JPWO2012173226A1 - Polystyrene sulfonate-containing pharmaceutical preparation - Google Patents
Polystyrene sulfonate-containing pharmaceutical preparation Download PDFInfo
- Publication number
- JPWO2012173226A1 JPWO2012173226A1 JP2013520598A JP2013520598A JPWO2012173226A1 JP WO2012173226 A1 JPWO2012173226 A1 JP WO2012173226A1 JP 2013520598 A JP2013520598 A JP 2013520598A JP 2013520598 A JP2013520598 A JP 2013520598A JP WO2012173226 A1 JPWO2012173226 A1 JP WO2012173226A1
- Authority
- JP
- Japan
- Prior art keywords
- water
- pharmaceutical preparation
- mass
- polystyrene sulfonate
- preparation according
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/795—Polymers containing sulfur
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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Abstract
【課題】服用時の吸水感及び灼熱感が従来品より抑制され、賦形剤の量の少ないポリスチレンスルホン酸塩含有の医薬製剤を提供することを課題とする。【解決手段】ポリスチレンスルホン酸塩と結合剤とを含有する核顆粒と、前記核顆粒の表面上に形成された1以上の被覆層とを有し、前記被覆層は少なくとも(a)水溶性高分子又は水不溶性高分子、及び(b)糖又は糖アルコールを含有する、ポリスチレンスルホン酸塩を有効成分とする医薬製剤。【選択図】 なしAn object of the present invention is to provide a pharmaceutical preparation containing polystyrene sulfonate, in which water absorption feeling and burning sensation at the time of taking are suppressed compared to conventional products, and the amount of excipient is small. A core granule containing polystyrene sulfonate and a binder, and one or more coating layers formed on the surface of the core granule, wherein the coating layer is at least (a) highly water-soluble. A pharmaceutical preparation comprising polystyrene sulfonate as an active ingredient, comprising a molecule or a water-insoluble polymer, and (b) a sugar or a sugar alcohol. [Selection figure] None
Description
本発明は、ポリスチレンスルホン酸塩を有効成分とする医薬製剤に関するものである。 The present invention relates to a pharmaceutical preparation containing polystyrene sulfonate as an active ingredient.
陽イオン交換樹脂であるポリスチレンスルホン酸塩は、高カリウム血症患者らに有効な治療薬であり、腸管内でのイオン交換作用によるカリウムの体外排出を行う。ポリスチレンスルホン酸塩は、水にほとんど溶けない粉末状の樹脂であり、水とともに懸濁して服用しても、砂を噛むようなじゃりじゃりとした違和感がある。懸濁せずにそのまま服用した場合には、口腔内で唾液が吸われ飲み込めず、口腔・咽頭部が熱く焼けた感じがして服用感が悪い。さらに、ポリスチレンスルホン酸塩は、1日あたりの服用量が多い(5〜15g/日)という問題もある。 Polystyrene sulfonate, which is a cation exchange resin, is an effective therapeutic drug for patients with hyperkalemia and performs extracorporeal potassium excretion by ion exchange in the intestine. Polystyrene sulfonate is a powdery resin that is almost insoluble in water, and even when suspended and taken with water, there is a sense of incongruity that feels like chewing sand. When taken as it is without suspending, the saliva is sucked in the mouth and cannot be swallowed. Furthermore, polystyrene sulfonate has a problem that the daily dose is large (5 to 15 g / day).
このように、ポリスチレンスルホン酸塩は非常に服用し難い製剤であることから、従来から様々な工夫がなされてきた。例えば、ポリスチレンスルホン酸塩に甘味剤及び/又は酸味剤を添加した散剤(特許文献1)、ポリスチレンスルホン酸塩とゲル化剤(CMC-Na)とを混合して製造した顆粒剤又はドライシロップ(特許文献2)、バインダー及び水分を含有するポリスチレンスルホン酸ポリマー錠剤(特許文献3)、ゼリー製剤(特許文献4、特許文献5)又はゲル状組成物(特許文献6、特許文献7、特許文献8)などがある。しかし、散剤、ドライシロップ及び錠剤などは、懸濁せずそのまま服用した際の服用性の悪さが未だ改善されていない。ゲル状組成物及びゼリー剤は、1回当りの服用量の多さが改善されていない。 Thus, since polystyrene sulfonate is a formulation that is very difficult to take, various devices have been conventionally made. For example, a powder or a dry syrup produced by mixing a polystyrene sulfonate with a sweetener and / or a sour agent (Patent Document 1), a polystyrene sulfonate and a gelling agent (CMC-Na). Document 2), polystyrene sulfonic acid polymer tablet containing binder and moisture (Patent Document 3), jelly preparation (Patent Document 4, Patent Document 5) or gel composition (Patent Document 6, Patent Document 7, Patent Document 8) and so on. However, powders, dry syrups, tablets, and the like have not yet been improved in ingestibility when taken as they are without being suspended. Gel compositions and jelly preparations are not improved in the amount of each dose.
苦味等をマスキングするため、顆粒の表面に水溶性高分子からなるコーティング層及びコーティング層を覆う糖衣層を施して丸剤とする手法が知られている(特許文献9)。しかし、ポリスチレンスルホン酸塩は1日あたり5〜30g服用する必要があるため、特許文献4に記載のように服用後一定時間口腔内で不快な味を呈する薬物が溶出しないような組成と厚みにすれば、賦形剤の量がさらに多量になるという問題がある。 In order to mask bitterness and the like, a technique is known in which a coating layer made of a water-soluble polymer and a sugar coating layer covering the coating layer are applied to the surface of the granule to form a pill (Patent Document 9). However, since it is necessary to take 5 to 30 g of polystyrene sulfonate per day, the composition and thickness are such that drugs exhibiting an unpleasant taste in the oral cavity do not elute for a certain time after taking as described in Patent Document 4. Then, there is a problem that the amount of the excipient is further increased.
ポリスチレンスルホン酸塩は、上述のように、その服用性改善が強く望まれているが、未だに吸水感及び灼熱感が抑制され、且つ賦形剤の量が少ない医薬製剤は提供されていない。従って、本発明は、服用時の吸水感及び灼熱感が抑制され、賦形剤の量の少ないポリスチレンスルホン酸塩含有の医薬製剤を提供することを課題とする。 As described above, polystyrene sulfonate has been strongly desired to improve its ingestibility, but a pharmaceutical preparation in which the water absorption feeling and the burning sensation are still suppressed and the amount of excipients is small is not provided. Accordingly, an object of the present invention is to provide a polystyrene sulfonate-containing pharmaceutical preparation containing a water-absorbing feeling and a burning sensation when taken and having a small amount of excipient.
本発明者らは、吸水感及び灼熱感といったポリスチレンスルホン酸塩特有の服用し難さを改善するためには、表面コーティングが有用であるとの発想のもと、鋭意検討を行った。そして、(a)水溶性高分子又は水不溶性高分子と、(b)糖又は糖アルコールと、を組み合わせて表面コーティングすることにより、ポリスチレンスルホン酸塩特有の服用感の悪さが著しく抑制され、且つ賦形剤の量を減らすことができることを見出し、本発明を完成させた。 The inventors of the present invention have made extensive studies based on the idea that a surface coating is useful in order to improve the difficulty of taking a polystyrene sulfonate salt, such as a water absorption feeling and a burning sensation. And, by coating the surface with a combination of (a) a water-soluble polymer or a water-insoluble polymer and (b) a sugar or sugar alcohol, the bad feeling of taking peculiar to polystyrene sulfonate is significantly suppressed, and The inventors have found that the amount of excipient can be reduced and have completed the present invention.
