | 2006-07-11 | 2008-02-21 | Taisho Pharmaceut Co Ltd | Pharmaceutical preparation particles containing drug having unpleasant taste |
| JP2009520704A (en) * | 2005-12-21 | 2009-05-28 | エーディーディー アドバンスト ドラッグ デリバリー テクノロジーズ リミテッド | Pellet containing core with water-soluble carrier |
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| JPH04273816A (en) * | 1991-02-26 | 1992-09-30 | Tanabe Seiyaku Co Ltd | Pulse-releasing nucleated tablet |
| JP2001055322A (en) * | 1999-08-18 | 2001-02-27 | Tanabe Seiyaku Co Ltd | Pulse release type preparation |
| JP2006016329A (en) * | 2004-06-30 | 2006-01-19 | Lion Corp | Granular medicine |
| JP2009520704A (en) * | 2005-12-21 | 2009-05-28 | エーディーディー アドバンスト ドラッグ デリバリー テクノロジーズ リミテッド | Pellet containing core with water-soluble carrier |
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