すなわち、本発明の主な構成は次のとおりである。
(1)ポリスチレンスルホン酸塩と結合剤とを含有する核顆粒と、前記核顆粒の表面上に形成された1以上の被覆層とを有し、前記被覆層が少なくとも(a)水溶性高分子又は水不溶性高分子、及び(b)糖又は糖アルコールを含有する、ポリスチレンスルホン酸塩を有効成分とする医薬製剤。
(2)前記ポリスチレンスルホン酸塩が、医薬製剤全体に対して65〜95質量%である、(1)に記載の医薬製剤。
(3)レーザー回折法による粉体粒度測定をしたときの、前記ポリスチレンスルホン酸塩の50%粒子径が5〜100μmである、(1)又は(2)に記載の医薬製剤。
(4)篩い分けをしたときの、前記核顆粒の粒子径が2mm未満である、(1)〜(3)のいずれかに記載の医薬製剤。
(5)前記医薬製剤の粒子径が、0.5mm未満の粒子が医薬製剤全体の30質量%未満であり、且つ1.4mm以上の粒子が医薬製剤全体の20質量%未満である、(1)〜(4)のいずれかに記載の医薬製剤。
(6)前記核顆粒内に含まれる結合剤が、ポリスチレンスルホン酸塩に対して2〜15質量%である、(1)〜(5)のいずれかに記載の医薬製剤。
(7)(a)水溶性高分子又は水不溶性高分子、及び(b)糖又は糖アルコールの合計が、医薬製剤全体に対して2〜25質量%である、(1)〜(6)のいずれかに記載の医薬製剤。
(8)前記(a)水溶性高分子又は水不溶性高分子が、医薬製剤全体に対して0.5〜24.5質量%であり、前記(b)糖又は糖アルコールが、医薬製剤全体に対して0.5〜24.5質量%であり、(a):(b)の比が1:20〜20:1である、(7)に記載の医薬製剤。
(9)前記被覆層が1層からなる、(1)〜(8)のいずれかに記載の医薬製剤。
(10)前記核顆粒が、押し出し造粒及び球形整粒により製造される、(1)〜(9)のいずれかに記載の医薬製剤。
(11)前記(a)水溶性高分子又は水不溶性高分子が、水溶性高分子である、(1)〜(10)のいずれかに記載の医薬製剤。
(12)前記水溶性高分子が、セルロース誘導体、プルラン、ポリビニルピロリドン、ビニルピロリドン・酢酸ビニル共重合体、ポリビニルアルコール−ポリエチレングリコールグラフト共重合体、ポリビニルアルコール、ポリエチレングリコール、メタアクリル酸共重合体、ポリエチレンオキサイド、アラビアゴム末、マクロゴール、及びショ糖脂肪酸エステルからなる群から選択される1種以上である、(11)に記載の医薬製剤。
(13)前記水溶性高分子がセルロース誘導体であり、当該セルロース誘導体の20±0.1℃における2質量%水溶液の粘度が、2〜15000mPa・mである、(12)に記載の医薬製剤。
(14)前記セルロース誘導体が、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、メチルセルロース、及びヒドロキシエチルセルロースからなる群から選択される1種以上である、(13)に記載の医薬製剤。
(15)前記(a)水溶性高分子又は水不溶性高分子が、水不溶性高分子である、(1)〜(10)のいずれかに記載の医薬製剤。
(16)前記水不溶性高分子が、エチルセルロース、メタクリル酸コポリマー、及びそれらの組み合わせである、(15)に記載の医薬製剤。
(17)前記(b)糖又は糖アルコールが、マンニトール、ソルビトール、キシリトール、エリスリトール、トレハロース、スクロース、スクラロース、ラクトース、ラクチトール、粉末還元麦芽糖水アメ、ぶどう糖、果糖、及びデキストリンからなる群から選択される1種以上である、(1)〜(16)のいずれかに記載の医薬製剤。
(18)前記結合剤が、デキストリン、結晶セルロース、ヒドロキシプロピルセルロース、エチルセルロース、プルラン、マンニトール、ポリビニルピロリドン、ヒドロキシプロピルメチルセルロース、低置換度ヒドロキシプロピルセルロース、トウモロコシデンプン、メチルセルロース、精製白糖、還元麦芽糖水アメ、及び還元麦芽糖からなる群から選択される1種以上である、(1)〜(17)のいずれかに記載の医薬製剤。That is, the main configuration of the present invention is as follows.
(1) a core granule containing polystyrene sulfonate and a binder, and one or more coating layers formed on the surface of the core granule, wherein the coating layer is at least (a) a water-soluble polymer Or a pharmaceutical preparation containing polystyrene sulfonate as an active ingredient, which contains a water-insoluble polymer and (b) a sugar or a sugar alcohol.
(2) The pharmaceutical preparation according to (1), wherein the polystyrene sulfonate is 65 to 95 mass% with respect to the whole pharmaceutical preparation.
(3) The pharmaceutical preparation according to (1) or (2), wherein the polystyrene sulfonate has a 50% particle size of 5 to 100 μm when powder particle size is measured by a laser diffraction method.
(4) The pharmaceutical preparation according to any one of (1) to (3), wherein the particle size of the core granule when screened is less than 2 mm.
(5) Particles having a particle size of less than 0.5 mm are less than 30% by mass of the whole pharmaceutical formulation, and particles having a particle size of 1.4 mm or more are less than 20% by mass of the entire pharmaceutical formulation. (4) The pharmaceutical preparation according to any one of the above.
(6) The pharmaceutical preparation according to any one of (1) to (5), wherein the binder contained in the core granule is 2 to 15% by mass relative to polystyrene sulfonate.
(7) The total of (a) a water-soluble polymer or a water-insoluble polymer, and (b) a sugar or a sugar alcohol is 2 to 25% by mass with respect to the whole pharmaceutical preparation, (1) to (6) The pharmaceutical formulation in any one.
(8) The (a) water-soluble polymer or water-insoluble polymer is 0.5 to 24.5% by mass with respect to the whole pharmaceutical preparation, and the (b) sugar or sugar alcohol is 0.5 to The pharmaceutical preparation according to (7), wherein the ratio is 24.5% by mass and the ratio of (a) :( b) is 1:20 to 20: 1.
(9) The pharmaceutical preparation according to any one of (1) to (8), wherein the coating layer comprises one layer.
(10) The pharmaceutical preparation according to any one of (1) to (9), wherein the core granule is produced by extrusion granulation and spherical granulation.
(11) The pharmaceutical preparation according to any one of (1) to (10), wherein the (a) water-soluble polymer or water-insoluble polymer is a water-soluble polymer.
(12) The water-soluble polymer is a cellulose derivative, pullulan, polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymer, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol, polyethylene glycol, methacrylic acid copolymer, The pharmaceutical preparation according to (11), which is at least one selected from the group consisting of polyethylene oxide, gum arabic powder, macrogol, and sucrose fatty acid ester.
(13) The pharmaceutical preparation according to (12), wherein the water-soluble polymer is a cellulose derivative, and the viscosity of a 2% by mass aqueous solution of the cellulose derivative at 20 ± 0.1 ° C. is 2 to 15000 mPa · m.
(14) The pharmaceutical preparation according to (13), wherein the cellulose derivative is one or more selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, and hydroxyethylcellulose.
(15) The pharmaceutical preparation according to any one of (1) to (10), wherein the water-soluble polymer or water-insoluble polymer (a) is a water-insoluble polymer.
(16) The pharmaceutical preparation according to (15), wherein the water-insoluble polymer is ethyl cellulose, a methacrylic acid copolymer, and a combination thereof.
(17) The (b) sugar or sugar alcohol is selected from the group consisting of mannitol, sorbitol, xylitol, erythritol, trehalose, sucrose, sucralose, lactose, lactitol, powdered reduced maltose syrup, glucose, fructose, and dextrin. The pharmaceutical preparation according to any one of (1) to (16), which is one or more kinds.
(18) The binder is dextrin, crystalline cellulose, hydroxypropylcellulose, ethylcellulose, pullulan, mannitol, polyvinylpyrrolidone, hydroxypropylmethylcellulose, low-substituted hydroxypropylcellulose, corn starch, methylcellulose, purified white sugar, reduced maltose water candy, And the pharmaceutical preparation according to any one of (1) to (17), which is at least one selected from the group consisting of reduced maltose.
本発明によれば、ポリスチレンスルホン酸塩を有効成分とする医薬製剤の服用感の改善と、医薬製剤中の賦形剤量の低減とを両立させることができる。 ADVANTAGE OF THE INVENTION According to this invention, improvement of the ingestion feeling of the pharmaceutical formulation which uses a polystyrene sulfonate as an active ingredient can be made compatible with reduction of the excipient | filler amount in a pharmaceutical formulation.
以下に、本発明のポリスチレンスルホン酸塩製剤について説明する。本発明に係る医薬製剤は、ポリスチレンスルホン酸塩を含有する核顆粒、及び(a)水溶性高分子又は水不溶性高分子と(b)糖又は糖アルコールとの組み合わせからなる被覆層、を有することを特徴とする医薬製剤である。前記(a)及び(b)で核顆粒を被覆することにより、服用感の改善と賦形剤の低減という相反する課題を解決することができる。 Below, the polystyrene sulfonate formulation of this invention is demonstrated. The pharmaceutical preparation according to the present invention has core granules containing polystyrene sulfonate, and (a) a coating layer made of a combination of a water-soluble polymer or water-insoluble polymer and (b) a sugar or a sugar alcohol. Is a pharmaceutical preparation characterized by By coating the core granules with the above (a) and (b), the conflicting problems of improving the feeling of taking and reducing the excipient can be solved.
ポリスチレンスルホン酸塩とは、陽イオン交換樹脂である。具体的には、ポリスチレンスルホン酸カルシウム及びポリスチレンスルホン酸ナトリウム等が挙げられる。レーザー回折法による粉体粒度測定をした時の、ポリスチレンスルホン酸塩の50%粒子径は、5〜100μmが好ましく、20〜60μmがより好ましい。ポリスチレンスルホン酸塩の50%粒子径が大きすぎると口腔内でザラツキを感じる。一方、小さすぎると口腔内に長時間残留するので、服用感が悪くなる。ここで、50%粒子径とは、エタノールに分散させてレーザー回折法による粉体粒度測定をした時、発生頻度の累積50%時点の粒子径をいう。 Polystyrene sulfonate is a cation exchange resin. Specific examples include calcium polystyrene sulfonate and sodium polystyrene sulfonate. The 50% particle size of polystyrene sulfonate when the powder particle size is measured by laser diffraction is preferably 5 to 100 μm, more preferably 20 to 60 μm. If the 50% particle size of polystyrene sulfonate is too large, it will feel rough in the oral cavity. On the other hand, if it is too small, it will remain in the oral cavity for a long time, resulting in a poor feeling of taking. Here, the 50% particle size refers to the particle size at the time when the cumulative frequency of occurrence is 50% when the particle size is measured by laser diffraction method after being dispersed in ethanol.
核顆粒は、ポリスチレンスルホン酸塩及び結合剤を含有する核顆粒であり、公知の方法に従って製造することができる。例えば、ポリスチレンスルホン酸塩を結合剤とともに練合し、球形整粒機などにより球形にすることができる。練合する際の溶媒としては、例えば、水、エタノール、及びこれらの混合物が挙げられ、当業者であれば適宜選択できる。 The core granule is a core granule containing polystyrene sulfonate and a binder, and can be produced according to a known method. For example, polystyrene sulfonate can be kneaded with a binder and formed into a spherical shape by a spherical granulator. Examples of the solvent for kneading include water, ethanol, and a mixture thereof, and those skilled in the art can appropriately select them.
結合剤は、医薬製剤が溶解したときに有効成分であるポリスチレンスルホン酸塩のカルシウム又はナトリウムとイオン交換が起こり難いものが好ましい。例えば、デキストリン、結晶セルロース、ヒドロキシプロピルセルロース(HPC)、エチルセルロース(EC)、マンニトール、ポリビニルピロリドン(PVP、ポビドン)、ヒドロキシプロピルメチルセルロース(HPMC)、低置換度ヒドロキシプロピルセルロース(L−HPC)、トウモロコシデンプン、メチルセルロース、精製白糖、還元麦芽糖水アメ、及び還元麦芽糖等が挙げられ、これらから選択される1種以上を適宜組み合わせて用いることができる。一方、アルギン酸ナトリウム、カゼインナトリウム、酒石酸ナトリウムカリウム、メタリン酸ナトリウム、ラウリル硫酸ナトリウム、カルボキシメチルスターチナトリウム、カルメロースカルシウム及びカルメロースナトリウムなどは、医薬製剤が溶解したときに有効成分であるポリスチレンスルホン酸塩のカルシウム又はナトリウムとイオン交換が起こり、その有効成分中のカルシウム又はナトリウム含量が変化し、カリウム交換容量に差を来たすため好ましくない。結合剤は、有効成分に対し、通常1〜25質量%、好ましくは2〜15質量%、より好ましくは3〜10質量%使用する。結合剤が、有効成分に対し25質量%より多いと、医薬製剤全量の服用量が多くなるため好ましくない。尚、結合剤は、ポリスチレンスルホン酸塩に対し概ね1質量%以上であれば、ポリスチレンスルホン酸塩を顆粒化することができると考えられる。 The binder is preferably one that hardly undergoes ion exchange with calcium or sodium polystyrene sulfonate as an active ingredient when the pharmaceutical preparation is dissolved. For example, dextrin, crystalline cellulose, hydroxypropylcellulose (HPC), ethylcellulose (EC), mannitol, polyvinylpyrrolidone (PVP, povidone), hydroxypropylmethylcellulose (HPMC), low substituted hydroxypropylcellulose (L-HPC), corn starch , Methyl cellulose, purified white sugar, reduced maltose water candy, reduced maltose and the like, and one or more selected from these can be used in appropriate combination. On the other hand, sodium alginate, sodium caseinate, sodium potassium tartrate, sodium metaphosphate, sodium lauryl sulfate, sodium carboxymethyl starch, carmellose calcium and carmellose sodium are polystyrene sulfonates that are active ingredients when the pharmaceutical preparation is dissolved This is not preferable because ion exchange occurs with calcium or sodium, and the content of calcium or sodium in the active ingredient changes, resulting in a difference in potassium exchange capacity. The binder is usually used in an amount of 1 to 25% by weight, preferably 2 to 15% by weight, more preferably 3 to 10% by weight, based on the active ingredient. When the amount of the binder is more than 25% by mass based on the active ingredient, it is not preferable because the dose of the whole pharmaceutical preparation increases. In addition, it is thought that a polystyrene sulfonate can be granulated if a binder is about 1 mass% or more with respect to a polystyrene sulfonate.
核顆粒の形状は、特に限定されないが、より均一な被覆層を施したい場合は、球状であることが望ましい。核顆粒を球状にする場合には、遠心転動造粒法、転動流動造粒法、流動造粒法、攪拌造粒法、押し出し造粒法などの方法により行うことができる。中でも押し出し造粒法により行うのが好ましい。これによれば、核顆粒の比容積を低減することができる。また、製造装置も限定されるものではないが、例えば、遠心転動造粒コーティング機のような複合造粒機を用いれば、操作性が良好で効率よく製造できる。また、押し出し造粒法に引き続き、球形整粒機を用いて球形整粒により製造することもできる。 The shape of the core granule is not particularly limited, but it is preferably spherical when a more uniform coating layer is desired. When the core granule is made spherical, it can be performed by a method such as centrifugal rolling granulation method, rolling fluid granulation method, fluid granulation method, stirring granulation method, extrusion granulation method or the like. Of these, the extrusion granulation method is preferable. According to this, the specific volume of the nuclear granule can be reduced. Also, the production apparatus is not limited. For example, if a composite granulator such as a centrifugal rolling granulation coating machine is used, the operability is good and the production can be efficiently performed. Further, following the extrusion granulation method, it can also be produced by spherical granulation using a spherical granulator.
核顆粒の粒子径は、目開き0.25mm、1.4mm、及び2mmの篩を用いて篩い分けを行うとき、2mm未満であることが好ましく、1.4mm未満であることがさらに好ましい。ただし、核顆粒の粒子径が細かすぎると、粒子径が大きいものより単位質量当たりの表面積が大きくなり、吸水感及び灼熱感の抑制がより難しくなると考えられるため、粒子径が0.25mm未満の核顆粒の割合をできる限り減らすのが好ましい。また、食感が悪くなるため、粒子径が2.0mm以上の核顆粒の割合をできる限り減らすのが好ましい。 The particle size of the core granule is preferably less than 2 mm, more preferably less than 1.4 mm when sieving is performed using a sieve having openings of 0.25 mm, 1.4 mm, and 2 mm. However, if the particle size of the core granule is too small, the surface area per unit mass will be larger than that of the larger particle size, and it will be more difficult to suppress water absorption and burning sensation. It is preferable to reduce the proportion of granules as much as possible. Moreover, since the texture becomes worse, it is preferable to reduce the proportion of core granules having a particle size of 2.0 mm or more as much as possible.
本発明の核顆粒の表面には被覆層が形成される。該被覆層は少なくとも(a)水溶性高分子又は水不溶性高分子と、(b)糖又は糖アルコールとの組み合わせからなる。被覆層は、1層又は2層以上であっても良い。前記(a)及び(b)を含む被覆層を1層以上形成しても良いし、前記(a)を含む被覆層(第1層)の上に更に、前記(b)を含む被覆層(第2層)を形成しても良い。製造工程を少なくするためには、被覆層は1層であることが好ましい。前記(a)と(b)とを組み合わせて被覆すれば、ポリスチレンスルホン酸塩を高含有し、賦形剤の量が少ない医薬製剤であっても、ポリスチレンスルホン酸塩服用時特有の吸水感及び灼熱感を著しく抑制することができる。前記(a)及び(b)を被覆する際の溶媒としては、例えば、水、エタノール、及びこれらの混合物が挙げられ、当業者であれば適宜選択できる。 A coating layer is formed on the surface of the core granule of the present invention. The coating layer comprises a combination of at least (a) a water-soluble polymer or a water-insoluble polymer and (b) a sugar or a sugar alcohol. The coating layer may be one layer or two or more layers. One or more coating layers containing (a) and (b) may be formed, and the coating layer containing (b) is further formed on the coating layer (first layer) containing (a). A second layer) may be formed. In order to reduce the number of manufacturing steps, the coating layer is preferably a single layer. When coated in combination with the above (a) and (b), even a pharmaceutical preparation containing a high amount of polystyrene sulfonate and a small amount of excipient, a water-absorbing feeling peculiar to taking polystyrene sulfonate and A burning sensation can be remarkably suppressed. Examples of the solvent for coating (a) and (b) include water, ethanol, and a mixture thereof, and those skilled in the art can appropriately select them.
前記(a)水溶性高分子又は水不溶性高分子は、医薬製剤全体に対し、通常0.5〜24.5質量%、好ましくは0.5〜20質量%、より好ましくは0.5〜10質量%、更に好ましくは0.5〜5質量%添加する。ポリスチレンスルホン酸塩に対しては、通常0.5〜30質量%、好ましくは0.5〜22質量%、より好ましくは0.5〜15質量%、更に好ましくは0.5〜6質量%添加する。具体的な添加量は、ポリスチレンスルホン酸塩5gに対して0.025〜1.5gが通常であり、0.025〜1.1gが好ましく、0.025〜0.75gがより好ましく、0.025〜0.3gが更に好ましい。 The (a) water-soluble polymer or water-insoluble polymer is usually 0.5 to 24.5% by mass, preferably 0.5 to 20% by mass, more preferably 0.5 to 10% by mass, and still more preferably 0.5 to Add 5% by weight. The polystyrene sulfonate is added in an amount of usually 0.5 to 30% by mass, preferably 0.5 to 22% by mass, more preferably 0.5 to 15% by mass, and further preferably 0.5 to 6% by mass. The specific addition amount is usually 0.025 to 1.5 g, preferably 0.025 to 1.1 g, more preferably 0.025 to 0.75 g, and still more preferably 0.025 to 0.3 g with respect to 5 g of polystyrene sulfonate.
前記水溶性高分子としては、例えば、セルロース誘導体、メチルビニルエーテル・無水マレイン酸共重合体、酢酸フタル酸セルロース、プルラン、キサンタンガム、トラガントガム、アラビアゴム末、寒天、ゼラチン、ポリエチレンオキサイド、ポリビニルピロリドン(PVP、ポビドン)、ポリビニルアルコール・ポリエチレングリコールグラフト共重合体、アミノアルキルメタクリラート共重合体、メタクリル酸共重合体、カルボキシビニルポリマー、ポリビニルアルコール、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、ビニルピロリドン・酢酸ビニル共重合体(コポリビドン)、及びポリエチレングリコール(マクロゴール)ショ糖脂肪酸エステル等が挙げられ、これらから選択される1種以上を適宜組み合わせて用いることができる。 Examples of the water-soluble polymer include cellulose derivatives, methyl vinyl ether / maleic anhydride copolymer, cellulose acetate phthalate, pullulan, xanthan gum, tragacanth gum, gum arabic powder, agar, gelatin, polyethylene oxide, polyvinylpyrrolidone (PVP, Povidone), polyvinyl alcohol / polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, vinylpyrrolidone / Vinyl acetate copolymer (copolyvidone), polyethylene glycol (macrogol) sucrose fatty acid ester, etc. are mentioned, and one or more selected from these are appropriately combined. It is possible to have.
前記セルロース誘導体としては、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、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシエチルセルロース、及びヒドロキシプロピルメチルセルロースアセテートサクシネートが挙げられる。これらそれぞれのセルロース誘導体においては、水又はエタノールに溶解した時の粘度が異なるものが存在するが、20±0.1℃における2質量%溶液の粘度が2〜15000mPa・mのものが好ましく、2〜12000mPa・mのものがより好ましい。粘度が高すぎるとコーティングし難くなり、粘度が低すぎると被覆製剤の保存安定性に影響が出易い。 Examples of the cellulose derivative include hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), methylcellulose, hydroxypropylmethylcellulose phthalate, hydroxyethylcellulose, and hydroxypropylmethylcellulose acetate succinate. Among these cellulose derivatives, those having different viscosities when dissolved in water or ethanol exist, but those having a viscosity of 2 to 15000 mPa · m at 2 ± 1% at 20 ± 0.1 ° C. are preferred, and 2 to 12000 mPa -M is more preferable. If the viscosity is too high, coating becomes difficult, and if the viscosity is too low, the storage stability of the coated preparation tends to be affected.
これら水溶性高分子の中でも、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ポリビニルピロリドン、プルラン、アミノアルキルメタクリラート共重合体、メタクリル酸共重合体、ポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体、及びショ糖脂肪酸エステルから選択される1種以上の組み合わせが好ましく、より好ましくは、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、プルラン、ポリビニルピロリドン、及びポリビニルアルコール・アクリル酸・メタクリル酸メチル共重合体から選択される1種以上の組み合わせが好ましい。一方、ポリアクリル酸ナトリウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム、及びカルメロースカルシウム又はカルメロースナトリウムなどは、溶解したときに有効成分であるポリスチレンスルホン酸塩のカルシウム又はナトリウムとイオン交換が起こり、その有効成分中のカルシウム又はナトリウム含量が変化し、カリウム交換容量に差を来たすため好ましくない。 Among these water-soluble polymers, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, pullulan, aminoalkyl methacrylate copolymer, methacrylic acid copolymer, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, And a combination of one or more selected from sucrose fatty acid esters, more preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, pullulan, polyvinylpyrrolidone, and polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer One or more selected combinations are preferred. On the other hand, sodium polyacrylate, croscarmellose sodium, carboxymethyl starch sodium, and carmellose calcium or carmellose sodium ion exchange occurs with calcium or sodium polystyrene sulfonate as an active ingredient when dissolved, This is not preferable because the calcium or sodium content in the active ingredient changes and causes a difference in potassium exchange capacity.
前記水不溶性高分子としては、例えば、エチルセルロース、メタクリル酸コポリマー、カルボキシルメチルセルロースナトリウム(CMC-Na)、コムギデンプン、コメデンプン、トウモロコシデンプン、バレイショデンプン、ヒドロキシプロピルスターチ、アミノアルキルメタクリレート共重合体、カルボキシビニルポリマー、ポリビニルアルコール(完全けん化物)、精製セラック、白色セラック、及びポリオキシエチレン硬化ヒマシ油等が挙げられ、これらから選択される1種以上を適宜組み合わせて用いることができる。好ましくは、エチルセルロース、カルボキシルメチルセルロースナトリウム、アミノアルキルメタクリレート共重合体、ポリビニルアルコール(完全けん化物)、及びポリオキシエチレン硬化ヒマシ油から選択される1種以上の組み合わせであり、より好ましくは、エチルセルロース、アミノアルキルメタクリレート共重合体、及びそれらの組み合わせである。 Examples of the water-insoluble polymer include ethyl cellulose, methacrylic acid copolymer, sodium carboxymethyl cellulose (CMC-Na), wheat starch, rice starch, corn starch, potato starch, hydroxypropyl starch, aminoalkyl methacrylate copolymer, and carboxyvinyl. Examples thereof include polymers, polyvinyl alcohol (completely saponified product), purified shellac, white shellac, and polyoxyethylene hydrogenated castor oil. One or more selected from these can be used in appropriate combination. Preferably, it is a combination of one or more selected from ethyl cellulose, sodium carboxymethyl cellulose, aminoalkyl methacrylate copolymer, polyvinyl alcohol (fully saponified product), and polyoxyethylene hydrogenated castor oil, more preferably ethyl cellulose, amino Alkyl methacrylate copolymers, and combinations thereof.
前記(b)糖又は糖アルコールは、医薬製剤全体に対し、通常0.5〜24.5質量%、好ましくは1〜20質量%、より好ましくは1.5〜10質量%添加する。また、ポリスチレンスルホン酸塩に対しては、通常0.5〜30質量%、好ましくは1〜25質量%、より好ましくは2〜15質量%添加する。具体的な添加量は、ポリスチレンスルホン酸塩5gに対して通常0.025〜1.5g、好ましくは0.05〜1.25g、より好ましくは0.10〜0.75gである。 The (b) sugar or sugar alcohol is usually added in an amount of 0.5 to 24.5% by mass, preferably 1 to 20% by mass, more preferably 1.5 to 10% by mass, based on the whole pharmaceutical preparation. Moreover, it is 0.5-30 mass% normally with respect to a polystyrene sulfonate, Preferably it is 1-25 mass%, More preferably, 2-15 mass% is added. The specific addition amount is usually 0.025 to 1.5 g, preferably 0.05 to 1.25 g, and more preferably 0.10 to 0.75 g with respect to 5 g of polystyrene sulfonate.
前記(b)糖又は糖アルコールは、溶解時に吸熱反応を示すものが好ましい。例えば、フルクトース、グルコース、ガラクトース、ソルビトール、マンニトール、キシロース、キシリトール、及びエリスリトールなどの単糖類、スクロース、マルトース、スクラロース、ラクトース、イソマルトース、トレハロース、マルチトール、ラクチトール、パラチノース、ラクツロース、及びパラチニットなどの二糖類、直鎖オリゴ糖、イソマルトオリゴ糖、マルトテトラオース、マルトペンタオース、大豆オリゴ糖、キシロオリゴ糖、乳果オリゴ糖、ガラクトオリゴ糖、及びフラクトオリゴ糖などのオリゴ糖、他に、水飴、還元水飴、カップリングシュガーなどの糖類、及びデキストリン等が挙げられる。これらの中では、ソルビトール、マンニトール、エリスリトール、スクラロース、及びラクトースが好ましいものとして挙げられる。糖又は糖アルコールは、これらから選択される1種以上を単独で又は適宜組み合わせて用いることができる。一方、糖又は糖アルコール以外の人工甘味料(例えばサッカリン等)を用いた場合、若しくはグリシン等の糖原性アミノ酸を用いた場合は、服用感の悪さは抑制し難い。 The (b) sugar or sugar alcohol preferably shows an endothermic reaction when dissolved. For example, two sugars such as fructose, glucose, galactose, sorbitol, mannitol, xylose, xylitol, and erythritol, sucrose, maltose, sucralose, lactose, isomaltose, trehalose, maltitol, lactitol, palatinose, lactulose, and palatinit Saccharides, linear oligosaccharides, isomaltoligosaccharides, maltotetraose, maltopentaose, soybean oligosaccharides, xylo-oligosaccharides, dairy oligosaccharides, galacto-oligosaccharides, and oligosaccharides such as fructooligosaccharides, Examples include sugars such as coupling sugar, and dextrin. Among these, sorbitol, mannitol, erythritol, sucralose, and lactose are preferable. As the sugar or sugar alcohol, one or more selected from these can be used alone or in appropriate combination. On the other hand, when an artificial sweetener (such as saccharin) other than sugar or sugar alcohol is used, or when a glycogenic amino acid such as glycine is used, the poor feeling of taking is difficult to suppress.
被覆層に使用する(a)水溶性高分子又は水不溶性高分子と(b)糖又は糖アルコールとの組み合わせとしては、例えば、以下の組み合わせが挙げられる。前記(a)として、ヒドロキシプロピルメチルセルロースを(i)、ヒドロキシプロピルセルロースを(ii)、メチルセルロースを(iii)、プルランを(iv)、ポリビニルピロリドンを(v)、メタクリル酸・アクリル酸エチル共重合体を(vi)、アラビアゴム末を(vii)、ポリエチレングリコールを(viii)、ショ糖脂肪酸エステルを(ix)として示す。前記(b)として、ソルビトールを(x)、マンニトールを(xi)、エリスリトールを(xii)、スクラロースを(xiii)、ラクトースを(xiv)、キシリトールを(xv)、トレハロースを(xvi)、ラクチトールを(xvii)、スクロースを(xviii)、粉末還元麦芽糖水飴を(xix)、ブドウ糖を(xx)、フルクトースを(xxi)、デキストリンを(xxii)として示すと、以下のようになる。
(i,x)、(i,xi)、(i,xii)、(i,xiii)、(i,xiv)、(i,xv)、(i,xvi)、(i,xvii)、(i,xviii)、(i,xix)、(i,xx)、(ii,x)、(ii,xi)、(ii,xii)、(ii,xiii)、(ii,xiv)、(ii,xv)、(ii,xvi)、(ii,xvii)、(ii,xviii)、(ii,xix)、(ii,xx)、(iii,x)、(iii,xi)、(iii,xii)、(iii,xiii)、(iii,xiv)、(iii,xv)、(iii,xvi)、(iii,xvii)、(iii,xviii)、(iii,xix)、(iii,xx)、(iv,x)、(iv,xi)、(iv,xii)、(iv,xiii)、(iv,xiv)、(iv,xv)、(iv,xvi)、(iv,xvii)、(iv,xviii)、(iv,xix)、(iv,xx)、(v,x)、(v,xi)、(v,xii)、(v,xiii)、(v,xiv)、(v,xv)、(v,xvi)、(v,xvii)、(v,xviii)、(v,xix)、(v,xx)、(vi,x)、(vi,xi)、(vi,xii)、(vi,xiii)、(vi,xiv)、(vi,xv)、(vi,xvi)、(vi,xvii)、(vi,xviii)、(vi,xix)、(vi,xx)、(vii,x)、(vii,xi)、(vii,xii)、(vii,xiii)、(vii,xiv)、(vii,xv)、(vii,xvi)、(vii,xvii)、(vii,xviii)、(vii,xix)、(vii,xx)、(viii,x)、(viii,xi)、(viii,xii)、(viii,xiii)、(viii,xiv)、(viii,xv)、(viii,xvi)、(viii,xvii)、(viii,xviii)、(viii,xix)、(viii,xx)、(ix,x)、(ix,xi)、(ix,xii)、(ix,xiii)、(ix,xiv)、(ix,xv)、(ix,xvi)、(ix,xvii)、(ix,xviii)、(ix,xix)、(ix,xx)、(i+viii,xii)、(i,xiv+viii)、(i,xi+viii)、(i,x+viii)、(i+viii,xi+viii)、(i,xi+xiii)Examples of the combination of (a) water-soluble polymer or water-insoluble polymer and (b) sugar or sugar alcohol used for the coating layer include the following combinations. As (a), hydroxypropyl methylcellulose (i), hydroxypropylcellulose (ii), methylcellulose (iii), pullulan (iv), polyvinylpyrrolidone (v), methacrylic acid / ethyl acrylate copolymer (Vi), gum arabic powder (vii), polyethylene glycol (viii), and sucrose fatty acid ester (ix). As (b), sorbitol (x), mannitol (xi), erythritol (xii), sucralose (xiii), lactose (xiv), xylitol (xv), trehalose (xvi), lactitol (Xvii), sucrose (xviii), powdered reduced maltose starch syrup (xix), glucose (xx), fructose (xxi) and dextrin (xxii) are as follows.
(I, x), (i, xi), (i, xii), (i, xiii), (i, xiv), (i, xv), (i, xvi), (i, xvii), (i , Xviii), (i, xix), (i, xx), (ii, x), (ii, xi), (ii, xii), (ii, xiii), (ii, xiv), (ii, xv ), (Ii, xvi), (ii, xvii), (ii, xviii), (ii, xix), (ii, xx), (iii, x), (iii, xi), (iii, xii), (Iii, xiii), (iii, xiv), (iii, xv), (iii, xvi), (iii, xvii), (iii, xviii), (iii, xix), (iii, xx), (iv , X), (iv, xi), (iv, xii), (iv, xiii), (iv, xiv), (iv, xv), (iv, xvi), (iv, xvii), (iv, xviii) ), (Iv, xix), (iv, xx), (v, x), (v, xi), (v, xii), (v, xiii), (v, xiv), (v, xv), (V, xvi), (v, xvii), (v, xviii), (v, xix), (v, xx), (vi, x), (vi, xi), (vi, xii), (vi , Xiii), (vi, xiv) (Vi, xv), (vi, xvi), (vi, xvii), (vi, xviii), (vi, xix), (vi, xx), (vii, x), (vii, xi), (vii , Xii), (vii, xiii), (vii, xiv), (vii, xv), (vii, xvi), (vii, xvii), (vii, xviii), (vii, xix), (vii, xx ), (Viii, x), (viii, xi), (viii, xii), (viii, xiii), (viii, xiv), (viii, xv), (viii, xvi), (viii, xvii), (Viii, xviii), (viii, xix), (viii, xx), (ix, x), (ix, xi), (ix, xii), (ix, xiii), (ix, xiv), (ix , Xv), (ix, xvi), (ix, xvii), (ix, xviii), (ix, xix), (ix, xx), (i + viii, xii), (i, xiv + viii), (i, xi + viii) ), (I, x + viii), (i + viii, xi + viii), (i, xi + xiii)
被覆層に含まれる(a)水溶性高分子又は水不溶性高分子と(b)糖又は糖アルコールとの合計は、医薬製剤全体に対して1〜30質量%、好ましくは2〜25質量%、より好ましくは3〜20質量%である。前記(a):(b)の比は1:20〜20:1、好ましくは1:12〜4:1、より好ましくは1:10〜2:1である。 The total of (a) water-soluble polymer or water-insoluble polymer and (b) sugar or sugar alcohol contained in the coating layer is 1 to 30% by mass, preferably 2 to 25% by mass, based on the whole pharmaceutical preparation, More preferably, it is 3-20 mass%. The ratio of (a) :( b) is 1:20 to 20: 1, preferably 1:12 to 4: 1, and more preferably 1:10 to 2: 1.
核顆粒の表面に被覆層を施すときは、流動造粒機、転動造粒機などの製造装置を使用し、(a)水溶性高分子又は水不溶性高分子と(b)糖又は糖アルコールとの組み合わせからなる被覆液で被覆することができる。当業者であれば、被覆液の最適濃度を適宜設定できる。本発明における被覆とは、液状物質で一時的に覆われた「被覆」状態、全体に均一な「被覆」状態、又は、全体に不均一な「被覆」状態を意味し、全体を被覆するもののみならず、部分的に被覆するものをも含む。前記本発明の組み合わせで核顆粒の表面被覆を行えば、均一に被覆されていなくともポリスチレンスルホン酸塩の服用感の悪さを抑制することができる。言い換えると、核顆粒をマスキングする組成と厚みでなくともポリスチレンスルホン酸塩の服用感の悪さを抑制することができる。 When applying a coating layer on the surface of the core granule, use a production apparatus such as a fluid granulator or a tumbling granulator, and (a) a water-soluble polymer or water-insoluble polymer and (b) a sugar or sugar alcohol. It can coat | cover with the coating liquid which consists of a combination. A person skilled in the art can appropriately set the optimum concentration of the coating liquid. The term “coating” in the present invention means a “coating” state temporarily covered with a liquid substance, a “coating” state that is uniform throughout, or a “coating” state that is non-uniform throughout, and covers the whole. As well as those that partially cover. If the surface coating of the core granule is performed with the combination of the present invention, it is possible to suppress the poor feeling of taking the polystyrene sulfonate even if it is not uniformly coated. In other words, it is possible to suppress the poor feeling of taking the polystyrene sulfonate even if the composition and thickness mask the core granules.
有効成分であるポリスチレンスルホン酸塩は、医薬製剤全体に対して65〜95質量%、好ましくは70〜93質量%、より好ましくは75〜90質量%含まれる。本発明の医薬製剤では、有効成分:賦形剤の組成比は95:5〜65:35であり、93:7〜70:30の範囲にあることが好ましく、90:10〜75:25の範囲にあることがさらに好ましい。本発明によれば、服用性を確保するために通常必要な賦形剤の量より少ない量で、ポリスチレンスルホン酸塩特有の服用感の悪さを抑制できる。尚、ポリスチレンスルホン酸塩の含有率(質量%)を下げ過ぎることは、服用する医薬製剤の体積を必要以上に増加させることになり、服用し辛い医薬製剤となってしまう。 The polystyrene sulfonate which is an active ingredient is contained at 65 to 95% by mass, preferably 70 to 93% by mass, and more preferably 75 to 90% by mass with respect to the whole pharmaceutical preparation. In the pharmaceutical preparation of the present invention, the composition ratio of active ingredient: excipient is 95: 5 to 65:35, preferably in the range of 93: 7 to 70:30, 90:10 to 75:25 More preferably, it is in the range. According to the present invention, it is possible to suppress the inferior taking feeling peculiar to polystyrene sulfonates in an amount smaller than the amount of excipients usually required for ensuring dosing. In addition, when the content rate (mass%) of a polystyrene sulfonate is reduced too much, it will increase the volume of the pharmaceutical formulation to take more than necessary, and will become a pharmaceutical formulation which is hard to take.
本発明の医薬製剤(被覆製剤)の粒子径は、目開き0.5mm、1.4mm、及び2.0mmの篩を用いて篩い分けを行うとき、0.5mm未満の粒子が医薬製剤全体の30質量%未満となるようにすることが好ましい。また、2.0mm以上の粒子は含まないことが好ましく、1.4mm以上2.0mm未満の粒子は、医薬製剤全体の20質量%未満となるようにすることが好ましい。従って、0.5mm未満の粒子が医薬製剤全体の30質量%未満であり、且つ1.4mm以上2.0mm未満の粒子が医薬製剤全体の20質量%未満であり、しかも、2.0mm以上の粒子を含まない本発明の医薬製剤(被覆製剤)は特に好ましいものである。実質的に考えると、0.5mm未満の粒子が医薬製剤全体の30質量%未満であり、且つ1.4mm以上の粒子が医薬製剤全体の20質量%未満となる本発明の医薬製剤(被覆製剤)は、特に好ましいものと言える。尚、粒子径0.25mm未満の被覆製剤の割合が多くなると吸水感及び灼熱感の抑制がより難しくなり、粒子径1.4mm以上の被覆製剤の割合が多くなると食感が悪くなる。 The particle diameter of the pharmaceutical preparation (coating preparation) of the present invention is less than 30% by mass of particles less than 0.5 mm when sieving is performed using a sieve having openings of 0.5 mm, 1.4 mm, and 2.0 mm. It is preferable that Moreover, it is preferable not to contain particles of 2.0 mm or more, and particles of 1.4 mm or more and less than 2.0 mm are preferably less than 20% by mass of the whole pharmaceutical preparation. Accordingly, particles less than 0.5 mm are less than 30% by mass of the whole pharmaceutical preparation, and particles of 1.4 mm or more and less than 2.0 mm are less than 20% by mass of the whole pharmaceutical preparation, and do not contain particles of 2.0 mm or more. The pharmaceutical preparation (coating preparation) of the present invention is particularly preferred. When considered substantially, the pharmaceutical preparation (coated preparation) of the present invention in which particles of less than 0.5 mm are less than 30% by weight of the whole pharmaceutical preparation and particles of 1.4 mm or more are less than 20% by weight of the whole pharmaceutical preparation, This is particularly preferable. In addition, when the ratio of the coating preparation having a particle size of less than 0.25 mm increases, it becomes more difficult to suppress the water absorption feeling and the burning feeling, and when the ratio of the coating preparation having a particle diameter of 1.4 mm or more increases, the texture becomes worse.
本発明の医薬製剤は、必要に応じて更に、通常使用されている甘味剤、着色料、香料、保存剤、防かび剤、界面活性剤等を添加することができる。これらは、核顆粒部分、又は被覆層部分に添加することができる。 If necessary, the pharmaceutical preparation of the present invention may further contain commonly used sweeteners, colorants, fragrances, preservatives, fungicides, surfactants and the like. These can be added to the core granule part or the coating layer part.
以下、実施例によって本発明を具体的に説明するが、これらは本発明の範囲を限定するものではない。 EXAMPLES Hereinafter, the present invention will be specifically described by way of examples, but these do not limit the scope of the present invention.
(発熱量試験方法)
10mLの精製水中に測定対象物質を投入し、一定間隔で精製水の温度を記録した。測定対象物質の投入量は日本薬局方ポリスチレンスルホン酸カルシウムの量として5gとした。服用感の観点から、発熱量は、口腔内へ投与10秒後で、5℃未満の温度上昇が好ましく、3℃未満の温度上昇が更に好ましい。(Heat generation test method)
The substance to be measured was put into 10 mL of purified water, and the temperature of the purified water was recorded at regular intervals. The input amount of the substance to be measured was 5 g as the amount of Japanese Pharmacopoeia polystyrene calcium sulfonate. From the viewpoint of taking feeling, the calorific value is preferably a temperature increase of less than 5 ° C., more preferably a temperature increase of less than 3 ° C. 10 seconds after administration into the oral cavity.
(吸水量試験方法)
吸水量測定装置を作成し、対象物質が吸水する水の量を測定した。吸水量測定装置の模式図を図1に示す。湿潤したろ紙上に測定対象物質を置き、その底面から37℃に調温された精製水が測定対象物質に浸透する量の時間変化を測定した。すなわち、先ず(e)を操作し、(j)から(f)が通水するようにし、(f)内に精製水を満たす。次いで(f)から(b)が通水するように(e)を操作し、(b)を十分湿潤させた。更に(j)より(d)を引き抜き、(d)から(f)が通水するように(e)を操作して精製水の水面を(g)の目盛りのゼロ点に合わせた。最後に(g)から(b)が通水するように(e)を操作し、(b)上に(a)を載せると同時に(h)にて(a)の状態を、(i)にて(g)の水面の位置を経過時間と同時に記録した。(i)に記録された経過時間及び水面位置情報により、(a)の吸水量を算出した。(Water absorption test method)
A water absorption measuring device was created and the amount of water absorbed by the target substance was measured. A schematic diagram of the water absorption measuring device is shown in FIG. The measurement target substance was placed on a wet filter paper, and the change over time in the amount of purified water adjusted to 37 ° C. from the bottom surface of the measurement target substance was measured. That is, first, (e) is operated so that water passes from (j) to (f), and (f) is filled with purified water. Next, (e) was operated so that (f) to (b) could pass water, and (b) was sufficiently wetted. Further, (d) was extracted from (j), and (e) was operated so that (d) to (f) could pass through, so that the surface of the purified water was adjusted to the zero point on the scale of (g). Finally, operate (e) so that (b) passes through (b) and place (a) on (b) .At the same time, (h) changes the state of (a) to (i). The position of the water surface in (g) was recorded simultaneously with the elapsed time. Based on the elapsed time and water surface position information recorded in (i), the water absorption amount in (a) was calculated.
(官能試験1の試験方法)
試験担当者1名が服用感テストを行った。各顆粒剤の陽イオン交換樹脂として5gに相当する量を懸濁せずに口に含み、その吸水感及び灼熱感について評価した。(Test method for sensory test 1)
One person in charge of the test performed a dosing test. An amount corresponding to 5 g as a cation exchange resin for each granule was included in the mouth without suspending, and its water absorption feeling and burning feeling were evaluated.
(官能試験2の試験方法)
49歳〜62歳のパネラー14名により官能試験を実施した。各パネラーは、各顆粒剤の陽イオン交換樹脂として5gに相当する量を懸濁せずに口に含んだ後、50mL以下の水を各パネラーが必要な量服用し、服用感の良かった順に順位をつけた。(Test method for sensory test 2)
A sensory test was conducted by 14 panelists aged 49 to 62 years. Each paneler contains 5 g of the cation exchange resin for each granule in the mouth without suspending it, then take 50 mL or less of water as needed by each paneler, in order of good feeling. Ranking.
(官能試験3の試験方法)
25歳〜35歳のパネラー9名により官能試験を実施した。各パネラーは、各顆粒剤の陽イオン交換樹脂として5gに相当する量を懸濁せずに口に含んだ後、水50mLを3回に分けて服用し、服用感の良かった順に順位をつけた。(Test method for sensory test 3)
A sensory test was conducted by nine panelists aged 25 to 35 years. Each paneler should take an amount equivalent to 5 g as a cation exchange resin for each granule in the mouth without suspending it, and then take 50 mL of water in three divided doses, and rank them in the order of good feeling. It was.
(官能試験4の試験方法)
24歳〜29歳のパネラー6名により官能試験を実施した。各パネラーは、各顆粒剤の陽イオン交換樹脂として5gに相当する量を懸濁せずに口に含んだ後、水50mLを3回に分けて服用し、服用感が非常に良い場合を9点、服用感が非常に悪い場合を1点とし、各顆粒剤に対して点数をつけた。(Test method for sensory test 4)
Sensory tests were conducted by six panelists aged 24 to 29 years. Each paneler should take the amount corresponding to 5 g as a cation exchange resin for each granule in the mouth without suspending it, and then take 50 mL of water in 3 divided doses. A score was assigned for each granule, with a score of 1 point when the feeling of administration was very poor.
(官能試験5の試験方法)
25歳〜36歳のパネラー6名により官能試験を実施した。官能試験4と同様の方法で行った。(Test method for sensory test 5)
A sensory test was conducted by 6 panelists aged 25 to 36 years. The same method as in sensory test 4 was performed.
(処方)
実施例の処方(質量部)を表1及び表2に示し、比較例の処方(質量部)を表3に示した。(Prescription)
The formulations (parts by mass) of the examples are shown in Tables 1 and 2, and the formulations (parts by mass) of the comparative examples are shown in Table 3.
(製造方法)
ポリスチレンスルホン酸カルシウム(以下、陽イオン交換樹脂という。)、結合剤、及び練合時溶媒を加えて、混練機(PNT-5T;入江商会製、又は品川式混合攪拌機)を用いて練合を行い、練合物を調製した。陽イオン交換樹脂は、レーザー回折法による粉体粒度測定をした時の50%粒子径が約30μmのものを用いた。得られた練合物を目開き1mm又は1.5mmのスクリーン(ドームダイ)を装着した押し出し造粒機(DOME GRAN;不二パウダル製)により押し出し、続いて球形整粒機(マルメライザー;不二パウダル製)により整粒し、流動層造粒機(FLO;フロイント産業製)にて乾燥させ、核顆粒を調製した。(Production method)
Add polystyrene sulfonate calcium (hereinafter referred to as cation exchange resin), binder, and solvent during kneading, and knead using a kneader (PNT-5T; manufactured by Irie Shokai Co., Ltd. or Shinagawa type mixing stirrer). The kneaded product was prepared. As the cation exchange resin, one having a 50% particle size of about 30 μm when the particle size of the powder was measured by a laser diffraction method was used. The resulting kneaded product is extruded by an extrusion granulator (DOME GRAN; manufactured by Fuji Powder) equipped with a 1 mm or 1.5 mm screen (dome die), followed by a spherical granulator (Malmerizer; Fuji Powder) And then dried with a fluidized bed granulator (FLO; manufactured by Freund Corporation) to prepare core granules.
乾燥後、得られた核顆粒を目開き1.4mm又は2mmの篩を用いて篩分けを行い、目開き2mm又は目開き1.4mmの篩を通過した核顆粒をコーティングに用いた。一部の実施例については、目開き0.25mm及び目開き2mmの篩を用いて篩分けを行い、目開き2mmの篩を通過し、目開き0.25mmの篩を通過しなかった核顆粒をコーティングに用いた。 After drying, the obtained nuclear granules were sieved using a sieve having an aperture of 1.4 mm or 2 mm, and the nuclear granules having passed through the sieve having an aperture of 2 mm or an aperture of 1.4 mm were used for coating. For some examples, sieving is performed using a sieve with an opening of 0.25 mm and an opening of 2 mm, and the core granules that pass through the sieve with an opening of 2 mm and do not pass through the sieve with an opening of 0.25 mm are coated. Used for.
表1又は2に従い、被覆層又は被覆層の第一層に記載された賦形剤を水に溶解してコーティング液1を調製した。流動層造粒機(FLO;フロイント産業製)を用いて核顆粒にコーティング液1をコーティングした後乾燥し、コーティング顆粒剤(1層)とした。一方、コーティング層が2層である実施例については、被覆層の第二層に記載された賦形剤を水に溶解してコーティング液2を調製し、流動層造粒機を用いてコーティング顆粒剤(1層)に更にコーティング液2をコーティングした後乾燥し、コーティング顆粒剤(2層)とした。 According to Table 1 or 2, the excipient | filler described in the coating layer or the 1st layer of the coating layer was melt | dissolved in water, and the coating liquid 1 was prepared. Using a fluidized bed granulator (FLO; manufactured by Freund Sangyo Co., Ltd.), the core granule was coated with the coating liquid 1 and then dried to obtain a coated granule (one layer). On the other hand, in the example having two coating layers, the excipient described in the second layer of the coating layer is dissolved in water to prepare coating liquid 2, and the coated granule is prepared using a fluidized bed granulator. The coating solution (1 layer) was further coated with the coating liquid 2 and dried to obtain a coated granule (2 layers).
<試験1>被覆層に使用する賦形剤の検討
前記官能試験1の試験方法により、実施例1〜43、及び比較例1〜6を用いて服用感の検討を行った。試験結果を表4に示す。表中の記号は、○;吸水感及び灼熱感を感じない、×;吸水感及び灼熱感を感じることを意味する。<Test 1> Examination of excipients used for coating layer According to the test method of sensory test 1, the feeling of dosing was examined using Examples 1-43 and Comparative Examples 1-6. The test results are shown in Table 4. Symbols in the table indicate ◯: No water absorption and burning sensation, x: Water absorption and burning sensation.
(a)水溶性高分子、及び(b)糖又は糖アルコールの組み合わせで表面コーティングが施された実施例1〜11、及び実施例14〜43は、いずれの処方も服用直後の激しい吸水感及び灼熱感が抑制されていた。(a)水不溶性高分子及び(b)糖又は糖アルコールの組み合わせで表面コーティングが施された実施例12及び13も同様であった。これは表面コーティングが1層であっても2層であっても同様であった。 Examples 1 to 11 and Examples 14 to 43 in which a surface coating was applied with a combination of (a) a water-soluble polymer, and (b) a sugar or a sugar alcohol, The burning sensation was suppressed. The same was true for Examples 12 and 13, which were surface coated with a combination of (a) a water-insoluble polymer and (b) a sugar or sugar alcohol. This was the same whether the surface coating was one layer or two layers.
一方、表面コーティングが施されていない比較例1〜比較例3は、いずれの処方も服用直後に陽イオン交換樹脂をそのまま服用した場合と同程度の激しい吸水感及び灼熱感を感じ、更にはザラツキを感じた。比較例2及び比較例3では、核顆粒部にさらに(b)糖又は糖アルコールを添加しているが、それでも吸水感及び灼熱感を感じた。このことから、服用直後の激しい吸水感及び灼熱感を抑えるためには、核顆粒部の表面コーティングが必要であることが示された。また、(a)水溶性高分子単独の表面コーティングが施された比較例4でも、激しい吸水感及び灼熱感を感じ、更にはザラツキ及び粘つきを感じた。(b)糖又は糖アルコール単独の表面コーティングを試みた比較例5も同様に、服用感が悪かった。すなわち、(a)水溶性高分子若しくは水不溶性高分子単独のコーティング、又は(b)糖若しくは糖アルコール単独のコーティングでは賦形剤の量を少なくすると服用感の悪さを抑制することが難しいが、(a)水溶性高分子又は水不溶性高分子と(b)糖又は糖アルコールとを組み合わせてコーティングすることにより、少ない賦形剤の量で服用感を改善することができると結論した。 On the other hand, Comparative Examples 1 to 3 in which the surface coating was not applied, all the formulations felt as intense water absorption and burning as when the cation exchange resin was taken as it was immediately after taking it. I felt. In Comparative Example 2 and Comparative Example 3, (b) sugar or sugar alcohol was further added to the core granule part, but still felt water absorption and burning. From this, it was shown that the surface coating of the core granule is necessary to suppress the intense water absorption and burning feeling immediately after taking. Further, in Comparative Example 4 in which (a) the surface coating of the water-soluble polymer alone was applied, a strong water absorption feeling and a burning sensation were felt, and further, roughness and stickiness were felt. (b) Comparative Example 5 which attempted to coat the surface with sugar or sugar alcohol alone also had a poor feeling of taking. That is, it is difficult to suppress the poor feeling of taking by reducing the amount of excipient in (a) coating of water-soluble polymer or water-insoluble polymer alone, or (b) coating of sugar or sugar alcohol alone, It was concluded that by taking a combination of (a) a water-soluble polymer or a water-insoluble polymer and (b) a sugar or a sugar alcohol, the feeling of dosing can be improved with a small amount of excipient.
<試験2>吸水量の検討
前記吸水量試験方法により、実施例43、比較例7(市販の血清カリウム抑制散剤、興和株式会社製)及び比較例8(市販の血清カリウム抑制DS剤、興和株式会社製)が吸収する水の量を測定した。<Test 2> Examination of water absorption amount According to the water absorption amount test method, Example 43, Comparative Example 7 (commercially available serum potassium inhibitor powder, manufactured by Kowa Co., Ltd.) and Comparative Example 8 (commercially available serum potassium inhibitor DS agent, Kowa Co., Ltd.) The amount of water absorbed by the company) was measured.
測定の結果を図2に示す。実施例43は試験開始20秒後まで比較例7及び比較例8よりも吸水量が少なかった。すなわち、実施例43、比較例7、及び比較例8を実際に服用した場合において、口腔内に製剤が存在する服用開始から嚥下完了までの時間内においては、実施例43の吸水量は少なく、且つその吸水スピードも緩やかであると推定される。このようなメカニズムにより、(a)水溶性高分子又は水不溶性高分子、及び(b)糖又は糖アルコールでコーティングした顆粒剤は、優れた服用感を示すと考えられる。 The measurement results are shown in FIG. In Example 43, the amount of water absorption was less than Comparative Examples 7 and 8 until 20 seconds after the start of the test. That is, when actually taking Example 43, Comparative Example 7, and Comparative Example 8, the amount of water absorption of Example 43 is small in the time from the start of taking the preparation present in the oral cavity to the completion of swallowing, And the water absorption speed is also estimated to be moderate. Due to such a mechanism, (a) a water-soluble polymer or a water-insoluble polymer, and (b) a granule coated with a sugar or a sugar alcohol is considered to exhibit excellent ingestion feeling.
<試験3>発熱量の検討
前記発熱量試験方法により、実施例43、比較例7、及び比較例8を水に投入した際の発熱量を測定した。<Test 3> Examination of calorific value The calorific value when Example 43, Comparative Example 7 and Comparative Example 8 were put into water was measured by the calorific value test method.
測定の結果を図3に示す。実施例43は、試験開始後20秒時点での上昇温度が比較例7及び比較例8より低く、且つ温度上昇速度も緩やかであった。すなわち、実施例43、比較例7、及び比較例8を実際に服用した場合において、口腔内に製剤が存在する服用開始から嚥下完了までの時間内においては、実施例43の発熱量は少なく、且つその発熱スピードも緩やかであると推定される。このようなメカニズムにより、(a)水溶性高分子又は水不溶性高分子、及び(b)糖又は糖アルコールでコーティングした顆粒剤は、優れた服用感を示すと考えられる。 The measurement results are shown in FIG. In Example 43, the temperature rise at the time of 20 seconds after the start of the test was lower than those of Comparative Examples 7 and 8, and the rate of temperature rise was also slow. That is, when actually taking Example 43, Comparative Example 7, and Comparative Example 8, the amount of heat generated in Example 43 is small in the time from the start of taking the preparation present in the oral cavity to the completion of swallowing, In addition, the heat generation speed is estimated to be moderate. Due to such a mechanism, (a) a water-soluble polymer or a water-insoluble polymer, and (b) a granule coated with a sugar or a sugar alcohol is considered to exhibit excellent ingestion feeling.
<試験4>官能試験による服用感の検討
前記官能試験2の試験方法により、実施例37及び比較例7を用いて官能試験による服用感の検討を行った。官能試験結果を表5に示す。服用感についてクレーマー検定を用いて検証した結果、実施例37(2層コーティング製剤)は比較例7より有意に(危険率5%)服用感が良かった。<Test 4> Examination of taking feeling by sensory test Using Example 37 and Comparative Example 7, the feeling of taking by the sensory test was examined by the test method of the sensory test 2. The sensory test results are shown in Table 5. As a result of verifying the feeling of ingestion using the Kramer test, Example 37 (two-layer coating preparation) was significantly better in the feeling of ingestion than Comparative Example 7 (
前記官能試験3の試験方法により、官能試験による服用感の検討を行った。試験には実施例1、比較例7、及び比較例8を使用した。官能試験結果を表6に示す。服用感についてクレーマー検定を用いて検証した結果、実施例1(1層コーティング製剤)は比較例7及び比較例8より有意に(危険率5%)服用感が良かった。
According to the test method of the sensory test 3, the feeling of dosing by the sensory test was examined. In the test, Example 1, Comparative Example 7, and Comparative Example 8 were used. The sensory test results are shown in Table 6. As a result of verifying the feeling of ingestion using the Kramer test, Example 1 (single-layer coating preparation) was significantly better in the feeling of ingestion than Comparative Example 7 and Comparative Example 8 (
以上の試験結果より、(a)水溶性高分子又は水不溶性高分子、及び(b)糖又は糖アルコールを含む被覆層であれば、被覆層が1層か2層かにかかわらず、服用感の悪さを抑制できるという結論に至った。 Based on the above test results, it was found that the coating layer containing (a) a water-soluble polymer or a water-insoluble polymer, and (b) a sugar or a sugar alcohol, was used regardless of whether the coating layer was one layer or two layers. It came to the conclusion that the badness of the can be suppressed.
<試験5>医薬製剤の粒子径の検討
実施例1と同様の処方で製造して得られた被覆顆粒を以下の条件で篩分けを行った。得られた顆粒を表7に記載の割合で混合し官能試験用の製剤とした。尚、0.5mm以上1.4mm未満の被覆顆粒とは条件1の被覆顆粒であり、0.5mm未満の被覆顆粒とは条件2の被覆顆粒である。<
条件1:目開き1.4mm及び目開き0.5mmの篩を用いて篩分けを行い、目開き1.4mmの篩を通過し、目開き0.5mmの篩を通過しなかった被覆顆粒
条件2:目開き0.5mmの篩を用いて篩分けを行い、目開き0.5mmの篩を通過した被覆顆粒Condition 1: Sieving using a sieve with an aperture of 1.4 mm and an aperture of 0.5 mm, coated granules passing through a sieve with an aperture of 1.4 mm and not passing through a sieve with an aperture of 0.5 mm Condition 2: Opening Coated granules that have been sieved using a 0.5 mm sieve and passed through a 0.5 mm sieve
前記製剤A〜Dについて、前記官能試験4の試験方法により服用感の検討を行った。官能試験結果を表8に示す。服用感について分散分析により検証した結果、0.5mm未満の被覆顆粒が製剤全体の30質量%未満のとき、有意に(危険率5%)服用感が良かった。
With respect to the preparations A to D, the ingestion feeling was examined by the test method of the sensory test 4. The sensory test results are shown in Table 8. As a result of verifying the ingestion by analysis of variance, when the coated granules of less than 0.5 mm were less than 30% by mass of the whole preparation, the ingestion was significantly good (
<試験6>粒子径の検討
実施例1と同様の処方で製造して得られた被覆顆粒を以下の条件で篩分けを行った。得られた顆粒を表9に記載の割合で混合し、官能試験用の製剤とした。尚、0.5mm以上1.4mm未満の被覆顆粒とは条件1の被覆顆粒であり、1.4mm以上2.0mm未満の被覆顆粒とは条件3の被覆顆粒である。<Test 6> Examination of particle diameter Coated granules obtained by the same formulation as in Example 1 were sieved under the following conditions. The obtained granule was mixed in the ratio of Table 9, and it was set as the formulation for a sensory test. The coated granules of 0.5 mm or more and less than 1.4 mm are the coated granules of Condition 1, and the coated granules of 1.4 mm or more and less than 2.0 mm are the coated granules of Condition 3.
条件1:目開き1.4mm及び目開き0.5mmの篩を用いて篩分けを行い、目開き1.4mmの篩を通過し、目開き0.5mmの篩を通過しなかった被覆顆粒
条件3:目開き2.0mmの篩を通過し、目開き1.4mmの篩を通過しなかった被覆顆粒Condition 1: Coated granule which screened using a sieve having an aperture of 1.4 mm and an aperture of 0.5 mm, passed through a sieve having an aperture of 1.4 mm, and not passed through a sieve having an aperture of 0.5 mm Condition 3: Opening Coated granules that passed through a 2.0 mm sieve and did not pass through a 1.4 mm sieve
前記製剤A、E、及びFについて、前記官能試験5の試験方法により服用感の検討を行った。官能試験結果を表10に示す。服用感について分散分析により検証した結果、1.4mm以上2.0mm未満の被覆顆粒が製剤全体の20質量%未満のとき、有意に(危険率5%)服用感が良かった。本試験では、2.0mm以上の被覆顆粒は先に除いているが、2.0mm以上の大きな被覆顆粒を含めて考えたとしても、1.4mm以上の被覆顆粒が製剤全体の20質量%未満であれば、良好な服用感を示すと考えられる。
With respect to the preparations A, E, and F, the ingestion feeling was examined by the test method of the
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